The TGF-β/Smad4 Signaling Pathway in Pancreatic Carcinogenesis and Its Clinical Significance

Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal human cancers due to its complicated genomic instability. PDAC frequently presents at an advanced stage with extensive metastasis, which portends a poor prognosis. The known risk factors associated with PDAC include advanced age, smoking, long-standing chronic pancreatitis, obesity, and diabetes. Its association with genomic and somatic mutations is the most important factor for its aggressiveness. The most common gene mutations associated with PDAC include KRas2, p16, TP53, and Smad4. Among these, Smad4 mutation is relatively specific and its inactivation is found in more than 50% of invasive pancreatic adenocarcinomas. Smad4 is a member of the Smad family of signal transducers and acts as a central mediator of transforming growth factor beta (TGF-β) signaling pathways. The TGF-β signaling pathway promotes many physiological processes, including cell growth, differentiation, proliferation, fibrosis, and scar formation. It also plays a major role in the development of tumors through induction of angiogenesis and immune suppression. In this review, we will discuss the molecular mechanism of TGF-β/Smad4 signaling in the pathogenesis of pancreatic adenocarcinoma and its clinical implication, particularly potential as a prognostic factor and a therapeutic target

Molecular docking and dynamics simulation study of medicinal fungi derived secondary metabolites as potential inhibitor for COVID-19 treatment

The severity of COVID-19, lack of specific treatment, and controversies on the vaccine's efficacy demand the development of new drugs against SARS-CoV-2. Fungi produce various metabolites with diverse molecular structures that have emerged as promising antiviral drug candidates. Therefore, the present study aimed to investigate medicinal fungi derived secondary metabolites as potential inhibitors of 3 different targets associated with viral entry (human TMPRSS2) and replication (main and papain-like protease) through molecular docking and dynamic simulation studies. Based on our findings, we identified Phelligridin E, Lepiotaprocerine G, and Inoscavin A as the potential blockers of SARS-CoV-2 main protease, papain-like protease, and human TMPRSS2, respectively. These compounds strongly interacted with their corresponding target, passed Lipinski Rule's and had acceptable ADMET properties. Drug-protein complexes showed good stability during MD simulation. Estimation of binding free energy using the MM-GBSA method validated the inhibitor potential of identified compounds. Taken together, we believe that further in vitro and in vivo investigations on our proposed molecules may contribute to expanding the therapeutic arsenal in our fight against COVID-19

Phytochemical screening and evaluation of cytotoxic and hypoglycemic properties of Mangifera indica peels

Objective: To investigate the presence of different phytoconstituents in Mangifera indica (M. indica) peel and evaluate its cytotoxicity to Artemia salina and hypoglycemic potential in Swiss albino mice. Methods: The methanolic extract of M. indica peel was used to determine the presence of phytoconstituents. Brine shrimp lethality bioassay method was followed to determine the cytotoxic potential of plant extract. In the case of hypoglycemic activity, oral administration of extract at 200 and 400 mg/kg and standard glibenclamide at 10 mg/kg was done, followed by determining the percentage of reduction of plasma glucose from the initial level. Results: The methanolic extract of M. indica peel showed the presence of flavonoid, saponin, steroid, tannins, terpenoids, glycosides and alkaloids. In brine shrimp lethality bioassay, the LC50 of the extract and standard vincristine sulfate was found to be 2.04 and 0.41 μg/mL, respectively. After 90 and 150 min, the methanolic extract at 200 and 400 mg/kg showed prominent plasma glucose reduction of 13.95%, 22.48% and 14.16%, 26.18% respectively compared to standard glibenclamide showing 14.90% and 20.67% plasma glucose reduction. Conclusions: This current research affirms prominent cytotoxic and moderate hypoglycemic potential of M. indica peel. Further bioactivity guided isolation of phytoconstituents and investigation on higher animals can lead to development of new drug molecules