Euphorbia antiquorum L. (Euphorbiaceae), a traditionally used Asian medicinal plant, was systematically evaluated for its antidiabetic efficacy through a bioactivity-guided approach integrating in vitro, in vivo, and in silico studies. Among the four solvent fractions of the ethanolic stem extract, the ethyl acetate fraction exhibited the highest antioxidant and glucose utilization activity. Column chromatography of the ethyl acetate fraction yielded several subfractions, among which Fraction 2 (CEA2) showed strong antioxidant activity and significantly enhanced glucose utilization and GLUT4 translocation (p < 0.01). In a 63-day high-fat high-fructose diet and low-dose streptozotocin-induced diabetic rat model, CEA2 (200 and 400 mg/kg) markedly reduced fasting blood glucose, improved body weight, restored biochemical parameters, and decreased TNF-α and IL-6 levels, while also improving pancreatic and hepatic histopathology. Western blotting confirmed significant upregulation of plasma membrane GLUT4 (p < 0.01). LC-MS profiling identified major compounds, including 3-O-trans-p-coumaroyltormentic acid and geranyl acetoacetate, which demonstrated strong binding to IRS-1 and Akt-PKB in docking and molecular dynamics analyses, key regulators of GLUT4 vesicle mobilization. This study provides one of the first comprehensive validations establishing CEA2 as a potent modulator of insulin signaling and GLUT4 mobilization, supporting E. antiquorum as a promising phytopharmaceutical candidate for type 2 diabetes management.

India, the world’s largest producer of bananas, faces up to 40

BACKGROUND:The development of drug resistance in Plasmodium falciparum is predominantly associated with the mutations in Plasmodium falciparum dihydrofolate reductase (pfDHFR) enzyme, a crucial target for antifolate antimalarial medications such as pyrimethamine and cycloguanil. Specific nucleotide substitutions in the pfDHFR gene, occurring either singly or in various combinations, substantially reduce the effectiveness of antifolate treatments, thus intensifying the worldwide struggle against malaria. METHODS:The present investigation, pharmacophore modeling assisted virtual screening, and, in vitro investigations were conducted to address this resistance issue by identifying novel inhibitors targeting mutant pfDHFR. A ligand-oriented pharmacophore model (r = 0.94) was developed utilizing a dataset of 17 compounds exhibiting inhibitory activity spanning four orders of magnitude. RESULT:The most statistically robust hypothesis designated Hypo1, was subsequently employed as a three-dimensional query to conduct screening of cheminformatics repositories. The screening process incorporated drug-likeness parameters, ADME/Tox assessment, and pharmacophore mapping and validation techniques. Through molecular docking analyses and molecular dynamics (MD) simulations, we have identified 28 compounds that exhibited robust binding affinities to resistant variants of pfDHFR. The most promising candidates displayed in vitro antimalarial efficacy, indicating their potential to circumvent anti-folate drug resistance. CONCLUSION:The top compound exhibited IC50 values of 30.822 μg/mL and 126.077 μg/mL against the 3D7 and Dd2 strains of P. falciparum, respectively, significantly outperforming other compounds (p < 0.05). This comprehensive approach underscores the critical role of integrating pharmacophore modeling with experimental methods to discover alternative antimalarial therapies.

Ethnopharmacological relevance: Tinospora sinensis (Lour.) Merr., from the family Menispermaceae, is widely used in Indian folk and Ayurvedic medicine. Indigenous tribes such as the Tea-tribe and Chorei-tribe of Assam use its bark and stem as a herbal remedy to treat malaria and it is also traditionally employed for conditions such as dyspepsia, inflammation, fever, ulcers, jaundice, diabetes and various urinary, skin, and liver diseases. Aim of the study: This study aims to identify and characterize antimalarial phytoconstituents from the active extract of T. sinensis stem by in vitro screening against both the Chloroquine-sensitive (Pf3D7) as well as Chloroquine-resistant (PfRKL-9) strains of Plasmodium falciparum, along with exploring potential targets and mechanisms using molecular docking and dynamics simulation studies. Materials and methods: T. sinensis stems were collected from Assam, India, and authenticated by the Botanical Survey of India. The plant materials were initially extracted with non-polar to polar solvents and screened for in vitro antimalarial potency against Pf3D7 and PfRKL-9. Then, the methanol extract was selected for bioassayguided isolation of phytoconstituent(s). The isolated phytoconstituent(s) were screened for antimalarial potential and active compounds were further evaluated for cytotoxicity using the HEK-293 cell line. Structural characterization of the active compounds involved the use of UV-VIS, IR, NMR and HRMS analyses. Molecular docking and dynamics simulation studies were performed on selected targets from P. falciparum to predict binding affinities and mechanisms of action. Results: From the methanol extract of T. sinensis stem, five phytoconstituents were isolated, including isoquinoline alkaloids Berberine (NG1) and Palmatine (NG2) showed the best antimalarial activity (IC50 < 1 mu g/ml) against both Pf3D7 and PfRKL-9. Cytotoxicity assays confirmed their safety and selectivity. Molecular docking and dynamic simulation studies revealed that Berberine and Palmatine formed stable complexes with P. falciparum lysyl-tRNA synthetase and P. falciparum aminopeptidase N, respectively, indicating their potential as antimalarial leads. Conclusion: This study identifies two potent antimalarial phytoconstituents in the stem of T. sinensis, validating its traditional use and demonstrating its safety and efficacy for potential global application in malaria treatment.

Ethnopharmacological relevance: Mahanine (MH), a naturally occurring carbazole alkaloid, isolated from Ayurvedic medicinal plant Murraya koenigii (L.) Spreng, has been shown to have various pharmacological properties, including its inhibitory activity against different breast cancers (BC) subtypes.Aim of the study: While MH triggers apoptosis in BC cells regardless of subtype, the specific mechanism of MH action is not fully understood. In this study, we show the effect of MH in preventing BC progression by inducing apoptosis in relation to estrogen receptor-alpha (ER alpha) and cell cycle regulatory proteins.Materials and methods: To assess the pharmacological activity in various in vitro and in vivo tests, isolated and pure MH was used. To conclude the study, cutting edged molecular biology techniques including Western blot analysis, enzyme-linked immunosorbent assay (ELISA), molecular simulation study, and other related software analysis were employed.Results: MH demonstrated dose dependent cell viability against drug sensitive (MCF-7 and MDA-MB-231) and paclitaxel resistant (MCF-7TR and MDA-MB-231TR) BC cells. MH also exhibited synergistic activity with tamoxifen (TAM) against estrogen receptor positive (ER+) BC cells by inhibiting ER alpha expression in MCF-7 cells and N-Methyl-N-nitrosourea (MNU)-induced mammary tumor in a dose-dependent manner while having no effect on vinculin expression. In addition, MH inhibited cell cycle regulatory genes namely CDK1/CDK4/CDK6/ CDC25A and neo-angiogenesis through downregulation of CD31/PECAMs in MCF-7, MDA-MB-231 cells and mammary tumors from MNU-induced rats. MH therapy has been shown to be significantly able to lower the serum leptin level and to be beneficial against the initiation of tumor development in SD rats for up to 12 weeks. Molecular modeling study revealed that MH has antagonized the effectiveness of several types of estrogen those bind to the ER alpha and has comparable binding efficacy to TAM.

The Wnt/β-Catenin pathway (Wnt/β-CatP) is implicated in accelerating carcinogenesis and cancer progression, contributing to increased morbidity and treatment resistance. Even though it holds promise as a focus for cancer treatment, its intricate nature and diverse physiological effects pose significant challenges. Recent years have witnessed significant advancements in this domain, with numerous natural products demonstrating promising preclinical anti-tumor effects and identified as inhibitors of the Wnt/β-CatP through various upstream and downstream mechanisms. This study provides a comprehensive overview of the current landscape of Wnt/β-Cat-targeted cancer therapy, examining the impact of natural products on Wnt/β-Cat signaling in both cancer prevention and therapeutic contexts. A comprehensive search was conducted on scientific databases like SciFinder, PubMed, and Google Scholar to retrieve relevant literature on Wnt-signaling, natural products, β-Catenin (β-Cat), and cancer from 2020 to January 2024. As per the analysis of the relevant reference within the specified period, it has been noted that a total of 58 phytoconstituents, predominantly phenolics, followed by triterpenoids and several other classes, along with a limited number of plant extracts, have exhibited activity targeting the Wnt/β-CatP. Most β-Cat regulating modulators restrict cancer cell development by suppressing β-Cat expression, facilitating proteasomal degradation, and inhibiting nuclear translocation. Multiple approaches have been devised to block the activity of β-Cat in cancer therapy, a key factor in cancer progression, leading to the discovery of various Wnt/β-CatP regulators. However, their exploration remains limited, necessitating further research using clinical models for potential clinical use in cancer prevention and therapeutics.

Medicinal plants play an important role as antimicrobials by inhibiting various key targets of diverse microorganisms. A major antimicrobial component of plants is its essential oil, which are increasingly being studied for their antimicrobial properties as well as for their potential role in the inhibition of biofilm formation. In the present study, essential oil from Kaempferia galanga L was isolated resulting in the identification of eleven compounds. Of these, two of the compounds, γ-elemene and caryophyllene were found to dock with the target proteins, CrtM and SarA of Staphylococcus aureus, which are essential for the formation of biofilm. γ-elemene demonstrated the best binding affinity with CrtM with binding energy of -8.1 kcal/mol whereas caryophyllene and its derivative isocaryophyllene showed the best binding with SarA with binding energy -6.1 kcal/mol. ADMET study of the compounds also revealed that the compounds are non-toxic and can be used as probable compounds for inhibition of biofilms. Molecular dynamic simulation studies revealed high affinity of binding and stability of the molecules with their targets. PCA analysis helped in identifying the principal motions occurring within a trajectory that are essential in inducing conformational changes.Communicated by Ramaswamy H. Sarma.

Type 2 Diabetes continues to be one of the major public health issues worldwide without any sustainable cure. The modulation of gut microbiota is believed to be caused by probiotic bacteria and several probiotic strains have previously shown antidiabetic activity. The present study aims to isolate potential probiotic bacteria from traditionally used fermented rice beer of Assam, India and to investigate its anti-hyperglycemic effect. Of the 20 isolated bacterial isolates, 5 isolates showed potential probiotic activities, of which, 2 isolates viz. Bacillus sp. FRB_A(A) and Acetobacter sp. FRB_B(S) showed good in vitro anti-oxidant and anti α-glucosidase activities. Based on the in vitro results, isolate Bacillus sp. FRB_A(A) was further used to evaluate the antidiabetic activity in streptozotocin induced diabetic rat model. After 21 days, the blood glucose level in diabetic rats with probiotic administration significantly lowered from 458.00 ± 46.62 mg/dl to 108.20 ± 6.76 mg/dl (p < 0.001), whereas, in diabetic rats without probiotic remained high (576.20 ± 29.48 mg/dl). On analyzing the endogenous antioxidant profile in various tissues of the experimental rats, reduced lipid peroxidation, glutathione level and superoxide dismutase and glutathione peroxidase activity were observed in probiotic administered rats in comparison to the streptozotocin treated diabetic controls. In conclusion, the bacteria Bacillus sp. FRB_A(A) isolated from fermented rice beer possesses probiotic attributes and exhibits significant anti-hyperglycemic activities.

The catastrophic effect of petroleum contamination on the environment is a severe problem of global concern. Bioremediation is probably the easiest and most cost-effective way to treat the contaminants. Several microorganisms ranging from bacteria, fungi, yeast, algae, etc., are known for their ability to biodegrade different hydrocarbons. Hydrocarbon degrading microorganisms are largely known for the release of biosurfactants and other surface-active biopolymers, which decrease the surface tension of oil particles into smaller entities for their easy degradation throughout the respective metabolic cycle. Such biopolymers are encoded by several genes and operon systems which are discussed briefly in this chapter. Information on such genes help in better understanding the molecular events involved in the microbial bioremediation of petroleum hydrocarbon.

EDITORIAL article Front. Pharmacol., 24 February 2023Sec. Pharmacology of Anti-Cancer Drugs Volume 14 - 2023 | https://doi.org/10.3389/fphar.2023.1156197

Allium hookeri (F: Liliaceae), an indigenous plant of Manipur, India, is traditionally used to treat various diseases and disorders like diabetes, hypertension, and stomach ache. In our previous study, the methanol extract of the plant showed significant antidiabetic potential in rats. In the present study, we evaluated the antidiabetic potential of a flavonoid compound named MEA isolated from the methanolic leaf extract of A. Hookeri in rats. Additionally, we assessed the compound's mode of action through the molecular docking study. The MEA reduced the blood glucose level from 317±12.8 to 99.4±6.67 mg/dl after 21 days of treatment. Besides, MEA also restored the body weights and other biochemical parameters including lipid profile significantly compared to the diabetic group (p<0.001). The histoarchitecture of the pancreatic tissues of the MEA treated group was also improved compared to the diabetic group. In the docking study, the compound showed good binding affinity in the active binding site of the two structures of pancreatic beta-cell SUR1 (Sulfonylurea Receptor 1) subunit with CDocker energy -31.556 kcal/mol and -39.703 kcal/mol, respectively. The compound MEA was found to be drug-like with non-carcinogenic, non-mutagenic and non-irritant properties. These findings indicate the antidiabetic potential of MEA, which might act by modulating the pancreatic beta-cell SUR1 subunit present in the KATP channel. Hence, the MEA would be a promising lead molecule to develop new antidiabetic drug candidates of the future.

Green synthesis of metal nanoparticles (NP) has emerged as a recent trend in green chemistry. However, their potential in the field of agriculture is yet underexplored. In this study, silver nanoparticles (Ag NPs) were synthesized by using the fruit juice and peel extract of Citrus maxima (Burm.) Merr. as a reducing and capping agent. The nano-primed seeds of Zea mays, Glycine max, and Cicer arietinum showed enhanced germination rate up to 90% as compared to the respective control (30-60%) and also enhanced plant growth. The HRTEM images of fruit-mediated Ag NPs showed well-dispersed particles. The XRD diffraction pattern confirmed the crystalline nature of Ag NPs with fcc lattice points of 101, 111, 200, 220, and 311 with an average crystal size of 19.1275±1.73 nm. On the other hand, the peel-mediated Ag NPs exhibited a size range of 10-20 nm with average crystal size of 19.09±1.71 nm. The FTIR spectra confirmed the presence of ʋC=C-H, ʋCH2, ʋC=O (stretch), ʋC=C (stretch), ʋC-H (bend), ʋC-O (bend) in the Ag NPs synthesized by the fruit and peel extract. The Ag NPs also showed potential antimicrobial effects against both Gram-positive (Staphylococcus aureus) and negative bacteria (Klebsiella pneumonia).

Background: Malaria is caused by different species of Plasmodium; among which P. falciparum is the most severe. Coptis teeta is an ethnomedicinal plant of enormous importance for tribes of north east India. Objective: In this study, the anti malarial activity of the methanol extracts of Coptis teeta was evaluated in vitro and lead identification via in silico study. Method: On the basis of the in vitro results, in silico analysis by application of different modules of Discovery Studio 2018 was performed on multiple targets of P. falciparum taking into consideration some of the compounds reported from C. teeta. Results: The IC50 of the methanol extract of Coptis teeta 0.08 µg/ml in 3D7 strain and 0.7 µg/ml in Dd2 strain of P. falciparum. From the docking study, noroxyhydrastatine was observed to have better binding affinity in comparison to chloroquine. The binding of noroxyhydrastinine with dihydroorotate dehydrogenase was further validated by molecular dynamics simulation and was observed to be significantly stable in comparison to the co-crystal inhibitor. During simulations it was observed that noroxyhydrastinine retained the interactions, giving strong indications of its effectiveness against the P. falciparum proteins and stability in the binding pocket. From the Density-functional theory analysis, the band gap energy of noroxyhydrastinine was found to be 0.186 Ha indicating a favourable interaction. Conclusion: The in silico analysis as an addition to the in vitro results provide strong evidence of noroxyhydrastinine as an anti malarial agent.

Huge vaccination drives are underway around the world for the ongoing COVID-19 pandemic. However, the search for antiviral drugs is equally crucial. As new drug discovery is a time-consuming process, repurposing of existing drugs or developing drug candidates against SARS-CoV-2 will make the process faster. Considering this, 63 approved and developing antimalarial compounds were selected to screen against main protease (Mpro) and papain-like protease (PLpro) of SARS-CoV-2 using in silico methods to find out possible new drug candidate(s). Out of 63 compounds, epoxomicin showed the best binding affinity against the Mpro with CDocker energy of − 57.511 kcal/mol without any toxic effect. This compound was further taken for molecular dynamic simulation study, where the Mpro-epoxomicin complex was found to be stable with binding free energy − 79.315 kcal/mol. The possible inhibitory potential of the selected compound was determined by 3D-QSAR analysis and found to be 0.4447 µM against SARS-CoV-2 Mpro. Finally, the structure activity relationship of the compound was analyzed and two fragments responsible for overall good binding affinity of the compound at the active site of Mpro were identified. This study suggests a safe antimalarial drug, namely epoxomicin, as a probable inhibitor of SARS-CoV-2 Mpro which needs further validation by in vitro/in vivo studies before clinical use.

Nanotechnology introduces revolutionary approaches for agriculture in the form of nano-based pesticides, fertilizers, sensors, weed-controlling agents, enhanced seed germination materials, etc. Even though metal-nanoparticles (NPs) have shown their potential to improve crop yield, the mode of action at the cellular level and fate in the human body and the environment are not well understood yet. Several metal-nanoparticles have been studied extensively by researchers for their active role in enhancing the rate of seed germination and crop quality augmentation which may happen due to several mechanisms such as increased porosity in nano-primed seeds inducing up-regulation of the expression of aquaporin and Reactive Oxygen Species (ROS) genes involved in water uptake, improving the root dehydrogenase activity to enhance the water absorption capability, etc. However, researchers have also demonstrated and reported the possible toxicity of NPs in the environment due to their agricultural practices. But the fate of NPs and their environmental impact are still unclear and largely vary based on several factors such as the size of NPs, coating material, mode of discharge and locations, etc. This review thoroughly focuses on the mode of action of various NPs in seed germination and accumulation, translocation through cells, and potential environmental and health risks.

Over the past two years, SARS-CoV-2 has dramatically spread worldwide and emerged as a major pandemic which has left an unprecedented mark on healthcare systems and economies worldwide. As our understanding of the virus and its epidemiology continues to grow, the acute phase clinical symptoms and long-term and vaccine-related complications are becoming more apparent. With heterogeneity in presentations, comparisons may be drawn between COVID-19-related sequelae and vaccination related adverse events. The present review article aims to address the currently available literature on the SARS-CoV-2 virus, immune responses, the pathophysiology of clinical presentations, and available vaccinations with its adverse events for the appraisal of its potential impact on the COVID-19 management system.

The incurable Type 2 diabetes mellitus (T2DM) has now been considered a pandemic with only supportive care in existence. Due to the adverse effects of available anti-diabetic drugs, there arises a great urgency to develop new drug molecules. One of the alternatives that can be considered for the treatment of T2DM are natural compounds from traditionally used herbal medicine. The present study undertakes, an integrated multidisciplinary concept of Network Pharmacology to evaluate the efficacy of potent anti-diabetic compound from traditionally used anti-diabetic plants of north east India and followed by DFT analysis. In the course of the study, 22 plant species were selected on the basis of their use in traditional medicine for the treatment of T2DM by various ethnic groups of the north eastern region of India. Initially, a library of 1053 compounds derived from these plants was generated. This was followed by network preparation between compounds and targets based on the docking result. The compounds having the best network property were considered for DFT analysis. We have identified that auraptene, a monoterpene coumarin for its activity in the management of Type 2 diabetes mellitus and deciphered its unexplored probable mechanisms. Molecular dynamics simulation of the ligand-protein complexes also reveals the stable binding of auraptene with the target proteins namely, Protein Kinase C θ, Glucocorticoid receptor, 11-β hydroxysteroid dehydrogenase 1 and Aldose Reductase, all of which form uniform interactions throughout the MD simulation trajectory. Therefore, this finding could provide new insights for the development of a new anti-diabetic drug.Communicated by Ramaswamy H. Sarma.

Genetic change, particularly epigenetic alteration, is one of the imperative factors for sporadic breast cancer development in the worldwide population of women. The DNA methylation process is essential and natural for human cellular renewal and tissue homeostasis, but its dysregulation contributes to many pathological changes, including breast tumorigenesis. Chemopreventive agents mainly protect the abnormal DNA methylation either by hindering the division of pre-malignant cells or looming the DNA damage, which leads to malignancy. The present review article is about understanding the potential role of dietary phytochemicals in breast cancer prevention. Accordingly, a literature search of the published article until August 2021 has been performed. Further, we have investigated the binding affinity of different phytochemicals isolated from diverse dietary sources against the various oncogenic proteins related to breast cancer initiation to understand the common target(s) in breast cancer prevention mechanisms. Various small phytochemicals, especially dietary phytochemicals including sulforaphane, mahanine, resveratrol, linolenic acid, diallyl sulfide, benzyl/phenethyl isothiocyanate, etc. are being investigated as the chemopreventive agent to manage breast cancer development, and some of them have shown promising outcomes in the cited research. In this present review, we discuss the recent advancement in acceptance of such types of potential dietary phytochemicals as a chemopreventive agent against breast cancer development and their inner lining mechanism. The critical clinical trials and cohort studies have also been considered to understand the progress in contemporary perspectives.

Nanotechnology introduces revolutionary approaches for agriculture in the form of nano-based pesticides, fertilizers, sensors, weed-controlling agents, enhanced seed germination materials, etc. Even though metal-nanoparticles (NPs) have shown their potential to improve crop yield, the mode of action at the cellular level and fate in the human body and the environment are not well understood yet. Several metal-nanoparticles have been studied extensively by researchers for their active role in enhancing the rate of seed germination and crop quality augmentation which may happen due to several mechanisms such as increased porosity in nano-primed seeds inducing up-regulation of the expression of aquaporin and Reactive Oxygen Species (ROS) genes involved in water uptake, improving the root dehydrogenase activity to enhance the water absorption capability, etc. However, researchers have also demonstrated and reported the possible toxicity of NPs in the environment due to their agricultural practices. But the fate of NPs and their environmental impact are still unclear and largely vary based on several factors such as the size of NPs, coating material, mode of discharge and locations, etc. This review thoroughly focuses on the mode of action of various NPs in seed germination and accumulation, translocation through cells, and potential environmental and health risks.

Increased numbers of reported cases of Mycobacterium tuberculosis (Mtb) resistance to the generally used antibiotics demand to identify novel therapeutic entities for better control of Tuberculosis. Most of the Structure-based Drug Discovery (SBDD) works reported earlier had screened compounds against a single drug target to avoid any off-target binding and related complications. Because of the development of Multi-Drug Resistant and Extensively Drug-Resistant strains of Mtb and looking into the incurable pathologies, targeting the right drug target with a promising ligand data set will result in effective therapeutics. Simultaneously, traditional knowledge-based drugs have earned little success in developing anti-tuberculosis drugs in recent studies. Combining the right-target approach and traditional herbal knowledge base, this in silico drug discovery study was carried out where 1236 compounds from two plants, traditionally used for TB treatment, Camellia sinensis, Ginkgo biloba along with the antibacterial compounds of DrugBank Database have been screened against Pantothenate synthetase of Mtb, a well-known drug target for anti-TB therapeutics. Through this analytics, Epigallocatechin gallate (EGCG) of Camellia sinensis has been reported through in silico docking studies and subsequent Molecular Dynamics simulation, as a promising anti-TB candidate due to its affinity towards Pantothenate synthetase of Mtb. EGCG was subjected to ADME-Tox studies as well as 3D QSAR analysis for the detection of its drug-like properties and for the determination of IC50 value. The EGCG showed the IC 50 value at 1404 nM, which is quite promising for a plant-origin compound. The selected ligand, EGCG, due to its promising affinity towards Pantothenate synthetase of Mtb with high drug-like properties, justifies its selection as a potential anti-tuberculosis compound.