Indigenous wisdom of a Kwatha to treat NASH: An insight into the mechanism.

ETHNOPHARMACOLOGICAL RELEVANCE: Nonalcoholic fatty liver disease (NAFLD) is the most common severe liver disease globally, progressing further into nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). Vasaguduchyadi Kwatha (VK) is an Ayurvedic formulation traditionally used to treat liver diseases and other metabolic complications. This study is an ethnopharmacological approach to unravel this indigenous remedy. AIM OF THE STUDY: We aimed to discover the probable mechanism of action of VK against NASH in this study, using network pharmacology, molecular docking, in vitro study, and preclinical investigation. METHODS AND RESULTS: Among the 55 components identified, 10 were confirmed based on mass, elution charecteristics, MS/MS analysis data, and fragmentation rules. Computational study indicated 92 targets involved in the central pathways of NASH, out of which only 15 targets and 9 VK constituents have significant docking scores. In vitro and in vivo analysis results showed that VK significantly reduces weight gain and improves insulin sensitivity, dyslipidemia, steatohepatitis and overall histological features of NASH compared to saroglitazar (SGZR). CONCLUSION: Our detailed study yielded three signalling pathways related to NASH on which VK has maximum effect, bringing up a probable alternative treatment for NASH.

Antiviral Activity of Cinchona officinalis, a Homeopathic Medicine, against COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a potentially fatal disease caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Several studies have shown that hydroxychloroquine (HCQ) significantly inhibits SARS-CoV-2 infections in vitro. OBJECTIVE: Since the phytoconstituents of Cinchona officinalis (CO) are similar to those of HCQ, the objective of this study was to test the antiviral potential of different homeopathic formulations of CO. METHODS: An analysis of the molecular composition of CO was carried out using ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry, followed by a detailed docking study. The constituents of CO were docked against various targets of SARS-CoV-2, and the binding potential of the phytoconstituents was compared and quantified. The ligand with the lowest Glide docking score is considered to have the best binding affinity. The cytotoxicity of several homeopathic formulations, including CO mother tincture (CO-MT), was also checked on VeroE6 cells. A known antiviral, remdesivir, was used as a positive control for the in vitro assays to evaluate the effects of CO-MT against SARS-CoV-2-infected VeroE6 cells. RESULTS: Molecular docking studies showed that constituents of CO exhibited binding potential to various targets of SARS-CoV-2, including Mpro, PLpro, RdRp, nucleocapsid protein, ACE2 (in host) and spike protein. Quinoline, one of the constituents of CO, can potentially bind the spike protein of SARS-CoV-2. Quinic acid showed better binding capabilities with Mpro, PLpro RdRp, nucleocapsid protein and ACE2 (allosteric site) than other constituents. Quinidine exhibited better binding to ACE2. Compared to HCQ, other phytoconstituents of CO had the equivalent potential to bind the RNA-dependent RNA polymerase, nucleocapsid protein, Mpro, PLpro and spike protein of SARS-CoV-2. In vitro assays showed that homeopathic CO-MT was not cytotoxic and that CO-MT and remdesivir respectively caused 89% and 99% inhibition of SARS-CoV-2 infection in VeroE6 cells. CONCLUSION: Based on this in silico and in vitro evidence, we propose CO-MT as a promising antiviral medicine candidate for treating COVID-19. In vivo investigation is required to clarify the therapeutic potential of CO-MT in COVID-19.

Network pharmacology and bioinformatics based investigation of Phyllanthus fraternus: herb-drug interaction study.

Phyllanthus fraternus (PF), a plant from the Euphorbiaceae family, is used extensively in ayurvedic formulations for its significant medicinal properties. When PF is administered alongside conventional drugs, there could be potential herb-drug interactions between the active compounds and the genes involved in drug transport and metabolism. Hence, this study was designed to investigate potential herb-drug interactions, focusing on elucidating their functional and pharmacological mechanisms, using an integrated approach of metabolite profiling and network pharmacology. We utilized LC-MS to generate metabolite profiling of PF and network pharmacology for predicting key targets and pathways. This comprehensive analysis involved the construction of networks illustrating the relationships among compounds, targets, and pathways and the exploration of protein-protein interactions and protein-ligand interactions. In this study, a total of 79 compounds were identified in LC-MS, such as alkaloids, steroids, saponins, flavonoids, lignans, phenolic acids, tannins, terpenoids, and fatty acids. The identified compound's physicochemical properties were predicted using SwissADME. Network analysis predicted 1076 PF-related genes and 1497 genes associated with drug transport and metabolism, identifying 417 overlapping genes, including 51 related to drug transport and metabolism. Based on the degree of interaction the hub targets like ABCB1, CYP1A1, CYP1A2, CYP2C9, and CYP3A4 were identified. In the compound-target-pathway network, 2,4-bis(1,1-dimethyl ethyl)-phenol; 5-Methoxy-N-[(5-Methylpyridin-2-yl) sulfonyl]-1h-Indole-2-Carboxamide; and E,E,Z-1,3,12-Nonadecatriene-5,14-diol possessed more interactions with the targets. This study helps identify bioactive compounds, essential targets, and pathways potentially implicated in these interactions, laying the foundation for future studies (in vitro and in vivo) to verify their potential to explore their clinical implications.Communicated by Ramaswamy H. Sarma.

Neuroprotective Effect of Methanolic Ajwa Seed Extract on Lipopolysaccharide-Induced Memory Dysfunction and Neuroinflammation: In Vivo, Molecular Docking and Dynamics Studies.

Islamic literature has indicated that daily consumption of Ajwa dates heals a variety of chronic diseases and disorders. The current research investigates the neuroprotective effect of methanolic Ajwa seed extract (MASE) on lipopolysaccharide (LPS)-induced cognitive deficits using multiple approaches. For animal studies, MASE (200 and 400 mg/kg, p.o.) was administrated for thirty consecutive days, and four doses of LPS (250 µg/kg, i.p.) were injected to induce neurotoxicity. Memory functions were evaluated using elevated plus-maze and novel object recognition tests. Acetylcholine (ACh) and neuroinflammatory markers (cyclooxygenase (COX)-2, tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-10, and transforming growth factor (TGF)-ß1) were estimated in brain tissues. Studies of molecular docking and dynamics were conducted to provide insight into the molecular-level mechanisms. MASE administration resulted in a significant reversal of LPS-induced memory impairment in both maze models. Both doses of MASE elevated the ACh levels in an LPS-treated rat brain. In addition, the extract lowered COX-2 and proinflammatory cytokines (TNF-α and IL-6) while increasing anti-inflammatory cytokines (IL-10 and TGF-ß1) in LPS-treated brain tissues. Molecular modeling results revealed that the compound's ellagic acid, epicatechin, catechin, kaempferol, quercetin, and apigenin have the potential to act as a dual inhibitor of acetylcholinesterase (AChE) and COX-2 and can be responsible for the improvement of both cholinergic and inflammatory conditions, while the cinnamic acid, hesperidin, hesperetin, narengin, and rutin compounds are responsible only for the improvement of cholinergic transmission. The above compounds acted by interacting with the key residues Trp84, Asp72, Gly118, Ser200, Tyr334, and His440, which are responsible for the hydrolysis of ACh in AChE, while the COX-2 is inhibited by interacting with the residues (Val349, Leu352, Tyr355, Tyr385, Ala527, Ser530, and Leu531) of the hydrophobic channel. By promoting cholinergic activity and protecting neuroinflammation in the rat brain, MASE provides neuroprotection against LPS-induced cognitive deficits. Our preliminary findings will help with further drug discovery processes related to neuroinflammation-related neurodegeneration.

Targeting the cytochrome bc1 complex for drug development in M. tuberculosis: review.

The terminal oxidases of the oxidative phosphorylation pathway play a significant role in the survival and growth of M. tuberculosis, targeting these components lead to inhibition of M. tuberculosis. Many drug candidates targeting various components of the electron transport chain in M. tuberculosis have recently been discovered. The cytochrome bc1-aa3 supercomplex is one of the most important components of the electron transport chain in M. tuberculosis, and it has emerged as the novel target for several promising candidates. There are two cryo-electron microscopy structures (PDB IDs: 6ADQ and 6HWH) of the cytochrome bc1-aa3 supercomplex that aid in the development of effective and potent inhibitors for M. tuberculosis. In recent years, a number of potential candidates targeting the QcrB subunit of the cytochrome bc1 complex have been developed. In this review, we describe the recently identified inhibitors that target the electron transport chain's terminal oxidase enzyme in M. tuberculosis, specifically the QcrB subunit of the cytochrome bc1 complex.

Investigation of anion-π interactions involving thiophene walls incorporated calix[4]pyrroles.

Thiophene containing "two-wall" aryl extended calix[4]pyrroles were synthesized for the first time, through acid catalyzed condensation of 2-acetylthiophenes with pyrrole. Isomeric "two-walled" calix[4]pyrroles (8a-10a and 8b-10b) were obtained in satisfactory yields and their halide anion binding strengths were investigated in the solution phase by (1)H NMR and in the gas phase by computational methods and mass spectrometry. Change in the chemical shifts of thiophene -CH-protons during the course of NMR titrations entailed participation of the thiophene rings in anion binding; this fact was further substantiated by computational methods. The α,α-(cis)-isomers (8a, 9a, and 10a) showed strong binding toward F(-) and Cl(-) anions when compared to their isomeric α,ß-(trans)-isomer (8b, 9b, and 10b). In both isomers, binding with F(-) anion was found to be stronger than that with Cl(-) anion. Both the solution-phase and gas-phase results revealed that the thiophene rings stabilize the anions through anion-π interactions.