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Sample records for potential hypokalemic agent

  1. Triuret as a Potential Hypokalemic Agent: Structure Characterization of Triuret and Triuret-Alkali Metal Adducts by Mass Spectrometric Techniques

    PubMed Central

    Palii, Sergiu P.; Contreras, Cesar S.; Steill, Jeffrey D.; Palii, Stela S.; Oomens, Jos; Eyler, John R.

    2013-01-01

    Triuret (also known as carbonyldiurea, dicarbamylurea, or 2,4-diimidotricarbonic diamide) is a byproduct of purine degradation in living organisms. An abundant triuret precursor is uric acid, whose level is altered in multiple metabolic pathologies. Triuret can be generated via urate oxidation by peroxynitrite, the latter being produced by the reaction of nitric oxide radical with superoxide radical anion. From this standpoint, an excess production of superoxide radical anions could indirectly favor triuret formation; however very little is known about the potential in vivo roles of this metabolite. Triuret’s structure is suggestive of its ability to adopt various conformations and act as a flexible ligand for metal ions. In the current study, HPLC-MS/MS, energy-resolved mass spectrometry, selected ion monitoring, collision-induced dissociation, IRMPD spectroscopy, Fourier transform-ion cyclotron resonance mass spectrometry and computational methods were employed to characterize the structure of triuret and its metal complexes, to determine the triuret-alkali metal binding motif, and to evaluate triuret affinity toward alkali metal ions, as well as its affinity for Na+ and K+ relative to other organic ligands. The most favored binding motif was determined to be a bidentate chelation of triuret with the alkali metal cation involving two carbonyl oxygens. Using the complexation selectivity method, it was observed that in solution triuret has an increased affinity for potassium ions, compared to sodium and other alkali metal ions. We propose that triuret may act as a potential hypokalemic agent under pathophysiological conditions conducive to its excessive formation and thus contribute to electrolyte disorders. The collision- or photo-induced fragmentation channels of deprotonated and protonated triuret, as well as its alkali metal adducts, are likely to mimic the triuret degradation pathways in vivo. PMID:20371222

  2. Hypokalemic periodic paralysis

    PubMed Central

    Abbas, Haider; Kothari, Nikhil; Bogra, Jaishri

    2012-01-01

    Hypokalemic periodic paralysis is a rare genetic disorder characterized by recurrent attacks of skeletal muscle weakness with associated hypokalemia which is precipitated by stress, cold, carbohydrate load, infection, glucose infusion, hypothermia, metabolic alkalosis, anesthesia, and steroids. We encountered one such incidence of prolonged recovery after general anesthesia, which on further evaluation revealed a case of hypokalemic paralysis. The key to successful management of such a patient was vigilant pre-operative evaluation, perioperative monitoring, and aggressive treatment of hypokalemia when it occurs. PMID:23833504

  3. Hypokalemic paralysis in pregnancy.

    PubMed

    Nair, A; Prashanth, M R; Indira, R; Rao, S; Javarajan, A

    2002-10-01

    Hypokalemic paralysis is an uncommon entity with varied etiology. Renal tubular acidosis is an unusual cause of this disorder. Its occurrence with pregnancy is rare. We report such a case and mention the implications of the association and review relevant literature breifly.

  4. Hypokalemic paraplegia in pregnancy.

    PubMed

    Kulkarni, Maitri; Tv, Srividya; Gopal, N

    2014-06-01

    Hypokalemic myopathy may range from numbness/weakness to complete paralysis. The aetiology may be congenital or acquired. It is characterized by acute muscular weakness with low levels of potassium (<3.5 meq/L). We present a case of 26-year-old multigravida at 36 weeks of gestation with gestational hypertension on treatment, who came with acute onset of pain, numbness and weakness of both legs which worsened following betamethasone injection. She was diagnosed to have Hypokalemic paralysis with potassium levels of 2.1 meq/L. The medical profile remitted promptly on intravenous potassium replacement. Pregnancy was continued till 37 weeks with oral potassium supplements, antihypertensives and regular monitoring of serum potassium levels. The pregnancy was terminated after 37 weeks in view of gestational hypertension. Postpartum period was uneventful, patient was discharged after two weeks when potassium levels and BP returned to normal.

  5. Hypokalemic Paraplegia in Pregnancy

    PubMed Central

    TV, Srividya; Gopal, N

    2014-01-01

    Hypokalemic myopathy may range from numbness/weakness to complete paralysis. The aetiology may be congenital or acquired. It is characterized by acute muscular weakness with low levels of potassium (<3.5 meq/L). We present a case of 26-year-old multigravida at 36 weeks of gestation with gestational hypertension on treatment, who came with acute onset of pain, numbness and weakness of both legs which worsened following betamethasone injection. She was diagnosed to have Hypokalemic paralysis with potassium levels of 2.1 meq/L. The medical profile remitted promptly on intravenous potassium replacement. Pregnancy was continued till 37 weeks with oral potassium supplements, antihypertensives and regular monitoring of serum potassium levels. The pregnancy was terminated after 37 weeks in view of gestational hypertension. Postpartum period was uneventful, patient was discharged after two weeks when potassium levels and BP returned to normal. PMID:25121034

  6. Hypokalemic quadriparesis in dengue.

    PubMed

    Mishra, Vikas; Harbada, Rishit; Sharma, Akhilesh; Mishra, Meenakshi

    2015-01-01

    Dengue infection is the leading cause of illness and death in tropical and subtropical regions of the world. The common complications associated with dengue fever are usual hematological abnormalities, shock, and organ failure. The neurological complications of dengue are uncommon. However, evidence of dengue virus neurotropism and complications has been slowly but surely rising as seen from increased literature on this subject over the last decade. We report an uncommon case of hypokalemic quadriparesis with dengue that had a favorable outcome.

  7. Hypokalemic paralysis in a professional bodybuilder.

    PubMed

    Mayr, Florian B; Domanovits, Hans; Laggner, Anton N

    2012-09-01

    Severe hypokalemia is a potentially life-threatening disorder and is associated with variable degrees of skeletal muscle weakness, even to the point of paralysis. On rare occasions, diaphragmatic paralysis from hypokalemia can lead to respiratory arrest. There may also be decreased motility of smooth muscle, manifesting with ileus or urinary retention. Rarely, severe hypokalemia may result in rhabdomyolysis. Other manifestations of severe hypokalemia include alteration of cardiac tissue excitability and conduction. Hypokalemia can produce electrocardiographic changes such as U waves, T-wave flattening, and arrhythmias, especially if the patient is taking digoxin. Common causes of hypokalemia include extrarenal potassium losses (vomiting and diarrhea) and renal potassium losses (eg, hyperaldosteronism, renal tubular acidosis, severe hyperglycemia, potassium-depleting diuretics) as well as hypokalemia due to potassium shifts (eg, insulin administration, catecholamine excess, familial periodic hypokalemic paralysis, thyrotoxic hypokalemic paralysis). Although the extent of diuretic misuse in professional bodybuilding is unknown, it may be regarded as substantial. Hence, diuretics must always be considered as a cause of hypokalemic paralysis in bodybuilders.

  8. Bacteriocins as Potential Anticancer Agents

    PubMed Central

    Kaur, Sumanpreet; Kaur, Sukhraj

    2015-01-01

    Cancer remains one of the leading causes of deaths worldwide, despite advances in its treatment and detection. The conventional chemotherapeutic agents used for the treatment of cancer have non-specific toxicity toward normal body cells that cause various side effects. Secondly, cancer cells are known to develop chemotherapy resistance in due course of treatment. Thus, the demand for novel anti-cancer agents is increasing day by day. Some of the experimental studies have reported the therapeutic potential of bacteriocins against various types of cancer cell lines. Bacteriocins are ribosomally-synthesized cationic peptides secreted by almost all groups of bacteria. Some bacteriocins have shown selective cytotoxicity toward cancer cells as compared to normal cells. This makes them promising candidates for further investigation and clinical trials. In this review article, we present the overview of the various cancer cell-specific cytotoxic bacteriocins, their mode of action and efficacies. PMID:26617524

  9. [Thyrotoxic hypokalemic periodic paralysis in patients of African descent].

    PubMed

    Maia, Morgana Lima e; Trevisam, Paula Grasiele Carvalho; Minicucci, Marcos; Mazeto, Glaucia M F S; Azevedo, Paula S

    2014-10-01

    Thyrotoxic hypokalemic periodic paralysis (THPP) is an endocrine emergency marked by recurrent attacks of muscle weakness associated with hypokalemia and thyrotoxicosis. Asiatic male patients are most often affected. On the other hand, African descents rarely present this disease. The case described shows an afrodescendant patient with hypokalemia and tetraparesis, whose diagnosis of hyperthyroidism was considered during this crisis. The THPP, although rare, is potentially lethal. Therefore, in cases of flaccid paresis crisis this diagnosis should always be considered, especially if associated with hypokalemia. In this situation, if no previous diagnosis of hyperthyroidism, this should also be regarded.

  10. [Hypokalemic periodic paralysis. A case report].

    PubMed

    Areta-Higuera, J D; Algaba-Montes, M; Oviedo-García, A Á

    2014-01-01

    Periodic paralysis is a rare disorder that causes episodes of severe muscle weakness that can be confused with other diseases, including epilepsy or myasthenia gravis. Hyperkalemic and hypokalemic paralysis are included within these diseases, the latter being divided into periodic paralysis (familial, thyrotoxic or sporadic) and non-periodic paralysis. In this regard, we present a case of familial hypokalemic periodic paralysis in an eighteen year-old female who was diagnosed with epilepsy in childhood, as well as a subclinical hypothyroidism (for which she received replacement therapy) months ago. The diagnosis was made by the anamnesis and the confirmation of hypokalemia.

  11. [Thyrotoxic hypokalemic periodic paralysis. A case report].

    PubMed

    Villar Jiménez, J; Ruiz Serrato, A E; Bautista Galán, C; Guerrero León, M Á

    2013-01-01

    Thyrotoxic hypokalemic periodic paralysis is an uncommon complication of thyrotoxicosis, characterized by attacks of generalized muscular weakness associated with hypokalemia in patients with hyperthyroidism, most frequently with Graves-Basedow disease. Treatment with antithyroid drugs and potassium supplements reversed the symptoms and the episodes of acute muscular weakness did not reappear.

  12. Baking soda pica: a case of hypokalemic metabolic alkalosis and rhabdomyolysis in pregnancy.

    PubMed

    Grotegut, Chad A; Dandolu, Vani; Katari, Sunita; Whiteman, Valerie E; Geifman-Holtzman, Ossie; Teitelman, Melissa

    2006-02-01

    We report a case of baking soda pica in a woman at 31 weeks of pregnancy causing severe hypokalemic metabolic alkalosis and rhabdomyolysis. A multigravida at 31 weeks of gestation presented with weakness and muscle pain. She was found to have severe hypokalemic metabolic alkalosis and rhabdomyolysis, with elevation in serum transaminases and hypertension. We initially thought the patient had an atypical presentation of preeclampsia until it was realized that she was ingesting 1 full box of baking soda (454 g sodium bicarbonate) per day. Symptoms and abnormal laboratory findings resolved with discontinuation of the patient's pica practices. Pica is a common but often overlooked practice that can potentially lead to life-threatening disorders. A thorough evaluation of a patient's dietary intake is extremely important, especially in the setting of atypical presentations of disease in pregnancy.

  13. [Clinical features of hypokalemic periodic paralysis].

    PubMed

    Wang, Wei; Zhao, Chun-yun; Gao, Yan-ming

    2009-12-18

    To explore the clinical features of hypokalemic periodic paralysis, and compare clinical features of primary group with those of thyrotoxicosis secondary group. Clinical data of 44 patients with hypokalemic periodic paralysis in Peking University First Hospital from 1996 December to 2008 December were retrospectively analyzed. There were 22 patients in primary group, and 22 in thyrotoxicosis group. Identical clinical features of both the groups: (1)It had a predilection in young men. (2)Main symptoms were limb movement disorder and fatigue, and paralysis recurrent attacked in most patients. (3) 40.9% to 68.2% patients had obvious incentives, and the common ones were a heavy meal, sweet drinks, or strenuous exercise. (4) Serum potassium levels of the two groups were obviously lower than the normal range. (5)In 20% patients of primary group and 25% patients of thyrotoxicosis secondary group, CK levels were higher than normal, while LDH and HBDH levels were normal. (6)The doses of potassium replishment were not correlated to serum potassium levels at the onset. Different clinical features of the two groups: (1) Patients of thyrotoxicosis group had hypermetabolism symptoms and thyroid dysfunction. Patients of primary group had no hypermetabolism symptoms, and all of them were euthyroid. (2)Serum potassium levels of thyrotoxicosis secondary group were lower than those of primary group significantly [(2.25 +/- 0.67) vs (2.78 +/- 0.49) mmol/L, P=0.007]. (3) Hyperkalemia is easier than primary group to rebound in thyrotoxicosis secondary group, after replenishment of potassium. Hypokalemic periodic paralysis has its clinical features, and patients with early diagnosis and replenishment of potassium in time have good prognosis. The doses of potassium replenishment are not determined by serum potassium levels at the onset. Hyperkalemia is easier to rebound in thyrotoxicosis secondary group after replenishment of potassium, serum potassium levels should be monitored closely

  14. Thyrotoxic hypokalemic periodic paralysis triggered by high carbohydrate diet.

    PubMed

    El-Hennawy, Adel S; Nesa, Mushammat; Mahmood, Aza K

    2007-01-01

    Thyrotoxic hypokalemic periodic paralysis is an uncommon disorder characterized by elevated thyroid hormone, muscle weakness or paralysis, and intracellular shifts of potassium leading to hypokalemia. This article presents a case of thyrotoxic hypokalemic periodic paralysis in a 22-year old Hispanic man with nonfamilial thyrotoxic hypokalemic periodic paralysis triggered by a high carbohydrate diet. Laboratory studies showed elevated thyroid hormone, decreased thyroid-stimulating hormone, and hypokalemia. Rapid reduction in thyroid hormone levels by giving antithyroid drugs such as propylthiouracil and prompt potassium therapy with frequent measurements of serum potassium levels during therapy to avoid catastrophic hyperkalemia when potassium starts to shift back from intracellular to extracellular compartments can lead to successful outcome.

  15. 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. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. Longitudinal growth in chronic hypokalemic disorders.

    PubMed

    Gil-Peña, Helena; Mejia, Natalia; Alvarez-Garcia, Oscar; Loredo, Vanessa; Santos, Fernando

    2010-04-01

    Growth retardation remains a major complication in children with primary tubular disorders, despite adequate supplemental treatment with electrolytes, water and bicarbonate. Chronic hypokalemia, characteristic of some tubulopathies, impairs growth by mechanisms that are not well known. Association with growth hormone deficiency has been reported in patients with Bartter's or Gitelman's syndrome. Tissue-specific alterations of growth hormone and insulin-like growth factor I axis have been described in experimental models of potassium depletion. Hypokalemic rats gain less body length and weight than pair-fed normokalemic animals and, by contrast, develop renal hypertrophy. These rats have low circulating concentrations of insulin-like growth factor I, depressed messenger ribonucleic acid (mRNA) levels of this peptide in the tibial growth plate, and they are resistant to the longitudinal growth-promoting effects of exogenous growth hormone. The reason for this resistance remains to be defined. No alterations in the intracellular signaling for growth hormone have been found in the liver of hypokalemic rats. However, treatment with high doses of growth hormone is unable to normalize hypertrophy of the epiphyseal cartilage chondrocytes, which are severely disturbed in potassium depletion and likely play an important role in the pathogenia of growth impairment in this condition.

  17. Expression patterns of two potassium channel genes in skeletal muscle cells of patients with familial hypokalemic periodic paralysis.

    PubMed

    Kim, June-Bum; Lee, Gyung-Min; Kim, Sung-Jo; Yoon, Dong-Ho; Lee, Young-Hyuk

    2011-01-01

    Familial hypokalemic periodic paralysis is an autosomal-dominant disorder characterized by episodic attacks of muscle weakness with hypokalemia. The combination of sarcolemmal depolarization and hypokalemia has been attributed to abnormalities of the potassium conductance governing the membrane potential; however, the molecular mechanism that causes hypokalemia has not yet been determined. To test the hypothesis that the expression patterns of delayed rectifier potassium channel genes in the skeletal muscle cells of patients with familial hypokalemic periodic paralysis differ from those in normal cells. We examined both mRNA and protein levels of two major delayed rectifier potassium channel genes KCNQ3 and KCNQ5 in the skeletal muscle cells from three patients with familial hypokalemic periodic paralysis and three healthy controls. When normal cells were exposed to 50 mM potassium buffer, which was used to induce depolarization, the KCNQ3 protein level significantly increased in the membrane fraction but decreased in the cytosolic fraction, whereas the opposite was true in patient cells. Abnormal subcellular distribution of the KCNQ3 protein was observed in patient cells. Our results suggest that the altered expression of KCNQ3 in patient cells exposed to high extracellular potassium levels could possibly hinder normal function of the channel protein. These findings may provide an important clue to understanding the molecular mechanism of familial hypokalemic periodic paralysis.

  18. Rhabdomyolysis following severe hypokalemia caused by familial hypokalemic periodic paralysis

    PubMed Central

    Jung, Young-Lee; Kang, Jae-Young

    2017-01-01

    Rhabdomyolysis continues to appear with increasing frequency and represents a medical emergency requiring rapid appropriate treatment. One of the unusual causes of nontraumatic rhabdomyolysis is hypokalemic periodic paralysis without secondary causes. Primary hypokalemic periodic paralysis is a rare genetic disease characterized by episodic attacks of muscle weakness due to decreases in serum potassium. A 30-year-old woman who had 3 episodic attacks of hypokalemic periodic paralysis was admitted in emergency room with sudden onset symmetrical muscle weakness. After several hours, she started to complain myalgia and severe ache in both calves without any changes. Laboratory test showed markedly elevated creatine phosphokinase, lactic dehydrogenase levels with hypokalemia, rhabdomyolysis resulting from hypokalemia was diagnosed. Here, we report an unusual case of rhabdomyolysis caused by severe hypokalemia, which was suggested a result of familial hypokalemic periodic paralysis. PMID:28255549

  19. Rodents as potential couriers for bioterrorism agents.

    PubMed

    Lõhmus, Mare; Janse, Ingmar; van de Goot, Frank; van Rotterdam, Bart J

    2013-09-01

    Many pathogens that can cause major public health, economic, and social damage are relatively easily accessible and could be used as biological weapons. Wildlife is a natural reservoir for many potential bioterrorism agents, and, as history has shown, eliminating a pathogen that has dispersed among wild fauna can be extremely challenging. Since a number of wild rodent species live close to humans, rodents constitute a vector for pathogens to circulate among wildlife, domestic animals, and humans. This article reviews the possible consequences of a deliberate spread of rodentborne pathogens. It is relatively easy to infect wild rodents with certain pathogens or to release infected rodents, and the action would be difficult to trace. Rodents can also function as reservoirs for diseases that have been spread during a bioterrorism attack and cause recurring disease outbreaks. As rats and mice are common in both urban and rural settlements, deliberately released rodentborne infections have the capacity to spread very rapidly. The majority of pathogens that are listed as potential agents of bioterrorism by the Centers for Disease Control and Prevention and the National Institute of Allergy and Infectious Diseases exploit rodents as vectors or reservoirs. In addition to zoonotic diseases, deliberately released rodentborne epizootics can have serious economic consequences for society, for example, in the area of international trade restrictions. The ability to rapidly detect introduced diseases and effectively communicate with the public in crisis situations enables a quick response and is essential for successful and cost-effective disease control.

  20. Potential of immunosuppressive agents in cerebral ischaemia

    PubMed Central

    Gupta, Yogendra Kumar; Chauhan, Anjali

    2011-01-01

    Ischaemic stroke is a disorder involving multiple mechanisms of injury progression including activation of glutamate receptors, release of proinflammatory cytokines, nitric oxide (NO), free oxygen radicals and proteases. Presently, recombinant tissue plasminogen activator (rtPA) is the only drug approved for the management of acute ischaemic stroke. This drug, however, is associated with limitations like narrow therapeutic window and increased risk of intracranial haemorrhage. A large number of therapeutic agents have been tested including N-methly-D-aspartate (NMDA) receptor antagonist, calcium channel blockers and antioxidants for management of stroke, but none has provided significant neuroprotection in clinical trials. Therefore, searching for other potentially effective drugs for ischaemic stroke management becomes important. Immunosuppressive agents with their wide array of mechanisms have potential as neuroprotectants. Corticosteroids, immunophilin ligands, mycophenolate mofetil and minocycline have shown protective effect on neurons by their direct actions or attenuating toxic effects of mediators of inflammation. This review focuses on the current status of corticosteroids, cyclosporine A, FK506, rapamycin, mycophenolate mofetil and minocycline in the experimental models of cerebral ischaemia. PMID:21321416

  1. Brucella as a potential agent of bioterrorism.

    PubMed

    Doganay, Gizem D; Doganay, Mehmet

    2013-04-01

    Perception on bioterrorism has changed after the deliberate release of anthrax by the postal system in the United States of America in 2001. Potential bioterrorism agents have been reclassified based on their dissemination, expected rate of mortality, availability, stability, and ability to lead a public panic. Brucella species can be easily cultured from infected animals and human materials. Also, it can be transferred, stored and disseminated easily. An intentional contamination of food with Brucella species could pose a threat with low mortality rate. Brucella spp. is highly infectious through aerosol route, making it an attractive pathogen to be used as a potential agent for biological warfare purposes. Recently, many studies have been concentrated on appropriate sampling of Brucella spp. from environment including finding ways for its early detection and development of new decontamination procedures such as new drugs and vaccines. There are many ongoing vaccine development studies; some of which recently received patents for detection and therapy of Brucella spp. However, there is still no available vaccine for humans. In this paper, recent developments and recent patents on brucellosis are reviewed and discussed.

  2. TRPV1 antagonists as potential antitussive agents.

    PubMed

    McLeod, Robbie L; Correll, Craig C; Jia, Yanlin; Anthes, John C

    2008-01-01

    Cough is an important defensive pulmonary reflex that removes irritants, fluids, or foreign materials from the airways. However, when cough is exceptionally intense or when it is chronic and/or nonproductive it may require pharmacologic suppression. For many patients, antitussive therapies consist of OTC products with inconsequential efficacies. On the other hand, the prescription antitussive market is dominated by older opioid drugs such as codeine. Unfortunately, "codeine-like" drugs suppress cough at equivalent doses that also often produce significant ancillary liabilities such as GI constipation, sedation, and respiratory depression. Thus, the discovery of a novel and effective antitussive drug with an improved side effect profile relative to codeine would fulfill an unmet clinical need in the treatment of cough. Afferent pulmonary nerves are endowed with a multitude of potential receptor targets, including TRPV1, that could act to attenuate cough. The evidence linking TRPV1 to cough is convincing. TRPV1 receptors are found on sensory respiratory nerves that are important in the generation of the cough reflex. Isolated pulmonary vagal afferent nerves are responsive to TRPV1 stimulation. In vivo, TRPV1 agonists such as capsaicin elicit cough when aerosolized and delivered to the lungs. Pertinent to the debate on the potential use of TRPV1 antagonist as antitussive agents are the observations that airway afferent nerves become hypersensitive in diseased and inflamed lungs. For example, the sensitivity of capsaicin-induced cough responses following upper respiratory tract infection and in airway inflammatory diseases such as asthma and COPD is increased relative to that of control responses. Indeed, we have demonstrated that TRPV1 antagonism can attenuate antigen-induced cough in the allergic guinea pig. However, it remains to be determined if the emerging pharmacologic profile of TRPV1 antagonists will translate into a novel human antitussive drug. Current

  3. Plants' metabolites as potential antiobesity agents.

    PubMed

    Gooda Sahib, Najla; Saari, Nazamid; Ismail, Amin; Khatib, Alfi; Mahomoodally, Fawzi; Abdul Hamid, Azizah

    2012-01-01

    Obesity and obesity-related complications are on the increase both in the developed and developing world. Since existing pharmaceuticals fail to come up with long-term solutions to address this issue, there is an ever-pressing need to find and develop new drugs and alternatives. Natural products, particularly medicinal plants, are believed to harbor potential antiobesity agents that can act through various mechanisms either by preventing weight gain or promoting weight loss amongst others. The inhibition of key lipid and carbohydrate hydrolyzing and metabolizing enzymes, disruption of adipogenesis, and modulation of its factors or appetite suppression are some of the plethora of targeted approaches to probe the antiobesity potential of medicinal plants. A new technology such as metabolomics, which deals with the study of the whole metabolome, has been identified to be a promising technique to probe the progression of diseases, elucidate their pathologies, and assess the effects of natural health products on certain pathological conditions. This has been applied to drug research, bone health, and to a limited extent to obesity research. This paper thus endeavors to give an overview of those plants, which have been reported to have antiobesity effects and highlight the potential and relevance of metabolomics in obesity research.

  4. Plants' Metabolites as Potential Antiobesity Agents

    PubMed Central

    Gooda Sahib, Najla; Saari, Nazamid; Ismail, Amin; Khatib, Alfi; Mahomoodally, Fawzi; Abdul Hamid, Azizah

    2012-01-01

    Obesity and obesity-related complications are on the increase both in the developed and developing world. Since existing pharmaceuticals fail to come up with long-term solutions to address this issue, there is an ever-pressing need to find and develop new drugs and alternatives. Natural products, particularly medicinal plants, are believed to harbor potential antiobesity agents that can act through various mechanisms either by preventing weight gain or promoting weight loss amongst others. The inhibition of key lipid and carbohydrate hydrolyzing and metabolizing enzymes, disruption of adipogenesis, and modulation of its factors or appetite suppression are some of the plethora of targeted approaches to probe the antiobesity potential of medicinal plants. A new technology such as metabolomics, which deals with the study of the whole metabolome, has been identified to be a promising technique to probe the progression of diseases, elucidate their pathologies, and assess the effects of natural health products on certain pathological conditions. This has been applied to drug research, bone health, and to a limited extent to obesity research. This paper thus endeavors to give an overview of those plants, which have been reported to have antiobesity effects and highlight the potential and relevance of metabolomics in obesity research. PMID:22666121

  5. Extracellular Potassium Homeostasis: Insights from Hypokalemic Periodic Paralysis

    PubMed Central

    Cheng, Chih-Jen; Kuo, Elizabeth; Huang, Chou-Long

    2014-01-01

    The extracellular potassium makes up only about 2% of the total body potassium store. The majority of the body potassium is distributed in the intracellular space, and of which about 80% is in skeletal muscle. Movement of potassium in and out of skeletal muscle thus plays a pivotal role in extracellular potassium homeostasis. The exchange of potassium between the extracellular space and skeletal muscle is mediated by specific membrane transporters. These include potassium uptake by Na+, K+-ATPase and release by inward rectifier K+ channels. These processes are regulated by circulating hormones, peptides, ions, and by physical activity of muscle as well as dietary potassium intake. Pharmaceutical agents, poisons and disease conditions also affect the exchange and alter extracellular potassium concentration. Here, we review extracellular potassium homeostasis focusing on factors and conditions that influence the balance of potassium movement in skeletal muscle. Recent findings that mutations of a skeletal muscle-specific inward rectifier K+ channel cause hypokalemic periodic paralysis provide interesting insights into the role of skeletal muscle in extracellular potassium homeostasis. These recent findings will be reviewed. PMID:23953801

  6. Extracellular potassium homeostasis: insights from hypokalemic periodic paralysis.

    PubMed

    Cheng, Chih-Jen; Kuo, Elizabeth; Huang, Chou-Long

    2013-05-01

    Extracellular potassium makes up only about 2% of the total body's potassium store. The majority of the body potassium is distributed in the intracellular space, of which about 80% is in skeletal muscle. Movement of potassium in and out of skeletal muscle thus plays a pivotal role in extracellular potassium homeostasis. The exchange of potassium between the extracellular space and skeletal muscle is mediated by specific membrane transporters. These include potassium uptake by Na(+), K(+)-adenosine triphosphatase and release by inward-rectifier K(+) channels. These processes are regulated by circulating hormones, peptides, ions, and by physical activity of muscle as well as dietary potassium intake. Pharmaceutical agents, poisons, and disease conditions also affect the exchange and alter extracellular potassium concentration. Here, we review extracellular potassium homeostasis, focusing on factors and conditions that influence the balance of potassium movement in skeletal muscle. Recent findings that mutations of a skeletal muscle-specific inward-rectifier K(+) channel cause hypokalemic periodic paralysis provide interesting insights into the role of skeletal muscle in extracellular potassium homeostasis. These recent findings are reviewed. Copyright © 2013 Elsevier Inc. All rights reserved.

  7. Polypodium leucotomos: a potential new photoprotective agent.

    PubMed

    Bhatia, Neal

    2015-04-01

    As the understanding of the immune system pathways, cytokine balances, and cellular interactions continues to expand, so must the potential applications of therapies that can impact the process of diseases instead of just controlling their symptoms. In the case of Polypodium leucotomos extract, which is derived from a tropical fern of the Polypodiaceae family, the future potential of applications in dermatology and beyond will be better understood as its incorporation into daily routines gives rise to the development of new regimens. Clinicians may position this agent as an option for daily maintenance, accept its use in combinations, or use it as a template for further development of oral supplementation that may evolve into a true immunomodulator. The antioxidant activity of P. leucotomos extract is primarily driven by caffeic acid and ferulic acid, resulting in the control of cutaneous responses to ultraviolet-induced erythema, in the interception of inflammatory mechanisms, and the promotion of other cytotoxic responses. Histologically, the impact of P. leucotomos extract induces an effect on the overall reduction of angiogenesis, photocarcinogenesis, and solar elastosis, while on the cellular level there are improvements in cell membrane integrity and elastin expression. Future applications for P. leucotomos extract could include the potential for photoprotective effects, and subsequent research efforts should focus on determining the optimal dosage regimen, duration of action, and utility of combinations with sunscreens, among other outcomes. Recently published data have also demonstrated how the antioxidant effects of oral P. leucotomos extract can delay tumor development in mice models, suggesting there might be a protective role that could be described with further clinical research. In addition, it is important to recognize the distinction between photoprotection and chemoprevention, in that there has yet to be any in vivo or controlled clinical trial

  8. Nigella sativa: A Potential Antiosteoporotic Agent

    PubMed Central

    Shuid, Ahmad Nazrun; Mohamed, Norazlina; Mohamed, Isa Naina; Othman, Faizah; Suhaimi, Farihah; Mohd Ramli, Elvy Suhana; Muhammad, Norliza; Soelaiman, Ima Nirwana

    2012-01-01

    Nigella sativa seeds (NS) has been used traditionally for various illnesses. The most abundant and active component of NS is thymoquinone (TQ). Animal studies have shown that NS and TQ may be used for the treatment of diabetes-induced osteoporosis and for the promotion of fracture healing. The mechanism involved is unclear, but it was postulated that the antioxidative, and anti-inflammatory activities may play some roles in the treatment of osteoporosis as this bone disease has been linked to oxidative stress and inflammation. This paper highlights studies on the antiosteoporotic effects of NS and TQ, the mechanisms behind these effects and their safety profiles. NS and TQ were shown to inhibit inflammatory cytokines such as interleukin-1 and 6 and the transcription factor, nuclear factor κB. NS and TQ were found to be safe at the current dosage for supplementation in human with precautions in children and pregnant women. Both NS and TQ have shown potential as antiosteoporotic agent but more animal and clinical studies are required to further assess their antiosteoporotic efficacies. PMID:22973403

  9. Bioactive peroxides as potential therapeutic agents.

    PubMed

    Dembitsky, Valery M

    2008-02-01

    Present review describes research on more than 280 natural anticancer agents isolated from terrestrial and marine sources and synthetic biologically active peroxides. Intensive searches for new classes of pharmacologically potent agents produced by terrestrial and marine organisms have resulted in the discovery of dozens of compounds possessing high cytotoxic, antibacterial, antimalarial, and other activities as an important source of leads for drug discovery.

  10. Hypokalemic Paralysis: A Hidden Card of Several Autoimmune Diseases

    PubMed Central

    Velarde-Mejía, Yelitza; Gamboa-Cárdenas, Rocío; Ugarte-Gil, Manuel; Asurza, César Pastor

    2017-01-01

    Acute hypokalemic paralysis is a rare and potentially fatal condition, with few related causes, one of which highlights distal renal tubular acidosis (dRTA). Distal renal tubular acidosis is a rare complication of several autoimmune diseases such as systemic lupus erythematosus, Sjögren’s syndrome, and Hashimoto thyroiditis. We report a case of a lupic patient who presented rapidly progressive quadriparesis in the context of active renal disease. Research revealed severe refractory hypokalemia, metabolic acidosis, and alkaline urine suggestive of dRTA. We diagnosed Sjögren’s syndrome based on sicca symptoms, an abnormal salivary glands’ nuclear scan and the presence of anti-Ro/SSA and anti-La/SSB. In addition, the finding of thyroid peroxidase, thyroglobulin antibodies, and hypothyroidism led us to the diagnosis of Hashimoto thyroiditis. Due to the active renal involvement on the context of systemic lupus erythematosus and Sjögren’s syndrome, the patient received immunosuppression with rituximab, resulting in a progressive and complete improvement. PMID:28839447

  11. Sporadic hypokalemic paralysis caused by osmotic diuresis in diabetes mellitus.

    PubMed

    Vishnu, Venugopalan Y; Kattadimmal, Anoop; Rao, Suparna A; Kadhiravan, Tamilarasu

    2014-07-01

    A wide variety of neurological manifestations are known in patients with diabetes mellitus. We describe a 40-year-old man who presented with hypokalemic paralysis. On evaluation, we found that the cause of the hypokalemia was osmotic diuresis induced by marked hyperglycemia due to undiagnosed diabetes mellitus. The patient had an uneventful recovery with potassium replacement, followed by glycemic control with insulin. Barring a few instances of symptomatic hypokalemia in the setting of diabetic emergencies, to our knowledge uncomplicated hyperglycemia has not been reported to result in hypokalemic paralysis.

  12. Dihydropyridine receptor mutations cause hypokalemic periodic paralysis

    SciTech Connect

    Ptacek, L.J.; Leppert, M.F.; Tawil, R.

    1994-09-01

    Hypokalemic periodic paralysis (hypoKPP) is an autosomal dominant skeletal muscle disorder manifested by episodic weakness associated with low serum potassium. Genetic linkage analysis has localized the hypoKPP gene to chromosome 1q31-q32 near a dihydropyridine receptor (DHP) gene. This receptor functions as a voltage-gated calcium channel and is also critical for excitation-contraction coupling in a voltage-sensitive and calcium-independent manner. We have characterized patient-specific DHP receptor mutations in 11 probands of 33 independent hypoKPP kindreds that occur at one of two adjacent nucleotides within the same codon and predict substitution of a highly conserved arginine in the S4 segment of domain 4 with either histidine or glycine. In one kindred, the mutation arose de novo. Taken together, these data establish the DHP receptor as the hypoKPP gene. We are unaware of any other human diseases presently known to result from DHP receptor mutations.

  13. Hypokalemic Paralysis due to Primary Sjögren Syndrome: Case Report and Review of the Literature

    PubMed Central

    Garza-Alpirez, A.; Esquivel-Valerio, J. A.; Villarreal-Alarcón, M. A.; Galarza-Delgado, D. A.

    2017-01-01

    Tubulointerstitial nephritis (TIN) is the main renal involvement associated with primary Sjögren syndrome (pSS). TIN can manifest as distal renal tubular acidosis (RTA), nephrogenic diabetes insipidus, proximal tubular dysfunction, and others. We present a 31-year-old female with hypokalemic paralysis due to distal RTA (dRTA). She received symptomatic treatment and hydroxychloroquine with a good response. There is insufficient information on whether to perform a kidney biopsy in these patients or not. The evidence suggests that there is an inflammatory background and therefore a potential serious affection to these patients, such as hypokalemic paralysis. We found 52 cases of hypokalemic paralysis due to dRTA in pSS patients. The majority of those patients were treated only with symptomatic medication. Patients who received corticosteroids had stable evolution even though they did not have another symptomatology. With such heterogeneous information, prospective studies are needed to assess the value of adding corticosteroids as a standardized treatment of this manifestation. PMID:28835864

  14. Efficient synthesis of benzamide riboside, a potential anticancer agent.

    PubMed

    Bonnac, Laurent F; Gao, Guang-Yao; Chen, Liqiang; Patterson, Steven E; Jayaram, Hiremagalur N; Pankiewicz, Krzysztof W

    2007-01-01

    An efficient five step synthesis of benzamide riboside (BR) amenable for a large scale synthesis has been developed. It allows for extensive pre-clinical studies of BR as a potential anticancer agent.

  15. Rhizoma Coptidis: A Potential Cardiovascular Protective Agent

    PubMed Central

    Tan, Hui-Li; Chan, Kok-Gan; Pusparajah, Priyia; Duangjai, Acharaporn; Saokaew, Surasak; Mehmood Khan, Tahir; Lee, Learn-Han; Goh, Bey-Hing

    2016-01-01

    Cardiovascular diseases (CVDs) are among the leading causes of morbidity and mortality in both the developed and developing world. Rhizoma coptidis (RC), known as Huang Lian in China, is the dried rhizome of medicinal plants from the family Ranunculaceae, such as Coptis chinensis Franch, C. deltoidea C.Y. Cheng et Hsiao, and C. teeta Wall which has been used by Chinese medicinal physicians for more than 2000 years. In China, RC is a common component in traditional medicines used to treat CVD associated problems including obesity, diabetes mellitus, hyperlipidemia, hyperglycemia and disorders of lipid metabolism. In recent years, numerous scientific studies have sought to investigate the biological properties of RC to provide scientific evidence for its traditional medical uses. RC has been found to exert significant beneficial effects on major risk factors for CVDs including anti-atherosclerotic effect, lipid-lowering effect, anti-obesity effect and anti-hepatic steatosis effect. It also has myocardioprotective effect as it provides protection from myocardial ischemia-reperfusion injury. These properties have been attributed to the presence of bioactive compounds contained in RC such as berberine, coptisine, palmatine, epiberberine, jatrorrhizine, and magnoflorine; all of which have been demonstrated to have cardioprotective effects on the various parameters contributing to the occurrence of CVD through a variety of pathways. The evidence available in the published literature indicates that RC is a herb with tremendous potential to reduce the risks of CVDs, and this review aims to summarize the cardioprotective properties of RC with reference to the published literature which overall indicates that RC is a herb with remarkable potential to reduce the risks and damage caused by CVDs. PMID:27774066

  16. Recurrent Hypokalemic Periodic Paralysis Unmasks Sjogren Syndrome without Sicca Symptoms.

    PubMed

    Hung, Yao-Min; Huang, Neng-Chyan; Wann, Shue-Ren; Chang, Yun-Te; Wang, Jyh-Seng

    2015-04-01

    Hypokalemic Periodic Paralysis (HPP) may occur as a rare complication of Sjogren Syndrome (SS) and Renal Tubular Acidosis (RTA). A 64-year male patient came with HPP, and was later diagnosed with distal RTA. The patient, who had no xerostomia and xerophthalmia, was diagnosed with primary SS from serologic and histologic findings of minor salivary gland biopsy. The patient recovered after potassium replacement therapy. Renal biopsy was also performed and revealed evidence of tubulointerstitial nephritis. Corticosteroids were administered and there was no recurrence of HPP during a 4-year follow-up period. The case highlights the significance of acute hypokalemia management in emergency department as it can unmask SS even if the SS is not associated with sicca symptoms. Hypokalemic paralysis associated with normal anion gap metabolic acidosis should prompt toward the diagnosis of SS.

  17. Hypokalemic myopathy in pregnancy caused by clay ingestion.

    PubMed

    Ukaonu, Chinwe; Hill, D Ashley; Christensen, Franklyn

    2003-11-01

    We present a case of severe hypokalemic myopathy during pregnancy caused by clay ingestion. A multigravida presented with fatigue, muscle weakness, and a 3-day history of extremity pain. Serum potassium levels were 1.5 mEq/L, requiring intravenous potassium replacement. The initial evaluation was unrewarding for the cause of the patient's hypokalemia until a family member reported that the patient frequently ate large quantities of clay. Discontinuation of clay ingestion led to normalization of potassium levels. Pica, the persistent ingestion of nonnutritive substances, can cause a number of medical problems. Pica of clay, called geophagia, can bind potassium in the intestine, leading to severe hypokalemic myopathy. Clinicians caring for pregnant women with fatigue, muscle weakness, and hypokalemia should consider geophagia as a possible cause.

  18. Betamethasone-induced hypokalemic periodic paralysis in pregnancy.

    PubMed

    Teagarden, Corey M; Picardo, Carla W

    2011-02-01

    Acute hypokalemic periodic paralysis may be induced by betamethasone injections during pregnancy. A healthy 23-year-old gravid woman at 32 weeks of gestation with preterm premature rupture of membranes received two doses of 12-mg intramuscular betamethasone 24 hours apart to accelerate fetal lung maturation. She developed significant proximal muscle weakness within 16 hours after the initial dose. Her serum potassium was 1.6 mEq/L. Oral and parenteral potassium replacement restored her neuromuscular function over several days. She delivered by repeat cesarean at 34 weeks of gestation without complications for her or the neonate. Hypokalemic periodic paralysis, a rare cause of weakness, may be induced by betamethasone injections during pregnancy and is reversible with low-risk interventions.

  19. [Bioterrorism, parasites as potential bioterrorism agents and biosecurity studies].

    PubMed

    Aksoy, Umit

    2006-01-01

    A variety of agents have a potential risk for being use as weapons of biological terrorism. However, the use of parasites as bioterrorism agents has not received so much attention. Parasites could contribute to the installation of fear in human population upon intentional addition to their food and water supplies. On the other hand, vector-borne parasites can also constitute risk of bioterrorism. Biosecurity issues are gaining importance as a consequence of globalization. Surveillance is critical in maintaining biosecurity and early detection of infectious disease agents is essential. In this review article, bioterrorism, the role of parasites as potential bioterrorism agents, studies on biosecurity and laboratory design for biosafety have been discussed under the light of recent literature.

  20. 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).

  1. Novel 2-Aminobenzamides as Potential Orally Active Antithrombotic Agents

    PubMed Central

    2012-01-01

    In an effort to develop potent antithrombotic agents, a series of novel 2-aminobenzamide derivatives were synthesized and screened for their in vivo antithrombotic activity. Among the 23 compounds tested, compound (8g) showed the most promising antithrombotic activity, which was comparable with clinically used aspirin or warfarin, but at variance with these standard drugs, 8g did not exhibit the increased bleeding time, suggesting its potential as a novel antithrombotic agent. PMID:24900559

  2. The R900S mutation in CACNA1S associated with hypokalemic periodic paralysis.

    PubMed

    Ke, Qing; He, Fangping; Lu, Lingping; Yu, Ping; Jiang, Yajian; Weng, Chen; Huang, Hui; Yi, Xin; Qi, Ming

    2015-12-01

    Primary hypokalemic periodic paralysis is an autosomal dominant skeletal muscle channelopathy. In the present study, we investigated the genotype and phenotype of a Chinese hypokalemic periodic paralysis family. We used whole-exome next-generation sequencing to identify a mutation in the calcium channel, voltage-dependent, L type, alpha subunit gene (CACNA1S), R900S, which is a rare mutation associated with hypokalemic periodic paralysis. We first present a clinical description of hypokalemic periodic paralysis patients harboring CACNA1SR900S mutations: they were non-responsive to acetazolamide, but combined treatment with triamterene and potassium supplements decreased the frequency of muscle weakness attacks. All male carriers of the R900S mutation experienced such attacks, but all three female carriers were asymptomatic. This study provides further evidence for the phenotypic variation and pharmacogenomics of hypokalemic periodic paralysis. Copyright © 2015 Elsevier B.V. All rights reserved.

  3. Insulin-mediated hypokalemia and paralysis in familial hypokalemic periodic paralysis.

    PubMed

    Minaker, K L; Meneilly, G S; Flier, J S; Rowe, J W

    1988-06-01

    To elucidate a potential role for insulin-mediated extra-renal potassium disposal in the clinical syndrome of hypokalemic periodic paralysis, an obese affected man was studied using the euglycemic insulin clamp, which, in normal and obese subjects, produces predictable, insulin dose-dependent declines in plasma potassium levels. During a 20 mU/m2/minute euglycemic clamp (insulin level, 88 microU/ml) procedure, while the patient with hypokalemic periodic paralysis demonstrated severe resistance to insulin-mediated glucose uptake (glucose uptake 50 percent of that of normal control subjects, n = 17), his plasma potassium declined to a degree similar to that seen in normal subjects. During a subsequent higher dose, 200 mU/m2/minute insulin infusion (insulin level, 914 microU/ml), plasma potassium declined to 2.5 meq/liter, a value significantly below that seen in normal (n = 19) (3.3 +/- 0.1 meq/liter) and obese (n = 6) (3.2 +/- 0.1 meq/liter) subjects. During this study, paralysis began in the patient's hand and forearm at the potassium nadir and lasted three hours, despite restoration of normokalemia 30 minutes after paralysis began. Glucose disposal rates during this high-dose insulin infusion were one-half that seen in lean control subjects (n = 19) and similar to those in obese control subjects. If these findings are representative of hypokalemic periodic paralysis and can be generalized to larger numbers of patients, they indicate several new features of this syndrome. The ability of insulin to induce hypokalemia is enhanced in this syndrome even in the presence of marked coexistent obesity-related resistance to the action of insulin to promote glucose utilization. Enhanced sensitivity of potassium uptake systems to activation by insulin (and other factors) may be a central feature of this syndrome. Additionally, paralytic hypokalemia can be induced during a euglycemic insulin clamp procedure, which could be utilized as a diagnostic test for this syndrome.

  4. Primary screen for potential sheep scab control agents.

    PubMed

    Dunn, J A; Prickett, J C; Collins, D A; Weaver, R J

    2016-07-15

    The efficacy of potential acaricidal agents were assessed against the sheep scab mite Psoroptes ovis using a series of in vitro assays in modified test arenas designed initially to maintain P. ovis off-host. The mortality effects of 45 control agents, including essential oils, detergents, desiccants, growth regulators, lipid synthesis inhibitors, nerve action/energy metabolism disruptors and ecdysteroids were assessed against adults and nymphs. The most effective candidates were the desiccants (diatomaceous earth, nanoclay and sorex), the growth regulators (buprofezin, hexythiazox and teflubenzuron), the lipid synthesis inhibitors (spirodiclofen, spirotetramat and spiromesifen) and the nerve action and energy metabolism inhibitors (fenpyroximate, spinosad, tolfenpyrad, and chlorantraniliprole).

  5. Etiology of Hypokalemic Paralysis in Korea: Data from a Single Center

    PubMed Central

    Wi, Jung-Kook; Lee, Hong Joo; Kim, Eun Young; Cho, Joo Hee; Chin, Sang Ouk; Rhee, Sang Youl; Moon, Ju-Young; Lee, Sang-Ho; Jeong, Kyung-Hwan; Ihm, Chun-Gyoo

    2012-01-01

    Recognizing the underlying causes of hypokalemic paralysis seems to be essential for the appropriate management of affected patients and their prevention of recurrent attacks. There is, however, a paucity of documented reports on the etiology of hypokalemic paralysis in Korea. We retrospectively analyzed 34 patients with acute flaccid weakness due to hypokalaemia who were admitted during the 5-year study period in order to determine the spectrum of hypokalemic paralysis in Korea and to identify the differences in clinical parameters all across the causes of hypokalemic paralysis. We divided those 34 patients into 3 groups; the 1st group, idiopathic hypokalemic periodic paralysis (HPP), the 2nd, thyrotoxic periodic paralysis (TPP), and the 3rd group, secondary hypokalemic paralysis (HP) without TPP. Seven of the patients (20.6%) were diagnosed as idiopathic HPP considered the sporadic form, and 27 patients (79.4%) as secondary HP. Among the patients diagnosed as secondary HP, 16 patients (47.1%) had TPP. Patients of secondary hypokalemic paralysis without TPP required a longer recovery time compared with those who had either idiopathic HPP or TPP. This is due to the fact that patients of secondary HP had a significantly negative total body potassium balance, whereas idiopathic HPP and TPP were only associated with intracellular shift of potassium. Most of the TPP patients included in our study had overt thyrotoxicosis while 3 patients had subclinical thyrotoxicosis. This study shows that TPP is the most common cause of hypokalemic paralysis in Korea. And we suggest that doctors should consider the presence of TPP in patients of hypokalemic paralysis even if they clinically appear to be euthyroid state. PMID:23508689

  6. Severe hypokalemic paralysis and rhabdomyolysis occurring after binge eating in a young bodybuilder: Case report.

    PubMed

    Lee, Tae Won; Bae, Eunjin; Hwang, Kyungo; Chang, Ha Nee; Park, Hee Jung; Jeon, Dae-Hong; Cho, Hyun Seop; Chang, Se-Ho; Park, Dong Jun

    2017-10-01

    Severe hypokalemia can be a potentially life-threatening disorder and is associated with variable degrees of skeletal muscle weakness. We report a case of severe hypokalemic paralysis and rhabdomyolysis in a 28-year-old bodybuilder. He was admitted to the emergency room due to progressive paralysis in both lower extremities, which had begun 12 hours earlier. He was a bodybuilder trainer and had participated in a regional competition 5 days earlier. He went on a binge, consuming large amounts of carbohydrates over 4 days, resulting in a gain of 10 kg in weight. He had no family history of paralysis and this was his first attack. He strongly denied drug abuse, such as anabolic steroids, thyroid and growth hormone, and diuretics. Neurological examinations revealed symmetrical flaccid paralysis in his lower extremities, but the patient was alert and his sensory system was intact. His initial serum potassium and phosphate level was 1.8 mmol/L and 1.4 mg/dL, respectively. The calculated transtubular potassium gradient (TTKG) was 2.02. His thyroid function was normal. Serum potassium levels increased to 3.8 mmol/L with intravenous infusion of about 50 mmol of potassium chloride over 20 hours. His muscular symptoms improved progressively and he was discharged from the hospital 7 days after admission on foot. He was followed in our outpatient clinic, without recurrence. Physicians should keep in mind that large intakes of food during short periods can provoke hypokalemic paralysis and rhabdomyolysis, especially in bodybuilders.

  7. Mustard: a potential agent of chemical warfare and terrorism.

    PubMed

    Saladi, R N; Smith, E; Persaud, A N

    2006-01-01

    As one of the most important vesicant agents, the destructive properties of mustards on the skin, eyes and respiratory system, combined with a lack of antidote, makes them effective weapons. Such weapons are inexpensive, easily obtainable and frequently stockpiled. Sulphur mustard (mustard gas) has been used as a chemical warfare agent in at least 10 conflicts. In this article, the use of mustard as a potential agent of chemical warfare and terrorism is outlined. The dose-dependent effects of acute sulphur mustard exposure on the skin, eyes, and respiratory system are described, as well as the possible extents of injuries, the mechanisms of action and the long-term complications. Prevention and management of mustard exposure are briefly discussed. The need for awareness and preparedness in the dermatological community regarding mustard exposure is emphasized.

  8. Histopathologic and MRI findings in hypokalemic myopathy induced by glycyrrhizin.

    PubMed

    Hayashi, K; Hayashi, R; Maruyama, K; Yanagisawa, N

    1995-08-01

    Histopathologic studies and magnetic resonance images of the leg muscles were conducted in two patients with glycyrrhizin-induced hypokalemic myopathy (GHM). Muscle biopsy showed myopathic changes and vacuolated fibers with light microscopy, and dilatation of the sarcoplasmic reticulum, various types of vacuoles and myofibrillar degeneration with electron microscopy. High signal intensities in T2-weighted images obtained during severe muscle weakness were widely distributed in the leg muscles, especially the pretibial and soleus muscles. These high signal intensities disappeared after full recovery of muscle weakness. We suggest that high signal intensity in T2-weighted images can be seen and correspond to histopathologic changes in the muscles of GHM patients.

  9. Hypokalemic rhabdomyolysis: an unusual presentation of Sjogren's syndrome

    PubMed Central

    Cherif, Eya; Ben Hassine, Lamia; Kechaou, Ines; Khalfallah, Narjess

    2013-01-01

    Hypokalaemic rhabdomyolysis represents a medical emergency requiring rapid diagnosis and appropriate aetiological treatment. Renal tubular acidosis is a common cause of hypokalemia which can be idiopathic or secondary to systemic disorders such as Sjogren's syndrome. It can remain asymptomatic or manifest with metabolic abnormalities including hypokalemia paralysis, hypocalcaemia and hyperchloremic metabolic acidosis. Rhabdomyolysis presenting with severe hypokalemia as the first manifestation of Sjogren's syndrome is rare. We report a case of a 59-year-old woman who presented to our department with severe weakness of all limbs. Laboratory examination demonstrated hypokalemic rhabdomyolysis caused by distal renal tubular acidosis. Investigations revealed Sjogren's syndrome as the underlying cause of the metabolic disorders. PMID:24165505

  10. Hypokalemic paralysis secondary to tenofovir induced fanconi syndrome

    PubMed Central

    Ramteke, Vishal V.; Deshpande, Rushi V.; Srivastava, Om; Wagh, Adinath

    2015-01-01

    Tenofovir induced fanconi syndrome (FS) presenting as hypokalemic paralysis is an extremely rare complication in patients on anti-retroviral therapy. We report a 50-year-old male with acquired immunodeficiency syndrome on tenofovir-based anti-retroviral therapy who presented with acute onset quadriparesis. On evaluation, he was found to have hypokalemia with hypophosphatemia, glucosuria and proteinuria suggesting FS. He regained normal power in limbs over next 12 h following correction of hypokalemia. Ours would be the second reported case in India. PMID:26692618

  11. [Two cases with dropped head syndrome caused by hypokalemic myopathy].

    PubMed

    Taniguchi, Koichiro; Okino, Iwao; Yamamoto, Nobuaki; Matsumoto, Shinichi; Tachibana, Naoko; Hamano, Toshiaki

    2011-02-01

    We reported two women (78 and 85 years of age) with dropped head syndrome caused by hypokalemic myopathy restricted to the posterior cervical muscles. Both presented with relatively rapid onset of severe neck extensor weakness. Needle EMG demonstrated myogenic changes in the cervical paraspinal muscles and there were high intensity signals in the posterior cervical muscles on the neck MRI. Dropped head syndrome resolved in both patients as potassium normalized. One of the patients relapsed 11 months later with recurrent hypokalemia, but recovered rapidly with supplementation of potassium. Focal myopathy localized in the posterior cervical muscles due to hypokalemia should be considered as one of the possible causes of dropped head syndrome.

  12. Nipah virus--a potential agent of bioterrorism?

    PubMed

    Lam, Sai-Kit

    2003-01-01

    Nipah virus, a newly emerging deadly paramyxovirus isolated during a large outbreak of viral encephalitis in Malaysia, has many of the physical attributes to serve as a potential agent of bioterrorism. The outbreak caused widespread panic and fear because of its high mortality and the inability to control the disease initially. There were considerable social disruptions and tremendous economic loss to an important pig-rearing industry. This highly virulent virus, believed to be introduced into pig farms by fruit bats, spread easily among pigs and was transmitted to humans who came into close contact with infected animals. From pigs, the virus was also transmitted to other animals such as dogs, cats, and horses. The Nipah virus has the potential to be considered an agent of bioterrorism.

  13. Annona species (Annonaceae): a rich source of potential antitumor agents?

    PubMed

    Tundis, Rosa; Xiao, Jianbo; Loizzo, Monica R

    2017-06-01

    Plants have provided the basis of traditional medicine systems throughout the world for thousands of years and continue to yield molecules for new remedies. We analyzed studies published from 2009 to 2016 on the Annona species (Annonaceae), including A. coriacea, A. crassifolia, A. hypoglauca, A. muricata, A. squamosa, A. sylvatica, and A. vepretorum, as sources of potential antitumor agents. Here, we report and discuss the mechanisms of action and structure-activity relationships of the most active Annona constituents. Annonaceous acetogenins are one of the most promising classes of natural products, owing to their potential antitumor activity. However, their neurotoxicity should not be underestimated. © 2017 New York Academy of Sciences.

  14. Discovery of potential antipsychotic agents possessing pro-cognitive properties.

    PubMed

    Lameh, Jelveh; McFarland, Krista; Ohlsson, Jorgen; Ek, Fredrik; Piu, Fabrice; Burstein, Ethan S; Tabatabaei, Ali; Olsson, Roger; Bradley, Stefania Risso; Bonhaus, Douglas W

    2012-03-01

    Current antipsychotic drug therapies for schizophrenia have limited efficacy and are notably ineffective at addressing the cognitive deficits associated with this disorder. The present study was designed to develop effective antipsychotic agents that would also ameliorate the cognitive deficits associated with this disease. In vitro studies comprised of binding and functional assays were utilized to identify compounds with the receptor profile that could provide both antipsychotic and pro-cognitive features. Antipsychotic and cognitive models assessing in vivo activity of these compounds included locomotor activity assays and novel object recognition assays. We developed a series of potential antipsychotic agents with a novel receptor activity profile comprised of muscarinic M(1) receptor agonism in addition to dopamine D(2) antagonism and serotonin 5-HT(2A) inverse agonism. Like other antipsychotic agents, these compounds reverse both amphetamine and dizocilpine-induced hyperactivity in animals. In addition, unlike other antipsychotic drugs, these compounds demonstrate pro-cognitive actions in the novel object recognition assay. The dual attributes of antipsychotic and pro-cognitive actions distinguish these compounds from other antipsychotic drugs and suggest that these compounds are prototype molecules in the development of novel pro-cognitive antipsychotic agents.

  15. Voltage sensor charge loss accounts for most cases of hypokalemic periodic paralysis.

    PubMed

    Matthews, E; Labrum, R; Sweeney, M G; Sud, R; Haworth, A; Chinnery, P F; Meola, G; Schorge, S; Kullmann, D M; Davis, M B; Hanna, M G

    2009-05-05

    Several missense mutations of CACNA1S and SCN4A genes occur in hypokalemic periodic paralysis. These mutations affect arginine residues in the S4 voltage sensors of the channel. Approximately 20% of cases remain genetically undefined. We undertook direct automated DNA sequencing of the S4 regions of CACNA1S and SCN4A in 83 cases of hypokalemic periodic paralysis. We identified reported CACNA1S mutations in 64 cases. In the remaining 19 cases, mutations in SCN4A or other CACNA1S S4 segments were found in 10, including three novel changes and the first mutations in channel domains I (SCN4A) and III (CACNA1S). All mutations affected arginine residues, consistent with the gating pore cation leak hypothesis of hypokalemic periodic paralysis. Arginine mutations in S4 segments underlie 90% of hypokalemic periodic paralysis cases.

  16. A pharmacological approach for the selection of potential anticancer agents.

    PubMed

    Double, John A

    2004-09-01

    Historically, the process of developing new anticancer agents was largely empirical. Today, because of improvements in our knowledge of the molecular processes involved in the development of cancer, the process of developing new agents is becoming more rational. Researchers from Cancer Research UK, the European Organisation for Research and Treatment of Cancer and the National Cancer Institute have shown that, by undertaking a pharmacological approach to the selection of potential anticancer agents, both meaningful antitumour data and an 80% reduction in animal usage can be obtained. It has also been demonstrated that a new pharmacological tool, the "hollow fibre system", in which tumour cells are grown in biocompatible fibres which are implanted into mice, can be used to produce meaningful antitumour data with pharmacodynamic endpoints. By increasing the amount of data that can be obtained from a single animal and opening up the possibility of eliminating the need for untreated control animals, the hollow fibre system has the potential to make a significant contribution to both reduction and refinement.

  17. Magnetic nanobeads as potential contrast agents for magnetic resonance imaging.

    PubMed

    Pablico-Lansigan, Michele H; Hickling, William J; Japp, Emily A; Rodriguez, Olga C; Ghosh, Anup; Albanese, Chris; Nishida, Maki; Van Keuren, Edward; Fricke, Stanley; Dollahon, Norman; Stoll, Sarah L

    2013-10-22

    Metal-oxo clusters have been used as building blocks to form hybrid nanomaterials and evaluated as potential MRI contrast agents. We have synthesized a biocompatible copolymer based on a water stable, nontoxic, mixed-metal-oxo cluster, Mn8Fe4O12(L)16(H2O)4, where L is acetate or vinyl benzoic acid, and styrene. The cluster alone was screened by NMR for relaxivity and was found to be a promising T2 contrast agent, with r1 = 2.3 mM(-1) s(-1) and r2 = 29.5 mM(-1) s(-1). Initial cell studies on two human prostate cancer cell lines, DU-145 and LNCap, reveal that the cluster has low cytotoxicity and may be potentially used in vivo. The metal-oxo cluster Mn8Fe4(VBA)16 (VBA = vinyl benzoic acid) can be copolymerized with styrene under miniemulsion conditions. Miniemulsion allows for the formation of nanometer-sized paramagnetic beads (~80 nm diameter), which were also evaluated as a contrast agent for MRI. These highly monodispersed, hybrid nanoparticles have enhanced properties, with the option for surface functionalization, making them a promising tool for biomedicine. Interestingly, both relaxivity measurements and MRI studies show that embedding the Mn8Fe4 core within a polymer matrix decreases r2 effects with little effect on r1, resulting in a positive T1 contrast enhancement.

  18. Hypoglycemic agents and potential anti-inflammatory activity

    PubMed Central

    Kothari, Vishal; Galdo, John A; Mathews, Suresh T

    2016-01-01

    Current literature shows an association of diabetes and secondary complications with chronic inflammation. Evidence of these immunological changes include altered levels of cytokines and chemokines, changes in the numbers and activation states of various leukocyte populations, apoptosis, and fibrosis during diabetes. Therefore, treatment of diabetes and its complications may include pharmacological strategies to reduce inflammation. Apart from anti-inflammatory drugs, various hypoglycemic agents have also been found to reduce inflammation that could contribute to improved outcomes. Extensive studies have been carried out with thiazolidinediones (peroxisome proliferator-activated receptor-γ agonist), dipeptidyl peptidase-4 inhibitors, and metformin (AMP-activated protein kinase activator) with each of these classes of compounds showing moderate-to-strong anti-inflammatory action. Sulfonylureas and alpha glucosidase inhibitors appeared to exert modest effects, while the injectable agents, insulin and glucagon-like peptide-1 receptor agonists, may improve secondary complications due to their anti-inflammatory potential. Currently, there is a lack of clinical data on anti-inflammatory effects of sodium–glucose cotransporter type 2 inhibitors. Nevertheless, for all these glucose-lowering agents, it is essential to distinguish between anti-inflammatory effects resulting from better glucose control and effects related to intrinsic anti-inflammatory actions of the pharmacological class of compounds. PMID:27114714

  19. 1,3,4-oxadiazole derivatives as potential biological agents.

    PubMed

    Sun, Juan; Makawana, Jigar A; Zhu, Hai-Liang

    2013-10-01

    The synthesis of novel compound libraries along with screening is a rapid and effective approach for the discovery of potential chemical agents, and it becomes an important method in pharmaceutical chemistry research. 1,3,4- oxadiazole derivatives as the typical heterocyclic compounds, exhibit a broad spectrum of biological activities and vital leading compounds for the development of chemical drugs. Herein, we focus on the synthesis and screening of novel 1,3,4-oxadiazoles derivatives with antimicrobial, antitumor or antiviral activities during the past decade. In this review, we discussed the synthetic development of 1,3,4-oxadiazoles derivatives, and also the relevant bioactivity and their prospects as the potential chemical drugs.

  20. Enkephalinase inhibitors: potential agents for the management of pain.

    PubMed

    Thanawala, V; Kadam, V J; Ghosh, R

    2008-10-01

    Management of acute and chronic pain has always been a key area of clinical research. Enkephalinase inhibitors (EIs) seem to be promising as therapeutic agents having antinociceptive action. They additionally possess anticraving, antidiarrhoeal and antidepressant actions. The antinociceptive action of EIs has been reported for over a decade however, their therapeutic potential is yet to be effectively explored. EIs may be broadly classified as endogenous and those that are obtained synthetically. Endogenous EIs include peptides like spinorphin and opiorphin. And compounds like RB 101, RB 120, RB 3007 constitute the synthetically obtained EIs. Endogenous and synthetic inhibitors enkephalin degrading enzymes have been studied in vivo using standard animal models. The potential EI targets appear to be APN (Aminopeptidase N), NEP (Neutral endopeptidase), DPP-III (Dipeptidyl peptidase). EIs possess the advantage that they lack the opioid side effects. This article reviews the mechanisms by which EIs act and elucidates the pathways involved.

  1. Turning on the Radio: Epigenetic Inhibitors as Potential Radiopriming Agents

    PubMed Central

    Oronsky, Bryan; Scicinski, Jan; Kim, Michelle M.; Cabrales, Pedro; Salacz, Michael E.; Carter, Corey A.; Oronsky, Neil; Lybeck, Harry; Lybeck, Michelle; Larson, Christopher; Reid, Tony R.; Oronsky, Arnold

    2016-01-01

    First introduced during the late 1800s, radiation therapy is fundamental to the treatment of cancer. In developed countries, approximately 60% of all patients receive radiation therapy (also known as the sixty percenters), which makes radioresistance in cancer an important and, to date, unsolved, clinical problem. Unfortunately, the therapeutic refractoriness of solid tumors is the rule not the exception, and the ubiquity of resistance also extends to standard chemotherapy, molecularly targeted therapy and immunotherapy. Based on extrapolation from recent clinical inroads with epigenetic agents to prime refractory tumors for maximum sensitivity to concurrent or subsequent therapies, the radioresistant phenotype is potentially reversible, since aberrant epigenetic mechanisms are critical contributors to the evolution of resistant subpopulations of malignant cells. Within the framework of a syllogism, this review explores the emerging link between epigenetics and the development of radioresistance and makes the case that a strategy of pre- or co-treatment with epigenetic agents has the potential to, not only derepress inappropriately silenced genes, but also increase reactive oxygen species production, resulting in the restoration of radiosensitivity. PMID:27384589

  2. Artocarpus plants as a potential source of skin whitening agents.

    PubMed

    Arung, Enos Tangke; Shimizu, Kuniyoshi; Kondo, Ryuichiro

    2011-09-01

    Artocarpus plants have been a focus of constant attention due to the potential for skin whitening agents. In the in vitro experiment, compounds from the Artocarpus plants, such as artocarpanone, norartocarpetin, artocarpesin, artogomezianol, andalasin, artocarbene, and chlorophorin showed tyrosinase inhibitory activity. Structure-activity investigations revealed that the 4-substituted resorcinol moiety in these compounds was responsible for their potent inhibitory activities on tyrosinase. In the in vitro assay, using B16 melanoma cells, the prenylated polyphenols isolated from Artocarpus plants, such as artocarpin, cudraflavone C, 6-prenylapigenin, kuwanon C, norartocarpin, albanin A, cudraflavone B, and brosimone I showed potent inhibitory activity on melanin formation. Structure-activity investigations revealed that the introduction of an isoprenoid moiety to a non-isoprenoid-substituted polyphenol enhanced the inhibitory activity of melanin production in B16 melanoma cells. In the in vivo investigation, the extract of the wood of Artocarpus incisus and a representative isolated compound from it, artocarpin had a lightening effect on the skin of guinea pigs' backs. Other in vivo experiments using human volunteers have shown that water extract of Artocarpus lakoocha reduced the melanin formation in the skin of volunteers. These results indicate that the extracts of Artocarpus plants are potential sources for skin whitening agents.

  3. Caffeine-induced hypokalemic paralysis in pregnancy.

    PubMed

    Appel, C C; Myles, T D

    2001-05-01

    Excessive ingestion of caffeine can induce hypokalemia, which affects the neuromuscular system and can lead to paralysis. A 24-year-old woman, gravida 3, para 2-0-0-2 at 33 weeks' gestation presented with muscular paralysis and hypokalemia secondary to drinking 6 to 7 L of cola per day with little other oral intake. After potassium replacement and stopping caffeine ingestion, the symptoms resolved quickly. The physiologic changes of pregnancy might potentiate the effect of caffeine on serum potassium concentration.

  4. Hypokalemic myopathy in primary aldosteronism: A case report

    PubMed Central

    Wu, Chuifen; Xin, Jun; Xin, Minghua; Zou, Hai; Jing, Lie; Zhu, Caoyong; Lei, Wenhui

    2016-01-01

    Primary aldosteronism (PA) is a rare disorder. The majority of patients with PA present with typical features and are easily diagnosed. This disorder is usually diagnosed with hypokalemia, hypertension or an adrenal mass. However, patients with atypical symptoms may present a challenge for diagnosis and treatment. In the present study, a case of PA is described that presented with hypokalemic myopathy simulating polymyositis. The patient was a 44-year-old woman who presented with weakness and difficulty walking. The patient was initially suspected to have PM and was treated with methylprednisolone. The patient was found to have hypokalemia which persisted despite high-dose supplementation of potassium. Adrenal computed tomography revealed a right adrenal mass. Surgical adrenalectomy was conducted. The final pathological diagnosis was benign adrenocortical adenoma. The serum tests remained normal and the patient's symptoms were resolved during the 8-month follow-up. PMID:28101185

  5. Evaluation of labdane derivatives as potential anti-inflammatory agents.

    PubMed

    Girón, Natalia; Pérez-Sacau, Elisa; López-Fontal, Raquel; Amaro-Luis, Juan M; Hortelano, Sonsoles; Estevez-Braun, Ana; de Las Heras, Beatriz

    2010-07-01

    In the present study, a series of labdane derivatives (2-9) were prepared from labdanediol (1) and their potential as anti-inflammatory agents were evaluated on lipopolysaccharide (LPS)-treated RAW 264.7 macrophages. All compounds were able to inhibit LPS-induced nitric oxide (NO), although compounds 1, 2, 5, 8 and 9 exhibited the most potent effects with a range of IC(50) values of 5-15 microM. Similarly to the inhibitory effects on NO release, these labdane derivatives also inhibited prostaglandin E(2) (PGE(2)) production. However, analysis of cell viability demonstrated that effects on NO release and (PGE(2)) production of compounds 1, 8 and 9 were due to citotoxicity, whereas compound 2 and 5 did not show any effect in the survival of RAW 264.7 macrophages. In addition to these in vitro data, compound 5 also showed anti-inflammatory activity in vivo, when tested in mice. They prevented the extent of swelling in the TPA-induced ear edema model and inhibited MPO activity, showing similar potency to that of the widely used anti-inflammatory drug indomethacin. These results indicate that compound 2 and in particular compound 5 might be used for the design of new anti-inflammatory agents. Copyright (c) 2010 Elsevier Masson SAS. All rights reserved.

  6. 3-Amidocoumarins as Potential Multifunctional Agents against Neurodegenerative Diseases.

    PubMed

    Matos, Maria João; Rodríguez-Enríquez, Fernanda; Borges, Fernanda; Santana, Lourdes; Uriarte, Eugenio; Estrada, Martín; Rodríguez-Franco, María Isabel; Laguna, Reyes; Viña, Dolores

    2015-12-01

    Monoamine oxidase (MAO) generates reactive oxygen species (ROS), which cause neuronal cell death, causing neurodegeneration. Agents that are able to concurrently inhibit MAO and scavenge free radicals represent promising multifunctional neuroprotective agents that could be used to delay or slow the progression of neurodegenerative diseases. In this work, variously substituted 3-amidocoumarins are described that exert neuroprotection in vitro against hydrogen peroxide in rat cortical neurons, as well as antioxidant activity in a 1,1-diphenyl-2-picrylhydrazyl (DPPH⋅) radical scavenging assay. Selective and reversible inhibitors of the MAO-B isoform were identified. Interestingly, in the case of the 3-benzamidocoumarins, substitution at position 4 with a hydroxy group abolishes MAO-B activity, but the compounds remain active in the neuroprotection model. Further evaluation of 3-heteroarylamide derivatives indicates that it is the nature of the heterocycle that determines the neuroprotective effects. Evaluation in a parallel artificial membrane permeability assay (PAMPA) highlighted the need to further improve the blood-brain barrier permeability of this compound class. However, the compounds described herein adhere to Lipinski's rule of five, suggesting that this novel scaffold has desirable properties for the development of potential drug candidates.

  7. Therapeutic potential of HMGB1-targeting agents in sepsis

    PubMed Central

    Wang, Haichao; Zhu, Shu; Zhou, Rongrong; Li, Wei; Sama, Andrew E.

    2008-01-01

    Sepsis refers to a systemic inflammatory response syndrome resulting from a microbial infection. The inflammatory response is partly mediated by innate immune cells (such as macrophages, monocytes and neutrophils), which not only ingest and eliminate invading pathogens but also initiate an inflammatory response upon recognition of pathogen-associated molecular patterns (PAMPs). The prevailing theories of sepsis as a dysregulated inflammatory response, as manifested by excessive release of inflammatory mediators such as tumour necrosis factor and high-mobility group box 1 protein (HMGB1), are supported by extensive studies employing animal models of sepsis. Here we review emerging evidence that support extracellular HMGB1 as a late mediator of experimental sepsis, and discuss the therapeutic potential of several HMGB1-targeting agents (including neutralising antibodies and steroid-like tanshinones) in experimental sepsis. PMID:18980707

  8. Potential Anti-HIV Agents from Marine Resources: An Overview

    PubMed Central

    Vo, Thanh-Sang; Kim, Se-Kwon

    2010-01-01

    Human immunodeficiency virus (HIV) infection causes acquired immune deficiency syndrome (AIDS) and is a global public health issue. Anti-HIV therapy involving chemical drugs has improved the life quality of HIV/AIDS patients. However, emergence of HIV drug resistance, side effects and the necessity for long-term anti-HIV treatment are the main reasons for failure of anti-HIV therapy. Therefore, it is essential to isolate novel anti-HIV therapeutics from natural resources. Recently, a great deal of interest has been expressed regarding marine-derived anti-HIV agents such as phlorotannins, sulfated chitooligosaccharides, sulfated polysaccharides, lectins and bioactive peptides. This contribution presents an overview of anti-HIV therapeutics derived from marine resources and their potential application in HIV therapy. PMID:21339954

  9. Aptamer Oligonucleotides: Novel Potential Therapeutic Agents in Autoimmune Disease.

    PubMed

    Li, Weibin; Lan, Xiaopeng

    2015-08-01

    Aptamers are single-stranded deoxyribonucleic acid or ribonucleic acid oligonucleotides generated in vitro based on affinity for certain target molecules by a process known as Systematic Evolution of Ligands by Exponential Enrichment. Aptamers can bind their target molecules with high specificity and selectivity by means of structure compatibility, stacking of aromatic rings, electrostatic and van der Waals interactions, and hydrogen bonding. With several advantages over monoclonal antibodies and other conventional small-molecule therapeutics, such as high specificity and affinity, negligible batch to batch variation, flexible modification and stability, lack of toxicity and low immunogenicity, aptamers are becoming promising novel diagnostic and therapeutic agents. This review focuses on the development of aptamers as potential therapeutics for autoimmune diseases, including diabetes mellitus, multiple sclerosis, rheumatoid arthritis, myasthenia gravis, and systemic lupus erythematosus.

  10. Synthesis, biological evaluation of chrysin derivatives as potential immunosuppressive agents.

    PubMed

    Lv, Peng-Cheng; Cai, Tian-Tian; Qian, Yong; Sun, Juan; Zhu, Hai-Liang

    2011-01-01

    A series of novel chrysin derivatives was firstly synthesized and evaluated on their immunosuppressive activity in the search for potential immunosuppressive agents. Among them, compounds 5c displayed the most potent immunosuppressive inhibitory activity with IC(50) of 0.78 μM, which was comparable to that of cyclosporin A (IC(50) = 0.06 μM). The preliminary mechanism of compound 5c inhibition effects was also detected by flow cytometry (FCM), and the compound exerted immunosuppressive activity via inducing the apoptosis of activated lymph node cells in a dose dependent manner. Furthermore, the estimated LD(50) (in mg/kg) in vivo of compound 5c is 738.2, which indicated that compound 5c was low toxic. Copyright © 2010 Elsevier Masson SAS. All rights reserved.

  11. Cows' milk fat components as potential anticarcinogenic agents.

    PubMed

    Parodi, P W

    1997-06-01

    The optimum approach to conquering cancer is prevention. Although the human diet contains components which promote cancer, it also contains components with the potential to prevent it. Recent research shows that milk fat contains a number of potential anticarcinogenic components including conjugated linoleic acid, sphingomyelin, butyric acid and ether lipids. Conjugated linoleic acid inhibited proliferation of human malignant melanoma, colorectal, breast and lung cancer cell lines. In animals, it reduced the incidence of chemically induced mouse epidermal tumors, mouse forestomach neoplasia and aberrant crypt foci in the rat colon. In a number of studies, conjugated linoleic acid, at near-physiological concentrations, inhibited mammary tumorigenesis independently of the amount and type of fat in the diet. In vitro studies showed that the milk phospholipid, sphingomyelin, through its biologically active metabolites ceramide and sphingosine, participates in three major antiproliferative pathways influencing oncogenesis, namely, inhibition of cell growth, and induction of differentiation and apoptosis. Mice fed sphingomyelin had fewer colon tumors and aberrant crypt foci than control animals. About one third of all milk triacylglycerols contain one molecule of butyric acid, a potent inhibitor of proliferation and inducer of differentiation and apoptosis in a wide range of neoplastic cell lines. Although butyrate produced by colonic fermentation is considered important for colon cancer protection, an animal study suggests dietary butyrate may inhibit mammary tumorigenesis. The dairy cow also has the ability to extract other potential anticarcinogenic agents such as beta-carotene, beta-ionone and gossypol from its feed and transfer them to milk. Animal studies comparing the tumorigenic potential of milk fat or butter with linoleic acid-rich vegetable oils or margarines are reviewed. They clearly show less tumor development with dairy products.

  12. Potential antifertility agents from plants: a comprehensive review.

    PubMed

    Kumar, Dinesh; Kumar, Ajay; Prakash, Om

    2012-03-06

    Traditional medicines are practiced worldwide for regulation fertility since ancient times. This review provides a comprehensive summary of medicinal flora inhabitating throughout the world regarding their traditional usage by various tribes/ethnic groups for fertility regulation in females. Bibliographic investigation was carried out by analyzing classical text books and peer reviewed papers, consulting worldwide accepted scientific databases from the last six decades. Plants/their parts/extracts traditionally used for abortion, contraception, emmenagogue and sterilization purposes have been considered as antifertility agents. Research status of selected potential plant species has been discussed. Further, compounds isolated from plants with attributed fertility regulating potentials are also classified into three categories: (a) phytoconstituents with anti-implantation activity, (b) phytoconstituents with abortifacient activity and (c) phytoconstituents with contraceptive activity. 577 plant species belonging to 122 families, traditionally used in fertility regulation in females, have been recorded, of which 298 plants have been mentioned as abortifacients (42%), 188 as contraceptives (31%), 149 as emmenagogues (24%), and 17 as sterilizers. Among 122 plant families, fabaceae constitutes 49.2%, asteraceae 40.98%, euphorbiaceae 19.7%, apiaceae 16.4%, poaceae 12.3%, labiateae 11.5%, and others in lesser proportion. Various plant parts used in fertility regulation include leaves (25%), roots (22%), fruits (15%), seeds (12%), stem/stem bark (37%), and flowers (4%). Some active compounds, isolated from about various plant species, have been reported to possess significant antifertility potential. This review clearly indicates that it is time to increase the number of experimental studies to find out novel potential chemical entities from such a vast array of unexploited plants having traditional role in fertility regulation. Also, the mechanisms of action by which

  13. Potential of Biological Agents in Decontamination of Agricultural Soil

    PubMed Central

    Javaid, Muhammad Kashif; Ashiq, Mehrban; Tahir, Muhammad

    2016-01-01

    Pesticides are widely used for the control of weeds, diseases, and pests of cultivated plants all over the world, mainly since the period after the Second World War. The use of pesticides is very extensive to control harm of pests all over the globe. Persistent nature of most of the synthetic pesticides causes serious environmental concerns. Decontamination of these hazardous chemicals is very essential. This review paper elaborates the potential of various biological agents in decontamination of agricultural soils. The agricultural crop fields are contaminated by the periodic applications of pesticides. Biodegradation is an ecofriendly, cost-effective, highly efficient approach compared to the physical and chemical methods which are expensive as well as unfriendly towards environment. Biodegradation is sensitive to the concentration levels of hydrogen peroxide and nitrogen along with microbial community, temperature, and pH changes. Experimental work for optimum conditions at lab scale can provide very fruitful results about specific bacterial, fungal strains. This study revealed an upper hand of bioremediation over physicochemical approaches. Further studies should be carried out to understand mechanisms of biotransformation. PMID:27293964

  14. Quercetin and rutin as potential agents antifungal against Cryptococcus spp.

    PubMed

    Oliveira, V M; Carraro, E; Auler, M E; Khalil, N M

    2016-01-01

    Amphotericin B is a fungicidal substance that is treatment of choice for most systemic fungal infections affecting as cryptococcosis the immunocompromised patients. However, severe side effects have limited the utility of this drug. The aim of this study was to evaluate the antifungal effect of the combination of amphotericin B with quercetin or rutin and as a protective of citotoxic effect. The antifungal activity to amphotericin B, quercetin and rutin alone and in combination was determined in Candida sp and Cryptococcus neoformans strains. Cytotoxicity test on erythrocytes was performed by spectrophotometric absorbance of hemoglobin. The amphotericin B MIC was reduced when used in combination with quercetin or rutin to C. neoformans ATCC strain and reduced when combined with rutin to a clinical isolate of C. neoformans. In addition, the combination of quercetin with amphotericin B may reduce the toxicity of amphotericin B to red blood cells. Our results suggest that quercetin and rutin are potential agents to combine with amphotericin B in order to reduce the amphotericin dose to lessen side effects and improve antifungal efficacy.

  15. 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

  16. Novel 'soft' beta-blockers as potential safe antiglaucoma agents.

    PubMed

    Bodor, N; elKoussi, A

    1988-04-01

    A series of novel "soft" beta-blockers was designed and synthesized based on the "inactive metabolite approach". Accordingly, the acidic metabolite of metoprolol was converted into various lipophilic esters. The new compounds were tested for their effect on the intraocular pressure (IOP) of rabbits using the ultra-short acting beta-adrenergic antagonist "Esmolol" as a reference compound. Most of the tested compounds displayed a higher and a more prolonged ocular hypotensive activity than the reference methyl ester. The adamantaneethyl ester 2 emerged as the best potential candidate for ophthalmic use as an antiglaucoma agent. This compound exhibited an effective and long lasting ocular hypotensive activity without local irritation to the eye. At the same time, it showed a very fast rate of hydrolysis in human blood (t1/2 = 7.0 minutes) to the inactive acid metabolite. This makes possible effective separation of the desired ocular activity from unwanted systemic beta-blocking action. Unilateral treatment with 2 produced reduction in the IOP only in the treated eye, consistent with the mechanism proposed.

  17. Marine Diterpenoids as Potential Anti-Inflammatory Agents

    PubMed Central

    González, Yisett; Torres-Mendoza, Daniel; Jones, Gillian E.; Fernandez, Patricia L.

    2015-01-01

    The inflammatory response is a highly regulated process, and its dysregulation can lead to the establishment of chronic inflammation and, in some cases, to death. Inflammation is the cause of several diseases, including rheumatoid arthritis, inflammatory bowel diseases, multiple sclerosis, and asthma. The search for agents inhibiting inflammation is a great challenge as the inflammatory response plays an important role in the defense of the host to infections. Marine invertebrates are exceptional sources of new natural products, and among those diterpenoids secondary metabolites exhibit notable anti-inflammatory properties. Novel anti-inflammatory diterpenoids, exclusively produced by marine organisms, have been identified and synthetic molecules based on those structures have been obtained. The anti-inflammatory activity of marine diterpenoids has been attributed to the inhibition of Nuclear Factor-κB activation and to the modulation of arachidonic acid metabolism. However, more research is necessary to describe the mechanisms of action of these secondary metabolites. This review is a compilation of marine diterpenoids, mainly isolated from corals, which have been described as potential anti-inflammatory molecules. PMID:26538822

  18. Radioiodinated carnitine and acylcarnitine analogs as potential myocardial imaging agents

    SciTech Connect

    McConnell, D.S.

    1991-01-01

    R-carnitine is extremely important in mammalian energy metabolism. Gamma-butyrobetaine, the immediate biosynthetic precursor to R-carnitine, is synthesized in many organs. However, only liver can hydroxylate gamma-butyrobetaine to carnitine. Thus the transport of carnitine from its site of synthesis to the site of utilization is of utmost importance. Carnitine is found in highest concentration in cardiac and skeletal muscle, where it is required for the transport of fatty acids into the mitochondria. Before fatty acids are utilized as fuel for the myocyte by beta-oxidation, they are bound to carnitine as an acylcarnitine ester at the 3-hydroxyl, and transported across the micochondrial membranes. R,S-Carnitine has been shown to be taken up by myocytes. The author has begun a study on the use of carnitine derivatives as potential carriers for the site-specific delivery of radioiodine to bidning sites in the myocardium. Such agents labeled with a gamma-emitting nuclide such as iodine-123 would be useful for the noninvasive imaging of these tissues. The aim was to synthesize a variety of radiolabeled analogs of carnitine and acylcarnitine to address questions of transport, binding and availability for myocardial metabolism. These analogs consist of N-alkylated derivatives of carnitine, acylcarnitine esters as well as carnitine amides and ethers. One C-alkylated derivative showed interesting biodistribution, elevated myocardial uptake and competition with carnitine for binding in the myocardium.

  19. Fetal Globin Gene Inducers: Novel Agents & New Potential

    PubMed Central

    Perrine, Susan P.; Castaneda, Serguei A.; Chui, David H.; Faller, Douglas V.; Berenson, Ronald J.; Fucharoen, Suthat

    2013-01-01

    Inducing expression of endogenous fetal globin (γ-globin) gene expression to 60-70% of alpha globin synthesis produces β-thalassemia trait globin synthetic ratios and can reduce anemia to a mild level. Several classes of therapeutics have induced γ-globin expression in beta thalassemia patients and subsequently raised total hemoglobin levels, demonstrating proof-of-concept of the approach. Butyrate treatment eliminated transfusion requirements in formerly transfusion-dependent patients with treatment for as long as 7 years. However, prior generations were not readily applicable for widespread use. Currently, a novel oral dual-action therapeutic sodium 2,2-dimethylbutyrate is in clinical trials, an oral decitabine formulation is under development, and agents with complementary mechanisms of action can be applied in combined regimens. Identification of 3 major genetic trait loci which modulate clinical severity provides avenues for developing tailored regimens. These refinements offer renewed potential to apply fetal globin induction as a treatment approach in patient-friendly regimens that can be used world-wide. PMID:20712788

  20. Marine Diterpenoids as Potential Anti-Inflammatory Agents.

    PubMed

    González, Yisett; Torres-Mendoza, Daniel; Jones, Gillian E; Fernandez, Patricia L

    2015-01-01

    The inflammatory response is a highly regulated process, and its dysregulation can lead to the establishment of chronic inflammation and, in some cases, to death. Inflammation is the cause of several diseases, including rheumatoid arthritis, inflammatory bowel diseases, multiple sclerosis, and asthma. The search for agents inhibiting inflammation is a great challenge as the inflammatory response plays an important role in the defense of the host to infections. Marine invertebrates are exceptional sources of new natural products, and among those diterpenoids secondary metabolites exhibit notable anti-inflammatory properties. Novel anti-inflammatory diterpenoids, exclusively produced by marine organisms, have been identified and synthetic molecules based on those structures have been obtained. The anti-inflammatory activity of marine diterpenoids has been attributed to the inhibition of Nuclear Factor-κB activation and to the modulation of arachidonic acid metabolism. However, more research is necessary to describe the mechanisms of action of these secondary metabolites. This review is a compilation of marine diterpenoids, mainly isolated from corals, which have been described as potential anti-inflammatory molecules.

  1. 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

  2. Astaxanthin: a potential therapeutic agent in cardiovascular disease.

    PubMed

    Fassett, Robert G; Coombes, Jeff S

    2011-03-21

    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.

  3. Potential of Biological Agents in Decontamination of Agricultural Soil.

    PubMed

    Javaid, Muhammad Kashif; Ashiq, Mehrban; Tahir, Muhammad

    2016-01-01

    Pesticides are widely used for the control of weeds, diseases, and pests of cultivated plants all over the world, mainly since the period after the Second World War. The use of pesticides is very extensive to control harm of pests all over the globe. Persistent nature of most of the synthetic pesticides causes serious environmental concerns. Decontamination of these hazardous chemicals is very essential. This review paper elaborates the potential of various biological agents in decontamination of agricultural soils. The agricultural crop fields are contaminated by the periodic applications of pesticides. Biodegradation is an ecofriendly, cost-effective, highly efficient approach compared to the physical and chemical methods which are expensive as well as unfriendly towards environment. Biodegradation is sensitive to the concentration levels of hydrogen peroxide and nitrogen along with microbial community, temperature, and pH changes. Experimental work for optimum conditions at lab scale can provide very fruitful results about specific bacterial, fungal strains. This study revealed an upper hand of bioremediation over physicochemical approaches. Further studies should be carried out to understand mechanisms of biotransformation.

  4. Animal Venom Peptides: Potential for New Antimicrobial Agents.

    PubMed

    Primon-Barros, Muriel; José Macedo, Alexandre

    2017-01-01

    Microbial infections affect people worldwide, causing diseases with significant impact on public health, indicating the need for research and development of new antimicrobial agents. Animal venoms represent a vast and largely unexploited source of biologically active molecules with attractive candidates for the development of novel therapeutics. Venoms consist of complex mixtures of molecules, including antimicrobial peptides (AMPs). Since the discovery of AMPs, they have been studied as promising new antimicrobial drugs. Amongst the remarkable sources of AMPs with known antimicrobial activities are ants, bees, centipedes, cone snails, scorpions, snakes, spiders, and wasps. The antimicrobial tests against bacteria, protozoans, fungi and viruses using 170 different peptides isolated directly from crude venoms or cDNA libraries of venom glands are listed and discussed in this review, as well as hemolytic ativity. The potential of venoms as source of new compounds, including AMPs, is extensively discussed. Currently, there are six FDA-approved drugs and many others are undergoing preclinical and clinical trials. The search for antimicrobial "weapons" makes the AMPs from venoms promising candidates. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  5. Wasp Venom Toxins as a Potential Therapeutic Agent.

    PubMed

    Dongol, Yashad; Dhananjaya, Bhadrapara L; Shrestha, Rakesh K; Aryal, Gopi

    2016-01-01

    It is high time now to discover novel drugs due to the increasing rate of drug resistance by the pathogen organisms and target cells as well as the dependence or tolerance of the body towards the drug. As it is obvious that significant numbers of the modern day pharmaceuticals are derived from natural products, it is equally astonishing to accept that venoms of various origins have therapeutic potentials. Wasp venoms are also a rich source of therapeutically important toxins which includes short cationic peptides, kinins, polyamines and polyDNA viruses, to name a few indentified. Wasp venom cationic peptides, namely mastoparan and its analogs, show a very important potency as an antimicrobial and anticancer agents of the future. They have proven to be the better candidates due to their lesser toxic effects and higher selectivity upon chemical modification and charge optimization. They also have superiority over the conventional chemical drugs as the target cells very rarely develop resistance against them because these peptides primarily imparts its effect through biophysical interaction with the target cell membrane which is dependent upon the net charge of the peptide, its hydrophobicity and anionicity and fluidity of the target cell membranes. Besides, the other components of wasp venom such as kinins, polyamines and polyDNA viruses show various pharmacological promise in the treatment of pain, inflammatory disease, and neurodegenerative diseases such as epilepsy and aversion.

  6. Massive Retinal Pigment Epithelial Detachment Following Acute Hypokalemic Quadriparesis in Dengue Fever.

    PubMed

    Goel, Neha; Bhambhwani, Vishaal; Jain, Pooja; Ghosh, Basudeb

    2016-01-01

    To describe an unusual retinal manifestation of dengue fever in an endemic region. A 35 year old male presenting with acute onset decreased vision in his right eye, was found to have a massive retinal pigment epithelial detachment (PED) extending up to the vascular arcades. He had been diagnosed with acute hypokalemic quadriparesis in dengue fever in the preceding week, which had resolved following treatment. The patient was managed conservatively. At three months follow up, there was spontaneous flattening of the PEDs with improvement in visual acuity. Dengue fever complicated by acute hypokalemic quadriparesis can be associated with PED, which can be large. The condition resolves spontaneously and bears a good prognosis.

  7. An unusual case of dengue infection presenting with hypokalemic paralysis with hypomagnesemia.

    PubMed

    Jain, Rajendra Singh; Gupta, Pankaj Kumar; Agrawal, Rakesh; Kumar, Sunil; Khandelwal, Kapil

    2015-08-01

    Neurological manifestations are unusual in dengue fever and can be due to neurotropic effect, systemic complications of dengue infection, or immune mediated. Acute hypokalemic paralysis is a rare systemic complication of dengue infection; however, hypokalemia along with hypomagnesemia has not been reported earlier. We herein report an extremely unusual and probably the first case of dengue infection in a 30-year-old male who presented to us with hypokalemic paralysis along with hypomagnesemia. This case report highlights that hypomagnesemia may be a significant complication in dengue infection. Correction of hypomagnesemia is of paramount importance to avoid refractory hypokalemia leading to severe consequences.

  8. Practical aspects in the management of hypokalemic periodic paralysis

    PubMed Central

    Levitt, Jacob O

    2008-01-01

    Management considerations in hypokalemic periodic paralysis include accurate diagnosis, potassium dosage for acute attacks, choice of diuretic for prophylaxis, identification of triggers, creating a safe physical environment, peri-operative measures, and issues in pregnancy. A positive genetic test in the context of symptoms is the gold standard for diagnosis. Potassium chloride is the favored potassium salt given at 0.5–1.0 mEq/kg for acute attacks. The oral route is favored, but if necessary, a mannitol solvent can be used for intravenous administration. Avoidance of or potassium prophylaxis for common triggers, such as rest after exercise, high carbohydrate meals, and sodium, can prevent attacks. Chronically, acetazolamide, dichlorphenamide, or potassium-sparing diuretics decrease attack frequency and severity but are of little value acutely. Potassium, water, and a telephone should always be at a patient's bedside, regardless of the presence of weakness. Perioperatively, the patient's clinical status should be checked frequently. Firm data on the management of periodic paralysis during pregnancy is lacking. Patient support can be found at . PMID:18426576

  9. Cardiac arrhythmias in hypokalemic periodic paralysis: Hypokalemia as only cause?

    PubMed

    Stunnenberg, Bas C; Deinum, Jaap; Links, Thera P; Wilde, Arthur A; Franssen, Hessel; Drost, Gea

    2014-09-01

    It is unknown how often cardiac arrhythmias occur in hypokalemic periodic paralysis (HypoPP) and if they are caused by hypokalemia alone or other factors. This systematic review shows that cardiac arrhythmias were reported in 27 HypoPP patients. Cases were confirmed genetically (13 with an R528H mutation in CACNA1S, 1 an R669H mutation in SCN4A) or had a convincing clinical diagnosis of HypoPP (13 genetically undetermined) if reported prior to the availability of genetic testing. Arrhythmias occurred during severe hypokalemia (11 patients), between attacks at normokalemia (4 patients), were treatment-dependent (2 patients), or unspecified (10 patients). Nine patients died from arrhythmia. Convincing evidence for a pro-arrhythmogenic factor other than hypokalemia is still lacking. The role of cardiac expression of defective skeletal muscle channels in the heart of HypoPP patients remains unclear. Clinicians should be aware of and prevent treatment-induced cardiac arrhythmia in HypoPP.

  10. Gitelman's syndrome presenting with hypocalcemic tetany and hypokalemic periodic paralysis.

    PubMed

    Gandhi, Kunal; Prasad, Dharmendra; Malhotra, Vinay; Agrawal, Dhananjai

    2016-01-01

    Gitelman's syndrome is an autosomal recessive renal tubular disorder characterized by hypomagnesemia, hypokalemia, hypocalciuria, and metabolic alkalosis. Hypocalcemic tetany as a presentation of Gitelman's syndrome has rarely been reported in literature. We report a rare case of Gitelman's syndrome presenting with hypocalcemic tetany along with hypokalemic periodic paralysis. A 17-year-old female was admitted to our hospital with a history of perioral numbness and carpal spasms of five days duration with progressive quadriparesis developing over a period of few hours. Past history was significant for three episodes of transient lower limb weakness. On examination, blood pressure was 110/70 mm Hg. Chvostek's sign and Trousseau's sign were positive. Neurologically, she was fully oriented. She had Grade 3 power in all the four limbs with intact sensation. Laboratory tests showed hypocalcemia (7.8 mg/dL), hypokalemia (2.2 mEq/L), hypomagnesemia (0.9 mEq/L), and hypocalciuria (104 mg/day). Arterial blood gas showed mild metabolic alkalosis with respiratory compensation. Thus, a clinical diagnosis of GS was made. The patient made a remarkable recovery after the correction of electrolyte imbalance. The aim of this case report is to re-emphasize the fact that hypocalcemia can rarely occur in Gitelman's syndrome.

  11. Disulfiram attenuates osteoclast differentiation in vitro: a potential antiresorptive agent.

    PubMed

    Ying, Hua; Qin, An; Cheng, Tak S; Pavlos, Nathan J; Rea, Sarah; Dai, Kerong; Zheng, Ming H

    2015-01-01

    Disulfiram (DSF), a cysteine modifying compound, has long been clinically employed for the treatment of alcohol addiction. Mechanistically, DSF acts as a modulator of MAPK and NF-κB pathways signaling pathways. While these pathways are crucial for osteoclast (OC) differentiation, the potential influence of DSF on OC formation and function has not been directly assessed. Here, we explore the pharmacological effects of DSF on OC differentiation, activity and the modulation of osteoclastogenic signaling cascades. We first analyzed cytotoxicity of DSF on bone marrow monocytes isolated from C57BL/6J mice. Upon the establishment of optimal dosage, we conducted osteoclastogenesis and bone resorption assays in the presence or absence of DSF treatment. Luciferase assays in RAW264.7 cells were used to examine the effects of DSF on major transcription factors activation. Western blot, reverse transcription polymerase chain reaction, intracellular acidification and proton influx assays were employed to further dissect the underlying mechanism. DSF treatment dose-dependently inhibited both mouse and human osteoclastogenesis, especially at early stages of differentiation. This inhibition correlated with a decrease in the expression of key osteoclastic marker genes including CtsK, TRAP, DC-STAMP and Atp6v0d2 as well as a reduction in bone resorption in vitro. Suppression of OC differentiation was found to be due, at least in part, to the blockade of several key receptor activators of nuclear factor kappa-B ligand (RANKL)-signaling pathways including ERK, NF-κB and NFATc1. On the other hand, DSF failed to suppress intracellular acidification and proton influx in mouse and human osteoclasts using acridine orange quenching and microsome-based proton transport assays. Our findings indicate that DSF attenuates OC differentiation via the collective suppression of several key RANKL-mediated signaling cascades, thus making it an attractive agent for the treatment of OC

  12. Disulfiram Attenuates Osteoclast Differentiation In Vitro: A Potential Antiresorptive Agent

    PubMed Central

    Cheng, Tak S.; Pavlos, Nathan J.; Rea, Sarah; Dai, Kerong; Zheng, Ming H.

    2015-01-01

    Disulfiram (DSF), a cysteine modifying compound, has long been clinically employed for the treatment of alcohol addiction. Mechanistically, DSF acts as a modulator of MAPK and NF-κB pathways signaling pathways. While these pathways are crucial for osteoclast (OC) differentiation, the potential influence of DSF on OC formation and function has not been directly assessed. Here, we explore the pharmacological effects of DSF on OC differentiation, activity and the modulation of osteoclastogenic signaling cascades. We first analyzed cytotoxicity of DSF on bone marrow monocytes isolated from C57BL/6J mice. Upon the establishment of optimal dosage, we conducted osteoclastogenesis and bone resorption assays in the presence or absence of DSF treatment. Luciferase assays in RAW264.7 cells were used to examine the effects of DSF on major transcription factors activation. Western blot, reverse transcription polymerase chain reaction, intracellular acidification and proton influx assays were employed to further dissect the underlying mechanism. DSF treatment dose-dependently inhibited both mouse and human osteoclastogenesis, especially at early stages of differentiation. This inhibition correlated with a decrease in the expression of key osteoclastic marker genes including CtsK, TRAP, DC-STAMP and Atp6v0d2 as well as a reduction in bone resorption in vitro. Suppression of OC differentiation was found to be due, at least in part, to the blockade of several key receptor activators of nuclear factor kappa-B ligand (RANKL)-signaling pathways including ERK, NF-κB and NFATc1. On the other hand, DSF failed to suppress intracellular acidification and proton influx in mouse and human osteoclasts using acridine orange quenching and microsome-based proton transport assays. Our findings indicate that DSF attenuates OC differentiation via the collective suppression of several key RANKL-mediated signaling cascades, thus making it an attractive agent for the treatment of OC

  13. Francisella tularensis as a potential agent of bioterrorism?

    PubMed

    Maurin, Max

    2015-02-01

    Francisella tularensis is a category A bioterrorism agent. It is the etiological agent of tularemia, a zoonotic disease found throughout the northern hemisphere. The intentional spread of F. tularensis aerosols would probably lead to severe and often fatal pneumonia cases, but also secondary cases from contaminated animals and environments. We are not ready to face such a situation. No vaccine is currently available. A few antibiotics are active against F. tularensis, but strains resistant to these antibiotics could be used in the context of bioterrorism. We need new therapeutic strategies to fight against category A bioterrorism agents, including development of new drugs inhibiting F. tularensis growth and/or virulence, or enhancing the host response to infection by this pathogen.

  14. Hypokalemic periodic paralysis, facial dysmorphism and ventricular arrhythmia (clinical triad of Andersen-Tawil syndrome).

    PubMed

    Thakkar, Mitesh; Biswas, T K; Desle, Hrishikesh B

    2012-11-01

    Andersen-Tawil Syndrome (ATS) is a rare potassium channel disorder, characterized by episodic weakness, ventricular arrhythmias and dysmorphic features (short stature, scoliosis, clinodactyly, hypertelorism, small or prominent low set ears, micrognathia and broad forehead). We report a case of hypokalemic periodic paralysis with dysmorphic facial features and ventricular arrhythmia resembling Andersen-Tawil syndrome.

  15. Synthesis of Potential Prophylactic Agents against Cyanide Intoxication

    DTIC Science & Technology

    1993-04-12

    compiles th« synthetic procedures described in reports submitted for quarters 9-12 of this contract. We have also colligated structures of all...tingle example of ihn compound class was submitted for biological evaluation this report period, and the physical properties of this agent (1) are...condensation of propiophenone »ith diethyl oxalate (Eq. II) The physical properties of these compounds are summarized in Table 2. a cr, 3 F 4 OCH3 5 CH3

  16. Analogues of [(triethylsilyl)ethynyl]estradiol as potential antifertility agents.

    PubMed

    Peters, R H; Crowe, D F; Avery, M A; Chong, W K; Tanabe, M

    1988-03-01

    Various 17 alpha-ethynylsteroids were prepared and derivatized as the corresponding triethylsilyl compounds 2-35, which were examined for a ratio of antifertility to estrogenic activity that would be more beneficial than that of the presently used agent. Among the triethylsilyl compounds evaluated, only 23 displayed this desired ratio, although two other compounds without the triethylsilyl moiety, 18 and 26, shared similar characteristics.

  17. Antioxidants: potential antiviral agents for Japanese encephalitis virus infection.

    PubMed

    Zhang, Yu; Wang, Zehua; Chen, Huan; Chen, Zongtao; Tian, Yanping

    2014-07-01

    Japanese encephalitis (JE) is prevalent throughout eastern and southern Asia and the Pacific Rim. It is caused by the JE virus (JEV), which belongs to the family Flaviviridae. Despite the importance of JE, little is known about its pathogenesis. The role of oxidative stress in the pathogenesis of viral infections has led to increased interest in its role in JEV infections. This review focuses mainly on the role of oxidative stress in the pathogenesis of JEV infection and the antiviral effect of antioxidant agents in inhibiting JEV production. First, this review summarizes the pathogenesis of JE. The pathological changes include neuronal death, astrocyte activation, and microglial proliferation. Second, the relationship between oxidative stress and JEV infection is explored. JEV infection induces the generation of oxidants and exhausts the supply of antioxidants, which activates specific signaling pathways. Finally, the therapeutic efficacy of a variety of antioxidants as antiviral agents, including minocycline, arctigenin, fenofibrate, and curcumin, was studied. In conclusion, antioxidants are likely to be developed into antiviral agents for the treatment of JE. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

  18. Microtubule-Stabilizing Agents as Potential Therapeutics for Neurodegenerative Disease

    PubMed Central

    Brunden, Kurt R.; Trojanowski, John Q.; Smith, Amos B.; Lee, Virginia M.-Y.; Ballatore, Carlo

    2014-01-01

    Microtubules (MTs)1, cytoskeletal elements found in all mammalian cells, play a significant role in cell structure and in cell division. They are especially critical in the proper functioning of post-mitotic central nervous system neurons, where MTs serve as the structures on which key cellular constituents are trafficked in axonal projections. MTs are stabilized in axons by the MT-associated protein tau, and in several neurodegenerative diseases, including Alzheimer’s disease, frontotemporal lobar degeneration, and Parkinson’s disease, tau function appears to be compromised due to the protein dissociating from MTs and depositing into insoluble inclusions referred to as neurofibrillary tangles. This loss of tau function is believed to result in alterations of MT structure and function, resulting in aberrant axonal transport that likely contributes to the neurodegenerative process. There is also evidence of axonal transport deficiencies in other neurodegenerative diseases, including amyotrophic lateral sclerosis and Huntington’s disease, which may result, at least in part, from MT alterations. Accordingly, a possible therapeutic strategy for such neurodegenerative conditions is to treat with MT-stabilizing agents, such as those that have been used in the treatment of cancer. Here, we review evidence of axonal transport and MT deficiencies in a number of neurodegenerative diseases, and summarize the various classes of known MT-stabilizing agents. Finally, we highlight the growing evidence that small molecule MT-stabilizing agents provide benefit in animal models of neurodegenerative disease and discuss the desired features of such molecules for the treatment of these central nervous system disorders. PMID:24433963

  19. Microtubule-stabilizing agents as potential therapeutics for neurodegenerative disease.

    PubMed

    Brunden, Kurt R; Trojanowski, John Q; Smith, Amos B; Lee, Virginia M-Y; Ballatore, Carlo

    2014-09-15

    Microtubules (MTs), cytoskeletal elements found in all mammalian cells, play a significant role in cell structure and in cell division. They are especially critical in the proper functioning of post-mitotic central nervous system neurons, where MTs serve as the structures on which key cellular constituents are trafficked in axonal projections. MTs are stabilized in axons by the MT-associated protein tau, and in several neurodegenerative diseases, including Alzheimer's disease, frontotemporal lobar degeneration, and Parkinson's disease, tau function appears to be compromised due to the protein dissociating from MTs and depositing into insoluble inclusions referred to as neurofibrillary tangles. This loss of tau function is believed to result in alterations of MT structure and function, resulting in aberrant axonal transport that likely contributes to the neurodegenerative process. There is also evidence of axonal transport deficiencies in other neurodegenerative diseases, including amyotrophic lateral sclerosis and Huntington's disease, which may result, at least in part, from MT alterations. Accordingly, a possible therapeutic strategy for such neurodegenerative conditions is to treat with MT-stabilizing agents, such as those that have been used in the treatment of cancer. Here, we review evidence of axonal transport and MT deficiencies in a number of neurodegenerative diseases, and summarize the various classes of known MT-stabilizing agents. Finally, we highlight the growing evidence that small molecule MT-stabilizing agents provide benefit in animal models of neurodegenerative disease and discuss the desired features of such molecules for the treatment of these central nervous system disorders. Copyright © 2014 Elsevier Ltd. All rights reserved.

  20. Monocarboxylate Transporter 1 Inhibitors as Potential Anticancer Agents

    PubMed Central

    2015-01-01

    Potent monocarboxylate transporter 1 inhibitors (MCT1) have been developed based on α-cyano-4-hydroxycinnamic acid template. Structure–activity relationship studies demonstrate that the introduction of p-N, N-dialkyl/diaryl, and o-methoxy groups into cyanocinnamic acid has maximal MCT1 inhibitory activity. Systemic toxicity studies in healthy ICR mice with few potent MCT1 inhibitors indicate normal body weight gains in treated animals. In vivo tumor growth inhibition studies in colorectal adenocarcinoma (WiDr cell line) in nude mice xenograft models establish that compound 27 exhibits single agent activity in inhibiting the tumor growth. PMID:26005533

  1. Monocarboxylate transporter 1 inhibitors as potential anticancer agents.

    PubMed

    Gurrapu, Shirisha; Jonnalagadda, Sravan K; Alam, Mohammad A; Nelson, Grady L; Sneve, Mary G; Drewes, Lester R; Mereddy, Venkatram R

    2015-05-14

    Potent monocarboxylate transporter 1 inhibitors (MCT1) have been developed based on α-cyano-4-hydroxycinnamic acid template. Structure-activity relationship studies demonstrate that the introduction of p-N, N-dialkyl/diaryl, and o-methoxy groups into cyanocinnamic acid has maximal MCT1 inhibitory activity. Systemic toxicity studies in healthy ICR mice with few potent MCT1 inhibitors indicate normal body weight gains in treated animals. In vivo tumor growth inhibition studies in colorectal adenocarcinoma (WiDr cell line) in nude mice xenograft models establish that compound 27 exhibits single agent activity in inhibiting the tumor growth.

  2. Non-peptidyl insulin mimetics as a potential antidiabetic agent.

    PubMed

    Nankar, Rakesh P; Doble, Mukesh

    2013-08-01

    Insulin has an important role in the maintenance of blood sugar. It is the only available therapeutic agent for the treatment of type 1 diabetes mellitus and there is a dire need for an oral substitute. Different categories of compounds including mono and di substituted benzoquinones, vanadium based compounds and natural products have been reported to cause insulin-like effects either by increasing phosphorylation of insulin receptor (IR) or inhibiting the protein tyrosine phosphatases. This review summarizes the development of various insulin mimetics with special emphasis on their structure-activity relationships and various biological actions they produce.

  3. Investigation of Vietnamese plants for potential anticancer agents

    PubMed Central

    Pérez, Lynette Bueno; Still, Patrick C.; Naman, C. Benjamin; Ren, Yulin; Pan, Li; Chai, Hee-Byung; Carcache de Blanco, Esperanza J.; Ninh, Tran Ngoc; Van Thanh, Bui; Swanson, Steven M.; Soejarto, Djaja D.

    2014-01-01

    Higher plants continue to afford humankind with many new drugs, for a variety of disease types. In this review, recent phytochemical and biological progress is presented for part of a collaborative multi-institutional project directed towards the discovery of new antitumor agents. The specific focus is on bioactive natural products isolated and characterized structurally from tropical plants collected in Vietnam. The plant collection, identification, and processing steps are described, and the natural products isolated from these species are summarized with their biological activities. PMID:25395897

  4. Pyrazoles as potential anti-angiogenesis agents: a contemporary overview

    PubMed Central

    Kasiotis, Konstantinos M.; Tzanetou, Evangelia N.; Haroutounian, Serkos A.

    2014-01-01

    Angiogenesis is a mulit-step process by which new blood vessels are formed from preexisting vasculature. It is a key rate limiting factor in tumor growth since new blood vessels are necessary to increase tumor size. In this context it has been shown that anti-angiogenic factors can be used in cancer therapy. Among the plethora of heterocyclic compounds administered as anti-angiogenesis agents, pyrazoles constitute one of the bottlenecks of this category. Currently, several pyrazole based compounds are administered or are in Phase II and III trials and new targets emerge. It is highly possible that the advent of the next two decades will lead to the discovery and use of additional pyrazoles whose anti-angiogenic profile will position them in the forefront of the battle of various malignancies. The present review is an attempt to focus on those pyrazoles that arise as anti-angiogenesis agents commenting both on the chemistry and bioactivity that these exhibit aiming to contribute to the perspectives that they hold for future research. PMID:25250310

  5. Ginsenoside Rd as a potential neuroprotective agent prevents trimethyltin injury

    PubMed Central

    Hou, Jingang; Xue, Jianjie; Lee, Mira; Sung, Changkeun

    2017-01-01

    Trimethyltin (TMT) is a potent neurotoxicant that affects various regions within the central nervous system, including the neocortex, cerebellum, and hippocampus. In the present study, ginsenoside Rd was investigated as a candidate neuroprotective agent in a primary hippocampal neuron culture and mouse models. TMT induced neurotoxicity in a seven-day primary hippocampal neuron culture in a dose-dependent manner (2.5–10 µM). However, pre-treatment with 20 µg/ml ginsenoside Rd for 24 h reversed the toxic action. ICR mice were administered a single injection of 2 mg/kg body weight TMT. Apparent tremor seizure and impaired passive avoidance tests demonstrated significant differences when compared with a saline treated control group. Nissl staining was performed to evaluate the neuronal loss in the hippocampus. In addition, immunostaining of glial fibrillary acidic protein characterized the features of astroglial activation. These results demonstrated that TMT markedly induced Cornu Ammonis 1 subregion neuronal loss and reactive astrocytes in the hippocampus, indicating disrupted hippocampal function. Notably, ginsenoside Rd attenuated the tremor seizures and cognitive decline in behavioral tests. Additionally, significantly reduced neuronal loss (P=0.018) and active astroglials (P=0.003) were observed in the ginsenoside Rd treated group. Ginsenoside Rd prevented TMT-induced cell apoptosis via regulation of B-cell lymphoma 2 (Bcl-2), bcl-2-like protein 4 and caspase-3. These results demonstrate that ginsenoside may be developed as a neuroprotective agent to prevent TMT-induced neurotoxicity. PMID:28413642

  6. Synthetic antiferromagnetic nanoparticles as potential contrast agents in MRI.

    PubMed

    Van Roosbroeck, Ruben; Van Roy, Willem; Stakenborg, Tim; Trekker, Jesse; D'Hollander, Antoine; Dresselaers, Tom; Himmelreich, Uwe; Lammertyn, Jeroen; Lagae, Liesbet

    2014-03-25

    We present the top-down synthesis of a novel type of MRI T2 contrast agent with great control over size and shape using a colloidal lithography technique. The resulting synthetic antiferromagnetic nanoparticles (SAF-NPs) yield improved relaxivities compared to superparamagnetic iron oxide alternatives (SPIONs). For T2 weighted imaging, the outer sphere relaxation theory has shown that the sensitivity of a T2 contrast agent is dependent on the particle size with an optimal size that exceeds the superparamagnetic limit of SPIONs. With the use of the interlayer exchange coupling effect, the SAF-NPs presented here do not suffer from this limit. Adjusting the outer sphere relaxation theory for spherical particles to SAF-NPs, we show both theoretically and experimentally that the SAF-NP size can be optimized to reach the r2 maximum. With measured r2 values up to 355 s(-1) mM(-1), our SAF-NPs show better performance than commercial alternatives and are competitive with the state-of-the-art. This performance is confirmed in an in vitro MRI study on SKOV3 cells.

  7. Pyrazoles as potential anti-angiogenesis agents: A contemporary overview

    NASA Astrophysics Data System (ADS)

    Kasiotis, Konstantinos; Tzanetou, Evangelia; Haroutounian, Serkos

    2014-09-01

    Angiogenesis is a mulit-step process by which new blood vessels are formed from preexisting vasculature. It is a key rate limiting factor in tumor growth since new blood vessels are necessary to increase tumor size. In this context it has been shown that anti-angiogenic factors can be used in cancer therapy. Among the plethora of heterocyclic compounds administered as anti-angiogenesis agents, pyrazoles constitute one of the bottlenecks of this category. Currently several pyrazole based compounds are administered or are in Phase II and III trials and new targets emerge. It is highly possible that the advent of the next two decades will lead to the discovery and use of additional pyrazoles whose anti-angiogenic profile will position them in the forefront of the battle of various malignancies. The present review is an attempt to focus on those pyrazoles that arise as anti-angiogenesis agents commenting both on the chemistry and bioactivity that these exhibit aiming to contribute to the perspectives that they hold for future research.

  8. Urine concentration and dilution in hypokalemic and hypercalcemic dogs

    PubMed Central

    Bennett, Cleaves M.

    1970-01-01

    The urine-concentrating mechanism was studied in chronic hypokalemia (seven dogs given a low K+, high NaCl diet plus injections of deoxycorticosterone acetate [DOCA]) and chronic hypercalcemia (seven dogs given vitamin D). In the potassium-depleted dogs, muscle, serum, and urine K+ fell markedly, but glomerular filtration rate (GFR) and body weight varied little. Maximum urine osmolality fell in all dogs (mean decrease = 45%); however, solute-free water reabsorption (TCH2O) at high rates of solute excretion remained normal in three of four dogs. Free water excretion (CH2O) increased normally or supranormally as a function of increasing Na+ delivery to Henle's loop in six dogs so tested. Hypercalcemia of several weeks duration caused a decrease in both GFR (mean 36%) as well as in maximum urine osmolality (mean 57%). Maximum TCH2O was not invariably depressed; in fact, when the values were adjusted for the reduced number of functioning nephrons (TCH2O/CIn), four of seven studies were normal. CH20/CIn increased normally (or supranormally) with increasing fractional Na delivery to Henle's loop in four of five dogs. I conclude that the lowered maximum urine osmolality in these hypokalemic and hypercalcemic dogs was not related to abnormal water reabsorption from the collecting ducts. Although not specifically measured in this study, it is very likely that solute accumulation in the renal medulla was reduced. This probably was not caused by abnormal delivery of sodium to, nor reabsorption of sodium from Henle's loop. It is likely that a more subtle defect exists in the countercurrent mechanisms for establishing a steep concentration gradient in the renal medulla. In the few hypercalcemic dogs in whom GFR was very low, I believe that injury to, and blockage of medullary tubules could account for most of the reduction in maximum UOsm. Although not specifically ruled out, there is no evidence here to suggest that high serum Ca+ or low serum K+ per se causes a defect in

  9. Therapeutic Potential of Hydrazones as Anti-Inflammatory Agents

    PubMed Central

    Bala, Suman; Sharma, Neha; Saini, Vipin

    2014-01-01

    Hydrazones are a special class of organic compounds in the Schiff base family. Hydrazones constitute a versatile compound of organic class having basic structure (R1R2C=NNR3R4). The active centers of hydrazone, that is, carbon and nitrogen, are mainly responsible for the physical and chemical properties of the hydrazones and, due to the reactivity toward electrophiles and nucleophiles, hydrazones are used for the synthesis of organic compound such as heterocyclic compounds with a variety of biological activities. Hydrazones and their derivatives are known to exhibit a wide range of interesting biological activities like antioxidant, anti-inflammatory, anticonvulsant, analgesic, antimicrobial, anticancer, antiprotozoal, antioxidant, antiparasitic, antiplatelet, cardioprotective, anthelmintic, antidiabetic, antitubercular, trypanocidal, anti-HIV, and so forth. The present review summarizes the efficiency of hydrazones as potent anti-inflammatory agents. PMID:25383223

  10. Ag+ complexes as potential therapeutic agents in medicine and pharmacy.

    PubMed

    Hecel, Aleksandra; Kolkowska, Paulina; Krzywoszynska, Karolina; Szebesczyk, Agnieszka; Rowinska-Zyrek, Magdalena; Kozlowski, Henryk

    2017-09-20

    Silver is a non-essential element, with promising antimicrobial and anticancer properties. This work is a detailed summary of the newest findings on the bioinorganic chemistry of silver, with a special focus on the applications of Ag+ complexes and nanoparticles. The coordination chemistry of silver is given a reasonable amount of attention, summarizing the most common silver binding sites and giving examples of such binding motifs in biologically important proteins. Possible applications of this metal and its complexes in medicine, in particular as antibacterial and antifungal agents and in cancer therapy is discussed in detail. The most recent data on silver nanoparticles are also summarized. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  11. Potential radiosensitizing agents. 5. 2-Substituted benzimidazole derivatives

    SciTech Connect

    Gupta, R.P.; Larroquette, C.A.; Agrawal, K.C.

    1982-11-01

    A series of 2-substituted benzimidazoles and their derivatives have been synthesized and tested for their ability to selectively sensitize hypoxic Chinese hamster cells (V-79) toward the lethal effect of ionizing radiation. These compounds were prepared by reacting the 2-substituted benzimidazoles with 1,2-epoxy-3-methoxypropane in the presence of potassium carbonate. Reaction of the 2-nitro and 2-methylfonyl analogue with the epoxide also yielded a cyclized material, which was confirmed to be a benzimidazo(2,1-b)oxazole. In an attempt to increase the electron affinity, 5- or 6-nitro-2-substituted-benzimidazoles were also synthesized and then reacted with the epoxide to yield the corresponding 1-substituted derivatives. The results of the biological tests for the radiosensitizing activity of these agents against Chinese hamster cells (V-79) in culture indicated that the 2-nitro-substituted analogues were the most effective sensitizers in this series.

  12. Enteric MRI contrast agents: comparative study of five potential agents in humans.

    PubMed

    Tart, R P; Li, K C; Storm, B L; Rolfes, R J; Ang, P G

    1991-01-01

    We compared the effectiveness of 1 mM Geritol, 12% corn oil emulsion, Kaolin-pectin, single contrast oral barium sulfate, and effervescent granules as enteric magnetic resonance imaging (MRI) contrast agents. Five volunteers were recruited. Each volunteer ingested for examinations, separated by at least one week, either 500 ml of each of the liquid preparations or two packets of the CO2 granules (producing 400 ml of CO2 per packet). Abdominal MR images were then obtained using a 1.5 T Magnetom imager and SE 550/22, SE 2000/45/90 and FISP 40/18/40 degrees pulse sequences. The oil emulsions were best tolerated. Barium sulfate caused the greatest amount of nausea, followed by Geritol and Kaolin-pectin. With FISP 40/18/40 degrees, 60%-80% of the small bowel was well delineated using oil emulsion, Kaolin-pectin, or barium sulfate. We conclude that oil emulsion was by far the best enteric MR contrast agent in our study. Good delineation of the small bowel and pancreas can be achieved using oil emulsion and gradient echo pulse sequences. The lack of side-effects and the excellent taste make it highly acceptable to human subjects.

  13. Biological agents with potential for misuse: a historical perspective and defensive measures.

    PubMed

    Bhalla, Deepak K; Warheit, David B

    2004-08-15

    Biological and chemical agents capable of producing serious illness or mortality have been used in biowarfare from ancient times. Use of these agents has progressed from crude forms in early and middle ages, when snakes and infected cadavers were used as weapons in battles, to sophisticated preparations for use during and after the second World War. Cults and terrorist organizations have attempted the use of biological agents with an aim to immobilize populations or cause serious harm. The reasons for interest in these agents by individuals and organizations include relative ease of acquisition, potential for causing mass casualty or panic, modest financing requirement, availability of technology, and relative ease of delivery. The Centers for Disease Control and Prevention has classified Critical Biological Agents into three major categories. This classification was based on several criteria, which include severity of impact on human health, potential for delivery in a weapon, capacity to cause panic and special needs for development, and stockpiling of medication. Agents that could cause the greatest harm following deliberate use were placed in category A. Category B included agents capable of producing serious harm and significant mortality but of lower magnitude than category A agents. Category C included emerging pathogens that could be developed for mass dispersion in future and their potential as a major health threat. A brief description of the category A bioagents is included and the pathophysiology of two particularly prominent agents, namely anthrax and smallpox, is discussed in detail. The potential danger from biological agents and their ever increasing threat to human populations have created a need for developing technologies for their early detection, for developing treatment strategies, and for refinement of procedures to ensure survival of affected individuals so as to attain the ultimate goal of eliminating the threat from intentional use of

  14. Neem components as potential agents for cancer prevention and treatment

    PubMed Central

    Hao, Fang; Kumar, Sandeep; Yadav, Neelu; Chandra, Dhyan

    2016-01-01

    Azadirachta indica, also known as neem, is commonly found in many semi-tropical and tropical countries including India, Pakistan, and Bangladesh. The components extracted from neem plant have been used in traditional medicine for the cure of multiple diseases including cancer for centuries. The extracts of seeds, leaves, flowers, and fruits of neem have consistently shown chemopreventive and antitumor effects in different types of cancer. Azadirachtin and nimbolide are among the few bioactive components in neem that have been studied extensively, but research on a great number of additional bioactive components is warranted. The key anticancer effects of neem components on malignant cells include inhibition of cell proliferation, induction of cell death, suppression of cancer angiogenesis, restoration of cellular reduction/oxidation (redox) balance, and enhancement of the host immune responses against tumor cells. While the underlying mechanisms of these effects are mostly unclear, the suppression of NF-κB signaling pathway is, at least partially, involved in the anticancer functions of neem components. Importantly, the anti-proliferative and apoptosis-inducing effects of neem components are tumor selective as the effects on normal cells are significantly weaker. In addition, neem extracts sensitize cancer cells to immunotherapy and radiotherapy, and enhance the efficacy of certain cancer chemotherapeutic agents. This review summarizes the current updates on the anticancer effects of neem components and their possible impact on managing cancer incidence and treatment. PMID:25016141

  15. Novel Oxadiazole Thioglycosides as Potential Anti-Acinetobacter Agents

    PubMed Central

    Akbari Dilmaghani, Karim; Nasuhi Pur, Fazel; Mahammad pour, Majid; Mahammad nejad, Jafar

    2016-01-01

    The glycosylation of 1,3,4-oxadiazole-2-thiones has been performed with peracetylated β-pyranosyl bromide in the presence of potassium carbonate. Deprotection of acetylated thioglycosides was necessary for increasing their antibacterial effects. The structures of nucleosides were confirmed by 1H NMR, 13C NMR and HRMS. The anomeric protons of nucleosides c1–4 were assigned to the doublet, confirming the β-configuration. The synthesized compounds were tested for their antimicrobial activity against Acinetobacter calcoaceticus (Gram-negetive) strain in-vitro in comparison with Ampicillin as a reference drug which is normally used for treating such infections. The synthetic compounds showed different inhibition zones against tested bacterial strain. Thioglycoside derivatives of 1,3,4-oxadiazole-2-thiones (c set) were more active against Acinetobacter calcoaceticus ATCC 23055 than “parent” 1,3,4-oxadiazole-2-thiones (a set), confirming the relation between glyco-conjugation and increasing of antiproliferative activity of antibiotic agents. The best result belonged to nucleoside bearing 2-furyl moiety in its heterocyclic nucleus (c4). The existence of m-PhNO2 group as Ar in structures of a set and their corresponding sugar derivatives decreased the antibacterial activity of them in comparison with the rest of synthetic compounds. PMID:28243273

  16. Thymol and eugenol derivatives as potential antileishmanial agents.

    PubMed

    de Morais, Selene Maia; Vila-Nova, Nadja Soares; Bevilaqua, Claudia Maria Leal; Rondon, Fernanda Cristina; Lobo, Carlos Henrique; de Alencar Araripe Noronha Moura, Arlindo; Sales, Antônia Débora; Rodrigues, Ana Paula Ribeiro; de Figuereido, José Ricardo; Campello, Claudio Cabral; Wilson, Mary E; de Andrade, Heitor Franco

    2014-11-01

    In Northeastern Brazil visceral leishmaniasis is endemic with lethal cases among humans and dogs. Treatment is toxic and 5-10% of humans die despite treatment. The aim of this work was to survey natural active compounds to find new molecules with high activity and low toxicity against Leishmania infantum chagasi. The compounds thymol and eugenol were chosen to be starting compounds to synthesize acetyl and benzoyl derivatives and to test their antileishmanial activity in vitro and in vivo against L. i. chagasi. A screening assay using luciferase-expressing promastigotes was used to measure the growth inhibition of promastigotes, and an ELISA in situ was performed to evaluate the growth inhibition of amastigote. For the in vivo assay, thymol and eugenol derivatives were given IP to BALB/c mice at 100mg/kg/day for 30 days. The thymol derivatives demonstrated the greater activity than the eugenol derivatives, and benzoyl-thymol was the best inhibitor (8.67 ± 0.28 μg/mL). All compounds demonstrated similar activity against amastigotes, and acetyl-thymol was more active than thymol and the positive control drug amphotericin B. Immunohistochemistry demonstrated the presence of Leishmania amastigote only in the spleen but not the liver of mice treated with acetyl-thymol. Thus, these synthesized derivatives demonstrated anti-leishmanial activity both in vitro and in vivo. These may constitute useful compounds to generate new agents for treatment of leishmaniasis.

  17. Thymol and eugenol derivatives as potential antileishmanial agents

    PubMed Central

    de Morais, Selene Maia; Vila-Nova, Nadja Soares; Bevilaqua, Claudia Maria Leal; Rondon, Fernanda Cristina; Lobo, Carlos Henrique; de Alencar Araripe Noronha Moura, Arlindo; Sales, Antônia Débora; Rodrigues, Ana Paula Ribeiro; de Figuereido, José Ricardo; Campello, Claudio Cabral; Wilson, Mary E.; de Andrade, Heitor Franco

    2016-01-01

    In Northeastern Brazil visceral leishmaniasis is endemic with lethal cases among humans and dogs. Treatment is toxic and 5–10% of humans die despite treatment. The aim of this work was to survey natural active compounds to find new molecules with high activity and low toxicity against Leishmania infantum chagasi. The compounds thymol and eugenol were chosen to be starting compounds to synthesize acetyl and benzoyl derivatives and to test their antileishmanial activity in vitro and in vivo against L. i. chagasi. A screening assay using luciferase-expressing promastigotes was used to measure the growth inhibition of promastigotes, and an ELISA in situ was performed to evaluate the growth inhibition of amastigote. For the in vivo assay, thymol and eugenol derivatives were given IP to BALB/c mice at 100 mg/kg/day for 30 days. The thymol derivatives demonstrated the greater activity than the eugenol derivatives, and benzoyl- thymol was the best inhibitor (8.67 ± 0.28 μg/mL). All compounds demonstrated similar activity against amastigotes, and acetyl-thymol was more active than thymol and the positive control drug amphotericin B. Immunohistochemistry demonstrated the presence of Leishmania amastigote only in the spleen but not the liver of mice treated with acetyl-thymol. Thus, these synthesized derivatives demonstrated anti-leishmanial activity both in vitro and in vivo. These may constitute useful compounds to generate new agents for treatment of leishmaniasis. PMID:25281268

  18. Potential serotonergic agents for the treatment of schizophrenia.

    PubMed

    Garay, Ricardo P; Bourin, Michel; de Paillette, Evelyne; Samalin, Ludovic; Hameg, Ahcène; Llorca, Pierre-Michel

    2016-01-01

    For the last 30 years, drugs targeting serotonin receptors (5-HTR) have been intensively investigated in schizophrenia. New drugs targeting 5-HTRs are under development in patients with schizophrenia. In this review, the authors describe the recent clinical trials for schizophrenia with selective serotonergic agents and provide an opinion on how the investigated drugs can help to fulfil current treatment needs. Clinical trials were found in US and EU clinical trial registries and in the medical literature. Relevant 5-HTR antagonists active in animal models of schizophrenia were also analysed. Antipsychotics reduce positive symptoms of schizophrenia (delusions, hallucinations and disordered thought), but have undesirable side effects. Moreover, satisfactory treatment of negative symptoms (apathy, poverty of speech, lack of interest in social interactions) and cognitive dysfunction is currently not available. The selective 5-HT2CR full agonist vabicaserin showed antipsychotic efficacy with fewer side effects than olanzapine. Adjunctive pimavanserin (a selective 5-HT2AR inverse agonist) facilitated antipsychotic dose and side-effect reductions. Selective 5-HT3R antagonists (ondansetron, tropisetron and granisetron) showed positive results on negative symptoms and/or cognitive impairments in phase II trials. Adjunctive ondansetron has now entered a phase III trial for such indications. Finally, 5-HTA5R and 5-HT7R antagonists have shown procognitive actions in animal models of schizophrenia. These novel serotonergic drugs seem promising for improving the current treatment of schizophrenia.

  19. Cotinine: a potential new therapeutic agent against Alzheimer's disease.

    PubMed

    Echeverria, Valentina; Zeitlin, Ross

    2012-07-01

    Tobacco smoking has been correlated with a lower incidence of Alzheimer's disease (AD). This negative correlation has been attributed to nicotine's properties. However, the undesired side-effects of nicotine and the absence of clear evidence of positive effects of this drug on the cognitive abilities of AD patients have decreased the enthusiasm for its therapeutic use. In this review, we discuss evidence showing that cotinine, the main metabolite of nicotine, has many of the beneficial effects but none of the negative side-effects of its precursor. Cotinine has been shown to be neuroprotective, to improve memory in primates as well as to prevent memory loss, and to lower amyloid-beta (Aβ)) burden in AD mice. In AD, cotinine's positive effect on memory is associated with the inhibition of Aβ aggregation, the stimulation of pro-survival factors such as Akt, and the inhibition of pro-apoptotic factors such as glycogen synthase kinase 3 beta (GSK3β). Because stimulation of the α7 nicotinic acetylcholine receptors (α7nAChRs) positively modulates these factors and memory, the involvement of these receptors in cotinine's effects are discussed. Because of its beneficial effects on brain function, good safety profile, and nonaddictive properties, cotinine may represent a new therapeutic agent against AD.

  20. Calcium fructoborate--potential anti-inflammatory agent.

    PubMed

    Scorei, Romulus Ion; Rotaru, Petre

    2011-12-01

    Calcium fructoborate is a boron-based nutritional supplement. Its chemical structure is similar to one of the natural forms of boron such as bis-manitol, bis-sorbitol, bis-fructose, and bis-sucrose borate complexes found in edible plants. In vitro studies revealed that calcium fructoborate is a superoxide ion scavenger and anti-inflammatory agent. It may influence macrophage production of inflammatory mediators, can be beneficial for the suppression of cytokine production, and inhibits progression of endotoxin-associated diseases, as well as the boric acid and other boron sources. The mechanisms by which calcium fructoborate exerts its beneficial anti-inflammatory effects are not entirely clear, but some of its molecular biological in vitro activities are understood: inhibition of the superoxide within the cell; inhibition of the interleukin-1β, interleukin-6, and nitric oxide release in the culture media; and increase of the tumor necrosis factor-α production. Also, calcium fructoborate has no effects on lipopolysaccharide-induced cyclooxygenase-2 protein express. The studies on animals and humans with a dose range of 1-7 mg calcium fructoborate (0.025-0.175 mg elemental boron)/kg body weight/day exhibited a good anti-inflammatory activity, and it also seemed to have negligible adverse effect on humans.

  1. Influence of potentially remineralizing agents on bleached enamel microhardness.

    PubMed

    Borges, Alessandra Bühler; Samezima, Leticia Yumi; Fonseca, Léila Pereira; Yui, Karen Cristina Kazue; Borges, Alexandre Luiz Souto; Torres, Carlos Rocha Gomes

    2009-01-01

    This study investigated the effect of the addition of calcium and fluoride into a 35% hydrogen peroxide gel on enamel surface and subsurface microhardness. Twenty extracted human third molars were sectioned to obtain enamel fragments and they were divided into four groups (n = 20) according to the bleaching treatment. Group 1 received no bleaching procedure (control). Group 2 was treated with a 35% hydrogen peroxide gel (Total Bleach), Groups 3 and 4 were bleached with Total Bleach modified by the addition of sodium fluoride and calcium chloride, respectively. The microhardness of the enamel surface was assessed using a Vickers microdurometer immediately after the bleaching treatment. The specimens were sectioned in the central portion, polished and evaluated to determine the microhardness of the enamel subsurface to a depth of 125 microm, with an interval of 25 microm between measures. There were significant differences among the groups. In terms of surface microhardness, the bleached group exhibited the lowest means, and the calcium-modified bleached group exhibited the highest means. Regarding subsurface microhardness, there were no significant differences among the groups for the depth and interaction factors. The bleached group exhibited the lowest means, and the calcium-modified bleached group presented the highest means. It was concluded that the bleaching treatment with 35% hydrogen peroxide significantly reduced the surface and subsurface microhardness of the enamel, and the addition of fluoride and calcium in the bleaching agent increased the microhardness means of the bleached enamel.

  2. Neem components as potential agents for cancer prevention and treatment.

    PubMed

    Hao, Fang; Kumar, Sandeep; Yadav, Neelu; Chandra, Dhyan

    2014-08-01

    Azadirachta indica, also known as neem, is commonly found in many semi-tropical and tropical countries including India, Pakistan, and Bangladesh. The components extracted from neem plant have been used in traditional medicine for the cure of multiple diseases including cancer for centuries. The extracts of seeds, leaves, flowers, and fruits of neem have consistently shown chemopreventive and antitumor effects in different types of cancer. Azadirachtin and nimbolide are among the few bioactive components in neem that have been studied extensively, but research on a great number of additional bioactive components is warranted. The key anticancer effects of neem components on malignant cells include inhibition of cell proliferation, induction of cell death, suppression of cancer angiogenesis, restoration of cellular reduction/oxidation (redox) balance, and enhancement of the host immune responses against tumor cells. While the underlying mechanisms of these effects are mostly unclear, the suppression of NF-κB signaling pathway is, at least partially, involved in the anticancer functions of neem components. Importantly, the anti-proliferative and apoptosis-inducing effects of neem components are tumor selective as the effects on normal cells are significantly weaker. In addition, neem extracts sensitize cancer cells to immunotherapy and radiotherapy, and enhance the efficacy of certain cancer chemotherapeutic agents. This review summarizes the current updates on the anticancer effects of neem components and their possible impact on managing cancer incidence and treatment.

  3. THE SYNTHESIS OF POTENTIAL ANTI-RADIATION AGENTS

    DTIC Science & Technology

    potentially capable of carrying it into nu leic acids, was completed. Since replacement of the sulfur of cysteamine with selenium does not destroy...products (2-aminoselenazolines and 2-selenoethylguanidines) were prepared. The bis Bunte salt of bis(2-mercaptoethyl)amine the doublearmed analog of cysteamine was synthesized. (Author)

  4. Repositioning of chlorambucil as a potential anti-schistosomal agent.

    PubMed

    Eissa, Maha M; Mossallam, Shereen F; Amer, Eglal I; Younis, Layla K; Rashed, Hoda A

    2017-02-01

    As parasites and cancer cells share many lifestyle and behavioral resemblances, repositioning of anti-cancerous agents as anti-parasitic is quite trendy, especially those sharing the same therapeutic targets. Therefore, the current study investigated the in vitro efficacy of ascending concentrations of chlorambucil (0.5-20μg/ml) against adult Schistosoma mansoni worms, over 72h. Additionally, its in vivo effects against the different developmental stages of the worm were assessed, after an oral dose of 2.5mg/kg/day for five successive days, through evaluating the worm load reduction and worms' morphological alterations and oogram changes. In addition to tissue egg count, a histopathological study of the liver was conducted. In vitro, chlorambucil demonstrated noticeable anti-schistosomal effects in the form of progressive reductions of the worms' viability in a dose dependent manner. Complete worm death was achieved at 72h incubation with 5μg/ml drug concentration. In vivo, chlorambucil induced a significant reduction in the total worm load against all developmental stages. Its highest impact was evident against the juvenile stage, where it induced 75.8% total worm load reduction, and 89.2% and 86.7% intestinal and hepatic egg counts reduction, respectively, along with ogram alterations. Besides, it induced significant shortening of both male and female worms and promoted an amelioration of hepatic histopathology. Results show that chlorambucil possesses favorable in vitro and in vivo anti-schistosomal activity. The highest in vivo efficacy was against the juvenile stage of S. mansoni, significantly superior to praziquantel, with extended potency to the adult stage. Further studies are recommended for chlorambucil target verification and to enhance its therapeutic efficacy. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. The toxicology of bioregulators as potential agents of bioterrorism.

    PubMed

    Bokan, Slavko

    2005-06-01

    Bioregulators or modulators are biochemical compounds such as peptides, that occur naturally in organisms. Advances in biotechnology create the potential for the misuse of peptide bioregulators in offensive biological weapons programmes. Bioregulators are a new class of weapons that can damage the nervous system, alter mood, trigger psychological changes and kill. Over the last twenty years, neuroscience has produced an explosion of knowledge about receptor systems in the nerve cells that are of critical importance in receiving chemical transmitter substances released by other nerve cells. Bioregulators are closely related to substances normally found in the body that regulates normal biological processes. The potential military or terrorist use of bioregulators is similar to that of toxins. Together with increased research into toxins, the bioregulators have also been studied and synthesized. This paper presents a review of bioregulators that could be used in terrorist or other hostile activities.

  6. Thyrotoxic hypokalemic periodic paralysis due to dietary weight-loss supplement.

    PubMed

    Akinyemi, Emmanuel; Bercovici, Silvia; Niranjan, Selvanayagam; Paul, Nisha; Hemavathy, Bhakthavatsalam

    2011-05-01

    Herbal and dietary supplements for weight loss and in treatment of obesity are growing in popularity and acceptance in the United States. Most of these supplements can be obtained over the counter and can have serious adverse effects associated with their consumption. We describe 2 patients who developed thyrotoxic hypokalemic periodic paralysis 2-3 weeks after consuming thyroxine-containing weight-loss supplements. This is the first known case of thyrotoxic hypokalemic periodic paralysis secondary to dietary supplements. It is important that patients and physicians are aware of the severe adverse reactions associated with dietary supplements. Physicians should as a routine inquire about herbal and dietary supplement consumption during all patient encounters.

  7. Synthesis of genistein 2,3-anhydroglycoconjugates -- potential antiproliferative agents.

    PubMed

    Goj, Katarzyna; Rusin, Aleksandra; Szeja, Wiesław; Kitel, Radosław; Komor, Roman; Grynkiewicz, Grzegorz

    2012-01-01

    The title compounds, variously protected 2.3-anhydrosugars linked with genistein through an alkyl chain, were synthesized in a sequence of reactions. First step involved Ferrier rearragement of 3,4-di-O-acetyl-L-rhamnal with 3-bromopropanol to obtain 2,3-unsaturated bromoalkylglycosides. The next step was epoxidation with m-CPBA and finally these compounds were connected with genistein in reaction of 7-O-genistein tetra-butylamonium salt with 2,3-anhydro bromoalkylglycosides. Obtained glycoconjugates differ in orientation of an oxirane ring and the protecting group in a sugar moiety. All compounds were tested in vitro for antiproliferative potential in cancer cells.

  8. First polymer "ruthenium-cyclopentadienyl" complex as potential anticancer agent.

    PubMed

    Valente, Andreia; Garcia, Maria Helena; Marques, Fernanda; Miao, Yong; Rousseau, Cyril; Zinck, Philippe

    2013-10-01

    d-glucose end-capped polylactide ruthenium cyclopentadienyl complex (RuPMC) was newly synthesized by a straightforward method. RuPMC was tested against human MCF7 and MDAMB231 breast and A2780 ovarian adenocarcinoma revealing IC50 values in the micromolar range. A pH dependent hydrolysis is advanced by preliminary UV-visible spectroscopy. Cellular distribution studies showed that RuPMC is predominantly found in the nucleus and in the membrane. Data suggest potential application of RuPMC as a new drug delivery system for Ru(II)Cp compounds. © 2013.

  9. Renal tubular dysfunction presenting as recurrent hypokalemic periodic quadriparesis in systemic lupus erythematosus

    PubMed Central

    Prasad, D.; Agarwal, D.; Malhotra, V.; Beniwal, P.

    2014-01-01

    We report recurrent hypokalemic periodic quadriparesis in a 30-year-old woman. Patient had also symptoms of multiple large and small joint pain, recurrent oral ulceration, photosensitivity and hair loss that were persisting since last 6 months and investigations revealed systemic lupus erythematosus (SLE) with distal tubular acidosis. Our patient was successfully treated with oral potassium chloride, sodium bicarbonate, hydroxychloroquine and a short course of steroids. Thus, tubular dysfunction should be carefully assessed in patients with SLE. PMID:25249723

  10. A cola-induced hypokalemic rhabdomyolysis with electromyographic evaluation: A case report.

    PubMed

    Ferrazzoli, Davide; Sabetta, Annarita; Palamara, Grazia; Caremani, Luca; Capobianco, Marina; Balbi, Pietro; Frazzitta, Giuseppe

    2017-01-01

    To report a rare case of hypokalemic rhabdomyolysis induced by the heavy and prolonged ingestion of cola-based beverages, and its uneventful recovery after kalemia normalization. We report a 38-year-old Caucasian male presented in our emergency room with a recent and progressive weakness of the lower limbs proximal muscles. A dietary history revealed a prolonged ingestion of cola-based beverages. Blood tests showed severe hypokalemia and marked increase in serum creatine phosphokinase. The analysis of cerebrospinal fluid resulted normal. Electromyography was suggestive for a myopathy. The clinical, laboratory and neurophysiological data were evocative for a cola-induced hypokalemic rhabdomyolysis. After kalemia normalization, the improvements of the electromyographic findings paralleled the clinical recovery. Chronic consumption of large amount of cola-based soft drinks may result in severe symptomatic hypokalemia, eventually leading in turn to myopathy. To our knowledge, this is the first description of the electromyographic findings of the cola-induced hypokalemic rhabdomyolysis. An early diagnosis and a prompt treatment appear to be crucial for a benign clinical course.

  11. A cola-induced hypokalemic rhabdomyolysis with electromyographic evaluation: A case report

    PubMed Central

    Ferrazzoli, Davide; Sabetta, Annarita; Palamara, Grazia; Caremani, Luca; Capobianco, Marina; Balbi, Pietro; Frazzitta, Giuseppe

    2017-01-01

    Objective: To report a rare case of hypokalemic rhabdomyolysis induced by the heavy and prolonged ingestion of cola-based beverages, and its uneventful recovery after kalemia normalization. Methods: We report a 38-year-old Caucasian male presented in our emergency room with a recent and progressive weakness of the lower limbs proximal muscles. Results: A dietary history revealed a prolonged ingestion of cola-based beverages. Blood tests showed severe hypokalemia and marked increase in serum creatine phosphokinase. The analysis of cerebrospinal fluid resulted normal. Electromyography was suggestive for a myopathy. The clinical, laboratory and neurophysiological data were evocative for a cola-induced hypokalemic rhabdomyolysis. After kalemia normalization, the improvements of the electromyographic findings paralleled the clinical recovery. Conclusion: Chronic consumption of large amount of cola-based soft drinks may result in severe symptomatic hypokalemia, eventually leading in turn to myopathy. To our knowledge, this is the first description of the electromyographic findings of the cola-induced hypokalemic rhabdomyolysis. An early diagnosis and a prompt treatment appear to be crucial for a benign clinical course. PMID:28321307

  12. A Case of Trigger-Point Injection-Induced Hypokalemic Paralysis.

    PubMed

    Soriano, Paolo K; Bhattarai, Mukul; Vogler, Carrie N; Hudali, Tamer H

    2017-04-26

    BACKGROUND Trigger-point injection (TPI) therapy is an effective modality for symptomatic treatment of myofascial pain. Serious adverse effects are rarely observed. In this report, we present the case of a 39-year-old man who experienced severe, transient hypokalemic paralysis in the context of TPI therapy with methylprednisolone, bupivacaine, and epinephrine. He was successfully treated with electrolyte replacement in a closely monitored setting. CASE REPORT A 39-year-old man with no past medical history except for chronic left hip pain from a work-related injury received a TPI with methylprednisolone and bupivacaine. The TPI targeted the left iliopsoas tendon and was administered using ultrasound guidance. There were no immediately perceived complications, but within 12 h he presented with severe hypokalemic paralysis with a serum potassium 1.7 mmol/L. Judicious potassium repletion was initiated. Repeated tests after 6 h consistently showed normal potassium levels of 4.5 mmol/L. CONCLUSIONS Severe hypokalemic paralysis in the context of trigger-point injection is an incredibly rare occurrence and this is the first case report in English literature. A high index of clinical suspicion and a systematic approach are therefore required for prompt diagnosis and management of this obscure iatrogenic entity. Clinicians can enhance patient safety by allowing the primary pathology to guide them.

  13. Potential Antiviral Agents from Marine Fungi: An Overview.

    PubMed

    Moghadamtousi, Soheil Zorofchian; Nikzad, Sonia; Kadir, Habsah Abdul; Abubakar, Sazaly; Zandi, Keivan

    2015-07-22

    Biodiversity of the marine world is only partially subjected to detailed scientific scrutiny in comparison to terrestrial life. Life in the marine world depends heavily on marine fungi scavenging the oceans of lifeless plants and animals and entering them into the nutrient cycle by. Approximately 150 to 200 new compounds, including alkaloids, sesquiterpenes, polyketides, and aromatic compounds, are identified from marine fungi annually. In recent years, numerous investigations demonstrated the tremendous potential of marine fungi as a promising source to develop new antivirals against different important viruses, including herpes simplex viruses, the human immunodeficiency virus, and the influenza virus. Various genera of marine fungi such as Aspergillus, Penicillium, Cladosporium, and Fusarium were subjected to compound isolation and antiviral studies, which led to an illustration of the strong antiviral activity of a variety of marine fungi-derived compounds. The present review strives to summarize all available knowledge on active compounds isolated from marine fungi with antiviral activity.

  14. Potential Antiosteoporotic Agents from Plants: A Comprehensive Review

    PubMed Central

    Jia, Min; Nie, Yan; Cao, Da-Peng; Xue, Yun-Yun; Wang, Jie-Si; Zhao, Lu; Rahman, Khalid; Zhang, Qiao-Yan; Qin, Lu-Ping

    2012-01-01

    Osteoporosis is a major health hazard and is a disease of old age; it is a silent epidemic affecting more than 200 million people worldwide in recent years. Based on a large number of chemical and pharmacological research many plants and their compounds have been shown to possess antiosteoporosis activity. This paper reviews the medicinal plants displaying antiosteoporosis properties including their origin, active constituents, and pharmacological data. The plants reported here are the ones which are commonly used in traditional medical systems and have demonstrated clinical effectiveness against osteoporosis. Although many plants have the potential to prevent and treat osteoporosis, so far, only a fraction of these plants have been thoroughly investigated for their physiological and pharmacological properties including their mechanism of action. An attempt should be made to highlight plant species with possible antiosteoporosis properties and they should be investigated further to help with future drug development for treating this disease. PMID:23365596

  15. 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.

  16. Melatonin as a Potential Agent in the Treatment of Sarcopenia

    PubMed Central

    Coto-Montes, Ana; Boga, Jose A.; Tan, Dun X.; Reiter, Russel J.

    2016-01-01

    Considering the increased speed at which the world population is aging, sarcopenia could become an epidemic in this century. This condition currently has no means of prevention or treatment. Melatonin is a highly effective and ubiquitously acting antioxidant and free radical scavenger that is normally produced in all organisms. This molecule has been implicated in a huge number of biological processes, from anticonvulsant properties in children to protective effects on the lung in chronic obstructive pulmonary disease. In this review, we summarize the data which suggest that melatonin may be beneficial in attenuating, reducing or preventing each of the symptoms that characterize sarcopenia. The findings are not limited to sarcopenia, but also apply to osteoporosis-related sarcopenia and to age-related neuromuscular junction dysfunction. Since melatonin has a high safety profile and is drastically reduced in advanced age, its potential utility in the treatment of sarcopenic patients and related dysfunctions should be considered. PMID:27783055

  17. 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

  18. Marine fish-derived bioactive peptides as potential antihypertensive agents.

    PubMed

    Kim, Se-Kwon; Ngo, Dai-Hung; Vo, Thanh-Sang

    2012-01-01

    Hypertension is the most widespread risk factor for many serious cardiovascular diseases. Angiotensin-converting enzyme (ACE) plays a crucial role in cardiovascular physiological regulation by converting angiotensin I to a potent vasoconstrictor, angiotensin II. Hence, the inhibition of ACE is a key target for antihypertensive activity. Recently, potent antihypertensive peptides have been purified widely by enzymatic hydrolysis of muscle protein, skin collagen, and gelatin of many different kinds of marine fishes. Marine fish-derived bioactive peptides can be developed as antihypertensive components in functional foods or nutraceuticals. This contribution presents an overview of the ACE inhibitory peptides derived from marine fishes and discusses their future prospects to be used as potential drug candidates for preventing and treating high blood pressure. Copyright © 2012 Elsevier Inc. All rights reserved.

  19. Pyrimidine derivatives as potential agents acting on central nervous system.

    PubMed

    Kumar, Sanjiv; Deep, Aakash; Narasimhan, Balasubramanian

    2015-01-01

    Pyrimidine and its derivatives are present in many of the bioactive aromatic compounds that are of wide interest because of their diverse biological and clinical applications. The utility of pyrimidines as synthon for various biologically active compounds has given impetus to these studies. The review article aims to review the work reported on pharmacological activities of central nervous system (CNS) such as anticonvulsant and antidepressant, which created interest among researchers to synthesize variety of pyrimidine and their derivatives. The present study shows, objective of the work can be summarized as pyrimidine derivative constitute an important class of compounds for new drug development. These observations have been given novel idea for the development of new pyrimidine derivative that possess varied biological activities. This article aims to review the recent works on pyrimidine moiety together with the biological potential during the past year.

  20. Melatonin as a Potential Agent in the Treatment of Sarcopenia.

    PubMed

    Coto-Montes, Ana; Boga, Jose A; Tan, Dun X; Reiter, Russel J

    2016-10-24

    Considering the increased speed at which the world population is aging, sarcopenia could become an epidemic in this century. This condition currently has no means of prevention or treatment. Melatonin is a highly effective and ubiquitously acting antioxidant and free radical scavenger that is normally produced in all organisms. This molecule has been implicated in a huge number of biological processes, from anticonvulsant properties in children to protective effects on the lung in chronic obstructive pulmonary disease. In this review, we summarize the data which suggest that melatonin may be beneficial in attenuating, reducing or preventing each of the symptoms that characterize sarcopenia. The findings are not limited to sarcopenia, but also apply to osteoporosis-related sarcopenia and to age-related neuromuscular junction dysfunction. Since melatonin has a high safety profile and is drastically reduced in advanced age, its potential utility in the treatment of sarcopenic patients and related dysfunctions should be considered.

  1. Potential Antiviral Agents from Marine Fungi: An Overview

    PubMed Central

    Zorofchian Moghadamtousi, Soheil; Nikzad, Sonia; Abdul Kadir, Habsah; Abubakar, Sazaly; Zandi, Keivan

    2015-01-01

    Biodiversity of the marine world is only partially subjected to detailed scientific scrutiny in comparison to terrestrial life. Life in the marine world depends heavily on marine fungi scavenging the oceans of lifeless plants and animals and entering them into the nutrient cycle by. Approximately 150 to 200 new compounds, including alkaloids, sesquiterpenes, polyketides, and aromatic compounds, are identified from marine fungi annually. In recent years, numerous investigations demonstrated the tremendous potential of marine fungi as a promising source to develop new antivirals against different important viruses, including herpes simplex viruses, the human immunodeficiency virus, and the influenza virus. Various genera of marine fungi such as Aspergillus, Penicillium, Cladosporium, and Fusarium were subjected to compound isolation and antiviral studies, which led to an illustration of the strong antiviral activity of a variety of marine fungi-derived compounds. The present review strives to summarize all available knowledge on active compounds isolated from marine fungi with antiviral activity. PMID:26204947

  2. A review of ceramide analogs as potential anticancer agents

    PubMed Central

    Liu, Jiawang; Beckman, Barbara S.; Foroozesh, Maryam

    2014-01-01

    Summary Ceramide serves as a central mediator in sphingolipid metabolism and signaling pathways, regulating many fundamental cellular responses. It is referred to as a “tumor suppressor lipid”, since it powerfully potentiates signaling events which drive apoptosis, cell cycle arrest, and autophagic responses. In the typical cancer cell, ceramide levels and signaling are usually suppressed by over-expression of ceramide-metabolizing enzymes or down-regulation of ceramide-generating enzymes. However, chemotherapeutic drugs as well as radiotherapy increase intracellular ceramide levels while exogenously treating cancer cells with short-chain ceramides leads to anti-cancer effects. All evidence currently points to the fact that the up-regulation of ceramide level is a promising anti-cancer target. In this review, we exhibited a full scroll of anti-cancer ceramide analogs as down-stream receptor agonists and ceramide metabolizing enzyme inhibitors. PMID:23919551

  3. Morphine as a Potential Oxidative Stress-Causing Agent.

    PubMed

    Skrabalova, Jitka; Drastichova, Zdenka; Novotny, Jiri

    2013-11-01

    Morphine exhibits important pharmacological effects for which it has been used in medical practice for quite a long time. However, it has a high addictive potential and can be abused. Long-term use of this drug can be connected with some pathological consequences including neurotoxicity and neuronal dysfunction, hepatotoxicity, kidney dysfunction, oxidative stress and apoptosis. Therefore, most studies examining the impact of morphine have been aimed at determining the effects induced by chronic morphine exposure in the brain, liver, cardiovascular system and macrophages. It appears that different tissues may respond to morphine diversely and are distinctly susceptible to oxidative stress and subsequent oxidative damage of biomolecules. Importantly, production of reactive oxygen/nitrogen species induced by morphine, which have been observed under different experimental conditions, can contribute to some pathological processes, degenerative diseases and organ dysfunctions occurring in morphine abusers or morphine-treated patients. This review attempts to provide insights into the possible relationship between morphine actions and oxidative stress.

  4. Natural products as a source of potential cancer chemotherapeutic and chemopreventive agents.

    PubMed

    Cassady, J M; Baird, W M; Chang, C J

    1990-01-01

    Recent advances in the chemistry of novel bioactive natural products are reported. This research is directed to the exploration of plants with confirmed activity in bioassays designed to detect potential cancer chemotherapeutic and chemopreventive agents. Structural work and chemical studies are reported for several cytotoxic agents from the plants Annona densicoma, Annona reticulata, Claopodium crispifolium, Polytrichum obioense, and Psorospermum febrifugum. Studies are also reported based on development of a mammalian cell culture benzo[a]pyrene metabolism assay for the detection of potential anticarcinogenic agents from natural products. In this study a number of isoflavonoids and flavonoids with antimutagenic activity have been discovered.

  5. Aminosugar derivatives as potential anti-human immunodeficiency virus agents.

    PubMed Central

    Karpas, A; Fleet, G W; Dwek, R A; Petursson, S; Namgoong, S K; Ramsden, N G; Jacob, G S; Rademacher, T W

    1988-01-01

    Recent data suggest that aminosugar derivatives which inhibit glycoprotein processing have potential anti-human immunodeficiency virus (HIV) activity. These inhibitory effects may be due to disruption of cell fusion and subsequent cell-cell transmission of the acquired immunodeficiency syndrome (AIDS) virus. Free virus particles able to bind CD4-positive cells are still produced in the presence of these compounds with only partial reduction of infectivity. We now report a method to score in parallel both the degree of antiviral activity and the effect on cell division of aminosugar derivatives. We find that (i) the compounds 1,4-dideoxy-1,4-imino-L-arabinitol and N-(5-carboxymethyl-1-pentyl)-1,5-imino-L-fucitol partially inhibit the cytopathic effect (giant cell formation, etc.) of HIV and yield of infectious virus; (ii) the compounds N-methyldeoxynojirimycin and N-ethyldeoxynojirimycin reduce the yield of infectious HIV by an order of four and three logarithms, respectively; and (iii) one compound, N-butyldeoxynojirimycin, of the 47 compounds previously screened reduces infectious viral particles by a logarithmic order greater than five at noncytotoxic concentrations. In addition, long-term growth of infected cells in the presence of N-butyldeoxynojirimycin gradually decreases the proportion of infected cells, leading to eventual elimination of HIV from culture. This result suggests that replication is associated with cytolysis. The ability to break the cycle of replication and reinfection has important implications in the chemotherapy of AIDS. PMID:3264071

  6. Remineralizing potential of various agents on dental erosion

    PubMed Central

    Somani, Rani; Jaidka, Shipra; Singh, Deepti Jawa; Arora, Vanika

    2014-01-01

    Aim The purpose of this study is to compare the effect of casein phosphopeptide-amorphous calcium phosphate (CPP-ACP, Tooth Mousse) containing and casein phosphopeptide-amorphous calcium phosphate with fluoride (CPP-ACPF, Tooth Mousse Plus) containing pastes on dental erosion. Materials and methods Thirty permanent non-carious premolars indicated for orthodontic extraction were included in this study and were sectioned in mesiodistal direction vertically. After immersion in the carbonated drink for 14 min, samples were treated with various remineralizing pastes which were CPP-ACP containing paste (Tooth Mousse) and CPP-ACPF containing paste (Tooth Mousse Plus) according to the manufacturer's instructions. Vickers Microhardness was recorded at baseline, after exposure to erosive drink and after treatment with remineralizing pastes. Data obtained was statistically analysed using Student t-test with a level of significance set at p < 0.05. Results CPP-ACP (Tooth Mousse) and CPP-ACP with fluoride (Tooth Mousse Plus) resulted in 30.52% and 38.98% increase in post-erosion microhardness values respectively. The remineralizing potential of CPP-ACP with fluoride containing paste (Tooth Mousse Plus) was significantly better than that of CPP-ACP containing paste (Tooth Mousse) (p < 0.05). Conclusion Casein phosphopeptide-amorphous calcium phosphate with fluoride (CPP-ACPF, Tooth Mousse Plus) can be recommended to be used in preventing erosive tooth wear from acidic beverages. PMID:25737926

  7. Investigation of Stilbenoids as Potential Therapeutic Agents for Rotavirus Gastroenteritis.

    PubMed

    Ball, Judith M; Medina-Bolivar, Fabricio; Defrates, Katelyn; Hambleton, Emily; Hurlburt, Megan E; Fang, Lingling; Yang, Tianhong; Nopo-Olazabal, Luis; Atwill, Richard L; Ghai, Pooja; Parr, Rebecca D

    2015-01-01

    Rotavirus (RV) infections cause severe diarrhea in infants and young children worldwide. Vaccines are available but cost prohibitive for many countries and only reduce severe symptoms. Vaccinated infants continue to shed infectious particles, and studies show decreased efficacy of the RV vaccines in tropical and subtropical countries where they are needed most. Continuing surveillance for new RV strains, assessment of vaccine efficacy, and development of cost effective antiviral drugs remain an important aspect of RV studies. This study was to determine the efficacy of antioxidant and anti-inflammatory stilbenoids to inhibit RV replication. Peanut (A. hypogaea) hairy root cultures were induced to produce stilbenoids, which were purified by high performance countercurrent chromatography (HPCCC) and analyzed by HPLC. HT29.f8 cells were infected with RV in the presence stilbenoids. Cell viability counts showed no cytotoxic effects on HT29.f8 cells. Viral infectivity titers were calculated and comparatively assessed to determine the effects of stilbenoid treatments. Two stilbenoids, trans-arachidin-1 and trans-arachidin-3, show a significant decrease in RV infectivity titers. Western blot analyses performed on the infected cell lysates complemented the infectivity titrations and indicated a significant decrease in viral replication. These studies show the therapeutic potential of the stilbenoids against RV replication.

  8. Potential New Agents for the Management of Hyperkalemia.

    PubMed

    Packham, David K; Kosiborod, Mikhail

    2016-02-01

    Hyperkalemia is a common electrolyte disturbance with multiple potential etiologies. It is usually observed in the setting of reduced renal function. Mild to moderate hyperkalemia is usually asymptomatic, but is associated with poor prognosis. When severe, hyperkalemia may cause serious acute cardiac arrhythmias and conduction abnormalities, and may result in sudden death. The rising prevalence of conditions associated with hyperkalemia (heart failure, chronic kidney disease, and diabetes) and broad use of renin-angiotensin-aldosterone system (RAAS) inhibitors and mineralocorticoid receptor antagonists (MRAs), which improve patient outcomes but increase the risk of hyperkalemia, have led to a significant rise in hyperkalemia-related hospitalizations and deaths. Current non-invasive therapies for hyperkalemia either do not remove excess potassium or have poor efficacy and tolerability. There is a clear need for safer, more effective potassium-lowering therapies suitable for both acute and chronic settings. Patiromer sorbitex calcium and sodium zirconium cyclosilicate (ZS-9) are two new potassium-lowering compounds currently in development. Although they have not yet been approved by the US FDA, both have demonstrated efficacy and safety in recent trials. Patiromer sorbitex calcium is a polymer resin and sorbitol complex that binds potassium in exchange for calcium; ZS-9, a non-absorbed, highly selective inorganic cation exchanger, traps potassium in exchange for sodium and hydrogen. This review discusses the merits of both novel drugs and how they may help optimize the future management of patients with hyperkalemia.

  9. Potential dermal wound healing agent in Blechnum orientale Linn

    PubMed Central

    2011-01-01

    Background Blechnum orientale Linn. (Blechnaceae) is used ethnomedicinally to treat wounds, boils, blisters or abscesses and sores, stomach pain and urinary bladder complaints. The aim of the study was to validate the ethnotherapeutic claim and to evaluate the effects of B. orientale water extract on wound healing activity. Methods Water extract of B. orientale was used. Excision wound healing activity was examined on Sprague-Dawley rats, dressed with 1% and 2% of the water extract. Control groups were dressed with the base cream (vehicle group, negative control) and 10% povidone-iodine (positive control) respectively. Healing was assessed based on contraction of wound size, mean epithelisation time, hydroxyproline content and histopathological examinations. Statistical analyses were performed using one way ANOVA followed by Tukey HSD test. Results Wound healing study revealed significant reduction in wound size and mean epithelisation time, and higher collagen synthesis in the 2% extract-treated group compared to the vehicle group. These findings were supported by histolopathological examinations of healed wound sections which showed greater tissue regeneration, more fibroblasts and angiogenesis in the 2% extract-treated group. Conclusions The ethnotherapeutic use of this fern is validated. The water extract of B. orientale is a potential candidate for the treatment of dermal wounds. Synergistic effects of both strong antioxidant and antibacterial activities in the extract are deduced to have accelerated the wound repair at the proliferative phase of the healing process. PMID:21835039

  10. Curcumin: a potential neuroprotective agent in Parkinson's disease.

    PubMed

    Mythri, R B; Bharath, M M Srinivas

    2012-01-01

    Parkinson's disease (PD) is an age-associated neurodegenerative disease clinically characterized as a movement disorder. The motor symptoms in PD arise due to selective degeneration of dopaminergic neurons in the substantia nigra of the ventral midbrain thereby depleting the dopamine levels in the striatum. Most of the current pharmacotherapeutic approaches in PD are aimed at replenishing the striatal dopamine. Although these drugs provide symptomatic relief during early PD, many patients develop motor complications with long-term treatment. Further, PD medications do not effectively tackle tremor, postural instability and cognitive deficits. Most importantly, most of these drugs do not exhibit neuroprotective effects in patients. Consequently, novel therapies involving natural antioxidants and plant products/molecules with neuroprotective properties are being exploited for adjunctive therapy. Curcumin is a polyphenol and an active component of turmeric (Curcuma longa), a dietary spice used in Indian cuisine and medicine. Curcumin exhibits antioxidant, anti-inflammatory and anti-cancer properties, crosses the blood-brain barrier and is neuroprotective in neurological disorders. Several studies in different experimental models of PD strongly support the clinical application of curcumin in PD. The current review explores the therapeutic potential of curcumin in PD.

  11. Morphine as a Potential Oxidative Stress-Causing Agent

    PubMed Central

    Skrabalova, Jitka; Drastichova, Zdenka; Novotny, Jiri

    2013-01-01

    Morphine exhibits important pharmacological effects for which it has been used in medical practice for quite a long time. However, it has a high addictive potential and can be abused. Long-term use of this drug can be connected with some pathological consequences including neurotoxicity and neuronal dysfunction, hepatotoxicity, kidney dysfunction, oxidative stress and apoptosis. Therefore, most studies examining the impact of morphine have been aimed at determining the effects induced by chronic morphine exposure in the brain, liver, cardiovascular system and macrophages. It appears that different tissues may respond to morphine diversely and are distinctly susceptible to oxidative stress and subsequent oxidative damage of biomolecules. Importantly, production of reactive oxygen/nitrogen species induced by morphine, which have been observed under different experimental conditions, can contribute to some pathological processes, degenerative diseases and organ dysfunctions occurring in morphine abusers or morphine-treated patients. This review attempts to provide insights into the possible relationship between morphine actions and oxidative stress. PMID:24376392

  12. Water-soluble platinum phthalocyanines as potential antitumor agents.

    PubMed

    Bologna, Giuseppina; Lanuti, Paola; D'Ambrosio, Primiano; Tonucci, Lucia; Pierdomenico, Laura; D'Emilio, Carlo; Celli, Nicola; Marchisio, Marco; d'Alessandro, Nicola; Santavenere, Eugenio; Bressan, Mario; Miscia, Sebastiano

    2014-06-01

    Breast cancer represents the second cause of death in the European female population. The lack of specific therapies together with its high invasive potential are the major problems associated to such a tumor. In the last three decades platinum-based drugs have been considered essential constituents of many therapeutic strategies, even though with side effects and frequent generation of drug resistance. These drugs have been the guide for the research, in last years, of novel platinum and ruthenium based compounds, able to overcome these limitations. In this work, ruthenium and platinum based phthalocyanines were synthesized through conventional techniques and their antiproliferative and/or cytotoxic actions were tested. Normal mammary gland (MCF10A) and several models of mammarian carcinoma at different degrees of invasiveness (BT474, MCF-7 and MDA-MB-231) were used. Cells were treated with different concentrations (5-100 μM) of the above reported compounds, to evaluate toxic concentration and to underline possible dose-response effects. The study included growth curves made by trypan blue exclusion test and scratch assay to study cellular motility and its possible negative modulation by phthalocyanine. Moreover, we investigated cell cycle and apoptosis through flow cytometry and AMNIS Image Stream cytometer. Among all the tested drugs, tetrasulfonated phthalocyanine of platinum resulted to be the molecule with the best cytostatic action on neoplastic cell lines at the concentration of 30 μM. Interestingly, platinum tetrasulfophtalocyanine, at low doses, had no antiproliferative effects on normal cells. Therefore, such platinum complex, appears to be a promising drug for mammarian carcinoma treatment.

  13. Role of sodium tungstate as a potential antiplatelet agent.

    PubMed

    Fernández-Ruiz, Rebeca; Pino, Marc; Hurtado, Begoña; García de Frutos, Pablo; Caballo, Carolina; Escolar, Ginés; Gomis, Ramón; Diaz-Ricart, Maribel

    2015-01-01

    Platelet inhibition is a key strategy in the management of atherothrombosis. However, the large variability in response to current strategies leads to the search for alternative inhibitors. The antiplatelet effect of the inorganic salt sodium tungstate (Na2O4W), a protein tyrosine phosphatase 1B (PTP1B) inhibitor, has been investigated in this study. Wild-type (WT) and PTP1B knockout (PTP1B(-/-)) mice were treated for 1 week with Na2O4W to study platelet function with the platelet function analyzer PFA-100, a cone-and-plate analyzer, a flat perfusion chamber, and thrombus formation in vivo. Human blood aliquots were incubated with Na2O4W for 1 hour to measure platelet function using the PFA-100 and the annular perfusion chamber. Aggregometry and thromboelastometry were also performed. In WT mice, Na2O4W treatment prolonged closure times in the PFA-100 and decreased the surface covered (%SC) by platelets on collagen. Thrombi formed in a thrombosis mice model were smaller in animals treated with Na2O4W (4.6±0.7 mg vs 8.9±0.7 mg; P<0.001). Results with Na2O4W were similar to those in untreated PTP1B(-)/(-) mice (5.0±0.3 mg). Treatment of the PTP1B(-)/(-) mice with Na2O4W modified only slightly this response. In human blood, a dose-dependent effect was observed. At 200 μM, closure times in the PFA-100 were prolonged. On denuded vessels, %SC and thrombi formation (%T) decreased with Na2O4W. Neither the aggregating response nor the viscoelastic clot properties were affected. Na2O4W decreases consistently the hemostatic capacity of platelets, inhibiting their adhesive and cohesive properties under flow conditions in mice and in human blood, resulting in smaller thrombi. Although Na2O4W may be acting on platelet PTP1B, other potential targets should not be disregarded.

  14. Role of sodium tungstate as a potential antiplatelet agent

    PubMed Central

    Fernández-Ruiz, Rebeca; Pino, Marc; Hurtado, Begoña; García de Frutos, Pablo; Caballo, Carolina; Escolar, Ginés; Gomis, Ramón; Diaz-Ricart, Maribel

    2015-01-01

    Purpose Platelet inhibition is a key strategy in the management of atherothrombosis. However, the large variability in response to current strategies leads to the search for alternative inhibitors. The antiplatelet effect of the inorganic salt sodium tungstate (Na2O4W), a protein tyrosine phosphatase 1B (PTP1B) inhibitor, has been investigated in this study. Methods Wild-type (WT) and PTP1B knockout (PTP1B−/−) mice were treated for 1 week with Na2O4W to study platelet function with the platelet function analyzer PFA-100, a cone-and-plate analyzer, a flat perfusion chamber, and thrombus formation in vivo. Human blood aliquots were incubated with Na2O4W for 1 hour to measure platelet function using the PFA-100 and the annular perfusion chamber. Aggregometry and thromboelastometry were also performed. Results In WT mice, Na2O4W treatment prolonged closure times in the PFA-100 and decreased the surface covered (%SC) by platelets on collagen. Thrombi formed in a thrombosis mice model were smaller in animals treated with Na2O4W (4.6±0.7 mg vs 8.9±0.7 mg; P<0.001). Results with Na2O4W were similar to those in untreated PTP1B−/− mice (5.0±0.3 mg). Treatment of the PTP1B−/− mice with Na2O4W modified only slightly this response. In human blood, a dose-dependent effect was observed. At 200 μM, closure times in the PFA-100 were prolonged. On denuded vessels, %SC and thrombi formation (%T) decreased with Na2O4W. Neither the aggregating response nor the viscoelastic clot properties were affected. Conclusion Na2O4W decreases consistently the hemostatic capacity of platelets, inhibiting their adhesive and cohesive properties under flow conditions in mice and in human blood, resulting in smaller thrombi. Although Na2O4W may be acting on platelet PTP1B, other potential targets should not be disregarded. PMID:26060394

  15. β-Nitrostyrenes as Potential Anti-leishmanial Agents

    PubMed Central

    Shafi, Syed; Afrin, Farhat; Islamuddin, Mohammad; Chouhan, Garima; Ali, Intzar; Naaz, Faatima; Sharma, Kalicharan; Zaman, Mohammad S.

    2016-01-01

    Development of new therapeutic approach to treat leishmaniasis has become a priority. In the present study, the antileishmanial effect of β-nitrostyrenes was investigated against in vitro promastigotes and amastigotes. A series of β-nitrostyrenes have been synthesized by using Henry reaction and were evaluated for their antimicrobial activities by broth microdilution assay and in vitro antileishmanial activities against Leishmania donovani promastigotes by following standard guidelines. The most active compounds were futher evaluated for their in vitro antileishmanial activities against intracellular amastigotes. Among the tested β-nitrostyrenes, compounds 7, 8, 9, 12, and 17 exhibited potential activities (MICs range, 0.25–8 μg/mL) against clinically significant human pathogenic fungi. However, the microbactericidal concentrations (MBCs) and the microfungicidal concentrations (MFCs) were found to be either similar or only two-fold greater than the MICs. Anti-leishmanial results demonstrated that compounds 9, 12, 14, and 18 were found to be most active among the tested samples and exhibited 50% inhibitory concentration (IC50) by 23.40 ± 0.71, 37.83 ± 3.74, 40.50 ± 1.47, 55.66 ± 2.84 nM against L. donovani promastigotes and 30.5 ± 3.42, 21.46 ± 0.96, 26.43 ± 2.71, and 61.63 ± 8.02 nM respectively against intracellular L. donovani promastigotes amastigotes respectively which are comparable with standard AmB (19.60 ± 1.71 nM against promastigotes and 27.83 ± 3.26 nM against amastigotes). Compounds 9, 12, 14, and 18 were found to have potent in vitro leishmanicidal activity against L. donovani and found to be non-toxic against mammalian macrophages even at a concentration of 25 μM. Nitric oxide (NO) estimation studies reveals that these compounds are moderately inducing NO levels. PMID:27635124

  16. Not so secret agents: Event-related potentials to semantic roles in visual event comprehension.

    PubMed

    Cohn, Neil; Paczynski, Martin; Kutas, Marta

    2017-09-09

    Research across domains has suggested that agents, the doers of actions, have a processing advantage over patients, the receivers of actions. We hypothesized that agents as "event builders" for discrete actions (e.g., throwing a ball, punching) build on cues embedded in their preparatory postures (e.g., reaching back an arm to throw or punch) that lead to (predictable) culminating actions, and that these cues afford frontloading of event structure processing. To test this hypothesis, we compared event-related brain potentials (ERPs) to averbal comic panels depicting preparatory agents (ex. reaching back an arm to punch) that cued specific actions with those to non-preparatory agents (ex. arm to the side) and patients that did not cue any specific actions. We also compared subsequent completed action panels (ex. agent punching patient) across conditions, where we expected an inverse pattern of ERPs indexing the differential costs of processing completed actions asa function of preparatory cues. Preparatory agents evoked a greater frontal positivity (600-900ms) relative to non-preparatory agents and patients, while subsequent completed actions panels following non-preparatory agents elicited a smaller frontal positivity (600-900ms). These results suggest that preparatory (vs. non-) postures may differentially impact the processing of agents and subsequent actions in real time. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Synthetic Ni3S2/Ni hybrid architectures as potential contrast agents in MRI

    NASA Astrophysics Data System (ADS)

    Ma, J.; Chen, K.

    2016-04-01

    Traditional magnetic resonance imaging (MRI) contrast agents mainly include superparamagnetic (SPM) iron oxide nanoparticle as T 2 contrast agent for liver and paramagnetic Gd (III)-chelate as T 1 contrast agent for all organs. In this work, weak ferromagnetic kale-like and SPM cabbage-like Ni3S2@Ni hybrid architectures were synthesized and evaluated as potential T 1 MRI contrast agents. Their relatively small r 2/r 1 ratios of 2.59 and 2.38, and high r 1 values of 11.27 and 4.89 mmol-1 L s-1 (for the kale-like and cabbage-like Ni3S2@Ni, respectively) will shed some light on the development of new-type MRI contrast agents.

  18. Natural resins and bioactive natural products thereof as potential antimicrobial agents.

    PubMed

    Termentzi, Aikaterini; Fokialakis, Nikolas; Skaltsounis, Alexios Leandros

    2011-01-01

    Natural products and their derivatives have historically been invaluable as a source of therapeutic agents and have contributed to the discovery of antimicrobial agents. However, today with the development of drug-resistant strains, new scaffolds and new sources of bioactive compounds are needed. To this end, plant derived natural resins are reviewed for their potential application as antimicrobial agents. Natural gums, extracts of the whole resins, as well as specific extracts, fractions, essential oils and isolated compounds from the above resins are discussed in terms of their antifungal, antibacterial, and antiprotozoal activity.

  19. Synthesis of amino Derivatives of Dithio Acids as Potential Radiation Protective Agents

    DTIC Science & Technology

    1984-08-01

    ation Management S SI ____ K> AD Synthesis of Amino Derivatives of Dithio Acids as Potential Radiation Protective Agents * 0 Annual Report "TIi: o DTIC...Sftcuntiy Clatuftcatio") Synthesis of Amino Derivatives of Dithio Acids as PotentitI- Radiation Protective Agents 12l PERISONAL. Ak.TI4OR(S) * William...methyl- picoline derivatives was accomplished. Use of N-mthyl-2,6-dimethylpyridine also allowed the synthesis of a bis(dithioacetic acid) function not

  20. The role of potential agents in making spatial perspective taking social

    PubMed Central

    Clements-Stephens, Amy M.; Vasiljevic, Katarina; Murray, Alexandra J.; Shelton, Amy L.

    2013-01-01

    A striking relationship between visual spatial perspective taking (VSPT) and social skills has been demonstrated for perspective-taking tasks in which the target of the imagined or inferred perspective is a potential agent, suggesting that the presence of a potential agent may create a social context for the seemingly spatial task of imagining a novel visual perspective. In a series of studies, we set out to investigate how and when a target might be viewed as sufficiently agent-like to incur a social influence on VSPT performance. By varying the perceptual and conceptual features that defined the targets as potential agents, we find that even something as simple as suggesting animacy for a simple wooden block may be sufficient. More critically, we found that experience with one potential agent influenced the performance with subsequent targets, either by inducing or eliminating the influence of social skills on VSPT performance. These carryover effects suggest that the relationship between social skills and VSPT performance is mediated by a complex relationship that includes the task, the target, and the context in which that target is perceived. These findings highlight potential problems that arise when identifying a task as belonging exclusively to a single cognitive domain and stress instead the highly interactive nature of cognitive domains and their susceptibility to cross-domain individual differences. PMID:24046735

  1. Realizing the Potential of Vascular Targeted Therapy: The Rationale for Combining Vascular Disrupting Agents and Anti-Angiogenic Agents to Treat Cancer.

    PubMed

    Siemann, D W; Chaplin, D J; Horsman, M R

    2017-09-14

    Vascular targeted therapies (VTTs) are agents that target tumor vasculature and can be classified into two categories: those that inhibit angiogenesis and those that directly interfere with established tumor vasculature. Although both the anti-angiogenic agents (AAs) and the vascular disrupting agents (VDAs) target tumor vasculature, they differ in their mechanism of action and therapeutic application. Combining these two agents may realize the full potential of VTT and produce an effective therapeutic regimen. Here, we review AAs and VDAs (monotherapy and in combination with conventional therapies). We also discuss the rationale of combined VTT and its potential to treat cancer.

  2. Agents.

    PubMed

    Chambers, David W

    2002-01-01

    Although health care is inherently an economic activity, it is inadequately described as a market process. An alternative, grounded in organizational economic theory, is to view professionals and many others as agents, contracted to advance the best interests of their principals (patients). This view untangles some of the ethical conflicts in dentistry. It also helps identify major controllable costs in dentistry and suggests that dentists can act as a group to increase or decrease agency costs, primarily by controlling the bad actors who damage the value of all dentists.

  3. Impact of wine manufacturing practice on the occurrence of fining agents with allergenic potential.

    PubMed

    Deckwart, Marina; Carstens, Carsten; Webber-Witt, Manuella; Schäfer, Volker; Eichhorn, Lisa; Schröter, Franziska; Fischer, Markus; Brockow, Knut; Christmann, Monika; Paschke-Kratzin, Angelika

    2014-01-01

    Proteinogenic wine fining agents are hidden allergens and could present a risk for consumers with allergies. Therefore, the European Parliament adopted Directive 2003/89/EC amending Directive 2000/13/EC to declare ingredients, contaminations and processing aids that are known to trigger allergic reactions. The Amendment Regulation (EU) 1266/2010 excluded the labelling of wines which are processed with hen's egg and products thereof until 30 June 2012 to get more scientific findings. After 1 July 2012 wine fining agents have to be declared if above 0.25 mg l(-1) (Regulation (EU) 579/2012 in conjunction with article 120 g of Regulation (EU) 1234/2007). The Organisation International de la Vigne et du Vin (OIV) advises this limit of detection (LOD) for potential allergenic residues of proteins. Wine fining agents are processing aids and according to the wine producer's knowledge will be removed after coagulation by filtration or other production steps. Due to lack of scientific data, residues of fining agents in the final product could not be excluded. In this risk assessment, highly sensitive ELISA methods for ovalbumin of known origin for wine have been developed. The objective was to investigate the presence of allergen residues in wine after certain technological treatments were applied to remove the wine fining agents. For all developed ELISA methods the LODs are in the low µg l(-1) range between 5 and 10 µg l(-1) fining agent, whereas the LOQ varies between 5 and 80 µg l(-1) fining agent. The results of the investigation of well-known wines and fining agents demonstrate that white wines fined with white or ovalbumin from hen's egg could retain allergens. The use of certain technological procedures during wine processing leads to different results. In white wine, bentonite or sheet filtration followed by sterile filtration lead to wines containing no detectable amounts of ovalbumin. In red wine, especially the final sterile filtration removes the fining agents.

  4. Macromolecular Imaging Agents Containing Lanthanides: Can Conceptual Promise Lead to Clinical Potential?

    PubMed Central

    Bryson, Joshua; Reineke, Jeffrey W.; Reineke, Theresa M.

    2012-01-01

    Macromolecular magnetic resonance imaging (MRI) contrast agents are increasingly being used to improve the resolution of this noninvasive diagnostic technique. All clinically-approved T1 contrast agents are small molecule chelates of gadolinium [Gd(III)] that affect bound water proton relaxivity. Both the small size and monomeric nature of these agents ultimately limits the image resolution enhancement that can be achieved for both contrast enhancement and pharmacokinetic/biodistribution reasons. The multimeric nature of macromolecules, such as polymers, dendrimers, and noncovalent complexes of small molecule agents with proteins, have been shown to significantly increase the image contrast and resolution due to their large size and ability to incorporate multiple Gd(III) chlelation sites. Also, macromolecular agents are advantageous as they have the ability to be designed to be nontoxic, hydrophilic, easily purified, aggregation-resistant, and have controllable three-dimensional macromolecular structure housing the multiple lanthanide chelation sites. For these reasons, large molecule diagnostics have the ability to significantly increase the relaxivity of water protons within the targeted tissues and thus the image resolution for many diagnostic applications. The FDA approval of a contrast agent that consists of a reversible, non-covalent coupling of a small Gd(III) chelate with serum albumin for blood pool imaging (marketed under the trade names of Vasovist and Ablivar) proved to be one of the first diagnostic agent to capitalize on these benefits from macromolecular association in humans. However, much research and development is necessary to optimize the safety of these unique agents for in vivo use and potential clinical development. To this end, recent work in the field of polymer, dendrimer, and noncovalent complex-based imaging agents are reviewed herein and the future outlook of this field is discussed. PMID:23467737

  5. [A case of hypokalemic myopathy induced by excessive drinking of a beverage containing green tea extract].

    PubMed

    Fukumoto, Megumi; Yamashiro, Nobuo; Kobayashi, Fumikazu; Nagasaka, Takamura; Takiyama, Yoshihisa

    2013-01-01

    A 49-year-old man subacutely developed muscle weakness in four extremities over a few days. He had no past or family history of muscle weakness. His blood tests showed significant hypokalemia without endocrinological abnormalities. With the diagnosis of hypokalemic myopathy, potassium was administered orally, and his symptoms improved. The patient had been drinking a beverage containing green tea extract too much two weeks before the symptoms developed, in addition to taking a cold remedy for ten years. Thus, hypokalemia is considered to be induced by the excessive intake of caffeine that accompanies the excessive consumption of the beverage and cold remedy.

  6. Imaging of hemorrhagic fever with renal syndrome: a potential bioterrorism agent of military significance.

    PubMed

    Bui-Mansfield, Liem T; Cressler, Dana K

    2011-11-01

    Hemorrhagic fever with renal syndrome (HFRS) is a potentially fatal infectious disease with worldwide distribution. Its etiologic agents are viruses of the genus Hantavirus of the virus family Bunyaviridae. Hypothetical ease of production and distribution of these agents, with their propensity to incapacitate victims and overwhelm health care resources, lend themselves as significant potential biological agents of terrorism. HFRS has protean clinical manifestations, which may mimic upper respiratory tract infection, nephrolithiasis, and Hantavirus pulmonary syndrome and may delay proper treatment. Sequelae of HFRS, such as hemorrhage, acute renal failure, retroperitoneal edema, pancreatitis, pulmonary edema, and neurologic symptoms, can be detected by different imaging modalities. Medical providers caring for HFRS patients must be aware of its radiologic features, which may help to confirm its clinical diagnosis. In this article, the authors review the epidemiology, pathophysiology, clinical presentation, diagnosis, treatment, and complications of HFRS.

  7. Potential biological control agents for management of cogongrass (Cyperales: Poaceae) in the southeastern USA

    USDA-ARS?s Scientific Manuscript database

    Cogongrass, Imperata cylindrica (L.) Palisot de Beauvois (Cyperales: Poaceae), is a noxious invasive weed in the southeastern USA. Surveys for potential biological control agents of cogongrass were conducted in Asia and East Africa from 2013 to 2016. Several insect herbivores were found that may hav...

  8. Biology and preliminary host range assessment of two potential kudzu biological control agents

    Treesearch

    Matthew J. Fyre; Judith Hough-Goldstein; Jiang-Hua Sun

    2007-01-01

    Two insect species from China, Gonioctena tredecimmaclliata (Jacoby) (Coleoptera: Chrysomelidae) and Ornatalcides (Mesalcidodes) trifidus (Pascoe) (Coleoptera: Curculionidae), were studied in quarantine in the United States as potential biological control agents for kudzu, Pueraria nwntana variety Zobata (Willd.) Maesen and S. Almeida...

  9. In vitro and In vivo Studies on Stilbene Analogs as Potential Treatment Agents for Colon Cancer

    USDA-ARS?s Scientific Manuscript database

    Based upon the potential of resveratrol as a cancer chemopreventive agent, 27 stilbenes analogs were synthesized and tested against colon cancer cell line HT-29. Among these compounds, amino derivative (Z)-4-(3,5-dimethoxystyryl) aniline (4), (Z)-methyl 4-(3,5-dimethoxystyryl) benzoate (6) and (Z)-1...

  10. Biology of Leptoypha hospita (Hemiptera: Tingidae), a Potential Biological Control Agent of Chinese Privet

    Treesearch

    Yanzhuo Zhang; James L. Hanula; Scott Horn; Kristine Braman; Jianghua Sun

    2011-01-01

    The biology of Leptoypha hospita Drake et Poor (Hemiptera: Tingidae), a potential biological control agent from China for Chinese privet, Ligustrum sinense Lour., was studied in quarantine in the United States. Both nymphs and adults feed on Chinese privet mesophyll cells that lead to a bleached appearance of leaves and dieback of branch tips. L. hospita has five...

  11. Complete Genome Sequence of Ralstonia solanacearum FJAT-1458, a Potential Biocontrol Agent for Tomato Wilt

    PubMed Central

    Chen, Deju; Zhu, Yujing; Wang, Jieping; Chen, Zheng; Che, Jiamei; Zheng, Xuefang; Chen, Xiaoqiang

    2017-01-01

    ABSTRACT An avirulent strain of Ralstonia solanacearum FJAT-1458 was isolated from a living tomato. Here, we report the complete R. solanacearum FJAT-1458 genome sequence of 6,059,899 bp and 5,241 genes. This bacterial strain is a potential candidate as a biocontrol agent in the form of a plant vaccine for bacterial wilt. PMID:28385834

  12. Cysteamine-related agents could be potential antidepressants through increasing central BDNF levels.

    PubMed

    Tsai, Shih-Jen

    2006-01-01

    Major depressive disorder (MDD) is a common mental disease, but with an unknown etiology. Antidepressants are the main biological treatment for MDD. However, current antidepressive agents have a slow onset of effect and a substantial proportion of MDD patients do not clinically improve, despite maximal medication. Thus, the exploration for new antidepressants with novel strategies may help to develop faster and more effective antidepressant agents. Studies in the recent decades have demonstrated that antidepressants increase central brain-derived neurotrophic factor (BDNF) levels and activating the BDNF-signaling pathway may play an important role in their therapeutic mechanism. Cysteamine is a natural product of cells and constitutes the terminal region of the CoA molecule. Recent work has found that cysteamine and a related agent, cystamine, have neuroprotective effects in Huntington's disease (HD) mice, through enhancing central BDNF levels. Furthermore, cystamine or cysteamine injection could increase serum BDNF levels in wild-type mice as well as HD mice. Since activation of the BDNF-dependent pathway plays an important role in the mechanism of antidepressant therapeutic action, cystamine or its derivatives could have potential antidepressant therapeutic effects. Among these agents, pantethine may be one of the most promising agents. It is a naturally occurring compound which can be administered orally with negligible side effects, and is metabolized to cysteamine. Further evaluation of the therapeutic and toxic effects of these cysteamine-related antidepressant agents in MDD animal models is needed before any clinical application.

  13. Progress in Nanotechnology Based Approaches to Enhance the Potential of Chemopreventive Agents

    PubMed Central

    Muqbil, Irfana; Masood, Ashiq; Sarkar, Fazlul H.; Mohammad, Ramzi M.; Azmi, Asfar S.

    2011-01-01

    Cancer chemoprevention is defined as the use of natural agents to suppress, reverse or prevent the carcinogenic process from turning into aggressive cancer. Over the last two decades, multiple natural dietary compounds with diverse chemical structures such flavonoids, tannins, curcumins and polyphenols have been proposed as chemopreventive agents. These agents have proven excellent anticancer potential in the laboratory setting, however, the observed effects in vitro do not translate in clinic where they fail to live up to their expectations. Among the various reasons for this discrepancy include inefficient systemic delivery and robust bioavailability. To overcome this barrier, researchers have focused towards coupling these agents with nano based encapsulation technology that in principle will enhance bioavailability and ultimately benefit clinical outcome. The last decade has witnessed rapid advancement in the development of nanochemopreventive technology with emergence of many nano encapsulated formulations of different dietary anticancer agents. This review summarizes the most up-to-date knowledge on the studies performed in nanochemoprevention, their proposed use in the clinic and future directions in which this field is heading. As the knowledge of the dynamics of nano encapsulation evolves, it is expected that researchers will bring forward newer and far more superior nanochemopreventive agents that may become standard drugs for different cancers. PMID:24212623

  14. A Review of the Disruptive Potential of Botulinum Neurotoxins as Chemical Warfare Agents

    DTIC Science & Technology

    2011-10-01

    SUBJECT TERMS Botulinum neurotoxin, national security, chemical agents, chemical warfare, force health protection 16. SECURITY CLASSIFICATION OF: 17...the local health -care infrastructure. For anybody trained in epidemiology and crisis management, this presents a “devil’s brew” of potential...mortality rates, the potential for major public health impact, the ability to cause public panic and social disruption, and the requirement for special

  15. Intelligent Agents and Their Potential for Future Design and Synthesis Environment

    NASA Technical Reports Server (NTRS)

    Noor, Ahmed K. (Compiler); Malone, John B. (Compiler)

    1999-01-01

    This document contains the proceedings of the Workshop on Intelligent Agents and Their Potential for Future Design and Synthesis Environment, held at NASA Langley Research Center, Hampton, VA, September 16-17, 1998. The workshop was jointly sponsored by the University of Virginia's Center for Advanced Computational Technology and NASA. Workshop attendees came from NASA, industry and universities. The objectives of the workshop were to assess the status of intelligent agents technology and to identify the potential of software agents for use in future design and synthesis environment. The presentations covered the current status of agent technology and several applications of intelligent software agents. Certain materials and products are identified in this publication in order to specify adequately the materials and products that were investigated in the research effort. In no case does such identification imply recommendation or endorsement of products by NASA, nor does it imply that the materials and products are the only ones or the best ones available for this purpose. In many cases equivalent materials and products are available and would probably produce equivalent results.

  16. Molecular effective coverage surface area of optical clearing agents for predicting optical clearing potential

    NASA Astrophysics Data System (ADS)

    Feng, Wei; Ma, Ning; Zhu, Dan

    2015-03-01

    The improvement of methods for optical clearing agent prediction exerts an important impact on tissue optical clearing technique. The molecular dynamic simulation is one of the most convincing and simplest approaches to predict the optical clearing potential of agents by analyzing the hydrogen bonds, hydrogen bridges and hydrogen bridges type forming between agents and collagen. However, the above analysis methods still suffer from some problem such as analysis of cyclic molecule by reason of molecular conformation. In this study, a molecular effective coverage surface area based on the molecular dynamic simulation was proposed to predict the potential of optical clearing agents. Several typical cyclic molecules, fructose, glucose and chain molecules, sorbitol, xylitol were analyzed by calculating their molecular effective coverage surface area, hydrogen bonds, hydrogen bridges and hydrogen bridges type, respectively. In order to verify this analysis methods, in vitro skin samples optical clearing efficacy were measured after 25 min immersing in the solutions, fructose, glucose, sorbitol and xylitol at concentration of 3.5 M using 1951 USAF resolution test target. The experimental results show accordance with prediction of molecular effective coverage surface area. Further to compare molecular effective coverage surface area with other parameters, it can show that molecular effective coverage surface area has a better performance in predicting OCP of agents.

  17. The Potential of Streptomyces as Biocontrol Agents against the Rice Blast Fungus, Magnaporthe oryzae (Pyricularia oryzae)

    PubMed Central

    Law, Jodi Woan-Fei; Ser, Hooi-Leng; Khan, Tahir M.; Chuah, Lay-Hong; Pusparajah, Priyia; Chan, Kok-Gan; Goh, Bey-Hing; Lee, Learn-Han

    2017-01-01

    Rice is a staple food source for more than three billion people worldwide. However, rice is vulnerable to diseases, the most destructive among them being rice blast, which is caused by the fungus Magnaporthe oryzae (anamorph Pyricularia oryzae). This fungus attacks rice plants at all stages of development, causing annual losses of approximately 10–30% in various rice producing regions. Synthetic fungicides are often able to effectively control plant diseases, but some fungicides result in serious environmental and health problems. Therefore, there is growing interest in discovering and developing new, improved fungicides based on natural products as well as introducing alternative measures such as biocontrol agents to manage plant diseases. Streptomyces bacteria appear to be promising biocontrol agents against a wide range of phytopathogenic fungi, which is not surprising given their ability to produce various bioactive compounds. This review provides insight into the biocontrol potential of Streptomyces against the rice blast fungus, M. oryzae. The ability of various Streptomyces spp. to act as biocontrol agents of rice blast disease has been studied by researchers under both laboratory and greenhouse/growth chamber conditions. Laboratory studies have shown that Streptomyces exhibit inhibitory activity against M. oryzae. In greenhouse studies, infected rice seedlings treated with Streptomyces resulted in up to 88.3% disease reduction of rice blast. Studies clearly show that Streptomyces spp. have the potential to be used as highly effective biocontrol agents against rice blast disease; however, the efficacy of any biocontrol agent may be affected by several factors including environmental conditions and methods of application. In order to fully exploit their potential, further studies on the isolation, formulation and application methods of Streptomyces along with field experiments are required to establish them as effective biocontrol agents. PMID:28144236

  18. The Potential of Streptomyces as Biocontrol Agents against the Rice Blast Fungus, Magnaporthe oryzae (Pyricularia oryzae).

    PubMed

    Law, Jodi Woan-Fei; Ser, Hooi-Leng; Khan, Tahir M; Chuah, Lay-Hong; Pusparajah, Priyia; Chan, Kok-Gan; Goh, Bey-Hing; Lee, Learn-Han

    2017-01-01

    Rice is a staple food source for more than three billion people worldwide. However, rice is vulnerable to diseases, the most destructive among them being rice blast, which is caused by the fungus Magnaporthe oryzae (anamorph Pyricularia oryzae). This fungus attacks rice plants at all stages of development, causing annual losses of approximately 10-30% in various rice producing regions. Synthetic fungicides are often able to effectively control plant diseases, but some fungicides result in serious environmental and health problems. Therefore, there is growing interest in discovering and developing new, improved fungicides based on natural products as well as introducing alternative measures such as biocontrol agents to manage plant diseases. Streptomyces bacteria appear to be promising biocontrol agents against a wide range of phytopathogenic fungi, which is not surprising given their ability to produce various bioactive compounds. This review provides insight into the biocontrol potential of Streptomyces against the rice blast fungus, M. oryzae. The ability of various Streptomyces spp. to act as biocontrol agents of rice blast disease has been studied by researchers under both laboratory and greenhouse/growth chamber conditions. Laboratory studies have shown that Streptomyces exhibit inhibitory activity against M. oryzae. In greenhouse studies, infected rice seedlings treated with Streptomyces resulted in up to 88.3% disease reduction of rice blast. Studies clearly show that Streptomyces spp. have the potential to be used as highly effective biocontrol agents against rice blast disease; however, the efficacy of any biocontrol agent may be affected by several factors including environmental conditions and methods of application. In order to fully exploit their potential, further studies on the isolation, formulation and application methods of Streptomyces along with field experiments are required to establish them as effective biocontrol agents.

  19. Rapid, Cell-Based Toxicity Screen of Potentially Therapeutic Post-Transcriptional Gene Silencing Agents

    PubMed Central

    Kolniak, Tiffany A.; Sullivan, Jack M.

    2011-01-01

    Post-transcriptional gene silencing (PTGS) agents such as antisense, ribozymes and RNA interference (RNAi) have great potential as therapeutics for a variety of eye diseases including retinal and macular degenerations, glaucoma, corneal degenerations, inflammatory and viral conditions. Despite their great potential and over thirty years of academic and corporate research only a single PTGS agent is currently approved for human therapy for a single disease. Substantial challenges exist to achieving both efficacious and safe PTGS agents. Efficacy, as measured in specific target mRNA and protein knockdown, depends upon a number of complex factors including the identification of rare regions of target mRNA accessibility, cellular colocalization of the PTGS agent in sufficient concentration with the target mRNA, and stability of the PTGS agent in the target cells in which it is delivered or expressed. Safety is commonly measured by lack of cytotoxicity or other deleterious cellular responses in cells in which the PTGS agent is delivered or expressed. To relieve major bottlenecks in RNA drug discovery novel, efficient, inexpensive, and rapid tools are needed to facilitate lead identification of the most efficacious PTGS agent, rational optimization of efficacy of the lead agent, and lead agent safety determinations. We have developed a technological platform using cell culture expression systems that permits lead identification and efficacy optimization of PTGS agents against arbitrary disease target mRNAs under relatively high throughput conditions. Here, we extend the technology platform to include PTGS safety determinations in cultured human cells that are expected to represent the common cellular housekeeping microenvironment. We developed a high throughput screening (HTS) cytotoxicity assay in 96-well plate format based around the SYTOX Green dye which is excluded from healthy viable cells and becomes substantially fluorescent only after entering cells and binding

  20. General guidelines for medically screening mixed population groups potentially exposed to nerve or vesicant agents

    SciTech Connect

    Watson, A.P.; Munro, N.B.; Sidell, F.R.; Leffingwell, S.S.

    1992-01-01

    A number of state and local planners have requested guidance on screening protocols and have expressed interest in sampling body fluids from exposed or potentially exposed individuals as a means of estimating agent dose. These guidelines have been developed to provide a clear statement that could be used by state and local emergency response personnel in the event of a nerve or vesicant agent incident resulting in off-post contamination; maximum protection from harm is the goal. The assumption is that any population group so exposed would be heterogeneous for age, gender, reproductive status, and state of health.

  1. General guidelines for medically screening mixed population groups potentially exposed to nerve or vesicant agents

    SciTech Connect

    Watson, A.P.; Munro, N.B. ); Sidell, F.R. ); Leffingwell, S.S. . Center for Environmental Health and Injury Control)

    1992-01-01

    A number of state and local planners have requested guidance on screening protocols and have expressed interest in sampling body fluids from exposed or potentially exposed individuals as a means of estimating agent dose. These guidelines have been developed to provide a clear statement that could be used by state and local emergency response personnel in the event of a nerve or vesicant agent incident resulting in off-post contamination; maximum protection from harm is the goal. The assumption is that any population group so exposed would be heterogeneous for age, gender, reproductive status, and state of health.

  2. The Potential Use of Pharmacological Agents to Modulate Orthodontic Tooth Movement (OTM)

    PubMed Central

    Kouskoura, Thaleia; Katsaros, Christos; von Gunten, Stephan

    2017-01-01

    The biological processes that come into play during orthodontic tooth movement (OTM) have been shown to be influenced by a variety of pharmacological agents. The effects of such agents are of particular relevance to the clinician as the rate of tooth movement can be accelerated or reduced as a result. This review aims to provide an overview of recent insights into drug-mediated effects and the potential use of drugs to influence the rate of tooth movement during orthodontic treatment. The limitations of current experimental models and the need for well-designed clinical and pre-clinical studies are also discussed. PMID:28228735

  3. Rifampin-associated tubulointersititial nephritis and Fanconi syndrome presenting as hypokalemic paralysis.

    PubMed

    Min, Hong Ki; Kim, Eun Oh; Lee, Sang Ju; Chang, Yoon Kyung; Suh, Kwang Sun; Yang, Chul Woo; Kim, Suk Young; Hwang, Hyeon Seok

    2013-01-16

    Rifampin is one of the most important drugs in first-line therapies for tuberculosis. The renal toxicity of rifampin has been reported sporadically and acute tubulointerstitial nephritis (ATIN) is a frequent histological finding. We describe for the first time a case of ATIN and Fanconi syndrome presenting as hypokalemic paralysis, associated with the use of rifampin. A 42-year-old man was admitted with sudden-onset lower extremity paralysis and mild renal insufficiency. He had been treated for pulmonary tuberculosis with isoniazid, rifampin, and ethambutol for 2 months. Laboratory tests revealed proteinuria, profound hypokalemia, hyperchloremic metabolic acidosis with a normal anion gap, positive urine anion gap, hypophosphatemia with hyperphosphaturia, hypouricemia with hyperuricosuria, glycosuria with normal serum glucose level, generalized aminoaciduria, and β2-microglobulinuria. A kidney biopsy revealed findings typical of ATIN and focal granular deposits of immunoglubulin A and complement 3 in the glomeruli and tubules. Electron microscopy showed epithelial foot process effacement and electron-dense deposits in the subendothelial and mesangial spaces. Cessation of rifampin resolved the patient's clinical presentation of Fanconi syndrome, and improved his renal function and proteinuria. This case demonstrates that rifampin therapy can be associated with Fanconi syndrome presenting as hypokalemic paralysis, which is a manifestation of ATIN. Kidney function and the markers of proximal tubular injury should be carefully monitored in patients receiving rifampin.

  4. Hypokalemic nephropathy in the rat. Role of ammonia in chronic tubular injury.

    PubMed

    Tolins, J P; Hostetter, M K; Hostetter, T H

    1987-05-01

    Chronic potassium deficiency results in progressive tubulointerstitial injury, associated with augmented renal ammoniagenesis. We investigated the role of elevated renal ammonia levels and the interaction of ammonia with the complement system in this injury. Potassium deficiency was induced in rats by feeding a low potassium diet. Experimental animals received 150 mM NaHCO3 or equimolar NaCl, as drinking water. After 3 wk, NaHCO3 supplemented rats demonstrated decreased ammonia production, less renal hypertrophy, less histologic evidence of injury, and less proteinuria. In in vitro studies on normal cortical tubular fragments, the addition of ammonia to serum in concentrations comparable to renal cortical levels in potassium-deficient animals significantly increased tubular deposition of C3 as quantitated by a radiolabeled antibody binding technique. Thus, alkali supplementation reduced chronic tubulointerstitial disease in a rat model of hypokalemic nephropathy. We propose that increased cortical ammonia levels contribute to hypokalemic nephropathy through ammonia-mediated activation of the alternative complement pathway.

  5. [The relationship between hyperinsulinemia and hypokalemic periodic paralysis in overweight/obesity subjects].

    PubMed

    Chen, Dong-Mei; Yu, Ye-Rong

    2013-07-01

    To study the relationship between hyperinsulinemia and primary periodic paralysis in overweight/obesity people. Overweight/obesity people with primary hypokalemic periodic paralysis were administrated as disease group. Serum potassium, insulin and glucose were analyzed at different time (0 h, 1 h, 2 h, 3 h, 4 h) after taking 100 g carbohydrates and the results were compared with that of control group matched by gender, age and body mass index (BMI). (1) Males were much more than females in disease group (14 males and 2 females), the onset age ranged from 20 to 50 years old. (2) Both the highest insulin level and the lowest potassium level appeared at one hour after taking the carbohydrates. And the highest insulin level of disease group was significant higher than that of control group. (3) The area under the curve of insulin and insulin/potassium of disease group was significant higher than that of control group. The postprandial hyperinsulinemia was an important factor in overweight/obesity people with hypokalemic periodic paralysis.

  6. A sodium channel knockin mutant (NaV1.4-R669H) mouse model of hypokalemic periodic paralysis

    PubMed Central

    Wu, Fenfen; Mi, Wentao; Burns, Dennis K.; Fu, Yu; Gray, Hillery F.; Struyk, Arie F.; Cannon, Stephen C.

    2011-01-01

    Hypokalemic periodic paralysis (HypoPP) is an ion channelopathy of skeletal muscle characterized by attacks of muscle weakness associated with low serum K+. HypoPP results from a transient failure of muscle fiber excitability. Mutations in the genes encoding a calcium channel (CaV1.1) and a sodium channel (NaV1.4) have been identified in HypoPP families. Mutations of NaV1.4 give rise to a heterogeneous group of muscle disorders, with gain-of-function defects causing myotonia or hyperkalemic periodic paralysis. To address the question of specificity for the allele encoding the NaV1.4-R669H variant as a cause of HypoPP and to produce a model system in which to characterize functional defects of the mutant channel and susceptibility to paralysis, we generated knockin mice carrying the ortholog of the gene encoding the NaV1.4-R669H variant (referred to herein as R669H mice). Homozygous R669H mice had a robust HypoPP phenotype, with transient loss of muscle excitability and weakness in low-K+ challenge, insensitivity to high-K+ challenge, dominant inheritance, and absence of myotonia. Recovery was sensitive to the Na+/K+-ATPase pump inhibitor ouabain. Affected fibers had an anomalous inward current at hyperpolarized potentials, consistent with the proposal that a leaky gating pore in R669H channels triggers attacks, whereas a reduction in the amplitude of action potentials implies additional loss-of-function changes for the mutant NaV1.4 channels. PMID:21881211

  7. Novel Hydrogel Material as a Potential Embolic Agent in Embolization Treatments

    NASA Astrophysics Data System (ADS)

    Zhou, Feng; Chen, Liming; An, Qingzhu; Chen, Liang; Wen, Ying; Fang, Fang; Zhu, Wei; Yi, Tao

    2016-08-01

    We report a novel graphene-oxide (GO) enhanced polymer hydrogel (GPH) as a promising embolic agent capable of treating cerebrovascular diseases and malignant tumors, using the trans-catheter arterial embolization (TAE) technique. Simply composed of GO and generation five poly(amidoamine) dendrimers (PAMAM-5), our rheology experiments reveal that GPH exhibits satisfactory mechanical strength, which resist the high pressures of blood flow. Subcutaneous experiments on Sprague-Dawley (SD) rats demonstrate the qualified biocompatibility of GPH. Finally, our in vivo experiments on New Zealand rabbits, which mix GPH with the X-ray absorbing contrast agent, Iohexol, reveal complete embolization of the artery. We also note that GPH shortens embolization time and exhibits low toxicity in follow-up experiments. Altogether, our study demonstrates that GPH has many advantages over the currently used embolic agents and has potential applications in clinical practice.

  8. The poultry red mite (Dermanyssus gallinae): a potential vector of pathogenic agents.

    PubMed

    Valiente Moro, Claire; De Luna, Carlos J; Tod, Alexander; Guy, Jonathan H; Sparagano, Olivier A E; Zenner, Lionel

    2009-06-01

    The poultry red mite, D. gallinae has been involved in the transmission of many pathogenic agents, responsible for serious diseases both in animals and humans. Nowadays, few effective methods are available to control the ectoparasite in poultry farms. Consequently, this is an emerging problem which must be taken into account to maintain good health in commercial egg production. This paper addresses the vector capacity of the ectoparasite with special emphasis on salmonellae, pathogenic agents responsible for many of the most important outbreaks of food-borne diseases worlwide. It has been experimentally shown that D. gallinae could act as a biological vector of S. enteritidis and natural carriage of these bacteria by the mite on poultry premises has also been reported. It was also found that D. gallinae carried other pathogens such as E. coli, Shigella sp., and Staphylococcus, thus increasing the list of pathogenic agents potentially transmitted by the mite.

  9. Novel Hydrogel Material as a Potential Embolic Agent in Embolization Treatments

    PubMed Central

    Zhou, Feng; Chen, Liming; An, Qingzhu; Chen, Liang; Wen, Ying; Fang, Fang; Zhu, Wei; Yi, Tao

    2016-01-01

    We report a novel graphene-oxide (GO) enhanced polymer hydrogel (GPH) as a promising embolic agent capable of treating cerebrovascular diseases and malignant tumors, using the trans-catheter arterial embolization (TAE) technique. Simply composed of GO and generation five poly(amidoamine) dendrimers (PAMAM-5), our rheology experiments reveal that GPH exhibits satisfactory mechanical strength, which resist the high pressures of blood flow. Subcutaneous experiments on Sprague-Dawley (SD) rats demonstrate the qualified biocompatibility of GPH. Finally, our in vivo experiments on New Zealand rabbits, which mix GPH with the X-ray absorbing contrast agent, Iohexol, reveal complete embolization of the artery. We also note that GPH shortens embolization time and exhibits low toxicity in follow-up experiments. Altogether, our study demonstrates that GPH has many advantages over the currently used embolic agents and has potential applications in clinical practice. PMID:27561915

  10. Opportunities for Web-based Drug Repositioning: Searching for Potential Antihypertensive Agents with Hypotension Adverse Events.

    PubMed

    Wang, Kejian; Wan, Mei; Wang, Rui-Sheng; Weng, Zuquan

    2016-04-01

    Drug repositioning refers to the process of developing new indications for existing drugs. As a phenotypic indicator of drug response in humans, clinical side effects may provide straightforward signals and unique opportunities for drug repositioning. We aimed to identify drugs frequently associated with hypotension adverse reactions (ie, the opposite condition of hypertension), which could be potential candidates as antihypertensive agents. We systematically searched the electronic records of the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) through the openFDA platform to assess the association between hypotension incidence and antihypertensive therapeutic effect regarding a list of 683 drugs. Statistical analysis of FAERS data demonstrated that those drugs frequently co-occurring with hypotension events were more likely to have antihypertensive activity. Ranked by the statistical significance of frequent hypotension reporting, the well-known antihypertensive drugs were effectively distinguished from others (with an area under the receiver operating characteristic curve > 0.80 and a normalized discounted cumulative gain of 0.77). In addition, we found a series of antihypertensive agents (particularly drugs originally developed for treating nervous system diseases) among the drugs with top significant reporting, suggesting the good potential of Web-based and data-driven drug repositioning. We found several candidate agents among the hypotension-related drugs on our list that may be redirected for lowering blood pressure. More important, we showed that a pharmacovigilance system could alternatively be used to identify antihypertensive agents and sustainably create opportunities for drug repositioning.

  11. Hypertension and vascular dementia in the elderly: the potential role of anti-hypertensive agents.

    PubMed

    Coca, Antonio

    2013-09-01

    Vascular dementia (VaD) - a severe form of vascular cognitive impairment - and cognitive decline are associated with hypertension and therefore it seems logical to consider that reducing BP with anti-hypertensive therapy may protect against the development/onset of cognitive function impairment or dementia. This narrative, non-systematic review discusses the available evidence on the potential correlation between the use of anti-hypertensive agents and the risk of VaD and cognitive decline. MEDLINE was searched for inclusion of relevant studies. No limitations in time were considered. A consensus on the potential effects of anti-hypertensive treatment in the reduction of VaD and associated cognitive decline has not been reached. A protective effect of anti-hypertensive agents has been observed in a number of studies although it is still unclear whether different classes of anti-hypertensive agents have a different effect on the development of VaD. The protective effect of anti-hypertensive agents appears to depend on the specific drug used - positive effects have been observed with calcium channel blockers (CCBs), such as lercanidipine and nitrendipine, the combination perindopril-indapamide and telmisartan.

  12. The potential role of natural agents in treatment of airway inflammation.

    PubMed

    Sharafkhaneh, Amir; Velamuri, Suryakanta; Badmaev, Vladimir; Lan, Charlie; Hanania, Nicola

    2007-12-01

    Obstructive airway diseases including asthma, chronic obstructive pulmonary disease and cystic fibrosis present with dyspnea and variety of other symptoms. Physiologically, they are characterized by maximal expiratory flow limitation and pathologically, by inflammation of the airways and the lung parenchyma. Inflammation plays a major role in the gradual worsening of the lung function resulting in worsening symptoms. For many years, scientists focused their efforts in identifying various pathways involved in the chronic inflammation present in these diseases. Further, studies are underway to identify various molecular targets in these pathways for the purpose of developing novel therapeutic agents. Natural agents have been used for thousands of years in various cultures for the treatment of several medical conditions and have mostly proven to be safe. Recent in vivo and in vitro studies show potential anti-inflammatory role for some of the existing natural agents. This review provides an overview of the literature related to the anti-inflammatory effects of some of the natural agents which have potential value in the treatment of inflammatory lung diseases.

  13. Development of male-fertility-regulating agents.

    PubMed

    Ray, S; Verma, P; Kumar, A

    1991-09-01

    Steroidal, nonsteroidal, plant-derived, gonadotropin-related and immunological agents investigated for control of male fertility are reviewed with brief descriptions of their effects, and illustrations of their structures. The physiology of the male reproductive system is presented as an introduction: an ideal male antifertility agent would inhibit spermatogenesis at the level of the Sertoli cells, without affecting endogenous androgen production by Leydig cells, needed for libido and potency. Androgens down-regulate their own production at physiological levels, but few long-acting orally active derivatives are available. Anti-androgens with mixed androgen and progestin activity, combined with a pure androgen are potentially useful. Androgen-progestin combinations are being tested by WHO as implants. Dozens of miscellaneous nonsteroidal compounds have been discovered serendipitously to have antifertility activity in men or male animals, including alkylating agents antimetabolites, antibiotics, sulfa derivatives, fungicides, trichomonocides, amebicides, alpha blockers, antimalarials, coumarins, and carbohydrate derivatives. Various plant alkaloids have been screened. Those of Hibiscus, Vitex and Plumbago species, as well as Tripterygium wilfordii glycosides, which are being evaluated in combination with gossypol, are mentioned here. Gossypol has been thoroughly tested in China, but rejected because of its side effects, particularly hypokalemic paralysis, its low therapeutic index, and uncertain recovery of fertility. Gonadotropin-releasing hormone (GnRH) agonists and antagonists are being researched in combination with androgens with some success. The GnRH antagonists to date have low activity , or cause histamine-related side effects at higher doses; the androgens require a new route such as a long-acting implant to overcome the need for daily injections. Immunological contraception for males has not progressed beyond the research stage.

  14. Potential Renoprotective Agents through Inhibiting CTGF/CCN2 in Diabetic Nephropathy

    PubMed Central

    Wang, Songyan; Li, Bing; Li, Chunguang; Cui, Wenpeng; Miao, Lining

    2015-01-01

    Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD). The development and progression of DN might involve multiple factors. Connective tissue growth factor (CCN2, originally known as CTGF) is the one which plays a pivotal role. Therefore, increasing attention is being paid to CCN2 as a potential therapeutic target for DN. Up to date, there are also many drugs or agents which have been shown for their protective effects against DN via different mechanisms. In this review, we only focus on the potential renoprotective therapeutic agents which can specifically abolish CCN2 expression or nonspecifically inhibit CCN2 expression for retarding the development and progression of DN. PMID:26421309

  15. The stimulation of bioluminescence in Photobacterium leiognathi as a potential prescreen for antitumor agents.

    PubMed

    Steinberg, D A; Peterson, G A; White, R J; Maiese, W M

    1985-10-01

    The stimulation of bioluminescence in Photobacterium leiognathi has previously been described as a test for genotoxic compounds. An adaptation of this procedure has been developed which uses a dim variant of P. leiognathi and permits the prescreening of microbial fermentation broths for potential antitumor agents. Bioluminescence in this organism was stimulated by compounds which bind to DNA or affect DNA synthesis. Antibiotics with target sites such as protein, cell wall or RNA synthesis, did not alter bioluminescence. Fermentation broths from over 5,000 soil isolates were prescreened in this assay and 95 (1.6%) were defined as active. Further analysis of selected cultures suggested that about half produced compound(s) with DNA-binding activity. These results suggest that the photobacterium induction assay (PIA) may be useful as a prescreen for potential antitumor agents. The assay is rapid, simple and requires only microgram quantities of material for testing.

  16. Potentiation of the depression by adenosine of rat cerebral cortical neurones by progestational agents.

    PubMed Central

    Phillis, J. W.

    1986-01-01

    The effects of four progestational agents pregnenolone sulphate, cyproterone acetate, norethindrone acetate and progesterone, on adenosine-evoked depression of the firing of rat cerebral cortical neurones have been studied. When applied iontophoretically, pregnenolone sulphate, cyproterone, and norethindrone enhanced the actions of iontophoretically applied adenosine and failed to potentiate the depressant effects of adenosine 5'-N-ethylcarboxamide and gamma-aminobutyric acid. Cyproterone acetate (50 micrograms kg-1) and progesterone (200 micrograms kg-1) administered intravenously enhanced the depressant actions of iontophoretically applied adenosine. When applied by large currents, cyproterone, and less frequently norethindrone, depressed the firing of cerebral cortical neurones. The depressant effects of cyproterone were antagonized by caffeine. Pregnenolone sulphate tended to excite cortical neurones but neither this action, nor its potentiation of adenosine were reproduced by application of sulphate ions. It is hypothesized that some of the psychotropic actions of progestational agents may involve an enhancement of 'purinergic' tone in the central nervous system. PMID:3814905

  17. Potential for Terahertz/Optical, Two Color Non-linear Sensing of Liquid Biochemical Agents

    DTIC Science & Technology

    2011-05-18

    solutions1,2 in the infrared frequency band. To explore the lowest frequency macromo- lecular modes of biomolecules, which occur at terahertz fre- quencies, in...resonant with elec- tronic excitations and macromolecular vibrations . A configuration that optimizes SDFG in the face of strong terahertz absorption by...REPORT Potential for terahertz /optical, two color non-linear sensing of liquid biochemical agents 14. ABSTRACT 16. SECURITY CLASSIFICATION OF: A high

  18. Synthesis, antifungal activities and qualitative structure activity relationship of carabrone hydrazone derivatives as potential antifungal agents.

    PubMed

    Wang, Hao; Ren, Shuang-Xi; He, Ze-Yu; Wang, De-Long; Yan, Xiao-Nan; Feng, Jun-Tao; Zhang, Xing

    2014-03-11

    Aimed at developing novel fungicides for relieving the ever-increasing pressure of agricultural production caused by phytopathogenic fungi, 28 new hydrazone derivatives of carabrone, a natural bioactive sesquisterpene, in three types were designed, synthesized and their antifungal activities against Botrytis cinerea and Colletotrichum lagenarium were evaluated. The result revealed that all the derivatives synthesized exhibited considerable antifungal activities in vitro and in vivo, which led to the improved activities for carabrone and its analogues and further confirmed their potential as antifungal agents.

  19. Natural product modulators of transient receptor potential (TRP) channels as potential anti-cancer agents.

    PubMed

    Rodrigues, Tiago; Sieglitz, Florian; Bernardes, Gonçalo J L

    2016-11-07

    Treatment of cancer is a significant challenge in clinical medicine, and its research is a top priority in chemical biology and drug discovery. Consequently, there is an urgent need for identifying innovative chemotypes capable of modulating unexploited drug targets. The transient receptor potential (TRPs) channels persist scarcely explored as targets, despite intervening in a plethora of pathophysiological events in numerous diseases, including cancer. Both agonists and antagonists have proven capable of evoking phenotype changes leading to either cell death or reduced cell migration. Among these, natural products entail biologically pre-validated and privileged architectures for TRP recognition. Furthermore, several natural products have significantly contributed to our current knowledge on TRP biology. In this Tutorial Review we focus on selected natural products, e.g. capsaicinoids, cannabinoids and terpenes, by highlighting challenges and opportunities in their use as starting points for designing natural product-inspired TRP channel modulators. Importantly, the de-orphanization of natural products as TRP channel ligands may leverage their exploration as viable strategy for developing anticancer therapies. Finally, we foresee that TRP channels may be explored for the selective pharmacodelivery of cytotoxic payloads to diseased tissues, providing an innovative platform in chemical biology and molecular medicine.

  20. Using serum CA125 to assess the activity of potential cytostatic agents in ovarian cancer.

    PubMed

    Hall, Marcia R; Petruckevitch, Ann; Pascoe, Joanna; Persic, Mojca; Tahir, Saad; Morgan, Jamie S; Gourley, Charlie; Stuart, Nick; Crawford, S Michael; Kornbrot, Diana E; Qian, Wendi; Rustin, Gordon J

    2014-05-01

    New strategies are required to rapidly identify novel cytostatic agents before embarking on large randomized trials. This study investigates whether a change in rate of rise (slope) of serum CA125 from before to after starting a novel agent could be used to identify cytostatic agents. Tamoxifen was used to validate this hypothesis. Asymptomatic patients with relapsed ovarian cancer who had responded to chemotherapy were enrolled and had CA125 measurements taken every 4 weeks, then more frequently when rising. Once levels reached 4 times the upper limit of normal or nadir, they started continuous tamoxifen 20 mg daily, as well as fortnightly CA125 measurements until symptomatic progression. Because of the potentially nonlinear relationship of CA125 over time, it was felt that to enable normal approximations to be utilized a natural logarithmic standard transformation [ln(CA125)] was the most suitable to improve linearity above the common logarithmic transformation to base 10. From 235 recruited patients, 81 started tamoxifen and had at least 4 CA125 measurements taken before and 4 CA125 measurements taken after starting tamoxifen, respectively. The mean regression slopes from using at least 4 1n(CA125) measurements immediately before and after starting tamoxifen were 0·0149 and 0·0093 [ln(CA125)/d], respectively. This difference is statistically significant, P = 0·001. Therefore, in a future trial with a novel agent, at least as effective as tamoxifen, using this effect size, the number of evaluable patients needed, at significance level of 5% and power of 80%, is 56. Further validation of this methodology is required, but there is potential to use comparison of mean regression slopes of ln(CA125) as an interim analysis measure of efficacy for novel cytostatic agents in relapsed ovarian cancer.

  1. Synthesis and biological evaluation of pseudolaric acid B derivatives as potential immunosuppressive agents.

    PubMed

    Chen, Shou-Qiang; Wang, Jie; Zhao, Chuan; Sun, Qiang-Wen; Wang, Yi-Teng; Ai, Ting; Li, Tan; Gao, Ying; Wang, Huo; Chen, Hong

    2015-01-01

    Pseudolaric acid B (PB) derivatives with immunosuppressive activity were found by our group. In order to find potential immunosuppressive agents with high efficacy and low toxicity, a series of novel PB derivatives were synthesized and evaluated on their immunosuppressive activities. Most of the synthesized compounds were tested in vitro on murine T and B proliferation. In particular, compound 11 exhibited excellent inhibitory activity toward murine T cells (up to 19-fold enhancement compared to that of mycophenolatemofetil) and little cytotoxicity toward normal murine spleen cells. These experimental data demonstrated that some of these PB derivatives have great potential for future immunosuppressive studies.

  2. Medicinal plants from Peru: a review of plants as potential agents against cancer.

    PubMed

    Gonzales, Gustavo F; Valerio, Luis G

    2006-09-01

    Natural products have played a significant role in drug discovery and development especially for agents against cancer and infectious disease. An analysis of new and approved drugs for cancer by the United States Food and Drug Administration over the period of 1981-2002 showed that 62% of these cancer drugs were of natural origin. Natural compounds possess highly diverse and complex molecular structures compared to small molecule synthetic drugs and often provide highly specific biological activities likely derived from the rigidity and high number of chiral centers. Ethnotraditional use of plant-derived natural products has been a major source for discovery of potential medicinal agents. A number of native Andean and Amazonian medicines of plant origin are used as traditional medicine in Peru to treat different diseases. Of particular interest in this mini-review are three plant materials endemic to Peru with the common names of Cat's claw (Uncaria tomentosa), Maca (Lepidium meyenii), and Dragon's blood (Croton lechleri) each having been scientifically investigated for a wide range of therapeutic uses including as specific anti-cancer agents as originally discovered from the long history of traditional usage and anecdotal information by local population groups in South America. Against this background, we present an evidence-based analysis of the chemistry, biological properties, and anti-tumor activities for these three plant materials. In addition, this review will discuss areas requiring future study and the inherent limitations in their experimental use as anti-cancer agents.

  3. Cobalt Zinc Ferrite Nanoparticles as a Potential Magnetic Resonance Imaging Agent: An In vitro Study

    PubMed Central

    Ghasemian, Zeinab; Shahbazi-Gahrouei, Daryoush; Manouchehri, Sohrab

    2015-01-01

    Background: Magnetic Nanoparticles (MNP) have been used for contrast enhancement in Magnetic Resonance Imaging (MRI). In recent years, research on the use of ferrite nanoparticles in T2 contrast agents has shown a great potential application in MR imaging. In this work, Co0.5Zn0.5Fe2O4 and Co0.5Zn0.5Fe2O4-DMSA magnetic nanoparticles, CZF-MNPs and CZF-MNPs-DMSA, were investigated as MR imaging contrast agents. Methods: Cobalt zinc ferrite nanoparticles and their suitable coating, DMSA, were investigated under in vitro condition. Human prostate cancer cell lines (DU145 and PC3) with bare (uncoated) and coated magnetic nanoparticles were investigated as nano-contrast MR imaging agents. Results: Using T2-weighted MR images identified that signal intensity of bare and coated MNPs was enhanced with increasing concentration of MNPs in water. The values of 1/T2 relaxivity (r2) for bare and coated MNPs were found to be 88.46 and 28.80 (mM−1 s−1), respectively. Conclusion: The results show that bare and coated MNPs are suitable as T2-weighted MR imaging contrast agents. Also, the obtained r2/r1 values (59.3 and 50) for bare and coated MNPs were in agreement with the results of other previous relevant works. PMID:26140183

  4. Cobalt Zinc Ferrite Nanoparticles as a Potential Magnetic Resonance Imaging Agent: An In vitro Study.

    PubMed

    Ghasemian, Zeinab; Shahbazi-Gahrouei, Daryoush; Manouchehri, Sohrab

    2015-01-01

    Magnetic Nanoparticles (MNP) have been used for contrast enhancement in Magnetic Resonance Imaging (MRI). In recent years, research on the use of ferrite nanoparticles in T2 contrast agents has shown a great potential application in MR imaging. In this work, Co0.5Zn0.5Fe2O4 and Co0.5Zn0.5Fe2O4-DMSA magnetic nanoparticles, CZF-MNPs and CZF-MNPs-DMSA, were investigated as MR imaging contrast agents. Cobalt zinc ferrite nanoparticles and their suitable coating, DMSA, were investigated under in vitro condition. Human prostate cancer cell lines (DU145 and PC3) with bare (uncoated) and coated magnetic nanoparticles were investigated as nano-contrast MR imaging agents. Using T2-weighted MR images identified that signal intensity of bare and coated MNPs was enhanced with increasing concentration of MNPs in water. The values of 1/T2 relaxivity (r2) for bare and coated MNPs were found to be 88.46 and 28.80 (mM (-1) s(-1)), respectively. The results show that bare and coated MNPs are suitable as T2-weighted MR imaging contrast agents. Also, the obtained r2/r1 values (59.3 and 50) for bare and coated MNPs were in agreement with the results of other previous relevant works.

  5. Life-Threatening Hypokalemic Paralysis in a Young Bodybuilder

    PubMed Central

    Cheung, Kitty K. T.; So, Wing-Yee; Kong, Alice P. S.; Ma, Ronald C. W.; Chow, Francis C. C.

    2014-01-01

    We report a case of life-threatening hypokalemia in a 28-year-old bodybuilder who presented with sudden onset bilateral lower limbs paralysis few days after his bodybuilding competition. His electrocardiogram (ECG) showed typical u-waves due to severe hypokalemia (serum potassium 1.6 mmol/L, reference range (RR) 3.5–5.0 mmol/L). He was admitted to the intensive care unit (ICU) and was treated with potassium replacement. The patient later admitted that he had exposed himself to weight loss agents of unknown nature, purchased online, and large carbohydrate loads in preparation for the competition. He made a full recovery after a few days and discharged himself from the hospital against medical advice. The severe hypokalemia was thought to be caused by several mechanisms to be discussed in this report. With the ever rising number of new fitness centers recently, the ease of online purchasing of almost any drug, and the increasing numbers of youngsters getting into the bodybuilding arena, clinicians should be able to recognize the possible causes of sudden severe hypokalemia in these patients in order to revert the pathophysiology. PMID:24660073

  6. Life-threatening hypokalemic paralysis in a young bodybuilder.

    PubMed

    Cheung, Kitty K T; So, Wing-Yee; Kong, Alice P S; Ma, Ronald C W; Chow, Francis C C

    2014-01-01

    We report a case of life-threatening hypokalemia in a 28-year-old bodybuilder who presented with sudden onset bilateral lower limbs paralysis few days after his bodybuilding competition. His electrocardiogram (ECG) showed typical u-waves due to severe hypokalemia (serum potassium 1.6 mmol/L, reference range (RR) 3.5-5.0 mmol/L). He was admitted to the intensive care unit (ICU) and was treated with potassium replacement. The patient later admitted that he had exposed himself to weight loss agents of unknown nature, purchased online, and large carbohydrate loads in preparation for the competition. He made a full recovery after a few days and discharged himself from the hospital against medical advice. The severe hypokalemia was thought to be caused by several mechanisms to be discussed in this report. With the ever rising number of new fitness centers recently, the ease of online purchasing of almost any drug, and the increasing numbers of youngsters getting into the bodybuilding arena, clinicians should be able to recognize the possible causes of sudden severe hypokalemia in these patients in order to revert the pathophysiology.

  7. THIOCYANATE: A potentially useful therapeutic agent with host defense and antioxidant properties✩

    PubMed Central

    Chandler, Joshua D.; Day, Brian J.

    2014-01-01

    Thiocyanate (SCN) functions in host defense as part of the secreted lactoperoxidase (LPO) microbicidal pathway. SCN is the preferred substrate for LPO-driven catalytic reduction of hydrogen peroxide (H2O2) forming hypothiocyanous acid (HOSCN). HOSCN is selectively generated by many peroxidase enzymes that can utilize SCN including: eosinophil peroxidase (EPO), gastric peroxidase (GPO), myeloperoxidase (MPO), salivary peroxidase (SPO), and thyroid peroxidase (TPO). These enzymes generate HOSCN through a two-electron halogenation reaction. HOSCN is a potent microbicidal agent that kills or nullifies invading pathogens but is better tolerated by host tissue. Some controversy exists as to whether physiologic levels of HOSCN are non-toxic to host tissue, but the disagreement appears to be based on results of enzymatic generation (yielding moderate steady-state exposure) versus direct high level acute exposure in mammalian cell lines. This apparent duality is also true of other endogenous oxidants such as hydrogen peroxide and relates to the difference between physiologically relevant oxidant production versus supra-physiologic bolus dosing approaches. SCN has antioxidant properties that include the ability to protect cells against oxidizing agents such as hypochlorous acid (HOCl) and repair protein chloramines. SCN is an important endogenous molecule that has the potential to interact in complex and elegant ways with its host environment and foreign organisms. SCN’s diverse properties as both host defense and antioxidant agent make it a potentially useful therapeutic. PMID:22968041

  8. Design, synthesis and biological evaluation of novel diphenylthiazole-based cyclooxygenase inhibitors as potential anticancer agents.

    PubMed

    Abdelazeem, Ahmed H; Gouda, Ahmed M; Omar, Hany A; Tolba, Mai F

    2014-12-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used medications as analgesics and antipyretics. Currently, there is a growing interest in their antitumor activity and their ability to reduce the risk and mortality of several cancers. While several studies revealed the ability of NSAIDs to induce apoptosis and inhibit angiogenesis in cancer cells, their exact anticancer mechanism is not fully understood. However, both cyclooxygenase (COX)-dependent and -independent pathways were reported to have a role. In an attempt to develop new anticancer agents, a series of diphenylthiazole substituted thiazolidinone derivatives was synthesized and evaluated for their anticancer activity against a panel of cancer cell lines. Additionally, the inhibitory activity of the synthesized derivatives against COX enzymes was investigated as a potential mechanism for the anticancer activity. Cytotoxicity assay results showed that compounds 15b and 16b were the most potent anticancer agents with half maximal inhibitory concentrations (IC50) between 8.88 and 19.25μM against five different human cancer cell lines. Interestingly, COX inhibition assay results were in agreement with that of the cytotoxicity assays where the most potent anticancer compounds showed good COX-2 inhibition comparable to that of celecoxib. Further support to our results were gained by the docking studies which suggested the ability of compound 15b to bind into COX-2 enzyme with low energy scores. Collectively, these results demonstrated the promising activity of the newly designed compounds as leads for subsequent development into potential anticancer agents.

  9. Evaluation of boronated EGF as a potential delivery agent for BNCT of brain tumors

    SciTech Connect

    Yang, Weilian; Barth, R.F.; Adams, D.M.

    1996-12-31

    The epidermal growth factor receptor (EGFR) gene is often amplified in human glioblastomas, but, reflecting the cellular heterogeneity of these tumors, the frequency of amplification is variable. Since the number of EGFR has been considered as a potential target for the specific delivery of diagnostic and therapeutic agents to brain tumors. Initially, the focus was on using anti-EGFR monoclonal antibodies or their fragments, but within the past few years there has been increasing interest in using EGF based bioconjugates as targeting agents. Recently, we have described a method for the boronation of EGF and have characterized the resulting bioconjugates in vitro. In the present study, we have investigated the potential usefulness of boronated EGF as a delivery agent for neutron capture therapy in rats bearing intracerebral implants of the C6 glioma, which has been transfected with the gene encoding EGFR. Our results indicate that following intratumoral injection, boronated EGF selectivity targeted the transfected EGFR positive C6 glioma, and that the amount of delivered to the tumor exceeded by 3-4 orders of magnitude that which could be delivered by intravenous injection.

  10. Xanthones from Mangosteen Extracts as Natural Chemopreventive Agents: Potential Anticancer Drugs

    PubMed Central

    Shan, T.; Ma, Q.; Guo, K.; Liu, J.; Li, W.; Wang, F.; Wu, E.

    2011-01-01

    Despite decades of research, the treatment and management of malignant tumors still remain a formidable challenge for public health. New strategies for cancer treatment are being developed, and one of the most promising treatment strategies involves the application of chemopreventive agents. The search for novel and effective cancer chemopreventive agents has led to the identification of various naturally occurring compounds. Xanthones, from the pericarp, whole fruit, heartwood, and leaf of mangosteen (Garcinia mangostana Linn., GML), are known to possess a wide spectrum of pharmacologic properties, including anti-oxidant, anti-tumor, anti-allergic, anti-inflammatory, anti-bacterial, anti-fungal, and anti-viral activities. The potential chemopreventive and chemotherapeutic activities of xanthones have been demonstrated in different stages of carcinogenesis (initiation, promotion, and progression) and are known to control cell division and growth, apoptosis, inflammation, and metastasis. Multiple lines of evidence from numerous in vitro and in vivo studies have confirmed that xanthones inhibit proliferation of a wide range of human tumor cell types by modulating various targets and signaling transduction pathways. Here we provide a concise and comprehensive review of preclinical data and assess the observed anticancer effects of xanthones, supporting its remarkable potential as an anticancer agent. PMID:21902651

  11. Synthesis and characterization of iodobenzamide analogues: Potential D-2 dopamine receptor imaging agents

    SciTech Connect

    Murphy, R.A.; Kung, H.F.; Kung, M.P.; Billings, J. )

    1990-01-01

    (S)-N-((1-Ethyl-2-pyrrolidinyl)methyl)-2-hydroxy-3-iodo-6- methoxybenzamide (({sup 123}I)IBZM) is a central nervous system (CNS) D-2 dopamine receptor imaging agent. In order to investigate the versatility of this parent structure in specific dopamine receptor localization and the potential for developing new dopamine receptor imaging agents, a series of new iodinated benzamides with fused ring systems, naphthalene (INAP) and benzofuran (IBF), was synthesized and radiolabeled, and the in vivo and in vitro biological properties were characterized. The best analogue of IBZM is IBF (21). The specific binding of ({sup 125}I)IBF (21) with rat striatal tissue preparation was found to be saturable and displayed a Kd of 0.106 {plus minus} 0.015 nM. Competition data of various receptor ligands for ({sup 125}I)IBF (21) binding show the following rank order of potency: spiperone greater than IBF (21) greater than IBZM greater than (+)-butaclamol greater than ({plus minus})-ADTN,6,7 greater than ketanserin greater than SCH-23390 much greater than propranolol. The in vivo biodistribution results confirm that ({sup 125}I)IBF (21) concentrated in the striatal area after iv injection into rats. The study demonstrates that ({sup 123}I)IBF (21) is a potential agent for imaging CNS D-2 dopamine receptors.

  12. Chlamydia gallinacea: a widespread emerging Chlamydia agent with zoonotic potential in backyard poultry.

    PubMed

    Li, L; Luther, M; Macklin, K; Pugh, D; Li, J; Zhang, J; Roberts, J; Kaltenboeck, B; Wang, C

    2017-10-01

    Chlamydia gallinacea, a new chlamydial agent, has been reported in four European countries as well as Argentina and China. Experimentally infected chickens with C. gallinacea in previous study showed no clinical signs but had significantly reduced gains in body weight (6·5-11·4%). Slaughterhouse workers exposed to infected chickens have developed atypical pneumonia, indicating C. gallinacea is likely a zoonotic agent. In this study, FRET-PCR confirmed that C. gallinacea was present in 12·4% (66/531) of oral-pharyngeal samples from Alabama backyard poultry. Phylogenetic comparisons based on ompA variable domain showed that 16 sequenced samples represented 14 biotypes. We report for the first time the presence of C. gallinacea in North America, and this warrants further research on the organism's pathogenicity, hosts, transmission, and zoonotic potential.

  13. Synthesis and biological evaluation of novel acylhydrazone derivatives as potential antitumor agents.

    PubMed

    Congiu, Cenzo; Onnis, Valentina

    2013-11-01

    We have designed, synthesized, and evaluated as potential antitumor agents a series of 2-hydroxybenzylidene derivatives of the N-(2-trifluoromethylpiridyn-4-yl)anthranilic acid hydrazide, and some analogues bearing a (2-trifluoromethyl)piridyn-4-ylamino group in 3- or 4-position of benzohydrazide or 4-position of phenylacetohydrazide. Compounds 12e, 13e, 15e, and 16e, bearing a 4-(diethylamino)salicylidene group exhibited potent cytotoxicity, with averaged GI50 values in sub-micromolar range, and a variety of cell selectivity at nanomolar concentrations. The determination of acute toxicity in athymic nudes mice proved some compounds to be non-toxic, making them good candidates for further study as antitumor agents. Copyright © 2013 Elsevier Ltd. All rights reserved.

  14. Design, synthesis, and biological evaluation of the first podophyllotoxin analogues as potential vascular-disrupting agents.

    PubMed

    Labruère, Raphaël; Gautier, Benoît; Testud, Marlène; Seguin, Johanne; Lenoir, Christine; Desbène-Finck, Stéphanie; Helissey, Philippe; Garbay, Christiane; Chabot, Guy G; Vidal, Michel; Giorgi-Renault, Sylviane

    2010-12-03

    We designed and synthesized two novel series of azapodophyllotoxin analogues as potential antivascular agents. A linker was inserted between the trimethoxyphenyl ring E and the tetracyclic ABCD moiety of the 4-aza-1,2-didehydropodophyllotoxins. In the first series, the linker enables free rotation between the two moieties; in the second series, conformational restriction of the E nucleus was considered. We have identified several new compounds with inhibitory activity toward tubulin polymerization similar to that of CA-4 and colchicine, while displaying low cytotoxic activity against normal and/or cancer cells. An aminologue and a methylenic analogue were shown to disrupt endothelial cell cords on Matrigel at subtoxic concentrations, and an original assay of drug washout allowed us to demonstrate the rapid reversibility of this effect. These two new analogues are promising leads for the development of vascular-disrupting agents in the podophyllotoxin series.

  15. Design, synthesis and evaluation of 4-dimethylamine flavonoid derivatives as potential multifunctional anti-Alzheimer agents.

    PubMed

    Luo, Wen; Wang, Ting; Hong, Chen; Yang, Ya-Chen; Chen, Ying; Cen, Juan; Xie, Song-Qiang; Wang, Chao-Jie

    2016-10-21

    A new series of 4-dimethylamine flavonoid derivatives were designed and synthesized as potential multifunctional anti-Alzheimer agents. The inhibition of cholinesterase activity, self-induced β-amyloid (Aβ) aggregation, and antioxidant activity by these derivatives was investigated. Most of the compounds exhibited potent acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity. A Lineweaver-Burk plot and molecular modeling study showed that these compounds targeted both the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. The derivatives showed potent self-induced Aβ aggregation inhibition and peroxyl radical absorbance activity. Moreover, compound 6d significantly protected PC12 neurons against H2O2-induced cell death at low concentrations. Thus, these compounds could become multifunctional agents for further development for the treatment of AD.

  16. Activation of the chemosensing transient receptor potential channel A1 (TRPA1) by alkylating agents.

    PubMed

    Stenger, Bernhard; Zehfuss, Franziska; Mückter, Harald; Schmidt, Annette; Balszuweit, Frank; Schäfer, Eva; Büch, Thomas; Gudermann, Thomas; Thiermann, Horst; Steinritz, Dirk

    2015-09-01

    The transient receptor potential ankyrin 1 (TRPA1) cation channel is expressed in different tissues including skin, lung and neuronal tissue. Recent reports identified TRPA1 as a sensor for noxious substances, implicating a functional role in the molecular toxicology. TRPA1 is activated by various potentially harmful electrophilic substances. The chemical warfare agent sulfur mustard (SM) is a highly reactive alkylating agent that binds to numerous biological targets. Although SM is known for almost 200 years, detailed knowledge about the pathophysiology resulting from exposure is lacking. A specific therapy is not available. In this study, we investigated whether the alkylating agent 2-chloroethyl-ethylsulfide (CEES, a model substance for SM-promoted effects) and SM are able to activate TRPA1 channels. CEES induced a marked increase in the intracellular calcium concentration ([Ca(2+)]i) in TRPA1-expressing but not in TRPA1-negative cells. The TRP-channel blocker AP18 diminished the CEES-induced calcium influx. HEK293 cells permanently expressing TRPA1 were more sensitive toward cytotoxic effects of CEES compared with wild-type cells. At low CEES concentrations, CEES-induced cytotoxicity was prevented by AP18. Proof-of-concept experiments using SM resulted in a pronounced increase in [Ca(2+)]i in HEK293-A1-E cells. Human A549 lung epithelial cells, which express TRPA1 endogenously, reacted with a transient calcium influx in response to CEES exposure. The CEES-dependent calcium response was diminished by AP18. In summary, our results demonstrate that alkylating agents are able to activate TRPA1. Inhibition of TRPA1 counteracted cellular toxicity and could thus represent a feasible approach to mitigate SM-induced cell damage.

  17. Opportunities for Web-based Drug Repositioning: Searching for Potential Antihypertensive Agents with Hypotension Adverse Events

    PubMed Central

    Wang, Kejian; Wan, Mei; Wang, Rui-Sheng

    2016-01-01

    Background Drug repositioning refers to the process of developing new indications for existing drugs. As a phenotypic indicator of drug response in humans, clinical side effects may provide straightforward signals and unique opportunities for drug repositioning. Objective We aimed to identify drugs frequently associated with hypotension adverse reactions (ie, the opposite condition of hypertension), which could be potential candidates as antihypertensive agents. Methods We systematically searched the electronic records of the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) through the openFDA platform to assess the association between hypotension incidence and antihypertensive therapeutic effect regarding a list of 683 drugs. Results Statistical analysis of FAERS data demonstrated that those drugs frequently co-occurring with hypotension events were more likely to have antihypertensive activity. Ranked by the statistical significance of frequent hypotension reporting, the well-known antihypertensive drugs were effectively distinguished from others (with an area under the receiver operating characteristic curve > 0.80 and a normalized discounted cumulative gain of 0.77). In addition, we found a series of antihypertensive agents (particularly drugs originally developed for treating nervous system diseases) among the drugs with top significant reporting, suggesting the good potential of Web-based and data-driven drug repositioning. Conclusions We found several candidate agents among the hypotension-related drugs on our list that may be redirected for lowering blood pressure. More important, we showed that a pharmacovigilance system could alternatively be used to identify antihypertensive agents and sustainably create opportunities for drug repositioning. PMID:27036325

  18. Hypokalemic periodic paralysis associated with thyrotoxicosis, renal tubular acidosis and nephrogenic diabetes insipidus.

    PubMed

    Im, Eun Joo; Lee, Jung Min; Kim, Ji Hyun; Chang, Sang Ah; Moon, Sung Dae; Ahn, Yu Bae; Son, Hyun Shik; Cha, Bong Yun; Lee, Kwang Woo; Son, Ho Young

    2010-01-01

    A 19-year-old girl presented at our emergency room with hypokalemic periodic paralysis. She had a thyrotoxic goiter and had experienced three paralytic attacks during the previous 2 years on occasions when she stopped taking antithyroid drugs. In addition to thyrotoxic periodic paralysis (TPP), she had metabolic acidosis, urinary potassium loss, polyuria and polydipsia. Her reduced ability to acidify urine during spontaneous metabolic acidosis was confirmed by detection of coexisting distal renal tubular acidosis (RTA). The polyuria and polydipsia were caused by nephrogenic diabetes insipidus, which was diagnosed using the water deprivation test and vasopressin administration. Her recurrent and frequent paralytic attacks may have been the combined effects of thyrotoxicosis and RTA. Although the paralytic attack did not recur after improving the thyroid function, mild acidosis and nephrogenic DI have been remained subsequently. Patients with TPP, especially females with atypical metabolic features, should be investigated for possible precipitating factors.

  19. Unilateral gynecomastia and hypokalemic periodic paralysis as first manifestations of Graves' disease.

    PubMed

    Wang, Yufan; Zhao, Li; Li, Fan; Chen, Hai-xi; Fang, Fang; Peng, Yong-de

    2013-06-01

    A 39-year-old Chinese man presented to the study hospital with right-sided gynecomastia. Underlying Graves' disease was not diagnosed until recurrent episodes of hypokalemic periodic paralysis were observed. The estradiol (E2) and progesterone levels and the E2-to-testosterone (T) (E2/T) ratio of the patient were elevated before treatment. Immediate intravenous potassium supplementation was started to reverse the paralysis. Additionally, antithyroid drugs were administered to restore a euthyroid state. After treatment, the patient gained strength. Gynecomastia regressed with a return to the euthyroid state; the E2 and progesterone levels normalized and the plasma E2/T ratio declined. In addition to the classic symptoms, some atypical symptoms of Graves' disease may also occur. One of the challenges lies in recognizing the underlying etiology. Early diagnosis and appropriate treatment can avoid unnecessary investigations and serious cardiopulmonary complications.

  20. Recurrent Attacks of Hypokalemic Quadriparesis: An Unusual Presentation of Primary Sjögren Syndrome.

    PubMed

    Seirafian, Shiva; Shafie, Mohammad; Abedini, Amin; Pakzad, Bahram; Roomizadeh, Peyman

    2016-01-01

    We herein report the case of a 64-year old woman with recurrent attacks of hypokalemic quadriparesis which resulted from distal renal tubular acidosis (dRTA) secondary to Sjögren syndrome. The patient presented with sudden onset quadriparesis. A physical examination showed symmetric weakness of all four limbs. Severe hypokalemia (1.8 mEq/L), accompanied by normal anion gap metabolic acidosis, a positive urine anion gap and an inappropriately high urine pH pointed toward the diagnosis of dRTA. Further investigations disclosed primary Sjögren syndrome, which had not previously been recognized. On the basis of the current report and a review of the literature we suggest investigating the possibility of Sjögren syndrome in all patients with clinically unexplained dRTA.

  1. Metal-oxo containing polymer nanobeads as potential contrast agents for magnetic resonance imaging

    NASA Astrophysics Data System (ADS)

    Pablico, Michele Huelar

    Magnetic resonance imaging (MRI) has greatly revolutionized the way diseases are detected and treated, as it is a non-invasive imaging modality solely based on the interaction of radiowaves and hydrogen nuclei in the presence of an external magnetic field. It is widely used today for the diagnosis of diseases as it offers an efficient method of mapping structure and function of soft tissues in the body. Most MRI examinations utilize paramagnetic materials known as contrast agents, which enhance the MR signal by decreasing the longitudinal (T1) and transverse (T2) relaxation times of the surrounding water protons in biological systems. This results into increased signal intensity differences thereby allowing better interpretation and analysis of pathological tissues. Contrast agents function by lowering the T1 or lowering the T2, resulting into bright and dark contrasts, respectively. The most common MRI contrast agents that are in clinical use today are gadolinium chelates and superparamagnetic iron oxide nanoparticles, both of which have their own advantages in terms of contrast enhancement properties. In the past few years, however, there has been interest in utilizing metal-containing clusters for MRI contrast enhancement as these materials bridge the gap between the constrained structure and magnetic properties of the gadolinium chelates with the superparamagnetic behavior of the iron oxide nanoparticles. Recently, metallic clusters containing Mn and Fe metal centers have received increased attention mainly because of their potential for high spin states and benign nature. In the quest to further develop novel imaging agents, this research has focused on investigating the use of metal-oxo clusters as potential contrast agents for MRI. The primary goal of this project is to identify clusters that meet the following criteria: high paramagnetic susceptibility, water-soluble, stable, cheap, contain environmentally benign metals, and easily derivatized. This work is

  2. Evaluation of a targeted nanobubble ultrasound contrast agent for potential tumor imaging

    NASA Astrophysics Data System (ADS)

    Li, Chunfang; Shen, Chunxu; Liu, Haijuan; Wu, Kaizhi; Zhou, Qibing; Ding, Mingyue

    2015-03-01

    Targeted nanobubbles have been reported to improve the contrast effect of ultrasound imaging due to the enhanced permeation and retention effects at tumor vascular leaks. In this work, the contrast enhancement abilities and the tumor targeting potential of a self-made VEGFR2-targeted nanobubble ultrasound contrast agent was evaluated in-vitro and in-vivo. Size distribution and zeta potential were assessed. Then the contrast-enhanced ultrasound imaging of the VEGFR2 targeted nanobubbles were evaluated with a custom-made experimental apparatus and in normal Wistar rats. Finally, the in-vivo tumor-targeting ability was evaluated on nude mice with subcutaneous tumor. The results showed that the target nanobubbles had uniform distribution with the average diameter of 208.1 nm, polydispersity index (PDI) of 0.411, and zeta potential of -13.21 mV. Significant contrast enhancement was observed in both in-vitro and in-vivo ultrasound imaging, demonstrating that the self-made target nanobubbles can enhance the contrast effect of ultrasound imaging efficiently. Targeted tumor imaging showed less promising result, due to the fact that the targeted nanobubbles arriving and permeating through tumor vessels were not many enough to produce significant enhancement. Future work will focus on exploring new imaging algorithm which is sensitive to targeted nanobubbles, so as to correctly detect the contrast agent, particularly at a low bubble concentration.

  3. Insights into the antimicrobial properties of hepcidins: advantages and drawbacks as potential therapeutic agents.

    PubMed

    Lombardi, Lisa; Maisetta, Giuseppantonio; Batoni, Giovanna; Tavanti, Arianna

    2015-04-10

    The increasing frequency of multi-drug resistant microorganisms has driven research into alternative therapeutic strategies. In this respect, natural antimicrobial peptides (AMPs) hold much promise as candidates for the development of novel antibiotics. However, AMPs have some intrinsic drawbacks, such as partial degradation by host proteases or inhibition by host body fluid composition, potential toxicity, and high production costs. This review focuses on the hepcidins, which are peptides produced by the human liver with a known role in iron homeostasis, as well by numerous other organisms (including fish, reptiles, other mammals), and their potential as antibacterial and antifungal agents. Interestingly, the antimicrobial properties of human hepcidins are enhanced at acidic pH, rendering these peptides appealing for the design of new drugs targeting infections that occur in body areas with acidic physiological pH. This review not only considers current research on the direct killing activity of these peptides, but evaluates the potential application of these molecules as coating agents preventing biofilm formation and critically assesses technical obstacles preventing their therapeutic application.

  4. Effects of Potential Therapeutic Agents on Copper Accumulations in Gill of Crassostrea virginica

    PubMed Central

    Luxama, Juan D.; Carroll, Margaret A.; Catapane, Edward J.

    2010-01-01

    Copper is an essential trace element for organisms, but when in excess, copper’s redox potential enhances oxyradical formation and increases cellular oxidative stress. Copper is a major pollutant in Jamaica Bay and other aquatic areas. Bivalves are filter feeders that accumulate heavy metals and other pollutants from their environment. Previously it was determined that seed from the bivalve Crassostrea virginica, transplanted from an oyster farm to Jamaica Bay readily accumulated copper and other pollutants into their tissues. In the present study we utilized Atomic Absorption Spectrometry to measure the uptake of copper into C. virginica gill in the presence and absence of three potential copper -blocking agents: diltiazem, lanthanum, and p-aminosalicyclic acid. Diltiazem and lanthanum are known calcium-channel blockers and p-aminosalicylic acid is an anti-infammarory agent with possible metal chelating properties. We also used the DMAB-Rhodanine histochemistry staining technique to confirm that copper was entering gill cells. Our result showed that diltiazem and p-aminosalicyclic acid reduced copper accumulations in the gill, while lanthanum did not. DMAB-Rhodanine histochemistry showed enhanced cellular copper staining in copper-treated samples and further demonstrated that diltiazem was able to reduce copper uptake. The accumulation of copper into oyster gill and its potential toxic effects could be of physiological significance to the growth and long term health of oysters and other marine animals living in a copper polluted environment. Identifying agents that block cellular copper uptake will further the understanding of metal transport mechanisms and may be beneficial in the therapeutic treatment of copper toxicity in humans. PMID:21841975

  5. Advances in diagnosis and management of hypokalemic and hyperkalemic emergencies.

    PubMed

    Pepin, Jeffrey; Shields, Christopher

    2012-02-01

    With up to 56% of individuals taking diuretics likely to develop hypokalemia, and comorbid disease and many other types of medications having the potential to induce hyperkalemia, potassium abnormalities are some of the most commonly seen electrolyte abnormalities in the emergency department (ED). Unless recognized and treated appropriately, they can also be some of the most deadly. Symptoms accompanying potassium abnormalities are often vague, involving multiple organ systems. This evidence-based review discusses the etiology, differential diagnosis, and diagnostic studies for detecting hypokalemia and hyperkalemia, including managing laboratory errors that lead to factitious potassium findings. Recognition and treatment of life-threatening dysrhythmias in hypokalemia and hyperkalemia are key to managing these potassium abnormalities. Electrocardiogram (ECG) findings, treatment algorithms, and controversies on treating potassium abnormalities in the ED are discussed, with recommendations on criteria for disposition.

  6. PPARγ and Its Ligands: Potential Antitumor Agents in the Digestive System.

    PubMed

    Shu, Linjing; Huang, Renhuan; Wu, Songtao; Chen, Zhaozhao; Sun, Ke; Jiang, Yan; Cai, Xiaoxiao

    2016-01-01

    Peroxisome proliferator-activated receptor γ (PPARγ) is a versatile member of the ligand-activated nuclear hormone receptor superfamily of transcription factors, with expression in several different cell lines, especially in the digestive system. After being activated by its ligand, PPARγ can suppress the growth of oral, esophageal, gastric, colorectal, liver, biliary, and pancreatic tumor cells, suggesting that PPARγ ligand is a potential anticancer agent in PPARγ-expressing tumors. This review highlights key advances in understanding the effects of PPARγ ligands in the treatment of tumors in the digestive system.

  7. Quercetin and rutin as potential sunscreen agents: determination of efficacy by an in vitro method.

    PubMed

    Choquenet, Benjamin; Couteau, Céline; Paparis, Eva; Coiffard, Laurence J M

    2008-06-01

    Given that flavonoids are known for their ultraviolet (UV)B photoprotective properties in plants that contain them, we chose to study quercetin (1) and rutin (2) as agents that could potentially be used in sunscreen products. These two substances proved to behave in similar ways. When incorporated in oil-in-water emulsions, at a concentration of 10% (w/w), 1 and 2 give sun protection factor (SPF) values similar to that of homosalate, a standard substance. These two flavonoids also provided a non-negligible level of photoprotection in the UVA range. When used in association with titanium dioxide, the SPF obtained was around 30.

  8. Molecules that mimic apolipoprotein A-I: potential agents for treating atherosclerosis.

    PubMed

    Leman, Luke J; Maryanoff, Bruce E; Ghadiri, M Reza

    2014-03-27

    Certain amphipathic α-helical peptides can functionally mimic many of the properties of full-length apolipoproteins, thereby offering an approach to modulate high-density lipoprotein (HDL) for combating atherosclerosis. In this Perspective, we summarize the key findings and advances over the past 25 years in the development of peptides that mimic apolipoproteins, especially apolipoprotein A-I (apoA-I). This assemblage of information provides a reasonably clear picture of the state of the art in the apolipoprotein mimetic field, an appreciation of the potential for such agents in pharmacotherapy, and a sense of the opportunities for optimizing the functional properties of HDL.

  9. Molecules that Mimic Apolipoprotein A-I: Potential Agents for Treating Atherosclerosis

    PubMed Central

    Leman, Luke J.; Maryanoff, Bruce E.; Ghadiri, M. Reza

    2013-01-01

    Certain amphipathic α-helical peptides can functionally mimic many of the properties of full-length apolipoproteins, thereby offering an approach to modulate high-density lipoprotein (HDL) for combating atherosclerosis. In this Perspective, we summarize the key findings and advances over the past 25 years in the development of peptides that mimic apolipoproteins, especially apolipoprotein A-I (apoA-I). This assemblage of information provides a reasonably clear picture of the state of the art in the apolipoprotein mimetic field, an appreciation of the potential for such agents in pharmacotherapy, and a sense of the opportunities for optimizing the functional properties of HDL. PMID:24168751

  10. The fabrication of novel nanobubble ultrasound contrast agent for potential tumor imaging.

    PubMed

    Xing, Zhanwen; Wang, Jinrui; Ke, Hengte; Zhao, Bo; Yue, Xiuli; Dai, Zhifei; Liu, Jibin

    2010-04-09

    Novel biocompatible nanobubbles were fabricated by ultrasonication of a mixture of Span 60 and polyoxyethylene 40 stearate (PEG40S) followed by differential centrifugation to isolate the relevant subpopulation from the parent suspensions. Particle sizing analysis and optical microscopy inspection indicated that the freshly generated micro/nanobubble suspension was polydisperse and the size distribution was bimodal with large amounts of nanobubbles. To develop a nano-sized contrast agent that is small enough to leak through tumor pores, a fractionation to extract smaller bubbles by variation in the time of centrifugation at 20g (relative centrifuge field, RCF) was suggested. The results showed that the population of nanobubbles with a precisely controlled mean diameter could be sorted from the initial polydisperse suspensions to meet the specified requirements. The isolated bubbles were stable over two weeks under the protection of perfluoropropane gas. The acoustic behavior of the nano-sized contrast agent was evaluated using power Doppler imaging in a normal rabbit model. An excellent power Doppler enhancement was found in vivo renal imaging after intravenous injection of the obtained nanobubbles. Given the broad spectrum of potential clinical applications, the nano-sized contrast agent may provide a versatile adjunct for ultrasonic imaging enhancement and/or treatment of tumors.

  11. Mustard vesicating agent-induced toxicity in the skin tissue and silibinin as a potential countermeasure.

    PubMed

    Tewari-Singh, Neera; Agarwal, Rajesh

    2016-06-01

    Exposure to the vesicating agents sulfur mustard (SM) and nitrogen mustard (NM) causes severe skin injury with delayed blistering. Depending upon the dose and time of their exposure, edema and erythema develop into blisters, ulceration, necrosis, desquamation, and pigmentation changes, which persist weeks and even years after exposure. Research advances have generated data that have started to explain the probable mechanism of action of vesicant-induced skin toxicity; however, despite these advances, effective and targeted therapies are still deficient. This review highlights studies on two SM analogs, 2-chloroethyl ethyl sulfide (CEES) and NM, and CEES- and NM-induced skin injury mouse models that have substantially added to the knowledge on the complex pathways involved in mustard vesicating agent-induced skin injury. Furthermore, employing these mouse models, studies under the National Institutes of Health Countermeasures Against Chemical Threats program have identified the flavanone silibinin as a novel therapeutic intervention with the potential to be developed as an effective countermeasure against skin injury following exposure to mustard vesicating agents.

  12. Double layered hydroxides as potential anti-cancer drug delivery agents.

    PubMed

    Riaz, Ufana; Ashraf, S M

    2013-04-01

    The emergence of nanotechnology has changed the scenario of the medical world by revolutionizing the diagnosis, monitoring and treatment of cancer. This nanotechnology has been proved miraculous in detecting cancer cells, delivering chemotherapeutic agents and monitoring treatment from non-specific to highly targeted killing of tumor cells. In the past few decades, a number of inorganic materials have been investigated such as calcium phosphate, gold, carbon materials, silicon oxide, iron oxide, and layered double hydroxide (LDH) for examining their efficacy in targeting drug delivery. The reason behind the selection of these inorganic materials was their versatile and unique features efficient in drug delivery, such as wide availability, rich surface functionality, good biocompatibility, potential for target delivery, and controlled release of the drug from these inorganic nanomaterials. Although, the drug-LDH hybrids are found to be quite instrumental because of their application as advanced anti-cancer drug delivery systems, there has not been much research on them. This mini review is set to highlight the advancement made in the use of layered double hydroxides (LDHs) as anti-cancer drug delivery agents. Along with the advantages of LDHs as anti-cancer drug delivery agents, the process of interaction of some of the common anti-cancer drugs with LDH has also been discussed.

  13. Antioxidants as potential medical countermeasures for chemical warfare agents and toxic industrial chemicals.

    PubMed

    McElroy, Cameron S; Day, Brian J

    2016-01-15

    The continuing horrors of military conflicts and terrorism often involve the use of chemical warfare agents (CWAs) and toxic industrial chemicals (TICs). Many CWA and TIC exposures are difficult to treat due to the danger they pose to first responders and their rapid onset that can produce death shortly after exposure. While the specific mechanism(s) of toxicity of these agents are diverse, many are associated either directly or indirectly with increased oxidative stress in affected tissues. This has led to the exploration of various antioxidants as potential medical countermeasures for CWA/TIC exposures. Studies have been performed across a wide array of agents, model organisms, exposure systems, and antioxidants, looking at an almost equally diverse set of endpoints. Attempts at treating CWAs/TICs with antioxidants have met with mixed results, ranging from no effect to nearly complete protection. The aim of this commentary is to summarize the literature in each category for evidence of oxidative stress and antioxidant efficacy against CWAs and TICs. While there is great disparity in the data concerning methods, models, and remedies, the outlook on antioxidants as medical countermeasures for CWA/TIC management appears promising.

  14. Identification of Aspergillus flavus isolates as potential biocontrol agents of aflatoxin contamination in crops.

    PubMed

    Rosada, L J; Sant'anna, J R; Franco, C C S; Esquissato, G N M; Santos, P A S R; Yajima, J P R S; Ferreira, F D; Machinski, M; Corrêa, B; Castro-Prado, M A A

    2013-06-01

    Aspergillus flavus, a haploid organism found worldwide in a variety of crops, including maize, cottonseed, almond, pistachio, and peanut, causes substantial and recurrent worldwide economic liabilities. This filamentous fungus produces aflatoxins (AFLs) B1 and B2, which are among the most carcinogenic compounds from nature, acutely hepatotoxic and immunosuppressive. Recent efforts to reduce AFL contamination in crops have focused on the use of nonaflatoxigenic A. flavus strains as biological control agents. Such agents are applied to soil to competitively exclude native AFL strains from crops and thereby reduce AFL contamination. Because the possibility of genetic recombination in A. flavus could influence the stability of biocontrol strains with the production of novel AFL phenotypes, this article assesses the diversity of vegetative compatibility reactions in isolates of A. flavus to identify heterokaryon self-incompatible (HSI) strains among nonaflatoxigenic isolates, which would be used as biological controls of AFL contamination in crops. Nitrate nonutilizing (nit) mutants were recovered from 25 A. flavus isolates, and based on vegetative complementation between nit mutants and on the microscopic examination of the number of hyphal fusions, five nonaflatoxigenic (6, 7, 9 to 11) and two nontoxigenic (8 and 12) isolates of A. flavus were phenotypically characterized as HSI. Because the number of hyphal fusions is reduced in HSI strains, impairing both heterokaryon formation and the genetic exchanges with aflatoxigenic strains, the HSI isolates characterized here, especially isolates 8 and 12, are potential agents for reducing AFL contamination in crops.

  15. Discovery of piperlongumine as a potential novel lead for the development of senolytic agents

    PubMed Central

    Wang, Yingying; Chang, Jianhui; Liu, Xingui; Zhang, Xuan; Zhang, Suping; Zhang, Xin; Zhou, Daohong; Zheng, Guangrong

    2016-01-01

    Accumulating evidence indicates that senescent cells play an important role in many age-associated diseases. The pharmacological depletion of senescent cells (SCs) with a “senolytic agent”, a small molecule that selectively kills SCs, is a potential novel therapeutic approach for these diseases. Recently, we discovered ABT-263, a potent and highly selective senolytic agent, by screening a library of rationally-selected compounds. With this screening approach, we also identified a second senolytic agent called piperlongumine (PL). PL is a natural product that is reported to have many pharmacological effects, including anti-tumor activity. We show here that PL preferentially killed senescent human WI-38 fibroblasts when senescence was induced by ionizing radiation, replicative exhaustion, or ectopic expression of the oncogene Ras. PL killed SCs by inducing apoptosis, and this process did not require the induction of reactive oxygen species. In addition, we found that PL synergistically killed SCs in combination with ABT-263, and initial structural modifications to PL identified analogs with improved potency and/or selectivity in inducing SC death. Overall, our studies demonstrate that PL is a novel lead for developing senolytic agents. PMID:27913811

  16. Rosemary (Rosmarinus officinalis L.) Extract as a Potential Complementary Agent in Anticancer Therapy.

    PubMed

    González-Vallinas, Margarita; Reglero, Guillermo; Ramírez de Molina, Ana

    2015-01-01

    Cancer remains an important cause of mortality nowadays and, therefore, new therapeutic approaches are still needed. Rosemary (Rosmarinus officinalis L.) has been reported to possess antitumor activities both in vitro and in animal studies. Some of these activities were attributed to its major components, such as carnosic acid, carnosol, ursolic acid, and rosmarinic acid. Initially, the antitumor effects of rosemary were attributed to its antioxidant activity. However, in recent years, a lack of correlation between antioxidant and antitumor effects exerted by rosemary was reported, and different molecular mechanisms were related to its tumor inhibitory properties. Moreover, supported by the U.S. Food and Drug Administration and the European Food and Safety Authority, specific compositions of rosemary extract were demonstrated to be safe for human health and used as antioxidant additive in foods, suggesting the potential easy application of this agent as a complementary approach in cancer therapy. In this review, we aim to summarize the reported anticancer effects of rosemary, the demonstrated molecular mechanisms related to these effects and the interactions between rosemary and currently used anticancer agents. The possibility of using rosemary extract as a complementary agent in cancer therapy in comparison with its isolated components is discussed.

  17. Marine Algae as a Potential Source for Anti-Obesity Agents

    PubMed Central

    Wan-Loy, Chu; Siew-Moi, Phang

    2016-01-01

    Obesity is a major epidemic that poses a worldwide threat to human health, as it is also associated with metabolic syndrome, type 2 diabetes and cardiovascular disease. Therapeutic intervention through weight loss drugs, accompanied by diet and exercise, is one of the options for the treatment and management of obesity. However, the only approved anti-obesity drug currently available in the market is orlistat, a synthetic inhibitor of pancreatic lipase. Other anti-obesity drugs are still being evaluated at different stages of clinical trials, while some have been withdrawn due to their severe adverse effects. Thus, there is a need to look for new anti-obesity agents, especially from biological sources. Marine algae, especially seaweeds are a promising source of anti-obesity agents. Four major bioactive compounds from seaweeds which have the potential as anti-obesity agents are fucoxanthin, alginates, fucoidans and phlorotannins. The anti-obesity effects of such compounds are due to several mechanisms, which include the inhibition of lipid absorption and metabolism (e.g., fucoxanthin and fucoidans), effect on satiety feeling (e.g., alginates), and inhibition of adipocyte differentiation (e.g., fucoxanthin). Further studies, especially testing bioactive compounds in long-term human trials are required before any new anti-obesity drugs based on algal products can be developed. PMID:27941599

  18. Facile Synthesis of Gd-Functionalized Gold Nanoclusters as Potential MRI/CT Contrast Agents.

    PubMed

    Le, Wenjun; Cui, Shaobin; Chen, Xin; Zhu, Huanhuan; Chen, Bingdi; Cui, Zheng

    2016-04-09

    Multi-modal imaging plays a key role in the earlier detection of disease. In this work, a facile bioinspired method was developed to synthesize Gd-functionalized gold nanoclusters (Gd-Au NCs). The Gd-Au NCs exhibit a uniform size, with an average size of 5.6 nm in dynamic light scattering (DLS), which is a bit bigger than gold clusters (3.74 nm, DLS), while the fluorescent properties of Gd-Au NCs are almost the same as that of Au NCs. Moreover, the Gd-Au NCs exhibit a high longitudinal relaxivity value (r1) of 22.111 s(-1) per mM of Gd in phosphate-buffered saline (PBS), which is six times higher than that of commercial Magnevist (A complex of gadolinium with a chelating agent, diethylenetriamine penta-acetic acid, Gd-DTPA, r1 = 3.56 mM(-1)·s(-1)). Besides, as evaluated by nano single photon emission computed tomography (SPECT) and computed tomography (CT) the Gd-Au NCs have a potential application as CT contrast agents because of the Au element. Finally, the Gd-Au NCs show little cytotoxicity, even when the Au concentration is up to 250 μM. Thus, the Gd-Au NCs can act as multi-modal imaging contrast agents.

  19. The fabrication of novel nanobubble ultrasound contrast agent for potential tumor imaging

    NASA Astrophysics Data System (ADS)

    Xing, Zhanwen; Wang, Jinrui; Ke, Hengte; Zhao, Bo; Yue, Xiuli; Dai, Zhifei; Liu, Jibin

    2010-04-01

    Novel biocompatible nanobubbles were fabricated by ultrasonication of a mixture of Span 60 and polyoxyethylene 40 stearate (PEG40S) followed by differential centrifugation to isolate the relevant subpopulation from the parent suspensions. Particle sizing analysis and optical microscopy inspection indicated that the freshly generated micro/nanobubble suspension was polydisperse and the size distribution was bimodal with large amounts of nanobubbles. To develop a nano-sized contrast agent that is small enough to leak through tumor pores, a fractionation to extract smaller bubbles by variation in the time of centrifugation at 20g (relative centrifuge field, RCF) was suggested. The results showed that the population of nanobubbles with a precisely controlled mean diameter could be sorted from the initial polydisperse suspensions to meet the specified requirements. The isolated bubbles were stable over two weeks under the protection of perfluoropropane gas. The acoustic behavior of the nano-sized contrast agent was evaluated using power Doppler imaging in a normal rabbit model. An excellent power Doppler enhancement was found in vivo renal imaging after intravenous injection of the obtained nanobubbles. Given the broad spectrum of potential clinical applications, the nano-sized contrast agent may provide a versatile adjunct for ultrasonic imaging enhancement and/or treatment of tumors.

  20. Therapeutic potential of the chemokine receptor CXCR4 antagonists as multifunctional agents.

    PubMed

    Tsutsumi, Hiroshi; Tanaka, Tomohiro; Ohashi, Nami; Masuno, Hiroyuki; Tamamura, Hirokazu; Hiramatsu, Kenichi; Araki, Takanobu; Ueda, Satoshi; Oishi, Shinya; Fujii, Nobutaka

    2007-01-01

    The chemokine receptor CXCR4 possesses multiple critical functions in normal and pathologic physiology. CXCR4 is a G-protein-coupled receptor that transduces signals of its endogenous ligand, the chemokine CXCL12 (stromal cell-derived factor-1, SDF-1). The interaction between CXCL12 and CXCR4 plays an important role in the migration of progenitors during embryologic development of the cardiovascular, hemopoietic, central nervous systems, and so on. This interaction is also known to be involved in several intractable disease processes, including HIV infection, cancer cell metastasis, leukemia cell progression, rheumatoid arthritis (RA), and pulmonary fibrosis. It is conjectured that this interaction may be a critical therapeutic target in all of these diseases, and several CXCR4 antagonists have been proposed as potential drugs. Fourteen-mer peptides, T140 and its analogues, were previously developed in our laboratory as specific CXCR4 antagonists that were identified as HIV-entry inhibitors, anti-cancer-metastatic agents, anti-chronic lymphocytic/acute lymphoblastic leukemia agents, and anti-RA agents. Cyclic pentapeptides, such as FC131 [cyclo(D-Tyr-Arg-Arg-L-3-(2-naphthyl)alanine-Gly)], were also previously found as CXCR4 antagonist leads based on pharmacophores of T140. This review article describes the elucidation of multiple functions of CXCR4 antagonists and the development of a number of low-molecular weight CXCR4 antagonists involving FC131 analogues and other compounds with different scaffolds including linear-type structures.

  1. Marine Algae as a Potential Source for Anti-Obesity Agents.

    PubMed

    Wan-Loy, Chu; Siew-Moi, Phang

    2016-12-07

    Obesity is a major epidemic that poses a worldwide threat to human health, as it is also associated with metabolic syndrome, type 2 diabetes and cardiovascular disease. Therapeutic intervention through weight loss drugs, accompanied by diet and exercise, is one of the options for the treatment and management of obesity. However, the only approved anti-obesity drug currently available in the market is orlistat, a synthetic inhibitor of pancreatic lipase. Other anti-obesity drugs are still being evaluated at different stages of clinical trials, while some have been withdrawn due to their severe adverse effects. Thus, there is a need to look for new anti-obesity agents, especially from biological sources. Marine algae, especially seaweeds are a promising source of anti-obesity agents. Four major bioactive compounds from seaweeds which have the potential as anti-obesity agents are fucoxanthin, alginates, fucoidans and phlorotannins. The anti-obesity effects of such compounds are due to several mechanisms, which include the inhibition of lipid absorption and metabolism (e.g., fucoxanthin and fucoidans), effect on satiety feeling (e.g., alginates), and inhibition of adipocyte differentiation (e.g., fucoxanthin). Further studies, especially testing bioactive compounds in long-term human trials are required before any new anti-obesity drugs based on algal products can be developed.

  2. Facile Synthesis of Gd-Functionalized Gold Nanoclusters as Potential MRI/CT Contrast Agents

    PubMed Central

    Le, Wenjun; Cui, Shaobin; Chen, Xin; Zhu, Huanhuan; Chen, Bingdi; Cui, Zheng

    2016-01-01

    Multi-modal imaging plays a key role in the earlier detection of disease. In this work, a facile bioinspired method was developed to synthesize Gd-functionalized gold nanoclusters (Gd-Au NCs). The Gd-Au NCs exhibit a uniform size, with an average size of 5.6 nm in dynamic light scattering (DLS), which is a bit bigger than gold clusters (3.74 nm, DLS), while the fluorescent properties of Gd-Au NCs are almost the same as that of Au NCs. Moreover, the Gd-Au NCs exhibit a high longitudinal relaxivity value (r1) of 22.111 s−1 per mM of Gd in phosphate-buffered saline (PBS), which is six times higher than that of commercial Magnevist (A complex of gadolinium with a chelating agent, diethylenetriamine penta-acetic acid, Gd-DTPA, r1 = 3.56 mM−1·s−1). Besides, as evaluated by nano single photon emission computed tomography (SPECT) and computed tomography (CT) the Gd-Au NCs have a potential application as CT contrast agents because of the Au element. Finally, the Gd-Au NCs show little cytotoxicity, even when the Au concentration is up to 250 μM. Thus, the Gd-Au NCs can act as multi-modal imaging contrast agents.

  3. The Potential Application and Risks Associated With the Use of Predatory Bacteria as a Biocontrol Agent Against Wound Infections

    DTIC Science & Technology

    2014-09-01

    Associated With the Use of Predatory Bacteria as a Biocontrol Agent Against Wound Infections PRINCIPAL INVESTIGATOR: Daniel E Kadouri, Ph.D...W81XWH-12-2-0067 4. TITLE AND SUBTITLE The Potential Application and Risks Associated With the Use of Predatory Bacteria as a Biocontrol Agent...serve as a novel therapeutic agent to control wound-related bacterial infections. In a previous study, we confirmed that predatory bacteria Bdellovibrio

  4. Silibinin, Dexamethasone, and Doxycycline as Potential Therapeutic Agents for Treating Vesicant-Inflicted Ocular Injuries

    PubMed Central

    Tewari-Singh, Neera; Jain, Anil K; Inturi, Swetha; Ammar, David A; Agarwal, Chapla; Tyagi, Puneet; Kompella, Uday B; Enzenauer, Robert W; Petrash, J Mark; Agarwal, Rajesh

    2014-01-01

    There are no effective and approved therapies against devastating ocular injuries caused by vesicating chemical agents sulfur mustard (SM) and nitrogen mustard (NM). Herein, studies were carried out in rabbit corneal cultures to establish relevant ocular injury biomarkers with NM for screening potential efficacious agents in laboratory settings. NM (100 nmol) exposure of the corneas for 2 h (cultured for 24 h), showed increases in epithelial thickness, ulceration, apoptotic cell death, epithelial detachment microbullae formation, and the levels of VEGF, cyclooxygenase-2 (COX-2) and matrix metalloproteinase-9 (MMP-9). Employing these biomarkers, efficacy studies were performed with agent treatments 2 h and every 4 h thereafter, for 24 h following NM exposure. Three agents were evaluated, including prescription drugs dexamethasone (0.1%; anti-inflammatory steroid) and doxycycline (100 nmol; antibiotic and MMP inhibitor) that have been studied earlier for treating vesicant-induced eye injuries. We also examined silibinin (100 µg), a non-toxic natural flavanone found to be effective in treating SM analog-induced skin injuries in our earlier studies. Treatments of doxycycline + dexamethasone, and silibinin were more effective than doxycycline or dexamethasone alone in reversing NM-induced epithelial thickening, microbullae formation, apoptotic cell death, and MMP-9 elevation. However, dexamethasone and silibinin alone were more effective in reversing NM-induced VEGF levels. Doxycycline, dexamethasone and silibinin were all effective in reversing NM-induced COX-2 levels. Apart from therapeutic efficacy of doxycycline and dexamethasone, these results show strong multifunctional efficacy of silibinin in reversing NM-induced ocular injuries, which could help develop effective and safe therapeutics against ocular injuries by vesicants. PMID:22841772

  5. Antitumoral, antioxidant, and antimelanogenesis potencies of Hawthorn, a potential natural agent in the treatment of melanoma.

    PubMed

    Mustapha, Nadia; Mokdad-Bzéouich, Imèn; Maatouk, Mouna; Ghedira, Kamel; Hennebelle, Thierry; Chekir-Ghedira, Leila

    2016-06-01

    The lack of an efficient agent that does not have the disadvantage of low activity (kojic acid), high cytotoxicity, and mutagenicity (hydroquinone), poor skin penetration (arbutin), or low stability in formulation (glabridin) led us to continue our research on new antipigmentation/skin-lightening agents. Therefore, research of natural products that can modulate the metabolism of pigmentation is of great interest. Otherwise, malignant melanoma is one of the most aggressive forms of skin cancer, with high metastatic potential, and currently, there is no effective chemotherapy against invasive melanoma. Therefore, it is necessary to develop new drugs with potent activity and weak side effects against melanoma. The in-vitro anticancer effect of hawthorn was analyzed against B16F10 melanoma cells using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The effect of isolated compounds from hawthorn on melanogenesis in B16F10 melanoma cells was investigated by measuring the amounts of melanin and tyrosinase spectrophotometrically at 475 nm. Balb/c mice models inoculated with B16F10 mouse tumor cells were used to evaluate the in-vivo antitumoral potential of hawthorn by assessing its effect on the growth of transplanted tumors. The antioxidant potential of tested samples was evaluated in B16F10 and primary human keratinocyte cells using a cellular antioxidant activity assay. Hawthorn tested samples inhibited effectively the growth of melanoma cells in vitro. Furthermore, it appears that tested samples from hawthorn reduced melanogenesis by inhibiting the tyrosinase activity of B16F10 cells in a dose-dependent manner. In-vivo studies showed that hawthorn total oligomer flavonoids extract treatment at a dose of 150 mg/kg body weight for 21 days in implanted tumor mice resulted in significant inhibition of the tumor growth volume and weight. In addition, tested samples showed significant cellular antioxidant capacity against the reactive oxygen species

  6. Naturally occurring and synthetic agents as potential anti-inflammatory and immunomodulants.

    PubMed

    Sultana, Nighat; Saify, Zafar Saeed

    2012-01-01

    Terpenes in general and triterpenes in particular showed anti-inflammatory activity and act as immunomodulators in nutraceutical agents. Antiinflammation, a useful and attractive approach in experimental oncology, helps to investigate the inflammation preventive potential of natural products and synthetic entities. During the course of our research work in natural product chemistry and synthesis of novel structures in the field of heterocyclic chemistry, we found interesting results. In natural product betulinic acid, α-amyrin acetate, lupeol acetate, oleanolic acid, ursolic acid and their derivatives showed interesting potential analgesic and anti-inflammatory activity. In this review specific reference has been made to novel classes and newly discovered compounds in the literature, which exhibited required activities. Indomethacine is a potent synthetic compound, which becomes the basis of novel anti-inflammatory agents. Shen postulated a receptor theory which indicates the physical parameters responsible for anti-inflammatory activity. Attempt has been made to cover almost all the anti-inflammatory agents which fall under the various chemical structural classes of compounds showing required activity. The objective of this review is to compile relevant data on the mechanism of action of terpenes isolated from active ethnomedicinal plants to examine the role terpenoids have in medicinal plants used against inflammatory diseases, especially those in which an immune response is implicated. In addition, a selection of several structurally related compounds has been compiled in order to analyze the possible structural characteristics and relationships between the different types of structures found in triterpenoids. The selection of active species was made on the basis of their immunomodulatory activity, and their role in the resolution of diseases in which the immune system is implicated to examine the mechanism by which they are useful as ethnopharmacological

  7. Disrupted coupling of gating charge displacement to Na+ current activation for DIIS4 mutations in hypokalemic periodic paralysis

    PubMed Central

    Mi, Wentao; Rybalchenko, Volodymyr

    2014-01-01

    Missense mutations at arginine residues in the S4 voltage-sensor domains of NaV1.4 are an established cause of hypokalemic periodic paralysis, an inherited disorder of skeletal muscle involving recurrent episodes of weakness in conjunction with low serum K+. Expression studies in oocytes have revealed anomalous, hyperpolarization-activated gating pore currents in mutant channels. This aberrant gating pore conductance creates a small inward current at the resting potential that is thought to contribute to susceptibility to depolarization in low K+ during attacks of weakness. A critical component of this hypothesis is the magnitude of the gating pore conductance relative to other conductances that are active at the resting potential in mammalian muscle: large enough to favor episodes of paradoxical depolarization in low K+, yet not so large as to permanently depolarize the fiber. To improve the estimate of the specific conductance for the gating pore in affected muscle, we sequentially measured Na+ current through the channel pore, gating pore current, and gating charge displacement in oocytes expressing R669H, R672G, or wild-type NaV1.4 channels. The relative conductance of the gating pore to that of the pore domain pathway for Na+ was 0.03%, which implies a specific conductance in muscle from heterozygous patients of ∼10 µS/cm2 or 1% of the total resting conductance. Unexpectedly, our data also revealed a substantial decoupling between gating charge displacement and peak Na+ current for both R669H and R672G mutant channels. This decoupling predicts a reduced Na+ current density in affected muscle, consistent with the observations that the maximal dV/dt and peak amplitude of the action potential are reduced in fibers from patients with R672G and in a knock-in mouse model of R669H. The defective coupling between gating charge displacement and channel activation identifies a previously unappreciated mechanism that contributes to the reduced excitability of affected

  8. Synthesis and evaluation of new 3-phenylcoumarin derivatives as potential antidepressant agents.

    PubMed

    Sashidhara, Koneni V; Rao, K Bhaskara; Singh, Seema; Modukuri, Ram K; Aruna Teja, G; Chandasana, Hardik; Shukla, Shubha; Bhatta, Rabi S

    2014-10-15

    A series of amine substituted 3-phenyl coumarin derivatives were designed and synthesized as potential antidepressant agents. In preliminary screening, all compounds were evaluated in forced swimming test (FST), a model to screen antidepressant activity in rodents. Among the series, compounds 5c and 6a potentially decreased the immobility time by 73.4% and 79.7% at a low dose of 0.5 mg/kg as compared to standard drug fluoxetine (FXT) which reduced the immobility time by 74% at a dose of 20 mg/kg, ip. Additionally, these active compounds also exhibited significant efficacy in tail suspension test (TST) (another model to screen antidepressant compounds). Interestingly, rotarod and locomotor activity tests confirmed that these two compounds do not have any motor impairment effect and neurotoxicity in mice. Our studies demonstrate that the new 3-phenylcoumarin derivatives may serve as a promising antidepressant lead and hence pave the way for further investigation around this chemical space.

  9. Isolation and characterization of soil Streptomyces species as potential biological control agents against fungal plant pathogens.

    PubMed

    Evangelista-Martínez, Zahaed

    2014-05-01

    The use of antagonist microorganisms against fungal plant pathogens is an attractive and ecologically alternative to the use of chemical pesticides. Streptomyces are beneficial soil bacteria and potential candidates for biocontrol agents. This study reports the isolation, characterization and antagonist activity of soil streptomycetes from the Los Petenes Biosphere Reserve, a Natural protected area in Campeche, Mexico. The results showed morphological, physiological and biochemical characterization of six actinomycetes and their inhibitory activity against Curvularia sp., Aspergillus niger, Helminthosporium sp. and Fusarium sp. One isolate, identified as Streptomyces sp. CACIS-1.16CA showed the potential to inhibit additional pathogens as Alternaria sp., Phytophthora capsici, Colletotrichum sp. and Rhizoctonia sp. with percentages ranging from 47 to 90 %. This study identified a streptomycete strain with a broad antagonist activity that could be used for biocontrol of plant pathogenic fungi.

  10. Chemical warfare agent and biological toxin-induced pulmonary toxicity: could stem cells provide potential therapies?

    PubMed

    Angelini, Daniel J; Dorsey, Russell M; Willis, Kristen L; Hong, Charles; Moyer, Robert A; Oyler, Jonathan; Jensen, Neil S; Salem, Harry

    2013-01-01

    Chemical warfare agents (CWAs) as well as biological toxins present a significant inhalation injury risk to both deployed warfighters and civilian targets of terrorist attacks. Inhalation of many CWAs and biological toxins can induce severe pulmonary toxicity leading to the development of acute lung injury (ALI) as well as acute respiratory distress syndrome (ARDS). The therapeutic options currently used to treat these conditions are very limited and mortality rates remain high. Recent evidence suggests that human stem cells may provide significant therapeutic options for ALI and ARDS in the near future. The threat posed by CWAs and biological toxins for both civilian populations and military personnel is growing, thus understanding the mechanisms of toxicity and potential therapies is critical. This review will outline the pulmonary toxic effects of some of the most common CWAs and biological toxins as well as the potential role of stem cells in treating these types of toxic lung injuries.

  11. Adsorption of histones on natural polysaccharides: The potential as agent for multiple organ failure in sepsis.

    PubMed

    Isobe, Takashi; Kofuji, Kyoko; Okada, Kenji; Fujimori, Junya; Murata, Mikio; Shigeyama, Masato; Hanioka, Nobumitsu; Murata, Yoshifumi

    2016-03-01

    Histones are intracellular proteins that are structural elements of nuclear chromatin and regulate gene transcription. However, the extracellular histones released in response to bacterial challenges have been identified as mediators contributing to endothelial dysfunction, organ failure, and death during sepsis. In the present study, the adsorption of histones as well as plasma proteins (α1-acid glycoprotein (AGP), albumin, and γ-globulin) on alginic acid, pectin, dextran, and chitosan was examined in order to evaluate the potential of natural polysaccharides as therapeutic agents for multiple organ failure in sepsis. Alginic acid and pectin strongly adsorbed histones, whereas the adsorption abilities of dextran and chitosan toward histones were very low or negligible. Among the natural polysaccharides examined, only alginic acid did not adsorb any of the plasma proteins. These results demonstrated that alginic acid strongly adsorbed histones, but not plasma proteins; therefore, it has potential as a candidate drug for the treatment of multiple organ failure in sepsis.

  12. Isolation and identification of potential cancer chemopreventive agents from methanolic extracts of green onion (Allium cepa).

    PubMed

    Xiao, Hang; Parkin, Kirk L

    2007-04-01

    Phase II xenobiotic metabolizing enzymes confer amelioration of risk arising from potentially carcinogenic chemicals derived both endogenously, and exogenously, from food and the environment. In this study, efforts were made to isolate and identify potentially cancer preventive constituents from methanolic extracts of green onion (Allium cepa) directed by the quinone reductase (QR) induction bioassay using murine hepatoma (Hepa 1c1c7) cells. Crude methanolic extracts of green onion tissue were solvent-partitioned, and subsequently fractionated by flash chromatography, thin layer chromatography and high pressure preparative liquid chromatography to afford pure QR-inducing isolates. Multiple isolates were found active at inducing QR. One newly identified compound, 5-hydroxy-3-methyl-4-propylsulfanyl-5H-furan-2-one (3), and four known compounds: 5-(hydroxymethyl) furfural (1), acetovanillone (2), methyl 4-hydroxyl cinnamate (4) and ferulic acid methyl ester (5), were isolated and identified as active agents.

  13. Avena sativa (Oat), a potential neutraceutical and therapeutic agent: an overview.

    PubMed

    Singh, Rajinder; De, Subrata; Belkheir, Asma

    2013-01-01

    The aim of the present review article is to summarize the available information related to the availability, production, chemical composition, pharmacological activity, and traditional uses of Avena sativa to highlight its potential to contribute to human health. Oats are now cultivated worldwide and form an important dietary staple for the people in number of countries. Several varieties of oats are available. It is a rich source of protein, contains a number of important minerals, lipids, β-glucan, a mixed-linkage polysaccharide, which forms an important part of oat dietary fiber, and also contains various other phytoconstituents like avenanthramides, an indole alkaloid-gramine, flavonoids, flavonolignans, triterpenoid saponins, sterols, and tocols. Traditionally oats have been in use since long and are considered as stimulant, antispasmodic, antitumor, diuretic, and neurotonic. Oat possesses different pharmacological activities like antioxidant, anti-inflammatory, wound healing, immunomodulatory, antidiabetic, anticholesterolaemic, etc. A wide spectrum of biological activities indicates that oat is a potential therapeutic agent.

  14. 4, 5-Dihydrooxazole-pyrazoline hybrids: Synthesis and their evaluation as potential antimalarial agents.

    PubMed

    Pandey, Ashutosh Kumar; Sharma, Supriya; Pandey, Minakshi; Alam, M Mumtaz; Shaquiquzzaman, M; Akhter, Mymoona

    2016-11-10

    A new series of oxazoline-pyrazoline hybrids (4a-p) were synthesized by condensation reaction of substituted oxazoline based chalcones (3a-m) and substituted hydrazines in methanol. Some of the compounds exhibited promising in vitro antimalarial activity for chloroquine sensitive CQ(S) (3D7) strain and chloroquine resistant CQ(R) (RKL9) strain. The most potent analogue 4i (IC50 0.322 μg/ml) exhibited significant in vivo antimalarial potential against Plasmodium berghei mouse model. The stable complex of 4i with hematin (1:1 stoichiometry) suggests that heme may be one possible target for these hybrid compounds. The study has revealed potential of title compounds as lead for the development of antimalarial agents. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  15. Potential Anti-HPV and Related Cancer Agents from Marine Resources: An Overview

    PubMed Central

    Wang, Shi-Xin; Zhang, Xiao-Shuang; Guan, Hua-Shi; Wang, Wei

    2014-01-01

    Recently, the studies on the prevention and treatment of human papillomavirus (HPV) which is closely related to the cervical cancer and other genital diseases are attracting more and more attention all over the world. Marine-derived polysaccharides and other bioactive compounds have been shown to possess a variety of anti-HPV and related cancer activities. This paper will review the recent progress in research on the potential anti-HPV and related cancer agents from marine resources. In particular, it will provide an update on the anti-HPV actions of heparinoid polysaccharides and bioactive compounds present in marine organisms, as well as the therapeutic vaccines relating to marine organisms. In addition, the possible mechanisms of anti-HPV actions of marine bioactive compounds and their potential for therapeutic application will also be summarized in detail. PMID:24705500

  16. Potential Bio-Control Agent from Rhodomyrtus tomentosa against Listeria monocytogenes.

    PubMed

    Odedina, Grace Fiyinfoluwa; Vongkamjan, Kitiya; Voravuthikunchai, Supayang Piyawan

    2015-09-07

    Listeria monocytogenes is an important foodborne pathogen implicated in many outbreaks of listeriosis. This study aimed at screening for the potential use of Rhodomyrtus tomentosa ethanolic leaf extract as a bio-control agent against L. monocytogenes. Twenty-two L. monocytogenes isolates were checked with 16 commercial antibiotics and isolates displayed resistance to 10 antibiotics. All the tested isolates were sensitive to the extract with inhibition zones ranging from 14 to 16 mm. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values ranged from 16 to 32 µg/mL and 128 to 512 µg/mL, respectively. Time-kill assay showed that the extract had remarkable bactericidal effects on L. monocytogenes. The extract at a concentration of 16 µg/mL reduced tolerance to 10% NaCl in L. monocytogenes in 4 h. Stationary phase L. monocytogenes cells were rapidly inactivated by greater than 3-log units within 30 min of contact time with R. tomentosa extract at 128 µg/mL. Electron microscopy revealed fragmentary bacteria with changes in the physical and morphological properties. Our study demonstrates the potential of the extract for further development into a bio-control agent in food to prevent the incidence of L. monocytogenes contamination.

  17. Potential water-quality effects from iron cyanide anticaking agents in road salt

    SciTech Connect

    Paschka, M.G.; Ghosh, R.S.; Dzombak, D.A.

    1999-10-01

    Water-soluble iron cyanide compounds are widely used as anticaking agents in road salt, which creates potential contamination of surface and groundwater with these compounds when the salt dissolves and is washed off roads in runoff. This paper presents a summary of available information on iron cyanide use in road salt and its potential effects on water quality. Also, estimates of total cyanide concentrations in snow-melt runoff from roadways are presented as simple mass-balance calculations. Although available information does not indicate a widespread problem, it also is clear that the water-quality effects of cyanide in road salt have not been examined much. Considering the large, and increasing, volume of road salt used for deicing, studies are needed to determine levels of total and free cyanide in surface and groundwater adjacent to salt storage facilities and along roads with open drainage ditches. Results could be combined with current knowledge of the fate and transport of cyanide to assess water-quality effects of iron cyanide anticaking agents used in road salt.

  18. Potential Bio-Control Agent from Rhodomyrtus tomentosa against Listeria monocytogenes

    PubMed Central

    Odedina, Grace Fiyinfoluwa; Vongkamjan, Kitiya; Voravuthikunchai, Supayang Piyawan

    2015-01-01

    Listeria monocytogenes is an important foodborne pathogen implicated in many outbreaks of listeriosis. This study aimed at screening for the potential use of Rhodomyrtus tomentosa ethanolic leaf extract as a bio-control agent against L. monocytogenes. Twenty-two L. monocytogenes isolates were checked with 16 commercial antibiotics and isolates displayed resistance to 10 antibiotics. All the tested isolates were sensitive to the extract with inhibition zones ranging from 14 to 16 mm. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values ranged from 16 to 32 µg/mL and 128 to 512 µg/mL, respectively. Time-kill assay showed that the extract had remarkable bactericidal effects on L. monocytogenes. The extract at a concentration of 16 µg/mL reduced tolerance to 10% NaCl in L. monocytogenes in 4 h. Stationary phase L. monocytogenes cells were rapidly inactivated by greater than 3-log units within 30 min of contact time with R. tomentosa extract at 128 µg/mL. Electron microscopy revealed fragmentary bacteria with changes in the physical and morphological properties. Our study demonstrates the potential of the extract for further development into a bio-control agent in food to prevent the incidence of L. monocytogenes contamination. PMID:26371033

  19. Effect of Hypobaric Hypoxia on Cognitive Functions and Potential Therapeutic Agents

    PubMed Central

    MUTHURAJU, Sangu; PATI, Soumya

    2014-01-01

    High altitude (HA), defined as approximately 3000–5000 m, considerably alters physiological and psychological parameters within a few hours. Chronic HA-mediated hypoxia (5000 m) results in permanent neuronal damage to the human brain that persists for one year or longer, even after returning to sea level. At HA, there is a decrease in barometric pressure and a consequential reduction in the partial pressure of oxygen (PO2), an extreme environmental condition to which humans are occasionally exposed. This condition is referred to as hypobaric hypoxia (HBH), which represents the most unfavourable characteristics of HA. HBH causes the disruption of oxygen availability to tissue. However, no review article has explored the impact of HBH on cognitive functions or the potential therapeutic agents for HBH. Therefore, the present review aimed to describe the impact of HBH on both physiological and cognitive functions, specifically learning and memory. Finally, the potential therapeutic agents for the treatment of HBH-induced cognitive impairment are discussed. PMID:25941462

  20. Mechanistic study of IR-780 dye as a potential tumor targeting and drug delivery agent.

    PubMed

    Zhang, Erlong; Luo, Shenglin; Tan, Xu; Shi, Chunmeng

    2014-01-01

    IR-780 iodide, a near-infrared fluorescent heptamethine dye, has been recently characterized to exhibit preferential accumulation property in the mitochondria of tumor cells. In this study, we investigated the possible mechanisms for its tumor selective activity and its potential as a drug delivery carrier. Results showed that the energy-dependent uptake of IR-780 iodide into the mitochondria of tumor cells was affected by glycolysis and plasma membrane potential. Moreover, OATP1B3 subtype of organic anion transporter peptides (OATPs) may play a dominant role in the transportation of IR-780 iodide into tumor cells, while cellular endocytosis, mitochondrial membrane potential and the ATP-binding cassette transporters did not show significant influence to its accumulation. We further evaluated the potential of IR-780 iodide as a drug delivery carrier by covalent conjugation of IR-780 with nitrogen mustard (IR-780NM). In vivo imaging showed that IR-780NM remained the tumor targeting property, indicating that IR-780 iodide could be potentially applied as a drug delivery agent for cancer targeted imaging and therapy.

  1. Silibinin, dexamethasone, and doxycycline as potential therapeutic agents for treating vesicant-inflicted ocular injuries

    SciTech Connect

    Tewari-Singh, Neera; Jain, Anil K.; Inturi, Swetha; Ammar, David A.; Agarwal, Chapla; Tyagi, Puneet; Kompella, Uday B.; Enzenauer, Robert W.; Petrash, J. Mark; Agarwal, Rajesh

    2012-10-01

    There are no effective and approved therapies against devastating ocular injuries caused by vesicating chemical agents sulfur mustard (SM) and nitrogen mustard (NM). Herein, studies were carried out in rabbit corneal cultures to establish relevant ocular injury biomarkers with NM for screening potential efficacious agents in laboratory settings. NM (100 nmol) exposure of the corneas for 2 h (cultured for 24 h), showed increases in epithelial thickness, ulceration, apoptotic cell death, epithelial detachment microbullae formation, and the levels of VEGF, cyclooxygenase-2 (COX-2) and matrix metalloproteinase-9 (MMP-9). Employing these biomarkers, efficacy studies were performed with agent treatments 2 h and every 4 h thereafter, for 24 h following NM exposure. Three agents were evaluated, including prescription drugs dexamethasone (0.1%; anti-inflammatory steroid) and doxycycline (100 nmol; antibiotic and MMP inhibitor) that have been studied earlier for treating vesicant-induced eye injuries. We also examined silibinin (100 μg), a non-toxic natural flavanone found to be effective in treating SM analog-induced skin injuries in our earlier studies. Treatments of doxycycline + dexamethasone, and silibinin were more effective than doxycycline or dexamethasone alone in reversing NM-induced epithelial thickening, microbullae formation, apoptotic cell death, and MMP-9 elevation. However, dexamethasone and silibinin alone were more effective in reversing NM-induced VEGF levels. Doxycycline, dexamethasone and silibinin were all effective in reversing NM-induced COX-2 levels. Apart from therapeutic efficacy of doxycycline and dexamethasone, these results show strong multifunctional efficacy of silibinin in reversing NM-induced ocular injuries, which could help develop effective and safe therapeutics against ocular injuries by vesicants. -- Highlights: ► Established injury biomarkers in rabbit corneal culture with nitrogen mustard (NM) ► This NM model is a cost effective

  2. Anti-ulcer agent teprenone inhibits hepatitis C virus replication: potential treatment for hepatitis C.

    PubMed

    Ikeda, Masanori; Kawai, Yoshinari; Mori, Kyoko; Yano, Masahiko; Abe, Ken-ichi; Nishimura, Go; Dansako, Hiromichi; Ariumi, Yasuo; Wakita, Takaji; Yamamoto, Kazuhide; Kato, Nobuyuki

    2011-07-01

    Previously we reported that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, statins, inhibited hepatitis C virus (HCV) RNA replication. Furthermore, recent reports revealed that the statins are associated with a reduced risk of hepatocellular carcinoma and lower portal pressure in patients with cirrhosis. The statins exhibited anti-HCV activity by inhibiting geranylgeranylation of host proteins essential for HCV RNA replication. Geranylgeranyl pyrophosphate (GGPP) is a substrate for geranylgeranyltransferase. Therefore, we examined the potential of geranyl compounds with chemical structures similar to those of GGPP to inhibit HCV RNA replication. We tested geranyl compounds [geranylgeraniol, geranylgeranoic acid, vitamin K(2) and teprenone (Selbex)] for their effects on HCV RNA replication using genome-length HCV RNA-replicating cells (the OR6 assay system) and a JFH-1 infection cell culture system. Teprenone is the major component of the anti-ulcer agent, Selbex. We also examined the anti-HCV activities of the geranyl compounds in combination with interferon (IFN)-α or statins. Among the geranyl compounds tested, only teprenone exhibited anti-HCV activity at a clinically achievable concentration. However, other anti-ulcer agents tested had no inhibitory effect on HCV RNA replication. The combination of teprenone and IFN-α exhibited a strong inhibitory effect on HCV RNA replication. Although teprenone alone did not inhibit geranylgeranylation, surprisingly, statins' inhibitory action against geranylgeranylation was enhanced by cotreatment with teprenone. The anti-ulcer agent teprenone inhibited HCV RNA replication and enhanced statins' inhibitory action against geranylgeranylation. This newly discovered function of teprenone may improve the treatment of HCV-associated liver diseases as an adjuvant to statins. © 2011 John Wiley & Sons A/S.

  3. Potential Molecular Targets for Narrow-Spectrum Agents to Combat Mycoplasma pneumoniae Infection and Disease.

    PubMed

    Balish, Mitchell F; Distelhorst, Steven L

    2016-01-01

    As Mycoplasma pneumoniae macrolide resistance grows and spreads worldwide, it is becoming more important to develop new drugs to prevent infection or limit disease. Because other mycoplasma species have acquired resistance to other classes of antibiotics, it is reasonable to presume that M. pneumoniae can do the same, so switching to commonly used antibiotics like fluoroquinolones will not result in forms of therapy with long-term utility. Moreover, broad-spectrum antibiotics can have serious consequences for the patient, as these drugs may have severe impacts on the natural microbiota of the individual, compromising the health of the patient either short-term or long-term. Therefore, developing narrow-spectrum antibiotics that effectively target only M. pneumoniae and no more than a small portion of the microbiota is likely to yield impactful, positive results that can be used perhaps indefinitely to combat M. pneumoniae. Development of these agents requires a deep understanding of the basic biology of M. pneumoniae, in many areas deeper than what is currently known. In this review, we discuss potential targets for new, narrow-spectrum agents and both the positive and negative aspects of selecting these targets, which include toxic molecules, metabolic pathways, and attachment and motility. By gathering this information together, we anticipate that it will be easier for researchers to evaluate topics of priority for study of M. pneumoniae.

  4. Understanding Virulence in the Brucellae and Francisellae: Towards Efficacious Treatments for Two Potential Biothreat Agents

    SciTech Connect

    Rasley, A; Parsons, D A; El-Etr, S; Roux, C; Tsolis, R

    2009-12-30

    Francisella tularensis, Yersinia pestis and Brucellae species are highly infectious pathogens classified as select agents by the Centers for Disease Control and Prevention (CDC) with the potential for use in bioterrorism attacks. These organisms are known to be facultative intracellular pathogens that preferentially infect human monocytes. As such, understanding how the host responds to infection with these organisms is paramount in detecting and combating human disease. We have compared the ability of fully virulent strains of each pathogen and their non-pathogenic near neighbors to enter and survive inside the human monocytic cell line THP-1 and have quantified the cellular response to infection with the goal of identifying both unique and common host response patterns. We expanded the scope of these studies to include experiments with pathogenic and non-pathogenic strains of Y. pestis, the causative agent of plague. Nonpathogenic strains of each organism were impaired in their ability to survive intracellularly compared with their pathogenic counterparts. Furthermore, infection of THP-1 cells with pathogenic strains of Y. pestis and F. tularensis resulted in marked increases in the secretion of the inflammatory chemokines IL-8, RANTES, and MIP-1{beta}. In contrast, B. melitensis infection failed to elicit any significant increases in a panel of cytokines tested. These differences may underscore distinct strategies in pathogenic mechanisms employed by these pathogens.

  5. Bismuth@US-tubes as a Potential Contrast Agent for X-ray Imaging Applications.

    PubMed

    Rivera, Eladio J; Tran, Lesa A; Hernández-Rivera, Mayra; Yoon, Diana; Mikos, Antonios G; Rusakova, Irene A; Cheong, Benjamin Y; Cabreira-Hansen, Maria da Graça; Willerson, James T; Perin, Emerson C; Wilson, Lon J

    2013-10-07

    The encapsulation of bismuth as BiOCl/Bi2O3 within ultra-short (ca. 50 nm) single-walled carbon nanocapsules (US-tubes) has been achieved. The Bi@US-tubes have been characterized by high-resolution transmission electron microscopy (HR-TEM), energy-dispersive X-ray spectroscopy (EDS), thermogravimetric analysis (TGA), X-ray photoelectron spectroscopy (XPS), and Raman spectroscopy. Bi@US-tubes have been used for intracellular labeling of pig bone marrow-derived mesenchymal stem cells (MSCs) to show high X-ray contrast in computed tomography (CT) cellular imaging for the first time. The relatively high contrast is achieved with low bismuth loading (2.66% by weight) within the US-tubes and without compromising cell viability. X-ray CT imaging of Bi@US-tubes-labeled MSCs showed a nearly two-fold increase in contrast enhancement when compared to unlabeled MSCs in a 100 kV CT clinical scanner. The CT signal enhancement from the Bi@US-tubes is 500 times greater than polymer-coated Bi2S3 nanoparticles and several-fold that of any clinical iodinated contrast agent (CA) at the same concentration. Our findings suggest that the Bi@US-tubes can be used as a potential new class of X-ray CT agent for stem cell labeling and possibly in vivo tracking.

  6. Design of novel dispirooxindolopyrrolidine and dispirooxindolopyrrolothiazole derivatives as potential antitubercular agents.

    PubMed

    Mhiri, Chourouk; Boudriga, Sarra; Askri, Moheddine; Knorr, Michael; Sriram, Dharmarajan; Yogeeswari, Perumal; Nana, Frédéric; Golz, Christopher; Strohmann, Carsten

    2015-10-01

    With the aim to develop new potent antitubercular agents, a series of novel dispirooxindolopyrrolidines and dispirooxindolopyrrolothiazoles have been synthesized via a three-component 1,3-dipolar cycloaddition of (Z)-3-arylidenebenzofuran-2-ones, substituted isatin derivatives and α-aminoacids. The stereochemistry of the spiroadducts has been confirmed by an X-ray diffraction analysis. All the target heterocycles were evaluated for in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv strain and the most active compounds were subjected to cytotoxicity studies against (RAW 264.7) cell lines. Among them, twelve compounds showed potent anti-tubercular activity with MIC ranging from 1.56 to 6.25 μg/mL. In particular dispirooxindolopyrrolothiazole derivatives 5c and 5f were found to be the most active (MIC of 1.56 μg/mL) with a good safety profile (27.53% and 20.74% at 50 μM, respectively). This is the first report demonstrating the benzofuranone oxindole hybrids as potential antimycobacterial agents.

  7. Pharmacophore modeling and in silico toxicity assessment of potential anticancer agents from African medicinal plants

    PubMed Central

    Ntie-Kang, Fidele; Simoben, Conrad Veranso; Karaman, Berin; Ngwa, Valery Fuh; Judson, Philip Neville; Sippl, Wolfgang; Mbaze, Luc Meva’a

    2016-01-01

    Molecular modeling has been employed in the search for lead compounds of chemotherapy to fight cancer. In this study, pharmacophore models have been generated and validated for use in virtual screening protocols for eight known anticancer drug targets, including tyrosine kinase, protein kinase B β, cyclin-dependent kinase, protein farnesyltransferase, human protein kinase, glycogen synthase kinase, and indoleamine 2,3-dioxygenase 1. Pharmacophore models were validated through receiver operating characteristic and Güner–Henry scoring methods, indicating that several of the models generated could be useful for the identification of potential anticancer agents from natural product databases. The validated pharmacophore models were used as three-dimensional search queries for virtual screening of the newly developed AfroCancer database (~400 compounds from African medicinal plants), along with the Naturally Occurring Plant-based Anticancer Compound-Activity-Target dataset (comprising ~1,500 published naturally occurring plant-based compounds from around the world). Additionally, an in silico assessment of toxicity of the two datasets was carried out by the use of 88 toxicity end points predicted by the Lhasa’s expert knowledge-based system (Derek), showing that only an insignificant proportion of the promising anticancer agents would be likely showing high toxicity profiles. A diversity study of the two datasets, carried out using the analysis of principal components from the most important physicochemical properties often used to access drug-likeness of compound datasets, showed that the two datasets do not occupy the same chemical space. PMID:27445461

  8. Pharmacophore modeling and in silico toxicity assessment of potential anticancer agents from African medicinal plants.

    PubMed

    Ntie-Kang, Fidele; Simoben, Conrad Veranso; Karaman, Berin; Ngwa, Valery Fuh; Judson, Philip Neville; Sippl, Wolfgang; Mbaze, Luc Meva'a

    2016-01-01

    Molecular modeling has been employed in the search for lead compounds of chemotherapy to fight cancer. In this study, pharmacophore models have been generated and validated for use in virtual screening protocols for eight known anticancer drug targets, including tyrosine kinase, protein kinase B β, cyclin-dependent kinase, protein farnesyltransferase, human protein kinase, glycogen synthase kinase, and indoleamine 2,3-dioxygenase 1. Pharmacophore models were validated through receiver operating characteristic and Güner-Henry scoring methods, indicating that several of the models generated could be useful for the identification of potential anticancer agents from natural product databases. The validated pharmacophore models were used as three-dimensional search queries for virtual screening of the newly developed AfroCancer database (~400 compounds from African medicinal plants), along with the Naturally Occurring Plant-based Anticancer Compound-Activity-Target dataset (comprising ~1,500 published naturally occurring plant-based compounds from around the world). Additionally, an in silico assessment of toxicity of the two datasets was carried out by the use of 88 toxicity end points predicted by the Lhasa's expert knowledge-based system (Derek), showing that only an insignificant proportion of the promising anticancer agents would be likely showing high toxicity profiles. A diversity study of the two datasets, carried out using the analysis of principal components from the most important physicochemical properties often used to access drug-likeness of compound datasets, showed that the two datasets do not occupy the same chemical space.

  9. [Emetogenic potential of antineoplastic agents based on clinical trials in Japan].

    PubMed

    Watanabe, Tomoki; Handa, Satoko; Kato, Yasuhisa

    2015-03-01

    Chemotherapy-induced nausea and vomiting (CINV) is one of the most common and distressing side effects of chemotherapy that decreases patients' quality of life and motivation for treatment. Therefore, prevention and treatment of CINV are essential for motivating patients to continue chemotherapy. International societies such as American Society of Clinical Oncology (ASCO), Multinational Association of Supportive Care in Cancer (MASCC)/European Society for Medical Oncology (ESMO), and National Comprehensive Cancer Network (NCCN) have published guidelines for using antiemetics, and these guidelines were published in Japan in May 2010. However, both the Japananese and international guidelines do not provide sufficient clinical trial-based evidence for antiemetic use in the Japanese population. In this study, we attempted to evaluate and clarify the frequency of CINV in clinical trials in Japan. We found that thet guidelines specify different emetogenic potentials of some antineoplastic agents such as gemcitabine. Therefore, we believe that it is necessary to reevaluate the emetogenic risk of such antineoplastic agents and to develop a practical and standard antiemetic therapy so that in the future, patients do not hesitate to undergo chemotherapy because of side effects.

  10. Bismuth@US-tubes as a Potential Contrast Agent for X-ray Imaging Applications

    PubMed Central

    Rivera, Eladio J.; Tran, Lesa A.; Hernández-Rivera, Mayra; Yoon, Diana; Mikos, Antonios G.; Rusakova, Irene A.; Cheong, Benjamin Y.; Cabreira-Hansen, Maria da Graça; Willerson, James T.; Perin, Emerson C.; Wilson, Lon J.

    2013-01-01

    The encapsulation of bismuth as BiOCl/Bi2O3 within ultra-short (ca. 50 nm) single-walled carbon nanocapsules (US-tubes) has been achieved. The Bi@US-tubes have been characterized by high-resolution transmission electron microscopy (HR-TEM), energy-dispersive X-ray spectroscopy (EDS), thermogravimetric analysis (TGA), X-ray photoelectron spectroscopy (XPS), and Raman spectroscopy. Bi@US-tubes have been used for intracellular labeling of pig bone marrow-derived mesenchymal stem cells (MSCs) to show high X-ray contrast in computed tomography (CT) cellular imaging for the first time. The relatively high contrast is achieved with low bismuth loading (2.66% by weight) within the US-tubes and without compromising cell viability. X-ray CT imaging of Bi@US-tubes-labeled MSCs showed a nearly two-fold increase in contrast enhancement when compared to unlabeled MSCs in a 100 kV CT clinical scanner. The CT signal enhancement from the Bi@US-tubes is 500 times greater than polymer-coated Bi2S3 nanoparticles and several-fold that of any clinical iodinated contrast agent (CA) at the same concentration. Our findings suggest that the Bi@US-tubes can be used as a potential new class of X-ray CT agent for stem cell labeling and possibly in vivo tracking. PMID:24288589

  11. Exploring simvastatin, an antihyperlipidemic drug, as a potential topical antibacterial agent

    PubMed Central

    Thangamani, Shankar; Mohammad, Haroon; Abushahba, Mostafa F. N.; Hamed, Maha I.; Sobreira, Tiago J. P.; Hedrick, Victoria E.; Paul, Lake N.; Seleem, Mohamed N.

    2015-01-01

    The rapid rise of bacterial resistance to traditional antibiotics combined with the decline in discovery of novel antibacterial agents has created a global public health crisis. Repurposing existing drugs presents an alternative strategy to potentially expedite the discovery of new antimicrobial drugs. The present study demonstrates that simvastatin, an antihyperlipidemic drug exhibited broad-spectrum antibacterial activity against important Gram-positive (including methicillin-resistant Staphylococcus aureus (MRSA)) and Gram-negative pathogens (once the barrier imposed by the outer membrane was permeabilized). Proteomics and macromolecular synthesis analyses revealed that simvastatin inhibits multiple biosynthetic pathways and cellular processes in bacteria, including selective interference of bacterial protein synthesis. This property appears to assist in simvastatin’s ability to suppress production of key MRSA toxins (α-hemolysin and Panton-Valentine leucocidin) that impair healing of infected skin wounds. A murine MRSA skin infection experiment confirmed that simvastatin significantly reduces the bacterial burden and inflammatory cytokines in the infected wounds. Additionally, simvastatin exhibits excellent anti-biofilm activity against established staphylococcal biofilms and demonstrates the ability to be combined with topical antimicrobials currently used to treat MRSA skin infections. Collectively the present study lays the foundation for further investigation of repurposing simvastatin as a topical antibacterial agent to treat skin infections. PMID:26553420

  12. Preparation and evaluation of radioiodinated 1-(dialkyl-aminoalkyl)-4-phenylpiperazines as potential brain imaging agents

    SciTech Connect

    Hanson, R.N.; Shourbagy, T.E.

    1985-05-01

    The interest in radioiodinated diamines stems from their similarity to /sup 125/I-HIPDM and to the 1-dialkvlamino-acyl-4-phenylpiperazines that the authors have previously examined as potential brain imaging agents. In this study they converted the 1-(dialkylaminoacyl)-4-phenylpiperazines to their corresponding 1-(dialkylaminoacyl) analogs via reduction with diborane in THF. Radioiodination at the no-carrier-added level with Na/sup 125/I and chloramine-T gave the final compounds, after chromatographic separation, in 30-50% yields. The tissue distributions were determined in rats at 0.25, and 4 hrs after an i.v. injection of the radiochemical. The results indicated that all of the agents were readily extracted by the brain (1.5-2.5% ID) with brain to blood ratios >20. The structure-distribution relationships for this series were, however, decidedly different from the aminoacyl compounds in that morpholino-derivatives had better uptake and retention than the piperidine derivatives. Neither extension of the alkyl chain nor the presence of carrier significantly altered the brain uptake and retention of the radiochemical. Further studies are in progress. In conclusion, they have identified a class of radiotracers that can be readily prepared and show a pattern of brain uptake and retention than the structurally similar 1-dialkylaminoacyl-4-phenylpiperazines.

  13. Design, synthesis, and biological evaluation of chalcone oxime derivatives as potential immunosuppressive agents.

    PubMed

    Luo, Yin; Song, Ran; Li, Yao; Zhang, Shuai; Liu, Zhi-Jun; Fu, Jie; Zhu, Hai-Liang

    2012-05-01

    A series of deoxybenzoin oximes were recently reported as potent immunosuppressive agents by our group. In order to continue the original research for potential immunosuppressive agents with high efficacy and low toxicity, we synthesized a series of new chalcone oximes and evaluated them for their cytotoxicities and immunosuppressive activities. Among the synthesized compounds, chalcone oximes 25 and 27 exhibited lower cytotoxicities and higher inhibitory activities on anti-CD3/anti-CD28 co-stimulated lymph node cells than other compounds. Specially, compound 27 displayed 200-fold lower cytotoxicity (CC(50)=2174.39 μM) than cyclosporin A (CC(50)=10.10 μM) and showed SI value (SI=176.69) close to cyclosporin A (SI=154.13). Besides, the preliminary mechanism of inhibition effect of compounds 25 and 27 was also detected by flow cytometry, and the compounds exerted immunosuppressive activities via inducing the apoptosis of activated lymph node cells in a dose dependent manner. Also, the deep mechanism of apoptosis was detected by Western blot analysis. Copyright © 2012 Elsevier Ltd. All rights reserved.

  14. Exploring simvastatin, an antihyperlipidemic drug, as a potential topical antibacterial agent.

    PubMed

    Thangamani, Shankar; Mohammad, Haroon; Abushahba, Mostafa F N; Hamed, Maha I; Sobreira, Tiago J P; Hedrick, Victoria E; Paul, Lake N; Seleem, Mohamed N

    2015-11-10

    The rapid rise of bacterial resistance to traditional antibiotics combined with the decline in discovery of novel antibacterial agents has created a global public health crisis. Repurposing existing drugs presents an alternative strategy to potentially expedite the discovery of new antimicrobial drugs. The present study demonstrates that simvastatin, an antihyperlipidemic drug exhibited broad-spectrum antibacterial activity against important Gram-positive (including methicillin-resistant Staphylococcus aureus (MRSA)) and Gram-negative pathogens (once the barrier imposed by the outer membrane was permeabilized). Proteomics and macromolecular synthesis analyses revealed that simvastatin inhibits multiple biosynthetic pathways and cellular processes in bacteria, including selective interference of bacterial protein synthesis. This property appears to assist in simvastatin's ability to suppress production of key MRSA toxins (α-hemolysin and Panton-Valentine leucocidin) that impair healing of infected skin wounds. A murine MRSA skin infection experiment confirmed that simvastatin significantly reduces the bacterial burden and inflammatory cytokines in the infected wounds. Additionally, simvastatin exhibits excellent anti-biofilm activity against established staphylococcal biofilms and demonstrates the ability to be combined with topical antimicrobials currently used to treat MRSA skin infections. Collectively the present study lays the foundation for further investigation of repurposing simvastatin as a topical antibacterial agent to treat skin infections.

  15. Lu-AA21004, a multimodal serotonergic agent, for the potential treatment of depression and anxiety.

    PubMed

    Adell, Albert

    2010-12-01

    Lu-AA21004, an oral, multimodal serotonergic agent, is currently under development by H Lundbeck and Takeda Pharmaceutical, for the potential treatment of depression and anxiety. Lu-AA21004 belongs to a novel chemical class of antidepressant agents, the bisarylsulfanyl amines, and possesses a novel pharmacological profile, with activity at serotonergic receptors 5-HT3, 5-HT7 and 5-HT1A, and also at the 5-HT transporter. Acute administration of Lu-AA21004 in rats inhibited the firing activity of serotonergic neurons of the dorsal raphe nucleus through 5-HT3 receptor blockade, with rapid recovery of firing activity upon cessation of treatment compared with an antidepressant of the SSRI class. Results from phase II clinical trials have reported improvement in depression and anxiety symptoms after 6 weeks of treatment. Lu-AA21004 was generally well tolerated, with adverse events related to sexual dysfunction occurring in a lower number of patients receiving Lu-AA21004 compared with venlafaxine. Phase III clinical trials with Lu-AA21004 in patients with major depressive disorder are underway and phase III trials in patients with generalized anxiety disorder have been completed. If initial outcomes from these clinical trials prove positive, Lu-AA21004 may pave the way for new multimodal therapies for the treatment of depression and anxiety.

  16. Lutetium texaphyrin (Lu-Tex): a potential new agent for ocular fundus angiography and photodynamic therapy.

    PubMed

    Blumenkranz, M S; Woodburn, K W; Qing, F; Verdooner, S; Kessel, D; Miller, R

    2000-03-01

    To investigate the suitability of lutetium texaphyrin (lu-tex) as a fluorescence imaging agent in the delineation of retinal vascular and choroidal vascular diseases. The utilization of an efficient fluorescent molecule that is also a photosensitizer represents a unique opportunity to couple diagnosis and therapy. Fundus fluorescence angiography comparing lu-tex (motexafin lutetium, Optrin, Pharmacyclics Inc, Sunnyvale, California) with the conventional angiographic dyes, sodium fluorescein, and indocynanine green (ICG), was performed on the eyes of normal and laser-injured New Zealand white rabbits. Plasma pharmacokinetic data and plasma protein binding were assessed in addition to light microscopy of the retina in both imaged and laser-injured eyes. Normal retinal and choroidal vasculature was well delineated by lu-tex angiography. Experimentally induced choroidal and retinal vascular lesions were enhanced by lu-tex and demonstrated different staining patterns than fluorescein or ICG, particularly at the margins of the lesions. Lu-tex cleared rapidly from the plasma, with 39.7% bound to the high-density lipoprotein (HDL) fraction while 15.8% was bound to the low-density lipoprotein (LDL) fraction. No evidence of retinal toxicity after dye administration was observed by either ophthalmoscopy and fundus photography or by light microscopy. Lu-tex angiography is a potentially valuable method for retinal vascular and choroidal vascular evaluation, and it has advantages over fluorescein and ICG angiography. The same agent could conceivably be used for both the identification of abnormal vasculature and subsequent photodynamic treatment.

  17. Bacillus amyloliquefaciens Q-426 as a potential biocontrol agent against Fusarium oxysporum f. sp. spinaciae.

    PubMed

    Zhao, Pengchao; Quan, Chunshan; Wang, Yingguo; Wang, Jianhua; Fan, Shengdi

    2014-05-01

    In recent years, Bacillus species have received considerable attention for the biological control of many fungal diseases. In this study, Bacillus amyloliquefaciens Q-426 was tested for its potential use against a variety of plant pathogens. Our screen for genes involved in the biosynthesis of antifungal agents revealed that the fen and bmy gene clusters are present in the Q-426 genome. Lipopeptides such as bacillomycin D, fengycin A, and fengycin B were purified from the bacterial culture broth and subsequently identified by ESI-mass spectrometry. The minimal inhibitory concentration of fengycin A against Fusarium oxysporum f. sp. spinaciae W.C. Snyder & H.N. Hansen O-27 was determined to be 31.25 μg ml(-1) . However, exposure of fungal cells to 50 μg ml(-1) of fengycin A did not allow permeation of fluorescein diacetate into the cytoplasm through the cell membrane. Moreover, leakage of intracellular inorganic cations, nucleic acid and protein were also not detected, indicating that the fungal cell membrane is not the primary target of action for fengycin A. Profound morphological changes were observed in the F. oxysporum strain and spore germination was completely inhibited, suggesting that 50 μg ml(-1) of fengycin A acts, at least, as a fungistatic agent.

  18. Theranostic Au cubic nano-aggregates as potential photoacoustic contrast and photothermal therapeutic agents.

    PubMed

    Hu, Juan; Zhu, Xianglong; Li, Hui; Zhao, Zhenghuan; Chi, Xiaoqin; Huang, Guoming; Huang, Dengtong; Liu, Gang; Wang, Xiaomin; Gao, Jinhao

    2014-01-01

    Multifunctional nanostructures combining diagnosis and therapy modalities into one entity have drawn much attention in the biomedical applications. Herein, we report a simple and cost-effective method to synthesize a novel cubic Au nano-aggregates structure with edge-length of 80 nm (Au-80 CNAs), which display strong near-infrared (NIR) absorption, excellent water-solubility, good photothermal stability, and high biocompatibility. Under 808 nm laser irradiation for 5 min, the temperature of the solution containing Au-80 CNAs (100 μg/mL) increased by ~38 °C. The in vitro and in vivo studies demonstrated that Au-80 CNAs could act as both photothermal therapeutic (PTT) agents and photoacoustic imaging (PAI) contrast agents, indicating that the only one nano-entity of Au-80 CNAs shows great potentials for theranostic applications. Moreover, this facile and cost-effective synthetic method provides a new strategy to prepare stable Au nanomaterials with excellent optical properties for biomedical applications.

  19. Novel benzothiazine-piperazine derivatives by peptide-coupling as potential anti-proliferative agents.

    PubMed

    Venkatesh, Ramineni; Kasaboina, Suresh; Bidayat, Deepthi; Nikhil Kumar, U; Jain, Nishant; Tangeda, Saritha Jostna; Bantu, Rajashaker; Janardhan, Sridhara; Nagarapu, Lingaiah

    2017-01-15

    In an attempt to develop potential and selective anti-proliferative agents, a series of novel benzothiazine-piperazine derivatives 8a-i and 10a-g were synthesized by coupling of 2H-1,4-benzothiazin-3(4H)-one with various amines 7a-i and 9a-g in excellent yields and evaluated for their in vitro anti-proliferative activity against four cancer cell lines, HeLa (cervical), MIAPACA (pancreatic), MDA-MB-231 (breast) and IMR32 (neuroblastoma). In vitro inhibitory activity indicated that compounds 8a, 8d, 8g, 10a, 10b, 10e, 10f were found to be good anti-proliferative agents. Among them the derivatives 8g, 10e and 10f were found to be the most active members exhibiting remarkable growth inhibitory activity. Molecular docking was undertaken to investigate the probable binding mode and key active site interactions in HDAC8 and EHMT2 proteins. The docking results are complementary to the experimental results.

  20. Glycans in magnetic resonance imaging: determinants of relaxivity to smart agents, and potential applications in biomedicine.

    PubMed

    Cipolla, Laura; Gregori, Maria; So, Po-Wah

    2011-01-01

    Carbohydrate chemistry and glycobiology have become a "hot" subject. These extensive, complex structures serve essential roles in cell surface phenomena, but we are only beginning to understand what some of these functions are; any advances in the development of synthetic and/or analytical tools for glycobiology are extremely useful for our understanding of the roles of carbohydrates in biology, and as biomarkers of physiological/pathological states. This review provides an outlook of the potential of carbohydrate chemistry/biology in magnetic resonance imaging (MRI), a major important and prominent technique in diagnostic clinical medicine and biomedical research. During the last 30 years, MRI has developed from an intriguing research project to an essential diagnostic method in the clinic. Although MRI contrast in endogenous tissues provides excellent sensitivity for detecting subtle changes in anatomy and function, MRI still has poor specificity for attributing image contrast to specific biological processes. To overcome this limitation, MRI methods are being developed that induce changes in MR image contrast in response to molecular compositions and functions that serve as early biomarkers of pathologies. Carbohydrates with their intriguing chemistry, not only can provide structures for novel MRI probes for imaging specific biological processes, but can themselves provide novel targets/biomarkers. For example, the glycan structure can simply provide a molecular scaffold for modulating the physicochemical properties of the imaging contrast agent, or can be used for the design of novel MR agents with the ability to disclose relevant physiological or pathological cellular events.

  1. Potentiation of DNA-reactive antineoplastic agents and protection against S-phase-specific agents by anguidine in Chinese hamster ovary cells.

    PubMed

    Hromas, R; Barlogie, B; Swartzendruber, D; Drewinko, B

    1983-07-01

    Anguidine, a protein synthesis inhibitor, has been shown to induce a reversible cell cycle arrest in exponentially growing Chinese hamster ovary cells. The effect of pretreatment with anguidine on the cytotoxicity of subsequently administered various chemotherapeutic agents, hyperthermia, and radiation was investigated. We found that anguidine greatly potentiated the cytotoxic activity of cis-dichlorodiammineplatinum(II) and melphalan by abolishing the initial shoulder and steepening the subsequent exponential portion of the survival curves. Bleomycin-induced cell kill was also potentiated by anguidine pretreatment but to a lesser extent. However, anguidine pretreatment did not substantially alter radiation cytotoxicity. In contrast, anguidine markedly reduced the lethal effect of hydroxyurea, 5-fluorouracil, and hyperthermia, three modalities with S-phase activity. To investigate whether both anguidine-induced potentiation and protection of cells by different antitumor agents were due to its induction of complete suspension of cycle traverse, experiments were also conducted with plateau-phase cultures. Whereas anguidine potentiated cis-dichlorodiammineplatinum(II) cytotoxicity in an identical fashion as noted in exponentially growing cells, its protective effect against lethal damage from Adriamycin was absent. Thus, it appears that the two opposite effects of anguidine modification of cell kill by cytotoxic agents (protection and potentiation) come about by two different mechanisms, with cell cycle arrest underlying cytoprotection and the mechanism of synergistic toxicity remaining obscure.

  2. Potential Use of Phenolic Acids as Anti-Candida Agents: A Review

    PubMed Central

    Teodoro, Guilherme R.; Ellepola, Kassapa; Seneviratne, Chaminda J.; Koga-Ito, Cristiane Y.

    2015-01-01

    There has been a sharp rise in the occurrence of Candida infections and associated mortality over the last few years, due to the growing body of immunocompromised population. Limited number of currently available antifungal agents, undesirable side effects and toxicity, as well as emergence of resistant strains pose a considerable clinical challenge for the treatment of candidiasis. Therefore, molecules that derived from natural sources exhibiting considerable antifungal properties are a promising source for the development of novel anti-candidal therapy. Phenolic compounds isolated from natural sources possess antifungal properties of interest. Particularly, phenolic acids have shown promising in vitro and in vivo activity against Candida species. However, studies on their mechanism of action alone or in synergism with known antifungals are still scarce. This review attempts to discuss the potential use, proposed mechanisms of action and limitations of the phenolic acids in anti-candidal therapy. PMID:26733965

  3. New multifunctional ligands for potential use in the design therapeutic or diagnostic radiopharmaceutical imaging agents

    DOEpatents

    Katti, Kattesh V.; Volkert, Wynn A.; Ketring, Alan R.; Singh, Prahlad R.

    1997-01-01

    A class of diagnostic and therapeutic compounds derived from phosphinimines that include ligands containing either a single phosphinimine functionality or both a phosphinimine group and a phosphine or arsine group, or an aminato group, or a second phosphinimine moiety. These phosphinimine ligands are complexed to early transition metal radionuclides (e.g. .sup.99m Tc or .sup.186 Re/.sup.188 Re) or late transition metals (e.g., .sup.105 Rh or .sup.109 Pd). The complexes with these metals .sup.186 Re/.sup.188 Re, .sup.99m Tc and .sup.109 Pd exhibit a high in vitro and high in vivo stability. The complexes are formed in high yields and can be neutral or charged. These ligands can also be used to form stable compounds with paramagnetic transition metals (e.g. Fe and Mn) for potential use as MRI contrast agents. Applications for the use of ligands and making the ligands are also disclosed.

  4. Lignin model compound in alginate hydrogel: a strong antimicrobial agent with high potential in wound treatment.

    PubMed

    Spasojević, Dragica; Zmejkoski, Danica; Glamočlija, Jasmina; Nikolić, Miloš; Soković, Marina; Milošević, Verica; Jarić, Ivana; Stojanović, Marijana; Marinković, Emilija; Barisani-Asenbauer, Talin; Prodanović, Radivoje; Jovanović, Miloš; Radotić, Ksenija

    2016-12-01

    Nowadays bacterial resistance to known antibiotics is a serious health problem. In order to achieve more efficient treatment, lately there is an effort to find new substances, such as certain biomaterials, that are non-toxic to humans with antibiotic potential. Lignins and lignin-derived compounds have been proposed to be good candidates for use in medicine and health maintenance. In this study, the antibacterial activity of the lignin model polymer dehydrogenate polymer (DHP) in alginate hydrogel (Alg) was studied. The obtained results show that DHP-Alg has strong antimicrobial activity against several bacterial strains and biofilms and does not have a toxic effect on human epithelial cells. These results strongly suggest its application as a wound healing agent or as an adjunct substance for wound treatments.

  5. Studies on the utilization of a plant SCE test in detecting potential mutagenic agents.

    PubMed

    Zhang, Z L; Yang, J; Zhang, Q A; Cao, X S

    1991-09-01

    In this paper a modified procedure for sister-chromatid differentiation in plant cells is reported. Using this procedure some chemicals were tested for SCE induction in Vicia faba, Hordeum vulgare and Secale cereale. The chemicals tested were ethanol, chromium oxide, sodium saccharin, fluorouracil, ascorbic acid (vitamin c), omethoate and phenol. The experimental results showed that most of them induced SCE increases in mouse spleen cells, human lymphocytes and plant cells. The increase of SCEs per cell in plant cells is in agreement with that found in human lymphocytes or in mouse spleen cells. In our opinion, the utilization of SCE in plants is a simple and inexpensive technique for detecting potential mutagenic agents in the environment.

  6. Structure-activity analysis of 2'-modified cinnamaldehyde analogues as potential anticancer agents.

    PubMed

    Gan, Fei Fei; Chua, Yee Shin; Scarmagnani, Silvia; Palaniappan, Puvithira; Franks, Mark; Poobalasingam, Thurka; Bradshaw, Tracey D; Westwell, Andrew D; Hagen, Thilo

    2009-10-02

    The natural product 2'-hydroxycinnamaldehyde (HCA) and its analogue, 2'-benzoyloxycinnamaldehyde (BCA), have been previously shown to have antiproliferative and proapoptotic effects in vitro and inhibit tumor growth in vivo. In this study, we use structure-activity analysis to define structural features that are important for the activity of cinnamaldehyde analogues. Our results emphasize an important role for both the propenal group as well as the modification at the 2'-position. Further studies were aimed to characterize the mechanism of action of BCA. Exposure to BCA induced cell death via caspase-dependent and -independent pathways. Cell death was not due to autophagy or necrosis as a result of energy depletion or induction of reactive oxygen species. Our findings have important implications for future drug design and highlight the importance of defining molecular drug targets for this promising class of potential anticancer agents.

  7. Oxidative stress and Alzheimer's disease: dietary polyphenols as potential therapeutic agents.

    PubMed

    Darvesh, Altaf S; Carroll, Richard T; Bishayee, Anupam; Geldenhuys, Werner J; Van der Schyf, Cornelis J

    2010-05-01

    Oxidative stress has been strongly implicated in the pathophysiology of neurodegenerative disorders such as Alzheimer's disease (AD). In recent years, antioxidants - especially those of dietary origin - have been suggested as possible agents useful for the prevention and treatment of AD. This article reviews the role of oxidative stress and the contribution of free radicals in the development of AD, and also discusses the use of antioxidants as a therapeutic strategy in the amelioration of this illness. The antioxidant potential of polyphenolic compounds obtained from dietary sources, such as anthocyanins from berries, catechins and theaflavins from tea, curcumin from turmeric, resveratrol from grapes and peanuts, the dihydrochalcones aspalathin and nothofagin from rooibos and the xanthone mangiferin from honeybush, are discussed in this review. The neuroprotective effects of these phytochemicals in preclinical models of AD are highlighted. Finally, innovative concepts, novel hypotheses, current challenges and future directions in the use of dietary polyphenols for the treatment of AD are discussed.

  8. Characteristics of gadolinium-DTPA complex: a potential NMR contrast agent

    SciTech Connect

    Weinmann, H.J.; Brasch, R.C.; Press, W.R.; Wesbey, G.E.

    1984-03-01

    Chelation of the rare-earth element gadolinium (Gd) with diethylenetriaminepentaacetic acid (DTPA) results in a strongly paramagnetic, stable complex that is well tolerated in animals. The strongly paramagnetic gadolinium complex reduces hydrogen-proton relaxation times even in low concentrations (less than 0.01 mmol/L). The pharmacokinetic behavior of intravenously delivered Gd-DTPA is similar to the well known iodinated contrast agents used in urography and angiography; excretion is predominately through the kidneys with greater than 90% recovery in 24 hr. The intravenous LD/sub 50/ of the meglumine salt of Gd-DTPA is 10 mmol/kg for the rat; in vivo there is no evidence of dissociation of the gadolinium ion from the DTPA ligand. The combination of strong proton relaxation, in-vivo stability, rapid urinary excretion, and high tolerance favors the further development and the potential clinical application of gadolinium-DTPA as a contrast enhancer in magnetic resonance imaging.

  9. Enterovirus infection in Korean children and anti-enteroviral potential candidate agents

    PubMed Central

    Park, Kwi Sung; Choi, Young Jin

    2012-01-01

    Although most enterovirus infections are not serious enough to be life threatening, several enteroviruses such as enterovirus 71 are responsible for severe, potentially life-threatening disease. The epidemic patterns of enteroviruses occur regularly during the year, but they may change due to environmental shifts induced by climate change due to global warming. Therefore, enterovirus epidemiological studies should be performed continuously as a basis for anti-viral studies. A great number of synthesized antiviral compounds that work against enteroviruses have been developed but only a few have demonstrated effectiveness in vivo. No proven effective antiviral agents are available for enterovirus disease therapy. The development of a new antiviral drug is a difficult task due to poor selective toxicity and cost. To overcome these limitations, one approach is to accelerate the availability of other existing antiviral drugs approved for antiviral effect against enteroviruses, and the other way is to screen traditional medicinal plants. PMID:23133481

  10. Gold nanocages: bioconjugation and their potential use as optical imaging contrast agents.

    PubMed

    Chen, Jingyi; Saeki, Fusayo; Wiley, Benjamin J; Cang, Hu; Cobb, Michael J; Li, Zhi-Yuan; Au, Leslie; Zhang, Hui; Kimmey, Michael B; Li, Xingde; Xia, Younan

    2005-03-01

    Gold nanocages of <40 nm in dimension have been synthesized using the galvanic replacement reaction between Ag nanocubes and HAuCl4 in an aqueous solution. By controlling the molar ratio between Ag and HAuCl4, the gold nanocages could be tuned to display surface plasmon resonance peaks around 800 nm, a wavelength commonly used in optical coherence tomography (OCT) imaging. OCT measurements on phantom samples indicate that these gold nanocages have a moderate scattering cross-section of approximately 8.10 x 10(-16) m2 but a very large absorption cross-section of approximately 7.26 x 10(-15) m2, suggesting their potential use as a new class of contrast agents for optical imaging. When bioconjugated with antibodies, the gold nanocages have also been demonstrated for specific targeting of breast cancer cells.

  11. Neuroinflammation in Alzheimer's disease: different molecular targets and potential therapeutic agents including curcumin.

    PubMed

    Ray, Balmiki; Lahiri, Debomoy K

    2009-08-01

    Alzheimer's disease (AD) is a neurodegenerative disorder of the elderly. Deposition of amyloid beta plaque and associated neuroinflammation are the major hallmarks of AD. Whereas reactive oxygen species (ROS) and activated microglial cells contribute to neuronal loss, nuclear factor kappaB and apolipoprotein E participate in inflammatory process of AD. Current FDA approved drugs provide only symptomatic relief in AD. For broad spectrum of activity, some natural products are also being tested. Turmeric is used as an anti-inflammatory medicine in various regions of Asia. Curcumin, which is a yellow colored polyphenol compound present in turmeric, showed anti-inflammatory properties. Herein, we discuss the neurobiological and neuroinflammatory pathways of AD, evaluate different molecular targets and potential therapeutic agents, including curcumin, for the treatment of AD.

  12. Sodium arsenite potentiates the clastogenicity and mutagenicity of DNA cross linking agents

    SciTech Connect

    Lee, T.C.; Lee, K.C.; Tzeng, Y.J.; Huang, R.Y.; Jan, K.Y.

    1986-01-01

    To see if sodium arsenite enhances the clastogenicity and the mutagenicity of DNA crosslinking agents, Chinese hamster ovary (CHO) cells and human skin fibroblasts were exposed to cis-diamminedichloroplatinum (II) (cis-Pt(II)) or 8-methoxypsoralen (8-MOP) plus long-wave ultraviolet light (UVA) and then to sodium arsenite. The results indicate that the clastogenicity of cis-Pt(II) and 8-MOP pllus UVA are enhanced by the post-treatment with sodium arsenite. Chromatid breaks and exchanges are predominantly increased in doubly treated cells. Furthermore, the mutagenicity of cis-Pt(II) at the hypoxanthine-guanine phosphoribosyl transferase locus is also potentiated by sodium arsenite in CHO cells

  13. Microtubule Stabilizing Agents as Potential Treatment for Alzheimer’s Disease and Related Neurodegenerative Tauopathies

    PubMed Central

    Ballatore, Carlo; Brunden, Kurt R.; Huryn, Donna M.; Trojanowski, John Q.; Lee, Virginia M.-Y.; Smith, Amos B.

    2012-01-01

    The microtubule (MT)-associated protein tau, which is highly expressed in the axons of neurons, is an endogenous MT-stabilizing agent that plays an important role in the axonal transport. Loss of MT-stabilizing tau function, caused by misfolding, hyperphosphorylation and sequestration of tau into insoluble aggregates, leads to axonal transport deficits with neuropathological consequences. Several in vitro and preclinical in vivo studies have shown that MT-stabilizing drugs can be utilized to compensate for the loss of tau function and to maintain/restore an effective axonal transport. These findings indicate that MT-stabilizing compounds hold considerable promise for the treatment of Alzheimer disease and related tauopathies. The present article provides a synopsis of the key findings demonstrating the therapeutic potential of MT-stabilizing drugs in the context of neurodegenerative tauopathies, as well as an overview of the different classes of MT-stabilizing compounds. PMID:23020671

  14. Animals living in polluted environments are potential source of antimicrobials against infectious agents.

    PubMed

    Lee, Simon; Siddiqui, Ruqaiyyah; Khan, Naveed Ahmed

    2012-08-01

    The antimicrobials crisis is a ticking time bomb which could lead to millions of people dying from untreatable infections. With the worsening trends of antimicrobial resistance, we are heading towards a pre-antibiotic era. Thus, there is a need for newer and more powerful antibiotic agents. The search for new antibiotic compounds originating from natural resources is a promising research area. Animals living in germ-infested environments are a potent source of antimicrobials. Under polluted milieus, organisms such as cockroaches encounter different types of bacteria, including superbugs. Such creatures survive the onslaught of superbugs and are able to ward off disease by producing antimicrobial substances which show potent activity in the nervous system. We hope that the discovery of antimicrobial activity in the cockroach brain will stimulate research in finding antimicrobials from unusual sources, and has potential for the development of novel antibiotics. Nevertheless, intensive research in the next few years will be required to approach or realize these expectations.

  15. Huperzine A, a potential therapeutic agent for treatment of Alzheimer's disease.

    PubMed

    Bai, D L; Tang, X C; He, X C

    2000-03-01

    HupA is a potent, reversible and selective inhibitor of AChE with a rapid absorption and penetration into the brain in animal tests. It exhibits memory-enhancing activities in animal and clinical trials. Compared to tacrine and donepezil, HupA possesses a longer duration of action and higher therapeutic index, and the peripheral cholinergic side effects are minimal at therapeutic doses. This review article deals with a comprehensive survey of the progress in chemical and pharmacological studies of HupA including the isolation and structure elucidation, pharmacological actions, total synthesis, SAR studies and the future development of HupA. Recently, it has been reported that HupA could reduce neuronal cell death caused by glutamate. The dual bio-activities of HupA would further enhance its value and potentiality as the therapeutic agent for Alzheimer s disease.

  16. Novel enterobactin analogues as potential therapeutic chelating agents: Synthesis, thermodynamic and antioxidant studies

    PubMed Central

    Zhang, Qingchun; Jin, Bo; Shi, Zhaotao; Wang, Xiaofang; Liu, Qiangqiang; Lei, Shan; Peng, Rufang

    2016-01-01

    A series of novel hexadentate enterobactin analogues, which contain three catechol chelating moieties attached to different molecular scaffolds with flexible alkyl chain lengths, were prepared. The solution thermodynamic stabilities of the complexes with uranyl, ferric(III), and zinc(II) ions were then investigated. The hexadentate ligands demonstrate effective binding ability to uranyl ion, and the average uranyl affinities are two orders of magnitude higher than 2,3-dihydroxy-N1,N4-bis[(1,2-hydroxypyridinone-6-carboxamide)ethyl]terephthalamide [TMA(2Li-1,2-HOPO)2] ligand with similar denticity. The high affinity of hexadentate ligands could be due to the presence of the flexible scaffold, which favors the geometric agreement between the ligand and the uranyl coordination preference. The hexadentate ligands also exhibit higher antiradical efficiency than butylated hydroxyanisole (BHA). These results provide a basis for further studies on the potential applications of hexadentate ligands as therapeutic chelating agents. PMID:27671769

  17. Novel enterobactin analogues as potential therapeutic chelating agents: Synthesis, thermodynamic and antioxidant studies

    NASA Astrophysics Data System (ADS)

    Zhang, Qingchun; Jin, Bo; Shi, Zhaotao; Wang, Xiaofang; Liu, Qiangqiang; Lei, Shan; Peng, Rufang

    2016-09-01

    A series of novel hexadentate enterobactin analogues, which contain three catechol chelating moieties attached to different molecular scaffolds with flexible alkyl chain lengths, were prepared. The solution thermodynamic stabilities of the complexes with uranyl, ferric(III), and zinc(II) ions were then investigated. The hexadentate ligands demonstrate effective binding ability to uranyl ion, and the average uranyl affinities are two orders of magnitude higher than 2,3-dihydroxy-N1,N4-bis[(1,2-hydroxypyridinone-6-carboxamide)ethyl]terephthalamide [TMA(2Li-1,2-HOPO)2] ligand with similar denticity. The high affinity of hexadentate ligands could be due to the presence of the flexible scaffold, which favors the geometric agreement between the ligand and the uranyl coordination preference. The hexadentate ligands also exhibit higher antiradical efficiency than butylated hydroxyanisole (BHA). These results provide a basis for further studies on the potential applications of hexadentate ligands as therapeutic chelating agents.

  18. Clinical Signs of Radiologic Pneumonia in Under-Five Hypokalemic Diarrheal Children Admitted to an Urban Hospital in Bangladesh

    PubMed Central

    Chisti, Mohammod Jobayer; Salam, Mohammed Abdus; Ashraf, Hasan; Faruque, Abu S. G.; Bardhan, Pradip Kumar; Das, Sumon Kumar; Shahunja, K. M.; Shahid, Abu S. M. S. B.; Ahmed, Tahmeed

    2013-01-01

    Background Clinical signs of pneumonia are often veiled in under-five diarrheal children presenting with hypokalemia, making clinical diagnosis of pneumonia very difficult in such population. However, there is no published report that describes the influences of hypokalemia on the clinical signs of pneumonia in diarrheal children. Our objective was to assess the influences of hypokalemia, and their outcome in such children. Methods We prospectively enrolled all under-five diarrheal children (n = 180) admitted to the Special Care Ward of the Dhaka Hospital of icddr,b from September-December 2007 with radiological pneumonia who also had their serum potassium estimated. We compared the clinical features and outcome of the diarrheal children having pneumonia with (cases = 55) and without hypokalemia (controls = 125). Results The case-fatality among the cases was 2 times higher compared to the controls, but the difference was not statistically significant (p = 0.202). In logistic regression analysis, after adjusting for potential confounders such as age of the patient, clinical dehydration, severe wasting, abnormally sleepy, lower chest wall in-drawing, nasal flaring and inability to drink on admission, under-five diarrheal children with pneumonia who presented with nutritional edema had 3 times more risk to have hypokalemia compared to those without nutritional edema (OR = 2.76, 95% CI = 1.01–7.51) and these hypokalemic children were 64% less likely to present with fast breathing (OR = 0.36, 95% CI = 0.17–0.74). Conclusion and significance The results of our analysis are simple but may have great public health implications and underscore the importance of diligent assessment for pneumonia in under-five diarrheal children having risk of hypokalemia as in children with nutritional edema even in absence of fast breathing, a useful sign of pneumonia. This may help for early initiation of first dose of parental antibiotics along with

  19. Evaluation of Gd-DTPA-monophytanyl and phytantriol nanoassemblies as potential MRI contrast agents.

    PubMed

    Gupta, Abhishek; de Campo, Liliana; Rehmanjan, Beenish; Willis, Scott A; Waddington, Lynne J; Stait-Gardner, Tim; Kirby, Nigel; Price, William S; Moghaddam, Minoo J

    2015-02-03

    Supramolecular self-assembling amphiphiles have been widely used in drug delivery and diagnostic imaging. In this report, we present the self-assembly of Gd (III) chelated DTPA-monophytanyl (Gd-DTPA-MP) amphiphiles incorporated within phytantriol (PT), an inverse bicontinuous cubic phase forming matrix at various compositions. The dispersed colloidal nanoassemblies were evaluated as potential MRI contrast agents at various magnetic field strengths. The homogeneous incorporation of Gd-DTPA-MP in PT was confirmed by polarized optical microscopy (POM) and synchrotron small-angle X-ray scattering (SAXS) of the bulk phases of the mixtures. The liquid crystalline nanostructures, morphology, and the size distribution of the nanoassemblies were studied by SAXS, cryogenic transmission electron microscopy (cryo-TEM), and dynamic light scattering (DLS). The dispersions with up to 2 mol % of Gd-DTPA-MP in PT retained inverse cubosomal nanoassemblies, whereas the rest of the dispersions transformed to liposomal nanoassemblies. In vitro relaxivity studies were performed on all the dispersions at 0.54, 9.40, and 11.74 T and compared to Magnevist, a commercially available contrast agent. All the dispersions showed much higher relaxivities compared to Magnevist at both low and high magnetic field strengths. Image contrast of the nanoassemblies was also found to be much better than Magnevist at the same Gd concentration at 11.74 T. Moreover, the Gd-DTPA-MP/PT dispersions showed improved relaxivities over the pure Gd-DTPA-MP dispersion at high magnetic fields. These stable colloidal nanoassemblies have high potential to be used as combined delivery matrices for diagnostics and therapeutics.

  20. Biocompatible nanotemplate-engineered nanoparticles containing gadolinium: stability and relaxivity of a potential MRI contrast agent.

    PubMed

    Zhu, Donghua; White, R D; Hardy, Peter A; Weerapreeyakul, Natthida; Sutthanut, Khaetthareeya; Jay, Michael

    2006-04-01

    In this article, we use a nanotemplate engineering approach to prepare biodegradable nanoparticles composed of FDA-approved materials and possessing accessible gadolinium (Gd) atoms and demonstrate their potential as a Magnetic Resonance Imaging (MRI) contrast agent. Nanoparticles containing dimyristoyl phosphoethanolamine diethylene triamine penta acetate (PE-DTPA) were prepared using 3.5 mg of Brij 78, 2.0 mg of emulsifying wax and 0.5 mg of PE-DTPA/ml from a microemulsion precursor. After the addition of GdCl3, the presence of Gd on the surface of nanoparticles was characterized using inductively coupled plasma atomic emission spectroscopy and Scanning Transmission Electron Microscopy (STEM). The in vitro relaxivities of the PE-DTPA-Gd nanoparticles in different media were assessed at different field strengths. The conditional stability constant of Gd binding to the nanoparticles was determined using competitive spectrophotometric titration. Transmetallation kinetics of the gadolinium ion from PE-DTPA-Gd nanoparticles with zinc as the competing ionic was measured using the relaxivity evolution method. Nanoparticles with a diameter of approximately 130 nm possessing surface chelating functions were made from GRAS (Generally Regarded As Safe) materials. STEM demonstrated the uniform distribution of Gd3+ on the surface of the nanoparticles. The thermodynamic binding constant for Gd3+ to the nanoparticles was approximately 10(18) M(-1) and transmetallation studies with Zn2+ yielded kinetic constants K1 and K(-1) of 0.033 and 0.022 1/h, respectively, with an equilibrium constant of 1.5. A payload of approximately 10(5) Gd/nanoparticle was achieved; enhanced relaxivities were observed, including a pH dependence of the transverse relaxivity (r2). Nanoparticles composed of materials that have been demonstrated to be hemocompatible and enzymatically metabolized and possessing accessible Gd ions on their surface induce relaxivities in the bulk water signal that make them

  1. Novel Penicillin Analogues as Potential Antimicrobial Agents; Design, Synthesis and Docking Studies

    PubMed Central

    Ashraf, Zaman; Bais, Abdul; Manir, Md. Maniruzzaman; Niazi, Umar

    2015-01-01

    A number of penicillin derivatives (4a-h) were synthesized by the condensation of 6-amino penicillinic acid (6-APA) with non-steroidal anti-inflammatory drugs as antimicrobial agents. In silico docking study of these analogues was performed against Penicillin Binding Protein (PDBID 1CEF) using AutoDock Tools 1.5.6 in order to investigate the antimicrobial data on structural basis. Penicillin binding proteins function as either transpeptidases or carboxypeptidases and in few cases demonstrate transglycosylase activity in bacteria. The excellent antibacterial potential was depicted by compounds 4c and 4e against Escherichia coli, Staphylococcus epidermidus and Staphylococcus aureus compared to the standard amoxicillin. The most potent penicillin derivative 4e exhibited same activity as standard amoxicillin against S. aureus. In the enzyme inhibitory assay the compound 4e inhibited E. coli MurC with an IC50 value of 12.5 μM. The docking scores of these compounds 4c and 4e also verified their greater antibacterial potential. The results verified the importance of side chain functionalities along with the presence of central penam nucleus. The binding affinities calculated from docking results expressed in the form of binding energies ranges from -7.8 to -9.2kcal/mol. The carboxylic group of penam nucleus in all these compounds is responsible for strong binding with receptor protein with the bond length ranges from 3.4 to 4.4 Ǻ. The results of present work ratify that derivatives 4c and 4e may serve as a structural template for the design and development of potent antimicrobial agents. PMID:26267242

  2. Hyperglycaemia Induced by Novel Anticancer Agents: An Undesirable Complication or a Potential Therapeutic Opportunity?

    PubMed

    Shah, Rashmi R

    2017-03-01

    Signalling pathways involving protein kinase, insulin-like growth factor 1, insulin receptors and the phosphoinositide 3 kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) system are critical in promoting oncogenesis. The use of anticancer agents that inhibit these pathways frequently results in hyperglycaemia, an on-target effect of these drugs. Hyperglycaemia induced by these agents denotes optimal inhibition of the desired pharmacological target. As hyperglycaemia can be treated successfully and effectively with metformin, managing this complication by reducing the dose of or discontinuing the anticancer drug may be counterproductive, especially if it is otherwise effective and clinically tolerated. The use of metformin to treat hyperglycaemia induced by anticancer drugs provides a valuable therapeutic opportunity of potentiating their clinical anticancer effects. Although evidence from randomised controlled trials is awaited, extensive preclinical evidence and clinical observational studies suggest that metformin has anticancer properties that improve overall survival in patients with diabetes and a variety of cancers. Metformin has also been reported to reverse resistance to epidermal growth factor receptor (EGFR)-inhibiting tyrosine kinase inhibitors. This review summarises briefly the role of the above signalling pathways in oncogenesis, the causal association between inhibition of these pathways and hyperglycaemia, and the effect of metformin on clinical outcomes resulting from its anticancer properties. The evidence reviewed herein, albeit almost exclusively from observational studies, provides support for a greater use of metformin not only in patients with cancer and diabetes or drug-induced hyperglycaemia but also potentially as an anticancer drug. However, prospective randomised controlled studies are needed in all these settings to better assess the effect on clinical outcomes of adding metformin to ongoing anticancer therapy.

  3. Ex vivo Confocal Imaging with Contrast Agents for the Detection of Oral Potentially Malignant Lesions

    PubMed Central

    Hallani, S. El; Poh, C. F.; Macaulay, C. E.; Follen, M.; Guillaud, M.; Lane, P.

    2013-01-01

    Objectives We investigated the potential use of real-time confocal microscpy in the non-invasive detection of occult oral potentially malignant lesions. Our objectives were to select the best fluorescence contrast agent for cellular morphology enhancement, to build an atlas of confocal microscopic images of normal human oral mucosa, and to determine the accuracy of confocal microscopy to recognise oral high-grade dysplasia lesions on live human tissue. Materials and Methods Five clinically used fluorescent contrast agents were tested in vitro on cultured human cells and validated ex vivo on human oral mucosa. Images acquired ex vivo from normal and diseased human oral biopsies with bench-top fluorescent confocal microscope were compared to conventional histology. Image analyzer software was used as an adjunct tool to objectively compare high-grade dysplasia versus low-grade dysplasia and normal epithelium. Results Acriflavine Hydrochloride provided the best cellular contrast by preferentially staining the nuclei of the epithelium. Using topical application of Acriflavine Hydrochloride followed by confocal microscopy, we could define morphological characteristics of each cellular layer of the normal human oral mucosa, building an atlas of histology-like images. Applying this technique to diseased oral tissue specimen, we were also able to accurately diagnose the presence of high-grade dysplasia through the increased cellularity and changes in nuclear morphological features. Objective measurement of cellular density by quantitative image analysis was a strong discriminant to differentiate between high-grade dysplasia and low-grade dysplasia lesions. Conclusions Pending clinical investigation, real-time confocal microscopy may become a useful adjunct to detect precancerous lesions that are at high risk of cancer progression, direct biopsy and delineate excision margins. PMID:23415144

  4. Novel Penicillin Analogues as Potential Antimicrobial Agents; Design, Synthesis and Docking Studies.

    PubMed

    Ashraf, Zaman; Bais, Abdul; Manir, Md Maniruzzaman; Niazi, Umar

    2015-01-01

    A number of penicillin derivatives (4a-h) were synthesized by the condensation of 6-amino penicillinic acid (6-APA) with non-steroidal anti-inflammatory drugs as antimicrobial agents. In silico docking study of these analogues was performed against Penicillin Binding Protein (PDBID 1CEF) using AutoDock Tools 1.5.6 in order to investigate the antimicrobial data on structural basis. Penicillin binding proteins function as either transpeptidases or carboxypeptidases and in few cases demonstrate transglycosylase activity in bacteria. The excellent antibacterial potential was depicted by compounds 4c and 4e against Escherichia coli, Staphylococcus epidermidus and Staphylococcus aureus compared to the standard amoxicillin. The most potent penicillin derivative 4e exhibited same activity as standard amoxicillin against S. aureus. In the enzyme inhibitory assay the compound 4e inhibited E. coli MurC with an IC50 value of 12.5 μM. The docking scores of these compounds 4c and 4e also verified their greater antibacterial potential. The results verified the importance of side chain functionalities along with the presence of central penam nucleus. The binding affinities calculated from docking results expressed in the form of binding energies ranges from -7.8 to -9.2kcal/mol. The carboxylic group of penam nucleus in all these compounds is responsible for strong binding with receptor protein with the bond length ranges from 3.4 to 4.4 Ǻ. The results of present work ratify that derivatives 4c and 4e may serve as a structural template for the design and development of potent antimicrobial agents.

  5. Berberine and Coptidis Rhizoma as potential anticancer agents: Recent updates and future perspectives.

    PubMed

    Wang, Ning; Tan, Hor-Yue; Li, Lei; Yuen, Man-Fung; Feng, Yibin

    2015-12-24

    The antineoplastic property of Coptidis Rhizoma and berberine was correlated with its traditional use of clearing internal fire, removing damp-heat and counteracting toxic pathogens. The anti-tumor effect of Coptidis Rhizoma and berberine was extensively studied since our last comprehensive review in 2009. This study aims to summarize the recent updates and give rise to perspectives of Coptidis Rhizoma and berberine as potential novel antineoplastic agents. Quality studies in recent 5 years were retrieved from PubMed, Medline and CNKI with keywords including Coptis, Coptidis Rhizoma, huanglian, berberine, tumor and cancer. Studies were focused on the pharmacological actions of Coptidis Rhizoma and berberine in cancer progression. It was shown that Coptidis Rhizoma extract and berberine may repress tumor progression by regressing abnormal cell proliferation, arresting cell cycle and inducing cell death. Studies also highlighted the actions of Coptidis Rhizoma extract and berberine in inhibiting tumor cell invasion and angiogenesis, which in turn abolish cancer metastasis. Some studies have also been conducted to reveal the potential effect of Coptidis Rhizoma extract and berberine in regulating tumor stromal microenvironment, as well as in preventing carcinogenesis. Most of the results have been demonstrated with in vivo models, but results of high-quality clinical trials are not yet available. Unspecified cancer type and staging, fluctuated dose information and variants of targets across studies of berberine/ Coptidis Rhizoma impede their clinical use for cancer treatment. Recent advances highlighted by this review may shed light on future direction of studies featuring Coptidis Rhizoma and berberine as novel antineoplastic agents, which should be repeatedly proven in future animal and clinical studies. Although more evidences on its specificity and clinical efficacy are necessary to support its clinical use, Coptidis Rhizoma and berberine are highly expected to be

  6. Aluminum and other metals in Alzheimer's disease: a review of potential therapy with chelating agents.

    PubMed

    Domingo, Jose L

    2006-11-01

    Alzheimer's disease (AD) is characterized by the presence of neuritic plaques and neurofibrillary tangles in the brain. Although the causes of AD remain still unknown, it seems that certain environmental factors may be involved in the etiology and pathogenesis of the disease. While AD is associated with the abnormal aggregation of beta-amyloid protein in the brain, evidence shows that certain metals play a role in the precipitation and cytotoxicity of this protein. Among these metals, the potential role of aluminum as a possible ethiopathogenic factor in AD has been especially controversial. This review is mainly focused on the role of aluminum and metals such as copper and zinc in AD, as well as on metal chelator therapy as a potential treatment for AD. The effects of desferrioxamine and other Al chelating agents have been reviewed. The role of the metal chelator clioquinol in AD, which has been reported to reduce beta-amyloid plaques, presumably by chelation associated with copper and zinc, is also revised. Finally, the potential role of silicon in AD is also discussed.

  7. Boron-containing folate receptor-targeted liposomes as potential delivery agents for neutron capture therapy.

    PubMed

    Pan, Xing Q; Wang, Huaqing; Shukla, Supriya; Sekido, Masaru; Adams, Dianne M; Tjarks, Werner; Barth, Rolf F; Lee, Robert J

    2002-01-01

    Boron neutron capture therapy (BNCT) depends on the selective delivery of a sufficient number of (10)B atoms to tumor cells to sustain a lethal (10)B(n,alpha)(7)Li reaction. Expression of FR frequently is amplified among human tumors. The goal of the present study was to investigate folate receptor (FR)-targeted liposomes as potential carriers for a series of boron-containing agents. Two highly ionized boron compounds, Na(2)[B(12)H(11)SH] and Na(3) (B(20)H(17)NH(3)), were incorporated into liposomes by passive loading with encapsulation efficiencies of 6% and 15%, respectively. In addition, five weakly basic boronated polyamines were investigated. Two were the spermidine derivatives: N(5)-(4-carboranylbutyl)spermidine.3HCl (SPD-5), N(5)-[4-(2-aminoethyl-o-carboranyl)butyl]spermidine.4HCl (ASPD-5). Three were the spermine derivatives: N(5)-(4-carboranylbutyl)spermine.4HCl (SPM-5), N(5)-[4-(2-aminoethyl-o-carboranyl)butyl]spermine.5HCl (ASPM-5), and N(5),N(10)-bis(4-carboranylbutyl)spermine.4 HCl (SPM-5,10). These were incorporated into liposomes by a pH-gradient-driven remote-loading method with varying loading efficiencies, which were influenced by the specific trapping agent and the structure of the boron compound. Greater loading efficiencies were obtained with lower molecular weight boron derivatives, using ammonium sulfate as the trapping agent, compared to those obtained with sodium citrate. The in vitro uptake of folate-derivatized, boronated liposomes was investigated using human KB squamous epithelial cancer cells, which have amplified FR expression. Higher cellular boron uptake (up to 1584 microg per 10(9) cells) was observed with FR-targeted liposomes than with nontargeted control liposomes (up to 154 microg per 10(9) cells), irrespective of the chemical form of the boron and the method used for liposomal preparation. KB cell binding of the FR-targeted liposomes was saturable and could be blocked by 1 mM free folic acid. Our findings suggest that further

  8. New Potential Antimalarial Agents: Design, Synthesis and Biological Evaluation of Some Novel Quinoline Derivatives as Antimalarial Agents.

    PubMed

    Radini, Ibrahim Ali M; Elsheikh, Tarek M Y; El-Telbani, Emad M; Khidre, Rizk E

    2016-07-14

    A novel series of dihydropyrimidines (DHPMs) 4a-j; 2-oxopyran-3-carboxylate 7a,b; 1-amino-1,2-dihydropyridine-3-carboxylate 8; and 1,3,4-oxadiazole derivatives 12 with quinolinyl residues have been synthesized in fairly good yields. The structure of the newly synthesized compounds was elucidated on the basis of analytical and spectral analyses. In vitro antimalarial evaluation of the synthesized quinoline derivatives against Plasmodium falciparum revealed them to possess moderate to high antimalarial activities, with IC50 values ranging from 0.014-5.87 μg/mL. Compounds 4b,g,i and 12 showed excellent antimalarial activity against to Plasmodium falciparum compared with the antimalarial agent chloroquine (CQ).

  9. Enhancing Potentially Plant-Available Lead Concentrations in Contaminated Residential Soils Using a Biodegradable Chelating Agent

    NASA Astrophysics Data System (ADS)

    Andra, S.; Datta, R.; Sarkar, D.; Saminathan, S.

    2007-12-01

    Chelation of heavy metals is an important factor in enhancing metal solubility and, hence, metal availability to plants to promote phytoremediation. In the present study, we compared the effects of application of a biodegradable chelating agent, namely, ethylenediaminedisuccinic acid (EDDS) on enhancing plant available form of lead (Pb) in Pb-based paint contaminated residential soils compared to that of a more commonly used, but non-biodegradable chelate, i.e., ethylenediaminetetraacetic acid (EDTA). Development of a successful phytoremediation model for metals such as Pb depends on a thorough understanding of the physical and chemical properties of the soil, along with the optimization of a chelate treatment to mobilize Pb from `unavailable' pools to potentially plant available fraction. In this context, we set out to perform batch incubation experiments to investigate the effectiveness of the two aforementioned chelates in enhancing plant available Pb at four different concentrations (0, 5, 10 and 15 mM/kg soil) and three treatment durations (0, 10 and 30 days). We selected 12 contaminated residential soils from two major metropolitan areas (San Antonio, TX and Baltimore, MD) with varying soil physico-chemical properties - the soils from San Antonio were primarily alkaline and those from Baltimore were typically acidic. Total soil Pb concentrations ranged between 256 mg/kg and 4,182 mg/kg. Our results show that both chelates increased the solubility of Pb, otherwise occluded in the complex soil matrix. For both EDTA and EDDS, the exchangeable concentrations of soil Pb also increased with increase in chelate concentration and incubation time. The most effective treatment was 15 mM chelate kg-1 soil incubated for 30 days, which caused many fold increase in potentially plant available Pb (a combination of the soluble and exchangeable fractions) relative to the unamended controls. Step wise multiple linear regression analysis using chelate-extractable Pb and soil

  10. The untapped potential of Gallium 68-PET: the next wave of ⁶⁸Ga-agents.

    PubMed

    Smith, Daniel L; Breeman, Wouter A P; Sims-Mourtada, Jennifer

    2013-06-01

    (68)Gallium-PET ((68)Ga-PET) agents have significant clinical promise. The radionuclide can be produced from a (68)Ge/(68)Ga generator on site and is a convenient alternative to cyclotron-based PET isotopes. The short half-life of (68)Ga permits imaging applications with sufficient radioactivity while maintaining patient dose to an acceptable level. Furthermore, due to superior resolution, (68)Ga-PET agents have the ability to replace current SPECT agents in many applications. This article outlines the upcoming agents and challenges faced during the translational development of (68)Ga agents. Copyright © 2012 Elsevier Ltd. All rights reserved.

  11. Recent developments in L-asparaginase discovery and its potential as anticancer agent.

    PubMed

    Shrivastava, Abhinav; Khan, Abdul Arif; Khurshid, Mohsin; Kalam, Mohd Abul; Jain, Sudhir K; Singhal, Pradeep K

    2016-04-01

    L-Asparaginase (EC3.5.1.1) is an enzyme, which is used for treatment of acute lymphoblastic leukaemia (ALL) and other related blood cancers from a long time. This enzyme selectively hydrolyzes the extracellular amino acid L-asparagine into L-aspartate and ammonia, leading to nutritional deficiencies, protein synthesis inhibition, and ultimately death of lymphoblastic cells by apoptosis. Currently, bacterial asparaginases are used for treatment purpose but offers scepticism due to a number of toxicities, including thrombosis, pancreatitis, hyperglycemia, and hepatotoxicity. Resistance towards bacterial asparaginase is another major disadvantage during cancer management. This situation attracted attention of researchers towards alternative sources of L-asparaginase, including plants and fungi. Present article discusses about potential of L-asparaginase as an anticancer agent, its mechanism of action, and adverse effects related to current asparaginase formulations. This article also provides an outlook for recent developments in L-asparaginase discovery from alternative sources and their potential as a less toxic alternative to current formulations.

  12. Gancidin W, a potential low-toxicity antimalarial agent isolated from an endophytic Streptomyces SUK10

    PubMed Central

    Zin, Noraziah Mohamad; Baba, Mohd Shukri; Zainal-Abidin, Abu Hassan; Latip, Jalifah; Mazlan, Noor Wini; Edrada-Ebel, RuAngelie

    2017-01-01

    Endophytic Streptomyces strains are potential sources for novel bioactive molecules. In this study, the diketopiperazine gancidin W (GW) was isolated from the endophytic actinobacterial genus Streptomyces, SUK10, obtained from the bark of Shorea ovalis tree, and it was tested in vivo against Plasmodium berghei PZZ1/100. GW exhibited an inhibition rate of nearly 80% at 6.25 and 3.125 μg kg−1 body weight on day four using the 4-day suppression test method on male ICR strain mice. Comparing GW at both concentrations with quinine hydrochloride and normal saline as positive and negative controls, respectively, 50% of the mice treated with 3.125 μg kg−1 body weight managed to survive for more than 11 months after infection, which almost reached the life span of normal mice. Biochemical tests of selected enzymes and proteins in blood samples of mice treated with GW were also within normal levels; in addition, no abnormalities or injuries were found on internal vital organs. These findings indicated that this isolated bioactive compound from Streptomyces SUK10 exhibits very low toxicity and is a good candidate for potential use as an antimalarial agent in an animal model. PMID:28223778

  13. Identification of Inhibitors of CD36-Amyloid Beta Binding as Potential Agents for Alzheimer's Disease.

    PubMed

    Doens, Deborah; Valiente, Pedro A; Mfuh, Adelphe M; X T Vo, Anh; Tristan, Adilia; Carreño, Lizmar; Quijada, Mario; Nguyen, Vu T; Perry, George; Larionov, Oleg V; Lleonart, Ricardo; Fernández, Patricia L

    2017-06-21

    Neuroinflammation is one of the hallmarks of Alzheimer's disease pathology. Amyloid β has a central role in microglia activation and the subsequent secretion of inflammatory mediators that are associated with neuronal toxicity. The recognition of amyloid β by microglia depends on the expression of several receptors implicated in the clearance of amyloid and in cell activation. CD36 receptor expressed on microglia interacts with fibrils of amyloid inducing the release of proinflammatory cytokines and amyloid internalization. The interruption of the interaction CD36-amyloid β compromises the activation of microglia cells. We have developed and validated a new colorimetric assay to identify potential inhibitors of the binding of amyloid β to CD36. We have found seven molecules, structural analogues of the Trichodermamide family of natural products that interfere with the interaction CD36-amyloid β. By combining molecular docking and dynamics simulations, we suggested the second fatty acids binding site within the large luminal hydrophobic tunnel, present in the extracellular domain of CD36, as the binding pocket of these compounds. Free energy calculations predicted the nonpolar component as the driving force for the binding of these inhibitors. These molecules also inhibited the production of TNF-α, IL-6, and IL-1β by peritoneal macrophages stimulated with fibrils of amyloid β. This work serves as a platform for the identification of new potential anti-inflammatory agents for the treatment of Alzheimer's disease.

  14. Triterpenoids as potential agents for the chemoprevention and therapy of breast cancer

    PubMed Central

    Bishayee, Anupam; Ahmed, Shamima; Brankov, Nikoleta; Perloff, Marjorie

    2010-01-01

    Breast cancer remains a major cause of death in the United States as well as the rest of the world. In view of the limited treatment options for patients with advanced breast cancer, preventive and novel therapeutic approaches play an important role in combating this disease. The plant-derived triterpenoids, commonly used for medicinal purposes in many Asian countries, posses various pharmacological properties. A large number of triterpenoids are known to exhibit cytotoxicity against a variety of tumor cells as well as anticancer efficacy in preclinical animal models. Numerous triterpenoids have been synthesized by structural modification of natural compounds. Some of these analogs are considered to be the most potent antiinflammatory and anticarcinogenic triterpenoids known. This review examines the potential role of natural triterpenoids and their derivatives in the chemoprevention and treatment of mammary tumors. Both in vitro and in vivo effects of these agents and related molecular mechanisms are presented. Potential challenges and future directions involved in the advancement of these promising compounds in the prevention and therapy of human breast cancer are also identified. PMID:21196213

  15. Screening for potential anti-infective agents towards Burkholderia pseudomallei infection

    NASA Astrophysics Data System (ADS)

    Eng, Su Anne; Nathan, Sheila

    2014-09-01

    The established treatment for melioidosis is antibiotic therapy. However, a constant threat to this form of treatment is resistance development of the causative agent, Burkholderia pseudomallei, towards antibiotics. One option to circumvent this threat of antibiotic resistance is to search for new alternative anti-infectives which target the host innate immune system and/or bacterial virulence. In this study, 29 synthetic compounds were evaluated for their potential to increase the lifespan of an infected host. The nematode Caenorhabditis elegans was adopted as the infection model as its innate immune pathways are homologous to humans. Screens were performed in a liquid-based survival assay containing infected worms exposed to individual compounds and survival of untreated and compound-treated worms were compared. A primary screen identified nine synthetic compounds that extended the lifespan of B. pseudomallei-infected worms. Subsequently, a disc diffusion test was performed on these selected compounds to delineate compounds into those that enhanced the survival of worms via antimicrobial activity i.e. reducing the number of infecting bacteria, or into those that did not target pathogen viability. Out of the nine hits selected, two demonstrated antimicrobial effects on B. pseudomallei. Therefore, the findings from this study suggest that the other seven identified compounds are potential anti-infectives which could protect a host against B. pseudomallei infection without developing the risk of drug resistance.

  16. Epidermal growth factor (EGF) as a potential targeting agent for delivery of boron to malignant gliomas

    SciTech Connect

    Capala, J.; Barth, R.F.; Adams, D.M.; Bailey, M.Q.; Soloway, A.H.; Carlsson, J.

    1994-12-31

    The majority of high grade gliomas express an amplified epidermal growth factor receptor (EGFR) gene, and this often is associated with an increase in cell surface receptor expression. The rapid internalization and degradation of EGF-EGFR complexes, as well as their high affinity make EGF a potential targeting agent for delivery of {sup 10}B to tumor cells with an amplified number of EGFR. Human glioma cells can expresses as many as 10{sup 5} {minus}10{sup 6} EGF receptors per cell, and if these could be saturated with boronated EGF, then > 10{sup 8} boron atoms would be delivered per cell. Since EGF has a comparatively low molecular weight ({approximately} 6 kD), this has allowed us to construct relatively small bioconjugates containing {approximately} 900 boron atoms per EGF molecule{sup 3}, which also had high affinity for EGFR on tumor cells. In the present study, the feasibility of using EGF receptors as a potential target for therapy of gliomas was investigated by in vivo scintigraphic studies using {sup 131}I{minus} or {sup 99m}{Tc}-labeled EGF in a rat brain tumor model. Our results indicate that intratumorally delivered boron- EGF conjugates might be useful for targeting EGFR on glioma cells if the boron containing moiety of the conjugates persisted intracellularly. Further studies are required, however, to determine if this approach can be used for BNCT of the rat glioma.

  17. Gancidin W, a potential low-toxicity antimalarial agent isolated from an endophytic Streptomyces SUK10.

    PubMed

    Zin, Noraziah Mohamad; Baba, Mohd Shukri; Zainal-Abidin, Abu Hassan; Latip, Jalifah; Mazlan, Noor Wini; Edrada-Ebel, RuAngelie

    2017-01-01

    Endophytic Streptomyces strains are potential sources for novel bioactive molecules. In this study, the diketopiperazine gancidin W (GW) was isolated from the endophytic actinobacterial genus Streptomyces, SUK10, obtained from the bark of Shorea ovalis tree, and it was tested in vivo against Plasmodium berghei PZZ1/100. GW exhibited an inhibition rate of nearly 80% at 6.25 and 3.125 μg kg(-1) body weight on day four using the 4-day suppression test method on male ICR strain mice. Comparing GW at both concentrations with quinine hydrochloride and normal saline as positive and negative controls, respectively, 50% of the mice treated with 3.125 μg kg(-1) body weight managed to survive for more than 11 months after infection, which almost reached the life span of normal mice. Biochemical tests of selected enzymes and proteins in blood samples of mice treated with GW were also within normal levels; in addition, no abnormalities or injuries were found on internal vital organs. These findings indicated that this isolated bioactive compound from Streptomyces SUK10 exhibits very low toxicity and is a good candidate for potential use as an antimalarial agent in an animal model.

  18. STATINS MORE THAN CHOLESTEROL LOWERING AGENTS IN ALZHEIMER DISEASE: THEIR PLEIOTROPIC FUNCTIONS AS POTENTIAL THERAPEUTIC TARGETS

    PubMed Central

    Barone, Eugenio; Domenico, Fabio Di; Butterfield, D. Allan

    2013-01-01

    Alzheimer disease (AD) is a progressive neurodegenerative disorder characterized by severe cognitive impairment, inability to perform activities of daily living and mood changes. Statins, long known to be beneficial in conditions where dyslipidemia occurs by lowering serum cholesterol levels, also have been proposed for use in neurodegenerative conditions, including AD. However, it is not clear that the purported effectiveness of statins in neurodegenerative disorders is directly related to cholesterol-lowering effects of these agents; rather, the pleiotropic functions of statins likely play critical roles. The aim of this review is to provide an overview on the new discoveries about the effects of statin therapy on the oxidative ad nitrosative stress levels as well as on the modulation of the heme oxygenase/biliverdin reductase (HO/BVR) system in the brain. We propose a novel mechanism of action for atorvastatin which, through the activation of HO/BVR-A system, may contribute to the neuroprotective effects thus suggesting a potential therapeutic role in AD and potentially accounting for the observation of decreased AD incidence with persons on statin. PMID:24231510

  19. Discovery of a Phosphodiesterase 9A Inhibitor as a Potential Hypoglycemic Agent

    PubMed Central

    2015-01-01

    Phosphodiesterase 9 (PDE9) inhibitors have been studied as potential therapeutics for treatment of diabetes and Alzheimer’s disease. Here we report a potent PDE9 inhibitor 3r that has an IC50 of 0.6 nM and >150-fold selectivity over other PDEs. The HepG2 cell-based assay shows that 3r inhibits the mRNA expression of phosphoenolpyruvate carboxykinase and glucose 6-phosphatase. These activities of 3r, together with the reasonable pharmacokinetic properties and no acute toxicity at 1200 mg/kg dosage, suggest its potential as a hypoglycemic agent. The crystal structure of PDE9-3r reveals significantly different conformation and hydrogen bonding pattern of 3r from those of previously published 28s. Both 3r and 28s form a hydrogen bond with Tyr424, a unique PDE9 residue (except for PDE8), but 3r shows an additional hydrogen bond with Ala452. This structure information might be useful for design of PDE9 inhibitors. PMID:25432025

  20. Statins more than cholesterol lowering agents in Alzheimer disease: their pleiotropic functions as potential therapeutic targets.

    PubMed

    Barone, Eugenio; Di Domenico, Fabio; Butterfield, D Allan

    2014-04-15

    Alzheimer disease (AD) is a progressive neurodegenerative disorder characterized by severe cognitive impairment, inability to perform activities of daily living and mood changes. Statins, long known to be beneficial in conditions where dyslipidemia occurs by lowering serum cholesterol levels, also have been proposed for use in neurodegenerative conditions, including AD. However, it is not clear that the purported effectiveness of statins in neurodegenerative disorders is directly related to cholesterol-lowering effects of these agents; rather, the pleiotropic functions of statins likely play critical roles. The aim of this review is to provide an overview on the new discoveries about the effects of statin therapy on the oxidative and nitrosative stress levels as well as on the modulation of the heme oxygenase/biliverdin reductase (HO/BVR) system in the brain. We propose a novel mechanism of action for atorvastatin which, through the activation of HO/BVR-A system, may contribute to the neuroprotective effects thus suggesting a potential therapeutic role in AD and potentially accounting for the observation of decreased AD incidence with persons on statin. Copyright © 2013 Elsevier Inc. All rights reserved.

  1. Genomic identification of potential targets unique to Candida albicans for the discovery of antifungal agents.

    PubMed

    Tripathi, Himanshu; Luqman, Suaib; Meena, Abha; Khan, Feroz

    2014-01-01

    Despite of modern antifungal therapy, the mortality rates of invasive infection with human fungal pathogen Candida albicans are up to 40%. Studies suggest that drug resistance in the three most common species of human fungal pathogens viz., C. albicans, Aspergillus fumigatus (causing mortality rate up to 90%) and Cryptococcus neoformans (causing mortality rate up to 70%) is due to mutations in the target enzymes or high expression of drug transporter genes. Drug resistance in human fungal pathogens has led to an imperative need for the identification of new targets unique to fungal pathogens. In the present study, we have used a comparative genomics approach to find out potential target proteins unique to C. albicans, an opportunistic fungus responsible for severe infection in immune-compromised human. Interestingly, many target proteins of existing antifungal agents showed orthologs in human cells. To identify unique proteins, we have compared proteome of C. albicans [SC5314] i.e., 14,633 total proteins retrieved from the RefSeq database of NCBI, USA with proteome of human and non-pathogenic yeast Saccharomyces cerevisiae. Results showed that 4,568 proteins were identified unique to C. albicans as compared to those of human and later when these unique proteins were compared with S. cerevisiae proteome, finally 2,161 proteins were identified as unique proteins and after removing repeats total 1,618 unique proteins (42 functionally known, 1,566 hypothetical and 10 unknown) were selected as potential antifungal drug targets unique to C. albicans.

  2. Rapid, Potentially Automatable, Method Extract Biomarkers for HPLC/ESI/MS/MS to Detect and Identify BW Agents

    DTIC Science & Technology

    1997-11-01

    status can sometimes be reflected in the infectious potential or drug resistance of those pathogens. For example, in Mycobacterium tuberculosis ... Mycobacterium tuberculosis , its antibiotic resistance and prediction of pathogenicity amongst Mycobacterium spp. based on signature lipid biomarkers ...TITLE AND SUBTITLE Rapid, Potentially Automatable, Method Extract Biomarkers for HPLC/ESI/MS/MS to Detect and Identify BW Agents 5a. CONTRACT NUMBER 5b

  3. Dimethyl sulfoxide (DMSO) as a potential contrast agent for brain tumors.

    PubMed

    Delgado-Goñi, T; Martín-Sitjar, J; Simões, R V; Acosta, M; Lope-Piedrafita, S; Arús, C

    2013-02-01

    Dimethyl sulfoxide (DMSO) is commonly used in preclinical studies of animal models of high-grade glioma as a solvent for chemotherapeutic agents. A strong DMSO signal was detected by single-voxel MRS in the brain of three C57BL/6 control mice during a pilot study of DMSO tolerance after intragastric administration. This led us to investigate the accumulation and wash-out kinetics of DMSO in both normal brain parenchyma (n=3 control mice) by single-voxel MRS, and in 12 GL261 glioblastomas (GBMs) by single-voxel MRS (n=3) and MRSI (n=9). DMSO accumulated differently in each tissue type, reaching its highest concentration in tumors: 6.18 ± 0.85 µmol/g water, 1.5-fold higher than in control mouse brain (p<0.05). A faster wash-out was detected in normal brain parenchyma with respect to GBM tissue: half-lives of 2.06 ± 0.58 and 4.57 ± 1.15 h, respectively. MRSI maps of time-course DMSO changes revealed clear hotspots of differential spatial accumulation in GL261 tumors. Additional MRSI studies with four mice bearing oligodendrogliomas (ODs) revealed similar results as in GBM tumors. The lack of T(1) contrast enhancement post-gadolinium (gadopentetate dimeglumine, Gd-DTPA) in control mouse brain and mice with ODs suggested that DMSO was fully able to cross the intact blood-brain barrier in both normal brain parenchyma and in low-grade tumors. Our results indicate a potential role for DMSO as a contrast agent for brain tumor detection, even in those tumors 'invisible' to standard gadolinium-enhanced MRI, and possibly for monitoring heterogeneities associated with progression or with therapeutic response.

  4. Synthesis and biological evaluation of 2-alkoxycarbonylallyl esters as potential anticancer agents.

    PubMed

    Ronayne, Conor T; Solano, Lucas N; Nelson, Grady L; Lueth, Erica A; Hubbard, Skyler L; Schumacher, Tanner J; Gardner, Zachary S; Jonnalagadda, Sravan K; Gurrapu, Shirisha; Holy, Jon; Mereddy, Venkatram R

    2017-02-15

    The reaction of carboxylic acids with Baylis-Hillman reaction derived α-bromomethyl acrylic esters readily provide 2-(alkoxycarbonyl)allyl esters in good to excellent yields. These functionalized allyl esters have been evaluated for their cell proliferation inhibition properties against breast cancer (MDA-MB-231 and 4T1) and pancreatic cancer (MIAPaCa-2) cell lines to explore their potential as anticancer agents. Several of the synthesized derivatives exhibit good potency against all three cancer cell lines. Our structure activity relationship (SAR) studies on 2-carboxycarbonyl allyl esters indicate that substituted aromatic carboxylic acids provide enhanced activity compared to substituted aliphatic carboxylic acid analogs. Di- and tri-allyl esters derived from di-and tri-carboxylic acids exhibit higher inhibition of cell proliferation than mono esters. Further SAR studies indicate that the double bond in the 2-(alkoxycarbonyl)allyl ester is required for its activity, and there is no increase in activity with increased chain length of the alkoxy group. Two lead candidate compounds have been identified from the cell proliferation inhibition studies and their preliminary mechanism of action as DNA damaging agents has been evaluated using epifluorescence and western blot analysis. One of the lead compounds has been further evaluated for its systemic toxicity in healthy CD-1 mice followed by anticancer efficacy in a triple negative breast cancer MDA-MB-231 xenograft model in NOD-SCID mice. These two in vivo studies indicate that the lead compound is well tolerated in healthy CD-1 mice and exhibits good tumor growth inhibition compared to breast cancer drug doxorubicin. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. The potential for substance P antagonists as anti-cancer agents in brain tumours.

    PubMed

    Harford-Wright, Elizabeth; Lewis, Kate M; Vink, Robert

    2013-04-01

    Despite recent advances in cancer treatment and diagnosis, the prognosis for patients with CNS tumours remains extremely poor. This is, in part, due to the difficulty in completely removing tumours surgically, and also because of the presence of the blood brain barrier, which can prevent the entry of chemotherapeutic agents typically used in cancer treatment. Despite the presence of the blood brain barrier, tumour cells are capable of entering and colonising the brain to form secondary brain tumours. Additionally, tumour related disruption of the blood brain barrier is associated with the clinical presentation of many patients, with accompanying increases in intracranial pressure due, in part, to the development of vasogenic oedema. Vasogenic oedema results because the newly formed angiogenic vessels within brain tumours do not retain the highly selective properties of the blood brain barrier, and thus allow for the extravasation of plasma proteins and water into the brain parenchyma. Tachykinins, and in particular substance P, have been implicated in blood brain barrier disruption and the genesis of cerebral oedema in other CNS insults via a process known as neurogenic inflammation. Recent evidence suggests that substance P may play a similar role in CNS tumours. It has been well established that an upregulation of substance P and its receptors occurs in a number of different cancer types, including CNS neoplasms. In addition to disrupting blood brain barrier permeability, substance P and the NK1 receptors facilitate promotion of tumour growth and the development of cerebral oedema. Accordingly, recent patents describe the potential of NK1 receptor antagonists as anti-cancer agents suggesting that substance P may provide a novel cancer treatment target. This review will examine the role of substance P in the development of CNS tumours.

  6. Natural potential therapeutic agents of neurodegenerative diseases from the traditional herbal medicine Chinese dragon's blood.

    PubMed

    Li, Ning; Ma, Zhongjun; Li, Mujie; Xing, Yachao; Hou, Yue

    2014-03-28

    Dragon's blood has been used as a famous traditional medicine since ancient times by many cultures. It is a deep red resin, obtained from more than 20 different species of four distinct genera. Red resin of Dracaena cochinchinensis S.C. Chen, known as Chinese dragon's blood or Yunnan dragon's blood, has been shown to promote blood circulation, alleviate inflammation, and to treat stomach ulcers, diarrhea, diabetes, and bleeding. This study investigated an effective approach to identify natural therapeutic agents for neurodegeneration from herbal medicine. The dichloride extract and isolated effective constituents of Chinese dragon's blood showed quinone oxidoreductase 1 (NQO1) inducing activity and anti-inflammatory effect significantly, which are therapy targets of various neurodegenerative diseases. Multiple chromatography and spectra analysis were utilized to afford effective constituents. Then Hepa 1c1c7 and BV-2 cells were employed to assay their NQO1 inducing and anti-inflammatory activities, respectively. Bioactivities guided isolation afforded 21 effective constituents, including two new polymers cochinchinenene E (1), cochinchinenene F (2) and a new steroid dracaenol C (16). The main constituent 3 (weight percent 0.2%), 5 (weight percent 0.017%), 4 (weight percent 0.009%), 9 (weight percent 0.094%), 10 (weight percent 0.017%) and 8 (weight percent 0.006%) are responsible for the anti-inflammatory activities of Chinese dragon's blood. While, new compounds 1, 2 and known compounds 5, 11 showed good NQO1 inducing activities. The brief feature of the activities and structures was discussed accordingly. Overviewing the bioactivities and phytochemical study result, 4'-hydroxy-2,4-dimethoxydihydrochalcone (3) and pterostilbene (5) as effective constituents of Chinese dragon's blood, were found to be potential candidate therapeutic agents for neurodegenerative diseases. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  7. N-Acetylcysteine as a Potential Antidote and Biomonitoring Agent of Methylmercury Exposure

    PubMed Central

    Aremu, David A.; Madejczyk, Michael S.; Ballatori, Nazzareno

    2008-01-01

    Background Many people, by means of consumption of seafood or other anthropogenic sources, are exposed to levels of methylmercury (MeHg) that are generally considered to be quite low, but that may nevertheless produce irreversible brain damage, particularly in unborn babies. The only way to prevent or ameliorate MeHg toxicity is to enhance its elimination from the body. Objectives Using N-acetylcysteine (NAC), we aimed to devise a monitoring protocol for early detection of acute exposure or relatively low MeHg levels in a rodent model, and to test whether NAC reduces MeHg levels in the developing embryo. Results NAC produced a transient, dose-dependent acceleration of urinary MeHg excretion in rats of both sexes. Approximately 5% of various MeHg doses was excreted in urine 2 hr after injection of 1 mmol/kg NAC. In pregnant rats, NAC markedly reduced the body burden of MeHg, particularly in target tissues such as brain, placenta, and fetus. In contrast, NAC had no significant effect on urinary MeHg excretion in preweanling rats. Conclusions Because NAC causes a transient increase in urinary excretion of MeHg that is proportional to the body burden, it is promising as a biomonitoring agent for MeHg in adult animals. In view of this and because NAC is effective at enhancing MeHg excretion when given either orally or intravenously, can decrease brain and fetal levels of MeHg, has minimal side effects, and is widely available in clinical settings, NAC should be evaluated as a potential antidote and biomonitoring agent in humans. PMID:18197295

  8. Foaming Betadine Spray as a potential agent for non-labor-intensive preoperative surgical site preparation.

    PubMed

    Kargupta, Roli; Hull, Garret J; Rood, Kyle D; Galloway, James; Matthews, Clinton F; Dale, Paul S; Sengupta, Shramik

    2015-04-02

    could potentially serve as a non-labor intensive antimicrobial agent for surgical site preparation.

  9. Induction of Lambda-Bacteriophage in Escherichia coli as a Screening Test for Potential Antitumor Agents1

    PubMed Central

    Heinemann, Bernard; Howard, Alma J.

    1964-01-01

    A simple, rapid, quantitative test procedure to measure induction of phage production in lysogenic Escherichia coli K-12 (λ) was described. This test was used in a study of 209 substances, including antibiotics, pyrimirines, purines, alkylating agents, thiols, amino acids, vitamins, and miscellaneous compounds. Minimal inducing concentrations for the 26 (12.5% of total tested) substances found to be effective inducing agents, as well as a listing of the inactive compounds, are presented. Since 21 of the 26 active agents reportedly have antineoplastic activity in rodent tumor systems, it was concluded that the induction test may provide a useful screen for the detection of potentially useful antitumor compounds. PMID:14170962

  10. Polyol synthesis, functionalisation, and biocompatibility studies of superparamagnetic iron oxide nanoparticles as potential MRI contrast agents

    NASA Astrophysics Data System (ADS)

    Hachani, Roxanne; Lowdell, Mark; Birchall, Martin; Hervault, Aziliz; Mertz, Damien; Begin-Colin, Sylvie; Thanh, Nguy&Ecirtil; N. Thi&Cmb. B. Dot; Kim

    2016-02-01

    Iron oxide nanoparticles (IONPs) of low polydispersity were obtained through a simple polyol synthesis in high pressure and high temperature conditions. The control of the size and morphology of the nanoparticles was studied by varying the solvent used, the amount of iron precursor and the reaction time. Compared with conventional synthesis methods such as thermal decomposition or co-precipitation, this process yields nanoparticles with a narrow particle size distribution in a simple, reproducible and cost effective manner without the need for an inert atmosphere. For example, IONPs with a diameter of ca. 8 nm could be made in a reproducible manner and with good crystallinity as evidenced by X-ray diffraction analysis and high saturation magnetization value (84.5 emu g-1). The surface of the IONPs could be tailored post synthesis with two different ligands which provided functionality and stability in water and phosphate buffer saline (PBS). Their potential as a magnetic resonance imaging (MRI) contrast agent was confirmed as they exhibited high r1 and r2 relaxivities of 7.95 mM-1 s-1 and 185.58 mM-1 s-1 respectively at 1.4 T. Biocompatibility and viability of IONPs in primary human mesenchymal stem cells (hMSCs) was studied and confirmed.Iron oxide nanoparticles (IONPs) of low polydispersity were obtained through a simple polyol synthesis in high pressure and high temperature conditions. The control of the size and morphology of the nanoparticles was studied by varying the solvent used, the amount of iron precursor and the reaction time. Compared with conventional synthesis methods such as thermal decomposition or co-precipitation, this process yields nanoparticles with a narrow particle size distribution in a simple, reproducible and cost effective manner without the need for an inert atmosphere. For example, IONPs with a diameter of ca. 8 nm could be made in a reproducible manner and with good crystallinity as evidenced by X-ray diffraction analysis and high

  11. Synthesis and evaluation of 18F labeled alanine derivatives as potential tumor imaging agents

    PubMed Central

    Wang, Limin; Zha, Zhihao; Qu, Wenchao; Qiao, Hongwen; Lieberman, Brian P.; Plössl, Karl; Kung, Hank F.

    2012-01-01

    Introduction This paper reports the synthesis and labeling of 18F alanine derivatives. We also investigate their biological characteristics as potential tumor imaging agents mediated by alanine-serine-cysteine preferring (ASC) transporter system. Methods Three new 18F alanine derivatives were prepared from corresponding tosylate-precursors through a two-step labelling reaction. In vitro uptake studies to evaluate and to compare these three analogs were carried out in 9L glioma and PC-3 prostate cancer cell lines. Potential transport mechanisms, protein incorporation and stability of 3-(1-[18F]fluoromethyl)-L-alanine (L[18F]FMA) were investigated in 9L glioma cells. Its biodistribution was determined in a rat-bearing 9L tumor model. PET imaging studies were performed on rat bearing 9L glioma tumors and transgenic mouse carrying spontaneous generated M/tomND tumor (mammary gland adenocarcinoma). Results New 18F alanine derivatives were prepared with 7–34% uncorrected radiochemical yields, excellent enantiomeric purity (>99%) and good radiochemical purity (>99%). In vitro uptake of the L-[18F]FMA in 9L glioma and PC-3 prostate cancer cells was higher than those observed for other two alanine derivatives and [18F]FDG in first 1 h. Inhibition of cell uptake studies suggested that L-[18F]FMA uptake in 9L glioma was predominantly via transport system ASC. After entering into cells, L-[18F]FMA remained stable and was not incorporated into protein within 2 h. In vivo biodistribution studies demonstrated that L-[18F]FMA had relatively high uptake in liver and kidney. Tumor uptake was fast, reaching a maximum within 30 min. The tumor-to-muscle, tumor-to-blood and tumor-to-brain ratios at 60 min post injection were 2.2, 1.9 and 3.0, respectively. In PET imaging studies, tumors were visualized with L-[18F]FMA in both 9L rat and transgenic mouse. Conclusion L-[18F]FMA showed promising properties as a PET imaging agent for up-regulated ASC transporter associated with tumor

  12. The potential value and toxicity of chromium picolinate as a nutritional supplement, weight loss agent and muscle development agent.

    PubMed

    Vincent, John B

    2003-01-01

    The element chromium apparently has a role in maintaining proper carbohydrate and lipid metabolism in mammals. As this role probably involves potentiation of insulin signalling, chromium dietary supplementation has been postulated to potentially have effects on body composition, including reducing fat mass and increasing lean body mass. Because the supplement is absorbed better than dietary chromium, most studies have focused on the use of chromium picolinate [Cr(pic)(3)]. Cr(pic)(3) has been amazingly popular with the general public, especially with athletes who may have exercise-induced increased urinary chromium loss; however, its effectiveness in manifesting body composition changes has been an area of intense debate in the last decade. Additionally, claims have appeared that the supplement might give rise to deleterious effects. However, over a decade of human studies with Cr(pic)(3) indicate that the supplement has not demonstrated effects on the body composition of healthy individuals, even when taken in combination with an exercise training programme. Recent cell culture and in vivo rat studies have indicated that Cr(pic)(3) probably generates oxidative damage of DNA and lipids and is mutagenic, although the significance of these results on humans taking the supplement for prolonged periods of time is unknown and should be a focus for future investigations. Given that in vitro studies suggest that other forms of chromium used as nutritional supplements, such as chromium chloride, are unlikely to be susceptible to generating this type of oxidative damage, the use of these compounds, rather than Cr(pic)(3), would appear warranted. Potential neurological effects (both beneficial and deleterious) from Cr(pic)(3) supplementation require further study.

  13. Expanding the potential of MRI contrast agents through multifunctional polymeric nanocarriers.

    PubMed

    Craciun, Ioana; Gunkel-Grabole, Gesine; Belluati, Andrea; Palivan, Cornelia G; Meier, Wolfgang

    2017-04-01

    MRI is a sought-after, noninvasive tool in medical diagnostics, yet the direct application of contrast agents to tissue suffers from several drawbacks. Hosting the contrast agents in polymeric nanocarriers can solve many of these issues while creating additional benefit through exploitation of the intrinsic characteristics of the polymeric carriers. In this report, the versatility is highlighted with recent examples of dendritic and hyperbranched polymers, polymer nanoparticles and micelles, and polymersomes as multifunctional bioresponsive nanocarriers for MRI contrast agents.

  14. The acquisition of dangerous biological materials: Technical facts sheets to assist risk assessments of 46 potential BW agents

    SciTech Connect

    Aceto, Donato Gonzalo; Astuto-Gribble, Lisa M.; Gaudioso, Jennifer M.

    2007-11-01

    Numerous terrorist organizations have openly expressed interest in producing and deploying biological weapons. However, a limiting factor for many terrorists has been the acquisition of dangerous biological agents, as evidenced by the very few successful instances of biological weapons use compared to the number of documented hoaxes. Biological agents vary greatly in their ability to cause loss of life and economic damage. Some agents, if released properly, can kill many people and cause an extensive number of secondary infections; other agents will sicken only a small number of people for a short period of time. Consequently, several biological agents can potentially be used to perpetrate a bioterrorism attack but few are likely capable of causing a high consequence event. It is crucial, from a US national security perspective, to more deeply understand the likelihood that terrorist organizations can acquire the range of these agents. Few studies have attempted to comprehensively compile the technical information directly relevant to the acquisition of dangerous bacteria, viruses and toxins. In this report, technical fact sheets were assembled for 46 potentially dangerous biological agents. Much of the information was taken from various research sources which could ultimately and significantly expedite and improve bioterrorism threat assessments. By systematically examining a number of specific agent characteristics included in these fact sheets, it may be possible to detect, target, and implement measures to thwart future terrorist acquisition attempts. In addition, the information in these fact sheets may be used as a tool to help laboratories gain a rudimentary understanding of how attractive a method laboratory theft is relative to other potential acquisition modes.

  15. Novel Azasterols as Potential Agents for Treatment of Leishmaniasis and Trypanosomiasis

    PubMed Central

    Lorente, Silvia Orenes; Rodrigues, Juliany C. F.; Jiménez, Carmen Jiménez; Joyce-Menekse, Miranda; Rodrigues, Carlos; Croft, Simon L.; Yardley, Vanessa; de Luca-Fradley, Kate; Ruiz-Pérez, Luis M.; Urbina, Julio; de Souza, Wanderley; Pacanowska, Dolores González; Gilbert, Ian H.

    2004-01-01

    This paper describes the design and evaluation of novel azasterols as potential compounds for the treatment of leishmaniasis and other diseases caused by trypanosomatid parasites. Azasterols are a known class of (S)-adenosyl-l-methionine: Δ24-sterol methyltransferase(24-SMT) inhibitors in fungi, plants, and some parasitic protozoa. The compounds prepared showed activity at micromolar and nanomolar concentrations when tested against Leishmania spp. and Trypanosoma spp. The enzymatic and sterol composition studies indicated that the most active compounds acted by inhibiting 24-SMT. The role of the free hydroxyl group at position 3 of the sterol nucleus was also probed. When an acetate was attached to the 3β-OH, the compounds did not inhibit the enzyme but had an effect on parasite growth and the levels of sterols in the parasite, suggesting that the acetate group was removed in the organism. Thus, an acetate group on the 3β-OH may have application as a prodrug. However, there may be an additional mode(s) of action for these acetate derivatives. These compounds were shown to have ultrastructural effects on Leishmania amazonensis promastigote membranes, including the plasma membrane, the mitochondrial membrane, and the endoplasmic reticulum. The compounds were also found to be active against the bloodstream form (trypomastigotes) of Trypanosoma brucei rhodesiense, a causative agent of African trypanosomiasis. PMID:15273104

  16. New multifunctional ligands for potential use in the design therapeutic or diagnostic radiopharmaceutical imaging agents

    DOEpatents

    Katti, K.V.; Volkert, W.A.; Ketring, A.R.; Singh, P.R.

    1997-02-11

    A class of diagnostic and therapeutic compounds are derived from phosphinimines that include ligands containing either a single phosphinimine functionality or both a phosphinimine group and a phosphine or arsine group, or an aminato group, or a second phosphinimine moiety. These phosphinimine ligands are complexed to early transition metal radionuclides (e.g., {sup 99m}Tc or {sup 186}Re/{sup 188}Re) or late transition metals (e.g., {sup 105}Rh or {sup 109}Pd). The complexes with these metals {sup 186}Re/{sup 188}Re, {sup 99m}Tc and {sup 109}Pd exhibit a high in vitro and high in vivo stability. The complexes are formed in high yields and can be neutral or charged. These ligands can also be used to form stable compounds with paramagnetic transition metals (e.g., Fe and Mn) for potential use as MRI contrast agents. Applications for the use of ligands and making the ligands are also disclosed.

  17. Scaffold Hopping Toward Agomelatine: Novel 3, 4-Dihydroisoquinoline Compounds as Potential Antidepressant Agents

    NASA Astrophysics Data System (ADS)

    Yang, Yang; Ang, Wei; Long, Haiyue; Chang, Ying; Li, Zicheng; Zhou, Liangxue; Yang, Tao; Deng, Yong; Luo, Youfu

    2016-10-01

    A scaffold-hopping strategy toward Agomelatine based on in silico screening and knowledge analysis was employed to design novel antidepressant agents. A series of 3, 4-dihydroisoquinoline compounds were selected for chemical synthesis and biological assessment. Three compounds (6a-1, 6a-2, 6a-9) demonstrated protective effects on corticosterone-induced lesion of PC12 cells. Compound 6a-1 also displayed low inhibitory effects on the growth of HEK293 and L02 normal cells and it was further evaluated for its potential antidepressant effects in vivo. The forced swim test (FST) results revealed that compound 6a-1 remarkably reduced the immobility time of rats and the open field test (OFT) results indicated a better general locomotor activity of the rats treated with compound 6a-1 than those with Agomelatine or Fluoxetine. Mechanism studies implied that compound 6a-1 can significantly reduce PC12 cell apoptosis by up-regulation of GSH and down-regulation of ROS in corticosterone-induced lesion of PC12 cells. Meanwhile, the down-regulation of calcium ion concentration and up-regulation of BDNF level in PC12 cells may account for the neuroprotective effects. Furthermore, compound 6a-1 can increase cell survival and cell proliferation, promote cell maturation in the rat hippocampus after chronic treatment. The acute toxicity data in vivo indicated compound 6a-1 exhibited less hepatotoxicity than Agomelatine.

  18. Cyclooxygenase‐2 facilitates dengue virus replication and serves as a potential target for developing antiviral agents

    PubMed Central

    Lin, Chun-Kuang; Tseng, Chin-Kai; Wu, Yu-Hsuan; Liaw, Chih-Chuang; Lin, Chun-Yu; Huang, Chung-Hao; Chen, Yen-Hsu; Lee, Jin-Ching

    2017-01-01

    Cyclooxygenase-2 (COX-2) is one of the important mediators of inflammation in response to viral infection, and it contributes to viral replication, for example, cytomegalovirus or hepatitis C virus replication. The role of COX-2 in dengue virus (DENV) replication remains unclear. In the present study, we observed an increased level of COX-2 in patients with dengue fever compared with healthy donors. Consistent with the clinical data, an elevated level of COX-2 expression was also observed in DENV-infected ICR suckling mice. Using cell-based experiments, we revealed that DENV-2 infection significantly induced COX-2 expression and prostaglandin E2 (PGE2) production in human hepatoma Huh-7 cells. The exogenous expression of COX-2 or PGE2 treatment dose-dependently enhanced DENV-2 replication. In contrast, COX-2 gene silencing and catalytic inhibition sufficiently suppressed DENV-2 replication. In an ICR suckling mouse model, we identified that the COX-2 inhibitor NS398 protected mice from succumbing to life-threatening DENV-2 infection. By using COX-2 promoter-based analysis and specific inhibitors against signaling molecules, we identified that NF-κB and MAPK/JNK are critical factors for DENV-2-induced COX-2 expression and viral replication. Altogether, our results reveal that COX-2 is an important factor for DENV replication and can serve as a potential target for developing therapeutic agents against DENV infection. PMID:28317866

  19. Evaluation of atoxigenic isolates of Aspergillus flavus as potential biocontrol agents for aflatoxin in maize.

    PubMed

    Atehnkeng, J; Ojiambo, P S; Ikotun, T; Sikora, R A; Cotty, P J; Bandyopadhyay, R

    2008-10-01

    Aflatoxin contamination resulting from maize infection by Aspergillus flavus is both an economic and a public health concern. Therefore, strategies for controlling aflatoxin contamination in maize are being investigated. The abilities of eleven naturally occurring atoxigenic isolates in Nigeria to reduce aflatoxin contamination in maize were evaluated in grain competition experiments and in field studies during the 2005 and 2006 growing seasons. Treatments consisted of inoculation of either grains in vials or ears at mid-silking stage in field plots, with the toxigenic isolate (La3228) or atoxigenic isolate alone and co-inoculation of each atoxigenic isolate and La3328. Aflatoxin B(1) + B(2) concentrations were significantly (p < 0.05) lower in the co-inoculation treatments compared with the treatment in which the aflatoxin-producing isolate La3228 was inoculated alone. Relative levels of aflatoxin B(1) + B(2) reduction ranged from 70.1% to 99.9%. Among the atoxigenics, two isolates from Lafia, La3279 and La3303, were most effective at reducing aflatoxin B(1) + B(2) concentrations in both laboratory and field trials. These two isolates have potential value as agents for the biocontrol of aflatoxin contamination in maize. Because these isolates are endemic to West Africa, they are both more likely than introduced isolates to be well adapted to West African environments and to meet regulatory concerns over their use throughout that region.

  20. Evaluation of Se-75 BISTAES as a potential articular cartilage imaging agent

    SciTech Connect

    Yu, S.W.K.

    1987-01-01

    The potential of Se-75 bis (..beta..-N,N,N-trimethylamino)-ethyl) selenide diiodide (Se-75 BISTAES) as an articular cartilage imaging agent for the early diagnosis of osteoarthritis was evaluated. The compound was synthesized and the identity was established. The radiochemical purity and stability were determined initially and over a two-month period of storage at three temperatures. The biodistribution of Se-75 BISTAES in rabbits and guinea pigs was studied. A high concentration of radioactivity was found in the knee and shoulder cartilage. The radioactivity in the cartilage was the highest at 15 minutes to one hour post-injection. In rabbits, the highest ratio of radioactivity in the cartilage to the surrounding tissues was about 30. A minimal ratio of 10 is required for nuclear medicine imaging. Nuclear medicine imaging conducted on rabbits demonstrated increased radioactivity in the articular cartilage in the knee and shoulder. The impression from the nuclear medicine images and the findings of the biodistribution study indicated that the route of excretion of Se-75 BISTAES was the urine. The in vitro binding between Se-75 BISTAES and chondroitin sulfate was determined by an equilibrium dialysis technique.

  1. Probiotics as potential alternative biocontrol agents in the agriculture and food industries: A review.

    PubMed

    Hossain, Md Iqbal; Sadekuzzaman, Mohammad; Ha, Sang-Do

    2017-10-01

    Pathogenic microorganisms are a potential threat to the agriculture and food industries. Food contamination can be happened in the production levels at any point in the chain by pathogenic microorganisms. Conventional methods, such as those involving antibiotics, disinfectants, and physical methods, are commonly used as microbial control strategies. Owing to the limitations of these methods, such as emergence of resistance, low effectiveness, high cost, and detrimental effects on food, health, and the environment, many countries have adopted laws and regulations restricting their use. To overcome these problems, an environmentally friendly, cost-effective alternative approach is urgently needed. Probiotics are live microorganisms that offer health benefits to the host, when consumed in adequate amounts, by providing pathogen protective action and nutritional benefits. From a food microbiological point of view, to use probiotics in animals, there is a reduction of zoonotic pathogens in the gastro-intestinal tract (GIT) among animals which prevent the transmission of these pathogens through food. Therefore, probiotics have been proposed as an alternative antimicrobial means to protect against pathogenic microorganisms for better healthcare and food safety. In this review, we discuss probiotics, their selection criteria, mechanisms of action, and their prospects as alternative biocontrol agents, with special emphasis on the agriculture (livestock and aquaculture sectors), and food industries. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. Indazole-based ligands for estrogen-related receptor α as potential anti-diabetic agents.

    PubMed

    Patch, Raymond J; Huang, Hui; Patel, Sharmila; Cheung, Wing; Xu, Guozhang; Zhao, Bao-Ping; Beauchamp, Derek A; Rentzeperis, Dionisios; Geisler, John G; Askari, Hossein B; Liu, Jianying; Kasturi, Jyotsna; Towers, Meghan; Gaul, Micheal D; Player, Mark R

    2017-09-29

    Estrogen-related receptor α (ERRα) is an orphan nuclear receptor that has been functionally implicated in the regulation of energy homeostasis. Herein is described the development of indazole-based N-alkylthiazolidenediones, which function in biochemical assays as selective inverse agonists against this receptor. Series optimization provided several potent analogues that inhibited the recruitment of a co-activator peptide fragment in vitro (IC50s < 50 nM) and reduced fasted circulating insulin and triglyceride levels in a sub-chronic pre-diabetic rat model when administered orally (10 mg/kg). A multi-parametric optimization strategy led to the identification of 50 as an advanced lead, which was more extensively evaluated in additional diabetic models. Chronic oral administration of 50 in two murine models of obesity and insulin resistance improved glucose control and reduced circulating triglycerides with efficacies similar to that of rosiglitazone. Importantly, these effects were attained without the concomitant weight gain that is typically observed with the latter agent. Thus, these studies provide additional support for the development of such molecules for the potential treatment of metabolic diseases. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  3. Design, synthesis, and biological evaluation of novel quinazolinyl-diaryl urea derivatives as potential anticancer agents.

    PubMed

    Chen, Jia-Nian; Wang, Xian-Fu; Li, Ting; Wu, De-Wen; Fu, Xiao-Bo; Zhang, Guang-Ji; Shen, Xing-Can; Wang, Heng-Shan

    2016-01-01

    Through a structure-based molecular hybridization approach, a series of novel quinazolinyl-diaryl urea derivatives were designed, synthesized, and screened for their in vitro antiproliferative activities against three cancer cell lines (HepG2, MGC-803, and A549). Six compounds (7 g, 7 m, 7 o, 8 e, 8 g, and 8 m) showed stronger activity against a certain cell line compared with the positive reference drugs sorafenib and gefitinib. Among the six compounds, 8 g exhibited the strongest activity. In particular, compound 8 g induced A549 apoptosis, arrested cell cycle at the G0/G1 phase, elevated intracellular reactive oxygen species level, and decreased mitochondrial membrane potential. This compound can also effectively regulate the expression of apoptosis- and cell cycle-related proteins, and influence the Raf/MEK/ERK pathway. Molecular docking and structure-activity relationship analyses revealed that it can bind well to the active site of the receptor c-Raf, which was consistent with the biological data. Therefore, compound 8 g may be a potent antitumor agent, representing a promising lead for further optimization.

  4. N-Substituted piperazinyl quinolones as potential cytotoxic agents: structure-activity relationships study.

    PubMed

    Foroumadi, Alireza; Emami, Saeed; Rajabalian, Saeed; Badinloo, Marziyeh; Mohammadhosseini, Negar; Shafiee, Abbas

    2009-03-01

    As part of a continuing search for new potential anticancer candidates in the piperazinyl quinolone series, the cytotoxicity evaluation of new N-substituted piperazinyl quinolones was of our interest. The growth inhibitory activities of 12 new compounds, namely N-[2-(5-chlorothiophen-2-yl)-2-oxoethyl] and N-[2-(5-chlorothiophen-2-yl)-2-oxyiminoethyl] piperazinyl quinolones 1-12 were determined against six cancer cell lines using MTT colorimetric assay. Preliminary screening showed that most of the new N-[2-(5-chlorothiophen-2-yl)ethyl]piperazinyl quinolones 4-12 containing (un)substituted oxime moiety showed significant cytotoxic activity and the modification of functionality on ethyl spacer produced a relatively minor change of activity. Thus, in the piperazinyl quinolone series, cytotoxic activity can be positively modulated through the introduction of 2-(5-chlorothiophen-2-yl)ethyl residue on the piperazine ring. The results revealed that the introduction of 2-(5-chlorothiophen-2-yl)ethyl moiety on the piperazine ring of quinolone antibacterials (ciprofloxacin, norfloxacin and enoxacin) changes the biological profile of piperazinyl quinolones from antibacterials to cytotoxic agents.

  5. Biology and preliminary host range assessment of two potential kudzu biological control agents.

    PubMed

    Frye, Matthew J; Hough-Goldstein, Judith; Sun, Jiang-Hua

    2007-12-01

    Two insect species from China, Gonioctena tredecimmaculata (Jacoby) (Coleoptera: Chrysomelidae) and Ornatalcides (Mesalcidodes) trifidus (Pascoe) (Coleoptera: Curculionidae), were studied in quarantine in the United States as potential biological control agents for kudzu, Pueraria montana variety lobata (Willd.) Maesen and S. Almeida. Adults of G. tredecimmaculata were ovoviviparous and reproduced throughout the summer, producing offspring that had an obligate adult diapause. In no-choice tests, adult and larval G. tredecimmaculata rejected most of the plant species tested, but consumed foliage and completed their life cycle on soybean (Glycine max L. Merr.) and on a native woodland plant, hog-peanut (Amphicarpaea bracteata L. Fernald), which are in the same subtribe as kudzu (Glycininae). Insects showed similar responses to field- and greenhouse-grown soybean and kudzu foliage, despite measurable differences in leaf traits: field-grown foliage of both plants had greater leaf toughness, higher total carbon content, higher trichome density, and lower water content than greenhouse foliage. O. trifidus adults also rejected most of the plants tested but fed on and severely damaged potted soybean and hog-peanut plants in addition to kudzu. Further tests in China are needed to determine whether these species will accept nontarget host plants under open-field conditions.

  6. The pigment epithelium-derived factor (PEDF): an important potential therapeutic agent for infantile hemangioma.

    PubMed

    Li, Ming; Chen, Yanru; Guo, Zhihui; Xie, Yide; Zhou, Yakuan; Jiang, Chenghong; Chen, Xiaosong

    2017-04-01

    In previous studies, the expression and the role of proangiogenic factors in infantile hemangiomas have been well studied. However, the role of angiogenic inhibitors has been revealed rarely. The expression of PEDF, as the strongest and safe endogenous inhibitor, is still unrecognized until the current study. In order to investigate the expression and significance of the pigment epithelium-derived factor (PEDF) in the proliferating and regressing phases of infantile hemangiomas, the expression of PEDF, VEGF, Ki-67, and CD34 protein in hemangioma tissues was examined with immunohistochemical polymer HRP method in 42 cases during the proliferative phase, 40 cases during the regressing phase, and 11 cases of non-involuting congenital hemangiomas (NICHs). Meanwhile, the mRNA expression of these factors was detected with quantitative realtime RT-PCR. We found the protein and mRNA expression of PEDF in regressing phase was significantly higher than those in proliferative phase and NICHs (P < 0.001), while the protein and mRNA expression of VEGF were much lower (P < 0.001). The microvessel density (MVD), Ki-67 changes, and the expression of PEDF and VEGF were found significantly correlated. These results indicated that the reduction of VEGF and increase in PEDF are causative to the evolution of infantile hemangioma. PEDF may play a key role in the spontaneous regression of infantile hemangioma and may become an important potential therapeutic agent for infantile hemangioma.

  7. Studies on potential biological control agents of immature mosquitoes in sewage wastewater in southern California.

    PubMed

    Mian, L S; Mulla, M S; Wilson, B A

    1986-09-01

    Three biological control agents, a copepod, Mesocyclops leuckarti pilosa, and two fish, Cyprinodon macularius and Poecilia reticulata, were evaluated for their survival in secondary sewage effluent (SSE) and predation potential on mosquito larvae. Results showed that the survival of M. l. pilosa was not significantly affected in SSE or SSE diluted (50%) with water. In predation tests, the copepod consumed from 50 to 90% of the 1st-instar larvae of Culex quinquefasciatus in 24 to 72 hr and P. reticulata fed on almost all stages (egg to pupa) of the test mosquitoes. Survivorship of P. reticulata and C. macularius in SSE was not significantly affected by SSE under both greenhouse and sewage aquaculture conditions. Poecilia reticulata was distributed towards the influent end and C. macularius towards the effluent end of the aquaculture ponds, indicating the former species can tolerate higher levels of pollution which exists at the influent end of the pond. However, low water temperature and dissolved oxygen may be detrimental to these fish species in sewage aquacultural systems.

  8. In vitro characterization of an Fe(8) cluster as potential MRI contrast agent.

    PubMed

    Rodríguez, Elisenda; Roig, Anna; Molins, Elies; Arús, Carles; Quintero, María Rosa; Cabañas, Miquel E; Cerdán, Sebastián; Lopez-Larrubia, Pilar; Sanfeliu, Coral

    2005-08-01

    The complex [(tacn)(6)Fe(8)(micro(3)-O)(2)(micro(2)-OH)(12)]Br(8).9H(2)O (Fe(8)) was evaluated in vitro as a new kind of possible MRI contrast agent. Relaxivities were measured at 1.41 and 9.4 T for Fe(8) and commercial Gd-DTPA dissolved in PBS. There was significant difference for r(1) and r(2) values between Fe(8) and Gd-DTPA at high field (9.4 T) and for r(1) at low field (1.4 T) (p<0.05). Phantom studies with T(1)-weighted MRI at 9.4 T suggest T(1) contrast potential for Fe(8). That is, up to 5.2 times higher intensity enhancement with respect to that of equimolar Gd-DTPA was obtained with an Fe(8) concentration, referred to the whole molecule, of 0.2 mM, for which no toxicity on C6 cells could be detected. No toxic effects on cultured C6 cells were observed up to a concentration of 1 mM Fe(8).

  9. Polyol synthesis, functionalisation, and biocompatibility studies of superparamagnetic iron oxide nanoparticles as potential MRI contrast agents.

    PubMed

    Hachani, Roxanne; Lowdell, Mark; Birchall, Martin; Hervault, Aziliz; Mertz, Damien; Begin-Colin, Sylvie; Thanh, Nguyen Thi Kim

    2016-02-14

    Iron oxide nanoparticles (IONPs) of low polydispersity were obtained through a simple polyol synthesis in high pressure and high temperature conditions. The control of the size and morphology of the nanoparticles was studied by varying the solvent used, the amount of iron precursor and the reaction time. Compared with conventional synthesis methods such as thermal decomposition or co-precipitation, this process yields nanoparticles with a narrow particle size distribution in a simple, reproducible and cost effective manner without the need for an inert atmosphere. For example, IONPs with a diameter of ca. 8 nm could be made in a reproducible manner and with good crystallinity as evidenced by X-ray diffraction analysis and high saturation magnetization value (84.5 emu g(-1)). The surface of the IONPs could be tailored post synthesis with two different ligands which provided functionality and stability in water and phosphate buffer saline (PBS). Their potential as a magnetic resonance imaging (MRI) contrast agent was confirmed as they exhibited high r1 and r2 relaxivities of 7.95 mM(-1) s(-1) and 185.58 mM(-1) s(-1) respectively at 1.4 T. Biocompatibility and viability of IONPs in primary human mesenchymal stem cells (hMSCs) was studied and confirmed.

  10. Design of vanadium mixed-ligand complexes as potential anti-protozoa agents.

    PubMed

    Benítez, Julio; Guggeri, Lucía; Tomaz, Isabel; Arrambide, Gabriel; Navarro, Maribel; Pessoa, João Costa; Garat, Beatriz; Gambino, Dinorah

    2009-04-01

    In the search for new therapeutic tools against Chagas' disease (American Trypanosomiasis) four novel mixed-ligand vanadyl complexes, [V(IV)O(L(2)-2H)(L(1))], including a bidentate polypyridyl DNA intercalator (L(1)) and a tridentate salycylaldehyde semicarbazone derivative (L(2)) as ligands were synthesized, characterized by a combination of techniques, and in vitro evaluated. EPR suggest a distorted octahedral geometry with the tridentate semicarbazone occupying three equatorial positions and the polypyridyl ligand coordinated in an equatorial/axial mode. Both complexes including dipyrido[3,2-a: 2',3'-c]phenazine (dppz) as polypyridyl coligand showed IC(50) values in the muM range against Dm28c strain (epimastigotes) of Trypanosoma cruzi, causative agent of the disease, being as active as the anti-trypanosomal reference drug Nifurtimox. To get an insight into the trypanocidal mechanism of action of these compounds, DNA was evaluated as a potential parasite target and EPR, and (51)V NMR experiments were also carried out upon aging aerated solutions of the complexes. Data obtained by electrophoretic analysis suggest that the mechanism of action of these complexes could include DNA interactions.

  11. Animals living in polluted environments are potential source of antimicrobials against infectious agents

    PubMed Central

    Lee, Simon; Siddiqui, Ruqaiyyah; Khan, Naveed Ahmed

    2012-01-01

    The antimicrobials crisis is a ticking time bomb which could lead to millions of people dying from untreatable infections. With the worsening trends of antimicrobial resistance, we are heading towards a pre-antibiotic era. Thus, there is a need for newer and more powerful antibiotic agents. The search for new antibiotic compounds originating from natural resources is a promising research area. Animals living in germ-infested environments are a potent source of antimicrobials. Under polluted milieus, organisms such as cockroaches encounter different types of bacteria, including superbugs. Such creatures survive the onslaught of superbugs and are able to ward off disease by producing antimicrobial substances which show potent activity in the nervous system. We hope that the discovery of antimicrobial activity in the cockroach brain will stimulate research in finding antimicrobials from unusual sources, and has potential for the development of novel antibiotics. Nevertheless, intensive research in the next few years will be required to approach or realize these expectations. PMID:23265422

  12. Mesocyclops brevisetosus (Cyclopoida: Cyclopoidae) as a potential biological control agent against mosquito larvae in Indonesia.

    PubMed

    Gionar, Yoyo R; Atmosoedjono, Soeroto; Bangs, Michael J

    2006-09-01

    Mesocyclops brevisetosus Dussart and Sarnita, an indigenous copepod in Indonesia, was evaluated as a potentially useful biological control agent against larval Aedes (Stegomyia). In the laboratory, female M. brevisetosus were found to readily consume mosquito larvae of species from 3 genera (Aedes aegypti, Culex quinquefaciatus, and Anopheles farauti). Mesocyclops brevisetosus preferentially fed on larvae of Ae. aegypti (mean 95% consumed), followed by Cx. quinquefasciatus (71%) and An. farauti (54%) during a 24-h period. An individual copepod consumed up to 43 1st and 2nd instars of Ae. aegypti within a 24-h period. In the field, a density of 25 adult copepods/400 ml of water in an artificial container prevented the establishment of Aedes mosquitoes by 98% compared to the control container (without copepods). A density of 50 copepods/400 ml of water completely prevented infestation with Aedes. Over a 12-wk period, evaluation of M. brevisetosus-treated ovitraps reduced Ae. aegypti by 38-100% compared to ovitraps without copepods. The introduced gravid copepods increased 2.5-6.7 times over the original cohort. Mesocyclops brevisetosus showed high fecundity in culture, with a mean of 58 nauplii produced per individual gestation cycle.

  13. Preliminary Evaluation of Animal Bone Char as Potential Metal Stabilization Agent in Metal Contaminated Soil.

    PubMed

    Gruden, Evelin; Bukovec, Peter; Zupančič, Marija

    2017-09-01

    The aim of this study was to evaluate the potential effect of animal bone char (ABC) addition on metal mobility in mine tailings. The mobility of metals after addition of ABC to tailings at four different application rates (0.6 g, 1.2 g, 1.8 g and 3.6 g ABC per 100 g of tailings) was evaluated by Toxicity Characteristic Leaching Procedure (TCLP) one step extraction. The obtained results indicated that the mobility of Pb, Cr and Cd gradually decreased with increasing quantity of added ABC. According to the TCLP, mobile concentrations of Pb in tailings exceeded threshold values for almost eight times. After ABC addition, Pb TCLP-extractable concentrations decreased from 39 mg L-1 in tailings to lower than the TCLP limit values of 5 mg L-1 at all ABC application rates, except in mixtures with the lowest addition of ABC. We concluded that ABC could be a successful metal stabilization agent for multi-metal contaminated soil, although attention should be paid at highly As contaminated soil.

  14. Indium-111-labeled LDL: A potential agent for imaging atherosclerotic disease and lipoprotein biodistribution

    SciTech Connect

    Rosen, J.M.; Butler, S.P.; Meinken, G.E.; Wang, T.S.; Ramakrishnan, R.; Srivastava, S.C.; Alderson, P.O.; Ginsberg, H.N. )

    1990-03-01

    Radiolabeling of low-density lipoprotein (LDL) and external imaging with a gamma camera would offer a means of taking advantage of the metabolic activity of developing atherosclerotic lesions in order to noninvasively detect and determine the extent of atherosclerotic cardiovascular disease. Indium-111-({sup 111}In) labeled LDL was prepared and its purity demonstrated by agarose electrophoresis and ultracentrifugation. In vitro studies with cultured human fibroblasts demonstrated significant inhibition of iodine-125-({sup 125}I) LDL binding to LDL receptors by {sup 111}In-LDL, although this was less than the inhibition produced by unlabeled LDL. Adrenal gland uptake of {sup 111}In-LDL by hypercholesterolemic rabbits was reduced by 86% compared to the level of uptake observed in normal rabbits. These results were compatible with downregulation of adrenal LDL receptors in the hypercholesterolemic rabbits. Uptake of {sup 111}In-LDL in the atherosclerotic proximal aorta of hypercholesterolemic rabbits was 2.5 times higher than in normal rabbits. These results suggest that {sup 111}In-LDL has the potential to be a useful agent for external imaging of atherosclerotic lesions and lipoprotein biodistribution.

  15. Natural flavonoids as potential multifunctional agents in prevention of diabetic cataract

    PubMed Central

    Stefek, Milan

    2011-01-01

    Cataract is one of the earliest secondary complications of diabetes mellitus. The lens is a closed system with limited capability to repair or regenerate itself. Current evidence supports the view that cataractogenesis is a multifactorial process. Mechanisms related to glucose toxicity, namely oxidative stress, processes of non-enzymatic glycation and enhanced polyol pathway significantly contribute to the development of eye lens opacity under conditions of diabetes. There is an urgent need for inexpensive, non-surgical approaches to the treatment of cataract. Recently, considerable attention has been devoted to the search for phytochemical therapeutics. Several pharmacological actions of natural flavonoids may operate in the prevention of cataract since flavonoids are capable of affecting multiple mechanisms or etiological factors responsible for the development of diabetic cataract. In the present paper, natural flavonoids are reviewed as potential agents that could reduce the risk of cataract formation via affecting multiple pathways pertinent to eye lens opacification. In addition, the bioavailability of flavonoids for the lens is considered. PMID:21753902

  16. The preclinical pharmacokinetic disposition of a series of perforin-inhibitors as potential immunosuppressive agents.

    PubMed

    Bull, M R; Spicer, J A; Huttunen, K M; Denny, W A; Ciccone, A; Browne, K A; Trapani, J A; Helsby, N A

    2015-12-01

    The cytolytic protein perforin is a key component of the immune response and is implicated in a number of human pathologies and therapy-induced conditions. A novel series of small molecule inhibitors of perforin function have been developed as potential immunosuppressive agents. The pharmacokinetics and metabolic stability of a series of 16 inhibitors of perforin was evaluated in male CD1 mice following intravenous administration. The compounds were well tolerated 6 h after dosing. After intravenous administration at 5 mg/kg, maximum plasma concentrations ranged from 532 ± 200 to 10,061 ± 12 ng/mL across the series. Plasma concentrations were greater than the concentrations required for in vitro inhibitory activity for 11 of the compounds. Following an initial rapid distribution phase, the elimination half-life values for the series ranged from 0.82 ± 0.25 to 4.38 ± 4.48 h. All compounds in the series were susceptible to oxidative biotransformation. Following incubations with microsomal preparations, a tenfold range in in vitro half-life was observed across the series. The data suggests that oxidative biotransformation was not singularly responsible for clearance of the compounds and no direct relationship between microsomal clearance and plasma clearance was observed. Structural modifications however, do provide some information as to the relative microsomal stability of the compounds, which may be useful for further drug development.

  17. N-( sup 18 F)fluoroacetyl-D-glucosamine: A potential agent for cancer diagnosis

    SciTech Connect

    Fujiwara, T.; Kubota, K.; Sato, T.; Matsuzawa, T.; Tada, M.; Iwata, R.; Itoh, M.; Hatazawa, J.; Sato, K.; Fukuda, H. )

    1990-10-01

    Positron labeled substrates such as sugars, amino acids, and nucleosides have been investigated for the in-vivo evaluation of biochemical processes in cancerous tissue. Hexosamines are obligatory structural components of many biologically important macromolecules, including membrane glycoproteins and mucopolysaccharide. We evaluated a new synthesized pharmaceutical, N-({sup 18}F)fluoroacetyl-D-glucosamine ({sup 18}F-FAG), which is a structural analog of N-acetyl-D-glucosamine. C3H/HeMsNRS mice bearing spontaneous hepatomas were used for the tissue distribution study. At 60 min after injection, high uptakes were found in tumor (5.16, mean value of %dose/g), liver (3.71), and kidney (3.27). The tumor uptake of 18F-FAG showed the highest value in all tissue. In the PET study, VX-2 carcinoma of the rabbit was clearly visualized. Our preliminary results suggest that {sup 18}F-FAG has potential as a new agent for tumor imaging.

  18. Sonorensin: A new bacteriocin with potential of an anti-biofilm agent and a food biopreservative.

    PubMed

    Chopra, Lipsy; Singh, Gurdeep; Kumar Jena, Kautilya; Sahoo, Debendra K

    2015-08-21

    The emergence of antibiotic resistant bacteria has led to exploration of alternative therapeutic agents such as ribosomally synthesized bacterial peptides known as bacteriocins. Biofilms, which are microbial communities that cause serious chronic infections, form environments that enhance antimicrobial resistance. Bacteria in biofilm can be upto thousand times more resistant to antibiotics than the same bacteria circulating in a planktonic state. In this study, sonorensin, predicted to belong to the heterocycloanthracin subfamily of bacteriocins, was found to be effectively killing active and non-multiplying cells of both Gram-positive and Gram-negative bacteria. Sonorensin showed marked inhibition activity against biofilm of Staphylococcus aureus. Fluorescence and electron microscopy suggested that growth inhibition occurred because of increased membrane permeability. Low density polyethylene film coated with sonorensin was found to effectively control the growth of food spoilage bacteria like Listeria monocytogenes and S. aureus. The biopreservative effect of sonorensin coated film showing growth inhibition of spoilage bacteria in chicken meat and tomato samples demonstrated the potential of sonorensin as an alternative to current antibiotics/ preservatives.

  19. Potential of Submergedly Cultivated Mycelia of Ganoderma spp. as Antioxidant and Antimicrobial Agents.

    PubMed

    Ćilerdžić, Jasmina; Stajic, Mirjana; Vukojevic, Jelena

    2016-01-01

    The study aimed to evaluate the antiradical and antimicrobial (antibacterial and antifungal) potentials of ethanol mycelial extracts of selected Ganoderma species and strains and to define interand intraspecies diversity among Ganoderma species and strains. Ganoderma lucidum strains were good DPPH• scavengers (neutralizing up to 57.12% radicals), contrary to G. applanatum (20.35%) and G. carnosum (17.04%). High correlations between the activities and contents of total phenols in the extracts showed that these compounds were carriers of the activity. Results obtained by both discdiffusion and microdilution methods indicated that the extract of G. lucidum BEOFB 433 was the most potent antibacterial agent that inhibited growth of almost all bacterial species at a concentration of 1.0 mg/mL. Salmonella typhimurium was the most sensitive species to the mycelium extracts. Extracts of G. lucidum BEOFB 431 and BEOFB 434 showed the best antifungal activity since in concentration of 0.5 mg/mL inhibited the growth of Aspergillus glaucus (BEOFB 431) and the growth of A. glaucus and Trichoderma viride (BEOFB 434). Extracts of G. applanatum and G. lucidum BEOFB 431 had the strongest fungicidal effects, with lethal outcomes for A. glaucus and T. viride, respectively, being noted at a concentration of 1.17 mg/mL. Aspergillus niger was proved as the most resistant species.

  20. Salvianolic Acid B, a Potential Chemopreventive Agent, for Head and Neck Squamous Cell Cancer

    PubMed Central

    Zhao, Yuan; Guo, Yinhan; Gu, Xinbin

    2011-01-01

    Head and neck squamous cell cancer (HNSCC) is one of the top ten cancers in the United States. The survival rate of HNSCC has only marginally improved over the last two decades. In addition, African-American men bear a disproportionate burden of this preventable disease. Therefore, a critical challenge of preventive health approaches is warranted. Salvianolic acid B (Sal-B) isolated from Salvia miltiorrhiza Bge, which is a well-know Chinese medicines has been safely used to treat and prevent aging diseases for thousand of years. Recently, the anticancer properties of Sal-B have received more attention. Sal-B significantly inhibits or delays the growth of HNSCC in both cultured HNSCC cells and HNSCC xenograft animal models. The following anticancer mechanisms have been proposed: the inhibition of COX-2/PGE-2 pathway, the promotion of apoptosis, and the modulation of angiogenesis. In conclusion, Sal-B is a potential HNSCC chemopreventive agent working through antioxidation and anti-inflammation mechanisms. PMID:21209716

  1. Sonorensin: A new bacteriocin with potential of an anti-biofilm agent and a food biopreservative

    PubMed Central

    Chopra, Lipsy; Singh, Gurdeep; Kumar Jena, Kautilya; Sahoo, Debendra K.

    2015-01-01

    The emergence of antibiotic resistant bacteria has led to exploration of alternative therapeutic agents such as ribosomally synthesized bacterial peptides known as bacteriocins. Biofilms, which are microbial communities that cause serious chronic infections, form environments that enhance antimicrobial resistance. Bacteria in biofilm can be upto thousand times more resistant to antibiotics than the same bacteria circulating in a planktonic state. In this study, sonorensin, predicted to belong to the heterocycloanthracin subfamily of bacteriocins, was found to be effectively killing active and non-multiplying cells of both Gram-positive and Gram-negative bacteria. Sonorensin showed marked inhibition activity against biofilm of Staphylococcus aureus. Fluorescence and electron microscopy suggested that growth inhibition occurred because of increased membrane permeability. Low density polyethylene film coated with sonorensin was found to effectively control the growth of food spoilage bacteria like Listeria monocytogenes and S. aureus. The biopreservative effect of sonorensin coated film showing growth inhibition of spoilage bacteria in chicken meat and tomato samples demonstrated the potential of sonorensin as an alternative to current antibiotics/ preservatives. PMID:26292786

  2. Recent Development of Multifunctional Agents as Potential Drug Candidates for the Treatment of Alzheimer's Disease

    PubMed Central

    Guzior, Natalia; ckowska,, Anna Wię; Panek, Dawid; Malawska, Barbara

    2015-01-01

    Alzheimer’s disease (AD) is a complex and progressive neurodegenerative disorder. The available therapy is limited to the symptomatic treatment and its efficacy remains unsatisfactory. In view of the prevalence and expected increase in the incidence of AD, the development of an effective therapy is crucial for public health. Due to the multifactorial aetiology of this disease, the multi-target-directed ligand (MTDL) approach is a promising method in search for new drugs for AD. This review updates information on the development of multifunctional potential anti-AD agents published within the last three years. The majority of the recently reported structures are acetylcholinesterase inhibitors, often endowed with some additional properties. These properties enrich the pharmacological profile of the compounds giving hope for not only symptomatic but also causal treatment of the disease. Among these advantageous properties, the most often reported are an amyloid-β anti-aggregation activity, inhibition of β-secretase and monoamine oxidase, an antioxidant and metal chelating activity, NO-releasing ability and interaction with cannabinoid, NMDA or histamine H3 receptors. The majority of novel molecules possess heterodimeric structures, able to interact with multiple targets by combining different pharmacophores, original or derived from natural products or existing therapeutics (tacrine, donepezil, galantamine, memantine). Among the described compounds, several seem to be promising drug candidates, while others may serve as a valuable inspiration in the search for new effective therapies for AD. PMID:25386820

  3. Platinum(II) metal complexes as potential anti-Trypanosoma cruzi agents.

    PubMed

    Vieites, Marisol; Otero, Lucía; Santos, Diego; Toloza, Jeannette; Figueroa, Roberto; Norambuena, Ester; Olea-Azar, Claudio; Aguirre, Gabriela; Cerecetto, Hugo; González, Mercedes; Morello, Antonio; Maya, Juan Diego; Garat, Beatriz; Gambino, Dinorah

    2008-01-01

    In the search for new therapeutic tools against Chagas' disease (American Trypanosomiasis) two series of new platinum(II) complexes with bioactive 5-nitrofuryl containing thiosemicarbazones as ligands were synthesized, characterized and in vitro evaluated. Most of the complexes showed IC50 values in the muM range against two different strains of Trypanosoma cruzi, causative agent of the disease, being as active as the anti-trypanosomal drug Nifurtimox. In particular, the coordination of L3 (4-ethyl-1-(5-nitrofurfurylidene)thiosemicarbazide) to Pt(II) forming [Pt(L3)2] lead to almost a five-fold activity increase in respect to the free ligand. Trying to get an insight into the trypanocidal mechanism of action of these compounds, DNA and redox metabolism (intra-parasite free radical production) were evaluated as potential parasite targets. Results suggest that the complexes could inhibit parasite growth through a dual mechanism of action involving production of toxic free radicals by bioreduction and DNA interaction.

  4. 4,5-diarylisoxazole Hsp90 chaperone inhibitors: potential therapeutic agents for the treatment of cancer.

    PubMed

    Brough, Paul A; Aherne, Wynne; Barril, Xavier; Borgognoni, Jenifer; Boxall, Kathy; Cansfield, Julie E; Cheung, Kwai-Ming J; Collins, Ian; Davies, Nicholas G M; Drysdale, Martin J; Dymock, Brian; Eccles, Suzanne A; Finch, Harry; Fink, Alexandra; Hayes, Angela; Howes, Robert; Hubbard, Roderick E; James, Karen; Jordan, Allan M; Lockie, Andrea; Martins, Vanessa; Massey, Andrew; Matthews, Thomas P; McDonald, Edward; Northfield, Christopher J; Pearl, Laurence H; Prodromou, Chrisostomos; Ray, Stuart; Raynaud, Florence I; Roughley, Stephen D; Sharp, Swee Y; Surgenor, Allan; Walmsley, D Lee; Webb, Paul; Wood, Mike; Workman, Paul; Wright, Lisa

    2008-01-24

    Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential chemotherapeutic agents for cancer. Here, we describe the structure-based design, synthesis, structure-activity relationships and pharmacokinetics of potent small-molecule inhibitors of Hsp90 based on the 4,5-diarylisoxazole scaffold. Analogues from this series have high affinity for Hsp90, as measured in a fluorescence polarization (FP) competitive binding assay, and are active in cancer cell lines where they inhibit proliferation and exhibit a characteristic profile of depletion of oncogenic proteins and concomitant elevation of Hsp72. Compound 40f (VER-52296/NVP-AUY922) is potent in the Hsp90 FP binding assay (IC50 = 21 nM) and inhibits proliferation of various human cancer cell lines in vitro, with GI50 averaging 9 nM. Compound 40f is retained in tumors in vivo when administered i.p., as evaluated by cassette dosing in tumor-bearing mice. In a human colon cancer xenograft model, 40f inhibits tumor growth by approximately 50%.

  5. Recent development of multifunctional agents as potential drug candidates for the treatment of Alzheimer's disease.

    PubMed

    Guzior, Natalia; Wieckowska, Anna; Panek, Dawid; Malawska, Barbara

    2015-01-01

    Alzheimer's disease (AD) is a complex and progressive neurodegenerative disorder. The available therapy is limited to the symptomatic treatment and its efficacy remains unsatisfactory. In view of the prevalence and expected increase in the incidence of AD, the development of an effective therapy is crucial for public health. Due to the multifactorial aetiology of this disease, the multi-target-directed ligand (MTDL) approach is a promising method in search for new drugs for AD. This review updates information on the development of multifunctional potential anti-AD agents published within the last three years. The majority of the recently reported structures are acetylcholinesterase inhibitors, often endowed with some additional properties. These properties enrich the pharmacological profile of the compounds giving hope for not only symptomatic but also causal treatment of the disease. Among these advantageous properties, the most often reported are an amyloid-β antiaggregation activity, inhibition of β-secretase and monoamine oxidase, an antioxidant and metal chelating activity, NOreleasing ability and interaction with cannabinoid, NMDA or histamine H3 receptors. The majority of novel molecules possess heterodimeric structures, able to interact with multiple targets by combining different pharmacophores, original or derived from natural products or existing therapeutics (tacrine, donepezil, galantamine, memantine). Among the described compounds, several seem to be promising drug candidates, while others may serve as a valuable inspiration in the search for new effective therapies for AD.

  6. Design, Synthesis, and Biological Evaluation of Novel Tetramethylpyrazine Derivatives as Potential Neuroprotective Agents.

    PubMed

    Chen, Haiyun; Tan, Guolian; Cao, Jie; Zhang, Gaoxiao; Yi, Peng; Yu, Pei; Sun, Yewei; Zhang, Zaijun; Wang, Yuqiang

    2017-01-01

    Oxidative stress plays a crucial role in neurological diseases, resulting in excessive production of reactive oxygen species, mitochondrial dysfunction and cell death. In this work, we designed and synthesized a series of tetramethylpyrazine (TMP) derivatives and investigated their abilities for scavenging free radicals and preventing against oxidative stress-induced neuronal damage in vitro. Among them, compound 22a, consisted of TMP, caffeic acid and a nitrone group, showed potent radical-scavenging activity. Compound 22a had broad neuroprotective effects, including rescuing iodoacetic acid-induced neuronal loss, preventing from tert-butylhydroperoxide (t-BHP)-induced neuronal injury. Compound 22a exerted its neuroprotective effect against t-BHP injury via activation of the phosphatidyl inositol 3-kinase (PI3K)/Akt signaling pathway. Furthermore, in a rat model of permanent middle cerebral artery occlusion, compound 22a significantly improved neurological deficits, and alleviated the infarct area and brain edema. In conclusion, our results suggest that compound 22a could be a potential neuroprotective agent for the treatment of neurological disease, particularly ischemic stroke.

  7. Nicotine as a potential neuroprotective agent for Parkinson’s disease

    PubMed Central

    Quik, Maryka; Perez, Xiomara A.; Bordia, Tanuja

    2012-01-01

    Converging research efforts suggest that nicotine and other drugs that act at nicotinic acetylcholine receptors (nAChRs) may be beneficial in the management of Parkinson’s disease. This idea initially stemmed from the results of epidemiological studies which demonstrate that smoking is associated with a decreased incidence of Parkinson’s disease. The subsequent finding that nicotine administration protected against nigrostriatal damage in parkinsonian animal models led to the idea that nicotine in tobacco products may contribute to this apparent protective action. Nicotine most likely exerts its effects by interacting at nAChRs. Accumulating research indicates that multiple subtypes, including α4β2, α6β2 and/or α7 containing nAChRs, may be involved. Stimulation of nAChRs initially activates various intracellular transduction pathways primarily via alterations in calcium signaling. Consequent adaptations in immune responsiveness and trophic factors may ultimately mediate nicotine’s ability to reduce/halt the neuronal damage that arises in Parkinson’s disease. In addition to a potential neuroprotective action, nicotine also has anti-depressant properties and improves attention/cognition. Altogether, these findings suggest that nicotine and nAChR drugs represent promising therapeutic agents for the management of Parkinson’s disease. PMID:22693036

  8. 1,3-Bis(aryloxy)propan-2-ols as potential antileishmanial agents.

    PubMed

    Lavorato, Stefânia N; Duarte, Mariana C; Lage, Daniela P; Tavares, Carlos A P; Coelho, Eduardo A F; Alves, Ricardo J

    2017-06-07

    We describe herein the synthesis and antileishmanial activity of 1,3-bis(aryloxy)propan-2-ols. Five compounds (2, 3, 13, 17, and 18) exhibited an effective antileishmanial activity against stationary promastigote forms of Leishmania amazonensis (IC50  < 15.0 μm), and an influence of compound lipophilicity on activity was suggested. Most of the compounds were poorly selective, as they showed toxicity toward murine macrophages, except 17 and 18, which presented good selective indexes (SI ≥ 10.0). The five more active compounds (2, 3, 13, 17, and 18) were selected for the treatment of infected macrophages, and all of them were able to reduce the number of internalized parasites by more than 80%, as well as the number of infected macrophages by more than 70% in at least one of the tested concentrations. Altogether, these results demonstrate the potential of these compounds as new hits of antileishmanial agents and open future possibilities for them to be tested in in vivo studies. © 2017 The Authors. Chemical Biology & Drug Design Published by John Wiley & Sons Ltd.

  9. Child as change agent. The potential of children to increase healthy food purchasing.

    PubMed

    Wingert, Katherine; Zachary, Drew A; Fox, Monica; Gittelsohn, Joel; Surkan, Pamela J

    2014-10-01

    Shoppers make many food choices while buying groceries. Children frequently accompany caregivers, giving them the potential to influence these choices. We aimed to understand low-income shoppers' perceptions of how children influence caregivers' purchasing decisions and how the supermarket environment could be manipulated to allow children to serve as change agents for healthy food purchasing in a primarily African-American community. We conducted thirty in-depth interviews, five follow-up interviews, one supermarket walk-through interview, and four focus groups with adult supermarket shoppers who were regular caregivers for children under age 16. We conducted one focus group with supermarket employees and one in-depth interview with a supermarket manager. Qualitative data were analyzed using iterative thematic coding and memo writing. Caregivers approached grocery shopping with efforts to save money, prevent waste and purchase healthy food for their families, but described children as promoting unplanned, unhealthy food purchases. This influence was exacerbated by the supermarket environment, which participants found to promote unhealthy options and provide limited opportunities for children to interact with healthier foods. Caregivers' suggestions for promoting healthy purchasing for shoppers with children included manipulating the placement of healthy and unhealthy foods and offering opportunities for children to taste and interact with healthy options.

  10. Mifepristone: a potential clinical agent based on its anti-progesterone and anti-glucocorticoid properties.

    PubMed

    Sun, Yayi; Fang, Marong; Davies, Henry; Hu, Zhiying

    2014-03-01

    Nowadays, unwanted pregnancy is a major globe tragedy for millions of women, associated with significant direct and indirect costs, no matter for individuals or society. The progesterone receptor antagonist steroid, mifepristone has been widely and effectively using throughout the world for medical abortion, but to a lesser extent for emergency contraception. In this review, we hope to explore the role of mifepristone as a contraceptive, particularly for emergency contraception. Studies of mifepristone have also been expanding to the fields of endometriosis and uterine fibroids. Furthermore, this initially considered reproductive medicine has been investigated in some psychotic diseases and various disorders of hypercortisolism, because of its glucocorticoid receptor antagonism. Mifepristone was approved suitable for patients with hyperglycemia secondary to Cushing's syndrome by the United States Food and Drug Administration (FDA) in 2012. The aim of this article is to review published reports on the anti-progesterone and anti-glucocorticoid properties of mifepristone as a clinical agent. There is a new insight into systematically describing and evaluating the potential efficiency of mifepristone administrated in the field of endocrine and neuroendocrine, not only in obstetrics and gynecology.

  11. Scaffold Hopping Toward Agomelatine: Novel 3, 4-Dihydroisoquinoline Compounds as Potential Antidepressant Agents

    PubMed Central

    Yang, Yang; Ang, Wei; Long, Haiyue; Chang, Ying; Li, Zicheng; Zhou, Liangxue; Yang, Tao; Deng, Yong; Luo, Youfu

    2016-01-01

    A scaffold-hopping strategy toward Agomelatine based on in silico screening and knowledge analysis was employed to design novel antidepressant agents. A series of 3, 4-dihydroisoquinoline compounds were selected for chemical synthesis and biological assessment. Three compounds (6a-1, 6a-2, 6a-9) demonstrated protective effects on corticosterone-induced lesion of PC12 cells. Compound 6a-1 also displayed low inhibitory effects on the growth of HEK293 and L02 normal cells and it was further evaluated for its potential antidepressant effects in vivo. The forced swim test (FST) results revealed that compound 6a-1 remarkably reduced the immobility time of rats and the open field test (OFT) results indicated a better general locomotor activity of the rats treated with compound 6a-1 than those with Agomelatine or Fluoxetine. Mechanism studies implied that compound 6a-1 can significantly reduce PC12 cell apoptosis by up-regulation of GSH and down-regulation of ROS in corticosterone-induced lesion of PC12 cells. Meanwhile, the down-regulation of calcium ion concentration and up-regulation of BDNF level in PC12 cells may account for the neuroprotective effects. Furthermore, compound 6a-1 can increase cell survival and cell proliferation, promote cell maturation in the rat hippocampus after chronic treatment. The acute toxicity data in vivo indicated compound 6a-1 exhibited less hepatotoxicity than Agomelatine. PMID:27698414

  12. Phyllanthus wightianus Müll. Arg.: A Potential Source for Natural Antimicrobial Agents

    PubMed Central

    Natarajan, D.; Srinivasan, R.; Shivakumar, M. S.

    2014-01-01

    Phyllanthus wightianus belongs to Euphorbiaceae family having ethnobotanical importance. The present study deals with validating the antimicrobial potential of solvent leaf extracts of P. wightianus. 11 human bacterial pathogens (Bacillus subtilis, Streptococcus pneumoniae, Staphylococcus epidermidis, Proteus vulgaris, Pseudomonas aeruginosa, Klebsiella pneumoniae, Salmonella typhimurium, Escherichia coli, Shigella flexneri, Proteus vulgaris, and Serratia marcescens) and 4 fungal pathogens (Candida albicans, Cryptococcus neoformans, Mucor racemosus, and Aspergillus niger) were also challenged with solvent leaf extracts usingagar well and disc diffusion methods. Further, identification of the active component present in the bioactive extract was done using GC-MS analysis. Results show that all extracts exhibited broad spectrum (6–29 mm) of antibacterial activity on most of the tested organisms. The results highlight the fact that the well in agar method was more effective than disc diffusion method. Significant antimicrobial activity was detected in methanol extract against S. pneumoniae (29 mm) with MIC and MBC values of 15.62 μg/mL. GC-MS analysis revealed that 29 bioactive constituents were present in methanolic extract of P. wightianus, of which 9,12-octadecaenioic acid (peak area 22.82%; RT-23.97) and N-hexadecanoic acid (peak area 21.55% RT-21.796) are the major compounds. The findings of this study show that P. wightianus extracts may be used as an anti-infective agent in folklore medicine. PMID:24883301

  13. Are retinoids potential therapeutic agents in disorders of social cognition including autism?

    PubMed

    Ebstein, Richard P; Mankuta, David; Yirmiya, Nurit; Malavasi, Fabio

    2011-06-06

    Increasing evidence suggests that the nonapeptide, oxytocin (OT), helps shape social and affiliative behaviors not only in lower mammals but also in humans. Recently, an essential mediator of brain OT release has been discovered, ADP-ribosyl cyclase and/or CD38. We have subsequently shown that polymorphisms across the CD38 gene are associated with autism spectrum disorders (ASD). Notably, CD38 expression in lymphoblastoid cells (LBC) is reduced in cell lines derived from ASD subjects compared to parental cell lines. Intriguingly, a correlation was observed between CD38 expression and measures of social function in ASD. Finally, we have shown that all-trans retinoic acid (ATRA), a known inducer of CD38 transcription, can rescue low CD38 expressing LBC lines derived from ASD subjects and restore normal levels of transcription of this ectoenzyme providing 'proof of principle' in a peripheral model that retinoids are potential therapeutic agents in ASD. Copyright © 2011 Federation of European Biochemical Societies. All rights reserved.

  14. Synthesis and Evaluation of Aminothiazole-Paeonol Derivatives as Potential Anticancer Agents.

    PubMed

    Tsai, Chia-Ying; Kapoor, Mohit; Huang, Ying-Pei; Lin, Hui-Hsien; Liang, Yu-Chuan; Lin, Yu-Ling; Huang, Su-Chin; Liao, Wei-Neng; Chen, Jen-Kun; Huang, Jer-Shing; Hsu, Ming-Hua

    2016-01-26

    In this study, novel aminothiazole-paeonol derivatives were synthesized and characterized using ¹H-NMR, (13)C-NMR, IR, mass spectroscopy, and high performance liquid chromatography. All the new synthesized compounds were evaluated according to their anticancer effect on seven cancer cell lines. The experimental results indicated that these compounds possess high anticancer potential regarding human gastric adenocarcinoma (AGS cells) and human colorectal adenocarcinoma (HT-29 cells). Among these compounds, N-[4-(2-hydroxy-4-methoxyphenyl)thiazol-2-yl]-4-methoxybenzenesulfonamide (13c) had the most potent inhibitory activity, with IC50 values of 4.0 µM to AGS, 4.4 µM to HT-29 cells and 5.8 µM to HeLa cells. The 4-fluoro-N-[4-(2-hydroxy-4-methoxyphenyl)thiazol-2-yl]benzenesulfonamide (13d) was the second potent compound, showing IC50 values of 7.2, 11.2 and 13.8 µM to AGS , HT-29 and HeLa cells, respectively. These compounds are superior to 5-fluorouracil (5-FU) for relatively higher potency against AGS and HT-29 human cancer cell lines along with lower cytotoxicity to fibroblasts. Novel aminothiazole-paeonol derivatives in this work might be a series of promising lead compounds to develop anticancer agents for treating gastrointestinal adenocarcinoma.

  15. Evaluation of flaxseed formulation as a potential therapeutic agent in mitigation of dyslipidemia.

    PubMed

    Saxena, Sonali; Katare, Charu

    2014-01-01

    Cardiovascular diseases (CVDs) are an increasing health problem all over the world. The search for natural hypolipidemic agents that can be used besides the synthetic drugs is still in its experimental stage. Plant seeds, particularly flaxseed (Linum usitatissimum), which is a rich source of n-3 fatty acids, lignans and phenolic compounds, have also received increasing attention for their potential role in preventing lipid disorders. The present study was undertaken to evaluate the therapeutic potential of flaxseeds in dyslipidemia. The study included 50 dyslipidemic subjects selected by purposive random sampling and were divided into two groups, a control and an experimental group. Both the groups were prescribed similar dietary guidelines. Subjects in the experimental group received 30 g of roasted flaxseed powder for 3 months. Anthropometric parameters, blood pressure, and blood lipid profile were estimated before the study and after completion of the study. Flaxseed supplementation resulted in a remarkable improvement in anthropometric measurements, blood pressure, and lipid profile in the experimental group. Body weight and body mass index (BMI) of the experimental group were significantly reduced (p < 0.01). A lowering of systolic and diastolic blood pressure (p < 0.05) was also recorded in the dyslipidemic subjects. Concomitantly, a highly significant reduction (p < 0.01) in total cholesterol, triglycerides, low density lipoprotein-cholesterol (LDL-C), and very low density lipoprotein-cholesterol (VLDL-C) levels, with simultaneous elevation (p < 0.01) in high density lipoprotein-cholesterol (HDL-C) levels was observed. Improvement in lipid levels resulted in reduction of atherogenic indices. The supplementation of roasted flaxseed powder for 3 months improved the BMI, blood pressure, and lipid profile of dyslipidemic subjects, thus exhibiting cardio protective effect.

  16. Hydroxychalcone inhibitors of Streptococcus mutans glucosyl transferases and biofilms as potential anticaries agents.

    PubMed

    Nijampatnam, Bhavitavya; Casals, Luke; Zheng, Ruowen; Wu, Hui; Velu, Sadanandan E

    2016-08-01

    Streptococcus mutans has been implicated as the major etiological agent in the initiation and the development of dental caries due to its robust capacity to form tenacious biofilms. Ideal therapeutics for this disease will aim to selectively inhibit the biofilm formation process while preserving the natural bacterial flora of the mouth. Several studies have demonstrated the efficacies of flavonols on S. mutans biofilms and have suggested the mechanism of action through their effect on S. mutans glucosyltransferases (Gtfs). These enzymes metabolize sucrose into water insoluble and soluble glucans, which are an integral measure of the dental caries pathogenesis. Numerous studies have shown that flavonols and polyphenols can inhibit Gtf and biofilm formation at millimolar concentrations. We have screened a group of 14 hydroxychalcones, synthetic precursors of flavonols, in an S. mutans biofilm assay. Several of these compounds emerged to be biofilm inhibitors at low micro-molar concentrations. Chalcones that contained a 3-OH group on ring A exhibited selectivity for biofilm inhibition. Moreover, we synthesized 6 additional analogs of the lead compound and evaluated their potential activity and selectivity against S. mutans biofilms. The most active compound identified from these studies had an IC50 value of 44μM against biofilm and MIC50 value of 468μM against growth displaying >10-fold selectivity inhibition towards biofilm. The lead compound displayed a dose dependent inhibition of S. mutans Gtfs. The lead compound also did not affect the growth of two commensal species (Streptococcus sanguinis and Streptococcus gordonii) at least up to 200μM, indicating that it can selectively inhibit cariogenic biofilms, while leaving commensal and/or beneficial microbes intact. Thus non-toxic compounds have the potential utility in public oral health regimes. Copyright © 2016. Published by Elsevier Ltd.

  17. Curcumin derivatives as metal-chelating agents with potential multifunctional activity for pharmaceutical applications.

    PubMed

    Ferrari, Erika; Benassi, Rois; Sacchi, Stefania; Pignedoli, Francesca; Asti, Mattia; Saladini, Monica

    2014-10-01

    Curcuminoids represent new perspectives for the development of novel therapeutics for Alzheimer's disease (AD), one probable mechanism of action is related to their metal complexing ability. In this work we examined the metal complexing ability of substituted curcuminoids to propose new chelating molecules with biological properties comparable with curcumin but with improved stability as new potential AD therapeutic agents. The K2T derivatives originate from the insertion of a -CH2COOC(CH3)3 group on the central atom of the diketonic moiety of curcumin. They retain the diketo-ketoenol tautomerism which is solvent dependent. In aqueous solution the prevalent form is the diketo one but the addition of metal ion (Ga(3+), Cu(2+)) causes the dissociation of the enolic proton creating chelate complexes and shifting the tautomeric equilibrium towards the keto-enol form. The formation of metal complexes is followed by both NMR and UV-vis spectroscopy. The density functional theory (DFT) calculations on K2T21 complexes with Ga(3+) and Cu(2+) are performed and compared with those on curcumin complexes. [Ga(K2T21)2(H2O)2](+) was found more stable than curcumin one. Good agreement is detected between calculated and experimental (1)H and (13)C NMR data. The calculated OH bond dissociation energy (BDE) and the OH proton dissociation enthalpy (PDE), allowed to predict the radical scavenging ability of the metal ion complexed with K2T21, while the calculated electronic affinity (EA) and ionization potential (IP) represent yardsticks of antioxidant properties. Eventually theoretical calculations suggest that the proton-transfer-associated superoxide-scavenging activity is enhanced after binding metal ions, and that Ga(3+) complexes display possible superoxide dismutase (SOD)-like activity.

  18. Novel glyoxalase-I inhibitors possessing a “zinc-binding feature” as potential anticancer agents

    PubMed Central

    Al-Balas, Qosay A; Hassan, Mohammad A; Al-Shar’i, Nizar A; Mhaidat, Nizar M; Almaaytah, Ammar M; Al-Mahasneh, Fatima M; Isawi, Israa H

    2016-01-01

    Background The glyoxalase system including two thiol-dependent enzymes, glyoxalase I (Glo-I) and glyoxalase II, plays an important role in a ubiquitous metabolic pathway involved in cellular detoxification of cytotoxic 2-oxoaldehydes. Tumor cells have high glycolytic activity, leading to increased cellular levels of these toxic metabolites. The increased activity of the detoxification system in cancerous cells makes this pathway a viable target for developing novel anticancer agents. In this study, we examined the potential utility of non-glutathione-based inhibitors of the Glo-I enzyme as novel anticancer drugs. Methods Computer-aided drug design techniques, such as customized pharmacophoric features, virtual screening, and flexible docking, were used to achieve the project goals. Retrieved hits were extensively filtered and subsequently docked into the active site of the enzyme. The biological activities of retrieved hits were assessed using an in vitro assay against Glo-I. Results Since Glo-I is a zinc metalloenzyme, a customized Zn-binding pharmacophoric feature was used to search for selective inhibitors via virtual screening of a small-molecule database. Seven hits were selected, purchased, and biologically evaluated. Three of the seven hits inhibited Glo-I activity, the most effective of which exerted 76.4% inhibition at a concentration of 25 µM. Conclusion We successfully identified a potential Glo-I inhibitor that can serve as a lead compound for further optimization. Moreover, our in silico and experimental results were highly correlated. Hence, the docking protocol adopted in this study may be efficiently employed in future optimization steps. PMID:27574401

  19. Novel glyoxalase-I inhibitors possessing a "zinc-binding feature" as potential anticancer agents.

    PubMed

    Al-Balas, Qosay A; Hassan, Mohammad A; Al-Shar'i, Nizar A; Mhaidat, Nizar M; Almaaytah, Ammar M; Al-Mahasneh, Fatima M; Isawi, Israa H

    2016-01-01

    The glyoxalase system including two thiol-dependent enzymes, glyoxalase I (Glo-I) and glyoxalase II, plays an important role in a ubiquitous metabolic pathway involved in cellular detoxification of cytotoxic 2-oxoaldehydes. Tumor cells have high glycolytic activity, leading to increased cellular levels of these toxic metabolites. The increased activity of the detoxification system in cancerous cells makes this pathway a viable target for developing novel anticancer agents. In this study, we examined the potential utility of non-glutathione-based inhibitors of the Glo-I enzyme as novel anticancer drugs. Computer-aided drug design techniques, such as customized pharmacophoric features, virtual screening, and flexible docking, were used to achieve the project goals. Retrieved hits were extensively filtered and subsequently docked into the active site of the enzyme. The biological activities of retrieved hits were assessed using an in vitro assay against Glo-I. Since Glo-I is a zinc metalloenzyme, a customized Zn-binding pharmacophoric feature was used to search for selective inhibitors via virtual screening of a small-molecule database. Seven hits were selected, purchased, and biologically evaluated. Three of the seven hits inhibited Glo-I activity, the most effective of which exerted 76.4% inhibition at a concentration of 25 µM. We successfully identified a potential Glo-I inhibitor that can serve as a lead compound for further optimization. Moreover, our in silico and experimental results were highly correlated. Hence, the docking protocol adopted in this study may be efficiently employed in future optimization steps.

  20. Kinase inhibitors of the IGF-1R as a potential therapeutic agent for rheumatoid arthritis.

    PubMed

    Tsushima, Hiroshi; Morimoto, Shinji; Fujishiro, Maki; Yoshida, Yuko; Hayakawa, Kunihiro; Hirai, Takuya; Miyashita, Tomoko; Ikeda, Keigo; Yamaji, Ken; Takamori, Kenji; Takasaki, Yoshinari; Sekigawa, Iwao; Tamura, Naoto

    2017-08-01

    We have previously shown that the inhibition of connective tissue growth factor (CTGF) is a potential therapeutic strategy against rheumatoid arthritis (RA). CTGF consists of four distinct modules, including the insulin-like growth factor binding protein (IGFBP). In serum, insulin-like growth factors (IGFs) bind IGFBPs, interact with the IGF-1 receptor (IGF-1 R), and regulate anabolic effects and bone metabolism. We investigated the correlation between IGF-1 and the pathogenesis of RA, and the inhibitory effect on osteoclastogenesis and angiogenesis of the small molecular weight kinase inhibitor of the IGF-1 R, NVP-AEW541, against pathogenesis of RA in vitro. Cell proliferation was evaluated by cell count and immunoblotting. The expression of IGF-1 and IGF-1 R was evaluated by RT-PCR. Osteoclastogenesis was evaluated using tartrate-resistant acid phosphatase staining, a bone resorption assay, and osteoclast-specific enzyme production. Angiogenesis was evaluated by a tube formation assay using human umbilical vein endothelial cells (HUVECs). The proliferation of MH7A cells was found to be inhibited in the presence of NVP-AEW541, and the phosphorylation of extracellular signal-regulated kinase (ERK) and Akt was downregulated in MH7A cells. IGF-1 and IGF-1 R mRNA expression levels were upregulated during formation of M-colony stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL)-mediated osteoclast formation. Moreover, osteoclastogenesis was suppressed in the presence of NVP-AEW541. The formation of the tubular network was enhanced by IGF-1, and this effect was neutralized by NVP-ARE541. Our findings suggest that NVP-AEW541 may be utilized as a potential therapeutic agent in the treatment of RA.

  1. Volatile Organic Compounds from Native Potato-associated Pseudomonas as Potential Anti-oomycete Agents

    PubMed Central

    De Vrieze, Mout; Pandey, Piyush; Bucheli, Thomas D.; Varadarajan, Adithi R.; Ahrens, Christian H.; Weisskopf, Laure; Bailly, Aurélien

    2015-01-01

    The plant kingdom represents a prominent biodiversity island for microbes that associate with the below- or aboveground organs of vegetal species. Both the root and the leaf represent interfaces where dynamic biological interactions influence plant life. Beside well-studied communication strategies based on soluble compounds and protein effectors, bacteria were recently shown to interact both with host plants and other microbial species through the emissions of volatile organic compounds (VOCs). Focusing on the potato late blight-causing agent Phytophthora infestans, this work addresses the potential role of the bacterial volatilome in suppressing plant diseases. In a previous study, we isolated and identified a large collection of strains with anti-Phytophthora potential from both the phyllosphere and the rhizosphere of potato. Here we report the characterization and quantification of their emissions of biogenic volatiles, comparing 16 Pseudomonas strains differing in (i) origin of isolation (phyllosphere vs. rhizosphere), (ii) in vitro inhibition of P. infestans growth and sporulation behavior, and (iii) protective effects against late blight on potato leaf disks. We systematically tested the pharmacological inhibitory activity of core and strain-specific single compounds against P. infestans mycelial growth and sporangial behavior in order to identify key effective candidate molecules present in the complex natural VOCs blends. We envisage the plant bacterial microbiome as a reservoir for functional VOCs and establish the basis for finding the primary enzymatic toolset that enables the production of active components of the volatile bouquet in plant-associated bacteria. Comprehension of these functional interspecies interactions will open perspectives for the sustainable control of plant diseases in forthcoming agriculture. PMID:26635763

  2. Safety evaluation of a potential ablation agent-hydrochloric acid in the rabbits' model.

    PubMed

    Yao, Wang; Gu, Yang-Kui; Wang, Jian; Gao, Fei; Liu, Wan-Li; Huang, Jin-Hua

    2014-10-01

    To evaluate the safety of a potential ablation agent-hydrochloric acid (HCl), which may apply to treat hepatocellular carcinoma (HCC). Eighty adult New Zealand rabbits were divided into five groups of equal size (n=16), i.e., untreated group, normal saline (NS) control group, 10% HCl group, 20% HCl group and 30% HCl group. Each group was divided into two subgroups: ten rabbits for two-week toxicology study at the time points of hours 0, 0.25, 0.5, 1, 3, 6 and days 2, 7, 14 and six rabbits for imaging and histopathology study at the time points of days 2, 7 and 14. In toxicology study we evaluated the safety of HCl from arterial blood gas status, hematology and hepatic and renal functions. In imaging and histopathology study, we observed the relationship between the sizes of lesion and the concentration of HCl, as well as extension of necrosis and concentration of HCl. In this study we also observed the microcosmic and macroscopic lesion that caused by HCl. In general condition, food, water consumption and body weight decreased notablely during the beginning of the experiment. In toxicology study, alanine aminotransferase, aspartate aminotransferase and lactic acid contents were higher in the 30% hydrochloric acid group than in other groups (P<0.005), all test items returned to normal on day 14. Imaging and histopathology study showed that 30% HCl caused larger lesion area than other HCl concentration and the necrosis that caused by HCl was complete. There was also a close relationship between the size of minor damaged area and HCl concentration. The 30% HCl caused larger minor damaged area than other HCl concentration. Because the damaged area was surrounded by a layer of fiber tissue, the lesion area became larger at days 7 and 14 time points. This study also demonstrated that the adjacent organs had no obvious damage, and all the damaged areas were limited in the liver. HCl is a safe ablation agent for local injection in the liver. HCl at a lower concentration is

  3. Entomopathogenic marine actinomycetes as potential and low-cost biocontrol agents against bloodsucking arthropods.

    PubMed

    Loganathan, Karthik; Kumar, Gaurav; Kirthi, Arivarasan Vishnu; Rao, Kokati Venkata Bhaskara; Rahuman, Abdul Abdul

    2013-11-01

    A novel approach to control strategies for integrated blood-feeding parasite management is in high demand, including the use of biological control agents. The present study aims to determine the efficacy of optimized crude extract of actinomycetes strain LK1 as biological control agent against the fourth-instar larvae of Anopheles stephensi and Culex tritaeniorhynchus (Diptera: Culicidae) and adults of Haemaphysalis bispinosa, Rhipicephalus (Boophilus) microplus (Acari: Ixodidae), and Hippobosca maculata (Diptera: Hippoboscidae). Antiparasitic activity was optimized using the Plackett-Burman method, and the design was developed using the software Design-Expert version 8.0.7.1. The production of the optimized crude actinomycetes LK1 strain extract was performed using response surface methodology to optimize the process parameters of protease inhibitor activity of marine actinobacteria for the independent variables like pH, temperature, glucose, casein, and NaCl at two levels (-1 and +1). The potential actinomycetes strain was identified as Saccharomonas spp., and the metamodeling surface simulation procedure was followed. It was studied using a computer-generated experimental design, automatic control of simulation experiments, and sequential optimization of the metamodels fitted to a simulation response surface function. The central composite design (CCD) used for the analysis of treatment showed that a second-order polynomial regression model was in good agreement with the experimental results at R (2) = 0.9829 (p < 0.05). The optimized values of the variables for antioxidant production were pH 6.00, glucose 1.3%, casein 0.09%, temperature 31.23 °C, and NaCl 0.10%. The LK1 strain-optimized crude extract was purified using reversed-phase high-pressure liquid chromatography, and the isolated protease inhibitor showed antiparasitic activity. The antiparasitic activity of optimized crude extract of LK1 was tested against larvae of A. stephensi (LC₅₀ = 31.82 ppm

  4. Characterization and Functionalization of Iron-Oxide Nanoparticles for Use as Potential Agents for Cancer Thermotherapy

    NASA Astrophysics Data System (ADS)

    O'Reilly, Nora

    This thesis presents experimental studies of iron oxide nanoparticle synthesis, functionalization, and intracellular hyperthermal effects on murine macrophages as a model in vitro system. Colloidal suspensions of magnetic nanoparticles (MNPs) are of particular interest in Magnetic Fluid Hyperthermia (MFH). Iron oxide nanoparticles (IONPs) have garnered great interest as economical, biocompatible hyperthermia agents due to their superparamagnetic activity. Here we seek to optimize the synthetic reproducibility and in vitro utilization of IONPs for application in MFH. We compared aqueous synthetic protocols and various protective coating techniques using various analytical techniques and in vitro assays to assess the biocompatibility and feasibility of the various preparations of nanoparticles. Using a co-precipitation of iron salts methodology, iron oxide nanoparticles (IONPs) with an average diameter of 6-8nm were synthesized and stabilized with carboxylates. By performing calorimetry measurements in an oscillating magnetic field (OMF) with a frequency of 500 kHz and field strength of 0.008Tesla the superparamagnetic behavior of these particles was confirmed. To further investigate these IONPs in a biological application, citric acid-stabilized particles, in conjunction with heat generated by these IONPs when exposed to an OMF, were assessed to determine their effects on cell viability in a RAW 267.4 murine macrophage model system. Our results show that 91.5-97% of cells that have ingested IONPs die follow exposure to an OMF. Importantly, neither the IONPs (at applicable concentrations) nor the OMF show cytotoxic effects. These particular particles have promising preliminary results as hyperthermic agents in both the current literature and simple, proof-of-concept experiments in our laboratory setting. We present experimental results for the synthesis, characterization, and utilization of iron oxide nanoparticles in MFH. Our results show that while IONPs have

  5. Antitumor Agents 250.† Design and Synthesis of New Curcumin Analogs as Potential Anti-Prostate Cancer Agents

    PubMed Central

    Lin, Li; Shi, Qian; Nyarko, Alexander K.; Bastow, Kenneth F.; Wu, Chin-Chung; Su, Ching-Yuan; Shih, Charles C.-Y; Lee, Kuo-Hsiung

    2008-01-01

    In a continuing study of curcumin analogs as potential drug candidates to treat prostate cancer at both androgen-dependent and androgen-refractory stages, we designed and synthesized over 40 new analogs classified into four series: monophenyl analogs (series A), heterocycle-containing analogs (series B), analogs bearing various substituents on the phenyl rings (series C) and analogs with various linkers (series D). These new compounds were tested for cytotoxicity against two human prostate cancer cell lines, androgen-dependent LNCaP and androgen-independent PC-3. Antiandrogenic activity was also evaluated in LNCaP cells and PC-3 cells transfected with wild-type androgen receptor. Ten compounds possessed potent cytotoxicity against both LNCaP and PC-3 cells; seven only against LNCaP; and one solely against PC-3. This study established an advanced structure-activity relationship (SAR), and these correlations will guide the further design of new curcumin analogs with better anti-prostate cancer activity. PMID:16789753

  6. MR cholangiography in potential liver donors: quantitative and qualitative improvement with administration of an oral effervescent agent.

    PubMed

    Kwon, Heon-Ju; Kim, Kyoung Won; Choi, Sang Hyun; Jung, Jin-Hee; Kim, So Yeon; Kim, Se-Young; Lee, Jeongjin; Jung, Dong-Hwan; Ha, Tae-Yong; Song, Gi-Won; Lee, Sung-Gyu

    2017-03-23

    To determine whether an oral effervescent agent improves magnetic resonance cholangiography (MRC) images, both qualitatively and quantitatively, in potential live liver donors. This retrospective study was approved by the Institutional Review Board, and informed consent was waived. Seventy potential liver donors underwent 2D MRC before and after administration of an oral effervescent agent. One radiologist measured relative contrast ratio (rC) and relative signal intensity (rS) for right and left intrahepatic ducts (RHD and LHD), and common hepatic duct (CHD). After assessment of overall image quality, two other radiologists independently scored visualization of five ductal segments (RHD, LHD, CHD, cystic, and common bile duct) and assessed the preferred image set. In consensus, they assessed the biliary anatomy. The data were analyzed using a paired t-test, Wilcoxon's signed-rank test, and chi-square test. Both rC and rS of RHD and CHD were significantly higher on MRC images after administration of an oral effervescent agent than before (P < 0.03). The overall image quality grades and biliary visualization scores for all five duct segments were significantly higher on MRC images after administration of an oral effervescent agent than before (P < 0.0001). Between these images, both readers more often preferred MRC images with an effervescent agent rather than those without this agent (reader 1: 56/70, 80.0%; reader 2: 55/70, 78.6%; P = 0.0003). The readers correctly assessed second-order biliary tract anatomy in two more subjects on MRC after administration of an effervescent agent than before. Oral administration of an effervescent agent improves MRC images, both qualitatively and quantitatively, in live liver donors. 3 J. Magn. Reson. Imaging 2017. © 2017 International Society for Magnetic Resonance in Medicine.

  7. Cytotoxic potential of vasoconstrictor experimental gingival retraction agents: in vitro study on primary human gingival fibroblasts.

    PubMed

    Nowakowska, D; Saczko, J; Kulbacka, J; Choromanska, A; Raszewski, Z

    2012-01-01

    The aim of this in vitro study was to evaluate the cytotoxic effects of the vasoconstrictor experimental gingival retraction agents (VEGRAs) in a dynamic setting. The strong cytotoxic effects of the astringent-based conventional gingival retraction agents (ACGRAs) on human gingival fibroblasts (HGFs) in vitro was our motivation to evaluate the biocompatibility of the vasoconstrictor-based experimental gingival retraction agents (VEGRAs) for the selected minimally invasive chemical agent. These agents were used to create three self-made retraction gels. Human gingival fibroblasts (HGFs) were treated with two groups of retraction agents: 1) three α- and β-adrenergic agents (VEGRA-αβ-s) based on 0.1%, 0.01% and 0.05% HCl-epinephrine, and 2) seven α-adrenergic agents (VEGRA-α-s), including two commercially available 0.05% HCl-tetrahydrozoline solutions, one 0.05% HCl-oxymetazoline solution, 10% HCl-phenylephrine solution, and three new self-made experimental 0.05% HCl-tetrahydro zoline-based gels. The methyl thiazolyl tetrazolium (MTT) colorimetric assay was performed to determine the oxidoreductive mitochondrial function after 3, 5, 10 min and 24 h of incubation. The cytotoxic effect, measured by cell viability lower than the 50% threshold, was not observed at any time period, even 24 h after application of 0.05% HCl-tetrahydrozolinebased self-manufactured retraction gels. High cell viability values of human gingival fibroblasts after the treatment with the three self-made 0.05% HCl-tetrahydrozoline- based gels may serve as a basis for further studies aimed at selecting the best retraction agents biocompatible with gingival margin tissues.

  8. Potential of Microbispora sp. V2 as biocontrol agent against Sclerotium rolfsii, the causative agent of southern blight of Zea mays L (Baby corn)--in vitro studies.

    PubMed

    Patil, N N; Waghmode, M S; Gaikwad, P S; Gajbhiye, M H; Gunjal, A B; Nawani, N N; Kapadnis, B P

    2014-11-01

    The study was undertaken with the aim of exploring novel and beneficial agro activities of rare actinomycetes like Microbispora sp. V2. The antagonistic activity of Microbispora sp. V2 was evaluated as a biocontrol agents against Sclerotium rolfsii, a soil-borne fungal plant pathogen. The methodology performed for evaluation of biocontrol agent was in vitro evaluation assay which comprised of three tests viz., cellophane overlay technique, seed germination test and Thiram (fungicide) tolerance of Microbispora sp. V2. The isolate was found to inhibit the fungal pathogen Sclerotium rolfsii to 91.43% in cellophane assay. In seed germination assay, Microbispora sp. V2 treated seeds resulted in 25.75% increased germination efficiency, as compared to seeds infected by Sclerotium rolfsii. The isolate Microbispora sp. V2 could tolerate 1000 microg mL(-1) of Thiram (fungicide). The in vitro assay studies proved that Microbispora sp. V2 can be used as antifungal antagonist and thus posses' great potential as biocontrol agent against southern blight caused by Sclerotium rolfsii in Zea mays L (Baby corn) which causes large economical losses.

  9. Omega-3 fatty acid is a potential preventive agent for recurrent colon cancer

    PubMed Central

    Vasudevan, Anita; Yu, Yingjie; Banerjee, Sanjeev; Woods, James; Farhana, Lulu; Rajendra, Sindhu G.; Patel, Aamil; Dyson, Gregory; Levi, Edi; Maddipati, Krishna Rao; Majumdar, Adhip P.N.; Nangia-Makker, Pratima

    2014-01-01

    Increasing evidence supports the contention that many malignancies, including sporadic colorectal cancer (CRC), are driven by the self-renewing, chemotherapy-resistant cancer stem/stem-like cells (CSCs/CSLCs) underscoring the need for improved preventive and therapeutic strategies targeting CSCs/CSLCs. Omega-3 polyunsaturated fatty acids (ω-3 PUFA), have been reported to inhibit the growth of primary tumors, but their potential as a preventive agent for recurring cancers is un-explored. The primary objectives of this investigation are to examine whether eicosapentaenoic acid (EPA; one of the ω-3 PUFA) synergizes with FuOx (5-FU+Oxaliplatin), the backbone of colon cancer chemotherapy, and (b) whether EPA by itself or in combination with conventional chemotherapy prevents the recurrence of colon cancer via eliminating/suppressing CSCs/CSLCs. FuOx-resistant (chemo-resistant; CR) colon cancer cells, highly enriched in CSCs, were utilized for this study. While EPA alone was effective, combination of EPA and FuOx was more potent in (a) inhibiting cell growth, colonosphere formation and sphere-forming frequency, (b) increasing sphere disintegration, (c) suppressing the growth of SCID mice xenografts of CR colon cancer cells, and (d) decreasing pro-inflammatory metabolites in mice. Additionally, EPA + FuOx caused a reduction in CSC/CSLC population. The growth reduction by this regimen is the result of increased apoptosis as evidenced by PARP cleavage. Furthermore, increased pPTEN, decreased pAkt, normalization of β-catenin expression, localization and transcriptional activity by EPA suggests a role for PTEN/Akt axis and Wnt signaling in regulating this process. Our data suggest that EPA by itself or in combination with FuOx could be an effective preventive strategy for recurring CRC. PMID:25193342

  10. Histone Deacetylase Inhibitor SAHA as Potential Targeted Therapy Agent for Larynx Cancer Cells.

    PubMed

    Grabarska, Aneta; Łuszczki, Jarogniew J; Nowosadzka, Ewa; Gumbarewicz, Ewelina; Jeleniewicz, Witold; Dmoszyńska-Graniczka, Magdalena; Kowalczuk, Krystyna; Kupisz, Krzysztof; Polberg, Krzysztof; Stepulak, Andrzej

    2017-01-01

    Objective: Laryngeal squamous cell carcinoma is one of the most common malignant tumors in the head and neck region. Due to the poor response to chemotherapeutics in patients and low survival rate, successful treatment of larynx cancer still remains a challenge. Therefore, the identification of novel treatment options is needed. We investigated the anticancer effects of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, on two different laryngeal cancer cell lines RK33 and RK45. We also studied the antiproliferative action of SAHA in combination with cisplatin and defined the type of pharmacological interaction between these drugs. Materials and Methods: Viability and proliferation of larynx cancer cell lines were studied by methylthiazolyldiphenyl-tetrazolium bromide method and 5-bromo-2-deoxyuridine incorporation assay, respectively. The type of interaction between SAHA and cisplatin was determined by an isobolographic analysis. Western blotting, flow cytometry and quantitative polymerase chain reaction method were used to determine acetylation of histone H3, cell cycle progression and genes expression, respectively. Apoptosis was assessed by means of nucleosomes released to cytosol. Results: SAHA alone or in combination with cisplatin inhibited larynx cancer cells proliferation, whereas displayed relatively low toxicity against normal cells - primary cultures of human skin fibroblasts. The mixture of SAHA with cisplatin exerted additive and synergistic interaction in RK33 and RK45 cells, respectively. We showed that SAHA induced hyperacetylation of histone H3 K9, K14 and K23 and triggered apoptosis. SAHA also caused cell cycle arrest by upregulation of CDKN1A and downregulation of CCND1 encoding p21WAF1/CIP1 and cyclin D1 proteins, respectively. Conclusion: Our studies demonstrated that SAHA may be considered as a potential therapeutic agent against larynx tumors.

  11. 3-O-sulfated glucuronide derivative as a potential anti-dengue virus agent.

    PubMed

    Hidari, Kazuya I P J; Ikeda, Kiyoshi; Watanabe, Ippei; Abe, Tomoko; Sando, Ayumi; Itoh, Yuji; Tokiwa, Hiroaki; Morita, Kouichi; Suzuki, Takashi

    2012-08-03

    A series of 12 carbohydrate compounds were synthesized by introduction of a sulfated group at specific positions and evaluated for their activities against dengue virus (DENV) infection as well as binding to BHK-21 cells. 3-O-sulfated GlcA was active against DENV infection, whereas 2-O-sulfated GlcA and 3,6-di-O-sulfated Glc showed negligible activity. Persulfated compounds did not inhibit DENV infection. These results provided a rationale for designing sulfated carbohydrate compounds with low molecular mass as anti-DENV agents targeting E protein functions. 3-O-Sulfated GlcA showed no significant cytotoxicity at 1mM. The EC(50) value (120 μM) was lower than that of sucrose octasulfate (SOS), a small molecular weight inhibitor of DENV infection. Two negatively charged groups, 3-O-sulfate and 6-C-carboxylic acid, appear to be essential for anti-DENV activity. We performed docking study to investigate the binding potential of 3-O-sulfated GlcA with respect to DENV E protein. The docking study showed that distance and conformation of these negative charges on the carbohydrate may be suitable for association with three amino acid residues of E protein critically involved in virus adsorption (Lys295, Ser145, and Gly159). This interaction may competitively prevent functional DENV binding to receptor(s) on host cells. In conclusion, 3-O-sulfated GlcA is a chemical probe that may facilitate exploration of the molecular mechanisms underlying manifestations of dengue diseases. Copyright © 2012 Elsevier Inc. All rights reserved.

  12. Glycine: A potential coupling agent to bond to helium plasma treated PEEK?

    PubMed

    Schmidlin, Patrick R; Eichberger, Marlis; Stawarczyk, Bogna

    2016-02-01

    To test the tensile bond strength (TBS) between two self-adhesive resin composite cements and PEEK after helium plasma treatment and used glycine as a potential coupling agent incorporated in different adhesives. In summary, 896 air-abraded PEEK specimens were fabricated. Half of the specimens were treated with cold active inert helium plasma and the other half were left non-treated. Both groups were then split in two groups: In group 1 (n=256), 64 specimens were pre-treated with: (a) soft-liner liquid, (b) visio.link, (c) Ambarino P60 and (d) no pre-treatment (control), respectively. In group 2 (n=192), specimens were conditioned accordingly, but the adhesive materials were modified by including a commercially available glycine (Air-Flow PERIO). PEEK specimens were then luted using either RelyX Unicem or Clearfil SA Cement and TBS was measured initially and after 14 days water storage combined with 10'000 thermal cycles (16 specimens/subgroup). Fracture type analysis was performed. For statistical analyses Kolmogorov-Smirnov, Shapiro-Wilk tests, 1-, 4-way ANOVA (post hoc: Scheffé), and t-test were used (p<0.001). Helium plasma pre-treatment without glycine showed no impact on initial TBS (p>0.348). In contrast, a combination between glycine application and Softline/Ambarino P60 allowed for significantly higher initial TBS was measured after helium plasma treatment (p=0.001). However, this effect was no evident after thermo-cycling. All groups conditioned with visio.link showed the highest TBS values. The introduction of amine groups by simple provision of amino acids in the form of glycine can improve the bond strength after helium plasma treatment using different adhesive materials. However, using this simple approach, the method cannot withstand thermal challenge yet. Copyright © 2015 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.

  13. Omega-3 fatty acid is a potential preventive agent for recurrent colon cancer.

    PubMed

    Vasudevan, Anita; Yu, Yingjie; Banerjee, Sanjeev; Woods, James; Farhana, Lulu; Rajendra, Sindhu G; Patel, Aamil; Dyson, Gregory; Levi, Edi; Maddipati, Krishna Rao; Majumdar, Adhip P N; Nangia-Makker, Pratima

    2014-11-01

    Increasing evidence supports the contention that many malignancies, including sporadic colorectal cancer, are driven by the self-renewing, chemotherapy-resistant cancer stem/stem-like cells (CSC/CSLC), underscoring the need for improved preventive and therapeutic strategies targeting CSCs/CSLCs. Omega-3 polyunsaturated fatty acids (ω-3 PUFA), have been reported to inhibit the growth of primary tumors, but their potential as a preventive agent for recurring cancers is unexplored. The primary objectives of this investigation are (i) to examine whether eicosapentaenoic acid (EPA; one of the ω-3 PUFA) synergizes with FuOx (5-FU+Oxaliplatin), the backbone of colon cancer chemotherapy, and (ii) whether EPA by itself or in combination with conventional chemotherapy prevents the recurrence of colon cancer via eliminating/suppressing CSCs/CSLCs. FuOx-resistant (chemoresistant; CR) colon cancer cells, highly enriched in CSCs, were used for this study. Although EPA alone was effective, combination of EPA and FuOx was more potent in (i) inhibiting cell growth, colonosphere formation, and sphere-forming frequency, (ii) increasing sphere disintegration, (iii) suppressing the growth of SCID mice xenografts of CR colon cancer cells, and (iv) decreasing proinflammatory metabolites in mice. In addition, EPA + FuOx caused a reduction in CSC/CSLC population. The growth reduction by this regimen is the result of increased apoptosis as evidenced by PARP cleavage. Furthermore, increased pPTEN, decreased pAkt, normalization of β-catenin expression, localization, and transcriptional activity by EPA suggests a role for the PTEN-Akt axis and Wnt signaling in regulating this process. Our data suggest that EPA by itself or in combination with FuOx could be an effective preventive strategy for recurring colorectal cancer.

  14. Novel Pharmacological Activity of Artesunate and Artemisinin: Their Potential as Anti-Tubercular Agents

    PubMed Central

    Choi, Won Hyung

    2017-01-01

    Tuberculosis is a major infectious disease that globally causes the highest human mortality. From this aspect, this study was carried out to evaluate novel pharmacological activities/effects of artesunate and artemisinin causing anti-tubercular activity/effects against Mycobacterium tuberculosis (Mtb). The anti-Mtb activities/effects of artesunate and artemisinin were evaluated using different anti-Mtb indicator assays, such as the resazurin microtiter assay, the Mycobacteria Growth Indicator Tube (MGIT) 960 system assay, and the Ogawa slant medium assay, as well as in vivo tests. Artesunate showed selective anti-Mtb effects by strongly inhibiting the growth of Mtb compared to artemisinin, and consistently induced anti-Mtb activity/effects by effectively inhibiting Mtb in the MGIT 960 system and in Ogawa slant medium for 21 days with a single dose; its minimum inhibitory concentration was 300 µg/mL in in vitro testing. Furthermore, artesunate demonstrated an anti-tubercular effect/action with a daily dose of 3.5 mg/kg in an in vivo test for four weeks, which did not indicate or induce toxicity and side effects. These results demonstrate that artesunate effectively inhibits the growth and/or proliferation of Mtb through novel pharmacological activities/actions, as well as induces anti-Mtb activity. This study shows its potential as a potent candidate agent for developing new anti-tuberculosis drugs of an effective/safe next generation, and suggests novel insights into its effective use by repurposing existing drugs through new pharmacological activity/effects as one of the substantive alternatives for inhibiting tuberculosis. PMID:28287416

  15. Bioinformatics prediction of siRNAs as potential antiviral agents against dengue viruses

    PubMed Central

    Villegas-Rosales, Paula M; Méndez-Tenorio, Alfonso; Ortega-Soto, Elizabeth; Barrón, Blanca L

    2012-01-01

    Dengue virus (DENV 1-4) represents the major emerging arthropod-borne viral infection in the world. Currently, there is neither an available vaccine nor a specific treatment. Hence, there is a need of antiviral drugs for these viral infections; we describe the prediction of short interfering RNA (siRNA) as potential therapeutic agents against the four DENV serotypes. Our strategy was to carry out a series of multiple alignments using ClustalX program to find conserved sequences among the four DENV serotype genomes to obtain a consensus sequence for siRNAs design. A highly conserved sequence among the four DENV serotypes, located in the encoding sequence for NS4B and NS5 proteins was found. A total of 2,893 complete DENV genomes were downloaded from the NCBI, and after a depuration procedure to identify identical sequences, 220 complete DENV genomes were left. They were edited to select the NS4B and NS5 sequences, which were aligned to obtain a consensus sequence. Three different servers were used for siRNA design, and the resulting siRNAs were aligned to identify the most prevalent sequences. Three siRNAs were chosen, one targeted the genome region that codifies for NS4B protein and the other two; the region for NS5 protein. Predicted secondary structure for DENV genomes was used to demonstrate that the siRNAs were able to target the viral genome forming double stranded structures, necessary to activate the RNA silencing machinery. PMID:22829722

  16. Characterization of novel diaryl oxazole-based compounds as potential agents to treat pancreatic cancer.

    PubMed

    Shaw, Arthur Y; Henderson, Meredith C; Flynn, Gary; Samulitis, Betty; Han, Haiyong; Stratton, Steve P; Chow, H-H Sherry; Hurley, Laurence H; Dorr, Robert T

    2009-11-01

    A series of diaryl- and fluorenone-based analogs of the lead compound UA-62784 [4-(5-(4-methoxyphenyl)oxazol-2-yl)-9H-fluoren-9-one] was synthesized with the intention of improving upon the selective cytotoxicity of UA-62784 against human pancreatic cancer cell lines with a deletion of the tumor suppressor gene deleted in pancreas cancer locus 4 (DPC-4, SMAD-4). Over 80 analogs were synthesized and tested for antitumor activity against pancreatic cancer (PC) cell lines (the PC series). Despite a structural relationship to UA-62784, which inhibits the mitotic kinesin centromere protein E (CENP-E), none of the analogs was selective for DPC-4-deleted pancreatic cancer cell lines. Furthermore, none of the analogs was a potent or selective inhibitor of four different mitotic kinesins (mitotic kinesin-5, CENP-E, mitotic kinesin-like protein-1, and mitotic centromere-associated kinesin). Therefore, other potential mechanisms of action were evaluated. A diaryl oxazole lead analog from this series, PC-046 [5-(4-methoxyphenyl)-2-(3-(3-methoxyphenyl)pyridin-4-yl) oxazole], was shown to potently inhibit several protein kinases that are overexpressed in human pancreatic cancers, including tyrosine receptor kinase B, interleukin-1 receptor-associated kinase-4, and proto-oncogene Pim-1. Cells exposed to PC-046 exhibit a cell cycle block in the S-phase followed by apoptotic death and necrosis. PC-046 effectively reduced MiaPaca-2 tumor growth in severe combined immunodeficiency mice by 80% compared with untreated controls. The plasma half-life was 7.5 h, and cytotoxic drug concentrations of >3 muM were achieved in vivo in mice. The diaryl oxazole series of compounds represent a new chemical class of anticancer agents that inhibit several types of cancer-relevant protein kinases.

  17. Antibacterial and antiinflammatory kinetics of curcumin as a potential antimucositis agent in cancer patients.

    PubMed

    Lüer, Sonja; Troller, Rolf; Aebi, Christoph

    2012-01-01

    The antiinflammatory agent curcumin (diferuloylmethane) has a potential to mitigate cancer therapy-induced mucositis. We assessed the in vitro extent of its bactericidal activity and determined the kinetics of its antiinflammatory effect on pharyngeal cells. Bactericidal activity was assessed using the LIVE/DEAD® Kit after 4 h of exposure to curcumin (50-200 μM) in 18 oropharyngeal species commonly associated with bacteremia in febrile neutropenia. Moraxella catarrhalis or its outer membrane vesicles were used to determine the inhibitory effect of curcumin on bacteria-induced proinflammatory activity as determined by cytokine release into the supernatant of Detroit 562 pharyngeal cells using the Luminex® xMAP® technology. Curcumin exerted a concentration-dependent bactericidal effect on all 18 species tested. After 4 h at 200 μM, 12 species tested were completely killed. Preincubation of Detroit cells with 200 μM curcumin for 5 to 60 min resulted in complete suppression of the release of tumor necrosis factor-α, interleukin (IL)-6, IL-8, monocyte chemoattractant protein 1, granulocyte macrophage-colony stimulating factor, and vascular endothelial growth factor. Fibroblast growth factor-2 and interferon-γ were not affected. Repetitive exposure to curcumin resulted in repetitive suppression of cytokine/chemokine expression lasting from 4 to 6 h. Through reduction of oral microbial density as well as suppression of inflammation cascades curcumin may prevent cancer therapy-induced oral mucositis, e.g., when applied as multiple daily mouth washes.

  18. Monascus Pigment Rubropunctatin: A Potential Dual Agent for Cancer Chemotherapy and Phototherapy.

    PubMed

    Zheng, Yunquan; Zhang, Yun; Chen, Deshan; Chen, Haijun; Lin, Ling; Zheng, Chengzhuo; Guo, Yanghao

    2016-03-30

    The Monascus pigment, rubropunctatin, was extracted and purified from red mold rice (RMR), and its cytotoxic activities against human cervical carcinoma HeLa cells were studied under the conditions with or without light irradiation. The IC50 value of rubropunctatin against HeLa cells in the dark was 93.71 ± 1.96 μM (24 h), while the cytotoxic activity was enhanced more than 3 times (IC50 = 24.02 ± 2.17 μM) under light irradiation (halogen lamp, 500 W; wavelength, 597-622 nm; and fluence rate, 15 mW cm(-2), for 30 min). However, the IC50 value of rubropunctatin against the immortalized human cervical epithelial H8 cells was more than 300 μM, even under light irradiation, indicating that rubropunctatin has a favorable selectivity index (SI). Treatment of HeLa cells with rubropunctatin in the dark or under light irradiation resulted in a dose-dependent apoptosis, as validated by the increase in the percentage of cells in the sub-G1 phase and phosphatidylserine externalization, and the inductive effect on HeLa cell apoptosis was boosted by the light irradiation. In addition, treatment with rubropunctatin alone or under light irradiation was found to induce apoptosis in HeLa cells via the mitochondrial pathway, including loss of mitochondrial membrane potential, activation of caspase-3, caspase-8, and caspase-9, and increase of the level of intracellular reactive oxygen species (ROS). It was suggested that rubropunctatin could be a promising natural dual anticancer agent for photodynamic therapy and chemotherapy.

  19. Synthesis, Biological Evaluation and Molecular Docking of New Benzenesulfonylhydrazone as Potential anti-Trypanosoma cruzi Agents.

    PubMed

    Elizondo-Jimenez, Silvia; Moreno-Herrera, Antonio; Reyes-Olivares, Rogelio; Dorantes-Gonzalez, Edith; Nogueda-Torres, Benjamín; Oliveira, Eduardo A Gamosa de; Romeiro, Nelilma C; Lima, Lidia M; Palos, Isidro; Rivera, Gildardo

    2017-01-01

    Chagas disease is a public health problem caused by Trypanosoma cruzi. Cruzain is a pharmacological target for designing a new drug against this parasite. Hydrazone and Nacylhydrazone derivatives have been traditionally associated as potential Cruzain inhibitors. Additionally, benzenesulfonyl derivatives show trypanocidal activity. Therefore, in this study, the combination of both structures has been taken into account for drug design. Seven benzenesulfonylhydrazone (BS-H) and seven N-propionyl benzenesulfonylhydrazone (BS-NAH) derivatives were synthetized and elucidated by infrared spectroscopy, nuclear magnetic resonance, and elemental analysis. All compounds were evaluated biologically in vitro against two strains of Trypanosoma cruzi (NINOA and INC-5), which are endemic in Mexico, and compared with the reference drugs nifurtimox and benznidazole. In order to gain insight into the putative molecular origin of the trypanocidal properties of these derivatives, docking studies were carried out with Cruzain. Compounds 4 and 6 (BS-H) and 10, 12-14 (BS-NAH) showed the best biological activity against NINOA and INC-5 strains, respectively. Compound 13 was the most potent trypanocidal compound showing a LC50 of 0.06 µM against INC-5 strain. However, compound 4 showed the best activity against both strains (LC50 <30 µM). Theoretical binding modes obtained suggested covalent binding that could explain their biological activity. Benzenesulfonyl and N-propionyl benzenesulfonyl hydrazone derivatives are good options for developing new trypanocidal agents. Particularly, compound 4 could be considered a lead compound. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  20. Shikimate kinase: a potential target for development of novel antitubercular agents.

    PubMed

    Pereira, José H; Vasconcelos, Igor B; Oliveira, Jaim S; Caceres, Rafael A; de Azevedo, Walter F; Basso, Luis A; Santos, Diógenes S

    2007-03-01

    Tuberculosis (TB) remains the leading cause of mortality due to a bacterial pathogen, Mycobacterium tuberculosis. However, no new classes of drugs for TB have been developed in the past 30 years. Therefore there is an urgent need to develop faster acting and effective new antitubercular agents, preferably belonging to new structural classes, to better combat TB, including MDR-TB, to shorten the duration of current treatment to improve patient compliance, and to provide effective treatment of latent tuberculosis infection. The enzymes in the shikimate pathway are potential targets for development of a new generation of antitubercular drugs. The shikimate pathway has been shown by disruption of aroK gene to be essential for the Mycobacterium tuberculosis. The shikimate kinase (SK) catalyses the phosphorylation of the 3-hydroxyl group of shikimic acid (shikimate) using ATP as a co-substrate. SK belongs to family of nucleoside monophosphate (NMP) kinases. The enzyme is an alpha/beta protein consisting of a central sheet of five parallel beta-strands flanked by alpha-helices. The shikimate kinases are composed of three domains: Core domain, Lid domain and Shikimate-binding domain. The Lid and Shikimate-binding domains are responsible for large conformational changes during catalysis. More recently, the precise interactions between SK and substrate have been elucidated, showing the binding of shikimate with three charged residues conserved among the SK sequences. The elucidation of interactions between MtSK and their substrates is crucial for the development of a new generation of drugs against tuberculosis through rational drug design.

  1. Potentiation of the mutagenicity and recombinagenicity of bleomycin in yeast by unconventional intercalating agents.

    PubMed

    Hoffmann, George R; Laterza, Amanda M; Sylvia, Katelyn E; Tartaglione, Jason P

    2011-03-01

    Interactions between bleomycin (BLM) and conventional or unconventional intercalating agents were analyzed in an assay for mitotic gene conversion at the trp5 locus and reversion of the ilv1-92 allele in Saccharomyces cerevisiae strain D7. BLM is a potent recombinagen and mutagen in the assay. Various chemicals modulate the genetic activity of BLM, producing either antimutagenic effects or enhanced genotoxicity. Effects of cationic amino compounds include enhancement of BLM activity by aminoacridines and protection against BLM by aliphatic amines. The potentiation of BLM is similar to findings in a micronucleus-based BLM amplification assay in Chinese hamster V79 cells. In this study, the amplification of BLM activity was explored in yeast using known intercalators, compounds structurally related to known intercalators, and unconventional intercalators that were identified on the basis of computer modeling or results in the Chinese hamster BLM amplification assay. As shown in previous studies, the classical intercalator 9-aminoacridine (9AA) caused dose-dependent enhancement of BLM activity. Other compounds found to enhance the induction of mitotic recombination and point mutations in strain D7 were chlorpromazine, chloroquine, mefloquine, tamoxifen, diphenhydramine, benzophenone, and 3-hydroxybenzophenone. The increased activity was detectable by cotreatment of yeast with BLM and the modulator compound in growth medium or by separate interaction of the intercalator with DNA followed by BLM treatment of nongrowing cells in buffer. The data support the interpretation drawn from micronucleus assays in mammalian cells that BLM enhancement results from DNA intercalation and may be useful in detecting noncovalent interactions with DNA. Environ. Copyright © 2010 Wiley-Liss, Inc.

  2. Fish and amphibians as potential reservoirs of Mycobacterium ulcerans, the causative agent of Buruli ulcer disease

    PubMed Central

    Willson, Sarah J.; Kaufman, Michael G.; Merritt, Richard W.; Williamson, Heather R.; Malakauskas, David M.; Benbow, Mark Eric

    2013-01-01

    Background Buruli ulcer is a skin disease often associated with proximity to certain water bodies in Africa. Much remains unknown about the reservoir and transmission of this disease. Previous studies have suggested that fish may concentrate Mycobacterium ulcerans, the etiological agent of the disease, in their gills and intestines and serve as passive reservoirs of the bacterium. The objective of this study was to test the hypothesis that fish and amphibians serve as natural reservoirs of M. ulcerans or other closely related mycolactone-producing mycobacteria. Methods Polymerase chain reaction targeting the enoyl reductase (ER) domain present in mlsA, which is required for mycolactone production, was used to screen water, fish, and amphibians from water bodies in Ghana for the presence of mycolactone-producing mycobacteria, and positive specimens were subjected to variable number tandem repeat (VNTR) typing. Results The use of VNTR typing revealed the presence of Mycobacterium liflandii in a tadpole and a fish, and M. ulcerans in an adult frog. Similarity percentage analysis (SIMPER) showed that the predatory cichlid Hemichromis bimaculatus was associated with ER-positive water bodies. No amphibian species or fish-feeding guild served as a reliable indicator of the presence of mycolactone-producing mycobacteria in a water body, and there was no significant difference between fish and amphibian positivity rates (P-value=0.106). There was a significant difference between water bodies in the total number of ER-positive specimens (P-value=0.0164). Conclusions Although IS2404-positive tadpoles and fish have been reported, this is the first VNTR confirmation of M. ulcerans or M. liflandii in wild amphibian and fish populations in West Africa. Results from this study suggest that amphibians should be carefully examined as potential reservoirs for M. ulcerans in West Africa, and that H. bimaculatus may be useful as an indicator of habitats likely to support mycolactone

  3. Pharmacological characterization of a novel gastrodin derivative as a potential anti-migraine agent.

    PubMed

    Wang, Ping-Han; Zhao, Li-Xue; Wan, Jing-Yu; Zhang, Liang; Mao, Xiao-Na; Long, Fang-Yi; Zhang, Shuang; Chen, Chu; Du, Jun-Rong

    2016-03-01

    Migraine is a highly prevalent neurovascular disorder in the brain. An optimal therapy for migraine has not yet been developed. Gastrodin (Gas), the main effective constitute from Gastrodiae Rhizoma (Tianma in Chinese), has been indicated for migraine treatment and prophylaxis more than 30 years, with demonstrated safety. However, Gas is a phenolic glycoside, with relatively low concentrations and weak efficacy in the central nervous system. To develop more effective anti-migraine agents, we synthesized a novel Gas derivative (Gas-D). In the present study, comparative pharmacodynamic evaluations of Gas and Gas-D were performed in a model of nitroglycerin (NTG)-induced migraine in rats and the hot-plate test in mice. Following behavioral testing in this migraine model, external jugular vein blood and the trigeminal nucleus caudalis (TNC) were collected to analyze plasma nitric oxide (NO) and calcitonin gene-related peptide (CGRP) concentrations and c-Fos expression in the TNC. The acute oral toxicity of Gas and Gas-D was also examined. We found that Gas-D had potent anti-migraine effects, likely attributable to inhibition of both trigeminal nerve activation at central sites and the peripheral release of CGRP following NO scavenging. Additionally, Gas-D exerted significant anti-nociceptive effect in response to thermal pain compared with Gas. Furthermore, a single dose of 2.048 g/kg Gas or Gas-D presented no acute oral toxicity in mice. Altogether, the potent anti-migraine and anti-hyperalgesic effects of Gas-D suggest that it might be a potentially novel drug candidate for migraine treatment or prophylaxis.

  4. Histone Deacetylase Inhibitor SAHA as Potential Targeted Therapy Agent for Larynx Cancer Cells

    PubMed Central

    Grabarska, Aneta; Łuszczki, Jarogniew J.; Nowosadzka, Ewa; Gumbarewicz, Ewelina; Jeleniewicz, Witold; Dmoszyńska-Graniczka, Magdalena; Kowalczuk, Krystyna; Kupisz, Krzysztof; Polberg, Krzysztof; Stepulak, Andrzej

    2017-01-01

    Objective: Laryngeal squamous cell carcinoma is one of the most common malignant tumors in the head and neck region. Due to the poor response to chemotherapeutics in patients and low survival rate, successful treatment of larynx cancer still remains a challenge. Therefore, the identification of novel treatment options is needed. We investigated the anticancer effects of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, on two different laryngeal cancer cell lines RK33 and RK45. We also studied the antiproliferative action of SAHA in combination with cisplatin and defined the type of pharmacological interaction between these drugs. Materials and Methods: Viability and proliferation of larynx cancer cell lines were studied by methylthiazolyldiphenyl-tetrazolium bromide method and 5-bromo-2-deoxyuridine incorporation assay, respectively. The type of interaction between SAHA and cisplatin was determined by an isobolographic analysis. Western blotting, flow cytometry and quantitative polymerase chain reaction method were used to determine acetylation of histone H3, cell cycle progression and genes expression, respectively. Apoptosis was assessed by means of nucleosomes released to cytosol. Results: SAHA alone or in combination with cisplatin inhibited larynx cancer cells proliferation, whereas displayed relatively low toxicity against normal cells - primary cultures of human skin fibroblasts. The mixture of SAHA with cisplatin exerted additive and synergistic interaction in RK33 and RK45 cells, respectively. We showed that SAHA induced hyperacetylation of histone H3 K9, K14 and K23 and triggered apoptosis. SAHA also caused cell cycle arrest by upregulation of CDKN1A and downregulation of CCND1 encoding p21WAF1/CIP1 and cyclin D1 proteins, respectively. Conclusion: Our studies demonstrated that SAHA may be considered as a potential therapeutic agent against larynx tumors. PMID:28123594

  5. Antibacterial Potential of an Antimicrobial Agent Inspired by Peroxidase-Catalyzed Systems

    PubMed Central

    Tonoyan, Lilit; Fleming, Gerard T. A.; Mc Cay, Paul H.; Friel, Ruairi; O'Flaherty, Vincent

    2017-01-01

    Antibiotic resistance is an increasingly serious threat to global health. Consequently, the development of non-antibiotic based therapies and disinfectants, which avoid induction of resistance, or cross-resistance, is of high priority. We report the synthesis of a biocidal complex, which is produced by the reaction between ionic oxidizable salts—iodide and thiocyanate—in the presence of hydrogen peroxide as an oxidation source. The reaction generates bactericidal reactive oxygen and iodine species. In this study, we report that the iodo-thiocyanate complex (ITC) is an effective bactericidal agent with activity against planktonic and biofilm cells of Gram-negative (Escherichia coli and Pseudomonas aeruginosa) and Gram-positive (Staphylococcus aureus and methicillin-resistant S. aureus) bacteria. The minimum bactericidal concentrations and the minimum biofilm eradication concentrations of the biocidal composite were in the range of 7.8–31.3 and 31.3–250 μg ml−1, respectively. As a result, the complex was capable to cause a rapid cell death of planktonic test cultures at between 0.5 and 2 h, and complete eradication of dual and mono-species biofilms between 30 s and 10 min. Furthermore, the test bacteria, including a MRSA strain, exposed to the cocktail failed to develop resistance after serial passages. The antimicrobial activity of the ITC appears to derive from the combinational effect of the powerful species capable of oxidizing the essential biomolecules of bacteria. The use of this composition may provide an effective and efficient method for killing potential pathogens, as well as for disinfecting and removing biofilm contamination. PMID:28512449

  6. Chiral lactic hydrazone derivatives as potential bioactive antibacterial agents: Synthesis, spectroscopic, structural and molecular docking studies

    NASA Astrophysics Data System (ADS)

    Noshiranzadeh, Nader; Heidari, Azam; Haghi, Fakhri; Bikas, Rahman; Lis, Tadeusz

    2017-01-01

    A series of novel chiral lactic-hydrazone derivatives were synthesized by condensation of (S)-lactic acid hydrazide with salicylaldehyde derivatives and characterized by elemental analysis and spectroscopic studies (FT-IR, 1H NMR and 13C NMR spectroscopy). The structure of one compound was determined by single crystal X-ray analysis. Antibacterial activity of the synthesized compounds was studied against Staphylococcus aureus, Streptococcus pneumonia, Escherichia coli and Pseudomonas aeruginosa as bacterial cultures by broth microdilution method. All of the synthesized compounds showed good antibacterial activity with MIC range of 64-512 μg/mL. Compounds (S,E)-2-hydroxy-N-(2-hydroxy-5-nitrobenzylidene)propanehydrazide (5) and (S,E)-2-hydroxy-N-((3-hydroxy-5-(hydroxymethyl)-2-methylpyridin-4-yl)propanehydrazide (7) were the most effective antibacterial derivatives against S. aureus and E. coli respectively with a MIC value of 64 μg/mL. Bacterial biofilm formation assay showed that these compounds significantly inhibited biofilm formation of P. aeruginosa. Also, in silico molecular docking studies were performed to show lipoteichoic acid synthase (LtaS) inhibitory effect of lactic hydrazone derivatives. The association between electronic and structural effects of some substituents on the benzylidene moiety and the biological activity of these chiral compounds were studied. Structural studies show that compound with higher hydrogen bonding interactions show higher antibacterial activity. The results show chiral hydrazone derivatives based on lactic acid hydrazide could be used as potential lead compounds for developing novel antibacterial agents.

  7. The in vitro metabolism of phospho-sulindac amide, a novel potential anticancer agent.

    PubMed

    Xie, Gang; Cheng, Ka-Wing; Huang, Liqun; Rigas, Basil

    2014-09-15

    Phospho-sulindac amide (PSA) is a novel potential anti-cancer and anti-inflammatory agent. Here we report the metabolism of PSA in vitro. PSA was rapidly hydroxylated at its butane-phosphate moiety to form two di-hydroxyl-PSA and four mono-hydroxyl-PSA metabolites in mouse and human liver microsomes. PSA also can be oxidized or reduced at its sulindac moiety to form PSA sulfone and PSA sulfide, respectively. PSA was mono-hydroxylated and cleared more rapidly in mouse liver microsomes than in human liver microsomes. Of eight major human cytochrome P450s (CYPs), CYP3A4 and CYP2D6 exclusively catalyzed the hydroxylation and sulfoxidation reactions of PSA, respectively. We also examined the metabolism of PSA by three major human flavin monooxygenases (FMOs). FMO1, FMO3 and FMO5 were all capable of catalyzing the sulfoxidation (but not hydroxylation) of PSA, with FMO1 being by far the most active isoform. PSA was predominantly sulfoxidized in human kidney microsomes because FMO1 is the dominant isoform in human kidney. PSA (versus sulindac) is a preferred substrate of both CYPs and FMOs, likely because of its greater lipophilicity and masked-COOH group. Ketoconazole (a CYP3A4 inhibitor) and alkaline pH strongly inhibited the hydroxylation of PSA, but moderately suppressed its sulfoxidation in liver microsomes. Together, our results establish the metabolic pathways of PSA, identify the major enzymes mediating its biotransformations and reveal significant inter-species and inter-tissue differences in its metabolism. Copyright © 2014 Elsevier Inc. All rights reserved.

  8. The in vitro metabolism of phospho-sulindac amide, a novel potential anticancer agent

    PubMed Central

    Xie, Gang; Cheng, Ka-Wing; Huang, Liqun; Rigas, Basil

    2014-01-01

    Phospho-sulindac amide (PSA) is a novel potential anti-cancer and anti-inflammatory agent. Here we report the metabolism of PSA in vitro. PSA was rapidly hydroxylated at its butane-phosphate moiety to form two di-hydroxyl-PSA and four mono-hydroxyl-PSA metabolites in mouse and human liver microsomes. PSA also can be oxidized or reduced at its sulindac moiety to form PSA sulfone and PSA sulfide, respectively. PSA was mono-hydroxylated and cleared more rapidly in mouse liver microsomes than in human liver microsomes. Of eight major human cytochrome P450s (CYPs), CYP3A4 and CYP2D6 exclusively catalyzed the hydroxylation and sulfoxidation reactions of PSA, respectively. We also examined the metabolism of PSA by three major human flavin monooxygenases (FMOs). FMO1, FMO3 and FMO5 were all capable of catalyzing the sulfoxidation (but not hydroxylation) of PSA, with FMO1 being by far the most active isoform. PSA was predominantly sulfoxidized in human kidney microsomes because FMO1 is the dominant isoform in human kidney. PSA (versus sulindac) is a preferred substrate of both CYPs and FMOs, likely because of its greater lipophilicity and masked –COOH group. Ketoconazole (a CYP3A4 inhibitor) and alkaline pH strongly inhibited the hydroxylation of PSA, but moderately suppressed its sulfoxidation in liver microsomes. Together, our results establish the metabolic pathways of PSA, identify the major enzymes mediating its biotransformations and reveal significant inter-species and inter-tissue differences in its metabolism. PMID:25044307

  9. Genotype-phenotype correlations in normotensive patients with primary renal tubular hypokalemic metabolic alkalosis.

    PubMed

    Bettinelli, A; Vezzoli, G; Colussi, G; Bianchetti, M G; Sereni, F; Casari, G

    1998-01-01

    phenotypic and genotypic data, we propose a clinical-pathophysiological and molecular approach to diagnose the different tubulopathies associated with hypokalemic metabolic alkalosis.

  10. Whole-Genome Sequence of Pseudomonas graminis Strain UASWS1507, a Potential Biological Control Agent and Biofertilizer Isolated in Switzerland

    PubMed Central

    Crovadore, Julien; Calmin, Gautier; Chablais, Romain; Cochard, Bastien; Schulz, Torsten

    2016-01-01

    We report here the whole-genome shotgun sequence of the strain UASWS1507 of the species Pseudomonas graminis, isolated in Switzerland from an apple tree. This is the first genome registered for this species, which is considered as a potential and valuable resource of biological control agents and biofertilizers for agriculture. PMID:27795260

  11. Whole-Genome Sequence of Pseudomonas graminis Strain UASWS1507, a Potential Biological Control Agent and Biofertilizer Isolated in Switzerland.

    PubMed

    Crovadore, Julien; Calmin, Gautier; Chablais, Romain; Cochard, Bastien; Schulz, Torsten; Lefort, François

    2016-10-06

    We report here the whole-genome shotgun sequence of the strain UASWS1507 of the species Pseudomonas graminis, isolated in Switzerland from an apple tree. This is the first genome registered for this species, which is considered as a potential and valuable resource of biological control agents and biofertilizers for agriculture. Copyright © 2016 Crovadore et al.

  12. Cold tolerance of Trissolcus japonicus and T. cultratus, potential biological control agents of Halyomorpha halys, the brown marmorated stink bug

    Treesearch

    Erica Nystrom Santacruz; Robert C. Venette; Christine Dieckhoff; Kim Hoelmer; Robert L. Koch

    2017-01-01

    Halyomorpha halys (Stål) (Hemiptera: Pentatomidae) is native to Asia and has become a severe agricultural and nuisance pest in the U.S. Therefore, foreign exploration was conducted in Asia to identify potential classical biological control agents. Several Trissolcus spp. (Hymenoptera: Scelionidae) parasitize H. halys...

  13. Superparamagnetic bifunctional bisphosphonates nanoparticles: a potential MRI contrast agent for osteoporosis therapy and diagnostic.

    PubMed

    Lalatonne, Y; Monteil, M; Jouni, H; Serfaty, J M; Sainte-Catherine, O; Lièvre, N; Kusmia, S; Weinmann, P; Lecouvey, M; Motte, L

    2010-06-15

    A bone targeting nanosystem is reported here which combined magnetic contrast agent for Magnetic Resonance Imaging (MRI) and a therapeutic agent (bisphosphonates) into one drug delivery system. This new targeting nanoplatform consists of superparamagnetic γFe(2)O(3) nanoparticles conjugated to 1,5-dihydroxy-1,5,5-tris-phosphono-pentyl-phosphonic acid (di-HMBPs) molecules with a bisphosphonate function at the outer of the nanoparticle surface for bone targeting. The as-synthesized nanoparticles were evaluated as a specific MRI contrast agent by adsorption study onto hydroxyapatite and MRI measurment. The strong adsorption of the bisphosphonates nanoparticles to hydroxyapatite and their use as MRI T2(∗) contrast agent were demonstrated. Cellular tests performed on human osteosarcoma cells (MG63) show that γFe(2)O(3)@di-HMBP hybrid nanomaterial has no citoxity effect in cell viability and may act as a diagnostic and therapeutic system.

  14. Superparamagnetic Bifunctional Bisphosphonates Nanoparticles: A Potential MRI Contrast Agent for Osteoporosis Therapy and Diagnostic

    PubMed Central

    Lalatonne, Y.; Monteil, M.; Jouni, H.; Serfaty, J. M.; Sainte-Catherine, O.; Lièvre, N.; Kusmia, S.; Weinmann, P.; Lecouvey, M.; Motte, L.

    2010-01-01

    A bone targeting nanosystem is reported here which combined magnetic contrast agent for Magnetic Resonance Imaging (MRI) and a therapeutic agent (bisphosphonates) into one drug delivery system. This new targeting nanoplatform consists of superparamagnetic γFe2O3 nanoparticles conjugated to 1,5-dihydroxy-1,5,5-tris-phosphono-pentyl-phosphonic acid (di-HMBPs) molecules with a bisphosphonate function at the outer of the nanoparticle surface for bone targeting. The as-synthesized nanoparticles were evaluated as a specific MRI contrast agent by adsorption study onto hydroxyapatite and MRI measurment. The strong adsorption of the bisphosphonates nanoparticles to hydroxyapatite and their use as MRI T2∗ contrast agent were demonstrated. Cellular tests performed on human osteosarcoma cells (MG63) show that γFe2O3@di-HMBP hybrid nanomaterial has no citoxity effect in cell viability and may act as a diagnostic and therapeutic system. PMID:20981332

  15. Potential production of palm oil-based foaming agent as fire extinguisher of peatlands in Indonesia: Literature review

    NASA Astrophysics Data System (ADS)

    Subekti, P.; Hambali, E.; Suryani, A.; Suryadarma, P.

    2017-05-01

    This study aims to analyze the potential aplication of of palm oil-based foaming agent as peat fires fighter in Indonesia. From literature review, it has been known that the foaming agent able to form foam to extinguish fire, wrap and refrigerate the burning peat. It is necessary to develop the production and application of foaming agent in Indonesia because peat fires occur almost every year that caused smoke haze. Potential raw material for the production of environmental friendly foaming agent as foam extinguishing for peat fires in Indonesia aong other is palm oil due to abundant availability, sustainable, and foam product easily degraded in the environment of the burnt areas. Production of foaming agent as fire-fighting in Indonesia is one alternative to reduce the time to control the fire and smog disaster impact. Application of palm oil as a raw material for fire-fighting is contribute to increase the value added and the development of palm oil downstream industry.

  16. Development and potential clinical impairment of ultra-short-acting neuromuscular blocking agents.

    PubMed

    Lien, C A

    2011-12-01

    Developing a non-depolarizing neuromuscular blocking agent that, like succinylcholine, has a rapid onset and a short duration of effect remains a goal of ongoing research. While rocuronium fills a portion of this need, the large doses required for rapid intubation render it a much longer-acting neuromuscular blocking agent. Postoperative residual neuromuscular block (NMB) is an increasingly recognized complication of non-depolarizing neuromuscular blocking agents. This occurs because of dosing choices for neuromuscular blocking agents and anticholinesterases as well as insensitivity of typically used monitors of depth of NMB. While antagonism of NMB is necessary with partial recovery, it is unnecessary with more complete recovery. Even when monitoring with an accelerograph, reversal of NMB is complicated. In addition to the pharmacodynamics of the individual neuromuscular blocking agents, factors such as timing of anticholinesterase administration, dose of anticholinesterase, concomitant medications, electrolyte abnormalities, and hepatic or renal disease can influence the degree of reversal. Sugammadex works differently than anticholinesterases and, when administered in appropriate doses, can reverse even profound block induced with vecuronium or rocuronium. Two new fumarate neuromuscular blocking agents have a rapid onset of effect and can be reversed at any time by administration of cysteine, which could significantly reduce the risk of postoperative residual NMB.

  17. Microtubule-targeting agents in oncology and therapeutic potential in hepatocellular carcinoma

    PubMed Central

    Loong, Herbert H; Yeo, Winnie

    2014-01-01

    In mammalian cells, microtubules are present both in interphase and dividing cells. In the latter, microtubules forming the mitotic spindle are highly dynamic and exquisitely sensitive to therapeutic inhibitors. Developed to alter microtubule function, microtubule-binding agents have been proven to be highly active as an anticancer treatment. Significant development of microtubule-binding agents has taken place in recent years, with newer anti-tubulin agents now showing novel properties of enhanced tumor specificity, reduced neurotoxicity, and insensitivity to chemoresistance mechanisms. Hepatocellular carcinoma remains one of the most difficult cancers to treat, with chemotherapies being relatively ineffective. There is now evidence to suggest that microtubule-binding agents may be effective in the treatment of hepatocellular carcinoma, especially when used in combination with mammalian target of rapamycin inhibitors. Preclinical models have suggested that the latter may be able to overcome resistance to microtubule binding agents. In this review article, recent developments of novel microtubule binding agents and their relevance to the treatment of hepatocellular carcinoma will be discussed. PMID:24790457

  18. Potential economic consequences of a cardioprotective agent for patients with myocardial infarction: modelling study.

    PubMed

    Verhoef, Talitha I; Morris, Stephen; Mathur, Anthony; Singer, Mervyn

    2015-11-13

    To investigate the cost-effectiveness of a hypothetical cardioprotective agent used to reduce infarct size in patients undergoing percutaneous coronary intervention (PCI) after anterior ST-elevation myocardial infarction. A cost-utility analysis using a Markov model. The National Health Service in the UK. Patients undergoing PCI after anterior ST-elevation myocardial infarction. A cardioprotective agent given at the time of reperfusion compared to no cardioprotection. We assumed the cardioprotective agent (given at the time of reperfusion) would reduce the risk and severity of heart failure (HF) after PCI and the risk of mortality after PCI (with a relative risk ranging from 0.6 to 1). The costs of the cardioprotective agent were assumed to be in the range £1000-4000. The incremental costs per quality-adjusted life-year (QALY) gained, using 95% CIs from 1000 simulations. Incremental costs ranged from £933 to £3820 and incremental QALYs from 0.04 to 0.38. The incremental cost-effectiveness ratio (ICER) ranged from £3311 to £63 480 per QALY gained. The results were highly dependent on the costs of a cardioprotective agent, patient age, and the relative risk of HF after PCI. The ICER was below the willingness-to-pay threshold of £20 000 per QALY gained in 71% of the simulations. A cardioprotective agent that can reduce the risk of HF and mortality after PCI has a high chance of being cost-effective. This chance depends on the price of the agent, the age of the patient and the relative risk of HF after PCI. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  19. The potential of combi-molecules with DNA-damaging function as anticancer agents.

    PubMed

    Sun, Guohui; Fan, Tengjiao; Zhao, Lijiao; Zhou, Yue; Zhong, Rugang

    2017-03-01

    DNA-damaging agents, such as methylating agents, chloroethylating agents and platinum-based agents, have been extensively used as anticancer drugs. However, the side effects, high toxicity, lack of selectivity and resistance severely limit their clinical applications. In recent years, a strategy combining a DNA-damaging agent with a bioactive molecule (e.g., enzyme inhibitors) or carrier (e.g., steroid hormone and DNA intercalators) to produce a new 'combi-molecule' with improved efficacy or selectivity has been attempted to overcome these drawbacks. The combi-molecule simultaneously acts on two targets and is expected to possess better potency than the parent compounds. Many studies have shown DNA-damaging combi-molecules exhibiting excellent anticancer activity in vitro and in vivo. This review focuses on the development of combi-molecules, which possess increased DNA-damaging potency, anticancer efficacy and tumor selectivity and reduced side reactions than the parent compounds. The future opportunities and challenges in the discovery of combi-molecules were also discussed.

  20. Development of immune-specific interaction potentials and their application in the multi-agent-system VaccImm.

    PubMed

    Woelke, Anna Lena; von Eichborn, Joachim; Murgueitio, Manuela S; Worth, Catherine L; Castiglione, Filippo; Preissner, Robert

    2011-01-01

    Peptide vaccination in cancer therapy is a promising alternative to conventional methods. However, the parameters for this personalized treatment are difficult to access experimentally. In this respect, in silico models can help to narrow down the parameter space or to explain certain phenomena at a systems level. Herein, we develop two empirical interaction potentials specific to B-cell and T-cell receptor complexes and validate their applicability in comparison to a more general potential. The interaction potentials are applied to the model VaccImm which simulates the immune response against solid tumors under peptide vaccination therapy. This multi-agent system is derived from another immune system simulator (C-ImmSim) and now includes a module that enables the amino acid sequence of immune receptors and their ligands to be taken into account. The multi-agent approach is combined with approved methods for prediction of major histocompatibility complex (MHC)-binding peptides and the newly developed interaction potentials. In the analysis, we critically assess the impact of the different modules on the simulation with VaccImm and how they influence each other. In addition, we explore the reasons for failures in inducing an immune response by examining the activation states of the immune cell populations in detail.In summary, the present work introduces immune-specific interaction potentials and their application to the agent-based model VaccImm which simulates peptide vaccination in cancer therapy.

  1. Development of Immune-Specific Interaction Potentials and Their Application in the Multi-Agent-System VaccImm

    PubMed Central

    Woelke, Anna Lena; von Eichborn, Joachim; Murgueitio, Manuela S.; Worth, Catherine L.; Castiglione, Filippo; Preissner, Robert

    2011-01-01

    Peptide vaccination in cancer therapy is a promising alternative to conventional methods. However, the parameters for this personalized treatment are difficult to access experimentally. In this respect, in silico models can help to narrow down the parameter space or to explain certain phenomena at a systems level. Herein, we develop two empirical interaction potentials specific to B-cell and T-cell receptor complexes and validate their applicability in comparison to a more general potential. The interaction potentials are applied to the model VaccImm which simulates the immune response against solid tumors under peptide vaccination therapy. This multi-agent system is derived from another immune system simulator (C-ImmSim) and now includes a module that enables the amino acid sequence of immune receptors and their ligands to be taken into account. The multi-agent approach is combined with approved methods for prediction of major histocompatibility complex (MHC)-binding peptides and the newly developed interaction potentials. In the analysis, we critically assess the impact of the different modules on the simulation with VaccImm and how they influence each other. In addition, we explore the reasons for failures in inducing an immune response by examining the activation states of the immune cell populations in detail. In summary, the present work introduces immune-specific interaction potentials and their application to the agent-based model VaccImm which simulates peptide vaccination in cancer therapy. PMID:21858048

  2. Organometallic Palladium Complexes with a Water-Soluble Iminophosphorane Ligand as Potential Anticancer Agents

    PubMed Central

    Carreira, Monica; Calvo-Sanjuán, Rubén; Sanaú, Mercedes; Marzo, Isabel; Contel, María

    2012-01-01

    The synthesis and characterization of a new water-soluble iminophosphorane ligand TPA=N-C(O)-2BrC6H4 (C,N-IM; TPA = 1,3,5-triaza-7-phosphaadamantane) 1 is reported. Oxidative addition of 1 to Pd2(dba)3 affords the orthopalladated dimer [Pd(μ-Br){C6H4(C(O)N=TPA-kC,N)-2}]2 (2) as a mixture of cis and trans isomers (1:1 molar ratio) where the iminophosphorane moeity behaves as a C,N-pincer ligand. By addition of different neutral or monoanionic ligands to 2, the bridging bromide can be cleaved and a variety of hydrophilic or water-soluble mononuclear organometallic palladium(II) complexes of the type [Pd{C6H4(C(O)N=TPA-kC,N)-2}(L-L)] (L-L = acac (3); S2CNMe2 (4); 4,7-Diphenyl-1,10-phenanthrolinedisulfonic acid disodium salt C12H6N2(C6H4SO3Na)2 (5)); [Pd{C6H4(C(O)N=TPA-kC,N)-2}(L)Br] (L = P(mC6H4SO3Na)3 (6); P(3-Pyridyl)3 (7)) and, [Pd(C6H4(C(O)N=TPA)-2}(TPA)2Br] (8) are obtained as single isomers. All new complexes were tested as potential anticancer agents and their cytotoxicity properties were evaluated in vitro against human Jurkat-T acute lymphoblastic leukemia cells, normal T-lymphocytes (PBMC) and DU-145 human prostate cancer cells. Compounds [Pd(μ-Br){C6H4(C(O)N=TPA-kC,N)-2}]2 (2) and [Pd{C6H4(C(O)N=TPA-kC,N)-2}(acac)] 3 (which has been crystallographically characterized) display the higher cytotoxicity against the above mentioned cancer cell lines while being less toxic to normal T-lymphocytes (peripheral blood mononuclear cells: PBMC). In addition, 3 is very toxic to cisplatin resistant Jurkat shBak indicating a cell death pathway that may be different to that of cisplatin. The interaction of 2 and 3 with plasmid (pBR322) DNA is much weaker than that of cisplatin pointing to an alternative biomolecular target for these cytotoxic compounds. All the compounds show an interaction with human serum albumin (HSA) faster than that of cisplatin. PMID:23066172

  3. The potential bioproduction of the pharmaceutical agent sakuranetin, a flavonoid phytoalexin in rice.

    PubMed

    Shimizu, Takafumi; Lin, Fengqiu; Hasegawa, Morifumi; Nojiri, Hideaki; Yamane, Hisakazu; Okada, Kazunori

    2012-01-01

    Sakuranetin, the major flavonoid phytoalexin in rice, can be induced by ultraviolet (UV) irradiation, treatment with CuCl 2 or jasmonic acid (JA), or phytopathogenic infection. In addition to sakuranetin's biological significance on disease resistance in rice, its broad bioactivities have recently been described. Results from these studies have shown that sakuranetin is a useful compound as a plant antibiotic and a potential pharmaceutical agent. Sakuranetin is biosynthesized from naringenin, a precursor of sakuranetin, by naringenin 7-O-methyltransferase (NOMT), but the relevant gene has not yet been identified in rice. Recently, we identified the OsNOMT gene, which is involved in the final step of sakuranetin biosynthesis in rice. In previous studies, OsNOMT was purified to apparent homogeneity from UV-treated wild-type rice leaves; however, the purified protein, termed OsCOMT1, exhibited caffeic acid 3-O-methyltransferase (COMT) activity, but not NOMT activity. Based on the analysis of an oscomt1 T-DNA tagged mutant, we determined that OsCOMT1 did not contribute to sakuranetin production in rice in vivo. Therefore, we took advantage of the oscomt1 mutant to purify OsNOMT. A crude protein preparation from UV-treated oscomt1 leaves was subjected to three sequential purification steps resulting in a 400-fold purification from the crude enzyme preparation with a minor band at an apparent molecular mass of 40 kDa in the purest enzyme preparation. Matrix-assisted laser desorption/ionization time of flight/time of flight analysis showed that the 40 kDa protein band included two O-methyltransferase-like proteins, but one of the proteins encoded by Os12g0240900 exhibited clear NOMT activity; thus, this gene was designated OsNOMT. Gene expression was induced by treatment with jasmonic acid in rice leaves prior to sakuranetin accumulation, and the recombinant protein showed reasonable kinetic properties to NOMT. Identification of the OsNOMT gene enables the production of

  4. Suberoylanilide hydroxamic acid as a potential therapeutic agent for human breast cancer treatment.

    PubMed Central

    Huang, L.; Pardee, A. B.

    2000-01-01

    BACKGROUND: Suberoylanilide hydroxamic acid (SAHA) is a prototype of the newly developed, second-generation, hybrid polar compounds. It is a novel histone deacetylase inhibitor with high potency for inducing cell differentiation of cultured murine erythroleukemia cells. Studies with SAHA have primarily been performed with hematopoietic tumor cells. Here we extent these studies with SAHA to human breast cancer cell lines in an attempt to find better therapeutic agents for breast cancer treatment. MATERIALS AND METHODS: Human breast cancer cell lines, MCF7, MDA-MB-231, and MDA-MB-435, as well as normal cells, including the normal breast epithelial cell line MCF-10A, and fibroblasts, were treated with SAHA. Cells assayed for cell survival by using trypan blue exclusion assay, colony formation assay, and cell cycle and apoptosis analysis. The effects of SAHA on cell cycle and apoptosis regulatory proteins were examined by Western blots analysis. The identification of additional target genes was carried out by differential display (DD) and reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: SAHA inhibited clonogenic growth of MCF7, MDA-MB-231, and MDA-MB-435 breast cancer cells. These cells were more sensitive to SAHA-mediated cytotoxic effects than normal breast epithelial cells and fibroblasts. The cytotoxic effects of SAHA on breast cancer cells were manifested by G1 and G2/M cell cycle arrest and eventual apoptosis. The pan-caspase inhibitor, Z-VAD.fmk, blocked SAHA-induced cell death, DNA laddering, and cleavage of poly(ADP-ribose) polymerase, indicating the involvement of caspases in SAHA-mediated apoptosis. In addition, SAHA modulated cell cycle and apoptosis regulatory proteins. For example, cyclin-dependent kinase (CDK) inhibitors p21WAF1/Cip1 and p27Kip1 were induced, and retinoblastoma protein pRb was hypophosphorylated. Moreover, SAHA induced several genes associated with differentiation and/ or growth inhibition. These genes encode gelsolin

  5. Severe blood loss during spinal reconstructive procedures: the potential usefulness of topical hemostatic agents.

    PubMed

    Block, Jon E

    2005-01-01

    Complex spinal reconstructive procedures are invariably associated with excessive intraoperative blood loss that significantly increases the risk of severe perioperative complications. In some cases, excessive hemorrhage is equivalent to estimated total blood volume. Unfortunately, widely exposed bony surfaces are not amenable to standard hemostatic maneuvers utilized during soft tissue surgery. This article evaluates the clinical effectiveness of several approaches to blood management in this setting, and hypothesizes that underappreciated topical hemostatic agents may provide benefit by reducing the need for autologous predonation, banked donor blood or antifibrinolytic agents. Topical agents combining collagen, thrombin and fibrin have demonstrated initial promise by inducing platelet aggregation and initiating the clotting cascade when applied directly to bleeding bony sites. Clinical studies are clearly warranted.

  6. Opportunities for new CT contrast agents to maximize the diagnostic potential of emerging spectral CT technologies.

    PubMed

    Yeh, Benjamin M; FitzGerald, Paul F; Edic, Peter M; Lambert, Jack W; Colborn, Robert E; Marino, Michael E; Evans, Paul M; Roberts, Jeannette C; Wang, Zhen J; Wong, Margaret J; Bonitatibus, Peter J

    2016-09-09

    The introduction of spectral CT imaging in the form of fast clinical dual-energy CT enabled contrast material to be differentiated from other radiodense materials, improved lesion detection in contrast-enhanced scans, and changed the way that existing iodine and barium contrast materials are used in clinical practice. More profoundly, spectral CT can differentiate between individual contrast materials that have different reporter elements such that high-resolution CT imaging of multiple contrast agents can be obtained in a single pass of the CT scanner. These spectral CT capabilities would be even more impactful with the development of contrast materials designed to complement the existing clinical iodine- and barium-based agents. New biocompatible high-atomic number contrast materials with different biodistribution and X-ray attenuation properties than existing agents will expand the diagnostic power of spectral CT imaging without penalties in radiation dose or scan time.

  7. [Evidences of physical agents action on bone metabolism and their potential clinical use].

    PubMed

    Lirani, Ana Paula R; Lazaretti-Castro, Marise

    2005-12-01

    The action of physical agents such as low level laser therapy, low-intensity pulsed ultrasound and electrical and electromagnetic fields on bone have been often studied, showing that they are able to promote osteogenesis, accelerate fracture consolidation and augment bone mass. The use of these therapeutic modalities was first based on the finding that bone is a piezoelectric material, that means it can generate polarization when deformed, transforming mechanical energy into electric energy, and this has widen therapeutic possibilities to bony tissue. The present work aims to present evidences of physiologic effects and mechanisms of action of these physical agents on bone metabolism, based on articles published in international scientific literature.

  8. Evaluation of FloSeal as a Potential Intracavitary Hemostatic Agent

    DTIC Science & Technology

    2006-02-01

    into the closed body cavity to provide hemostasis via a combination of coagulative and tamponade effects. FloSeal is an agent containing collagen and...bovine thrombin. When exposed to blood, FloSeal gelatin granules expand by 20% to provide a certain amount of tamponade ,6,7 and thrombin converts

  9. Synthesis and biological evaluation of novel gigantol derivatives as potential agents in prevention of diabetic cataract

    USDA-ARS?s Scientific Manuscript database

    As a continuation of our efforts directed towards the development of natural anti-diabetic cataract agents, gigantol was isolated from Herba dendrobii and was found to inhibit both aldose reductase (AR) and inducible nitric oxide synthase (iNOS) activity, which play a significant role in the develop...

  10. Exposure of hospital operating room personnel to potentially harmful environmental agents

    SciTech Connect

    Sass-Kortsak, A.M.; Purdham, J.T.; Bozek, P.R.; Murphy, J.H. )

    1992-03-01

    Epidemiologic studies of risk to reproductive health arising from the operating room environment have been inconclusive and lack quantitative exposure information. This study was undertaken to quantify exposure of operating room (OR) personnel to anesthetic agents, x-radiation, methyl methacrylate, and ethylene oxide and to determine how exposure varies with different operating room factors. Exposures of anesthetists and nurses to these agents were determined in selected operating rooms over three consecutive days. Each subject was asked to wear an x-radiation dosimeter for 1 month. Exposure to anesthetic agents was found to be influenced by the age of the OR facility, type of surgical service, number of procedures carried out during the day, type of anesthetic circuitry, and method of anesthesia delivery. Anesthetists were found to have significantly greater exposures than OR nurses. Exposure of OR personnel to ethylene oxide, methyl methacrylate, and x-radiation were well within existing standards. Exposure of anesthetists and nurses to anesthetic agents, at times, was in excess of Ontario exposure guidelines, despite improvements in the control of anesthetic pollution.

  11. Simulations of population dynamics of hemlock woolly adelgid and potential impact of biological control agents

    Treesearch

    Joseph S. Elkinton; Robert T. Trotter; Ann F. Paradis

    2011-01-01

    The hemlock woolly adelgid (Adelges tsugae) is a small invasive Hemipteran herbivore that threatens the continued presence and abundance of hemlock in eastern North America. Efforts to control the adelgid have focused on the introduction of classical biological control agents. These biological controls include six different species of predatory...

  12. Potential of Pest and Host Phenological Data in the Attribution of Regional Forest Disturbance Detection Maps According to Causal Agent

    NASA Technical Reports Server (NTRS)

    Spruce, Joseph; Hargrove, William; Norman Steve; Christie, William

    2014-01-01

    Near real time forest disturbance detection maps from MODIS NDVI phenology data have been produced since 2010 for the conterminous U.S., as part of the on-line ForWarn national forest threat early warning system. The latter has been used by the forest health community to identify and track many regional forest disturbances caused by multiple biotic and abiotic damage agents. Attribution of causal agents for detected disturbances has been a goal since project initiation in 2006. Combined with detailed cover type maps, geospatial pest phenology data offer a potential means for narrowing the candidate causal agents responsible for a given biotic disturbance. U.S. Aerial Detection Surveys (ADS) employ such phenology data. Historic ADS products provide general locational data on recent insect-induced forest type specific disturbances that may help in determining candidate causal agents for MODIS-based disturbance maps, especially when combined with other historic geospatial disturbance data (e.g., wildfire burn scars and drought maps). Historic ADS disturbance detection polygons can show severe and extensive regional forest disturbances, though they also can show polygons with sparsely scattered or infrequent disturbances. Examples will be discussed that use various historic disturbance data to help determine potential causes of MODIS-detected regional forest disturbance anomalies.

  13. Recent advances in inhibitors of bacterial fatty acid synthesis type II (FASII) system enzymes as potential antibacterial agents.

    PubMed

    Wang, Yi; Ma, Shutao

    2013-10-01

    Bacterial infections are a constant and serious threat to human health. With the increase of multidrug resistance of clinically pathogenic bacteria, common antibiotic therapies have been less effective. Fatty acid synthesis type II (FASII) system enzymes are essential for bacterial membrane lipid biosynthesis and represent increasingly promising targets for the discovery of antibacterial agents with new mechanisms of action. This review highlights recent advances in inhibitors of bacterial FASII as potential antibacterial agents, paying special attention to the activities, mechanisms, and structure-activity relationships of those inhibitors that mainly target β-ketoacyl-ACP synthase, β-ketoacyl-ACP reductase, β-hydroxyacyl-ACP dehydratase, and enoyl-ACP reductase. Although inhibitors with low nanomolar and selective activity against various bacterial FASII have entered clinical trials, further research is needed to expand upon both available and yet unknown scaffolds to identify new FASII inhibitors that may have antibacterial potential, particularly against resistant bacterial strains.

  14. In vitro and in vivo evaluation of chitosan microspheres with different deacetylation degree as potential embolic agent.

    PubMed

    Zhou, Xuan; Kong, Ming; Cheng, Xiao Jie; Feng, Chao; Li, Jing; Li, Jing Jing; Chen, Xi Guang

    2014-11-26

    To evaluate the potential of N-acetylated chitosan microspheres used as a chemoembolic agent in vivo and in vitro. Calibrated spherical chitosan microspheres (CMs) were prepared via Water-in-Oil emulsification method and CMs were acetylated (ACMs). The swelling rate of CMs was greatly affected by pH than that of ACMs and both of them affected by temperature. Microspheres with excellent thermal stability demonstrated controllable degradation in lysozyme solution. Doxorubicin was released from microspheres in vitro and exhibited excellent control release profile. ACMs caused hemolysis less than CMs (<5% of the time). Co-culture with mouse embryo fibroblasts revealed that microspheres have non-cytotoxic nature. Microspheres planted in a rat gluteal muscle demonstrated that it were biodegradable and biocompatible. ACMs were performed in rabbit ear embolization model and ischemic necrosis on ear was visible due to the vascular occlusion after 15 days. Acetylated chitosan microspheres could be used as potential biocompatible and biodegradable embolic agents.

  15. Syntheses And Evaluation Of Asymmetric Curcumin Analogues As Potential Multifunctional Agents For The Treatment Of Alzheimer's Disease.

    PubMed

    Zhai, Peng; Xia, Chun-Li; Tan, Jia-Heng; Li, Ding; Ou, Tian-Miao; Huang, Shi-Liang; Gu, Lian-Quan; Huang, Zhi-Shu

    2015-01-01

    A series of new asymmetric curcumin analogues were synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer's disease. Our results showed that most of these synthetic compounds had better inhibitory properties against Aβ aggregation compared with curcumin, and better anti-oxidative properties compared with the reference compound Trolox through the study of oxygen radical absorbance capacity (ORAC). Some compounds showed good properties in selectively chelating metal ions such as copper and iron. Besides, some compounds were found to be able to dissociate Aβ protein which had already aggregated. The structure-activity relationships (SAR) of these synthetic compounds were studied. The present investigation indicated that our synthetic asymmetric curcumin derivatives could be potential multifunctional agents for the treatment of Alzheimer's disease (AD).

  16. Design of multivalent galactosyl carborane as a targeting specific agent for potential application to boron neutron capture therapy.

    PubMed

    Lai, Chian-Hui; Lin, Yu-Chuan; Chou, Fong-In; Liang, Chien-Fu; Lin, En-Wei; Chuang, Yung-Jen; Lin, Chun-Cheng

    2012-01-14

    A multivalent galactosyl carborane derivative 10 (dendritic glyco-borane, DGB) was synthesized and demonstrated as a potential cell-targeting agent in BNCT with HepG2 cells. DGB 10 improved the delivery of boron to HepG2 cells and neutron irradiation data show DGB 10 with ten-fold improvement at killing the HepG2 cells over BSH. This journal is © The Royal Society of Chemistry 2012

  17. Synthesis of Sugar-Boronic Acid Derivatives: A Class of Potential Agents for Boron Neutron Capture Therapy.

    PubMed

    Imperio, Daniela; Del Grosso, Erika; Fallarini, Silvia; Lombardi, Grazia; Panza, Luigi

    2017-04-07

    To date, sugar analogues that contain boronic acids as substitutes for hydroxyl groups are a class of compounds nearly unknown in the literature. The challenging synthesis of two sugar-boronic acid analogues is described, and data are retrieved on their solution behavior, stability, and toxicity. As these compounds were expected to mimic the behavior of carbohydrates, they were tested in regards to their future development as potential boron neutron capture therapy agents.

  18. Metabolomic analysis of Ranunculus spp. as potential agents involved in the etiology of equine grass sickness.

    PubMed

    Michl, Johanna; Modarai, Maryam; Edwards, Sarah; Heinrich, Michael

    2011-09-28

    Identification of toxic or harmful agents continues to be a key goal in agricultural chemistry. This paper reports a metabolomic analysis of Ranunculus repens and related species, which were recently postulated to be cocausative agents in the etiology of equine grass sickness (EGS). Specifically, samples collected at EGS sites were compared with those from non-EGS sites. Furthermore, interspecific and seasonal variations and the species' response to edaphic and climatic factors were investigated. (1)H NMR spectroscopy in combination with multivariate data analysis was applied to the crude methanol extracts of the Ranunculus samples, as well as their chloroform fractions. Samples from EGS sites were significantly different from control samples. The metabolite composition varied greatly between different Ranunculus species. No significant changes could be observed between samples collected in different seasons. This work provides strong evidence that Ranunculus is involved in the etiology of EGS and has implications for agricultural management of pastures.

  19. Is there potential for therapeutic drug monitoring of biologic agents in rheumatoid arthritis?

    PubMed

    Bastida, Carla; Ruíz, Virginia; Pascal, Mariona; Yagüe, Jordi; Sanmartí, Raimon; Soy, Dolors

    2016-12-19

    The use of biologics has significantly changed the management of rheumatoid arthritis over the last decade, becoming the cornerstone treatment for many patients. The current therapeutic arsenal consists of just under 10 biologic agents, with four different mechanisms of action. Several studies have demonstrated a large interindividual pharmacokinetic variability, which translates to unpredictability in clinical response among individuals. The present review focuses on the pharmacokinetics and pharmacodynamics of biologic agents approved for rheumatoid arthritis. The literature relating to their concentration-effect relationship and the use of pharmacokinetic-pharmacodynamic modelling to optimize drug regimens is analysed. Due to the scarcity and complexity of these studies, the current dosing strategy is based on clinical indexes/aspects. In general, dose individualization for biologics should be implemented increasingly in clinical practice as there is a direct benefit for treated rheumatoid arthritis patients. Moreover, there is an indirect benefit in terms of cost-effectiveness.

  20. Evaluation of Degradation Properties of Polyglycolide and Its Potential as Delivery Vehicle for Anticancer Agents

    SciTech Connect

    Noorsal, K.; Ghani, S. M.; Yunos, D. M.; Mohamed, M. S. W.; Yahya, A. F.

    2010-03-11

    Biodegradable polymers offer a unique combination of properties that can be tailored to suit nearly any controlled drug delivery application. The most common biodegradable polymers used for biomedical applications are semicrystalline polyesters and polyethers which possess good mechanical properties and have been used in many controlled release applications. Drug release from these polymers may be controlled by several mechanisms and these include diffusion of drug through a matrix, dissolution of polymer matrix and degradation of the polymer. This study aims to investigate the degradation and drug release properties of polyglycolide (1.03 dL/g), in which, cis platin, an anticancer agent was used as the model drug. The degradation behaviour of the chosen polymer is thought to largely govern the release of the anticancer agent in vitro.

  1. Hydroxy double salts intercalated with Mn(II) complexes as potential contrast agents

    NASA Astrophysics Data System (ADS)

    Jin, Miao; Li, Wanjing; Spillane, Dominic E. M.; Geraldes, Carlos F. G. C.; Williams, Gareth R.; Bligh, S. W. Annie

    2016-03-01

    A series of Mn(II) aminophosphonate complexes were successfully synthesized and intercalated into the hydroxy double salt [Zn5(OH)8]Cl2·yH2O. Complex incorporation led to an increase in the interlayer spacing from 7.8 to 10-12 Å. Infrared spectroscopy showed the presence of the characteristic vibration peaks of the Mn(II) complexes in the intercalates' spectra, indicating successful incorporation. The complex-loaded composites had somewhat lower proton relaxivities than the pure complexes. Nevertheless, these intercalates may have use as MRI contrast agents for patients with poor kidney function, where traditional Gd(III)-based contrast agents cause severe renal failure.

  2. Potential New Pharmacological Agents Derived From Medicinal Plants for the Treatment of Pancreatic Cancer.

    PubMed

    Azimi, Haniye; Khakshur, Ali Asghar; Abdollahi, Mohammad; Rahimi, Roja

    2015-01-01

    In the present article, we reviewed plants and phytochemical compounds demonstrating beneficial effects in pancreatic cancer to find new sources of pharmaceutical agents. For this purpose, Scopus, PubMed, Web of Science, and Google scholar were searched for plants or herbal components with beneficial effects in the treatment of pancreatic cancer. Data were collected up to January 2013. The search terms were "plant," "herb," "herbal therapy," or "phytotherapy" and "pancreatic cancer" or "pancreas." All of the human in vivo and in vitro studies were included. According to studies, among diverse plants and phytochemicals, 12 compounds including apigenin, genistein, quercetin, resveratrol, epigallocatechin gallate, benzyl isothiocyanate, sulforaphane, curcumin, thymoquinone, dihydroartemisinin, cucurbitacin B, and perillyl alcohol have beneficial action against pancreatic cancer cells through 4 or more mechanisms. Applying their plausible synergistic effects can be an imperative approach for finding new efficient pharmacological agents in the treatment of pancreatic cancer.

  3. Possible Application of Biotechnology to the Development of Biological Agents by Potential Enemies

    DTIC Science & Technology

    1987-06-01

    for -28- t-: & penicillinase (bcta-lactamasc). Other plasmids carry resistance to heavy metals , erythromycin, chloramphenicol, tetracyclines...to conduct BW research for defensive purposes only and to limit studies to those that would protect the soldier from the effects of BW agents...resulting effect on the infected troops reduced the tactical value. Also, the impossibility of controlling the spread of the organisms following

  4. A Novel Swine Model for Evaluation of Potential Intravascular Hemostatic Agents

    DTIC Science & Technology

    2007-06-01

    Michael Scherer, and Jacqueline Crissey as well as the outstanding staff of the Veterinary Service Support Branch at the US Army Institute of...blood coagulation time and platelet retention by glass beads in rats. Thromb Res 8:179–193. 9. Dejana E , Villa S, de Gaetano G. 1982. Bleeding time in...Dickneite G, Nicolay U, Friesen HJ, Reers M. 1998. Development of an anti-bleeding agent for recombinant hirudin induced skin bleeding in the pig

  5. Non-aflatoxigenic Aspergillus flavus as potential biocontrol agents to reduce aflatoxin contamination in peanuts harvested in Northern Argentina.

    PubMed

    Alaniz Zanon, María Silvina; Barros, Germán Gustavo; Chulze, Sofía Noemí

    2016-08-16

    Biological control is one of the most promising strategies for preventing aflatoxin contamination in peanuts at field stage. A population of 46 native Aspergillus flavus nonaflatoxin producers were analysed based on phenotypic, physiological and genetic characteristics. Thirty-three isolates were characterized as L strain morphotype, 3 isolates as S strain morphotype, and 10 isolates did not produce sclerotia. Only 11 of 46 non-aflatoxigenic isolates did not produce cyclopiazonic acid. The vegetative compatibility group (VCG) diversity index for the population was 0.37. For field trials we selected the non-aflatoxigenic A. flavus AR27, AR100G and AFCHG2 strains. The efficacy of single and mixed inocula as potential biocontrol agents in Northern Argentina was evaluated through a 2-year study (2014-2015). During the 2014 peanut growing season, most of the treatments reduced the incidence of aflatoxigenic strains in both soil and peanut kernel samples, and no aflatoxin was detected in kernels. During the 2015 growing season, there was a reduction of aflatoxigenic strains in kernel samples from the plots treated with the potential biocontrol agents. Reductions of aflatoxin contamination between 78.36% and 89.55% were observed in treated plots in comparison with the un-inoculated control plots. This study provides the first data on aflatoxin biocontrol based on competitive exclusion in the peanut growing region of Northern Argentina, and proposes bioproducts with potential use as biocontrol agents. Copyright © 2016. Published by Elsevier B.V.

  6. Potential Novel Treatments for Bipolar Depression: Ketamine, Fatty Acids, Anti-inflammatory Agents, and Probiotics.

    PubMed

    Vázquez, G H; Camino, S; Tondo, L; Baldessarini, Ross J

    2017-07-28

    Treatments for depression in bipolar disorder (BD) are far less well developed than for unipolar major depressive disorder. Several innovative and experimental approaches have been emerging recently, including use of the dissociative anesthetic ketamine and other antagonists of central NMDA glutamate receptors, as well as unsaturated fatty acids, anti-inflammatory agents, and possibly probiotic methods. We reviewed relevant reports from the past decade. Ketamine, a phencyclidine-like NMDA-glutamate receptor antagonist, has emerged as a highly innovative, experimental treatment for treatment-resistant unipolar major depression, possibly in bipolar depression, and with brief antisuicidal effects. Its limitations include poor bioavailability, rapid but short-lived effects, and little information about long-term benefits and safety of repeated administration. Polyunsaturated fatty acids critical for the structure and functioning of neuronal and other cell membranes have some evidence of benefit as experimental treatments for depression including in BD. There also is evidence of altered expression of peptides associated with inflammation in mood disorder patients, encouraging experimental treatment with anti-inflammatory agents; of these, the COX-II inhibitor celecoxib has shown some evidence of benefit. The concept of altering intestinal flora with probiotic treatments to treat mood disorders remains speculative. Ketamine represents an innovative, rapidly acting, experimental treatment for bipolar depression with practical limitations. Unsaturated fatty acids and anti-inflammatory agents have inconsistent support; probiotic treatments lack evidence. These innovative approaches require much more clinical investigation. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  7. The potential of antiviral agents to control classical swine fever: a modelling study.

    PubMed

    Backer, Jantien A; Vrancken, Robert; Neyts, Johan; Goris, Nesya

    2013-09-01

    Classical swine fever (CSF) represents a continuous threat to pig populations that are free of disease without vaccination. When CSF virus is introduced, the minimal control strategy imposed by the EU is often insufficient to mitigate the epidemic. Additional measures such as preemptive culling encounter ethical objections, whereas emergency vaccination leads to prolonged export restrictions. Antiviral agents, however, provide instantaneous protection without inducing an antibody response. The use of antiviral agents to contain CSF epidemics is studied with a model describing within- and between-herd virus transmission. Epidemics are simulated in a densely populated livestock area in The Netherlands, with farms of varying sizes and pig types (finishers, piglets and sows). Our results show that vaccination and/or antiviral treatment in a 2 km radius around an infected herd is more effective than preemptive culling in a 1 km radius. However, the instantaneous but temporary protection provided by antiviral treatment is slightly less effective than the delayed but long-lasting protection offered by vaccination. Therefore, the most effective control strategy is to vaccinate animals when allowed (finishers and piglets) and to treat with antiviral agents when vaccination is prohibited (sows). As independent control measure, antiviral treatment in a 1 km radius presents an elevated risk of epidemics running out of control. A 2 km control radius largely eliminates this risk.

  8. Synthesis and mechanisms of action of novel harmine derivatives as potential antitumor agents

    PubMed Central

    Zhang, Xiao-Fei; Sun, Rong-qin; Jia, Yi-fan; Chen, Qing; Tu, Rong-Fu; Li, Ke-ke; Zhang, Xiao-Dong; Du, Run-Lei; Cao, Ri-hui

    2016-01-01

    A series of novel harmine derivatives bearing a benzylindine substituent in position-1 of β-carboline ring were synthesized and evaluated as antitumor agents. The N2-benzylated β-carboline derivatives 3a–g represented the most interesting anticancer activities and compound 3c was found to be the most active agent to diverse cancer cell lines such as gastric carcinoma, melanoma and colorectal cancer. Notably, compound 3c showed low toxicity to normal cells. The treatment significantly induced cell apoptosis. Mechanistically, PI3K/AKT signaling pathway mediated compound 3c-induced apoptosis. Compound 3c inhibited phosphorylation of AKT and promoted the production of reactive oxygen species (ROS). The ROS scavenger, LNAC and GSH, could disturb the effect of compound 3c induced apoptosis and PI3K activity inhibitor LY294002 synergistically enhanced compound 3c efficacy. Moreover, the results from nude mice xenograft model showed that compound 3c treatment effectively inhibited tumor growth and decreased tumor weight. Collectively, our results demonstrated that compound 3c exerts apoptotic effect in cancer cells via suppression of phosphorylated AKT and evocation of ROS generation, which suggested that compound 3c might be served as a promising therapeutic agent for cancer treatment. PMID:27625151

  9. Vitamin B12-mediated transport: a potential tool for tumor targeting of antineoplastic drugs and imaging agents.

    PubMed

    Gupta, Yashwant; Kohli, Dharm Veer; Jain, Sanjay K

    2008-01-01

    The uptake of vitamin B12 (cyanocobalamin, Cbl/VB12) in mammalian cells is mediated by specific, high-affinity receptors for the vitamin B12-binding protein, transcobalamin II, which is expressed on the plasma membrane. The receptor for vitamin B12 is overexpressed on a number of human tumors, including cancers of the ovary, kidney, uterus, testis, brain, colon, lung, and myelocytic blood cells. Furthermore, the affinity of cyanocobalamin conjugates for cell surface transcobalamin II receptors seems to be high enough so that vitamin B12 derivatization with the cytotoxic agent or carriers bearing cytotoxic drugs allows the selective delivery of diagnostic and therapeutic agents to cancer cells. Thus, conjugates of vitamin B12 enter receptor-expressing cancer cells via receptor-mediated endocytosis, and targeting may be accomplished by multiple mechanisms, depending on the drug-delivery strategy. This review summarizes the applications of vitamin B12 as a targeting ligand and highlights the various methods being developed for delivery of therapeutic and imaging agents to cancer cells in vitro and in vivo. This review reflects the potentiality of vitamin B12 for tumor targeting of chemotherapeutic and diagnostic agents.

  10. Synthesis, characterization, and relaxation studies of Gd-DO3A conjugate of chlorambucil as a potential theranostic agent.

    PubMed

    Kaur, Jasleen; Tsvetkova, Yoanna; Arroub, Karim; Sahnoun, Sabri; Kiessling, Fabian; Mathur, Sanjay

    2017-02-01

    DO3A-based macrocycles serve as attractive templates from which clinically useful theranostic agents can be obtained after coupling with molecular targeted therapeutic drugs. In this study, we describe the chemical synthesis, relaxation, and cytotoxicity studies of a new DO3A conjugate of chlorambucil (CHL) as a magnetic resonance imaging (MRI) theranostic agent. A convenient route of synthesis is reported, which allowed conjugation of the macrocyclic ligand (DO3A) to the chemotherapeutic drug (CHL) via tyrosine for the preparation of an attractive chelate-drug ensemble (DO3A-TR-CHL). The structures of all intermediates and final compound have been determined by (1) H, (13) C NMR, and MS. The efficacy of DO3A-TR-CHL as a non-ionic magnetic contrast agent was tested by performing relaxometric studies on its gadolinium complex. The complex exhibited relaxivities (7.11 mm(-1) /s) higher than that of currently used MR contrast agents and showed enhanced contrast in T1 -weighted images. MTT assays revealed that both DO3A-TR-CHL and Gd(III)-DO3A-TR-CHL conjugates exhibited dose-dependent toxicity and an enhanced antiproliferative activity against tumor (A549 and HeLa) cell lines compared to that of parent drug (CHL), thereby demonstrating their potential to be used as a magnetic resonance imaging theranostic for improved molecular imaging and therapy of human cancers. © 2017 John Wiley & Sons A/S.

  11. Synthesis and Biological Evaluation of Novel Gigantol Derivatives as Potential Agents in Prevention of Diabetic Cataract

    PubMed Central

    Li, Xue; Fang, Hua; Wan, Wencheng; Yang, Qiaohong; Sun, Xiaosheng; Wang, Meiling; Hu, Xiaohong; Chen, C.-Y. Oliver; Wei, Xiaoyong

    2015-01-01

    As a continuation of our efforts directed towards the development of natural anti-diabetic cataract agents, gigantol was isolated from Herba dendrobii and was found to inhibit both aldose reductase (AR) and inducible nitric oxide synthase (iNOS) activity, which play a significant role in the development and progression of diabetic cataracts. To improve its bioefficacy and facilitate use as a therapeutic agent, gigantol (compound 14f) and a series of novel analogs were designed and synthesized. Analogs were formulated to have different substituents on the phenyl ring (compounds 4, 5, 8, 14a-e), substitute the phenyl ring with a larger steric hindrance ring (compounds 10, 17c) or modify the carbon chain (compounds 17a, 17b, 21, 23, 25). All of the analogs were tested for their effect on AR and iNOS activities and on D-galactose-induced apoptosis in cultured human lens epithelial cells. Compounds 5, 10, 14a, 14b, 14d, 14e, 14f, 17b, 17c, 23, and 25 inhibited AR activity, with IC50 values ranging from 5.02 to 288.8 μM. Compounds 5, 10, 14b, and 14f inhibited iNOS activity with IC50 ranging from 432.6 to 1188.7 μM. Compounds 5, 8, 10, 14b, 14f, and 17c protected the cells from D-galactose induced apoptosis with viability ranging from 55.2 to 76.26%. Of gigantol and its analogs, compound 10 showed the greatest bioefficacy and is warranted to be developed as a therapeutic agent for diabetic cataracts. PMID:26517726

  12. Synthesis of fluorine-18 labeled rhodamine B: A potential PET myocardial perfusion imaging agent

    PubMed Central

    Heinrich, Tobias K.; Gottumukkala, Vijay; Snay, Erin; Dunning, Patricia; Fahey, Frederic H; Treves, S. Ted; Packard, Alan B.

    2009-01-01

    There is considerable interest in developing an 18F-labeled PET myocardial perfusion agent. Rhodamine dyes share several properties with 99mTc-MIBI, the most commonly used single-photon myocardial perfusion agent, suggesting that an 18F-labeled rhodamine dye might prove useful for this application. In addition to being lipophilic cations, like 99mTc-MIBI, rhodamine dyes are known to accumulate in the myocardium and are substrates for Pgp, the protein implicated in MDR1 multidrug resistance. As the first step in determining whether 18F-labeled rhodamines might be useful as myocardial perfusion agents for PET, our objective was to develop synthetic methods for preparing the 18F-labeled compounds so that they could be evaluated in vivo. Rhodamine B was chosen as the prototype compound for development of the synthesis because the ethyl substituents on the amine moieties of rhodamine B protect them from side reactions, thus eliminating the need to include (and subsequently remove) protecting groups. The 2′-[18F]fluoroethyl ester of rhodamine B was synthesized by heating rhodamine B lactone with [18F]fluoroethyltosylate in acetonitrile at 165°C for 30 min.using [18F]fluoroethyl tosylate, which was prepared by the reaction of ethyleneglycol ditosylate with Kryptofix 2.2.2, K2CO3, and [18F]NaF in acetonitrile for 10 min. at 90°C. The product was purified by semi-preparative HPLC to produce the 2′-[18F]-fluoroethylester in >97% radiochemical purity with a specific activity of 1.3 GBq/μmol, an isolated decay corrected yield of 35%, and a total synthesis time of 90 min. PMID:19783150

  13. Potential antitumor agents. 29. Quantitative structure-activity relationships for the antileukemic bisquaternary ammonium heterocycles.

    PubMed

    Denny, W A; Atwell, G J; Baguley, B C; Cain, B F

    1979-02-01

    Quantitative relationships between physicochemical drug properties and antileukemic (L1210) efficacy have been examined for a series of bisquaternary ammonium heterocycles employing multiple variable regression analysis. Three measures of biologic response were examined: ILSmax, the percentage increase in mean life span of leukemic animals at the LD10 dose; D40, the drug dose necessary to provide 40% increase in life span; and CI (=LD 10/D40), the chemotherapeutic index. A cross correlation matrix between these three measures and the LD10 values demonstrates ILSmax and CI to be independent of toxicity. D40 is highly inversely correlated with LD10 and positively correlated with ILSmax, suggesting that this parameter measures a composite of both drug selectivity and toxicity. Superior regression equations resulted at all stages employing ILSmax as a measure of antitumor selectivity. Acceptable equations modeling LD10 could not be obtained. There was a parabolic relationship between agent lipophilic-hydrophilic balance, measured as chromatographic Rm values, and ILSmax. To reduce residual variance in the L1210 screening data, not accepted by this parabolic equation, measures of agent-DNA interaction were investigated as possible indices of site fit. Relative levels of drug-DNA interaction were obtained by spectrofluorimetric quantitation of drug displacement of DNA-bound ethidium. Addition to regression equations of agent C50 values for calf thymus DNA, those micromolar drug concentrations necessary to displace 50% of the ethidium bound to that DNA, provided a significant reduction in the screening data variance. C50 values for drug interactions with poly[d(A-T)] and poly[d(G-C)] were also investigated as possible indicators of drug selectivity towards different DNA sites. Marked differences were observed in the C50 values for the two synthetic nucleic acids, with those for calf thymus DNA and poly[d(G-C)] proving highly covariant. A regression equation containing a

  14. (Bifunctional chelates of Rh-105, Au-199, and other metallic radionuclides as potential radiotherapeutic agents)

    SciTech Connect

    Not Available

    1991-01-01

    Progress during this period is reported under the following headings: Diethylenetriamine based and related bifunctional chelating agents and their complexation with Rh-105, Au-198, Pd-109, cu-67, In-111, and Co-57; studies of Pd-109, Rh-105 and Tc-99m with bifunctional chelates based on phenylenediamine; establishment of an appropriate protein assay method for conjugated proteins; studies of new bifunctional Bi, Tri and tetradentate amine oxime ligands with Rh-105; IgG and antibody B72.3 conjugation studies by HPLC Techniques with bifunctional metal chelates; and progress on ligand systems for Au(III).

  15. [Bifunctional chelates of Rh-105, Au-199, and other metallic radionuclides as potential radiotherapeutic agents

    SciTech Connect

    Not Available

    1991-12-31

    Progress during this period is reported under the following headings: Diethylenetriamine based and related bifunctional chelating agents and their complexation with Rh-105, Au-198, Pd-109, cu-67, In-111, and Co-57; studies of Pd-109, Rh-105 and Tc-99m with bifunctional chelates based on phenylenediamine; establishment of an appropriate protein assay method for conjugated proteins; studies of new bifunctional Bi, Tri and tetradentate amine oxime ligands with Rh-105; IgG and antibody B72.3 conjugation studies by HPLC Techniques with bifunctional metal chelates; and progress on ligand systems for Au(III).

  16. Lepidopterans as Potential Agents for the Biological Control of the Invasive Plant, Miconia calvescens

    PubMed Central

    Morais, Elisangela G.F.; Picanço, Marcelo C.; Semeão, Altair A.; Barreto, Robert W.; Rosado, Jander F.; Martins, Julio C.

    2012-01-01

    This work investigated eight species of Lepidoptera associated with Miconia calvescens DC. (Myrtales: Melastomataceae) in Brazil, including six defoliators, Salbia lotanalis Druce (Lepidoptera: Pyralidae), Druentia inscita Schaus (Mimallonidae), Antiblemma leucocyma Hampson (Noctuidae), three Limacodidae species, a fruit borer Carposina cardinata Meyrick (Carposinidae), and a damager of flowers Pleuroprucha rudimentaria Guenée (Geometridae). Based on host specificity and the damage caused to plants, S. lotanalis and D. inscita are the most promising species for biological control of M. calvescens. Furthermore, if C. cardinata and P. rudimentaria have host specificity in future tests, these caterpillars could also be considered as appropriate biocontrol agents. PMID:22938203

  17. Glycans in pathogenic bacteria--potential for targeted covalent therapeutics and imaging agents.

    PubMed

    Tra, Van N; Dube, Danielle H

    2014-05-11

    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.

  18. Selecting bioactive phenolic compounds as potential agents to inhibit proliferation and VEGF expression in human ovarian cancer cells

    PubMed Central

    HE, ZHIPING; LI, BO; RANKIN, GARY O.; ROJANASAKUL, YON; CHEN, YI CHARLIE

    2015-01-01

    Ovarian cancer is a disease that continues to cause mortality in female individuals worldwide. Ovarian cancer is challenging to treat due to emerging resistance to chemotherapy, therefore, the identification of effective novel chemotherapeutic agents is important. Polyphenols have demonstrated potential in reducing the risk of developing numerous types of cancer, as well reducing the risk of cancer progression, due to their ability to reduce cell viability and vascular endothelial growth factor (VEGF) expression. In the present study, eight phenolic compounds were screened in two human ovarian cancer cell lines (OVCAR-3 and A2780/CP70) to determine their effect on proliferation suppression and VEGF protein secretion inhibition, in comparison to cisplatin, a conventional chemotherapeutic agent. The current study identified that 40 μM gallic acid (GA) exhibited the greatest inhibitory effect on OVCAR-3 cell viability, compared with all of the phenolic compounds investigated. Similarly to cisplatin, baicalein, GA, nobiletin, tangeretin and baicalin were all identified to exhibit significant VEGF inhibitory effects from ELISA results. Furthermore, western blot analysis indicated that GA effectively decreased the level of the VEGF-binding protein hypoxia-inducible factor-1α in the ovarian cancer cell line. Considering the results of the present study, GA appears to inhibit cell proliferation and, thus, is a potential agent for the treatment of ovarian cancer. PMID:25663929

  19. N,N-dimethylhexadecyl carboxymethyl chitosan as a potential carrier agent for rotenone.

    PubMed

    Kamari, A; Aljafree, N F A; Yusoff, S N M

    2016-07-01

    In this study, an amphiphilic chitosan derivative namely N,N-dimethylhexadecyl carboxymethyl chitosan (DCMC) was synthesised and applied for the first time as a carrier agent for rotenone. The physical and chemical properties of DCMC were characterised by using Fourier Transform Infrared Spectrometer (FTIR), Proton Nuclear Magnetic Resonance Spectrometer ((1)H NMR), CHN-O Elemental Analyser, Thermogravimetric Analyser (TGA) and Differential Scanning Calorimeter (DSC). DCMC was soluble in acidic (except pH 4), neutral and basic media with percent of transmittance (%T) values ranged from 67.2 to 99.4%. The critical micelle concentration (CMC) was determined as 0.095mg/mL. Transmission Electron Microscopy (TEM) analysis confirmed that DCMC has formed self-aggregates and exhibited spherical shape with the size of 65.5-137.0nm. The encapsulation efficiency (EE) and loading capacity (LC) of DCMC micelles with different weight ratios (DCMC:rotenone; 5:1, 50:1 and 100:1) were determined by using High Performance Liquid Chromatography (HPLC). The weight ratio of 100:1 gave the best EE with the value of more than 95.0%. DCMC micelles performed an excellent ability to control the release of rotenone, of which 99.0% of rotenone was released within 48h. Overall, DCMC has several key features to be an effective carrier agent for pesticide formulations. Copyright © 2016 Elsevier B.V. All rights reserved.

  20. Novel C6-substituted 1,3,4-oxadiazinones as potential anti-cancer agents

    PubMed Central

    Jung, Yujin; Yun, Hye Jeong; Min, Hye-Young; Lee, Ho Jin; Pham, Phuong Chi; Moon, Jayoung; Kwon, Dah In; Lim, Bumhee; Suh, Young-Ger; Lee, Jeeyeon; Lee, Ho-Young

    2015-01-01

    The insulin-like growth factor 1 receptor (IGF-1R) is a membrane receptor tyrosine kinase over-expressed in a number of tumors. However, combating resistance is one of the main challenges in the currently available IGF-1R inhibitor-based cancer therapies. Increased Src activation has been reported to confer resistance to anti-IGF-1R therapeutics in various tumor cells. An urgent unmet need for IGF-1R inhibitors is to suppress Src rephosphorylation induced by current anti-IGF-1R regimens. In efforts to develop effective anticancer agents targeting the IGF-1R signaling pathway, we explored 2-aryl-1,3,4-oxadiazin-5-ones as a novel scaffold that is structurally unrelated to current tyrosine kinase inhibitors (TKIs). The compound, LL-2003, exhibited promising antitumor effects in vitro and in vivo; it effectively suppressed IGF-1R and Src and induced apoptosis in various non-small cell lung cancer cells. Further optimizations for enhanced potency in cellular assays need to be followed, but our strategy to identify novel IGF-1R/Src inhibitors may open a new avenue to develop more efficient anticancer agents. PMID:26515601

  1. 2,3-DIPHENYL-1,4-NAPHTHOQUINONE: A POTENTIAL CHEMOTHERAPEUTIC AGENT AGAINST TRYPANOSOMA CRUZI

    PubMed Central

    Ramos, Enrique I.; Garza, Kristine M.; Krauth-Siegel, R. L.; Bader, Julia; Martinez, Luiz E.; Maldonado, Rosa A.

    2010-01-01

    Chagas disease, caused by Trypanosoma cruzi, is a wide spread infection in Latin America. Currently, only 2 partially effective and highly toxic drugs, i.e., benznidazole and nifurtimox, are available for the treatment of this disease and several efforts are underway in the search for better chemotherapeutic agents. Here, we have determined the trypanocidal activity of 2,3-diphenyl-1,4-naphthoquinone (DPNQ), a novel quinone derivative. In vitro, DPNQ was highly cytotoxic at a low, micromolar concentration (LD50 = 2.5 μM) against epimastigote, cell-derived trypomastigote, and intracellular amastigote forms of T. cruzi, but not against mammalian cells (LD50 = 130 μM). In vivo studies on the murine model of Chagas disease revealed that DPNQ-treated animals (3 doses of 10 mg/kg/day) showed a significant delay in parasitemia peak and higher (up to 60%) survival rate 70 days post-infection, when compared to control group (infected, untreated). We also observed a 2-fold decrease in the parasitemia between the control group (infected, untreated) and the treated group (infected, treated). No apparent drug toxicity effects were noticed in the control group (uninfected, treated). In addition, we determined that DPNQ is the first competitive inhibitor of T. cruzi lipoamide dehydrogenase (TcLipDH) thus far described. Our results indicate that DPNQ is a promising chemotherapeutic agent against T. cruzi. PMID:18788881

  2. Phylogenetic Analysis of Entomoparasitic Nematodes, Potential Control Agents of Flea Populations in Natural Foci of Plague

    PubMed Central

    Koshel, E. I.; Aleshin, V. V.; Eroshenko, G. A.; Kutyrev, V. V.

    2014-01-01

    Entomoparasitic nematodes are natural control agents for many insect pests, including fleas that transmit Yersinia pestis, a causative agent of plague, in the natural foci of this extremely dangerous zoonosis. We examined the flea samples from the Volga-Ural natural focus of plague for their infestation with nematodes. Among the six flea species feeding on different rodent hosts (Citellus pygmaeus, Microtus socialis, and Allactaga major), the rate of infestation varied from 0 to 21%. The propagation rate of parasitic nematodes in the haemocoel of infected fleas was very high; in some cases, we observed up to 1,000 juveniles per flea specimen. Our study of morphology, life cycle, and rDNA sequences of these parasites revealed that they belong to three distinct species differing in the host specificity. On SSU and LSU rRNA phylogenies, these species representing three genera (Rubzovinema, Psyllotylenchus, and Spilotylenchus), constitute a monophyletic group close to Allantonema and Parasitylenchus, the type genera of the families Allantonematidae and Parasitylenchidae (Nematoda: Tylenchida). We discuss the SSU-ITS1-5.8S-LSU rDNA phylogeny of the Tylenchida with a special emphasis on the suborder Hexatylina. PMID:24804197

  3. Paramagnetic viral nanoparticles as potential high-relaxivity magnetic resonance contrast agents.

    PubMed

    Allen, Mark; Bulte, Jeff W M; Liepold, Lars; Basu, Gautam; Zywicke, Holly A; Frank, Joseph A; Young, Mark; Douglas, Trevor

    2005-10-01

    In order to compensate for the inherent high threshold of detectability of MR contrast agents, there has been an active interest in the development of paramagnetic nanoparticles incorporating high payloads of Gd(3+) with high molecular relaxivities. Toward this end, the protein cage of Cowpea chlorotic mottle virus (CCMV), having 180 metal binding sites, is being explored. In vivo CCMV binds Ca(2+) at specific metal binding sites; however, Gd(3+) can also bind at these sites. Using fluorescence resonance energy transfer we have characterized the binding affinity of Gd(3+) to the metal binding sites by competition experiments with Tb(3+). The measured dissociation constant (K(d)) for Gd(3+) bound to the virus is 31 microM. The T(1) and T(2) relaxivities of solvent water protons in the presence of Gd(3+)-bound CCMV were 202 and 376 mM(-1) s(-1), respectively, at 61 MHz Larmor frequency. The unusually high relaxivity values of the Gd(3+)-CCMV are largely a result of the nanoparticle virus size and the large number of Gd(3+) ions bound to the virus. These preliminary results should encourage further investigations into the use of viral protein cages as a new platform for MR contrast agents. Copyright 2005 Wiley-Liss, Inc.

  4. Paramagnetic nanoparticles as potential MRI contrast agents: characterization, NMR relaxation, simulations and theory.

    PubMed

    Vuong, Quoc Lam; Van Doorslaer, Sabine; Bridot, Jean-Luc; Argante, Corradina; Alejandro, Gabriela; Hermann, Raphaël; Disch, Sabrina; Mattea, Carlos; Stapf, Siegfried; Gossuin, Yves

    2012-12-01

    Paramagnetic nanoparticles, mainly rare earth oxides and hydroxides, have been produced these last few years for use as MRI contrast agents. They could become an interesting alternative to iron oxide particles. However, their relaxation properties are not well understood. Magnetometry, (1)H and (2)H NMR relaxation results at different magnetic fields and electron paramagnetic resonance are used to investigate the relaxation induced by paramagnetic particles. When combined with computer simulations of transverse relaxation, they allow an accurate description of the relaxation induced by paramagnetic particles. For gadolinium hydroxide particles, both T(1) and T(2) relaxation are due to a chemical exchange of protons between the particle surface and bulk water, called inner sphere relaxation. The inner sphere is also responsible for T(1) relaxation of dysprosium, holmium, terbium and erbium containing particles. However, for these latter compounds, T(2) relaxation is caused by water diffusion in the field inhomogeneities created by the magnetic particle, the outer-sphere relaxation mechanism. The different relaxation behaviors are caused by different electron relaxation times (estimated by electron paramagnetic resonance). These findings may allow tailoring paramagnetic particles: ultrasmall gadolinium oxide and hydroxide particles for T(1) contrast agents, with shapes ensuring the highest surface-to-volume ratio. All the other compounds present interesting T(2) relaxation performance at high fields. These results are in agreement with computer simulations and theoretical predictions of the outer-sphere and static dephasing regime theories. The T(2) efficiency would be optimum for spherical particles of 40-50 nm radius.

  5. Phylogenetic analysis of entomoparasitic nematodes, potential control agents of flea populations in natural foci of plague.

    PubMed

    Koshel, E I; Aleshin, V V; Eroshenko, G A; Kutyrev, V V

    2014-01-01

    Entomoparasitic nematodes are natural control agents for many insect pests, including fleas that transmit Yersinia pestis, a causative agent of plague, in the natural foci of this extremely dangerous zoonosis. We examined the flea samples from the Volga-Ural natural focus of plague for their infestation with nematodes. Among the six flea species feeding on different rodent hosts (Citellus pygmaeus, Microtus socialis, and Allactaga major), the rate of infestation varied from 0 to 21%. The propagation rate of parasitic nematodes in the haemocoel of infected fleas was very high; in some cases, we observed up to 1,000 juveniles per flea specimen. Our study of morphology, life cycle, and rDNA sequences of these parasites revealed that they belong to three distinct species differing in the host specificity. On SSU and LSU rRNA phylogenies, these species representing three genera (Rubzovinema, Psyllotylenchus, and Spilotylenchus), constitute a monophyletic group close to Allantonema and Parasitylenchus, the type genera of the families Allantonematidae and Parasitylenchidae (Nematoda: Tylenchida). We discuss the SSU-ITS1-5.8S-LSU rDNA phylogeny of the Tylenchida with a special emphasis on the suborder Hexatylina.

  6. New (68)Ga-PhenA bisphosphonates as potential bone imaging agents.

    PubMed

    Wu, Zehui; Zha, Zhihao; Choi, Seok Rye; Plössl, Karl; Zhu, Lin; Kung, Hank F

    2016-06-01

    In vivo positron emission tomography (PET) imaging of the bone using [(68)Ga]bisphosphonates may be a valuable tool for cancer diagnosis and monitoring therapeutic treatment. We have developed new [(68)Ga]bisphosphonates based on the chelating group, AAZTA (6-[bis(hydroxycarbonyl-methyl)amino]-1,4-bis(hydroxycarbonyl methyl)-6-methylperhydro-1,4-diazepine). Phenoxy derivative of AAZTA (2,2'-(6-(bis(carboxymethyl)amino)-6-((4-(2-carboxyethyl)phenoxy)methyl)-1,4-diazepane-1,4-diyl)diacetic acid), PhenA, 2, containing a bisphosphonate group (PhenA-BPAMD, 3, and PhenA-HBP, 4) was prepared. Labeling of these chelating agents with (68)Ga was evaluated. The ligands reacted rapidly in a sodium acetate buffer with [(68)Ga]GaCl3 eluted from a commercially available (68)Ge/(68)Ga generator (pH4, >95% labeling at room temperature in 5min) to form [(68)Ga]PhenA-BPAMD, 3, and [(68)Ga]PhenA-HBP, 4. The improved labeling condition negates the need for further purification. The (68)Ga bisphosphonate biodistribution and autoradiography of bone sections in normal mice after an iv injection showed excellent bone uptake. New (68)Ga labeled bisphosphonates may be useful as in vivo bone imaging agents in conjunction with positron emission tomography (PET). Copyright © 2016 Elsevier Inc. All rights reserved.

  7. Synthesis and Evaluation of Ester Derivatives of 10-Hydroxycanthin-6-one as Potential Antimicrobial Agents.

    PubMed

    Zhao, Fei; Dai, Jiang-Kun; Liu, Dan; Wang, Shi-Jun; Wang, Jun-Ru

    2016-03-21

    As part of our continuing research on canthin-6-one antimicrobial agents, a new series of ester derivatives of 10-hydroxycanthin-6-one were synthesized using a simple and effective synthetic route. The structure of each compound was characterized by NMR, ESI-MS, FT-IR, UV, and elemental analysis. The antimicrobial activity of these compounds against three phytopathogenic fungi (Alternaria solani, Fusarium graminearum, and Fusarium solani) and four bacteria (Bacillus cereus, Bacillus subtilis, Ralstonia solanacearum, and Pseudomonas syringae) were evaluated using the mycelium linear growth rate method and micro-broth dilution method, respectively. The structure-activity relationship is discussed. Of the tested compounds, 4 and 7s displayed significant antifungal activity against F. graminearum, with inhibition rates of 100% at a concentration of 50 μg/mL. Compounds 5, 7s, and 7t showed the best inhibitory activity against all the tested bacteria, with minimum inhibitory concentrations (MICs) between 3.91 and 31.25 μg/mL. Thus, 7s emerged as a promising lead compound for the development of novel canthine-6-one antimicrobial agents.

  8. Functionality study of santalin as tyrosinase inhibitor: A potential depigmentation agent.

    PubMed

    Hridya, Hemachandran; Amrita, Anantharaman; Mohan, Sankari; Gopalakrishnan, Mohan; Dakshinamurthy, Thirumal Kumar; Doss, George Priya; Siva, Ramamoorthy

    2016-05-01

    Excessive melanin production leads to hyperpigmentation disorders which results in distressing aesthetic values. Though there are some synthetic depigmentation agents available it has been reported to possess cytotoxic and mutagenic effects. Hence there is a need for the development of safe and non toxic natural tyrosinase inhibitors. Here we report the role of santalin, the chief constituent of Pterocarpus santalinus in inhibition of tyrosinase and melanin synthesis. Santalin inhibited tyrosinase activity dose dependently. Inhibitory kinetic studies revealed mixed type of inhibition with reversible mechanism. Santalin was found to interact with the fluorophore amino acid residue of tyrosinase. Analysis of circular dichroism spectra showed the binding of santalin to tyrosinase which induced the loss of secondary helical structure. Molecular docking result suggested that santalin interact with the catalytic core of tyrosinase through strong hydrogen and hydrophobic bonding. The results of in vitro studies showed santalin inhibited melanogenesis through down regulation of MITF, tyrosinase, TRP-1 and TRP-2 without any cytotoxic effects towards B16F0 melanoma cells. Therefore, our results suggested that santalin possesses anti-tyrosinase activity, which could be utilized as a safe depigmentation agent in the cosmetic field for the treatment of hyperpigmentation disorder. Copyright © 2016 Elsevier B.V. All rights reserved.

  9. Novel epigallocatechin gallate analogs as potential anticancer agents: a patent review (2009 – present)

    PubMed Central

    Landis-Piwowar, Kristin; Chen, Di; Foldes, Robert; Chan, Tak-Hang; Dou, Qing Ping

    2013-01-01

    Introduction Over the past three years numerous patents and patent applications have been published relating to scientific advances in the use of the green tea polyphenol epigallocatechin gallate (EGCG) (the most abundant, and bioactive compound in green tea) and its analogs as anticancer agents. EGCG affects multiple molecular targets involved in cancer cell proliferation and survival; however, polyphenolic catechins, such as EGCG, generally exhibit poor oral bioavailability. Since the anticancer activity of polyphenols largely depends on their susceptibility to biotransformation reactions, numerous EGCG derivatives, analogs and prodrugs have been designed to improve the stability, bioavailability and anticancer potency of the native compound. Areas covered This review focuses on the applications of EGCG and its analogs, derivatives and prodrugs in the prevention and treatment of human cancers. A comprehensive description of patents related to EGCG and its derivatives, analogs and prodrugs and their uses as anticancer agents is included. Expert opinion EGCG targets multiple essential survival proteins and pathways in human cancer cells. Because it is unstable physiologically, numerous alterations to the EGCG molecule have been patented, either to improve the integrity of the native compound or to generate a more stable yet similarly efficacious molecule. EGCG and its derivatives, analogs and prodrugs could be developed into future drugs for chemoprevention, chemosensitization, radiosensitization and/or cancer interception. PMID:23230990

  10. A preliminary investigation of the psychoactive agent 4-bromo-2,5-dimethoxyphenethylamine: a potential drug of abuse.

    PubMed

    Glennon, R A; Titeler, M; Lyon, R A

    1988-07-01

    4-Bromo-2,5-dimethoxyphenethylamine (alpha-desMe DOB) is a psychoactive agent that may possess significant abuse potential. Because of its structural similarity to the established hallucinogen 1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane (DOB), and because almost no pharmacological data are available on this agent, we undertook this preliminary investigation. alpha-DesMe DOB (Ki = 1 nM), like DOB itself (Ki = 0.79 nM), displays a high affinity for [3H]DOB-labeled central 5-HT2 serotonin receptors. However, unlike DOB, the alpha-desmethyl derivative also binds with significant affinity to 5-HT1A, 5-HT1B, and 5-HT1C serotonin receptors and, as such, is less selective than DOB. In drug discrimination studies using rats trained to discriminate either DOM (i.e., the 4-methyl analog of DOB) or R(-)DOB from saline, stimulus generalization occurred in both groups of animals. However, stimulus generalization was associated with extensive disruption of behavior, alpha-DesMe DOB may produce stimulus effects similar, but not identical, to those of DOM and R(-)DOB; in addition, this agent may be capable of producing other, as yet undefined, central effects at comparable doses. These other effects may be reflective of the lack of selectivity of alpha-desMe DOB for 5-HT2 serotonin receptors. Because other hallucinogenic agents display high affinity for 5-HT2 serotonin receptors and result in stimulus generalization in DOM- and/or DOB-trained animals, it is tentatively concluded that alpha-desMe DOB is a psychoactive agent with at least some hallucinogenic or DOB-like properties.

  11. Synthesis and biological evaluation of benzimidazole acridine derivatives as potential DNA-binding and apoptosis-inducing agents.

    PubMed

    Gao, Chunmei; Li, Bin; Zhang, Bin; Sun, Qinsheng; Li, Lulu; Li, Xi; Chen, Changjun; Tan, Chunyan; Liu, Hongxia; Jiang, Yuyang

    2015-04-15

    The discovery of new effective DNA-targeted antitumor agent is needed because of their clinical significance. As acridines can intercalate into DNA and benzimidazoles have the ability to bind in the DNA minor groove, a series of novel benzimidazole acridine derivatives were designed and synthesized to be new DNA-targeted compounds. MTT assay indicated that most of the synthesized compounds displayed good antiproliferative activity, among which compound 8l demonstrated the highest activity against both K562 and HepG-2 cells. Further experiments showed that 8l displayed good DNA-binding capability and inhibited topoisomerase I activity. Moreover, compound 8l could induce apoptosis in K562 cell lines through mitochondrial pathway. These data suggested that compound 8l might be potential as new DNA-binding and apoptosis-inducing antitumor agents.

  12. Late potentials in the signal-averaged electrocardiogram in schizophrenia patients maintained on antipsychotic agents: a preliminary naturalistic study.

    PubMed

    Nahshoni, Eitan; Strasberg, Boris; Imbar, Shula; Rotem, Ofer; Gur, Shay; Hermesh, Hagai; Weizman, Abaraham

    2010-03-01

    In the present, preliminary, naturalistic study, cardiac ventricular late potentials (LPs), were measured in 33 physically healthy schizophrenia patients (13 - females and 26 - males, age - 45.5+/-8.8years) maintained on typical and atypical antipsychotic agents. These LPs represent delayed ventricular activation that might predispose to fatal ventricular arrhythmias and sudden cardiac death (SCD) in cardiac patients. Sixteen of the 33 patients ( approximately 48%) were found to be positive for LPs (compared to 3.7-6% in the general population). No association was found with any of the following: drug type, anti-cholinergic burden, daily dose of antipsychotic agents, age, gender, disease duration, QT(c) interval and QT dispersion. Further large-scale longitudinal prospective studies are warranted to substantiate our findings and to clarify their impact on the excess cardiac morbidity and mortality in schizophrenia patients.

  13. Gadolinium(III) Complexes with N-Alkyl-N-methylglucamine Surfactants Incorporated into Liposomes as Potential MRI Contrast Agents

    PubMed Central

    Silva, Simone Rodrigues; Duarte, Érica Correia; Ramos, Guilherme Santos; Kock, Flávio Vinícius Crizóstomo; Andrade, Fabiana Diuk; Frézard, Frédéric; Colnago, Luiz Alberto; Demicheli, Cynthia

    2015-01-01

    Complexes of gadolinium(III) with N-octanoyl-N-methylglucamine (L8) and N-decanoyl-N-methylglucamine (L10) with 1 : 2 stoichiometry were synthesized and characterized by elemental analysis, electrospray ionization-tandem mass spectrometry (ESI-MS), infrared (IR) spectroscopy, and molar conductivity measurements. The transverse (r2) and longitudinal (r1) relaxivity protons were measured at 20 MHz and compared with those of the commercial contrasts. These complexes were incorporated in liposomes, resulting in the increase of the vesicle zeta potential. Both the free and liposome-incorporated gadolinium complexes showed high relaxation effectiveness, compared to commercial contrast agent gadopentetate dimeglumine (Magnevist). The high relaxivity of these complexes was attributed to the molecular rotation that occurs more slowly, because of the elevated molecular weight and incorporation in liposomes. The results establish that these paramagnetic complexes are highly potent contrast agents, making them excellent candidates for various applications in molecular MR imaging. PMID:26347596

  14. Identification of black market products and potential doping agents in Germany 2010-2013.

    PubMed

    Krug, Oliver; Thomas, Andreas; Walpurgis, Katja; Piper, Thomas; Sigmund, Gerd; Schänzer, Wilhelm; Laussmann, Tim; Thevis, Mario

    2014-11-01

    The desire to increase the athletic performance, to 'optimize' an individual's appearance, and to complement but also to arguably substitute exercise by means of drugs and drug candidates has generated a considerable (illicit) market for compounds such as anabolic-androgenic steroids, stimulants, growth promoting peptide hormones, and so on. Genuinely developed for therapeutic use, their abuse/misuse generates enormous health risks, which has necessitated comprehensive controls of compound trafficking by customs and anti-doping authorities. From 2012 to 2013, the Bureau of Customs Investigation confiscated products containing anabolic-androgenic steroids (AAS; 259 kg), stimulants (13 kg), selective estrogen receptor modulators (SERMs; 24 kg), and human growth hormone (hGH; 3500 ampules). In cooperation with the Bureau and under the umbrella of the European Monitoring Center for Emerging Doping Agents (EuMoCEDA), the Cologne Anti-Doping Laboratory analyzed an additional 337 (black market) products between 2010 and 2013, allowing to monitor developments in drug use and, hence, the anticipation of new challenges in sports drug testing. Main tools utilized in characterizing confiscated materials were liquid chromatography-high resolution mass spectrometry (LC-HRMS), gas chromatography-high resolution mass spectrometry (GC-HRMS), and polyacrylamide gel electrophoresis (PAGE) with subsequent bottom-up identification of peptidic compounds using nano liquid chromatography-tandem mass spectrometry (nanoLC-MS/MS). Among the 337 substances analyzed in the doping control laboratory in Cologne, 67 active ingredients were found, 49 of which being categorized as doping agents by the World Anti-Doping Agency (WADA). A total of 83.7 % accounted for steroidal substances (predominantly testosterone, trenbolone, and nandrolone and corresponding esters), 12.8 % accounted for peptide hormones and growth factors (predominantly hGH and growth hormone releasing peptides (GHRPs)), 3.2 % of

  15. Potential new approaches for the development of brain imaging agents for single-photon applications

    SciTech Connect

    Knapp, F.F. Jr.; Srivastava, P.C.

    1984-01-01

    This paper describes new strategies for the brain-specific delivery of radionuclides that can be used to evaluate regional cerebral perfusion by single photon imaging techniques. A description of several examples of interesting new strategies that have recently been reported is presented. A new approach at this institution for the brain-specific delivery of radioiodinated iodophenylalkyl-substituted dihyronicotinamide systems is described which shows good brain uptake and retention in preliminary studies in rats. Following transport into the brain these agents appear to undergo facile intracerebral oxidation to the quaternized analogues which do not recross the intact blood-brain barrier and so are effectively trapped in the brain. 49 refs., 9 figs., 1 tab.

  16. Novel conjugates of aminoadamantanes with carbazole derivatives as potential multitarget agents for AD treatment.

    PubMed

    Bachurin, Sergey O; Shevtsova, Elena F; Makhaeva, Galina F; Grigoriev, Vladimir V; Boltneva, Natalia P; Kovaleva, Nadezhda V; Lushchekina, Sofya V; Shevtsov, Pavel N; Neganova, Margarita E; Redkozubova, Olga M; Bovina, Elena V; Gabrelyan, Alexey V; Fisenko, Vladimir P; Sokolov, Vladimir B; Aksinenko, Alexey Yu; Echeverria, Valentina; Barreto, George E; Aliev, Gjumrakch

    2017-03-30

    A new group of compounds, promising for the design of original multitarget therapeutic agents for treating neurodegenerative diseases, based on conjugates of aminoadamantane and carbazole derivatives was synthesized and investigated. Compounds of these series were found to interact with a group of targets that play an important role in the development of this type of diseases. First of all, these compounds selectively inhibit butyrylcholinesterase, block NMDA receptors containing NR2B subunits while maintaining the properties of MK-801 binding site blockers, exert microtubules stabilizing properties, and possess the ability to protect nerve cells from death at the calcium overload conditions. The leading compound C-2h has been shown the most promising effects on all analyzed parameters. Thus, these compounds can be regarded as promising candidates for the design of multi-target disease-modifying drugs for treatment of AD and/or similar neuropathologies.

  17. Potentials and limits for the use of ozone as a fish disease control agent

    USGS Publications Warehouse

    Wedemeyer, Gary A.; Nelson, Nancy C.; Yasutake, Wm. T.

    1979-01-01

    Ozone and chlorine inactivation curves were determined in three types of freshwater at 20 C for the destruction of the fish pathogens Aeromonas salmonicida the etiologic agent of furunculosis, and Yersinia ruckeri the enteric redmouth bacterium (ERM). Ozone and chlorine inactivation curves were also obtained in the same water types at 10 C for the fish pathogenic viruses infectious hematopoietic necrosis (IHNV), and infectious pancreatic necrosis (IPNV). Acute toxicity tests using the rainbow trout as a representative salmonid revealed that ozone was highly toxic at the dose levels used. Partial chronic (3. mo.) testing revealed that ozone exposure at 2 μg/L causes only minimal physiological changes, none of which would be expected to compromise biological function.

  18. Novel conjugates of aminoadamantanes with carbazole derivatives as potential multitarget agents for AD treatment

    PubMed Central

    Bachurin, Sergey O.; Shevtsova, Elena F.; Makhaeva, Galina F.; Grigoriev, Vladimir V.; Boltneva, Natalia P.; Kovaleva, Nadezhda V.; Lushchekina, Sofya V.; Shevtsov, Pavel N.; Neganova, Margarita E.; Redkozubova, Olga M.; Bovina, Elena V.; Gabrelyan, Alexey V.; Fisenko, Vladimir P.; Sokolov, Vladimir B.; Aksinenko, Alexey Yu; Echeverria, Valentina; Barreto, George E.; Aliev, Gjumrakch

    2017-01-01

    A new group of compounds, promising for the design of original multitarget therapeutic agents for treating neurodegenerative diseases, based on conjugates of aminoadamantane and carbazole derivatives was synthesized and investigated. Compounds of these series were found to interact with a group of targets that play an important role in the development of this type of diseases. First of all, these compounds selectively inhibit butyrylcholinesterase, block NMDA receptors containing NR2B subunits while maintaining the properties of MK-801 binding site blockers, exert microtubules stabilizing properties, and possess the ability to protect nerve cells from death at the calcium overload conditions. The leading compound C-2h has been shown the most promising effects on all analyzed parameters. Thus, these compounds can be regarded as promising candidates for the design of multi-target disease-modifying drugs for treatment of AD and/or similar neuropathologies. PMID:28358144

  19. Coumarin derivatives as potential antitumor agents: Growth inhibition, apoptosis induction and multidrug resistance reverting activity.

    PubMed

    Bisi, Alessandra; Cappadone, Concettina; Rampa, Angela; Farruggia, Giovanna; Sargenti, Azzurra; Belluti, Federica; Di Martino, Rita M C; Malucelli, Emil; Meluzzi, Alessia; Iotti, Stefano; Gobbi, Silvia

    2017-02-15

    A small library of coumarins, carrying butynyl-amino chains, was synthesized continuing our studies in the field of MDR reverting ageEnts and in order to obtain multipotent agents to combat malignancies. In particular, the reported anticancer and chemopreventive natural product 7-isopentenyloxycoumarin was linked to different terminal amines, selected on the basis of our previously reported results. The anticancer behaviour and the MDR reverting ability of the new compounds were evaluated on human colon cancer cells, particularly prone to develop the MDR phenotype. Some of the new derivatives showed promising effects, directly acting as cytotoxic compounds and/or counteracting MDR phenomenon. Compound 1e emerged as the most interesting of this series, showing a multipotent biological profile and suggesting that conjugation of an appropriate coumarin core with a properly selected butynyl-amino chain allows to obtain novel hybrid molecules endowed with improved in vitro antitumor activity.

  20. Design, Synthesis, and Evaluation of Novel Ferroquine and Phenylequine Analogues as Potential Antiplasmodial Agents.

    PubMed

    Jacobs, Leon; de Kock, Carmen; de Villiers, Katherine A; Smith, Peter J; Smith, Vincent J; van Otterlo, Willem A L; Blackie, Margaret A L

    2015-12-01

    7-Chloroquinoline-based antimalarial drugs are effective in the inhibition of hemozoin formation in the food vacuole of the Plasmodium parasite, the causative agent of malaria. We synthesized five series of ferroquine (FQ) and phenylequine (PQ) derivatives, which display good in vitro efficacy toward both the chloroquine-sensitive (CQS) NF54 (IC50 : 4.2 nm) and chloroquine-resistant (CQR) Dd2 (IC50 : 33.7 nm) strains of P. falciparum. Several compounds were found to have good inhibitory activity against β-hematin formation in an NP-40 detergent assay, with IC50 values ranging between 10.4 and 19.2 μm.

  1. Potential disease agents in domestic goats and relevance to bighorn sheep (Ovis canadensis) management.

    PubMed

    Drew, Mark L; Weiser, Glen C

    2017-01-01

    Domestic goats are raised for meat, milk and hair production, in herds for rangeland weed control, and as pack animals. Domestic sheep, goats and wild bighorn sheep are all susceptible to a multifactorial pneumonia. We sampled 43 herd goats from 7 herds and 48 pack goats from 11 herds for viral and bacterial serology, parasitology, and Pasteurellaceae microbiology. The goats in this study were in generally good health, although most goats did harbor various pathogens and parasites including several bacteria, specifically Pasteurellaceae, which have been associated with pneumonia in free-ranging bighorn sheep. It is not known if domestic goats can transmit the Pasteurellaceae or other pathogens found in this study readily to wild bighorn sheep. However, due the possibility of transmission, domestic goats in areas in or near bighorn sheep habitat should be managed to minimize the risk of spreading disease agents to bighorn sheep.

  2. Potent and Orally Bioavailable Antiplatelet Agent, PLD-301, with the Potential of Overcoming Clopidogrel Resistance

    PubMed Central

    Chen, Jingyu; Wang, Michael Zhiyan

    2016-01-01

    PLD-301, a phosphate prodrug of clopidogrel thiolactone discovered by Prelude Pharmaceuticals with the aim to overcome clopidogrel resistance, was evaluated for its in vivo inhibitory effect on ADP-induced platelet aggregation in rats. The potency of PLD-301 was similar to that of prasugrel, but much higher than that of clopidogrel. The results of pharmacokinetic analysis showed that the oral bioavailability of clopidogrel thiolactone converted from PLD-301 was 4- to 5-fold higher than that of the one converted from clopidogrel, suggesting that in comparison with clopidogrel, lower doses of PLD-301 could be used clinically. In summary, PLD-301 presents a potent and orally bioavailable antiplatelet agent that might have some advantages over clopidogrel, such as overcoming clopidogrel resistance for CYP2C19-allele loss-of-function carriers, and lowering dose-related toxicity due to a much lower effective dose. PMID:27594816

  3. Phototherapies: photosensitized inactivation of viral and protozoan infectious agents and potential application in blood banking

    NASA Astrophysics Data System (ADS)

    Judy, Millard M.; Matthews, James Lester; Sogandares-Bernal, Franklin M.; Newman, Joseph T.; Chanh, Tran C.; Marengo-Rowe, Alain J.

    1992-06-01

    More than 10 million units of human blood components are processed annually in the United States. Although donor screening and testing have greatly lowered the risk of transmission of viral and protozoan infectious agents, additional sterilization procedures which also preserve blood component function would be of significant value. Use of UV-A and visible-light-range photosensitizers for sterilization of blood platelets and red blood cells, respectively, is currently being aggressively investigated in laboratory-scale optical-mechanical systems. With successful demonstration of the efficacy and safety of these sterilization techniques, implementation in the blood bank setting will require scale-up to optical-mechanical systems capable of handling approximately 25,000 units daily in 500 - 1,000 blood banks in the United States.

  4. Potential of medicinal plants as antimicrobial and antioxidant agents in food industry: a hypothesis.

    PubMed

    Ortega-Ramirez, Luis Alberto; Rodriguez-Garcia, Isela; Leyva, Juan Manuel; Cruz-Valenzuela, Manuel Reynaldo; Silva-Espinoza, Brenda Adriana; Gonzalez-Aguilar, Gustavo A; Siddiqui, Wasim; Ayala-Zavala, Jesus Fernando

    2014-02-01

    Many food preservation strategies can be used for the control of microbial spoilage and oxidation; however, these quality problems are not yet controlled adequately. Although synthetic antimicrobial and antioxidant agents are approved in many countries, the use of natural safe and effective preservatives is a demand of food consumers and producers. This paper proposes medicinal plants, traditionally used to treat health disorders and prevent diseases, as a source of bioactive compounds having food additive properties. Medicinal plants are rich in terpenes and phenolic compounds that present antimicrobial and antioxidant properties; in addition, the literature revealed that these bioactive compounds extracted from other plants have been effective in food systems. In this context, the present hypothesis paper states that bioactive molecules extracted from medicinal plants can be used as antimicrobial and antioxidant additives in the food industry.

  5. Immunomodulation in Plasmodium falciparum malaria: experiments in nature and their conflicting implications for potential therapeutic agents

    PubMed Central

    Frosch, Anne EP; John, Chandy C

    2013-01-01

    Effective Plasmodium falciparum immunity requires a precisely timed and balanced response of inflammatory and anti-inflammatory immune regulators. These responses begin with innate immune effectors and are modulated over the course of an infection and between episodes to limit inflammation. To date, there are no effective immunomodulatory therapies for severe malaria. Some of the most potent immunomodulators are naturally occurring infections, including helminthic and chronic viral infections. This review examines malaria coinfection with these organisms, and their impact on malaria morbidity and immune responses. Overall, there is compelling evidence to suggest that chronic coinfections can modulate deleterious malaria-specific immune responses, suggesting that therapeutic agents may be effective if utilized early in infection. Examination of the mechanisms of these effects may serve as a platform to identify more targeted and effective malaria immunomodulatory therapeutics. PMID:23241191

  6. Potential disease agents in domestic goats and relevance to bighorn sheep (Ovis canadensis) management

    PubMed Central

    Weiser, Glen C.

    2017-01-01

    Domestic goats are raised for meat, milk and hair production, in herds for rangeland weed control, and as pack animals. Domestic sheep, goats and wild bighorn sheep are all susceptible to a multifactorial pneumonia. We sampled 43 herd goats from 7 herds and 48 pack goats from 11 herds for viral and bacterial serology, parasitology, and Pasteurellaceae microbiology. The goats in this study were in generally good health, although most goats did harbor various pathogens and parasites including several bacteria, specifically Pasteurellaceae, which have been associated with pneumonia in free-ranging bighorn sheep. It is not known if domestic goats can transmit the Pasteurellaceae or other pathogens found in this study readily to wild bighorn sheep. However, due the possibility of transmission, domestic goats in areas in or near bighorn sheep habitat should be managed to minimize the risk of spreading disease agents to bighorn sheep. PMID:28282407

  7. Thymbra capitata essential oil as potential therapeutic agent against Gardnerella vaginalis biofilm-related infections.

    PubMed

    Machado, Daniela; Gaspar, Carlos; Palmeira-de-Oliveira, Ana; Cavaleiro, Carlos; Salgueiro, Lígia; Martinez-de-Oliveira, José; Cerca, Nuno

    2017-04-01

    To evaluate the antibacterial activity of Thymbra capitata essential oil and its main compound, carvacrol, against Gardnerella vaginalis grown planktonically and as biofilms, and its effect of vaginal lactobacilli. Minimal inhibitory concentration, minimal lethal concentration determination and flow cytometry analysis were used to assess the antibacterial effect against planktonic cells. Antibiofilm activity was measured through quantification of biomass and visualization of biofilm structure by confocal laser scanning microscopy. T. capitata essential oil and carvacrol exhibited a potent antibacterial activity against G. vaginalis cells. Antibiofilm activity was more evident with the essential oil than carvacrol. Furthermore, vaginal lactobacilli were significantly more tolerant to the essential oil. T. capitata essential oil stands up as a promising therapeutic agent against G. vaginalis biofilm-related infections.

  8. Leaf extract of Azadirachta indica (neem): a potential antibiofilm agent for Pseudomonas aeruginosa.

    PubMed

    Harjai, Kusum; Bala, Anju; Gupta, Ravi K; Sharma, Radhika

    2013-10-01

    Pseudomonas aeruginosa is well known for its ability to form biofilm on indwelling medical devices. These biofilms are difficult to remove because of their high tolerance to conventional antibiotics. Therefore, there is a need to look for alternative agents such as medicinal plants, which can eradicate or inhibit biofilm effectively. This study evaluated the role of neem in inhibiting biofilm formation by P aeruginosa Factors contributing to adherence and biofilm formation were also studied. Results demonstrated that neem leaves extract was quite effective in disrupting formation and structure of biofilms. Moreover, the level of exopolysaccharide, alginate, hydrophobic interactions and uroepithelial cell attachment, which contributes to biofilm formation, was also affected significantly. Results confirm the effectiveness of neem extract in inhibiting biofilm formation. Such studies can lead to the discovery of safe antimicrobial drugs from natural sources without the risk of resistance.

  9. Discovery of novel diaryl urea derivatives bearing a triazole moiety as potential antitumor agents.

    PubMed

    Qin, Mingze; Yan, Shuang; Wang, Lei; Zhang, Haotian; Zhao, Yanfang; Wu, Shasha; Wu, Di; Gong, Ping

    2016-06-10

    Herein, we report a novel series of diaryl urea derivatives bearing a triazole moiety, from which potent antitumor agents have been identified. With a modified triazole, most compounds showed high level activity in both cellular and enzymatic assays, accompanied with a suitable ClogD7.4 value. The most active compound, 13i, effectively suppressed proliferation of HT-29, H460 and MDA-MB-231 cancer cells, with IC50 values of 0.90, 0.85 and 1.54 μM, respectively. Compound 13i also exhibited significant inhibition of tyrosine kinases including c-Kit, RET and FLT3. Furthermore, compound 13i could obviously induce apoptosis of HT-29 cells in a concentration-dependent manner. The study of structure-activity relationships also revealed that a hydrophilic tail at the 4-position of the triazole was crucial for high activity of the compound.

  10. [Chlamydial diseases of domestic animals--zoonotic potential of the agents and diagnostic issues].

    PubMed

    Sachse, K; Grossmann, E

    2002-04-01

    The role of chlamydiae as agents of a number of important animal and human diseases is still the subject of intensive research. Recently, a proposal for taxonomic reclassification of this group of obligate intracellular bacteria was published, which was based on a large amount of new data on genetic relatedness. According to this proposal, the family Chlamydiaceae now comprises two genera (Chlamydia and Chlamydophila) with 9 largely host-related species. The previously accepted classification scheme had distinguished 4 species within the genus Chlamydia. The most important animal chlamydiosis with zoonotic character is psittacosis, a systemic disease in psittacine birds of acute, protracted, chronic or subclinical manifestation. The analogous infection in domestic and wild fowl is known as ornithosis. Avian strains of C. psittaci (new classification: Chlamydophila psittaci) can also infect humans, the symptoms being mainly unspecific and influenza-like, but severe pneumonia, endocarditis and encephalitis are also known. The main group of persons facing an elevated risk of infection includes those having frequent contact with domestic and companion birds at work or in their spare time. In Germany, the annual average of notified cases is approximately 100. Cases of transmission to humans were repeatedly reported in connection with enzootic abortion in sheep (causative agent: C. psittaci or Chlamydophila abortus, respectively). Various chlamydial species occur as pathogens and commensals as well in cattle, pigs, horses, and cats. The assessment of the actual epidemiological importance is, however, often difficult because of their almost ubiquitous spread. Likewise, those strains of C. pneumoniae (new classification: Chlamydophila pneumoniae) found in several animal species can not yet be assessed for pathogenic properties. The possibilities for diagnostic detection of chlamydiae have considerably improved following the introduction of molecular methods, particularly

  11. A Novel Synthesized Sulfonamido-Based Gallate—JEZ-C as Potential Therapeutic Agents for Osteoarthritis

    PubMed Central

    Lin, Xiao; Lin, Cuiwu; Liu, Buming; Zheng, Li; Zhao, Jinmin

    2015-01-01

    Gallic acid (GA) and its derivatives are anti-inflammatory agents reported to have an effect on osteoarthritis (OA). However, GA has much weaker anti-oxidant effects and inferior bioactivity compared with its derivatives. We modified GA with the introduction of sulfonamide to synthesize a novel compound named JEZ-C and analyzed its anti-arthritis and chondro-protective effects. Comparison of JEZ-C with its sources i.e. GA and Sulfamethoxazole (SMZ) was also performed. Results showed that JEZ-C could effectively inhibit the IL-1-mediated induction of MMP-1 and MMP-13 and could induce the expression of TIMP-1, which demonstrated its ability to reduce the progression of OA. JEZ-C can also exert chondro-protective effects by promoting cell proliferation and maintaining the phenotype of articular chondrocytes, as evidenced by improved cell growth, enhanced synthesis of cartilage specific markers such as aggrecan, collagen II and Sox9. Meanwhile, expression of the collagen I gene was effectively downregulated, revealing the inhibition of chondrocytes dedifferentiation by JEZ-C. Hypertrophy that may lead to chondrocyte ossification was also undetectable in JEZ-C groups. The recommended dose of JEZ-C ranges from 6.25×10-7 μg/ml to 6.25×10-5 μg/ml, among which the most profound response was observed with 6.25×10-6 μg/ml. In contrast, its source products of GA and SMZ have a weak effect not only in the inhibition of OA but also in the bioactivity of chondrocytes, which indicated the significance of this modification. This study revealed JEZ-C as a promising novel agent in the treatment of chondral and osteochondral lesions. PMID:26107568

  12. Novel angular benzophenazines: dual topoisomerase I and topoisomerase II inhibitors as potential anticancer agents.

    PubMed

    Vicker, Nigel; Burgess, Luke; Chuckowree, Irina S; Dodd, Rory; Folkes, Adrian J; Hardick, David J; Hancox, Timothy C; Miller, Warren; Milton, John; Sohal, Sukhjit; Wang, Shouming; Wren, Stephen P; Charlton, Peter A; Dangerfield, Wendy; Liddle, Chris; Mistry, Prakash; Stewart, Alistair J; Denny, William A

    2002-01-31

    A series of substituted angular benzophenazines were prepared using a new synthetic route via a novel regiocontrolled condensation of 1,2-naphthoquinones and 2,3-diaminobenzoic acids. The synthesis and biological activity of this new series of substituted 8,9-benzo[a]phenazine carboxamide systems are described. The analogues were evaluated against the H69 parental human small cell lung carcinoma cell line and H69/LX4 resistant cell line which overexpresses P-glycoprotein. Selected analogues were evaluated against the COR-L23 parental human non small cell lung carcinoma cell line and the COR-L23/R resistant cell line which overexpresses multidrug resistance protein. This series of novel angular benzophenazines were potent cytotoxic agents in these cell lines and may be able to circumvent multidrug resistance mechanisms which result in the lack of efficacy of many drugs in cancer chemotherapy. These compounds show dual inhibition of topoisomerase I and topoisomerase II and thus target two key enzymes responsible for the topology of DNA that are active at different points in the cell cycle. The introduction of chirality into the carboxamide side chain of these novel benzophenazine carboxamides has resulted in the discovery of a potent enantiospecific series of cytotoxic agents, exemplified by 4-methoxy-benzo[a]phenazine-11-carboxylic acid (2-(dimethylamino)-1-(R)-methyl-ethyl)-amide, XR11576 ((R)-4j' '). In vivo activity has been demonstrated for 4-methoxy-benzo[a]phenazine-11-carboxylic acid (2-(dimethylamino)-1-(R)-methyl-ethyl)-amide, XR11576, after intravenous administration to female mice, and this compound has been selected as a development candidate for further evaluation.

  13. Potentiating effects of caffeine on teratogenicity of alkylating agents in mice

    SciTech Connect

    Fujii, T.; Nakatsuka, T.

    1983-08-01

    Teratogenic to subteratogenic doses of x-ray, mitomycin C, MNNG, thio-TEPA, cyclophosphamide, and chlorambucil were administered to pregnant ICR mice together with caffeine at doses of 12.5, 25, or 50 mg/kg on day 11 of gestation. Fetuses were examined for gross malformations on day 18 of gestation. The teratogenicity of mitomycin C was significantly potentiated by caffeine at a dose as low as 12.5 mg/kg. The teratogenicity of chlorambucil was also significantly potentiated by caffeine at 50 mg/kg, but similar potentiation was not observed for x-ray, MNNG, thio-TEPA, and cyclophosphamide.

  14. The potential of agent-based modelling for verification of people trajectories based on smartphone sensor data

    NASA Astrophysics Data System (ADS)

    Hillen, F.; Höfle, B.; Ehlers, M.; Reinartz, P.

    2014-02-01

    In this paper the potential of smartphone sensor data for verification of people trajectories derived from airborne remote sensing data are investigated and discussed based on simulated test recordings in the city of Osnabrueck, Germany. For this purpose, the airb