Alzheimer's disease and clinical trials.

Alzheimer's disease (AD) is spreading its root disproportionately among the worldwide population. Many genes have been identified as the hallmarks of AD. Based upon the knowledge, many clinical trials have been designed and conducted. Attempts have been made to alleviate the pathology associated with AD by targeting the molecular products of these genes. Irrespective of the understanding on the genetic component of AD, many clinical trials have failed and imposed greater challenges on the path of drug discovery. Therefore, this review aims to identify research and review articles to pinpoint the limitations of drug candidates (thiethylperazine, CT1812, crenezumab, CNP520, and lecanemab), which are under or withdrawn from clinical trials. Thorough analysis of the cross-talk pathways led to the identification of many confounding factors, which could interfere with the success of clinical trials with drug candidates such as thiethylperazine, CT1812, crenezumab, and CNP520. Though these drug candidates were enrolled in clinical trials, yet literature review shows many limitations. These limitations raise many questions on the rationale behind the enrollments of these drug candidates in clinical trials. A meticulous prior assessment of the outcome of clinical studies may stop risky clinical trials at their inceptions. This may save time, money, and resources.

Curative role of natural PPARγ agonist in non-alcoholic fatty liver disease (NAFLD).

NAFLD is a condition that develops when the liver accumulates excess fat without alcohol consumption. This chronic liver ailment progresses along with insulin resistant and is typically not diagnosed until the patients have cirrhosis. Nuclear hormone receptor superfamily PPARs are essential for metabolism of fatty acids and glucose. In liver, lipid metabolism is regulated by nuclear receptors and PPARα, and PPARß/δ encourages fatty acid ß-oxidation. PPAR-γ, an energy-balanced receptor is a crucial regulator in NAFLD. The partial activation of PPAR-γ could lead to increased level of adiponectin and insulin sensitivity, thus improved NAFLD. Because of less side effects, natural compounds are emerged as potential therapeutic agents for NAFLD by PPARγ agonists. Although the results from preclinical studies are promising, further research is needed to determine the potential dosing and efficacy of mentioned compounds in human subjects. In this review, we summarize the effect of natural PPARγ agonist in the NAFLD.

Cucurbita pepo seeds improve peripheral neuropathy in diabetic rats by modulating the inflammation and oxidative stress in rats.

BACKGROUND: Cucurbita pepo (C. pepo) is cultivated and used traditionally as vegetable as well as medicine in different parts of the world. The aim of current study was to investigate the potential of C. pepo in attenuation of diabetic neuropathy via using streptozotocin (STZ)-induced diabetes model in male wistar rats. MATERIALS AND METHODS: Diabetic neuropathy was induced by administration of STZ; 65 mg/kg, i.p. and Nicotinamide (NAD; 230 mg/kg i.p.) and assessed by measuring thermal hyperalgesia, mechanical hyperalgesia and motor nerve conduction velocity (MNCV) in experimental animals. Treatment with different doses of (100, 200 and 400 mg/kg, p.o.) petroleum ether extract of C. pepo (CPE) and hydroethanolic extract of C. pepo (CHE) was started from the 60th day of STZ/NAD administration and continued upto 90th day. RESULTS: CPE and CHE significantly attenuated the behavioural changes including hyperalgesia, allodynia and MNCV linked to diabetic neuropathy. Moreover, the oxidative stress and level of TNF-α, TGF-ß and IL-1ß was found to be significantly attenuated in experimental animals. CONCLUSION: Thus C. pepo might ameliorate the progression of diabetic neuropathy via modulation of chronic hyperglycemia and therefore and have therapeutic potential for treatment of diabetic neuropathic pain.

Structure based docking and molecular dynamics studies: Peroxisome proliferator-activated receptors -α/γ dual agonists for treatment of metabolic disorders.

Diabetes is a foremost health problem globally susceptible to increased mortality and morbidity. The present therapies in the antidiabetic class have sound adverse effects and thus, emphasis on the further need to develop effective medication therapy. Peroxisome proliferator-activated receptor alpha-gamma dual approach represents an interesting target for developing novel anti-diabetic drug along with potential anti-hyperlipidimic activity. In the current study, the peroxisome proliferator-activated receptor alpha-gamma agonistic hits were screened by hierarchical virtual screening of drug like compounds followed by molecular dynamics simulation and knowledge-based structure-activity relation analysis. The key amino acid residues of binding pockets of both target proteins were acknowledged as essential and were found to be associated in the key interactions with the most potential dual hit. This dual targeted approach of structure based computational technique was undertaken to identify prevalent promising hits for both targets with binding energy and absorption distribution metabolism excretion prediction supported the analysis of their pharmacokinetic potential. In addition, stability analysis using molecular dynamics simulation of the target protein complexes was performed with the most promising dual targeted hit found in this study. Further, comparative analysis of binding site of both targets was done for the development of knowledge-based structure-activity relationship, which may useful for successful designing of dual agonistic candidates. AbbreviationsADMEabsorption distribution metabolism excretionHTVShighthroughput virtual screeningMDmolecular dynamicsMMGBSAmolecular mechanics generalized bonn solvation accessiblePDBprotein data bankPPARperoxisome proliferator-activated receptorRMSDRoot mean square deviationRMSFRoot mean square fluctuationSARstructural activity relationshipSPsimple precisionT2DMTypeII diabetes mellitusXPExtra precisionCommunicated by Ramaswamy H. Sarma.

Barleria cristata: perspective towards phytopharmacological aspects.

OBJECTIVES: Barleria cristata (Family: Acanthaceae), commonly known as Philippine violet, is used in different ethnomedical systems for the treatment of a wide range of ailments. This review aimed to provide a scientific overview of B. cristata with reference to its ethnobotanical aspects, geographical distribution, medicinal uses, phytochemistry and pharmacological activity, and critical analyses research gaps and future research opportunities for investigations on this plant. KEY FINDINGS: Ethnomedical uses of the plant have been observed in lungs disorders, inflammatory conditions, toothache, anaemia, snake bite, diabetes and tuberculosis. The exhaustive bibliographic research carried out on this plant revealed that the plant parts are rich in various phytochemical constituents including triterpenes, phenolic compounds, glycosides and flavonoids type phenolic compounds. Furthermore, the plant was also investigated in terms of its anti-inflammatory, antibacterial, antidiabetic, antifungal, hepatoprotective and antioxidant activity. CONCLUSIONS: This review confirms that B. cristata is a potential herb for the treatment of a wide range of diseases especially lung disorders and inflammatory conditions. Modern pharmacological studies have also validated many ethnobotanical uses of B. cristata, though data regarding many aspects of this plant such as mechanism of action, adverse effects of extracts and active compounds are still limited which call for additional studies.

Deciphering PPARγ activation in cardiometabolic syndrome: studies by in silico and in vivo experimental assessment.

Cardiometabolic syndrome (CMetS) is a consolidation of metabolic disorders characterized by insulin resistance, dyslipidemia and hypertension. Curcumin, a natural bioactive compound, has been shown to possess notable anti-oxidant activity and it has also been included as a super natural herb in the super natural herbs database. Most of the beneficial effects of Curcumin are possibly due to activation of the nuclear receptor, peroxisome proliferator-activated receptor gamma (PPARγ). The present study investigates molecular interactions of curcumin with PPARγ protein through molecular docking and molecular dynamics (MD) simulation studies. Further, effect of curcumin on high fat diet induced CMetS was studied in rats along with western blot for PPARγ and nuclear factor-κB (NF-κB) expressions and histopathological studies. Computational studies presented several significant molecular interactions of curcumin including Ser289, His323, His449 and Tyr473 of PPARγ. The in vivo results further confirmed that curcumin was able to ameliorate the abnormal changes and also, increased PPARγ expressions. The results confirm our hypothesis that activation of PPARγ by curcumin possesses the therapeutic potential to ameliorate the altered levels of metabolic changes in rats in the treatment of CMetS. This is the first report of CMetS treatment by curcumin and study of its underlying mechanism through in silico as well as in vivo experiments.

Total pancreatic lipomatosis with malabsorption syndrome.

Total fat replacement of the pancreas is rare. Focal fatty replacement is the most common degenerative lesion of pancreas. Focal fatty deposits have no major clinical significance; however, extreme fat replacement is of pathologic significance, as it is associated with marked reduction in exocrine function of pancreas, resulting in malabsorption due to pancreatic enzyme insufficiency.