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.

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.

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.

The metal dependence of single-metal mediated phosphodiester bond cleavage: a QM/MM study of a multifaceted human enzyme.

Nucleases catalyze the cleavage of phosphodiester bonds in nucleic acids using a range of metal cofactors. Although it is well accepted that many nucleases rely on two metal ions, the one-metal mediated pathway is debated. Furthermore, one-metal mediated nucleases maintain activity in the presence of many different metals, but the underlying reasons for this broad metal specificity are unknown. The human apurinic/apyrimidinic endonuclease (APE1), which plays a key role in DNA repair, transcription regulation, and gene expression, is a prototypical example of a one-metal dependent nuclease. Although Mg2+ is the native metal cofactor, APE1 remains catalytically active in the presence of several metals, with the rate decreasing as Mg2+ > Mn2+ > Ni2+ > Zn2+, while Ca2+ completely abolished the activity. The present work uses quantum mechanics-molecular mechanics techniques to map APE1-facilitated phosphodiester bond hydrolysis in the presence of these metals. The structural differences in stationary points along the reaction pathway shed light on the interplay between several factors that allow APE1 to remain catalytically active for various metals, with the trend in the barrier heights correlating with the experimentally reported APE1 catalytic activity. In contrast, Ca2+ significantly changes the metal coordination and active site geometry, and thus completely inhibits catalysis. Our work thereby provides support for the controversial single-metal mediated phosphodiester bond cleavage and clarifies uncertainties regarding the role of the metal and metal identity in this important reaction. This information is key for future medicinal and biotechnological applications including disease diagnosis and treatment, and protein engineering.

Free fatty acid receptor 1: a ray of hope in the therapy of type 2 diabetes mellitus.

Free fatty acid receptor 1 (FFAR1) is a G-protein coupled receptor with prominent expression on pancreatic beta cells, bones, intestinal cells as well as the nerve cells. This receptor mediates a multitude of functions in the body including release of incretins, secretion of insulin as well as sensation of pain. Since FFAR1 causes secretion of insulin and regulates glucose metabolism, efforts were made to unfold its structure followed by discovering agonists for the receptor and the utilization of these agonists in the therapy of type 2 diabetes mellitus. Development of such functional FFAR1 agonists is a necessity because the currently available therapy for type 2 diabetes mellitus has numerous drawbacks, of which, the major one is hypoglycemia. Since the most prominent effect of the FFAR1 agonists is on glucose concentration in the body, so the major research is focused on treating type 2 diabetes mellitus, though the agonists could benefit other metabolic disorders and neurological disorders as well. The agonists developed so far had one major limitation, i.e., hepatotoxicity. Although, the only agonist that could reach phase 3 clinical trials was TAK-875 developed by Takeda Pharmaceuticals but it was also withdrawn due to toxic effects on the liver. Thus, there are numerous agonists for the varied binding sites of the receptor but no drug available yet. There does seem to be a ray of hope in the drugs that target FFAR1 but a lot more efforts towards drug discovery would result in the successful management of type 2 diabetes mellitus.

Review on pulp and paper activated sludge pretreatment, inhibitory effects and detoxification strategies for biovalorization.

Biovalorization of pulp and paper activated sludge to value-added products could be an effective alternative to traditional sludge management methods, which tend to pose serious environmental issues. Since pulp and paper activated sludge consists of microbial biomass, cellulose, hemicellulose and lignin and thus, could be subjected to different hydrolysis methods to solubilize sludge solids and release simple sugars to form value-added products by the microbial fermentation process. Hence, different sludge hydrolysis methods have been summarized in this review paper. However, hydrolysis of lignocellulosic materials generates variety of toxic compounds during hydrolysis and causes detrimental effects. Therefore, different toxic compounds and their impact on microorganisms, cellulolytic enzymes and fermentation process have been discussed in detail and recent strategies to counteract the problems of inhibitors have also been briefly explained.

Fluorescent Sensing Assay for Trinitrotoluene Using Fluorescein Isothiocyanate Conjugated Mesoporous MCM-41 Particles.

In the present study, Trinitrotoluene (TNT) has been detected by the formation of Meisenheimer complex using Fluorescein isothiocyanate (FITC) dye loaded Mesoporous silica particles (MCM-41). FITC dye loaded mesoporous silica particles (MCM-41/FITC) have been synthesized using (3-Aminopropyl)trimethoxysilane, APTMS (λex = 490 nm and λem = 512 nm). TNT forms Meisenheimer complex with the amine group of APTMS present on MCM-41 particles. The loading of FITC in the pores of MCM-41 particles has been confirmed by different advanced characterization techniques. The average diameter of mesoporous MCM-41 particles was found about 130 nm. Pore volume is observed to decrease from 1.06 cm3/g to 0.49 cm3/g after FITC loading. The selective detection of TNT up to 0.1 ppb level makes MCM-41/FITC particles a potential sensing material for TNT detection.

Composition and Concentration Gradient Induced Structural Transition from Micelles to Vesicles in the Mixed System of Ionic Liquid-Diclofenac Sodium.

Catanionic surfactant-hydrotrope mixtures have proven to be a striking alternative to tune microstructures over a wide range of compositions and also to minimize precipitation that is normally observed in catanionic mixtures at an equimolar ratio. These mixtures are supposed to be of great relevance in biological systems when a hydrotrope is a "drug". Keeping this in view, here we report composition- and dilution-induced structural changes in a catanionic mixture comprising ionic liquids (ILs), such as 1-dodecyl-3-methylimidazolium bromide (C12mimBr)/1-tetradecyl-3-methylimidazolium bromide (C14mimBr), and a drug, diclofenac sodium (DFNa), in aqueous solution. The structural changes are probed by small-angle neutron scattering (SANS), dynamic light scattering (DLS), and zeta-potential measurements. SANS data and size distribution curves clearly depict the formation of low curvature structures on going from the cation-rich to anion-rich composition up to a 0.7 mole fraction of DFNa (XDFNa). The amphiphilic nature of DFNa is supposed to alter the surface charge density, which is provoked by its incorporation into resulting aggregates, as confirmed by modified zeta-potential values. The modification of the average packing parameter resulting from the IL and DFNa complexation equilibrium seems to play a vital role in bringing out structural transitions of mixed aggregates. We also focused our attention to study the effect of dilution in concentrations ranging from 100 to 25 mM. At XDFNa = 0.0 and 0.1, the size of prolate ellipsoids decreases on dilution, mimicking classic behavior, but an opposite trend is observed at other XDFNa values. Dilution-induced transformation to larger aggregates is thought to be driven by the release of DFNa molecules from the mixed micelles on account of the critical micelle concentration (cmc) (solubility) mismatch between the two components. The role of other interactions such as cation-π and π-π in stabilizing the mixed aggregates in addition to hydrophobic interactions is probed by (1)H NMR.

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.

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.

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. METHOD AND MATERIAL: The main target i.e. acetylcholinesterase proteins was selected for the molecular docking study. RESULT: 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.

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.

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.

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.

Influence of headgroup on the aggregation and interactional behavior of twin-tailed cationic surfactants with pluronics.

The surface tension measurements have been employed to characterize the micellar and interfacial behavior of pure and mixed systems of twin-tailed cationic surfactants: dimethylene bis(decyldimethylammonium bromide) (10-2-10), didecydimethylammonium bromide (DDAB), and 1,3-didecyl-2-methylimidazolium chloride (DDIC) with pluronics P84 and F108 in the aqueous solution. The interactions of each surfactant with both pluronics are found to be nonideal and synergistic except for the mixed system of 10-2-10 + F108, for which interactions are antagonistic and every interaction has been studied on the basis of headgroup disparity. Dynamic light scattering (DLS), zeta (ζ) potential, and small angle neutron scattering (SANS) measurements have been used to determine the influence of the mixing ratio on the morphology of the various mixed aggregates that are formed. Pure DDAB is found to form unilamellar vesicles whereas pure 10-2-10 and DDIC form prolate ellipsoidal micelles. The unilamellar vesicles of DDAB are destructed to yield spherical mixed micelles on addition of pluronics via expansion or contraction of vesicles. However, the pure pluronics and their mixed systems with 10-2-10 and DDIC form charged spherical micelles, and charge is confirmed by thenfractional charge and ζ values. The ζ values of pure surfactants are found to decrease on addition of pluronics, indicating a decrease in surface charge on inclusion of pluronics.

Diabetic Neuropathy: A Repercussion of Vitamin D Deficiency.

Diabetes mellitus is a crucial health issue worldwide. The worldwide ubiquity is 8.8% among adults, which is predicted to rise to 10.4% by 2040. Diabetic neuropathy is a long-term complication associated with the diabetes mellitus condition, which primarily targets Schwann cells, peripheral axons and cell bodies (perikarya) in DRG (dorsal root ganglia). It can be accompanied by different factors such as metabolic factors such as insulin resistance, hypertension, obesity, low HDL level, and hypertriglyceridemia. The etiology of DPN is multifactorial. It is caused by hyperglycemia, micro-angiopathy, HbA1c, duration of diabetes, smoking status, high-density lipoprotein cholesterol and hypertension. Also, increased glucose conditions decrease vitamin D levels. Vitamin D, which is involved in neurotrophins such as NGF (nerve growth factor) and NCH (neuronal calcium homeostasis), plays a neuroprotective role in peripheral nerves. Depletionleads to vitamin D deficiency which further develops peripheral neuropathy in diabetic patients. Accumulation of AGEs (advanced glycation end product) plays a significant role in the pathogenesis of sensory neuronal damage. It contributes to microangiopathy and endoneurial vascular dysfunction in peripheral nerves. With vitamin D supplementation, the neuropathy pain scores were improved.

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.

Repurposing of Various Current Medicines as Radioprotective Agents.

BACKGROUND: The side effects of ionising radiation include skin changes, dry mouth, hair loss, low blood count, and the mutagenic effect on normal cells when utilized in radiotherapy for cancer treatment. These radiations can cause damage to the cell membrane, lipids, proteins, and DNA and generate free radicals. Evidence reports stated that radiotherapy accounts for 17-19% of secondary malignancies, labelling this treatment option a double-edged sword. OBJECTIVE: Radioprotective molecules are used for mitigating radiotherapy's side effects. These agents show free radical scavenging, antioxidant, collagen synthesis inhibition, protease inhibition, immune stimulation, increased cytokine production, electron transfer, and toxicity reduction properties. The most frequently used amifostine has an array of cancer applications, showing multitarget action as nephroprotective to cisplatin and reducing the chances of xerostomia. Many other agents, such as metformin, edaravone, mercaptopropionylglycine, in specific diseases, such as diabetes, cerebral infarction, cystinuria, have shown radioprotective action. This article will discuss potentially repurposed radioprotectors that can be used in the clinical setting, along with a brief discussion on specific synthetic agents like amifostine and PrC-210. METHODS: Rigorous literature search using various electronic databases, such as PubMed, ScienceDirect, Scopus, EMBASE, Bentham Science, Cochrane Library, etc., was made. Peer-review research and review papers were selected, studied, reviewed, and analysed. CONCLUSION: Safety and risk-free treatment can be guaranteed with the repurposed agents. Agents like metformin, captopril, nifedipine, simvastatin, and various others have shown potent radioprotective action in various studies. This review compiled repurposed synthetic radioprotective agents.