Prediction of molecular targets for antidepressant potential of hydroalcoholic extract of Tamarindus indica using network pharmacology approach and evaluating its efficacy in Chronic Unpredictable Mild Stress model in mice.

The prevalence of psychological disorders has surged since the 1990s, posing a significant global health burden with depressed individuals averaging six lost hours per week and contributing to over 20% of all missed workdays. Current antidepressants, while effective for some, have limited efficacy, dietary restrictions, and adverse effects, including liver damage and hypertension. Natural remedies offer promising therapeutic potential with minimal side effects. Tamarindus indica (TI) is a plant that grows in the shape of a tree. Network pharmacology of TI revealed the key targets MAPK, D1-6, 5HT, DAT, MAO, COMT, PKA, PKC, AKT, and VMAT, which are linked to prominent key pathways such as dopaminergic and serotonergic. The cell viability assays on SH-Sy5y cells indicated a favourable safety profile with an IC50 of 573.99 µg/ml and further, the in vivo efficacy was observed through Chronic Unpredictable Mild Stress (CUMS) model in mice. The hydroalcoholic extract of TI demonstrated antidepressant effects, significantly reducing immobility time in the Tail Suspension Test (TST) and Forced Swim Test (FST). Additionally, locomotor activity, assessed via the Open Field Test (OFT), was significantly increased in the treatment group compared to CUMS mice. Biochemical analyses revealed elevated Brain Derived Neurotropic Factor (BDNF), decreased cortisol levels, and reduced catechol-O-methyltransferase (COMT) concentration in TI-treated (50 mg/kg) groups. These findings underscore the potential of TI as a natural antidepressant, offering a promising avenue for further therapeutic development in depression management. The current study did not evaluate the level of neurotransmitters in the brain, which will be evaluated in future studies.

Arsenic induced cardiotoxicity: An approach for molecular markers, epigenetic predictors and targets.

Arsenic, a ubiquitous environmental toxicant, has been acknowledged as a significant issue for public health due to its widespread pollution of drinking water and food supplies. The present review aimed to study the toxicity associated with the cardiac system. Prolonged exposure to arsenic has been associated with several harmful health outcomes, especially cardiotoxicity. Arsenic-induced cardiotoxicity encompasses a range of cardiovascular abnormalities, including cardiac arrhythmias, ischemic heart disease, and cardiomyopathy. To tackle this toxicity, understanding the molecular markers, epigenetic predictors, and targets involved in arsenic-induced cardiotoxicity is essential for creating preventative and therapeutic approaches. For preventive measures against this heavy metal poisoning of groundwater, it is crucial to regularly monitor water quality, re-evaluate scientific findings, and educate the public about the possible risks. This review thoroughly summarised what is currently known in this field, highlighting the key molecular markers, epigenetic modifications, and potential therapeutic targets associated with arsenic-induced cardiotoxicity.

Naringin and temozolomide combination suppressed the growth of glioblastoma cells by promoting cell apoptosis: network pharmacology, in-vitro assays and metabolomics based study.

Introduction: Glioblastoma, which affects a large number of patients every year and has an average overall lifespan of around 14.6 months following diagnosis stands out as the most lethal primary invasive brain tumor. Currently, surgery, radiation, and chemotherapy with temozolomide (TMZ) are the three major clinical treatment approaches. However, the ability to treat patients effectively is usually limited by TMZ resistance. Naringin, a bioflavonoid with anti-cancer, antioxidant, metal-chelating, and lipid-lowering effects, has emerged as a promising therapeutic option. Methods: To explore the targets and pathways of naringin and TMZ in glioblastoma network pharmacology, cell line-based ELISA, flow cytometry, immunocytochemistry, western blotting, and LC-HRMS based metabolomics study were used. Results: The findings through the network pharmacology suggested that the key targets of naringin in the chemosensitization of glioblastoma would be Poly [ADP-ribose] polymerase 1 (PARP-1), O-6-Methylguanine-DNA Methyltransferase (MGMT), and caspases. The functional enrichment analysis revealed that these targets were significantly enriched in important pathways such as p53 signaling, apoptosis, and DNA sensing. Further, the results of the in-vitro study in U87-MG and T98-G glioblastoma cells demonstrated that TMZ and naringin together significantly reduced the percentage of viability and inhibited the DNA repair enzymes PARP-1 and MGMT, and PI3K/AKT which led to chemosensitization and, in turn, induced apoptosis, which was indicated by increased p53, caspase-3 expression and decreased Bcl2 expression. Additionally, a metabolomics study in T98-G glioblastoma cells using liquid chromatography high-resolution mass spectrometry (LC-HRMS) revealed downregulation of C8-Carnitine (-2.79), L-Hexanoylcarnitine (-4.46), DL-Carnitine (-2.46), Acetyl-L-carnitine (-3.12), Adenine (-1.3), Choline (-2.07), Propionylcarnitine (-1.69), Creatine (-1.33), Adenosine (-0.84), Spermine (-1.42), and upregulation of Palmitic Acid (+1.03) and Sphingosine (+0.89) in the naringin and TMZ treatment groups. Discussion: In conclusion, it can be said that naringin in combination with TMZ chemosensitized TMZ antiglioma response and induced apoptosis in tumor cells.

NLRP3 inflammasome in depression: A review.

The present article provides a detailed concept of the role of NLRP3 inflammasome in the pathophysiology of depression-like chronic diseases where inflammation and release of various cytokines plays a pivotal role in exaggerating the condition. The various pathways involved in NLRP3 activation are the main target of NLRP3 inhibitors for the therapeutic management of depression as per the recent clinical and research studies conducted so far. Further various drug inhibitors for NLRP3 available in preclinical and clinical trials have been discussed in detail. Hence, blockage of the action of NLRP3 inflammasome is crucial to anticipate the inflammatory cytokine release from the mediators that contributes to cause depression.

4-Methylesculetin ameliorates LPS-induced depression-like behavior through the inhibition of NLRP3 inflammasome.

The pathophysiology of depression is heavily dependent on inflammation. Evidence suggests that the etiology of depression is linked with NLRP3 inflammasome-induced inflammation. Therefore, blocking the activated NLRP3 inflammasome may be beneficial for treating depression. Due to the limitations of currently available antidepressants, it is necessary to develop novel, safe, and affordable drugs for the treatment of depression. A natural coumarin derivative named 4-methylesculetin (4-MESC) possesses anti-inflammatory properties. However, the role of 4-MESC as an antidepressant has not been elucidated. Therefore, in this study, we explored the antidepressant-like effects of 4-MESC and its underlying molecular mechanism through the modulation of the NLRP3 inflammasome. The docking and molecular dynamic simulation studies revealed that 4-MESC has a higher affinity for the NLRP3 PYD. Blood-brain barrier permeability was confirmed using the SwissADME pharmacokinetic tool. High doses (50 mg/kg) of 4-MESC significantly reduced the immobility duration in the tail-suspension test (TST) and forced swim test (FST) without changing the overall locomotor activity in the female Swiss albino mice that were subjected to lipopolysaccharide (LPS). LPS-induced pro-inflammatory cytokines such as IL-6 and TNF-α were reduced in serum and brain tissues using 4-MESC. 4-MESC's neuroprotective effects are mediated by increased brain-derived neurotrophic factor (BDNF) and decreased cortisol levels. 4-MESC markedly reduced LPS-induced elevated levels of ROS and lipid peroxidation (malondialdehyde levels) and enhanced the superoxide dismutase (SOD) activity and glutathione levels, which revealed its anti-oxidant potential against oxidative stress. 4-MESC diminished the expression levels of NF-κBp65, IL-6, NLRP3, caspase-1, gasdermin D, and IL-1ß in the hippocampus. These findings demonstrated that 4-MESC exhibited antidepressant-like effects by inhibiting the NLRP3 inflammasome. However, other antidepressant mechanisms might also be involved which require further studies.

RNA Interference and CRISPR/Cas Gene Editing for Crop Improvement: Paradigm Shift towards Sustainable Agriculture.

With the rapid population growth, there is an urgent need for innovative crop improvement approaches to meet the increasing demand for food. Classical crop improvement approaches involve, however, a backbreaking process that cannot equipoise with increasing crop demand. RNA-based approaches i.e., RNAi-mediated gene regulation and the site-specific nuclease-based CRISPR/Cas9 system for gene editing has made advances in the efficient targeted modification in many crops for the higher yield and resistance to diseases and different stresses. In functional genomics, RNA interference (RNAi) is a propitious gene regulatory approach that plays a significant role in crop improvement by permitting the downregulation of gene expression by small molecules of interfering RNA without affecting the expression of other genes. Gene editing technologies viz. the clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein (CRISPR/Cas) have appeared prominently as a powerful tool for precise targeted modification of nearly all crops' genome sequences to generate variation and accelerate breeding efforts. In this regard, the review highlights the diverse roles and applications of RNAi and CRISPR/Cas9 system as powerful technologies to improve agronomically important plants to enhance crop yields and increase tolerance to environmental stress (biotic or abiotic). Ultimately, these technologies can prove to be important in view of global food security and sustainable agriculture.

Heavy metals biosorption mechanism of partially delignified products derived from mango (Mangifera indica) and guava (Psidium guiag) barks.

This paper evaluates the biosorption of toxic metal ions onto the bioadsorbents derived from mango (Mangifera indica) and guava (Psidium guiag) barks and their metal fixation mechanisms. Maximum metal biosorption capacities of the mango bioadsorbent were found in the following increasing order (mg/g): Hg (16.24) < Cu (22.24) < Cd (25.86) < Pb (60.85). Maximum metal biosorption capacities of guava bioadsorbent follow similar order (mg/g): Hg (21.48) < Cu (30.36) < Cd (32.54) < Pb (70.25), but with slightly higher adsorption capacities. The removal mechanisms of heavy metals using bioadsorbents have been ascertained by studying their surface properties and functional groups using various spectrometric, spectroscopic, and microscopic methods. Whewellite (C2CaO4·H2O) has been identified in bioadsorbents based on the characterization of their surface properties using X-ray techniques (XPS and XRD), facilitating the ion exchange of metal ions with Ca2+ bonded with carboxylate moieties. For both the bioadsorbents, the Pb2+, Cu2+, and Cd2+ are biosorbed completely by ion exchange with Ca2+ (89-94%) and Mg2+ (7-12%), whereas Hg2+ is biosorbed partially (57-66%) by ion exchange with Ca2+ (38-42%) and Mg2+ (19-24%) due to involvement of other cations in the ion exchange processes. Bioadsorbents contain lignin which act as electron donor and reduced Cr(VI) into Cr(III) (29.87 and 37.25 mg/g) in acidic medium. Anionic Cr(VI) was not adsorbed onto bioadsorbents at higher pH due to their electrostatic repulsion with negatively charged carboxylic functional groups.

Abiotic Stress Responses and Microbe-Mediated Mitigation in Plants: The Omics Strategies.

Abiotic stresses are the foremost limiting factors for agricultural productivity. Crop plants need to cope up adverse external pressure created by environmental and edaphic conditions with their intrinsic biological mechanisms, failing which their growth, development, and productivity suffer. Microorganisms, the most natural inhabitants of diverse environments exhibit enormous metabolic capabilities to mitigate abiotic stresses. Since microbial interactions with plants are an integral part of the living ecosystem, they are believed to be the natural partners that modulate local and systemic mechanisms in plants to offer defense under adverse external conditions. Plant-microbe interactions comprise complex mechanisms within the plant cellular system. Biochemical, molecular and physiological studies are paving the way in understanding the complex but integrated cellular processes. Under the continuous pressure of increasing climatic alterations, it now becomes more imperative to define and interpret plant-microbe relationships in terms of protection against abiotic stresses. At the same time, it also becomes essential to generate deeper insights into the stress-mitigating mechanisms in crop plants for their translation in higher productivity. Multi-omics approaches comprising genomics, transcriptomics, proteomics, metabolomics and phenomics integrate studies on the interaction of plants with microbes and their external environment and generate multi-layered information that can answer what is happening in real-time within the cells. Integration, analysis and decipherization of the big-data can lead to a massive outcome that has significant chance for implementation in the fields. This review summarizes abiotic stresses responses in plants in-terms of biochemical and molecular mechanisms followed by the microbe-mediated stress mitigation phenomenon. We describe the role of multi-omics approaches in generating multi-pronged information to provide a better understanding of plant-microbe interactions that modulate cellular mechanisms in plants under extreme external conditions and help to optimize abiotic stresses. Vigilant amalgamation of these high-throughput approaches supports a higher level of knowledge generation about root-level mechanisms involved in the alleviation of abiotic stresses in organisms.

Effect of Plant Growth Promoting Bacteria Associated with Halophytic Weed (Psoralea corylifolia L) on Germination and Seedling Growth of Wheat Under Saline Conditions.

Halotolerant bacteria associated with Psoralea corylifolia L., a luxuriantly growing annual weed in salinity-affected semi-arid regions of western Maharashtra, India were evaluated for their plant growth-promoting activity in wheat. A total of 79 bacteria associated with different parts viz., root, shoot and nodule endophytes, rhizosphere, rhizoplane, and leaf epiphytes, were isolated and grouped based on their habitat. Twelve bacteria isolated for their potential in plant growth promotion were further selected for in vitro studies. Molecular identification showed the presence of the genera Bacillus, Pantoea, Marinobacterium, Acinetobacter, Enterobacter, Pseudomonas, Rhizobium, and Sinorhizobium (LC027447-53; LC027455; LC027457, LC027459, and LC128410). The phylogenetic studies along with carbon source utilization profiles using the Biolog® indicated the presence of novel species and the in planta studies revealed promising results under salinity stress. Whereas the nodule endophytes had minute plant growth-promoting (PGP) activity, the cell free culture filtrates of these strains enhanced seed germination of wheat (Triticum aestivum L). The maximum vigor index was monitored in isolate Y7 (Enterobacter sp strain NIASMVII). Indole acetic acid (IAA) production by the isolates ranged between 0.22 and 25.58 µg mL-1. This signifies the need of exploration of their individual metabolites for developing next-generation bio-inoculants through co-inoculation with other compatible microbes. This study has potential in utilization of the weed-associated microbiome in terms of alleviation of salinity stress in crop plants.