Biodegradation of PVCs through in-vitro identification of Bacillus albus and computational pathway analysis of ABH enzyme.

Microplastics pose significant challenges to ecosystems and organisms. They can be ingested by marine and terrestrial species, leading to potential health risks and ecological disruptions. This study aims to address the urgent need for effective remediation strategies by focusing on the biodegradation of microplastics, specifically polyvinyl chloride (PVC) derivatives, using the bacterial strain Bacillus albus. The study provides a comprehensive background on the accumulation of noxious substances in the environment and the importance of harnessing biodegradation as an eco-friendly method for pollutant elimination. The specific objective is to investigate the enzymatic capabilities of Bacillus albus, particularly the alpha/beta hydrolases (ABH), in degrading microplastics. To achieve this, in-silico studies were conducted, including analysis of the ABH protein sequence and its interaction with potential inhibitors targeting PVC derivatives. Docking scores of - 7.2 kcal/mol were obtained to evaluate the efficacy of the interactions. The study demonstrates the promising bioremediation prospects of Bacillus albus for microplastics, highlighting its potential as a key player in addressing microplastic pollution. The findings underscore the urgent need for further experimental validation and practical implementation of Bacillus albus in environmental remediation strategies.

Statistical design and optimization of nano-transfersomes based chitosan gel for transdermal delivery of cefepime.

OBJECTIVES: This research aimed to overcome challenges posed by cefepime excessive elimination rate and poor patient compliance by developing transdermal delivery system using nano-transfersomes based chitosan gel. METHODS: Rotary evaporation-sonication method and the Box-Behnken model were used to prepare cefepime loaded nano-transfersomes (CPE-NTFs). The physiochemical characterization of CPE-NTFs were analyzed including DLS, deformability index, DSC and antimicrobial study. Optimized CPE-NTFs loaded into chitosan gel and appropriately characterized. In vitro release, ex vivo and in vivo studies were performed. RESULTS: The CPE-NTFs were physically stable with particle size 222.6 ± 1.8 nm, polydispersity index 0.163 ± 0.02, zeta potential -20.8 ± 0.1 mv, entrapment efficiency 81.4 ± 1.1% and deformability index 71 ± 0.2. DSC analysis confirmed successful drug loading and thermal stability. FTIR analysis showed no chemical interaction among the excipients of CPE-NTFs gel. The antibacterial activity demonstrated a remarkable reduction in the minimum inhibitory concentration of cefepime when incorporated into nano-transfersomes. CPE-NTFs based chitosan gel (CPE-NTFs gel) showed significant physicochemical properties. In vitro release studies exhibited sustained release behavior over 24 h, and ex vivo studies indicated enhanced permeation and retention compared to conventional cefepime gel. In vivo skin irritation studies confirmed CPE-NTFs gel was nonirritating and biocompatible for transdermal delivery. CONCLUSION: This research showed nano-transfersomes based chitosan gel is a promising approach for cefepime transdermal delivery and provides sustained release of cefepime.

Role of diosmin in preventing doxorubicin-induced cardiac oxidative stress, inflammation, and hypertrophy: A mechanistic approach.

Chemotherapeutic drugs, such as doxorubicin (Dox), are commonly used to treat a variety of malignancies. However, Dox-induced cardiotoxicity limits the drug's clinical applications. Hence, this study intended to investigate whether diosmin could prevent or limit Dox-induced cardiotoxicity in an animal setting. Thirty-two rats were separated into four distinct groups of controls, those treated with Dox (20 mg/kg, intraperitoneal, i.p.), those treated with diosmin 100 mg plus Dox, and those treated with diosmin 200 mg plus Dox. At the end of the experiment, rats were anesthetized and sacrificed and their blood and hearts were collected. Cardiac toxicity markers were analyzed in the blood, and the heart tissue was analyzed by the biochemical assays MDA, GSH, and CAT, western blot analysis (NF-kB, IL-6, TLR-4, TNF-α, iNOS, and COX-2), and gene expression analysis (ß-MHC, BNP). Formalin-fixed tissue was used for histopathological studies. We demonstrated that a Dox insult resulted in increased oxidative stress, inflammation, and hypertrophy as shown by increased MDA levels and reduced GSH content and CAT activity. Furthermore, Dox treatment induced cardiac hypertrophy and damage, as evidenced by the biochemical analysis, ELISA, western blot analysis, and gene expression analysis. However, co-administration of diosmin at both doses, 100 mg and 200 mg, mitigated these alterations. Data derived from the current research revealed that the cardioprotective effect of diosmin was likely due to its ability to mitigate oxidative stress and inflammation. However, further study is required to investigate the protective effects of diosmin against Dox-induced cardiotoxicity.

Anti-oxidant and anti-inflammatory potential of different polymer-based mesalamine delayed-release granules in TNBS-induced ulcerative colitis in wistar rats.

Ulcerative colitis (UC) is an inflammatory condition of colon characterized by severe damage to the innermost colon tissues. A number of studies described the use of medication delivery systems based on natural polymers like polysaccharides for the purpose of reaching the colon. In this research, polymer-based mesalamine delayed-release granules (DRGs) were tested for their antioxidant and anti-inflammatory efficacy against UC. Chitosan (C), pectin (P), and pectin-chitosan (PC) mesalamine (M) DRGs were prepared and characterized. Data revealed satisfactory compatibility, flow, packing properties, drug release pattern, and delayed drug release by DRGs. Wistar rats were treated with 2,4,6-trinitrobenzenesulfonic acid (TNBS) (100 mg/kg) via rectal administration. Mesalamine and mesalamine DRGs (50 mg/kg) were administered orally separately for 14 days. Biomarkers of oxidative stress, inflammation, hematological tests, colon profile, and histopathology were performed. The findings demonstrated the good efficacy of the polysaccharides in delivering mesalamine to colon. Mesalamine and mesalamine DRGs based on various polymers showed significant antioxidant and anti-inflammatory effects in rats with UC. Mesalamine granules significantly attenuated colon lipid peroxidation, nitrites, myeloperoxidase activity, and interleukin-1ß levels, and improved anti-oxidants (GSH, SOD). Data showed upregulation of Nrf2 activity by mesalamine granules with CM-DRGs showing maximum effect. Mesalamine and different polymer-based mesalamine DRGs significantly attenuated TNBS-induced decline in body weight, ulcer severity, and colon damage. CM-DRGs showed the most pronounced ameliorative effect on colon and hematology parameters via anti-oxidant and anti-inflammatory activities. Chitosan can be used as a carrier for oral colon delivery of mesalamine in DRG formulation for enhanced therapeutic efficacy in UC.

Synthesis, Antioxidant, Molecular Docking and DNA Interaction Studies of Metal-Based Imine Derivatives.

Currently, numerous ongoing studies are investigating the interaction of free radicals with biological systems, such as lipids, DNA and protein. In the present work, synthesis, characterization, antioxidant, DNA binding and molecular docking studies of Schiff base ligand and its Ni(II), Co(II), Cu(II) and Zn(II) were evaluated. The metal complexes have shown significant dose-dependent antioxidant activities higher than those of the free ligand but lesser than those of the standard antioxidant, ascorbic acid. The DNA binding constants (Kb) were found in the order Zn(pimp)2 {9.118 × 105 M-1} > H-pimp {3.487 × 105 M-1} > Co(pimp)2 {3.090 × 105 M-1} > Ni(pimp)2 {1.858 × 105 M-1} > Cu(pimp)2 {1.367 × 105 M-1}. Binding constants (Kb) values calculated from the molecular docking analysis were found to be in close agreement with the experimental results. The obtained results indicate the importance of synthesis complexes as a source of synthetic antioxidants and anticancer drugs.

Biosynthesis and Mathematical Interpretation of Zero-Valent Iron NPs Using Nigella sativa Seed Tincture for Indemnification of Carcinogenic Metals Present in Industrial Effluents.

Zero-valent iron nanoparticles (ZVI-NPs) are utilized for the indemnification of a wide range of environmental pollutants. Among the pollutants, heavy metal contamination is the major environmental concern due to their increasing prevalence and durability. In this study, heavy metal remediation capabilities are determined by the green synthesis of ZVI-NPs using aqueous seed extract of Nigella sativa which is a convenient, environmentally friendly, efficient, and cost-effective technique. The seed extract of Nigella sativa was utilized as a capping and reducing agent for the generation of ZVI-NPs. UV-visible spectrophotometry (UV-vis), scanning electron microscopy coupled with energy-dispersive X-ray spectroscopy (SEM-EDX), and Fourier transform infrared spectroscopy (FTIR) was used to investigate the ZVI-NP composition, shape, elemental constitution, and perspective functional groups, respectively. The biosynthesized ZVI-NPs displayed a peak of plasmon resonance spectra at 340 nm. The synthesized NPs were cylindrical in shape, with a size of 2 nm and (-OH) hydroxyl, (C-H) alkanes and alkynes N-C, N=C, C-O, =CH functional groups attached to the surface of ZVI-NPs. Heavy metals were successfully remediated from industrial wastewater collected from the various tanneries of Kasur. During the reaction duration of 24 h, different concentrations of ZVI-NPs (10 µg, 20 µg and 30 µg) per 100 mL were utilized for the removal of heavy metals from industrial wastewater. The 30 µg/100 mL of ZVI-NPs proved the pre-eminent concentration of NPs as it removed >90% of heavy metals. The synthesized ZVI-NPs were analyzed for compatibility with the biological system resulting in 87.7% free radical scavenging, 96.16% inhibition of protein denaturation, 60.29% and 46.13% anti-cancerism against U87-MG and HEK 293 cell lines, respectively. The physiochemical and exposure mathematical models of ZVI-NPs represented them as stable and ecofriendly NPs. It proved that biologically synthesized NPs from a seed tincture of Nigella sativa have a strong potential to indemnify heavy metals found in industrial effluent samples.

Quorum Quenchers from Reynoutria japonica in the Battle against Methicillin-Resistant Staphylococcus aureus (MRSA).

Over the past decade, methicillin-resistant Staphylococcus aureus (MRSA) has become a major source of biofilm formation and a major contributor to antimicrobial resistance. The genes that govern biofilm formation are regulated by a signaling mechanism called the quorum-sensing system. There is a need for new molecules to treat the infections caused by dangerous pathogens like MRSA. The current study focused on an alternative approach using juglone derivatives from Reynoutria japonica as quorum quenchers. Ten bioactive compounds from this plant, i.e., 2-methoxy-6-acetyl-7-methyljuglone, emodin, emodin 8-o-b glucoside, polydatin, resveratrol, physcion, citreorosein, quercetin, hyperoside, and coumarin were taken as ligands and docked with accessory gene regulator proteins A, B, and C and the signal transduction protein TRAP. The best ligand was selected based on docking score, ADMET properties, and the Lipinski rule. Considering all these parameters, resveratrol displayed all required drug-like properties with a docking score of -8.9 against accessory gene regulator protein C. To further assess the effectiveness of resveratrol, it was compared with the commercially available antibiotic drug penicillin. A comparison of all drug-like characteristics showed that resveratrol was superior to penicillin in many aspects. Penicillin showed a binding affinity of -6.7 while resveratrol had a score of -8.9 during docking. This was followed by molecular dynamic simulations wherein inhibitors in complexes with target proteins showed stability inside the active site during the 100 ns simulations. Structural changes due to ligand movement inside the cavity were measured in the protein targets, but they remained static due to hydrogen bonds. The results showed acceptable pharmacokinetic properties for resveratrol as compared to penicillin. Thus, we concluded that resveratrol has protective effects against Staphylococcus aureus infections and that it suppresses the quorum-sensing ability of this bacterium by targeting its infectious proteins.

Evaluation of Antimicrobial, Anticholinesterase Potential of Indole Derivatives and Unexpectedly Synthesized Novel Benzodiazine: Characterization, DFT and Hirshfeld Charge Analysis.

The pharmacological effectiveness of indoles, benzoxazepines and benzodiazepines initiated our synthesis of indole fused benoxazepine/benzodiazepine heterocycles, along with enhanced biological usefulness of the fused rings. Activated indoles 5, 6 and 7 were synthesized using modified Bischler indole synthesis rearrangement. Indole 5 was substituted with the trichloroacetyl group at the C7 position, yielding 8, exclusively due to the increased nucleophilic character of C7. When trichloroacylated indole 8 was treated with basified ethanol or excess amminia, indole acid 9 and amide 10 were yielded, respectively. Indole amide 10 was expected to give indole fused benoxazepine/benzodiazepine 11a/11b on treatment with alpha halo ester followed by a coupling agent, but when the reaction was tried, an unexpectedly rearranged novel product, 1,3-bezodiazine 12, was obtained. The synthetic compounds were screened for anticholinesterase and antibacterial potential; results showed all products to be very important candidates for both activities, and their potential can be explored further. In addition, 1,3-bezodiazine 12 was explored by DFT studies, Hirshfeld surface charge analysis and structural insight to obrain a good picture of the structure and reactivity of the products for the design of derivatised drugs from the novel compound.

Purification of Galacto-oligosaccharide (GOS) by fermentation with Kluyveromyces lactis and Interaction between GOS and casein under simulated acidic fermentation conditions.

In the enzymatic synthesis of galacto-oligosaccharide (GOS), the primary by-products include glucose, galactose and unreacted lactose. This This study was aimed to provide a method to to purify GOS by yeat fermentation and explore the interaction between GOS and CAS with a view for expanding the prospects of GOS application in the food industry. The crude GOS(25.70 g/L) was purified in this study using the fermentation method with Kluyveromyces lactis CICC 1773. Optimal conditions for purification with the yeast were 75 g/L of the yeast inoculation rate and 50 g/L of the initial crude GOS concentration for 12 h of incubation. After removing ethanol produced by yeast by low-temperature distillation, GOS content could reach 90.17%. A study of the interaction between GOS and casein (CAS) in a simulated acidic fermentation system by D-(+)-gluconic acid δ-lactone (GDL) showed that the GOS/CAS complexes with higher GOS concentrations, e.g., 4% and 6% (w/v), was more viscoelastic with higher water-holding capacity, but decreased hardness, elasticity, and cohesiveness at 6% (w/v) of GOS. The addition of GOS to CAS suspension significantly caused (p<0.05) decreased particle sizes of the formed GOS/CAS complexes, and the suspension system became more stable. FT-IR spectra confirmed the existence of different forms of molecular interactions between CAS and GOS, e.g., hydrogen bonding and hydrophobic interaction, and the change of secondary structure after CAS binding to GOS.

Development and optimization of film forming non-pressurized liquid bandage for wound healing by Box-Behnken statistical design.

The goal of the current investigation was to develop a non-pressurized liquid bandage to promote the healing of wounds by using silver sulfadiazine. A three-factor three level box-behnken statistical design was employed to optimize the drug-loaded liquid bandage. Film-forming liquid bandage was developed by using ethyl-cellulose, dibutyl sebacate, and glycerol. For optimization, ethyl cellulose, dibutyl sebacate, and isopropyl myristate were taken as independent variables while tensile strength, water vapor absorption value, and drying time were taken as dependent variables. The film-forming liquid bandage was evaluated for various parameters like tensile strength, water vapor absorption value, drying time, viscosity, pH, in-vitro drug release studies, in-vivo wound healing studies, and stability studies. The optimized formulation was found with the tensile strength of 68.24 ± 0.24 MPa, water vapor absorption value of 2.00 ± 0.25 %, drying time of 1.75 ± 0.14 min, viscosity of 60 ± 0.5 cPs, pH of 6.0 ± 0.5 and good physicochemical properties with satisfactory film-forming ability. The in-vitro study shows that the release of test formulations was better than the marketed formulation. After 6 h of study, the liquid bandage and marketed formulation showed 41.02 % and 29.32 % of drug release respectively. Significant results were obtained for the in-vivo wound healing studies. Upon comparison with the control group (2.61 mm) and marketed formulation (1.44 mm), rats treated with the optimized formulation exhibited a noticeable improvement in wound contraction (0.8 mm). The liquid bandage after three months of stability testing was found to be stable with optimum. The film-forming liquid bandage was found to be an effective alternative to conventional topical preparations as it develops a thin polymeric layer on the wound and the skin around it and improves comfort for the patient by protecting the wound from external factors and physical harm.

Synthesis, molecular structure and urease inhibitory activity of novel bis-Schiff bases of benzyl phenyl ketone: A combined theoretical and experimental approach.

Background: Urease belongs to the family of amid hydrolases with two nickel atoms in their core structure. On the basis of literature survey, this research work is mainly focused on the study of bis-Schiff base derivatives of benzyl phenyl ketone nucleus. Objective: Synthesis of benzyl phenyl ketone based bis-Schiff bases in search of potent urease inhibitors. Method: In the current work, bis-Schiff bases were synthesized through two steps reaction by reacting benzyl phenyl ketone with excess of hydrazine hydrate in ethanol solvent in the first step to get the desired hydrazone. In last, different substituted aromatic aldehydes were refluxed in catalytic amount of acetic acid with the desired hydrazone to obtain bis-Schiff base derivatives in tremendous yields. Using various spectroscopic techniques including FTIR, HR-ESI-MS, and 1H NMR spectroscopy were used to clarify the structures of the created bis-Schiff base derivatives. Results: The prepared compounds were finally screened for their in-vitro urease inhibition activity. All the synthesized derivatives (3-9) showed excellent to less inhibitory activity when compared with standard thiourea (IC50 = 21.15 ± 0.32 µM). Compounds 3 (IC50 = 22.21 ± 0.42 µM), 4 (IC50 = 26.11 ± 0.22 µM) and 6 (IC50 = 28.11 ± 0.22 µM) were found the most active urease inhibitors near to standard thiourea among the synthesized series. Similarly, compound 5 having IC50 value of 34.32 ± 0.65 µM showed significant inhibitory activity against urease enzyme. Furthermore, three compounds 7, 8, and 9 exhibited less activity with IC50 values of 45.91 ± 0.14, 47.91 ± 0.14, and 48.33 ± 0.72 µM respectively. DFT used to calculate frontier molecular orbitals including; HOMO and LUMO to indicate the charge transfer from molecule to biological transfer, and MEP map to indicate the chemically reactive zone suitable for drug action. The electron localization function (ELF), non-bonding orbitals, AIM charges are also calculated. The docking study contributed to the analysis of urease protein binding.

Exploring the synthesis, structure, spectroscopy and biological activities of novel 4-benzylidene-1-(2-(2,4-dichloro phenyl)acetyl) thiosemicarbazide derivatives: An integrated experimental and theoretical investigation.

Background: Novel α-amylase inhibitors play a crucial role in managing diabetes and obesity, contributing to improved public health by addressing these challenging and prevalent conditions. Moreover, the synthesis of anti-oxidant agents is essential due to their potential in combating oxidative stress-related diseases and promoting overall health. Objective: Synthesis of thoisemicarbazone derivatives of 2,4-dichlorophenyl acetic acid and to screened them for their biological activities. Method: Thiosemicarbazone derivatives (4-13) were synthesized by refluxing 2,4-dichlorophenyl acetic acid with sulfuric acid in ethanol to get the ester (2), which was further refluxed with thiosemicarbazide to get compound (3). Finally, different aromatic aldehydes were refluxed with compound (3) in ethanol in catalytic amount of acetic acid to obtained the final products (4-13). Using modern spectroscopic techniques including HR-ESI-MS, 13C-, and 1H NMR, the structures of the created derivatives were confirmed. Results: The synthesized derivatives showed excellent to good inhibitory activity in the range of IC50 values of 4.95 ± 0.44 to 69.71 ± 0.05 µM against α-amylase enzyme when compared to standard drug acarbose (IC50 = 21.55 ± 1.31 µM). In case of iron chelating activity, these products showed potent activity better than standard EDTA (IC50 = 66.43 ± 1.07 µM) in the range of IC50 values of 22.43 ± 2.09 to 61.21 ± 2.83 µM. However, the obtained products also show excellent to good activity in the range of IC50 values of 28.30 ± 1.17 to 64.66 ± 2.43 µM against hydroxyl radical scavenging activity when compared with standard vitamin C (IC50 = 60.51 ± 1.02 µM). DFT used to calculate different reactivity factors including ionization potential, electronegativity, electron affinity, chemical softness, and chemical hardness were calculated using frontier molecular orbital (FMO) computations. The molecular docking studies for the synthesized derivatives with α-amylase were carried out using the AutoDock Vina to understand the binding affinities with active sites of the protein.

Genotoxicity and cytotoxicity potential of organoselenium compounds in human leukocytes in vitro.

In the current work, cytotoxicity and genotoxicity of different organoselenium compounds were examined using Trypan blue exclusion and alkaline comet assays with silver staining respectively. Leukocytes were subjected to a 3-hour incubation with organoselenium compounds at concentrations of 1, 5, 10, 25, 50, and 75 µM, or with the control vehicle (DMSO), at a temperature of 37 °C. The viability of the cells was evaluated using the Trypan blue exclusion method, while DNA damage was analyzed through the alkaline comet assay with silver staining. The exposure of leukocytes to different organoselenium compounds including i.e. (Z)-N-(pyridin-2-ylmethylene)-1-(2-((2-(1-((E)-pyridin-2-ylmethyleneamino)ethyl)phenyl)diselanyl)phenyl)ethanamine (C1), 2,2'(1Z,1'E)-(1,1'-(2,2'-diselanediylbis(2,1-phenylene))bis(ethane-1,1-diyl)) bis(azan-1-yl-1-ylidene)bis -methan-1-yl-1-ylidene)diphenol (C2), and dinaphthyl diselenide (NapSe)2, At concentrations ranging from 1 to 5 µM, no significant DNA damage was observed, as indicated by the absence of a noteworthy increase in the Damage Index (DI). Our results suggest that the organoselenium selenium compounds tested were not genotoxic and cytotoxic to human leukocytes in vitro at lower concentration. This study offers further insights into the genotoxicity profile of these organochalcogens in human leukocytes. Their genotoxicity and cytotoxicity effects at higher concentration are probably mediated through reactive oxygen species generation and their ability to catalyze thiol oxidation.

Phyllanthus emblica (Amla) methanolic extract regulates multiple checkpoints in 15-lipoxygenase mediated inflammopathies: Computational simulation and in vitro evidence.

Amla (Phyllanthus emblica) has long been used in traditional folk medicine to prevent and cure a variety of inflammatory diseases. In this study, the antioxidant activity (DPPH scavenging and reducing power), anti-inflammatory activity (RBC Membrane Stabilization and 15-LOX inhibition), and anticoagulation activity (Serin protease inhibition and Prothrombin Time assays) of the methanolic extract of amla were conducted. Amla exhibited a substantial amount of phenolic content (TPC: 663.53 mg GAE/g) and flavonoid content (TFC: 418.89 mg GAE/g). A strong DPPH scavenging effect was observed with an IC50 of 311.31 µg/ml as compared to standard ascorbic acid with an IC50 of 130.53 µg/ml. In reducing power assay, the EC50 value of the extract was found to be 196.20 µg/ml compared to standard ascorbic acid (EC50 = 33.83 µg/ml). The IC50 value of the RBC membrane stabilization and 15-LOX assays was observed as 101.08 µg/ml (IC50 of 58.62 µg/ml for standard aspirin) and 195.98 µg/ml (IC50 of 19.62 µg/ml for standard quercetin), respectively. The extract also strongly inhibited serine protease (trypsin) activity with an IC50 of 505.81 µg/ml (IC50 of 295.44 µg/ml for standard quercetin). The blood coagulation time (PTT) was found to be 11.91 min for amla extract and 24.11 min for standard Warfarin. Thus, the findings of an in vitro study revealed that the methanolic extract of amla contains significant antioxidant, anti-inflammatory, and anticoagulation activity. Furthermore, in silico docking and simulation of reported phytochemicals of amla with human 15-LOXA and 15-LOXB were carried out to validate the anti-inflammatory activity of amla. In this analysis, epicatechin and catechin showed greater molecular interaction and were considerably stable throughout the 100 ns simulation with 15-lipoxygenase A (15-LOXA) and 15-lipoxygenase B (15-LOXB) respectively.

Lck signaling inhibition causes improvement in clinical features of psoriatic inflammation through reduction in inflammatory cytokines in CD4+ T cells in imiquimod mouse model.

Psoriasis is a chronic dermal inflammatory disease with a world-wide prevalence in which different immune/non-immune cells, e.g. T cells, macrophages, neutrophils, and keratinocytes play a decisive role. These immune cells interact among themselves by releasing multiple mediators which eventually cause characteristic psoriatic plaques in the skin. T cells are reported to be significant contributors to psoriatic inflammation through release of multiple cytokines which are controlled by several kinases, one of them being Lymphocyte-specific protein tyrosine kinase (Lck). Lck has been reported to be crucial for expression/production of several key inflammatory cytokines though modulation of several other kinases/transcription factors in T cells. Therefore, in this investigation, effect of Lck inhibitor, A-770041 was examined on PLCγ, p38MAPK, NFATc1, NFkB and STAT3, TNF-α, IFN-γ, Foxp3, IL-17A, in CD4+ T cells in imiquimod (IMQ)-induced psoriatic inflammation in mice. Results from the present study exhibit that p-Lck expression is enhanced in CD4+ T cells of IMQ-treated mice which is concomitant with enhanced clinical features of psoriatic inflammation (ear/back skin thickness, MPO activity, acanthosis/leukocytic infiltration) and molecular parameters (enhanced expression of p-Lck, p-PLCγ, p-p38-MAPK, NFATc1, p-NFkB, TNF-α, IFN-γ, p-STAT3, and IL-17A in CD4+ T cells). Inhibition of Lck signaling led to amelioration of clinical features of psoriasis through attenuation of Th1/Th17 immune responses and upregulation of Treg cells in IMQ-treated mice. In summary, current investigations reveal that Lck signaling is a crucial executor of inflammatory signaling in CD4+ T cells in the context of psoriatic inflammation. Therefore, Lck inhibition may be pursued as an effective strategy to counteract psoriatic inflammation.

Venetoclax Induces Cardiotoxicity through Modulation of Oxidative-Stress-Mediated Cardiac Inflammation and Apoptosis via NF-κB and BCL-2 Pathway.

Cardiovascular damage induced by anticancer therapy has become the main health problem after tumor elimination. Venetoclax (VTX) is a promising novel agent that has been proven to have a high efficacy in multiple hematological diseases, especially acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL). Considering its mechanism of action, the possibility that VTX may cause cardiotoxicity cannot be ruled out. Therefore, this study was designed to investigate the toxic effect of VTX on the heart. Male Sprague-Dawley rats were randomly divided into three groups: control, low-dose VTX (50 mg/kg via oral gavage), and high-dose VTX (100 mg/kg via oral gavage). After 21 days, blood and tissue samples were collected for histopathological, biochemical, gene, and protein analyses. We demonstrated that VTX treatment resulted in cardiac damages as evidenced by major changes in histopathology and markedly elevated cardiac enzymes and hypertrophic genes markers. Moreover, we observed a drastic increase in oxidative stress, as well as inflammatory and apoptotic markers, with a remarkable decline in the levels of Bcl-2. To the best of our knowledge, this study is the first to report the cardiotoxic effect of VTX. Further experiments and future studies are strongly needed to comprehensively understand the cardiotoxic effect of VTX.

Guggulsterone Mediated JAK/STAT and PPAR-Gamma Modulation Prevents Neurobehavioral and Neurochemical Abnormalities in Propionic Acid-Induced Experimental Model of Autism.

Autism spectrum disorder is a neurodevelopmental disorder marked by repetitive behaviour, challenges in verbal and non-verbal communication, poor socio-emotional health, and cognitive impairment. An increased level of signal transducer and activator of transcription 3 (STAT3) and a decreased level of peroxisome proliferator-activated receptor (PPAR) gamma have been linked to autism pathogenesis. Guggulsterone (GST) has a neuroprotective effect on autistic conditions by modulating these signalling pathways. Consequently, the primary objective of this study was to examine potential neuroprotective properties of GST by modulating JAK/STAT and PPAR-gamma levels in intracerebroventricular propionic acid (ICV PPA) induced experimental model of autism in adult rats. In this study, the first 11 days of ICV-PPA injections in rats resulted in autism-like behavioural, neurochemical, morphological, and histopathological changes. The above modifications were also observed in various biological samples, including brain homogenate, CSF, and blood plasma. GST was also observed to improve autism-like behavioural impairments in autistic rats treated with PPA, including locomotion, neuromuscular coordination, depression-like behaviour, spatial memory, cognition, and body weight. Prolonged GST treatment also restored neurochemical deficits in a dose-dependent manner. Chronic PPA administration increased STAT3 and decreased PPAR gamma in autistic rat brain, CSF, and blood plasma samples, which were reversed by GST. GST also restored the gross and histopathological alterations in PPA-treated rat brains. Our results indicate the neuroprotective effects of GST in preventing autism-related behavioural and neurochemical alterations.

Activation of IGF-1/GLP-1 Signalling via 4-Hydroxyisoleucine Prevents Motor Neuron Impairments in Experimental ALS-Rats Exposed to Methylmercury-Induced Neurotoxicity.

Amyotrophic lateral sclerosis (ALS) is a severe adult motor neuron disease that causes progressive neuromuscular atrophy, muscle wasting, weakness, and depressive-like symptoms. Our previous research suggests that mercury levels are directly associated with ALS progression. MeHg+-induced ALS is characterised by oligodendrocyte destruction, myelin basic protein (MBP) depletion, and white matter degeneration, leading to demyelination and motor neuron death. The selection of MeHg+ as a potential neurotoxicant is based on our evidence that it has been connected to the development of ALS-like characteristics. It causes glutamate-mediated excitotoxicity, calcium-dependent neurotoxicity, and an ALS-like phenotype. Dysregulation of IGF-1/GLP-1 signalling has been associated with ALS progression. The bioactive amino acid 4-hydroxyisoleucine (HI) from Trigonella foenum graecum acts as an insulin mimic in rodents and increases insulin sensitivity. This study examined the neuroprotective effects of 4-HI on MeHg+-treated adult Wistar rats with ALS-like symptoms, emphasising brain IGF1/GLP-1 activation. Furthermore, we investigated the effect of 4-HI on MBP levels in rat brain homogenate, cerebrospinal fluid (CSF), blood plasma, and cell death indicators such as caspase-3, Bax, and Bcl-2. Rats were assessed for muscular strength, locomotor deficits, depressed behaviour, and spatial learning in the Morris water maze (MWM) to measure neurobehavioral abnormalities. Doses of 4-HI were given orally for 42 days in the MeHg+ rat model at 50 mg/kg or 100 mg/kg to ameliorate ALS-like neurological dysfunctions. Additionally, neurotransmitters and oxidative stress markers were examined in rat brain homogenates. Our findings suggest that 4-HI has neuroprotective benefits in reducing MeHg+-induced behavioural, neurochemical, and histopathological abnormalities in ALS-like rats exposed to methylmercury.

Virtual Screening of Artemisia annua Phytochemicals as Potential Inhibitors of SARS-CoV-2 Main Protease Enzyme.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a human coronaviruses that emerged in China at Wuhan city, Hubei province during December 2019. Subsequently, SARS-CoV-2 has spread worldwide and caused millions of deaths around the globe. Several compounds and vaccines have been proposed to tackle this crisis. Novel recommended in silico approaches have been commonly used to screen for specific SARS-CoV-2 inhibitors of different types. Herein, the phytochemicals of Pakistani medicinal plants (especially Artemisia annua) were virtually screened to identify potential inhibitors of the SARS-CoV-2 main protease enzyme. The X-ray crystal structure of the main protease of SARS-CoV-2 with an N3 inhibitor was obtained from the protein data bank while A. annua phytochemicals were retrieved from different drug databases. The docking technique was carried out to assess the binding efficacy of the retrieved phytochemicals; the docking results revealed that several phytochemicals have potential to inhibit the SARS-CoV-2 main protease enzyme. Among the total docked compounds, the top-10 docked complexes were considered for further study and evaluated for their physiochemical and pharmacokinetic properties. The top-3 docked complexes with the best binding energies were as follows: the top-1 docked complex with a -7 kcal/mol binding energy score, the top-2 docked complex with a -6.9 kcal/mol binding energy score, and the top-3 docked complex with a -6.8 kcal/mol binding energy score. These complexes were subjected to a molecular dynamic simulation analysis for further validation to check the dynamic behavior of the selected top-complexes. During the whole simulation time, no major changes were observed in the docked complexes, which indicated complex stability. Additionally, the free binding energies for the selected docked complexes were also estimated via the MM-GB/PBSA approach, and the results revealed that the total delta energies of MMGBSA were -24.23 kcal/mol, -26.38 kcal/mol, and -25 kcal/mol for top-1, top-2, and top-3, respectively. MMPBSA calculated the delta total energy as -17.23 kcal/mol (top-1 complex), -24.75 kcal/mol (top-2 complex), and -24.86 kcal/mol (top-3 complex). This study explored in silico screened phytochemicals against the main protease of the SARS-CoV-2 virus; however, the findings require an experimentally based study to further validate the obtained results.

Integrating Pharmacological and Computational Approaches for the Phytochemical Analysis of Syzygium cumini and Its Anti-Diabetic Potential.

Diabetes mellitus (DM) is a metabolic disease caused by improper insulin secretion leading to hyperglycemia. Syzygium cumini has excellent therapeutic properties due to its high levels of phytochemicals. The current research aimed to evaluate the anti-diabetic potential of S. cumini plant's seeds and the top two phytochemicals (kaempferol and gallic acid) were selected for further analysis. These phytochemicals were selected via computational tools and evaluated for α-Glucosidase inhibitory activity via enzymatic assay. Gallic acid (IC50 0.37 µM) and kaempferol (IC50 0.87 µM) have shown a stronger α-glucosidase inhibitory capacity than acarbose (5.26 µM). In addition, these phytochemicals demonstrated the highest binding energy, hydrogen bonding, protein-ligand interaction and the best MD simulation results at 100 ns compared to acarbose. Furthermore, the ADMET properties of gallic acid and kaempferol also fulfilled the safety criteria. Thus, it was concluded that S. cumini could potentially be used to treat DM. The potential bioactive molecules identified in this study (kaempferol and gallic acid) may be used as lead drugs against diabetes.