A Step Towards Optimization of Amide-Linked Coumarin Pharmacophore: As an Anti-HIV Agent.

The aim of the present investigation is to identify effective anti-HIV drugs through the in-silico virtual screening of the coumarin pharmacophore with or without substituents. Virtual screening started with target identification through computation docking and interactions, binding affinity through molecular dynamics, and the ADMET profile through the use of various enzymes. The target study suggests that the target is involved in various stages of HIV replication and in determining the ways in which non-nucleoside reverse transcriptase inhibitors (RTIs) influence it. The interaction pattern and simulation study conclude the specific affinity of coumarin pharmacophore to the HIV's reverse transcriptase enzyme, especially 3HVT. Moreover, the amide linkage worked as a synergistic bridge to provide more interaction to the pharmacophore. The initial results led to the determination of 83 virtual amide-like molecules, which were screened through docking and MD studies (100 ns) on the best-suited enzyme HIV's reverse transcriptase enzyme, such as PDB ID "3HVT". The virtual screening study revealed the high affinity of compounds 7d and 7e with the lowest IC50 values of 0.729 and 0.658 µM; moreover, their metabolism pattern study, toxicity, and QED values in a range of 0.31-0.40 support a good drug candidate. The two compounds were also synthesized and characterized for future in vitro and in vivo studies. The in silico-based descriptor of compounds 7d and 7e indicates the potential future and provides the best two molecules and their synthetic route for the development of a more effective drug to combat HIV/AIDS epidemics.

HER-2 Receptor and αvß3 Integrin Dual-Ligand Surface-Functionalized Liposome for Metastatic Breast Cancer Therapy.

Human epidermal growth factor receptor-2 (HER2)-positive breast cancer metastasis remains the primary cause of mortality among women globally. Targeted therapies have revolutionized treatment efficacy, with Trastuzumab (Trast), a monoclonal antibody, targeting HER2-positive advanced breast cancer. The tumor-homing peptide iRGD enhances the intratumoral accumulation and penetration of therapeutic agents. Liposomes serve as versatile nanocarriers for both hydrophilic and hydrophobic drugs. Gefitinib (GFB) is a potential anticancer drug against HER2-positive breast cancer, while Lycorine hydrochloride (LCH) is a natural compound with anticancer and anti-inflammatory properties. This study developed TPGS-COOH-coated liposomes co-loaded with GFB and LCH, prepared by the solvent injection method, and surface-functionalized with Trast and iRGD. The dual surface-decorated liposomes (DSDLs) were characterized for their particle size (PS), polydispersity index (PDI), zeta potential (ZP), surface chemistry, surface morphology, and their crystallinity during in-vitro drug release, drug encapsulation, and in-vitro cell line studies on SK-BR-3 and MDA-MB-231 breast cancer cells. The half-maximum inhibitory concentration (IC-50) values of single decorated liposomes (SDLs), iRGD-LP, and Trast-LP, as well as DSDLs (iRGD-Trast-LP) on SK-BR-3 cells, were 6.10 ± 0.42, 4.98 ± 0.36, and 4.34 ± 0.32 µg/mL, respectively. Moreover, the IC-50 values of SDLs and DSDLs on MDA-MB-231 cells were 15.12 ± 0.68, 13.09 ± 0.59, and 11.08 ± 0.48 µg/mL, respectively. Cellular uptake studies using confocal laser scanning microscopy (CLSM) showed that iRGD and Trast functionalization significantly enhanced cellular uptake in both cell lines. The wound-healing assay demonstrated a significant reduction in SDL and DSDL-treated MDA-MB-231 cell migration compared to the control. Additionally, the blood compatibility study showed minimal hemolysis (less than 5% RBC lysis), indicating good biocompatibility and biosafety. Overall, these findings suggest that TPGS-COOH-coated, GFB and LCH co-loaded, dual-ligand (iRGD and Trast) functionalized, multifunctional liposomes could be a promising therapeutic strategy for treating HER2-positive metastatic breast cancer.

Therapeutic potential of bark extracts from Macaranga denticulata on renal fibrosis in streptozotocin-induced diabetic rats.

Macaranga denticulata (MD) bark is commonly utilized in traditional medicine for diabetes prevention and treatment. The bark extract of MD is rich in prenyl or farnesyl flavonoids and stilbenes, which possess antioxidant properties. Although data suggest the potential therapeutic benefits of the use of MD in treating diabetic nephropathy (DN), the precise mechanisms underlying MD-initiated protective effects against DN are not well understood. This study aimed to assess the renoprotective properties of MD extract by examining renofibrosis inhibition, oxidative stress, and inflammation utilizing streptozotocin-induced DN male Sprague - Dawley rats. Diabetic rats were intraperitoneally injected with streptozotocin (STZ) to induce diabetes. After 6 days, these rats were orally administered MD extract (200 mg/kg/day) or metformin (200 mg/kg/day) for 14 days. The administration of MD extract significantly lowered blood glucose levels, restored body weight, and reduced urine levels of various biomarkers associated with kidney functions. Histopathological analysis revealed protective effects in both kidneys and pancreas. Further, MD extract significantly restored abnormalities in advanced glycation end products, oxidative stress biomarkers, and proinflammatory cytokine levels in STZ-treated rats. MD extract markedly reduced renal fibrosis biomarker levels, indicating recovery from renal injury, and reversed dysregulation of sirtuins and claudin-1 in the kidneys of rats with STZ-induced diabetes. In conclusion, data demonstrated the renoprotective role of MD extract, indicating plant extract's ability to suppress oxidative stress and regulate proinflammatory pathways during pathological changes in diabetic nephropathy.

Unsettling trend: The alarming rise of human abuse of veterinary drugs and its consequences.

Veterinary practitioners often prescribe many controlled drugs to animals that may include sedatives, tranquilizers, and painkillers. Unfortunately, many of these drugs are drugs that can be abused by humans, especially among the pet owners. Adequate measures are required to prevent or detect the misuse of veterinary drugs. In this article, the phenomenon of the rising misuse of veterinary medications by humans and their potential health hazards which can accompany the unsettling trends in society has been highlighted. This article aims to shed light on the extent of issues, exploring reasons behind human abuse and its consequences.

A novel ultra-performance liquid chromatography detection method development and validation for paclitaxel and its major metabolite in human plasma.

BACKGROUND: Paclitaxel is a promising anticancer drug for patients with ovarian, breast, lung, gastrointestinal, genitourinary, prostate, and head-and-neck cancers. Paclitaxel follows nonlinear pharmacokinetics. The major metabolite of paclitaxel is 6-alpha-hydroxy paclitaxel, mediated by CYP2C8, while metabolism to two of its minor metabolites, 3'-p-hydroxypaclitaxel and 6a, 3'- p-dihydroxypaclitaxel, is catalyzed by CYP3A4. Therapeutic drug monitoring of paclitaxel could be a promising approach to improve the efficacy and safety of paclitaxel correct personalized doses and improve the overall benefit-risk ratio. A novel and highly sensitive chromatographic method for the detection of paclitaxel and its metabolite has been proposed that allows quantification in human plasma with 100% accuracy in terms of recovery without significant intraday or interday variations. MATERIALS AND METHODS: The present study was planned following bioanalytical method validation guidance according to the U.S. Food and Drug Administration requirements. The validation of the analytical procedure was performed as per ICH Q2(R1) guidelines. It was done to assure the reliability of the results obtained for various parameters such as linearity, accuracy, precision, limit of detection (LOD), limit of quantification, robustness, stability, and system suitability. RESULTS: The specificity of the method was established by ensuring no interference with peak obtained from paclitaxel and 6-alpha-hydroxy paclitaxel. LOD was found to be 0.05 and 0.033 while the limit of quantitation was 0.14 and 0.099 for paclitaxel and 6-alpha-hydroxy paclitaxel, respectively. Median (±interquartile range) accuracy for paclitaxel and 6-alpha-hydroxy paclitaxel was found to be 102.73 (±13.581) and 100.87 (±7.573), respectively. CONCLUSION: This novel method of simultaneous detection of paclitaxel and its major metabolite 6-alpha-hydroxy paclitaxel demonstrated significant resolution and was sensitive enough for its quantification in human plasma.

Nanomedicine in Management of Cerebral Infarction and Brain Cancer: Role of Inflammation.

INTRODUCTION: Cerebral infarction, the blockage of blood vessels in the brain, is generally an age-related illness. Factors such as unhealthy diets, stressful behaviours and decreased environmental consistency with physiological barriers also contribute to increased casualties. Long-term brain function reconstruction and successful drug therapy are needed. The most frequent malignant brain tumour, glioblastoma, has been linked to variations in mitochondrial ROS, chaperone-mediated autophagy, and the interaction between lncRNA (BC200) and miRNA. Glioblastoma stem cells express high levels of ATP/P2X7 receptors, promoting survival by activating M2 muscarinic receptors. AREAS COVERED: This expert opinion provides an overview of the latest experimental drug therapies aimed at protecting against and restoring cerebral stroke. EXPERT OPINION: Nanomedicine overcomes the challenges associated with traditional therapy and physiological obstacles in the treatment of cerebral infarction by improving stroke management, including diagnosis, imaging, and treatment, addressing a diverse range of associated factors.

Polyphasic approaches to identify and understand α-glucosidase inhibitory potential of secondary metabolites of Withania coagulans fruit.

Withania coagulans (WC) is used in traditional and Ayurveda medicine to treat various ailments, including diabetes. Our investigation found that WC fruit hexane extract effectively suppresses α-glucosidase activity (IC50 = 0.013 mg/ml, Ki = 0.012 mg/ml). The purified molecule has an IC50 of 0.004 mg/ml and Ki of 0.0037 mg/ml. FTIR examination indicates distinctive peaks at 3500, 2900, 1770, and 1500 cm-1 corresponding to functional groups OH bending, CH stretching, CO stretching, and CO stretching. GCMS analysis reveals plant secondary metabolites (PSM) such as n-hexadecenoic acid and methyl 9,10-octadecadienoate. NMR confirms the existence of olefinic fatty acids. The bioactive fraction recorded a non-competitive mode of inhibition of α-glucosidase activity. The cytotoxicity exhibited against HELA cell was IC50 0.4 mg/ml and found positive in inhibiting the growth of Bacillus cereus, Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus, and Pseudomonas aeruginosa. Additionally, ensemble docking and molecular dynamic simulation showed that, out of the four PSMs examined, methyl 12,13-tetradecadienoate interacted with the α-glucosidase enzyme's allosteric site (BE -128.78 kJ/mol) and changed the configurations of the catalytic sites, as demonstrated by the enzyme's decreased affinity for isomaltose. The study found that PSMs from WC fruit may inhibit α-glucosidase, making them viable candidates for antidiabetic medication development.

Proteomic Identification and Label-Free Quantification of Proteins Implicated in Neurite and Spine Formation.

The molecular mechanisms underlying neurite formation include multiple crosstalk between pathways such as membrane trafficking, intracellular signaling, and actin cytoskeletal rearrangement. To study the proteins involved in such complex pathways, we present a detailed workflow of the sample preparation for mass spectrometry-based proteomics and data analysis. We have also included steps to perform label-free quantification of proteins that will help researchers quantify changes in the expression levels of key regulators of neuronal morphogenesis on a global scale.

KREH2 helicase represses ND7 mRNA editing in procyclic-stage Trypanosoma brucei by opposite modulation of canonical and 'moonlighting' gRNA utilization creating a proposed mRNA structure.

Unknown factors regulate mitochondrial U-insertion/deletion (U-indel) RNA editing in procyclic-form (PCF) and bloodstream-form (BSF) T. brucei. This editing, directed by anti-sense gRNAs, creates canonical protein-encoding mRNAs and may developmentally control respiration. Canonical editing by gRNAs that specify protein-encoding mRNA sequences occurs amid massive non-canonical editing of unclear sources and biological significance. We found PCF-specific repression at a major early checkpoint in mRNA ND7, involving helicase KREH2-dependent opposite modulation of canonical and non-canonical 'terminator' gRNA utilization. Terminator-programmed editing derails canonical editing and installs proposed repressive structure in 30% of the ND7 transcriptome. BSF-to-PCF differentiation in vitro recreated this negative control. Remarkably, KREH2-RNAi knockdown relieved repression and increased editing progression by reverting canonical/terminator gRNA utilization. ND7 transcripts lacking early terminator-directed editing in PCF exhibited similar negative editing control along the mRNA sequence, suggesting global modulation of gRNA utilization fidelity. The terminator is a 'moonlighting' gRNA also associated with mRNA COX3 canonical editing, so the gRNA transcriptome seems multifunctional. Thus, KREH2 is the first identified repressor in developmental editing control. This and our prior work support a model whereby KREH2 activates or represses editing in a stage and substrate-specific manner. KREH2's novel dual role tunes mitochondrial gene expression in either direction during development.

Effect of bispectral index on intra-operative awareness: A meta-analysis of randomized controlled studies.

Background: Randomized controlled trials (RCTs) investigating the efficacy of bispectral index (BIS) to reduce intra-operative awareness (IOA) have reported conflicting results. The purpose of this meta-analysis is to consolidate results from RCTs to assess the efficacy of BIS in reducing IOA when compared to controls. Secondary outcomes included time to extubation, time to spontaneous and/or verbal eye opening, PACU discharge time, and utilization of inhaled anesthetics. Methods: RCTs which reported on one of the primary and/or secondary outcomes were included. Literature search utilized keywords "randomized control trial" and "intraoperative awareness." Meta-analysis was performed using RevMan 5. Results: Twenty-seven RCTs were included in the study with a total of 35,585 patients, with 18,146 patients in the BIS and 17,439 in the control group. Eighteen of 14,062 patients (0.12%) and 42 of 16,765 (0.25%) reported definite IOA in the BIS and control group, respectively, with no statistically significant difference. BIS was effective in reducing the time to spontaneous eye opening by an average of 1.3 minutes and the time to extubation by an average of 1.97 minutes. There was no difference in PACU discharge times among the groups. There was a significant decrease in consumption of sevoflurane but no difference in desflurane and propofol compared to the control group. Conclusion: While BIS monitoring results in decreased incidence of intra-operative awareness by half, it was not statistically significant. BIS provides modest benefits with regard to reducing the time to extubation, the time to spontaneous eye opening, and consumption of sevoflurane.Level of evidence: I.

The utility of Streptococcus mutans undecaprenol kinase for the chemoenzymatic synthesis of diverse non-natural isoprenoids.

Isoprene chemoenzymatic cascades (ICCs) overcome the complexity of natural pathways by leveraging a streamlined two-enzyme cascade, facilitating efficient synthesis of C5-isoprene diphosphate precursors from readily available alcohol derivatives. Despite the documented promiscuity of enzymes in ICCs, exploration of their potential for accessing novel compounds remains limited, and existing methods require additional enzymes for generating longer-chain diphosphates. In this study, we present the utility of Streptococcus mutans undecaprenol kinase (SmUdpK) for the chemoenzymatic synthesis of diverse non-natural isoprenoids. Using a library of 50 synthetic alcohols, we demonstrate that SmUdpK's promiscuity extends to allylic chains as small as four carbons and benzylic alcohols with various substituents. Subsequently, SmUdpK is utilized in an ICC with isopentenyl phosphate kinase and aromatic prenyltransferase to generate multiple non-natural isoprenoids. This work provides evidence that, with proper optimization, SmUdpK can act as the first enzyme in these ICCs, enhancing access to both valuable and novel compounds.

Real-World Clinical Profile and Safety of Nintedanib in Systemic Sclerosis-Associated Interstitial Lung Disease: A Subgroup Analysis of Interstitial Lung Disease Data From an Interstitial Lung Disease (ILD) Specialty Clinic in India.

INTRODUCTION:  Systemic sclerosis (SSc) is a multisystem autoimmune disorder characterized by dysregulated innate and adaptive immunity. Interstitial lung disease (ILD) is a common and serious complication of SSc, often leading to significant morbidity and mortality. Consistent demographic characteristics that aid in the early diagnosis of ILD in SSc are lacking. This study aims to identify clinical and demographic parameters associated with ILD in SSc patients and assess the safety and tolerability of nintedanib with other immunosuppressants. MATERIALS AND METHODS: This study is a subgroup analysis of data from the ILD clinic at All India Institute of Medical Sciences Raipur, collected between January 2022 and January 2024. We assessed the clinical and demographic profiles, high-resolution computed tomography thorax patterns, autoantibody profiles, lung function, and treatments used in the patients. RESULTS: We enrolled 57 patients with SSc-associated ILD. The mean age of the participants was 39.0 ± 11.1 years, with 53 (92.9%) being women. The mean body mass index was 20.4 ± 4.32 kg/m². Dyspnea was the most common symptom, followed by skin tightening and cough. Antinuclear antibody tests were positive in 92.9% of patients, and anti-Scl-70 antibodies were positive in 57.9%. Rheumatoid arthritis-SSc overlap was observed in 15.8% of patients. The mean predicted forced vital capacity was 46.5 ± 19.9%, the mean predicted total lung capacity was 64.5 ± 20.4%, and the mean predicted diffusing capacity for carbon monoxide was 46.2 ± 15.7%. The mean six-minute walk distance was 360.3 ± 81.2 meters, and the mean King's Brief Interstitial Lung Disease score was 63.9 ± 10.7. Common radiological abnormalities included ground-glass opacities in 57.8%, traction bronchiectasis in 43.8%, and honeycombing in 28.07%. The predominant ILD pattern was nonspecific interstitial pneumonia. Patients received a combination of prednisolone (5 mg/day) with mycophenolate mofetil (63.2%), hydroxychloroquine (17.5%), cyclophosphamide (12.3%), and methotrexate (7.02%). Nintedanib, the only antifibrotic used, was administered to 17 (29.8%) patients. CONCLUSIONS: ILD is relatively common in SSc, particularly in patients with diffuse cutaneous SSc and those with anti-topoisomerase antibodies. Female patients comprised the predominant population in this study. Patients tolerated mycophenolate mofetil and cyclophosphamide well. Nintedanib was the only antifibrotic used, and all patients tolerated the combination of antifibrotics and immunosuppressants well. Early diagnosis is crucial to slow disease progression and preserve lung function. Our results highlight the need for vigilant screening in high-risk groups and suggest that MMF, cyclophosphamide, and nintedanib can be safely incorporated into treatment regimens, offering a potential strategy to improve patient outcomes.

Purifying selection drove the adaptation of mitochondrial genes along with correlation of gene rearrangements and evolutionary rates in two subfamilies of Whitefly (Insecta: Hemiptera).

Insect mitochondrial genomes (mitogenomes) are usually represented by a conserved gene order. Whiteflies exhibit gene rearrangement in their mitogenomes; however, understanding how nucleotide substitution rates shape gene rearrangement in whiteflies is unclear due to the limited number of mitogenomes. Additionally, the mechanisms by which selection pressure drives adaptations in mitochondrial genes in the two subfamilies of whiteflies are not yet known. Here, we analyzed 18 whitefly mitogenomes, including one newly generated mitogenome, to compare nucleotide substitution rates, selection pressure, and gene arrangements. The newly generated mitogenome is reported along with reannotation of Pealius mori and comparisons to other whitefly mitogenomes. Comparative studies on nucleotide composition of 18 whiteflies revealed the positive GC skewness, confirming the reversal of strand asymmetry. We found 11 rearranged gene orders within two subfamilies of whiteflies with 8-18 breakpoints of gene rearrangements. Members of the subfamily Aleyrodinae exhibit more complex pathways in the evolution of gene order as compared to the subfamily Aleurodicinae. Our findings also revealed that the increase or reduction of nucleotide substitution rates does not have an impact on any of the gene rearrangement scenarios depicting neutral correlation. Selection pressure analysis revealed that the mitogenomes from members of both the subfamilies Aleurodicinae and Aleyrodinae are characterized by intense purifying selection pressure.

Metformin's dual impact on Gut microbiota and cardiovascular health: A comprehensive analysis.

Cardiovascular diseases (CVD) cause significant global morbidity, mortality and public health burden annually. CVD alters richness, diversity, and composition of Gut microbiota along with RAS and histopathological differences. Present study explores Metformin role in mitigating doxorubicin induced cardiovascular toxicity/remodeling. Animals were divided into 4 groups with n=6: Group I (N. Control) free access to diet and water; Group II (MET. Control) on oral Metformin (250 mg/kg) daily; Group III (DOX. Control) alternate day intraperitoneal Doxorubicin (3 mg/kg) totaling 18 mg/kg; Group IV (DOX. MET. Control) received both daily oral Metformin (250 mg/kg) and alternate day Doxorubicin (3 mg/kg). Gut microbial analysis was made from stool before animals were sacrificed for biochemical and histopathological analysis. Significant alterations were observed in ɑ and ß-diversity with new genus from Firmicutes, specifically Clostridia_UCG-014, Eubacterium ruminantium, and Tunicibacter, were prevalent in both the DOX. Control and DOX.MET groups. Proteobacteria, represented by Succinivibrio, were absent in all groups. Additionally, Parabacteroides from the Bacteroidia phylum was absent in all groups except the N. control. In the DOX.MET Control group, levels of Angiotensin II ( 7.75± 0.49 nmol/min, p<0.01) and Renin (2.60±0.26 ng/ml/hr) were significantly reduced. Conversely, levels of CK-MB, Fibrinogen, Troponin, CRP ( p < 0.0001), and TNFɑ (p < 0.05) were elevated. Histopathological examination revealed substantial cardiac changes, including Fibrinogen and fat deposition and eosinophilic infiltration, as well as liver damage characterized by binucleated cells and damaged hepatocytes, along with altered renal tissues in the DOX.MET.Control group. The findings suggest that MET. significantly modifies gut microbiota, particularly impacting the Firmicutes and Proteobacteria phyla. The reduction in Angiotensin II levels, alongside increased inflammatory markers and myocardial damage, highlights the complex interactions and potential adverse effects associated with MET therapy on cardiovascular health.

Mitigating target interference challenges in bridging immunogenicity assay to detect anti-tocilizumab antibodies.

Aim: An assay to detect anti-tocilizumab antibodies in the presence of high levels of circulating target and drug is needed for immunogenicity assessment in comparative clinical studies.Methods: An assay was developed and validated using a combination of blocking agents and dilutions to overcome target interference challenges.Results: No false-positive signal was detected in serum samples spiked with 350-500 ng/ml of IL-6 receptor. As low as 50 ng/ml of positive control antibodies could be detected in the presence of either 500 ng/ml of IL-6 or 250 µg/ml of the drug product. Assay also demonstrated high sensitivity, selectivity and precision.Conclusion: A robust, easy to perform immunogenicity assay was developed and validated for detecting anti-tocilizumab antibodies.

[Box: see text].

Valorization of corn silk through incorporation in instant mix and analyzing its shelf life by kinetic modelling.

Corn silk (Zea mays L.), an abundant agricultural waste, contains various bioactive compounds that exhibit promising health benefits. The current study focuses on development and optimization of corn silk-based instant mix using response surface methodology. The optimized product, with 14.66% corn silk, 10% sugar and 0.22% xanthan gum in a skim milk powder base, scored 0.925 desirability. The physico-chemical and sensory parameters of optimized mix closely aligned with expected values. The instant mix packaged in metallised polyester yielded superior preservation of quality indicators over 120 days compared to low-density polyethylene (LDPE) and high-density polyethylene (HDPE). The microbial load in corn silk instant mix was observed across packaging materials and highlighting hydroxyl methyl furfural (HMF) as the primary predictor of product stability, the study calculated a 94.95 days half-life at 10 °C. Corn silk's rich bioactive compound supports its integration into nutraceuticals and instant mixes, mitigating food waste while enhancing nutritional value. Novelty statement. In this study, corn silk powder was utilized for the development of the instant mix. This innovative approach transforms corn silk, typically discarded as agricultural waste, into a commercially sustainable product that delivers the nutrients of corn silk to a broader population. Despite fresh corn silk being a perishable commodity, it has very low storage shelf life. The developed instant mix effectively preserves its nutritional value for up to six months, offering a sustainable and nutritious option for consumers.

Discovery of Novel Allosteric SHP2 Inhibitor Using Pharmacophore-Based Virtual Screening, Molecular Docking, Molecular Dynamics Simulation, and Principal Component Analysis.

SHP2 belongs to a cytoplasmic non-receptor protein tyrosine phosphatase class. It plays a critical role in the development of various cancers, such as gastric cancer, leukemia, and breast cancer. Thus, SHP2 has gained the interest of researchers as a potential target for inhibiting tumor cell proliferation in SHP2-dependent cancers. This study employed pharmacophore-based virtual screening, molecular docking, molecular dynamic (MD) simulations, MM/PBSA, and principal component analysis (PCA), followed by ADME prediction. We selected three potential hits from a collective database of more than one million chemical compounds. The stability of these selected hit-protein complexes was analyzed using 500 ns MD simulations and binding free energy calculations. The identified hits Lig_1, Lig_6, and Lig_14 demonstrated binding free energies of -161.49 kJ/mol, -151.28 kJ/mol, and -107.13 kJ/mol, respectively, compared to the reference molecule (SHP099) with a ΔG of -71.48 kJ/mol. Our results showed that the identified compounds could be used as promising candidates for selective SHP2 allosteric inhibition in cancer.

Chemoenzymatic Modification of Daptomycin: Aromatic Group Installation on Trp1.

Daptomycin is a cyclic lipodepsipeptide antibiotic used to treat infections caused by Gram-positive pathogens, including multi-drug resistant strains such as methicillin-resistant Staphylococcus au-reus (MRSA) and vancomycin-resistant enterococci (VRE). The emergence of daptomycin-resistant bacterial strains has renewed interest in generating daptomycin analogs. Previous studies have shown that replacing the tryptophan of daptomycin with aromatic groups can generate analogs with enhanced potency. Additionally, we have demonstrated that aromatic prenyltransferases can attach diverse groups to the tryptophan of daptomycin. Here, we report the use of the prenyltransferase CdpNPT to derivatize the tryptophan of daptomycin with a library of benzylic and heterocyclic pyrophosphates. An analytical-scale study revealed that CdpNPT can transfer various aromatic groups onto daptomycin. Subsequent scaled-up and purified reactions indicated that the enzyme can attach aromatic groups to N1, C2, C5 and C6 positions of Trp1 of daptomycin. In vitro antibacterial activity assays using six of these purified compounds identified aromatic substituted daptomycin analogs show potency against both daptomycin-susceptible and resistant strains of Gram-positive bacteria. These findings suggest that installing aromatic groups on the Trp1 of daptomycin can lead to the generation of potent daptomycin analogs.

Trends in Serum Shifts: Unveiling Hyperglycaemia Links PostCOVID-19 Vaccination.

BACKGROUND: Clinical endocrinology has observed emerging endocrine complications following COVID-19 vaccination, amidst successful reductions in COVID-19 hospitalizations and deaths. The Pfizer-BioNTech and Moderna mRNA vaccines have demonstrated efficacy. Reports indicate a potential association between SARS-CoV-2 vaccination and diabetes, exploring interactions with ACE-2 receptors and molecular mimicry. Additionally, altered liver and kidney function tests post-vaccination prompt investigation into their role in predicting type 2 diabetes. This study aims to explore these biochemical abnormalities in a case-control, single-centre prospective study. MATERIALS AND METHODS: This prospective study aimed to evaluate a total of five hundred healthy donors, out of which 203 qualified for final analysis. Participants were selected based on their vaccination status with a COVID-19 vaccine and prior exposure to the SARS-CoV-2 virus. Donors without prior SARS-CoV-2 infection were excluded from the study. Included participants were adults who had received three doses of the COVID-19 vaccine. RESULTS: A total of 203 individuals were included in the study, comprising 104 with type 2 diabetes mellitus (T2DM) and 99 without. Demographic characteristics including age, sex, nationality, Rh factors, ABO blood groups, liver function tests (LFT), kidney function tests (KFT), lactate dehydrogenase (LDH), and mineral ion levels were analysed. Among the participants, the distribution based on HbA1c levels showed 47.8% with HbA1c <7% classified as normal, 38.48% with HbA1c 8-10% classified as high, and 16.64% with HbA1c <10% classified as uncontrolled diabetes. Significant findings included a decrease in magnesium levels to 0.77±0.82 mmol/L (p<0.04*), an increase in LDH levels to 420.70±356.26 µL (p<0.01*), and elevated levels of alkaline phosphatase (143.22 ± 142.62 µL, p<0.001), gamma-glutamyl transferase (GGT) (55.70 ± 32.20 µL, p<0.001), and serum bilirubin (9.23 ± 4.87 µmol/L, p<0.001). Creatinine levels were significantly lower at 116.75 ± 101.94 µmol/L (p#60;0.001), while uric acid levels were significantly elevated at 305.92 ± 145.04 µmol/L (p<0.001) in individuals with uncontrolled HbA1c <10%. A majority of these individuals belonged to the O+ blood group. CONCLUSION: This study underscores significant shifts in serum biomarkers and their complex interplay with mRNA-based SARS-CoV-2 vaccination and diabetes, particularly in uncontrolled cases. The findings suggest potential autoimmune reactions triggered by the self-adjuvant properties of mRNA and polyethylene glycol lipid conjugates. Variations observed among different blood groups may correspond to racial disparities influencing molecular mimicry mechanisms. Despite these insights, the underlying pathophysiological mechanisms remain unclear, highlighting the critical need for further research to validate and expand upon these findings.

Study of risk factors and clinical management of patients with clinical non-response due to low plasma levels of anti-tubercular drugs.

This study was carried out to assess the role of therapeutic drug monitoring of crucial first-line anti-tubercular drugs: rifampicin (R) and isoniazid (H) among 75 non-responding proven drug-sensitive tuberculosis patients on treatment followed by intervention in field conditions. The intervention was done in the form of either an increase in the dosage of R and H in patients with minimally low drug levels or a modification of the regimen in a certain group of patients with significantly low drug levels by augmenting it with three or four second-line drugs in addition to standard first-line drugs. This study also aimed to determine the relationship between the measured plasma concentration of anti-tubercular drugs and various demographic, microbiological, radiological, and malabsorption factors and the presence of co-morbidities affecting them. The study also focused on the clinical impact of the intervention for low plasma levels of anti-TB drugs on TB treatment outcomes. In our study overall, 85.5% of patients had low levels of any drug. In 85.3% of patients, R levels were low, and in 39.1%, H levels were low. On univariate analysis, low body mass index (BMI), hypoalbuminemia, bilateral disease on chest X-rays, and the presence of cavities were found to be significantly associated with low drug levels, while none of the factors were independently significantly associated. Low BMI, pulmonary tuberculosis and disseminated tuberculosis, far-advanced disease and bilateral disease on chest X-ray, presence of cavities, and only low R levels were associated with unfavorable outcomes, with none of the factors found to be significant on multivariate analysis. In our study, it was seen that the treatment outcome was favorable in 59.6% of patients in whom this intervention was done by augmenting the treatment regimen with three/four second-line drugs along with increasing the dose of R and H. To conclude, various factors may be associated with low plasma levels of anti-tubercular drugs. If such patients show clinical non-response after >6 months of treatment and have significantly low drug levels, with an absence of drug resistance, their treatment regimen may need augmentation with three/four second-line drugs along with an increase in the dose of R and H, which may lead to a favorable outcome.