Mechanism of Nucleic Acid Phosphodiester Bond Cleavage by Human Endonuclease V: MD and QM/MM Calculations Reveal a Versatile Metal Dependence.

Human endonuclease V (EndoV) catalytically removes deaminated nucleobases by cleaving the phosphodiester bond as part of RNA metabolism. Despite being implicated in several diseases (cancers, cardiovascular diseases, and neurological disorders) and potentially being a useful tool in biotechnology, details of the human EndoV catalytic pathway remain unclear due to limited experimental information beyond a crystal structure of the apoenzyme and select mutational data. Since a mechanistic understanding is critical for further deciphering the central roles and expanding applications of human EndoV in medicine and biotechnology, molecular dynamics (MD) simulations and quantum mechanics/molecular mechanics (QM/MM) calculations were used to unveil the atomistic details of the catalytic pathway. Due to controversies surrounding the number of metals required for nuclease activity, enzyme-substrate models with different numbers of active site metals and various metal-substrate binding configurations were built based on structural data for other nucleases. Subsequent MD simulations revealed the structure and stability of the human EndoV-substrate complex for a range of active site metal binding architectures. Four unique pathways were then characterized using QM/MM that vary in metal number (one versus two) and modes of substrate coordination [direct versus indirect (water-mediated)], with several mechanisms being fully consistent with experimental structural, kinetic, and mutational data for related nucleases, including members of the EndoV family. Beyond uncovering key roles for several active site amino acids (D240 and K155), our calculations highlight that while one metal is essential for human EndoV activity, the enzyme can benefit from using two metals due to the presence of two suitable metal binding sites. By directly comparing one- versus two-metal-mediated P-O bond cleavage reactions within the confines of the same active site, our work brings a fresh perspective to the "number of metals" controversy.

Wormhole Mesoporous Silica Framework with Enhanced Thiol Loading for Improved Hg²âº Sequestration.

Thiol-functionalized mesoporous silica and materials potentially dedicated to diverse applications of composite materials, metal colloids, and metal catalysts, etc. Here, we developed a new synthesis route for 3-methacryloxypropyl trimethoxy silane (MPTMS) functionalized mesoporous silica (KIT-6), achieving a 71.5% enhancement in thiol functionalization on KIT-6 surfaces. Characterization using XRD, TEM, BET, FTIR, Raman, 29Si NMR, XPS, and ICP-OES revealed structural and morphological features. XRD, TEM, and BET confirmed the three-dimensional structural stabilization of mesoporous silica with ~4 nm pore diameter and a surface area of 1451 m2 g-1. FTIR, Raman, and 29Si NMR studies established the mechanism of thiol functionalization, the formation of a new wormhole chain structural framework (WCSF), and stabilization through hydrogen bonding within the mesopores. The 29Si NMR spectra showed characteristic peaks (T3, T2, Q4, Q3) indicating self-condensed functionalized thiols with siloxane networks. XPS analysis validated enhanced thiol functionalization, indicating a structurally homogeneous WCSF suitable for mercury adsorption. ICP-OES measured a mercury adsorption capacity of 3199.6 mg g-1 for KIT-6, with an Hg2+/S ratio of 1.8, corroborated by molecular structure and mechanism analysis. This innovative thiol functionalization approach enhances the efficacy of applications such as extracting Hg2+ from contaminated sources.

A QbD-Navigated Approach to the Development and Evaluation of Etodolac-Phospholipid Complex Containing Polymeric Films for Improved Anti-Inflammatory Effect.

The current study focuses on development of phospholipid complex-loaded films of etodolac for enhanced transdermal permeation and anti-inflammatory effect. An etodolac-phospholipid complex was developed using the solvent evaporation method and was characterized by DSC, XRD, FTIR, and 1H-NMR studies. The formation of the complex led to conversion of a crystalline drug to an amorphous form. A stoichiometric ratio of 1:1 (drug-phospholipid) was selected as the optimized ratio. Further, the developed complex was incorporated into films and systematic optimization using a central composite design was carried out using a response surface methodological approach. The desirable design space based on minimum contact angle and maximum tensile strength was selected, while the water vapour transmission rate and swelling index were set within limits. The results for swelling index, contact angle, tensile strength, and water vapour transmission rate were 60.14 ± 1.01%, 31.6 ± 0.03, 2.44 ± 0.39 kg/cm2, and 15.38 g/hm2, respectively. These values exhibited a good correlation with the model-predicted values. The optimized formulation exhibited improved diffusion and permeation across skin. In vivo studies revealed enhanced anti-inflammatory potential of the developed films in comparison to the un-complexed drug. Hence, the study demonstrated that etodolac-phospholipid complex-loaded films improve the transdermal permeation and provided enhanced anti-inflammatory effect.

Electrochemical Charge Transfer Kinetics of Ferrocene in the Light of Different Working Electrodes.

Ferrocene is an accidentally discovered organometallic compound that serves as a crucial redox probe in investigating electrochemical charge transfer dynamics. Besides solution phase studies, ferrocene derivatives are well-explored in molecular thin films, including self-assembled monolayers on various electrodes for understanding on-surface redox behavior, molecular electronics, and charge storage applications. Heterogeneous charge transfer is an imperative parameter for efficient charge transport in spin-dependent electrochemistry, photoelectrochemistry, and molecular electronic devices. In this work, we aim to study the electrochemical charge transfer of ferrocene on various electrodes such as commercially obtained glassy carbon, graphite rod, indium tin oxide (ITO), and as-prepared gold, and nickel to determine the impact of the nature of the working electrode on the electron transfer rate, diffusion coefficient, and reversibility of the redox process. Both the direct current and alternating current-based electrochemical experiments are performed, followed by digitization of the experimental results. The kinetics of electron transfer and electrochemical reversibility reveal a strong dependence on the nature of the working electrode, as the electrochemically driven oxidation and reduction of the material of interest are directly related to the Fermi energy and electronic structure of the working electrode.

To determine the role of transcutaneous retrobulbar amphotericin B in COVID-19-related rhino-orbital-cerebral mucormycosis.

PURPOSE: The purpose of this study was to determine the role of transcutaneous retrobulbar amphotericin B (TRAMB) injection in COVID-19-related rhino-orbital-cerebral mucormycosis (ROCM). MATERIALS AND METHODS: This prospective interventional case series included 7 eyes of 7 patients diagnosed with COVID-19 ROCM presenting from May to September 2021 at a tertiary care center in North India. Active or recovered cases of COVID-19 with clinical features suggestive of ROCM and early orbital involvement were included. Following functional endoscopic sinus surgery, patients were given TRAMB 3.5 mg/ml in single ocular quadrant depending upon the muscle involved on contrast-enhanced magnetic resonance imaging (MRI). Patients were followed up for a period of 12 weeks. RESULTS: All patients were diabetic and COVID-19 reverse transcription-polymerase chain reaction positive. The mean age of patients was 48.4 years ± 11 years, out of which 5 patients were male and 2 were female. The left eye was involved in 57.14% of cases whereas 42.85% of cases had right eye involvement. Presenting complaints were drooping of the upper lid (57.14%; n = 4), proptosis (28.57%; n = 2), facial pain and swelling (85.71%; n = 6), and nasal block (57.14%; n = 4). Stagewise distribution was 3a in four patients (57.14%), 3b in two patients (28.57%), and 4a in one patient. TRAMB injections (median - 3) were given, and improvement was seen in all patients in terms of ocular movements, ptosis, proptosis, and muscle enhancement on MRI scan. Three patients had an increase in intraocular pressure and inflammation which settled within a week with favorable anatomical and functional outcomes. CONCLUSION: Transcutaneous retrobulbar amphotericin B should be considered an adjunctive treatment modality for ROCM patients with limited orbital disease to preserve ocular function.

Clinical Characteristics of Migraine and Their Association With the Retinal Nerve Fiber Layer Thickness.

BACKGROUND: Migraine is characterized by recurrent episodes of unilateral, pulsating headaches. At the cerebral and ocular levels, it is recognized that the vascular narrowing and loss of blood flow are transient; however, the chronic nature of migraine may result in long-term functional and structural changes in these structures. It could result in axonal loss and an alteration in the thickness of the retinal nerve fiber layers (RNFL). This study aimed to measure the RNFL thickness, which provides a useful indication of the state of the axons and the loss of ganglion cells in migraine patients, and to find out if RNFL thickness and the clinical features of migraine are correlated. MATERIALS AND METHODS: Sixty patients with migraine and 60 age-gender-matched controls were recruited. A complete neurological and ophthalmological examination was performed, and spectral-domain optical coherence tomography (SD-OCT) was done to measure RNFL. RESULTS: All quadrants of the retina on both sides showed non-statistically significant differences in RNFL thickness between migraine patients and controls (p-value >0.05). Furthermore, in all retinal quadrants on both sides, there was no statistically significant difference in RNFL thickness between migraine patients with aura and those without aura (p-value >0.05). Significant correlations were found between the duration of migraine disease and the superior RNFL thickness of both eyes, as well as the inferior RNFL in the right eye. There was also a significant correlation between the headache attack duration and RNFL thickness of the superior retina (p<0.05), Conclusion: Our key finding was that when comparing migraine patients to controls, RNFL thickness did not significantly change; however, the duration of migraine disease did significantly affect RNFL thickness.

Healthcare Cost of Cochlear Implantation in India.

Making evidence-based policy decisions is challenging when there is a lack of information, especially when deciding provider payment rates for publicly funded health insurance plans. Therefore, the goal of this study was to estimate the cost of a cochlear implant operation in a tertiary care setting in India. We also looked at the patients' out-of-pocket (OOP) expenses for the cochlear implant surgery. From the perspectives of the patients and the healthcare systems, we assessed the financial costs of the cochlear implantation procedure. A bottom-up pricing model was used to assess the cost that the healthcare system would bear for a cochlear implant procedure. Information on all the resources (both capital and ongoing) required to offer cochlear implantation services for hearing loss was gathered over the course of a year. 120 individuals with hearing loss who had cochlear implantation surgery disclosed their out-of-pocket (OOP) costs, which included both direct medical and non-medical expenses. All costs for the budgetary year 2018-2019 were anticipated. The unit health system spent ₹ 151($2), ₹ 578($7.34) and ₹ 37,449($478) on ear exams, audiological evaluations, and cochlear implant surgeries, respectively. Per bed-day in the otolaryngology ward, hospitalization cost ₹ 202($2.6), or ₹ 1211($15.5). The estimated average out-of-pocket cost for a cochlear implant operation was ₹ 682,230($8710). Our research can be used to establish package rates for publicly funded insurance plans in India, plan the growth of public sector hearing care services, and do cost-effectiveness assessments on various hearing care models. Supplementary Information: The online version contains supplementary material available at 10.1007/s12070-023-04389-7.

Yohimbine Treatment Alleviates Cardiac Inflammation/Injury and Improves Cardiac Hemodynamics by Modulating Pro-Inflammatory and Oxidative Stress Indicators.

Acute myocarditis, also known as myocardial inflammation, is a self-limited condition caused by systemic infection with cardiotropic pathogens, primarily viruses, bacteria, or fungi. Despite significant research, inflammatory cardiomyopathy exacerbated by heart failure, arrhythmia, or left ventricular dysfunction and it has a dismal prognosis. In this study, we aimed to evaluate the therapeutic effect of yohimbine against lipopolysaccharide (LPS) induced myocarditis in rat model. The anti-inflammatory activity of yohimbine was assessed in in-vitro using RAW 264.7 and H9C2 cells. Myocarditis was induced in rats by injecting LPS (10 mg/kg), following the rats were treated with dexamethasone (2 mg/kg) or yohimbine (2.5, 5, and 10 mg/kg) for 12 h and their therapeutic activity was examined using various techniques. Yohimbine treatment significantly attenuated the LPS-mediated inflammatory markers expression in the in-vitro model. In-vivo studies proved that yohimbine treatment significantly reduced the LPS-induced increase of cardiac-specific markers, inflammatory cell counts, and pro-inflammatory markers expression compared to LPS-control samples. LPS administration considerably affected the ECG, RR, PR, QRS, QT, ST intervals, and hemodynamic parameters, and caused abnormal pathological parameters, in contrast, yohimbine treatment substantially improved the cardiac parameters, mitigated the apoptosis in myocardial cells and ameliorated the histopathological abnormalities that resulted in an improved survival rate. LPS-induced elevation of cardiac troponin-I, myeloperoxidase, CD-68, and neutrophil elastase levels were significantly attenuated upon yohimbine treatment. Further investigation showed that yohimbine exerts an anti-inflammatory effect partly by modulating the MAPK pathway. This study emphasizes yohimbine's therapeutic benefit against LPS-induced myocarditis and associated inflammatory markers response by regulating the MAPK pathway.

Elucidation of the catalytic mechanism of a single-metal dependent homing endonuclease using QM and QM/MM approaches: the case study of I-PpoI.

Homing endonucleases (HEs) are highly specific DNA cleaving enzymes, with I-PpoI having been suggested to use a single metal to accelerate phosphodiester bond cleavage. Although an I-PpoI mechanism has been proposed based on experimental structural data, no consensus has been reached regarding the roles of the metal or key active site amino acids. This study uses QM cluster and QM/MM calculations to provide atomic-level details of the I-PpoI catalytic mechanism. Minimal QM cluster and large-scale QM/MM models demonstrate that the experimentally-proposed pathway involving direct Mg2+ coordination to the substrate coupled with leaving group protonation through a metal-activated water is not feasible due to an inconducive I-PpoI active site alignment. Despite QM cluster models of varying size uncovering a pathway involving leaving group protonation by a metal-activated water, indirect (water-mediated) metal coordination to the substrate is required to afford this pathway, which renders this mechanism energetically infeasible. Instead, QM cluster models reveal that the preferred pathway involves direct Mg2+-O3' coordination to stabilize the charged substrate and assist leaving group departure, while H98 activates the water nucleophile. These calculations also underscore that both catalytic residues that directly interact with the substrate and secondary amino acids that position or stabilize these residues are required for efficient catalysis. QM/MM calculations on the solvated enzyme-DNA complex verify the preferred mechanism, which is fully consistent with experimental kinetic, structural, and mutational data. The fundamental understanding of the I-PpoI mechanism of action, gained from the present work can be used to further explore potential uses of this enzyme in biotechnology and medicine, and direct future computational investigations of other members of the understudied HE family.

Nitrogen-containing heterocyclic compounds: A ray of hope in depression?

Depression is not similar to daily mood fluctuations and temporary emotional responses to day-to-day activities. Depression is not a passing problem; it is an ongoing problem. It deals with different episodes consisting of several symptoms that last for at least 2 weeks. It can be seen for several weeks, months, or years. At its final stage, or can say, in its worst condition, it can lead to suicide. Antidepressants are used to inhibit the reuptake of the neurotransmitters by some selective receptors, which increase the concentration of specific neurotransmitters around the nerves in the brain. Drugs that are currently being used for the management of various types of depression include selective serotonin reuptake inhibitors, tricyclic antidepressants, atypical antidepressants, serotonin, noradrenaline reuptake inhibitors, etc. In this review, we have outlined different symptoms, causes, and recent advancements in nitrogen-containing heterocyclic drug candidates for the management of depression. This article highlights the various structural features along with the structure-activity relationship (SAR) of nitrogen-containing heterocyclics that play a key role in binding at target sites for potential antidepressant action. The in silico studies were carried out to determine the binding interactions of the target ligands with the receptor site to determine the potential role of substitution patterns at core pharmacophoric features. This article will help medicinal chemists, biochemists, and other interested researchers in identifying the potential pharmacophores as lead compounds for further development of new potent antidepressants.

Exploration of oxadiazole clubbed benzhydrylpiperazine pharmacophoric features as structural feature for antidepressant activity: In vitro, in vivo and in silico analysis.

Arylpiperazine clubbed various heterocyclic molecules present potential pharmacophoric structural features for the development of psychoactive drugs. There are various CNS active molecules possessing arylpiperazine moiety in their pharmacophore approved by USFDA. In the current study, we have explored the benzhydrylpiperazine moiety clubbed with various substituted oxadiazole moieties (AP1-12) for their monoamine oxidase (MAO) inhibition and antidepressant potential. Compounds AP3 and AP12 exhibited highly potent and selective MAO-A inhibition with IC50 values of 1.34 ± 0.93 µM and 1.13 ± 0.54 µM, respectively, and a selectivity index of 10- and 13-folds, respectively. Both the compounds displayed reversible binding character at the active site of MAO-A. In further in vivo evaluation, both the compounds AP3 and AP12 displayed potential antidepressant-like character in FST and TST studies via significantly reduced immobility time in comparison to non-treated animals. These compounds displayed no cytotoxicity in SH-SY5Y cell lines, which indicates that these compounds are safe for further evaluation. In silico studies reveal that synthesized compounds possess drug-likeness with minimal to no toxicity. In silico studies were conducted to understand the binding interactions and stability of compounds at the binding pocket of enzyme and observed that both the best compounds fit well at the active site of MAO-A lined by amino acid residues Tyr69, Asn181, Phe208, Ile335, Leu337, Phe352, and Tyr444 similar to standard MAO-A inhibitor clorgiline. The molecular dynamic studies demonstrated that AP3 and AP12 formed quite a stable complex at the active site of MAO-A and did not break under small abruption forces. The favourable binding interactions and appropriate ADMET properties present the benzhydrylpiperazine clubbed oxadiazole pharmacophoric features as a potential structural skeleton for further clinical evaluation and development of a new antidepressant drug molecule.

Pyrazoline Derivatives as Promising MAO-A Targeting Antidepressants: An Update.

Depression is one of the key conditions addressed by the Mental Health Gap Action Programme (mhGAP) of WHO that can lead to self-harm and suicide. Depression is associated with low levels of neurotransmitters, which eventually play a key role in the progression and development of mental illness. The nitrogen-containing heterocyclic compounds exhibit the most prominent pharmacological profile as antidepressants. Pyrazoline, a dihydro derivative of pyrazole, is a well-known five-membered heterocyclic moiety that exhibits a broad spectrum of biological activities. Many researchers have reported pyrazoline scaffold-containing molecules as potential antidepressant agents with selectivity for monoamine oxidase enzyme (MAO) isoforms. Several studies indicated a better affinity of pyrazoline-based moiety as (monoamine oxidase inhibitors) MAOIs. In this review, we have focused on the recent advancements (2019-2023) in the development of pyrazoline-containing derivatives exhibiting promising inhibition of MAO-A enzyme to treat depression. This review provides structural insights on pyrazoline-based molecules along with their SAR analysis, in silico exploration of binding interactions between pyrazoline derivatives and MAO-A enzyme, and clinical trial status of various drug molecules against depression. The in-silico exploration of potent pyrazoline derivatives at the active site of the MAOA enzyme will provide further insights into the development of new potential MAO-A inhibitors for the treatment of depression.

Is Metal Stabilization of the Leaving Group Required or Can Lysine Facilitate Phosphodiester Bond Cleavage in Nucleic Acids? A Computational Study of EndoV.

Endonuclease V (EndoV) is a single-metal-dependent enzyme that repairs deaminated DNA nucleobases in cells by cleaving the phosphodiester bond, and this enzyme has proven to be a powerful tool in biotechnology and medicine. The catalytic mechanism used by EndoV must be understood to design new disease detection and therapeutic solutions and further exploit the enzyme in interdisciplinary applications. This study has used a mixed molecular dynamics (MD) and quantum mechanics/molecular mechanics (QM/MM) approach to compare eight distinct catalytic pathways and provides the first proposed mechanism for bacterial EndoV. The calculations demonstrate that mechanisms involving either direct or indirect metal coordination to the leaving group of the substrate previously proposed for other nucleases are unlikely for EndoV, regardless of the general base (histidine, aspartate, and substrate phosphate moiety). Instead, distinct catalytic pathways are characterized for EndoV that involve K139 stabilizing the leaving group, a metal-coordinated water stabilizing the transition structure, and either H214 or a substrate phosphate group activating the water nucleophile. In silico K139A and H214A mutational results support the newly proposed roles of these residues. Although this is a previously unseen combination of general base, general acid, and metal-binding architecture for a one-metal-dependent endonuclease, our proposed catalytic mechanisms are fully consistent with experimental kinetic, structural, and mutational data. In addition to substantiating a growing body of literature, suggesting that one metal is enough to catalyze P-O bond cleavage in nucleic acids, this new fundamental understanding of the catalytic function will promote the exploration of new and improved applications of EndoV.

Exploring the Therapeutic Potential of Alkaloids in Alzheimer's Disease Management.

BACKGROUND: Alkaloids are important phytoconstituents obtained from various plant sources. The study's primary goal is to assess the anti-Alzheimer potential of alkaloids using a molecular docking study. Alzheimer's disease (AD) is considered a gradual decline in memory, reasoning, decision-making, orientation to one's physical surroundings, and language. MATERIALS AND METHODS: The main target i.e. acetylcholinesterase proteins was selected for the molecular docking study. RESULTS: The structures of various alkaloids were drawn using Chem Draw Software, PDB was retrieved from the RCSB PDB database, and molecular docking study was performed on Molergo Virtual Docker. The potential alkaloids were identified with anti-Alzheimer potency. CONCLUSION: Reserpine, vinblastine, ergotamine, and tubocurarine were found to exhibit potential anti-Alzheimer potency.

Pesticides: An alarming detrimental to health and environment.

Pesticides are chemical substances of natural or synthetic origin that are used to eradicate pests and insects. These are indispensable in the agricultural processes for better crop production. Pesticide use aims to promote crop yield and protect the crops from diseases and damage. Pesticides must be handled carefully and disposed of appropriately because they are dangerous to people and other species by default. Environmental pollution occurs when pesticide contamination spreads away from the intended plants. Older pesticides such as lindane and dichlorodiphenyltrichloroethane (DDT) may remain in water and soil for a longer time. These accumulate in various parts of the food chain and cause damage to the ecosystem. Biological techniques in the management of pest control such as importation, augmentation, and conservation, and the accompanying procedures are more efficient, less expensive, and ecologically sound than other ways. This review mainly focuses on the consequences on the targeted and non-targeted organisms including the health and well-being of humans by the use of pesticides and their toxicity. The side effects that occur when a pesticide's LD50 exceeds the accepted limit through oral or skin penetration due to their binding to various receptors such as estrogen receptors, GABA, EGFR, and others. These pesticide classes include carbamates, pyrethroids, organochlorides, organophosphorus, and others. The current study seeks to highlight the urgent requirement for a novel agricultural concept that includes a major reduction in the use of chemical pesticides.

Nintedanib solid lipid nanoparticles improve oral bioavailability and ameliorate pulmonary fibrosis in vitro and in vivo models.

Nintedanib (NIN) and pirfenidone are the only approved drugs for the treatment of Idiopathic Pulmonary Fibrosis (IPF). However, NIN and pirfenidone have low oral bioavailability and limited therapeutic potential, requiring higher dosages to increase their efficacy, which causes significant liver and gastrointestinal toxicities. In this study, we aimed to develop nintedanib-loaded solid lipid nanoparticles (NIN-SLN) to improve the oral bioavailability and therapeutic potential against TGF-ß-induced differentiation in IPF fibroblasts and bleomycin (BLM)-induced lung fibrosis in rat models. NIN-SLN was prepared using a double-emulsification method and characterization studies (Particle size, zeta potential, entrapment efficiency and other parameters) were performed using various techniques. NIN-SLN treatment significantly (p < 0.001) downregulated α-SMA and COL3A1 expression in TGF-ß stimulated DHLF and LL29 cells. NIN-SLN showed a 2.87-fold increase in the bioavailability of NIN and also improved the NIN levels in lung tissues compared to NIN alone. Pharmacodynamic investigation revealed that NIN-SLN (50 mg/Kg) treatment significantly attenuated BLM-induced lung fibrosis by inhibiting epithelial-to-mesenchymal-transition (EMT), extracellular matrix remodelling, and collagen deposition compared to free NIN. Additionally, in the BLM model of fibrosis, NIN-SLN greatly improved the BLM-caused pathological changes, attenuated the NIN-induced gastrointestinal abnormalities, and significantly improved the lung functional indices compared to free NIN. Collectively, NIN-SLN could be a promising nanoformulation for the management of pulmonary fibrosis.

In-Silico Investigation of Ginseng Phytoconstituents as Novel Therapeutics Against MAO-A.

BACKGROUND: Ginseng (Panax ginseng) is a herb of medicinal and nutritional importance. Ginseng has been used since ancient times for the treatment of numerous ailments as it has many therapeutic properties. Several phytoconstituents are present in Panax ginseng that possess a variety of beneficial pharmacological properties. OBJECTIVE: To explore the potential of phytoconstituents of Panax ginseng in the treatment of depression, a molecular modeling technique was utilized targeting monoamine oxidase-A (MAOA). METHODS: A total of sixty-one phytoconstituents of ginseng were drawn with the help of ChemBioDraw Ultra 12.0 software and PDBs for MAO-A enzyme were retrieved from the RCSB PDB database. The prepared ligands were screened for MAO-A properties using the software Molegro Virtual Docker (MVD 2010.4.1.0). All the prepared ligands were evaluated for drug-likeliness properties using Swiss ADME. RESULT: Among the docking studies of 60 Ginseng phytochemicals including one standard, 15 phytoconstituents with the highest dock score and better binding interactions were selected further for absorption, distribution, metabolism and excretion (ADME) studies. Stachyose (-227.287, 17 interactions), Raffinose (-222.157, 14 interactions), and Ginsenoside Rg1 (-216.593, 10 interactions) were found to possess better interactions as compared to Clorgyline taken as a standard drug. CONCLUSION: Stachyose was found to be the most potent inhibitor of MAO-A enzyme under investigation and can be a potential lead molecule for the development of newer phytochemical-based treatment of depression.

Target protein degradation by protacs: A budding cancer treatment strategy.

Cancer is one of the most common causes of death. So, its lethal effect increases with time. Near about hundreds of cancers are known in humans. Cancer treatment is done to cure or prolonged remission, and shrinkage of the tumor. Cytotoxic agents, biological agents/targeted drugs, hormonal drugs, surgery, radiotherapy/proton therapy, chemotherapy, immunotherapy, and gene therapy are currently used in the treatment of cancer but their cost is high and cause various side effects. Seeing this, some new targeted strategies such as PROTACs are the need of the time. Proteolysis targeting chimera (PROTAC) has become one of the most discussed topics regarding cancer treatment. Few of the PROTAC molecules are in the trial phases. PROTACs have many advantages over other strategies such as modularity, compatibility, sub-stoichiometric activity, acting on undruggable targets, molecular design, and acts on intracellular targets, selectivity and specificity can be recruited for any cancer, versatility, and others. PROTACs are having some unclear questions on their pharmacokinetics, heavy-molecular weight, etc. PROTACs are anticipated to bring about a conversion in current healthcare and will emerge as booming treatments. In this review article we summarize PROTACs, their mechanism of action, uses, advantages, disadvantages, challenges, and future aspects for the successful development of potent PROTACs as a drug strategy.

Evolving Advances in the Cosmetic Use of Probiotics and Postbiotics: Health, Regulatory and Marketing Aspects.

Ongoing development in cosmetics is increasingly making use of probiotics, which are defined as "live microorganisms with health-enhancing properties mediated through ingestion or topical application to the host". The observation that several bacterial strains augment normal processes of healthy tissue maintenance, particularly for the skin, has opened up new avenues for the use of bacterial strains in cosmetics. A principal feature of such "cosmeceuticals" is an application of increasing insight into the biochemical nature of the skin's normal microbial flora, also called its microbiome. The opportunity of manipulating the skin microbiome to address various skin disorders has revealed novel routes for treatment. The skin microbiome manipulation approaches to address various skin disorders include skin microbiome transplantation, skin bacteriotherapy, and prebiotic stimulation. Research in this field has revealed that medical outcome-targeted manipulation of skin microbiome bacterial strain makeup may significantly increase skin health and appearance. Commercial availability of probiotic skincare products is rapidly expanding worldwide due to satisfactory laboratory results and public perception of probiotics as being intrinsically more wholesome than other bioactive substances, such as synthetics. Major outcomes of probiotic use include a significant reduction in skin wrinkling, acne and other conditions adversely affecting skin appearance and healthy function. Moreover, probiotics may additionally promote normal skin hydration, resulting in a vibrant and lustrous appearance. Nevertheless, significant technical challenges remain for the full optimization of probiotics in cosmetic products. This article summarizes the evolving nature of this field and explores current probiotic research initiatives, along with regulatory aspects and significant challenges in the manufacturing of cosmetics in the context of market expansion for these products.

Alkaloids as Potential Anti-HIV Agents.

BACKGROUND: Alkaloids are nitrogen-containing compounds that are naturally occurring and have a variety of biological activities, including antimicrobial properties. In this study, the authors used a molecular docking approach to evaluate the anti-HIV potential of 64 alkaloids. METHODS: The authors used the Molegro Virtual Docker software to dock the alkaloids into the active sites of three HIV enzymes: protease, integrase, and non-nucleoside reverse transcriptase (NNRT). The docking scores were used to assess the potential of the alkaloids to inhibit the enzymes. RESULTS: The results showed the alkaloids to have good potential to inhibit the enzymes. Tubocurarine and reserpine were found to be the most potent alkaloids, with docking scores of -123.776 and - 114.956, respectively. CONCLUSION: The authors concluded that tubocurarine and reserpine could be further promoted as potential lead molecules for the development of new anti-HIV drugs.