Potent Molecule Research Articles

Design and Efficient Synthesis of New 4-Amino-Substituted 2-(4-Bromobenzyl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines of Anticancer Interest and Their In Silico Study

AbstractThienopyrimidines are an emerging class of fused pyrimidines due to their broad spectrum of pharmacological properties, including antimicrobial, anti-inflammatory, antimalarial, anticancer, etc. The anticancer activity of these compounds has been mechanistically proven via the inhibition of validated drug targets, such as EGFR, VEGFR-2, PI3K, and c-kit. In this research article, we designed and synthesized new 4-amino-substituted 2-(4-bromobenzyl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines to explore their anticancer potential. These heterocycles were designed based on pharmacophoric features of the core heterocycle, varying its C4 substitution with a variety of amines and considering cancer protein-ligand interactions with the aim to obtain potent lead molecules. The target compound-protein interaction complexes were analyzed, and lead compounds were identified based on their better binding affinity in molecular docking studies.

Computational insights into rational design and virtual screening of pyrazolopyrimidine derivatives targeting Janus kinase 3 (JAK3).

The Janus kinase 3 (JAK3) family, particularly JAK3, is pivotal in initiating autoimmune diseases such as rheumatoid arthritis. Recent advancements have focused on developing antirheumatic drugs targeting JAK3, leading to the discovery of novel pyrazolopyrimidine-based compounds as potential inhibitors. This research employed covalent docking, ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) analysis, molecular dynamics modeling, and MM/GBSA (Molecular Mechanics Generalized Born Surface Area) binding free energy techniques to screen 41 in silico-designed pyrazolopyrimidine derivatives. Initially, 3D structures of the JAK3 enzyme were generated using SWISS-MODEL, followed by virtual screening and covalent docking via AutoDock4 (AD4). The selection process involved the AMES test, binding affinity assessment, and ADMET analysis, narrowing down the candidates to 27 compounds that passed the toxicity test. Further covalent docking identified compounds 21 and 41 as the most promising due to their high affinity and favourable ADMET profiles. Subsequent development led to the creation of nine potent molecules, with derivatives 43 and 46 showing exceptional affinity upon evaluation through molecular dynamics simulation and MM/GBSA calculations over 300 nanoseconds, comparable to tofacitinib, an approved RA drug. However, compounds L21 and L46 demonstrated stable performance, suggesting their effectiveness in treating rheumatoid arthritis and other autoimmune conditions associated with JAK3 inhibition.

Novel triterpenoid, Schidigeragenin B resourced from the mother tincture of Conium maculatum: A promising future Antidiabetic drug

As of 2021, an estimated 537 million people had diabetes worldwide, accounting for 10.5 % of the adult population, with type 2 making up about 90 % of all cases. The common antidiabetic drugs have several problems like hypoglycemia, skin rash and itching, weight gain, kidney complications, etc. So, there is a need to explore safer alternative medications from natural sources. This study examines the antidiabetic potential and metabolomic profiling of Conium maculatum, a homeopathic medicine prescribed for diabetic patients. Potent DPPH scavenging of the sample was observed with an IC50 value of 75.05 ± 6.33 μg/mL. α-Amylase and α-glucosidase enzyme inhibition by the mother tincture of Conium maculatum was evaluated through in-vitro studies, highlighting effective antidiabetic activity with IC50 values of 86.53±1.76 μg/mL and 124±7.903 μg/mL, respectively. Metabolomic profiling of the mother tincture of Conium maculatum was done by LC-MS/MS to identify a total of 47 phyto-compounds that were subjected to ADMET profiling, followed by in-silico docking and MDS with target receptors associated with diabetes. Six compounds were short-listed for in-silico docking studies with five target proteins, α-amylase, α-glucosidase, GLUT-4, GLP-1, and IRS1. Three compounds, Schidigeragenin B, 10-oxo-11-octadecen-13-olide, and Distichonic acid A, showed strong binding affinities to these protein receptors, crucial for diabetes remediation. Among these compounds, Schidigeragenin B, a novel triterpenoid shows the strongest binding affinities towards these receptors, and the ADMET properties highlighted its drug likeness. Conclusively, the present study identified Schidigeragenin B, resourced from the mother tincture of Conium maculatum, as the potent bioactive antidiabetic molecule for combating diabetes.

Identification of Novel PBP2B Protein Inhibitors against Streptococcus pneumoniae in Marine Natural Products using an In-Silico Approach

Background: The aim of this research is to identify marine natural compounds derived from green, red, and brown algae that might possibly inhibit the Penicillin-Binding Proteins (PBPs) protein, which is responsible for the development of antibiotic resistance in Streptococcus pneumoniae (mutated resistant 5204-PBP2B strain). We obtained this by using virtual screening and molecular docking. In AutoDock Vina and the Schrodinger suite software, we screened a library of marine natural chemicals and discovered four intriguing candidates that had strong binding affinities to the active region of the PBPs protein. Based on our findings, four naturally occurring marine chemicals show great promise as new inhibitors of S. pneumoniae 5204-PBP2B protein. These discoveries reveal important new information on the potential application of marine natural products as a source of new drugs to combat antibiotic resistance in Streptococcus pneumoniae and other bacterial infections. Methods: The 3318 compounds in the Comprehensive Marine Natural Products Database (CMNPD) derived from green algae (293 compounds), brown algae (1212 compounds) and red algae (1813 compounds) were taken into consideration for this study. Through virtual screening and molecular docking investigations, we found the optimum compounds for the Penicillin-Binding Proteins (PBPs) protein in Streptococcus pneumoniae. Utilizing AutoDock Vina and Schrodinger Suite software, the 5204-PBP2B protein selected for this investigation was examined. The structure and binding interaction have been displayed using PyMOL software. Results: Through virtual screening and molecular docking investigations for the 5204-PBP2B protein in Streptococcus pneumoniae, we were able to identify four marine natural products that are present in brown algae from the Comprehensive Marine Natural Products Database. Conclusion: The study has indicated that the main cause of bacterial resistance to antibiotics is 5204-PBP2B in S. pneumoniae. This study's methodology has been shown to be effective in identifying four strong inhibitors of the CMNPD. In this work, potent molecules from CMNPD compounds were screened using the 3D structure of mutated resistant 5204 strain, named 5204- PBP2B (PDB ID: 2WAE) of S. pneumoniae. Out of 3318 compounds that showed strong interactions with PBP2B, docking studies revealed that four of the compounds were inhibitory for the protein and could be used to treat PBP2B. These four marine products were selected as a result of our earlier research on Klebsiella pneumonia’s New Delhi metallo-β-lactamase-1 (NDM-1) protein. This study thus reveals the importance of marine natural products for improving the drug development process, as well as the ability of four marine products generated from brown algae to inhibit both the NDM-1 protein of Klebsiella pneumoniae and the 5204-PBP2B protein in Streptococcus pneumoniae. It is also possible to expand this approach by investigating how different receptor inhibitors interact in a lab setting. Potential inhibitors can be discovered by evaluating the biological activity of the drugs and applying virtual screening and molecular docking techniques.

Structure of a model lipid membrane oxidized by human 15-lipoxygenase-2

Enzyme-mediated lipid oxidation is an important regulatory event in cell signaling, with oxidized lipids being potent signaling molecules that can illicit dramatic changes in cell behavior. For example, peroxidation of an arachidonoyl poly-unsaturated fatty acid by the human enzyme 15-lipoxygenase-2 (15-LOX-2) has been associated with formation of atherosclerotic plaques. Previous work on synthetically oxidized membranes has shown that oxidized lipid tails will change their conformation to facilitate interactions between the peroxide group and the lipid headgroups. However, this phenomenon has not been directly observed for a lipid membrane that has undergone enzyme-catalyzed oxidation. In this study, we report on the structure of a model lipid membrane before and after oxidation by 15-LOX-2. A model lipid membrane monolayer at the air-liquid interface was constructed from 1-stearoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (SAPC) in a Langmuir trough, and X-ray reflectivity measurements were conducted to determine the electron density profile of the system. Exposure to 15-LOX-2 caused a dramatic change in the SAPC structure, namely a blurred distinction between the lipid tail/head layers and shortening of the average lipid tail length by ∼3 Å. The electron density profile of the oxidized SAPC monolayer is similar to that of a synthetically oxidized substrate mimic. Overall, this reported observation of an enzymatically-oxidized membrane structure in situ is helping to bridge a gap in the literature between structural studies on synthetically oxidized membranes and cellular studies aiming to understand physiological responses.

Development of a novel bacterial production system for recombinant bioactive proteins completely free from endotoxin contamination.

Endotoxins, or lipopolysaccharides (LPS), are potent immunostimulatory molecules of critical concern in bacterial recombinant protein expression systems. The gram-negative bacterium Acinetobacter baumannii exhibits an interesting and unique phenotype characterized by the complete loss of LPS. In this study, we developed a novel system for producing recombinant proteins completely devoid of endotoxin contamination using LPS-deficient A. baumannii. We purified endotoxin-free functional green fluorescent protein, which reduced endotoxin contamination by approximately three orders of magnitude, and also purified the functional cytokine tumor necrosis factor (TNF)-α. Additionally, utilization of the Omp38 signal peptide of A. baumannii enabled the extracellular production of variable domain of heavy chain of heavy chain (VHH) antibodies. With these advantages, mNb6-tri-20aa, a multivalent VHH that specifically binds to the spike protein of severe acute respiratory syndrome coronavirus 2, was purified from the culture supernatant, and endotoxin contamination was reduced by a factor of approximately 2 × 105 compared with that in conventional expression systems. A virus neutralization assay demonstrated the functionality of the purified antibody in suppressing viral infections. Moreover, we applied our system to produce ozoralizumab, a multispecific VHH that binds to human TNF-α and albumin and are marketed as a rheumatoid arthritis drug. We successfully purified a functional antibody from endotoxin contamination. This system establishes a new, completely endotoxin-free platform for the expression of recombinant proteins, which distinguishes it from other bacterial expression systems, and holds promise for future applications.

Foliar application of salicylic acid improved morpho-anatomical features of potato by irrigating with wastewater

BackgroundThis study aimed to evaluate the suitability of using drain water as a source of irrigation and its effects along with salicylic acid on morphological, anatomical, physico-chemical as well as yield attributes of potato. For this study, potato tubers were grown in pots and irrigated with different concentrations of drain water. Salicylic acid treatments vis. 0, 0.5 and 1.0 mM were applied foliarly. Pre- and post-harvest analysis was carried out to determine different attributes of soil, water and plants after 60 days.ResultsThe growth of potato plant was increased as the concentration of SA increased through increasing shoot length, fresh/dry weight and tuber number/plant. In this research work, plant respond to overcome metal stresses by up regulating antioxidant defense system such as, peroxidase, catalase and superoxide dismutase) by application of highest treatment of SA when irrigated with 6% drain water. Plants accumulated the highest concentrations of Cd, Cr, and Pb in the leaves when treated with 1 mM of SA, compared to other plant parts. It was observed that photosynthetic pigment enhanced in 6% drain water treated plants when applied with 1mM SA as compared to control. An increase in epidermis and cortical cell thickness, as well as stomatal closure, was observed, helping to maintain water loss under stress conditions.ConclusionsAccording to these results, it can be suggested that SA is potent signaling molecule can play an essential role in maintaining potato growth when irrigated with drain water containing heavy metals through stimulating metal up take and up regulation of antioxidant enzymes.

Targeting non-classical autophagy-dependent ferroptosis and the subsequent HMGB1/TfR1 feedback loop accounts for alleviating solar dermatitis by senkyunolide I

Given the substantial risks associated with ultraviolet B (UVB) radiation-induced solar dermatitis, enhancing current strategies to combat UVB regarding skin diseases is imperative. The cross-talk between ferroptosis and inflammation has been proven to be an essential factor in UVB-induced solar dermatitis, whereas detailed process of how their interaction contributes to this remains unclear. Therefore, further investigation of ferroptosis-mediated processes and identification of corresponding inhibitory approaches hold promise for repairing skin damage. Senkyunolide I (Sen I), a bioactive component mainly extracted from the traditional Chinese medicinal plants, Ligusticum chuanxiong Hort. and Angelica sinensis (Oliv.) Diels, has demonstrated efficacy in combating oxidative stress and inflammation. In this study, we utilized UVB-irradiated HaCaT cells as an in vitro model and C57BL/6J mice as an in vivo model of solar dermatitis. Our findings revealed the pivotal roles of autophagy and ferroptosis in inducing skin inflammation, particularly emphasizing the activation of ferroptosis through macroautophagy. Surprisingly, this mechanism operated independently of ferritinophagy, a classical autophagy-driven ferroptosis pathway. Instead, our results highlighted Transferrin Receptor 1 (TfR1), tightly controlled by autophagy, as a crucial mediator of ferroptosis execution and amplifier of subsequent lethal signals. Furthermore, extracellular High Mobility Group Box 1 protein (HMGB1), released following UVB-induced ferroptotic cells from activated autophagic flux, initiated a feedback loop with TfR1, propagating ferroptosis to neighboring cells and exacerbating damage. Remarkably, Sen I administration showed a significant protective effect against UVB damage in both in vitro and in vivo models by interrupting this cascade. Consequently, we have illuminated a novel therapeutic pathway post-UVB exposure and identified Sen I as a potent natural molecule that safeguarded against UVB-induced solar dermatitis by suppressing the autophagy-ferroptosis-HMGB1-TfR1 axis, highlighting a new frontier in photoprotection.

Cyclization increases bactericidal activity of arginine-rich cationic cell-penetrating peptide for Neisseria gonorrhoeae.

We previously reported that a linear cationic 12-amino acid cell-penetrating peptide (CPP) was bactericidal for Neisseria gonorrhoeae. In this study, our objectives were to determine the effect of cyclization of the linear CPP on its antibacterial activity for N. gonorrhoeae and cytotoxicity for human cells. We compared the bactericidal effect of 4-hour treatment with the linear CPP to that of CPPs cyclized by a thioether or a disulfide bond on human challenge and multi-drug resistant (MDR) strains of N. gonorrhoeae grown in cell culture media with 10% fetal bovine serum (FBS). The effect of lipooligosaccharide (LOS) sialylation on bactericidal activity was analyzed. We determined the ability of the CPPs to treat human cells infected in vitro with N. gonorrhoeae, to reduce the inflammatory response of human monocytic cells to gonococci, to kill strains of three commensal Neisseria species, and to inhibit gonococcal biofilms. The cyclized CPPs killed 100% of gonococci from all strains at 100 µM and >90% at 20 µM and were more potent than the linear form. The thioether-linked but not the disulfide-linked CPP was less cytotoxic for human cervical cells compared to the linear CPP. LOS sialylation had minimal effect on bactericidal activity. In treating infected human cells, the thioether-linked CPP at 20 µM killed >60% of extra- and intracellular bacteria and reduced TNF-α expression by THP-1 cells. The potency of the CPPs for the pathogenic and the commensal Neisseria was similar. The thioether-linked CPP partially eradicated gonococcal biofilms. Future studies will focus on determining efficacy in the female mouse model of gonorrhea.IMPORTANCENeisseria gonorrhoeae remains a major cause of sexually transmitted infections with 82 million cases worldwide in 2020, and 710,151 confirmed cases in the US in 2021, up 25% from 2017. N. gonorrhoeae can infect multiple tissues including the urethra, cervix, rectum, pharynx, and conjunctiva. The most serious sequelae are suffered by infected women as gonococci ascend to the upper reproductive tract and cause pelvic inflammatory disease, chronic pelvic pain, and infertility in 10%-20% of women. Control of gonococcal infection is widely recognized as increasingly challenging due to the lack of any vaccine. N. gonorrhoeae has quickly developed resistance to all but one class of antibiotics and the emergence of multidrug-resistant strains could result in untreatable infections. As such, gonorrhea is classified by the Center for Disease Control (CDC) as an urgent public health threat. The research presented herein on new therapeutics for gonorrhea has identified a cyclic cell-penetrating peptide (CPP) as a potent molecule targeting N. gonorrhoeae.

2-Chloro-3-cyano-4-nitrobenzyl pyridinium bromide as a potent anti-lung cancer molecule prepared using a single-step solvent-free method.

Mono-/dimeric-substituted pyridinium and pyrazolium bromides were prepared under conventional and solvent-free silica-supported domestic microwave conditions. The atom economy, environmental product mass intensity and product mass intensity for solvent-free reactions showed significant importance for the synthesis of target molecules. 4-Nitrobenzyl-substituted pyridinium bromide showed potent anticancer properties compared with mono-/dimeric-substituted pyridinium and pyrazolium bromides against a lung cancer cell line (A-549). Molecular simulation studies were carried out for mono-/dimeric-substituted pyridinium and pyrazolium bromide against protein human CDK1/cyclinB1/CKS2 using the AutoDock program.

Arsenic-induced transition of thymic inflammation-to-fibrosis involves Stat3-Twist1 interaction: Melatonin to the rescue.

Groundwater arsenic is a notorious toxicant and exposure to environmentally relevant concentrations persists as a healthcare burden across the world. Arsenic has been reported to jeopardize the normal functioning of the immune system, but there are still gaps in the understanding of thymic T cell biology. Immunotoxic influence of arsenic in thymic integrity demands a potent restorative molecule. The objectives of this study were to examine key signaling cross-talks associated with arsenic-induced immune alterations in the thymus and propose melatonin as a potential candidate against immunological complications arising from arsenic exposure. Swiss albino mice were exposed to sodium arsenite (0.05 mg/L; in drinking water) and melatonin (IP:10 mg/kg BW) for 28 days. Melatonin successfully protected thymus from arsenic-mediated tissue degeneration and maintained immune homeostasis including T cell maturation and proliferation by mitigating oxidative stress through Nrf2 upregulation. Additionally, melatonin exerted ameliorative effect against arsenic-induced apoptosis and inflammation by inhibiting p53-mediated mitochondrial cell death pathway and NF-κB-p65/STAT3-mediated proinflammatory pathway, respectively. For the first time, we showed that arsenic-induced profibrotic changes were inhibited by melatonin through targeting of inflammation-associated EMT. Our findings clearly demonstrate that melatonin can be a viable and promising candidate in combating arsenic-induced immune toxicity with no collateral damage, making it an important research target.

A Natural deep eutectic solvent as an effective material for dual debridement and antibiofilm effects in chronic wound treatment

In chronic wound treatment, the debridement of devitalized tissue and the eradication of the biofilm must balance aggressiveness with care to protect regenerating tissues. In this study, urea, a potent chaotropic molecule, was modulated through the formation of a Natural Deep Eutectic Solvent (NADES) with betaine to develop a new debriding material (BU) suitable for application into injured dermal tissues. To evaluate BU’s debriding capacity, along with its antibiofilm effect and biocompatibility, pre-clinical to clinical methods were employed. In vitro determinations using artificial and clinical slough samples indicate that BU has a high debriding capacity. Additionally, BU’s de-structuring effects lead to a strong antibiofilm capability, demonstrated by a reduced bacterial load compared to the antiseptic PHMB-Betaine or medical honey, evaluated in artificial slough and ex vivo human skin. Furthermore, BU’s efficacy was evaluated in a murine model of diabetic wound, demonstrating significant effects on debriding and antibiofilm capacity, similar to those observed in PHMB-Betaine and medical honey-treated animals. Finally, BU was clinically evaluated in leg ulcers, showing superiority in reduction of bacterial load and wound area compared to honey, with no adverse effects. Thus, BU represents a simple and non-biocidal option that could contributes to chronic wound care.

Investigation on the Anticancer Activity of [6]-Gingerol of Zingiber officinale and its Structural Analogs against Skin Cancer.

Skin cancer is the most common type of cancer caused by the uncontrolled growth of abnormal cells in the epidermis and the outermost skin layer. This study aimed to study the anti-skin cancer potential of [6]-Gingerol and 21 related structural analogs using in vitro</i> and in silico</i> studies. The ethanolic crude extract of the selected plant was subjected to phytochemical and GC-MS analysis to confirm the presence of the [6]-gingerol. The anticancer activity of the extract was evaluated by MTT (3-[4, 5-dimethylthiazol-2-y]-2, 5-diphenyl tetrazolium bromide) assay using the A431 human skin adenocarcinoma cell line. The GC-MS analysis confirmed the presence of [6]-Gingerol compound, and its promising cytotoxicity IC50 was found at 81.46 ug/ml in the MTT assay. Furthermore, the in silico studies used [6]-Gingerol and 21 structural analogs collected from the PubChem database to investigate the anticancer potential and drug-likeliness properties. Skin cancer protein, DDX3X, was selected as a target that regulates all stages of RNA metabolism. It was docked with 22 compounds, including [6]-Gingerol and 21 structural analogs. The potent lead molecule was selected based on the lowest binding energy value. Thus, the [6]-Gingerol and its structure analogs could be used as lead molecules against skin cancer and future drug development process.

Computational Investigations to Identify Potent Natural Flavonoid Inhibitors of the Nonstructural Protein (NSP) 16/10 Complex Against Coronavirus.

Globally, the viral pandemic has spread rapidly, resulting in widespread infections. The coronavirus family (CoVs) is one of the various viral families capable of infecting mammals, causing diseases related to the gastrointestinal, neurological, and respiratory systems. Flavonoid compounds have been identified as potentially effective antiviral agents, specifically targeting the virus's nonstructural protein (NSP) 16/10. Flavonoids have also been shown to inhibit virus replication and viral attachment to host cells, making them a promising candidate for antiviral treatment. Further research is needed to understand the full potential of flavonoids as antiviral agents. This study investigated natural compounds derived from medicinal plants using in silico screening. In addition to assessing drug-likeness, pharmacokinetics, docking, molecular dynamics simulation, bioavailability assessment, and exploration of molecular targets, the screening process entailed analyses of molecular targets and bioavailability. The molecular properties and potential antiviral efficacy of these phytochemical candidates were determined by analyzing them as drug candidates. The results of the study showed that these compounds had potential antiviral activity and could be developed as therapeutic agents. Furthermore, the study showed that the compounds had good bioavailability, suggesting that they are suitable for use as therapeutic agents. An in silico method was used to identify flavonoid compounds for potent antiviral drug molecules against the coronavirus protein complex NSP16/10 protein. The NSP16/10 complex protein binding energy values were -6.14 for isoquercetin, -6.902 for narirutin, -6.052 for myricetin, -7.10 for hesperidin, -4.392 for silibinin, -3.997 for baicalein, -3.712 for taxifolin, and -3.321 for petunidin. Molecular dynamics simulations showed that isoquercetin, hesperidin, and narirutin flavonoids interacted with the COVID-19 virus protein complex NSP16/10 protease up to 100 nanoseconds.

Click-chemistry-inspired synthesis of new series of 1,2,3-triazole fused chromene with glucose triazole conjugates: Antibacterial activity assessment with molecular docking evaluation

A series of new 1,2,3-triazole fused chromene based glucose triazole conjugates were synthesized from chromene fused 1,2,3-triazolyl extended alkyne and 2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl azide in good to excellent yield by a copper catalyzed azide-alkyne cycloaddition (CuAAC) reaction. The major advantages include mild reaction conditions, high yield, good substrate scope, and shorter reaction time. The antibacterial efficacy of the compounds were assessed in vitro against human pathogenic Gram-negative E. coli and Gram-positive S. aureus bacteria. Compound 24j was found to be the most potent molecule with zone of inhibition (ZI) of 17 mm and minimum inhibitory concentration (MIC) of 25 μg mL−1 in E. coli and ZI of 16 mm and MIC of 25 μg mL−1 in S. aureus. Also, it significantly inhibited E. coli DNA-gyrase in silico with a binding affinity of −9.4 kcal/mol. Among all the synthesized compounds, 24i, 24d, 24e and 24f showed significant antibacterial activity against both strains and inhibited DNA-gyrase in silico with good binding affinities. Hence, these 1,2,3-triazole fused chromene based glucose triazole conjugates may evolve to be powerful antibacterial agents in recent future, according to structure-activity relationships based on strong antibacterial properties and molecular docking studies.

In vivo -Active Soluble Epoxide Hydrolase-targeting PROTACs with Improved Potency and Stability.

Soluble epoxide hydrolase (sEH) is a bifunctional enzyme involved in fatty acid metabolism and promising drug target. We previously reported first-generation sEH proteolysis-targeting chimeras (PROTACs) with limited degradation potency and low aqueous and metabolic stability. Herein, we report the development of next-generation sEH PROTAC molecules with improved stability and degradation potency. One of the most potent molecules (compound 8 ) exhibits a half-maximal degradation concentration in the sub-nM range, is stable in vivo , and effectively degrades sEH in mouse livers and brown adipose tissues. Given the role played by sEH in many metabolic and nonmetabolic diseases, the presented molecules provide useful chemical probes for the study of sEH biology. They also hold potential for therapeutic development against a range of disease conditions, including diabetes, inflammation, and metabolic disorders.

B Cell-activating factor (BAFF): A promising trans-nosographic biomarker of inflammation and autoimmunity in bipolar disorder and schizophrenia

Immune dysregulation is an important aspect of schizophrenia (SZ) and bipolar disorders (BD) pathophysiology, including not only inflammatory but also autoimmune process reflective of abnormal humoral immune responses. Given that B cell-activating factor (BAFF) is an integral aspect of B lymphocyte regulation, the current study investigated BAFF in SZ and BD. 255 SZ patients, 407 BD patients and 185 healthy controls (HC) were investigated across three aspects of soluble BAFF (sBAFF) by (i) comparing sBAFF circulatory levels across SZ, BD and HC, (ii) determining potential correlations between the circulating levels of sBAFF and the genotype distribution of a functionally relevant polymorphism, namely the TNFSF13B 3′UTR insertion-deletion polymorphism (GCTGT>A), (iii) analyzing relationships between both sBAFF levels and 3′UTR insertion-deletion genotypes and disease risk, patients clinical characteristics and circulating levels of potent inflammatory molecules. In addition, in subsets of patients, we also searched for possible correlations between sBAFF levels and stigma of past infectious events as well as positivity for circulating systemic autoantibodies or those directed against central nervous system (CNS) structures. Studying blood derived serum and DNA, weobserved that circulating sBAFF levels were significantly higher in SZ and BD patients, versus HC (p = 5.3*10-10and p = 4.4*10-09). Patients experiencing acute episodes, versus stable patients, in between acute episodes, exhibited higher sBAFF levels (p = 0.017).In SZ patients, positive correlations were observed between elevated sBAFF levels and: (i) elevated positive psychotic symptoms (PANSS pos), (ii) history of childhood trauma (physical abuse), and (iii) low scores on global functioning (GAF) (p = 0.024, p = 0.024, and p = 0.041).We also found that the distribution of the BAFF Ins/Del genotypes was significantly correlated with circulating sBAFF levels in SZ and BD patients (p = 0.0004). Elevated sBAFF levels were also correlated with increased levels of pro-inflammatory markers in both SZ and BD cohorts (p < 0.001). Regarding infectious stigma, only patients seropositive, versus seronegative, for herpes simplex virus (HSV)1 immunoglobulin (Ig)G antibodies exhibited a significant association with high sBAFF levels (p = 0.013). In contrast, positivity for systemic or CNS autoantibodies was significantly associated with reduced sBAFF levels, compared to patients without autoantibodies (p = 0.0017). Overall, our findings indicate that BAFF may be a promising trans-nosographic biomarker of inflammation that is likely to offer predictive, diagnostic, and prognostic tools for the management of SZ and BD. The results therefore have practicable clinical utility given the availability of immunotherapeutic treatment options including targeted monoclonal antibodies against BAFF.

Comparative efficacy of four potent bioactive molecules of fenugreek seed in holistic management of type 1 diabetes

Comparative efficacy of four potent bioactive molecules of fenugreek seed in holistic management of type 1 diabetes

Natural hypoglycaemic bioactives: Newer avenues and newer possibilities.

The incidences of endocrine and metabolic disorders like diabetes have increased worldwide. Several proposed molecular pathways mechanisms for the management of diabetes have been identified, but glycaemic control is still a challenging task in the drug discovery process. Most of the drug discovery processes lead to numerous scaffolds that are prominent in natural products. The review deals with the natural bioactives as an α-amylase inhibitors, α-glucosidase inhibitors, protein tyrosine phosphatase-1B inhibitors, dipeptidyl peptidase-IV inhibitors, G-protein coupled receptors-40 agonists, PPAR-γ agonists and the activators of 5'-adenosine monophosphate-activated protein kinase and glucokinase. So, in this review, we focused on the hypoglycaemic bioactives, which will assist scientific developers, traditional medicinal practitioners, and readers to discover some potent antidiabetic molecules. Strategies like chemometric approaches, scaffold hopping, and total synthesis of natural products by group modification or ring opening/closing mechanism could be useful for the development of novel hit/lead antidiabetic molecules. The study concludes that each phyto molecule inherits a potential to get explored by repurposing techniques for various antidiabetic targets and offer an alternative antidiabetic therapeutic medicinal potential.

In Silico Prediction of Binding Affinities of Hybrid Molecules of Benzothiazole Linked with Hydroxamic Acid by Disulfide Bond and Certain Linkers with HDAC8 Enzyme

A new hybrid molecule of Benzothiazole cross-linked with hydroxamic acid through an amino acid or aminoalkanoic acid were synthesised. All the synthesized hybrid molecules (1-5) were subjected to molecular docking studies to evaluate their binding affinities with histone deacetylase enzyme (HDAC8, PDB ID: 1T69) and recorded lower ΔG (-8.276, -10.093, -8.647, -6.315, -8.676 kcal/mole, respectively) than the reference ligand (Vorinostat, suberoylanilide hydroxamic acid, SAHA -5.375 kcal/mole). Molecular docking studies were performed using the maestro software (Schrödinger, version 2022-1). Moreover, compound 2, which is Benzothiazole-p-amino benzoic acid-hydroxamate has recorded the lowest binding score (-10.093). This may indicate that this compound is the most potent hybrid molecule. There were no violations from Lipinski’s rule and all the synthesized hybrid molecules comply with all parameters. Swiss ADME server was employed for the in silico molecular docking for prediction of the physicochemical and ADME properties of the investigated compounds. All hybrid molecules showed low possible passive oral absorption and no penetration into BBB. The hybrid molecules 1and 3 may be considered as P-gp substrates.