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Abstract An environmentally friendly, versatile multicomponent reaction for synthesizing isoxazol-5-one and pyrazol-3-one derivatives has been developed, utilizing a freshly prepared g-C3N4· OH nanocomposite as a highly efficient catalyst at room temperature in aqueous environment. This innovative approach yielded all the desired products with exceptionally high yields and concise reaction durations. The catalyst was well characterized by FT-IR, XRD, SEM, EDAX, and TGA/DTA studies. Notably, the catalyst demonstrated outstanding recyclability, maintaining its catalytic efficacy over six consecutive cycles without any loss. The sustainability of this methodology was assessed through various eco-friendly parameters, including E-factor and eco-score, confirming its viability as a green synthetic route in organic chemistry. Additionally, the gram-scale synthesis verifies its potential for industrial applications. The ten synthesized compounds were also analyzed via a PASS online tool to check their several pharmacological activities. The study is complemented by in silico molecular docking, pharmacokinetics, and molecular dynamics simulation studies. These studies discover 5D as a potential candidate for drug development, supported by its favorable drug-like properties, ADMET studies, docking interaction, and stable behavior in the protein binding cavity.

Uncontrolled cell proliferation, primarily regulated by cyclin-dependent kinases (CDKs), is a critical driver of cancer progression, with dysregulation of CDKs contributing to various cancer types. CDKs have emerged as well-established targets for cancer therapy; however, traditional drug development methods have often proven to be time-consuming, challenging, and expensive. Recent advancements in CDK inhibitors (CDKIs) have shown immense clinical potential but many first-generation CDKIs face issues of non-selectivity and significant toxicity, limiting their clinical approval. To address these challenges, innovative computational approaches, particularly pharmacophore modeling, have the potential to streamline drug discovery. These methods can guide the selection of small molecules through target-specific structure-activity relationship (SAR) models and chemotypes screening across databases, thereby accelerating the identification of effective CDKIs. This review paper summarizes the latest developments on CDK inhibitors, highlights their structural features, and the methodologies (key databases & software tools) that can provide further suggestions for future drug development.

Calix[n]arene is a class of macrocyclic compounds and has been investigated to improve the physicochemical properties of water insoluble molecules. In this work, a complex of morin hydrate (MH) drug was prepared using p-sulfocalix[4]arene (SC[4]A) as complexing agent to increase its water solubility, dissolution rate and stability. Solvent evaporation methanol was used to prepare the inclusion complex (MH-SC[4]A) between pure MH and SC[4]A and analysed by FTIR, NMR, UV, DLS, TEM, and DSC techniques. Concentration-dependent solubility study showed 22 folds enhancement of MH at 8 mM concentration of SC[4]A. The in vitro anticancer efficacy of MH against A549 cells was increased after complex formation. AO/EtBr staining study showed the more apoptosis mediated anticancer activity than native MH. Molecular geometry, stabilizing interactions, release behaviour and full-unwinding pathway of the complex were characterized by the computed Potential of Mean Force (PMF) using extended umbrella sampling. The combined computational and experimental data confirmed that our designed MH-SC[4]A complex could be utilized as a promising drug delivery carrier for hydrophobic MH.

Abstract Cancer has been viewed as one of the deadliest diseases worldwide. Among various types of cancer, breast cancer is the most common type of cancer in women. Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a promising druggable target and is overexpressed in cancerous cells, like, breast cancer. We conducted structure-based modeling on the allosteric site of the enzyme. Targeting the allosteric site avoids the problem of drug resistance. Pharmacophore modeling, molecular docking, HYDE assessment, drug-likeness, ADMET predictions, simulations, and free-energy calculations were performed. The RMSD, RMSF, RoG, SASA, and Hydrogen-bonding studies showed that seven candidates displayed stable behaviour. As per the literature, average superimposed simulated structures revealed a similar protein conformational change in the αEʹ-βfʹ loop, causing its displacement away from the allosteric site. The MM-PBSA showed tight binding of six compounds with the allosteric pocket. The effect of inhibitors interacting in the allosteric site causes a decrease in the binding energy of J49 (active-site inhibitor), suggesting the effect of allosteric binding. The PCA and FEL analysis revealed the significance of the docked compounds in the stable behaviour of the complexes. The outcome can contribute to the development of potential natural products with drug-like properties that can inhibit the MTHFD2 enzyme.

Diabetic kidney disease (DKD) is a major microvascular complication of both type 1 and type 2 diabetes. DKD is characterised by injury to both glomerular and tubular compartments, leading to kidney dysfunction over time. It is one of the most common causes of chronic kidney disease (CKD) and end-stage renal disease (ESRD). Persistent high blood glucose levels can damage the small blood vessels in the kidneys, impairing their ability to filter waste and fluids from the blood effectively. Other factors like high blood pressure (hypertension), genetics, and lifestyle habits can also contribute to the development and progression of DKD. The key features of renal complications of diabetes include morphological and functional alterations to renal glomeruli and tubules leading to mesangial expansion, glomerulosclerosis, homogenous thickening of the glomerular basement membrane (GBM), albuminuria, tubulointerstitial fibrosis and progressive decline in renal function. In advanced stages, DKD may require treatments such as dialysis or kidney transplant to sustain life. Therefore, early detection and proactive management of diabetes and its complications are crucial in preventing DKD and preserving kidney function.

Background: The purpose of the present study was to evaluate the serum levels of homocysteine in individuals diagnosed with idiopathic ischemic stroke, and to establish a correlation between its clinical relevance and other risk factors associated with ischemic stroke, utilizing a case-control study design. Methods: The study was conducted at the Department of Medicine, DMCH, Lehariasarai. The study comprised a total of 21 individuals diagnosed with non-diabetic ischemic conditions, alongside 21 controls. Inclusion criteria included individuals of adult age, who exhibited no prior diagnosis of diabetes and presented with first-ever ischemic stroke. Confirmation of the ischemic stroke was confirmed through CT scanning of the cranial region. Exclusion criteria consisted of individuals diagnosed with diabetes mellitus, haemorrhagic stroke, individuals who encountered an embolic stroke, receiving vitamin supplementation, and phenytoin usage. The patient underwent regular examinations, including serum homocysteine level and fasting serum lipid profile assessment. Results: The research showed a statistically relevant elevation in the mean serum homo-cysteine level among patients diagnosed with ischemic stroke, aged above 60 years, male gender, diagnosed with hypertension, and exhibiting a normal fasting lipid profile as compared to the controls. The statistical analysis was employed to determine the significance of the observed difference by utilization of the Chi-Square test, and Yate's correction. Conclusions: A statistically relevant correlation was found among all the investigated factors for risk in non-diabetic individuals and the levels of serum homocysteine. The assessment of serum homocysteine levels is strongly advised for the comprehensive evaluation of idiopathic ischemic strokes, with the aim of conducting a prognostic assessment.

Background: Diabetes Mellitus (DM), affects various systems within the body. Patients with untreated treated diabetes are at risk of developing a range of complications that contribute to increased morbidity and mortality rates. Diabetes Mellitus exerts various persistent impacts on the Urogenital system. UTIs have been widely acknowledged as a substantial concern among individuals diagnosed with DM. Methods: A potential observational research was conducted consisting of individuals with diabetes mellitus exhibiting positive indications of urinary tract infection. Exclusion criteria encompassed gestational diabetes, patients with compromised immune systems, and individuals presenting with congenital kidney malformations. Results: The study encompassed a total of 110 incidents of UTIs. Among them were a total of 35 males, and 75 females. The age group predominantly comprised between the ages of 55 and 70 years. Escherichia coli was identified as the prevailing microorganism isolated in the sample. Gram-positive organisms proved a sensitivity rate of 100% to Linezolid and Vancomycin. Gram-negative microbes demonstrated a sensitivity rate of 100% to Polymyxin B. Conclusion: Urogenital tract infection is a commonly observed difficulty in individuals with diabetes mellitus. The identification of the most prevalent causative organisms and their corresponding antibiotic sensitivity patterns is imperative within a tertiary care hospital setting in order to establish an enhanced antibiotic policy. Recommendation: It is strongly recommended that further studies be conducted with a larger sample size in order to provide additional support for the findings obtained in this study.

Chronic hyperglycemia induces intrarenal oxidative stress due to the excessive production of reactive oxygen species (ROS), leading to a cascade of events that contribute to the development and progression of diabetic kidney disease (DKD). NOX5, a pro-oxidant NADPH oxidase isoform, has been identified as a significant contributor to renal ROS in humans. Elevated levels of renal ROS contribute to endothelial cell dysfunction and associated inflammation, causing increased endothelial permeability, which can disrupt the renal ecosystem, leading to progressive albuminuria and renal fibrosis in DKD. This study specifically examines the contribution of endothelial cell-specific human NOX5 expression in renal pathology in a transgenic mouse model of DKD. This study additionally compares NOX5 with the previously characterized NADPH oxidase, NOX4, in terms of their relative roles in DKD. Regardless of NOX4 pathway, this study found that endothelial cell-specific expression of NOX5 exacerbates renal injury, albuminuria and fibrosis. This is attributed to the activation of the endothelial mesenchymal transition (EMT) pathway via enhanced ROS formation and the modulation of redox-sensitive factors. These findings underscore the potential therapeutic significance of NOX5 inhibition in human DKD. The study proposes that inhibiting NOX5 could be a promising approach for mitigating the progression of DKD and strengthens the case for the development of NOX5-specific inhibitors as a potential therapeutic intervention.

Marine biofouling has been an issue since antiquity whose solutions have a history of negative environmental impact. The development of environmentally sustainable solutions is paramount as society is becoming more conscious of anthropogenic impacts on the global ecosystem, particularly the global oceans. Herein we include a brief overview of common strategies in the development of sustainable marine antifouling coatings in terms of their efficacy, durability, and environmental impact. We discuss technical challenges to the development of sustainable antifouling coatings; barriers and incentives to their market uptake; and advocate the necessity of multi-stakeholder collaboration, including scientists, engineers, industry groups, and regulators, toward the development of marketable and sustainable antifouling coating solutions.

The present work quantifies metal-contaminant interactions between palladium substrates and three salient chlorinated organic contaminants, namely trichloroethylene 1,3,5-trichlorobenzene (TCB), and 3,3′,4,4′-tetrachlorobiphenyl (PCB77). Given that Pd is one of the conventional catalytically active materials known for contaminant removal, maximizing catalytic efficiency through optimal adsorption dynamics reduces the cost of remediation of contaminants that are persistent water pollutants chronically affecting public health. Adsorption efficiency analyses from all-atom molecular dynamics (MD) simulations advance the understanding of reaction mechanisms available from density functional theory (DFT) calculations to an extractable feature scale that can fit the parametric design of supported metal catalytic systems and feed into high throughput catalyst selection. Data on residence time, site-specific adsorption, binding energies, packing geometries, orientation profiles, and the effect of adsorbate size show the anomalous behaviour of organic contaminant adsorption on the undercoordinated {110} surface as compared to the {111} and {100} surfaces. The intermolecular interaction within contaminants from molecular dynamics simulation exhibits refreshing results than ordinary single molecule density functional theory calculation. Since complete adsorption and dechlorination is an essential step for chlorinated organic contaminant remediation pathways, the presented profiles provide essential information for designing efficient remediation systems through facet-controlled palladium nanoparticles.

The present pathway involves synthesis of isonicotinohydrazide derivatives using isoniazid and diversely substituted aldehydes in the presence of EtOH and catalytic amount of glycerol based carbon sulfonic acid catalyst. The developed pathway has so many merits like excellent yields (91–98%), short reaction time (4–10 min), easy reaction set up, no need of column chromatography, large substrate scope, easily recyclable and reusable catalyst. The synthesized compounds were screened for antimicrobial and anti-tubercular activity and it was observed that compounds possessed high biological potency against the Gram positive and Gram negative bacterial and fungal strains. Regarding anti-tubercular activity, compound 3m exhibited high % inhibition against Mycobacterium tuberculosis H37RV strain. Based on the outcome of in vitro studies, all the synthesized compounds were docked against E. coli (1KZN), C. albicans (1IYL), and M. tuberculosis H37Rv strain (2NSD). The synthesized derivatives were docked within the binding site of 1KZN, and 1IYL. However, with 2NSD, apart from 3h, all the derivatives displayed interaction within the binding cavity of the protein. All the crucial interactions with Asn46, Asp73, and Arg136 in 1KZN, His227, Leu451 in 1IYL, and Tyr158 in 2NSD were witnessed in the top-scored docked candidates. Molecular docking studies revealed the importance of the substitution at R position on isonicotinohydrazide scaffold. The nitrogen atoms of hydrazide moiety were involved in forming hydrogen bonding with the active site amino acids, and the substitution at the R position occupy the hydrophobic position in the binding pocket. Also, the functional groups present on the substituted R position were involved in forming hydrogen bonding with the crucial active site residues.

Background: Health can be defined as more than an absence or lack of disease. It is generally related to personal, physical, social, along with spiritual wellness. However, the importance of good health is comparable with a progressive physical and cognitive limitations due to aging and hence, its clear definition is not possible. Hence, most of the important aims or goals in aging are unrelated to finding a cure but rather toward achieving an optimal function. Thus, a healthy aging process that encompasses physical, mental, psychological, and spiritual well-being is always much desired. Aim and Objectives: The aim and objective of this study is to assess the oral health status and degree of cognitive impairment along with dementia, if present. Materials and Methods: This is a prospective and cross-sectional analysis comprising of 300 study participants of which 150 are males while 150 are females. Cognitive ability is assessed using the Standardized Mini-Mental State Examination (SMMSE) scoring test. A score value lesser than or equal to 23 is considered as low, whereas a score of 24 and above represents normal cognitive abilities. Subjects with low score are selected for the study. Oral health status is assessed by examining a) total numbers of teeth present; b) presence or absence of denture use; and c) capacity for masticatory or chewing ability (recorded as yes or no). Demographic variables parameters include age, gender, and presence of smoking habit. Clinical parameters or variables are analyzed by employing the independent t-test and Chi-square test. Pearson's correlation analysis is used to test a correlation between impairment of cognitive capacity, oral health status, masticatory capability, and use of dentures, if present. Two-tailed t-test is used to derive a P value for significance. Results: The total numbers of teeth present are significantly correlated with a lower SMMSE score (R = + 0.56; P = 0.03) while a significant association is noted between ability for mastication and lower SMMSE score (P = 0.05). Conclusion: This study concluded that loss of cognition or dementia is closely related to a poor oral health status.

Abstract Background Helicobacter pylori (H. pylori) is well-known for its role in chronic gastritis and gastric cancer. Eradication of these carcinogenic bacteria from the gut is one of the challenges for clinicians. The complexity of treatment mainly owes to antibiotic resistance and relapse due to an additional reservoir in the oral cavity. Our study emphases the isolation of H. pylori from distinct habitats of the gut microenvironment (gastric biopsy and gastric juice) and its subsequent characterization. We have also evaluated the effect of various oral rinses on isolated H. pylori from different anatomical locations of included subjects. Results The possible strains isolated from two different habitats of the same subject shows a striking difference in their growth pattern. Promisingly, some of the included oral rinses are efficient in growth inhibition as per recommended 30 s treatment. The subsequent evaluation shows that oral rinse B (among A-E) is most effective and down-regulates the expression of one of the potent H. pylori gene, CagA, in the infected gastric adenocarcinoma (AGS) cells. Conclusion Our study, for the first time, revealed that H. pylori, isolated from the different habitat of the same subject, show a different growth pattern. The expression of H. pylori pathogenic gene (CagA) was down-regulated by the use of oral rinses. Hence, oral rinses will reduce the H. pylori in the oral cavity and help to control its migration from oral to the gastric compartment and may be used as an adjuvant treatment option for its re-infection.

The prevalence of diabetes is growing at an alarming rate with increased disability, morbidity, and often premature mortality because of the various complications of this disorder. Chronic hyperglycemia, dyslipidemia, and other metabolic alterations lead to the development and progression of macro- and microvascular complications of diabetes including cardiovascular, retinal and kidney disease. Despite advances in glucose and lipid lowering treatments, a large number of diabetic individuals develop one or more types of these complications, ultimately leading to end-organ damage over the time. Atherosclerosis is the major macro-vascular complications of diabetes and the primary underlying cause of cardiovascular disease (CVD) posing heavy burden on the health care system. In this review, we discuss the involvement of dyslipidemia in the progression of atherosclerosis by activating the pro-inflammatory cytokines and oxidative stress-related factors. In addition, we also provide information on various pharmacological agents that provides protection against diabetic atherosclerosis by reducing inflammation and oxidative stress.

Chickpea is sensitive to cold stress, especially at reproductive stage, resulting in flower and pod abortion that significantly reduces seed yield. In the present study, we evaluated (a) whether cold acclimation imparts reproductive cold tolerance in chickpea; (b) how genotypes with contrasting sensitivity respond to cold acclimation; and (c) the involvement of cryoprotective solutes and antioxidants in anthers and ovules in cold acclimation. Four chickpea genotypes with contrasting cold sensitivity (cold-tolerant: ICC 17258, ICC 16349; cold-sensitive: ICC 15567, GPF 2) were grown in an outdoor environment for 40 days in November (average maximum/minimum temperature 24.9/15.9 °C) before being subjected to cold stress (13/7 °C), with or without cold acclimation in a controlled environment of walk-in-growth chambers. The 42-d cold acclimation involved 7 d exposure at each temperature beginning with 23/15 °C, 21/13 °C, 20/12 °C, 20/10 °C, 18/8 °C, 15/8 °C (12 h/12 h day/night), prior to exposing the plants to cold stress (13/7 °C, 12 h/12 h day/night; 700 μmol m−2 s−1 light intensity; 65–70% relative humidity). Cold acclimation remarkably reduced low temperature-induced leaf damage (as membrane integrity, leaf water status, stomatal conductance, photosynthetic pigments, and chlorophyll fluorescence) under cold stress in all four genotypes. It only reduced anther and ovule damage in cold-tolerant genotypes due to improved antioxidative ability, measured as enzymatic (superoxide dismutase, catalase, ascorbate peroxidase, and glutathione reductase) and non-enzymatic (ascorbate and reduced glutathione), solutes (particularly sucrose and γ-aminobutyric acid) leading to improving reproductive function and yield traits, whereas cold-sensitive genotypes were not responsive. The study concluded that cold tolerance in chickpea appears to be related to the better ability of anthers and ovules to acclimate, involving various antioxidants and cryoprotective solutes. This information will be useful in directing efforts toward increasing cold tolerance in chickpea.