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Sample records for potential therapeutic strategies

  1. Potential therapeutic strategy to treat substance abuse related disorders.

    PubMed

    Chang, Sulie L

    2013-12-01

    The "Potential Therapeutic Strategy to Treat Substance Abuse Related Disorders" session was chaired by Dr. Sulie Chang, director of NeuroImmune Phamacology at Seton University. The four presenters (and their topics) were: Dr. Wen-zhe Ho (Miniway to stop HIV/HCV), Dr. Ru-Band Lu (Low dose of memantine in the treatment of opioid dependence in human), Dr. Ping Zhang (Treatment of alcohol-related disorders-Learning from stem/progenitor cell), and Chia-Hsiang Chen (Treatment of methamphetamine abuse: an antibody-based immunotherapy approach). PMID:25267886

  2. Oligo/Polynucleotide-Based Gene Modification: Strategies and Therapeutic Potential

    PubMed Central

    Sargent, R. Geoffrey; Kim, Soya

    2011-01-01

    Oligonucleotide- and polynucleotide-based gene modification strategies were developed as an alternative to transgene-based and classical gene targeting-based gene therapy approaches for treatment of genetic disorders. Unlike the transgene-based strategies, oligo/polynucleotide gene targeting approaches maintain gene integrity and the relationship between the protein coding and gene-specific regulatory sequences. Oligo/polynucleotide-based gene modification also has several advantages over classical vector-based homologous recombination approaches. These include essentially complete homology to the target sequence and the potential to rapidly engineer patient-specific oligo/polynucleotide gene modification reagents. Several oligo/polynucleotide-based approaches have been shown to successfully mediate sequence-specific modification of genomic DNA in mammalian cells. The strategies involve the use of polynucleotide small DNA fragments, triplex-forming oligonucleotides, and single-stranded oligodeoxynucleotides to mediate homologous exchange. The primary focus of this review will be on the mechanistic aspects of the small fragment homologous replacement, triplex-forming oligonucleotide-mediated, and single-stranded oligodeoxynucleotide-mediated gene modification strategies as it relates to their therapeutic potential. PMID:21417933

  3. Antioxidants as a Potential Preventive and Therapeutic Strategy for Cadmium.

    PubMed

    Brzóska, Malgorzata M; Borowska, Sylwia; Tomczyk, Michal

    2016-01-01

    Epidemiological studies provide a growing number of evidences that chronic exposure to relatively low levels of cadmium (Cd), nowadays taking place in industrialized countries, may cause health hazard. Thus, growing interest has been focused on effective ways of protection from adverse effects of exposure to this heavy metal. Because numerous effects to Cd's toxic action result from its prooxidative properties, it seems reasonable that special attention should be directed to agents that can prevent or reduce this metal-induced oxidative stress and its consequences in tissues, organs and systems at risk of toxicity, including liver, kidneys, testes, ears, eyes, cardiovascular system and nervous system as well as bone tissue. This review discusses a wide range of natural (plant and animal origin) and synthetic antioxidants together with many plant extracts (e.g. black and green tea, Aronia melanocarpa, Allium sativum, Allium cepa, Ocimum sanctum, Phoenix dactylifera, Physalis peruviana, Zingiber officinale) that have been shown to prevent from Cd toxicity. Moreover, some attention has been focused on the fact that substances not possessing antioxidative potential may also prevent Cd-induced oxidative stress and its consequences. So far, most of the data on the protective effects of the natural and synthetic antioxidants and plant extracts come from studies in animals' models; however, numerous of them seem to be promising preventive/therapeutic strategies for Cd toxicity in humans. Further investigation of prophylactic and therapeutic use of antioxidants in populations exposed to Cd environmentally and occupationally is warranted, given that therapeutically effective chelation therapy for this toxic metal is currently lacking. PMID:25944010

  4. Current and Potential Therapeutic Strategies for Hemodynamic Cardiorenal Syndrome

    PubMed Central

    Obi, Yoshitsugu; Kim, Taehee; Kovesdy, Csaba P.; Amin, Alpesh N.; Kalantar-Zadeh, Kamyar

    2016-01-01

    Background Cardiorenal syndrome (CRS) encompasses conditions in which cardiac and renal disorders co-exist and are pathophysiologically related. The newest classification of CRS into seven etiologically and clinically distinct types for direct patient management purposes includes hemodynamic, uremic, vascular, neurohumoral, anemia- and/or iron metabolism-related, mineral metabolism-related and protein-energy wasting-related CRS. This classification also emphasizes the pathophysiologic pathways. The leading CRS category remains hemodynamic CRS, which is the most commonly encountered type in patient care settings and in which acute or chronic heart failure leads to renal impairment. Summary This review focuses on selected therapeutic strategies for the clinical management of hemodynamic CRS. This is often characterized by an exceptionally high ratio of serum urea to creatinine concentrations. Loop diuretics, positive inotropic agents including dopamine and dobutamine, vasopressin antagonists including vasopressin receptor antagonists such as tolvaptan, nesiritide and angiotensin-neprilysin inhibitors are among the pharmacologic agents used. Additional therapies include ultrafiltration (UF) via hemofiltration or dialysis. The beneficial versus unfavorable effects of these therapies on cardiac decongestion versus renal blood flow may act in opposite directions. Some of the most interesting options for the outpatient setting that deserve revisiting include portable continuous dobutamine infusion, peritoneal dialysis and outpatient UF via hemodialysis or hemofiltration. Key Messages The new clinically oriented CRS classification system is helpful in identifying therapeutic targets and offers a systematic approach to an optimal management algorithm with better understanding of etiologies. Most interventions including UF have not shown a favorable impact on outcomes. Outpatient portable dobutamine infusion is underutilized and not well studied. Revisiting traditional and

  5. Potential Therapeutic Benefits of Strategies Directed to Mitochondria

    PubMed Central

    Lesnefsky, Edward J.; Stowe, David F.

    2010-01-01

    Abstract The mitochondrion is the most important organelle in determining continued cell survival and cell death. Mitochondrial dysfunction leads to many human maladies, including cardiovascular diseases, neurodegenerative disease, and cancer. These mitochondria-related pathologies range from early infancy to senescence. The central premise of this review is that if mitochondrial abnormalities contribute to the pathological state, alleviating the mitochondrial dysfunction would contribute to attenuating the severity or progression of the disease. Therefore, this review will examine the role of mitochondria in the etiology and progression of several diseases and explore potential therapeutic benefits of targeting mitochondria in mitigating the disease processes. Indeed, recent advances in mitochondrial biology have led to selective targeting of drugs designed to modulate and manipulate mitochondrial function and genomics for therapeutic benefit. These approaches to treat mitochondrial dysfunction rationally could lead to selective protection of cells in different tissues and various disease states. However, most of these approaches are in their infancy. Antioxid. Redox Signal. 13, 279–347. PMID:20001744

  6. Helminth products as a potential therapeutic strategy for inflammatory diseases.

    PubMed

    Soares, Maria Fernanda de Macedo; Araújo, Claudia A

    2008-06-01

    Helminths secrete several molecules that can modulate the immune responses, favoring their evasion and perpetuate their survival in the host. These molecules interfere with antigen presentation, cell proliferation and activation, antibody production, cause cell death, and stimulate regulatory responses. Here, we focus on some helminth products and address their immunomodulatory effects in the host immune system and, also, we describe some anti-inflammatory properties of an Ascaris suum-derived immunomodulatory molecule, named PAS-1. This protein is a 200-kDa molecule isolated by affinity chromatography using MAIP-1 (monoclonal antibody which recognizes PAS-1), coupled to Sepharose 4B. It suppresses the inflammatory responses in murine models of delayed-type hypersensitivity, lung allergic inflammation and LPS-induced inflammation into air pouches. PAS-1 also stimulates the secretion of regulatory cytokines such as IL-10 and TGF-beta and primes IFN-gamma-secreting CD8+ and IL-10/ TGF-beta-secreting CD4+CD25+ cell clones that avoid the lung inflammation. Thus, this protein is a potent immunomodulatory component that may be used for therapeutic interventions in inflammatory diseases. PMID:18691141

  7. Potential Therapeutic Strategies for Alzheimer's Disease Targeting or Beyond β-Amyloid: Insights from Clinical Trials

    PubMed Central

    Jia, Qiutian; Qing, Hong

    2014-01-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder with two hallmarks: β-amyloid plagues and neurofibrillary tangles. It is one of the most alarming illnesses to elderly people. No effective drugs and therapies have been developed, while mechanism-based explorations of therapeutic approaches have been intensively investigated. Outcomes of clinical trials suggested several pitfalls in the choice of biomarkers, development of drug candidates, and interaction of drug-targeted molecules; however, they also aroused concerns on the potential deficiency in our understanding of pathogenesis of AD, and ultimately stimulated the advent of novel drug targets tests. The anticipated increase of AD patients in next few decades makes development of better therapy an urgent issue. Here we attempt to summarize and compare putative therapeutic strategies that have completed clinical trials or are currently being tested from various perspectives to provide insights for treatments of Alzheimer's disease. PMID:25136630

  8. Potential antitumor therapeutic strategies of human amniotic membrane and amniotic fluid-derived stem cells.

    PubMed

    Kang, N-H; Hwang, K-A; Kim, S U; Kim, Y-B; Hyun, S-H; Jeung, E-B; Choi, K-C

    2012-08-01

    As stem cells are capable of self-renewal and can generate differentiated progenies for organ development, they are considered as potential source for regenerative medicine and tissue replacement after injury or disease. Along with this capacity, stem cells have the therapeutic potential for treating human diseases including cancers. According to the origins, stem cells are broadly classified into two types: embryonic stem cells (ESCs) and adult stem cells. In terms of differentiation potential, ESCs are pluripotent and adult stem cells are multipotent. Amnion, which is a membranous sac that contains the fetus and amniotic fluid and functions in protecting the developing embryo during gestation, is another stem cell source. Amnion-derived stem cells are classified as human amniotic membrane-derived epithelial stem cells, human amniotic membrane-derived mesenchymal stem cells and human amniotic fluid-derived stem cells. They are in an intermediate stage between pluripotent ESCs and lineage-restricted adult stem cells, non-tumorigenic, and contribute to low immunogenicity and anti-inflammation. Furthermore, they are easily available and do not cause any controversial issues in their recovery and applications. Not only are amnion-derived stem cells applicable in regenerative medicine, they have anticancer capacity. In non-engineered stem cells transplantation strategies, amnion-derived stem cells effectively target the tumor and suppressed the tumor growth by expressing cytotoxic cytokines. Additionally, they also have a potential as novel delivery vehicles transferring therapeutic genes to the cancer formation sites in gene-directed enzyme/prodrug combination therapy. Owing to their own advantageous properties, amnion-derived stem cells are emerging as a new candidate in anticancer therapy. PMID:22653384

  9. Therapeutic Strategies for Neuropathic Pain: Potential Application of Pharmacosynthetics and Optogenetics.

    PubMed

    Lee, Gum Hwa; Kim, Sang Seong

    2016-01-01

    Chronic pain originating from neuronal damage remains an incurable symptom debilitating patients. Proposed molecular modalities in neuropathic pain include ion channel expressions, immune reactions, and inflammatory substrate diffusions. Recent advances in RNA sequence analysis have discovered specific ion channel expressions in nociceptors such as transient receptor potential (TRP) channels, voltage-gated potassium, and sodium channels. G protein-coupled receptors (GPCRs) also play an important role in triggering surrounding immune cells. The multiple protein expressions complicate therapeutic development for neuropathic pain. Recent progress in optogenetics and pharmacogenetics may herald the development of novel therapeutics for the incurable pain. Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) facilitate the artificial manipulation of intracellular signaling through excitatory or inhibitory G protein subunits activated by biologically inert synthetic ligands. Expression of excitatory channelrhodopsins and inhibitory halorhodopsins on injured neurons or surrounding cells can attenuate neuropathic pain precisely controlled by light stimulation. To achieve the discrete treatment of injured neurons, we can exploit the transcriptome database obtained by RNA sequence analysis in specific neuropathies. This can recommend the suitable promoter information to target the injury sites circumventing intact neurons. Therefore, novel strategies benefiting from pharmacogenetics, optogenetics, and RNA sequencing might be promising for neuropathic pain treatment in future. PMID:26884648

  10. Therapeutic Strategies for Neuropathic Pain: Potential Application of Pharmacosynthetics and Optogenetics

    PubMed Central

    Lee, Gum Hwa; Kim, Sang Seong

    2016-01-01

    Chronic pain originating from neuronal damage remains an incurable symptom debilitating patients. Proposed molecular modalities in neuropathic pain include ion channel expressions, immune reactions, and inflammatory substrate diffusions. Recent advances in RNA sequence analysis have discovered specific ion channel expressions in nociceptors such as transient receptor potential (TRP) channels, voltage-gated potassium, and sodium channels. G protein-coupled receptors (GPCRs) also play an important role in triggering surrounding immune cells. The multiple protein expressions complicate therapeutic development for neuropathic pain. Recent progress in optogenetics and pharmacogenetics may herald the development of novel therapeutics for the incurable pain. Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) facilitate the artificial manipulation of intracellular signaling through excitatory or inhibitory G protein subunits activated by biologically inert synthetic ligands. Expression of excitatory channelrhodopsins and inhibitory halorhodopsins on injured neurons or surrounding cells can attenuate neuropathic pain precisely controlled by light stimulation. To achieve the discrete treatment of injured neurons, we can exploit the transcriptome database obtained by RNA sequence analysis in specific neuropathies. This can recommend the suitable promoter information to target the injury sites circumventing intact neurons. Therefore, novel strategies benefiting from pharmacogenetics, optogenetics, and RNA sequencing might be promising for neuropathic pain treatment in future. PMID:26884648

  11. NF-κB pathway activators as potential ageing biomarkers: targets for new therapeutic strategies

    PubMed Central

    2013-01-01

    Chronic inflammation is a major biological mechanism underpinning biological ageing process and age-related diseases. Inflammation is also the key response of host defense against pathogens and tissue injury. Current opinion sustains that during evolution the host defense and ageing process have become linked together. Thus, the large array of defense factors and mechanisms linked to the NF-κB system seem to be involved in ageing process. This concept leads us in proposing inductors of NF-κB signaling pathway as potential ageing biomarkers. On the other hand, ageing biomarkers, represented by biological indicators and selected through apposite criteria, should help to characterize biological age and, since age is a major risk factor in many degenerative diseases, could be subsequently used to identify individuals at high risk of developing age-associated diseases or disabilities. In this report, some inflammatory biomarkers will be discussed for a better understanding of the concept of biological ageing, providing ideas on eventual working hypothesis about potential targets for the development of new therapeutic strategies and improving, as consequence, the quality of life of elderly population. PMID:23786653

  12. Bone-cartilage interface crosstalk in osteoarthritis: potential pathways and future therapeutic strategies.

    PubMed

    Yuan, X L; Meng, H Y; Wang, Y C; Peng, J; Guo, Q Y; Wang, A Y; Lu, S B

    2014-08-01

    Currently, osteoarthritis (OA) is considered a disease of the entire joint, which is not simply a process of wear and tear but rather abnormal remodelling and joint failure of an organ. The bone-cartilage interface is therefore a functioning synergistic unit, with a close physical association between subchondral bone and cartilage suggesting the existence of biochemical and molecular crosstalk across the OA interface. The crosstalk at the bone-cartilage interface may be elevated in OA in vivo and in vitro. Increased vascularisation and formation of microcracks associated with abnormal bone remodelling in joints during OA facilitate molecular transport from cartilage to bone and vice versa. Recent reports suggest that several critical signalling pathways and biological factors are key regulators and activate cellular and molecular processes in crosstalk among joint compartments. Therapeutic interventions including angiogenesis inhibitors, agonists/antagonists of molecules and drugs targeting bone remodelling are potential candidates for this interaction. This review summarised the premise for the presence of crosstalk in bone-cartilage interface as well as the current knowledge of the major signalling pathways and molecular interactions that regulate OA progression. A better understanding of crosstalk in bone-cartilage interface may lead to development of more effective strategies for treating OA patients. PMID:24928319

  13. Therapeutic potential of MEK inhibition in acute myelogenous leukemia: rationale for "vertical" and "lateral" combination strategies.

    PubMed

    Ricciardi, Maria Rosaria; Scerpa, Maria Cristina; Bergamo, Paola; Ciuffreda, Ludovica; Petrucci, Maria Teresa; Chiaretti, Sabina; Tavolaro, Simona; Mascolo, Maria Grazia; Abrams, Stephen L; Steelman, Linda S; Tsao, Twee; Marchetti, Antonio; Konopleva, Marina; Del Bufalo, Donatella; Cognetti, Francesco; Foà, Robin; Andreeff, Michael; McCubrey, James A; Tafuri, Agostino; Milella, Michele

    2012-10-01

    In hematological malignancies, constitutive activation of the RAF/MEK/ERK pathway is frequently observed, conveys a poor prognosis, and constitutes a promising target for therapeutic intervention. Here, we investigated the molecular and functional effects of pharmacological MEK inhibition in cell line models of acute myeloid leukemia (AML) and freshly isolated primary AML samples. The small-molecule, ATP-non-competitive, MEK inhibitor PD0325901 markedly inhibited ERK phosphorylation and growth of several AML cell lines and approximately 70 % of primary AML samples. Growth inhibition was due to G(1)-phase arrest and induction of apoptosis. Transformation by constitutively active upstream pathway elements (HRAS, RAF-1, and MEK) rendered FDC-P1 cells exquisitely prone to PD0325901-induced apoptosis. Gene and protein expression profiling revealed a selective effect of PD0325901 on ERK phosphorylation and compensatory upregulation of the RAF/MEK and AKT/p70( S6K ) kinase modules, potentially mediating resistance to drug-induced growth inhibition. Consequently, in appropriate cellular contexts, both "vertical" (i.e., inhibition of RAF and MEK along the MAPK pathway) and "lateral" (i.e., simultaneous inhibition of the MEK/ERK and mTOR pathways) combination strategies may result in synergistic anti-leukemic effects. Overall, MEK inhibition exerts potent growth inhibitory and proapoptotic activity in preclinical models of AML, particularly in combination with other pathway inhibitors. Deeper understanding of the molecular mechanisms of action of MEK inhibitors will likely translate into more effective targeted strategies for the treatment of AML. PMID:22399013

  14. Systematically Altering Bacterial SOS Activity under Stress Reveals Therapeutic Strategies for Potentiating Antibiotics.

    PubMed

    Mo, Charlie Y; Manning, Sara A; Roggiani, Manuela; Culyba, Matthew J; Samuels, Amanda N; Sniegowski, Paul D; Goulian, Mark; Kohli, Rahul M

    2016-01-01

    The bacterial SOS response is a DNA damage repair network that is strongly implicated in both survival and acquired drug resistance under antimicrobial stress. The two SOS regulators, LexA and RecA, have therefore emerged as potential targets for adjuvant therapies aimed at combating resistance, although many open questions remain. For example, it is not well understood whether SOS hyperactivation is a viable therapeutic approach or whether LexA or RecA is a better target. Furthermore, it is important to determine which antimicrobials could serve as the best treatment partners with SOS-targeting adjuvants. Here we derived Escherichia coli strains that have mutations in either lexA or recA genes in order to cover the full spectrum of possible SOS activity levels. We then systematically analyzed a wide range of antimicrobials by comparing the mean inhibitory concentrations (MICs) and induced mutation rates for each drug-strain combination. We first show that significant changes in MICs are largely confined to DNA-damaging antibiotics, with strains containing a constitutively repressed SOS response impacted to a greater extent than hyperactivated strains. Second, antibiotic-induced mutation rates were suppressed when SOS activity was reduced, and this trend was observed across a wider spectrum of antibiotics. Finally, perturbing either LexA or RecA proved to be equally viable strategies for targeting the SOS response. Our work provides support for multiple adjuvant strategies, while also suggesting that the combination of an SOS inhibitor with a DNA-damaging antibiotic could offer the best potential for lowering MICs and decreasing acquired drug resistance. IMPORTANCE Our antibiotic arsenal is becoming depleted, in part, because bacteria have the ability to rapidly adapt and acquire resistance to our best agents. The SOS pathway, a widely conserved DNA damage stress response in bacteria, is activated by many antibiotics and has been shown to play central role in

  15. Systematically Altering Bacterial SOS Activity under Stress Reveals Therapeutic Strategies for Potentiating Antibiotics

    PubMed Central

    Mo, Charlie Y.; Manning, Sara A.; Roggiani, Manuela; Culyba, Matthew J.; Samuels, Amanda N.; Sniegowski, Paul D.; Goulian, Mark

    2016-01-01

    ABSTRACT The bacterial SOS response is a DNA damage repair network that is strongly implicated in both survival and acquired drug resistance under antimicrobial stress. The two SOS regulators, LexA and RecA, have therefore emerged as potential targets for adjuvant therapies aimed at combating resistance, although many open questions remain. For example, it is not well understood whether SOS hyperactivation is a viable therapeutic approach or whether LexA or RecA is a better target. Furthermore, it is important to determine which antimicrobials could serve as the best treatment partners with SOS-targeting adjuvants. Here we derived Escherichia coli strains that have mutations in either lexA or recA genes in order to cover the full spectrum of possible SOS activity levels. We then systematically analyzed a wide range of antimicrobials by comparing the mean inhibitory concentrations (MICs) and induced mutation rates for each drug-strain combination. We first show that significant changes in MICs are largely confined to DNA-damaging antibiotics, with strains containing a constitutively repressed SOS response impacted to a greater extent than hyperactivated strains. Second, antibiotic-induced mutation rates were suppressed when SOS activity was reduced, and this trend was observed across a wider spectrum of antibiotics. Finally, perturbing either LexA or RecA proved to be equally viable strategies for targeting the SOS response. Our work provides support for multiple adjuvant strategies, while also suggesting that the combination of an SOS inhibitor with a DNA-damaging antibiotic could offer the best potential for lowering MICs and decreasing acquired drug resistance. IMPORTANCE Our antibiotic arsenal is becoming depleted, in part, because bacteria have the ability to rapidly adapt and acquire resistance to our best agents. The SOS pathway, a widely conserved DNA damage stress response in bacteria, is activated by many antibiotics and has been shown to play central role

  16. miRNAs in pancreatic cancer: therapeutic potential, delivery challenges and strategies.

    PubMed

    Chitkara, Deepak; Mittal, Anupama; Mahato, Ram I

    2015-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is a severe pancreatic malignancy and is predicted to victimize 1.5% of men and women during their lifetime (Cancer statistics: SEER stat fact sheet, National Cancer Institute, 2014). miRNAs have emerged as a promising prognostic, diagnostic and therapeutic tool to fight against pancreatic cancer. miRNAs could modulate gene expression by imperfect base-pairing with target mRNA and hence provide means to fine-tune multiple genes simultaneously and alter various signaling pathways associated with the disease. This exceptional miRNA feature has provided a paradigm shift from the conventional one drug one target concept to one drug multiple target theory. However, in vivo miRNA delivery is not fully realized due to challenges posed by this special class of therapeutic molecules, which involves thorough understanding of the biogenesis and physicochemical properties of miRNA and delivery carriers along with the pathophysiology of the PDAC. This review highlights the delivery strategies of miRNA modulators (mimic/inhibitor) in cancer with special emphasis on PDAC since successful delivery of miRNA in vivo constitutes the major challenge in clinical translation of this promising class of therapeutics. PMID:25252098

  17. Radioimmunotherapy: potential as a therapeutic strategy in non-Hodgkin's lymphoma.

    PubMed

    Wun, T; Kwon, D S; Tuscano, J M

    2001-01-01

    Lymphomas are the fifth most common malignancy in the United States and are increasing in incidence. Despite being among the most responsive malignancies to radiation and chemotherapy, the majority of patients relapse or have progressive disease. Monoclonal antibodies (MAbs) directed at cell-specific surface antigens have been useful in the diagnosis of lymphomas and, more recently, the therapeutic mouse-human chimeric MAb rituximab has demonstrated effectiveness in B cell lymphomas. Conjugating MAbs to radionuclides is a strategy for improving the efficacy of MAb lymphoma therapy by delivering radiation in close proximity to the tumour (radioimmunotherapy or RIT). In addition, the low dose rate of the delivered radiation may exert a greater antitumour activity than an equivalent dose of conventional external beam radiation. The antigenic targets for MAb therapy have included CD20, CD22, HLA-DR, and B cell idiotype. Radionuclides that have been used include iodine-131, yttrium-90, and copper-67; there are relative merits and disadvantages to each source of radiation. Clinical studies to date have focused on relapsed and refractory patients with both indolent and aggressive lymphomas, although more recent studies have included previously untreated patients with indolent lymphoma. Radioimmunoconjugate has been delivered as either single or multiple doses. Response rates have varied widely, dependent on the patient population and the response criteria. Of note, complete responses can be achieved in this typically refractory patient group. Toxicities have generally consisted of mild infusion-related nausea, fever, chills, and asthenia. Neutropenia and thrombocytopenia are the dose-limiting toxicities and have prompted the incorporation of autologous stem cell support as a means of achieving dose escalation. To date, RIT has been delivered to highly selected patients in relatively few centres with requisite equipment and specialised personnel. In addition to these

  18. The potential utilizations of hydrogen as a promising therapeutic strategy against ocular diseases

    PubMed Central

    Tao, Ye; Geng, Lei; Xu, Wei-Wei; Qin, Li-Min; Peng, Guang-Hua; Huang, Yi-Fei

    2016-01-01

    Hydrogen, one of the most well-known natural molecules, has been used in numerous medical applications owing to its ability to selectively neutralize cytotoxic reactive oxygen species and ameliorate hazardous inflammations. Hydrogen can exert protective effects on various reactive oxygen species-related diseases, including the transplantation-induced intestinal graft injury, chronic inflammation, ischemia–reperfusion injuries, and so on. Especially in the eye, hydrogen has been used to counteract multiple ocular pathologies in the ophthalmological models. Herein, the ophthalmological utilizations of hydrogen are systematically reviewed and the underlying mechanisms of hydrogen-induced beneficial effects are discussed. It is our hope that the protective effects of hydrogen, as evidenced by these pioneering studies, would enrich our pharmacological knowledge about this natural element and cast light into the discovery of a novel therapeutic strategy against ocular diseases. PMID:27279745

  19. Regulation of autophagy by polyphenolic compounds as a potential therapeutic strategy for cancer

    PubMed Central

    Hasima, N; Ozpolat, B

    2014-01-01

    Autophagy, a lysosomal degradation pathway for cellular constituents and organelles, is an adaptive and essential process required for cellular homeostasis. Although autophagy functions as a survival mechanism in response to cellular stressors such as nutrient or growth factor deprivation, it can also lead to a non-apoptotic form of programmed cell death (PCD) called autophagy-induced cell death or autophagy-associated cell death (type II PCD). Current evidence suggests that cell death through autophagy can be induced as an alternative to apoptosis (type I PCD), with therapeutic purpose in cancer cells that are resistant to apoptosis. Thus, modulating autophagy is of great interest in cancer research and therapy. Natural polyphenolic compounds that are present in our diet, such as rottlerin, genistein, quercetin, curcumin, and resveratrol, can trigger type II PCD via various mechanisms through the canonical (Beclin-1 dependent) and non-canonical (Beclin-1 independent) routes of autophagy. The capacity of these compounds to provide a means of cancer cell death that enhances the effects of standard therapies should be taken into consideration for designing novel therapeutic strategies. This review focuses on the autophagy- and cell death-inducing effects of these polyphenolic compounds in cancer. PMID:25375374

  20. [Potentiation strategies].

    PubMed

    Doumy, Olivier; Bennabi, Djamila; El-Hage, Wissam; Allaïli, Najib; Bation, Rémy; Bellivier, Frank; Holtzmann, Jérôme; Bubrovszky, Maxime; Camus, Vincent; Charpeaud, Thomas; Courvoisier, Pierre; d'Amato, Thierry; Garnier, Marion; Haesebaert, Frédéric; Bougerol, Thierry; Lançon, Christophe; Moliere, Fanny; Nieto, Isabel; Richieri, Raphaëlle; Saba, Ghassen; Courtet, Philippe; Vaiva, Guillaume; Leboyer, Marion; Llorca, Pierre-Michel; Aouizerate, Bruno; Haffen, Emmanuel

    2016-03-01

    Lithium is among the most classically recommended add-on therapeutic strategy for the management of depressive patients showing unsuccessful response to standard antidepressant medications. The effectiveness of the add-on strategy with lithium requires achieving plasma levels above 0.5 mEq/L. Mood-stabilizing antiepileptic drugs such as carbamazepine, valproate derivatives or lamotrigine have not demonstrated conclusive therapeutic effects for the management of depressive patients showing unsuccessful response to standard antidepressant medications. Thyroid hormones are considered among the currently recommended add-on therapeutic strategy for the management of depressive patients showing unsuccessful response to standard antidepressant medications. The effectiveness of the add-on strategy with thyroid hormones requires achieving plasma concentration of TSH close to the lower limits at the normal range (0.4 μUI/L) or even below it. Second-generation antipsychotics such as aripiprazole or quetiapine have consistently demonstrated significant therapeutic effects for the management of depressive patients showing unsuccessful response to standard antidepressant medications. Second-generation antipsychotics however require the careful monitoring of both cardiovascular and metabolic adverse effects. PMID:26970936

  1. Targeting Nicotinamide Phosphoribosyltransferase as a Potential Therapeutic Strategy to Restore Adult Neurogenesis.

    PubMed

    Wang, Shu-Na; Xu, Tian-Ying; Li, Wen-Lin; Miao, Chao-Yu

    2016-06-01

    Adult neurogenesis is the process of generating new neurons throughout life in the olfactory bulb and hippocampus of most mammalian species, which is closely related to aging and disease. Nicotinamide phosphoribosyltransferase (NAMPT), also an adipokine known as visfatin, is the rate-limiting enzyme for mammalian nicotinamide adenine dinucleotide (NAD) salvage synthesis by generating nicotinamide mononucleotide (NMN) from nicotinamide. Recent findings from our laboratory and other laboratories have provided much evidence that NAMPT might serve as a therapeutic target to restore adult neurogenesis. NAMPT-mediated NAD biosynthesis in neural stem/progenitor cells is important for their proliferation, self-renewal, and formation of oligodendrocytes in vivo and in vitro. Therapeutic interventions by the administration of NMN, NAD, or recombinant NAMPT are effective for restoring adult neurogenesis in several neurological diseases. We summarize adult neurogenesis in aging, ischemic stroke, traumatic brain injury, and neurodegenerative disease and review the advances of targeting NAMPT in restoring neurogenesis. Specifically, we provide emphasis on the P7C3 family, a class of proneurogenic compounds that are potential NAMPT activators, which might shed light on future drug development in neurogenesis restoration. PMID:27018006

  2. Targeting the Central Pocket in Human Transcription Factor TEAD as a Potential Cancer Therapeutic Strategy.

    PubMed

    Pobbati, Ajaybabu V; Han, Xiao; Hung, Alvin W; Weiguang, Seetoh; Huda, Nur; Chen, Guo-Ying; Kang, CongBao; Chia, Cheng San Brian; Luo, Xuelian; Hong, Wanjin; Poulsen, Anders

    2015-11-01

    The human TEAD family of transcription factors (TEAD1-4) is required for YAP-mediated transcription in the Hippo pathway. Hyperactivation of TEAD's co-activator YAP contributes to tissue overgrowth and human cancers, suggesting that pharmacological interference of TEAD-YAP activity may be an effective strategy for anticancer therapy. Here we report the discovery of a central pocket in the YAP-binding domain (YBD) of TEAD that is targetable by small-molecule inhibitors. Our X-ray crystallography studies reveal that flufenamic acid, a non-steroidal anti-inflammatory drug (NSAID), binds to the central pocket of TEAD2 YBD. Our biochemical and functional analyses further demonstrate that binding of NSAIDs to TEAD inhibits TEAD-YAP-dependent transcription, cell migration, and proliferation, indicating that the central pocket is important for TEAD function. Therefore, our studies discover a novel way of targeting TEAD transcription factors and set the stage for therapeutic development of specific TEAD-YAP inhibitors against human cancers. PMID:26592798

  3. Nanocarriers for spleen targeting: anatomo-physiological considerations, formulation strategies and therapeutic potential.

    PubMed

    Jindal, Anil B

    2016-10-01

    There are several clinical advantages of spleen targeting of nanocarriers. For example, enhanced splenic concentration of active agents could provide therapeutic benefits in spleen resident infections and hematological disorders including malaria, hairy cell leukemia, idiopathic thrombocytopenic purpura, and autoimmune hemolytic anemia. Furthermore, spleen delivery of immunosuppressant agents using splenotropic carriers may reduce the chances of allograft rejection in organ transplantation. Enhanced concentration of radiopharmaceuticals in the spleen may improve visualization of the organ, which could provide benefit in the diagnosis of splenic disorders. Unique anatomical features of the spleen including specialized microvasculature environment and slow blood circulation rate enable it an ideal drug delivery site. Because there is a difference in blood flow between spleen and liver, splenic delivery is inversely proportional to the hepatic uptake. It is therefore desirable engineering of nanocarriers, which, upon intravenous administration, can avoid uptake by hepatic Kupffer cells to enhance splenic localization. Stealth and non-spherical nanocarriers have shown enhanced splenic delivery of active agents by avoiding hepatic uptake. The present review details the research in the field of splenotropy. Formulation strategies to design splenotropic drug delivery systems are discussed. The review also highlights the clinical relevance of spleen targeting of nanocarriers and application in diagnostics. PMID:27334277

  4. Mcl-1 antagonism is a potential therapeutic strategy in a subset of solid cancers.

    PubMed

    Modugno, Michele; Banfi, Patrizia; Gasparri, Fabio; Borzilleri, Robert; Carter, Percy; Cornelius, Lyndon; Gottardis, Marco; Lee, Ving; Mapelli, Claudio; Naglich, Joseph G; Tebben, Andrew; Vite, Gregory; Pastori, Wilma; Albanese, Clara; Corti, Emiliana; Ballinari, Dario; Galvani, Arturo

    2015-03-15

    Cancer cell survival is frequently dependent on the elevated levels of members of the Bcl-2 family of prosurvival proteins that bind to and inactivate BH3-domain pro-apoptotic cellular proteins. Small molecules that inhibit the protein-protein interactions between prosurvival and proapoptotic Bcl-2 family members (so-called "BH3 mimetics") have a potential therapeutic value, as indicated by clinical findings obtained with ABT-263 (navitoclax), a Bcl-2/Bcl-xL antagonist, and more recently with GDC-0199/ABT-199, a more selective antagonist of Bcl-2. Here, we report study results of the functional role of the prosurvival protein Mcl-1 against a panel of solid cancer cell lines representative of different tumor types. We observed silencing of Mcl-1 expression by small interfering RNAs (siRNAs) significantly reduced viability and induced apoptosis in almost 30% of cell lines tested, including lung and breast adenocarcinoma, as well as glioblastoma derived lines. Most importantly, we provide a mechanistic basis for this sensitivity by showing antagonism of Mcl-1 function with specific BH3 peptides against isolated mitochondria induces Bak oligomerization and cytochrome c release, therefore demonstrating that mitochondria from Mcl-1-sensitive cells depend on Mcl-1 for their integrity and that antagonizing Mcl-1 function is sufficient to induce apoptosis. Thus, our results lend further support for considering Mcl-1 as a therapeutic target in a number of solid cancers and support the rationale for development of small molecule BH3-mimetics antagonists of this protein. PMID:25486070

  5. Association between SNAP-25 gene polymorphisms and cognition in autism: functional consequences and potential therapeutic strategies

    PubMed Central

    Braida, D; Guerini, F R; Ponzoni, L; Corradini, I; De Astis, S; Pattini, L; Bolognesi, E; Benfante, R; Fornasari, D; Chiappedi, M; Ghezzo, A; Clerici, M; Matteoli, M; Sala, M

    2015-01-01

    Synaptosomal-associated protein of 25 kDa (SNAP-25) is involved in different neuropsychiatric disorders, including schizophrenia and attention-deficit/hyperactivity disorder. Consistently, SNAP-25 polymorphisms in humans are associated with hyperactivity and/or with low cognitive scores. We analysed five SNAP-25 gene polymorphisms (rs363050, rs363039, rs363043, rs3746544 and rs1051312) in 46 autistic children trying to correlate them with Childhood Autism Rating Scale and electroencephalogram (EEG) abnormalities. The functional effects of rs363050 single-nucleotide polymorphism (SNP) on the gene transcriptional activity, by means of the luciferase reporter gene, were evaluated. To investigate the functional consequences that SNAP-25 reduction may have in children, the behaviour and EEG of SNAP-25+/− adolescent mice (SNAP-25+/+) were studied. Significant association of SNAP-25 polymorphism with decreasing cognitive scores was observed. Analysis of transcriptional activity revealed that SNP rs363050 encompasses a regulatory element, leading to protein expression decrease. Reduction of SNAP-25 levels in adolescent mice was associated with hyperactivity, cognitive and social impairment and an abnormal EEG, characterized by the occurrence of frequent spikes. Both EEG abnormalities and behavioural deficits were rescued by repeated exposure for 21 days to sodium salt valproate (VLP). A partial recovery of SNAP-25 expression content in SNAP-25+/− hippocampi was also observed by means of western blotting. A reduced expression of SNAP-25 is responsible for the cognitive deficits in children affected by autism spectrum disorders, as presumably occurring in the presence of rs363050(G) allele, and for behavioural and EEG alterations in adolescent mice. VLP treatment could result in novel therapeutic strategies. PMID:25629685

  6. ROS and Brain Gliomas: An Overview of Potential and Innovative Therapeutic Strategies.

    PubMed

    Rinaldi, Mariagrazia; Caffo, Maria; Minutoli, Letteria; Marini, Herbert; Abbritti, Rosaria Viola; Squadrito, Francesco; Trichilo, Vincenzo; Valenti, Andrea; Barresi, Valeria; Altavilla, Domenica; Passalacqua, Marcello; Caruso, Gerardo

    2016-01-01

    Reactive oxygen species (ROS) represent reactive products belonging to the partial reduction of oxygen. It has been reported that ROS are involved in different signaling pathways to control cellular stability. Under normal conditions, the correct function of redox systems leads to the prevention of cell oxidative damage. When ROS exceed the antioxidant defense system, cellular stress occurs. The cellular redox impairment is strictly related to tumorigenesis. Tumor cells, through the generation of hydrogen peroxide, tend to the alteration of cell cycle phases and, finally to cancer progression. In adults, the most common form of primary malignant brain tumors is represented by gliomas. The gliomagenesis is characterized by numerous molecular processes all characterized by an altered production of growth factor receptors. The difficulty to treat brain cancer depends on several biological mechanisms such as failure of drug delivery through the blood-brain barrier, tumor response to chemotherapy, and intrinsic resistance of tumor cells. Understanding the mechanisms of ROS action could allow the formulation of new therapeutic protocols to treat brain gliomas. PMID:27338365

  7. ROS and Brain Gliomas: An Overview of Potential and Innovative Therapeutic Strategies

    PubMed Central

    Rinaldi, Mariagrazia; Caffo, Maria; Minutoli, Letteria; Marini, Herbert; Abbritti, Rosaria Viola; Squadrito, Francesco; Trichilo, Vincenzo; Valenti, Andrea; Barresi, Valeria; Altavilla, Domenica; Passalacqua, Marcello; Caruso, Gerardo

    2016-01-01

    Reactive oxygen species (ROS) represent reactive products belonging to the partial reduction of oxygen. It has been reported that ROS are involved in different signaling pathways to control cellular stability. Under normal conditions, the correct function of redox systems leads to the prevention of cell oxidative damage. When ROS exceed the antioxidant defense system, cellular stress occurs. The cellular redox impairment is strictly related to tumorigenesis. Tumor cells, through the generation of hydrogen peroxide, tend to the alteration of cell cycle phases and, finally to cancer progression. In adults, the most common form of primary malignant brain tumors is represented by gliomas. The gliomagenesis is characterized by numerous molecular processes all characterized by an altered production of growth factor receptors. The difficulty to treat brain cancer depends on several biological mechanisms such as failure of drug delivery through the blood-brain barrier, tumor response to chemotherapy, and intrinsic resistance of tumor cells. Understanding the mechanisms of ROS action could allow the formulation of new therapeutic protocols to treat brain gliomas. PMID:27338365

  8. Translational and therapeutic potential of oxytocin as an anti-obesity strategy: Insights from rodents, nonhuman primates and humans.

    PubMed

    Blevins, James E; Baskin, Denis G

    2015-12-01

    The fact that more than 78 million adults in the US are considered overweight or obese highlights the need to develop new, effective strategies to treat obesity and its associated complications, including type 2 diabetes, kidney disease and cardiovascular disease. While the neurohypophyseal peptide oxytocin (OT) is well recognized for its peripheral effects to stimulate uterine contraction during parturition and milk ejection during lactation, release of OT within the brain is implicated in prosocial behaviors and in the regulation of energy balance. Previous findings indicate that chronic administration of OT decreases food intake and weight gain or elicits weight loss in diet-induced obese (DIO) mice and rats. Furthermore, chronic systemic treatment with OT largely reproduces the effects of central administration to reduce weight gain in DIO and genetically obese rodents at doses that do not appear to result in tolerance. These findings have now been recently extended to more translational models of obesity showing that chronic subcutaneous or intranasal OT treatment is sufficient to elicit body weight loss in DIO nonhuman primates and pre-diabetic obese humans. This review assesses the potential use of OT as a therapeutic strategy for treatment of obesity in rodents, nonhuman primates, and humans, and identifies potential mechanisms that mediate this effect. PMID:26013577

  9. Activation of the Tumor Suppressor PP2A Emerges as a Potential Therapeutic Strategy for Treating Prostate Cancer

    PubMed Central

    Cristóbal, Ion; González-Alonso, Paula; Daoud, Lina; Solano, Esther; Torrejón, Blanca; Manso, Rebeca; Madoz-Gúrpide, Juan; Rojo, Federico; García-Foncillas, Jesús

    2015-01-01

    Protein phosphatase 2A (PP2A) is a tumor suppressor complex that has recently been reported as a novel and highly relevant molecular target in prostate cancer (PCa). However, its potential therapeutic value remains to be fully clarified. We treated PC-3 and LNCaP cell lines with the PP2A activators forskolin and FTY720 alone or combined with the PP2A inhibitor okadaic acid. We examined PP2A activity, cell growth, prostasphere formation, levels of PP2A phosphorylation, CIP2A and SET expression, and AKT and ERK activation. Interestingly, both forskolin and FTY720 dephosphorylated and activated PP2A, impairing proliferation and prostasphere formation and inducing changes in AKT and ERK phosphorylation. Moreover, FTY720 led to reduced CIP2A levels. Treatment with okadaic acid impaired PP2A activation thus demonstrating the antitumoral PP2A-dependent mechanism of action of both forskolin and FTY720. Levels of PP2A phosphorylation together with SET and CIP2A protein expression were studied in 24 PCa patients and both were associated with high Gleason scores and presence of metastatic disease. Altogether, our results suggest that PP2A inhibition could be involved in PCa progression, and the use of PP2A-activating drugs might represent a novel alternative therapeutic strategy for treating PCa patients. PMID:26023836

  10. The Potential for iPS-Derived Stem Cells as a Therapeutic Strategy for Spinal Cord Injury: Opportunities and Challenges

    PubMed Central

    Khazaei, Mohamad; Siddiqui, Ahad M.; Fehlings, Michael G.

    2014-01-01

    Spinal cord injury (SCI) is a devastating trauma causing long-lasting disability. Although advances have occurred in the last decade in the medical, surgical and rehabilitative treatments of SCI, the therapeutic approaches are still not ideal. The use of cell transplantation as a therapeutic strategy for the treatment of SCI is promising, particularly since it can target cell replacement, neuroprotection and regeneration. Cell therapies for treating SCI are limited due to several translational roadblocks, including ethical and practical concerns regarding cell sources. The use of iPSCs has been particularly attractive, since they avoid the ethical and moral concerns that surround other stem cells. Furthermore, various cell types with potential for application in the treatment of SCI can be created from autologous sources using iPSCs. For applications in SCI, the iPSCs can be differentiated into neural precursor cells, neurons, oligodendrocytes, astrocytes, neural crest cells and mesenchymal stromal cells that can act by replacing lost cells or providing environmental support. Some methods, such as direct reprogramming, are being investigated to reduce tumorigenicity and improve reprogramming efficiencies, which have been some of the issues surrounding the use of iPSCs clinically to date. Recently, iPSCs have entered clinical trials for use in age-related macular degeneration, further supporting their promise for translation in other conditions, including SCI. PMID:26237017

  11. Recent Advances in the Pathobiology of Hodgkin's Lymphoma: Potential Impact on Diagnostic, Predictive, and Therapeutic Strategies

    PubMed Central

    Banerjee, Diponkar

    2011-01-01

    From its first description by Thomas Hodgkin in 1832, Hodgkin's disease, now called Hodgkin's lymphoma, has continued to be a fascinating neoplasm even to this day. In this review, historical aspects, epidemiology, diagnosis, tumor biology, new observations related to host-microenvironment interactions, gene copy number variation, and gene expression profiling in this complex neoplasm are described, with an exploration of chemoresistance mechanisms and potential novel therapies for refractory disease. PMID:21318045

  12. Plasma jet-induced tissue oxygenation: potentialities for new therapeutic strategies

    NASA Astrophysics Data System (ADS)

    Collet, G.; Robert, E.; Lenoir, A.; Vandamme, M.; Darny, T.; Dozias, S.; Kieda, C.; Pouvesle, J. M.

    2014-02-01

    The lack of oxygen is a major reason for the resistance of tumor cells to treatments such as radiotherapies. A large number of recent publications on non-thermal plasma applications in medicine report cell behavior modifications and modulation of soluble factors. This in vivo study tested whether such modifications can lead to vascular changes in response to plasma application. Two in situ optical-based methods were used simultaneously, in real time, to assess the effect of non-thermal plasma on tissue vasculature. Tissue oxygen partial pressure (pO2) was measured using a time-resolved luminescence-based optical probe, and the microvascular erythrocyte flow was determined by laser Doppler flowmetry. When plasma treatment was applied on mouse skin, a rapid pO2 increase (up to 4 times) was subcutaneously measured and correlated with blood flow improvement. Such short duration, i.e. 5 min, plasma-induced effects were shown to be locally restricted to the treated area and lasted over 120 min. Further investigations should elucidate the molecular mechanisms of these processes. However, improvement of oxygenation and perfusion open new opportunities for tumor treatments in combination with radiotherapy, and for tumor blood vessel normalization based strategies.

  13. Partial adenosine A1 receptor agonism: a potential new therapeutic strategy for heart failure.

    PubMed

    Greene, Stephen J; Sabbah, Hani N; Butler, Javed; Voors, Adriaan A; Albrecht-Küpper, Barbara E; Düngen, Hans-Dirk; Dinh, Wilfried; Gheorghiade, Mihai

    2016-01-01

    Heart failure (HF) represents a global public health and economic problem associated with unacceptable rates of death, hospitalization, and healthcare expenditure. Despite available therapy, HF carries a prognosis comparable to many forms of cancer with a 5-year survival rate of ~50%. The current treatment paradigm for HF with reduced ejection fraction (EF) centers on blocking maladaptive neurohormonal activation and decreasing cardiac workload with therapies that concurrently lower blood pressure and heart rate. Continued development of hemodynamically active medications for stepwise addition to existing therapies carries the risk of limited tolerability and safety. Moreover, this treatment paradigm has thus far failed for HF with preserved EF. Accordingly, development of hemodynamically neutral HF therapies targeting primary cardiac pathologies must be considered. In this context, a partial adenosine A1 receptor (A1R) agonist holds promise as a potentially hemodynamically neutral therapy for HF that could simultaneous improve cardiomyocyte energetics, calcium homeostasis, cardiac structure and function, and long-term clinical outcomes when added to background therapies. In this review, we describe the physiology and pathophysiology of HF as it relates to adenosine agonism, examine the existing body of evidence and biologic rationale for modulation of adenosine A1R activity, and review the current state of drug development of a partial A1R agonist for the treatment of HF. PMID:26701329

  14. Multi-platform molecular profiling of a large cohort of glioblastomas reveals potential therapeutic strategies

    PubMed Central

    Xiu, Joanne; Piccioni, David; Juarez, Tiffany; Pingle, Sandeep C.; Hu, Jethro; Rudnick, Jeremy; Fink, Karen; Spetzler, David B.; Maney, Todd; Ghazalpour, Anatole; Bender, Ryan; Gatalica, Zoran; Reddy, Sandeep; Sanai, Nader; Idbaih, Ahmed; Glantz, Michael; Kesari, Santosh

    2016-01-01

    Glioblastomas (GBM) are the most aggressive and prevalent form of gliomas with abysmal prognosis and limited treatment options. We analyzed clinically relevant molecular aberrations suggestive of response to therapies in 1035 GBM tumors. Our analysis revealed mutations in 39 genes of 48 tested. IHC revealed expression of PD-L1 in 19% and PD-1 in 46%. MGMT-methylation was seen in 43%, EGFRvIII in 19% and 1p19q co-deletion in 2%. TP53 mutation was associated with concurrent mutations, while IDH1 mutation was associated with MGMT-methylation and TP53 mutation and was mutually exclusive of EGFRvIII mutation. Distinct biomarker profiles were seen in GBM compared with WHO grade III astrocytoma, suggesting different biology and potentially different treatment approaches. Analysis of 17 metachronous paired tumors showed frequent biomarker changes, including MGMT-methylation and EGFR aberrations, indicating the need for a re-biopsy for tumor profiling to direct subsequent therapy. MGMT-methylation, PR and TOPO1 appeared as significant prognostic markers in sub-cohorts of GBM defined by age. The current study represents the largest biomarker study on clinical GBM tumors using multiple technologies to detect gene mutation, amplification, protein expression and promoter methylation. These data will inform planning for future personalized biomarker-based clinical trials and identifying effective treatments based on tumor biomarkers. PMID:26933808

  15. Multi-platform molecular profiling of a large cohort of glioblastomas reveals potential therapeutic strategies.

    PubMed

    Xiu, Joanne; Piccioni, David; Juarez, Tiffany; Pingle, Sandeep C; Hu, Jethro; Rudnick, Jeremy; Fink, Karen; Spetzler, David B; Maney, Todd; Ghazalpour, Anatole; Bender, Ryan; Gatalica, Zoran; Reddy, Sandeep; Sanai, Nader; Idbaih, Ahmed; Glantz, Michael; Kesari, Santosh

    2016-04-19

    Glioblastomas (GBM) are the most aggressive and prevalent form of gliomas with abysmal prognosis and limited treatment options. We analyzed clinically relevant molecular aberrations suggestive of response to therapies in 1035 GBM tumors. Our analysis revealed mutations in 39 genes of 48 tested. IHC revealed expression of PD-L1 in 19% and PD-1 in 46%. MGMT-methylation was seen in 43%, EGFRvIII in 19% and 1p19q co-deletion in 2%. TP53 mutation was associated with concurrent mutations, while IDH1 mutation was associated with MGMT-methylation and TP53 mutation and was mutually exclusive of EGFRvIII mutation. Distinct biomarker profiles were seen in GBM compared with WHO grade III astrocytoma, suggesting different biology and potentially different treatment approaches. Analysis of 17 metachronous paired tumors showed frequent biomarker changes, including MGMT-methylation and EGFR aberrations, indicating the need for a re-biopsy for tumor profiling to direct subsequent therapy. MGMT-methylation, PR and TOPO1 appeared as significant prognostic markers in sub-cohorts of GBM defined by age. The current study represents the largest biomarker study on clinical GBM tumors using multiple technologies to detect gene mutation, amplification, protein expression and promoter methylation. These data will inform planning for future personalized biomarker-based clinical trials and identifying effective treatments based on tumor biomarkers. PMID:26933808

  16. Strategies for therapeutic hypometabothermia

    PubMed Central

    Liu, Shimin; Chen, Jiang-Fan

    2013-01-01

    Although therapeutic hypothermia and metabolic suppression have shown robust neuroprotection in experimental brain ischemia, systemic complications have limited their use in treating acute stroke patients. The core temperature and basic metabolic rate are tightly regulated and maintained in a very stable level in mammals. Simply lowering body temperature or metabolic rate is actually a brutal therapy that may cause more systemic as well as regional problems other than providing protection. These problems are commonly seen in hypothermia and barbiturate coma. The main innovative concept of this review is to propose thermogenically optimal and synergistic reduction of core temperature and metabolic rate in therapeutic hypometabothermia using novel and clinically practical approaches. When metabolism and body temperature are reduced in a systematically synergistic manner, the outcome will be maximal protection and safe recovery, which happen in natural process, such as in hibernation, daily torpor and estivation. PMID:24179563

  17. [Liver metastasis: therapeutic strategy].

    PubMed

    Gennari, L; Doci, R; Bignami, P

    1996-01-01

    The liver is one of the most frequent sites of metastatic growth, in particular from digestive malignancies (DM). The first goal is to reduce the incidence of metastases. Adjuvant systemic chemotherapies have been demonstrated to reduce the recurrence rate and to improve survival in Dukes C colon cancer. Fluorouracil is the pivot of adjuvant treatment modulated by Leucovorin or Levamisol. A short postoperative administration of fluorouracil by intraportal route has been tested, but the results are controversial. Adjuvant treatments for different DM are under investigation. When hepatic metastases are clinically evident, therapeutic decisions depend on several factors: site and nature of primary, extent of hepatic and extrahepatic disease, patient characteristics, efficacy of treatments. A staging system should be adopted to allow a rational approach. In selected cases a locoregional treatment can achieve consistent results. Hepatic Intrarterial Chemotherapy (HIAC) for colorectal metastases achieves objective responses in more than 50% of patients. Survival seems positively affected. When feasible, Ro hepatic resection is the most effective treatment, five-year survival rate being about 30% when metastases are from colorectal cancer. Since the liver is the most frequent site of recurrence after resection, repeat resection have been successfully performed. PMID:9214269

  18. [Other therapeutic strategies].

    PubMed

    Saba, Ghassen; Nieto, Isabel; Bation, Rémy; Allaïli, Najib; Bennabi, Djamila; Moliere, Fanny; Richieri, Raphaëlle; Holtzmann, Jérôme; Bubrovszky, Maxime; Camus, Vincent; Charpeaud, Thomas; Courtet, Philippe; Courvoisier, Pierre; Haesebaert, Frédéric; Doumy, Olivier; El-Hage, Wissam; Garnier, Marion; d'Amato, Thierry; Bougerol, Thierry; Lançon, Christophe; Haffen, Emmanuel; Llorca, Pierre-Michel; Vaiva, Guillaume; Bellivier, Frank; Leboyer, Marion; Aouizerate, Bruno

    2016-03-01

    Non-selective and irreversible MAOI have become as third or fourth-line strategy for the management of treatment-resistant depression. Non-selective and irreversible MAOI requires careful monitoring of drug interactions and dietary restrictions. Nutritional supplements such as omega-3 have been found to produce beneficial effects in the management of treatment-resistant depression when administered in combination with the ongoing antidepressant treatment. The glutamate antagonist ketamine has been found to produce beneficial effects in the management of treatment-resistant depression while administered alone. Dopamine and/or norepinephrine agonists, such as methylphenidate, modafinil or pramipexole, have been found to produce beneficial effects in the management of treatment-resistant depression when administered in combination with the ongoing antidepressant treatment. PMID:26995510

  19. Therapeutic Strategies in Huntington's Disease

    PubMed Central

    2006-01-01

    This article provides an overview of the therapeutic strategies, from ordinary classical drugs to the modern molecular strategy at experimental level, for Huntington's disease. The disease is characterized by choreic movements, psychiatric disorders, striatal atrophy with selective small neuronal loss, and autosomal dominant inheritance. The genetic abnormality is CAG expansion in huntingtin gene. Mutant huntingtin with abnormally long glutamine stretch aggregates and forms intranuclear inclusions. In this review, I summarize the results of previous trials from the following aspects; 1. symptomatic/palliative therapies including drugs, stereotaxic surgery and repetitive transcranial magnetic stimulation, 2. anti-degenerative therapies including anti-excitotoxicity, reversal of mitochondrial dysfunction and anti-apoptosis, 3. restorative/reparative therapies including neural trophic factors and tissue or stem cell transplantation, and 4. molecular targets in specific and radical therapies including inhibition of truncation of huntingtin, inhibition of aggregate formation, normalization of transcriptional dysregulation, enhancement of autophagic clearance of mutant huntingtin, and specific inhibition of huntingtin expression by sRNAi. Although the strategies mentioned in the latter two categories are mostly at laboratory level at present, we are pleased that one can discuss such "therapeutic strategies", a matter absolutely impossible before the causal gene of Huntington's disease was identified more than 10 years ago. It is also true, however, that some of the "therapeutic strategies" mentioned here would be found difficult to implement and abandoned in the future. PMID:20396523

  20. Trans-synaptic (GABA-dopamine) modulation of cocaine induced dopamine release: A potential therapeutic strategy for cocaine abuse

    SciTech Connect

    Dewey, S.L.; Straughter-Moore, R.; Chen, R.

    1995-05-01

    We recently developed a new experimental strategy for measuring interactions between functionally-linked neurotransmitter systems in the primate and human brain with PET. As part of this research, we demonstrated that increases in endogenous GABA concentrations significantly reduced striatal dopamine concentrations in the primate brain. We report here the application of the neurotransmitter interaction paradigm with PET and with microdialysis to the investigation of a novel therapeutic strategy for treating cocaine abuse based on the ability of GABA to inhibit cocaine induced increases in striatal dopamine. Using gamma-vinyl GABA (GVG, a suicide inhibitor of GABA transaminase), we performed a series of PET studies where animals received a baseline PET scan with labeled raclopride injection, animals received cocaine (2.0 mg/kg). Normally, a cocaine challenge significantly reduces the striatal binding of {sup 11}C-raclopride. However, in animals pretreated with GVG, {sup 11}C-raclopride binding was less affected by a cocaine challenge compared to control studies. Furthermore, microdialysis studies in freely moving rats demonstrate that GVG (300 mg/kg) significantly inhibited cocaine-induced increases in extracellular dopamine release. GVG also attenuated cocaine-induced increases in locomotor activity. However, at a dose of 100 mg/kg, GVG had no effect. Similar findings were obtained with alcohol. Alcohol pretreatment dose dependantly (1-4 g/kg) inhibited cocaine-induced increases in extracellular dopamine concentrations in freely moving rats. Taken together, these studies suggest that therapeutic strategies targeted at increasing central GABA concentrations may be beneficial for the treatment of cocaine abuse.

  1. Targeting the Sonic Hedgehog-Gli1 Pathway as a Potential New Therapeutic Strategy for Myelodysplastic Syndromes

    PubMed Central

    Zou, Jixue; Zhou, Zhigang; Wan, Liping; Tong, Yin; Qin, Youwen; Wang, Chun; Zhou, Kun

    2015-01-01

    The complex mechanistic array underlying the pathogenesis of myelodysplastic syndrome (MDS) is still unclear. Although dysregulations of different signaling pathways involved in MDS have been described, the identification of specific biomarkers and therapy targets remains an important task in order to establish novel therapeutic approaches. Here, we demonstrated that the Shh signaling pathway is active in MDS and correlated it with disease progression. Additionally, the knockdown of Gli1 significantly inhibited cell proliferation in vitro and in vivo. Gli1 silencing also induced apoptosis and G0/G1 phase arrest. Furthermore, Gli1 silencing enhanced the demethylating effect of 5-aza-2'-deoxycytidine on the p15 gene promoter and subsequently promoted its expression by inhibiting DNA methyltransferase 1(DNMT1). Our findings show that the Shh signaling pathway plays a role in the pathogenesis and disease progression of MDS, and proceeds by modulating DNA methylation. This pathway may prove to be a potential therapeutic target for enhancing the therapeutic effects of 5-azacytidine on malignant transformation of MDS. PMID:26317501

  2. Tumour vasculature--a potential therapeutic target.

    PubMed Central

    Baillie, C. T.; Winslet, M. C.; Bradley, N. J.

    1995-01-01

    The tumour vasculature is vital for the establishment, growth and metastasis of solid tumours. Its physiological properties limit the effectiveness of conventional anti-cancer strategies. Therapeutic approaches directed at the tumour vasculature are reviewed, suggesting the potential of anti-angiogenesis and the targeting of vascular proliferation antigens as cancer treatments. PMID:7543770

  3. Contribution of reactive oxygen species to cartilage degradation in rheumatic diseases: molecular pathways, diagnosis and potential therapeutic strategies.

    PubMed

    Schiller, J; Fuchs, B; Arnhold, J; Arnold, K

    2003-10-01

    Inflammatory joint diseases are of considerable socio-economic significance. However, mechanisms of cartilage destruction are so far only poorly understood. This review is dedicated to reactive oxygen species (ROS) like superoxide anion radicals, hydrogen peroxide, singlet oxygen, hypochlorous acid, hydroxyl radicals and nitric oxide that are generated under inflammatory conditions and also to their potential contribution to cartilage degradation. First, the relevance of rheumatic diseases and potential mechanisms of cartilage degradation are discussed in this review, followed by the description of the chemical constituents and the molecular architecture of articular cartilage as well as the different cell types that play a role in inflammation and cartilage destruction. Methods of the assessment of cartilage degeneration are also shortly discussed. In the main chapter of this review the characteristics of individual ROS, their generation under in vivo conditions as well as their reactivities with individual cartilage components are discussed. Because of the low selectivity of ROS, useful "markers" of cartilage degradation allowing the differentiation of effects induced by individual ROS are also discussed. In the last chapter current therapeutic concepts of the treatment of rheumatic diseases are reviewed. The recently developed "anti-TNF-alpha" therapy that is primarily directed against neutrophilic granulocytes that are powerful sources of ROS and, therefore, important mediators of joint degeneration are emphasised. PMID:12871089

  4. [Therapeutic potential of optogenetic neuromodulation].

    PubMed

    Vandecasteele, Marie; Senova, Yann-Suhan; Palfi, Stéphane; Dugué, Guillaume P

    2015-04-01

    Optogenetic neuromodulation techniques, which have emerged during the last 15 years, have considerably enhanced our ability to probe the functioning of neural circuits by allowing the excitation and inhibition of genetically-defined neuronal populations using light. Having gained tremendous popularity in the field of fundamental neuroscience, these techniques are now opening new therapeutic avenues. Optogenetic neuromodulation is a method of choice for studying the physiopathology of neurological and neuropsychiatric disorders in a range of animal models, and could accelerate the discovery of new therapeutic strategies. New therapeutic protocols employing optogenetic neuromodulation may also emerge in the near future, offering promising alternative approaches for disorders which lack appropriate treatments, such as pharmacoresistant epilepsy and inherited retinal degeneration. PMID:25958759

  5. Regulation of Sclerostin Expression in Multiple Myeloma by Dkk-1: A Potential Therapeutic Strategy for Myeloma Bone Disease.

    PubMed

    Eda, Homare; Santo, Loredana; Wein, Marc N; Hu, Dorothy Z; Cirstea, Diana D; Nemani, Neeharika; Tai, Yu-Tzu; Raines, Sarah E; Kuhstoss, Stuart Allen; Munshi, Nikhil C; Kronenberg, Henry M; Raje, Noopur S

    2016-06-01

    Sclerostin is a potent inhibitor of osteoblastogenesis. Interestingly, newly diagnosed multiple myeloma (MM) patients have high levels of circulating sclerostin that correlate with disease stage and fractures. However, the source and impact of sclerostin in MM remains to be defined. Our goal was to determine the role of sclerostin in the biology of MM and its bone microenvironment as well as investigate the effect of targeting sclerostin with a neutralizing antibody (scl-Ab) in MM bone disease. Here we confirm increased sclerostin levels in MM compared with precursor disease states like monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM. Furthermore, we found that a humanized MM xenograft mouse model bearing human MM cells (NOD-SCID.CB17 male mice injected intravenously with 2.5 million of MM1.S-Luc-GFP cells) demonstrated significantly higher concentrations of mouse-derived sclerostin, suggesting a microenvironmental source of sclerostin. Associated with the increased sclerostin levels, activated β-catenin expression levels were lower than normal in MM mouse bone marrow. Importantly, a high-affinity grade scl-Ab reversed osteolytic bone disease in this animal model. Because scl-Ab did not demonstrate significant in vitro anti-MM activity, we combined it with the proteasome inhibitor carfilzomib. Our data demonstrated that this combination therapy significantly inhibited tumor burden and improved bone disease in our in vivo MM mouse model. In agreement with our in vivo data, sclerostin expression was noted in marrow stromal cells and osteoblasts of MM patient bone marrow samples. Moreover, MM cells stimulated sclerostin expression in immature osteoblasts while inhibiting osteoblast differentiation in vitro. This was in part regulated by Dkk-1 secreted by MM cells and is a potential mechanism contributing to the osteoblast dysfunction noted in MM. Our data confirm the role of sclerostin as a potential therapeutic target in MM bone disease

  6. Strategies for the discovery of therapeutic Aptamers

    PubMed Central

    Yang, Xianbin; Li, Na; Gorenstein, David G.

    2010-01-01

    Importance of the field Therapeutic aptamers are synthetic, structured oligonucleotides that bind to a very broad range of targets with high affinity and specificity. They are an emerging class of targeting ligand that show great promise for treating a number of diseases. A series of aptamers currently in various stages of clinical development highlights the potential of aptamers for therapeutic applications. Area covered in this review This review will cover in vitro selection of oligonucleotide ligands, called aptamers, from a combinatorial library using the Systematic Evolution of Ligands by Exponential Enrichment (SELEX) process as well as the other known strategies for finding aptamers against various targets. What the reader will gain Readers will gain an understanding of the highly useful strategies for successful aptamer discovery. They may also be able combine two or more of the presented strategies for their aptamer discovery projects. Take home message Although many processes are available for discovering aptamers, it is not trivial to discover an aptamer candidate that is ready to move toward pharmaceutical drug development. It is also apparent that there have been relatively few therapeutic advances and clinical trials undertaken due to the small number of companies that participate in aptamer development. PMID:21359096

  7. Potentiation of cytotoxicity of paclitaxel in combination with Cl-IB-MECA in human C32 metastatic melanoma cells: A new possible therapeutic strategy for melanoma.

    PubMed

    Soares, Ana S; Costa, Vera M; Diniz, Carmen; Fresco, Paula

    2013-10-01

    Metastatic melanoma monotherapies with drugs such as dacarbazine, cisplatin or paclitaxel (PXT) are associated with significant toxicity and low efficacy rates. These facts reinforce the need for development of novel agents or combinatory strategies. Cl-IB-MECA is a small molecule, orally bioavailable, well tolerated and currently under clinical trials as an anticancer agent. Our aim was to investigate a possible combinatory therapeutic strategy using PXT and Cl-IB-MECA on human C32 melanoma cells and its underlying mechanisms. Cytotoxicity was evaluated using MTT reduction, lactate dehydrogenase leakage and neutral red uptake assays, for different concentrations and combinations of both agents, at 24 and 48 h. Apoptosis was also assessed using fluorescence microscopy and through the evaluation of caspases 8, 9, and 3 activities. We demonstrated, for the first time, that combination of PXT and Cl-IB-MECA significantly increases cytotoxicity for clinically relevant concentrations. This combination seems to act synergistically in disrupting membrane integrity, but also causing lysosomal and mitochondrial dysfunction. When using the lowest PTX concentration (10 ng/mL), co-incubation with CI-IB-MECA (micromolar concentrations) potentiated overall cytotoxic effects and morphological signs of apoptosis. All combinations studied enhanced caspase 8, 9, and 3 activities, suggesting the involvement of both intrinsic and extrinsic apoptotic pathways. The possibility that cytotoxicity elicited by Cl-IB-MECA, alone or in combination with PXT, involves adenosine receptor activation was discarded and results confirmed that oxidative stress is only involved in cytotoxicity after treatment with PXT, alone. Being melanoma a very apoptosis-resistance cancer, this combination seems to hold promise as a new therapeutic strategy for melanoma. PMID:24035253

  8. Antioxidants as potential therapeutics for neuropsychiatric disorders

    PubMed Central

    Pandya, Chirayu D; Howell, Kristy R; Pillai, Anilkumar

    2012-01-01

    Oxidative stress has been implicated in the pathophysiology of many neuropsychiatric disorders such as schizophrenia, bipolar disorder, major depression etc. Both genetic and nongenetic factors have been found to cause increased cellular levels of reactive oxygen species beyond the capacity of antioxidant defense mechanism in patients of psychiatric disorders. These factors trigger oxidative cellular damage to lipids, proteins and DNA, leading to abnormal neural growth and differentiation. Therefore, novel therapeutic strategies such as supplementation with antioxidants can be effective for long-term treatment management of neuropsychiatric disorders. The use of antioxidants and PUFAs as supplements in the treatment of neuropsychiatric disorders has provided some promising results. At the same time, one should be cautious with the use of antioxidants since excessive antioxidants could dangerously interfere with some of the protective functions of reactive oxygen species. The present article will give an overview of the potential strategies and outcomes of using antioxidants as therapeutics in psychiatric disorders. PMID:23123357

  9. SERINE ARGININE PROTEIN KINASE-1 (SRPK1) INHIBITION AS A POTENTIAL NOVEL TARGETED THERAPEUTIC STRATEGY IN PROSTATE CANCER

    PubMed Central

    Mavrou, Athina; Brakspear, Karen; Hamdollah-Zadeh, Maryam; Damodaran, Gopinath; Babaei-Jadidi, Roya; Oxley, Jon; Gillatt, David A; Ladomery, Michael R; Harper, Steven J; Bates, David O; Oltean, Sebastian

    2014-01-01

    Angiogenesis is required for tumour growth and is induced principally by VEGF-A. VEGF-A pre-mRNA is alternatively spliced at the terminal exon to produce two families of isoforms, pro- and anti-angiogenic, only the former of which is upregulated in prostate cancer. In renal epithelial cells and colon cancer cells, the choice of VEGF splice isoforms is controlled by the splicing factor SRSF1, phosphorylated by SRPK1. Immunohistochemistry staining of human samples revealed a significant increase in SRPK1 expression both in prostate intra-epithelial neoplasia lesions as well as malignant adenocarcinoma compared to benign prostate tissue. We therefore tested the hypothesis that the selective upregulation of pro-angiogenic VEGF in prostate cancer may be under the control of SRPK1 activity. A switch in the expression of VEGF165 towards the anti-angiogenic splice isoform, VEGF165b, was seen in PC-3 cells with SRPK1 knock-down (KD). PC-3 SRPK1-KD cells resulted in tumours that grew more slowly in xenografts, with decreased microvessel density. No effect was seen as a result of SRPK1-KD on growth, proliferation, migration and invasion capabilities of PC-3 cells in vitro. Small molecule inhibitors of SRPK1 switched splicing towards the anti-angiogenic isoform VEGF165b in PC3 cells and decreased tumour growth when administered intraperitoneally in an orthotopic mouse model of prostate cancer. Our study suggests that modulation of SRPK1 and subsequent inhibition of tumour angiogenesis by regulation of VEGF splicing can alter prostate tumour growth and supports further studies into the use of SRPK1 inhibition as a potential anti-angiogenic therapy in prostate cancer. PMID:25381816

  10. Serine-arginine protein kinase 1 (SRPK1) inhibition as a potential novel targeted therapeutic strategy in prostate cancer.

    PubMed

    Mavrou, A; Brakspear, K; Hamdollah-Zadeh, M; Damodaran, G; Babaei-Jadidi, R; Oxley, J; Gillatt, D A; Ladomery, M R; Harper, S J; Bates, D O; Oltean, S

    2015-08-13

    Angiogenesis is required for tumour growth and is induced principally by vascular endothelial growth factor A (VEGF-A). VEGF-A pre-mRNA is alternatively spliced at the terminal exon to produce two families of isoforms, pro- and anti-angiogenic, only the former of which is upregulated in prostate cancer (PCa). In renal epithelial cells and colon cancer cells, the choice of VEGF splice isoforms is controlled by the splicing factor SRSF1, phosphorylated by serine-arginine protein kinase 1 (SRPK1). Immunohistochemistry staining of human samples revealed a significant increase in SRPK1 expression both in prostate intra-epithelial neoplasia lesions as well as malignant adenocarcinoma compared with benign prostate tissue. We therefore tested the hypothesis that the selective upregulation of pro-angiogenic VEGF in PCa may be under the control of SRPK1 activity. A switch in the expression of VEGF165 towards the anti-angiogenic splice isoform, VEGF165b, was seen in PC-3 cells with SRPK1 knockdown (KD). PC-3 SRPK1-KD cells resulted in tumours that grew more slowly in xenografts, with decreased microvessel density. No effect was seen as a result of SRPK1-KD on growth, proliferation, migration and invasion capabilities of PC-3 cells in vitro. Small-molecule inhibitors of SRPK1 switched splicing towards the anti-angiogenic isoform VEGF165b in PC-3 cells and decreased tumour growth when administered intraperitoneally in an orthotopic mouse model of PCa. Our study suggests that modulation of SRPK1 and subsequent inhibition of tumour angiogenesis by regulation of VEGF splicing can alter prostate tumour growth and supports further studies for the use of SRPK1 inhibition as a potential anti-angiogenic therapy in PCa. PMID:25381816

  11. Therapeutic potential of cannabinoid medicines.

    PubMed

    Robson, P J

    2014-01-01

    Cannabis was extensively used as a medicine throughout the developed world in the nineteenth century but went into decline early in the twentieth century ahead of its emergence as the most widely used illicit recreational drug later that century. Recent advances in cannabinoid pharmacology alongside the discovery of the endocannabinoid system (ECS) have re-ignited interest in cannabis-based medicines. The ECS has emerged as an important physiological system and plausible target for new medicines. Its receptors and endogenous ligands play a vital modulatory role in diverse functions including immune response, food intake, cognition, emotion, perception, behavioural reinforcement, motor co-ordination, body temperature, wake/sleep cycle, bone formation and resorption, and various aspects of hormonal control. In disease it may act as part of the physiological response or as a component of the underlying pathology. In the forefront of clinical research are the cannabinoids delta-9-tetrahydrocannabinol and cannabidiol, and their contrasting pharmacology will be briefly outlined. The therapeutic potential and possible risks of drugs that inhibit the ECS will also be considered. This paper will then go on to review clinical research exploring the potential of cannabinoid medicines in the following indications: symptomatic relief in multiple sclerosis, chronic neuropathic pain, intractable nausea and vomiting, loss of appetite and weight in the context of cancer or AIDS, psychosis, epilepsy, addiction, and metabolic disorders. PMID:24006213

  12. Follicular lymphoma: evolving therapeutic strategies.

    PubMed

    Kahl, Brad S; Yang, David T

    2016-04-28

    Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma in the Western hemisphere. After decades of stagnation, the natural history of FL appears to have been favorably impacted by the introduction of rituximab. Randomized clinical trials have demonstrated that the addition of rituximab to standard chemotherapy induction has improved the overall survival. Maintenance rituximab strategies can improve progression-free survival. Even chemotherapy platforms have changed in the past 5 years, as bendamustine combined with rituximab has rapidly become a standard frontline strategy in North America and parts of Europe. Recent discoveries have identified patients at high risk for poor outcomes to first-line therapy (m7-Follicular Lymphoma International Prognostic Index [m7-FLIPI]) and for poor outcomes after frontline therapy (National LymphoCare Study). However, several unmet needs remain, including a better ability to identify high-risk patients at diagnosis, the development of predictive biomarkers for targeted agents, and strategies to reduce the risk of transformation. The development of targeted agents, exploiting our current understanding of FL biology, is a high research priority. A multitude of novel therapies are under investigation in both the frontline and relapsed/refractory settings. It will be critical to identify the most appropriate populations for new agents and to develop validated surrogate end points, so that novel agents can be tested (and adopted, if appropriate) efficiently. PMID:26989204

  13. Thymoquinone and its therapeutic potentials.

    PubMed

    Darakhshan, Sara; Bidmeshki Pour, Ali; Hosseinzadeh Colagar, Abasalt; Sisakhtnezhad, Sajjad

    2015-01-01

    Herbal medicine has attracted great attention in the recent years and is increasingly used as alternatives to chemical drugs. Several lines of evidence support the positive impact of medicinal plants in the prevention and cure of a wide range of diseases. Thymoquinone (TQ) is the most abundant constituent of the volatile oil of Nigella sativa seeds and most properties of N sativa are mainly attributed to TQ. A number of pharmacological actions of TQ have been investigated including anti-oxidant, anti-inflammatory, immunomodulatory, anti-histaminic, anti-microbial and anti-tumor effects. It has also gastroprotective, hepatoprotective, nephroprotective and neuroprotective activities. In addition, positive effects of TQ in cardiovascular disorders, diabetes, reproductive disorders and respiratory ailments, as well as in the treatment of bone complications as well as fibrosis have been shown. In addition, a large body of data shows that TQ has very low adverse effects and no serious toxicity. More recently, a great deal of attention has been given to this dietary phytochemical with an increasing interest to investigate it in pre-clinical and clinical researches for assessing its health benefits. Here we report on and analyze numerous properties of the active ingredient of N. sativa seeds, TQ, in the context of its therapeutic potentials for a wide range of illnesses. We also summarize the drug's possible mechanisms of action. The evidence reported sugests that TQ should be developed as a novel drug in clinical trials. PMID:25829334

  14. [Therapeutic strategy against multiple sclerosis].

    PubMed

    Suzumura, Akio

    2008-11-01

    The pathogenesis of multiple sclerosis (MS) remains to be elucidated and there is no curative therapy against MS, though we have several disease modifying drugs. In this symposium. I introduce several new strategies against development of autoimmune processes and axonal degeneration in MS. Several mechanisms regulate immune system not to attack self components. One of the most potent regulatory cells is CD4 + CD25 + FoxP + regulatory T cells (Treg), which suppress development of both T helper 1 and 2. Thus, to increase the number and function of Treg is an approach to suppress autoimmune diseases. We have found recently that midkine suppresses the development of Treg. and that suppression of midkine by RNA aptamer alleviates symptoms of experimental autoimmune encephalomyetitis, an animal model of MS. by expanding Treg. Another important strategy against MS is to suppress axonal degeneration which reportedly occurs from an early stage of MS. We have found that the most toxic agent from activated macrophages and microglia is glutamate that was produced by glutaminase and released through gap-junction. Thus, inhibitor for glutaminase and gap-junction may be other candidates to treat MS. Interferon-beta also effectively suppress glutamate production by these cells and subsequently suppress development of axonal degeneration. PMID:19198124

  15. [Therapeutic strategies against myasthenia gravis].

    PubMed

    Utsugisawa, Kimiaki; Nagane, Yuriko

    2013-05-01

    Many patients with myasthenia gravis (MG) still find it difficult to maintain daily activities due to chronic residual fatigability and long-term side effects of oral corticosteroids, since full remission is not common. Our analysis demonstrated that disease severity, oral corticosteroids, and depressive state are the major factors negatively associated with QOL, and that QOL of MM status patients taking < or = 5 mg prednisolne/day is identically good as that seen in CSR and is a target of treatment. In order to achieve early MM or better status with prednisolne < or = 5 mg/day, we advocate the early aggressive treatment strategy that can achieve early improvement by performing an aggressive therapy using combined treatment with plasmapheresis and high-dose intravenous methylprednisolone and then maintain an improved status using low-dose oral corticosteroids and calcineurin inhibitors. PMID:23777099

  16. Therapeutic Potential of Metabotropic Glutamate Receptor Modulators

    PubMed Central

    Hovelsø, N; Sotty, F; Montezinho, L.P; Pinheiro, P.S; Herrik, K.F; Mørk, A

    2012-01-01

    Glutamate is the main excitatory neurotransmitter in the central nervous system (CNS) and is a major player in complex brain functions. Glutamatergic transmission is primarily mediated by ionotropic glutamate receptors, which include NMDA, AMPA and kainate receptors. However, glutamate exerts modulatory actions through a family of metabotropic G-protein-coupled glutamate receptors (mGluRs). Dysfunctions of glutamatergic neurotransmission have been implicated in the etiology of several diseases. Therefore, pharmacological modulation of ionotropic glutamate receptors has been widely investigated as a potential therapeutic strategy for the treatment of several disorders associated with glutamatergic dysfunction. However, blockade of ionotropic glutamate receptors might be accompanied by severe side effects due to their vital role in many important physiological functions. A different strategy aimed at pharmacologically interfering with mGluR function has recently gained interest. Many subtype selective agonists and antagonists have been identified and widely used in preclinical studies as an attempt to elucidate the role of specific mGluRs subtypes in glutamatergic transmission. These studies have allowed linkage between specific subtypes and various physiological functions and more importantly to pathological states. This article reviews the currently available knowledge regarding the therapeutic potential of targeting mGluRs in the treatment of several CNS disorders, including schizophrenia, addiction, major depressive disorder and anxiety, Fragile X Syndrome, Parkinson’s disease, Alzheimer’s disease and pain. PMID:22942876

  17. Protein Kinase C Activation as a Potential Therapeutic Strategy in Alzheimer's Disease: Is there a Role for Embryonic Lethal Abnormal Vision-like Proteins?

    PubMed

    Talman, Virpi; Pascale, Alessia; Jäntti, Maria; Amadio, Marialaura; Tuominen, Raimo K

    2016-08-01

    Alzheimer's disease (AD), the most common cause of dementia, is an irreversible and progressive neurodegenerative disorder. It affects predominantly brain areas that are critical for memory and learning and is characterized by two main pathological hallmarks: extracellular amyloid plaques and intracellular neurofibrillary tangles. Protein kinase C (PKC) has been classified as one of the cognitive kinases controlling memory and learning. By regulating several signalling pathways involved in amyloid and tau pathologies, it also plays an inhibitory role in AD pathophysiology. Among downstream targets of PKC are the embryonic lethal abnormal vision (ELAV)-like RNA-binding proteins that modulate the stability and the translation of specific target mRNAs involved in synaptic remodelling linked to cognitive processes. This MiniReview summarizes the current evidence on the role of PKC and ELAV-like proteins in learning and memory, highlighting how their derangement can contribute to AD pathophysiology. This last aspect emphasizes the potential of pharmacological activation of PKC as a promising therapeutic strategy for the treatment of AD. PMID:27001133

  18. Therapeutic potential of atmospheric neutrons

    PubMed Central

    Voyant, Cyril; Roustit, Rudy; Tatje, Jennifer; Biffi, Katia; Leschi, Delphine; Briançon, Jérome; Marcovici, Céline Lantieri

    2010-01-01

    Background Glioblastoma multiform (GBM) is the most common and most aggressive type of primary brain tumour in humans. It has a very poor prognosis despite multi-modality treatments consisting of open craniotomy with surgical resection, followed by chemotherapy and/or radiotherapy. Recently, a new treatment has been proposed – Boron Neutron Capture Therapy (BNCT) – which exploits the interaction between Boron-10 atoms (introduced by vector molecules) and low energy neutrons produced by giant accelerators or nuclear reactors. Methods The objective of the present study is to compute the deposited dose using a natural source of neutrons (atmospheric neutrons). For this purpose, Monte Carlo computer simulations were carried out to estimate the dosimetric effects of a natural source of neutrons in the matter, to establish if atmospheric neutrons interact with vector molecules containing Boron-10. Results The doses produced (an average of 1 μGy in a 1 g tumour) are not sufficient for therapeutic treatment of in situ tumours. However, the non-localised yet specific dosimetric properties of 10B vector molecules could prove interesting for the treatment of micro-metastases or as (neo)adjuvant treatment. On a cellular scale, the deposited dose is approximately 0.5 Gy/neutron impact. Conclusion It has been shown that BNCT may be used with a natural source of neutrons, and may potentially be useful for the treatment of micro-metastases. The atmospheric neutron flux is much lower than that utilized during standard NBCT. However the purpose of the proposed study is not to replace the ordinary NBCT but to test if naturally occurring atmospheric neutrons, considered to be an ionizing pollution at the Earth's surface, can be used in the treatment of a disease such as cancer. To finalize this study, it is necessary to quantify the biological effects of the physically deposited dose, taking into account the characteristics of the incident particles (alpha particle and Lithium

  19. International intellectual property strategies for therapeutic antibodies

    PubMed Central

    2011-01-01

    Therapeutic antibodies need international patent protection as their markets expand to include industrialized and emerging countries. Because international intellectual property strategies are frequently complex and costly, applicants require sound information as a basis for decisions regarding the countries in which to pursue patents. While the most important factor is the size of a given market, other factors should also be considered. PMID:22123063

  20. International intellectual property strategies for therapeutic antibodies.

    PubMed

    Storz, Ulrich

    2011-01-01

    Therapeutic antibodies need international patent protection as their markets expand to include industrialized and emerging countries. Because international intellectual property strategies are frequently complex and costly, applicants require sound information as a basis for decisions regarding the countries in which to pursue patents. While the most important factor is the size of a given market, other factors should also be considered. PMID:22123063

  1. Neurosteroids, stress and depression: Potential therapeutic opportunities

    PubMed Central

    Zorumski, Charles F.; Paul, Steven M.; Izumi, Yukitoshi; Covey, Douglas F.; Mennerick, Steven

    2012-01-01

    Neurosteroids are potent and effective neuromodulators that are synthesized from cholesterol in the brain. These agents and their synthetic derivatives influence the function of multiple signaling pathways including receptors for γ-aminobutyric acid (GABA) and glutamate, the major inhibitory and excitatory neurotransmitters in the central nervous system (CNS). Increasing evidence indicates that dysregulation of neurosteroid production plays a role in the pathophysiology of stress and stress-related psychiatric disorders, including mood and anxiety disorders. In this paper, we review the mechanisms of neurosteroid action in brain with an emphasis on those neurosteroids that potently modulate the function of GABAA receptors. We then discuss evidence indicating a role for GABA and neurosteroids in stress and depression, and focus on potential strategies that can be used to manipulate CNS neurosteroid synthesis and function for therapeutic purposes. PMID:23085210

  2. Jo Spence's auto-therapeutic survival strategies.

    PubMed

    Dennett, Terry

    2011-05-01

    The use of the camera as a therapeutic tool is now being increasingly applied within clinical practice (photo-therapy) and, by the public, is being used as a form of non-clinical therapeutic photography. The subject of the present article, the late Jo Spence, was a pioneer and advocate of this approach and worked out a number of strategies that might usefully be passed on to a younger generation. Jo Spence's work is complex and multi-sided. For this reason, this article expands on some of the categories discussed in earlier publications, placing them in their historical context, as well as adding key photographic illustrations. PMID:21335361

  3. Therapeutic strategies targeting cancer stem cells

    PubMed Central

    Ning, Xiaoyan; Shu, Jianchang; Du, Yiqi; Ben, Qiwen; Li, Zhaoshen

    2013-01-01

    Increasing studies have demonstrated a small proportion of cancer stem cells (CSCs) exist in the cancer cell population. CSCs have powerful self-renewal capacity and tumor-initiating ability and are resistant to chemotherapy and radiation. Conventional anticancer therapies kill the rapidly proliferating bulk cancer cells but spare the relatively quiescent CSCs, which cause cancer recurrence. So it is necessary to develop therapeutic strategies acting specifically on CSCs. In recent years, studies have shown that therapeutic agents such as metformin, salinomycin, DECA-14, rapamycin, oncostatin M (OSM), some natural compounds, oncolytic viruses, microRNAs, cell signaling pathway inhibitors, TNF-related apoptosis inducing ligand (TRAIL), interferon (IFN), telomerase inhibitors, all-trans retinoic acid (ATRA) and monoclonal antibodies can suppress the self-renewal of CSCs in vitro and in vivo. A combination of these agents and conventional chemotherapy drugs can significantly inhibit tumor growth, metastasis and recurrence. These strategies targeting CSCs may bring new hopes to cancer therapy. PMID:23358473

  4. [Therapeutic strategies for systemic lupus erythematosus].

    PubMed

    Schneider, M

    2015-04-01

    Therapeutic strategy means the definition of a long-term target, which should be reached by a chosen management. As for rheumatoid arthritis, the treat to target initiative recommends remission as the target for systemic lupus erythematosus (SLE) but the command variables of remission are not yet defined. The basis of a therapeutic strategy is first the analysis of those factors that may influence the achievement of the objectives: SLE disease activity, the differentiation of damage, organ manifestations, comorbidities, genetics, sex, age of onset and considering the pathophysiological basis are some of these factors. The next step is the analysis of the available substances and concepts that allow the target to be reached. Finally, rules for management (e.g. guidelines) are needed that enrich the possibility to reach the target and improve the prognosis of patients suffering from SLE. PMID:25854154

  5. Therapeutic strategies targeting cancer stem cells.

    PubMed

    Ning, Xiaoyan; Shu, Jianchang; Du, Yiqi; Ben, Qiwen; Li, Zhaoshen

    2013-04-01

    Increasing studies have demonstrated a small proportion of cancer stem cells (CSCs) exist in the cancer cell population. CSCs have powerful self-renewal capacity and tumor-initiating ability and are resistant to chemotherapy and radiation. Conventional anticancer therapies kill the rapidly proliferating bulk cancer cells but spare the relatively quiescent CSCs, which cause cancer recurrence. So it is necessary to develop therapeutic strategies acting specifically on CSCs. In recent years, studies have shown that therapeutic agents such as metformin, salinomycin, DECA-14, rapamycin, oncostatin M (OSM), some natural compounds, oncolytic viruses, microRNAs, cell signaling pathway inhibitors, TNF-related apoptosis inducing ligand (TRAIL), interferon (IFN), telomerase inhibitors, all-trans retinoic acid (ATRA) and monoclonal antibodies can suppress the self-renewal of CSCs in vitro and in vivo. A combination of these agents and conventional chemotherapy drugs can significantly inhibit tumor growth, metastasis and recurrence. These strategies targeting CSCs may bring new hopes to cancer therapy. PMID:23358473

  6. Advanced Glycation End-Products and Their Receptors: Related Pathologies, Recent Therapeutic Strategies, and a Potential Model for Future Neurodegeneration Studies.

    PubMed

    Pinkas, Adi; Aschner, Michael

    2016-05-16

    Advanced glycation end products (AGEs) are the result of a nonenzymatic reaction between sugars and proteins, lipids, or nucleic acids. AGEs are both consumed and endogenously formed; their accumulation is accelerated under hyperglycemic and oxidative stress conditions, and they are associated with the onset and complication of many diseases, such as cardiovascular diseases, diabetes, and Alzheimer's disease. AGEs exert their deleterious effects by either accumulating in the circulation and tissues or by receptor-mediated signal transduction. Several receptors bind AGEs: some are specific and contribute to clearance of AGEs, whereas others, like the RAGE receptor, are nonspecific, associated with inflammation and oxidative stress, and considered to be mediators of the aforementioned AGE-related diseases. Although several anti-AGE compounds have been studied, understanding the underlying mechanisms of RAGE and targeting it as a therapeutic strategy is becoming increasingly desirable. For achieving these goals efficiently and expeditiously, the C. elegans model has been suggested. This model is already used for studying several human diseases and, by expressing RAGE, could also be used to study RAGE-related pathways and pathologies to facilitate the development of novel therapeutic strategies. PMID:27054356

  7. Therapeutic Strategies Based on Polymeric Microparticles

    PubMed Central

    Vilos, C.; Velasquez, L. A.

    2012-01-01

    The development of the field of materials science, the ability to perform multidisciplinary scientific work, and the need for novel administration technologies that maximize therapeutic effects and minimize adverse reactions to readily available drugs have led to the development of delivery systems based on microencapsulation, which has taken one step closer to the target of personalized medicine. Drug delivery systems based on polymeric microparticles are generating a strong impact on preclinical and clinical drug development and have reached a broad development in different fields supporting a critical role in the near future of medical practice. This paper presents the foundations of polymeric microparticles based on their formulation, mechanisms of drug release and some of their innovative therapeutic strategies to board multiple diseases. PMID:22665988

  8. Novel therapeutic strategies for adult obese asthmatics

    PubMed Central

    Linderholm, Angela; Bratt, Jennifer; Schuster, Gertrud; Zeki, Amir; Kenyon, Nicholas J.

    2014-01-01

    Synopsis Asthma is a complex syndrome that affects an estimated 26 million people in the United States but gaps exist in the recognition and management of asthmatic subgroups. In this manuscript, we propose alternative approaches for future treatments of adult obese asthmatics that do not respond to standard controller therapies of inhaled corticosteroids, bronchodilators, and anti-leukotriene drugs. We draw parallels between seemingly disparate therapeutics through their common signaling pathways. Specifically, we describe how metformin and statins can potentially improve airway inflammation and suggest supplements, for example L-arginine, which can be used in combination with conventional therapies. A move towards more targeted therapies for asthma subgroups is needed. These therapies address asthma and the comorbidities that accompany obesity and metabolic syndrome to provide the greatest therapeutic potential. PMID:25282293

  9. gp130 receptor ligands as potential therapeutic targets for obesity

    PubMed Central

    Febbraio, Mark A.

    2007-01-01

    Obesity and its related cluster of pathophysiologic conditions including insulin resistance, glucose intolerance, dyslipidemia, and hypertension are recognized as growing threats to world health. It is now estimated that 10% of the world’s population is overweight or obese. As a result, new therapeutic options for the treatment of obesity are clearly warranted. Recent research has focused on the role that gp130 receptor ligands may play as potential therapeutic targets in obesity. One cytokine in particular, ciliary neurotrophic factor (CNTF), acts both centrally and peripherally and mimics the biologic actions of the appetite control hormone leptin, but unlike leptin, CNTF appears to be effective in obesity and as such may have therapeutic potential. In addition, CNTF suppresses inflammatory signaling cascades associated with lipid accumulation in liver and skeletal muscle. This review examines the potential role of gp130 receptor ligands as part of a therapeutic strategy to treat obesity. PMID:17404609

  10. Therapeutic vaccination strategies to treat nasopharyngeal carcinoma.

    PubMed

    Taylor, Graham S; Steven, Neil M

    2016-04-01

    Epstein-Barr virus (EBV) infects most people worldwide. EBV has oncogenic potential and is strongly associated with several lymphomas and carcinomas, including nasopharyngeal carcinoma (NPC), that together total 200,000 cases of cancer each year. All EBV-associated cancers express viral proteins that allow highly selective immunotherapeutic targeting of the malignant cells. A number of therapeutic EBV vaccines have been tested in clinical trials with evidence of immune boosting and clinical responses in NPC patients. Therapeutic vaccination could be used after adoptive T-cell transfer to increase and sustain the number of infused T-cells or combined with immunotherapies acting at different stages of the cancer immunity cycle to increase efficacy. The therapeutic EBV vaccines tested to date have been well tolerated with minimal off-target toxicity. A safe therapeutic vaccine that was also able to be mass produced could, in principle, be used to vaccinate large numbers of patients after first line therapy to reduce recurrence. PMID:27121883

  11. Therapeutic Vaccine Strategies against Human Papillomavirus

    PubMed Central

    Khallouf, Hadeel; Grabowska, Agnieszka K.; Riemer, Angelika B.

    2014-01-01

    High-risk types of human papillomavirus (HPV) cause over 500,000 cervical, anogenital and oropharyngeal cancer cases per year. The transforming potential of HPVs is mediated by viral oncoproteins. These are essential for the induction and maintenance of the malignant phenotype. Thus, HPV-mediated malignancies pose the unique opportunity in cancer vaccination to target immunologically foreign epitopes. Therapeutic HPV vaccination is therefore an ideal scenario for proof-of-concept studies of cancer immunotherapy. This is reflected by the fact that a multitude of approaches has been utilized in therapeutic HPV vaccination design: protein and peptide vaccination, DNA vaccination, nanoparticle- and cell-based vaccines, and live viral and bacterial vectors. This review provides a comprehensive overview of completed and ongoing clinical trials in therapeutic HPV vaccination (summarized in tables), and also highlights selected promising preclinical studies. Special emphasis is given to adjuvant science and the potential impact of novel developments in vaccinology research, such as combination therapies to overcome tumor immune suppression, the use of novel materials and mouse models, as well as systems vaccinology and immunogenetics approaches. PMID:26344626

  12. Therapeutic potential of curcumin in gastrointestinal diseases.

    PubMed

    Rajasekaran, Sigrid A

    2011-02-15

    Curcumin, also known as diferuloylmethane, is derived from the plant Curcuma longa and is the active ingredient of the spice turmeric. The therapeutic activities of curcumin for a wide variety of diseases such as diabetes, allergies, arthritis and other chronic and inflammatory diseases have been known for a long time. More recently, curcumin's therapeutic potential for preventing and treating various cancers is being recognized. As curcumin's therapeutic promise is being explored more systematically in various diseases, it has become clear that, due to its increased bioavailability in the gastrointestinal tract, curcumin may be particularly suited to be developed to treat gastrointestinal diseases. This review summarizes some of the current literature of curcumin's anti-inflammatory, anti-oxidant and anti-cancer potential in inflammatory bowel diseases, hepatic fibrosis and gastrointestinal cancers. PMID:21607160

  13. Conotoxins: Structure, Therapeutic Potential and Pharmacological Applications.

    PubMed

    Mir, Rafia; Karim, Sajjad; Kamal, Mohammad Amjad; Wilson, Cornelia M; Mirza, Zeenat

    2016-01-01

    Cone snails, also known as marine gastropods, from Conus genus produce in their venom a diverse range of small pharmacologically active structured peptides called conotoxins. The cone snail venoms are widely unexplored arsenal of toxins with therapeutic and pharmacological potential, making them a treasure trove of ligands and peptidic drug leads. Conotoxins are small disulfide bonded peptides, which act as remarkable selective inhibitors and modulators of ion channels (calcium, sodium, potassium), nicotinic acetylcholine receptors, noradrenaline transporters, N-methyl-D-aspartate receptors, and neurotensin receptors. They are highly potent and specific against several neuronal targets making them valuable as research tools, drug leads and even therapeutics. In this review, we discuss their gene superfamily classification, nomenclature, post-translational modification, structural framework, pharmacology and medical applications of the active conopeptides. We aim to give an overview of their structure and therapeutic potential. Understanding these aspects of conopeptides will help in designing more specific peptidic analogues. PMID:26601961

  14. Crizotinib resistance: implications for therapeutic strategies.

    PubMed

    Dagogo-Jack, I; Shaw, A T

    2016-09-01

    In 2007, a chromosomal rearrangement resulting in a gene fusion leading to expression of a constitutively active anaplastic lymphoma kinase (ALK) fusion protein was identified as an oncogenic driver in non-small-cell lung cancer (NSCLC). ALK rearrangements are detected in 3%-7% of patients with NSCLC and are particularly enriched in younger patients with adenocarcinoma and a never or light smoking history. Fortuitously, crizotinib, a small molecule tyrosine kinase inhibitor initially developed to target cMET, was able to be repurposed for ALK-rearranged (ALK+) NSCLC. Despite dramatic and durable initial responses to crizotinib; however, the vast majority of patients will develop resistance within a few years. Diverse molecular mechanisms underlie resistance to crizotinib. This review will describe the clinical activity of crizotinib, review identified mechanisms of crizotinib resistance, and end with a survey of emerging therapeutic strategies aimed at overcoming crizotinib resistance. PMID:27573756

  15. Transferrin: structure, function and potential therapeutic actions.

    PubMed

    Gomme, Peter T; McCann, Karl B; Bertolini, Joseph

    2005-02-15

    There are many proteins that can multi-task. Transferrin, widely known as an iron-binding protein, is one such example of a multi-tasking protein. In this review, the multiple biological actions of transferrin, including its growth and cytoprotective activities, are discussed with the view of highlighting the potential therapeutic applications of this protein. PMID:15708745

  16. Therapeutic and prevention strategies against human enterovirus 71 infection.

    PubMed

    Kok, Chee Choy

    2015-05-12

    Human enterovirus 71 (HEV71) is the cause of hand, foot and mouth disease and associated neurological complications in children under five years of age. There has been an increase in HEV71 epidemic activity throughout the Asia-Pacific region in the past decade, and it is predicted to replace poliovirus as the extant neurotropic enterovirus of highest global public health significance. To date there is no effective antiviral treatment and no vaccine is available to prevent HEV71 infection. The increase in prevalence, virulence and geographic spread of HEV71 infection over the past decade provides increasing incentive for the development of new therapeutic and prevention strategies against this emerging viral infection. The current review focuses on the potential, advantages and disadvantages of these strategies. Since the explosion of outbreaks leading to large epidemics in China, research in natural therapeutic products has identified several groups of compounds with anti-HEV71 activities. Concurrently, the search for effective synthetic antivirals has produced promising results. Other therapeutic strategies including immunotherapy and the use of oligonucleotides have also been explored. A sound prevention strategy is crucial in order to control the spread of HEV71. To this end the ultimate goal is the rapid development, regulatory approval and widespread implementation of a safe and effective vaccine. The various forms of HEV71 vaccine designs are highlighted in this review. Given the rapid progress of research in this area, eradication of the virus is likely to be achieved. PMID:25964873

  17. Therapeutic and prevention strategies against human enterovirus 71 infection

    PubMed Central

    Kok, Chee Choy

    2015-01-01

    Human enterovirus 71 (HEV71) is the cause of hand, foot and mouth disease and associated neurological complications in children under five years of age. There has been an increase in HEV71 epidemic activity throughout the Asia-Pacific region in the past decade, and it is predicted to replace poliovirus as the extant neurotropic enterovirus of highest global public health significance. To date there is no effective antiviral treatment and no vaccine is available to prevent HEV71 infection. The increase in prevalence, virulence and geographic spread of HEV71 infection over the past decade provides increasing incentive for the development of new therapeutic and prevention strategies against this emerging viral infection. The current review focuses on the potential, advantages and disadvantages of these strategies. Since the explosion of outbreaks leading to large epidemics in China, research in natural therapeutic products has identified several groups of compounds with anti-HEV71 activities. Concurrently, the search for effective synthetic antivirals has produced promising results. Other therapeutic strategies including immunotherapy and the use of oligonucleotides have also been explored. A sound prevention strategy is crucial in order to control the spread of HEV71. To this end the ultimate goal is the rapid development, regulatory approval and widespread implementation of a safe and effective vaccine. The various forms of HEV71 vaccine designs are highlighted in this review. Given the rapid progress of research in this area, eradication of the virus is likely to be achieved. PMID:25964873

  18. [Type 2 diabetes: what therapeutic strategy?].

    PubMed

    Grimaldi, A; Hartemann-Heurtier, A

    2001-02-17

    GOAL OF TREATMENT: Prevention of diabetic micro and macroangiopathy is the goal of treatment in type 2 diabetes mellitus. A well-controlled glucose level is the key to prevention of microangiopathy; there is no threshold level. Antihypertensive treatment, with the goal of blood pressure below 130/80 mmHg is also beneficial in preventing aggravation of microangiopathy. For macroangiopathy, prevention is based in priority on treatment of other risk factors for cardiovascular disease; the threshold level for drug treatment and the therapeutic objective are those defined for secondary prevention in non-diabetic patients, i.e. blood pressure below 140/80 mmHg and LDL cholesterol under 1.30 g/l. The beneficial effect of lower glucose levels on preventing macrovascular risk was not formally demonstrated by the UKPDS, probably because the difference between the control and the treatment group HbA1c levels was minimal, 0.9 points. REVISITING STRATEGY: It is thus time to revisit the preventive strategy for type 2 diabetes mellitus, i.e. step-by-step increments, as currently proposed for worsening glucose levels. Metformine should be prescribed if the HbA1c is above normal in order to achieve the demonstrated benefit in prevention of microangiopathy and in the hope, motivated by pathophysiology data, of preventing insulin failure. Slow-release insulin at bedtime should be added to the oral hypoglycemiants if fasting glucose exceeds 1.60 or 1.80 g/l, even if the HbA1c remains below 8%. NEW HYPOGLYCEMIANTS: The role of these new agents in this more "aggressive" strategy remains to be defined. Glinides will have to demonstrate their superiority over sulfamides (fewer episodes of hypoglycemia with comparable efficacy) to justify their high cost. Glitazones will have to demonstrate a beneficial effect in second intention combination with metformine on cardiovascular morbidity mortality in type 2 diabetes patients with a metabolic insulin-resistance syndrome and visceral obesity

  19. Novel therapeutic strategies for treatment of visceral leishmaniasis.

    PubMed

    Jain, Keerti; Jain, Narendra K

    2013-12-01

    Leishmaniasis reveals itself in two forms, cutaneous and visceral, but the later exerts serious complications and may lead to death, if untreated. The availability of limited number of antileishmanial chemotherapeutic agents, the high cost of treatment, growing incidences of resistance to first line drugs as well as severe toxicities associated with the drugs complicate the treatment of visceral leishmaniasis. To overcome these problems, critical investigation of new therapeutic strategies with potential antileishmanial activity and good tolerability are essential. In this review we explore the different facets of novel therapeutic strategies for treatment of visceral leishmaniasis with a purpose to summarize all the possible treatment tactics, which will help scientists working in this arena to implement their research in a systematic manner. PMID:23973338

  20. Repurposing antipsychotics as glioblastoma therapeutics: Potentials and challenges

    PubMed Central

    LEE, JIN-KU; NAM, DO-HYUN; LEE, JEONGWU

    2016-01-01

    Glioblastoma multiforme (GBM) is the most common and most lethal primary brain tumor, with tragically little therapeutic progress over the last 30 years. Surgery provides a modest benefit, and GBM cells are resistant to radiation and chemotherapy. Despite significant development of the molecularly targeting strategies, the clinical outcome of GBM patients remains dismal. The challenges inherent in developing effective GBM treatments have become increasingly clear, and include resistance to standard treatments, the blood-brain barrier, resistance of GBM stem-like cells, and the genetic complexity and molecular adaptability of GBM. Recent studies have collectively suggested that certain antipsychotics harbor antitumor effects and have potential utilities as anti-GBM therapeutics. In the present review, the anti-tumorigenic effects and putative mechanisms of antipsychotics, and the challenges for the potential use of antipsychotic drugs as anti-GBM therapeutics are reviewed. PMID:26893731

  1. New Therapeutic Strategies for Primary Sclerosing Cholangitis.

    PubMed

    Williamson, Kate D; Chapman, Roger W

    2016-02-01

    Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease, which in the majority of patients progresses to liver transplantation or death. To date, no medical treatment has been proven to be of benefit, although ursodeoxycholic acid is widely used. The etiopathogenesis of PSC is unclear, although it is associated with inflammatory bowel disease. Various hypotheses have been suggested, which have led to different therapeutic strategies. Recent studies have suggested that the microbiome may play a role in PSC, raising the possibility of efficacy of antibiotics and fecal microbiota transplantation. Gut-homing T cells may be important in the pathogenesis of PSC, and several agents are in development, targeting various receptors, integrins, and ligands on this pathway, including VAP-1, MAdCAM-1, α4β7, and CCR9. Nuclear receptor agonists such as obeticholic acid and fibrates hold promise, as do other therapies that alter bile acid composition such as norUDCA. Antifibrotic agents such as Loxl2 inhibitors are also being assessed. In conclusion, it is likely that an effective drug therapy for PSC will become available over the next decade. PMID:26870928

  2. [Progresses in therapeutic strategies for thymic rejuvenation].

    PubMed

    Tan, Jian-Xin; Wang, Ya-Jun; Zhu, Xi-Ke

    2016-02-25

    The thymus is a vital primary lymphoid organ that provides unique microenvironments for the proliferation, differentiation, and maturation of T cells. With advancing age, however, the thymus gradually undergoes age-related involution and reduction in immune function, which are characterized by decreases in tissue size, cellularity, and naïve T cell output. This dynamic process leads to the reduced efficacy of the immune system with age and contributes to the increased susceptibility to infection, autoimmune disease, and cancer. In addition, bone marrow transplantation, radio-chemotherapy and virus infection also impair the thymus and give rise to the decline in immune function. Therefore, understanding the molecular mechanisms involved in age-related thymic involution and development of novel therapeutic strategies for thymic rejuvenation have gained considerable interests in recent years. This review emphasizes thymic microenvironments and thymocyte-stromal cell interactions and summarizes our current knowledge about thymic rejuvenation in terms of sex steroid, cytokines, growth factors, hormones, transcription factors, cell graft, and microRNAs. At the end of each discussion, we also highlight unanswered issues and describe possible future research directions. PMID:26915325

  3. [Current therapeutic strategies in smoking cessation].

    PubMed

    Borgne, Anne; Aubin, Henri-Jean; Berlin, Ivan

    2004-11-15

    Smoking is a behaviour maintained and enhanced by a dependence mainly induced by nicotine. Despite awareness and knowledge of the associated health risks many smokers find it considerably difficult to quit. The untoward effects of nicotine withdrawal such as apparition of depressive mood, or weight gain, etc. justify the numerous unsuccessful attempts to quit smoking. Treatments with demonstrated efficacy are available and international evidence-based recommendations for cessation interventions have been established. These are: brief advice, assessing the smoking status of each patient and encouraging cessation; nicotine replacement therapies (NRT) [transdermal patch, gum, sublingual tablet or inhalator to be used at sufficiently individualised doses combining, if necessary, two or more NRT products]; bupropion, a more recent treatment: psychotropic drug, a noradrenaline and dopamine re-uptake inhibitor more recently approved for marketing; behavioural and cognitive therapies on their own or combined with pharmacotherapy. Measuring nicotine dependence using the Fagerström Test for Nicotine Dependence may help to define the therapeutic strategy. It is obvious that therapies can only work for smokers who are motivated to stop smoking. Before reaching the decision to quit, the smoker goes through a process in the course of which the role of health professionals' advice is paramount. PMID:15655912

  4. Diagnostic and therapeutic strategies for eosinophilic esophagitis

    PubMed Central

    Zaidi, Asifa K; Mussarat, Ahad; Mishra, Anil

    2014-01-01

    Eosinophilic esophagitis (EoE) is a recently recognized allergic disorder, characterized by eosophageal dysfunction, accumulation of ≥15 eosinophils/high-powered field, eosinophil microabssess, basal cell hyperplasia, extracellular eosinophilic granules in the esophageal epithelial mucosal biopsy and a lack of response to a 8-week proton pump inhibitor treatment. Despite the increased incidences and considerable progress made in understanding EoE pathogenesis, there are limited diagnostic and therapeutic options available for EoE. Currently, the only criterion for diagnosing EoE is repetitive esophageal endoscopic biopsies and histopathological evaluation. Antigen elimination or corticosteroid therapies are effective therapies for EoE but are expensive and have limitations, if continued in the long term. Hence, there is a great necessity for novel noninvasive diagnostic biomarkers that can easily diagnose EoE and assess effectiveness of therapy. Herein, we have provided an update on key molecules involved in the disease initiation, and progression and proposed novel noninvasive diagnostic molecules and strategies for EoE therapy. PMID:25400904

  5. Therapeutic potential of cannabis-related drugs.

    PubMed

    Alexander, Stephen P H

    2016-01-01

    In this review, I will consider the dual nature of Cannabis and cannabinoids. The duality arises from the potential and actuality of cannabinoids in the laboratory and clinic and the 'abuse' of Cannabis outside the clinic. The therapeutic areas currently best associated with exploitation of Cannabis-related medicines include pain, epilepsy, feeding disorders, multiple sclerosis and glaucoma. As with every other medicinal drug of course, the 'trick' will be to maximise the benefit and minimise the cost. After millennia of proximity and exploitation of the Cannabis plant, we are still playing catch up with an understanding of its potential influence for medicinal benefit. PMID:26216862

  6. Targeting histone deacetylases: A novel therapeutic strategy for atrial fibrillation.

    PubMed

    Lkhagva, Baigalmaa; Kao, Yu-Hsun; Chen, Yao-Chang; Chao, Tze-Fan; Chen, Shih-Ann; Chen, Yi-Jen

    2016-06-15

    Atrial fibrillation (AF) is a common cardiac arrhythmia associated with high mortality and morbidity. Current treatments of AF have limited efficacy and considerable side effects. Histone deacetylases (HDACs) play critical roles in the pathophysiology of cardiovascular diseases and contribute to the genesis of AF. Therefore, HDAC inhibition may prove a novel therapeutic strategy for AF through upstream therapy and modifications of AF electrical and structural remodeling. In this review, we provide an update of the knowledge of the effects of HDACs and HDAC inhibitors on AF, and dissect potential underlying mechanisms. PMID:27089819

  7. [Myeloproliferative neoplasms: pathophysiology and therapeutic strategy].

    PubMed

    Kubuki, Yoko; Hidaka, Tomonori; Shimoda, Kazuya

    2015-10-01

    Myeloproliferative neoplasms (MPNs) arise from hematopoietic stem cells (HSCs) with genetic abnormalities in combination with mutations in JAK2, MPL or CALR, which induce autosomal JAK-STAT pathway activation, and mutations in epigenetic regulator genes such as TET2 or DNMT3A. The prognosis of patients with polycythemia vera (PV) or essential thrombocythemia (ET) is relatively good, and the therapeutic goal in cases with PV or ET is to prevent thrombohemorrhagic complications. PV or ET patients at least 60 years of age or with a history of thrombosis are in a high-risk category, and are managed with low dose aspirin and cytoreductive therapy. Phlebotomy to maintain Ht<0.45 is also used to manage PV patients. The median survival for Japanese primary myelofibrosis (MF) patients is 3.9 years. Several factors including age>65 years, Hb<10 g/dl, the presence of constitutional symptoms, and the presence of blasts in blood were identified as being associated with shorter survival in MF patients. Those patients in the high-risk category are candidates for allogenic HSC transplantation (allo-HSCT), which is potentially curative but is also associated with higher therapy-related mortality. High-risk MF patients without indications for allo-HSCT are treated with JAK inhibitors, which can markedly ameliorate constitutional symptoms and splenomegaly, and might thereby lead to a degree of improvement in survival. PMID:26458438

  8. Spinal Muscular Atrophy: Current Therapeutic Strategies

    NASA Astrophysics Data System (ADS)

    Kiselyov, Alex S.; Gurney, Mark E.

    Proximal spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by death of motor neurons in the spinal cord. SMA is caused by deletion and/or mutation of the survival motor neuron gene (SMN1) on chromosome 5q13. There are variable numbers of copies of a second, related gene named SMN2 located in the proximity to SMN1. Both genes encode the same protein (Smn). Loss of SMN1 and incorrect splicing of SMN2 affect cellular levels of Smn triggering death of motor neurons. The severity of SMA is directly related to the normal number of copies of SMN2 carried by the patient. A considerable effort has been dedicated to identifying modalities including both biological and small molecule agents that increase SMN2 promoter activity to upregulate gene transcription and produce increased quantities of full-length Smn protein. This review summarizes recent progress in the area and suggests potential target product profile for an SMA therapeutic.

  9. Cannabidiol and epilepsy: Rationale and therapeutic potential.

    PubMed

    Leo, Antonio; Russo, Emilio; Elia, Maurizio

    2016-05-01

    Despite the introduction of new antiepileptic drugs (AEDs), the quality of life and therapeutic response for patients with epilepsy remains still poor. Unfortunately, besides several advantages, these new AEDs have not satisfactorily reduced the number of refractory patients. Therefore, the need for different other therapeutic options to manage epilepsy is still a current issue. To this purpose, emphasis has been given to phytocannabinoids, which have been medicinally used since ancient time in the treatment of neurological disorders including epilepsy. In particular, the nonpsychoactive compound cannabidiol (CBD) has shown anticonvulsant properties, both in preclinical and clinical studies, with a yet not completely clarified mechanism of action. However, it should be made clear that most phytocannabinoids do not act on the endocannabinoid system as in the case of CBD. In in vivo preclinical studies, CBD has shown significant anticonvulsant effects mainly in acute animal models of seizures, whereas restricted data exist in chronic models of epilepsy as well as in animal models of epileptogenesis. Likewise, clinical evidence seems to indicate that CBD is able to manage epilepsy both in adults and children affected by refractory seizures, with a favourable side effect profile. However, to date, clinical trials are both qualitatively and numerically limited, thus yet inconsistent. Therefore, further preclinical and clinical studies are undoubtedly needed to better evaluate the potential therapeutic profile of CBD in epilepsy, although the actually available data is promising. PMID:26976797

  10. Biopharmaceutics and Therapeutic Potential of Engineered Nanomaterials

    PubMed Central

    Liang, Xing-Jie; Chen, Chunying; Zhao, Yuliang; Jia, Lee; Wang, Paul C.

    2009-01-01

    Engineered nanomaterials are at the leading edge of the rapidly developing nanosciences and are founding an important class of new materials with specific physicochemical properties different from bulk materials with the same compositions. The potential for nanomaterials is rapidly expanding with novel applications constantly being explored in different areas. The unique size-dependent properties of nanomaterials make them very attractive for pharmaceutical applications. Investigations of physical, chemical and biological properties of engineered nanomaterials have yielded valuable information. Cytotoxic effects of certain engineered nanomaterials towards malignant cells form the basis for one aspect of nanomedicine. It is inferred that size, three dimensional shape, hydrophobicity and electronic configurations make them an appealing subject in medicinal chemistry. Their unique structure coupled with immense scope for derivatization forms a base for exciting developments in therapeutics. This review article addresses the fate of absorption, distribution, metabolism and excretion (ADME) of engineered nanoparticles in vitro and in vivo. It updates the distinctive methodology used for studying the biopharmaceutics of nanoparticles. This review addresses the future potential and safety concerns and genotoxicity of nanoparticle formulations in general. It particularly emphasizes the effects of nanoparticles on metabolic enzymes as well as the parenteral or inhalation administration routes of nanoparticle formulations. This paper illustrates the potential of nanomedicine by discussing biopharmaceutics of fullerene derivatives and their suitability for diagnostic and therapeutic purposes. Future direction is discussed as well. PMID:18855608

  11. [Lactoferrin - a glycoprotein of great therapeutic potentials].

    PubMed

    Lauterbach, Ryszard; Kamińska, Ewa; Michalski, Piotr; Lauterbach, Jan Paweł

    2016-01-01

    Lactoferrin is an iron-binding glycoprotein, which is present in most biological fluids with particularly high levels in colostrum and in mammalian milk. Bovine lactoferrin is more than 70% homologous with human lactoferrin. Most of the clinical trials have used bovine lactoferrin for supplementation. This review summarizes the recent advances in explaining the mechanisms, which are responsible for the multifunctional roles of lactoferrin, and presents its potential prophylactic and therapeutic applications. On the ground of the results of preliminary clinical observations, authors suggest beneficial effect of lactoferrin supplementation on the prevalence of necrotizing enterocolitis in infants with birth weight below 1250 grams. PMID:27442696

  12. Ursolic acid (UA): A metabolite with promising therapeutic potential.

    PubMed

    Kashyap, Dharambir; Tuli, Hardeep Singh; Sharma, Anil K

    2016-02-01

    Plants are known to produce a variety of bioactive metabolites which are being used to cure various life threatening and chronic diseases. The molecular mechanism of action of such bioactive molecules, may open up new avenues for the scientific community to develop or improve novel therapeutic approaches to tackle dreadful diseases such as cancer and cardiovascular and neurodegenerative disorders. Ursolic acid (UA) is one among the categories of such plant-based therapeutic metabolites having multiple intracellular and extracellular targets that play role in apoptosis, metastasis, angiogenesis and inflammatory processes. Moreover, the synthetic derivatives of UA have also been seen to be involved in a range of pharmacological applications, which are associated with prevention of diseases. Evidences suggest that UA could be used as a potential candidate to develop a comprehensive competent strategy towards the treatment and prevention of health disorders. The review article herein describes the possible therapeutic effects of UA along with putative mechanism of action. PMID:26775565

  13. Autophagy: a potential therapeutic target in lung diseases

    PubMed Central

    Nakahira, Kiichi

    2013-01-01

    Macroautophagy (hereafter referred to as autophagy) is an evolutionally conserved intracellular process to maintain cellular homeostasis by facilitating the turnover of protein aggregates, cellular debris, and damaged organelles. During autophagy, cytosolic constituents are engulfed into double-membrane-bound vesicles called “autophagosomes,” which are subsequently delivered to the lysosome for degradation. Accumulated evidence suggests that autophagy is critically involved not only in the basal physiological states but also in the pathogenesis of various human diseases. Interestingly, a diverse variety of clinically approved drugs modulate autophagy to varying extents, although they are not currently utilized for the therapeutic purpose of manipulating autophagy. In this review, we highlight the functional roles of autophagy in lung diseases with focus on the recent progress of the potential therapeutic use of autophagy-modifying drugs in clinical medicine. The purpose of this review is to discuss the merits, and the pitfalls, of modulating autophagy as a therapeutic strategy in lung diseases. PMID:23709618

  14. Phytochemical and therapeutic potential of cucumber.

    PubMed

    Mukherjee, Pulok K; Nema, Neelesh K; Maity, Niladri; Sarkar, Birendra K

    2013-01-01

    Cucumber (Cucumis sativus L.) is a member of the Cucurbitaceae family like melon, squash and pumpkins. It is a popular vegetable crop used in Indian traditional medicine since ancient times. This vegetable is very high in water content and very low in calories. It has potential antidiabetic, lipid lowering and antioxidant activity. Cucumber has a cleansing action within the body by removing accumulated pockets of old waste materials and chemical toxins. Fresh fruit juice is used for nourishing the skin. It gives a soothing effect against skin irritations and reduces swelling. Cucumber also has the power to relax and alleviate the sunburn's pain. The fruit is refrigerant, haemostatic, tonic and useful in hyperdipsia, thermoplegia etc. The seeds also have a cooling effect on the body and they are used to prevent constipation. Several bioactive compounds have been isolated from cucumber including cucurbitacins, cucumegastigmanes I and II, cucumerin A and B, vitexin, orientin, isoscoparin 2″-O-(6‴-(E)-p-coumaroyl) glucoside, apigenin 7-O-(6″-O-p-coumaroylglucoside) etc. Despite huge exploration of cucumber in agricultural field, comparatively very few studies have been published about its chemical profile and its therapeutic potential. This article reviews the therapeutic application, pharmacological and phytochemical profile of different parts of C. sativus. In this review we have explored the current phytochemical and pharmacological knowledge available with this well known plant and several promising aspects for research on cucumber. PMID:23098877

  15. Garlic: a review of potential therapeutic effects

    PubMed Central

    Bayan, Leyla; Koulivand, Peir Hossain; Gorji, Ali

    2014-01-01

    Throughout history, many different cultures have recognized the potential use of garlic for prevention and treatment of different diseases. Recent studies support the effects of garlic and its extracts in a wide range of applications. These studies raised the possibility of revival of garlic therapeutic values in different diseases. Different compounds in garlic are thought to reduce the risk for cardiovascular diseases, have anti-tumor and anti-microbial effects, and show benefit on high blood glucose concentration. However, the exact mechanism of all ingredients and their long-term effects are not fully understood. Further studies are needed to elucidate the pathophysiological mechanisms of action of garlic as well as its efficacy and safety in treatment of various diseases. PMID:25050296

  16. Potential and effective meaning in therapeutic ritual.

    PubMed

    McCreery, J L

    1979-03-01

    Anthropologists who accept the functionalist dogma that everything in a culture is related to everything else can easily demonstrate from their own point of view that any ritual is richly meaningful. If, then, the healing power of therapeutic ritual depends on making illness meaningful, any ritual, if seen from this perspective, should be efficacious. We must distinguish, however, between potential and effective meaning, i.e. what a ritual might mean and what it does mean to participants in it who generally lack an anthropologist's global view of their culture. Effective meaning can be assessed by examining a ritual's relevance to the situation in which it occurs and factors which facilitate or hinder communication of what it might mean to particular persons. This argument is illustrated by analyzing the meaning of a Chinese healing ritual in two different situations in which it occurs. PMID:498802

  17. Control of Granule Cell Dispersion by Natural Materials Such as Eugenol and Naringin: A Potential Therapeutic Strategy Against Temporal Lobe Epilepsy.

    PubMed

    Kim, Sang Ryong

    2016-08-01

    The hippocampus is an important brain area where abnormal morphological characteristics are often observed in patients with temporal lobe epilepsy (TLE), typically showing the loss of the principal neurons in the CA1 and CA3 areas of the hippocampus. TLE is frequently associated with widening of the granule cell layer of the dentate gyrus (DG), termed granule cell dispersion (GCD), in the hippocampus, suggesting that the control of GCD with protection of hippocampal neurons may be useful for preventing and inhibiting epileptic seizures. We previously reported that eugenol (EUG), which is an essential component of medicinal herbs and has anticonvulsant activity, is beneficial for treating epilepsy through its ability to inhibit GCD via suppression of mammalian target of rapamycin complex 1 (mTORC1) activation in the hippocampal DG in a kainic acid (KA)-treated mouse model of epilepsy in vivo. In addition, we reported that naringin, a bioflavonoid in citrus fruits, could exert beneficial effects, such as antiautophagic stress and antineuroinflammation, in the KA mouse model of epilepsy, even though it was unclear whether naringin might also attenuate the seizure-induced morphological changes of GCD in the DG. Similar to the effects of EUG, we recently observed that naringin treatment significantly reduced KA-induced GCD and mTORC1 activation, which are both involved in epileptic seizures, in the hippocampus of mouse brain. Therefore, these observations suggest that the utilization of natural materials, which have beneficial properties such as inhibition of GCD formation and protection of hippocampal neurons, may be useful in developing a novel therapeutic agent against TLE. PMID:27404051

  18. Protein Engineering for Cardiovascular Therapeutics: Untapped Potential for Cardiac Repair

    PubMed Central

    Jay, Steven M.; Lee, Richard T.

    2013-01-01

    Numerous new and innovative approaches for repairing damaged myocardium are currently under investigation, with several encouraging results. In addition to the progression of stem cell-based approaches and gene therapy/silencing methods, evidence continues to emerge that protein therapeutics may be used to directly promote cardiac repair and even regeneration. However, proteins are often limited in their therapeutic potential by short local half-lives and insufficient bioavailability and/or bioactivity, and many academic laboratories studying cardiovascular diseases are more comfortable with molecular and cellular biology compared with protein biochemistry. Protein engineering has been employed broadly to overcome weaknesses traditionally associated with protein therapeutics and has the potential to specifically enhance the efficacy of molecules for cardiac repair. Yet protein engineering as a strategy has not yet been employed in the development of cardiovascular therapeutics to the degree that it has in other fields. In this review, we discuss the role of engineered proteins in cardiovascular therapies to date. Further, we address the promise of applying emerging protein engineering technologies to cardiovascular medicine and the barriers that must be overcome to enable the ultimate success of this approach. PMID:24030023

  19. Immune evasion in cancer: Mechanistic basis and therapeutic strategies.

    PubMed

    Vinay, Dass S; Ryan, Elizabeth P; Pawelec, Graham; Talib, Wamidh H; Stagg, John; Elkord, Eyad; Lichtor, Terry; Decker, William K; Whelan, Richard L; Kumara, H M C Shantha; Signori, Emanuela; Honoki, Kanya; Georgakilas, Alexandros G; Amin, Amr; Helferich, William G; Boosani, Chandra S; Guha, Gunjan; Ciriolo, Maria Rosa; Chen, Sophie; Mohammed, Sulma I; Azmi, Asfar S; Keith, W Nicol; Bilsland, Alan; Bhakta, Dipita; Halicka, Dorota; Fujii, Hiromasa; Aquilano, Katia; Ashraf, S Salman; Nowsheen, Somaira; Yang, Xujuan; Choi, Beom K; Kwon, Byoung S

    2015-12-01

    Cancer immune evasion is a major stumbling block in designing effective anticancer therapeutic strategies. Although considerable progress has been made in understanding how cancers evade destructive immunity, measures to counteract tumor escape have not kept pace. There are a number of factors that contribute to tumor persistence despite having a normal host immune system. Immune editing is one of the key aspects why tumors evade surveillance causing the tumors to lie dormant in patients for years through "equilibrium" and "senescence" before re-emerging. In addition, tumors exploit several immunological processes such as targeting the regulatory T cell function or their secretions, antigen presentation, modifying the production of immune suppressive mediators, tolerance and immune deviation. Besides these, tumor heterogeneity and metastasis also play a critical role in tumor growth. A number of potential targets like promoting Th1, NK cell, γδ T cell responses, inhibiting Treg functionality, induction of IL-12, use of drugs including phytochemicals have been designed to counter tumor progression with much success. Some natural agents and phytochemicals merit further study. For example, use of certain key polysaccharide components from mushrooms and plants have shown to possess therapeutic impact on tumor-imposed genetic instability, anti-growth signaling, replicative immortality, dysregulated metabolism etc. In this review, we will discuss the advances made toward understanding the basis of cancer immune evasion and summarize the efficacy of various therapeutic measures and targets that have been developed or are being investigated to enhance tumor rejection. PMID:25818339

  20. Therapeutic strategies for cancer pain management.

    PubMed Central

    Miller, T. W.; Spiro, K.; Jay, L. L.

    1990-01-01

    Clinical issues related to treating the oncology pain patient have gained considerable attention in the medical and health care literature. Addressed are management strategies which focus specifically on cognitive-behavioral, psychosocial, and pharmacologic approaches to treating the oncology pain patient. Each strategy possesses unique qualities that can benefit the care and management of the cancer patient and provide a better understanding of the disease entity and the patient's ability to develop coping strategies that may be effective in understanding and confronting pain associated with cancer. PMID:2097904

  1. Therapeutic Strategies to Alter Oxygen Affinity of Sickle Hemoglobin

    PubMed Central

    Safo, Martin K.; Kato, Gregory J.

    2014-01-01

    The fundamental pathophysiology of sickle cell disease involves the polymerization of sickle hemoglobin in its T-state which develops under low oxygen saturation. One therapeutic strategy is to develop pharmacologic agents to stabilize the R-state of hemoglobin, which has higher oxygen affinity and would be expected to have slower kinetics of polymerization, potentially delaying the sickling of red cells during circulation. This therapeutic strategy has stimulated the laboratory investigation of aromatic aldehydes, aspirin derivatives, thiols and isothiocyanates that can stabilize the R-state of hemoglobin in vitro. One representative aromatic aldehyde agent, 5-hydoxymethyl-2-furfural (5-HMF, also known as Aes-103) increases oxygen affinity of sickle hemoglobin and reduces hypoxia-induced sickling in vitro and protects sickle cell mice from effects of hypoxia. It has completed pre-clinical testing and has entered clinical trials. The development of Hb allosteric modifiers as direct anti-sickling agents is an attractive investigational goal for the treatment of sickle cell disease. PMID:24589263

  2. Therapeutic Strategies in HCC: Radiation Modalities

    PubMed Central

    Gallicchio, R.; Nardelli, A.; Mainenti, P.; Nappi, A.; Capacchione, D.; Simeon, V.; Sirignano, C.; Abbruzzi, F.; Barbato, F.; Landriscina, M.

    2016-01-01

    Patients with hepatocellular carcinoma (HCC) comply with an advanced disease and are not eligible for radical therapy. In this distressed scenario new treatment options hold great promise; among them transarterial chemoembolization (TACE) and transarterial metabolic radiotherapy (TAMR) have shown efficacy in terms of both tumor shrinking and survival. External radiation therapy (RTx) by using novel three-dimensional conformal radiotherapy has also been used for HCC patients with encouraging results while its role had been limited in the past for the low tolerance of surrounding healthy liver. The rationale of TAMR derives from the idea of delivering exceptional radiation dose locally to the tumor, with cell killing intent, while preserving normal liver from undue exposition and minimizing systemic irradiation. Since the therapeutic efficacy of TACE is being continuously disputed, the TAMR with 131I Lipiodol or 90Y microspheres has gained consideration providing adequate therapeutic responses regardless of few toxicities. The implementation of novel radioisotopes and technological innovations in the field of RTx constitutes an intriguing field of research with important translational aspects. Moreover, the combination of different therapeutic approaches including chemotherapy offers captivating perspectives. We present the role of the radiation-based therapies in hepatocellular carcinoma patients who are not entitled for radical treatment. PMID:27563661

  3. Therapeutic Strategies in HCC: Radiation Modalities.

    PubMed

    Gallicchio, R; Nardelli, A; Mainenti, P; Nappi, A; Capacchione, D; Simeon, V; Sirignano, C; Abbruzzi, F; Barbato, F; Landriscina, M; Storto, G

    2016-01-01

    Patients with hepatocellular carcinoma (HCC) comply with an advanced disease and are not eligible for radical therapy. In this distressed scenario new treatment options hold great promise; among them transarterial chemoembolization (TACE) and transarterial metabolic radiotherapy (TAMR) have shown efficacy in terms of both tumor shrinking and survival. External radiation therapy (RTx) by using novel three-dimensional conformal radiotherapy has also been used for HCC patients with encouraging results while its role had been limited in the past for the low tolerance of surrounding healthy liver. The rationale of TAMR derives from the idea of delivering exceptional radiation dose locally to the tumor, with cell killing intent, while preserving normal liver from undue exposition and minimizing systemic irradiation. Since the therapeutic efficacy of TACE is being continuously disputed, the TAMR with (131)I Lipiodol or (90)Y microspheres has gained consideration providing adequate therapeutic responses regardless of few toxicities. The implementation of novel radioisotopes and technological innovations in the field of RTx constitutes an intriguing field of research with important translational aspects. Moreover, the combination of different therapeutic approaches including chemotherapy offers captivating perspectives. We present the role of the radiation-based therapies in hepatocellular carcinoma patients who are not entitled for radical treatment. PMID:27563661

  4. Neurosteroids and potential therapeutics: Focus on pregnenolone.

    PubMed

    Vallée, Monique

    2016-06-01

    Considerable evidence from preclinical and clinical studies shows that steroids and in particular neurosteroids are important endogenous modulators of several brain-related functions. In this context, it remains to be elucidated whether neurosteroids may serve as biomarkers in the diagnosis of disorders and might have therapeutic potential for the treatment of these disorders. Pregnenolone (PREG) is the main steroid synthesized from cholesterol in mammals and invertebrates. PREG has three main sources of synthesis, the gonads, adrenal glands and brain and is submitted to various metabolizing pathways which are modulated depending on various factors including species, steroidogenic tissues and steroidogenic enzymes. Looking at the whole picture of steroids, PREG is often known as the precursor to other steroids and not as an active steroid per se. Actually, physiological and brain functions have been studied mainly for steroids that are very active either binding to specific intracellular receptors, or modulating with high affinity the abundant membrane receptors, GABAA or NMDA receptors. However, when high sensitive and specific methodological approaches were available to analyze low concentrations of steroids and then match endogenous levels of different steroid metabolomes, several studies have reported more significant alterations in PREG than in other steroids in extraphysiological or pathological conditions, suggesting that PREG could play a functional role as well. Additionally, several molecular targets of PREG were revealed in the mammalian brain and beneficial effects of PREG have been demonstrated in preclinical and clinical studies. On this basis, this review will be divided into three parts. The first provides a brief overview of the molecular targets of PREG and the pharmacological effects observed in animal and human studies. The second will focus on the possible functional role of PREG with an outline of the modulation of PREG levels in animal and in

  5. Cyclic depsipeptides as potential cancer therapeutics.

    PubMed

    Kitagaki, Jirouta; Shi, Genbin; Miyauchi, Shizuka; Murakami, Shinya; Yang, Yili

    2015-03-01

    Cyclic depsipeptides are polypeptides in which one or more amino acid is replaced by a hydroxy acid, resulting in the formation of at least one ester bond in the core ring structure. Many natural cyclic depsipeptides possessing intriguing structural and biological properties, including antitumor, antifungal, antiviral, antibacterial, anthelmintic, and anti-inflammatory activities, have been identified from fungi, plants, and marine organisms. In particular, the potent effects of cyclic depsipeptides on tumor cells have led to a number of clinical trials evaluating their potential as chemotherapeutic agents. Although many of the trials have not achieved the desired results, romidepsin (FK228), a bicyclic depsipeptide that inhibits histone deacetylase, has been shown to have clinical efficacy in patients with refractory cutaneous T-cell lymphoma and has received Food and Drug Administration approval for use in treatment. In this review, we discuss antitumor cyclic depsipeptides that have undergone clinical trials and focus on their structural features, mechanisms, potential applications in chemotherapy, and pharmacokinetic and toxicity data. The results of this study indicate that cyclic depsipeptides could be a rich source of new cancer therapeutics. PMID:25419631

  6. Cannabinoids and Schizophrenia: Risks and Therapeutic Potential.

    PubMed

    Manseau, Marc W; Goff, Donald C

    2015-10-01

    A convergence of evidence shows that use of Cannabis sativa is associated with increased risk of developing psychotic disorders, including schizophrenia, and earlier age at which psychotic symptoms first manifest. Cannabis exposure during adolescence is most strongly associated with the onset of psychosis amongst those who are particularly vulnerable, such as those who have been exposed to child abuse and those with family histories of schizophrenia. Schizophrenia that develops after cannabis use may have a unique clinical phenotype, and several genetic polymorphisms may modulate the relationship between cannabis use and psychosis. The endocannabinoid system has been implicated in psychosis both related and unrelated to cannabis exposure, and studying this system holds potential to increase understanding of the pathophysiology of schizophrenia. Anandamide signaling in the central nervous system may be particularly important. Δ(9)-Tetrahydrocannabinol in cannabis can cause symptoms of schizophrenia when acutely administered, and cannabidiol (CBD), another compound in cannabis, can counter many of these effects. CBD may have therapeutic potential for the treatment of psychosis following cannabis use, as well as schizophrenia, possibly with better tolerability than current antipsychotic treatments. CBD may also have anti-inflammatory and neuroprotective properties. Establishing the role of CBD and other CBD-based compounds in treating psychotic disorders will require further human research. PMID:26311150

  7. Deferoxamine Preconditioning of Neural-Like Cells Derived from Human Wharton's Jelly Mesenchymal Stem Cells as a Strategy to Promote Their Tolerance and Therapeutic Potential: An In Vitro Study.

    PubMed

    Nouri, Fatemeh; Salehinejad, Parvin; Nematollahi-Mahani, Seyed Noureddin; Kamarul, Tunku; Zarrindast, Mohammad Reza; Sharifi, Ali Mohammad

    2016-07-01

    Transplantation of neural-like cells is considered as a promising therapeutic strategy developed for neurodegenerative disease in particular for ischemic stroke. Since cell survival is a major concern following cell implantation, a number of studies have underlined the protective effects of preconditioning with hypoxia or hypoxia mimetic pharmacological agents such as deferoxamine (DFO), induced by activation of hypoxia inducible factor-1 (HIF-1) and its target genes. The present study has investigated the effects of DFO preconditioning on some factors involved in cell survival, angiogenesis, and neurogenesis of neural-like cells derived from human Wharton's jelly mesenchymal stem cells (HWJ-MSCs) in presence of hydrogen peroxide (H2O2). HWJ-MSCs were differentiated toward neural-like cells for 14 days and neural cell markers were identified using immunocytochemistry. HWJ-MSC-derived neural-like cells were then treated with 100 µM DFO, as a known hypoxia mimetic agent for 48 h. mRNA and protein expression of HIF-1 target genes including brain-derived neurotrophic factors (BDNF) and vascular endothelial growth factor (VEGF) significantly increased using RT-PCR and Western blotting which were reversed by HIF-1α inhibitor, while, gene expression of Akt-1, Bcl-2, and Bax did not change significantly but pAkt-1 was up-regulated as compared to poor DFO group. However, addition of H2O2 to DFO-treated cells resulted in higher resistance to H2O2-induced cell death. Western blotting analysis also showed significant up-regulation of HIF-1α, BDNF, VEGF, and pAkt-1, and decrease of Bax/Bcl-2 ratio as compared to poor DFO. These results may suggest that DFO preconditioning of HWJ-MSC-derived neural-like cells improves their tolerance and therapeutic potential and might be considered as a valuable strategy to improve cell therapy. PMID:26242172

  8. Understanding the Mechanism of Hepatic Fibrosis and Potential Therapeutic Approaches

    PubMed Central

    Ahmad, Areeba; Ahmad, Riaz

    2012-01-01

    Hepatic fibrosis (HF) is a progressive condition with serious clinical complications arising from abnormal proliferation and amassing of tough fibrous scar tissue. This defiance of collagen fibers becomes fatal due to ultimate failure of liver functions. Participation of various cell types, interlinked cellular events, and large number of mediator molecules make the fibrotic process enormously complex and dynamic. However, with better appreciation of underlying cellular and molecular mechanisms of fibrosis, the assumption that HF cannot be cured is gradually changing. Recent findings have underlined the therapeutic potential of a number of synthetic compounds as well as plant derivatives for cessation or even the reversal of the processes that transforms the liver into fibrotic tissue. It is expected that future inputs will provide a conceptual framework to develop more specific strategies that would facilitate the assessment of risk factors, shortlist early diagnosis biomarkers, and eventually guide development of effective therapeutic alternatives. PMID:22626794

  9. Therapeutic potential of chalcones as cardiovascular agents.

    PubMed

    Mahapatra, Debarshi Kar; Bharti, Sanjay Kumar

    2016-03-01

    Cardiovascular diseases are the leading cause of death affecting 17.3 million people across the globe and are estimated to affect 23.3 million people by year 2030. In recent years, about 7.3 million people died due to coronary heart disease, 9.4 million deaths due to high blood pressure and 6.2 million due to stroke, where obesity and atherosclerotic progression remain the chief pathological factors. The search for newer and better cardiovascular agents is the foremost need to manage cardiac patient population across the world. Several natural and (semi) synthetic chalcones deserve the credit of being potential candidates to inhibit various cardiovascular, hematological and anti-obesity targets like angiotensin converting enzyme (ACE), cholesteryl ester transfer protein (CETP), diacylglycerol acyltransferase (DGAT), acyl-coenzyme A: cholesterol acyltransferase (ACAT), pancreatic lipase (PL), lipoprotein lipase (LPL), calcium (Ca(2+))/potassium (K(+)) channel, COX-1, TXA2 and TXB2. In this review, a comprehensive study of chalcones, their therapeutic targets, structure activity relationships (SARs), mechanisms of actions (MOAs) have been discussed. Chemically diverse chalcone scaffolds, their derivatives including structural manipulation of both aryl rings, replacement with heteroaryl scaffold(s) and hybridization through conjugation with other pharmacologically active scaffold have been highlighted. Chalcones which showed promising activity and have a well-defined MOAs, SARs must be considered as prototype for the design and development of potential anti-hypertensive, anti-anginal, anti-arrhythmic and cardioprotective agents. With the knowledge of these molecular targets, structural insights and SARs, this review may be helpful for (medicinal) chemists to design more potent, safe, selective and cost effective chalcone derivatives as potential cardiovascular agents. PMID:26876916

  10. Anticancer therapeutic potential of soy isoflavone, genistein.

    PubMed

    Ravindranath, Mepur H; Muthugounder, Sakunthala; Presser, Naftali; Viswanathan, Subramanian

    2004-01-01

    to recombinant EGF to target cancers overexpressing the EGF receptor. Although genistein has many potentially therapeutic actions against cancer, its biphasic bioactivity (inhibitory at high concentrations and activating at low concentrations) requires caution in determining therapeutic doses of genistein alone or in combination with chemotherapy, radiation therapy, and/or immunotherapies. Of the more than 4500 genistein studies in peer-reviewed primary publications, almost one fifth pertain to its antitumor capabilities and more than 400 describe its mechanism of action in normal and malignant human and animal cells, animal models, in vitro experiments, or phase I/II clinical trials. Several biotechnological firms in Japan, Australia and in the United States (e.g., Nutrilite) manufacture genistein as a natural supplement under quality controlled and assured conditions. PMID:15584372

  11. Therapeutic Strategies for Hereditary Kidney Cancer.

    PubMed

    Sidana, Abhinav; Srinivasan, Ramaprasad

    2016-08-01

    The study of hereditary forms of kidney cancer has vastly increased our understanding of metabolic and genetic pathways involved in the development of both inherited and sporadic kidney cancers. The recognition that diverse molecular events drive different forms of kidney cancers has led to the preclinical and clinical development of specific pathway-directed strategies tailored to treat distinct subgroups of kidney cancer. Here, we describe the molecular mechanisms underlying the pathogenesis of several different types of hereditary renal cancers, review their clinical characteristics, and summarize the treatment strategies for the management of these cancers. PMID:27325049

  12. Escherichia coli biofilm: development and therapeutic strategies.

    PubMed

    Sharma, G; Sharma, S; Sharma, P; Chandola, D; Dang, S; Gupta, S; Gabrani, R

    2016-08-01

    Escherichia coli biofilm consists of a bacterial colony embedded in a matrix of extracellular polymeric substances (EPS) which protects the microbes from adverse environmental conditions and results in infection. Besides being the major causative agent for recurrent urinary tract infections, E. coli biofilm is also responsible for indwelling medical device-related infectivity. The cell-to-cell communication within the biofilm occurs due to quorum sensors that can modulate the key biochemical players enabling the bacteria to proliferate and intensify the resultant infections. The diversity in structural components of biofilm gets compounded due to the development of antibiotic resistance, hampering its eradication. Conventionally used antimicrobial agents have a restricted range of cellular targets and limited efficacy on biofilms. This emphasizes the need to explore the alternate therapeuticals like anti-adhesion compounds, phytochemicals, nanomaterials for effective drug delivery to restrict the growth of biofilm. The current review focuses on various aspects of E. coli biofilm development and the possible therapeutic approaches for prevention and treatment of biofilm-related infections. PMID:26811181

  13. Immunological and Therapeutic Strategies against Salmonid Cryptobiosis

    PubMed Central

    Woo, Patrick T. K.

    2010-01-01

    Salmonid cryptobiosis is caused by the haemoflagellate, Cryptobia salmositica. Clinical signs of the disease in salmon (Oncorhynchus spp.) include exophthalmia, general oedema, abdominal distension with ascites, anaemia, and anorexia. The disease-causing factor is a metalloprotease and the monoclonal antibody (mAb-001) against it is therapeutic. MAb-001 does not fix complement but agglutinates the parasite. Some brook charr, Salvelinus fontinalis cannot be infected (Cryptobia-resistant); this resistance is controlled by a dominant Mendelian locus and is inherited. In Cryptobia-resistant charr the pathogen is lysed via the Alternative Pathway of Complement Activation. However, some charr can be infected and they have high parasitaemias with no disease (Cryptobia-tolerant). In infected Cryptobia-tolerant charr the metalloprotease is neutralized by a natural antiprotease, α2 macroglobulin. Two vaccines have been developed. A single dose of the attenuated vaccine protects 100% of salmonids (juveniles and adults) for at least 24 months. Complement fixing antibody production and cell-mediated response in vaccinated fish rise significantly after challenge. Fish injected with the DNA vaccine initially have slight anaemias but they recover and have agglutinating antibodies. On challenge, DNA-vaccinated fish have lower parasitaemias, delayed peak parasitaemias and faster recoveries. Isometamidium chloride is therapeutic against the pathogen and its effectiveness is increased after conjugation to antibodies. PMID:20052385

  14. Immunological and therapeutic strategies against salmonid cryptobiosis.

    PubMed

    Woo, Patrick T K

    2010-01-01

    Salmonid cryptobiosis is caused by the haemoflagellate, Cryptobia salmositica. Clinical signs of the disease in salmon (Oncorhynchus spp.) include exophthalmia, general oedema, abdominal distension with ascites, anaemia, and anorexia. The disease-causing factor is a metalloprotease and the monoclonal antibody (mAb-001) against it is therapeutic. MAb-001 does not fix complement but agglutinates the parasite. Some brook charr, Salvelinus fontinalis cannot be infected (Cryptobia-resistant); this resistance is controlled by a dominant Mendelian locus and is inherited. In Cryptobia-resistant charr the pathogen is lysed via the Alternative Pathway of Complement Activation. However, some charr can be infected and they have high parasitaemias with no disease (Cryptobia-tolerant). In infected Cryptobia-tolerant charr the metalloprotease is neutralized by a natural antiprotease, alpha2 macroglobulin. Two vaccines have been developed. A single dose of the attenuated vaccine protects 100% of salmonids (juveniles and adults) for at least 24 months. Complement fixing antibody production and cell-mediated response in vaccinated fish rise significantly after challenge. Fish injected with the DNA vaccine initially have slight anaemias but they recover and have agglutinating antibodies. On challenge, DNA-vaccinated fish have lower parasitaemias, delayed peak parasitaemias and faster recoveries. Isometamidium chloride is therapeutic against the pathogen and its effectiveness is increased after conjugation to antibodies. PMID:20052385

  15. Therapeutic potential of monoamine transporter substrates.

    PubMed

    Rothman, Richard B; Baumann, Michael H

    2006-01-01

    Monoamine transporter proteins are targets for many psychoactive compounds, including therapeutic and abused stimulant drugs. This paper reviews recent work from our laboratory investigating the interaction of stimulants with transporters in brain tissue. We illustrate how determining the precise mechanism of stimulant drug action (uptake inhibitor vs. substrate) can provide unique opportunities for medication discovery. An important lesson learned from this work is that drugs which display equipotent substrate activity at dopamine (DA) and serotonin (5-HT) transporters have minimal abuse liability and few stimulant side-effects, yet are able to suppress ongoing drug-seeking behavior. As a specific example, we describe the development of PAL-287 (alpha-methylnapthylethylamine), a dual DA/5-HT releasing agent that suppresses cocaine self-administration in rhesus monkeys, without the adverse effects associated with older phenylethylamine 5-HT releasers (e.g., fenfluramine) and DA releasers (e.g., amphetamine). Our findings demonstrate the feasibility of developing non-amphetamine releasing agents as potential treatments for substance abuse disorders and other psychiatric conditions. PMID:17017961

  16. Therapeutic potential of berberine against neurodegenerative diseases.

    PubMed

    Jiang, WenXiao; Li, ShiHua; Li, XiaoJiang

    2015-06-01

    Berberine (BBR) is an organic small molecule isolated from various plants that have been used in traditional Chinese medicine. Isolation of this compound was its induction into modern medicine, and its usefulness became quickly apparent as seen in its ability to combat bacterial diarrhea, type 2 diabetes, hypercholesterolemia, inflammation, heart diseases, and more. However, BBR's effects on neurodegenerative diseases remained relatively unexplored until its ability to stunt Alzheimer's disease (AD) progression was characterized. In this review, we will delve into the multi-faceted defensive capabilities and bio-molecular pathways of BBR against AD, Parkinson's disease (PD), and trauma-induced neurodegeneration. The multiple effects of BBR, some of which enhance neuro-protective factors/pathways and others counteract targets that induce neurodegeneration, suggest that there are many more branches to the diverse capabilities of BBR that have yet to be uncovered. The promising results seen provide a convincing and substantial basis to support further scientific exploration and development of the therapeutic potential of BBR against neurodegenerative diseases. PMID:25749423

  17. Therapeutic potential of monoacylglycerol lipase inhibitors.

    PubMed

    Mulvihill, Melinda M; Nomura, Daniel K

    2013-03-19

    Marijuana and aspirin have been used for millennia to treat a wide range of maladies including pain and inflammation. Both cannabinoids, like marijuana, that exert anti-inflammatory action through stimulating cannabinoid receptors, and cyclooxygenase (COX) inhibitors, like aspirin, that suppress pro-inflammatory eicosanoid production have shown beneficial outcomes in mouse models of neurodegenerative diseases and cancer. Both cannabinoids and COX inhibitors, however, have untoward effects that discourage their chronic usage, including cognitive deficits and gastrointestinal toxicity, respectively. Recent studies have uncovered that the serine hydrolase monoacylglycerol lipase (MAGL) links the endocannabinoid and eicosanoid systems together through hydrolysis of the endocannabinoid 2-arachidonoylglycerol (2-AG) to provide the major arachidonic acid (AA) precursor pools for pro-inflammatory eicosanoid synthesis in specific tissues. Studies in recent years have shown that MAGL inhibitors elicit anti-nociceptive, anxiolytic, and anti-emetic responses and attenuate precipitated withdrawal symptoms in addiction paradigms through enhancing endocannabinoid signaling. MAGL inhibitors have also been shown to exert anti-inflammatory action in the brain and protect against neurodegeneration through lowering eicosanoid production. In cancer, MAGL inhibitors have been shown to have anti-cancer properties not only through modulating the endocannabinoid-eicosanoid network, but also by controlling fatty acid release for the synthesis of protumorigenic signaling lipids. Thus, MAGL serves as a critical node in simultaneously coordinating multiple lipid signaling pathways in both physiological and disease contexts. This review will discuss the diverse (patho)physiological roles of MAGL and the therapeutic potential of MAGL inhibitors in treating a vast array of complex human diseases. PMID:23142242

  18. Therapeutic strategy in unresectable metastatic colorectal cancer

    PubMed Central

    Tournigand, Christophe; André, Thierry; de Gramont, Aimery

    2012-01-01

    While surgery is the cornerstone treatment for early-stage colorectal cancer, chemotherapy is the first treatment option for metastatic disease when tumor lesions are frequently not fully resectable at presentation. Mortality from colon cancer has decreased over the past 30 years, but there is still a huge heterogeneity in survival rates that can be mainly explained by patient and tumor characteristics, host response factors, and treatment modalities. The management of unresectable metastatic colorectal cancer is a global treatment strategy, which applies several lines of therapy, salvage surgery, maintenance, and treatment-free intervals. The individualization of cancer treatment is based on the evaluation of prognostic factors for survival (serum lactate dehydrogenase level, performance status), and predictive factors for treatment efficacy [Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation status]. The available treatment modalities for metastatic colorectal cancer are chemotherapy (fluoropyrimidine, oxaliplatin, irinotecan), anti-angiogenic agents (e.g. bevacizumab), and anti-epidermal growth factor agents (cetuximab, panitumumab). The increasing number of active compounds dictates the strategy of trials evaluating these treatments either in combination or sequentially. Alternative outcomes that can be measured earlier than overall survival are needed to shorten the duration and reduce the size and cost of clinical trials. PMID:22423266

  19. Molecular pathogenesis and therapeutic strategies of human osteosarcoma

    PubMed Central

    Denduluri, Sahitya K; Wang, Zhongliang; Yan, Zhengjian; Wang, Jing; Wei, Qiang; Mohammed, Maryam K; Haydon, Rex C; Luu, Hue H; He, Tong-Chuan

    2016-01-01

    Abstract Osteosarcoma (OS) is a devastating illness with rapid rates of dissemination and a poor overall prognosis, despite aggressive standard-of-care surgical techniques and combination chemotherapy regimens. Identifying the molecular mechanisms involved in disease pathogenesis and progression may offer insight into new therapeutic targets. Defects in mesenchymal stem cell differentiation, abnormal expression of oncogenes and tumor suppressors, and dysregulation within various important signaling pathways have all been implicated in development of various disease phenotypes. As such, a variety of basic science and translational studies have shown promise in identifying novel markers and modulators of these disease-specific aberrancies. Born out of these and similar investigations, a variety of emerging therapies are now undergoing various phases of OS clinical testing. They broadly include angiogenesis inhibitors, drugs that act on the bone microenvironment, receptor tyrosine kinase inhibitors, immune system modulators, and other radio- or chemo-sensitizing agents. As new forms of drug delivery are being developed simultaneously, the possibility of targeting tumors locally while minimizing systemic toxicityis is seemingly more achievable now than ever. In this review, we not only summarize our current understanding of OS disease processes, but also shed light on the multitude of potential therapeutic strategies the scientific community can use to make long-term improvements in patient prognosis.

  20. Notochordal Cell-Derived Therapeutic Strategies for Discogenic Back Pain

    PubMed Central

    Purmessur, D.; Cornejo, M. C.; Cho, S. K.; Hecht, A. C.; Iatridis, J. C.

    2013-01-01

    An understanding of the processes that occur during development of the intervertebral disk can help inform therapeutic strategies for discogenic pain. This article reviews the literature to identify candidates that are found in or derived from the notochord or notochordal cells and evaluates the theory that such factors could be isolated and used as biologics to target the structural disruption, inflammation, and neurovascular ingrowth often associated with discogenic back pain. A systematic review using PubMed was performed with a primary search using keywords “(notochordal OR notochord) And (nerves OR blood vessels OR SHH OR chondroitin sulfate OR notch OR CTGF) NOT chordoma.” Secondary searches involved keywords associated with the intervertebral disk and pain. Several potential therapeutic candidates from the notochord and their possible targets were identified. Studies are needed to further identify candidates, explore mechanisms for effect, and to validate the theory that these candidates can promote structural restoration and limit or inhibit neurovascular ingrowth using in vivo studies. PMID:24436871

  1. Cell encapsulation technology as a therapeutic strategy for CNS malignancies.

    PubMed Central

    Visted, T.; Bjerkvig, R.; Enger, P. O.

    2001-01-01

    Gene therapy using viral vectors has to date failed to reveal its definitive clinical usefulness. Cell encapsulation technology represents an alternative, nonviral approach for the delivery of biologically active compounds to tumors. This strategy involves the use of genetically engineered producer cells that secrete a protein with therapeutic potential. The cells are encapsulated in an immunoisolating material that makes them suitable for transplantation. The capsules, or bioreactors, permit the release of recombinant proteins that may assert their effects in the tumor microenvironment. During the last decades, there has been significant progress in the development of encapsulation technologies that comprise devices for both macro- and microencapsulation. The polysaccharide alginate is the most commonly used material for cell encapsulation and is well tolerated by various tissues. A wide spectrum of cells and tissues has been encapsulated and implanted, both in animals and humans, indicating the general applicability of this approach for both research and medical purposes, including CNS malignancies. Gliomas most frequently recur at the resection site. To provide local and sustained drug delivery, the bioreactors can be implanted in the brain parenchyma or in the ventricular system. The development of comprehensive analyses of geno- and phenotypic profiles of a tumor (genomics and proteomics) may provide new and important guidelines for choosing the optimal combination of bioreactors and recombinant proteins for therapeutic use. PMID:11465401

  2. [Therapeutic strategy for secondary lung cancer].

    PubMed

    Miura, Hiroyuki; Nakajima, Norio; Takahashi, Hidenobu; Kinoshita, Masao; Ikeda, Norihiko

    2010-10-01

    Among 659 resected lung cancer cases from 1994 to 2009, 57 secondary lung cancers (8.6%) were evaluated. The secondary tumors were synchronous, located in the same lobe in 10, the ipsilateral different lobe in 17, and the contralateral lobe in 13, or metachronous, located in the contralateral lobe in 15, and the ipsilateral different lobe in 5. Both the tumors were removed in 49 cases. Chemotherapy, stereotactic radiotherapy (SRT), photo dynamic therapy (PDT), or best supportive care (BSC) was selected after a lobectomy or segmentectomy of the 1st tumor in 8 cases considering the patient's condition. Lobectomy or segmentectomy should be indicated for the 1st tumor considering curability. Bilobectomy is adopted for multiple cancers involving middle lobe. According to the operability or pulmonary function, the same strategy is adopted for secondary cancer. Considering the patient's condition, possibility of metastases and the tumor location and histologic type, partial resection, SRT, PDT, or BSC could be selected. PMID:20954350

  3. Macrophages associated with tumors as potential targets and therapeutic intermediates.

    PubMed

    Vinogradov, Serguei; Warren, Galya; Wei, Xin

    2014-04-01

    Tumor-associated macrophages (TAMs) form approximately 50% of tumor mass. TAMs were shown to promote tumor growth by suppressing immunocompetent cells, inducing neovascularization and supporting cancer stem cells. TAMs retain mobility in tumor mass, which can potentially be employed for better intratumoral biodistribution of nanocarriers and effective tumor growth inhibition. Due to the importance of TAMs, they are increasingly becoming principal targets of novel therapeutic approaches. In this review, we compare features of macrophages and TAMs that are essential for TAM-directed therapies, and illustrate the advantages of nanomedicine that are related to the preferential capture of nanocarriers by Mϕ in the process of drug delivery. We discuss recent efforts in reprogramming or inhibiting tumor-protecting properties of TAMs, and potential strategies to increase efficacy of conventional chemotherapy by combining with macrophage-associated delivery of nanodrugs. PMID:24827844

  4. Therapeutic aptamers: developmental potential as anticancer drugs

    PubMed Central

    Lee, Ji Won; Kim, Hyun Jung; Heo, Kyun

    2015-01-01

    Aptamers, composed of single-stranded DNA or RNA oligonucleotides that interact with target molecules through a specific three-dimensional structure, are selected from pools of combinatorial oligonucleotide libraries. With their high specificity and affinity for target proteins, ease of synthesis and modification, and low immunogenicity and toxicity, aptamers are considered to be attractive molecules for development as anticancer therapeutics. Two aptamers - one targeting nucleolin and a second targeting CXCL12 - are currently undergoing clinical trials for treating cancer patients, and many more are under study. In this mini-review, we present the current clinical status of aptamers and aptamer-based cancer therapeutics. We also discuss advantages, limitations, and prospects for aptamers as cancer therapeutics. [BMB Reports 2015; 48(4): 234-237] PMID:25560701

  5. Molecular Strategies for Targeting Antioxidants to Mitochondria: Therapeutic Implications

    PubMed Central

    2015-01-01

    Abstract Mitochondrial function and specifically its implication in cellular redox/oxidative balance is fundamental in controlling the life and death of cells, and has been implicated in a wide range of human pathologies. In this context, mitochondrial therapeutics, particularly those involving mitochondria-targeted antioxidants, have attracted increasing interest as potentially effective therapies for several human diseases. For the past 10 years, great progress has been made in the development and functional testing of molecules that specifically target mitochondria, and there has been special focus on compounds with antioxidant properties. In this review, we will discuss several such strategies, including molecules conjugated with lipophilic cations (e.g., triphenylphosphonium) or rhodamine, conjugates of plant alkaloids, amino-acid- and peptide-based compounds, and liposomes. This area has several major challenges that need to be confronted. Apart from antioxidants and other redox active molecules, current research aims at developing compounds that are capable of modulating other mitochondria-controlled processes, such as apoptosis and autophagy. Multiple chemically different molecular strategies have been developed as delivery tools that offer broad opportunities for mitochondrial manipulation. Additional studies, and particularly in vivo approaches under physiologically relevant conditions, are necessary to confirm the clinical usefulness of these molecules. Antioxid. Redox Signal. 22, 686–729. PMID:25546574

  6. Pharmacological Drug Delivery Strategies for Improved Therapeutic Effects: Recent Advances.

    PubMed

    Savaliya, Reema; Singh, Poornima; Singh, Sanjay

    2016-01-01

    The latest pharmacologic research has resulted number of new molecules with the potential to modernize the prevention or treatment of different complex diseases, including cancer. The therapeutics generally include moieties such as proteins, drugs and genes, etc. Current activities in the pharmacological field include the development of novel drug-delivery systems to overcome pharmacokinetic glitches such as limited bioavailability, unwanted distribution, drug resistant, and stability, etc. Therefore, to address these issues various biotechnological and pharmacological techniques has been introduced. However, effective drug delivery with improved efficacy remains challenging. This review is focused towards different strategies such as physical and biological methods for efficacious delivery at desired tissues and even sub-cellular targeting. Emphasis is also given about nanotechnology based drug or gene delivery strategies and co-delivery of drug-drug; gene-gene or combinations of drug-gene, etc. are the current cuttingedge methods, which are under clinical or pre-clinical stage of research. Uses of biodegradable materials, such as liposomes and polymeric particles are another class of drug delivery vehicles, which have shown tremendous success, are also discussed. Towards the end, future directions of pharmacological drug delivery methods have also been summarized. PMID:26654439

  7. Therapeutic Strategies for Targeting Ras Proteins

    PubMed Central

    Gysin, Stephan; Salt, Megan; Young, Amy; McCormick, Frank

    2011-01-01

    Ras genes are frequently activated in cancer. Attempts to develop drugs that target mutant Ras proteins have, so far, been unsuccessful. Tumors bearing these mutations, therefore, remain among the most difficult to treat. Most efforts to block activated Ras have focused on pathways downstream. Drugs that inhibit Raf kinase have shown clinical benefit in the treatment of malignant melanoma. However, these drugs have failed to show clinical benefit in Ras mutant tumors. It remains unclear to what extent Ras depends on Raf kinase for transforming activity, even though Raf proteins bind directly to Ras and are certainly major effectors of Ras action in normal cells and in development. Furthermore, Raf kinase inhibitors can lead to paradoxical activation of the MAPK pathway. MEK inhibitors block the Ras-MAPK pathway, but often activate the PI3’-kinase, and have shown little clinical benefit as single agents. This activation is mediated by EGF-R and other receptor tyrosine kinases through relief of a negative feedback loop from ERK. Drug combinations that target multiple points within the Ras signaling network are likely to be necessary to achieve substantial clinical benefit. Other effectors may also contribute to Ras signaling and provide a source of targets. In addition, unbiased screens for genes necessary for Ras transformation have revealed new potential targets and have added to our understanding of Ras cancer biology. PMID:21779505

  8. Human-derived natural antibodies: biomarkers and potential therapeutics

    PubMed Central

    Xu, Xiaohua; Ng, Sher May; Hassouna, Eamonn; Warrington, Arthur; Oh, Sang-Hyun; Rodriguez, Moses

    2015-01-01

    The immune system generates antibodies and antigen-specific T-cells as basic elements of the immune networks that differentiate self from non-self in a finely tuned manner. The antigen-specific nature of immune responses ensures that normal immune activation contains non-self when tolerating self. Here we review the B-1 subset of lymphocytes which produce self-reactive antibodies. By analyzing the IgM class of natural antibodies that recognize antigens from the nervous system, we emphasize that natural antibodies are biomarkers of how the immune system monitors the host. The immune response activated against self can be detrimental when triggered in an autoimmune genetic background. In contrast, tuning immune activity with natural antibodies is a potential therapeutic strategy. PMID:25678860

  9. Tackling Ebola: new insights into prophylactic and therapeutic intervention strategies.

    PubMed

    de Wit, Emmie; Feldmann, Heinz; Munster, Vincent J

    2011-01-01

    Since its discovery in 1976, Ebolavirus has caused periodic outbreaks of viral hemorrhagic fever associated with severe and often fatal disease. Ebolavirus is endemic in Central Africa and the Philippines. Although there is currently no approved treatment available, the past 10 years has seen remarkable progress in our understanding of the pathogenicity of Ebolavirus and the development of prophylactic and post-exposure therapies against it. In vitro and in vivo experiments have shown that Ebolavirus pathogenicity is multifactorial, including viral and host determinants. Besides their function in the virus replication cycle, the viral glycoprotein, nucleoprotein, minor matrix protein and polymerase cofactor are viral determinants of pathogenicity, with evasion of the host innate and adaptive immune responses as the main mechanism. Although no licensed Ebolavirus vaccines are currently available, vaccine research in non-human primates, the 'gold standard' animal model for Ebolavirus, has produced several promising candidates. A combination of DNA vaccination and a recombinant adenovirus serotype 5 boost resulted in cross-protective immunity in non-human primates. A recombinant vesicular stomatitis vaccine vector protected non-human primates in pre- and post-exposure challenge studies. Several antiviral therapies are currently under investigation, but only a few of these have been tested in non-human primate models. Antisense therapies, in which oligonucleotides inhibit viral replication, have shown promising results in non-human primates following post-exposure treatment. In light of the severity of Ebolavirus disease and the observed increase in Ebolavirus outbreaks over the past decade, the expedited translation of potential candidate therapeutics and vaccines from bench to bedside is currently the most challenging task for the field. Here, we review the current state of Ebolavirus research, with emphasis on prophylactic and therapeutic intervention strategies

  10. Therapeutic potential of curcumin in digestive diseases

    PubMed Central

    Dulbecco, Pietro; Savarino, Vincenzo

    2013-01-01

    Curcumin is a low-molecular-weight hydrophobic polyphenol that is extracted from turmeric, which possesses a wide range of biological properties including anti-inflammatory, anti-oxidant, anti-proliferative and anti-microbial activities. Despite its diverse targets and substantial safety, clinical applications of this molecule for digestive disorders have been largely limited to case series or small clinical trials. The poor bioavailability of curcumin is likely the major hurdle for its more widespread use in humans. However, complexation of curcumin into phytosomes has recently helped to bypass this problem, as it has been demonstrated that this new lecithin formulation enables increased absorption to a level 29-fold higher than that of traditional curcuminoid products. This allows us to achieve much greater tissue substance delivery using significantly lower doses of curcumin than have been used in past clinical studies. As curcumin has already been shown to provide good therapeutic results in some small studies of both inflammatory and neoplastic bowel disorders, it is reasonable to anticipate an even greater efficacy with the advent of this new technology, which remarkably improves its bioavailability. These features are very promising and may represent a novel and effective therapeutic approach to both functional and organic digestive diseases. PMID:24409053

  11. Therapeutic potential of curcumin in digestive diseases.

    PubMed

    Dulbecco, Pietro; Savarino, Vincenzo

    2013-12-28

    Curcumin is a low-molecular-weight hydrophobic polyphenol that is extracted from turmeric, which possesses a wide range of biological properties including anti-inflammatory, anti-oxidant, anti-proliferative and anti-microbial activities. Despite its diverse targets and substantial safety, clinical applications of this molecule for digestive disorders have been largely limited to case series or small clinical trials. The poor bioavailability of curcumin is likely the major hurdle for its more widespread use in humans. However, complexation of curcumin into phytosomes has recently helped to bypass this problem, as it has been demonstrated that this new lecithin formulation enables increased absorption to a level 29-fold higher than that of traditional curcuminoid products. This allows us to achieve much greater tissue substance delivery using significantly lower doses of curcumin than have been used in past clinical studies. As curcumin has already been shown to provide good therapeutic results in some small studies of both inflammatory and neoplastic bowel disorders, it is reasonable to anticipate an even greater efficacy with the advent of this new technology, which remarkably improves its bioavailability. These features are very promising and may represent a novel and effective therapeutic approach to both functional and organic digestive diseases. PMID:24409053

  12. Lipoic acid - biological activity and therapeutic potential.

    PubMed

    Gorąca, Anna; Huk-Kolega, Halina; Piechota, Aleksandra; Kleniewska, Paulina; Ciejka, Elżbieta; Skibska, Beata

    2011-01-01

    α-Lipoic acid (LA; 5-(1,2-dithiolan-3-yl)pentanoic acid) was originally isolated from bovine liver by Reed et al. in 1951. LA was once considered a vitamin. Subsequently, it was found that LA is not a vitamin and is synthesized by plants and animals. LA is covalently bound to the ε-amino group of lysine residues and functions as a cofactor for mitochondrial enzymes by catalyzing the oxidative decarboxylation of pyruvate, α-ketoglutarate and branched-chain α-keto acids. LA and its reduced form - dihydrolipoic acid (DHLA), meet all the criteria for an ideal antioxidant because they can easily quench radicals, can chelate metals, have an amphiphlic character and they do not exhibit any serious side effects. They interact with other antioxidants and can regenerate them. For this reason, LA is called an antioxidant of antioxidants. LA has an influence on the second messenger nuclear factor κB (NF-κB) and attenuates the release of free radicals and cytotoxic cytokines. The therapeutic action of LA is based on its antioxidant properties. Current studies support its use in the ancillary treatment of many diseases, such as diabetes, cardiovascular, neurodegenerative, autoimmune diseases, cancer and AIDS. This review was undertaken to gather the most recent information regarding the therapeutic properties of LA and its possible utility in disease treatment. PMID:22001972

  13. The therapeutic potential of regulated hypothermia.

    PubMed

    Gordon, C J

    2001-03-01

    Reducing body temperature of rodents has been found to improve their survival to ischaemia, hypoxia, chemical toxicants, and many other types of insults. Larger species, including humans, may also benefit from a lower body temperature when recovering from CNS ischaemia and other traumatic insults. Rodents subjected to these insults undergo a regulated hypothermic response (that is, decrease in set point temperature) characterised by preference for cooler ambient temperatures, peripheral vasodilatation, and reduced metabolic rate. However, forced hypothermia (that is, body temperature forced below set point) is the only method used in the study and treatment of human pathological insults. The therapeutic efficacy of the hypothermic treatment is likely to be influenced by the nature of the reduction in body temperature (that is, forced versus regulated). Homeostatic mechanisms counter forced reductions in body temperature resulting in physiological stress and decreased efficacy of the hypothermic treatment. On the other hand, regulated hypothermia would seem to be the best means of achieving a therapeutic benefit because thermal homeostatic systems mediate a controlled reduction in core temperature. PMID:11300205

  14. Harnessing the Therapeutic Potential of Th17 Cells

    PubMed Central

    Bystrom, Jonas; Taher, Taher E.; Muhyaddin, M. Sherwan; Clanchy, Felix I.; Mangat, Pamela; Jawad, Ali S.; Williams, Richard O.; Mageed, Rizgar A.

    2015-01-01

    Th17 cells provide protective immunity to infections by fungi and extracellular bacteria as well as cancer but are also involved in chronic inflammation. The cells were first identified by their ability to produce interleukin 17A (IL-17A) and, subsequently, associated with chronic inflammation and autoimmunity. Th17 cells have some gene profile similarity with stem cells and can remain dormant in mucosal tissues for long periods. Indeed, recent studies suggest that functionally distinct subsets of pro- and anti-inflammatory Th17 cells can interchange phenotype and functions. For development, Th17 cells require activation of the transcription factors STAT3 and RORγt while RUNX1, c-Maf, and Aiolos are involved in changes of phenotype/functions. Attempts to harness Th17 cells against pathogens and cancer using vaccination strategies are being explored. The cells gain protective abilities when induced to produce interferon γ (IFNγ). In addition, treatment with antibodies to IL-17 is effective in treating patients with psoriasis, psoriatic arthritis, and refectory rheumatoid arthritis. Moreover, since RORγt is a nuclear receptor, it is likely to be a potential future drug target for modulating Th17 functions. This review explores pathways through which Th17 subsets are induced, the molecular basis of their plasticity, and potential therapeutic strategies for their modulation in diseases. PMID:26101460

  15. Non-coding RNAs: Therapeutic Strategies and Delivery Systems.

    PubMed

    Ling, Hui

    2016-01-01

    The vast majority of the human genome is transcribed into RNA molecules that do not code for proteins, which could be small ones approximately 20 nucleotide in length, known as microRNAs, or transcripts longer than 200 bp, defined as long noncoding RNAs. The prevalent deregulation of microRNAs in human cancers prompted immediate interest on the therapeutic value of microRNAs as drugs and drug targets. Many features of microRNAs such as well-defined mechanisms, and straightforward oligonucleotide design further make them attractive candidates for therapeutic development. The intensive efforts of exploring microRNA therapeutics are reflected by the large body of preclinical studies using oligonucleotide-based mimicking and blocking, culminated by the recent entry of microRNA therapeutics in clinical trial for several human diseases including cancer. Meanwhile, microRNA therapeutics faces the challenge of effective and safe delivery of nucleic acid therapeutics into the target site. Various chemical modifications of nucleic acids and delivery systems have been developed to increase targeting specificity and efficacy, and reduce the associated side effects including activation of immune response. Recently, long noncoding RNAs become attractive targets for therapeutic intervention because of their association with complex and delicate phenotypes, and their unconventional pharmaceutical activities such as capacity of increasing output of proteins. Here I discuss the general therapeutic strategies targeting noncoding RNAs, review delivery systems developed to maximize noncoding RNA therapeutic efficacy, and offer perspectives on the future development of noncoding RNA targeting agents for colorectal cancer. PMID:27573903

  16. Sarcopenia in heart failure: mechanisms and therapeutic strategies

    PubMed Central

    Collamati, Agnese; Marzetti, Emanuele; Calvani, Riccardo; Tosato, Matteo; D'Angelo, Emanuela; Sisto, Alex N; Landi, Francesco

    2016-01-01

    Chronic heart failure (CHF) is a highly prevalent condition among the elderly and is associated with considerable morbidity, institutionalization and mortality. In its advanced stages, CHF is often accompanied by the loss of muscle mass and strength. Sarcopenia is a geriatric syndrome that has been actively studied in recent years due to its association with a wide range of adverse health outcomes. The goal of this review is to discuss the relationship between CHF and sarcopenia, with a focus on shared pathophysiological pathways and treatments. Malnutrition, systemic inflammation, endocrine imbalances, and oxidative stress appear to connect sarcopenia and CHF. At the muscular level, alterations of the ubiquitin proteasome system, myostatin signaling, and apoptosis have been described in both sarcopenia and CHF and could play a role in the loss of muscle mass and function. Possible therapeutic strategies to impede the progression of muscle wasting in CHF patients include protein and vitamin D supplementation, structured physical exercise, and the administration of angiotensin-converting enzyme inhibitors and β-blockers. Hormonal supplementation with growth hormone, testosterone, and ghrelin is also discussed as a potential treatment. PMID:27605943

  17. Sarcopenia in heart failure: mechanisms and therapeutic strategies.

    PubMed

    Collamati, Agnese; Marzetti, Emanuele; Calvani, Riccardo; Tosato, Matteo; D'Angelo, Emanuela; Sisto, Alex N; Landi, Francesco

    2016-07-01

    Chronic heart failure (CHF) is a highly prevalent condition among the elderly and is associated with considerable morbidity, institutionalization and mortality. In its advanced stages, CHF is often accompanied by the loss of muscle mass and strength. Sarcopenia is a geriatric syndrome that has been actively studied in recent years due to its association with a wide range of adverse health outcomes. The goal of this review is to discuss the relationship between CHF and sarcopenia, with a focus on shared pathophysiological pathways and treatments. Malnutrition, systemic inflammation, endocrine imbalances, and oxidative stress appear to connect sarcopenia and CHF. At the muscular level, alterations of the ubiquitin proteasome system, myostatin signaling, and apoptosis have been described in both sarcopenia and CHF and could play a role in the loss of muscle mass and function. Possible therapeutic strategies to impede the progression of muscle wasting in CHF patients include protein and vitamin D supplementation, structured physical exercise, and the administration of angiotensin-converting enzyme inhibitors and β-blockers. Hormonal supplementation with growth hormone, testosterone, and ghrelin is also discussed as a potential treatment. PMID:27605943

  18. New therapeutic strategies for BRAF mutant colorectal cancers

    PubMed Central

    2015-01-01

    Oncogenic BRAF mutations are found in ~10% of colorectal cancers (CRCs) and predict poor prognosis. Although BRAF inhibitors have demonstrated striking efficacy in BRAF mutant melanomas, BRAF inhibitor monotherapy is ineffective in BRAF mutant CRC. Over the past few years, studies have begun to define the molecular mechanisms underlying the relative resistance of BRAF mutant CRC to BRAF inhibitors, leading to the development of novel therapeutic strategies that are showing promising clinical activity in initial clinical trials. Our current understanding of the mechanisms of BRAF inhibitor resistance in BRAF mutant CRC and the therapeutic approaches currently in clinical trials for BRAF mutant CRC are reviewed herein. PMID:26697198

  19. Engineered pharmabiotics with improved therapeutic potential.

    PubMed

    Sleator, Roy D; Hill, Colin

    2008-01-01

    Although described for over a century, scientists and clinicians alike are only now beginning to realize the significant medical applications of probiotic cultures. Given the increasing commercial and clinical relevance of probiotics, improving their stress tolerance profile and ability to overcome the physiochemical defences of the host is an important biological goal. Patho-biotechnology describes the application of pathogen derived (ex vivo and in vivo) stress survival strategies for the design of more technologically robust and effective probiotic cultures with improved biotechnological and clinical applications as well as the development of novel vaccine and drug delivery platforms. PMID:18682694

  20. Telomerase and its potential for therapeutic intervention

    PubMed Central

    Phatak, P; Burger, A M

    2007-01-01

    Telomerase and telomeres are attractive targets for anticancer therapy. This is supported by the fact that the majority of human cancers express the enzyme telomerase which is essential to maintain their telomere length and thus, to ensure indefinite cell proliferation – a hallmark of cancer. Tumours have relatively shorter telomeres compared to normal cell types, opening the possibility that human cancers may be considerably more susceptible to killing by agents that inhibit telomere replication than normal cells. Advances in the understanding of the regulation of telomerase activity and the telomere structure, as well as the identification of telomerase and telomere associated binding proteins have opened new avenues for therapeutic intervention. Here, we review telomere and telomerase biology and the various approaches which have been developed to inhibit the telomere/telomerase complex over the past decade. They include inhibitors of the enzyme catalytic subunit and RNA component, agents that target telomeres, telomerase vaccines and drugs targeting binding proteins. The emerging role of telomerase in cancer stem cells and the implications for cancer therapy are also discussed. PMID:17603541

  1. Barriers to Effective Counseling with Blacks and Therapeutic Strategies for Overcoming Them.

    ERIC Educational Resources Information Center

    Tucker, Carolyn M.; And Others

    1981-01-01

    Presents strategies for counselors working with Black clients. Suggests awareness of potential barriers to effective counseling enables the therapist to gear the initial sessions toward overcoming these obstacles and thus make early observations of tangible therapeutic gains. Proposes such advances are important in overcoming client skepticism and…

  2. [Pleural mesothelioma: impact of the staging for the therapeutic strategy].

    PubMed

    Greillier, L; Scherpereel, A; Astoul, P

    2007-10-01

    Realistic improvement has been recently done for the treatment of malignant pleural mesothelioma. Besides new findings for the epidemiology of the disease, medico-social impact for patients, the knowledge of biological parameters for diagnosis, prognosis and future therapeutic targets as well, the early diagnosis of the disease mainly based on more extended practice of thoracoscopy allows in association with new imaging techniques a careful staging of the disease and consequently new therapeutic implications. Indeed if new balistic assessment of the disease improves the efficacy of radiotherapy and new combined chemotherapy have shown antitumoral responses, surgical strategy takes part in the armamenterium for this disease and combined with others therapeutic modalities seems to be a raisonnable approach despite the lack of prospective, comparative, randomized study and the drawback of current staging. However, the most important point is the multidisciplinary concertation induced by the management of this disease which represents a "model" in thoracic oncology. PMID:18235408

  3. Glycosylation of Therapeutic Proteins: An Effective Strategy to Optimize Efficacy

    PubMed Central

    Solá, Ricardo J.; Griebenow, Kai

    2009-01-01

    During their development and administration, protein-based drugs routinely display suboptimum therapeutic efficacies due to their poor physicochemical and pharmacological properties. These innate liabilities have driven the development of molecular level strategies to improve the therapeutic behavior of protein drugs. Among, the currently developed approaches, glycoengineering is one of the most promising due fact that it has been shown to simultaneously afford improvements over most of the parameters necessary for optimization of protein drug in vivo efficacy (e.g., in vitro and in vivo molecular stability, pharmacodynamic responses, and pharmacokinetic profiles) while allowing for targeting to the desired site of action. The intent of this article is to provide an account of the effects that glycosylation has on the therapeutic efficacy of protein drugs and to describe the current understanding of the mechanisms by which glycosylation leads to such effects. PMID:20055529

  4. Novel bifunctional natriuretic peptides as potential therapeutics.

    PubMed

    Dickey, Deborah M; Burnett, John C; Potter, Lincoln R

    2008-12-12

    Synthetic atrial natriuretic peptide (carperitide) and B-type natriuretic peptide (BNP; nesiritide) are used to treat congestive heart failure. However, despite beneficial cardiac unloading properties, reductions in renal perfusion pressures limit their clinical effectiveness. Recently, CD-NP, a chimeric peptide composed of C-type natriuretic peptide (CNP) fused to the C-terminal tail of Dendroaspis natriuretic peptide (DNP), was shown to be more glomerular filtration rate-enhancing than BNP in dogs. However, the molecular basis for the increased responsiveness was not determined. Here, we show that the DNP tail has a striking effect on CNP, converting it from a non-agonist to a partial agonist of natriuretic peptide receptor (NPR)-A while maintaining the ability to activate NPR-B. This effect is specific for human receptors because CD-NP was only a slightly better activator of rat NPR-A due to the promiscuous nature of CNP in this species. Interesting, the DNP tail alone had no effect on any NPR even though it is effective in vivo. To further increase the potency of CD-NP for NPR-A, we converted two different triplet sequences within the CNP ring to their corresponding residues in BNP. Both variants demonstrated increased affinity and full agonist activity for NPR-A, whereas one was as potent as any NPR-A activator known. In contrast to a previous report, we found that DNP binds the natriuretic peptide clearance receptor (NPR-C). However, none of the chimeric peptides bound NPR-C with significantly higher affinity than endogenous ligands. We suggest that bifunctional chimeric peptides represent a new generation of natriuretic peptide therapeutics. PMID:18940797

  5. Novel Bifunctional Natriuretic Peptides as Potential Therapeutics*

    PubMed Central

    Dickey, Deborah M.; Burnett, John C.; Potter, Lincoln R.

    2008-01-01

    Synthetic atrial natriuretic peptide (carperitide) and B-type natriuretic peptide (BNP; nesiritide) are used to treat congestive heart failure. However, despite beneficial cardiac unloading properties, reductions in renal perfusion pressures limit their clinical effectiveness. Recently, CD-NP, a chimeric peptide composed of C-type natriuretic peptide (CNP) fused to the C-terminal tail of Dendroaspis natriuretic peptide (DNP), was shown to be more glomerular filtration rate-enhancing than BNP in dogs. However, the molecular basis for the increased responsiveness was not determined. Here, we show that the DNP tail has a striking effect on CNP, converting it from a non-agonist to a partial agonist of natriuretic peptide receptor (NPR)-A while maintaining the ability to activate NPR-B. This effect is specific for human receptors because CD-NP was only a slightly better activator of rat NPR-A due to the promiscuous nature of CNP in this species. Interesting, the DNP tail alone had no effect on any NPR even though it is effective in vivo. To further increase the potency of CD-NP for NPR-A, we converted two different triplet sequences within the CNP ring to their corresponding residues in BNP. Both variants demonstrated increased affinity and full agonist activity for NPR-A, whereas one was as potent as any NPR-A activator known. In contrast to a previous report, we found that DNP binds the natriuretic peptide clearance receptor (NPR-C). However, none of the chimeric peptides bound NPR-C with significantly higher affinity than endogenous ligands. We suggest that bifunctional chimeric peptides represent a new generation of natriuretic peptide therapeutics. PMID:18940797

  6. Potential new therapeutic targets for pathological pruritus.

    PubMed

    Kuraishi, Yasushi

    2013-01-01

    Very few approved medications are indicated for the treatment of pruritus, and drug development for pruritic diseases is awaited. During the past two decades, progress has been made in understanding the molecular basis of the physiology and pathophysiology of pruritus. Newly identified potential targets for pathological pruritus include receptors (histamine H4 receptor, leukotriene B4 receptors, interleukin-31 receptor A, bombesin BB2 receptor, toll-like receptor 3, α-adrenoceptor, and opioid μ- and κ-receptors), channels (transient receptor potential (TRP) V3 and TRPA1 channels), and enzymes (histidine decarboxylase, sphingomyelin glucosylceramide deacylase, 5-lipoxygenase, leukotriene A4 hydrolase, and autotaxin). The development of specific, effective blockers and agonists/antagonists of these targets is awaited. PMID:23902965

  7. The Therapeutic Potential of Medicinal Foods

    PubMed Central

    Ramalingum, Nelvana; Mahomoodally, M. Fawzi

    2014-01-01

    Pharmaceutical and nutritional sciences have recently witnessed a bloom in the scientific literature geared towards the use of food plants for their diversified health benefits and potential clinical applications. Health professionals now recognize that a synergism of drug therapy and nutrition might confer optimum outcomes in the fight against diseases. The prophylactic benefits of food plants are being investigated for potential use as novel medicinal remedies due to the presence of pharmacologically active compounds. Although the availability of scientific data is rapidly growing, there is still a paucity of updated compilation of data and concerns about the rationale of these health-foods still persist in the literature. This paper attempts to congregate the nutritional value, phytochemical composition, traditional uses, in vitro and in vivo studies of 10 common medicinal food plants used against chronic noncommunicable and infectious diseases. Food plants included were based on the criteria that they are consumed as a common food in a typical diet as either fruit or vegetable for their nutritive value but have also other parts which are in common use in folk medicine. The potential challenges of incorporating these medicinal foods in the diet which offers prospective opportunities for future drug development are also discussed. PMID:24822061

  8. The Therapeutic Potential of Brown Adipocytes in Humans.

    PubMed

    Porter, Craig; Chondronikola, Maria; Sidossis, Labros S

    2015-01-01

    Obesity and its metabolic consequences represent a significant clinical problem. From a thermodynamic standpoint, obesity results from a discord in energy intake and expenditure. To date, lifestyle interventions based on reducing energy intake and/or increasing energy expenditure have proved ineffective in the prevention and/or treatment of obesity, owing to poor long-term adherence to such interventions. Thus, an effective strategy to prevent or correct obesity is currently lacking. As the combustion engines of our cells, mitochondria play a critical role in energy expenditure. At a whole-body level, approximately 80% of mitochondrial membrane potential generated by fuel oxidation is used to produce ATP, and the remaining 20% is lost through heat-producing uncoupling reactions. The coupling of mitochondrial respiration to ATP production represents an important component in whole-body energy expenditure. Brown adipose tissue (BAT) is densely populated with mitochondria containing the inner mitochondrial proton carrier uncoupling protein 1 (UCP1). UCP1 uncouples oxidative phosphorylation, meaning that mitochondrial membrane potential is dissipated as heat. The recent rediscovery of BAT depots in adult humans has rekindled scientific interest in the manipulation of mitochondrial uncoupling reactions as a means to increase metabolic rate, thereby counteracting obesity and its associated metabolic phenotype. In this article, we discuss the evidence for the role BAT plays in metabolic rate and glucose and lipid metabolism in humans and the potential for UCP1 recruitment in the white adipose tissue of humans. While the future holds much promise for a therapeutic role of UCP1 expressing adipocytes in human energy metabolism, particularly in the context of obesity, tissue-specific strategies that activate or recruit UCP1 in human adipocytes represent an obligatory translational step for this early promise to be realized. PMID:26528238

  9. The Therapeutic Potential of Brown Adipocytes in Humans

    PubMed Central

    Porter, Craig; Chondronikola, Maria; Sidossis, Labros S.

    2015-01-01

    Obesity and its metabolic consequences represent a significant clinical problem. From a thermodynamic standpoint, obesity results from a discord in energy intake and expenditure. To date, lifestyle interventions based on reducing energy intake and/or increasing energy expenditure have proved ineffective in the prevention and/or treatment of obesity, owing to poor long-term adherence to such interventions. Thus, an effective strategy to prevent or correct obesity is currently lacking. As the combustion engines of our cells, mitochondria play a critical role in energy expenditure. At a whole-body level, approximately 80% of mitochondrial membrane potential generated by fuel oxidation is used to produce ATP, and the remaining 20% is lost through heat-producing uncoupling reactions. The coupling of mitochondrial respiration to ATP production represents an important component in whole-body energy expenditure. Brown adipose tissue (BAT) is densely populated with mitochondria containing the inner mitochondrial proton carrier uncoupling protein 1 (UCP1). UCP1 uncouples oxidative phosphorylation, meaning that mitochondrial membrane potential is dissipated as heat. The recent rediscovery of BAT depots in adult humans has rekindled scientific interest in the manipulation of mitochondrial uncoupling reactions as a means to increase metabolic rate, thereby counteracting obesity and its associated metabolic phenotype. In this article, we discuss the evidence for the role BAT plays in metabolic rate and glucose and lipid metabolism in humans and the potential for UCP1 recruitment in the white adipose tissue of humans. While the future holds much promise for a therapeutic role of UCP1 expressing adipocytes in human energy metabolism, particularly in the context of obesity, tissue-specific strategies that activate or recruit UCP1 in human adipocytes represent an obligatory translational step for this early promise to be realized. PMID:26528238

  10. The therapeutic potential of stem cells

    PubMed Central

    Watt, Fiona M.; Driskell, Ryan R.

    2010-01-01

    In recent years, there has been an explosion of interest in stem cells, not just within the scientific and medical communities but also among politicians, religious groups and ethicists. Here, we summarize the different types of stem cells that have been described: their origins in embryonic and adult tissues and their differentiation potential in vivo and in culture. We review some current clinical applications of stem cells, highlighting the problems encountered when going from proof-of-principle in the laboratory to widespread clinical practice. While some of the key genetic and epigenetic factors that determine stem cell properties have been identified, there is still much to be learned about how these factors interact. There is a growing realization of the importance of environmental factors in regulating stem cell behaviour and this is being explored by imaging stem cells in vivo and recreating artificial niches in vitro. New therapies, based on stem cell transplantation or endogenous stem cells, are emerging areas, as is drug discovery based on patient-specific pluripotent cells and cancer stem cells. What makes stem cell research so exciting is its tremendous potential to benefit human health and the opportunities for interdisciplinary research that it presents. PMID:20008393

  11. Therapeutic Potential of Resveratrol in Lymphoid Malignancies.

    PubMed

    Khan, Omar S; Bhat, Ajaz A; Krishnankutty, Roopesh; Mohammad, Ramzi M; Uddin, Shahab

    2016-01-01

    Natural products have always been sought as a dependable source for the cure of many fatal diseases including cancer. Resveratrol (RSV), a naturally occurring plant polyphenol, has been of recent research interest and is being investigated for its beneficial biological properties that include antioxidant, anti-inflammatory, proapoptotic, and growth inhibitory activities. These effects are mainly mediated by cell cycle arrest, upregulation of proapoptotic proteins, loss of mitochondrial potential, and generation of reactive oxygen species. Among the beneficial properties of RSV, the anticancer property has been of the prime focus and extensively explored during the last few years. Although reports exist on the chemopreventive role of RSV in many solid tumors, limited information is available on the antiproliferative activity of RSV in human lymphoma cells and experimental models. Potential mechanisms for its antiproliferative effect include induction of cell differentiation, apoptosis, and inhibition of DNA synthesis. In this review, the different kinds of lymphoid malignancies and the main mechanisms of cell death induced by resveratrol are discussed. The challenges are limiting in vivo experimental studies involving resveratrol. An attempt for the translation of this compound into a clinical drug also forms a part of this review. PMID:27028800

  12. Overview of the therapeutic potential of piplartine (piperlongumine).

    PubMed

    Bezerra, Daniel P; Pessoa, Claudia; de Moraes, Manoel O; Saker-Neto, Nicolau; Silveira, Edilberto R; Costa-Lotufo, Leticia V

    2013-02-14

    Piplartine (piperlongumine, 5,6-dihydro-1-[(2E)-1-oxo-3-(3,4,5-trimethoxyphenyl)-2-propenyl]-2(1H)-pyridinone) is a biologically active alkaloid/amide from peppers, as from long pepper (Piper longum L. - Piperaceae). Long pepper is one of the most widely used in Ayurvedic medicine, which is used to treat many diseases, including tumors. The purpose of the current paper is to address to the chemical structure establishment and to systematically survey the published articles and highlight recent advances in the knowledge of the therapeutic potential of piplartine, establishing new goals for future research. The reported pharmacological activities of piplartine include cytotoxic, genotoxic, antitumor, antiangiogenic, antimetastatic, antiplatelet aggregation, antinociceptive, anxiolytic, antidepressant, anti-atherosclerotic, antidiabetic, antibacterial, antifungal, leishmanicidal, trypanocidal, and schistosomicidal activities. Among the multiple pharmacological effects of piplartine, its anticancer property is the most promising. Therefore, the preclinical anticancer potential of piplartine has been extensively investigated, which recently resulted in one patent. This compound is selectively cytotoxic against cancer cells by induction of oxidative stress, induces genotoxicity, as an alternative strategy to killing tumor cells, has excellent oral bioavailability in mice, inhibits tumor growth in mice, and presents only weak systemic toxicity. In summary, we conclude that piplartine is effective for use in cancer therapy and its safety using chronic toxicological studies should be addressed to support the viability of clinical trials. PMID:23238172

  13. DNA Triple Helices: biological consequences and therapeutic potential

    PubMed Central

    Jain, Aklank; Wang, Guliang; Vasquez, Karen M.

    2008-01-01

    DNA structure is a critical element in determining its function. The DNA molecule is capable of adopting a variety of non-canonical structures, including three-stranded (i.e. triplex) structures, which will be the focus of this review. The ability to selectively modulate the activity of genes is a long-standing goal in molecular medicine. DNA triplex structures, either intermolecular triplexes formed by binding of an exogenously applied oligonucleotide to a target duplex sequence, or naturally occurring intramolecular triplexes (H-DNA) formed at endogenous mirror repeat sequences, present exploitable features that permit site-specific alteration of the genome. These structures can induce transcriptional repression and site-specific mutagenesis or recombination. Triplex-forming oligonucleotides (TFOs) can bind to duplex DNA in a sequence specific fashion with high affinity, and can be used to direct DNA-modifying agents to selected sequences. H-DNA plays important roles in vivo and is inherently mutagenic and recombinogenic, such that elements of the H-DNA structure may be pharmacologically exploitable. In this review we discuss the biological consequences and therapeutic potential of triple helical DNA structures. We anticipate that the information provided will stimulate further investigations aimed toward improving DNA triplex-related gene targeting strategies for biotechnological and potential clinical applications. PMID:18331847

  14. DNA triple helices: biological consequences and therapeutic potential.

    PubMed

    Jain, Aklank; Wang, Guliang; Vasquez, Karen M

    2008-08-01

    DNA structure is a critical element in determining its function. The DNA molecule is capable of adopting a variety of non-canonical structures, including three-stranded (i.e. triplex) structures, which will be the focus of this review. The ability to selectively modulate the activity of genes is a long-standing goal in molecular medicine. DNA triplex structures, either intermolecular triplexes formed by binding of an exogenously applied oligonucleotide to a target duplex sequence, or naturally occurring intramolecular triplexes (H-DNA) formed at endogenous mirror repeat sequences, present exploitable features that permit site-specific alteration of the genome. These structures can induce transcriptional repression and site-specific mutagenesis or recombination. Triplex-forming oligonucleotides (TFOs) can bind to duplex DNA in a sequence-specific fashion with high affinity, and can be used to direct DNA-modifying agents to selected sequences. H-DNA plays important roles in vivo and is inherently mutagenic and recombinogenic, such that elements of the H-DNA structure may be pharmacologically exploitable. In this review we discuss the biological consequences and therapeutic potential of triple helical DNA structures. We anticipate that the information provided will stimulate further investigations aimed toward improving DNA triplex-related gene targeting strategies for biotechnological and potential clinical applications. PMID:18331847

  15. Pseudomonas aeruginosa biofilm: potential therapeutic targets.

    PubMed

    Sharma, Garima; Rao, Saloni; Bansal, Ankiti; Dang, Shweta; Gupta, Sanjay; Gabrani, Reema

    2014-01-01

    Pseudomonas aeruginosa is a gram-negative pathogen that has become an important cause of infection, especially in patients with compromised host defense mechanisms. It is frequently related to nosocomial infections such as pneumonia, urinary tract infections (UTIs) and bacteremia. The biofilm formed by the bacteria allows it to adhere to any surface, living or non-living and thus Pseudomonal infections can involve any part of the body. Further, the adaptive and genetic changes of the micro-organisms within the biofilm make them resistant to all known antimicrobial agents making the Pseudomonal infections complicated and life threatening. Pel, Psl and Alg operons present in P. aeruginosa are responsible for the biosynthesis of extracellular polysaccharide which plays an important role in cell-cell and cell-surface interactions during biofilm formation. Understanding the bacterial virulence which depends on a large number of cell-associated and extracellular factors is essential to know the potential drug targets for future studies. Current novel methods like small molecule based inhibitors, phytochemicals, bacteriophage therapy, photodynamic therapy, antimicrobial peptides, monoclonal antibodies and nanoparticles to curtail the biofilm formed by P. aeruginosa are being discussed in this review. PMID:24309094

  16. Therapeutic Potential of Dietary Phenolic Acids

    PubMed Central

    Saibabu, Venkata; Fatima, Zeeshan; Khan, Luqman Ahmad; Hameed, Saif

    2015-01-01

    Although modern lifestyle has eased the quality of human life, this lifestyle's related patterns have imparted negative effects on health to acquire multiple diseases. Many synthetic drugs are invented during the last millennium but most if not all of them possess several side effects and proved to be costly. Convincing evidences have established the premise that the phytotherapeutic potential of natural compounds and need of search for novel drugs from natural sources are of high priority. Phenolic acids (PAs) are a class of secondary metabolites spread throughout the plant kingdom and generally involved in plethora of cellular processes involved in plant growth and reproduction and also produced as defense mechanism to sustain various environmental stresses. Extensive research on PAs strongly suggests that consumption of these compounds hold promise to offer protection against various ailments in humans. This paper focuses on the naturally derived PAs and summarizes the action mechanisms of these compounds during disease conditions. Based on the available information in the literature, it is suggested that use of PAs as drugs is very promising; however more research and clinical trials are necessary before these bioactive molecules can be made for treatment. Finally this review provides greater awareness of the promise that natural PAs hold for use in the disease prevention and therapy. PMID:26442119

  17. Therapeutic strategies for Alzheimer's disease in clinical trials.

    PubMed

    Godyń, Justyna; Jończyk, Jakub; Panek, Dawid; Malawska, Barbara

    2016-02-01

    Alzheimer's disease (AD) is considered to be the most common cause of dementia and is an incurable, progressive neurodegenerative disorder. Current treatment of the disease, essentially symptomatic, is based on three cholinesterase inhibitors and memantine, affecting the glutamatergic system. Since 2003, no new drugs have been approved for treatment of AD. This article presents current directions in the search for novel, potentially effective agents for the treatment of AD, as well as selected promising treatment strategies. These include agents acting upon the beta-amyloid, such as vaccines, antibodies and inhibitors or modulators of γ- and β-secretase; agents directed against the tau protein as well as compounds acting as antagonists of neurotransmitter systems (serotoninergic 5-HT6 and histaminergic H3). Ongoing clinical trials with Aβ antibodies (solanezumab, gantenerumab, crenezumab) seem to be promising, while vaccines against the tau protein (AADvac1 and ACI-35) are now in early-stage trials. Interesting results have also been achieved in trials involving small molecules such as inhibitors of β-secretase (MK-8931, E2609), a combination of 5-HT6 antagonist (idalopirdine) with donepezil, inhibition of advanced glycation end product receptors by azeliragon or modulation of the acetylcholine response of α-7 nicotinic acetylcholine receptors by encenicline. Development of new effective drugs acting upon the central nervous system is usually a difficult and time-consuming process, and in the case of AD to-date clinical trials have had a very high failure rate. Most phase II clinical trials ending with a positive outcome do not succeed in phase III, often due to serious adverse effects or lack of therapeutic efficacy. PMID:26721364

  18. Prostanoid receptor antagonists: development strategies and therapeutic applications

    PubMed Central

    Jones, RL; Giembycz, MA; Woodward, DF

    2009-01-01

    Identification of the primary products of cyclo-oxygenase (COX)/prostaglandin synthase(s), which occurred between 1958 and 1976, was followed by a classification system for prostanoid receptors (DP, EP1, EP2 …) based mainly on the pharmacological actions of natural and synthetic agonists and a few antagonists. The design of potent selective antagonists was rapid for certain prostanoid receptors (EP1, TP), slow for others (FP, IP) and has yet to be achieved in certain cases (EP2). While some antagonists are structurally related to the natural agonist, most recent compounds are ‘non-prostanoid’ (often acyl-sulphonamides) and have emerged from high-throughput screening of compound libraries, made possible by the development of (functional) assays involving single recombinant prostanoid receptors. Selective antagonists have been crucial to defining the roles of PGD2 (acting on DP1 and DP2 receptors) and PGE2 (on EP1 and EP4 receptors) in various inflammatory conditions; there are clear opportunities for therapeutic intervention. The vast endeavour on TP (thromboxane) antagonists is considered in relation to their limited pharmaceutical success in the cardiovascular area. Correspondingly, the clinical utility of IP (prostacyclin) antagonists is assessed in relation to the cloud hanging over the long-term safety of selective COX-2 inhibitors. Aspirin apart, COX inhibitors broadly suppress all prostanoid pathways, while high selectivity has been a major goal in receptor antagonist development; more targeted therapy may require an intermediate position with defined antagonist selectivity profiles. This review is intended to provide overviews of each antagonist class (including prostamide antagonists), covering major development strategies and current and potential clinical usage. PMID:19624532

  19. [Multiple sclerosis: potential therapeutic options and update of ongoing studies].

    PubMed

    Wiendl, H; Lehmann, H C; Hohlfeld, R; Hartung, H-P; Kieseier, B C

    2004-06-01

    The therapeutic options for the treatment of multiple sclerosis (MS) have experienced enormous progress over recent years. Despite these encouraging developments, available therapies are only partially effective, and the ultimate goal of curing MS is still far from being attained. The improved understanding of the cellular and molecular mechanisms of MS (immune) pathogenesis together with recent shifts in paradigms led to a variety of new therapeutic targets and approaches. In addition to modulation of the inflammatory process, therapeutic approaches focussing on active neuroprotection, remyelinization, and regeneration have become increasingly important. Based on current concepts of the MS pathogenesis, this article summarizes new therapeutic approaches. Substances and strategies currently tested in clinical trials are reviewed. PMID:15257377

  20. Identification of potential glucocorticoid receptor therapeutic targets in multiple myeloma

    PubMed Central

    Thomas, Alexandra L.; Coarfa, Cristian; Qian, Jun; Wilkerson, Joseph J.; Rajapakshe, Kimal; Krett, Nancy L.; Gunaratne, Preethi H.; Rosen, Steven T.

    2015-01-01

    Glucocorticoids (GC) are a cornerstone of combination therapies for multiple myeloma. However, patients ultimately develop resistance to GCs frequently based on decreased glucocorticoid receptor (GR) expression. An understanding of the direct targets of GC actions, which induce cell death, is expected to culminate in potential therapeutic strategies for inducing cell death by regulating downstream targets in the absence of a functional GR. The specific goal of our research is to identify primary GR targets that contribute to GC-induced cell death, with the ultimate goal of developing novel therapeutics around these targets that can be used to overcome resistance to GCs in the absence of GR. Using the MM.1S glucocorticoid-sensitive human myeloma cell line, we began with the broad platform of gene expression profiling to identify glucocorticoid-regulated genes further refined by combination treatment with phosphatidylinositol-3’-kinase inhibition (PI3Ki). To further refine the search to distinguish direct and indirect targets of GR that respond to the combination GC and PI3Ki treatment of MM.1S cells, we integrated 1) gene expression profiles of combination GC treatment with PI3Ki, which induces synergistic cell death; 2) negative correlation between genes inhibited by combination treatment in MM.1S cells and genes over-expressed in myeloma patients to establish clinical relevance and 3) GR chromatin immunoprecipitation with massively parallel sequencing (ChIP-Seq) in myeloma cells to identify global chromatin binding for the glucocorticoid receptor (GR). Using established bioinformatics platforms, we have integrated these data sets to identify a subset of candidate genes that may form the basis for a comprehensive picture of glucocorticoid actions in multiple myeloma. As a proof of principle, we have verified two targets, namely RRM2 and BCL2L1, as primary functional targets of GR involved in GC-induced cell death. PMID:26715915

  1. Survivin and Tumorigenesis: Molecular Mechanisms and Therapeutic Strategies

    PubMed Central

    Chen, Xun; Duan, Ning; Zhang, Caiguo; Zhang, Wentao

    2016-01-01

    Survivin is the smallest member of the inhibitor of apoptosis protein family, which has key roles in regulating cell division and inhibiting apoptosis by blocking caspase activation. Survivin is highly expressed in most human cancers, such as lung, pancreatic and breast cancers, relative to normal tissues. Aberrant survivin expression is associated with tumor cell proliferation, progression, angiogenesis, therapeutic resistance, and poor prognosis. Studies on the underlying molecular mechanisms indicate that survivin is involved in the regulation of cytokinesis and cell cycle progression, as well as participates in a variety of signaling pathways such as the p53, Wnt, hypoxia, transforming growth factor, and Notch signaling pathways. In this review, recent progress in understanding the molecular basis of survivin is discussed. Therapeutic strategies targeting survivin in preclinical studies are also briefly summarized. PMID:26918045

  2. Targeting ischemic penumbra: part I - from pathophysiology to therapeutic strategy

    PubMed Central

    Liu, Shimin; Levine, Steven R.; Winn, H. Richard

    2010-01-01

    Penumbra is the viable tissue around the irreversibly damaged ischemic core. The purpose of acute stroke treatment is to salvage penumbral tissue and to improve brain function. However, the majority of acute stroke patients who have treatable penumbra are left untreated. Therefore, developing an effective non-recanalizational therapeutics, such as neuroprotective agents, has significant clinical applications. Part I of this serial review on “targeting penumbra” puts special emphases on penumbral pathophysiology and the development of therapeutic strategies. Bioenergetic intervention by massive metabolic suppression and direct energy delivery would be a promising future direction. An effective drug delivery system for this purpose should be able to penetrate BBB and achieve high local tissue drug levels while non-ischemic region being largely unaffected. Selective drug delivery to ischemic stroke penumbra is feasible and deserves intensive research. PMID:20607107

  3. Physiological effects and therapeutic potential of proinsulin C-peptide

    PubMed Central

    Maric-Bilkan, Christine; Luppi, Patrizia; Wahren, John

    2014-01-01

    Connecting Peptide, or C-peptide, is a product of the insulin prohormone, and is released with and in amounts equimolar to those of insulin. While it was once thought that C-peptide was biologically inert and had little biological significance beyond its role in the proper folding of insulin, it is now known that C-peptide binds specifically to the cell membranes of a variety of tissues and initiates specific intracellular signaling cascades that are pertussis toxin sensitive. Although it is now clear that C-peptide is a biologically active molecule, controversy still remains as to the physiological significance of the peptide. Interestingly, C-peptide appears to reverse the deleterious effects of high glucose in some tissues, including the kidney, the peripheral nerves, and the vasculature. C-peptide is thus a potential therapeutic agent for the treatment of diabetes-associated long-term complications. This review addresses the possible physiologically relevant roles of C-peptide in both normal and disease states and discusses the effects of the peptide on sensory nerve, renal, and vascular function. Furthermore, we highlight the intracellular effects of the peptide and present novel strategies for the determination of the C-peptide receptor(s). Finally, a hypothesis is offered concerning the relationship between C-peptide and the development of microvascular complications of diabetes. PMID:25249503

  4. Silk polymer-based adenosine release: therapeutic potential for epilepsy.

    PubMed

    Wilz, Andrew; Pritchard, Eleanor M; Li, Tianfu; Lan, Jing-Quan; Kaplan, David L; Boison, Detlev

    2008-09-01

    Adenosine augmentation therapies (AAT) make rational use of the brain's own adenosine-based seizure control system and hold promise for the therapy of refractory epilepsy. In an effort to develop an AAT compatible with future clinical application, we developed a novel silk protein-based release system for adenosine. Adenosine releasing brain implants with target release doses of 0, 40, 200, and 1000ng adenosine per day were prepared by embedding adenosine containing microspheres into nanofilm-coated silk fibroin scaffolds. In vitro, the respective polymers released 0, 33.4, 170.5, and 819.0ng adenosine per day over 14 days. The therapeutic potential of the implants was validated in a dose-response study in the rat model of kindling epileptogenesis. Four days prior to the onset of kindling, adenosine releasing polymers were implanted into the infrahippocampal cleft and progressive acquisition of kindled seizures was monitored over a total of 48 stimulations. We document a dose-dependent retardation of seizure acquisition. In recipients of polymers releasing 819ng adenosine per day, kindling epileptogenesis was delayed by one week corresponding to 18 kindling stimulations. Histological analysis of brain samples confirmed the correct location of implants and electrodes. We conclude that silk-based delivery of around 1000ng adenosine per day is a safe and efficient strategy to suppress seizures. PMID:18514814

  5. Islet neogenesis: a potential therapeutic tool in type 1 diabetes.

    PubMed

    Lipsett, Mark; Aikin, Reid; Castellarin, Mauro; Hanley, Stephen; Jamal, Al-Maleek; Laganiere, Simon; Rosenberg, Lawrence

    2006-01-01

    Current therapies for type 1 diabetes, including fastidious blood glucose monitoring and multiple daily insulin injections, are not sufficient to prevent complications of the disease. Though pancreas and possibly islet transplantation can prevent the progression of complications, the scarcity of donor organs limits widespread application of these approaches. Understanding the mechanisms of beta-cell mass expansion as well as the means to exploit these pathways has enabled researchers to develop new strategies to expand and maintain islet cell mass. Potential new therapeutic avenues include ex vivo islet expansion and improved viability of islets prior to implantation, as well as the endogenous expansion of beta-cell mass within the diabetic patient. Islet neogenesis, through stem cell activation and/or transdifferentiation of mature fully differentiated cells, has been proposed as a means of beta-cell mass expansion. Finally, any successful new therapy for type 1 diabetes via beta-cell mass expansion will require prevention of beta-cell death and maintenance of long-term endocrine function. PMID:16216541

  6. Islet neogenesis: a potential therapeutic tool in type 1 diabetes.

    PubMed

    Lipsett, Mark; Aikin, Reid; Hanley, Stephen; Al-Maleek, Jamal; Laganiere, Simon; Rosenburg, Lawrence

    2006-01-01

    Current therapies for type 1 diabetes, including fastidious blood glucose monitoring and multiple daily insulin injections, are not sufficient to prevent complications of the disease. Though pancreas and possibly islet transplantation can prevent the progression of complications, the scarcity of donor organs limits widespread application of these approaches. Understanding the mechanisms of beta-cell mass expansion as well as the means to exploit these pathways has enabled researchers to develop new strategies to expand and maintain islet cell mass. Potential new therapeutic avenues include ex vivo islet expansion and improved viability of islets prior to implantation, as well as the endogenous expansion of beta-cell mass within the diabetic patient. Islet neogenesis, through stem cell activation and/or transdifferentiation of mature fully differentiated cells, has been proposed as a means of beta-cell mass expansion. Finally, any successful new therapy for type 1 diabetes via beta-cell mass expansion will require prevention of beta-cell death and maintenance of long-term endocrine function. PMID:16607698

  7. Therapeutic potential of chemokine signal inhibition for metastatic breast cancer

    PubMed Central

    Kitamura, Takanori; Pollard, Jeffrey W.

    2015-01-01

    Metastatic breast cancer is incurable by current therapies including chemotherapy and immunotherapy. Accumulating evidence indicates that tumor-infiltrating macrophages promote establishment of the lethal metastatic foci and contribute to therapeutic resistance. Recent studies suggest that the accumulation of these macrophages is regulated by a chemokine network established in the tumor microenvironment. In this perspective paper, we elaborate on the chemokine signals that can attract monocytes/macrophages to the site of metastasis, and discuss whether inhibition of these chemokine signals can represent a new therapeutic strategy for metastatic breast cancer. PMID:26275794

  8. Pathogenesis of and therapeutic strategies to ameliorate the transthyretin amyloidoses.

    PubMed

    Sekijima, Yoshiki; Kelly, Jeffery W; Ikeda, Shu-ichi

    2008-01-01

    Transthyretin (TTR) is a homotetrameric serum and cerebrospinal fluid protein that transports both thyroxine (T(4)) and the retinol-retinol binding protein complex (holoRBP). Rate-limiting tetramer dissociation and rapid monomer misfolding and misassembly of variant TTR results in familial amyloid polyneuropathy (FAP), familial amyloid cardiomyopathy (FAC), or familial central nervous system amyloidosis. Analogous misfolding of wild-type TTR results in senile systemic amyloidosis (SSA) characterized by sporadic amyloidosis in elderly populations. With the availability of genetic and immunohistochemical diagnostic tests, patients with TTR amyloidosis have been found in many nations worldwide. Recent studies indicate that TTR amyloidosis is not a rare endemic disease as previously thought. The only effective treatment for the familial TTR amyloidoses is liver transplantation; however, this strategy has a number of limitations, including a shortage of donors, a requirement for surgery for both the recipient and living donor, and the high cost. Furthermore, a large number of patients are not good transplant candidates. Recent studies focused on the TTR gene and protein have provided insight into the pathogenesis of TTR amyloidosis and suggested new strategies for therapeutic intervention. TTR tetramer (native state) kinetic stabilization by small molecule binding, immune therapy, and gene therapy with small interfering RNAs, antisense oligonucleotides, and single-stranded oligonucleotides are promising strategies based on our understanding of the pathogenesis of TTR amyloidosis. Among these, native state kinetic stabilization by diflunisal and Fx-1006A, a novel therapeutic strategy against protein misfolding diseases, are currently in Phase II/III clinical trials. PMID:19075702

  9. Faster, better, stronger: towards new antidepressant therapeutic strategies.

    PubMed

    O'Leary, Olivia F; Dinan, Timothy G; Cryan, John F

    2015-04-15

    Major depression is a highly prevalent disorder and is predicted to be the second leading cause of disease burden by 2020. Although many antidepressant drugs are currently available, they are far from optimal. Approximately 50% of patients do not respond to initial first line antidepressant treatment, while approximately one third fail to achieve remission following several pharmacological interventions. Furthermore, several weeks or months of treatment are often required before clinical improvement, if any, is reported. Moreover, most of the commonly used antidepressants have been primarily designed to increase synaptic availability of serotonin and/or noradrenaline and although they are of therapeutic benefit to many patients, it is clear that other therapeutic targets are required if we are going to improve the response and remission rates. It is clear that more effective, rapid-acting antidepressants with novel mechanisms of action are required. The purpose of this review is to outline the current strategies that are being taken in both preclinical and clinical settings for identifying superior antidepressant drugs. The realisation that ketamine has rapid antidepressant-like effects in treatment resistant patients has reenergised the field. Further, developing an understanding of the mechanisms underlying the rapid antidepressant effects in treatment-resistant patients by drugs such as ketamine may uncover novel therapeutic targets that can be exploited to meet the Olympian challenge of developing faster, better and stronger antidepressant drugs. PMID:25092200

  10. Assessing the therapeutic potential of lab-made hepatocytes.

    PubMed

    Rezvani, Milad; Grimm, Andrew A; Willenbring, Holger

    2016-07-01

    Hepatocyte transplantation has potential as a bridge or even alternative to whole-organ liver transplantation. Because donor livers are scarce, realizing this potential requires the development of alternative cell sources. To be therapeutically effective, surrogate hepatocytes must replicate the complex function and ability to proliferate of primary human hepatocytes. Ideally, they are also autologous to eliminate the need for immune suppression, which can have severe side effects and may not be sufficient to prevent rejection long term. In the past decade, several methods have been developed to generate hepatocytes from other readily and safely accessible somatic cells. These lab-made hepatocytes show promise in animal models of liver diseases, supporting the feasibility of autologous liver cell therapies. Here, we review recent preclinical studies exemplifying different types of lab-made hepatocytes that can potentially be used in autologous liver cell therapies. To define the therapeutic efficacy of current lab-made hepatocytes, we compare them to primary human hepatocytes, focusing on engraftment efficiency and posttransplant proliferation and function. In addition to summarizing published results, we discuss animal models and assays effective in assessing therapeutic efficacy. This analysis underscores the therapeutic potential of current lab-made hepatocytes, but also highlights deficiencies and uncertainties that need to be addressed in future studies aimed at developing liver cell therapies with lab-made hepatocytes. (Hepatology 2016;64:287-294). PMID:27014802

  11. Strategy Choices of Potential Entrepreneurs

    ERIC Educational Resources Information Center

    Alstete, Jeffrey W.

    2014-01-01

    The author examined the written business plans of 380 students who completed courses in entrepreneurship and small business management over an 11-year period. An analysis categorized the plans into five generic competitive strategy types, and the results found that 58% chose a traditional, focused differentiation approach. A large portion (28%)…

  12. Adrenomedullin: A potential therapeutic target for retinochoroidal disease.

    PubMed

    Iesato, Yasuhiro; Yuda, Kentaro; Chong, Kelvin Teo Yi; Tan, Xue; Murata, Toshinori; Shindo, Takayuki; Yanagi, Yasuo

    2016-05-01

    Adrenomedullin (AM) is a 52-amino acid peptide with anti-inflammatory, anti-apoptotic, and anti-oxidative properties discovered in a human pheochromocytoma. It is a member of the calcitonin peptide superfamily, and its signal is mediated by calcitonin receptor-like receptor (CLR). CLR interacts with receptor activity-modifying proteins (RAMPs), among which RAMP-2 and RAMP-3 carry CLR from the endoplasmic reticulum to the cellular membrane to confer high affinity for AM. In addition to being implicated in a variety of systemic diseases, AM is a critical contributor to the pathogenesis of retinochoroidal disease. It is robustly upregulated in retinochoroidal disease models of oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularisation (CNV) as well as in human patients with retinochoroidal diseases. In this review, we discuss the most salient recent findings that strongly illustrate the role of AM in retinochoroidal disease. In the OIR model, AM was identified as a key angiogenic mediator of retinal vascularisation, and AM inhibition suppressed only pathological angiogenesis, not physiological angiogenesis. On the contrary, lesion size was larger in AM(+/-) CNV model mice, presumably due to the anti-inflammatory function of AM. Despite the success of anti-vascular endothelial growth factor agents for the treatment of retinochoroidal disease, therapeutic shortcomings remain. Finding ways to modulate AM activity will provide new treatment avenues. Potential treatment strategies modulating the action of AM and its signaling pathway have been studied extensively. AM and its signaling molecules are intriguing future treatment targets for retinochoroidal disease. PMID:26791747

  13. Physiology and therapeutic potential of the thymic peptide thymulin.

    PubMed

    Reggiani, Paula C; Schwerdt, Jose I; Console, Gloria M; Roggero, Eduardo A; Dardenne, Mireille; Goya, Rodolfo G

    2014-01-01

    Thymulin is a thymic hormone exclusively produced by the epithelial cells of the thymus. After its discovery and initial characterization in the '70s, it was demonstrated that the production and secretion of thymulin are strongly influenced by the neuro-endocrine system. Conversely, a growing body of evidence, to be reviewed here, suggests that thymulin is a hypophysiotropic peptide. Additionally, a substantial body of information pointing to thymulin and a synthetic analog as anti-inflammatory and analgesic peptides in the central nervous system brain and other organs will be also reviewed. In recent years, a synthetic DNA sequence encoding a biologically active analog of thymulin, metFTS, was constructed and cloned in a number of adenovectors. These include bidirectional regulatable Tet-Off vector systems that simultaneously express metFTS and green fluorescent protein and that can be down-regulated reversibly by the addition of the antibiotic doxycycline. A number of recent studies indicate that gene therapy for thymulin may be an effective therapeutic strategy to prevent some of the hormonal and reproductive abnormalities that typically appear in congenitally athymic (nude) mice, used as a suitable model of neuroendocrine and reproductive aging. Summing up, this article briefly reviews the publications on the physiology of the thymulin-neuroendocrine axis and the anti-inflammatory properties of the molecule and its analog. The availability of novel biotechnological tools should boost basic studies on the molecular biology of thymulin and should also allow an assessment of the potential of gene therapy to restore circulating thymulin levels in thymodeficient animal models and eventually, in humans. PMID:24588820

  14. PEI-g-PEG-RGD/Small Interference RNA Polyplex-Mediated Silencing of Vascular Endothelial Growth Factor Receptor and Its Potential as an Anti-Angiogenic Tumor Therapeutic Strategy

    PubMed Central

    Kim, Jihoon; Kim, Sung Wan

    2011-01-01

    Tumor angiogenesis appears to be achieved by the expression of vascular endothelial growth factor (VEGF) within solid tumors that stimulate host vascular endothelial cell mitogenesis and possibly chemotaxis. VEGF's angiogenic actions are mediated through its high-affinity binding to 2 endothelium-specific receptor tyrosine kinase, Flt-1 (VEGFR1), and Flk-1/KDR (VEGFR2). RNA interference-mediated knockdown of protein expression at the messenger RNA level provides a new therapeutic strategy to overcome various diseases. To achieve high efficacy in RNA interference-mediated therapy, it is critical to develop an efficient delivering system to deliver small interference RNA (siRNA) into tissues or cells site-specifically. We previously reported an angiogenic endothelial cell-targeted polymeric gene carrier, PEI-g-PEG-RGD. This targeted carrier was developed by the conjugation of the ανβ3/ανβ5 integrin-binding RGD peptide (ACDCRGDCFC) to the cationic polymer, branched polyethylenimine, with a hydrophilic polyethylene glycol (PEG) spacer. In this study, we used PEI-g-PEG-RGD to deliver siRNA against VEGFR1 into tumor site. The physicochemical properties of PEI-g-PEG-RGD/siRNA complexes was evaluated. Further, tumor growth profile was also investigated after systemic administration of PEI-g-PEG-RGD/siRNA complexes. PMID:21375397

  15. Protease inhibition as new therapeutic strategy for GI diseases

    PubMed Central

    Vergnolle, Nathalie

    2016-01-01

    The GI tract is the most exposed organ to proteases, both in physiological and pathophysiological conditions. For digestive purposes, the lumen of the upper GI tract contains large amounts of pancreatic proteases, but studies have also demonstrated increased proteolytic activity into mucosal tissues (both in the upper and lower GI tract), associated with pathological conditions. This review aims at outlining the evidences for dysregulated proteolytic homeostasis in GI diseases and the pathogenic mechanisms of increased proteolytic activity. The therapeutic potential of protease inhibition in GI diseases is discussed, with a particular focus on IBDs, functional GI disorders and colorectal cancer. PMID:27196587

  16. Protease inhibition as new therapeutic strategy for GI diseases.

    PubMed

    Vergnolle, Nathalie

    2016-07-01

    The GI tract is the most exposed organ to proteases, both in physiological and pathophysiological conditions. For digestive purposes, the lumen of the upper GI tract contains large amounts of pancreatic proteases, but studies have also demonstrated increased proteolytic activity into mucosal tissues (both in the upper and lower GI tract), associated with pathological conditions. This review aims at outlining the evidences for dysregulated proteolytic homeostasis in GI diseases and the pathogenic mechanisms of increased proteolytic activity. The therapeutic potential of protease inhibition in GI diseases is discussed, with a particular focus on IBDs, functional GI disorders and colorectal cancer. PMID:27196587

  17. Current therapeutic strategies for premature ejaculation and future perspectives

    PubMed Central

    Xin, Zhong-Cheng; Zhu, Yi-Chen; Yuan, Yi-Ming; Cui, Wan-Shou; Jin, Zhe; Li, Wei-Ren; Liu, Tao

    2011-01-01

    Premature ejaculation (PE) is a common sexual disorder in men that is mediated by disturbances in the peripheral and central nervous systems. Although all pharmaceutical treatments for PE are currently used ‘off-label', some novel oral agents and some newer methods of drug administration now provide important relief to PE patients. However, the aetiology of this condition has still not been unified, primarily because of the lack of a standard animal model for basic research and the absence of a widely accepted definition and assessment tool for evidence-based clinical studies in patients with PE. In this review, we focus on the current therapeutic strategies and future treatment perspectives for PE. PMID:21532601

  18. Therapeutic strategies for Leber's hereditary optic neuropathy: A current update.

    PubMed

    Gueven, Nuri; Faldu, Dharmesh

    2013-11-01

    Leber's hereditary optic neuropathy (LHON) is a rare mitochondrial retinopathy, caused by mutations in subunits of complex I of the respiratory chain, which leads to elevated levels of oxidative stress and an insufficient energy supply. This molecular pathology is thought to be responsible for the dysfunction and eventual apoptotic loss of retinal ganglion cells in the eye, which ultimately results in blindness. Many strategies, ranging from neuroprotectants, antioxidants, anti-apoptotic- and anti-inflammatory compounds have been tested with mixed results. Currently, the most promising compounds are short-chain quinones that have been shown to protect the vision of LHON patients during the early stages of the disease. This commentary gives a brief overview on the current status of tested therapeutics and also addresses future developments such as the use of gene therapy that hopefully will provide safe and efficient therapy options for all LHON patients. PMID:25343117

  19. Novel hepatocellular carcinoma molecules with prognostic and therapeutic potentials

    PubMed Central

    Scaggiante, Bruna; Kazemi, Maryam; Pozzato, Gabriele; Dapas, Barbara; Farra, Rosella; Grassi, Mario; Zanconati, Fabrizio; Grassi, Gabriele

    2014-01-01

    Hepatocellular carcinoma (HCC), the predominant form of primary liver cancer, is the sixth most common cancer worldwide and the third leading cause of cancer-related death. The difficulty to diagnose early cancer stages, the aggressive behaviors of HCC, and the poor effectiveness of therapeutic treatments, represent the reasons for the quite similar deaths per year and incidence number. Considering the fact that the diagnosis of HCC typically occurs in the advanced stages of the disease when the therapeutic options have only modest efficacy, the possibility to identify early diagnostic markers could be of significant benefit. So far, a large number of biomarkers have been associated to HCC progression and aggressiveness, but many of them turned out not to be of practical utility. This is the reason why active investigations are ongoing in this field. Given the huge amount of published works aimed at the identification of HCC biomarkers, in this review we mainly focused on the data published in the last year, with particular attention to the role of (1) molecular and biochemical cellular markers; (2) micro-interfering RNAs; (3) epigenetic variations; and (4) tumor stroma. It is worth mentioning that a significant number of the HCC markers described in the present review may be utilized also as targets for novel therapeutic approaches, indicating the tight relation between diagnosis and therapy. In conclusion, we believe that integrated researches among the different lines of investigation indicated above should represent the winning strategies to identify effective HCC markers and therapeutic targets. PMID:24574801

  20. Human Papillomavirus: Current and Future RNAi Therapeutic Strategies for Cervical Cancer

    PubMed Central

    Jung, Hun Soon; Rajasekaran, Nirmal; Ju, Woong; Shin, Young Kee

    2015-01-01

    Human papillomaviruses (HPVs) are small DNA viruses; some oncogenic ones can cause different types of cancer, in particular cervical cancer. HPV-associated carcinogenesis provides a classical model system for RNA interference (RNAi) based cancer therapies, because the viral oncogenes E6 and E7 that cause cervical cancer are expressed only in cancerous cells. Previous studies on the development of therapeutic RNAi facilitated the advancement of therapeutic siRNAs and demonstrated its versatility by siRNA-mediated depletion of single or multiple cellular/viral targets. Sequence-specific gene silencing using RNAi shows promise as a novel therapeutic approach for the treatment of a variety of diseases that currently lack effective treatments. However, siRNA-based targeting requires further validation of its efficacy in vitro and in vivo, for its potential off-target effects, and of the design of conventional therapies to be used in combination with siRNAs and their drug delivery vehicles. In this review we discuss what is currently known about HPV-associated carcinogenesis and the potential for combining siRNA with other treatment strategies for the development of future therapies. Finally, we present our assessment of the most promising path to the development of RNAi therapeutic strategies for clinical settings. PMID:26239469

  1. New strategies to maximize therapeutic opportunities for NAMPT inhibitors in oncology.

    PubMed

    Roulston, Anne; Shore, Gordon C

    2016-01-01

    Nicotinamide phosphoribosyltransferase (NAMPT) is crucial for nicotinamide adenine dinucleotide (NAD(+)) biosynthesis in mammalian cells. NAMPT inhibitors represent multifunctional anticancer agents that act on NAD(+) metabolism to shut down glycolysis, nucleotide biosynthesis, and ATP generation and act indirectly as PARP and sirtuin inhibitors. The selectivity of NAMPT inhibitors preys on the increased metabolic requirements to replenish NAD(+) in cancer cells. Although initial clinical studies with NAMPT inhibitors did not achieve single-agent therapeutic levels before dose-limiting toxicities were reached, a new understanding of alternative rescue pathways and a biomarker that can be used to select patients provides new opportunities to widen the therapeutic window and achieve efficacious doses in the clinic. Recent work has also illustrated the potential for drug combination strategies to further enhance the therapeutic opportunities. This review summarizes recent discoveries in NAD(+)/NAMPT inhibitor biology in the context of exploiting this new knowledge to optimize the clinical outcomes for this promising new class of agents. PMID:27308565

  2. The immune system and cancer evasion strategies: therapeutic concepts.

    PubMed

    Muenst, S; Läubli, H; Soysal, S D; Zippelius, A; Tzankov, A; Hoeller, S

    2016-06-01

    The complicated interplay between cancer and the host immune system has been studied for decades. New insights into the human immune system as well as the mechanisms by which tumours evade immune control have led to the new and innovative therapeutic strategies that are considered amongst the medical breakthroughs of the last few years. Here, we will review the current understanding of cancer immunology in general, including immune surveillance and immunoediting, with a detailed look at immune cells (T cells, B cells, natural killer cells, macrophages and dendritic cells), immune checkpoints and regulators, sialic acid-binding immunoglobulin-like lectins (Siglecs) and other mechanisms. We will also present examples of new immune therapies able to reverse immune evasion strategies of tumour cells. Finally, we will focus on therapies that are already used in daily oncological practice such as the blockade of immune checkpoints cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death-1 (PD-1) in patients with metastatic melanoma or advanced lung cancer, or therapies currently being tested in clinical trials such as adoptive T-cell transfer. PMID:26748421

  3. The therapeutic potential of cannabinoids for movement disorders.

    PubMed

    Kluger, Benzi; Triolo, Piera; Jones, Wallace; Jankovic, Joseph

    2015-03-01

    There is growing interest in the therapeutic potential of marijuana (cannabis) and cannabinoid-based chemicals within the medical community and, particularly, for neurological conditions. This interest is driven both by changes in the legal status of cannabis in many areas and increasing research into the roles of endocannabinoids within the central nervous system and their potential as symptomatic and/or neuroprotective therapies. We review basic science as well as preclinical and clinical studies on the therapeutic potential of cannabinoids specifically as it relates to movement disorders. The pharmacology of cannabis is complex, with over 60 neuroactive chemicals identified to date. The endocannabinoid system modulates neurotransmission involved in motor function, particularly within the basal ganglia. Preclinical research in animal models of several movement disorders have shown variable evidence for symptomatic benefits, but more consistently suggest potential neuroprotective effects in several animal models of Parkinson's (PD) and Huntington's disease (HD). Clinical observations and clinical trials of cannabinoid-based therapies suggests a possible benefit of cannabinoids for tics and probably no benefit for tremor in multiple sclerosis or dyskinesias or motor symptoms in PD. Data are insufficient to draw conclusions regarding HD, dystonia, or ataxia and nonexistent for myoclonus or RLS. Despite the widespread publicity about the medical benefits of cannabinoids, further preclinical and clinical research is needed to better characterize the pharmacological, physiological, and therapeutic effects of this class of drugs in movement disorders. PMID:25649017

  4. The Therapeutic Potential of Cannabinoids for Movement Disorders

    PubMed Central

    Kluger, Benzi; Triolo, Piera; Jones, Wallace; Jankovic, Joseph

    2014-01-01

    Background There is growing interest in the therapeutic potential of marijuana (cannabis) and cannabinoid-based chemicals within the medical community and particularly for neurologic conditions. This interest is driven both by changes in the legal status of cannabis in many areas and increasing research into the roles of endocannabinoids within the central nervous system and their potential as symptomatic and/or neuroprotective therapies. We review basic science, preclinical and clinical studies on the therapeutic potential of cannabinoids specifically as it relates to movement disorders. Results The pharmacology of cannabis is complex with over 60 neuroactive chemicals identified to date. The endocannabinoid system modulates neurotransmission involved in motor function, particularly within the basal ganglia. Preclinical research in animal models of several movement disorders have shown variable evidence for symptomatic benefits but more consistently suggest potential neuroprotective effects in several animal models of Parkinson’s (PD) and Huntington’s disease (HD). Clinical observations and clinical trials of cannabinoid-based therapies suggests a possible benefit of cannabinoids for tics and probably no benefit for tremor in multiple sclerosis or dyskinesias or motor symptoms in PD. Data are insufficient to draw conclusions regarding HD, dystonia or ataxia and nonexistent for myoclonus or restless legs syndrome. Conclusions Despite the widespread publicity about the medical benefits of cannabinoids, further preclinical and clinical research is needed to better characterize the pharmacological, physiological and therapeutic effects of this class of drugs in movement disorders. PMID:25649017

  5. Mesenchymal stem cell subpopulations: phenotype, property and therapeutic potential.

    PubMed

    Mo, Miaohua; Wang, Shan; Zhou, Ying; Li, Hong; Wu, Yaojiong

    2016-09-01

    Mesenchymal stem cells (MSC) are capable of differentiating into cells of multiple cell lineages and have potent paracrine effects. Due to their easy preparation and low immunogenicity, MSC have emerged as an extremely promising therapeutic agent in regenerative medicine for diverse diseases. However, MSC are heterogeneous with respect to phenotype and function in current isolation and cultivation regimes, which often lead to incomparable experimental results. In addition, there may be specific stem cell subpopulations with definite differentiation capacity toward certain lineages in addition to stem cells with multi-differentiation potential. Recent studies have identified several subsets of MSC which exhibit distinct features and biological activities, and enhanced therapeutic potentials for certain diseases. In this review, we give an overview of these subsets for their phenotypic, biological and functional properties. PMID:27141940

  6. Aquaporin 1, a potential therapeutic target for migraine with aura

    PubMed Central

    2010-01-01

    The pathophysiology of migraine remains largely unknown. However, evidence regarding the molecules participating in the pathophysiology of migraine has been accumulating. Water channel proteins, known as aquaporins (AQPs), notably AQP-1 and AQP-4, appears to be involved in the pathophysiology of several neurological diseases. This review outlines newly emerging evidence indicating that AQP-1 plays an important role in pain signal transduction and migraine and could therefore serve as a potential therapeutic target for these diseases. PMID:20969805

  7. The pharmacology and therapeutic potential of (−)-huperzine A

    PubMed Central

    Tun, Maung Kyaw Moe; Herzon, Seth B

    2012-01-01

    (−)-Huperzine A (1) is an alkaloid isolated from a Chinese club moss. Due to its potent neuroprotective activities, it has been investigated as a candidate for the treatment of neurodegenerative diseases, including Alzheimer’s disease. In this review, we will discuss the pharmacology and therapeutic potential of (−)-huperzine A (1). Synthetic studies of (−)-huperzine A (1) aimed at enabling its development as a pharmaceutical will be described.

  8. Hepatitis C virus-host interactions: Etiopathogenesis and therapeutic strategies

    PubMed Central

    Hassan, Mohamed; Selimovic, Denis; El-Khattouti, Abdelouahid; Ghozlan, Hanan; Haikel, Youssef; Abdelkader, Ola

    2012-01-01

    Hepatitis C virus (HCV) is a significant health problem facing the world. This virus infects more than 170 million people worldwide and is considered the major cause of both acute and chronic hepatitis. Persons become infected mainly through parenteral exposure to infected material by blood transfusions or injections with nonsterile needles. Although the sexual behavior is considered as a high risk factor for HCV infection, the transmission of HCV infection through sexual means, is less frequently. Currently, the available treatment for patients with chronic HCV infection is interferon based therapies alone or in combination with ribavirin and protease inhibitors. Although a sustained virological response of patients to the applied therapy, a great portion of patients did not show any response. HCV infection is mostly associated with progressive liver diseases including fibrosis, cirrhosis and hepatocellular carcinoma. Although the focus of many patients and clinicians is sometimes limited to that problem, the natural history of HCV infection (HCV) is also associated with the development of several extrahepatic manifestations including dermatologic, rheumatologic, neurologic, and nephrologic complications, diabetes, arterial hypertension, autoantibodies and cryglobulins. Despite the notion that HCV-mediated extrahepatic manifestations are credible, the mechanism of their modulation is not fully described in detail. Therefore, the understanding of the molecular mechanisms of HCV-induced alteration of intracellular signal transduction pathways, during the course of HCV infection, may offer novel therapeutic targets for HCV-associated both hepatic and extrahepatic manifestations. This review will elaborate the etiopathogenesis of HCV-host interactions and summarize the current knowledge of HCV-associated diseases and their possible therapeutic strategies. PMID:24520529

  9. The Natural Flavonoid Pinocembrin: Molecular Targets and Potential Therapeutic Applications.

    PubMed

    Lan, Xi; Wang, Wenzhu; Li, Qiang; Wang, Jian

    2016-04-01

    Pinocembrin is a natural flavonoid compound extracted from honey, propolis, ginger roots, wild marjoram, and other plants. In preclinical studies, it has shown anti-inflammatory and neuroprotective effects as well as the ability to reduce reactive oxygen species, protect the blood-brain barrier, modulate mitochondrial function, and regulate apoptosis. Considering these pharmaceutical characteristics, pinocembrin has potential as a drug to treat ischemic stroke and other clinical conditions. In this review, we summarize its pharmacologic characteristics and discuss its mechanisms of action and potential therapeutic applications. PMID:25744566

  10. Managing fatigue: clinical correlates, assessment procedures and therapeutic strategies.

    PubMed

    Penner, Ik; Calabrese, P

    2010-01-01

    The majority of patients with Multiple Sclerosis (MS) experience fatigue and for many susabjects concerned it is the most disabling symptom. Fatigue is most prominent in the afternoon and may be aggravated by heat. It has a tremendous negative impact on quality of life and is often one of the major reasons for early retirement and unemployment. Against further assumptions, fatigue can occur at all stages and is often present at the onset of the disease. Reliable assessment however, is difficult as it is a subjectively perceived lack of physical and/or mental energy interfering with intended activities and has to be differentiated from depression, consequences of sleep disorders, cognitive decline, and side-effects of medication. Moreover, fatigue is not directly related to overall disease evolution, to disability levels or localized lesions, although an association with dysfunction of fronto-thalamo-basal-ganglia circuits seems likely. Several therapeutic approaches including pharmacological as well as non-pharmacological strategies are available but an evidence-based specific gold-standard for the treatment of fatigue is still missing. PMID:20663419

  11. MicroRNA: A new therapeutic strategy for cardiovascular diseases.

    PubMed

    Samanta, Saheli; Balasubramanian, Sathyamoorthy; Rajasingh, Sheeja; Patel, Urmi; Dhanasekaran, Anuradha; Dawn, Buddhadeb; Rajasingh, Johnson

    2016-07-01

    Myocardial infarction, atherosclerosis, and hypertension are the most common heart-related diseases that affect both the heart and the blood vessels. Multiple independent risk factors have been shown to be responsible for cardiovascular diseases. The combination of a healthy diet, exercise, and smoking cessation keeps these risk factors in check and helps maintain homeostasis. The dynamic monolayer endothelial cell integrity and cell-cell communication are the fundamental mechanisms in maintaining homeostasis. Recently, it has been revealed that small noncoding RNAs (ncRNAs) play a critical role in regulation of genes involved in either posttranscriptional or pretranslational modifications. They also control diverse biological functions like development, differentiation, growth, and metabolism. Among ncRNAs, the short interfering RNAs (siRNAs), and microRNAs (miRNAs) have been extensively studied, but their specific functions remain largely unknown. In recent years, miRNAs are efficiently studied as one of the important candidates for involvement in most biological processes and have been implicated in many human diseases. Thus, the identification and the respective targets of miRNAs may provide novel molecular insight and new therapeutic strategies to treat diseases. This review summarizes the recent developments and insight on the role of miRNAs in cardiovascular disease prognosis, diagnostic and clinical applications. PMID:27013138

  12. Gut microbiota role in irritable bowel syndrome: New therapeutic strategies

    PubMed Central

    Distrutti, Eleonora; Monaldi, Lorenzo; Ricci, Patrizia; Fiorucci, Stefano

    2016-01-01

    In the last decade the impressive expansion of our knowledge of the vast microbial community that resides in the human intestine, the gut microbiota, has provided support to the concept that a disturbed intestinal ecology might promote development and maintenance of symptoms in irritable bowel syndrome (IBS). As a correlate, manipulation of gut microbiota represents a new strategy for the treatment of this multifactorial disease. A number of attempts have been made to modulate the gut bacterial composition, following the idea that expansion of bacterial species considered as beneficial (Lactobacilli and Bifidobacteria) associated with the reduction of those considered harmful (Clostridium, Escherichia coli, Salmonella, Shigella and Pseudomonas) should attenuate IBS symptoms. In this conceptual framework, probiotics appear an attractive option in terms of both efficacy and safety, while prebiotics, synbiotics and antibiotics still need confirmation. Fecal transplant is an old treatment translated from the cure of intestinal infective pathologies that has recently gained a new life as therapeutic option for those patients with a disturbed gut ecosystem, but data on IBS are scanty and randomized, placebo-controlled studies are required. PMID:26900286

  13. Gut microbiota role in irritable bowel syndrome: New therapeutic strategies.

    PubMed

    Distrutti, Eleonora; Monaldi, Lorenzo; Ricci, Patrizia; Fiorucci, Stefano

    2016-02-21

    In the last decade the impressive expansion of our knowledge of the vast microbial community that resides in the human intestine, the gut microbiota, has provided support to the concept that a disturbed intestinal ecology might promote development and maintenance of symptoms in irritable bowel syndrome (IBS). As a correlate, manipulation of gut microbiota represents a new strategy for the treatment of this multifactorial disease. A number of attempts have been made to modulate the gut bacterial composition, following the idea that expansion of bacterial species considered as beneficial (Lactobacilli and Bifidobacteria) associated with the reduction of those considered harmful (Clostridium, Escherichia coli, Salmonella, Shigella and Pseudomonas) should attenuate IBS symptoms. In this conceptual framework, probiotics appear an attractive option in terms of both efficacy and safety, while prebiotics, synbiotics and antibiotics still need confirmation. Fecal transplant is an old treatment translated from the cure of intestinal infective pathologies that has recently gained a new life as therapeutic option for those patients with a disturbed gut ecosystem, but data on IBS are scanty and randomized, placebo-controlled studies are required. PMID:26900286

  14. New strategies and patent therapeutics in EBV-associated diseases.

    PubMed

    Villegas, E; Santiago, O; Sorlózano, A; Gutierrez, J

    2010-09-01

    Epstein-Barr virus (EBV) is a virus present all throughout the world that causes infectious mononucleosis (IM) and is highly associated with certain malignancies. This study is a review of current knowledge concerning the pathogenic mechanisms of EBV in tumor and auto-immune diseases and the different new strategies to treat EBV associated pathologies. Phenomena surrounding the proliferation and immortalization of B lymphocytes, the mechanisms of immune escape and the role of CD8+ and CD4+ T cells in the infection by EBV are explained. An analysis is made of the role of EBV proteins during the biological events that take place in primary infection, persistent chronic infection together with an update of the approaches of novel patented therapeutics. Currently there is no vaccine protecting against EBV-associated disorders and no treatment that may inhibit or eliminate their progression. Thus, it is crucial to obtain additional information on the function and importance of genes that play a role on the development of those diseases with which it is associated, as well as on the humoral and cellular immune processes involved in them. PMID:21034415

  15. Drugs or diet? – Developing novel therapeutic strategies targeting the free fatty acid family of GPCRs

    PubMed Central

    Dranse, H J; Kelly, M E M; Hudson, B D

    2013-01-01

    Free fatty acids (FFAs) are metabolic intermediates that may be obtained through the diet, synthesized endogenously, or produced via fermentation of carbohydrates by gut microbiota. In addition to serving as an important source of energy, FFAs are known to produce a variety of both beneficial and detrimental effects on metabolic and inflammatory processes. While historically, FFAs were believed to produce these effects only through intracellular targets such as peroxisome proliferator-activated receptors, it has now become clear that FFAs are also agonists for several GPCRs, including a family of four receptors now termed FFA1-4. Increasing evidence suggests that FFA1-4 mediate many of the beneficial properties of FFAs and not surprisingly, this has generated significant interest in the potential of these receptors as therapeutic targets for the treatment of a variety of metabolic and inflammatory disorders. In addition to the traditional strategy of developing small-molecule therapeutics targeting these receptors, there has also been some consideration given to alternate therapeutic approaches, specifically by manipulating endogenous FFA concentrations through alteration of either dietary intake, or production by gut microbiota. In this review, the current state of knowledge for FFA1-4 will be discussed, together with their potential as therapeutic targets in the treatment of metabolic and inflammatory disorders. In particular, the evidence in support of small molecule versus dietary and microbiota-based therapeutic approaches will be considered to provide insight into the development of novel multifaceted strategies targeting the FFA receptors for the treatment of metabolic and inflammatory disorders. PMID:23937426

  16. Therapeutic potential of icatibant (HOE-140, JE-049).

    PubMed

    Cruden, Nicholas L M; Newby, David E

    2008-09-01

    There is now a substantial body of work implicating bradykinin, an endogenous peptide neurohormone, in the pathophysiology of a variety of inflammatory conditions in man. Icatibant (HOE-140, JE-049), a highly selective antagonist at the bradykinin B2 receptor, blocks the vasodilatation and increased vascular permeability associated with exogenous bradykinin administration both in experimental models and in vivo in man. Recent attention has focused on the therapeutic potential of icatibant in a number of human disease states. The most promising of these is hereditary angioedema in which Phase III clinical trials have recently been completed and regulatory approval is currently being sought in Europe and the USA. A therapeutic role for icatibant has also been proposed in several other human conditions including drug-induced angioedema, airways disease, thermal injury, refractory ascites in patients with liver cirrhosis, and acute pancreatitis, although this work remains largely experimental. PMID:18710362

  17. Hsp90 as a Potential Therapeutic Target in Retinal Disease.

    PubMed

    Aguilà, Mònica; Cheetham, Michael E

    2016-01-01

    The molecular chaperone heat shock protein 90 (Hsp90) is a pivotal cellular regulator involved in the folding, activation and assembly of a wide range of proteins. Hsp90 has multiple roles in the retina and the use of different Hsp90 inhibitors has been shown to prevent retinal degeneration in models of retinitis pigmentosa and age-related macular degeneration. Hsp90 is also a potential target in uveal melanoma. Mechanistically, Hsp90 inhibition can evoke a dual response in the retina; stimulating a stress response with molecular chaperone expression. Thereby leading to an improvement in visual function and photoreceptor survival; however, prolonged inhibition can also stimulate the degradation of Hsp90 client proteins potentially deleteriously affect vision. Here, we review the multiple roles of Hsp90 in the retina and the therapeutic potential of Hsp90 as a target. PMID:26427407

  18. Alveolar bone loss: mechanisms, potential therapeutic targets, and interventions.

    PubMed

    Intini, G; Katsuragi, Y; Kirkwood, K L; Yang, S

    2014-05-01

    This article reviews recent research into mechanisms underlying bone resorption and highlights avenues of investigation that may generate new therapies to combat alveolar bone loss in periodontitis. Several proteins, signaling pathways, stem cells, and dietary supplements are discussed as they relate to periodontal bone loss and regeneration. RGS12 is a crucial protein that mediates osteoclastogenesis and bone destruction, and a potential therapeutic target. RGS12 likely regulates osteoclast differentiation through regulating calcium influx to control the calcium oscillation-NFATc1 pathway. A working model for RGS10 and RGS12 in the regulation of Ca(2+) oscillations during osteoclast differentiation is proposed. Initiation of inflammation depends on host cell-microbe interactions, including the p38 mitogen-activated protein kinase (MAPK) signaling pathway. Oral p38 inhibitors reduced lipopolysaccharide (LPS)-induced bone destruction in a rat periodontitis model but showed unsatisfactory safety profiles. The p38 substrate MK2 is a more specific therapeutic target with potentially superior tolerability. Furthermore, MKP-1 shows anti-inflammatory activity, reducing inflammatory cytokine biosynthesis and bone resorption. Multipotent skeletal stem cell (SSC) populations exist within the bone marrow and periosteum of long bones. These bone-marrow-derived SSCs and periosteum-derived SSCs have shown therapeutic potential in several applications, including bone and periodontal regeneration. The existence of craniofacial bone-specific SSCs is suggested based on existing studies. The effects of calcium, vitamin D, and soy isoflavone supplementation on alveolar and skeletal bone loss in post-menopausal women were investigated. Supplementation resulted in stabilization of forearm bone mass density and a reduced rate of alveolar bone loss over 1 yr, compared with placebo. Periodontal attachment levels were also well-maintained and alveolar bone loss suppressed during 24 wk of

  19. Commercially available interactive video games in burn rehabilitation: therapeutic potential.

    PubMed

    Parry, Ingrid S; Bagley, Anita; Kawada, Jason; Sen, Soman; Greenhalgh, David G; Palmieri, Tina L

    2012-06-01

    Commercially available interactive video games (IVG) like the Nintendo Wii™ (NW) and PlayStation™II Eye Toy (PE) are increasingly used in the rehabilitation of patients with burn. Such games have gained popularity in burn rehabilitation because they encourage range of motion (ROM) while distracting from pain. However, IVGs were not originally designed for rehabilitation purposes but rather for entertainment and may lack specificity for achieving rehabilitative goals. Objectively evaluating the specific demands of IVGs in relation to common burn therapy goals will determine their true therapeutic benefit and guide their use in burn rehabilitation. Upper extremity (UE) motion of 24 normal children was measured using 3D motion analysis during play with the two types of IVGs most commonly described for use after burn: NW and PE. Data was analyzed using t-tests and One-way Analysis of Variance. Active range of motion for shoulder flexion and abduction during play with both PE and NW was within functional range, thus supporting the idea that IVGs offer activities with therapeutic potential to improve ROM. PE resulted in higher demands and longer duration of UE motion than NW, and therefore may be the preferred tool when UE ROM or muscular endurance are the goals of rehabilitation. When choosing a suitable IVG for application in rehabilitation, the user's impairment together with the therapeutic attributes of the IVG should be considered to optimize outcome. PMID:22385641

  20. Genetic determinants and potential therapeutic targets for pancreatic adenocarcinoma

    PubMed Central

    Reznik, Robert; Hendifar, Andrew E.; Tuli, Richard

    2014-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer deaths in both men and women in the United States, carrying a 5-year survival rate of approximately 5%, which is the poorest prognosis of any solid tumor type. Given the dismal prognosis associated with PDAC, a more thorough understanding of risk factors and genetic predisposition has important implications not only for cancer prevention, but also for screening techniques and the development of personalized therapies. While screening of the general population is not recommended or practicable with current diagnostic methods, studies are ongoing to evaluate its usefulness in people with at least 5- to 10-fold increased risk of PDAC. In order to help identify high-risk populations who would be most likely to benefit from early detection screening tests for pancreatic cancer, discovery of additional pancreatic cancer susceptibility genes is crucial. Thus, specific gene-based, gene-product, and marker-based testing for the early detection of pancreatic cancer are currently being developed, with the potential for these to be useful as potential therapeutic targets as well. The goal of this review is to provide an overview of the genetic basis for PDAC with a focus on germline and familial determinants. A discussion of potential therapeutic targets and future directions in screening and treatment is also provided. PMID:24624093

  1. Fatty acids and their therapeutic potential in neurological disorders.

    PubMed

    Lei, Enie; Vacy, Kristina; Boon, Wah Chin

    2016-05-01

    There is little doubt that we are what we eat. Fatty acid supplementation and diets rich in fatty acids are being promoted as ways to a healthier brain. Short chain fatty acids are a product of intestinal microbiota metabolism of dietary fibre; and their derivatives are used as an anti-convulstant. They demonstrated therapeutic potential in neurodegenerative conditions as HDAC inhibitors; and while the mechanism is not well understood, have been shown to lower amyloid β in Alzheimer's Disease in preclinical studies. Medium chain fatty acids consumed as a mixture in dietary oils can induce ketogenesis without the need for a ketogentic diet. Hence, this has the potential to provide an alternative energy source to prevent neuronal cell death due to lack of glucose. Long chain fatty acids are commonly found in the diet as omega fatty acids. They act as an anti-oxidant protecting neuronal cell membranes from oxidative damage and as an anti-inflammatory mediator in the brain. We review which agents, from each fatty acid class, have the most therapeutic potential for neurological disorders (primarily Alzheimer's disease, Parkinson's disease, Autism Spectrum Disorder as well as possible applications to traumatic brain injury), by discussing what is known about their biological mechanisms from preclinical studies. PMID:26939763

  2. Leveraging biodiversity knowledge for potential phyto-therapeutic applications

    PubMed Central

    Sharma, Vivekanand; Sarkar, Indra Neil

    2013-01-01

    Objective To identify and highlight the feasibility, challenges, and advantages of providing a cross-domain pipeline that can link relevant biodiversity information for phyto-therapeutic assessment. Materials and methods A public repository of clinical trials information (ClinicalTrials.gov) was explored to determine the state of plant-based interventions under investigation. Results The results showed that ∼15% of drug interventions in ClinicalTrials.gov were potentially plant related, with about 60% of them clustered within 10 taxonomic families. Further analysis of these plant-based interventions identified ∼3.7% of associated plant species as endangered as determined from the International Union for the Conservation of Nature Red List. Discussion The diversity of the plant kingdom has provided human civilization with life-sustaining food and medicine for centuries. There has been renewed interest in the investigation of botanicals as sources of new drugs, building on traditional knowledge about plant-based medicines. However, data about the plant-based biodiversity potential for therapeutics (eg, based on genetic or chemical information) are generally scattered across a range of sources and isolated from contemporary pharmacological resources. This study explored the potential to bridge biodiversity and biomedical knowledge sources. Conclusions The findings from this feasibility study suggest that there is an opportunity for developing plant-based drugs and further highlight taxonomic relationships between plants that may be rich sources for bioprospecting. PMID:23518859

  3. Codonopsis lanceolata: A Review of Its Therapeutic Potentials.

    PubMed

    Hossen, Muhammad Jahangir; Kim, Mi-Yeon; Kim, Jong-Hoon; Cho, Jae Youl

    2016-03-01

    Codonopsis lanceolata (Campanulaceae) is dicotyledonous herbaceous perennial plant, predominantly found in Central, East, and South Asia. This plant has been widely used in traditional medicine and is considered to have medicinal properties to treat diseases and symptoms such as bronchitis, coughs, spasm, psychoneurosis, cancer, obesity, hyperlipidemia, edema, hepatitis, colitis, and lung injury. C. lanceolata contains many biologically active compounds, including polyphenols, saponins, tannins, triterpene, alkaloids, and steroids, which contribute to its numerous pharmacological activities. Through systematic studies, the pharmacological actions of these compounds have been revealed. Therapeutic potentialities of C. lanceolata and its previously reported molecular mechanisms are described in this review. PMID:26931614

  4. Antimicrobial Peptides and Their Analogs: Searching for New Potential Therapeutics

    PubMed Central

    Midura-Nowaczek, Krystyna; Markowska, Agnieszka

    2014-01-01

    Antimicrobial peptides (AMPs) are an essential part of innate immunity. These compounds have been considered as potential therapeutics because of their broad-spectrum activities and proven ability to avoid antimicrobial resistance, but their clinical and commercial developments have some limitations, such as susceptibility to proteases and a high cost of peptide production. To overcome these problems, many researchers have tried to develop short active peptides, their modifications and mimics with better properties while retaining their basic features of natural AMPs such as cationic charge and the amphipathic structure. PMID:25374459

  5. Inflammation and hypertension: new understandings and potential therapeutic targets.

    PubMed

    De Miguel, Carmen; Rudemiller, Nathan P; Abais, Justine M; Mattson, David L

    2015-01-01

    Research studying the role of inflammation in hypertension and cardiovascular disease has flourished in recent years; however, the exact mechanisms by which the activated immune cells lead to the development and maintenance of hypertension remain to be elucidated. The objectives of this brief review are to summarize and discuss the most recent findings in the field, with special emphasis on potential therapeutics to treat or prevent hypertension. This review will cover novel immune cell subtypes recently associated to the disease including the novel role of cytokines, toll-like receptors, and inflammasomes in hypertension. PMID:25432899

  6. Hedgehog pathway aberrations and gastric cancer; evaluation of prognostic impact and exploration of therapeutic potentials.

    PubMed

    Abdel-Rahman, Omar

    2015-03-01

    Gastric cancer is an important cause for mortality and morbidity worldwide; it lies in the fourt rank as a cause of cancer-related death in males and in the fifth rank of cancer-related death in women. The prognosis of advanced/metastatic gastric cancer cases looks poor with the majority of available therapeutics. Thus, novel therapeutic strategies in this setting have been considered a priority for leading cooperative oncology groups. Hedgehog(Hh) pathway aberrations have sparked particular interest as prognostic markers with data from multiple studies showing consistent evidence of a poor prognostic value of Gli over expression in gastric cancer while on the other hand the prognostic significance of Hh protein over expression (particularly SHH) was not consistent among different studies. This review article revises the prognostic and potential therapeutic opportunities in the targeting of hedgehog pathway in gastric cancer. PMID:25680409

  7. Delivery of therapeutic radioisotopes using nanoparticle platforms: potential benefit in systemic radiation therapy

    PubMed Central

    Zhang, Longjiang; Chen, Hongwei; Wang, Liya; Liu, Tian; Yeh, Julie; Lu, Guangming; Yang, Lily; Mao, Hui

    2010-01-01

    Radiation therapy is an effective cancer treatment option in conjunction with chemotherapy and surgery. Emerging individualized internal and systemic radiation treatment promises significant improvement in efficacy and reduction of normal tissue damage; however, it requires cancer cell targeting platforms for efficient delivery of radiation sources. With recent advances in nanoscience and nanotechnology, there is great interest in developing nanomaterials as multifunctional carriers to deliver therapeutic radioisotopes for tumor targeted radiation therapy, to monitor their delivery and tumor response to the treatment. This paper provides an overview on developing nanoparticles for carrying and delivering therapeutic radioisotopes for systemic radiation treatment. Topics discussed in the review include: selecting nanoparticles and radiotherapy isotopes, strategies for targeting nanoparticles to cancers, together with challenges and potential solutions for the in vivo delivery of nanoparticles. Some examples of using nanoparticle platforms for the delivery of therapeutic radioisotopes in preclinical studies of cancer treatment are also presented. PMID:24198480

  8. Innovative therapeutic strategies for recessive dystrophic epidermolysis bullosa.

    PubMed

    Larcher, F; Del Río, M

    2015-06-01

    Recessive dystrophic epidermolysis bullosa (RDEB) is among the most serious rare skin diseases. It is also the rare skin disease for which most effort has been expended in developing advanced therapeutic interventions. RDEB is caused by collagen VII deficiency resulting from COL7A1 mutations. Therapeutic approaches seek to replenish collagen VII and thus restore dermal-epidermal adhesion. Therapeutic options under development include protein therapy and different cell-based and gene-based therapies. In addition to treating skin defects, some of these therapies may also target internal mucosa. In the coming years, these novel therapeutic approaches should substantially improve the quality of life of patients with RDEB. PMID:25796272

  9. Apoptotic cell clearance: basic biology and therapeutic potential

    PubMed Central

    Poon, Ivan K. H.; Lucas, Christopher D.

    2014-01-01

    Prompt removal of apoptotic cells by phagocytes is important for maintaining tissue homeostasis. The molecular and cellular events that underpin apoptotic cell recognition and uptake, and the subsequent biological responses are increasingly better defined. The detection and disposal of apoptotic cells generally promote an anti-inflammatory response at the tissue level, as well as immunological tolerance. Consequently, defects in apoptotic cell clearance have been linked with a variety of inflammatory diseases and autoimmunity. Conversely, under certain conditions such as killing tumour cells by specific cell death inducers, the recognition of apoptotic tumour cells can promote an immunogenic response and anti-tumour immunity. Here, we review the current understanding of the complex process of apoptotic cell clearance in physiology and pathology, and discuss how this knowledge could be harnessed for new therapeutic strategies. PMID:24481336

  10. Sphingosine kinase-1--a potential therapeutic target in cancer.

    PubMed

    Cuvillier, Olivier

    2007-02-01

    Sphingolipid metabolites play critical functions in the regulation of a number of fundamental biological processes including cancer. Whereas ceramide and sphingosine mediate and trigger apoptosis or cell growth arrest, sphingosine 1-phosphate promotes proliferation and cell survival. The delicate equilibrium between the intracellular levels of each of these sphingolipids is controlled by the enzymes that either produce or degrade these metabolites. Sphingosine kinase-1 is a crucial regulator of this two-pan balance, because it produces the prosurvival sphingosine 1-phosphate, and reduces the content of both ceramide and sphingosine, the proapoptotic sphingolipids. Sphingosine kinase-1 controls the levels of sphingolipids having opposite effects on cell survival/death, its gene was found to be of oncogenic nature, its mRNA is overexpressed in many solid tumors, its overexpression protects cells from apoptosis and its activity is decreased during anticancer treatments. Therefore, sphingosine kinase-1 appears to be a target of interest for therapeutic manipulation via its pharmacological inhibition. Strategies to kill tumor cells by increasing their ceramide and/or sphingosine content while blocking sphingosine 1-phosphate generation should have a favorable therapeutic index. PMID:17159597

  11. Clinical application: Restoration of immune homeostasis by autophagy as a potential therapeutic target in sepsis

    PubMed Central

    ZHANG, LEMENG; AI, YUHANG; TSUNG, ALLAN

    2016-01-01

    Sepsis-induced lymphocyte and dendritic cell apoptosis contributes to immunosuppression, resulting in an inability to eradicate the primary infection and a propensity to acquire secondary infections. However, the inhibition of apoptosis may produce unexpected and undesirable consequences. Another cellular process, autophagy, is also activated in immune cells. There is increasing evidence to suggest that autophagy confers a protective effect in sepsis. The protective mechanisms underlying this effect include limiting apoptotic cell death and maintaining cellular homeostasis. Therefore, understanding the regulation of immune cell autophagy and apoptosis may provide insight into novel therapeutic strategies. The present review examined potential novel therapeutic strategies aimed at restoring immune homeostasis by inducing autophagy. The restoration of balance between apoptosis and autophagy may be a novel approach for improving sepsis-induced immunosuppression and decreasing susceptibility to sepsis. PMID:27073416

  12. Exploring the Potential of Monoclonal Antibody Therapeutics for HIV-1 Eradication

    PubMed Central

    Euler, Zelda

    2015-01-01

    Abstract The HIV field has seen an increased interest in novel cure strategies. In particular, new latency reversal agents are in development to reverse latency to flush the virus out of its hiding place. Combining these efforts with immunotherapeutic approaches may not only drive the virus out of latency, but allow for the rapid elimination of these infected cells in a “shock and kill” approach. Beyond cell-based approaches, growing interest lies in the potential use of functionally enhanced “killer” monoclonal therapeutics to purge the reservoir. Here we discuss prospects for a monoclonal therapeutic-based “shock and kill” strategy that may lead to the permanent elimination of replication-competent virus, making a functional cure a reality for all patients afflicted with HIV worldwide. PMID:25385703

  13. Role of advanced glycation endproducts and potential therapeutic interventions in dialysis patients.

    PubMed

    Mallipattu, Sandeep K; He, John C; Uribarri, Jaime

    2012-01-01

    It has been nearly 100 years since the first published report of advanced glycation end products (AGEs) by the French chemist Maillard. Since then, our understanding of AGEs in diseased states has dramatically changed. Especially in the last 25 years, AGEs have been implicated in complications related to aging, neurodegenerative diseases, diabetes, and chronic kidney disease. Although AGE formation has been well characterized by both in vitro and in vivo studies, few prospective human studies exist demonstrating the role of AGEs in patients on chronic renal replacement therapy. As the prevalence of end-stage renal disease (ESRD) in the United States rises, it is essential to identify therapeutic strategies that either delay progression to ESRD or improve morbidity and mortality in this population. This article reviews the role of AGEs, especially those of dietary origin, in ESRD patients as well as potential therapeutic anti-AGE strategies in this population. PMID:22548330

  14. The evolution strategy--a search strategy used in individual optimization of electrical parameters for therapeutic carotid sinus nerve stimulation.

    PubMed

    Peters, T K; Koralewski, H E; Zerbst, E W

    1989-07-01

    Optimization problems, arising in the search for parameters and/or techniques of functional electrostimulation (FES), disproportionally increase when multiple electrodes, electrode configurations, electrical parameters, and stimulation modes may be applied. When computational or investigational effort precludes systematic studies in FES, we propose to apply and evaluate Rechenberg's evolution strategy, which in technical use and numerical optimization has been valid in comparison to more traditional methods. This strategy implements mutation and selection processes in analogy to biological evolution. The effect of combined multiple input variables on a quality function (Q) is experimentally evaluated. The actual computed value of Q serves as a selection criterion for those input variable combinations which lead Q to approach a target value (maximization), similar to a hill-climbing procedure. In radiofrequency controlled, therapeutic electrical carotid sinus nerve stimulation (CSNS), we varied (mutated) combinations of pulse frequency and pulse amplitude parameters, according to the evolution strategy, in individual patients. CSNS lowers blood pressure and decreases heart rate. Q was computed from blood pressure and heart rate responses to CSNS. The strategy individually optimized electrical parameters to achieve large depressor responses upon CSNS. Although, in contrast to technical usage, only two input variables were investigated, and biomedical experience with the evolution strategy is limited so far, its potential use in other fields of FES, especially when more input variables are to be optimized, is discussed and encouraged. PMID:2787277

  15. Adult stem cells: the therapeutic potential of skeletal muscle.

    PubMed

    Saini, Amarjit; Stewart, Claire E H

    2006-05-01

    Embryonic stem cells have revolutionised our understanding of normal and deregulated growth and development. The potential to produce cells and tissues as needed offers enormous therapeutic potential. The use of these cells, however, is accompanied by ongoing ethical, religious and biomedical issues. The expansion potential and plasticity of adult stem cells have therefore received much interest. Adult skeletal muscle is highly adaptable, responding to both the hypertrophic and degenerative stresses placed upon it. This extreme plasticity is in part regulated by resident stem cells. In addition to regenerating muscle, if exposed to osteogenic or adipogenic inducers, these cells spontaneously form osteoblasts or adipocytes. The potential for and heterogeneity of muscle stem cells is underscored by the observation that CD45+ muscle side population cells are capable of reconstituting bone marrow in lethally irradiated mice and of contributing to neo-vascularisation of regenerating muscle. Finally, first attempts to replace infarcted myocardium relied on injection of skeletal myoblasts into the heart. Cells successfully engrafted and cardiac function was improved. Harnessing their differentiation/trans-differentiation capacity provides enormous potential for adult stem cells. In this review, current understanding of the different stem cells within muscle will be discussed as will their potential utility for regenerative medicine. PMID:18220864

  16. Glutamate carboxypeptidase II (NAALADase) inhibition as a novel therapeutic strategy.

    PubMed

    Thomas, Ajit G; Wozniak, Krystyna M; Tsukamoto, Takashi; Calvin, David; Wu, Ying; Rojas, Camilo; Vornov, James; Slusher, Barbara S

    2006-01-01

    GCP II inhibition decreases extracellular excitotoxic glutamate and increases extracellular NAAG, both of which provide neuroprotection. We have demonstrated with our potent and selective GCP II inhibitors efficacy in models of stroke, ALS and neuropathic pain. GCP II inhibition may have significant potential benefits over existing glutamate-based neuroprotection strategies. The upstream mechanism seems selective for excitotoxic induced glutamate release, as GCP II inhibitors in normal animals induced no change in basal glutamate. This suggestion has recently been corroborated by Lieberman and coworkers24 who found that both NAAG release and increase in GCP II activity appear to be induced by electrical stimulation in crayfish nerve fibers and that subsequent NAAG hydrolysis to glutamate contributes, at least in part, to subsequent NMDA receptor activation. Interestingly, even at relatively high doses of compounds, GCP II inhibition did not appear to be associated with learning/memory deficits in animals. Additionally, quantitative neurophysiological testing data and visual analog scales for 'psychedelic effects' in Phase I single dose and repeat dose studies showed GCP II inhibition to be safe and well tolerated by both healthy volunteers and diabetic patients. GCP II inhibition may represent a novel glutamate regulating strategy devoid of the side effects that have hampered the development of postsynaptic glutamate receptor antagonists. PMID:16802724

  17. Gadolinium oxide nanoparticles as potential multimodal imaging and therapeutic agents.

    PubMed

    Kim, Tae Jeong; Chae, Kwon Seok; Chang, Yongmin; Lee, Gang Ho

    2013-01-01

    Potentials of hydrophilic and biocompatible ligand coated gadolinium oxide nanoparticles as multimodal imaging agents, drug carriers, and therapeutic agents are reviewed. First of all, they can be used as advanced T1 magnetic resonance imaging (MRI) contrast agents because they have r1 larger than those of Gd(III)-chelates due to a high density of Gd(III) per nanoparticle. They can be further functionalized by conjugating other imaging agents such as fluorescent imaging (FI), X-ray computed tomography (CT), positron emission tomography (PET), and single photon emission tomography (SPECT) agents. They can be also useful for drug carriers through morphology modifications. They themselves are also potential CT and ultrasound imaging (USI) contrast and thermal neutron capture therapeutic (NCT) agents, which are superior to commercial iodine compounds, air-filled albumin microspheres, and boron ((10)B) compounds, respectively. They, when conjugated with targeting agents such as antibodies and peptides, will provide enhanced images and be also very useful for diagnosis and therapy of diseases (so called theragnosis). PMID:23432005

  18. Leptin, ghrelin, and endocannabinoids: potential therapeutic targets in anorexia nervosa.

    PubMed

    Støving, René Klinkby; Andries, Alin; Brixen, Kim; Flyvbjerg, Allan; Hørder, Kirsten; Frystyk, Jan

    2009-04-01

    Anorexia nervosa (AN) has the highest mortality rate between psychiatric disorders, and evidence for managing it is still very limited. So far, pharmacological treatment has focused on a narrow range of drugs and only a few controlled studies have been performed. Furthermore, the studies have been of short duration and included a limited number of subjects, often heterogenic with regard to stage and acute nutritive status. Thus, novel approaches are urgently needed. Body weight homeostasis is tightly regulated throughout life. With the discovery of orexigenic and anorectic signals, an array of new molecular targets to control eating behavior has emerged. This review focuses on recent advances in three important signal systems: leptin, ghrelin, and endocannabinoids toward the identification of potential therapeutical breakthroughs in AN. Our review of the current literature shows that leptin may have therapeutic potentials in promoting restoration of menstrual cycles in weight restored patients, reducing motor restlessness in severely hyperactive patients, and preventing osteoporosis in chronic patients. Ghrelin and endocannabinoids exert orexigenic effects which may facilitate nutritional restoration. Leptin and endocannabinoids may exert antidepressive and anxiolytic effects. Finally, monitoring serum concentration of leptin may be useful in order to prevent refeeding syndrome. PMID:18926548

  19. Therapeutic Potential of Steroidal Alkaloids in Cancer and Other Diseases.

    PubMed

    Jiang, Qi-Wei; Chen, Mei-Wan; Cheng, Ke-Jun; Yu, Pei-Zhong; Wei, Xing; Shi, Zhi

    2016-01-01

    Steroidal alkaloids are a class of secondary metabolites isolated from plants, amphibians, and marine invertebrates. Evidence accumulated in the recent two decades demonstrates that steroidal alkaloids have a wide range of bioactivities including anticancer, antimicrobial, anti-inflammatory, antinociceptive, etc., suggesting their great potential for application. It is therefore necessary to comprehensively summarize the bioactivities, especially anticancer activities and mechanisms of steroidal alkaloids. Here we systematically highlight the anticancer profiles both in vitro and in vivo of steroidal alkaloids such as dendrogenin, solanidine, solasodine, tomatidine, cyclopamine, and their derivatives. Furthermore, other bioactivities of steroidal alkaloids are also discussed. The integrated molecular mechanisms in this review can increase our understanding on the utilization of steroidal alkaloids and contribute to the development of new drug candidates. Although the therapeutic potentials of steroidal alkaloids look promising in the preclinical and clinical studies, further pharmacokinetic and clinical studies are mandated to define their efficacy and safety in cancer and other diseases. PMID:25820039

  20. Therapeutic Potential of 5-HT6 Receptor Agonists.

    PubMed

    Karila, Delphine; Freret, Thomas; Bouet, Valentine; Boulouard, Michel; Dallemagne, Patrick; Rochais, Christophe

    2015-10-22

    Given its predominant expression in the central nervous system (CNS), 5-hydroxytryptamine (5-HT: serotonin) subtype 6 receptor (5-HT6R) has been considered as a valuable target for the development of CNS drugs with limited side effects. After 2 decades of intense research, numerous selective ligands have been developed to target this receptor; this holds potential interest for the treatment of neuropathological disorders. In fact, some agents (mainly antagonists) are currently undergoing clinical trial. More recently, a series of potent and selective agonists have been developed, and preclinical studies have been conducted that suggest the therapeutic interest of 5-HT6R agonists. This review details the medicinal chemistry of these agonists, highlights their activities, and discusses their potential for treating cognitive issues associated with Alzheimer's disease (AD), depression, or obesity. Surprisingly, some studies have shown that both 5-HT6R agonists and antagonists exert similar procognitive activities. This article summarizes the hypotheses that could explain this paradox. PMID:26099069

  1. Therapeutic potential and health benefits of Sargassum species

    PubMed Central

    Yende, Subhash R.; Harle, Uday N.; Chaugule, Bhupal B.

    2014-01-01

    Sargassum species are tropical and sub-tropical brown macroalgae (seaweed) of shallow marine meadow. These are nutritious and rich source of bioactive compounds such as vitamins, carotenoids, dietary fibers, proteins, and minerals. Also, many biologically active compounds like terpenoids, flavonoids, sterols, sulfated polysaccharides, polyphenols, sargaquinoic acids, sargachromenol, pheophytine were isolated from different Sargassum species. These isolated compounds exhibit diverse biological activities like analgesic, anti-inflammatory, antioxidant, neuroprotective, anti-microbial, anti-tumor, fibrinolytic, immune-modulatory, anti-coagulant, hepatoprotective, anti-viral activity etc., Hence, Sargassum species have great potential to be used in pharmaceutical and neutralceutical areas. This review paper explores the current knowledge of phytochemical, therapeutic potential, and health benefits of different species of genus Sargassum. PMID:24600190

  2. Retinopathy of Prematurity: Therapeutic Strategies Based on Pathophysiology.

    PubMed

    Cayabyab, Rowena; Ramanathan, Rangasamy

    2016-01-01

    retinal detachment. Long-term complications such as refractory errors, recurrence of ROP and risk of retinal detachment require continued follow-up with an ophthalmologist through adolescence and beyond. Optimal nutrition including adequate intake of omega-3 polyunsaturated fatty acids and decreasing infection/inflammation to promote normal vascularization are important strategies. Screening guidelines for ROP based on local incidence of ROP in different regions of the world are very important. Oxygen therapy is clearly a modifiable risk factor to decrease ROP that needs further study. Understanding the two phases of ROP will help to identify appropriate therapeutic strategies and improve visual outcomes in many preterm infants globally. PMID:27251645

  3. Therapeutic potential of targeting acinar cell reprogramming in pancreatic cancer

    PubMed Central

    Wong, Chi-Hin; Li, You-Jia; Chen, Yang-Chao

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is a common pancreatic cancer and the fourth leading cause of cancer death in the United States. Treating this life-threatening disease remains challenging due to the lack of effective prognosis, diagnosis and therapy. Apart from pancreatic duct cells, acinar cells may also be the origin of PDAC. During pancreatitis or combined with activating KRasG12D mutation, acinar cells lose their cellular identity and undergo a transdifferentiation process called acinar-to-ductal-metaplasia (ADM), forming duct cells which may then transform into pancreatic intraepithelial neoplasia (PanIN) and eventually PDAC. During ADM, the activation of mitogen-activated protein kinases, Wnt, Notch and phosphatidylinositide 3-kinases/Akt signaling inhibits the transcription of acinar-specific genes, including Mist and amylase, but promotes the expression of ductal genes, such as cytokeratin-19. Inhibition of this transdifferentiation process hinders the development of PanIN and PDAC. In addition, the transdifferentiated cells regain acinar identity, indicating ADM may be a reversible process. This provides a new therapeutic direction in treating PDAC through cancer reprogramming. Many studies have already demonstrated the success of switching PanIN/PDAC back to normal cells through the use of PD325901, the expression of E47, and the knockdown of Dickkopf-3. In this review, we discuss the signaling pathways involved in ADM and the therapeutic potential of targeting reprogramming in order to treat PDAC. PMID:27610015

  4. Cell migration in paediatric glioma; characterisation and potential therapeutic targeting

    PubMed Central

    Cockle, J V; Picton, S; Levesley, J; Ilett, E; Carcaboso, A M; Short, S; Steel, L P; Melcher, A; Lawler, S E; Brüning-Richardson, A

    2015-01-01

    Background: Paediatric high grade glioma (pHGG) and diffuse intrinsic pontine glioma (DIPG) are highly aggressive brain tumours. Their invasive phenotype contributes to their limited therapeutic response, and novel treatments that block brain tumour invasion are needed. Methods: Here, we examine the migratory characteristics and treatment effect of small molecule glycogen synthase kinase-3 inhibitors, lithium chloride (LiCl) and the indirubin derivative 6-bromoindirubin-oxime (BIO), previously shown to inhibit the migration of adult glioma cells, on two pHGG cell lines (SF188 and KNS42) and one patient-derived DIPG line (HSJD-DIPG-007) using 2D (transwell membrane, immunofluorescence, live cell imaging) and 3D (migration on nanofibre plates and spheroid invasion in collagen) assays. Results: All lines were migratory, but there were differences in morphology and migration rates. Both LiCl and BIO reduced migration and instigated cytoskeletal rearrangement of stress fibres and focal adhesions when viewed by immunofluorescence. In the presence of drugs, loss of polarity and differences in cellular movement were observed by live cell imaging. Conclusions: Ours is the first study to demonstrate that it is possible to pharmacologically target migration of paediatric glioma in vitro using LiCl and BIO, and we conclude that these agents and their derivatives warrant further preclinical investigation as potential anti-migratory therapeutics for these devastating tumours. PMID:25628092

  5. Superoxide Dismutase Mimics: Chemistry, Pharmacology, and Therapeutic Potential

    PubMed Central

    Rebouças, Júlio S.; Spasojević, Ivan

    2010-01-01

    Abstract Oxidative stress has become widely viewed as an underlying condition in a number of diseases, such as ischemia–reperfusion disorders, central nervous system disorders, cardiovascular conditions, cancer, and diabetes. Thus, natural and synthetic antioxidants have been actively sought. Superoxide dismutase is a first line of defense against oxidative stress under physiological and pathological conditions. Therefore, the development of therapeutics aimed at mimicking superoxide dismutase was a natural maneuver. Metalloporphyrins, as well as Mn cyclic polyamines, Mn salen derivatives and nitroxides were all originally developed as SOD mimics. The same thermodynamic and electrostatic properties that make them potent SOD mimics may allow them to reduce other reactive species such as peroxynitrite, peroxynitrite-derived CO3·−, peroxyl radical, and less efficiently H2O2. By doing so SOD mimics can decrease both primary and secondary oxidative events, the latter arising from the inhibition of cellular transcriptional activity. To better judge the therapeutic potential and the advantage of one over the other type of compound, comparative studies of different classes of drugs in the same cellular and/or animal models are needed. We here provide a comprehensive overview of the chemical properties and some in vivo effects observed with various classes of compounds with a special emphasis on porphyrin-based compounds. Antioxid. Redox Signal. 13, 877–918. PMID:20095865

  6. Vitamin D: preventive and therapeutic potential in Parkinson's disease.

    PubMed

    Liu, Yan; Li, Yan-Wu; Tang, Ya-Lan; Liu, Xin; Jiang, Jun-Hao; Li, Qing-Gen; Yuan, Jian-Yong

    2013-11-01

    Vitamin D is one of the important nuclear steroid transcription regulators that controls transcriptions of a large number of genes. Vitamin D supplement is commonly recommended for the elderly to prevent bone diseases. Amounting new evidence has indicated that vitamin D plays a crucial role in brain development, brain function regulation and neuroprotection. Parkinson's disease (PD) is a degenerative disorder commonly seen in the elderly, characterized by movement disorders including tremor, akinesia, and loss of postural reflexes. The motor symptoms largely result from the continued death of dopaminergic neurons in the substantia nigra, despite use of current therapeutic interventions. The cause and mechanism of neuron death is currently unknown. Vitamin D deficiency is common in patients with PD suggesting its preventive and therapeutic potential. Vitamin D may exert protective and neurotropic effects directly at cellular level, e.g. protection of dopamine system, and/or by regulating gene expression. This review summarizes the epidemiological, genetic and translational evidence implicating vitamin D as a candidate for prevention and treatment for PD. PMID:24160295

  7. Melanocyte Stem Cells as Potential Therapeutics in Skin Disorders

    PubMed Central

    Lee, Ju Hee; Fisher, David E.

    2015-01-01

    Introduction Melanocytes produce pigment granules that color both skin and hair. In the hair follicles melanocytes are derived from stem cells (MelSC) that are present in hair bulges or sub-bulge regions and function as melanocyte reservoirs. Quiescence, maintenance, activation, and proliferation of MelSC are controlled by specific activities in the microenvironment that can influence the differentiation and regeneration of melanocytes. Therefore, understanding MelSC and their niche may lead to use of MelSC in new treatments for various pigmentation disorders. Areas covered We describe here pathophysiological mechanisms by which melanocyte defects lead to skin pigmentation disorders such as vitiligo and hair graying. The development, migration, and proliferation of melanocytes and factors involved in the survival, maintenance, and regeneration of MelSC are reviewed with regard to the biological roles and potential therapeutic applications in skin pigmentation diseases. Expert Opinion MelSC biology and niche factors have been studied mainly in murine experimental models. Human MelSC markers or methods to isolate them are much less well understood. Identification, isolation and culturing of human MelSC would represent a major step toward new biological therapeutic options for patients with recalcitrant pigmentary disorders or hair graying. By modulating the niche factors for MelSC it may one day be possible to control skin pigmentary disorders and prevent or reverse hair graying. PMID:25104310

  8. Biochemistry and therapeutic potential of hydrogen sulfide - reality or fantasy?

    PubMed

    Brodek, Paulina; Olas, Beata

    2016-01-01

    Hydrogen sulfide (H2S) is a signaling gasotransmitter, involved in different physiological and pathological processes. H2S regulates apoptosis, the cell cycle and oxidative stress. H2S exerts powerful effects on smooth muscle cells, endothelial cells, inflammatory cells, endoplasmic reticulum, mitochondria and nuclear transcription factors. H2S is known to be produced from L-cysteine, D-cysteine and L-homocysteine in the body. Four enzymes - cystathionine-b synthase (CBS), mercaptopyruvate sulfurtransferase (3-MST), cystathionine-γ lyase (CSE) and cysteine aminotransferase (CAT) - are involved in H2S synthesis. The biosynthetic pathway for the production of H2S from D-cysteine involves 3-MST and D-amino acid oxidase (DAO). The therapeutic potential of H2S is not clear. However, recently results have demonstrated that H2S has protective action for ischemic heart disease or hypertension, and protects against ischemia of the brain. This review summarizes the negative and the positive roles of H2S in various biological systems, for example the cardiovascular system and nervous system. We also discuss the function of classical, therapeutic and natural (for example garlic) donors of H2S in pre-clinical and clinical studies. PMID:27516569

  9. Zinc is a potential therapeutic for chemoresistant ovarian cancer.

    PubMed

    Bastow, Max; Kriedt, Christopher L; Baldassare, Joseph; Shah, Maulik; Klein, Claudette

    2011-01-01

    Ovarian cancer is the leading cause of death from gynecological cancer. The high mortality rate reflets the lack of early diagnosis and limited treatment alternatives. We have observed a number of properties of zinc cytotoxicity that make it attractive from a therapeutic standpoint. Using SKOV3 and ES2 cells, ovarian cancer cell lines that demonstrate varied degrees of resistance to known therapeutics, we show that zinc killing is time and concentration dependent. Death is preceded by distinct changes in cell shape and size. The effects of zinc are additive with cisplatin or doxorubicin, whose morphological effects are distinct from those of zinc. Cytotoxicity of paclitaxel is minimal, making it difficult to determine additivity with zinc. Paclitaxel results in changes in cell shape and size similar to those of zinc but has different effects on cell cycle progression and cyclin expression. The data indicate that the means by which zinc kills ovarian cancer cells is distinct from currently used chemotherapeutics. Based on the properties reported here, zinc has the potential to be developed as either a primary treatment or as a second line of defense against cancers that have developed resistance to currently used chemotherapeutics. PMID:22070048

  10. Therapeutic potential of targeting acinar cell reprogramming in pancreatic cancer.

    PubMed

    Wong, Chi-Hin; Li, You-Jia; Chen, Yang-Chao

    2016-08-21

    Pancreatic ductal adenocarcinoma (PDAC) is a common pancreatic cancer and the fourth leading cause of cancer death in the United States. Treating this life-threatening disease remains challenging due to the lack of effective prognosis, diagnosis and therapy. Apart from pancreatic duct cells, acinar cells may also be the origin of PDAC. During pancreatitis or combined with activating KRas(G12D) mutation, acinar cells lose their cellular identity and undergo a transdifferentiation process called acinar-to-ductal-metaplasia (ADM), forming duct cells which may then transform into pancreatic intraepithelial neoplasia (PanIN) and eventually PDAC. During ADM, the activation of mitogen-activated protein kinases, Wnt, Notch and phosphatidylinositide 3-kinases/Akt signaling inhibits the transcription of acinar-specific genes, including Mist and amylase, but promotes the expression of ductal genes, such as cytokeratin-19. Inhibition of this transdifferentiation process hinders the development of PanIN and PDAC. In addition, the transdifferentiated cells regain acinar identity, indicating ADM may be a reversible process. This provides a new therapeutic direction in treating PDAC through cancer reprogramming. Many studies have already demonstrated the success of switching PanIN/PDAC back to normal cells through the use of PD325901, the expression of E47, and the knockdown of Dickkopf-3. In this review, we discuss the signaling pathways involved in ADM and the therapeutic potential of targeting reprogramming in order to treat PDAC. PMID:27610015

  11. Selection, design, and characterization of a new potentially therapeutic ribozyme.

    PubMed Central

    Zinnen, Shawn P; Domenico, Kristal; Wilson, Mike; Dickinson, Brent A; Beaudry, Amber; Mokler, Victor; Daniher, Andrew T; Burgin, Alex; Beigelman, Leonid

    2002-01-01

    An in vitro selection was designed to identify RNA-cleaving ribozymes predisposed for function as a drug. The selection scheme required the catalyst to be trans-acting with phosphodiesterase activity targeting a fragment of the Kras mRNA under simulated physiological conditions. To increase stabilization against nucleases and to offer the potential for improved functionality, modified sequence space was sampled by transcribing with the following NTPs: 2'-F-ATP, 2'-F-UTP, or 2'-F-5-[(N-imidazole-4-acetyl) propylamine]-UTP, 2'-NH2-CTP, and GTP. Active motifs were identified and assessed for their modified NMP and divalent metal dependence. The minimization of the ribozyme's size and the ability to substitute 2'-OMe for 2'-F and 2'-NH2 moieties yielded the motif from these selections most suited for both nuclease stability and therapeutic development. This motif requires only two 2'-NH2-Cs and functions as a 36-mer. Its substrate sequence requirements were determined to be 5'-Y-G-H-3'. Its half-life in human serum is >100 h. In physiologically relevant magnesium concentrations [approximately 1 mM] its kcat = 0.07 min(-1), Km = 70 nM. This report presents a novel nuclease stable ribozyme, designated Zinzyme, possessing optimal activity in simulated physiological conditions and ready for testing in a therapeutic setting. PMID:11911367

  12. Neutral endopeptidase inhibition and the natriuretic peptide system: an evolving strategy in cardiovascular therapeutics

    PubMed Central

    Mangiafico, Sarah; Costello-Boerrigter, Lisa C.; Andersen, Ingrid A.; Cataliotti, Alessandro; Burnett, John C.

    2013-01-01

    Hypertension and heart failure (HF) are common diseases that, despite advances in medical therapy, continue to be associated with high morbidity and mortality. Therefore, innovative therapeutic strategies are needed. Inhibition of the neutral endopeptidase (NEPinh) had been investigated as a potential novel therapeutic approach because of its ability to increase the plasma concentrations of the natriuretic peptides (NPs). Indeed, the NPs have potent natriuretic and vasodilator properties, inhibit the activity of the renin–angiotensin–aldosterone system, lower sympathetic drive, and have antiproliferative and antihypertrophic effects. Such potentially beneficial effects can be theoretically achieved by the use of NEPinh. However, studies have shown that NEPinh alone does not result in clinically meaningful blood pressure-lowering actions. More recently, NEPinh has been used in combination with other cardiovascular agents, such as angiotensin-converting enzyme inhibitors, and antagonists of the angiotensin receptor. Another future possible combination would be the use of NEPinh with NPs or their newly developed chimeric peptides. This review summarizes the current knowledge of the use and effects of NEPinh alone or in combination with other therapeutic agents for the treatment of human cardiovascular disease such as HF and hypertension. PMID:22942338

  13. Hepatic macrophages in liver fibrosis: pathogenesis and potential therapeutic targets

    PubMed Central

    Li, Hai; You, Hong; Fan, Xu; Jia, Jidong

    2016-01-01

    Hepatic macrophages account for the largest non-parenchymal cell population in the liver. Recent studies have found that hepatic macrophages have different functions in different stages of experimental liver fibrosis. Some studies found that there are different types of hepatic macrophages in the liver, although others have suggested that hepatic macrophages could switch to different phenotypes in different environments. Many studies demonstrated that while hepatic macrophages promoted fibrosis through the recruitment of proinflammatory immune cells, and the secretion of proinflammatory cytokines and chemokines in the early stages, these also promoted the resolution of hepatic fibrosis through the secretion of matrix metalloproteinases in the late stages. This article will review the current role played by hepatic macrophages in liver fibrosis and the potential therapeutic targets that modulate hepatic macrophages. PMID:27252881

  14. Functions of astrocytes and their potential as therapeutic targets

    PubMed Central

    Kimelberg, Harold K.; Nedergaard, Maiken

    2010-01-01

    Astrocytes are often referred to, and historically have been regarded as, support cells of the mammalian CNS. Work over the last decade suggests otherwise, that astrocytes may in fact play a more active role in higher neural processing than previously recognized. Because astrocytes can potentially serve as novel therapeutic targets, it is critical to understand how astrocytes execute their diverse supportive tasks while maintaining neuronal health. To that end, this review will focus on the supportive roles of astrocytes, a line of study relevant to essentially all acute and chronic neurological diseases. Furthermore, this review will critically re-evaluate our concepts of the functional properties of astrocytes and relate these tasks to their intricate morphology. PMID:20880499

  15. Revisiting Metal Toxicity in Neurodegenerative Diseases and Stroke: Therapeutic Potential

    PubMed Central

    Mitra, Joy; Vasquez, Velmarini; Hegde, Pavana M; Boldogh, Istvan; Mitra, Sankar; Kent, Thomas A; Rao, Kosagi S; Hegde, Muralidhar L

    2015-01-01

    Excessive accumulation of pro-oxidant metals, observed in affected brain regions, has consistently been implicated as a contributor to the brain pathology including neurodegenerative diseases and acute injuries such as stroke. Furthermore, the potential interactions between metal toxicity and other commonly associated etiological factors, such as misfolding/aggregation of amyloidogenic proteins or genomic damage, are poorly understood. Decades of research provide compelling evidence implicating metal overload in neurological diseases and stroke. However, the utility of metal toxicity as a therapeutic target is controversial, possibly due to a lack of comprehensive understanding of metal dyshomeostasis-mediated neuronal pathology. In this article, we discuss the current understanding of metal toxicity and the challenges associated with metal-targeted therapies. PMID:25717476

  16. The preventive and therapeutic potential of natural polyphenols on influenza.

    PubMed

    Bahramsoltani, Roodabeh; Sodagari, Hamid Reza; Farzaei, Mohammad Hosein; Abdolghaffari, Amir Hossein; Gooshe, Maziar; Rezaei, Nima

    2016-01-01

    Influenza virus belongs to orthomyxoviridae family. This virus is a major public health problems, with high rates of morbidity and mortality. Despite a wide range of pharmacotherapeutic choices inhibiting specific sequences of pathological process of influenza, developing more effective therapeutic options is an immediate challenge. In this paper, a comprehensively review of natural polyphenolic products used worldwide for the management of influenza infection is presented. Cellular and molecular mechanisms of the natural polyphenols on influenza infection including suppressing virus replication cycle, viral hemagglutination, viral adhesion and penetration into the host cells, also intracellular transductional signaling pathways have been discussed in detail. Based on cellular, animal, and human evidence obtained from several studies, the current paper demonstrates that natural polyphenolic compounds possess potential effects on both prevention and treatment of influenza, which can be used as adjuvant therapy with conventional chemical drugs for the management of influenza and its complications. PMID:26567957

  17. Vitamin D: Implications for Ocular Disease and Therapeutic Potential

    PubMed Central

    Reins, Rose Y.; McDermott, Alison M.

    2015-01-01

    Vitamin D is a multifunctional hormone that is now known to play a significant role in a variety of biological functions in addition to its traditional role in regulating calcium homeostasis. There are a large number of studies demonstrating that adequate vitamin D levels are important in maintaining health and show that vitamin D is able to be utilized at local tissue sites. In the eye, we have increasing evidence of the association between disease and vitamin D. In this narrative review, we summarize recent findings on vitamin D and its relationship to various ocular pathologies and the therapeutic potential for some of these, as well as examine the basic science studies that demonstrate that vitamin D is biologically relevant in the eye. PMID:25724179

  18. High therapeutic potential of Spilanthes acmella: A review

    PubMed Central

    Prachayasittikul, Veda; Prachayasittikul, Supaluk; Ruchirawat, Somsak; Prachayasittikul, Virapong

    2013-01-01

    Spilanthes acmella, a well known antitoothache plant with high medicinal usages, has been recognized as an important medicinal plant and has an increasingly high demand worldwide. From its traditional uses in health care and food, extensive phytochemical studies have been reported. This review provides an overview and general description of the plant species, bioactive metabolites and important pharmacological activities including the preparation, purification and in vitro large-scale production. Structure-activity relationships of the bioactive compounds have been discussed. Considering data from the literature, it could be demonstrated that S. acmella possesses diverse bioactive properties and immense utilization in medicine, health care, cosmetics and as health supplements. As a health food, it is enriched with high therapeutic value with high potential for further development. PMID:27092032

  19. Health Promoting Schools: Consensus, Strategies, and Potential

    ERIC Educational Resources Information Center

    Macnab, Andrew J.; Gagnon, Faith A.; Stewart, Donald

    2014-01-01

    Purpose: The purpose of this paper is to summarize a consensus statement generated on the current challenges, strategies, and potential of health promoting schools (HPS) at a 2011 colloquium at the Stellenbosch Institute for Advanced Study where 40 people from five continents came together to share their global and regional experience surrounding…

  20. The potential therapeutic effects of THC on Alzheimer's disease.

    PubMed

    Cao, Chuanhai; Li, Yaqiong; Liu, Hui; Bai, Ge; Mayl, Jonathan; Lin, Xiaoyang; Sutherland, Kyle; Nabar, Neel; Cai, Jianfeng

    2014-01-01

    The purpose of this study was to investigate the potential therapeutic qualities of Δ9-tetrahydrocannabinol (THC) with respect to slowing or halting the hallmark characteristics of Alzheimer's disease. N2a-variant amyloid-β protein precursor (AβPP) cells were incubated with THC and assayed for amyloid-β (Aβ) levels at the 6-, 24-, and 48-hour time marks. THC was also tested for synergy with caffeine, in respect to the reduction of the Aβ level in N2a/AβPPswe cells. THC was also tested to determine if multiple treatments were beneficial. The MTT assay was performed to test the toxicity of THC. Thioflavin T assays and western blots were performed to test the direct anti-Aβ aggregation significance of THC. Lastly, THC was tested to determine its effects on glycogen synthase kinase-3β (GSK-3β) and related signaling pathways. From the results, we have discovered THC to be effective at lowering Aβ levels in N2a/AβPPswe cells at extremely low concentrations in a dose-dependent manner. However, no additive effect was found by combining caffeine and THC together. We did discover that THC directly interacts with Aβ peptide, thereby inhibiting aggregation. Furthermore, THC was effective at lowering both total GSK-3β levels and phosphorylated GSK-3β in a dose-dependent manner at low concentrations. At the treatment concentrations, no toxicity was observed and the CB1 receptor was not significantly upregulated. Additionally, low doses of THC can enhance mitochondria function and does not inhibit melatonin's enhancement of mitochondria function. These sets of data strongly suggest that THC could be a potential therapeutic treatment option for Alzheimer's disease through multiple functions and pathways. PMID:25024327

  1. Therapeutic potential of intermittent hypoxia: a matter of dose

    PubMed Central

    Navarrete-Opazo, Angela

    2014-01-01

    Intermittent hypoxia (IH) has been the subject of considerable research in recent years, and triggers a bewildering array of both detrimental and beneficial effects in multiple physiological systems. Here, we review the extensive literature concerning IH and its impact on the respiratory, cardiovascular, immune, metabolic, bone, and nervous systems. One major goal is to define relevant IH characteristics leading to safe, protective, and/or therapeutic effects vs. pathogenesis. To understand the impact of IH, it is essential to define critical characteristics of the IH protocol under investigation, including potentially the severity of hypoxia within episodes, the duration of hypoxic episodes, the number of hypoxic episodes per day, the pattern of presentation across time (e.g., within vs. consecutive vs. alternating days), and the cumulative time of exposure. Not surprisingly, severe/chronic IH protocols tend to be pathogenic, whereas any beneficial effects are more likely to arise from modest/acute IH exposures. Features of the IH protocol most highly associated with beneficial vs. pathogenic outcomes include the level of hypoxemia within episodes and the number of episodes per day. Modest hypoxia (9–16% inspired O2) and low cycle numbers (3–15 episodes per day) most often lead to beneficial effects without pathology, whereas severe hypoxia (2–8% inspired O2) and more episodes per day (48–2,400 episodes/day) elicit progressively greater pathology. Accumulating evidence suggests that “low dose” IH (modest hypoxia, few episodes) may be a simple, safe, and effective treatment with considerable therapeutic potential for multiple clinical disorders. PMID:25231353

  2. Drug delivery strategies for therapeutic angiogenesis and antiangiogenesis

    PubMed Central

    Bhise, Nupura S; Shmueli, Ron B; Sunshine, Joel C; Tzeng, Stephany Y; Green, Jordan J

    2014-01-01

    Introduction Angiogenesis is essential to human biology and of great clinical significance. Excessive or reduced angiogenesis can result in, or exacerbate, several disease states, including tumor formation, exudative age-related macular degeneration (AMD) and ischemia. Innovative drug delivery systems can increase the effectiveness of therapies used to treat angiogenesis-related diseases. Areas covered This paper reviews the basic biology of angiogenesis, including current knowledge about its disruption in diseases, with the focus on cancer and AMD. Anti- and proangiogenic drugs available for clinical use or in development are also discussed, as well as experimental drug delivery systems that can potentially improve these therapies to enhance or reduce angiogenesis in a more controlled manner. Expert opinion Laboratory and clinical results have shown pro- or antiangiogenic drug delivery strategies to be effective in drastically slowing disease progression. Further research in this area will increase the efficacy, specificity and duration of these therapies. Future directions with composite drug delivery systems may make possible targeting of multiple factors for synergistic effects. PMID:21338327

  3. Myeloid-Derived Suppressor Cells and Therapeutic Strategies in Cancer

    PubMed Central

    Katoh, Hiroshi; Watanabe, Masahiko

    2015-01-01

    Development of solid cancer depends on escape from host immunosurveillance. Various types of immune cells contribute to tumor-induced immune suppression, including tumor associated macrophages, regulatory T cells, type 2 NKT cells, and myeloid-derived suppressor cells (MDSCs). Growing body of evidences shows that MDSCs play pivotal roles among these immunosuppressive cells in multiple steps of cancer progression. MDSCs are immature myeloid cells that arise from myeloid progenitor cells and comprise a heterogeneous immune cell population. MDSCs are characterized by the ability to suppress both adaptive and innate immunities mainly through direct inhibition of the cytotoxic functions of T cells and NK cells. In clinical settings, the number of circulating MDSCs is associated with clinical stages and response to treatment in several cancers. Moreover, MDSCs are reported to contribute to chemoresistant phenotype. Collectively, targeting MDSCs could potentially provide a rationale for novel treatment strategies in cancer. This review summarizes recent understandings of MDSCs in cancer and discusses promissing clinical approaches in cancer patients. PMID:26078490

  4. Therapeutic and Prophylactic Potential of Morama (Tylosema esculentum): A Review.

    PubMed

    Chingwaru, Walter; Vidmar, Jerneja; Kapewangolo, Petrina T; Mazimba, Ofentse; Jackson, Jose

    2015-10-01

    Tylosema esculentum (morama) is a highly valued traditional food and source of medicine for the San and other indigenous populations that inhabit the arid to semi-arid parts of Southern Africa. Morama beans are a rich source of phenolic acids, flavonoids, certain fatty acids, non-essential amino acids, certain phytosterols, tannins and minerals. The plant's tuber contains griffonilide, behenic acid and starch. Concoctions of extracts from morama bean, tuber and other local plants are frequently used to treat diarrhoea and digestive disorders by the San and other indigenous populations. Information on composition and bioactivity of phytochemical components of T. esculentum suggests that the polyphenol-rich extracts of the bean testae and cotyledons have great potential as sources of chemicals that inhibit infectious microorganisms (viral, bacterial and fungal, including drug-resistant strains), offer protection against certain non-communicable diseases and promote wound healing and gut health. The potential antinutritional properties of a few morama components are also highlighted. More research is necessary to reveal the full prophylactic and therapeutic potential of the plant against diseases of the current century. Research on domestication and conservation of the plant offers new hope for sustainable utilisation of the plant. PMID:26206567

  5. Terpenoids as potential chemopreventive and therapeutic agents in liver cancer

    PubMed Central

    Thoppil, Roslin J; Bishayee, Anupam

    2011-01-01

    Despite significant advances in medicine, liver cancer, predominantly hepatocellular carcinoma remains a major cause of death in the United States as well as the rest of the world. As limited treatment options are currently available to patients with liver cancer, novel preventive control and effective therapeutic approaches are considered to be reasonable and decisive measures to combat this disease. Several naturally occurring dietary and non-dietary phytochemicals have shown enormous potential in the prevention and treatment of several cancers, especially those of the gastrointestinal tract. Terpenoids, the largest group of phytochemicals, traditionally used for medicinal purposes in India and China, are currently being explored as anticancer agents in clinical trials. Terpenoids (also called “isoprenoids”) are secondary metabolites occurring in most organisms, particularly plants. More than 40 000 individual terpenoids are known to exist in nature with new compounds being discovered every year. A large number of terpenoids exhibit cytotoxicity against a variety of tumor cells and cancer preventive as well as anticancer efficacy in preclinical animal models. This review critically examines the potential role of naturally occurring terpenoids, from diverse origins, in the chemoprevention and treatment of liver tumors. Both in vitro and in vivo effects of these agents and related cellular and molecular mechanisms are highlighted. Potential challenges and future directions involved in the advancement of these promising natural compounds in the chemoprevention and therapy of human liver cancer are also discussed. PMID:21969877

  6. The therapeutic potential of genome editing for β-thalassemia

    PubMed Central

    Glaser, Astrid; McColl, Bradley; Vadolas, Jim

    2015-01-01

    The rapid advances in the field of genome editing using targeted endonucleases have called considerable attention to the potential of this technology for human gene therapy. Targeted correction of disease-causing mutations could ensure lifelong, tissue-specific expression of the relevant gene, thereby alleviating or resolving a specific disease phenotype. In this review, we aim to explore the potential of this technology for the therapy of β-thalassemia. This blood disorder is caused by mutations in the gene encoding the β-globin chain of hemoglobin, leading to severe anemia in affected patients. Curative allogeneic bone marrow transplantation is available only to a small subset of patients, leaving the majority of patients dependent on regular blood transfusions and iron chelation therapy. The transfer of gene-corrected autologous hematopoietic stem cells could provide a therapeutic alternative, as recent results from gene therapy trials using a lentiviral gene addition approach have demonstrated. Genome editing has the potential to further advance this approach as it eliminates the need for semi-randomly integrating viral vectors and their associated risk of insertional mutagenesis. In the following pages we will highlight the advantages and risks of genome editing compared to standard therapy for β-thalassemia and elaborate on lessons learned from recent gene therapy trials. PMID:26918126

  7. Terpenoids as potential chemopreventive and therapeutic agents in liver cancer.

    PubMed

    Thoppil, Roslin J; Bishayee, Anupam

    2011-09-27

    Despite significant advances in medicine, liver cancer, predominantly hepatocellular carcinoma remains a major cause of death in the United States as well as the rest of the world. As limited treatment options are currently available to patients with liver cancer, novel preventive control and effective therapeutic approaches are considered to be reasonable and decisive measures to combat this disease. Several naturally occurring dietary and non-dietary phytochemicals have shown enormous potential in the prevention and treatment of several cancers, especially those of the gastrointestinal tract. Terpenoids, the largest group of phytochemicals, traditionally used for medicinal purposes in India and China, are currently being explored as anticancer agents in clinical trials. Terpenoids (also called "isoprenoids") are secondary metabolites occurring in most organisms, particularly plants. More than 40 000 individual terpenoids are known to exist in nature with new compounds being discovered every year. A large number of terpenoids exhibit cytotoxicity against a variety of tumor cells and cancer preventive as well as anticancer efficacy in preclinical animal models. This review critically examines the potential role of naturally occurring terpenoids, from diverse origins, in the chemoprevention and treatment of liver tumors. Both in vitro and in vivo effects of these agents and related cellular and molecular mechanisms are highlighted. Potential challenges and future directions involved in the advancement of these promising natural compounds in the chemoprevention and therapy of human liver cancer are also discussed. PMID:21969877

  8. The therapeutic potential of genome editing for β-thalassemia.

    PubMed

    Glaser, Astrid; McColl, Bradley; Vadolas, Jim

    2015-01-01

    The rapid advances in the field of genome editing using targeted endonucleases have called considerable attention to the potential of this technology for human gene therapy. Targeted correction of disease-causing mutations could ensure lifelong, tissue-specific expression of the relevant gene, thereby alleviating or resolving a specific disease phenotype. In this review, we aim to explore the potential of this technology for the therapy of β-thalassemia. This blood disorder is caused by mutations in the gene encoding the β-globin chain of hemoglobin, leading to severe anemia in affected patients. Curative allogeneic bone marrow transplantation is available only to a small subset of patients, leaving the majority of patients dependent on regular blood transfusions and iron chelation therapy. The transfer of gene-corrected autologous hematopoietic stem cells could provide a therapeutic alternative, as recent results from gene therapy trials using a lentiviral gene addition approach have demonstrated. Genome editing has the potential to further advance this approach as it eliminates the need for semi-randomly integrating viral vectors and their associated risk of insertional mutagenesis. In the following pages we will highlight the advantages and risks of genome editing compared to standard therapy for β-thalassemia and elaborate on lessons learned from recent gene therapy trials. PMID:26918126

  9. Therapeutic potential of mesenchymal stem cells for pulmonary complications associated with preterm birth.

    PubMed

    Laube, Mandy; Stolzing, Alexandra; Thome, Ulrich H; Fabian, Claire

    2016-05-01

    Preterm infants frequently suffer from pulmonary complications resulting in significant morbidity and mortality. Physiological and structural lung immaturity impairs perinatal lung transition to air breathing resulting in respiratory distress. Mechanical ventilation and oxygen supplementation ensure sufficient oxygen supply but enhance inflammatory processes which might lead to the establishment of a chronic lung disease called bronchopulmonary dysplasia (BPD). Current therapeutic options to prevent or treat BPD are limited and have salient side effects, highlighting the need for new therapeutic approaches. Mesenchymal stem cells (MSCs) have demonstrated therapeutic potential in animal models of BPD. This review focuses on MSC-based therapeutic approaches to treat pulmonary complications and critically compares results obtained in BPD models. Thereby bottlenecks in the translational systems are identified that are preventing progress in combating BPD. Notably, current animal models closely resemble the so-called "old" BPD with profound inflammation and injury, whereas clinical improvements shifted disease pathology towards a "new" BPD in which arrest of lung maturation predominates. Future studies need to evaluate the utility of MSC-based therapies in animal models resembling the "new" BPD though promising in vitro evidence suggests that MSCs do possess the potential to stimulate lung maturation. Furthermore, we address the mode-of-action of MSC-based therapies with regard to lung development and inflammation/fibrosis. Their therapeutic efficacy is mainly attributed to an enhancement of regeneration and immunomodulation due to paracrine effects. In addition, we discuss current improvement strategies by genetic modifications or precondition of MSCs to enhance their therapeutic efficacy which could also prove beneficial for BPD therapies. PMID:26928452

  10. Therapeutic Potential of Traditional Chinese Medicine on Inflammatory Diseases

    PubMed Central

    Tsai, Wen-Hsin; Yang, Chih-Ching; Li, Ping-Chia; Chen, Wang-Chuan; Chien, Chiang-Ting

    2013-01-01

    Increased oxidative stress induces inflammation to several tissues/organs leading to cell death and long-term injury. Traditional Chinese Medicine (TCM) with antioxidant, anti-inflammatory, anti-apoptotic, and autophagic regulatory functions has been widely used as preventive or therapeutic strategy in modern medicine. Oxidative stress and inflammation have been widely reported to contribute to cigarette smoke-induced lung inflammation, hepatotoxicity, or sympathetic activation-induced liver inflammation, lipopolysaccharide-induced renal inflammation, and substance P-mediated neurogenic hyperactive bladder based on clinical findings. In this review, we introduce several evidences for TCM treatment including Monascus adlay (MA) produced by inoculating adlay (Cois lachrymal-jobi L. var. ma-yuen Stapf) with Monascus purpureus on lung injury, Amla (Emblica officinalis Gaertn. of Euphorbiaceae family) on hepatotoxin-induced liver inflammation, Virgate Wormwood Decoction (Yīn Chén Hāo tāng) and its active component genipin on sympathetic activation–induced liver inflammation, and green tea extract and its active components, catechins, or a modified TCM formula Five Stranguries Powder (Wǔ Lén Sǎn) plus Crataegi Fructus (Shān Zhā) on hyperactive bladder. The pathophysiologic and molecular mechanisms of TCM on ameliorating inflammatory diseases are discussed in the review. PMID:24716170

  11. [Mechanisms and potential of the therapeutic stimulation of arteriogenesis].

    PubMed

    Schirmer, S H; van Royen, N; Laufs, U; Böhm, M

    2009-02-01

    The stimulation of collateral artery growth (arteriogenesis) is a promising alternative approach to non-invasively treat arterial obstructive disease, such as coronary, peripheral or cerebral artery disease. Patients unable to undergo conventional revascularization strategies may benefit from adaptive arteriogenesis. Underlying mechanisms are experimentally validated and include an increase in shear stress after obstruction or occlusion of a major artery; monocyte adhesion, transmigration and perivascular accumulation, secretion of growth factors; and smooth muscle and endothelial cell proliferation and growth of pre-existent collateral arteries. Therapeutic stimulation of arteriogenesis with cytokines has been successfully performed in experimental models. Translation into clinical practice, however, has hitherto been problematic. Reasons for this include differences between the healthy laboratory animal and an often severely diseased patient, possible harmful effects of pro-arteriogenic therapies and unsuitable clinical endpoints for the detection of collateral artery growth. Recent investigations of human arteriogenesis demonstrate significant inter-individual differences and point towards the importance of anti-arteriogenic mechanisms in patients with impaired adaptive arteriogenesis and high cardiovascular risk factors. PMID:19197812

  12. Therapeutic potential of traditional chinese medicine on inflammatory diseases.

    PubMed

    Tsai, Wen-Hsin; Yang, Chih-Ching; Li, Ping-Chia; Chen, Wang-Chuan; Chien, Chiang-Ting

    2013-07-01

    Increased oxidative stress induces inflammation to several tissues/organs leading to cell death and long-term injury. Traditional Chinese Medicine (TCM) with antioxidant, anti-inflammatory, anti-apoptotic, and autophagic regulatory functions has been widely used as preventive or therapeutic strategy in modern medicine. Oxidative stress and inflammation have been widely reported to contribute to cigarette smoke-induced lung inflammation, hepatotoxicity, or sympathetic activation-induced liver inflammation, lipopolysaccharide-induced renal inflammation, and substance P-mediated neurogenic hyperactive bladder based on clinical findings. In this review, we introduce several evidences for TCM treatment including Monascus adlay (MA) produced by inoculating adlay (Cois lachrymal-jobi L. var. ma-yuen Stapf) with Monascus purpureus on lung injury, Amla (Emblica officinalis Gaertn. of Euphorbiaceae family) on hepatotoxin-induced liver inflammation, Virgate Wormwood Decoction (Yīn Chén Hāo tāng) and its active component genipin on sympathetic activation-induced liver inflammation, and green tea extract and its active components, catechins, or a modified TCM formula Five Stranguries Powder (Wǔ Lén Sǎn) plus Crataegi Fructus (Shān Zhā) on hyperactive bladder. The pathophysiologic and molecular mechanisms of TCM on ameliorating inflammatory diseases are discussed in the review. PMID:24716170

  13. GEMINs: potential therapeutic targets for spinal muscular atrophy?

    PubMed Central

    Borg, Rebecca; Cauchi, Ruben J.

    2014-01-01

    The motor neuron degenerative disease spinal muscular atrophy (SMA) remains one of the most frequently inherited causes of infant mortality. Afflicted patients loose the survival motor neuron 1 (SMN1) gene but retain one or more copies of SMN2, a homolog that is incorrectly spliced. Primary treatment strategies for SMA aim at boosting SMN protein levels, which are insufficient in patients. SMN is known to partner with a set of diverse proteins collectively known as GEMINs to form a macromolecular complex. The SMN-GEMINs complex is indispensible for chaperoning the assembly of small nuclear ribonucleoproteins (snRNPs), which are key for pre-mRNA splicing. Pharmaceutics that alleviate the neuromuscular phenotype by restoring the fundamental function of SMN without augmenting its levels are also crucial in the development of an effective treatment. Their use as an adjunct therapy is predicted to enhance benefit to patients. Inspired by the surprising discovery revealing a premier role for GEMINs in snRNP biogenesis together with in vivo studies documenting their requirement for the correct function of the motor system, this review speculates on whether GEMINs constitute valid targets for SMA therapeutic development. PMID:25360080

  14. Centipede Venoms and Their Components: Resources for Potential Therapeutic Applications

    PubMed Central

    Hakim, Md Abdul; Yang, Shilong; Lai, Ren

    2015-01-01

    Venomous animals have evolved with sophisticated bio-chemical strategies to arrest prey and defend themselves from natural predators. In recent years, peptide toxins from venomous animals have drawn considerable attention from researchers due to their surprising chemical, biochemical, and pharmacological diversity. Similar to other venomous animals, centipedes are one of the crucial venomous arthropods that have been used in traditional medicine for hundreds of years in China. Despite signifying pharmacological importance, very little is known about the active components of centipede venoms. More than 500 peptide sequences have been reported in centipede venomous glands by transcriptome analysis, but only a small number of peptide toxins from centipede has been functionally described. Like other venomous animals such as snakes, scorpions, and spiders, the venom of centipedes could be an excellent source of peptides for developing drugs for treatments as well as bio-insecticides for agrochemical applications. Although centipede venoms are yet to be adequately studied, the venom of centipedes as well as their components described to date, should be compiled to help further research. Therefore, based on previous reports, this review focusses on findings and possible therapeutic applications of centipede venoms as well as their components. PMID:26593947

  15. Centipede venoms and their components: resources for potential therapeutic applications.

    PubMed

    Hakim, Md Abdul; Yang, Shilong; Lai, Ren

    2015-11-01

    Venomous animals have evolved with sophisticated bio-chemical strategies to arrest prey and defend themselves from natural predators. In recent years, peptide toxins from venomous animals have drawn considerable attention from researchers due to their surprising chemical, biochemical, and pharmacological diversity. Similar to other venomous animals, centipedes are one of the crucial venomous arthropods that have been used in traditional medicine for hundreds of years in China. Despite signifying pharmacological importance, very little is known about the active components of centipede venoms. More than 500 peptide sequences have been reported in centipede venomous glands by transcriptome analysis, but only a small number of peptide toxins from centipede has been functionally described. Like other venomous animals such as snakes, scorpions, and spiders, the venom of centipedes could be an excellent source of peptides for developing drugs for treatments as well as bio-insecticides for agrochemical applications. Although centipede venoms are yet to be adequately studied, the venom of centipedes as well as their components described to date, should be compiled to help further research. Therefore, based on previous reports, this review focusses on findings and possible therapeutic applications of centipede venoms as well as their components. PMID:26593947

  16. Therapeutic potential of mesenchymal stem cell based therapy for osteoarthritis.

    PubMed

    Burke, John; Hunter, Monte; Kolhe, Ravindra; Isales, Carlos; Hamrick, Mark; Fulzele, Sadanand

    2016-12-01

    Osteoarthritis (OA) is a chronic degenerative disease affecting articular cartilage in joints, and it is a leading cause of disability in the United States. Current pharmacological treatment strategies are ineffective to prevent the OA progression; however, cellular therapies have the potential to regenerate the lost cartilage, combat cartilage degeneration, provide pain relief, and improve patient mobility. One of the most promising sources of cellular regenerative medicine is from mesenchymal stem cells (MSCs). MSCs can be isolated from adipose tissue, bone marrow, synovial tissue, and other sources. The aim of this review is to compile recent advancement in cellular based therapy more specifically in relation to MSCs in the treatment of osteoarthritis. PMID:27510262

  17. Therapeutic Strategies to Treat Dry Eye in an Aging Population

    PubMed Central

    Ezuddin, Nisreen S.; Alawa, Karam A.; Galor, Anat

    2015-01-01

    Dry eye (DE) is a prevalent ocular disease that primarily affects the elderly. Affecting up to 30% of adults aged 50 years and older, dry eye affects both visual function and quality of life. Symptoms of dry eye which include ocular pain (aching, burning), visual disturbances, and tearing can be addressed with therapeutic agents that target dysfunction of the meibomian glands, lacrimal glands, goblet cells, ocular surface and/or neural network. This review provides an overview of the efficacy, use, and limitations of current therapeutic interventions being used to treat DE. PMID:26123947

  18. Therapeutic potential of PDE modulation in treating heart disease

    PubMed Central

    Knight, Walter; Yan, Chen

    2014-01-01

    Altered cyclic nucleotide-mediated signaling plays a critical role in the development of cardiovascular pathology. By degrading cAMP/cGMP, the action of cyclic nucleotide PDEs is essential for controlling cyclic nucleotide-mediated signaling intensity, duration, and specificity. Altered expression, localization and action of PDEs have all been implicated in causing changes in cyclic nucleotide signaling in cardiovascular disease. Accordingly, pharmacological inhibition of PDEs has gained interest as a treatment strategy and as an area of drug development. While targeting of certain PDEs has the potential to ameliorate cardiovascular disease, inhibition of others might actually worsen it. This review will highlight recent research on the physiopathological role of cyclic nucleotide signaling, especially with regard to PDEs. While the physiological roles and biochemical properties of cardiovascular PDEs will be summarized, the primary emphasis will be pathological. Research into the potential benefits and hazards of PDE inhibition will also be discussed. PMID:24047267

  19. Pharmacology and therapeutic potential of sigma(1) receptor ligands.

    PubMed

    Cobos, E J; Entrena, J M; Nieto, F R; Cendán, C M; Del Pozo, E

    2008-12-01

    Sigma (sigma) receptors, initially described as a subtype of opioid receptors, are now considered unique receptors. Pharmacological studies have distinguished two types of sigma receptors, termed sigma(1) and sigma(2). Of these two subtypes, the sigma(1) receptor has been cloned in humans and rodents, and its amino acid sequence shows no homology with other mammalian proteins. Several psychoactive drugs show high to moderate affinity for sigma(1) receptors, including the antipsychotic haloperidol, the antidepressant drugs fluvoxamine and sertraline, and the psychostimulants cocaine and methamphetamine; in addition, the anticonvulsant drug phenytoin allosterically modulates sigma(1) receptors. Certain neurosteroids are known to interact with sigma(1) receptors, and have been proposed to be their endogenous ligands. These receptors are located in the plasma membrane and in subcellular membranes, particularly in the endoplasmic reticulum, where they play a modulatory role in intracellular Ca(2+) signaling. Sigma(1) receptors also play a modulatory role in the activity of some ion channels and in several neurotransmitter systems, mainly in glutamatergic neurotransmission. In accordance with their widespread modulatory role, sigma(1) receptor ligands have been proposed to be useful in several therapeutic fields such as amnesic and cognitive deficits, depression and anxiety, schizophrenia, analgesia, and against some effects of drugs of abuse (such as cocaine and methamphetamine). In this review we provide an overview of the present knowledge of sigma(1) receptors, focussing on sigma(1) ligand neuropharmacology and the role of sigma(1) receptors in behavioral animal studies, which have contributed greatly to the potential therapeutic applications of sigma(1) ligands. PMID:19587856

  20. Immune repertoire: A potential biomarker and therapeutic for hepatocellular carcinoma.

    PubMed

    Han, Yingxin; Li, Hongmei; Guan, Yanfang; Huang, Jian

    2016-09-01

    The immune repertoire (IR) refers to the sum of B cells and T cells with functional diversity in the circulatory system of one individual at any given time. Immune cells, which reside within microenvironments and are responsible for protecting the human body, include T cells, B cells, macrophages, and dendritic cells. These dedicated immune cells have a characteristic structure and function. T and B cells are the main lymphocytes and are responsible for cellular immunity and humoral immunity, respectively. The T cell receptor (TCR) and B cell receptor (BCR) are composed of multiple peptide chains with antigen specificity. The amino acid composition and sequence order are more diverse in the complementarity-determining regions (including CDR1, CDR2 and CDR3) of each peptide chain, allowing a vast library of TCRs and BCRs. IR research is becoming increasingly focused on the study of CDR3 diversity. Deep profiling of CDR3s using high-throughput sequencing is a powerful approach for elucidating the composition and distribution of the CDR3s in a given sample, with in-depth information at the sequence level. Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world. To identify novel biomarkers for diagnosis and drug targets for therapeutic interventions, several groups attempted to describe immune repertoire characteristics of the liver in the physiological environment or/and pathological conditions. This paper reviews the recent progress in IR research on human diseases, including hepatocellular carcinoma, attempting to depict the relationships between hepatocellular carcinogenesis and the IR, and discusses the possibility of IR as a potential biomarker and therapeutic for hepatocellular carcinoma. PMID:26188280

  1. Pharmacological induction of mitochondrial biogenesis as a therapeutic strategy for the treatment of type 2 diabetes.

    PubMed

    Zamora, Mònica; Pardo, Rosario; Villena, Josep A

    2015-11-01

    Defects in mitochondrial oxidative function have been associated with the onset of type 2 diabetes. Although the causal relationship between mitochondrial dysfunction and diabetes has not been fully established, numerous studies indicate that improved glucose homeostasis achieved via lifestyle interventions, such as exercise or calorie restriction, is tightly associated with increased mitochondrial biogenesis and oxidative function. Therefore, it is conceivable that potentiating mitochondrial biogenesis by pharmacological means could constitute an efficacious therapeutic strategy that would particularly benefit those diabetic patients who cannot adhere to comprehensive programs based on changes in lifestyle or that require a relatively rapid improvement in their diabetic status. In this review, we discuss several pharmacological targets and drugs that modulate mitochondrial biogenesis as well as their potential use as treatments for insulin resistance and diabetes. PMID:26212547

  2. 5-Hydroxytryptamine Receptor Subtypes and their Modulators with Therapeutic Potentials

    PubMed Central

    Pithadia, Anand B.; Jain, Sunita M.

    2009-01-01

    5-hydroxytryptamine (5-HT) has become one of the most investigated and complex biogenic amines. The main receptors and their subtypes, e.g., 5-HTI (5-HT1A, 5-HT1B, 5-HTID, 5-HTIE and 5-HT1F), 5-HT2 (5-HT2A, 5-HT2B and 5-HT2C), 5-HT3, 5-HT4, 5-HT5 (5-HT5A, 5-HT5B), 5-HT6 and 5-HT7 have been identified. Specific drugs which are capable of either selectively stimulating or inhibiting these receptor subtypes are being designed. This has generated therapeutic potentials of 5-HT receptor modulators in a variety of disease conditions. Conditions where 5-HT receptor modulators have established their use with distinct efficacy and advantages include migraine, anxiety, psychosis, obesity and cancer therapy-induced vomiting by cytotoxic drugs and radiation. Discovery of 5-HT, its biosynthesis, metabolism, physiological role and the potential of 5-HT receptor modulators in various nervous, cardiovascular and gastrointestinal tract disorders, bone growth and micturition have been discussed in this article. Keywords 5-hydroxytryptamine (5-HT) receptors; Modulators; Biogenic amines PMID:22505971

  3. New therapeutic potentials of milk thistle (Silybum marianum).

    PubMed

    Milić, Natasa; Milosević, Natasa; Suvajdzić, Ljiljana; Zarkov, Marija; Abenavoli, Ludovico

    2013-12-01

    Silymarin is a bioflavonoid complex extract derived from dry seeds of Milk thistle [(Silybum marianum(L.) Gaemrnt. (Fam. Asteraceae/Compositaceae)] whose hepatoprotective effect has clinically been proved. Low toxicity, favorable pharmacokinetics, powerful antioxidant, detoxifying, preventive, protective and regenerative effects and side effects similar to placebo make silymarin extremely attractive and safe for therapeutic use. The medicinal properties of silymarin and its main component silibinin have been studied in the treatment of Alzheimer's disease, Parkinson's disease, sepsis, burns, osteoporosis, diabetes, cholestasis and hypercholesterolemia. Owing to its apoptotic effect, without cytotoxic effects, silymarin possesses potential applications in the treatment of various cancers. Silymarin is being examined as a neuro-, nephro- and cardio-protective in the damage of different etiologies due to its strong antioxidant potentials. Furthermore, it has fetoprotective (against the influence of alcohol) and prolactin effects and is safe to be used during pregnancy and lactation. Finally, the cosmetics industry is examining the antioxidant and UV-protective effects of silymarin. Further clinical studies and scientific evidence that silymarin and silibinin are effective in the therapy of various pathologies are indispensable in order to confirm their different flavonolignan pharmacological effects. PMID:24555302

  4. Therapeutic Potential of Temperate Forage Legumes: A Review.

    PubMed

    Cornara, Laura; Xiao, Jianbo; Burlando, Bruno

    2016-07-29

    The discovery of bioactive molecules from botanical sources is an expanding field, preferentially oriented to plants having a tradition of use in medicine and providing high yields and availability. Temperate forage legumes are Fabaceae species that include worldwide-important crops. These plants possess therapeutic virtues that have not only been used in veterinary and folk medicine, but have also attracted the interest of official medicine. We have examined here Medicago sativa (alfalfa), Trifolium pratense and T. repens (clovers), Melilotus albus and M. officinalis (sweet clovers), Lotus corniculatus (birdsfoot trefoil), Onobrychis viciifolia (sainfoin), Lespedeza capitata (roundhead lespedeza), and Galega officinalis (goat's rue). The phytochemical complexes of these species contain secondary metabolites whose pharmacological potentials deserve investigation. Major classes of compounds include alkaloids and amines, cyanogenic glycosides, flavonoids, coumarins, condensed tannins, and saponins. Some of these phytochemicals have been related to antihypercholesterolemia, antidiabetic, antimenopause, anti-inflammatory, antiedema, anthelmintic, and kidney protective effects. Two widely prescribed drugs have been developed starting from temperate forage legumes, namely, the antithrombotic warfarin, inspired from sweet clover's coumarin, and the antidiabetic metformin, a derivative of sainfoin's guanidine. Available evidence suggests that temperate forage legumes are a potentially important resource for the extraction of active principles to be used as nutraceuticals and pharmaceuticals. PMID:26507574

  5. Therapeutic Potential of Mesenchymal Stem Cells in Regenerative Medicine

    PubMed Central

    Patel, Devang M.; Shah, Jainy; Srivastava, Anand S.

    2013-01-01

    Mesenchymal stem cells (MSCs) are stromal cells that have the ability to self-renew and also exhibit multilineage differentiation into both mesenchymal and nonmesenchymal lineages. The intrinsic properties of these cells make them an attractive candidate for clinical applications. MSCs are of keen interest because they can be isolated from a small aspirate of bone marrow or adipose tissues and can be easily expanded in vitro. Moreover, their ability to modulate immune responses makes them an even more attractive candidate for regenerative medicine as allogeneic transplant of these cells is feasible without a substantial risk of immune rejection. MSCs secrete various immunomodulatory molecules which provide a regenerative microenvironment for a variety of injured tissues or organ to limit the damage and to increase self-regulated tissue regeneration. Autologous/allogeneic MSCs delivered via the bloodstream augment the titers of MSCs that are drawn to sites of tissue injury and can accelerate the tissue repair process. MSCs are currently being tested for their potential use in cell and gene therapy for a number of human debilitating diseases and genetic disorders. This paper summarizes the current clinical and nonclinical data for the use of MSCs in tissue repair and potential therapeutic role in various diseases. PMID:23577036

  6. Potential novel therapeutic strategies in cystic fibrosis: antimicrobial and anti-biofilm activity of natural and designed α-helical peptides against Staphylococcus aureus, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia

    PubMed Central

    2012-01-01

    Background Treatment of cystic fibrosis-associated lung infections is hampered by the presence of multi-drug resistant pathogens, many of which are also strong biofilm producers. Antimicrobial peptides, essential components of innate immunity in humans and animals, exhibit relevant in vitro antimicrobial activity although they tend not to select for resistant strains. Results Three α-helical antimicrobial peptides, BMAP-27 and BMAP-28 of bovine origin, and the artificial P19(9/B) peptide were tested, comparatively to Tobramycin, for their in vitro antibacterial and anti-biofilm activity against 15 Staphylococcus aureus, 25 Pseudomonas aeruginosa, and 27 Stenotrophomonas maltophilia strains from cystic fibrosis patients. All assays were carried out in physical-chemical experimental conditions simulating a cystic fibrosis lung. All peptides showed a potent and rapid bactericidal activity against most P. aeruginosa, S. maltophilia and S. aureus strains tested, at levels generally higher than those exhibited by Tobramycin and significantly reduced biofilm formation of all the bacterial species tested, although less effectively than Tobramycin did. On the contrary, the viability-reducing activity of antimicrobial peptides against preformed P. aeruginosa biofilms was comparable to and, in some cases, higher than that showed by Tobramycin. Conclusions The activity shown by α-helical peptides against planktonic and biofilm cells makes them promising “lead compounds” for future development of novel drugs for therapeutic treatment of cystic fibrosis lung disease. PMID:22823964

  7. New strategies to maximize therapeutic opportunities for NAMPT inhibitors in oncology

    PubMed Central

    Roulston, Anne; Shore, Gordon C.

    2016-01-01

    ABSTRACT Nicotinamide phosphoribosyltransferase (NAMPT) is crucial for nicotinamide adenine dinucleotide (NAD+) biosynthesis in mammalian cells. NAMPT inhibitors represent multifunctional anticancer agents that act on NAD+ metabolism to shut down glycolysis, nucleotide biosynthesis, and ATP generation and act indirectly as PARP and sirtuin inhibitors. The selectivity of NAMPT inhibitors preys on the increased metabolic requirements to replenish NAD+ in cancer cells. Although initial clinical studies with NAMPT inhibitors did not achieve single-agent therapeutic levels before dose-limiting toxicities were reached, a new understanding of alternative rescue pathways and a biomarker that can be used to select patients provides new opportunities to widen the therapeutic window and achieve efficacious doses in the clinic. Recent work has also illustrated the potential for drug combination strategies to further enhance the therapeutic opportunities. This review summarizes recent discoveries in NAD+/NAMPT inhibitor biology in the context of exploiting this new knowledge to optimize the clinical outcomes for this promising new class of agents. PMID:27308565

  8. Potential therapeutic effects of pigment epithelium-derived factor for treatment of diabetic retinopathy.

    PubMed

    Liu, Xiao; Chen, Hui-Hui; Zhang, Li-Wei

    2013-01-01

    Diabetic retinopathy (DR), a major micro-vascular complication of diabetes, has emerged as a leading cause of visual impairment and blindness among working adults in the worldwide. The pathobiology of DR involves multiple molecular pathways and is characterized chronic neurovascular degeneration. Current approaches to prevent or to treat DR are still far from satisfactory. Therefore, it is important to develop new therapeutic strategies for the prevention and treatment to DR. Pigment epithelium-derived factor (PEDF), a 50-kDa secreted glycoprotein, has been described as a multi-functional protein. Some emerging evidences indicate that PEDF are able to target multiple pathways exerting neurotropic, neuroprotective, anti-angiogenic, antivasopermeability, anti-inflammation, anti-thrombogenic and anti-oxidative effects in DR. In this review, we addressed the functions of PEDF in different pathways, which could lead to potential therapeutics on the treatment to DR. PMID:23638428

  9. RNA Inhibition Highlights Cyclin D1 as a Potential Therapeutic Target for Mantle Cell Lymphoma

    PubMed Central

    Weinstein, Shiri; Emmanuel, Rafi; Jacobi, Ashley M.; Abraham, Avigdor; Behlke, Mark A.; Sprague, Andrew G.; Novobrantseva, Tatiana I.; Nagler, Arnon; Peer, Dan

    2012-01-01

    Mantle cell lymphoma is characterized by a genetic translocation results in aberrant overexpression of the CCND1 gene, which encodes cyclin D1. This protein functions as a regulator of the cell cycle progression, hence is considered to play an important role in the pathogenesis of the disease. In this study, we used RNA interference strategies to examine whether cyclin D1 might serve as a therapeutic target for mantle cell lymphoma. Knocking down cyclin D1 resulted in significant growth retardation, cell cycle arrest, and most importantly, induction of apoptosis. These results mark cyclin D1 as a target for mantle cell lymphoma and emphasize the therapeutic potential hidden in its silencing. PMID:22905260

  10. Multi-therapeutic potential of autoantibodies induced by immune complexes trapped on follicular dendritic cells

    PubMed Central

    El Shikh, Mohey Eldin; Kmieciak, Maciej; Manjili, Masoud H; Szakal, Andras K; Pitzalis, Costantino; Tew, John G

    2013-01-01

    Induction of autoantibodies (autoAbs) targeting disease drivers / mediators is emerging as a potential immunotherapeutic strategy. Auto-immune complex (IC)-retaining follicular dendritic cells (FDCs) critically regulate pathogenic autoAb production in autoreactive germinal centers (GCs); however, their ability to induce potentially therapeutic autoAbs has not been explored. We hypothesized that deliberate display of clinically targeted antigens (Ags) in the form of ICs on FDC membranes induces target-specific autoreactive GCs and autoAbs that may be exploited therapeutically. To test our hypothesis, three therapeutically relevant Ags: TNF-α, HER2/neu and IgE, were investigated. Our results indicated that TNF-α-, HER2/neu- and IgE-specific autoAbs associated with strong GC reactions were induced by TNF-α-, HER2/neu- and IgE-IC retention on FDCs. Moreover, the induced anti-TNF-α autoAbs neutralized mouse and human TNF-α with half maximal Inhibitory Concentration (IC50) of 7.1 and 1.6 nM respectively. In addition, we demonstrated that FDC-induced Ab production could be non-specifically inhibited by the IgG-specific Endo-S that accessed the light zones of GCs and interfered with FDC-IC retention. In conclusion, the ability of FDCs to productively present autoAgs raises the potential for a novel immunotherapeutic platform targeting mediators of autoimmune disorders, allergic diseases, and Ab responsive cancers. PMID:23836278

  11. Strategies for Delivery of Therapeutics into the Central Nervous System for Treatment of Lysosomal Storage Disorders

    PubMed Central

    Muro, Silvia

    2014-01-01

    Lysosomal storage disorders (LSDs) are a group of about fifty life-threatening conditions caused by genetic defects affecting lysosomal components. The underscoring molecular deficiency leads to widespread cellular dysfunction through most tissues in the body, including peripheral organs and the central nervous system (CNS). Efforts during the last few decades have rendered a remarkable advance regarding our knowledge, medical awareness, and early detection of these genetic defects, as well as development of several treatment modalities. Clinical and experimental strategies encompassing enzyme replacement, gene and cell therapies, substrate reduction, and chemical chaperones are showing considerable potential in attenuating the peripheral pathology. However, a major drawback has been encountered regarding the suboptimal impact of these approaches on the CNS pathology. Particular anatomical and biochemical constraints of this tissue pose a major obstacle to the delivery of therapeutics into the CNS. Approaches to overcome these obstacles include modalities of local administration, strategies to enhance the blood-CNS permeability, intranasal delivery, use of exosomes, and those exploiting targeting of transporters and transcytosis pathways in the endothelial lining. The later two approaches are being pursued at the time by coupling therapeutic agents to affinity moieties and drug delivery systems capable of targeting these natural transport routes. This approach is particularly promising, as using paths naturally active at this interface may render safe and effective delivery of LSD therapies into the CNS. PMID:24688886

  12. No-reflow: a heterogeneous clinical phenomenon with multiple therapeutic strategies.

    PubMed

    Galiuto, Leonarda; Crea, Filippo

    2006-01-01

    Previously defined as the failure to achieve uniform intramyocardial reperfusion after prolonged but reversible coronary occlusion, only recently has no-reflow phenomenon been characterized as a heterogeneous clinical condition. In fact, in about half of post-infarct patients that show no-reflow after 24 hours from coronary recanalization by either thrombolysis or PTCA, no-reflow phenomenon is spontaneously reversible. Reversible no-reflow is associated with favorable left ventricular remodeling even in the absence of significant improvement in regional contractile function. Thus, it may be a clinical marker of yet unknown mechanisms, which may favorably affect myocardial response to necrosis. Based on the pathogenesis and on the time-course of no-reflow, the phenomenon may be associated with lack of patency or with loss of anatomic integrity of microvessels, with the former being potentially reversible while the latter associated with definitive tissue damage. As a consequence, possible therapeutic strategies of no-reflow have to be designed according to not only the main target [microvessel patency or integrity], but also taking into account the timing of development of the damage. This "mini review" is focused on recent advances on the pathogenesis and clinical presentation on no-reflow. These data will give the opportunity to formulate novel interpretation and classification of the phenomenon and consequently, to propose adequate therapeutic strategies. PMID:17073679

  13. MicroRNA-based Therapeutic Strategies for Targeting Mutant and Wild Type RAS in Cancer

    PubMed Central

    Sharma, Sriganesh B.; Ruppert, J. Michael

    2015-01-01

    MicroRNAs (miRs) have been causally implicated in the progression and development of a wide variety of cancers. miRs modulate the activity of key cell signaling networks by regulating the translation of pathway component proteins. Thus, the pharmacological targeting of miRs that regulate cancer cell signaling networks, either by promoting (using miR-supplementation) or by suppressing (using anti-sense oligonucleotide based strategies) miR activity is an area of intense research. The RAS-Extracellular signal regulated kinase (ERK) pathway represents a major miR-regulated signaling network that endows cells with some of the classical hallmarks of cancer, and is often inappropriately activated in malignancies by somatic genetic alteration through point mutation or alteration of gene copy number. In addition, recent progress indicates that many tumors may be deficient in GTPase activating proteins (GAPs) due to the collaborative action of oncogenic microRNAs. Recent studies also suggest that in tumors harboring a mutant RAS allele there is a critical role for wild type RAS proteins in determining overall RAS-ERK pathway activity. Together, these two advances comprise a new opportunity for therapeutic intervention. In this review, we evaluate miR-based therapeutic strategies for modulating RAS-ERK signaling in cancers, in particular for more direct modulation of RAS-GTP levels, with the potential to complement current strategies in order to yield more durable treatment responses. To this end, we discuss the potential for miR-based therapies focused on three prominent miRs including the pan-RAS regulator let-7 and the GAP regulator comprised of miR-206 and miR-21 (miR-206/21). PMID:26284568

  14. Understanding glioma stem cells: rationale, clinical relevance and therapeutic strategies

    PubMed Central

    Ahmed, Atique U; Auffinger, Brenda; Lesniak, Maciej S

    2015-01-01

    Glioblastoma multiforme is one of the most aggressive brain tumors in adults. Despite the use of the best available multimodal therapeutic approaches, the prognosis remains dismal. The identification of glioma stem cells (GSCs) has offered new hope to affected patients, since it could explain, in part, the highly heterogeneous nature of this tumor and its chemo- and radio-resistance. Although still in its infancy, GSC research has unveiled many of its complexities and the theory itself remains controversial. GSC phenotype can significantly vary between patients and a single tumor may present several distinct GSCs. New therapeutic solutions that effectively target this population are of utmost importance, since they may be able to decrease neoplastic recurrence and improve patient survival. Here, we discuss the mechanisms by which GSCs lead to glioma relapse, the main controversies in this field and the most recent treatments that could successfully target this population. PMID:23621311

  15. Understanding glioma stem cells: rationale, clinical relevance and therapeutic strategies.

    PubMed

    Ahmed, Atique U; Auffinger, Brenda; Lesniak, Maciej S

    2013-05-01

    Glioblastoma multiforme is one of the most aggressive brain tumors in adults. Despite the use of the best available multimodal therapeutic approaches, the prognosis remains dismal. The identification of glioma stem cells (GSCs) has offered new hope to affected patients, since it could explain, in part, the highly heterogeneous nature of this tumor and its chemo- and radio-resistance. Although still in its infancy, GSC research has unveiled many of its complexities and the theory itself remains controversial. GSC phenotype can significantly vary between patients and a single tumor may present several distinct GSCs. New therapeutic solutions that effectively target this population are of utmost importance, since they may be able to decrease neoplastic recurrence and improve patient survival. Here, we discuss the mechanisms by which GSCs lead to glioma relapse, the main controversies in this field and the most recent treatments that could successfully target this population. PMID:23621311

  16. Therapeutic Strategies for Treatment of Pulmonary Lymphangioleiomyomatosis (LAM)

    PubMed Central

    Krymskaya, Vera P.

    2015-01-01

    Introduction Pulmonary lymphangioleiomyomatosis (LAM) is a rare progressive lung disease affecting almost exclusively women. Neoplastic growth of atypical smooth muscle-like cells in the lung induces destruction of lung parenchyma leading to the formation of lung cysts, rupture of which results in spontaneous pneumothorax. LAM occurs sporadically or in association with inherited hamartoma syndrome tuberous sclerosis complex (TSC). Progression of LAM often results in loss of pulmonary function and death. Increasing understanding of neoplastic LAM cell growth is driving the development of therapeutic approaches targeting the disease progression. Areas covered This review provides background to understand the rationale for current treatments used in patients with LAM, to critically appraise the evidence for these treatments, and to discuss future treatment approaches. The literature review includes publications from PubMed and clinicaltrials.gov/. Expert Opinion Targeting mTOR activation with rapamycin analogs sirolimus and everolimus are awaiting approval by the FDA for treatment of LAM. A number of other treatment options have been investigated and are currently tested in clinical trials to target LAM cell survival and metastasis. Key remaining and poorly understood areas for development and validation of therapeutic targeting in LAM are destruction of lungs, pathological lymphangiogenesis, and hormonal regulation. Future will reveal whether they could be targeted therapeutically. PMID:26779398

  17. The therapeutic potential of the cerebellum in schizophrenia

    PubMed Central

    Parker, Krystal L.; Narayanan, Nandakumar S.; Andreasen, Nancy C.

    2014-01-01

    The cognitive role of the cerebellum is critically tied to its distributed connections throughout the brain. Accumulating evidence from anatomical, structural and functional imaging, and lesion studies advocate a cognitive network involving indirect connections between the cerebellum and non-motor areas in the prefrontal cortex. Cerebellar stimulation dynamically influences activity in several regions of the frontal cortex and effectively improves cognition in schizophrenia. In this manuscript, we summarize current literature on the cingulocerebellar circuit and we introduce a method to interrogate this circuit combining opotogenetics, neuropharmacology, and electrophysiology in awake-behaving animals while minimizing incidental stimulation of neighboring cerebellar nuclei. We propose the novel hypothesis that optogenetic cerebellar stimulation can restore aberrant frontal activity and rescue impaired cognition in schizophrenia. We focus on how a known cognitive region in the frontal cortex, the anterior cingulate, is influenced by the cerebellum. This circuit is of particular interest because it has been confirmed using tracing studies, neuroimaging reveals its role in cognitive tasks, it is conserved from rodents to humans, and diseases such as schizophrenia and autism appear in its aberrancy. Novel tract tracing results presented here provide support for how these two areas communicate. The primary pathway involves a disynaptic connection between the cerebellar dentate nuclei (DN) and the anterior cingulate cortex. Secondarily, the pathway from cerebellar fastigial nuclei (FN) to the ventral tegmental area, which supplies dopamine to the prefrontal cortex, may play a role as schizophrenia characteristically involves dopamine deficiencies. We hope that the hypothesis described here will inspire new therapeutic strategies targeting currently untreatable cognitive impairments in schizophrenia. PMID:25309350

  18. New vitamin D analogs as potential therapeutics in melanoma

    PubMed Central

    Szyszka, Paulina; Zmijewski, Michal A; Slominski, Andrzej T

    2012-01-01

    Extensive evidence shows that the active form of vitamin D3 – 1α,25-dihydroxyvitamin D3 – plays an important role in cancer prevention, has tumorostatic activity and may potentially be used in therapy for melanoma. Vitamin D3 and its analogs (secosteroids) exert multiple effects on cancer cells, including inhibition of cell growth and induction of differentiation. Activity of secosteroids depends on multiple cellular factors, including expression of the vitamin D receptor. Despite its endogenous origin, the key drawback for the use of pharmacologically effective doses of 1α,25-dihydroxyvitamin D3 is its hypercalcemic effect leading to profound toxicity. The solution may lie in properties of vitamin D3 analogs with modified side chains, which demonstrate low calcemic activity but conserve the anti-tumor properties. Noncalcemic vitamin D compounds were found to be potent in multiple studies that mandate further clinical testing. Finally, recent studies revealed alternative metabolic pathways for secosteroids and new targets in the cells, which opens up new therapeutic possibilities. PMID:22594894

  19. Innate inflammatory responses in stroke: mechanisms and potential therapeutic targets

    PubMed Central

    Kim, Jong Youl; Kawabori, Masahito; Yenari, Midori A.

    2014-01-01

    Stroke is a frequent cause of long-term disability and death worldwide. Ischemic stroke is more commonly encountered compared to hemorrhagic stroke, and leads to tissue death by ischemia due to occlusion of a cerebral artery. Inflammation is known to result as a result of ischemic injury, long thought to be involved in initiating the recovery and repair process. However, work over the past few decades indicates that aspects of this inflammatory response may in fact be detrimental to stroke outcome. Acutely, inflammation appears to have a detrimental effect, and anti-inflammatory treatments have been been studied as a potential therapeutic target. Chronically, reports suggest that post-ischemic inflammation is also essential for the tissue repairing and remodeling. The majority of the work in this area has centered around innate immune mechanisms, which will be the focus of this review. This review describes the different key players in neuroinflammation and their possible detrimental and protective effects in stroke. A better understanding of the roles of the different immune cells and their temporal profile of damage versus repair will help to clarify more effective modulation of inflammation post stroke. Introduction Stroke refers to conditions caused by occlusion and/or rupture of blood vessels in the brain, and is a leading cause of death and disability in the industrialized world. PMID:24372209

  20. Astaxanthin: A Potential Therapeutic Agent in Cardiovascular Disease

    PubMed Central

    Fassett, Robert G.; Coombes, Jeff S.

    2011-01-01

    Astaxanthin is a xanthophyll carotenoid present in microalgae, fungi, complex plants, seafood, flamingos and quail. It is an antioxidant with anti-inflammatory properties and as such has potential as a therapeutic agent in atherosclerotic cardiovascular disease. Synthetic forms of astaxanthin have been manufactured. The safety, bioavailability and effects of astaxanthin on oxidative stress and inflammation that have relevance to the pathophysiology of atherosclerotic cardiovascular disease, have been assessed in a small number of clinical studies. No adverse events have been reported and there is evidence of a reduction in biomarkers of oxidative stress and inflammation with astaxanthin administration. Experimental studies in several species using an ischaemia-reperfusion myocardial model demonstrated that astaxanthin protects the myocardium when administered both orally or intravenously prior to the induction of the ischaemic event. At this stage we do not know whether astaxanthin is of benefit when administered after a cardiovascular event and no clinical cardiovascular studies in humans have been completed and/or reported. Cardiovascular clinical trials are warranted based on the physicochemical and antioxidant properties, the safety profile and preliminary experimental cardiovascular studies of astaxanthin. PMID:21556169

  1. Potential prognostic, diagnostic and therapeutic markers for human gastric cancer

    PubMed Central

    Tsai, Ming-Ming; Wang, Chia-Siu; Tsai, Chung-Ying; Chi, Hsiang-Cheng; Tseng, Yi-Hsin; Lin, Kwang-Huei

    2014-01-01

    The high incidence of gastric cancer (GC) and its consequent mortality rate severely threaten human health. GC is frequently not diagnosed until a relatively advanced stage. Surgery is the only potentially curative treatment. Thus, early screening and diagnosis are critical for improving prognoses in patients with GC. Gastroscopy with biopsy is an appropriate method capable of aiding the diagnosis of specific early GC tumor types; however, the stress caused by this method together with it being excessively expensive makes it difficult to use it as a routine method for screening for GC on a population basis. The currently used tumor marker assays for detecting GC are simple and rapid, but their use is limited by their low sensitivity and specificity. In recent years, several markers have been identified and tested for their clinical relevance in the management of GC. Here, we review the serum-based tumor markers for GC and their clinical significance, focusing on discoveries from microarray/proteomics research. We also review tissue-based GC tumor markers and their clinical application, focusing on discoveries from immunohistochemical research. This review provides a brief description of various tumor markers for the purposes of diagnosis, prognosis and therapeutics, and we include markers already in clinical practice and various forthcoming biomarkers. PMID:25320517

  2. Dopamine transporter ligands: recent developments and therapeutic potential.

    PubMed

    Runyon, Scott P; Carroll, F Ivy

    2006-01-01

    The dopamine transporter (DAT) is a target for the development of pharmacotherapies for a number of central disorders including Parkinson's disease, Alzheimer's disease, schizophrenia, Tourette's syndrome, Lesch-Nyhan disease, attention deficit hyperactivity disorder (ADHD), obesity, depression, and stimulant abuse as well as normal aging. Considerable effort continues to be devoted to the development of new ligands for the DAT. In this review, we present some of the more interesting ligands developed during the last few years from the 3-phenytropane, 1,4-dialkylpiperazine, phenylpiperidine, and benztropine classes of DAT uptake inhibitors as well as a few less studied miscellaneous DAT uptake inhibitors. Studies related to the therapeutic potential of some of the more studied compounds are presented. A few of the compounds have been studied as pharmacotherapies for Parkinson's disease, ADHD, and obesity. However, most of the drug discovery studies have been directed toward pharmacotherapies for stimulant abuse (mainly cocaine). A number of the compounds showed decreased cocaine maintained responding in rhesus monkeys trained to self-administer cocaine. One compound, GBR 12,909, was evaluated in a Phase 1 clinical trial. PMID:17017960

  3. Chelating polymeric beads as potential therapeutics for Wilson's disease.

    PubMed

    Mattová, Jana; Poučková, Pavla; Kučka, Jan; Skodová, Michaela; Vetrík, Miroslav; Stěpánek, Petr; Urbánek, Petr; Petřík, Miloš; Nový, Zbyněk; Hrubý, Martin

    2014-10-01

    Wilson's disease is a genetic disorder caused by a malfunction of ATPase 7B that leads to high accumulation of copper in the organism and consequent toxic effects. We propose a gentle therapy to eliminate the excessive copper content with oral administration of insoluble non-resorbable polymer sorbents containing selective chelating groups for copper(II). Polymeric beads with the chelating agents triethylenetetramine, N,N-di(2-pyridylmethyl)amine, and 8-hydroxyquinoline (8HQB) were investigated. In a preliminary copper uptake experiment, we found that 8HQB significantly reduced copper uptake (using copper-64 as a radiotracer) after oral administration in Wistar rats. Furthermore, we measured organ radioactivity in rats to demonstrate that 8HQB radiolabelled with iodine-125 is not absorbed from the gastrointestinal tract after oral administration. Non-resorbability and the blockade of copper uptake were also confirmed with small animal imaging (PET/CT) in mice. In a long-term experiment with Wistar rats fed a diet containing the polymers, we have found that there were no signs of polymer toxicity and the addition of polymers to the diet led to a significant reduction in the copper contents in the kidneys, brains, and livers of the rats. We have shown that polymers containing specific ligands could potentially be novel therapeutics for Wilson's disease. PMID:24815561

  4. Targeting CBLB as a potential therapeutic approach for disseminated candidiasis.

    PubMed

    Xiao, Yun; Tang, Juan; Guo, Hui; Zhao, Yixia; Tang, Rong; Ouyang, Song; Zeng, Qiuming; Rappleye, Chad A; Rajaram, Murugesan V S; Schlesinger, Larry S; Tao, Lijian; Brown, Gordon D; Langdon, Wallace Y; Li, Belinda T; Zhang, Jian

    2016-08-01

    Disseminated candidiasis has become one of the leading causes of hospital-acquired blood stream infections with high mobility and mortality. However, the molecular basis of host defense against disseminated candidiasis remains elusive, and treatment options are limited. Here we report that the E3 ubiquitin ligase CBLB directs polyubiquitination of dectin-1 and dectin-2, two key pattern-recognition receptors for sensing Candida albicans, and their downstream kinase SYK, thus inhibiting dectin-1- and dectin-2-mediated innate immune responses. CBLB deficiency or inactivation protects mice from systemic infection with a lethal dose of C. albicans, and deficiency of dectin-1, dectin-2, or both in Cblb(-/-) mice abrogates this protection. Notably, silencing the Cblb gene in vivo protects mice from lethal systemic C. albicans infection. Our data reveal that CBLB is crucial for homeostatic control of innate immune responses mediated by dectin-1 and dectin-2. Our data also indicate that CBLB represents a potential therapeutic target for protection from disseminated candidiasis. PMID:27428899

  5. Novel endogenous angiogenesis inhibitors and their therapeutic potential

    PubMed Central

    Rao, Nithya; Lee, Yu Fei; Ge, Ruowen

    2015-01-01

    Angiogenesis, the formation of new blood vessels from the pre-existing vasculature is essential for embryonic development and tissue homeostasis. It also plays critical roles in diseases such as cancer and retinopathy. A delicate balance between pro- and anti-angiogenic factors ensures normal physiological homeostasis. Endogenous angiogenesis inhibitors are proteins or protein fragments that are formed in the body and have the ability to limit angiogenesis. Many endogenous angiogenesis inhibitors have been discovered, and the list continues to grow. Endogenous protein/peptide inhibitors are relatively less toxic, better tolerated and have a lower risk of drug resistance, which makes them attractive as drug candidates. In this review, we highlight ten novel endogenous protein angiogenesis inhibitors discovered within the last five years, including ISM1, FKBPL, CHIP, ARHGAP18, MMRN2, SOCS3, TAp73, ZNF24, GPR56 and JWA. Although some of these proteins have been well characterized for other biological functions, we focus on their new and specific roles in angiogenesis inhibition and discuss their potential for therapeutic application. PMID:26364800

  6. Pueraria tuberosa: a review on its phytochemical and therapeutic potential.

    PubMed

    Maji, Amal K; Pandit, Subrata; Banerji, Pratim; Banerjee, Debdulal

    2014-01-01

    Pueraria tuberosa (Willd.) DC is a perennial herb commonly known as 'vidarikanda', distributed throughout south east Asia. The plant's tuber is widely used in ethanomedicine as well as in traditional systems of medicine, particularly in ayurveda. It has been used in various ayurvedic formulations as restorative tonic, antiaging, spermatogenic and immune booster and has been recommended for the treatment of cardiovascular diseases, hepatosplenomegaly, fertility disorders, menopausal syndrome, sexual debility and spermatorrhoea. Numerous bioactive phytochemicals, mostly isoflavonoids such as puerarin, genistein, daidzein, tuberosin and so on have been identified in the tuber. In vivo and in vitro studies have provided the support against traditional demands of the tuber as spermatogenic, immune booster, aphrodisiac, anti-inflammatory, cardiotonic and brain tonic. However, further studies are required to define the active phytochemical compositions and to validate its clinical utilisation in the herbal formulations for human uses. This review provides an overview of traditional applications, current knowledge on the phytochemistry, pharmacology and toxicology of P. tuberosa. This review also provides plausible hypotheses about how various isoflavones particularly puerarin, genistein and daidzein, individually or collectively, may be responsible for the therapeutic potential against a wide range of ailments. PMID:24980468

  7. Epigenetic targeting of histone deacetylase: therapeutic potential in Parkinson's disease?

    PubMed

    Harrison, Ian F; Dexter, David T

    2013-10-01

    Parkinson's disease (PD) is the most common movement disorder affecting more than 4million people worldwide. The primary motor symptoms of the disease are due to degeneration of dopaminergic nigrostriatal neurons. Dopamine replacement therapies have therefore revolutionised disease management by partially controlling these symptoms. However these drugs can produce debilitating side effects when used long term and do not protect degenerating neurons against death. Recent evidence has highlighted a pathological imbalance in PD between the acetylation and deacetylation of the histone proteins around which deoxyribonucleic acid (DNA) is coiled, in favour of excessive histone deacetylation. This mechanism of adding/removing acetyl groups to histone lysine residues is one of many epigenetic regulatory processes which control the expression of genes, many of which will be essential for neuronal survival. Hence, such epigenetic modifications may have a pathogenic role in PD. It has therefore been hypothesised that if this pathological imbalance can be corrected with the use of histone deacetylase inhibiting agents then neurodegeneration observed in PD can be ameliorated. This article will review the current literature with regard to epigenetic changes in PD and the use of histone deacetylase inhibitors (HDACIs) in PD: examining the evidence of the neuroprotective effects of numerous HDACIs in cellular and animal models of Parkinsonian cell death. Ultimately answering the question: does epigenetic targeting of histone deacetylases hold therapeutic potential in PD? PMID:23711791

  8. Metabotropic glutamate receptors: their therapeutic potential in anxiety.

    PubMed

    Spooren, Will; Lesage, Anne; Lavreysen, Hilde; Gasparini, Fabrizio; Steckler, Thomas

    2010-01-01

    Psychiatric and neurological disorders are linked to changes in synaptic excitatory processes with a key role for glutamate, that is, the most abundant excitatory amino-acid. Molecular cloning of the metabotropic glutamate (mGlu) receptors has led to the identification of eight mGlu receptors, which, in contrast to ligand-gated ion channels (responsible for fast excitatory transmission), modulate and fine-tune the efficacy of synaptic transmission. mGlu receptors are G protein-coupled and constitute a new group of "drugable" targets for the treatment of various CNS disorders. The recent discovery of small molecules that selectively bind to receptors of Groups I (mGlu1 and mGlu5) and II (mGlu2 and mGlu3) allowed significant advances in our understanding of the roles of these receptors in brain function and dysfunction including anxiety. Although investigation of the role of the Group III (mGlu4, 6, 7, and 8) receptors is less advanced, the generation of genetically manipulated animals and recent advances in the identification of subtype-selective compounds have revealed some first insights into the therapeutic potential of this group of receptors. PMID:21309118

  9. The therapeutic potential of milk thistle in diabetes.

    PubMed

    Kazazis, Christos E; Evangelopoulos, Angelos A; Kollas, Aris; Vallianou, Natalia G

    2014-01-01

    Milk thistle has been known for more than 2.000 years as a herbal remedy for a variety of disorders. It has mainly been used to treat liver and gallbladder diseases. Silibum marianum, the Latin term for the plant, and its seeds contain a whole family of natural compounds, called flavonolignans. Silimarin is a dry mixture of these compounds; it is extracted after processing with ethanol, methanol, and acetone. Silimarin contains mainly silibin A, silibin B, taxifolin, isosilibin A, isosilibin B, silichristin A, silidianin, and other compounds in smaller concentrations. Apart from its use in liver and gallbladder disorders, milk thistle has recently gained attention due to its hypoglycemic and hypolipidemic properties. Recently, a substance from milk thistle has been shown to possess peroxisome proliferator-activated receptor γ (PPARγ) agonist properties. PPARγ is the molecular target of thiazolidinediones, which are used clinically as insulin sensitizers to lower blood glucose levels in diabetes type 2 patients. The thiazolidinedione type of PPARγ ligands is an agonist with a very high binding affinity. However, this ligand type demonstrates a range of undesirable side effects, thus necessitating the search for new effective PPARγ agonists. Interestingly, studies indicate that partial agonism of PPARγ induces promising activity patterns by retaining the positive effects attributed to the full agonists, with reduced side effects. In this review, the therapeutic potential of milk thistle in the management of diabetes and its complications are discussed. PMID:25396404

  10. Glucocorticoid analogues: potential therapeutic alternatives for treating inflammatory muscle diseases.

    PubMed

    Reeves, Erica K M; Rayavarapu, Sree; Damsker, Jesse M; Nagaraju, Kanneboyina

    2012-03-01

    Glucocorticoids (GCs) have been prescribed to treat a variety of diseases, including inflammatory myopathies and Duchenne muscular dystrophy for over 50 years. However, their prescription remains controversial due to the significant side effects associated with the chronic treatment. It is a common belief that the clinical efficacy of GCs is due to their transrepression of pro-inflammatory genes through inhibition of inflammatory transcription factors (i.e. NF-κB, AP-1) whereas the adverse side effects are attributed to the glucocorticoid receptor (GR)-mediated transcription of target genes (transactivation). The past decade has seen an increased interest in the development of GR modulators that maintain the effective anti-inflammatory properties but lack the GR-dependent transcriptional response as a safe alternative to traditional GCs. Many of these analogues or "dissociative" compounds show potential promise in in vitro studies but fail to reach human clinical trials. In this review, we discuss molecular effects of currently prescribed GCs on skeletal muscle and also discuss the current state of development of GC analogues as alternative therapeutics for inflammatory muscle diseases. PMID:22214335

  11. The Therapeutic Potential of Milk Thistle in Diabetes

    PubMed Central

    Kazazis, Christos E.; Evangelopoulos, Angelos A.; Kollas, Aris; Vallianou, Natalia G.

    2014-01-01

    Milk thistle has been known for more than 2.000 years as a herbal remedy for a variety of disorders. It has mainly been used to treat liver and gallbladder diseases. Silibum marianum, the Latin term for the plant, and its seeds contain a whole family of natural compounds, called flavonolignans. Silimarin is a dry mixture of these compounds; it is extracted after processing with ethanol, methanol, and acetone. Silimarin contains mainly silibin A, silibin B, taxifolin, isosilibin A, isosilibin B, silichristin A, silidianin, and other compounds in smaller concentrations. Apart from its use in liver and gallbladder disorders, milk thistle has recently gained attention due to its hypoglycemic and hypolipidemic properties. Recently, a substance from milk thistle has been shown to possess peroxisome proliferator-activated receptor γ (PPARγ) agonist properties. PPARγ is the molecular target of thiazolidinediones, which are used clinically as insulin sensitizers to lower blood glucose levels in diabetes type 2 patients. The thiazolidinedione type of PPARγ ligands is an agonist with a very high binding affinity. However, this ligand type demonstrates a range of undesirable side effects, thus necessitating the search for new effective PPARγ agonists. Interestingly, studies indicate that partial agonism of PPARγ induces promising activity patterns by retaining the positive effects attributed to the full agonists, with reduced side effects. In this review, the therapeutic potential of milk thistle in the management of diabetes and its complications are discussed. PMID:25396404

  12. New therapeutic strategies for the treatment of male lower urinary tract symptoms

    PubMed Central

    Dimitropoulos, Konstantinos; Gravas, Stavros

    2016-01-01

    Male lower urinary tract symptoms (LUTS) are prevalent in the general population, especially in those of advanced age, and are characterized by notable diversity in etiology and presentation, and have been proven to cause various degrees of impairment on quality of life. The prostate has traditionally been regarded as the core cause of male LUTS. As a result, medical treatment aims to provide symptomatic relief and effective management of progression of male LUTS due to benign prostatic enlargement. In this context, α1-blockers, phosphodiesterase-5 inhibitors, and 5α-reductase inhibitors have long been used as monotherapies or in combination treatment to control voiding LUTS. There is accumulating evidence, however, that highlights the role of the bladder in the pathogenesis of male LUTS. Current research interests have shifted to bladder disorders, and medical management is aimed at the bladder. Muscarinic receptor antagonists and the newly approved β3-adrenergic agonist mirabegron aim to alleviate the most bothersome storage LUTS and thus improve quality of life. As voiding and storage LUTS frequently coexist, combination therapeutic strategies with α1-blockers and antimuscarinics or β3-agonists have been introduced to manage symptoms effectively. Anti-inflammatory agents, vitamin D3-receptor analogs, and cannabinoids represent treatment modalities currently under investigation for use in LUTS patients. Furthermore, luteinizing hormone-releasing hormone antagonists, transient receptor-potential channel blockers, purinergic neurotransmission antagonists, Rho-kinase inhibitors, and inhibitors of endothelin-converting enzymes could have therapeutic potential in LUTS management, but still remain in the experimental setting. This article reviews new strategies for the medical treatment of male LUTS, which are dictated by the potential role of the bladder and the risk of benign prostatic hyperplasia progression. Moreover, combination treatments and therapies

  13. Potential therapeutic mechanism of K(+) channel block for MS.

    PubMed

    Baker, Mark D

    2013-10-01

    While the potential use of K(+) channel blockers in MS has been explored over many years, the approval in the US, and more recently in the UK, of fampyra (fampridine, 4-aminopyridine, 4-AP) as a symptomatic treatment for walking disability, has reawakened interest. Recent years have seen a real improvement in the treatment options for relapsing remitting MS, but the disease remains inadequately treated, with the progressive phase (characterised by irreversible functional loss) lacking any effective therapy. Whether the symptomatic relief afforded by 4-AP translates into neuroprotection, remains poorly investigated, although there is no clear reason why this would be expected. Importantly, future clinical studies may shed light on this question. This review includes an overview of axonal K(+) channel expression and pharmacology, and the logic of the use of K(+) channel blockers derived from observations in experimental studies of demyelination and synaptic transmission. It provides an insight into the probable biophysical actions of 4-AP, and how its action may aid in the symptomatic treatment of MS. The key message of this review is that 4-AP is a blocker of neuronal K(+) channels, and its administration is known to be of value in the symptomatic treatment of some patients. The details of the mechanism underlying the beneficial effects remain somewhat vague, and the molecular target has not been properly defined. The useful mechanism is likely to include an action on synaptic function, but whether it is the presynaptic terminal or the presynaptic axon that is the primary target is unknown. It is argued that because of the apparent inability of 4-AP to increase safety factor in experimental demyelination when clinically relevant concentrations are used, it cannot be the ideal pharmacological agent for treating demyelination by the widening of axonal action potentials. That said, it remains a possibility that the useful therapeutic effect of 4-AP may involve subtle

  14. Therapeutic cell carriers: a potential road to cure glioma.

    PubMed

    Young, Jacob S; Kim, Julius W; Ahmed, Atique U; Lesniak, Maciej S

    2014-06-01

    Many different experimental molecular therapeutic approaches have been evaluated in an attempt to treat brain cancer. However, despite the success of these experimental molecular therapies, research has shown that the specific and efficient delivery of therapeutic agents to tumor cells is a limitation. In this regard, cell carrier systems have garnered significant attraction due to their capacity to be loaded with therapeutic agents and carry them specifically to tumor sites. Furthermore, cell carriers can be genetically modified to express therapeutic agents that can directly eradicate cancerous cells or can modulate tumor microenvironments. This review describes the current state of cell carriers, their use as vehicles for the delivery of therapeutic agents to brain tumors, and future directions that will help overcome the present obstacles to cell carrier mediated therapy for brain cancer. PMID:24852229

  15. Triterpenoid inducers of Nrf2 signaling as potential therapeutic agents in sickle cell disease: a review.

    PubMed

    Owusu-Ansah, Amma; Choi, Sung Hee; Petrosiute, Agne; Letterio, John J; Huang, Alex Yee-Chen

    2015-03-01

    Sickle cell disease (SCD) is an inherited disorder of hemoglobin in which the abnormal hemoglobin S polymerizes when deoxygenated. This polymerization of hemoglobin S not only results in hemolysis and vasoocclusion but also precipitates inflammation, oxidative stress and chronic organ dysfunction. Oxidative stress is increasingly recognized as an important intermediate in these pathophysiological processes and is therefore an important target for therapeutic intervention. The transcription factor nuclear erythroid derived-2 related factor 2 (Nrf2) controls the expression of anti-oxidant enzymes and is emerging as a protein whose function can be exploited with therapeutic intent. This review article is focused on triterpenoids that activate Nrf2, and their potential for reducing oxidative stress in SCD as an approach to prevent organ dysfunction associated with this disease. A brief overview of oxidative stress in the clinical context of SCD is accompanied by a discussion of several pathophysiological mechanisms contributing to oxidative stress. Finally, these mechanisms are then related to current management strategies in SCD that are either utilized currently or under evaluation. The article concludes with a perspective on the potential of the various therapeutic interventions to reduce oxidative stress and morbidity associated with SCD. PMID:25511620

  16. Moving towards effective therapeutic strategies for Neuronal Ceroid Lipofuscinosis.

    PubMed

    Geraets, Ryan D; Koh, Seung yon; Hastings, Michelle L; Kielian, Tammy; Pearce, David A; Weimer, Jill M

    2016-01-01

    The Neuronal Ceroid Lipofuscinoses (NCLs) are a family of autosomal recessive neurodegenerative disorders that annually affect 1:100,000 live births worldwide. This family of diseases results from mutations in one of 14 different genes that share common clinical and pathological etiologies. Clinically, the diseases are subcategorized into infantile, late-infantile, juvenile and adult forms based on their age of onset. Though the disease phenotypes may vary in their age and order of presentation, all typically include progressive visual deterioration and blindness, cognitive impairment, motor deficits and seizures. Pathological hallmarks of NCLs include the accumulation of storage material or ceroid in the lysosome, progressive neuronal degeneration and massive glial activation. Advances have been made in genetic diagnosis and counseling for families. However, comprehensive treatment programs that delay or halt disease progression have been elusive. Current disease management is primarily targeted at controlling the symptoms rather than "curing" the disease. Recognizing the growing need for transparency and synergistic efforts to move the field forward, this review will provide an overview of the therapeutic approaches currently being pursued in preclinical and clinical trials to treat different forms of NCL as well as provide insight to novel therapeutic approaches in development for the NCLs. PMID:27083890

  17. [New therapeutic strategies for remyelination in multiple sclerosis].

    PubMed

    Kremer, D; Hartung, H-P; Stangel, M; Küry, P

    2015-08-01

    Multiple sclerosis (MS) is characterized by oligodendrocyte death and myelin sheath destruction of the central nervous system (CNS) in response to autoinflammatory processes. Besides demyelination axonal degeneration constitutes the second histopathological hallmark of this disease. A large number of immunomodulatory and targeted immunosuppression treatments have been approved for relapsing remitting (RR) MS where they effectively reduce relapse rates; however, currently no treatment options exist to repair injured axonal tracts or myelin damage that accumulates over time particularly in progressive MS. In light of the growing available therapeutic repertoire of highly potent immunomodulatory medications there is an increasing interest in the development of therapies aimed at neutralizing neurodegenerative damage. Endogenous remyelination processes occur mainly as a result of oligodendrocyte precursor cell (OPC) activation, recruitment and maturation; however, this repair activity appears to be limited and increasingly fails during disease progression. Based on these observations OPCs are considered as promising targets for the regenerative treatment of all stages of MS. This article presents an overview of approved medications with a suggested role in regeneration, regenerative treatments that are currently being tested in clinical trials, as well as promising future therapeutic approaches derived from basic glial cell research aiming at the promotion of the endogenous repair activity of the brain. PMID:26122637

  18. Personalized therapeutic strategies for patients with retinitis pigmentosa

    PubMed Central

    Zheng, Andrew; Li, Yao

    2015-01-01

    Introduction Retinitis pigmentosa (RP) encompasses many different hereditary retinal degenerations that are caused by a vast array of different gene mutations and have highly variable disease presentations and severities. This heterogeneity poses a significant therapeutic challenge, although an answer may eventually be found through two recent innovations: induced pluripotent stem cells (iPSCs) and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas genome editing. Areas covered This review discusses the wide-ranging applications of iPSCs and CRISPR–including disease modelling, diagnostics and therapeutics – with an ultimate view towards understanding how these two technologies can come together to address disease heterogeneity and orphan genes in a novel personalized medicine platform. An extensive literature search was conducted in PubMed and Google Scholar, with a particular focus on high-impact research published within the last 1 – 2 years and centered broadly on the subjects of retinal gene therapy, iPSC-derived outer retina cells, stem cell transplantation and CRISPR/Cas gene editing. Expert opinion For the retinal pigment epithelium, autologous transplantation of gene-corrected grafts derived from iPSCs may well be technically feasible in the near future. Photoreceptor transplantation faces more significant unresolved technical challenges but remains an achievable, if more distant, goal given the rapid pace of advancements in the field. PMID:25613576

  19. Metallic ions as therapeutic agents in tissue engineering scaffolds: an overview of their biological applications and strategies for new developments

    PubMed Central

    Mouriño, Viviana; Cattalini, Juan Pablo; Boccaccini, Aldo R.

    2012-01-01

    This article provides an overview on the application of metallic ions in the fields of regenerative medicine and tissue engineering, focusing on their therapeutic applications and the need to design strategies for controlling the release of loaded ions from biomaterial scaffolds. A detailed summary of relevant metallic ions with potential use in tissue engineering approaches is presented. Remaining challenges in the field and directions for future research efforts with focus on the key variables needed to be taken into account when considering the controlled release of metallic ions in tissue engineering therapeutics are also highlighted. PMID:22158843

  20. Role and therapeutic potential of G-protein coupled receptors in breast cancer progression and metastases

    PubMed Central

    Singh, Anukriti; Nunes, Jessica J.; Ateeq, Bushra

    2015-01-01

    G-protein-coupled receptors (GPCRs) comprise a large family of cell-surface receptors, which have recently emerged as key players in tumorigenesis, angiogenesis and metastasis. In this review, we discussed our current understanding of the many roles played by GPCRs in general, and particularly Angiotensin II type I receptor (AGTR1), a member of the seven-transmembrane-spanning G-protein coupled receptor superfamily, and its significance in breast cancer progression and metastasis. We have also discussed different strategies for targeting AGTR1, and its ligand Angiotension II (Ang II), which might unravel unique opportunities for breast cancer prevention and treatment. For example, AGTR1 blockers (ARBs) which are already in clinical use for treating hypertension, merit further investigation as a therapeutic strategy for AGTR1-positive cancer patients and may have the potential to prevent Ang II-AGTR1 signalling mediated cancer pathogenesis and metastases. PMID:25981295

  1. Role and therapeutic potential of G-protein coupled receptors in breast cancer progression and metastases.

    PubMed

    Singh, Anukriti; Nunes, Jessica J; Ateeq, Bushra

    2015-09-15

    G-protein-coupled receptors (GPCRs) comprise a large family of cell-surface receptors, which have recently emerged as key players in tumorigenesis, angiogenesis and metastasis. In this review, we discussed our current understanding of the many roles played by GPCRs in general, and particularly Angiotensin II type I receptor (AGTR1), a member of the seven-transmembrane-spanning G-protein coupled receptor superfamily, and its significance in breast cancer progression and metastasis. We have also discussed different strategies for targeting AGTR1, and its ligand Angiotension II (Ang II), which might unravel unique opportunities for breast cancer prevention and treatment. For example, AGTR1 blockers (ARBs) which are already in clinical use for treating hypertension, merit further investigation as a therapeutic strategy for AGTR1-positive cancer patients and may have the potential to prevent Ang II-AGTR1 signalling mediated cancer pathogenesis and metastases. PMID:25981295

  2. Enhanced Delivery of Gold Nanoparticles with Therapeutic Potential for Targeting Human Brain Tumors

    NASA Astrophysics Data System (ADS)

    Etame, Arnold B.

    The blood brain barrier (BBB) remains a major challenge to the advancement and application of systemic anti-cancer therapeutics into the central nervous system. The structural and physiological delivery constraints of the BBB significantly limit the effectiveness of conventional chemotherapy, thereby making systemic administration a non-viable option for the vast majority of chemotherapy agents. Furthermore, the lack of specificity of conventional systemic chemotherapy when applied towards malignant brain tumors remains a major shortcoming. Hence novel therapeutic strategies that focus both on targeted and enhanced delivery across the BBB are warranted. In recent years nanoparticles (NPs) have emerged as attractive vehicles for efficient delivery of targeted anti-cancer therapeutics. In particular, gold nanoparticles (AuNPs) have gained prominence in several targeting applications involving systemic cancers. Their enhanced permeation and retention within permissive tumor microvasculature provide a selective advantage for targeting. Malignant brain tumors also exhibit transport-permissive microvasculature secondary to blood brain barrier disruption. Hence AuNPs may have potential relevance for brain tumor targeting. However, the permeation of AuNPs across the BBB has not been well characterized, and hence is a potential limitation for successful application of AuNP-based therapeutics within the central nervous system (CNS). In this dissertation, we designed and characterized AuNPs and assessed the role of polyethylene glycol (PEG) on the physical and biological properties of AuNPs. We established a size-dependent permeation profile with respect to core size as well as PEG length when AuNPs were assessed through a transport-permissive in-vitro BBB. This study was the first of its kind to systematically examine the influence of design on permeation of AuNPs through transport-permissive BBB. Given the significant delivery limitations through the non

  3. Amyloid Beta and Tau Proteins as Therapeutic Targets for Alzheimer's Disease Treatment: Rethinking the Current Strategy

    PubMed Central

    Mondragón-Rodríguez, Siddhartha; Perry, George; Zhu, Xiongwei; Boehm, Jannic

    2012-01-01

    Alzheimer's disease (AD) is defined by the concurrence of accumulation of abnormal aggregates composed of two proteins: Amyloid beta (Aβ) and tau, and of cellular changes including neurite degeneration and loss of neurons and cognitive functions. Based on their strong association with disease, genetically and pathologically, it is not surprising that there has been a focus towards developing therapies against the aggregated structures. Unfortunately, current therapies have but mild benefit. With this in mind we will focus on the relationship of synaptic plasticity with Aβ and tau protein and their role as potential targets for the development of therapeutic drugs. Finally, we will provide perspectives in developing a multifactorial strategy for AD treatment. PMID:22482074

  4. [Mantle cell lymphoma: Towards a personalized therapeutic strategy?].

    PubMed

    Navarro Matilla, Belén; García-Marco, José A

    2015-06-22

    Mantle cell lymphoma (MCL) is a clinically heterogeneous non-Hodgkin lymphoma with an aggressive clinical behaviour and short survival in some cases and an indolent course in others. Advances in the biology and pathogenesis of MCL have unveiled several genes involved in deregulation of cell cycle checkpoints and the finding of subclonal populations with specific recurrent mutations (p53, ATM, NOTCH2) with an impact on disease progression and refractoriness to treatment. Prognostic stratification helps to distinguish between indolent and aggressive forms of MCL. Currently, younger fit patients benefit from more intensive front line chemotherapy regimens and consolidation with autologous transplantation, while older or frail patients are treated with less intensive regimens and rituximab maintenance. For relapsing disease, the introduction of bortezomib and lenalidomide containing regimens and B-cell receptor pathway inhibitors such as ibrutinib and idelalisib in combination with immunochemotherapy have emerged as therapeutic agents with promising clinical outcomes. PMID:25023849

  5. Therapeutic potential of thalidomide for gemcitabine-resistant bladder cancer.

    PubMed

    Huang, Yen Ta; Cheng, Chuan Chu; Chiu, Ted H; Lai, Pei Chun

    2015-11-01

    Controversial effects of thalidomide for solid malignancies have been reported. In the present study, we evaluate the effects of thalidomide for transitional cell carcinoma (TCC), the most common type of bladder cancer. Thalidomide precipitates were observed when its DMSO solution was added to the culture medium. No precipitation was found when thalidomide was dissolved in 45% γ-cyclodextrin, and this concentration of γ-cyclodextrin elicited slight cytotoxicity on TCC BFTC905 and primary human urothelial cells. Thalidomide-γ-cyclodextrin complex exerted a concentration-dependent cytotoxicity in TCC cells, but was relatively less cytotoxic (with IC50 of 200 µM) in BFTC905 cells than the other 3 TCC cell lines, possibly due to upregulation of Bcl-xL and HIF-1α mediated carbonic anhydrase IX, and promotion of quiescence. Gemcitabine-resistant BFTC905 cells were chosen for additional experiments. Thalidomide induced apoptosis through downregulation of survivin and securin. The secretion of VEGF and TNF-α was ameliorated by thalidomide, but they did not affect cell proliferation. Immune-modulating lenalidomide and pomalidomide did not elicit cytotoxicity. In addition, cereblon did not play a role in the thalidomide effect. Oxidative DNA damage was triggered by thalidomide, and anti-oxidants reversed the effect. Thalidomide also inhibited TNF-α induced invasion through inhibition of NF-κB, and downregulation of effectors, ICAM-1 and MMP-9. Thalidomide inhibited the growth of BFTC905 xenograft tumors in SCID mice via induction of DNA damage and suppression of angiogenesis. Higher average body weight, indicating less chachexia, was observed in thalidomide treated group. Sedative effect was observed within one-week of treatment. These pre-clinical results suggest therapeutic potential of thalidomide for gemcitabine-resistant bladder cancer. PMID:26398114

  6. Myostatin/activin pathway antagonism: molecular basis and therapeutic potential.

    PubMed

    Han, H Q; Zhou, Xiaolan; Mitch, William E; Goldberg, Alfred L

    2013-10-01

    Muscle wasting is associated with a wide range of catabolic diseases. This debilitating loss of muscle mass and functional capacity reduces the quality of life and increases the risks of morbidity and mortality. Major progress has been made in understanding the biochemical mechanisms and signaling pathways regulating muscle protein balance under normal conditions and the enhanced protein loss in atrophying muscles. It is now clear that activation of myostatin/activin signaling is critical in triggering the accelerated muscle catabolism that causes muscle loss in multiple disease states. Binding of myostatin and activin to the ActRIIB receptor complex on muscle cell membrane leads to activation of Smad2/3-mediated transcription, which in turn stimulates FoxO-dependent transcription and enhanced muscle protein breakdown via ubiquitin-proteasome system and autophagy. In addition, Smad activation inhibits muscle protein synthesis by suppressing Akt signaling. Pharmacological blockade of the myostatin/activin-ActRIIB pathway has been shown to prevent or reverse the loss of muscle mass and strength in various disease models including cancer cachexia and renal failure. Moreover, it can markedly prolong the lifespan of animals with cancer-associated muscle loss. Furthermore, inhibiting myostatin/activin actions also improves insulin sensitivity, reduces excessive adiposity, attenuates systemic inflammation, and accelerates bone fracture healing in disease models. Based on these exciting advances, the potential therapeutic benefits of myostatin/activin antagonism are now being tested in multiple clinical settings. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting. PMID:23721881

  7. Human rhabdomyosarcoma cells express functional erythropoietin receptor: Potential therapeutic implications

    PubMed Central

    PONIEWIERSKA-BARAN, AGATA; SUSZYNSKA, MALWINA; SUN, WENYUE; ABDELBASET-ISMAIL, AHMED; SCHNEIDER, GABRIELA; BARR, FREDERIC G.; RATAJCZAK, MARIUSZ Z.

    2015-01-01

    The erythropoietin receptor (EpoR) is expressed by cells from the erythroid lineage; however, evidence has accumulated that it is also expressed by some solid tumors. This is an important observation, because recombinant erythropoietin (EPO) is employed in cancer patients to treat anemia related to chemo/radiotherapy. In our studies we employed eight rhabdomyosarcoma (RMS) cell lines (three alveolar-type RMS cell lines and five embrional-type RMS cell lines), and mRNA samples obtained from positive, PAX7-FOXO1-positive, and fusion-negative RMS patient samples. Expression of EpoR was evaluated by RT-PCR, gene array and FACS. The functionality of EpoR in RMS cell lines was evaluated by chemotaxis, adhesion, and direct cell proliferation assays. In some of the experiments, RMS cells were exposed to vincristine (VCR) in the presence or absence of EPO to test whether EPO may impair the therapeutic effect of VCR. We report for a first time that functional EpoR is expressed in human RMS cell lines as well as by primary tumors from RMS patients. Furthermore, EpoR is detectably expressed in both embryonal and alveolar RMS subtypes. At the functional level, several human RMS cell lines responded to EPO stimulation by enhanced proliferation, chemotaxis, cell adhesion, and phosphorylation of MAPKp42/44 and AKT. Moreover, RMS cells became more resistant to VCR treatment in the presence of EPO. Our findings have important potential clinical implications, indicating that EPO supplementation in RMS patients may have the unwanted side effect of tumor progression. PMID:26412593

  8. Human rhabdomyosarcoma cells express functional erythropoietin receptor: Potential therapeutic implications.

    PubMed

    Poniewierska-Baran, Agata; Suszynska, Malwina; Sun, Wenyue; Abdelbaset-Ismail, Ahmed; Schneider, Gabriela; Barr, Frederic G; Ratajczak, Mariusz Z

    2015-11-01

    The erythropoietin receptor (EpoR) is expressed by cells from the erythroid lineage; however, evidence has accumulated that it is also expressed by some solid tumors. This is an important observation, because recombinant erythropoietin (EPO) is employed in cancer patients to treat anemia related to chemo/radiotherapy. In our studies we employed eight rhabdomyosarcoma (RMS) cell lines (three alveolar-type RMS cell lines and five embrional-type RMS cell lines), and mRNA samples obtained from positive, PAX7-FOXO1-positive, and fusion-negative RMS patient samples. Expression of EpoR was evaluated by RT-PCR, gene array and FACS. The functionality of EpoR in RMS cell lines was evaluated by chemotaxis, adhesion, and direct cell proliferation assays. In some of the experiments, RMS cells were exposed to vincristine (VCR) in the presence or absence of EPO to test whether EPO may impair the therapeutic effect of VCR. We report for a first time that functional EpoR is expressed in human RMS cell lines as well as by primary tumors from RMS patients. Furthermore, EpoR is detectably expressed in both embryonal and alveolar RMS subtypes. At the functional level, several human RMS cell lines responded to EPO stimulation by enhanced proliferation, chemotaxis, cell adhesion, and phosphorylation of MAPKp42/44 and AKT. Moreover, RMS cells became more resistant to VCR treatment in the presence of EPO. Our findings have important potential clinical implications, indicating that EPO supplementation in RMS patients may have the unwanted side effect of tumor progression. PMID:26412593

  9. Llama Nanoantibodies with Therapeutic Potential against Human Norovirus Diarrhea

    PubMed Central

    Garaicoechea, Lorena; Aguilar, Andrea; Parra, Gabriel I.; Bok, Marina; Sosnovtsev, Stanislav V.; Canziani, Gabriela; Green, Kim Y.; Bok, Karin; Parreño, Viviana

    2015-01-01

    Noroviruses are a major cause of acute gastroenteritis, but no vaccines or therapeutic drugs are available. Llama-derived single chain antibody fragments (also called VHH) are small, recombinant monoclonal antibodies of 15 kDa with several advantages over conventional antibodies. The aim of this study was to generate recombinant monoclonal VHH specific for the two major norovirus (NoV) genogroups (GI and GII) in order to investigate their potential as immunotherapy for the treatment of NoV diarrhea. To accomplish this objective, two llamas were immunized with either GI.1 (Norwalk-1968) or GII.4 (MD2004) VLPs. After immunization, peripheral blood lymphocytes were collected and used to generate two VHH libraries. Using phage display technology, 10 VHH clones specific for GI.1, and 8 specific for GII.4 were selected for further characterization. All VHH recognized conformational epitopes in the P domain of the immunizing VP1 capsid protein, with the exception of one GII.4 VHH that recognized a linear P domain epitope. The GI.1 VHHs were highly specific for the immunizing GI.1 genotype, with only one VHH cross-reacting with GI.3 genotype. The GII.4 VHHs reacted with the immunizing GII.4 strain and showed a varying reactivity profile among different GII genotypes. One VHH specific for GI.1 and three specific for GII.4 could block the binding of homologous VLPs to synthetic HBGA carbohydrates, saliva, and pig gastric mucin, and in addition, could inhibit the hemagglutination of red blood cells by homologous VLPs. The ability of Nov-specific VHHs to perform well in these surrogate neutralization assays supports their further development as immunotherapy for NoV treatment and immunoprophylaxis. PMID:26267898

  10. REOVIRUS: A TARGETED THERAPEUTIC – PROGRESS AND POTENTIAL

    PubMed Central

    Maitra, Radhashree; Ghalib, Mohammad H.; Goel, Sanjay

    2013-01-01

    Medical therapy of patients with malignancy requires a paradigm shift through development of new drugs with a good safety record and novel mechanisms of activity. While there is no dearth of such molecules, one particular agent, “reovirus” is promising by its ability to target cancer cells with aberrant signaling pathways. This double stranded RNA virus has been therapeutically formulated and has rapidly progressed from pre-clinical validation of anti cancer activity to a phase III registration study in platinum refractory metastatic squamous cell carcinoma of the head and neck. During this process, reovirus has demonstrated safety both as a single agent when administered intratumorally and intravenously, as well as in combination therapy, with multiple chemotherapeutics such as gemcitabine, carboplatin/paclitaxel, and docetaxel; and similarly with radiation. The scientific rationale for its development as an anticancer agent stems from the fact that it preferentially replicates in and induces lyses of cells with an activated Kras pathway. As documented in many previous studies, the initial observation of greater tropism in Kras compromised situation might certainly not be the sole and possibly not even the predominant reason for enhanced virulence. All the same, scientists have emphasized on Kras optimistically due to its high prevalence in various types of cancers. Incidence of Kras mutation has been found to be highest in pancreatic cancer (85–90%) followed by colorectal (35–45%) and lung (25–30%). Reovirus, in fact has the potential not only as a therapy but also as a tool to unravel the aberrant cellular pathway leading to carcinogenicity. PMID:23038811

  11. Llama nanoantibodies with therapeutic potential against human norovirus diarrhea.

    PubMed

    Garaicoechea, Lorena; Aguilar, Andrea; Parra, Gabriel I; Bok, Marina; Sosnovtsev, Stanislav V; Canziani, Gabriela; Green, Kim Y; Bok, Karin; Parreño, Viviana

    2015-01-01

    Noroviruses are a major cause of acute gastroenteritis, but no vaccines or therapeutic drugs are available. Llama-derived single chain antibody fragments (also called VHH) are small, recombinant monoclonal antibodies of 15 kDa with several advantages over conventional antibodies. The aim of this study was to generate recombinant monoclonal VHH specific for the two major norovirus (NoV) genogroups (GI and GII) in order to investigate their potential as immunotherapy for the treatment of NoV diarrhea. To accomplish this objective, two llamas were immunized with either GI.1 (Norwalk-1968) or GII.4 (MD2004) VLPs. After immunization, peripheral blood lymphocytes were collected and used to generate two VHH libraries. Using phage display technology, 10 VHH clones specific for GI.1, and 8 specific for GII.4 were selected for further characterization. All VHH recognized conformational epitopes in the P domain of the immunizing VP1 capsid protein, with the exception of one GII.4 VHH that recognized a linear P domain epitope. The GI.1 VHHs were highly specific for the immunizing GI.1 genotype, with only one VHH cross-reacting with GI.3 genotype. The GII.4 VHHs reacted with the immunizing GII.4 strain and showed a varying reactivity profile among different GII genotypes. One VHH specific for GI.1 and three specific for GII.4 could block the binding of homologous VLPs to synthetic HBGA carbohydrates, saliva, and pig gastric mucin, and in addition, could inhibit the hemagglutination of red blood cells by homologous VLPs. The ability of Nov-specific VHHs to perform well in these surrogate neutralization assays supports their further development as immunotherapy for NoV treatment and immunoprophylaxis. PMID:26267898

  12. Ebola virus outbreak, updates on current therapeutic strategies.

    PubMed

    Elshabrawy, Hatem A; Erickson, Timothy B; Prabhakar, Bellur S

    2015-07-01

    Filoviruses are enveloped negative-sense single-stranded RNA viruses, which include Ebola and Marburg viruses, known to cause hemorrhagic fever in humans with a case fatality of up to 90%. There have been several Ebola virus outbreaks since the first outbreak in the Democratic Republic of Congo in 1976 of which, the recent 2013-2015 epidemic in Guinea, Liberia, and Sierra Leone is the largest in recorded history. Within a few months of the start of the outbreak in December 2013, thousands of infected cases were reported with a significant number of deaths. As of March 2015, according to the Centers for Disease Control and Prevention, there have been nearly 25,000 suspected cases, with 15,000 confirmed by laboratory testing, and over 10,000 deaths. The large number of cases and the high mortality rate, combined with the lack of effective Food and Drug Administration-approved treatments, necessitate the development of potent and safe therapeutic measures to combat the current and future outbreaks. Since the beginning of the outbreak, there have been considerable efforts to develop and characterize protective measures including vaccines and antiviral small molecules, and some have proven effective in vitro and in animal models. Most recently, a cocktail of monoclonal antibodies has been shown to be highly effective in protecting non-human primates from Ebola virus infection. In this review, we will discuss what is known about the nature of the virus, phylogenetic classification, genomic organization and replication, disease transmission, and viral entry and highlight the current approaches and efforts, in the development of therapeutics, to control the outbreak. PMID:25962887

  13. PHARMACOLOGICAL ANTIOXIDANT STRATEGIES AS THERAPEUTIC INTERVENTIONS FOR COPD

    PubMed Central

    2011-01-01

    Cigarette/tobacco smoke/biomass fuel-induced oxidative and aldehyde/carbonyl stress are intimately associated with the progression and exacerbation of chronic obstructive pulmonary disease (COPD). Therefore, targeting systemic and local oxidative stress with antioxidants/redox modulating agents, or boosting the endogenous levels of antioxidants are likely to have beneficial effects in the treatment/management of COPD. Various antioxidant agents, such as thiol molecules (glutathione and mucolytic drugs, such as N-acetyl-L-cysteine and N-acystelyn, erdosteine, fudosteine, ergothioneine, and carbocysteine), all have been reported to modulate various cellular and biochemical aspects of COPD. These antioxidants have been found to scavenge and detoxify free radicals and oxidants, regulate of glutathione biosynthesis, control nuclear factor-kappaB (NF-kappaB) activation, and hence inhibiting inflammatory gene expression. Synthetic molecules, such as specific spin traps like α-phenyl-N-tert-butyl nitrone, a catalytic antioxidant (ECSOD mimetic), porphyrins (AEOL 10150 and AEOL 10113), and a superoxide dismutase mimetic M40419, iNOS inhibitors, lipid peroxidation inhibitors/blockers edaravone, and lazaroids/tirilazad have also been shown to have beneficial effects by inhibiting the cigarette smoke-induced inflammatory responses and other carbonyl/oxidative stress-induced cellular alterations. A variety of oxidants, free radicals, and carbonyls/aldehydes are implicated in the pathogenesis of COPD, it is therefore, possible that therapeutic administration or supplementation of multiple antioxidants and/or boosting the endogenous levels of antioxidants will be beneficial in the treatment of COPD. This review discusses various novel pharmacological approaches adopted to enhance lung antioxidant levels, and various emerging beneficial and/or prophylactic effects of antioxidant therapeutics in halting or intervening the progression of COPD. PMID:22101076

  14. Current Diagnostic and Therapeutic Strategies in Microvascular Angina

    PubMed Central

    Mumma, Bryn; Flacke, Nathalie

    2014-01-01

    Microvascular angina is common among patients with signs and symptoms of acute coronary syndrome and is associated with an increased risk of cardiovascular and cerebrovascular events. Unfortunately, microvascular is often under-recognized in clinical settings. The diagnosis of microvascular angina relies on assessment of the functional status of the coronary microvasculature. Invasive strategies include acetylcholine provocation, intracoronary Doppler ultrasound, and intracoronary thermodilution; noninvasive strategies include cardiac positron emission tomography (PET), cardiac magnetic resonance, and Doppler echocardiography. Once the diagnosis of microvascular angina is established, treatment is focused on improving symptoms and reducing future risk of cardiovascular and cerebrovascular events. Pharmacologic options and lifestyle modifications for patients with microvascular angina are similar to those for patients with coronary artery disease. PMID:25685641

  15. Targeting inflammation as a therapeutic strategy for drug-resistant epilepsies

    PubMed Central

    Vitaliti, Giovanna; Pavone, Piero; Mahmood, Fahad; Nunnari, Giuseppe; Falsaperla, Raffaele

    2014-01-01

    An increasing body of literature data suggests that inflammation, and in particular neuroinflammation, is involved in the pathophysiology of particular forms of epilepsy and convulsive disorders. Animal models have been used to identify inflammatory triggers in epileptogenesis and inflammation has recently been shown to enhance seizures. For example, pharmacological blockade of the IL-1beta/IL-1 receptor type 1 axis during epileptogenesis has been demonstrated to provide neuroprotection in temporal lobe epilepsy. Furthermore, experimental models have suggested that neural damage and the onset of spontaneous recurrent seizures are modulated via complex interactions between innate and adaptive immunity. However, it has also been suggested that inflammation can occur as a result of epilepsy, since animal models have also shown that seizure activity can induce neuroinflammation, and that recurrent seizures maintain chronic inflammation, thereby perpetuating seizures. On the basis of these observations, it has been suggested that immune-mediated therapeutic strategies may be beneficial for treating some drug resistant epilepsies with an underlying demonstrable inflammatory process. Although the potential mechanisms of immunotherapeutic strategies in drug-resistant seizures have been extensively discussed, evidence on the efficacy of such therapy is limited. However, recent research efforts have been directed toward utilizing the potential therapeutic benefits of anti-inflammatory agents in neurological disease and these are now considered prime candidates in the ongoing search for novel anti-epileptic drugs. The objective of our review is to highlight the immunological features of the pathogenesis of seizures and to analyze possible immunotherapeutic approaches for drug resistant epilepsies that can alter the immune-mediated pathogenesis. PMID:24609096

  16. Strategies and Advancement in Antibody-Drug Conjugate Optimization for Targeted Cancer Therapeutics

    PubMed Central

    Kim, Eunhee G.; Kim, Kristine M.

    2015-01-01

    Antibody-drug conjugates utilize the antibody as a delivery vehicle for highly potent cytotoxic molecules with specificity for tumor-associated antigens for cancer therapy. Critical parameters that govern successful antibody-drug conjugate development for clinical use include the selection of the tumor target antigen, the antibody against the target, the cytotoxic molecule, the linker bridging the cytotoxic molecule and the antibody, and the conjugation chemistry used for the attachment of the cytotoxic molecule to the antibody. Advancements in these core antibody-drug conjugate technology are reflected by recent approval of Adectris® (anti-CD30-drug conjugate) and Kadcyla® (anti-HER2 drug conjugate). The potential approval of an anti-CD22 conjugate and promising new clinical data for anti-CD19 and anti-CD33 conjugates are additional advancements. Enrichment of antibody-drug conjugates with newly developed potent cytotoxic molecules and linkers are also in the pipeline for various tumor targets. However, the complexity of antibody-drug conjugate components, conjugation methods, and off-target toxicities still pose challenges for the strategic design of antibody-drug conjugates to achieve their fullest therapeutic potential. This review will discuss the emergence of clinical antibody-drug conjugates, current trends in optimization strategies, and recent study results for antibody-drug conjugates that have incorporated the latest optimization strategies. Future challenges and perspectives toward making antibody-drug conjugates more amendable for broader disease indications are also discussed. PMID:26535074

  17. Cystic fibrosis transmembrane conductance regulator protein repair as a therapeutic strategy in cystic fibrosis

    PubMed Central

    Sloane, Peter A.; Rowe, Steven M.

    2013-01-01

    Purpose of review Recent progress in understanding the production, processing, and function of the cystic fibrosis gene product, the cystic fibrosis transmembrane conductance regulator (CFTR), has revealed new therapeutic targets to repair the mutant protein. Classification of CFTR mutations and new treatment strategies to address each will be described here. Recent findings High-throughput screening and other drug discovery efforts have identified small molecules that restore activity to mutant CFTR. Compounds such as VX-770 that potentiate CFTR have demonstrated exciting results in recent clinical trials and demonstrate robust effects across several CFTR mutation classes in the laboratory. A number of novel F508del CFTR processing correctors restore protein to the cell surface and improve ion channel function in vitro and are augmented by coadministration of CFTR potentiators. Ongoing discovery efforts that target protein folding, CFTR trafficking, and cell stress have also indicated promising results. Aminoglycosides and the novel small molecule ataluren induce translational readthrough of nonsense mutations in CFTR and other genetic diseases in vitro and in vivo and have shown activity in proof of concept trials, and ataluren is now being studied in confirmatory trials. Summary An improved understanding of the molecular mechanisms underlying the basic genetic defect in cystic fibrosis have led to new treatment strategies to repair the mutant protein. PMID:20829696

  18. A 3-step therapeutic strategy for severe alveolar proteinosis.

    PubMed

    Noirez, Leslie; Koutsokera, Angela; Pantet, Olivier; Duss, François-Régis; Eggimann, Philippe; Tozzi, Piergiorgio; Gonzalez, Michel; Coronado, Marcos; Nicod, Laurent P; Lovis, Alban

    2015-04-01

    Pulmonary alveolar proteinosis (PAP) is characterized by accumulation of lipoproteinaceous material in the terminal airways. Whole lung lavage (WLL) remains the gold standard treatment but may be particularly challenging in cases of severe hypoxemia. We present a 3-step strategy that was used in a patient with PAP-associated refractory hypoxemia and that combined venovenous extracorporeal membrane oxygenation (vvECMO), double-lumen orotracheal intubation, and bilateral multisegmental sequential lavage (MSL). The procedure was well tolerated and permitted weaning from the ventilator. PMID:25841841

  19. The chicken TH1 response: potential therapeutic applications of ChIFN-γ.

    PubMed

    Guo, Pengju; Thomas, Jesse D; Bruce, Matthew P; Hinton, Tracey M; Bean, Andrew G D; Lowenthal, John W

    2013-11-01

    The outcomes of viral infections are costly in terms of human and animal health and welfare worldwide. The observed increase in the virulence of some viruses and failure of many vaccines to stop these infections has lead to the apparent need to develop new anti-viral strategies. One approach to dealing with viral infection may be to employ the therapeutic administration of recombinant cytokines to act as 'immune boosters' to assist in augmenting the host response to virus. With this in mind, a greater understanding of the immune response, particularly cell mediated T-helper-1 (TH1) type responses, is imperative to the development of new anti-viral and vaccination strategies. Following the release of the chicken genome, a number of TH1-type cytokines have been identified, including chicken interleukin-12 (ChIL-12), ChIL-18 and interferon-γ ChIFN-γ), highlighting the nature of the TH1-type response in this non-mammalian vertebrate. To date a detailed analysis of the in vivo biological function of these cytokines has been somewhat hampered by access to large scale production techniques. This review describes the role of TH-1 cytokines in immune responses to viruses and explores their potential use in enhancing anti-viral treatment strategies in chickens. Furthermore, this review focuses on the example of ChIFN-γ treatment of Chicken Anemia Virus (CAV) infection. CAV causes amongst other things thymocyte depletion and thymus atrophy, as well as immunosuppression in chickens. However, due to vaccination, clinical disease appears less often, nevertheless, the subclinical form of the disease is often associated with secondary complicating infections due to an immunocompromised state. Since CAV-induced immunosuppression can cause a marked decrease in the immune response against other pathogens, understanding this aspect of the disease is critically important, as well as providing insights into developing new control approaches. With increasing emphasis on developing

  20. Clinical Appearance of Oral Candida Infection and Therapeutic Strategies

    PubMed Central

    Patil, Shankargouda; Rao, Roopa S.; Majumdar, Barnali; Anil, Sukumaran

    2015-01-01

    Candida species present both as commensals and opportunistic pathogens of the oral cavity. For decades, it has enthralled the clinicians to investigate its pathogenicity and to improvise newer therapeutic regimens based on the updated molecular research. Candida is readily isolated from the oral cavity, but simple carriage does not predictably result in development of an infection. Whether it remains as a commensal, or transmutes into a pathogen, is usually determined by pre-existing or associated variations in the host immune system. The candida infections may range from non-life threatening superficial mucocutaneous disorders to invasive disseminated disease involving multiple organs. In fact, with the increase in number of AIDS cases, there is a resurgence of less common forms of oral candida infections. The treatment after confirmation of the diagnosis should include recognizing and eliminating the underlying causes such as ill-fitting oral appliances, history of medications (antibiotics, corticosteroids, etc.), immunological and endocrine disorders, nutritional deficiency states and prolonged hospitalization. Treatment with appropriate topical antifungal agents such as amphotericin, nystatin, or miconazole usually resolves the symptoms of superficial infection. Occasionally, administration of systemic antifungal agents may be necessary in immunocompromised patients, the selection of which should be based upon history of recent azole exposure, a history of intolerance to an antifungal agent, the dominant Candida species and current susceptibility data. PMID:26733948

  1. Therapeutic Potential of Hyporesponsive CD4+ T Cells in Autoimmunity

    PubMed Central

    Maggi, Jaxaira; Schafer, Carolina; Ubilla-Olguín, Gabriela; Catalán, Diego; Schinnerling, Katina; Aguillón, Juan C.

    2015-01-01

    The interaction between dendritic cells (DCs) and T cells is crucial on immunity or tolerance induction. In an immature or semi-mature state, DCs induce tolerance through T-cell deletion, generation of regulatory T cells, and/or induction of T-cell anergy. Anergy is defined as an unresponsive state that retains T cells in an “off” mode under conditions in which immune activation is undesirable. This mechanism is crucial for the control of T-cell responses against self-antigens, thereby preventing autoimmunity. Tolerogenic DCs (tDCs), generated in vitro from peripheral blood monocytes of healthy donors or patients with autoimmune pathologies, were shown to modulate immune responses by inducing T-cell hyporesponsiveness. Animal models of autoimmune diseases confirmed the impact of T-cell anergy on disease development and progression in vivo. Thus, the induction of T-cell hyporesponsiveness by tDCs has become a promising immunotherapeutic strategy for the treatment of T-cell-mediated autoimmune disorders. Here, we review recent findings in the area and discuss the potential of anergy induction for clinical purposes. PMID:26441992

  2. Dementia and cognitive impairment in ESRD: diagnostic and therapeutic strategies

    PubMed Central

    Tamura, Manjula Kurella; Yaffe, Kristine

    2011-01-01

    Cognitive impairment, including dementia, is a common but poorly recognized problem among patients with end-stage renal disease (ESRD), affecting 16–38% of patients. Dementia is associated with high risks of death, dialysis withdrawal, hospitalization, and disability among patients with ESRD; thus, recognizing and effectively managing cognitive impairment may improve clinical care. Dementia screening strategies should take into account patient factors, the time available, the timing of assessments relative to dialysis treatments, and the implications of a positive screen for subsequent management (for example, transplantation). Additional diagnostic testing in patients with cognitive impairment, including neuroimaging, is largely based on the clinical evaluation. There is limited data on the efficacy and safety of pharmacotherapy for dementia in the setting of ESRD; therefore, decisions about the use of these medications should be individualized. Management of behavioral symptoms, evaluation of patient safety, and advance care planning are important components of dementia management. Prevention strategies targeting vascular risk factor modification, and physical and cognitive activity have shown promise in the general population and may be reasonably extrapolated to the ESRD population. Modification of ESRD-associated factors such as anemia and dialysis dose or frequency require further study before they can be recommended for treatment or prevention of cognitive impairment. PMID:20861818

  3. Therapeutic strategies targeting B-cells in multiple sclerosis.

    PubMed

    Milo, Ron

    2016-07-01

    Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system (CNS) that traditionally has been considered to be mediated primarily by T-cells. Increasing evidence, however, suggests the fundamental role of B-cells in the pathogenesis of the disease. Recent strategies targeting B-cells in MS have demonstrated impressive and sometimes surprising results: B-cell depletion by monoclonal antibodies targeting the B-cell surface antigen CD20 (e.g. rituximab, ocrelizumab, ofatumumab) was shown to exert profound anti-inflammatory effect in MS with favorable risk-benefit ratio, with ocrelizumab demonstrating efficacy in both relapsing-remitting (RR) and primary-progressive (PP) MS in phase III clinical trials. Depletion of CD52 expressing T- and B-cells and monocytes by alemtuzumab resulted in impressive and durable suppression of disease activity in RRMS patients. On the other hand, strategies targeting B-cell cytokines such as atacicept resulted in increased disease activity. As our understanding of the biology of B-cells in MS is increasing, new compounds that target B-cells continue to be developed which promise to further expand the armamentarium of MS therapies and allow for more individualized therapy for patients with this complex disease. PMID:26970489

  4. MicroRNAs Determining Inflammation as Novel Biomarkers and Potential Therapeutic Targets.

    PubMed

    Kotsinas, Athanassios; Sigala, Fragkiska; Garbis, Spiros D; Galyfos, Giorgos; Filis, Konstantinos; Vougas, Konstantinos; Papalampros, Alexandros; Johnson, Elizabeth E; Chronopoulos, Efstathios; Georgakilas, Alexandros G; Gorgoulis, Vassilis G

    2015-01-01

    Cardiovascular diseases (CVDs) have become a predominant cause of death worldwide. Although CVDs encompass a variety of pathological conditions that affect the heart and blood vasculature, they can be classified into two major groups according to their basic pathophysiologic mechanisms, namely atherosclerosis and aneurysm formation. Increasing evidence implicates micro-RNAs (miRNAs or miRs) as vital factors both in the initiation and progression processes of CVDs. Some miRs have a promoting role in CVD development, while others have a protective role. Today, miRs have been shown to be potential biomarkers for several types of CVDs, while strategies targeting miRs are under consideration as potential tools for exploitation in therapeutic approaches for CVD treatments. In this review, we present the available data on the involvement of miRs in CVDs, focusing on their role as regulators of the inflammatory process as an initiating and driving component of CVDs. PMID:26180004

  5. The potential of sarcospan in adhesion complex replacement therapeutics for the treatment of muscular dystrophy.

    PubMed

    Marshall, Jamie L; Kwok, Yukwah; McMorran, Brian J; Baum, Linda G; Crosbie-Watson, Rachelle H

    2013-09-01

    Three adhesion complexes span the sarcolemma and facilitate critical connections between the extracellular matrix and the actin cytoskeleton: the dystrophin- and utrophin-glycoprotein complexes and α7β1 integrin. Loss of individual protein components results in a loss of the entire protein complex and muscular dystrophy. Muscular dystrophy is a progressive, lethal wasting disease characterized by repetitive cycles of myofiber degeneration and regeneration. Protein-replacement therapy offers a promising approach for the treatment of muscular dystrophy. Recently, we demonstrated that sarcospan facilitates protein-protein interactions amongst the adhesion complexes and is an important potential therapeutic target. Here, we review current protein-replacement strategies, discuss the potential benefits of sarcospan expression, and identify important experiments that must be addressed for sarcospan to move to the clinic. PMID:23601082

  6. The expanding GRK interactome: Implications in cardiovascular disease and potential for therapeutic development.

    PubMed

    Hullmann, Jonathan; Traynham, Christopher J; Coleman, Ryan C; Koch, Walter J

    2016-08-01

    Heart failure (HF) is a global epidemic with the highest degree of mortality and morbidity of any disease presently studied. G protein-coupled receptors (GPCRs) are prominent regulators of cardiovascular function. Activated GPCRs are "turned off" by GPCR kinases (GRKs) in a process known as "desensitization". GRKs 2 and 5 are highly expressed in the heart, and known to be upregulated in HF. Over the last 20 years, both GRK2 and GRK5 have been demonstrated to be critical mediators of the molecular alterations that occur in the failing heart. In the present review, we will highlight recent findings that further characterize "non-canonical" GRK signaling observed in HF. Further, we will also present potential therapeutic strategies (i.e. small molecule inhibition, microRNAs, gene therapy) that may have potential in combating the deleterious effects of GRKs in HF. PMID:27180008

  7. Anticancer strategies based on the metabolic profile of tumor cells: therapeutic targeting of the Warburg effect

    PubMed Central

    Chen, Xi-sha; Li, Lan-ya; Guan, Yi-di; Yang, Jin-ming; Cheng, Yan

    2016-01-01

    Tumor cells rely mainly on glycolysis for energy production even in the presence of sufficient oxygen, a phenomenon termed the Warburg effect, which is the most outstanding characteristic of energy metabolism in cancer cells. This metabolic adaptation is believed to be critical for tumor cell growth and proliferation, and a number of onco-proteins and tumor suppressors, including the PI3K/Akt/mTOR signaling pathway, Myc, hypoxia-inducible factor and p53, are involved in the regulation of this metabolic adaptation. Moreover, glycolytic cancer cells are often invasive and impervious to therapeutic intervention. Thus, altered energy metabolism is now appreciated as a hallmark of cancer and a promising target for cancer treatment. A better understanding of the biology and the regulatory mechanisms of aerobic glycolysis has the potential to facilitate the development of glycolysis-based therapeutic interventions for cancer. In addition, glycolysis inhibition combined with DNA damaging drugs or chemotherapeutic agents may be effective anticancer strategies through weakening cell damage repair capacity and enhancing drug cytotoxicity. PMID:27374491

  8. Peptide inhibition of p22phox and Rubicon interaction as a therapeutic strategy for septic shock.

    PubMed

    Kim, Ye-Ram; Koh, Hyun-Jung; Kim, Jae-Sung; Yun, Jin-Seung; Jang, Kiseok; Lee, Joo-Youn; Jung, Jae U; Yang, Chul-Su

    2016-09-01

    Sepsis is a clinical syndrome that complicates severe infection and is characterized by the systemic inflammatory response syndrome (SIRS), is a life threatening disease characterized by inflammation of the entire body. Upon microbial infection, p22phox-gp91phox NADPH oxidase (NOX) complexes produce reactive oxygen species (ROS) that are critical for the elimination of invading microbes. However, excess production of ROS represents a key element in the cascade of deleterious processes in sepsis. We have previously reported direct crosstalk between autophagy and phagocytosis machineries by demonstrating that the Rubicon protein interacts with p22phox upon microbial infection, facilitating phagosomal trafficking of the p22phox-gp91phox NOX complex to induce a ROS burst, inflammatory cytokine production, and thereby, potent anti-microbial activities. Here, we showed N8 peptide, an N-terminal 8-amino acid peptide derived from p22phox, was sufficient for Rubicon interaction and thus, capable of robustly blocking the Rubicon-p22phox interaction and profoundly suppressing ROS and inflammatory cytokine production. Consequently, treatment with the Tat-N8 peptide or a N8 peptide-mimetic small-molecule dramatically reduced the mortality associated with Cecal-Ligation-and-Puncture-induced polymicrobial sepsis in mice. This study demonstrates a new anti-sepsis therapeutic strategy by blocking the crosstalk between autophagy and phagocytosis innate immunity machineries, representing a potential paradigm shift for urgently needed therapeutic intervention against this life-threatening SIRS. PMID:27267627

  9. Future therapeutical strategies dictated by pre-clinical evidence in ALS.

    PubMed

    Fornai, Francesco; Meininger, Vincent; Silani, Vincent

    2011-03-01

    Classic concepts on amyotrophic lateral sclerosis led to define the disease as a selective degeneration of upper and lower motor neurons. At present such selectivity is questioned by novel findings. For instance, the occurrence of frontotemporal dementia is now increasingly recognized in the course of ALS. Again, areas outside the central nervous system are targeted in ALS. In keeping with motor areas other cell types surrounding motor neurons such as glia and interneurons are key in the pathogenesis of ALS. This multiple cell involvement may be due to a prion-like diffusion of specific misfolded proteins which are altered in ALS. This is the case of FUS and TDP-43 which harbor a prion domain prone to pathological misfolding. These misfolded proteins are metabolized by the autophagy, but in ALS there is evidence for a specific deficit of autophagy which impedes the clearance of these proteins. These concepts lead to re-analyze the potential therapeutics of ALS. In fact, mere cell substitution (stem cell) therapy appears insufficient to contrast all the alterations in the various pathways affected by ALS. Although preclinical data speed the application of stem cells in human clinical trials, several hurdles limit their translation into new therapies. Future treatments are expected to consider the need to target both motor neurons and neighboring cells which may contribute to the diffusion and persistence of the disease. On this basis the present manuscript describes which future strategies need to be pursued in order to design optimal therapeutic trial in ALS. PMID:21412723

  10. Anticancer strategies based on the metabolic profile of tumor cells: therapeutic targeting of the Warburg effect.

    PubMed

    Chen, Xi-Sha; Li, Lan-Ya; Guan, Yi-di; Yang, Jin-Ming; Cheng, Yan

    2016-08-01

    Tumor cells rely mainly on glycolysis for energy production even in the presence of sufficient oxygen, a phenomenon termed the Warburg effect, which is the most outstanding characteristic of energy metabolism in cancer cells. This metabolic adaptation is believed to be critical for tumor cell growth and proliferation, and a number of onco-proteins and tumor suppressors, including the PI3K/Akt/mTOR signaling pathway, Myc, hypoxia-inducible factor and p53, are involved in the regulation of this metabolic adaptation. Moreover, glycolytic cancer cells are often invasive and impervious to therapeutic intervention. Thus, altered energy metabolism is now appreciated as a hallmark of cancer and a promising target for cancer treatment. A better understanding of the biology and the regulatory mechanisms of aerobic glycolysis has the potential to facilitate the development of glycolysis-based therapeutic interventions for cancer. In addition, glycolysis inhibition combined with DNA damaging drugs or chemotherapeutic agents may be effective anticancer strategies through weakening cell damage repair capacity and enhancing drug cytotoxicity. PMID:27374491

  11. Targeting hydrogen sulfide as a promising therapeutic strategy for atherosclerosis.

    PubMed

    Xu, Suowen; Liu, Zhiping; Liu, Peiqing

    2014-03-15

    Physiological concentrations of nitric oxide (NO) and carbon monoxide (CO) have multiple protective effects in the cardiovascular system. Recent studies have implicated hydrogen sulfide (H2S) as a new member of vasculoprotective gasotransmitter family, behaving similarly to NO and CO. H2S has been demonstrated to inhibit multiple key aspects of atherosclerosis, including atherogenic modification of LDL, monocytes adhesion to the endothelial cells, macrophage-derived foam cell formation and inflammation, smooth muscle cell proliferation, neointimal hyperplasia, vascular calcification, and thrombogenesis. H2S also decreases plasma homocysteine levels in experimental animal models. In the human body, H2S production is predominantly catalyzed by cystathionine-β-synthase (CBS) and cystathionine γ-lyase (CSE). CSE is the primary H2S-producing enzyme in the vasculature. Growing evidence suggests that atherosclerosis is associated with vascular CSE/H2S deficiency and that H2S supplementation by exogenous H2S donors (such as NaHS and GYY4137) attenuates, and H2S synthesis suppression by inhibitors (such as D, L-propargylglycine) aggravates the development of atherosclerotic plaques. However, it remains elusive whether CSE deficiency plays a causative role in atherosclerosis. A recent study (Circulation. 2013; 127: 2523-2534) demonstrates that decreased endogenous H2S production by CSE genetic deletion accelerates atherosclerosis in athero-prone ApoE-/- mice, pinpointing that endogenously produced H2S by CSE activation may be of benefit in the prevention and treatment of atherosclerosis. This study will facilitate the development of H2S-based pharmaceuticals with therapeutic applications in atherosclerosis-related cardiovascular diseases. PMID:24491853

  12. Therapeutic strategy in unresectable metastatic colorectal cancer: an updated review.

    PubMed

    Chibaudel, Benoist; Tournigand, Christophe; Bonnetain, Franck; Richa, Hubert; Benetkiewicz, Magdalena; André, Thierry; de Gramont, Aimery

    2015-05-01

    Systemic therapy is the standard care for patients with unresectable advanced colorectal cancer (CRC), but salvage surgery of metastatic disease should be considered in the case of adequate tumor shrinkage. Several drugs and combinations are now available for use in treating patients with advanced CRC, but the optimal sequence of therapy remains unknown. Moreover, the administration of antitumor therapy can be modulated by periods of maintenance or treatment breaks rather than delivered as full therapy until disease progression or unacceptable toxicity, followed by reintroduction of prior full therapy when required, before switching to other drugs. Consequently, randomized strategy trials are needed to define the optimal treatment sequences. Molecular testing for Kirsten rat sarcoma viral oncogene homolog (KRAS) and neuroblastoma RAS viral oncogene homolog (NRAS) is mandatory but not sufficient to select appropriate patients for epidermal growth factor receptor (EGFR) monoclonal antibody (MoAb) therapy. PMID:26673925

  13. Opportunistic yeast pathogens: reservoirs, virulence mechanisms, and therapeutic strategies.

    PubMed

    Polvi, Elizabeth J; Li, Xinliu; O'Meara, Teresa R; Leach, Michelle D; Cowen, Leah E

    2015-06-01

    Life-threatening invasive fungal infections are becoming increasingly common, at least in part due to the prevalence of medical interventions resulting in immunosuppression. Opportunistic fungal pathogens of humans exploit hosts that are immunocompromised, whether by immunosuppression or genetic predisposition, with infections originating from either commensal or environmental sources. Fungal pathogens are armed with an arsenal of traits that promote pathogenesis, including the ability to survive host physiological conditions and to switch between different morphological states. Despite the profound impact of fungal pathogens on human health worldwide, diagnostic strategies remain crude and treatment options are limited, with resistance to antifungal drugs on the rise. This review will focus on the global burden of fungal infections, the reservoirs of these pathogens, the traits of opportunistic yeast that lead to pathogenesis, host genetic susceptibilities, and the challenges that must be overcome to combat antifungal drug resistance and improve clinical outcome. PMID:25700837

  14. Treatment strategies for atopic dermatitis: optimizing the available therapeutic options.

    PubMed

    Paller, Amy S; Simpson, Eric L; Eichenfield, Lawrence F; Ellis, Charles N; Mancini, Anthony J

    2012-09-01

    Bathing and moisturization to control dryness, applications of topical anti-inflammatory agents (including corticosteroids and calcineurin inhibitors [TCIs]) to control flares, minimization of the risk for infection, and relief of pruritus are the cornerstones of effective therapy for atopic dermatitis. Education of parents and patients is crucial to enhance adherence. Strategies for reduced Staphylococcus aureus colonization may help control re-emergence of flares following cessation of antimicrobial treatment for infection; these include dilute bleach baths and minimizing the risk for contamination of topical agents. In severe, refractory cases, more aggressive therapy with systemic immunosuppressants may be considered, but appropriate laboratory testing must be included as part of patient monitoring during treatment. The value of adjuvant therapy with wet wraps to "cool down" particularly erythematous and pruritic flares is becoming increasingly recognized. PMID:23021780

  15. The therapeutic efficacy of two antibabesial strategies against Babesia gibsoni.

    PubMed

    Lin, Emerald Cheng-Yi; Chueh, Ling-Ling; Lin, Chao-Nan; Hsieh, Li-En; Su, Bi-Ling

    2012-05-25

    Various combination strategies for treating Babesia gibsoni have been described. However, relapses after administering some combinations of antibabesial drugs and the presence of drug-resistant B. gibsoni still pose significant challenges to veterinarians. To compare the efficacy of a combination of clindamycin, diminazene, and imidocarb (CDI) to that of a combination of atovaquone and azithromycin (AA) for the treatment of B. gibsoni and to correlate drug efficacy with B. gibsoni mutations, 30 client-owned dogs with natural B. gibsoni infections were collected in the study. 17 dogs were treated with AA, and 13 dogs were treated with CDI combination. Hematological parameters were recorded on the day that the dogs were presented for treatment and during treatment. To detect the parasitic DNA, the B. gibsoni 18S rRNA gene was amplified, and to analyze the mutations, the cytochrome b (CYTb) gene was sequenced. The therapy duration for all of the dogs that recovered was 23.3±7.8 days in the AA group and 41.7±12.4 days in the CDI group. Nine of the 17 dogs in the AA group and 11 of the 13 dogs in the CDI group completely recovered. Seven dogs in the AA group and 2 dogs in the CDI group relapsed after treatment. The M121I mutation in the B. gibsoni CYTb gene was detected in all of the samples that were collected from AA-relapsed and AA-nonremission dogs. The dogs in the CDI group exhibited higher recovery rates and lower relapse rates during treatment for B. gibsoni infection. In addition, the detected M121I mutation was associated with AA treatment. The CDI combination is a promising alternative treatment strategy for B. gibsoni. PMID:22222008

  16. Protein Processing and Inflammatory Signaling in Cystic Fibrosis: Challenges and Therapeutic Strategies

    PubMed Central

    Belcher, C.N.; Vij, N.

    2010-01-01

    Cystic Fibrosis (CF) is an autosomal recessive disorder caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) that regulates epithelial surface fluid secretion in respiratory and gastrointestinal tracts. The deletion of phenylalanine at position 508 (ΔF508) in CFTR is the most common mutation that results in a temperature sensitive folding defect, retention of the protein in the endoplasmic reticulum (ER), and subsequent degradation by the proteasome. ER associated degradation (ERAD) is a major quality control pathway of the cell. The majority (99%) of the protein folding, ΔF508-, mutant of CFTR is known to be degraded by this pathway to cause CF. Recent studies have revealed that inhibition of ΔF508-CFTR ubiquitination and proteasomal degradation can increase its cell surface expression and may provide an approach to treat CF. The finely tuned balance of ER membrane interactions determine the cytosolic fate of newly synthesized CFTR. These ER membrane interactions induce ubiquitination and proteasomal targeting of ΔF508- over wild type- CFTR. We discuss here challenges and therapeutic strategies targeting protein processing of ΔF508-CFTR with the goal of rescuing functional ΔF508-CFTR to the cell surface. It is evident from recent studies that CFTR plays a critical role in inflammatory response in addition to its well-described ion transport function. Previous studies in CF have focused only on improving chloride efflux as a marker for promising treatment. We propose that methods quantifying the therapeutic efficacy and recovery from CF should not include only changes in chloride efflux, but also recovery of the chronic inflammatory signaling, as evidenced by positive changes in inflammatory markers (in vitro and ex vivo), lung function (pulmonary function tests, PFT), and chronic lung disease (state of the art molecular imaging, in vivo). This will provide novel therapeutics with greater opportunities of potentially

  17. Scutellarin as a Potential Therapeutic Agent for Microglia-Mediated Neuroinflammation in Cerebral Ischemia.

    PubMed

    Yuan, Yun; Fang, Ming; Wu, Chun-Yun; Ling, Eng-Ang

    2016-09-01

    The cerebral ischemia is one of the most common diseases in the central nervous system that causes progressive disability or even death. In this connection, the inflammatory response mediated by the activated microglia is believed to play a central role in this pathogenesis. In the event of brain injury, activated microglia can clear the cellular debris and invading pathogens, release neurotrophic factors, etc., but in chronic activation microglia may cause neuronal death through the release of excessive inflammatory mediators. Therefore, suppression of microglial over-reaction and microglia-mediated neuroinflammation is deemed to be a therapeutic strategy of choice for cerebral ischemic damage. In the search for potential herbal extracts that are endowed with the property in suppressing the microglial activation and amelioration of neuroinflammation, attention has recently been drawn to scutellarin, a Chinese herbal extract. Here, we review the roles of activated microglia and the effects of scutellarin on activated microglia in pathological conditions especially in ischemic stroke. We have further extended the investigation with special reference to the effects of scutellarin on Notch signaling, one of the several signaling pathways known to be involved in microglial activation. Furthermore, in light of our recent experimental evidence that activated microglia can regulate astrogliosis, an interglial "cross-talk" that was amplified by scutellarin, it is suggested that in designing of a more effective therapeutic strategy for clinical management of cerebral ischemia both glial types should be considered collectively. PMID:27103430

  18. Therapeutic strategies for complications secondary to hydatid cyst rupture

    PubMed Central

    Cobanoglu, Ufuk; Sayır, Fuat; Şehitoğlu, Abidin; Bilici, Salim; Melek, Mehmet

    2011-01-01

    Objective: Clinical approach and therapeutic methods are important in cases with complicated hydatid cysts of the lung. This study was designed to retrospectively investigate cases with hydatid cysts, thereby discussing diagnostic methods, treatment modalities, and rates of morbidity and mortality in line with the literature. Methods: 176 cases with perforated hydatid cysts, who presented to our clinic and underwent surgery between 2003 and 2011, were included in the study. There were 71 (40.34%) females and 105 males (59.66%) with a mean age of 27.80±14.07. The most common symptom was dyspnea (44.31%) and the most common radiological finding was the water lily sign (21.02%). 88.06% of the cases were surgically treated by Cystotomy+closure of bronchial opening+ capitonnage, 3.97% by wedge resection, 4.54% by segmentectomy and 3.40% by lobectomy. Results: The cysts exhibited multiple localization in 24 cases (13.63%), bilateral localization in 14 cases (7.95%), with the most common localization (43.75%) being the right lower lobe. While the hydatid cyst rupture occurred due to delivery in three (1.70%), trauma in 11 (6.25%), and iatrogenic causes in seven (3.97%) cases, it occurred spontaneously in the rest of the cases (88.08%). Fourteen of the cases with spontaneously occurring rupture (7.95%) were detected to have received anthelmintic treatment for hydatid cyst during the preoperative period (albendazole). The rate of morbidity was 27.27% and the rate of mortality was 1.13% in our study. Two cases recurred during a one-year follow-up (1.13%). Conclusion: Hydatid cyst rupture should be considered in the differential diagnosis of cases with pleural effusion, empyema, pneumothorax and pneumonia occurring in endemic regions. Symptoms occurring during and after perforation lead to errors in differential diagnosis. Performing the surgery without delay favorably affects postoperative morbidity and mortality. While parenchyma-preserving surgery is preferential, there

  19. Chemical Conjugation of Evans Blue Derivative: A Strategy to Develop Long-Acting Therapeutics through Albumin Binding

    PubMed Central

    Chen, Haojun; Wang, Guohao; Lang, Lixin; Jacobson, Orit; Kiesewetter, Dale O.; Liu, Yi; Ma, Ying; Zhang, Xianzhong; Wu, Hua; Zhu, Lei; Niu, Gang; Chen, Xiaoyuan

    2016-01-01

    The efficacy of therapeutic drugs is highly dependent on their optimal in vivo pharmacokinetics. Albumin conjugation is considered to be one of the most effective means of protracting the short lifespan of peptides and proteins. In this study, we proposed a novel platform for developing long lasting therapeutics by conjugating a small molecular albumin binding moiety, truncated Evans blue, to either peptides or proteins. Using the anti-diabetic peptide drug Exendin-4 as a model peptide, we synthesized a new long-acting Exendin-4 derivative (denoted as Abextide). Through complexation with albumin in situ, the biological half-life of Abextide was significantly extended. The hypoglycemic effect of Abextide was also improved remarkably over Exendin-4. Thus, Abextide has considerable potential to treat type 2 diabetes. This strategy as a general technology platform can be applied to other small molecules and biologics for the development of long-acting therapeutic drugs. PMID:26877782

  20. Oxidative stress and metabolic disorders: Pathogenesis and therapeutic strategies.

    PubMed

    Rani, Vibha; Deep, Gagan; Singh, Rakesh K; Palle, Komaraiah; Yadav, Umesh C S

    2016-03-01

    Increased body weight and metabolic disorder including insulin resistance, type 2 diabetes and cardiovascular complications together constitute metabolic syndrome. The pathogenesis of metabolic syndrome involves multitude of factors. A number of studies however indicate, with some conformity, that oxidative stress along with chronic inflammatory condition pave the way for the development of metabolic diseases. Oxidative stress, a state of lost balance between the oxidative and anti-oxidative systems of the cells and tissues, results in the over production of oxidative free radicals and reactive oxygen species (ROS). Excessive ROS generated could attack the cellular proteins, lipids and nucleic acids leading to cellular dysfunction including loss of energy metabolism, altered cell signalling and cell cycle control, genetic mutations, altered cellular transport mechanisms and overall decreased biological activity, immune activation and inflammation. In addition, nutritional stress such as that caused by high fat high carbohydrate diet also promotes oxidative stress as evident by increased lipid peroxidation products, protein carbonylation, and decreased antioxidant system and reduced glutathione (GSH) levels. These changes lead to initiation of pathogenic milieu and development of several chronic diseases. Studies suggest that in obese person oxidative stress and chronic inflammation are the important underlying factors that lead to development of pathologies such as carcinogenesis, obesity, diabetes, and cardiovascular diseases through altered cellular and nuclear mechanisms, including impaired DNA damage repair and cell cycle regulation. Here we discuss the aspects of metabolic disorders-induced oxidative stress in major pathological conditions and strategies for their prevention and therapy. PMID:26851532

  1. Advances in genetic therapeutic strategies for Duchenne muscular dystrophy

    PubMed Central

    Guiraud, Simon; Chen, Huijia; Burns, David T.

    2015-01-01

    New Findings What is the topic of this review? This review highlights recent progress in genetically based therapies targeting the primary defect of Duchenne muscular dystrophy. What advances does it highlight? Over the last two decades, considerable progress has been made in understanding the mechanisms underlying Duchenne muscular dystrophy, leading to the development of genetic therapies. These include manipulation of the expression of the gene or related genes, the splicing of the gene and its translation, and replacement of the gene using viral approaches. Duchenne muscular dystrophy is a lethal X‐linked disorder caused by mutations in the dystrophin gene. In the absence of the dystrophin protein, the link between the cytoskeleton and extracellular matrix is destroyed, and this severely compromises the strength, flexibility and stability of muscle fibres. The devastating consequence is progressive muscle wasting and premature death in Duchenne muscular dystrophy patients. There is currently no cure, and despite exhaustive palliative care, patients are restricted to a wheelchair by the age of 12 years and usually succumb to cardiac or respiratory complications in their late 20s. This review provides an update on the current genetically based therapies and clinical trials that target or compensate for the primary defect of this disease. These include dystrophin gene‐replacement strategies, genetic modification techniques to restore dystrophin expression, and modulation of the dystrophin homologue, utrophin, as a surrogate to re‐establish muscle function. PMID:26140505

  2. The Cytokine Model of Schizophrenia: Emerging Therapeutic Strategies

    PubMed Central

    Brown, Alan S.

    2014-01-01

    We discuss the rationale for a trial of a novel biologic immunotherapy in schizophrenia (SZ). Available antipsychotic treatments for SZ are often limited by partial effectiveness and significant side effects. Thus, the search for novel medications is of high priority. All current antipsychotics function primarily by blocking D2-type dopamine receptors. An emerging theory of SZ postulates disturbances of cytokines and inflammatory mediators (i.e., the cytokine model), possibly originating in part from infectious exposures. Cytokines are one of the most important components of the immune system that orchestrate the response to infectious and other exogenous insults. Preclinical models of SZ support a convergence between a role for certain cytokines in the pathophysiology of SZ and major neurochemical postulates of the disorder, including the dopamine and glutamate hypotheses. Furthermore, several cytokines are elevated in plasma in SZ, and Positron Emission Tomography (PET) studies have shown active inflammation in the brains of individuals with psychosis. Treatment studies of certain anti-inflammatory agents, such as celecoxib and aspirin, in patients with SZ have provided further support for neuroinflammation in this disorder. The recent development of approved biological therapies for autoimmune diseases provides us with new opportunities to directly target cytokine signaling as a novel treatment strategy in SZ. In addition, advances in imaging, immunology, and psychopharmacology have paved the way for utilizing measures of target engagement of neuroimmune components that would facilitate the identification of patient subgroups who are most likely to benefit from cytokine modulation. PMID:24439555

  3. Current Research Therapeutic Strategies for Alzheimer's Disease Treatment

    PubMed Central

    Folch, Jaume; Petrov, Dmitry; Ettcheto, Miren; Abad, Sonia; Sánchez-López, Elena; García, M. Luisa; Olloquequi, Jordi; Beas-Zarate, Carlos; Auladell, Carme; Camins, Antoni

    2016-01-01

    Alzheimer's disease (AD) currently presents one of the biggest healthcare issues in the developed countries. There is no effective treatment capable of slowing down disease progression. In recent years the main focus of research on novel pharmacotherapies was based on the amyloidogenic hypothesis of AD, which posits that the beta amyloid (Aβ) peptide is chiefly responsible for cognitive impairment and neuronal death. The goal of such treatments is (a) to reduce Aβ production through the inhibition of β and γ secretase enzymes and (b) to promote dissolution of existing cerebral Aβ plaques. However, this approach has proven to be only modestly effective. Recent studies suggest an alternative strategy centred on the inhibition of the downstream Aβ signalling, particularly at the synapse. Aβ oligomers may cause aberrant N-methyl-D-aspartate receptor (NMDAR) activation postsynaptically by forming complexes with the cell-surface prion protein (PrPC). PrPC is enriched at the neuronal postsynaptic density, where it interacts with Fyn tyrosine kinase. Fyn activation occurs when Aβ is bound to PrPC-Fyn complex. Fyn causes tyrosine phosphorylation of the NR2B subunit of metabotropic glutamate receptor 5 (mGluR5). Fyn kinase blockers masitinib and saracatinib have proven to be efficacious in treating AD symptoms in experimental mouse models of the disease. PMID:26881137

  4. Current Therapeutic Strategies and Novel Approaches in Osteosarcoma

    PubMed Central

    Ando, Kosei; Heymann, Marie-Françoise; Stresing, Verena; Mori, Kanji; Rédini, Françoise; Heymann, Dominique

    2013-01-01

    Osteosarcoma is the most frequent malignant primary bone tumor and a main cause of cancer-related death in children and adolescents. Although long-term survival in localized osteosarcoma has improved to about 60% during the 1960s and 1970s, long-term survival in both localized and metastatic osteosarcoma has stagnated in the past several decades. Thus, current conventional therapy consists of multi-agent chemotherapy, surgery and radiation, which is not fully adequate for osteosarcoma treatment. Innovative drugs and approaches are needed to further improve outcome in osteosarcoma patients. This review describes the current management of osteosarcoma as well as potential new therapies. PMID:24216993

  5. Polymersome-based drug-delivery strategies for cancer therapeutics

    PubMed Central

    Anajafi, Tayebeh; Mallik, Sanku

    2015-01-01

    Polymersomes are stable vesicles prepared from amphiphilic polymers and are more stable compared with liposomes. Although these nanovesicles have many attractive properties for in vitro/in vivo applications, liposome-based drug delivery systems are still prevalent in the market. In order to expedite the translational potential and to provide medically valuable formulations, the polymersomes need to be biocompatible and biodegradable. In this review, recent developments for biocompatible and biodegradable polymersomes, including the design of intelligent, targeted, and stimuli-responsive vesicles are summarized. PMID:25996048

  6. Endocannabinoid System and Psychiatry: In Search of a Neurobiological Basis for Detrimental and Potential Therapeutic Effects

    PubMed Central

    Marco, Eva M.; García-Gutiérrez, María S.; Bermúdez-Silva, Francisco-Javier; Moreira, Fabricio A.; Guimarães, Francisco; Manzanares, Jorge; Viveros, María-Paz

    2011-01-01

    Public concern on mental health has noticeably increased given the high prevalence of neuropsychiatric disorders. Cognition and emotionality are the most affected functions in neuropsychiatric disorders, i.e., anxiety disorders, depression, and schizophrenia. In this review, most relevant literature on the role of the endocannabinoid (eCB) system in neuropsychiatric disorders will be presented. Evidence from clinical and animal studies is provided for the participation of CB1 and CB2 receptors (CB1R and CB2R) in the above mentioned neuropsychiatric disorders. CBRs are crucial in some of the emotional and cognitive impairments reported, although more research is required to understand the specific role of the eCB system in neuropsychiatric disorders. Cannabidiol (CBD), the main non-psychotropic component of the Cannabis sativa plant, has shown therapeutic potential in several neuropsychiatric disorders. Although further studies are needed, recent studies indicate that CBD therapeutic effects may partially depend on facilitation of eCB-mediated neurotransmission. Last but not least, this review includes recent findings on the role of the eCB system in eating disorders. A deregulation of the eCB system has been proposed to be in the bases of several neuropsychiatric disorders, including eating disorders. Cannabis consumption has been related to the appearance of psychotic symptoms and schizophrenia. In contrast, the pharmacological manipulation of this eCB system has been proposed as a potential strategy for the treatment of anxiety disorders, depression, and anorexia nervosa. In conclusion, the eCB system plays a critical role in psychiatry; however, detrimental consequences of manipulating this endogenous system cannot be underestimated over the potential and promising perspectives of its therapeutic manipulation. PMID:22007164

  7. Evaluation of Potential LSST Spatial Indexing Strategies

    SciTech Connect

    Nikolaev, S; Abdulla, G; Matzke, R

    2006-10-13

    The LSST requirement for producing alerts in near real-time, and the fact that generating an alert depends on knowing the history of light variations for a given sky position, both imply that the clustering information for all detections is available at any time during the survey. Therefore, any data structure describing clustering of detections in LSST needs to be continuously updated, even as new detections are arriving from the pipeline. We call this use case ''incremental clustering'', to reflect this continuous updating of clustering information. This document describes the evaluation results for several potential LSST incremental clustering strategies, using: (1) Neighbors table and zone optimization to store spatial clusters (a.k.a. Jim Grey's, or SDSS algorithm); (2) MySQL built-in R-tree implementation; (3) an external spatial index library which supports a query interface.

  8. Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities.

    PubMed

    Pertwee, Roger G

    2012-12-01

    Human tissues express cannabinoid CB(1) and CB(2) receptors that can be activated by endogenously released 'endocannabinoids' or exogenously administered compounds in a manner that reduces the symptoms or opposes the underlying causes of several disorders in need of effective therapy. Three medicines that activate cannabinoid CB(1)/CB(2) receptors are now in the clinic: Cesamet (nabilone), Marinol (dronabinol; Δ(9)-tetrahydrocannabinol (Δ(9)-THC)) and Sativex (Δ(9)-THC with cannabidiol). These can be prescribed for the amelioration of chemotherapy-induced nausea and vomiting (Cesamet and Marinol), stimulation of appetite (Marinol) and symptomatic relief of cancer pain and/or management of neuropathic pain and spasticity in adults with multiple sclerosis (Sativex). This review mentions several possible additional therapeutic targets for cannabinoid receptor agonists. These include other kinds of pain, epilepsy, anxiety, depression, Parkinson's and Huntington's diseases, amyotrophic lateral sclerosis, stroke, cancer, drug dependence, glaucoma, autoimmune uveitis, osteoporosis, sepsis, and hepatic, renal, intestinal and cardiovascular disorders. It also describes potential strategies for improving the efficacy and/or benefit-to-risk ratio of these agonists in the clinic. These are strategies that involve (i) targeting cannabinoid receptors located outside the blood-brain barrier, (ii) targeting cannabinoid receptors expressed by a particular tissue, (iii) targeting upregulated cannabinoid receptors, (iv) selectively targeting cannabinoid CB(2) receptors, and/or (v) adjunctive 'multi-targeting'. PMID:23108552

  9. Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities

    PubMed Central

    Pertwee, Roger G.

    2012-01-01

    Human tissues express cannabinoid CB1 and CB2 receptors that can be activated by endogenously released ‘endocannabinoids’ or exogenously administered compounds in a manner that reduces the symptoms or opposes the underlying causes of several disorders in need of effective therapy. Three medicines that activate cannabinoid CB1/CB2 receptors are now in the clinic: Cesamet (nabilone), Marinol (dronabinol; Δ9-tetrahydrocannabinol (Δ9-THC)) and Sativex (Δ9-THC with cannabidiol). These can be prescribed for the amelioration of chemotherapy-induced nausea and vomiting (Cesamet and Marinol), stimulation of appetite (Marinol) and symptomatic relief of cancer pain and/or management of neuropathic pain and spasticity in adults with multiple sclerosis (Sativex). This review mentions several possible additional therapeutic targets for cannabinoid receptor agonists. These include other kinds of pain, epilepsy, anxiety, depression, Parkinson's and Huntington's diseases, amyotrophic lateral sclerosis, stroke, cancer, drug dependence, glaucoma, autoimmune uveitis, osteoporosis, sepsis, and hepatic, renal, intestinal and cardiovascular disorders. It also describes potential strategies for improving the efficacy and/or benefit-to-risk ratio of these agonists in the clinic. These are strategies that involve (i) targeting cannabinoid receptors located outside the blood-brain barrier, (ii) targeting cannabinoid receptors expressed by a particular tissue, (iii) targeting upregulated cannabinoid receptors, (iv) selectively targeting cannabinoid CB2 receptors, and/or (v) adjunctive ‘multi-targeting’. PMID:23108552

  10. Tailoring therapeutic strategies for treating posttraumatic stress disorder symptom clusters

    PubMed Central

    Norrholm, Seth D; Jovanovic, Tanja

    2010-01-01

    According to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, posttraumatic stress disorder (PTSD) is characterized by three major symptom clusters following an event that elicited fear, helplessness, or horror. This review will examine each symptom cluster of PTSD separately, giving case study examples of patients who exhibit a preponderance of a given symptom domain. We use a translational approach in describing the underlying neurobiology that is relevant to particular symptoms and treatment options, thus showing how clinical practice can benefit from current research. By focusing on symptom clusters, we provide a more specific view of individual patient’s clinical presentations, in order to better address treatment needs. Finally, the review will also address potential genetic approaches to treatment as another form of individualized treatment. PMID:20856915

  11. Tailoring therapeutic strategies for treating posttraumatic stress disorder symptom clusters.

    PubMed

    Norrholm, Seth D; Jovanovic, Tanja

    2010-01-01

    According to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, posttraumatic stress disorder (PTSD) is characterized by three major symptom clusters following an event that elicited fear, helplessness, or horror. This review will examine each symptom cluster of PTSD separately, giving case study examples of patients who exhibit a preponderance of a given symptom domain. We use a translational approach in describing the underlying neurobiology that is relevant to particular symptoms and treatment options, thus showing how clinical practice can benefit from current research. By focusing on symptom clusters, we provide a more specific view of individual patient's clinical presentations, in order to better address treatment needs. Finally, the review will also address potential genetic approaches to treatment as another form of individualized treatment. PMID:20856915

  12. Mitochondrial optic neuropathies – Disease mechanisms and therapeutic strategies

    PubMed Central

    Yu-Wai-Man, Patrick; Griffiths, Philip G.; Chinnery, Patrick F.

    2011-01-01

    paraplegia, and multiple sclerosis, where mitochondrial dysfunction is also thought to be an important pathophysiological player. A number of vertebrate and invertebrate disease models has recently been established to circumvent the lack of human tissues, and these have already provided considerable insight by allowing direct RGC experimentation. The ultimate goal is to translate these research advances into clinical practice and new treatment strategies are currently being investigated to improve the visual prognosis for patients with mitochondrial optic neuropathies. PMID:21112411

  13. Stratification and therapeutic potential of PML in metastatic breast cancer

    PubMed Central

    Martín-Martín, Natalia; Piva, Marco; Urosevic, Jelena; Aldaz, Paula; Sutherland, James D.; Fernández-Ruiz, Sonia; Arreal, Leire; Torrano, Verónica; Cortazar, Ana R.; Planet, Evarist; Guiu, Marc; Radosevic-Robin, Nina; Garcia, Stephane; Macías, Iratxe; Salvador, Fernando; Domenici, Giacomo; Rueda, Oscar M.; Zabala-Letona, Amaia; Arruabarrena-Aristorena, Amaia; Zúñiga-García, Patricia; Caro-Maldonado, Alfredo; Valcárcel-Jiménez, Lorea; Sánchez-Mosquera, Pilar; Varela-Rey, Marta; Martínez-Chantar, Maria Luz; Anguita, Juan; Ibrahim, Yasir H.; Scaltriti, Maurizio; Lawrie, Charles H.; Aransay, Ana M.; Iovanna, Juan L.; Baselga, Jose; Caldas, Carlos; Barrio, Rosa; Serra, Violeta; dM Vivanco, Maria; Matheu, Ander; Gomis, Roger R.; Carracedo, Arkaitz

    2016-01-01

    Patient stratification has been instrumental for the success of targeted therapies in breast cancer. However, the molecular basis of metastatic breast cancer and its therapeutic vulnerabilities remain poorly understood. Here we show that PML is a novel target in aggressive breast cancer. The acquisition of aggressiveness and metastatic features in breast tumours is accompanied by the elevated PML expression and enhanced sensitivity to its inhibition. Interestingly, we find that STAT3 is responsible, at least in part, for the transcriptional upregulation of PML in breast cancer. Moreover, PML targeting hampers breast cancer initiation and metastatic seeding. Mechanistically, this biological activity relies on the regulation of the stem cell gene SOX9 through interaction of PML with its promoter region. Altogether, we identify a novel pathway sustaining breast cancer aggressiveness that can be therapeutically exploited in combination with PML-based stratification. PMID:27553708

  14. Stratification and therapeutic potential of PML in metastatic breast cancer.

    PubMed

    Martín-Martín, Natalia; Piva, Marco; Urosevic, Jelena; Aldaz, Paula; Sutherland, James D; Fernández-Ruiz, Sonia; Arreal, Leire; Torrano, Verónica; Cortazar, Ana R; Planet, Evarist; Guiu, Marc; Radosevic-Robin, Nina; Garcia, Stephane; Macías, Iratxe; Salvador, Fernando; Domenici, Giacomo; Rueda, Oscar M; Zabala-Letona, Amaia; Arruabarrena-Aristorena, Amaia; Zúñiga-García, Patricia; Caro-Maldonado, Alfredo; Valcárcel-Jiménez, Lorea; Sánchez-Mosquera, Pilar; Varela-Rey, Marta; Martínez-Chantar, Maria Luz; Anguita, Juan; Ibrahim, Yasir H; Scaltriti, Maurizio; Lawrie, Charles H; Aransay, Ana M; Iovanna, Juan L; Baselga, Jose; Caldas, Carlos; Barrio, Rosa; Serra, Violeta; Vivanco, Maria dM; Matheu, Ander; Gomis, Roger R; Carracedo, Arkaitz

    2016-01-01

    Patient stratification has been instrumental for the success of targeted therapies in breast cancer. However, the molecular basis of metastatic breast cancer and its therapeutic vulnerabilities remain poorly understood. Here we show that PML is a novel target in aggressive breast cancer. The acquisition of aggressiveness and metastatic features in breast tumours is accompanied by the elevated PML expression and enhanced sensitivity to its inhibition. Interestingly, we find that STAT3 is responsible, at least in part, for the transcriptional upregulation of PML in breast cancer. Moreover, PML targeting hampers breast cancer initiation and metastatic seeding. Mechanistically, this biological activity relies on the regulation of the stem cell gene SOX9 through interaction of PML with its promoter region. Altogether, we identify a novel pathway sustaining breast cancer aggressiveness that can be therapeutically exploited in combination with PML-based stratification. PMID:27553708

  15. Asparagus racemosus: a review on its phytochemical and therapeutic potential.

    PubMed

    Singh, Ram

    2016-09-01

    Asparagus racemosus (Willd.) is a widely found medicinal plant in tropical and subtropical parts of India. The therapeutic applications of this plant have been reported in Indian and British Pharmacopoeias and in traditional system of medicine, such as Ayurveda, Unani and Siddha. The crude, semi-purified and purified extracts obtained from different parts of this plant have been useful in therapeutic applications. Numerous bioactive phytochemicals mostly saponins and flavonoids have been isolated and identified from this plant which are responsible alone or in combination for various pharmacological activities. This review aims to give a comprehensive overview of traditional applications, current knowledge on the phytochemistry, pharmacology and overuse of A. racemosus. PMID:26463825

  16. Therapeutic potential of vitamin D-binding protein.

    PubMed

    Gomme, Peter T; Bertolini, Joseph

    2004-07-01

    Vitamin D-binding protein (DBP) is a multi-functional plasma protein with many important functions. These include transport of vitamin D metabolites, control of bone development, binding of fatty acids, sequestration of actin and a range of less-defined roles in modulating immune and inflammatory responses. Exploitation of the unique properties of DBP could enable the development of important therapeutic agents for the treatment of a variety of diseases. PMID:15245906

  17. Therapeutic Potential of Non-Psychotropic Cannabidiol in Ischemic Stroke

    PubMed Central

    Hayakawa, Kazuhide; Mishima, Kenichi; Fujiwara, Michihiro

    2010-01-01

    Cannabis contains the psychoactive component delta9-tetrahydrocannabinol (delta9-THC), and the non-psychoactive components cannabidiol (CBD), cannabinol, and cannabigerol. It is well-known that delta9-THC and other cannabinoid CB1 receptor agonists are neuroprotective during global and focal ischemic injury. Additionally, delta9-THC also mediates psychological effects through the activation of the CB1 receptor in the central nervous system. In addition to the CB1 receptor agonists, cannabis also contains therapeutically active components which are CB1 receptor independent. Of the CB1 receptor-independent cannabis, the most important is CBD. In the past five years, an increasing number of publications have focused on the discovery of the anti-inflammatory, anti-oxidant, and neuroprotective effects of CBD. In particular, CBD exerts positive pharmacological effects in ischemic stroke and other chronic diseases, including Parkinson’s disease, Alzheimer’s disease, and rheumatoid arthritis. The cerebroprotective action of CBD is CB1 receptor-independent, long-lasting, and has potent anti-oxidant activity. Importantly, CBD use does not lead to tolerance. In this review, we will discuss the therapeutic possibility of CBD as a cerebroprotective agent, highlighting recent pharmacological advances, novel mechanisms, and therapeutic time window of CBD in ischemic stroke.

  18. Virogenetic and Optogenetic Mechanisms to Define Potential Therapeutic Targets in Psychiatric Disorders

    PubMed Central

    Han, Ming-Hu; Friedman, Allyson K.

    2011-01-01

    A continuously increasing body of knowledge shows that the brain is an extremely complex neural network and single neurons possess their own complicated interactive signaling pathways. Such complexity of the nervous system makes it increasingly difficult to investigate the functions of specific neural components such as genes, proteins, transcription factors, neurons and nuclei in the brain. Technically, it has been even more of a significant challenge to identify the molecular and cellular adaptations that are both sufficient and necessary to underlie behavioral functions in health and disease states. Defining such neural adaptations is a critical step to identify the potential therapeutic targets within the complex neural network that are beneficial to treat psychiatric disorders. Recently, the newly development and extensive application of in vivo viral-mediated gene transfer (virogenetics) and optical manipulation of specific neurons or selective neural circuits in freely-moving animals (optogenetics) make it feasible, through loss- and gain-of-function approaches, to reliably define sufficient and necessary neuroadaptations in the behavioral models of psychiatric disorders, including drug addiction, depression, anxiety and bipolar disorders. In this article, we focus on recent studies that successfully employ these advanced virogenetic and optogenetic techniques as a powerful tool to identify potential targets in the brain, and to provide highly useful information in the development of novel therapeutic strategies for psychiatric disorders. PMID:21945288

  19. Alcohol Versus Cannabinoids: A Review of Their Opposite Neuro-Immunomodulatory Effects and Future Therapeutic Potentials

    PubMed Central

    Nair, Madhavan P.; Figueroa, Gloria; Casteleiro, Gianna; Muñoz, Karla; Agudelo, Marisela

    2015-01-01

    Due to the legalization of marijuana and the increased demand for cannabis and alcohol consumption, research efforts highlighting the biomedical consequences of the use of alcohol and cannabinoids are not only relevant to the substance abuse scientific field, but are also of public health interest. Moreover, an overview of the recent literature about alcohol and cannabinoids neuro-immunomodulatory effects highlighting their future therapeutic potentials will provide a significant contribution to science and medicine. Therefore, in the current review, we will first discuss briefly the prevalence of alcohol and marijuana abuse, followed by a discussion on the individual effects of alcohol and cannabinoids on the immune system; then, we will focus on the role of endocannabinoids on the alcohol-induced inflammatory effects. In addition, the review also incorporates cytokine array data obtained from human monocyte-derived dendritic cells, providing a different perspective on the alcohol and cannabinoid abuse divergent effects on cytokine production. The final section will highlight the therapeutic potential of cannabinoid receptors and the novel strategies to treat alcohol dependence as determined by in vitro, in vivo and clinical studies. PMID:26478902

  20. Therapeutic Potential and Challenges of Natural Killer Cells in Treatment of Solid Tumors

    PubMed Central

    Gras Navarro, Andrea; Björklund, Andreas T.; Chekenya, Martha

    2015-01-01

    Natural killer (NK) cells are innate lymphoid cells that hold tremendous potential for effective immunotherapy for a broad range of cancers. Due to the mode of NK cell killing, requiring one-to-one target engagement and site-directed release of cytolytic granules, the therapeutic potential of NK cells has been most extensively explored in hematological malignancies. However, their ability to precisely kill antibody coated cells, cancer stem cells, and genotoxically altered cells, while maintaining tolerance to healthy cells makes them appealing therapeutic effectors for all cancer forms, including metastases. Due to their release of pro-inflammatory cytokines, NK cells may potently reverse the anti-inflammatory tumor microenvironment (TME) and augment adaptive immune responses by promoting differentiation, activation, and/or recruitment of accessory immune cells to sites of malignancy. Nevertheless, integrated and coordinated mechanisms of subversion of NK cell activity against the tumor and its microenvironment exist. Although our understanding of the receptor ligand interactions that regulate NK cell functionality has evolved remarkably, the diversity of ligands and receptors is complex, as is their mechanistic foundations in regulating NK cell function. In this article, we review the literature and highlight how the TME manipulates the NK cell phenotypes, genotypes, and tropism to evade tumor recognition and elimination. We discuss counter strategies that may be adopted to augment the efficacy of NK cell anti-tumor surveillance, the clinical trials that have been undertaken so far in solid malignancies, critically weighing the challenges and opportunities with this approach. PMID:25972872

  1. Expression Profiling Identifies Bezafibrate as Potential Therapeutic Drug for Lung Adenocarcinoma.

    PubMed

    Liu, Xinyan; Yang, Xiaoqin; Chen, Xinmei; Zhang, Yantao; Pan, Xuebin; Wang, Guiping; Ye, Yun

    2015-01-01

    Drug-induced gene expression patterns that invert disease profiles have recently been illustrated to be a new strategy for drug-repositioning. In the present study, we validated this approach and focused on prediction of novel drugs for lung adenocarcinoma (AC), for which there is a pressing need to find novel therapeutic compounds. Firstly, connectivity map (CMap) analysis computationally predicted bezafibrate as a putative compound against lung AC. Then this hypothesis was verified by in vitro assays of anti-proliferation and cell cycle arrest. In silico docking evidence indicated that bezafibrate could target cyclin dependent kinase 2(CDK2), which regulates progression through the cell cycle. Furthermore, we found that bezafibrate can significantly down-regulate the expression of CDK2 mRNA and p-CDK2. Using a nude mice xenograft model, we also found that bezafibrate could inhibit tumor growth of lung AC in vivo. In conclusion, this study proposed bezafibrate as a potential therapeutic option for lung AC patients, illustrating the potential of in silico drug screening. PMID:26535062

  2. Therapeutic Potential of Moringa oleifera Leaves in Chronic Hyperglycemia and Dyslipidemia: A Review

    PubMed Central

    Mbikay, Majambu

    2012-01-01

    Moringa oleifera (M. oleifera) is an angiosperm plant, native of the Indian subcontinent, where its various parts have been utilized throughout history as food and medicine. It is now cultivated in all tropical and sub-tropical regions of the world. The nutritional, prophylactic, and therapeutic virtues of this plant are being extolled on the Internet. Dietary consumption of its part is therein promoted as a strategy of personal health preservation and self-medication in various diseases. The enthusiasm for the health benefits of M. oleifera is in dire contrast with the scarcity of strong experimental and clinical evidence supporting them. Fortunately, the chasm is slowly being filled. In this article, I review current scientific data on the corrective potential of M. oleifera leaves in chronic hyperglycemia and dyslipidemia, as symptoms of diabetes and cardiovascular disease (CVD) risk. Reported studies in experimental animals and humans, although limited in number and variable in design, seem concordant in their support for this potential. However, before M. oleifera leaf formulations can be recommended as medication in the prevention or treatment of diabetes and CVD, it is necessary that the scientific basis of their efficacy, the therapeutic modalities of their administration and their possible side effects be more rigorously determined. PMID:22403543

  3. Therapeutic strategies for preventing skeletal muscle fibrosis after injury

    PubMed Central

    Garg, Koyal; Corona, Benjamin T.; Walters, Thomas J.

    2015-01-01

    Skeletal muscle repair after injury includes a complex and well-coordinated regenerative response. However, fibrosis often manifests, leading to aberrant regeneration and incomplete functional recovery. Research efforts have focused on the use of anti-fibrotic agents aimed at reducing the fibrotic response and improving functional recovery. While there are a number of mediators involved in the development of post-injury fibrosis, TGF-β1 is the primary pro-fibrogenic growth factor and several agents that inactivate TGF-β1 signaling cascade have emerged as promising anti-fibrotic therapies. A number of these agents are FDA approved for other conditions, clearing the way for rapid translation into clinical treatment. In this article, we provide an overview of muscle's host response to injury with special emphasis on the cellular and non-cellular mediators involved in the development of fibrosis. This article also reviews the findings of several pre-clinical studies that have utilized anti-fibrotic agents to improve muscle healing following most common forms of muscle injuries. Although some studies have shown positive results with anti-fibrotic treatment, others have indicated adverse outcomes. Some concerns and questions regarding the clinical potential of these anti-fibrotic agents have also been presented. PMID:25954202

  4. Therapeutic Strategies for the Treatment of Alcoholic Hepatitis.

    PubMed

    Singal, Ashwani K; Shah, Vijay H

    2016-02-01

    Acute alcoholic hepatitis is a unique clinical syndrome among patients with chronic and active heavy alcohol use. Presenting with acute or chronic liver failure, a severe episode has a potential for 30 to 40% mortality at 1 month from presentation, if not recognized and left untreated. Alcoholic hepatitis patients need supportive therapy for abstinence and nutritional supplementation for those patients with markedly reduced caloric intake. Results of the recently published STOPAH (Steroids or Pentoxifylline for Alcoholic Hepatitis) Study showed only a benefit of corticosteroids on short-term mortality without any benefit of pentoxifylline. Neither of these two drugs impacts medium- and long-term mortality, which is mainly driven by abstinence from alcohol. With the emerging data on the benefits of liver transplantation, liver transplantation could be an important salvage option for a very highly select group of AH patients. More data are needed on the use of liver transplantation in AH as the basis for deriving protocols for selecting cases and for posttransplant management. Currently, many clinical trials are examining the efficacy and safety of new or repurposed compounds in severe AH. These drugs are targeted at various pathways in the pathogenesis of AH: the gut-liver axis, the inflammatory cascade, and liver injury. With increasing interest of researchers and clinicians, supported by funding from the National Institute on Alcohol Abuse and Alcoholism, the future seems promising for the development of effective and safe pharmacological interventions for severe AH. PMID:26870933

  5. Therapeutic strategy for small-sized lung cancer.

    PubMed

    Iwata, Hisashi

    2016-08-01

    Minimizing the volume of lung resection without diminishing curability has recently become an important issue in primary lung cancer. In this review, we will discuss the current state of the feasibility of sublobar resection and specific issues for a segmentectomy procedure. A previous randomized controlled trial showed that lobectomy must still be considered the standard surgical procedure compared with sublobar resection for T1N0 non-small cell lung cancer with a tumor less than 3 cm in size. Since then, supporting studies for segmentectomy of lung cancer with a tumor less than 2 cm in size were reported. In addition, segmentectomy seems to be feasible for clinical stage I adenocarcinoma less than 2 cm in size, in women younger than 70 years old, with a low tumor 18F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) standardized uptake value (SUV) from propensity-matching studies. In a meta-analysis of sublobar resection vs. lobectomy, intentionally performed sublobar resection showed equivalent outcomes to lobectomy. In the near future, two ongoing prospective, randomized trials will report results. As specific issues for the surgical procedure of segmentectomy, achieving a sufficient surgical margin is an important issue for preventing loco-regional recurrence. More studies regarding the regional lymph node dissection area for segmentectomy are needed. Sublobar resection has the potential to become the standard procedure for peripheral small-sized lung cancer less than 2 cm. However, more information is needed about the characteristics of this cancer and the surgical procedure, including nodal dissection. PMID:27300350

  6. Therapeutic application of mesenchymal stem cell-derived exosomes: A promising cell-free therapeutic strategy in regenerative medicine.

    PubMed

    Motavaf, M; Pakravan, K; Babashah, S; Malekvandfard, F; Masoumi, M; Sadeghizadeh, M

    2016-01-01

    Mesenchymal stem cells have emerged as promising therapeutic candidates in regenerative medicine. The mechanisms underlying mesenchymal stem cells regenerative properties were initially attributed to their engraftment in injured tissues and their subsequent transdifferentiation to repair and replace damaged cells. However, studies in animal models and patients indicated that the low number of transplanted mesenchymal stem cells localize to the target tissue and transdifferentiate to appropriate cell lineage. Instead the regenerative potential of mesenchymal stem cells has been found - at least in part - to be mediated via their paracrine actions. Recently, a secreted group of vesicles, called "exosome" has been identified as major mediator of mesenchymal stem cells therapeutic efficacy. In this review, we will summarize the current literature on administration of exosomes released by mesenchymal stem cells in regenerative medicine and suggest how they could help to improve tissue regeneration following injury. PMID:27453276

  7. The evidence for natural therapeutics as potential anti-scarring agents in burn-related scarring.

    PubMed

    Mehta, M; Branford, O A; Rolfe, K J

    2016-01-01

    Though survival rate following severe thermal injuries has improved, the incidence and treatment of scarring have not improved at the same speed. This review discusses the formation of scars and in particular the formation of hypertrophic scars. Further, though there is as yet no gold standard treatment for the prevention or treatment of scarring, a brief overview is included. A number of natural therapeutics have shown beneficial effects both in vivo and in vitro with the potential of becoming clinical therapeutics in the future. These natural therapeutics include both plant-based products such as resveratrol, quercetin and epigallocatechin gallate as examples and includes the non-plant-based therapeutic honey. The review also includes potential mechanism of action for the therapeutics, any recorded adverse events and current administration of the therapeutics used. This review discusses a number of potential 'treatments' that may reduce or even prevent scarring particularly hypertrophic scarring, which is associated with thermal injuries without compromising wound repair. PMID:27574685

  8. Therapeutic potential of resveratrol in obesity and type 2 diabetes: new avenues for health benefits?

    PubMed

    Timmers, Silvie; Hesselink, Matthijs K C; Schrauwen, Patrick

    2013-07-01

    The number of people suffering from metabolic disorders is dramatically increasing worldwide. The need for new therapeutic strategies to combat this growing epidemic of metabolic diseases is therefore also increasing. In 2003, resveratrol was discovered to be a small molecule activator of sirtuin 1 (SIRT1), an important molecular target regulating cellular energy metabolism and mitochondrial homeostasis. Rodent studies have clearly demonstrated the potential of resveratrol to improve various metabolic health parameters. To date, however, only limited clinical data are available that have systematically examined the health benefits of resveratrol in metabolically challenged humans. This short review will give an overview of the currently available clinical studies examining the effects of resveratrol on obesity and type 2 diabetes from a human perspective. PMID:23855469

  9. The potential of sarcospan in adhesion complex replacement therapeutics for the treatment of muscular dystrophy

    PubMed Central

    Marshall, Jamie L.; Kwok, Yukwah; McMorran, Brian; Baum, Linda G.; Crosbie-Watson, Rachelle H.

    2013-01-01

    Three adhesion complexes span the sarcolemma and facilitate critical connections between the extracellular matrix and the actin cytoskeleton: the dystrophin- and utrophin-glycoprotein complexes and α7β1 integrin. Loss of individual protein components results in a loss of the entire protein complex and muscular dystrophy. Muscular dystrophy is a progressive, lethal wasting disease characterized by repetitive cycles of myofiber degeneration and regeneration. Protein replacement therapy offers a promising approach for the treatment of muscular dystrophy. Recently, we demonstrated that sarcospan facilitates protein-protein interactions amongst the adhesion complexes and is an important therapeutic target. Here, we review current protein replacement strategies, discuss the potential benefits of sarcospan expression, and identify important experiments that must be addressed for sarcospan to move to the clinic. PMID:23601082

  10. Heat Shock Proteins: Pathogenic Role in Atherosclerosis and Potential Therapeutic Implications

    PubMed Central

    Kilic, Arman; Mandal, Kaushik

    2012-01-01

    Heat shock proteins (HSPs) are a highly conserved group of proteins that are constitutively expressed and function as molecular chaperones, aiding in protein folding and preventing the accumulation of misfolded proteins. In the arterial wall, HSPs have a protective role under normal physiologic conditions. In disease states, however, HSPs expressed on the vascular endothelial cell surface can act as targets for detrimental autoimmunity due to their highly conserved sequences. Developing therapeutic strategies for atherosclerosis based on HSPs is challenged by the need to balance such physiologic and pathologic roles of these proteins. This paper summarizes the role of HSPs in normal vascular wall processes as well as in the development and progression of atherosclerosis. The potential implications of HSPs in clinical therapies for atherosclerosis are also discussed. PMID:23304456

  11. Potential Diagnostic, Prognostic and Therapeutic Targets of MicroRNAs in Human Gastric Cancer

    PubMed Central

    Tsai, Ming-Ming; Wang, Chia-Siu; Tsai, Chung-Ying; Huang, Hsiang-Wei; Chi, Hsiang-Cheng; Lin, Yang-Hsiang; Lu, Pei-Hsuan; Lin, Kwang-Huei

    2016-01-01

    Human gastric cancer (GC) is characterized by a high incidence and mortality rate, largely because it is normally not identified until a relatively advanced stage owing to a lack of early diagnostic biomarkers. Gastroscopy with biopsy is the routine method for screening, and gastrectomy is the major therapeutic strategy for GC. However, in more than 30% of GC surgical patients, cancer has progressed too far for effective medical resection. Thus, useful biomarkers for early screening or detection of GC are essential for improving patients’ survival rate. MicroRNAs (miRNAs) play an important role in tumorigenesis. They contribute to gastric carcinogenesis by altering the expression of oncogenes and tumor suppressors. Because of their stability in tissues, serum/plasma and other body fluids, miRNAs have been suggested as novel tumor biomarkers with suitable clinical potential. Recently, aberrantly expressed miRNAs have been identified and tested for clinical application in the management of GC. Aberrant miRNA expression profiles determined with miRNA microarrays, quantitative reverse transcription-polymerase chain reaction and next-generation sequencing approaches could be used to establish sample specificity and to identify tumor type. Here, we provide an up-to-date summary of tissue-based GC-associated miRNAs, describing their involvement and that of their downstream targets in tumorigenic and biological processes. We examine correlations among significant clinical parameters and prognostic indicators, and discuss recurrence monitoring and therapeutic options in GC. We also review plasma/serum-based, GC-associated, circulating miRNAs and their clinical applications, focusing especially on early diagnosis. By providing insights into the mechanisms of miRNA-related tumor progression, this review will hopefully aid in the identification of novel potential therapeutic targets. PMID:27322246

  12. Potential Diagnostic, Prognostic and Therapeutic Targets of MicroRNAs in Human Gastric Cancer.

    PubMed

    Tsai, Ming-Ming; Wang, Chia-Siu; Tsai, Chung-Ying; Huang, Hsiang-Wei; Chi, Hsiang-Cheng; Lin, Yang-Hsiang; Lu, Pei-Hsuan; Lin, Kwang-Huei

    2016-01-01

    Human gastric cancer (GC) is characterized by a high incidence and mortality rate, largely because it is normally not identified until a relatively advanced stage owing to a lack of early diagnostic biomarkers. Gastroscopy with biopsy is the routine method for screening, and gastrectomy is the major therapeutic strategy for GC. However, in more than 30% of GC surgical patients, cancer has progressed too far for effective medical resection. Thus, useful biomarkers for early screening or detection of GC are essential for improving patients' survival rate. MicroRNAs (miRNAs) play an important role in tumorigenesis. They contribute to gastric carcinogenesis by altering the expression of oncogenes and tumor suppressors. Because of their stability in tissues, serum/plasma and other body fluids, miRNAs have been suggested as novel tumor biomarkers with suitable clinical potential. Recently, aberrantly expressed miRNAs have been identified and tested for clinical application in the management of GC. Aberrant miRNA expression profiles determined with miRNA microarrays, quantitative reverse transcription-polymerase chain reaction and next-generation sequencing approaches could be used to establish sample specificity and to identify tumor type. Here, we provide an up-to-date summary of tissue-based GC-associated miRNAs, describing their involvement and that of their downstream targets in tumorigenic and biological processes. We examine correlations among significant clinical parameters and prognostic indicators, and discuss recurrence monitoring and therapeutic options in GC. We also review plasma/serum-based, GC-associated, circulating miRNAs and their clinical applications, focusing especially on early diagnosis. By providing insights into the mechanisms of miRNA-related tumor progression, this review will hopefully aid in the identification of novel potential therapeutic targets. PMID:27322246

  13. MicroRNAs as potential therapeutic targets in kidney disease

    PubMed Central

    Gomez, Ivan G; Grafals, Monica; Portilla, Didier; Duffield, Jeremy S

    2014-01-01

    One cornerstone of Chronic Kidney Disease (CKD) is fibrosis, as kidneys are susceptible due to their high vascularity and predisposition to ischemia. Presently, only therapies targeting the angiotensin receptor are used in clinical practice to retard the progression of CKD. Thus, there is a pressing need for new therapies designed to treat the damaged kidney. Several independent laboratories have identified a number of microRNAs that are dysregulated in human and animal models of CKD. We will explore the evidence suggesting that by blocking the activity of such dysregulated microRNAs, new therapeutics could be developed to treat the progression of CKD. PMID:23660218

  14. Transplantation directs oocyte maturation from embryonic stem cells and provides a therapeutic strategy for female infertility

    PubMed Central

    Nicholas, Cory R.; Haston, Kelly M.; Grewall, Amarjeet K.; Longacre, Teri A.; Reijo Pera, Renee A.

    2009-01-01

    Ten to 15% of couples are infertile, with the most common causes being linked to the production of few or no oocytes or sperm. Yet, our understanding of human germ cell development is poor, at least in part due to the inaccessibility of early stages to genetic and developmental studies. Embryonic stem cells (ESCs) provide an in vitro system to study oocyte development and potentially treat female infertility. However, most studies of ESC differentiation to oocytes have not documented fundamental properties of endogenous development, making it difficult to determine the physiologic relevance of differentiated germ cells. Here, we sought to establish fundamental parameters of oocyte development during ESC differentiation to explore suitability for basic developmental genetic applications using the mouse as a model prior to translating to the human system. We demonstrate a timeline of definitive germ cell differentiation from ESCs in vitro that initially parallels endogenous oocyte development in vivo by single-cell expression profiling and analysis of functional milestones including responsiveness to defined maturation media, shared genetic requirement of Dazl, and entry into meiosis. However, ESC-derived oocyte maturation ultimately fails in vitro. To overcome this obstacle, we transplant ESC-derived oocytes into an ovarian niche to direct their functional maturation and, thereby, present rigorous evidence of oocyte physiologic relevance and a potential therapeutic strategy for infertility. PMID:19696121

  15. Emerging antibody-based therapeutic strategies for bladder cancer: A systematic review.

    PubMed

    Azevedo, Rita; Ferreira, José Alexandre; Peixoto, Andreia; Neves, Manuel; Sousa, Nuno; Lima, Aurea; Santos, Lucio Lara

    2015-09-28

    Bladder cancer is the most common malignancy of the urinary tract, presents the highest recurrence rate among solid tumors and is the second leading cause of death in genitourinary cancers. Despite recent advances in understanding of pathophysiology of the disease, the management of bladder cancer patients remains a clinically challenging problem. Particularly, bladder tumors invading the muscularis propria and disseminated disease are often not responsive to currently available therapeutic approaches, which include surgery and conventional chemotherapy. Antibody-based therapeutic strategies have become an established treatment option for over a decade in several types of cancer. However, bladder cancer has remained mostly an "orphan disease" regarding the introduction of these novel therapeutics, which has been translated in few improvements in patients overall survival. In order to shift this paradigm, several clinical studies involving antibody-based therapeutic strategies targeting the most prominent bladder cancer-related biomolecular pathways and immunological mediators are ongoing. This systematic review explores antibody-based therapeutics for bladder cancer undergoing clinical trial and discusses the future perspectives in this field, envisaging the development of more effective guided therapeutics. PMID:26196222

  16. Ferulic Acid: Therapeutic Potential Through Its Antioxidant Property

    PubMed Central

    Srinivasan, Marimuthu; Sudheer, Adluri R.; Menon, Venugopal P.

    2007-01-01

    There has been considerable public and scientific interest in the use of phytochemicals derived from dietary components to combat human diseases. They are naturally occurring substances found in plants. Ferulic acid (FA) is a phytochemical commonly found in fruits and vegetables such as tomatoes, sweet corn and rice bran. It arises from metabolism of phenylalanine and tyrosine by Shikimate pathway in plants. It exhibits a wide range of therapeutic effects against various diseases like cancer, diabetes, cardiovascular and neurodegenerative. A wide spectrum of beneficial activity for human health has been advocated for this phenolic compound, at least in part, because of its strong antioxidant activity. FA, a phenolic compound is a strong membrane antioxidant and known to positively affect human health. FA is an effective scavenger of free radicals and it has been approved in certain countries as food additive to prevent lipid peroxidation. It effectively scavenges superoxide anion radical and inhibits the lipid peroxidation. It possesses antioxidant property by virtue of its phenolic hydroxyl group in its structure. The hydroxy and phenoxy groups of FA donate electrons to quench the free radicals. The phenolic radical in turn forms a quinone methide intermediate, which is excreted via the bile. The past few decades have been devoted to intense research on antioxidant property of FA. So, the present review deals with the mechanism of antioxidant property of FA and its possible role in therapeutic usage against various diseases. PMID:18188410

  17. Exploring Therapeutic Potentials of Baicalin and Its Aglycone Baicalein for Hematological Malignancies

    PubMed Central

    Chen, Haijun; Gao, Yu; Wu, Jianlei; Chen, Yingyu; Chen, Buyuan; Hu, Jianda; Zhou, Jia

    2014-01-01

    Despite tremendous advances in the targeted therapy for various types of hematological malignancies with successful improvements in the survival rates, emerging resistance issues are startlingly high and novel therapeutic strategies are urgently needed. In addition, chemoprevention is currently becoming an elusive goal. Plant-derived natural products have garnered considerable attention in recent years due to the potential dual functions as chemotherapeutics and dietary chemoprevention. One of the particularly ubiquitous families is the polyphenolic flavonoids. Among them, baicalin and its aglycone baicalein have been widely investigated in hematological malignancies because both of them exhibit remarkable pharmacological properties. This review focuses on the recent achievements in drug discovery research associated with baicalin and baicalein for hematological malignancy therapies. The promising anticancer activities of these two flavonoids targeting diverse signaling pathways and their potential biological mechanisms in different types of hematological malignancies, as well as the combination strategy with baicalin or baicalein as chemotherapeutic adjuvants for recent therapies in these intractable diseases are discussed. Meanwhile, the biotransformation of baicalin and baicalein and the relevant approaches to improve their bioavailability are also summarized. PMID:25128647

  18. Molecular and Therapeutic Potential and Toxicity of Valproic Acid

    PubMed Central

    Chateauvieux, Sébastien; Morceau, Franck; Dicato, Mario; Diederich, Marc

    2010-01-01

    Valproic acid (VPA), a branched short-chain fatty acid, is widely used as an antiepileptic drug and a mood stabilizer. Antiepileptic properties have been attributed to inhibition of Gamma Amino Butyrate (GABA) transaminobutyrate and of ion channels. VPA was recently classified among the Histone Deacetylase Inhibitors, acting directly at the level of gene transcription by inhibiting histone deacetylation and making transcription sites more accessible. VPA is a widely used drug, particularly for children suffering from epilepsy. Due to the increasing number of clinical trials involving VPA, and interesting results obtained, this molecule will be implicated in an increasing number of therapies. However side effects of VPA are substantially described in the literature whereas they are poorly discussed in articles focusing on its therapeutic use. This paper aims to give an overview of the different clinical-trials involving VPA and its side effects encountered during treatment as well as its molecular properties. PMID:20798865

  19. [Mitochondrial dynamics: a potential new therapeutic target for heart failure].

    PubMed

    Kuzmicic, Jovan; Del Campo, Andrea; López-Crisosto, Camila; Morales, Pablo E; Pennanen, Christian; Bravo-Sagua, Roberto; Hechenleitner, Jonathan; Zepeda, Ramiro; Castro, Pablo F; Verdejo, Hugo E; Parra, Valentina; Chiong, Mario; Lavandero, Sergio

    2011-10-01

    Mitochondria are dynamic organelles able to vary their morphology between elongated interconnected mitochondrial networks and fragmented disconnected arrays, through events of mitochondrial fusion and fission, respectively. These events allow the transmission of signaling messengers and exchange of metabolites within the cell. They have also been implicated in a variety of biological processes including embryonic development, metabolism, apoptosis, and autophagy. Although the majority of these studies have been confined to noncardiac cells, emerging evidence suggests that changes in mitochondrial morphology could participate in cardiac development, the response to ischemia-reperfusion injury, heart failure, and diabetes mellitus. In this article, we review how the mitochondrial dynamics are altered in different cardiac pathologies, with special emphasis on heart failure, and how this knowledge may provide new therapeutic targets for treating cardiovascular diseases. PMID:21820793

  20. The pharmacological landscape and therapeutic potential of serine hydrolases.

    PubMed

    Bachovchin, Daniel A; Cravatt, Benjamin F

    2012-01-01

    Serine hydrolases perform crucial roles in many biological processes, and several of these enzymes are targets of approved drugs for indications such as type 2 diabetes, Alzheimer's disease and infectious diseases. Despite this, most of the human serine hydrolases (of which there are more than 200) remain poorly characterized with respect to their physiological substrates and functions, and the vast majority lack selective, in vivo-active inhibitors. Here, we review the current state of pharmacology for mammalian serine hydrolases, including marketed drugs, compounds that are under clinical investigation and selective inhibitors emerging from academic probe development efforts. We also highlight recent methodological advances that have accelerated the rate of inhibitor discovery and optimization for serine hydrolases, which we anticipate will aid in their biological characterization and, in some cases, therapeutic validation. PMID:22212679

  1. The Pharmacological Landscape and Therapeutic Potential of Serine Hydrolases

    PubMed Central

    Bachovchin, Daniel A.; Cravatt, Benjamin F.

    2013-01-01

    Serine hydrolases play critical roles in many biological processes, and several are targets of approved drugs for indications such as type 2 diabetes, Alzheimer’s disease, and infectious disease. Despite this, most of the 200+ human serine hydrolases remain poorly characterized with respect to their physiological substrates and functions, and the vast majority lack selective, in vivo-active inhibitors. Here, we review the current state of pharmacology for mammalian serine hydrolases, including marketed drugs, compounds under clinical investigation, and selective inhibitors emerging from academic probe development efforts. We also highlight recent methodological advances that have accelerated the rate of inhibitor discovery and optimization for serine hydrolases, which we anticipate will aid in their biological characterization and, in some cases, therapeutic validation. PMID:22212679

  2. Bcl-2-regulated apoptosis: mechanism and therapeutic potential.

    PubMed

    Adams, Jerry M; Cory, Suzanne

    2007-10-01

    Apoptosis is essential for tissue homeostasis, particularly in the hematopoietic compartment, where its impairment can elicit neoplastic or autoimmune diseases. Whether stressed cells live or die is largely determined by interplay between opposing members of the Bcl-2 protein family. Bcl-2 and its closest homologs promote cell survival, but two other factions promote apoptosis. The BH3-only proteins sense and relay stress signals, but commitment to apoptosis requires Bax or Bak. The BH3-only proteins appear to activate Bax and Bak indirectly, by engaging and neutralizing their pro-survival relatives, which otherwise constrain Bax and Bak from permeabilizing mitochondria. The Bcl-2 family may also regulate autophagy and mitochondrial fission/fusion. Its pro-survival members are attractive therapeutic targets in cancer and perhaps autoimmunity and viral infections. PMID:17629468

  3. Hepatitis B vaccines: protective efficacy and therapeutic potential.

    PubMed

    Michel, M-L; Tiollais, P

    2010-08-01

    Worldwide, two billion people have at some time been infected by hepatitis B virus, 370 millions suffer from chronic infection and around one million die each year from HBV-related liver diseases of which liver cancer is the ultimate stage. Vaccination is the measure that is most effective in reducing the global incidence of hepatitis B and hepatitis B vaccines have now been available for over 20 years. The first hepatitis B vaccine was prepared from inactivated hepatitis B surface antigen particles purified from plasma of asymptomatic carriers of hepatitis B virus. Knowledge of the structure and genomic organization of hepatitis B virus has led to development of the first DNA recombinant vaccine. In preventing hepatocellular carcinoma development, hepatitis B virus vaccines are considered as the first available cancer vaccine. HBV vaccines have recently taken on a new role as therapeutic vaccines as an attempt to cure or to control hepatitis B virus infection in persistently infected individuals. PMID:20382485

  4. The Bcl-2-regulated apoptosis switch: mechanism and therapeutic potential

    PubMed Central

    Adams, Jerry M; Cory, Suzanne

    2009-01-01

    Apoptosis is essential for tissue homeostasis, particularly in the hematopoietic compartment, where its impairment can elicit neoplastic or autoimmune diseases. Whether stressed cells live or die is largely determined by interplay between opposing members of the Bcl-2 protein family. Bcl-2 and its closest homologs promote cell survival, but two other factions promote apoptosis. The BH3-only proteins sense and relay stress signals, but commitment to apoptosis requires Bax or Bak. The BH3-only proteins appear to activate Bax and Bak indirectly, by engaging and neutralizing their pro-survival relatives, which otherwise constrain Bax and Bak from permeabilizing mitochondria. The Bcl-2 family may also regulate autophagy and mitochondrial fission/fusion. Its pro-survival members are attractive therapeutic targets in cancer and perhaps autoimmunity and viral infections. PMID:17629468

  5. Yoga school of thought and psychiatry: Therapeutic potential.

    PubMed

    Rao, Naren P; Varambally, Shivarama; Gangadhar, Bangalore N

    2013-01-01

    Yoga is a traditional life-style practice used for spiritual reasons. However, the physical components like the asanas and pranayaamas have demonstrated physiological and therapeutic effects. There is evidence for Yoga as being a potent antidepressant that matches with drugs. In depressive disorder, yoga 'corrects' an underlying cognitive physiology. In schizophrenia patients, yoga has benefits as an add-on intervention in pharmacologically stabilized subjects. The effects are particularly notable on negative symptoms. Yoga also helps to correct social cognition. Yoga can be introduced early in the treatment of psychosis with some benefits. Elevation of oxytocin may be a mechanism of yoga effects in schizophrenia. Certain components of yoga have demonstrated neurobiological effects similar to those of vagal stimulation, indicating this (indirect or autogenous vagal stimulation) as a possible mechanism of its action. It is time, psychiatrists exploited the benefits if yoga for a comprehensive care in their patients. PMID:23858245

  6. Potential role of bromelain in clinical and therapeutic applications

    PubMed Central

    Rathnavelu, Vidhya; Alitheen, Noorjahan Banu; Sohila, Subramaniam; Kanagesan, Samikannu; Ramesh, Rajendran

    2016-01-01

    Pineapple has been used as part of traditional folk medicine since ancient times and it continues to be present in various herbal preparations. Bromelain is a complex mixture of protease extracted from the fruit or stem of the pineapple plant. Although the complete molecular mechanism of action of bromelain has not been completely identified, bromelain gained universal acceptability as a phytotherapeutic agent due to its history of safe use and lack of side effects. Bromelain is widely administered for its well-recognized properties, such as its anti-inflammatory, antithrombotic and fibrinolytic affects, anticancer activity and immunomodulatory effects, in addition to being a wound healing and circulatory improvement agent. The current review describes the promising clinical applications and therapeutic properties of bromelain. PMID:27602208

  7. Addiction and the potential for therapeutic drug development.

    PubMed

    Janssen, P A

    1994-01-01

    Therapeutic drug development in alcoholism could be targeted at any of the following: direct antagonism, substitution, treatment of abstinence, enhancement of aversion, modification of biodisposition, or craving. Ritanserin is a potent, centrally acting, highly selective 5-HT1C/2 antagonist which, in addition to having a sleep-regulating and anti-depression/anti-axiety effect, displays a unique pharmacological action in several animal paradigms of substance abuse which assess drug-craving. In fact, the latter pharmacological action was demonstrated after initial clinical observations suggested an effect of ritanserin in the chronic withdrawal phase after detoxification from alcohol in patients. The results of a recent double-blind, placebo-controlled, trial indicated that ritanserin did not induce aversion to drink alcohol in normal volunteers who display social drinking, but are not suffering alcohol dependence. Currently, a full clinical development program of ritanserin in cocaine and alcohol abuse is ongoing. Three major double-blind, placebo-controlled trials in alcohol dependent patients are in progress. Patients of different severity levels, ranging from mild to very severe, are studied. The dosages of ritanserin tested (2.5 mg, 5 mg, and 10 mg o.d.) are known to be well tolerated and safe. Two trials aim for relapse prevention--clinically defined in one, biochemically defined in the other-, and one trial has improved (reduced) drinking behaviour as a therapeutic goal. This program, which involves close to 900 alcohol-dependent patients, is well under way, and is still picking up momentum. PMID:8032167

  8. Improving peripheral nerve regeneration: from molecular mechanisms to potential therapeutic targets.

    PubMed

    Chan, K Ming; Gordon, Tessa; Zochodne, Douglas W; Power, Hollie A

    2014-11-01

    Peripheral nerve injury is common especially among young individuals. Although injured neurons have the ability to regenerate, the rate is slow and functional outcomes are often poor. Several potential therapeutic agents have shown considerable promise for improving the survival and regenerative capacity of injured neurons. These agents are reviewed within the context of their molecular mechanisms. The PI3K/Akt and Ras/ERK signaling cascades play a key role in neuronal survival. A number of agents that target these pathways, including erythropoietin, tacrolimus, acetyl-l-carnitine, n-acetylcysteine and geldanamycin have been shown to be effective. Trk receptor signaling events that up-regulate cAMP play an important role in enhancing the rate of axonal outgrowth. Agents that target this pathway including rolipram, testosterone, fasudil, ibuprofen and chondroitinase ABC hold considerable promise for human application. A tantalizing prospect is to combine different molecular targeting strategies in complementary pathways to optimize their therapeutic effects. Although further study is needed prior to human trials, these modalities could open a new horizon in the clinical arena that has so far been elusive. PMID:25220611

  9. Molecular and Cellular Effects of Hydrogen Peroxide on Human Lung Cancer Cells: Potential Therapeutic Implications

    PubMed Central

    2016-01-01

    Lung cancer has a very high mortality-to-incidence ratio, representing one of the main causes of cancer mortality worldwide. Therefore, new treatment strategies are urgently needed. Several diseases including lung cancer have been associated with the action of reactive oxygen species (ROS) from which hydrogen peroxide (H2O2) is one of the most studied. Despite the fact that H2O2 may have opposite effects on cell proliferation depending on the concentration and cell type, it triggers several antiproliferative responses. H2O2 produces both nuclear and mitochondrial DNA lesions, increases the expression of cell adhesion molecules, and increases p53 activity and other transcription factors orchestrating cancer cell death. In addition, H2O2 facilitates the endocytosis of oligonucleotides, affects membrane proteins, induces calcium release, and decreases cancer cell migration and invasion. Furthermore, the MAPK pathway and the expression of genes related to inflammation including interleukins, TNF-α, and NF-κB are also affected by H2O2. Herein, we will summarize the main effects of hydrogen peroxide on human lung cancer leading to suggesting it as a potential therapeutic tool to fight this disease. Because of the multimechanistic nature of this molecule, novel therapeutic approaches for lung cancer based on the use of H2O2 may help to decrease the mortality from this malignancy. PMID:27375834

  10. Molecular and Cellular Effects of Hydrogen Peroxide on Human Lung Cancer Cells: Potential Therapeutic Implications.

    PubMed

    Vilema-Enríquez, Gabriela; Arroyo, Aurora; Grijalva, Marcelo; Amador-Zafra, Ricardo Israel; Camacho, Javier

    2016-01-01

    Lung cancer has a very high mortality-to-incidence ratio, representing one of the main causes of cancer mortality worldwide. Therefore, new treatment strategies are urgently needed. Several diseases including lung cancer have been associated with the action of reactive oxygen species (ROS) from which hydrogen peroxide (H2O2) is one of the most studied. Despite the fact that H2O2 may have opposite effects on cell proliferation depending on the concentration and cell type, it triggers several antiproliferative responses. H2O2 produces both nuclear and mitochondrial DNA lesions, increases the expression of cell adhesion molecules, and increases p53 activity and other transcription factors orchestrating cancer cell death. In addition, H2O2 facilitates the endocytosis of oligonucleotides, affects membrane proteins, induces calcium release, and decreases cancer cell migration and invasion. Furthermore, the MAPK pathway and the expression of genes related to inflammation including interleukins, TNF-α, and NF-κB are also affected by H2O2. Herein, we will summarize the main effects of hydrogen peroxide on human lung cancer leading to suggesting it as a potential therapeutic tool to fight this disease. Because of the multimechanistic nature of this molecule, novel therapeutic approaches for lung cancer based on the use of H2O2 may help to decrease the mortality from this malignancy. PMID:27375834

  11. Inhibiting neuroinflammation: The role and therapeutic potential of GABA in neuro-immune interactions.

    PubMed

    Crowley, Tadhg; Cryan, John F; Downer, Eric J; O'Leary, Olivia F

    2016-05-01

    The central nervous system, once thought to be a site of immunological privilege, has since been found to harbour immunocompetent cells and to communicate with the peripheral nervous system. In the central nervous system (CNS), glial cells display immunological responses to pathological and physiological stimuli through pro- and anti-inflammatory cytokine and chemokine signalling, antigen presentation and the clearing of cellular debris through phagocytosis. While this neuroinflammatory signalling can act to reduce neuronal damage and comprises a key facet of CNS homeostasis, persistent inflammation or auto-antigen-mediated immunoreactivity can induce a positive feedback cycle of neuroinflammation that ultimately results in necrosis of glia and neurons. Persistent neuroinflammation has been recognised as a major pathological component of virtually all neurodegenerative diseases and has also been a focus of research into the pathology underlying psychiatric disorders. Thus, pharmacological strategies to curb the pathological effects of persistent neuroinflammation are of interest for many disorders of the CNS. Accumulating evidence suggests that GABAergic activities are closely bound to immune processes and signals, and thus the GABAergic neurotransmitter system might represent an important therapeutic target in modulating neuroinflammation. Here, we review evidence that inflammation induces changes in the GABA neurotransmitter system in the CNS and that GABAergic signalling exerts a reciprocal influence over neuroinflammatory processes. Together, the data support the hypothesis that the GABA system is a potential therapeutic target in the modulation of central inflammation. PMID:26851553

  12. Chemopreventive and therapeutic potential of "naringenin," a flavanone present in citrus fruits.

    PubMed

    Mir, Irfan Ahmad; Tiku, Ashu Bhan

    2015-01-01

    Cancer is one of the major causes of deaths in developed countries and is emerging as a major public health burden in developing countries too. Changes in cancer prevalence patterns have been noticed due to rapid urbanization and changing lifestyles. One of the major concerns is an influence of dietary habits on cancer rates. Approaches to prevent cancer are many and chemoprevention or dietary cancer prevention is one of them. Therefore, nutritional practices are looked at as effective types of dietary cancer prevention strategies. Attention has been given to identifying plant-derived dietary agents, which could be developed as a promising chemotherapeutic with minimal toxic side effects. Naringenin, a phytochemical mainly present in citrus fruits and tomatoes, is a frequent component of the human diet and has gained increasing interest because of its positive health effects not only in cancer prevention but also in noncancer diseases. In the last few years, significant progress has been made in studying the biological effects of naringenin at cellular and molecular levels. This review examines the cancer chemopreventive/therapeutic effects of naringenin in an organ-specific format, evaluating its limitations, and its considerable potential for development as a cancer chemopreventive/therapeutic agent. PMID:25514618

  13. Sphingosine-1-Phosphate Receptor-2 Antagonists: Therapeutic Potential and Potential Risks

    PubMed Central

    Blankenbach, Kira V.; Schwalm, Stephanie; Pfeilschifter, Josef; Meyer zu Heringdorf, Dagmar

    2016-01-01

    The sphingosine-1-phosphate (S1P) signaling system with its specific G-protein-coupled S1P receptors, the enzymes of S1P metabolism and the S1P transporters, offers a multitude of promising targets for drug development. Until today, drug development in this area has nearly exclusively focused on (functional) antagonists at the S1P1 receptor, which cause a unique phenotype of immunomodulation. Accordingly, the first-in class S1P1 receptor modulator, fingolimod, has been approved for the treatment of relapsing-remitting multiple sclerosis, and novel S1P1 receptor (functional) antagonists are being developed for autoimmune and inflammatory diseases such as psoriasis, inflammatory bowel disease, lupus erythematodes, or polymyositis. Besides the S1P1 receptor, also S1P2 and S1P3 are widely expressed and regulate many diverse functions throughout the body. The S1P2 receptor, in particular, often exerts cellular functions which are opposed to the functions of the S1P1 receptor. As a consequence, antagonists at the S1P2 receptor have the potential to be useful in a contrasting context and different areas of indication compared to S1P1 antagonists. The present review will focus on the therapeutic potential of S1P2 receptor antagonists and discuss their opportunities as well as their potential risks. Open questions and areas which require further investigations will be emphasized in particular. PMID:27445808

  14. Targeting cancer’s weaknesses (not its strengths): Therapeutic strategies suggested by the atavistic model

    PubMed Central

    Lineweaver, Charles H.; Davies, Paul C.W.; Vincent, Mark D.

    2014-01-01

    In the atavistic model of cancer progression, tumor cell dedifferentiation is interpreted as a reversion to phylogenetically earlier capabilities. The more recently evolved capabilities are compromised first during cancer progression. This suggests a therapeutic strategy for targeting cancer: design challenges to cancer that can only be met by the recently evolved capabilities no longer functional in cancer cells. We describe several examples of this target-the-weakness strategy. Our most detailed example involves the immune system. The absence of adaptive immunity in immunosuppressed tumor environments is an irreversible weakness of cancer that can be exploited by creating a challenge that only the presence of adaptive immunity can meet. This leaves tumor cells more vulnerable than healthy tissue to pathogenic attack. Such a target-the-weakness therapeutic strategy has broad applications, and contrasts with current therapies that target the main strength of cancer: cell proliferation. PMID:25043755

  15. COGNITION AS A THERAPEUTIC TARGET IN LATE-LIFE DEPRESSION: POTENTIAL FOR NICOTINIC THERAPEUTICS

    PubMed Central

    Zurkovsky, Lilia; Taylor, Warren D.; Newhouse, Paul A.

    2013-01-01

    Depression is associated with impairments to cognition and brain function at any age, but such impairments in the elderly are particularly problematic because of the additional burden of normal cognitive aging and in some cases, structural brain pathology. Individuals with late-life depression exhibit impairments in cognition and brain structural integrity, alongside mood dysfunction. Antidepressant treatment improves symptoms in some but not all patients, and those who benefit may not return to the cognitive and functional level of nondepressed elderly. Thus, for comprehensive treatment of late-life depression, it may be necessary to address both the affective and cognitive deficits. In this review, we propose a model for the treatment of late-life depression in which nicotinic stimulation is used to improve cognitive performance and improve the efficacy of an antidepressant treatment of the syndrome of late-life depression. The cholinergic system is well-established as important to cognition. Although muscarinic stimulation may exacerbate depressive symptoms, nicotinic stimulation may improve cognition and neural functioning without a detriment to mood. While some studies of nicotinic subtype specific receptor agonists have shown promise in improving cognitive performance, less is known regarding how nicotinic receptor stimulation affects cognition in depressed elderly patients. Late-life depression thus represents a new therapeutic target for the development of nicotinic agonist drugs and parallel treatment of cognitive dysfunction along with medical and psychological approaches to treating mood dysfunction may be necessary to ensure full resolution of depressive illness in aging. PMID:23933385

  16. Adult mesenchymal stem cells: differentiation potential and therapeutic applications.

    PubMed

    Jackson, L; Jones, D R; Scotting, P; Sottile, V

    2007-01-01

    Adult mesenchymal stem cells (MSCs) are a population of multipotent cells found primarily in the bone marrow. They have long been known to be capable of osteogenic, adipogenic and chondrogenic differentiation and are currently the subject of a number of trials to assess their potential use in the clinic. Recently, the plasticity of these cells has come under close scrutiny as it has been suggested that they may have a differentiation potential beyond the mesenchymal lineage. Myogenic and in particular cardiomyogenic potential has been shown in vitro. MSCs have also been shown to have the ability to form neural cells both in vitro and in vivo, although the molecular mechanisms underlying these apparent transdifferentiation events are yet to be elucidated. We describe here the cellular characteristics and differentiation potential of MSCs, which represent a promising stem cell population for future applications in regenerative medicine. PMID:17495381

  17. Henipavirus outbreaks to antivirals: the current status of potential therapeutics.

    PubMed

    Broder, Christopher C

    2012-04-01

    The henipaviruses, Hendra virus and Nipah virus, are classic examples of recently emerged viral zoonoses. In a relatively short time since their discoveries in the mid and late 1990s, respectively, a great deal of new information has been accumulated detailing their biology and certain unique characteristics. Their broad species tropism and abilities to cause severe and often fatal respiratory and/or neurologic disease in both animals and humans has sparked considerable interest in developing effective antiviral strategies to prevent or treat henipavirus infection and disease. Here, recent findings on the few most advanced henipavirus countermeasures are summarized and discussed. PMID:22482714

  18. Therapeutic Potential of α7 Nicotinic Acetylcholine Receptors.

    PubMed

    Bertrand, Daniel; Lee, Chih-Hung L; Flood, Dorothy; Marger, Fabrice; Donnelly-Roberts, Diana

    2015-10-01

    Progress in the fields of neuroscience and molecular biology has identified the forebrain cholinergic system as being important in many higher order brain functions. Further analysis of the genes encoding the nicotinic acetylcholine receptors (nAChRs) has highlighted, in particular, the role of α7 nAChRs in these higher order brain functions as evidenced by their peculiar physiologic and pharmacological properties. As this receptor has gained the attention of scientists from academia and industry, our knowledge of its roles in various brain and bodily functions has increased immensely. We have also seen the development of small molecules that have further refined our understanding of the roles of α7 nAChRs, and these molecules have begun to be tested in clinical trials for several indications. Although a large body of data has confirmed a role of α7 nAChRs in cognition, the translation of small molecules affecting α7 nAChRs into therapeutics has to date only progressed to the stage of testing in clinical trials. Notably, however, most recent human genetic and biochemical studies are further underscoring the crucial role of α7 nAChRs and associated genes in multiple organ systems and disease states. The aim of this review is to discuss our current knowledge of α7 nAChRs and their relevance as a target in specific functional systems and disease states. PMID:26419447

  19. Synthetic and natural iron chelators: therapeutic potential and clinical use

    PubMed Central

    Hatcher, Heather C; Singh, Ravi N; Torti, Frank M; Torti, Suzy V

    2013-01-01

    Iron-chelation therapy has its origins in the treatment of iron-overload syndromes. For many years, the standard for this purpose has been deferoxamine. Recently, considerable progress has been made in identifying synthetic chelators with improved pharmacologic properties relative to deferoxamine. Most notable are deferasirox (Exjade®) and deferiprone (Ferriprox®), which are now available clinically. In addition to treatment of iron overload, there is an emerging role for iron chelators in the treatment of diseases characterized by oxidative stress, including cardiovascular disease, atherosclerosis, neurodegenerative diseases and cancer. While iron is not regarded as the underlying cause of these diseases, it does play an important role in disease progression, either through promotion of cellular growth and proliferation or through participation in redox reactions that catalyze the formation of reactive oxygen species and increase oxidative stress. Thus, iron chelators may be of therapeutic benefit in many of these conditions. Phytochemicals, many of which bind iron, may also owe some of their beneficial properties to iron chelation. This review will focus on the advances in iron-chelation therapy for the treatment of iron-overload disease and cancer, as well as neurodegenerative and chronic inflammatory diseases. Established and novel iron chelators will be discussed, as well as the emerging role of dietary plant polyphenols that effectively modulate iron biochemistry. PMID:21425984

  20. Cardiovascular disorders in anorexia nervosa and potential therapeutic targets.

    PubMed

    Di Cola, Giovanni; Jacoangeli, Francesca; Jacoangeli, Fabrizio; Lombardo, Mauro; Iellamo, Ferdinando

    2014-10-01

    Anorexia nervosa (AN) is an eating disorder in which a distorted self-perception of body image and an excessive fear of gaining weight result in extreme restrictions in eating habits. AN may be divided into two types: a "binge-eating/purging type" during which the individual regularly engages in overeating and then purging behavior, and a "restricting type", in which she does not. AN is a serious medical problem in young people in Western societies. It is widely reported that patients with AN exhibit an enhanced mortality rate as compared with age-matched healthy subjects, which has been mainly ascribed to cardiac complications. At least one-third of all deaths in patients with anorexia nervosa are estimated to be due to cardiac causes, mainly sudden death. Cardiovascular complications of AN can be present in up to 80% of cases, and among them alterations in cardiac electrical activity, structure and hemodynamics have been reported as causes of morbidity and mortality. The objective of this brief review is to summarize current knowledge on the main cardiovascular complications of AN, their underlying mechanisms and the possible therapeutic approaches. PMID:25056404

  1. MPHOSPH1: a potential therapeutic target for hepatocellular carcinoma.

    PubMed

    Liu, Xinran; Zhou, Yafan; Liu, Xinyuan; Peng, Anlin; Gong, Hao; Huang, Lizi; Ji, Kaige; Petersen, Robert B; Zheng, Ling; Huang, Kun

    2014-11-15

    MPHOSPH1 is a critical kinesin protein that functions in cytokinesis. Here, we show that MPHOSPH1 is overexpressed in hepatocellular carcinoma (HCC) cells, where it is essential for proliferation. Attenuating MPHOSPH1 expression with a tumor-selective shRNA-expressing adenovirus (Ad-shMPP1) was sufficient to arrest HCC cell proliferation in a manner associated with an accumulation of multinucleated polyploid cells, induction of postmitotic apoptosis, and increased sensitivity to taxol cytotoxicity. Mechanistic investigations showed that attenuation of MPHOSPH1 stabilized p53, blocked STAT3 phosphorylation, and prolonged mitotic arrest. In a mouse subcutaneous xenograft model of HCC, tumoral injection of Ad-shMPP1 inhibited MPHOSPH1 expression and tumor growth in a manner correlated with induction of apoptosis. Combining Ad-shMPP1 injection with taxol administration enhanced antitumor efficacy relative to taxol alone. Furthermore, Ad-shMPP1 tail vein injection suppressed formation of orthotopic liver nodules and prevented hepatic dysfunction. Taken together, our results identify MPHOSPH1 as an oncogenic driver and candidate therapeutic target in HCC. PMID:25269478

  2. Purinergic receptors as potential therapeutic targets in Alzheimer's disease.

    PubMed

    Woods, Lucas T; Ajit, Deepa; Camden, Jean M; Erb, Laurie; Weisman, Gary A

    2016-05-01

    Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive loss of memory and cognitive ability and is a serious cause of mortality. Many of the pathological characteristics associated with AD are revealed post-mortem, including amyloid-β plaque deposition, neurofibrillary tangles containing hyperphosphorylated tau proteins and neuronal loss in the hippocampus and cortex. Although several genetic mutations and risk factors have been associated with the disease, the causes remain poorly understood. Study of disease-initiating mechanisms and AD progression in humans is inherently difficult as most available tissue specimens are from late-stages of disease. Therefore, AD researchers rely on in vitro studies and the use of AD animal models where neuroinflammation has been shown to be a major characteristic of AD. Purinergic receptors are a diverse family of proteins consisting of P1 adenosine receptors and P2 nucleotide receptors for ATP, UTP and their metabolites. This family of receptors has been shown to regulate a wide range of physiological and pathophysiological processes, including neuroinflammation, and may contribute to the pathogenesis of neurodegenerative diseases like Parkinson's disease, multiple sclerosis and AD. Experimental evidence from human AD tissue has suggested that purinergic receptors may play a role in AD progression and studies using selective purinergic receptor agonists and antagonists in vitro and in AD animal models have demonstrated that purinergic receptors represent novel therapeutic targets for the treatment of AD. This article is part of the Special Issue entitled 'Purines in Neurodegeneration and Neuroregeneration'. PMID:26519903

  3. Autophagy and mitophagy in the myocardium: therapeutic potential and concerns.

    PubMed

    Jimenez, Rebecca E; Kubli, Dieter A; Gustafsson, Åsa B

    2014-04-01

    The autophagic-lysosomal degradation pathway is critical for cardiac homeostasis, and defects in this pathway are associated with development of cardiomyopathy. Autophagy is responsible for the normal turnover of organelles and long-lived proteins. Autophagy is also rapidly up-regulated in response to stress, where it rapidly clears dysfunctional organelles and cytotoxic protein aggregates in the cell. Autophagy is also important in clearing dysfunctional mitochondria before they can cause harm to the cell. This quality control mechanism is particularly important in cardiac myocytes, which contain a very high volume of mitochondria. The degradation of proteins and organelles also generates free fatty acids and amino acids, which help maintain energy levels in myocytes during stress conditions. Increases in autophagy have been observed in various cardiovascular diseases, but a major question that remains to be answered is whether enhanced autophagy is an adaptive or maladaptive response to stress. This review discusses the regulation and role of autophagy in the myocardium under baseline conditions and in various aetiologies of heart disease. It also discusses whether this pathway represents a new therapeutic target to treat or prevent cardiovascular disease and the concerns associated with modulating autophagy. PMID:24148024

  4. Targeting survivin with YM155 (Sepantronium Bromide): a novel therapeutic strategy for paediatric acute myeloid leukaemia.

    PubMed

    Smith, Amanda M; Little, Erica B; Zivanovic, Andjelija; Hong, Priscilla; Liu, Alfred K S; Burow, Rachel; Stinson, Caedyn; Hallahan, Andrew R; Moore, Andrew S

    2015-04-01

    Despite aggressive chemotherapy, approximately one-third of children with acute myeloid leukaemia (AML) relapse. More effective treatments are urgently needed. Survivin is an inhibitor-of-apoptosis protein with key roles in regulating cell division, proliferation and apoptosis. Furthermore, high expression of Survivin has been associated with poor clinical outcome in AML. The survivin suppressant YM155 (Sepantronium Bromide) has pre-clinical activity against a range of solid cancers and leukemias, although data in AML is limited. Therefore, we undertook a comprehensive pre-clinical evaluation of YM155 in paediatric AML. YM155 potently inhibited cell viability in a diverse panel of AML cell lines. All paediatric cell lines were particularly sensitive, with a median IC50 of 0.038 μM. Cell cycle analyses demonstrated concentration-dependent increases in a sub-G1 population with YM155 treatment, suggestive of apoptosis that was subsequently confirmed by an increase in annexin-V positivity. YM155-mediated apoptosis was confirmed across a panel of 8 diagnostic bone marrow samples from children with AML. Consistent with the proposed mechanism of action, YM155 treatment was associated with down-regulation of survivin mRNA and protein expression and induction of DNA damage. These data suggest that YM155-mediated inhibition of survivin is a potentially beneficial therapeutic strategy for AML, particularly paediatric disease, and warrants further evaluation. PMID:25659731

  5. New Insights to Clathrin and Adaptor Protein 2 for the Design and Development of Therapeutic Strategies.

    PubMed

    Poulsen, Ebbe Toftgaard; Larsen, Agnete; Zollo, Alen; Jørgensen, Arne L; Sanggaard, Kristian W; Enghild, Jan J; Matrone, Carmela

    2015-01-01

    The Amyloid Precursor Protein (APP) has been extensively studied for its role as the precursor of the β-amyloid protein (Aβ) in Alzheimer's disease (AD). However, our understanding of the normal function of APP is still patchy. Emerging evidence indicates that a dysfunction in APP trafficking and degradation can be responsible for neuronal deficits and progressive degeneration in humans. We recently reported that the Y682 mutation in the 682YENPTY687 domain of APP affects its binding to specific adaptor proteins and leads to its anomalous trafficking, to defects in the autophagy machinery and to neuronal degeneration. In order to identify adaptors that influence APP function, we performed pull-down experiments followed by quantitative mass spectrometry (MS) on hippocampal tissue extracts of three month-old mice incubated with either the 682YENPTY687 peptide, its mutated form, 682GENPTY687 or its phosphorylated form, 682pYENPTY687. Our experiments resulted in the identification of two proteins involved in APP internalization and trafficking: Clathrin heavy chain (hc) and its Adaptor Protein 2 (AP-2). Overall our results consolidate and refine the importance of Y682 in APP normal functions from an animal model of premature aging and dementia. Additionally, they open the perspective to consider Clathrin hc and AP-2 as potential targets for the design and development of new therapeutic strategies. PMID:26690411

  6. Sulphonamides as anti-inflammatory agents: old drugs for new therapeutic strategies in neutrophilic inflammation?

    PubMed

    Ottonello, L; Dapino, P; Scirocco, M C; Balbi, A; Bevilacqua, M; Dallegri, F

    1995-03-01

    1. It is well known that neutrophils act as mediators of tissue injury in a variety of inflammatory diseases. Their histotoxic activity is presently thought to involve proteinases and oxidants, primarily hypochlorous acid (HOCl). This oxidant is also capable of inactivating the specific inhibitor of neutrophil elastase (alpha 1-antitrypsin), thereby favouring digestion of the connective matrix. 2. In the present work, we found that sulphanilamide and some sulphanilamide-related anti-inflammatory drugs such as dapsone, nimesulide and sulphapyridine reduce the availability of HOCl in the extracellular microenvironment of activated neutrophils and prevent the inactivation of alpha 1-antitrypsin by these cells in a dose-dependent manner. The ability of each drug to prevent alpha 1-antitrypsin from inactivation by neutrophils correlates significantly with its capacity to reduce the recovery of HOCl from neutrophils. Five other non-steroidal anti-inflammatory drugs were completely ineffective. 3. Therefore, sulphanilamide-related drugs, i.e. dapsone, nimesulide and sulphapyridine, have the potential to reduce the bioavailability of neutrophil-derived HOCl and, in turn, to favour the alpha 1-antitrypsin-dependent control of neutrophil elastolytic activity. These drugs appear as a well-defined group of agents which are particularly prone to attenuate neutrophil histotoxicity. They can also be viewed as a previously unrecognized starting point for the development of new compounds in order to plan rational therapeutic strategies for controlling tissue injury during neutrophilic inflammation. PMID:7736703

  7. New strategies in metastatic melanoma: oncogene-defined taxonomy leads to therapeutic advances.

    PubMed

    Flaherty, Keith T; Fisher, David E

    2011-08-01

    The discovery of BRAF and KIT mutations provided the first basis for a molecular classification of cutaneous melanoma on therapeutic grounds. As BRAF-targeted therapy quickly moves toward regulatory approval and incorporation as standard therapy for patients with metastatic disease, proof of concept has also been established for targeting mutated KIT in melanoma. NRAS mutations have long been known to be present in a subset of melanomas and represent an elusive subgroup for targeted therapies. Matching patient subgroups defined by genetic aberrations in the phosphoinositide 3-kinase and p16/cyclin dependent kinase 4 (CDK4) pathways with appropriate targeted therapies has not yet been realized. And, an increasing understanding of lineage-specific transcriptional regulators, most notably MITF, and how they may play a role in melanoma pathophysiology, has provided another axis to approach with therapies. The foundation has been established for individual oncogene targeting, and current investigations seek to understand the intersection of these susceptibilities and other described potential targets and pathways. The melanoma field stands poised to take the lead among cancer subtypes in advancing combination therapy strategies that simultaneously target multiple biologic underpinnings of the disease. PMID:21670085

  8. New Insights to Clathrin and Adaptor Protein 2 for the Design and Development of Therapeutic Strategies

    PubMed Central

    Poulsen, Ebbe Toftgaard; Larsen, Agnete; Zollo, Alen; Jørgensen, Arne L.; Sanggaard, Kristian W.; Enghild, Jan J.; Matrone, Carmela

    2015-01-01

    The Amyloid Precursor Protein (APP) has been extensively studied for its role as the precursor of the β-amyloid protein (Aβ) in Alzheimer’s disease (AD). However, our understanding of the normal function of APP is still patchy. Emerging evidence indicates that a dysfunction in APP trafficking and degradation can be responsible for neuronal deficits and progressive degeneration in humans. We recently reported that the Y682 mutation in the 682YENPTY687 domain of APP affects its binding to specific adaptor proteins and leads to its anomalous trafficking, to defects in the autophagy machinery and to neuronal degeneration. In order to identify adaptors that influence APP function, we performed pull-down experiments followed by quantitative mass spectrometry (MS) on hippocampal tissue extracts of three month-old mice incubated with either the 682YENPTY687 peptide, its mutated form, 682GENPTY687 or its phosphorylated form, 682pYENPTY687. Our experiments resulted in the identification of two proteins involved in APP internalization and trafficking: Clathrin heavy chain (hc) and its Adaptor Protein 2 (AP-2). Overall our results consolidate and refine the importance of Y682 in APP normal functions from an animal model of premature aging and dementia. Additionally, they open the perspective to consider Clathrin hc and AP-2 as potential targets for the design and development of new therapeutic strategies. PMID:26690411

  9. Marine Compounds with Therapeutic Potential in Gram-Negative Sepsis

    PubMed Central

    Solov’eva, Tamara; Davydova, Viktoria; Krasikova, Inna; Yermak, Irina

    2013-01-01

    This paper concerns the potential use of compounds, including lipid A, chitosan, and carrageenan, from marine sources as agents for treating endotoxemic complications from Gram-negative infections, such as sepsis and endotoxic shock. Lipid A, which can be isolated from various species of marine bacteria, is a potential antagonist of bacterial endotoxins (lipopolysaccharide (LPSs)). Chitosan is a widespread marine polysaccharide that is derived from chitin, the major component of crustacean shells. The potential of chitosan as an LPS-binding and endotoxin-neutralizing agent is also examined in this paper, including a discussion on the generation of hydrophobic chitosan derivatives to increase the binding affinity of chitosan to LPS. In addition, the ability of carrageenan, which is the polysaccharide of red alga, to decrease the toxicity of LPS is discussed. We also review data obtained using animal models that demonstrate the potency of carrageenan and chitosan as antiendotoxin agents. PMID:23783404

  10. Synthetic approaches, functionalization and therapeutic potential of quinazoline and quinazolinone skeletons: the advances continue.

    PubMed

    Khan, Imtiaz; Ibrar, Aliya; Ahmed, Waqas; Saeed, Aamer

    2015-01-27

    The presence of N-heterocycles as an essential structural motif in a variety of biologically active substances has stimulated the development of new strategies and technologies for their synthesis. Among the various N-heterocyclic scaffolds, quinazolines and quinazolinones form a privileged class of compounds with their diverse spectrum of therapeutic potential. The easy generation of complex molecular diversity through broadly applicable, cost-effective, practical and sustainable synthetic methods in a straightforward fashion along with the importance of these motifs in medicinal chemistry, received significant attention from researchers engaged in drug design and heterocyclic methodology development. In this perspective, the current review article is an effort to recapitulate recent developments in the eco-friendly and green procedures for the construction of highly challenging and potentially bioactive quinazoline and quinazolinone compounds in order to help medicinal chemists in designing and synthesizing novel and potent compounds for the treatment of different disorders. The key mechanistic insights for the synthesis of these heterocycles along with potential applications and manipulations of the products have also been conferred. This article also aims to highlight the promising future directions for the easy access to these frameworks in addition to the identification of more potent and specific products for numerous biological targets. PMID:25461317

  11. Anti-Transcription Factor RNA Aptamers as Potential Therapeutics

    PubMed Central

    Mondragón, Estefanía

    2016-01-01

    Transcription factors (TFs) are DNA-binding proteins that play critical roles in regulating gene expression. These proteins control all major cellular processes, including growth, development, and homeostasis. Because of their pivotal role, cells depend on proper TF function. It is, therefore, not surprising that TF deregulation is linked to disease. The therapeutic drug targeting of TFs has been proposed as a frontier in medicine. RNA aptamers make interesting candidates for TF modulation because of their unique characteristics. The products of in vitro selection, aptamers are short nucleic acids (DNA or RNA) that bind their targets with high affinity and specificity. Aptamers can be expressed on demand from transgenes and are intrinsically amenable to recognition by nucleic acid-binding proteins such as TFs. In this study, we review several natural prokaryotic and eukaryotic examples of RNAs that modulate the activity of TFs. These examples include 5S RNA, 6S RNA, 7SK, hepatitis delta virus-RNA (HDV-RNA), neuron restrictive silencer element (NRSE)-RNA, growth arrest-specific 5 (Gas5), steroid receptor RNA activator (SRA), trophoblast STAT utron (TSU), the 3′ untranslated region of caudal mRNA, and heat shock RNA-1 (HSR1). We then review examples of unnatural RNA aptamers selected to inhibit TFs nuclear factor-kappaB (NF-κB), TATA-binding protein (TBP), heat shock factor 1 (HSF1), and runt-related transcription factor 1 (RUNX1). The field of RNA aptamers for DNA-binding proteins continues to show promise. PMID:26509637

  12. Prophylaxis and therapeutic potential of ozone in buiatrics: Current knowledge.

    PubMed

    Đuričić, Dražen; Valpotić, Hrvoje; Samardžija, Marko

    2015-08-01

    Ozone therapy has been in use since 1896 in the USA. As a highly reactive molecule, ozone may inactivate bacteria, viruses, fungi, yeasts and protozoans, stimulate the oxygen metabolism of tissue, treat diseases, activate the immune system, and exhibit strong analgesic activity. More recently, ozone has been used in veterinary medicine, particularly in buiatrics, but still insufficiently. Medical ozone therapy has shown effectiveness as an alternative to the use of antibiotics, which are restricted to clinical use and have been withdrawn from non-clinical use as in-feed growth promoters in animal production. This review is an overview of current knowledge regarding the preventive and therapeutic effects of ozone in ruminants for the treatment of puerperal diseases and improvement in their fertility. In particular, ozone preparations have been tested in the treatment of reproductive tract lesions, urovagina and pneumomovagina, metritis, endometritis, fetal membrane retention and mastitis, as well as in the functional restoration of endometrium in dairy cows and goats. In addition, the preventive use of the intrauterine application of ozone has been assessed in order to evaluate its effectiveness in improving reproductive efficiency in dairy cows. No adverse effects were observed in cows and goats treated with ozone preparations. Moreover, there is a lot of evidence indicating the advantages of ozone preparation therapy in comparison to the application of antibiotics. However, there are certain limitations on ozone use in veterinary medicine and buiatrics, such as inactivity against intracellular microbes and selective activity against the same bacterial species, as well as the induction of tissue inflammation through inappropriate application of the preparation. PMID:26059777

  13. Therapeutic potential of green tea in nonalcoholic fatty liver disease.

    PubMed

    Masterjohn, Christopher; Bruno, Richard S

    2012-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a constellation of progressive liver disorders that are closely related to obesity, diabetes, and insulin resistance and may afflict over 70 million Americans. NAFLD may occur as relatively benign, nonprogressive liver steatosis, but in many individuals it may progress in severity to nonalcoholic steatohepatitis, fibrosis, cirrhosis, and liver failure or hepatocellular carcinoma. No validated treatments currently exist for NAFLD except for weight loss, which has a poor long-term success rate. Thus, dietary strategies that prevent the development of liver steatosis or its progression to nonalcoholic steatohepatitis are critically needed. Green tea is rich in polyphenolic catechins that have hypolipidemic, thermogenic, antioxidant, and anti-inflammatory activities that may mitigate the occurrence and progression of NAFLD. This review presents the experimental evidence demonstrating the hepatoprotective properties of green tea and its catechins and the proposed mechanisms by which these targeted dietary agents protect against NAFLD. PMID:22221215

  14. Oxidative stress in psoriasis and potential therapeutic use of antioxidants.

    PubMed

    Lin, Xiran; Huang, Tian

    2016-06-01

    The pathophysiology of psoriasis is complex and dynamic. Recently, the involvement of oxidative stress in the pathogenesis of psoriasis has been proposed. Oxidative stress is an imbalance between oxidants and antioxidants in favor of the oxidants, leading to a disruption of redox signaling and control and/or molecular damage. In this article, the published studies on the role of oxidative stress in psoriasis pathogenesis are reviewed, focusing on the impacts of oxidative stress on dendritic cells, T lymphocytes, and keratinocytes, on angiogenesis and on inflammatory signaling (mitogen-activated protein kinase, nuclear factor-κB, and Janus kinase/signal transducer and activator of transcription). As there is compelling evidence that oxidative stress is involved in the pathogenesis of psoriasis, the possibility of using this information to develop novel strategies for treatment of patients with psoriasis is of considerable interest. In this article, we also review the published studies on treating psoriasis with antioxidants and drugs with antioxidant activity. PMID:27098416

  15. Glycans in pathogenic bacteria – potential for targeted covalent therapeutics and imaging agents

    PubMed Central

    Tra, Van N.; Dube, Danielle H.

    2014-01-01

    A substantial obstacle to the existing treatment of bacterial diseases is the lack of specific probes that can be used to diagnose and treat pathogenic bacteria in a selective manner while leaving the microbiome largely intact. To tackle this problem, there is an urgent need to develop pathogen-specific therapeutics and diagnostics. Here, we describe recent evidence that indicates distinctive glycans found exclusively on pathogenic bacteria could form the basis of targeted therapeutic and diagnostic strategies. In particular, we highlight the use of metabolic oligosaccharide engineering to covalently deliver therapeutics and imaging agents to bacterial glycans. PMID:24647371

  16. Biological treatment strategies for disc degeneration: potentials and shortcomings

    PubMed Central

    Nerlich, Andreas G.; Boos, Norbert

    2006-01-01

    Recent advances in molecular biology, cell biology and material sciences have opened a new emerging field of techniques for the treatment of musculoskeletal disorders. These new treatment modalities aim for biological repair of the affected tissues by introducing cell-based tissue replacements, genetic modifications of resident cells or a combination thereof. So far, these techniques have been successfully applied to various tissues such as bone and cartilage. However, application of these treatment modalities to cure intervertebral disc degeneration is in its very early stages and mostly limited to experimental studies in vitro or in animal studies. We will discuss the potential and possible shortcomings of current approaches to biologically cure disc degeneration by gene therapy or tissue engineering. Despite the increasing number of studies examining the therapeutic potential of biological treatment strategies, a practicable solution to routinely cure disc degeneration might not be available in the near future. However, knowledge gained from these attempts might be applied in a foreseeable future to cure the low back pain that often accompanies disc degeneration and therefore be beneficial for the patient. PMID:16983559

  17. Delivery strategies and potential targets for siRNA in major cancer types.

    PubMed

    Lee, So Jin; Kim, Min Ju; Kwon, Ick Chan; Roberts, Thomas M

    2016-09-01

    Small interfering RNA (siRNA) has gained attention as a potential therapeutic reagent due to its ability to inhibit specific genes in many genetic diseases. For many years, studies of siRNA have progressively advanced toward novel treatment strategies against cancer. Cancer is caused by various mutations in hundreds of genes including both proto-oncogenes and tumor suppressor genes. In order to develop siRNAs as therapeutic agents for cancer treatment, delivery strategies for siRNA must be carefully designed and potential gene targets carefully selected for optimal anti-cancer effects. In this review, various modifications and delivery strategies for siRNA delivery are discussed. In addition, we present current thinking on target gene selection in major tumor types. PMID:27259398

  18. CEP Biomarkers as Potential Tools for Monitoring Therapeutics

    PubMed Central

    Rayborn, Mary E.; Crabb, John S.; Salomon, Robert G.; Collier, Robert J.; Kapin, Michael A.; Romano, Carmelo; Hollyfield, Joe G.; Crabb, John W.

    2013-01-01

    Background Carboxyethylpyrrole (CEP) adducts are oxidative modifications derived from docosahexaenoate-containing lipids that are elevated in ocular tissues and plasma in age-related macular degeneration (AMD) and in rodents exposed to intense light. The goal of this study was to determine whether light-induced CEP adducts and autoantibodies are modulated by pretreatment with AL-8309A under conditions that prevent photo-oxidative damage of rat retina. AL-8309A is a serotonin 5-HT1A receptor agonist. Methods Albino rats were dark adapted prior to blue light exposure. Control rats were maintained in normal cyclic light. Rats were injected subcutaneously 3x with 10 mg/kg AL-8309A (2 days, 1 day and 0 hours) before light exposure for 6 h (3.1 mW/cm2, λ=450 nm). Animals were sacrificed immediately following light exposure and eyes, retinas and plasma were collected. CEP adducts and autoantibodies were quantified by Western analysis or ELISA. Results ANOVA supported significant differences in mean amounts of CEP adducts and autoantibodies among the light + vehicle, light + drug and dark control groups from both retina and plasma. Light-induced CEP adducts in retina were reduced ~20% following pretreatment with AL-8309A (n = 62 rats, p = 0.006) and retinal CEP immunoreactivity was less intense by immunohistochemistry. Plasma levels of light-induced CEP adducts were reduced at least 30% (n = 15 rats, p = 0.004) by drug pretreatment. Following drug treatment, average CEP autoantibody titer in light exposed rats (n = 22) was unchanged from dark control levels, and ~20% (p = 0.046) lower than in vehicle-treated rats. Conclusions Light-induced CEP adducts in rat retina and plasma were significantly decreased by pretreatment with AL-8309A. These results are consistent with and extend previous studies showing AL-8309A reduces light-induced retinal lesions in rats and support CEP biomarkers as possible tools for monitoring the efficacy of select therapeutics. PMID:24098476

  19. A Therapeutic Potential for Marine Skeletal Proteins in Bone Regeneration

    PubMed Central

    Green, David W.; Padula, Matthew P.; Santos, Jerran; Chou, Joshua; Milthorpe, Bruce; Ben-Nissan, Besim

    2013-01-01

    A vital ingredient for engineering bone tissue, in the culture dish, is the use of recombinant matrix and growth proteins to help accelerate the growth of cultivated tissues into clinically acceptable quantities. The skeletal organic matrices of calcifying marine invertebrates are an untouched potential source of such growth inducing proteins. They have the advantage of being ready-made and retain the native state of the original protein. Striking evidence shows that skeleton building bone morphogenic protein-2/4 (BMP) and transforming growth factor beta (TGF-β) exist within various marine invertebrates such as, corals. Best practice mariculture and the latest innovations in long-term marine invertebrate cell cultivation can be implemented to ensure that these proteins are produced sustainably and supplied continuously. This also guarantees that coral reef habitats are not damaged during the collection of specimens. Potential proteins for bone repair, either extracted from the skeleton or derived from cultivated tissues, can be identified, evaluated and retrieved using chromatography, cell assays and proteomic methods. Due to the current evidence for bone matrix protein analogues in marine invertebrates, together with the methods established for their production and retrieval there is a genuine prospect that they can be used to regenerate living bone for potential clinical use. PMID:23574983

  20. The apelin-APJ axis: A novel potential therapeutic target for organ fibrosis.

    PubMed

    Huang, Shifang; Chen, Linxi; Lu, Liqun; Li, Lanfang

    2016-05-01

    Apelin, an endogenous ligand of the G-protein-coupled receptor APJ, is expressed in a diverse number of organs. The apelin-APJ axis helps to control the processes of pathological and physiological fibrosis, including renal fibrosis, cardiac fibrosis, liver fibrosis and pulmonary fibrosis. However, the role of apelin-APJ in organ fibrosis remains controversial due to conflicting study results. The apelin-APJ axis is a detrimental mechanism which promotes liver fibrosis mainly via up-regulation the expression of collagen-II and platelet-derived growth factor receptor β (PDGFRβ). On the contrary, the apelin-APJ axis is beneficial for renal fibrosis, cardiac fibrosis and pulmonary fibrosis. The apelin-APJ axis alleviates renal fibrosis by restraining the expression of transforming growth factor-β1 (TGF-β1). In addition, the apelin-APJ axis attenuates cardiac fibrosis through multiple pathways. Furthermore, the apelin-APJ axis has beneficial effects on experimental bronchopulmonary dysplasia (BPD) and acute respiratory distress syndrome (ARDS) which suggest the apelin-APJ axis potentially alleviates pulmonary fibrosis. In this article, we review the controversies associated with apelin-APJ in organ fibrosis and introduce the drugs that target apelin-APJ. We conclude that future studies should place more emphasis on the relationship among apelin isoforms, APJ receptor subtypes and organ fibrosis. The apelin-APJ axis will be a potential therapeutic target and those drugs targeted for apelin-APJ may constitute a novel therapeutic strategy for renal fibrosis, cardiac fibrosis, liver fibrosis and pulmonary fibrosis. PMID:26944568

  1. Increased midkine expression correlates with desmoid tumour recurrence: a potential biomarker and therapeutic target.

    PubMed

    Colombo, Chiara; Creighton, Chad J; Ghadimi, Markus P; Bolshakov, Svetlana; Warneke, Carla L; Zhang, Yiqun; Lusby, Kristelle; Zhu, Shirley; Lazar, Alexander J; West, Robert B; van de Rijn, Matt; Lev, Dina

    2011-12-01

    Desmoid tumours (DTs) are soft tissue monoclonal neoplasms exhibiting a unique phenotype, consisting of aggressive local invasiveness without metastatic capacity. While DTs can infrequently occur as part of familial adenomatosis polyposis, most cases arise sporadically. Sporadic DTs harbour a high prevalence of CTNNB1 mutations and hence increased β-catenin signalling. However, β-catenin downstream transcriptional targets and other molecular deregulations operative in DT inception and progression are currently not well defined, contributing to the lack of sensitive molecular prognosticators and efficacious targeted therapeutic strategies. We compared the gene expression profiles of 14 sporadic DTs to those of five corresponding normal tissues and six solitary fibrous tumour specimens. A DT expression signature consisting of 636 up- and 119 down-regulated genes highly enriched for extracellular matrix, cell adhesion and wound healing-related proteins was generated. Furthermore, 98 (15%) of the over-expressed genes were demonstrated to contain a TCF/LEF consensus binding site in their promoters, possibly heralding direct β-catenin downstream targets relevant to DT. The protein products of three of the up-regulated DT genes: ADAM12, MMP2 and midkine, were found to be commonly expressed in a large cohort of human DT samples assembled on a tissue microarray. Interestingly, enhanced midkine expression significantly correlated with a higher propensity and decreased time for primary DT recurrence (log-rank p = 0.0025). Finally, midkine was found to enhance the migration and invasion of primary DT cell cultures. Taken together, these studies provide insights into potential DT molecular aberrations and novel β-catenin transcriptional targets. Further studies to confirm the utility of midkine as a clinical DT molecular prognosticator and a potential therapeutic target are therefore warranted. Raw gene array data can be found at: http://smd.stanford.edu/ PMID:21826666

  2. Potential therapeutic drug target identification in Community Acquired-Methicillin Resistant Staphylococcus aureus (CA-MRSA) using computational analysis

    PubMed Central

    Yadav, Pramod Kumar; Singh, Gurmit; Singh, Satendra; Gautam, Budhayash; Saad, Esmaiel IF

    2012-01-01

    The emergence of multidrug-resistant strain of community-acquired methicillin resistant Staphylococcus aureus (CA-MRSA) strain has highlighted the urgent need for the alternative and effective therapeutic approach to combat the menace of this nosocomial pathogen. In the present work novel potential therapeutic drug targets have been identified through the metabolic pathways analysis. All the gene products involved in different metabolic pathways of CA-MRSA in KEGG database were searched against the proteome of Homo sapiens using the BLASTp program and the threshold of E-value was set to as 0.001. After database searching, 152 putative targets were identified. Among all 152 putative targets, 39 genes encoding for putative targets were identified as the essential genes from the DEG database which are indispensable for the survival of CA-MRSA. After extensive literature review, 7 targets were identified as potential therapeutic drug target. These targets are Fructose-bisphosphate aldolase, Phosphoglyceromutase, Purine nucleoside phosphorylase, Uridylate kinase, Tryptophan synthase subunit beta, Acetate kinase and UDP-N-acetylglucosamine 1-carboxyvinyltransferase. Except Uridylate kinase all the identified targets were involved in more than one metabolic pathways of CA-MRSA which underlines the importance of drug targets. These potential therapeutic drug targets can be exploited for the discovery of novel inhibitors for CA-MRSA using the structure based drug design (SBDD) strategy. PMID:23055607

  3. Therapeutical Strategies for Spinal Cord Injury and a Promising Autologous Astrocyte-Based Therapy Using Efficient Reprogramming Techniques.

    PubMed

    Yang, Hao; Liu, Cui-Cui; Wang, Chun-Yu; Zhang, Qian; An, Jiang; Zhang, Lingling; Hao, Ding-Jun

    2016-07-01

    Spinal cord injury (SCI) is a traumatic event resulting in disturbances to normal sensory, motor, or autonomic functions, which ultimately impacts a patient's physical, psychological, and social well-being. Until now, no available therapy for SCI can effectively slow down or halt the disease progression. Compared to traditional treatments, e.g., medication, surgery, and functional electrical stimulation, stem cell replacement therapy shows high potential for repair and functional plasticity. Thus, stem cell therapy may provide a promising strategy in curative treatment of SCI, specifically when considering the requirement of neuron replenishment in the spinal cord after distinct acute injuries. However, the therapeutic application of neural stem cells (NSCs) still faces enormous challenges, such as ethical issues, possible inflammatory reactions, graft rejection, and tumor formation. Therefore, it is of vital interest to identify more suitable sources of cells with stem cell potential, which might potentially be harnessed for local neural repair. Due to abovementioned possible drawbacks, these cells should be autologous. Reprogramming of astrocytes to generate the desired neuronal cell types would open the door to autologous cell transplantation and treatment of SCI without possible severe side effects. In this paper, we review the relevant therapeutic strategies for SCI, and conversion of astrocyte into NSCs, suggesting this procedure as a possible treatment option. PMID:25863960

  4. DNA damage responses in cancer stem cells: Implications for cancer therapeutic strategies

    PubMed Central

    Wang, Qi-En

    2015-01-01

    The identification of cancer stem cells (CSCs) that are responsible for tumor initiation, growth, metastasis, and therapeutic resistance might lead to a new thinking on cancer treatments. Similar to stem cells, CSCs also display high resistance to radiotherapy and chemotherapy with genotoxic agents. Thus, conventional therapy may shrink the tumor volume but cannot eliminate cancer. Eradiation of CSCs represents a novel therapeutic strategy. CSCs possess a highly efficient DNA damage response (DDR) system, which is considered as a contributor to the resistance of these cells from exposures to DNA damaging agents. Targeting of enhanced DDR in CSCs is thus proposed to facilitate the eradication of CSCs by conventional therapeutics. To achieve this aim, a better understanding of the cellular responses to DNA damage in CSCs is needed. In addition to the protein kinases and enzymes that are involved in DDR, other processes that affect the DDR including chromatin remodeling should also be explored. PMID:26322164

  5. Mitophagy: therapeutic potentials for liver disease and beyond.

    PubMed

    Lee, Sooyeon; Kim, Jae-Sung

    2014-12-01

    Mitochondrial integrity is critical for maintaining proper cellular functions. A key aspect of regulating mitochondrial homeostasis is removing damaged mitochondria through autophagy, a process called mitophagy. Autophagy dysfunction in various disease states can inactivate mitophagy and cause cell death, and defects in mitophagy are becoming increasingly recognized in a wide range of diseases from liver injuries to neurodegenerative diseases. Here we highlight our current knowledge on the mechanisms of mitophagy, and discuss how alterations in mitophagy contribute to disease pathogenesis. We also discuss mitochondrial dynamics and potential interactions between mitochondrial fusion, fission and mitophagy. PMID:25584143

  6. Potential therapeutic use of herbal extracts in trypanosomiasis

    PubMed Central

    Teixeira, Thaise L; Teixeira, Samuel Cota; da Silva, Claudio Vieira; de Souza, Maria A

    2014-01-01

    The aim of the present study was to evaluate the effects of crude extracts from Handroanthus impetiginosa, Ageratum conyzoides, and Ruta graveolens on Leishmania amazonensis and Trypanosoma cruzi infection in vitro. The results showed that the extracts caused significant toxicity in promastigotes and trypomastigotes. A significant decrease in the rate of cell invasion by pretreated trypomastigotes and promastigotes was also observed. The extracts caused a significant reduction of the multiplication of intracellular amastigotes of both parasites. Therefore, these herbal extracts may be potential candidates for the development of drugs for the treatment of leishmaniasis and Chagas disease. PMID:24548158

  7. Monoclonal Antibody Shows Promise as Potential Therapeutic for MERS | Poster

    Cancer.gov

    A monoclonal antibody has proven effective in preventing Middle Eastern Respiratory Syndrome (MERS) in lab animals, suggesting further development as a potential intervention for the deadly disease in humans, according to new research. MERS is a newly emerged coronavirus first detected in humans in 2012. Most cases have occurred in the Middle East, but the disease has appeared elsewhere. In all, MERS has infected more than 1,700 individuals and killed more than 600, according to the World Health Organization. No vaccines or antiviral therapies currently exist. Several candidate vaccines are being developed, and some have been tested in animal models, a prerequisite to human clinical trials.

  8. G-quadruplexes in viruses: function and potential therapeutic applications

    PubMed Central

    Métifiot, Mathieu; Amrane, Samir; Litvak, Simon; Andreola, Marie-Line

    2014-01-01

    G-rich nucleic acids can form non-canonical G-quadruplex structures (G4s) in which four guanines fold in a planar arrangement through Hoogsteen hydrogen bonds. Although many biochemical and structural studies have focused on DNA sequences containing successive, adjacent guanines that spontaneously fold into G4s, evidence for their in vivo relevance has recently begun to accumulate. Complete sequencing of the human genome highlighted the presence of ∼300 000 sequences that can potentially form G4s. Likewise, the presence of putative G4-sequences has been reported in various viruses genomes [e.g., Human immunodeficiency virus (HIV-1), Epstein–Barr virus (EBV), papillomavirus (HPV)]. Many studies have focused on telomeric G4s and how their dynamics are regulated to enable telomere synthesis. Moreover, a role for G4s has been proposed in cellular and viral replication, recombination and gene expression control. In parallel, DNA aptamers that form G4s have been described as inhibitors and diagnostic tools to detect viruses [e.g., hepatitis A virus (HAV), EBV, cauliflower mosaic virus (CaMV), severe acute respiratory syndrome virus (SARS), simian virus 40 (SV40)]. Here, special emphasis will be given to the possible role of these structures in a virus life cycle as well as the use of G4-forming oligonucleotides as potential antiviral agents and innovative tools. PMID:25332402

  9. Therapeutic Potential of Pterocarpus santalinus L.: An Update

    PubMed Central

    Bulle, Saradamma; Reddyvari, Hymavathi; Nallanchakravarthula, Varadacharyulu; Vaddi, Damodara Reddy

    2016-01-01

    Recently there has been increasing interest in plants and plant-derived compounds as raw food and medicinal agents. In Ayurveda, an Indian system of traditional medicine, a wide spectrum of medicinal properties of Pterocarpus santalinus is described. Many important bioactive phytocompounds have been extracted and identified from the heartwood of P. santalinus. Bioactive compounds typically occur in small amounts and have more subtle effects than nutrients. These bioactive compounds influence cellular activities that modify the risk of disease rather than prevent deficiency diseases. A wide array of biological activities and potential health benefits of P. santalinus have been reported, including antioxidative, antidiabetic, antimicrobial, anticancer, and anti-inflammatory properties, and protective effects on the liver, gastric mucosa, and nervous system. All these protective effects were attributed to bioactive compounds present in P. santalinus. The major bioactive compounds present in the heartwood of P. santalinus are santalin A and B, savinin, calocedrin, pterolinus K and L, and pterostilbenes. The bioactive compounds have potentially important health benefits: These compounds can act as antioxidants, enzyme inhibitors and inducers, inhibitors of receptor activities, and inducers and inhibitors of gene expression, among other actions. The present review aims to understand the pharmacological effects of P. santalinus on health and disease with “up-to-date” discussion. PMID:27041873

  10. Therapeutic Potential of Pterocarpus santalinus L.: An Update.

    PubMed

    Bulle, Saradamma; Reddyvari, Hymavathi; Nallanchakravarthula, Varadacharyulu; Vaddi, Damodara Reddy

    2016-01-01

    Recently there has been increasing interest in plants and plant-derived compounds as raw food and medicinal agents. In Ayurveda, an Indian system of traditional medicine, a wide spectrum of medicinal properties of Pterocarpus santalinus is described. Many important bioactive phytocompounds have been extracted and identified from the heartwood of P. santalinus. Bioactive compounds typically occur in small amounts and have more subtle effects than nutrients. These bioactive compounds influence cellular activities that modify the risk of disease rather than prevent deficiency diseases. A wide array of biological activities and potential health benefits of P. santalinus have been reported, including antioxidative, antidiabetic, antimicrobial, anticancer, and anti-inflammatory properties, and protective effects on the liver, gastric mucosa, and nervous system. All these protective effects were attributed to bioactive compounds present in P. santalinus. The major bioactive compounds present in the heartwood of P. santalinus are santalin A and B, savinin, calocedrin, pterolinus K and L, and pterostilbenes. The bioactive compounds have potentially important health benefits: These compounds can act as antioxidants, enzyme inhibitors and inducers, inhibitors of receptor activities, and inducers and inhibitors of gene expression, among other actions. The present review aims to understand the pharmacological effects of P. santalinus on health and disease with "up-to-date" discussion. PMID:27041873

  11. Fatty acid synthase as a potential therapeutic target in cancer

    PubMed Central

    Flavin, Richard; Peluso, Stephane; Nguyen, Paul L; Loda, Massimo

    2011-01-01

    Fatty acid synthase (FASN) is a key enzyme involved in neoplastic lipogenesis. Overexpression of FASN is common in many cancers, and accumulating evidence suggests that it is a metabolic oncogene with an important role in tumor growth and survival, making it an attractive target for cancer therapy. Early small-molecule FASN inhibitors such as cerulenin, C75 and orlistat have been shown to induce apoptosis in several cancer cell lines and to induce tumor growth delay in several cancer xenograft models but their mechanism is still not well understood. These molecules suffer from pharmacological limitations and weight loss as a side effect that prevent their development as systemic drugs. Several potent inhibitors have recently been reported that may help to unravel and exploit the full potential of FASN as a target for cancer therapy in the near future. Furthermore, novel sources of FASN inhibitors, such as green tea and dietary soy, make both dietary manipulation and chemoprevention potential alternative modes of therapy in the future. PMID:20373869

  12. Therapeutic potential of melatonin in oral medicine and periodontology.

    PubMed

    Najeeb, Shariq; Khurshid, Zohaib; Zohaib, Sana; Zafar, Muhammad Sohail

    2016-08-01

    Melatonin (N-acetyl-5-methoxy tryptamine) is a substance secreted by multiple organs in vertebrates. In addition to playing a part in the circadian cycle of the body, melatonin is known to have antioxidant, antiinflammatory, and antioncotic effects on human tissues. Oral cavity is affected by a number of conditions such as periodontitis, mucositis, cancers, and cytotoxicity from various drugs or biomaterials. Research has suggested that melatonin is effective in treating the aforementioned pathologies. Furthermore, melatonin has been observed to enhance osseointegration and bone regeneration. The aim of this review is to critically analyze and summarize the research focusing on the potential of melatonin in the field of oral medicine. Topical administration of melatonin has a positive effect on periodontal health and osseointegration. Furthermore, melatonin is particularly effective in improving the periodontal parameters of diabetic patients with periodontitis. Melatonin exerts a regenerative effect on periodontal bone and may be incorporated into of periodontal scaffolds. The cytotoxic effect of various drugs and dental materials may be countered by the antioxidant properties of melatonin. Topical administration of melatonin promotes the healing of tooth extraction sockets and may also impede the progression of oral cancer. Although, there are a number of current and potential applications of melatonin, further long term clinical and animal studies are needed to assess its efficacy. Moreover, the role of melatonin supplements in the management of periodontitis should also be assessed. PMID:27523451

  13. Cardiovascular gene therapy: current status and therapeutic potential

    PubMed Central

    Gaffney, M M; Hynes, S O; Barry, F; O'Brien, T

    2007-01-01

    Gene therapy is emerging as a potential treatment option in patients suffering from a wide spectrum of cardiovascular diseases including coronary artery disease, peripheral vascular disease, vein graft failure and in-stent restenosis. Thus far preclinical studies have shown promise for a wide variety of genes, in particular the delivery of genes encoding growth factors such as vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) to treat ischaemic vascular disease both peripherally and in coronary artery disease. VEGF as well as other genes such as TIMPs have been used to target the development of neointimal hyperplasia to successfully prevent vein graft failure and in-stent restenosis in animal models. Subsequent phase I trials to examine safety of these therapies have been successful with low levels of serious adverse effects, and albeit in the absence of a placebo group some suggestion of efficacy. Phase 2 studies, which have incorporated a placebo group, have not confirmed this early promise of efficacy. In the next generation of clinical gene therapy trials for cardiovascular disease, many parameters will need to be adjusted in the search for an effective therapy, including the identification of a suitable vector, appropriate gene or genes and an effective vector delivery system for a specific disease target. Here we review the current status of cardiovascular gene therapy and the potential for this approach to become a viable treatment option. PMID:17558439

  14. Crosstalk Between Apoptosis and Autophagy: Molecular Mechanisms and Therapeutic Strategies in Cancer

    PubMed Central

    El-Khattouti, Abdelouahid; Selimovic, Denis; Haikel, Youssef; Hassan, Mohamed

    2013-01-01

    Both apoptosis and autophagy are highly conserved processes that besides their role in the maintenance of the organismal and cellular homeostasis serve as a main target of tumor therapeutics. Although their important roles in the modulation of tumor therapeutic strategies have been widely reported, the molecular actions of both apoptosis and autophagy are counteracted by cancer protective mechanisms. While apoptosis is a tightly regulated process that is implicated in the removal of damaged or unwanted cells, autophagy is a cellular catabolic pathway that is involved in lysosomal degradation and recycling of proteins and organelles, and thereby is considered an important survival/protective mechanism for cancer cells in response to metabolic stress or chemotherapy. Although the relationship between autophagy and cell death is very complicated and has not been characterized in detail, the molecular mechanisms that control this relationship are considered to be a relevant target for the development of a therapeutic strategy for tumor treatment. In this review, we focus on the molecular mechanisms of apoptosis, autophagy, and those of the crosstalk between apoptosis and autophagy in order to provide insight into the molecular mechanisms that may be essential for the balance between cell survival and death as well as their role as targets for the development of novel therapeutic approaches. PMID:25278778

  15. Therapeutic radiation and the potential risk of second malignancies.

    PubMed

    Kamran, Sophia C; Berrington de Gonzalez, Amy; Ng, Andrea; Haas-Kogan, Daphne; Viswanathan, Akila N

    2016-06-15

    Radiation has long been associated with carcinogenesis. Nevertheless, it is an important part of multimodality therapy for many malignancies. It is critical to assess the risk of secondary malignant neoplasms (SMNs) after radiation treatment. The authors reviewed the literature with a focus on radiation and associated SMNs for primary hematologic, breast, gynecologic, and pediatric tumors. Radiation appeared to increase the risk of SMN in all of these; however, this risk was found to be associated with age, hormonal influences, chemotherapy use, environmental influences, genetic predisposition, infection, and immunosuppression. The risk also appears to be altered with modern radiotherapy techniques. Practitioners of all specialties who treat cancer survivors in follow-up should be aware of this potential risk. Cancer 2016;122:1809-21. © 2016 American Cancer Society. PMID:26950597

  16. Nutraceuticals as potential therapeutic agents for colon cancer: a review

    PubMed Central

    Kuppusamy, Palaniselvam; Yusoff, Mashitah M.; Maniam, Gaanty Pragas; Ichwan, Solachuddin Jauhari Arief; Soundharrajan, Ilavenil; Govindan, Natanamurugaraj

    2014-01-01

    Colon cancer is a world-wide health problem and the second-most dangerous type of cancer, affecting both men and women. The modern diet and lifestyles, with high meat consumption and excessive alcohol use, along with limited physical activity has led to an increasing mortality rate for colon cancer worldwide. As a result, there is a need to develop novel and environmentally benign drug therapies for colon cancer. Currently, nutraceuticals play an increasingly important role in the treatment of various chronic diseases such as colon cancer, diabetes and Alzheimer׳s disease. Nutraceuticals are derived from various natural sources such as medicinal plants, marine organisms, vegetables and fruits. Nutraceuticals have shown the potential to reduce the risk of colon cancer and slow its progression. These dietary substances target different molecular aspects of colon cancer development. Accordingly, this review briefly discusses the medicinal importance of nutraceuticals and their ability to reduce the risk of colorectal carcinogenesis. PMID:26579381

  17. Nutraceuticals as potential therapeutic agents for colon cancer: a review.

    PubMed

    Kuppusamy, Palaniselvam; Yusoff, Mashitah M; Maniam, Gaanty Pragas; Ichwan, Solachuddin Jauhari Arief; Soundharrajan, Ilavenil; Govindan, Natanamurugaraj

    2014-06-01

    Colon cancer is a world-wide health problem and the second-most dangerous type of cancer, affecting both men and women. The modern diet and lifestyles, with high meat consumption and excessive alcohol use, along with limited physical activity has led to an increasing mortality rate for colon cancer worldwide. As a result, there is a need to develop novel and environmentally benign drug therapies for colon cancer. Currently, nutraceuticals play an increasingly important role in the treatment of various chronic diseases such as colon cancer, diabetes and Alzheimer׳s disease. Nutraceuticals are derived from various natural sources such as medicinal plants, marine organisms, vegetables and fruits. Nutraceuticals have shown the potential to reduce the risk of colon cancer and slow its progression. These dietary substances target different molecular aspects of colon cancer development. Accordingly, this review briefly discusses the medicinal importance of nutraceuticals and their ability to reduce the risk of colorectal carcinogenesis. PMID:26579381

  18. Bronchoconstriction and airway biology: potential impact and therapeutic opportunities.

    PubMed

    Gosens, Reinoud; Grainge, Chris

    2015-03-01

    Recent work has demonstrated that mechanical forces occurring in the airway as a consequence of bronchoconstriction are sufficient to not only induce symptoms but also influence airway biology. Animal and human in vitro and in vivo work demonstrates that the airways are structurally and functionally altered by mechanical stress induced by bronchoconstriction. Compression of the airway epithelium and mechanosensing by the airway smooth muscle trigger the activation and release of growth factors, causing cell proliferation, extracellular matrix protein accumulation, and goblet cell differentiation. These effects of bronchoconstriction are of major importance to asthma pathophysiology and appear sufficient to induce remodeling independent of the inflammatory response. We review these findings in detail and discuss previous studies in light of this new evidence regarding the influence of mechanical forces in the airways. Furthermore, we highlight potential impacts of therapies influencing mechanical forces on airway structure and function in asthma. PMID:25732446

  19. Therapeutic Potential of Autologous Stem Cell Transplantation for Cerebral Palsy

    PubMed Central

    Purandare, Chaitanya; Shitole, D. G.; Belle, Vaijayantee; Kedari, Aarti; Bora, Neeta; Joshi, Meghnad

    2012-01-01

    Background. Cerebral palsy (CP) is a severe disabling disease with worldwide incidence being 2 to 3 per 1000 live births. CP was considered as a noncurable, nonreparative disorder, but stem cell therapy offers a potential treatment for CP. Objective. The present study evaluates the safety and efficacy of autologous bone-marrow-derived mononuclear cell (BMMNCs) transplantation in CP patient. Material and Methods. In the present study, five infusions of autologous stem cells were injected intrathecally. Changes in neurological deficits and improvements in function were assessed using Gross Motor Function Classification System (GMFCS-E&R) scale. Results. Significant motor, sensory, cognitive, and speech improvements were observed. Bowel and bladder control has been achieved. On the GMFCS-E&R level, the patient was promoted from grade III to I. Conclusion. In this study, we report that intrathecal infusion of autologous BMMNCs seems to be feasible, effective, and safe with encouraging functional outcome improvements in CP patient. PMID:23259143

  20. Therapeutic issues and intervention strategies with young adult lesbian clients: a developmental approach.

    PubMed

    Browning, C

    1987-01-01

    This paper examines the coming out process within an adult developmental context. Therapeutic issues which surface for the young adult lesbian client include separation from parents, development of social support, exploration of career/vocational goals, and the establishment of intimate relationships. Intervention strategies are suggested which facilitate the coming out process and help the client integrate her sexual orientation within her emerging adult identity. PMID:3655351

  1. Epigenetic Control and Cancer: The Potential of Histone Demethylases as Therapeutic Targets

    PubMed Central

    Lizcano, Fernando; Garcia, Jeison

    2012-01-01

    The development of cancer involves an immense number of factors at the molecular level. These factors are associated principally with alterations in the epigenetic mechanisms that regulate gene expression profiles. Studying the effects of chromatin structure alterations, which are caused by the addition/removal of functional groups to specific histone residues, are of great interest as a promising way to identify markers for cancer diagnosis, classify the disease and determine its prognosis, and these markers could be potential targets for the treatment of this disease in its different forms. This manuscript presents the current point of view regarding members of the recently described family of proteins that exhibit histone demethylase activity; histone demethylases are genetic regulators that play a fundamental role in both the activation and repression of genes and whose expression has been observed to increase in many types of cancer. Some fundamental aspects of their association with the development of cancer and their relevance as potential targets for the development of new therapeutic strategies at the epigenetic level are discussed in the following manuscript. PMID:24280700

  2. MicroRNAs serving as potential biomarkers and therapeutic targets in nasopharyngeal carcinoma: A critical review.

    PubMed

    Lee, Katherine Ting-Wei; Tan, Juan-King; Lam, Alfred King-Yin; Gan, Sook-Yee

    2016-07-01

    Despite significant medical advancement, nasopharyngeal carcinoma (NPC) remains one of the most difficult cancers to detect and treat where it continues to prevail especially among the Asian population. miRNAs could act as tumour suppressor genes or oncogenes in NPC. They play important roles in the pathogenesis of NPC by regulating specific target genes which are involved in various cellular processes and pathways. In particular, studies on miRNAs related to the Epstein Barr virus (EBV)-encoded latent membrane protein one (LMP1) and EBVmiRNA- BART miRNA confirmed the link between EBV and NPC. Both miRNA and its target genes could potentially be exploited for prognostic and therapeutic strategies. They are also important in predicting the sensitivity of NPC to radiotherapy and chemotherapy. The detection of stable circulating miRNAs in plasma of NPC patients has raised the potential of miRNAs as novel diagnostic markers. To conclude, understanding the roles of miRNA in NPC will identify ways to improve the management of patients with NPC. PMID:27179594

  3. The microbiota-gut-brain axis and its potential therapeutic role in autism spectrum disorder.

    PubMed

    Li, Q; Zhou, J-M

    2016-06-01

    Autism spectrum disorder (ASD) is a series of neurodevelopmental disorders that are characterized by deficits in both social and cognitive functions. Although the exact etiology and pathology of ASD remain unclear, a disorder of the microbiota-gut-brain axis is emerging as a prominent factor in the generation of autistic behaviors. Clinical studies have shown that gastrointestinal symptoms and compositional changes in the gut microbiota frequently accompany cerebral disorders in patients with ASD. A disturbance in the gut microbiota, which is usually induced by a bacterial infection or chronic antibiotic exposure, has been implicated as a potential contributor to ASD. The bidirectional microbiota-gut-brain axis acts mainly through neuroendocrine, neuroimmune, and autonomic nervous mechanisms. Application of modulators of the microbiota-gut-brain axis, such as probiotics, helminthes and certain special diets, may be a promising strategy for the treatment of ASD. This review mainly discusses the salient observations of the disruptions of the microbiota-gut-brain axis in the pathogenesis of ASD and reveals its potential therapeutic role in autistic deficits. PMID:26964681

  4. Multi-Functional Diarylurea Small Molecule Inhibitors of TRPV1 with Therapeutic Potential for Neuroinflammation.

    PubMed

    Feng, Zhiwei; Pearce, Larry V; Zhang, Yu; Xing, Changrui; Herold, Brienna K A; Ma, Shifan; Hu, Ziheng; Turcios, Noe A; Yang, Peng; Tong, Qin; McCall, Anna K; Blumberg, Peter M; Xie, Xiang-Qun

    2016-07-01

    Transient receptor potential vanilloid type 1 (TRPV1), a heat-sensitive calcium channel protein, contributes to inflammation as well as to acute and persistent pain. Since TRPV1 occupies a central position in pathways of neuronal inflammatory signaling, it represents a highly attractive potential therapeutic target for neuroinflammation. In the present work, we have in silico identified a series of diarylurea analogues for hTRPV1, of which 11 compounds showed activity in the nanomolar to micromolar range as validated by in vitro biological assays. Then, we utilized molecular docking to explore the detailed interactions between TRPV1 and the compounds to understand the contributions of the different substituent groups. Tyr511, Leu518, Leu547, Thr550, Asn551, Arg557, and Leu670 were important for the recognition of the small molecules by TRPV1. A hydrophobic group in R2 or a polar/hydrophilic group in R1 contributed significantly to the activities of the antagonists at TRPV1. In addition, the subtle different binding pose of meta-chloro in place of para-fluoro in the R2 group converted antagonism into partial agonism, as was predicted by our short-term molecular dynamics (MD) simulation and validated by bioassay. Importantly, compound 15, one of our best TRPV1 inhibitors, also showed potential binding affinity (1.39 μM) at cannabinoid receptor 2 (CB2), which is another attractive target for immuno-inflammation diseases. Furthermore, compound 1 and its diarylurea analogues were predicted to target the C-X-C chemokine receptor 2 (CXCR2), although bioassay validation of CXCR2 with these compounds still needs to be performed. This prediction from the modeling is of interest, since CXCR2 is also a potential therapeutic target for chronic inflammatory diseases. Our findings provide novel strategies to develop a small molecule inhibitor to simultaneously target two or more inflammation-related proteins for the treatment of a wide range of inflammatory disorders including

  5. Silibinin as a potential therapeutic for sulfur mustard injuries.

    PubMed

    Balszuweit, Frank; John, Harald; Schmidt, Annette; Kehe, Kai; Thiermann, Horst; Steinritz, Dirk

    2013-12-01

    Sulfur mustard (SM) is a vesicating chemical warfare agent causing skin blistering, ulceration, impaired wound healing, prolonged hospitalization and permanent lesions. Silibinin, the lead compound from Silybum marianum, has also been discussed as a potential antidote to SM poisoning. However, its efficacy has been demonstrated only with regard to nitrogen mustards. Moreover, there are no data on the efficacy of the water-soluble prodrug silibinin-bis-succinat (silibinin-BS). We investigated the effect of SIL-BS treatment against SM toxicity in HaCaT cells with regard to potential reduction of necrosis, apoptosis and inflammation including dose-dependency of any protective effects. We also demonstrated the biotransformation of the prodrug into free silibinin. HaCaT cells were exposed to SM (30, 100, and 300μM) for 30min and treated thereafter with SIL-BS (10, 50, and 100μM) for 24h. Necrosis and apoptosis were quantified using the ToxiLight BioAssay and the nucleosome ELISA (CDDE). Pro-inflammatory interleukins-6 and -8 were determined by ELISA. HaCaT cells, incubated with silibinin-BS were lysed and investigated by LC-ESI MS/MS. LC-ESI MS/MS results suggest that SIL-BS is absorbed by HaCaT cells and biotransformed into free silibinin. SIL-BS dose-dependently reduced SM cytotoxicity, even after 300μM exposure. Doses of 50-100μM silibinin-BS were required for significant protection. Apoptosis and interleukin production remained largely unchanged by 10-50μM silibinin-BS but increased after 100μM treatment. Observed reductions of SM cytotoxicity by post-exposure treatment with SIL-BS suggest this as a promising approach for treatment of SM injuries. While 100μM SIL-BS is most effective to reduce necrosis, 50μM may be safer to avoid pro-inflammatory effects. Pro-apoptotic effects after high doses of SIL-BS are in agreement with findings in literature and might even be useful to eliminate cells irreversibly damaged by SM. Further investigations will focus on the

  6. The rodent endovascular puncture model of subarachnoid hemorrhage: mechanisms of brain damage and therapeutic strategies

    PubMed Central

    2014-01-01

    Subarachnoid hemorrhage (SAH) represents a considerable health problem. To date, limited therapeutic options are available. In order to develop effective therapeutic strategies for SAH, the mechanisms involved in SAH brain damage should be fully explored. Here we review the mechanisms of SAH brain damage induced by the experimental endovascular puncture model. We have included a description of similarities and distinctions between experimental SAH in animals and human SAH pathology. Moreover, several novel treatment options to diminish SAH brain damage are discussed. SAH is accompanied by cerebral inflammation as demonstrated by an influx of inflammatory cells into the cerebral parenchyma, upregulation of inflammatory transcriptional pathways and increased expression of cytokines and chemokines. Additionally, various cell death pathways including cerebral apoptosis, necrosis, necroptosis and autophagy are involved in neuronal damage caused by SAH. Treatment strategies aiming at inhibition of inflammatory or cell death pathways demonstrate the importance of these mechanisms for survival after experimental SAH. Moreover, neuroregenerative therapies using stem cells are discussed as a possible strategy to repair the brain after SAH since this therapy may extend the window of treatment considerably. We propose the endovascular puncture model as a suitable animal model which resembles the human pathology of SAH and which could be applied to investigate novel therapeutic therapies to combat this debilitating insult. PMID:24386932

  7. Biflavonoids as Potential Small Molecule Therapeutics for Alzheimer's Disease.

    PubMed

    Thapa, Arjun; Chi, Eva Y

    2015-01-01

    Flavonoids are naturally occurring phytochemicals found in a variety of fruits and vegetables and offer color, flavor, aroma, nutritional and health benefits. Flavonoids have been found to play a neuroprotective role by inhibiting and/or modifying the self-assembly of the amyloid-β (Aβ) peptide into oligomers and fibrils, which are linked to the pathogenesis of Alzheimer's disease. The neuroprotective efficacy of flavonoids has been found to strongly depend on their structure and functional groups. Flavonoids may exist in monomeric, as well as di-, tri-, tetra- or polymeric form through C-C or C-O-C linkages. It has been shown that flavonoids containing two or more units, e.g., biflavonoids, exert greater biological activity than their respective monoflavonoids. For instance, biflavonoids have the ability to distinctly alter Aβ aggregation and more effectively reduce the toxicity of Aβ oligomers compared to the monoflavonoid moieties. Although the molecular mechanisms remain to be elucidated, flavonoids have been shown to alter the Aβ aggregation pathway to yield non-toxic, unstructured Aβ aggregates, as well as directly exerting a neuroprotective effect to cells. In this chapter, we review biflavonoid-mediated Aβ aggregation and toxicity, and highlight the beneficial roles biflavonoids can potentially play in the prevention and treatment of Alzheimer's disease. PMID:26092626

  8. Therapeutic Potential of Tea Tree Oil for Scabies

    PubMed Central

    Thomas, Jackson; Carson, Christine F.; Peterson, Greg M.; Walton, Shelley F.; Hammer, Kate A.; Naunton, Mark; Davey, Rachel C.; Spelman, Tim; Dettwiller, Pascale; Kyle, Greg; Cooper, Gabrielle M.; Baby, Kavya E.

    2016-01-01

    Globally, scabies affects more than 130 million people at any time. In the developed world, outbreaks in health institutions and vulnerable communities result in a significant economic burden. A review of the literature demonstrates the emergence of resistance toward classical scabicidal treatments and the lack of effectiveness of currently available scabicides in reducing the inflammatory skin reactions and pyodermal progression that occurs in predisposed patient cohorts. Tea tree oil (TTO) has demonstrated promising acaricidal effects against scabies mites in vitro and has also been successfully used as an adjuvant topical medication for the treatment of crusted scabies, including cases that did not respond to standard treatments. Emerging acaricide resistance threatens the future usefulness of currently used gold standard treatments (oral ivermectin and topical permethrin) for scabies. The imminent development of new chemical entities is doubtful. The cumulative acaricidal, antibacterial, antipruritic, anti-inflammatory, and wound healing effects of TTO may have the potential to successfully reduce the burden of scabies infection and the associated bacterial complications. This review summarizes current knowledge on the use of TTO for the treatment of scabies. On the strength of existing data for TTO, larger scale, randomized controlled clinical trials are warranted. PMID:26787146

  9. Ion Channels in Obesity: Pathophysiology and Potential Therapeutic Targets.

    PubMed

    Vasconcelos, Luiz H C; Souza, Iara L L; Pinheiro, Lílian S; Silva, Bagnólia A

    2016-01-01

    Obesity is a multifactorial disease related to metabolic disorders and associated with genetic determinants. Currently, ion channels activity has been linked to many of these disorders, in addition to the central regulation of food intake, energetic balance, hormone release and response, as well as the adipocyte cell proliferation. Therefore, the objective of this work is to review the current knowledge about the influence of ion channels in obesity development. This review used different sources of literature (Google Scholar, PubMed, Scopus, and Web of Science) to assess the role of ion channels in the pathophysiology of obesity. Ion channels present diverse key functions, such as the maintenance of physiological homeostasis and cell proliferation. Cell biology and pharmacological experimental evidences demonstrate that proliferating cells exhibit ion channel expression, conductance, and electrical properties different from the resting cells. Thereby, a large variety of ion channels has been identified in the pathogenesis of obesity such as potassium, sodium, calcium and chloride channels, nicotinic acetylcholine receptor and transient receptor potential channels. The fundamental involvement of these channels on the generation of obesity leads to the progress in the knowledge about the mechanisms responsible for the obesity pathophysiology, consequently emerging as new targets for pharmacological modulation. PMID:27065858

  10. Conundrum and therapeutic potential of curcumin in drug delivery.

    PubMed

    Kumar, Anil; Ahuja, Alka; Ali, Javed; Baboota, Sanjula

    2010-01-01

    Turmeric, the source of the polyphenolic active compound curcumin (diferuloylmethane), has been used extensively in traditional medicine since ancient times as a household remedy against various diseases, including hepatic disorders, cough, sinusitis, rheumatism, and biliary disorders. In the past few decades, a number of studies have been done on curcumin showing its potential role in treating inflammatory disorders, cardiovascular disease, cancer, AIDS, and neurological disorders. However, the main drawback associated with curcumin is its poor aqueous solubility and stability in gastrointestinal fluids, which leads to poor bioavailability. Multifarious novel drug-delivery approaches, including microemulsions, nanoemulsions, liposomes, solid lipid nanoparticles, microspheres, solid dispersion, polymeric nanoparticles, and self-microemulsifying drug-delivery systems have been used to enhance the bioavailability and tissue-targeting ability of curcumin. These attempts have revealed promising results for enhanced bioavailability and targeting to disease such as cancer, but more extensive research on tissue-targeting and stability-related issues is needed. Tissue targeting and enhanced bioavailability of curcumin using novel drug-delivery methods with minimum side effects will in the near future bring this promising natural product to the forefront of therapy for the treatment of human diseases such as cancer and cardiovascular ailments. We provide a detailed analysis of prominent research in the field of curcumin drug delivery with special emphasis on bioavailability-enhancement approaches and novel drug-delivery system approaches. PMID:20932240

  11. Honey: A Potential Therapeutic Agent for Managing Diabetic Wounds

    PubMed Central

    Islam, Md. Asiful; Gan, Siew Hua; Khalil, Md. Ibrahim

    2014-01-01

    Diabetic wounds are unlike typical wounds in that they are slower to heal, making treatment with conventional topical medications an uphill process. Among several different alternative therapies, honey is an effective choice because it provides comparatively rapid wound healing. Although honey has been used as an alternative medicine for wound healing since ancient times, the application of honey to diabetic wounds has only recently been revived. Because honey has some unique natural features as a wound healer, it works even more effectively on diabetic wounds than on normal wounds. In addition, honey is known as an “all in one” remedy for diabetic wound healing because it can combat many microorganisms that are involved in the wound process and because it possesses antioxidant activity and controls inflammation. In this review, the potential role of honey's antibacterial activity on diabetic wound-related microorganisms and honey's clinical effectiveness in treating diabetic wounds based on the most recent studies is described. Additionally, ways in which honey can be used as a safer, faster, and effective healing agent for diabetic wounds in comparison with other synthetic medications in terms of microbial resistance and treatment costs are also described to support its traditional claims. PMID:25386217

  12. Therapeutic Potential of Tea Tree Oil for Scabies.

    PubMed

    Thomas, Jackson; Carson, Christine F; Peterson, Greg M; Walton, Shelley F; Hammer, Kate A; Naunton, Mark; Davey, Rachel C; Spelman, Tim; Dettwiller, Pascale; Kyle, Greg; Cooper, Gabrielle M; Baby, Kavya E

    2016-02-01

    Globally, scabies affects more than 130 million people at any time. In the developed world, outbreaks in health institutions and vulnerable communities result in a significant economic burden. A review of the literature demonstrates the emergence of resistance toward classical scabicidal treatments and the lack of effectiveness of currently available scabicides in reducing the inflammatory skin reactions and pyodermal progression that occurs in predisposed patient cohorts. Tea tree oil (TTO) has demonstrated promising acaricidal effects against scabies mites in vitro and has also been successfully used as an adjuvant topical medication for the treatment of crusted scabies, including cases that did not respond to standard treatments. Emerging acaricide resistance threatens the future usefulness of currently used gold standard treatments (oral ivermectin and topical permethrin) for scabies. The imminent development of new chemical entities is doubtful. The cumulative acaricidal, antibacterial, antipruritic, anti-inflammatory, and wound healing effects of TTO may have the potential to successfully reduce the burden of scabies infection and the associated bacterial complications. This review summarizes current knowledge on the use of TTO for the treatment of scabies. On the strength of existing data for TTO, larger scale, randomized controlled clinical trials are warranted. PMID:26787146

  13. The potential for emerging therapeutic options for Clostridium difficile infection

    PubMed Central

    Mathur, Harsh; Rea, Mary C; Cotter, Paul D; Ross, R Paul; Hill, Colin

    2014-01-01

    Clostridium difficile is mainly a nosocomial pathogen and is a significant cause of antibiotic-associated diarrhea. It is also implicated in the majority of cases of pseudomembranous colitis. Recently, advancements in next generation sequencing technology (NGS) have highlighted the extent of damage to the gut microbiota caused by broad-spectrum antibiotics, often resulting in C. difficile infection (CDI). Currently the treatment of choice for CDI involves the use of metronidazole and vancomycin. However, recurrence and relapse of CDI, even after rounds of metronidazole/vancomycin administration is a problem that must be addressed. The efficacy of alternative antibiotics such as fidaxomicin, rifaximin, nitazoxanide, ramoplanin and tigecycline, as well as faecal microbiota transplantation has been assessed and some have yielded positive outcomes against C. difficile. Some bacteriocins have also shown promising effects against C. difficile in recent years. In light of this, the potential for emerging treatment options and efficacy of anti-C. difficile vaccines are discussed in this review. PMID:25564777

  14. Hydrogen Sulfide as a Potential Therapeutic Target in Fibrosis

    PubMed Central

    Zhang, Shufang; Pan, Chuli; Zhou, Feifei; Yuan, Zhi; Wang, Huiying; Cui, Wei; Zhang, Gensheng

    2015-01-01

    Hydrogen sulfide (H2S), produced endogenously by the activation of two major H2S-generating enzymes (cystathionine β-synthase and cystathionine γ-lyase), plays important regulatory roles in different physiologic and pathologic conditions. The abnormal metabolism of H2S is associated with fibrosis pathogenesis, causing damage in structure and function of different organs. A number of in vivo and in vitro studies have shown that both endogenous H2S level and the expressions of H2S-generating enzymes in plasma and tissues are significantly downregulated during fibrosis. Supplement with exogenous H2S mitigates the severity of fibrosis in various experimental animal models. The protective role of H2S in the development of fibrosis is primarily attributed to its antioxidation, antiapoptosis, anti-inflammation, proangiogenesis, and inhibition of fibroblasts activities. Future studies might focus on the potential to intervene fibrosis by targeting the pathway of endogenous H2S-producing enzymes and H2S itself. PMID:26078809

  15. A small peptide with therapeutic potential for inflammatory acne vulgaris.

    PubMed

    Zhang, Zhiye; Mu, Lixian; Tang, Jing; Duan, Zilei; Wang, Fengyu; Wei, Lin; Rong, Mingqiang; Lai, Ren

    2013-01-01

    A designed peptide named LZ1 with 15 amino acid residues containing strong antimicrobial activity against bacteria pathogens of acne vulgaris including Propionibacterium acnes, Staphylococcus epidermidis and S. aureus. Especially, it exerted strong anti-P. acnes ability. The minimal inhibitory concentration against three strains of P. acnes was only 0.6 µg/ml, which is 4 times lower than that of clindamycin. In experimental mice skin colonization model, LZ1 significantly reduced the number of P. acnes colonized on the ear, P. acnes-induced ear swelling, and inflammatory cell infiltration. It ameliorated inflammation induced by P. acnes by inhibiting the secretion of inflammatory factors including tumor necrosis factor-α (TNF-α) and interleukin (IL)-1β. LZ1 showed little cytotoxicity on human keratinocyte and hemolytic activity on human blood red cells. Furthermore, LZ1 was very stable in human plasma. Combined with its potential bactericidal and anti-inflammatory properties, simple structure and high stability, LZ1 might be an ideal candidate for the treatment of acne. PMID:24013774

  16. Anaplerotic diet therapy in inherited metabolic disease: therapeutic potential.

    PubMed

    Roe, Charles R; Mochel, Fanny

    2006-01-01

    Beginning with phenylketonuria, dietary therapy for inborn errors has focused primarily on the restriction of the precursor to an affected catabolic pathway in an attempt to limit the production of potential toxins. Anaplerotic therapy is based on the concept that there may exist an energy deficit in these diseases that might be improved by providing alternative substrate for both the citric acid cycle (CAC) and the electron transport chain for enhanced ATP production. This article focuses on this basic problem, as it may relate to most catabolic disorders, and provides our current experience involving inherited diseases of mitochondrial fat oxidation, glycogen storage, and pyruvate metabolism using the anaplerotic compound triheptanoin. The observations have led to a realization that 'inter-organ' signalling and 'nutrient sensors' such as adenylate monophosphate mediated-protein kinase (AMPK) and mTOR (mammalian target of rapamycin) appear to play a significant role in the intermediary metabolism of these diseases. Activated AMPK turns on catabolic pathways to augment ATP production while turning off synthetic pathways that consume ATP. Information is provided regarding the inter-organ requirements for more normal metabolic function during crisis and how anaplerotic therapy using triheptanoin, as a direct source of substrate to the CAC for energy production, appears to be a more successful approach to an improved quality of life for these patients. PMID:16763896

  17. Ion Channels in Obesity: Pathophysiology and Potential Therapeutic Targets

    PubMed Central

    Vasconcelos, Luiz H. C.; Souza, Iara L. L.; Pinheiro, Lílian S.; Silva, Bagnólia A.

    2016-01-01

    Obesity is a multifactorial disease related to metabolic disorders and associated with genetic determinants. Currently, ion channels activity has been linked to many of these disorders, in addition to the central regulation of food intake, energetic balance, hormone release and response, as well as the adipocyte cell proliferation. Therefore, the objective of this work is to review the current knowledge about the influence of ion channels in obesity development. This review used different sources of literature (Google Scholar, PubMed, Scopus, and Web of Science) to assess the role of ion channels in the pathophysiology of obesity. Ion channels present diverse key functions, such as the maintenance of physiological homeostasis and cell proliferation. Cell biology and pharmacological experimental evidences demonstrate that proliferating cells exhibit ion channel expression, conductance, and electrical properties different from the resting cells. Thereby, a large variety of ion channels has been identified in the pathogenesis of obesity such as potassium, sodium, calcium and chloride channels, nicotinic acetylcholine receptor and transient receptor potential channels. The fundamental involvement of these channels on the generation of obesity leads to the progress in the knowledge about the mechanisms responsible for the obesity pathophysiology, consequently emerging as new targets for pharmacological modulation. PMID:27065858

  18. The therapeutic potential of orphan GPCRs, GPR35 and GPR55.

    PubMed

    Shore, Derek M; Reggio, Patricia H

    2015-01-01

    The G protein-coupled receptor (GPCR) superfamily of integral proteins is the largest family of signal transducers, comprised of ∼1000 members. Considering their prevalence and functional importance, it's not surprising that ∼60% of drugs target GPCRs. Regardless, there exists a subset of the GPCR superfamily that is largely uncharacterized and poorly understood; specifically, more than 140 GPCRs have unknown endogenous ligands-the so-called orphan GPCRs. Orphan GPCRs offer tremendous promise, as they may provide novel therapeutic targets that may be more selective than currently known receptors, resulting in the potential reduction in side effects. In addition, they may provide access to signal transduction pathways currently unknown, allowing for new strategies in drug design. Regardless, orphan GPCRs are an important area of inquiry, as they represent a large gap in our understanding of signal transduction at the cellular level. Here, we focus on the therapeutic potential of two recently deorphanized GPCRs: GPR35/CXCR8 and GPR55. First, GPR35/CXCR8 has been observed in numerous tissues/organ systems, including the gastrointestinal tract, liver, immune system, central nervous system, and cardiovascular system. Not surprisingly, GPR35/CXCR8 has been implicated in numerous pathologies involving these tissues/systems. While several endogenous ligands have been identified, GPR35/CXCR8 has recently been observed to bind the chemokine CXCL17. Second, GPR55 has been observed to be expressed in the central nervous system, adrenal glands, gastrointestinal tract, lung, liver, uterus, bladder, kidney, and bone, as well as, other tissues/organ systems. Likewise, it is not surprising that GPR55 has been implicated in pathologies involving these tissues/systems. GPR55 was initially deorphanized as a cannabinoid receptor and this receptor does bind many cannabinoid compounds. However, the GPR55 endogenous ligand has been found to be a non

  19. The therapeutic potential of orphan GPCRs, GPR35 and GPR55

    PubMed Central

    Shore, Derek M.; Reggio, Patricia H.

    2015-01-01

    The G protein-coupled receptor (GPCR) superfamily of integral proteins is the largest family of signal transducers, comprised of ∼1000 members. Considering their prevalence and functional importance, it’s not surprising that ∼60% of drugs target GPCRs. Regardless, there exists a subset of the GPCR superfamily that is largely uncharacterized and poorly understood; specifically, more than 140 GPCRs have unknown endogenous ligands—the so-called orphan GPCRs. Orphan GPCRs offer tremendous promise, as they may provide novel therapeutic targets that may be more selective than currently known receptors, resulting in the potential reduction in side effects. In addition, they may provide access to signal transduction pathways currently unknown, allowing for new strategies in drug design. Regardless, orphan GPCRs are an important area of inquiry, as they represent a large gap in our understanding of signal transduction at the cellular level. Here, we focus on the therapeutic potential of two recently deorphanized GPCRs: GPR35/CXCR8 and GPR55. First, GPR35/CXCR8 has been observed in numerous tissues/organ systems, including the gastrointestinal tract, liver, immune system, central nervous system, and cardiovascular system. Not surprisingly, GPR35/CXCR8 has been implicated in numerous pathologies involving these tissues/systems. While several endogenous ligands have been identified, GPR35/CXCR8 has recently been observed to bind the chemokine CXCL17. Second, GPR55 has been observed to be expressed in the central nervous system, adrenal glands, gastrointestinal tract, lung, liver, uterus, bladder, kidney, and bone, as well as, other tissues/organ systems. Likewise, it is not surprising that GPR55 has been implicated in pathologies involving these tissues/systems. GPR55 was initially deorphanized as a cannabinoid receptor and this receptor does bind many cannabinoid compounds. However, the GPR55 endogenous ligand has been found to be a non

  20. Metabotropic glutamate receptor ligands as potential therapeutics for addiction

    PubMed Central

    Olive, M. F.

    2009-01-01

    There is now compelling evidence that the excitatory amino acid neurotransmitter glutamate plays a pivotal role in drug addiction and alcoholism. As a result, there has been increasing interest in developing glutamate-based therapies for the treatment of addictive disorders. Receptors for glutamate are primarily divided into two classes: ionotropic glutamate receptors (iGluRs) that mediate fast excitatory glutamate transmission, and metabotropic glutamate receptors (mGluRs), which are G-protein coupled receptors that mediate slower, modulatory glutamate transmission. Most iGluR antagonists, while showing some efficacy in animal models of addiction, exhibit serious side effects when tested in humans. mGluR ligands, on the other hand, which have been advanced to testing in clinical trials for various medical conditions, have demonstrated the ability to reduce drug reward, reinforcement, and relapse-like behaviors in animal studies. mGluR ligands that have been shown to be primarily effective are Group I (mGluR1 and mGluR5) negative allosteric modulators and Group II (mGluR2 and mGluR3) orthosteric presynaptic autoreceptor agonists. In this review, we will summarize findings from animal studies suggesting that these mGluR ligands may be of potential benefit in reducing on-going drug self-administration and may aid in the prevention of relapse. The neuroanatomical distribution of mGluR1, mGluR2/3, and mGluR5 receptors and the pharmacological properties of Group I negative allosteric modulators and Group II agonists will also be overviewed. Finally, we will discuss the current status of mGluR ligands in human clinical trials. PMID:19630739

  1. Therapeutic strategy for hair regeneration: Hair cycle activation, niche environment modulation, wound-induced follicle neogenesis and stem cell engineering

    PubMed Central

    Chueh, Shan-Chang; Lin, Sung-Jan; Chen, Chih-Chiang; Lei, Mingxing; Wang, Ling Mei; Widelitz, Randall B.; Hughes, Michael W.; Jiang, Ting-Xing; Chuong, Cheng Ming

    2013-01-01

    Introduction There are major new advancements in the fields of stem cell biology, developmental biology, regenerative hair cycling, and tissue engineering. The time is ripe to integrate, translate and apply these findings to tissue engineering and regenerative medicine. Readers will learn about new progress in cellular and molecular aspects of hair follicle development, regeneration and potential therapeutic opportunities these advances may offer. Areas covered Here we use hair follicle formation to illustrate this progress and to identify targets for potential strategies in therapeutics. Hair regeneration is discussed in four different categories. (1) Intra-follicle regeneration (or renewal) is the basic production of hair fibers from hair stem cells and dermal papillae in existing follicles. (2) Chimeric follicles via epithelial-mesenchymal recombination to identify stem cells and signaling centers. (3) Extra-follicular factors including local dermal and systemic factors can modulate the regenerative behavior of hair follicles, and may be relatively easy therapeutic targets. (4) Follicular neogenesis means the de novo formation of new follicles. In addition, scientists are working to engineer hair follicles, which require hair forming competent epidermal cells and hair inducing dermal cells. Expert opinion Ideally self-organizing processes similar to those occurring during embryonic development should be elicited with some help from biomaterials. PMID:23289545

  2. Caspase-3 short hairpin RNAs: a potential therapeutic agent in neurodegeneration of aluminum-exposed animal model.

    PubMed

    Zhang, Qinli; Li, Na; Jiao, Xia; Qin, Xiujun; Kaur, Ramanjit; Lu, Xiaoting; Song, Jing; Wang, Linping; Wang, Junming; Niu, Qiao

    2014-01-01

    There is abundant evidence supporting the role of caspases in the development of neurodegenerative disease, including Alzheimer's disease (AD). Therefore, regulating the activity of caspases has been considered as a therapeutic target. However, all the efforts on AD therapy using pan-caspase inhibitors have failed because of uncontrolled adverse effects. Alternatively, the specific knockdown of caspase-3 gene through RNA interference (RNAi) could serve as a future potential therapeutic strategy. The aim of the present study is to down-regulate the expression of caspase-3 gene using lentiviral vector-mediated caspase-3 short hairpin RNA (LV-Caspase-3 shRNA). The effect of LV-Caspase-3 shRNA on apoptosis induced by aluminum (Al) was investigated in primary cultured cortical neurons and validated in C57BL/6J mice. The results indicated an increase in apoptosis and caspase-3 expression in primary cultured neurons and the cortex ofmice exposed to Al, which could be down-regulated by LV-Caspase-3 shRNA. Furthermore, LV-Caspase-3 shRNA reduced neural cell death and improved learning and memory in C57BL/6J mice treated with Al. Our results suggest that LV-caspase-3 shRNA is a potential therapeutic agent to prevent neurodegeneration and cognitive dysfunction in aluminum- exposed animal models. The findings provide a rational gene therapy strategy for AD. PMID:25387335

  3. Cell adhesion antagonists: therapeutic potential in asthma and chronic obstructive pulmonary disease.

    PubMed

    Woodside, Darren G; Vanderslice, Peter

    2008-01-01

    Chronic obstructive pulmonary disease (COPD) and asthma are inflammatory diseases of the lung where a hallmark feature is excessive leukocyte infiltration that leads to tissue injury. Cell adhesion molecules (e.g. selectins and integrins) play a key role in cell trafficking, and in the lung they regulate leukocyte extravasation, migration within the interstitium, cellular activation, and tissue retention. All selectin family members (including L-selectin, P-selectin, and E-selectin) and many of the beta1 and beta2 integrins appear to be important therapeutic targets, as numerous animal studies have demonstrated essential roles for these cell adhesion molecules in lung inflammation. Not surprisingly, these families of adhesion molecules have been under intense investigation by the pharmaceutical industry for the development of novel therapeutics. Integrins are validated drug targets, as drugs that antagonize integrin alphaIIbbeta3 (e.g. abciximab), integrin alphaLbeta2 (efalizumab), and integrin alpha4beta1 (natalizumab) are currently US FDA-approved for acute coronary syndromes, psoriasis, and multiple sclerosis, respectively. However, none has been approved for indications related to asthma or COPD. Here, we provide an overview of roles played by selectins and integrins in lung inflammation. We also describe recent clinical results (both failures and successes) in developing adhesion molecule antagonists, with specific emphasis on those targets that may have potential benefit in asthma and COPD. Early clinical trials using selectin and integrin antagonists have met with limited success. However, recent positive phase II clinical trials with a small-molecule selectin antagonist (bimosiamose) and a small-molecule integrin alpha4beta1 antagonist (valategrast [R411]), have generated enthusiastic anticipation that novel strategies to treat asthma and COPD may be forthcoming. PMID:18345706

  4. Aerosol Droplet Delivery of Mesoporous Silica Nanoparticles: A Strategy for Respiratory-Based Therapeutics

    PubMed Central

    Li, Xueting; Xue, Min; Raabe, Otto G.; Aaron, Holly L.; Eisen, Ellen A.; Evans, James E.; Hayes, Fred A.; Inaga, Sumire; Tagmout, Abderrahmane; Takeuchi, Minoru; Vulpe, Chris; Zink, Jeffrey I.; Risbud, Subhash H.; Pinkerton, Kent E.

    2015-01-01

    A highly versatile nanoplatform that couples mesoporous silica nanoparticles (MSN) with an aerosol technology to achieve direct nanoscale delivery to the respiratory tract is described. This novel method can deposit MSN nanoparticles throughout the entire respiratory tract, including nasal, tracheobronchial and pulmonary regions using a water-based aerosol. This delivery method was successfully tested in mice by inhalation. The MSN nanoparticles used have the potential for carrying and delivering therapeutic agents to highly specific target sites of the respiratory tract. The approach provides a critical foundation for developing therapeutic treatment protocols for a wide range of diseases where aerosol delivery to the respiratory system would be desirable. PMID:25819886

  5. Hypoxia-regulated therapeutic gene as a preemptive treatment strategy against ischemia/reperfusion tissue injury

    NASA Astrophysics Data System (ADS)

    Pachori, Alok S.; Melo, Luis G.; Hart, Melanie L.; Noiseux, Nicholas; Zhang, Lunan; Morello, Fulvio; Solomon, Scott D.; Stahl, Gregory L.; Pratt, Richard E.; Dzau, Victor J.

    2004-08-01

    Ischemia and reperfusion represent major mechanisms of tissue injury and organ failure. The timing of administration and the duration of action limit current treatment approaches using pharmacological agents. In this study, we have successfully developed a preemptive strategy for tissue protection using an adenoassociated vector system containing erythropoietin hypoxia response elements for ischemia-regulated expression of the therapeutic gene human heme-oxygenase-1 (hHO-1). We demonstrate that a single administration of this vector several weeks in advance of ischemia/reperfusion injury to multiple tissues such as heart, liver, and skeletal muscle yields rapid and timely induction of hHO-1 during ischemia that resulted in dramatic reduction in tissue damage. In addition, overexpression of therapeutic transgene prevented long-term pathological tissue remodeling and normalized tissue function. Application of this regulatable system using an endogenous physiological stimulus for expression of a therapeutic gene may be a feasible strategy for protecting tissues at risk of ischemia/reperfusion injury.

  6. PTP1B inhibition suggests a therapeutic strategy for Rett syndrome

    PubMed Central

    Krishnan, Navasona; Krishnan, Keerthi; Connors, Christopher R.; Choy, Meng S.; Page, Rebecca; Peti, Wolfgang; Van Aelst, Linda; Shea, Stephen D.; Tonks, Nicholas K.

    2015-01-01

    The X-linked neurological disorder Rett syndrome (RTT) presents with autistic features and is caused primarily by mutations in a transcriptional regulator, methyl CpG–binding protein 2 (MECP2). Current treatment options for RTT are limited to alleviating some neurological symptoms; hence, more effective therapeutic strategies are needed. We identified the protein tyrosine phosphatase PTP1B as a therapeutic candidate for treatment of RTT. We demonstrated that the PTPN1 gene, which encodes PTP1B, was a target of MECP2 and that disruption of MECP2 function was associated with increased levels of PTP1B in RTT models. Pharmacological inhibition of PTP1B ameliorated the effects of MECP2 disruption in mouse models of RTT, including improved survival in young male (Mecp2–/y) mice and improved behavior in female heterozygous (Mecp2–/+) mice. We demonstrated that PTP1B was a negative regulator of tyrosine phosphorylation of the tyrosine kinase TRKB, the receptor for brain-derived neurotrophic factor (BDNF). Therefore, the elevated PTP1B that accompanies disruption of MECP2 function in RTT represents a barrier to BDNF signaling. Inhibition of PTP1B led to increased tyrosine phosphorylation of TRKB in the brain, which would augment BDNF signaling. This study presents PTP1B as a mechanism-based therapeutic target for RTT, validating a unique strategy for treating the disease by modifying signal transduction pathways with small-molecule drugs. PMID:26214522

  7. [Recent advances in pathogenic concepts and therapeutic strategies in Rasmussen's encephalitis].

    PubMed

    Bahi-Buisson, N; Nabbout, R; Plouin, P; Bulteau, C; Delalande, O; Hertz Pannier, L; Dulac, O; Chiron, C

    2005-04-01

    Rasmussen's encephalitis (RE) is a rare inflammatory brain disease mainly affecting children and characterised by intractable epilepsy involving a single hemisphere that undergoes progressive atrophy. RE is characterized by refractory focal seizures, often associated with epilepsia partialis continua, progressive unilateral motor defect, slow EEG activity over the entire contralateral hemisphere, with focal white matter hyperintensity and insular cortical atrophy on neuroimaging. Surgical exclusion of the affected hemisphere is the only treatment that interrupts progression of the disease. Pathogenic concepts have considered viruses, autoimmune antibodies and autoimmune cytotoxic T lymphocytes that might contribute to the initiating or perpetuating events in the central nervous system. Based on these concepts, different therapeutic strategies have been pursued, such as antiviral agents, plasmapheresis, immuno-adsorption, immunosuppression or immunomodulation with intravenous immunoglobulins. However, due to the lack of large studies, to date there is no established therapeutic strategy for this devastating condition. In this review, we give an overview of the current state of immunopathogenic concepts for Rasmussen's encephalitis and discuss the different therapeutic options for future perspectives. PMID:15924075

  8. PTP1B inhibition suggests a therapeutic strategy for Rett syndrome.

    PubMed

    Krishnan, Navasona; Krishnan, Keerthi; Connors, Christopher R; Choy, Meng S; Page, Rebecca; Peti, Wolfgang; Van Aelst, Linda; Shea, Stephen D; Tonks, Nicholas K

    2015-08-01

    The X-linked neurological disorder Rett syndrome (RTT) presents with autistic features and is caused primarily by mutations in a transcriptional regulator, methyl CpG-binding protein 2 (MECP2). Current treatment options for RTT are limited to alleviating some neurological symptoms; hence, more effective therapeutic strategies are needed. We identified the protein tyrosine phosphatase PTP1B as a therapeutic candidate for treatment of RTT. We demonstrated that the PTPN1 gene, which encodes PTP1B, was a target of MECP2 and that disruption of MECP2 function was associated with increased levels of PTP1B in RTT models. Pharmacological inhibition of PTP1B ameliorated the effects of MECP2 disruption in mouse models of RTT, including improved survival in young male (Mecp2-/y) mice and improved behavior in female heterozygous (Mecp2-/+) mice. We demonstrated that PTP1B was a negative regulator of tyrosine phosphorylation of the tyrosine kinase TRKB, the receptor for brain-derived neurotrophic factor (BDNF). Therefore, the elevated PTP1B that accompanies disruption of MECP2 function in RTT represents a barrier to BDNF signaling. Inhibition of PTP1B led to increased tyrosine phosphorylation of TRKB in the brain, which would augment BDNF signaling. This study presents PTP1B as a mechanism-based therapeutic target for RTT, validating a unique strategy for treating the disease by modifying signal transduction pathways with small-molecule drugs. PMID:26214522

  9. Hypoxia-regulated therapeutic gene as a preemptive treatment strategy against ischemia/reperfusion tissue injury.

    PubMed

    Pachori, Alok S; Melo, Luis G; Hart, Melanie L; Noiseux, Nicholas; Zhang, Lunan; Morello, Fulvio; Solomon, Scott D; Stahl, Gregory L; Pratt, Richard E; Dzau, Victor J

    2004-08-17

    Ischemia and reperfusion represent major mechanisms of tissue injury and organ failure. The timing of administration and the duration of action limit current treatment approaches using pharmacological agents. In this study, we have successfully developed a preemptive strategy for tissue protection using an adenoassociated vector system containing erythropoietin hypoxia response elements for ischemia-regulated expression of the therapeutic gene human heme-oxygenase-1 (hHO-1). We demonstrate that a single administration of this vector several weeks in advance of ischemia/reperfusion injury to multiple tissues such as heart, liver, and skeletal muscle yields rapid and timely induction of hHO-1 during ischemia that resulted in dramatic reduction in tissue damage. In addition, overexpression of therapeutic transgene prevented long-term pathological tissue remodeling and normalized tissue function. Application of this regulatable system using an endogenous physiological stimulus for expression of a therapeutic gene may be a feasible strategy for protecting tissues at risk of ischemia/reperfusion injury. PMID:15302924

  10. Skeletal muscle atrophy: Potential therapeutic agents and their mechanisms of action.

    PubMed

    Dutt, Vikas; Gupta, Sanjeev; Dabur, Rajesh; Injeti, Elisha; Mittal, Ashwani

    2015-09-01

    Over the last two decades, new insights into the etiology of skeletal muscle wasting/atrophy under diverse clinical settings including denervation, AIDS, cancer, diabetes, and chronic heart failure have been reported in the literature. However, the treatment of skeletal muscle wasting remains an unresolved challenge to this day. About nineteen potential drugs that can regulate loss of muscle mass have been reported in the literature. This paper reviews the mechanisms of action of all these drugs by broadly classifying them into six different categories. Mechanistic data of these drugs illustrate that they regulate skeletal muscle loss either by down-regulating myostatin, cyclooxygenase2, pro-inflammatory cytokines mediated catabolic wasting or by up-regulating cyclic AMP, peroxisome proliferator-activated receptor gamma coactivator-1α, growth hormone/insulin-like growth factor1, phosphatidylinositide 3-kinases/protein kinase B(Akt) mediated anabolic pathways. So far, five major proteolytic systems that regulate loss of muscle mass have been identified, but the majority of these drugs control only two or three proteolytic systems. In addition to their beneficial effect on restoring the muscle loss, many of these drugs show some level of toxicity and unwanted side effects such as dizziness, hypertension, and constipation. Therefore, further research is needed to understand and develop treatment strategies for muscle wasting. For successful management of skeletal muscle wasting either therapeutic agent which regulates all five known proteolytic systems or new molecular targets/proteolytic systems must be identified. PMID:26048279

  11. Specific quorum sensing-disrupting activity (A QSI) of thiophenones and their therapeutic potential.

    PubMed

    Yang, Qian; Scheie, Anne Aamdal; Benneche, Tore; Defoirdt, Tom

    2015-01-01

    Disease caused by antibiotic resistant pathogens is becoming a serious problem, both in human and veterinary medicine. The inhibition of quorum sensing, bacterial cell-to-cell communication, is a promising alternative strategy to control disease. In this study, we determined the quorum sensing-disrupting activity of 20 thiophenones towards the quorum sensing model bacterium V. harveyi. In order to exclude false positives, we propose a new parameter (AQSI) to describe specific quorum sensing activity. AQSI is defined as the ratio between inhibition of quorum sensing-regulated activity in a reporter strain and inhibition of the same activity when it is independent of quorum sensing. Calculation of AQSI allowed to exclude five false positives, whereas the six most active thiophenones (TF203, TF307, TF319, TF339, TF342 and TF403) inhibited quorum sensing at 0.25 μM, with AQSI higher than 10. Further, we determined the protective effect and toxicity of the thiophenones in a highly controlled gnotobiotic model system with brine shrimp larvae. There was a strong positive correlation between the specific quorum sensing-disrupting activity of the thiophenones and the protection of brine shrimp larvae against pathogenic V. harveyi. Four of the most active quorum sensing-disrupting thiophenones (TF 203, TF319, TF339 and TF342) were considered to be promising since they have a therapeutic potential of at least 10. PMID:26647822

  12. Specific quorum sensing-disrupting activity (AQSI) of thiophenones and their therapeutic potential

    PubMed Central

    Yang, Qian; Aamdal Scheie, Anne; Benneche, Tore; Defoirdt, Tom

    2015-01-01

    Disease caused by antibiotic resistant pathogens is becoming a serious problem, both in human and veterinary medicine. The inhibition of quorum sensing, bacterial cell-to-cell communication, is a promising alternative strategy to control disease. In this study, we determined the quorum sensing-disrupting activity of 20 thiophenones towards the quorum sensing model bacterium V. harveyi. In order to exclude false positives, we propose a new parameter (AQSI) to describe specific quorum sensing activity. AQSI is defined as the ratio between inhibition of quorum sensing-regulated activity in a reporter strain and inhibition of the same activity when it is independent of quorum sensing. Calculation of AQSI allowed to exclude five false positives, whereas the six most active thiophenones (TF203, TF307, TF319, TF339, TF342 and TF403) inhibited quorum sensing at 0.25 μM, with AQSI higher than 10. Further, we determined the protective effect and toxicity of the thiophenones in a highly controlled gnotobiotic model system with brine shrimp larvae. There was a strong positive correlation between the specific quorum sensing-disrupting activity of the thiophenones and the protection of brine shrimp larvae against pathogenic V. harveyi. Four of the most active quorum sensing-disrupting thiophenones (TF 203, TF319, TF339 and TF342) were considered to be promising since they have a therapeutic potential of at least 10. PMID:26647822

  13. Myelin Basic Protein Citrullination in Multiple Sclerosis: A Potential Therapeutic Target for the Pathology.

    PubMed

    Yang, Lei; Tan, Dewei; Piao, Hua

    2016-08-01

    Multiple sclerosis (MS) is a multifactorial demyelinating disease characterized by neurodegenerative events and autoimmune response against myelin component. Citrullination or deimination, a post-translational modification of protein-bound arginine into citrulline, catalyzed by Ca(2+) dependent peptidylarginine deiminase enzyme (PAD), plays an essential role in physiological processes include gene expression regulation, apoptosis and the plasticity of the central nervous system, while aberrant citrullination can generate new epitopes, thus involving in the initiation and/or progression of autoimmune disorder like MS. Myelin basic protein (MBP) is the major myelin protein and is generally considered to maintain the stability of the myelin sheath. This review describes the MBP citrullination and its consequence, as well as offering further support for the "inside-out" hypothesis that MS is primarily a neurodegenerative disease with secondary inflammatory demyelination. In addition, it discusses the role of MBP citrullination in the immune inflammation and explores the potential of inhibition of PAD enzymes as a therapeutic strategy for the disease. PMID:27097548

  14. Skeletal Muscle MicroRNAs: Their Diagnostic and Therapeutic Potential in Human Muscle Diseases

    PubMed Central

    Alexander, Matthew S.; Kunkel, Louis M.

    2016-01-01

    MicroRNAs (miRNAs) are small 21–24 nucleotide RNAs that are capable of regulating multiple signaling pathways across multiple tissues. MicroRNAs are dynamically regulated and change in expression levels during periods of early development, tissue regeneration, cancer, and various other disease states. Recently, microRNAs have been isolated from whole serum and muscle biopsies to identify unique diagnostic signatures for specific neuromuscular disease states. Functional studies of microRNAs in cell lines and animal models of neuromuscular diseases have elucidated their importance in contributing to neuromuscular disease progression and pathologies. The ability of microRNAs to alter the expression of an entire signaling pathway opens up their unique ability to be used as potential therapeutic entry points for the treatment of disease. Here, we will review the recent findings of key microRNAs and their dysregulation in various neuromuscular diseases. Additionally, we will highlight the current strategies being used to regulate the expression of key microRNAs as they have become important players in the clinical treatment of some of the neuromuscular diseases.

  15. Preventive or Potential Therapeutic Value of Nutraceuticals against Ionizing Radiation-Induced Oxidative Stress in Exposed Subjects and Frequent Fliers

    PubMed Central

    Giardi, Maria Teresa; Touloupakis, Eleftherios; Bertolotto, Delfina; Mascetti, Gabriele

    2013-01-01

    Humans are constantly exposed to ionizing radiation deriving from outer space sources or activities related to medical care. Absorption of ionizing radiation doses over a prolonged period of time can result in oxidative damage and cellular dysfunction inducing several diseases, especially in ageing subjects. In this report, we analyze the effects of ionizing radiation, particularly at low doses, in relation to a variety of human pathologies, including cancer, and cardiovascular and retinal diseases. We discuss scientific data in support of protection strategies by safe antioxidant formulations that can provide preventive or potential therapeutic value in response to long-term diseases that may develop following exposure. PMID:23965979

  16. MicroRNAs as potential novel therapeutic targets and tools for regulating paracrine function of endothelial progenitor cells

    PubMed Central

    Xu, Shengjie; Jin, Chongying; Shen, Xiaohua; Ding, Fang; Zhu, Junhui; Fu, Guosheng

    2012-01-01

    Summary Endothelial progenitor cells (EPCs) play a protective role in the cardiovascular system by enhancing the maintenance of endothelium homeostasis and the process of new vessel formation. Recent studies show that EPCs may induce vascular regeneration and neovascularization mainly through paracrine signaling, that is, through the secretion of growth factors and pro-angiogenic cytokines [1]. However, multiple factors might function synergistically and therefore make it difficult to manipulate EPC paracrine effects. MicroRNAs, a family of small, non-coding RNAs, are characterized by post-transcriptionally regulating multiple functionally related genes, which renders them potentially powerful therapeutic targets or tools. In this paper we propose the hypothesis that microRNAs can be utilized as a novel therapeutic strategy for regulating EPC paracrine secretion. PMID:22739741

  17. Bioprospecting the Curculigoside-Cinnamic Acid-Rich Fraction from Molineria latifolia Rhizome as a Potential Antioxidant Therapeutic Agent.

    PubMed

    Ooi, Der Jiun; Chan, Kim Wei; Sarega, Nadarajan; Alitheen, Noorjahan Banu; Ithnin, Hairuszah; Ismail, Maznah

    2016-01-01

    Increasing evidence from both experimental and clinical studies depicts the involvement of oxidative stress in the pathogenesis of various diseases. Specifically, disruption of homeostatic redox balance in accumulated body fat mass leads to obesity-associated metabolic syndrome. Strategies for the restoration of redox balance, potentially by exploring potent plant bioactives, have thus become the focus of therapeutic intervention. The present study aimed to bioprospect the potential use of the curculigoside-cinnamic acid-rich fraction from Molineria latifolia rhizome as an antioxidant therapeutic agent. The ethyl acetate fraction (EAF) isolated from M. latifolia rhizome methanolic extract (RME) contained the highest amount of phenolic compounds, particularly curculigoside and cinnamic acid. EAF demonstrated glycation inhibitory activities in both glucose- and fructose-mediated glycation models. In addition, in vitro chemical-based and cellular-based antioxidant assays showed that EAF exhibited high antioxidant activities and a protective effect against oxidative damage in 3T3-L1 preadipocytes. Although the efficacies of individual phenolics differed depending on the structure and concentration, a correlational study revealed strong correlations between total phenolic contents and antioxidant capacities. The results concluded that enriched phenolic contents in EAF (curculigoside-cinnamic acid-rich fraction) contributed to the overall better reactivity. Our data suggest that this bioactive-rich fraction warrants therapeutic potential against oxidative stress-related disorders. PMID:27322226

  18. The arsenal of pathogens and antivirulence therapeutic strategies for disarming them

    PubMed Central

    Brannon, John R; Hadjifrangiskou, Maria

    2016-01-01

    Pathogens deploy an arsenal of virulence factors (VFs) to establish themselves within their infectious niche. The discovery of antimicrobial compounds and their development into therapeutics has made a monumental impact on human and microbial populations. Although humans have used antimicrobials for medicinal and agricultural purposes, microorganism populations have developed and shared resistance mechanisms to persevere in the face of classical antimicrobials. However, a positive substitute is antivirulence therapy; antivirulence therapeutics prevent or interrupt an infection by counteracting a pathogen’s VFs. Their application can reduce the use of broad-spectrum antimicrobials and dampen the frequency with which resistant strains emerge. Here, we summarize the contribution of VFs to various acute and chronic infections. In correspondence with this, we provide an overview of the research and development of antivirulence strategies. PMID:27313446

  19. Peroxisome Proliferator-Activated Receptor Ligands and Their Role in Chronic Myeloid Leukemia: Therapeutic Strategies.

    PubMed

    Yousefi, Bahman; Samadi, Nasser; Baradaran, Behzad; Shafiei-Irannejad, Vahid; Zarghami, Nosratollah

    2016-07-01

    Imatinib therapy remains the gold standard for treatment of chronic myeloid leukemia; however, the acquired resistance to this therapeutic agent in patients has urged the scientists to devise modalities for overcoming this chemoresistance. For this purpose, initially therapeutic agents with higher tyrosine kinase activity were introduced, which had the potential for inhibiting even mutant forms of Bcr-Abl. Furthermore, coupling imatinib with peroxisome proliferator-activated receptor ligands also showed beneficial effects in chronic myeloid leukemia cell proliferation. These combination protocols inhibited cell growth and induced apoptosis as well as differentiation in chronic myeloid leukemia cell lines. In addition, peroxisome proliferator-activated receptors ligands increased imatinib uptake by upregulating the expression of human organic cation transporter 1. Taken together, peroxisome proliferator-activated receptors ligands are currently being considered as novel promising therapeutic candidates for chronic myeloid leukemia treatment, because they can synergistically enhance the efficacy of imatinib. In this article, we reviewed the potential of peroxisome proliferator-activated receptors ligands for use in chronic myeloid leukemia treatment. The mechanism of action of these therapeutics modalities are also presented in detail. PMID:26841308

  20. Age-related deficits in voluntary control over saccadic eye movements: consideration of electrical brain stimulation as a therapeutic strategy.

    PubMed

    Chen, Po Ling; Machado, Liana

    2016-05-01

    Sudden changes in our visual environment trigger reflexive eye movements, so automatically they often go unnoticed. Consequently, voluntary control over reflexive eye movements entails considerable effort. In relation to frontal-lobe deterioration, adult aging adversely impacts voluntary saccadic eye movement control in particular, which compromises effective performance of daily activities. Here, we review the nature of age-related changes in saccadic control, focusing primarily on the antisaccade task because of its assessment of 2 key age-sensitive control functions: reflexive saccade inhibition and voluntary saccade generation. With an ultimate view toward facilitating development of therapeutic strategies, we systematically review the neuroanatomy underpinning voluntary control over saccadic eye movements and natural mechanisms that kick in to compensate for age-related declines. We then explore the potential of noninvasive electrical brain stimulation to counteract aging deficits. Based on evidence that anodal transcranial direct current stimulation can confer a range of benefits specifically relevant to aging brains, we put forward this neuromodulation technique as a therapeutic strategy for improving voluntary saccadic eye movement control in older adults. PMID:27103518

  1. Multitarget strategies in Alzheimer's disease: benefits and challenges on the road to therapeutics.

    PubMed

    Rosini, Michela; Simoni, Elena; Caporaso, Roberta; Minarini, Anna

    2016-04-01

    Alzheimer's disease is a multifactorial syndrome, for which effective cures are urgently needed. Seeking for enhanced therapeutic efficacy, multitarget drugs have been increasingly sought after over the last decades. They offer the attractive prospect of tackling intricate network effects, but with the benefits of a single-molecule therapy. Herein, we highlight relevant progress in the field, focusing on acetylcholinesterase inhibition and amyloid pathways as two pivotal features in multitarget design strategies. We also discuss the intertwined relationship between selected molecular targets and give a brief glimpse into the power of multitarget agents as pharmacological probes of Alzheimer's disease molecular mechanisms. PMID:27079260

  2. Molecular basis and current strategies of therapeutic arginine depletion for cancer.

    PubMed

    Fultang, Livingstone; Vardon, Ashley; De Santo, Carmela; Mussai, Francis

    2016-08-01

    Renewed interest in the use of therapeutic enzymes combined with an improved knowledge of cancer cell metabolism, has led to the translation of several arginine depletion strategies into early phase clinical trials. Arginine auxotrophic tumors are reliant on extracellular arginine, due to the downregulation of arginosuccinate synthetase or ornithine transcarbamylase-key enzymes for intracellular arginine recycling. Engineered arginine catabolic enzymes such as recombinant human arginase (rh-Arg1-PEG) and arginine deiminase (ADI-PEG) have demonstrated cytotoxicity against arginine auxotrophic tumors. In this review, we discuss the molecular events triggered by extracellular arginine depletion that contribute to tumor cell death. PMID:26913960

  3. Inertial fusion: strategy and economic potential

    SciTech Connect

    Nuckolls, J.H.

    1983-01-01

    Inertial fusion must demonstrate that the high target gains required for practical fusion energy can be achieved with driver energies not larger than a few megajoules. Before a multi-megajoule scale driver is constructed, inertial fusion must provide convincing experimental evidence that the required high target gains are feasible. This will be the principal objective of the NOVA laser experiments. Implosions will be conducted with scaled targets which are nearly hydrodynamically equivalent to the high gain target implosions. Experiments which demonstrate high target gains will be conducted in the early nineties when multi-megajoule drivers become available. Efficient drivers will also be demonstrated by this time period. Magnetic fusion may demonstrate high Q at about the same time as inertial fusion demonstrates high gain. Beyond demonstration of high performance fusion, economic considerations will predominate. Fusion energy will achieve full commercial success when it becomes cheaper than fission and coal. Analysis of the ultimate economic potential of inertial fusion suggests its costs may be reduced to half those of fission and coal. Relative cost escalation would increase this advantage. Fusions potential economic advantage derives from two fundamental properties: negligible fuel costs and high quality energy (which makes possible more efficient generation of electricity).

  4. Microencapsulation technology by nature: Cell derived extracellular vesicles with therapeutic potential.

    PubMed

    Kittel, A; Falus, A; Buzás, E

    2013-06-01

    Cell derived extracellular vesicles are submicron structures surrounded by phospholipid bilayer and released by both prokaryotic and eukaryotic cells. The sizes of these vesicles roughly fall into the size ranges of microbes, and they represent efficient delivery platforms targeting complex molecular information to professional antigen presenting cells. Critical roles of these naturally formulated units of information have been described in many physiological and pathological processes. Extracellular vesicles are not only potential biomarkers and possible pathogenic factors in numerous diseases, but they are also considered as emerging therapeutic targets and therapeutic vehicles. Strikingly, current drug delivery systems, designed to convey therapeutic proteins and peptides (such as liposomes), show many similarities to extracellular vesicles. Here we review some aspects of therapeutic implementation of natural, cell-derived extracellular vesicles in human diseases. Exploration of molecular and functional details of extracellular vesicle release and action may provide important lessons for the design of future drug delivery systems. PMID:24265924

  5. Microencapsulation technology by nature: Cell derived extracellular vesicles with therapeutic potential

    PubMed Central

    Falus, A.; Buzás, E.

    2013-01-01

    Cell derived extracellular vesicles are submicron structures surrounded by phospholipid bilayer and released by both prokaryotic and eukaryotic cells. The sizes of these vesicles roughly fall into the size ranges of microbes, and they represent efficient delivery platforms targeting complex molecular information to professional antigen presenting cells. Critical roles of these naturally formulated units of information have been described in many physiological and pathological processes. Extracellular vesicles are not only potential biomarkers and possible pathogenic factors in numerous diseases, but they are also considered as emerging therapeutic targets and therapeutic vehicles. Strikingly, current drug delivery systems, designed to convey therapeutic proteins and peptides (such as liposomes), show many similarities to extracellular vesicles. Here we review some aspects of therapeutic implementation of natural, cell-derived extracellular vesicles in human diseases. Exploration of molecular and functional details of extracellular vesicle release and action may provide important lessons for the design of future drug delivery systems. PMID:24265924

  6. Therapeutic potential and functional interaction of carfilzomib and vorinostat in T-cell leukemia/lymphoma.

    PubMed

    Gao, Minjie; Chen, Gege; Wang, Houcai; Xie, Bingqian; Hu, Liangning; Kong, Yuanyuan; Yang, Guang; Tao, Yi; Han, Ying; Wu, Xiaosong; Zhang, Yiwen; Dai, Bojie; Shi, Jumei

    2016-05-17

    We previously showed that the proteasome inhibitor carfilzomib and the histone deacetylase inhibitor (HDACI) vorinostat cooperated to induce cell apoptosis in one T-cell leukemia cell line in vitro, implying the possibility of the combination treatment of carfilzomib and vorinostat as a potential therapeutic strategy in human T-cell leukemia/lymphoma. Here we report that combination treatment of carfilzomib and vorinostat enhanced cell apoptosis and induced a marked increase in G2-M arrest, reactive oxygen species (ROS) generation, and activated the members of mitogen-activated protein kinases (MAPK) family, including the stress-activated kinases JNK, p38MAPK, and ERK1/2. Carfilzomib/vorinostat-mediated apoptosis was blocked by the ROS scavenger N-acetylcysteine (NAC). The JNK inhibitor SP600125 and the p38MAPK inhibitor SB203580 but not the MEK1/2 inhibitor U0126 significantly attenuated carfilzomib/vorinostat-induced apoptosis, suggesting that p38MAPK and JNK activation contribute to carfilzomib and vorinostat-induced apoptosis. This was further confirmed via short hairpin (shRNA) RNA knockdown of p38MAPK and JNK. Interestingly, the ROS scavenger NAC attenuated carfilzomib/vorinostat-mediated activation of p38MAPK and JNK. However, p38MAPK shRNA but not JNK shRNA diminished carfilzomib/vorinostat-mediated ROS generation. In contrast, overexpression of p38MAPK significantly increased carfilzomib/vorinostat-mediated ROS generation, suggesting that an amplification loop exists between ROS and p38MAPK pathway. Combination treatment of carfilzomib and vorinostat enhanced their individual antitumor activity in both a human xenograft model as well as human primary T-cell leukemia/lymphoma cells. These data suggest the potential clinical benefit and underlying molecular mechanism of combining carfilzomib with vorinostat in the treatment of human T-cell leukemia/lymphoma. PMID:27074555

  7. Superparamagnetic iron oxide nanoparticles: diagnostic magnetic resonance imaging and potential therapeutic applications in neurooncology and central nervous system inflammatory pathologies, a review

    PubMed Central

    Weinstein, Jason S; Varallyay, Csanad G; Dosa, Edit; Gahramanov, Seymur; Hamilton, Bronwyn; Rooney, William D; Muldoon, Leslie L; Neuwelt, Edward A

    2010-01-01

    Superparamagnetic iron oxide nanoparticles have diverse diagnostic and potential therapeutic applications in the central nervous system (CNS). They are useful as magnetic resonance imaging (MRI) contrast agents to evaluate: areas of blood–brain barrier (BBB) dysfunction related to tumors and other neuroinflammatory pathologies, the cerebrovasculature using perfusion-weighted MRI sequences, and in vivo cellular tracking in CNS disease or injury. Novel, targeted, nanoparticle synthesis strategies will allow for a rapidly expanding range of applications in patients with brain tumors, cerebral ischemia or stroke, carotid atherosclerosis, multiple sclerosis, traumatic brain injury, and epilepsy. These strategies may ultimately improve disease detection, therapeutic monitoring, and treatment efficacy especially in the context of antiangiogenic chemotherapy and antiinflammatory medications. The purpose of this review is to outline the current status of superparamagnetic iron oxide nanoparticles in the context of biomedical nanotechnology as they apply to diagnostic MRI and potential therapeutic applications in neurooncology and other CNS inflammatory conditions. PMID:19756021

  8. HIV-1 Latency: An Update of Molecular Mechanisms and Therapeutic Strategies

    PubMed Central

    Battistini, Angela; Sgarbanti, Marco

    2014-01-01

    The major obstacle towards HIV-1 eradication is the life-long persistence of the virus in reservoirs of latently infected cells. In these cells the proviral DNA is integrated in the host’s genome but it does not actively replicate, becoming invisible to the host immune system and unaffected by existing antiviral drugs. Rebound of viremia and recovery of systemic infection that follows interruption of therapy, necessitates life-long treatments with problems of compliance, toxicity, and untenable costs, especially in developing countries where the infection hits worst. Extensive research efforts have led to the proposal and preliminary testing of several anti-latency compounds, however, overall, eradication strategies have had, so far, limited clinical success while posing several risks for patients. This review will briefly summarize the more recent advances in the elucidation of mechanisms that regulates the establishment/maintenance of latency and therapeutic strategies currently under evaluation in order to eradicate HIV persistence. PMID:24736215

  9. Bioactive factor delivery strategies from engineered polymer hydrogels for therapeutic medicine.

    PubMed

    Nguyen, Minh Khanh; Alsberg, Eben

    2014-07-01

    Polymer hydrogels have been widely explored as therapeutic delivery matrices because of their ability to present sustained, localized and controlled release of bioactive factors. Bioactive factor delivery from injectable biopolymer hydrogels provides a versatile approach to treat a wide variety of diseases, to direct cell function and to enhance tissue regeneration. The innovative development and modification of both natural-(e.g., alginate (ALG), chitosan, hyaluronic acid (HA), gelatin, heparin (HEP), etc.) and synthetic-(e.g., polyesters, polyethyleneimine (PEI), etc.) based polymers has resulted in a variety of approaches to design drug delivery hydrogel systems from which loaded therapeutics are released. This review presents the state-of-the-art in a wide range of hydrogels that are formed though self-assembly of polymers and peptides, chemical crosslinking, ionic crosslinking and biomolecule recognition. Hydrogel design for bioactive factor delivery is the focus of the first section. The second section then thoroughly discusses release strategies of payloads from hydrogels for therapeutic medicine, such as physical incorporation, covalent tethering, affinity interactions, on demand release and/or use of hybrid polymer scaffolds, with an emphasis on the last 5 years. PMID:25242831

  10. Bone and brain metastasis in lung cancer: recent advances in therapeutic strategies

    PubMed Central

    Passaro, Antonio; Gori, Bruno; Del Signore, Ester; Migliorino, Maria Rita; Ricciardi, Serena; Fulvi, Alberto; de Marinis, Filippo

    2014-01-01

    Bone and brain metastases are a very common secondary localization of disease in patients with lung cancer. The prognosis of these patients is still poor with a median survival of less than 1 year. Current therapeutic approaches include palliative radiotherapy and systemic therapy with chemotherapy and targeted agents. For bone metastasis, zoledronic acid is the most commonly used bisphosphonate to prevent, reduce the incidence and delay the onset of skeletal-related events (SREs). Recently, denosumab, a fully human monoclonal antibody directed against the receptor activator of nuclear factor κB (RANK) ligand inhibiting the maturation of pre-osteoclasts into osteoclasts, showed increased time to SREs and overall survival compared with zoledronic acid. The treatment of brain metastasis is still controversial. Available standard therapeutic options, such as whole brain radiation therapy and systemic chemotherapy, provide a slight improvement in local control, overall survival and symptom relief. More recently, novel target agents such as the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) erlotinib, gefitinib and afatinib have shown activity in patients with brain metastasis. Inter alia, in patients harboring EGFR mutations, the administration of EGFR TKIs is followed by a response rate of 70–80%, and a longer progression-free and overall survival than those obtained with standard chemotherapeutic regimens. This review is focused on the evidence for therapeutic strategies in bone and brain metastases due to lung cancer. PMID:24790650

  11. Hepatic macrophages in homeostasis and liver diseases: from pathogenesis to novel therapeutic strategies

    PubMed Central

    Ju, Cynthia; Tacke, Frank

    2016-01-01

    Macrophages represent a major cell type of innate immunity and have emerged as a critical player and therapeutic target in many chronic inflammatory diseases. Hepatic macrophages consist of Kupffer cells, which are originated from the fetal yolk-sack, and infiltrated bone marrow-derived monocytes/macrophages. Hepatic macrophages play a central role in maintaining homeostasis of the liver and in the pathogenesis of liver injury, making them an attractive therapeutic target for liver diseases. However, the various populations of hepatic macrophages display different phenotypes and exert distinct functions. Thus, more research is required to better understand these cells to guide the development of macrophage-based therapeutic interventions. This review article will summarize the current knowledge on the origins and composition of hepatic macrophages, their functions in maintaining hepatic homeostasis, and their involvement in both promoting and resolving liver inflammation, injury, and fibrosis. Finally, the current strategies being developed to target hepatic macrophages for the treatment of liver diseases will be reviewed. PMID:26908374

  12. Mechanisms of drug resistance in colon cancer and its therapeutic strategies

    PubMed Central

    Hu, Tao; Li, Zhen; Gao, Chun-Ying; Cho, Chi Hin

    2016-01-01

    Drug resistance develops in nearly all patients with colon cancer, leading to a decrease in the therapeutic efficacies of anticancer agents. This review provides an up-to-date summary on over-expression of ATP-binding cassette (ABC) transporters and evasion of apoptosis, two representatives of transport-based and non-transport-based mechanisms of drug resistance, as well as their therapeutic strategies. Different ABC transporters were found to be up-regulated in colon cancer, which can facilitate the efflux of anticancer drugs out of cancer cells and decrease their therapeutic effects. Inhibition of ABC transporters by suppressing their protein expressions or co-administration of modulators has been proven as an effective approach to sensitize drug-resistant cancer cells to anticancer drugs in vitro. On the other hand, evasion of apoptosis observed in drug-resistant cancers also results in drug resistance to anticancer agents, especially to apoptosis inducers. Restoration of apoptotic signals by BH3 mimetics or epidermal growth factor receptor inhibitors and inhibition of cancer cell growth by alternative cell death pathways, such as autophagy, are effective means to treat such resistant cancer types. Given that the drug resistance mechanisms are different among colon cancer patients and may change even in a single patient at different stages, personalized and specific combination therapy is proposed to be more effective and safer for the reversal of drug resistance in clinics. PMID:27570424

  13. Bioactive factor delivery strategies from engineered polymer hydrogels for therapeutic medicine

    PubMed Central

    Nguyen, Minh Khanh; Alsberg, Eben

    2014-01-01

    Polymer hydrogels have been widely explored as therapeutic delivery matrices because of their ability to present sustained, localized and controlled release of bioactive factors. Bioactive factor delivery from injectable biopolymer hydrogels provides a versatile approach to treat a wide variety of diseases, to direct cell function and to enhance tissue regeneration. The innovative development and modification of both natural-(e.g., alginate (ALG), chitosan, hyaluronic acid (HA), gelatin, heparin (HEP), etc.) and synthetic-(e.g., polyesters, polyethyleneimine (PEI), etc.) based polymers has resulted in a variety of approaches to design drug delivery hydrogel systems from which loaded therapeutics are released. This review presents the state-of-the-art in a wide range of hydrogels that are formed though self-assembly of polymers and peptides, chemical crosslinking, ionic crosslinking and biomolecule recognition. Hydrogel design for bioactive factor delivery is the focus of the first section. The second section then thoroughly discusses release strategies of payloads from hydrogels for therapeutic medicine, such as physical incorporation, covalent tethering, affinity interactions, on demand release and/or use of hybrid polymer scaffolds, with an emphasis on the last 5 years. PMID:25242831

  14. Simultaneous suppression of the MAP kinase and NF-κB pathways provides a robust therapeutic potential for thyroid cancer.

    PubMed

    Tsumagari, Koji; Abd Elmageed, Zakaria Y; Sholl, Andrew B; Friedlander, Paul; Abdraboh, Mohamed; Xing, Mingzhao; Boulares, A Hamid; Kandil, Emad

    2015-11-01

    The MAP kinase and NF-κB signaling pathways play an important role in thyroid cancer tumorigenesis. We aimed to examine the therapeutic potential of dually targeting the two pathways using AZD6244 and Bortezomib in combination. We evaluated their effects on cell proliferation, cell-cycle progression, apoptosis, cell migration assay, and the activation of the MAPK pathway in vitro and the in vivo using tumor size and immunohistochemical changes of Ki67 and ppRB. We found inhibition of cell growth rate by 10%, 20%, and 56% (p <0.05), migration to 55%, 61%, and 29% (p <0.05), and induction of apoptosis to 10%, 15%, and 38% (p <0.05) with AZD6244, Bortezomib, or combination, respectively. Induction of cell cycle arrest occurred only with drug combination. Dual drug treatment in the xenograft model caused a 94% reduction in tumor size (p <0.05) versus 15% with AZD6244 and 34% with Bortezomib (p < 0.05) and also reduced proliferative marker Ki67, and increased pRb dephosphorylation. Our results demonstrate a robust therapeutic potential of combining AZD6244 and Bortezomib as an effective strategy to overcome drug resistance encountered in monotherapy in the treatment of thyroid cancer, strongly supporting clinical trials to further test this strategy. PMID:26208433

  15. Neuroprotective and Therapeutic Strategies against Parkinson’s Disease: Recent Perspectives

    PubMed Central

    Sarkar, Sumit; Raymick, James; Imam, Syed

    2016-01-01

    Parkinsonism is a progressive motor disease that affects 1.5 million Americans and is the second most common neurodegenerative disease after Alzheimer’s. Typical neuropathological features of Parkinson’s disease (PD) include degeneration of dopaminergic neurons located in the pars compacta of the substantia nigra that project to the striatum (nigro-striatal pathway) and depositions of cytoplasmic fibrillary inclusions (Lewy bodies) which contain ubiquitin and α-synuclein. The cardinal motor signs of PD are tremors, rigidity, slow movement (bradykinesia), poor balance, and difficulty in walking (Parkinsonian gait). In addition to motor symptoms, non-motor symptoms that include autonomic and psychiatric as well as cognitive impairments are pressing issues that need to be addressed. Several different mechanisms play an important role in generation of Lewy bodies; endoplasmic reticulum (ER) stress induced unfolded proteins, neuroinflammation and eventual loss of dopaminergic neurons in the substantia nigra of mid brain in PD. Moreover, these diverse processes that result in PD make modeling of the disease and evaluation of therapeutics against this devastating disease difficult. Here, we will discuss diverse mechanisms that are involved in PD, neuroprotective and therapeutic strategies currently in clinical trial or in preclinical stages, and impart views about strategies that are promising to mitigate PD pathology. PMID:27338353