Acute lung injury (ALI) is a serious clinical condition with high incidence and mortality. The inflammatory response induced by gram-positive bacteria, especially Staphylococcus aureus (S. aureus), is a key factor contributing to ALI progression and other infectious diseases. Matrine, known for its diverse biological and pharmacological properties, has not been fully explored for its potential to prevent or treat S. aureus-induced ALI. Our study demonstrated that matrine exerts a protective effect against lung injury in mice infected with S. aureus. Specifically, matrine reduced pulmonary edema and decreased neutrophil infiltration in the infected lungs. Furthermore, matrine significantly reduced the expression of high-mobility group box protein 1 (HMGB1) and hyaluronic acid-binding protein 2 (HABP2) in the lungs of infected mice. Additionally, matrine modulated the production of inflammatory mediators, including tumor necrosis factor-α (TNF-α); interleukin-1β (IL-1β); regulated upon activation normal T cell expressed and secreted (RANTES) and Interleukin 10 (IL-10), in both infected lungs and macrophages, suggesting a protective role against tissue damage. Moreover, matrine influenced the secretion of proinflammatory cytokines and regulated the activation of the mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) signaling pathways, along with the activation of Nod-like receptor pyrin domain-containing protein 3 (NLRP3) and Mixed-lineage kinase domain-like protein (MLKL) in macrophages. Notably, when MLKL, but not NLRP3, is deleted, the ability of matrine to regulate damage-associated proteins and prevent tissue injury is diminished. These findings suggest that matrine may be a promising therapeutic agent for the prevention and treatment of ALI.

Carbonic anhydrases (CAs) play a vital role in various physiological processes by catalyzing the reversible hydration of CO2 into HCO3-, hence maintaining the fluid and pH balance. Overexpression of carbonic anhydrases II (CA II) is associated with diseases, such as glaucoma, and epilepsy; therefore, it is considered as an important clinical target. Therapeutically used CA inhibitors exhibit several undesirable effects; therefore, there is an urgent need to identify new, safe, and effective inhibitors of the CAs. Keeping in view the importance of CA II inhibition, a library of new 1,3-disubstituted-1,2,3-triazole analogues of sulfanilamide is synthesized via Click chemistry, starting from sulfanilamide azide and different substituted propargyl ethers, incorporating benzyl and heteroarylmethyl moieties. The new derivatives showed significant CA II inhibitory activity (IC50 ranging between 0.19 0.66 μM) when compared with the standard inhibitor, acetazolamide (0.13 ± 0.01 μM). Among all, compounds 16 and 17 showed the most potent activity (IC50 = 0.19 μM) followed by compounds 23, and 18 (IC50 = 0.24 ± 0.014 and 0.26 ± 0.04 μM, respectively). Kinetics studies showed that all compounds are competitive inhibitors of bCA II enzyme (Ki ranging between 0.14-0.68 μM). Additionally, molecular docking studies revealed that all compounds formed network of interactions with the active site residues of the bCA II enzyme. All compounds were found to be non-toxic against BJ Human fibroblast cells. From in-vivo studies, we found that CA activity was significantly inhibited by the intraperitoneal administration of compounds 16 and 17 for up to 5 h. In conclusion, new 1,2,3-triazole analogues of sulfanilamide were identified as good CA II inhibitors.

This study aimed to explore the efficacy and mechanisms of raspberry (Rubus idaeus L. fruit) aqueous extract (RE) in alleviating high-fat diet (HFD)-induced metabolic-associated fatty liver disease (MAFLD). The MAFLD mouse model was established to examine the effects of RE through liver transcriptome and metabolomics analysis. In this study, RE supplementation significantly alleviated HFD-induced liver injury, hepatosteatosis, inflammation, and insulin resistance. Liver transcriptome analysis demonstrated that RE supplementation favorably regulated signaling pathways involved in fatty acid metabolism and inflammation, including the AMPK signaling pathway, PPAR signaling pathway, apoptosis, etc. Furthermore, the injection of compound C, an antagonist of AMPK, notably reversed the hepatoprotective effects of RE, evidenced by increased lipid profile levels, accelerated fatty acid-related gene disorder, and increased positive tunnel staining area. Furthermore, liver metabolomics analysis demonstrated that RE treatment led to substantial enrichment of the liver tissue metabolite umbelliferone (UMB), which has the potential to ameliorate lipid accumulation and hepatocyte injury through the AMPK signaling pathway. In summary, RE intervention mitigated HFD-induced liver dysfunction in mice, with UMB likely being the primary component responsible for its therapeutic efficacy in the liver. In addition, this study provided new insights, suggesting that RE could be used as a promising therapeutic approach for modulating MAFLD via apoptosis and the AMPK/PPARα signaling pathway.

Nitroxoline (NIT) has been approved for the treatment of uncomplicated urinary tract infections (UTIs) for more than half a century, yet its antimicrobial properties remain incompletely understood. Here, we determined the intricate connections between NIT's metal-chelating capabilities and its antibacterial activity. Metal ion binding characteristics were measured by Ultraviolet-visible (UV-vis) spectroscopy. Biochemical assays and molecular docking studies were performed to elucidate the underlying mechanism. We found that NIT could interact with a diverse array of metal ions, including Cu2+, Fe2+, Zn2+ and Mn2+. While, the addition of Cu2+ significantly decreased NIT's antibacterial effect against uropathogenic Escherichia coli (UPEC) strain J96 and multidrug resistant E coli B2, with the minimum inhibitory concentration (MIC) increased from 8 mg/L to 64 mg/L. Mechanically, NIT significantly decreased the intracellular copper ion levels and reduced bacterial transmembrane electrical potential. Furthermore, NIT promoted production of nitric oxide, peroxynitrite (ONOO-), and reactive oxygen species (ROS). However, the interaction of Cu2+ with NIT suppressed the induced generation of ROS but not the generation of ONOO- in E coli, suggesting that the antibacterial activity of NIT arose from multiple functional groups within its molecular structure. Moreover, NIT triggered intracellular acidification concomitant with enhanced glucose uptake, yet paradoxically suppressed ATP generation, suggesting a potential uncoupling between glycolytic flux and oxidative phosphorylation. Finally, the action of NIT was predicted to bind to the CuB-metal redox centers of cytochrome bo(3) ubiquinol oxidase through molecular docking analyses. Collectively, these data illuminate the antibacterial activity of NIT as a potent copper-related metalloantibiotic against UPEC.

Patients undergoing anti-cancer therapy with doxorubicin (DOX) face the risk of cumulative, irreversible cardiotoxicity. In failing hearts, the overexpressed and activated G protein-coupled receptor kinase 2 (GRK2) initiates pathological signaling, leading to cardiomyocyte death. This study aimed to investigate the potential role of GRK2 in DOX-induced cardiotoxicity (DIC).

Mice were administered intraperitoneal injections of DOX (5 mg/kg) weekly for four weeks to induce DIC. Small interfering RNAs (siRNAs) targeting GRK2, ADH1, and PABPC1 were employed in H9c2 cells. Oxidative stress and cell apoptosis were assessed using Reactive Oxygen Species (ROS) staining and TUNEL staining, respectively. Co-immunoprecipitation (Co-IP) was utilized to detect the interaction between GRK2 and PABPC1. RNA immunoprecipitation (RIP) assay was employed to evaluate the binding between PABPC1 and ADH1 mRNA.

GRK2 was found to be upregulated in DOX-treated mouse hearts and H9c2 cells. Cardiomyocyte-specific GRK2 knockout partially mitigated oxidative stress, apoptosis, and cardiac dysfunction. Additionally, GRK2 knockdown attenuated DOX-induced oxidative damage and apoptosis both in vivo and in H9c2 cells. Furthermore, a reduction in ADH1 expression was observed in DOX-treated hearts and cardiomyocytes, with a pronounced increase following GRK2 knockdown. Notably, the beneficial effects of GRK2 knockdown in H9c2 cells were abolished after ADH1 knockdown. Mechanistically, GRK2 knockdown promoted the binding of PABPC1 to ADH1 mRNA, thereby inhibiting the degradation of ADH1 mRNA. Increased ADH1 expression alleviated DOX-induced oxidative stress and apoptosis in cardiomyocytes.

In conclusion, our study demonstrates that targeting GRK2 may represent a promising therapeutic strategy for mitigating DOX-associated cardiotoxicity.

Due to the multifarious nature of cancer, finding a single definitive cure for this dreadful disease remains an elusive challenge. The dysregulation of the apoptotic pathway or programmed cell death, governed by the Bcl-2 family of proteins plays a crucial role in cancer development and progression. Bcl-B stands out as a unique anti-apoptotic protein from the Bcl-2 family that selectively binds to Bax which inhibits its pro-apoptotic function. Although several inhibitors are reported for Bcl-2 family proteins, no specific inhibitors are available against the anti-apoptotic Bcl-B protein. This study aims to address this research gap by using virtual screening of an in-house library of phytochemicals from seven anti-cancer medicinal plants to identify lead molecules against Bcl-B protein. Through pharmacokinetic analysis and molecular docking studies, we identified three lead candidates (Enterolactone, Piperine, and Protopine) based on appreciable drug-likeliness, ADME properties, and binding affinity values. The identified molecules also exhibited specific interactions with critical amino acid residues of the binding cleft, highlighting their potential as lead candidates. Finally, molecular dynamics simulations and MM/PBSA based binding free energy analysis revealed that Enterolactone (CID_114739) and Piperine (CID_638024) molecules were on par with Obatoclax (CID_11404337), which is a known inhibitor of the Bcl-2 family proteins.

Breast cancer (BC) is the most prevalent malignancy among women around the world. The epidermal growth factor receptor (EGFR) is a tyrosine kinase receptor (RTK) of the ErbB/HER family. It is essential for triggering the cellular signaling cascades that control cell growth and survival. However, perturbations in EGFR signaling lead to cancer development and progression. Hence, EGFR is regarded as a prominent therapeutic target for breast cancer. Therefore, in the current investigation, EGFR was targeted with phytochemicals from Clerodendrum inerme (L.) Gaertn (C. inerme). A total of 121 phytochemicals identified by gas chromatography-mass spectrometry (GC-MS) analysis were screened against EGFR through molecular docking, ADMET analyses (Absorption, Distribution, Metabolism, Excretion, and Toxicity), PASS predictions, and molecular dynamics simulation, which revealed three potential hit compounds with CIDs 10586 [i.e. alpha-bisabolol (-6.4 kcal/mol)], 550281 [i.e. 2,(4,4-Trimethyl-3-hydroxymethyl-5a-(3-methyl-but-2-enyl)-cyclohexene) (-6.5 kcal/mol)], and 161271 [i.e. salvigenin (-7.4 kcal/mol)]. The FDA-approved drug gefitinib was used to compare the inhibitory effects of the phytochemicals. The top selected compounds exhibited good ADMET properties and obeyed Lipinski's rule of five (ROF). The molecular docking analysis showed that salvigenin was the best among the three compounds and formed bonds with the key residue Met 793. Furthermore, the molecular mechanics generalized born surface area (MMGBSA) calculations, molecular dynamics simulation, and normal mode analysis validated the binding affinity of the compounds and also revealed the strong stability and compactness of phytochemicals at the docked site. Additionally, DFT and DOS analyses were done to study the reactivity of the compounds and to further validate the selected phytochemicals. These results suggest that the identified phytochemicals possess high inhibitory potential against the target EGFR and can treat breast cancer. However, further in vitro and in vivo investigations are warranted towards the development of these constituents into novel anti-cancer drugs.

Human T-cell leukemia virus 1 (HTLV-1) associated lymphoma is a devastating malignancy triggered by HTLV-1 infections. We employeda comprehensive drug design and computational strategy in this work to explore the inhibitory activitiesof Astilbin derivatives against HTLV-1-associated lymphoma. We evaluated the stability, binding affinities, and various computational analysis of Astilbin derivatives against target proteins, such as HTLV-1 main protease and HTLV-1 capsid protein. The root mean square deviation (RMSD), root mean square fluctuation, radius of gyration, hydrogen bond analysis, principal component analysis (PCA) and dynamic cross-correlation matrix (DCCM) were applied to characterize these protein-ligand interactions further. Ligand-03 and ligand-04 exhibited notable binding affinity to HTLV-1 capsid protein, while ligand-05 displayed high binding affinity to HTLV-1 protease. MD simulation analysis revealed that ligand-03, bound to HTLV-1 capsid protein, demonstrated enhanced stability with lower RMSD values and fewer conformational changes, suggesting a promising binding orientation. Ligand-04, despite stable binding, exhibited increased structural deviations, making it less suitable. Ligand-05 demonstrated stable binding to HTLV-1 protease throughout the simulation period at 100 nanoseconds. Hydrogen bond analysis indicated that ligand-05 formed persistent hydrogen bonds with significantresidues, contributing to its stability. PCA highlighted ligand-03's more remarkable conformational changes, while DCCM showed ligand-05's distinct dynamics, indicating its different behavior in the complex. Furthermore, binding free energy calculations supported the favorable interactions of ligand-03 and ligand-04 with HTLV-1 capsid protein, while ligand-05 showed weaker interactions with HTLV-1 protease. Molecular electrostatic potential and frontier molecular orbital analyses provided insights into these compounds' charge distribution and stability. In conclusion, this research found Astilbin derivatives as potential inhibitors of HTLV-1-associated lymphoma. Future attempts at drug development will benefit from the steady interaction landscape provided by Ligand-03, Ligand-04 and Ligand-05, which showed the most attractive binding profile with the target protein. These results open up new opportunities for innovative drug development, and more experimental testing should be done between Astilbin derivatives and HTLV-1-associated lymphoma.

Myocarditis is one of the common causes of sudden death in adolescents, and autoimmune response and inflammation play an essential role in the development of myocarditis. Quercetin is a natural flavonoid compound with anti-inflammatory and cardioprotective effects. However, the mechanism of quercetin in autoimmune myocarditis remains unclear. This study observed that quercetin significantly improved cardiac function, inflammation and fibrosis in mice with experimental autoimmune myocarditis (EAM). In addition, Network pharmacology predicts the key target C/EBPβ and signalling pathway MAPK for quercetin treatment of autoimmune myocarditis. CESTA and DARTS experiments verified that quercetin and C/EBPβ have strong binding ability. It is shown that quercetin down-regulates MCP-1 expression in H9C2 cells by dephosphorylation of ERK1/2 and C/EBPβ. Specifically, quercetin reduced the binding of C/EBPβ to the MCP-1 promoter, resulting in decreased expression of MCP-1, which was associated with decreased ERK1/2 dependent phosphorylation at the C/EBPβ threonine 188 site. This inhibitory effect of quercetin could be further enhanced by the ERK1/2 inhibitor PD98059. The biological relevance of this regulatory network is demonstrated in EAM mice. In conclusion, these results illustrate the protective effect of quercetin against autoimmune myocarditis. A novel regulatory mechanism was revealed, namely the down-regulation of MCP-1 through the ERK1/2-C/EBPβ axis. This provides a new therapeutic strategy for autoimmune myocarditis.

Glioma-associated mesenchymal stem cells (GA-MSCs) are one of the key factors limiting the effectiveness of glioblastoma (GBM) treatment and contributing to poor patient prognosis, making them a potential therapeutic target for GBM. In-depth research into the complex crosstalk between GA-MSCs and GBM cells not only aids in understanding the mechanisms of GBM progression but also provides valuable insights for developing new potential drugs.

We conducted a comprehensive bioinformatics analysis aimed at identifying shared dysregulated genes between GBM and GA-MSCs. Through hub gene enrichment and immune infiltration analyses, we explored key molecular pathways and the immune landscape. Additionally, Cox regression analysis was employed to identify key factors influencing overall survival in GBM. The expression patterns and functional roles of hub genes were validated across various cancer types and datasets. Finally, dynamic simulations were used to assess the binding affinity of potential drugs to the targets, further supporting their potential as therapeutic candidates.

We identified 32 candidate genes primarily involved in the 1-kappa-B kinase/NF-kappa-B and MAPK signaling pathways, both of which played critical roles in tumor survival, proliferation, and invasion. Notable hub genes included DUSP1, FYN, FLNC, FN1, G3BP1, MYO1B, and WLS, each contributing uniquely to GBM progression. Among them, FLNC was highlighted as a key regulatory factor in GBM progression. Molecular dynamics simulations further revealed its potential as a therapeutic target, particularly demonstrating a high binding affinity with staurosporine. Additionally, a high proportion of dendritic cells contributed to the formation of the GBM immune microenvironment.

This study revealed the co-expression patterns and metabolic pathways between GA-MSCs and GBM, providing new insights into the molecular mechanisms of GBM progression. Targeting FLNC with staurosporine presents a promising therapeutic strategy for GBM. Aditionally, targeting the shared pathways of both may offer a valuable approach for treating malignant brain tumors.

Osteoporosis (OP) is a metabolic bone disease characterized by reduced bone density and fragility, impairing quality of life. Traditional treatments often overlook symptoms like back and joint pain, increasing burden. This study aims to map relationships between natural medicines, targets, and symptom clusters, demonstrating their effectiveness in personalized OP treatment to enhance clinical strategies and self-assessment. We used compounds and targets, applying Summary data-based Mendelian Randomisation (SMR) analysis for biological process and molecular function enrichment. Additionally, we employed Phenome-Wide Association Studies (PheWAS) to select two natural drugs-Rhizoma Drynariae (RD) and Lycii Fructus (LF)-for case analysis. The study found that RD primarily improves symptoms such as indigestion, constipation, fatigue, polyuria, and depression, while LF significantly ameliorates symptoms related to the nervous and muscular systems, such as hoarseness, dizziness, vertigo, and fever symptoms. This analysis successfully differentiated two groups of symptoms and precisely constructed a logical chain among "natural Medicines-molecular tArGets-Illness-symptom Clusters" (MAGIC chain) achieving a refined classification of OP. The results of this study support the effectiveness of implementing personalized medical strategies in the treatment of OP, providing a scientific basis for the clinical application of natural medicines and patient self-management.

The impact of metformin on sarcopenia remains uncertain. This study aimed to investigate whether metformin influences sarcopenia risk and evaluate the effects of potential drug targets on sarcopenia traits.

We analyzed data from the National Health and Nutrition Examination Survey (NHANES) (n = 3549) to assess the association between metformin use and sarcopenia risk in elderly patients with type 2 diabetes. Mendelian randomization (MR) analysis using genome-wide association studies (GWAS) from UK Biobank (n = 1,366,167) and FinnGen (n = 218,007), with expression quantitative trait loci (eQTL) as instrumental variables, examined the causal effect of metformin-related targets on sarcopenia traits, while molecular docking explored the interaction between metformin and its drug targets.

Metformin use was associated with increased grip strength (OR = 2.46; 95% CI 1.49-2.38) and skeletal muscle mass (OR = 1.24; 95% CI 0.20-2.28), as well as reduced mortality (HR = 0.62; 95% CI 0.54-0.71). MR analysis suggested a possible link between GDF15 gene expression and sarcopenia traits, with no evidence of genetic confounding. Molecular docking indicated stable binding between metformin and GDF15.

This study suggests that metformin may lower sarcopenia risk, particularly in elderly patients with type 2 diabetes, with GDF15 identified as a promising target for sarcopenia treatment.

Ferulic acid (FA) has shown potential in treating atherosclerosis (AS) by improving lipid metabolism and exerting anti-hypoxic effects. This study aimed to validate the mechanism of FA in AS through in vitro experiments.

Network analysis was employed to predict the mechanisms underlying the therapeutic effects of FA on AS. An in vitro foam cell model was established using RAW 264.7 cells treated with ox-LDL. Cellular lipid accumulation was detected using Oil Red O staining; cell viability was assessed by cell counting kit-8; mitochondrial morphology and function were evaluated by transmission electron microscopy and JC-1 staining; apoptosis levels were detected by TUNEL and DAPI staining; mitochondrial Fe2+ content was measured by Mito-FerroGreen; and Western blot was performed to determine the protein expression levels of HIF-1α, Bax, Bcl2, GPX4, and EGFR.

Network analysis suggested that FA may exert its therapeutic effects on AS through the HIF-1 signaling pathway and is closely associated with the regulation of ferroptosis and apoptosis. FA upregulated the expression of ALOX5, BCL2, ERN1, GPX4, NOS3, and SLC2A1 mRNA and downregulated the expression of BAX, CYCS, EGFR, FLT1, HIF1A, NFKB1, NOS2, PARP1, and STAT3 mRNA. In vitro experiments demonstrated that FA reduces lipid accumulation, increases cell viability, improves mitochondrial function, and decreases reactive oxygen species content. Additionally, FA inhibited ferroptosis and apoptosis by suppressing the HIF-1 signaling pathway, up-regulating the expression of GPX4 and Bcl2, and down-regulating the expression of HIF-1α and Bax protein. HIF-1 agonists reversed these effects by activating the HIF-1 signaling pathway.

FA improves mitochondrial function and suppresses ferroptosis and apoptosis by inhibiting the HIF-1 signaling pathway, thereby treating AS.

Zuojin pill is a well-known traditional Chinese medicine (TCM) for treating gastric disorders. The modified Zuojin pill (SQQT) has been used in the treatment of gastric metaplasia (GM) in China for decades. However, the mechanisms of SQQT treat GM remain unclear.

Our goals are to evaluate the effect of SQQT on GM and to investigate its potential mechanisms.

An animal model of metaplasia was established to study the mechanism of SQQT. RNA-seq was employed to analyze the pathogenesis of GM. Network pharmacological approaches and molecular docking were used to elucidate the mechanisms of SQQT. Common targets of the SQQT and GM mechanism pathways are defined as the key mechanisms of SQQT's treatment in GM. The key mechanisms were validated through in vivo and in vitro experiments.

RNA-seq analysis of GM animals and network pharmacology of SQQT indicated that SQQT might treat GM via 20 pathways, including the PPAR pathway. Among the 3 core targets of the PPAR pathway, only PPARG is related to GM progression. Besides, the core components of SQQT have a lower affinity for binding to PPARG. The main mechanism of SQQT ameliorated GM is related to PPARG. In animal experiments, SQQT ameliorated GM through ROS decreasing, mitochondrial damage repairing, and protein marker rectification. In cell experiments, SQQT notably decreased the levels of ferroptosis and metaplasia markers including GPX4, PPARG, MUC6, and ACSL4.

SQQT ameliorated gastric metaplasia by inhibiting the PPARG/ferroptosis pathway.

Left ventricular hypertrophy (LVH) associated with hypertension and psoriasis (PSO) are linked by poor prognosis. Neutrophil extracellular traps (NETs) are implicated in both conditions, but the mechanisms remain unclear.

We integrated bulk and single-cell RNA sequencing, mendelian randomization, immune microenvironment analysis, and molecular docking to explore the molecular interactions between LVH and PSO, focusing on NET-related pathways. Prediction models were also developed, and gene function was validated through in vivo and in vitro experiments.

Our findings identified NETs-associated genes, AKT serine/threonine kinase 1 (AKT1), and receptor-interacting protein kinase 1 (RIPK1), regulating inflammation, fibroblast activation, and apoptosis in LVH and PSO. Functional enrichment analysis revealed mitochondrial metabolic disorders and extensive inflammation as the most prominent shared features of LVH and PSO diseases. Additionally, resveratrol exhibited a high binding affinity to the AKT1 and RIPK1 proteins. Functional validation showed that knockdown of AKT1 reduced LVH cell hypertrophy and PSO cell apoptosis.

This study highlights molecular pathways linking LVH and PSO, suggesting novel targets for treating cardiac involvement in PSO patients with LVH.

The study assessed the peptide production by using potent Lactiplantibacillus plantarum KGL3A (MG722814) culture to ferment the sheep milk for evaluation of α-glucosidase inhibition, ACE inhibition, α-amylase inhibition, & inhibiting lipase activities. The maximal ACE inhibitory, α-amylase, α-glucosidase, & lipase inhibiting actions were 71.69 %, 71.32 %, 67.14 %, and 64.15 %, respectively, at 37 °C after 48 h. Proteolytic activity was tested at various incubation times & inoculation rates to maximise the conditions for growth and the greatest action (9.38 mg/mL) was reported at 2.5 % rate of inoculation after incubation of 48 h. The anti-diabetic as well as ACE inhibitory properties of less than 3 kDa were maximum in contrast to >3 kDa, <10 kDa, and > 10 kDa cut-off fractions. Further, when LPS stimulation is applied to RAW 267.4 macrophage cells, the overabundance generation of IL-6, IL-1β, NO, and TNF-α is greatly reduced by using KGL3A to ferment sheep milk. 2D gel electrophoresis & SDS-PAGE were utilized in relation to protein purifications. Maximum numbers of sheep milk's fermented protein bands were present, about 10 to 124 kDa by SDS-PAGE, and 38 spots of protein were discovered using 2D gel chromatography. Ultra-filtered fractions water soluble extracts (WSEs) were employed in RP-HPLC to differentiate between various peptide fractions. The peptide sequences produced were matched using the databases of AHTPDB and BIOPEP to match hypertensive peptides & antidiabetic peptides, respectively. Furthermore, the discovered peptide sequences from the fermenting sheep milk was studied due to their penchant for binding against the active locations of human bile salt activated lipase (hBAL); human maltase-glucoamylase (hMGA); human pancreatic alpha-amylase (hPAM); & human angiotensin-converting enzyme (hACE) through molecular docking.

Parkinson's disease (PD), the second most prevalent neurodegenerative disorder, poses significant challenges to single-target therapeutic strategies due to its complex etiology. This has driven interest in multi-target approaches, particularly those leveraging natural compounds. Pingchan granules (PCG), a traditional Chinese medicine composed of plant- and animal-derived compounds, have shown efficacy in alleviating PD symptoms. Here, we identify 96 PCG-associated anti-PD targets, enriched in neuronal synaptic signaling and G protein-coupled receptor pathways. Through protein-protein interaction network analysis of anti-PD targets and random forest modeling of substantia nigra transcriptomic data from PD patients, SLC6A3 and SRC emerged as central hub targets, with Mendelian randomization further validating SRC as a potential therapeutic target. Molecular docking and single-cell sequencing reveal that dauricine, PCG's principal active compound, binds strongly to SLC6A3 and SRC, modulating glucose metabolism pathways in dopaminergic neurons. These findings illuminate the molecular basis of PCG's therapeutic effects, offer a foundation for future drug development, and underscore the potential of dauricine as a targeted treatment for PD.

Natural products often show enhanced therapeutic effects after processing, largely due to changes in their chemical profiles. However, identifying the key chemical classes and components responsible for these improvements remains a challenge. In this study, we present a novel workflow for mass spectrometry data analysis, based on our previously developed MCnebula, combined with in vivo and in vitro testing to identify contributors to the anti-diabetic effects of processed natural products. Cornus officinalis (CO), a traditional food and medicinal plant, showed strong α-glucosidase inhibition, particularly its steamed and wine-steamed products, outperforming acarbose in both in vitro and in vivo testing. MCnebula analysis revealed that flavonoids underwent the most significant changes during processing. Further validation of selected flavonoid compounds, such as quercetin and kaempferol, demonstrated their α-glucosidase inhibitory effects to be 207 and 263 times more potent than acarbose, respectively. The combined use of MCnebula analysis and bioactivity validation revealed the key compounds that contribute to the enhanced anti-glucose effects of CO after processing, offering insights into the chemical transformations with bioactive potential as anti-diabetic dietary supplements and agents.

The nucleotide-binding oligomerization domain (NOD)-like receptor (NLR), leucine-rich-repeat (LRR), and pyrin domain containing 3 (NLRP3) is one of the key players in neuroinflammation, which is a major pathological hallmark of Alzheimer's Disease (AD). Activated NLRP3 causes release of pro-inflammatory molecules that aggravate neurodegeneration. Thus, pharmacologically inhibiting the NLRP3 inflammasome has the potential to alleviate the inflammatory injury to the neurons. Coumarin is a multifunctional nucleus with potent anti-inflammatory properties and can be utilized to develop novel drugs for the treatment and management of AD. In the present study, we have explored the NLRP3-inhibitory activities of a library of coumarin derivatives through a computational drug discovery approach. Drug-like, PAINS free, and potentially BBB permeable compounds were screened out and subjected to molecular docking and in silico ADMET studies, resulting in three virtual hits, i.e. MolPort-050-872-358, MolPort-050-884-068, and MolPort-051-135-630. The hits exhibited better NLRP3-binding affinity than MCC950, a selective inhibitor of NLRP3. Further, molecular dynamics (MD) simulations, post-MD simulation analyses, and binding free energy calculations of the hits established their potential as promising virtual leads with a common coumarin scaffold for the inhibition of NLRP3 inflammasome.

Datura Stramonium is a well-known and important medicinal plant that is widely used in various medical systems to treat conditions such as asthma, diabetes, and inflammatory diseases. The aim of this study was to prepare extracts of D. stramonium seeds in different solvent polarities for assessing phytochemical potential, in vitro biological activities, and molecular docking studies. Phytochemical screening was conducted to determine the phytochemical composition, while GC-MS analysis was used to identify secondary metabolites of D. Stramonium. The seed extracts were molecularly docked to evaluate bioactive and antioxidant activity. The minimum inhibitory concentration (MIC) of the extracts against bacteria such as S. aureus, E. coli, Bacillus subtilis, and Proteus mirabilis was determined. Antifungal activity was also tested against fungi including Aspergillus flavus, Fusarium oxysporum, Aspergillus niger, and Candida albicans. The results of phytochemical screening indicated that the primary plant constituents in all extracts of different polarities are alkaloids, flavonoids, tannins, mucilage, sterols, heterosides, triterpenoids, and cardiac glycosides. Most molecules in the hexane, ether, and chloroform extracts consist of fatty acids, sterols, glycosides, triterpenoids, alkaloids, and phenolic compounds, as revealed by GC-MS analysis. Conversely, extracts from polar solvents like methanol, ethanol, and water are abundant in alkaloids. In vitro antibacterial and antifungal activities demonstrated that ether, methanol, and ethanol extracts were more effective than inhibiting the four bacterial strains compared to the antibiotics Oxacillin and Cefuroxime. The ether and methanol extracts exhibited better zones of inhibition and significant MIC values against A. niger and C. albicans compared to the control and fluconazole. The free radical inhibition (DPPH) (24.92 ± 5.31 μg/mL) for the ethanol extract indicates Datura's antioxidant capacity. It is believed that the main phytochemicals are responsible for the enhanced antioxidant activity observed in other studies. The docking study revealed that the bioactive compounds linoleic acid and atropine formed better hydrogen bonding interactions with proteins than pi-alkyl and alkyl bonds.

Cancer is the second foremost cause of fatalities associated with non-communicable diseases across the globe, affecting multiple organs and often necessitating costly treatments with adverse side effects. Apoptosis, the body's natural cell death process, plays a crucial role in the prevention of cancer, but it's often disrupted in cancer cells, allowing uncontrolled proliferation. Restoring apoptosis in cancer cells is one of the promising therapeutic strategies to curb tumor growth and enhance clinical outcomes. Bcl-B, an anti-apoptotic protein within the Bcl-2 family, interacts with Bax to mitigate apoptosis, indicating it as a druggable target for cancer therapy. There's a critical need for natural, cost-effective alternatives with minimal adverse effects to reduce morbidity rates of cancer patients. Plant-based immunoprotective medications, particularly from sustainable sources like known medicinal plants, offer substantial potential for cancer treatment. This study involves comprehensive in silico approaches (byte) to evaluate the inhibition potential of the phytochemicals derived from Withania somnifera against the anti-apoptotic Bcl-B protein. Research into Bcl-B's binding affinity with 80 phytochemicals from this plant aims to identify interaction sites for promising anticancer agents. This study's focus on Bcl-B protein highlights its potential in modulating apoptotic pathways and exploring novel anti-cancer therapeutics. Through comprehensive screening based on drug-likeness and pharmacokinetic properties, combined with in-house virtual screening, molecular docking, molecular dynamics simulations, and MM/PBSA-based binding free energy analysis, three promising candidate inhibitors-Withanolide L (IMPHY009438), Withanolide M (IMPHY003143), and Withanolide A (IMPHY000090)-were identified and prioritized. These candidates showed favorable estimated binding free energy values, along with desirable drug-likeness and pharmacokinetic profiles. The results demonstrated that the selected and prioritized phytochemicals, Withanolide L, Withanolide M, and Withanolide A display comparable efficacy to Obatoclax (CID: 11404337) and other known synthetic, semi-synthetic, and natural inhibitors of Bcl-2 family proteins. These findings establish a strong bench foundation for further experimental validation and bedside application, potentially offering an alternative natural approach to cancer therapy.

Lung adenocarcinoma (LUAD) remains a significant global health challenge, with an urgent need for innovative predictive, preventive, and personalized medicine (PPPM) strategies to improve patient outcomes. This study leveraged multi-omics and machine learning approaches to uncover the prognostic roles of B cells in LUAD, thereby reinforcing the PPPM approach.

We integrated multi-omics data, including bulk RNA, ATAC-seq, single-cell RNA, and spatial transcriptomics sequencing, to characterize the B cell landscape in LUAD within the PPPM framework. Subsequently, we developed an integrative machine learning program that generated the Scissor+ related B cell score (SRBS). This score was validated in the training and validation sets, and its prognostic value was assessed along with clinical features to develop predictive nomograms. This study further assessed the role of SRBS and SRBS genes in response to immunotherapy and identified personalized drug targets for distinct risk subgroups, with gene expression verified experimentally to ensure tailored medical interventions.

Our analysis identified 79 Scissor+ B cell genes linked to LUAD prognosis, supporting the predictive aspect of PPPM. The SRBS model, which utilizes multiple machine learning algorithms, performed excellently in predicting prognosis and clinical transformation, embodying the preventive and personalized aspects of PPPM. Multifactorial analysis confirmed that SRBS was an independent prognostic factor. We observed varying biological functions and immune cell infiltration in the tumor immune microenvironment (TIME) between the high- and low-SRBS groups, underscoring personalized treatment approaches. Notably, patients with elevated SRBS may exhibit resistance to immunotherapy but show increased sensitivity to chemotherapy and targeted therapies. Additionally, we found that LDHA, as an SRBS gene with significant clinical implications, may regulate the sensitivity of LUAD cells to cisplatin.

This study presents a B cell-associated gene signature that serves as a prognostic marker to facilitate personalized treatment for patients with LUAD, adhering to the principles of PPPM.

The online version contains supplementary material available at 10.1007/s13167-024-00390-4.

A higher death rate is associated with multiple factors, including medication resistance and co-infection with the human immunodeficiency virus (HIV). This shows the need to obtain new and effective drug candidates in improving tuberculosis (TB) treatment. In addition, the phosphatidylinositol mannosyltransferase (PimA) enzyme starts the production of phosphatidyl-myo-inositol. PimA has been identified as a key enzyme and an important area for further research in the development of anti-TB drugs. Previous research investigated various applications including marine resources driven by a deeper understanding of the distinctive features of the ecosystem and the diverse array of organisms. Therefore, this research aims to investigate the potential of Indonesian marine compounds as inhibitors of PimA, with a focus on binding energy, interaction modes, and stability using docking and molecular dynamics (MD) investigation methodologies. The results show that a total of 84 Indonesian marine compounds are effectively docked to the PimA to obtain compounds 21, 27, and 33 for further investigation. Based on the MD analysis, compound 27 (desulfohaplosamate) is the most promising candidate among the new MTB-PimA inhibitors. Compounds bind to PimA, as shown by a strong affinity of -30.09 kJ/mol, and form hydrogen bonds with the key amino acid residue Gly16. Furthermore, a stable complex is formed to easily analyze the antibacterial agents targeting MTB in the future.

Characterized by a cascade of profound changes in nucleus pulposus (NP) cells, extracellular matrix (ECM), and biomechanics, intervertebral disc degeneration is a common multifactorial condition that may lead to various degenerative lumbar disorders. Therapeutic strategies targeting a single factor have shown limited efficacy in treating disc degeneration, and approaches that address multiple pathological ingredients are barely reported. In this study, engineered cell membrane-encapsulated keratin nanoparticles are developed to simultaneously alleviate NP cell senescence and promote ECM remodeling. To achieve this, salivary acid glycoengineered adipose mesenchymal stem cell membranes are used to coat keratin, a core protein for structural support and cellular protection. The synthesized cell membrane-coated keratin nanoparticles (MKNs) effectively protected mitochondrial integrity in NP cells from oxidative stress-induced damage. Moreover, MKNs modulate mitochondrial metabolism and attenuate NP cell senescence. In addition, MKNs activate integrins at the cell membrane and enhance the interactions between NP cells and ECM, resulting in increased ECM anabolism and decreased catabolism. The proposed multi-targeted strategy to block the degenerative cycle inside the disc is efficacious for treating disc degeneration and may have the potential for clinical application.

Cardiac glycosides (CGs), traditionally prescribed for heart failure and arrhythmias, show anticancer potential. However, their mechanisms for preferential inhibition of tumour tissue and constituent malignant cells are not fully elucidated. This study aims to elucidate the therapeutic benefits of CGs in targeting specific tumours and dissect their multi-targeting mechanisms that confer their cytotoxicity against malignant cells.

We designed an integrated workflow to identify therapeutic CGs with high toxicity to certain cancers, investigating their multi-target effects, assessing their toxicity to malignant cells and analysing the prognostic relevance of CGs' target genes. The computational findings were confirmed through gene knockdown, cell viability assays, reactive oxygen species (ROS) measurements and so forth.

CGs modulate multiple genes crucial for ion homeostasis, oxidative stress and apoptosis, with a particularly strong inhibitory effects on uveal melanoma (UVM). Notably, digitoxin suppresses UVM cell proliferation and induces ROS levels by simultaneously targeting STAT3 and KLF5. Single-cell transcriptomic analysis revealed that malignant cells are likely more vulnerable to CGs due to their higher expression of CG target genes compared with surrounding cells in the UVM microenvironment.

Given UVM's limited options, our study highlights the potential of digitoxin as a promising novel therapeutic agent for this aggressive and rare ocular cancer. Our comprehensive approach is effective in identifying the potent, cancer-specific therapeutic agents from herbal plants.

One approach to accelerate the availability of new cancer drugs is to test drugs approved for other conditions as anticancer agents. During recent decades, penciclovir (PNV) has been frequently utilized as a potent antiviral drug, in particular against infections caused by herpes viruses. Many antivirals interact with DNA and change their expression level, so determining the binding mode is of great importance. In our laboratory, we have focused our attention to design improved drugs that target cellular DNA, to understand the mechanism of action at the molecular level, and also to investigate the effect of antiviral drugs as anticancer agents. The results of ct-DNA-PNV interactions at physiological pH using fluorescence spectroscopy, UV-visible absorption spectroscopy, and molecular modeling reveal this drug binds well to ct-DNA through groove binding. The circular dichroism measurements displayed that PNV caused a slight change in the DNA structure which affirmed that the binding of PNV with the DNA occurs through the groove mode. Besides, multi-spectroscopic and molecular docking were used to evaluate how PNV interacts with human serum albumin under physiological conditions. The findings of fluorescence quenching suggested that static quenching was involved in the spontaneous development of HSA-PNV complex through hydrophobic force. The docking simulation results validated the findings of spectroscopic techniques.

Despite the significant fatality rates associated with Nipah virus (NiV) outbreaks in South Asia, including Bangladesh, and India, till today, there is no approved medications to treat it. In this context, small molecules in propolis were computationally screened through pharmacokinetic and toxicity studies followed by molecular docking and dynamics simulation with Nipah virus glycoprotein (NiV-G protein) to assess their anti-Nipah potential. A thorough literature analysis was performed to identify antiviral compounds in propolis from a pool of 84 experimental articles. Following ADMET analysis, 27 molecules out of 34 were docked against NiV-G and compared with a control ligand, ribavirin, which is an investigational drug against Nipah. The molecular docking revealed that bauer-7-en-3β-yl acetate (BA) and moronic acid (MA) bound more strongly to the active site of NiV-G than ribavirin and other ligands. Investigation of root-mean-square deviation (RMSD), root mean square fluctuations (RMSF), radius of gyration (Rg), solvent accessible surface area (SASA), molecular surface area (MolSA), binding free energy (MM-PBSA), the complexity of hydrogen bonds (HBs), and secondary structure of ligand-target interactions for 100 ns by molecular dynamics (MD) simulation study further supported the docked complex's stability and compactness. Therefore, the in silico molecular interaction analysis reports that both molecules may be the possible candidates against Nipah infection.

Ferroptosis represents a significant target for mitigating myocardial ischemia-reperfusion (I/R) injury. Existing literature indicates that estrogen (17β-estradiol, E2) can alleviate such injuries through various pathways. However, the specific mechanisms by which E2 may confer protection against myocardial I/R injury through the inhibition of ferroptosis remain to be fully elucidated. This study employed a mouse model of left anterior descending coronary artery ligation to investigate the protective effects of E2 on myocardial I/R injury, with a particular focus on its inhibitory effects on ferroptosis and PHLDA3 in both hypoxia-reoxygenation (H/R) and I/R models. A bioinformatics analysis was conducted to evaluate the impact of estrogen receptor GPER knockout on PHLDA3 expression and ferroptosis. Loss-of-function approaches were employed to elucidate the role of PHLDA3 in ferroptosis during myocardial I/R injury. Our findings demonstrate that E2 can ameliorate myocardial I/R injury, primarily by inhibiting ferroptosis. Notably, PHLDA3 expression levels were significantly elevated during ischemia-reperfusion events; however, E2 was observed to suppress this expression. Bioinformatics analysis indicated that PHLDA3 levels increased following GPER knockdown, and the inhibitory effect of E2 on PHLDA3 expression could be partially reversed by GPER inhibitors (G15) in animal models. Furthermore, the suppression of PHLDA3 reduced ferroptosis and mitigated the severity of myocardial I/R injury. Utilizing mass spectrometry and co-immunoprecipitation methodologies, we have elucidated a potential mechanism in which PHLDA3 directly binds to and interacts with proteins involved in the process of ferroptosis. Our findings demonstrate that E2 effectively suppresses ferroptosis and mitigates myocardial I/R injury by downregulating PHLDA3 expression through the activation of the GPER receptor.

The 3C-like protease of severe acute respiratory syndrome coronavirus 2, known as the main protease (Mpro), is an attractive drug target for the treatment of coronavirus disease 2019. This study reports the discovery of novel Mpro inhibitors using several in silico techniques, including docking, molecular dynamics (MD), and fragment molecular orbital (FMO) calculations. We performed docking calculations on 5950 compounds with bioactivity, and 12 compounds were selected. An enzymatic assay was conducted, revealing that BP-1-102 exhibits significant Mpro inhibitory activity with an IC50 of 11.1 μM. The identification of seed compounds from the experiments on a few compounds demonstrates the effectiveness of our docking calculations. Furthermore, the detailed analyses using MD and FMO calculations suggested an interaction mechanism in which the hydroxyl group of BP-1-102 forms a hydrogen bond with E166 of Mpro. The Mpro inhibitory activity of SH-4-54, a derivative without the aforementioned hydroxyl group, was investigated and observed to be significantly reduced, with an IC50 of 81.5 μM. This result strongly supports the suggested interaction mechanism.

Algal blooms along the West African coast threaten ecosystems and human health due to nutrient enrichment and rising temperatures. This remote-sensing study examined the relationships between chlorophyll-a concentrations, environmental variables, and the potential for microplastic retention in blooms using molecular docking models for predictive insights. Correlation analyses revealed region-specific associations, with moderate positive correlations between chlorophyll and temperature along the southwest Nigeria-Togo coastline and near Liberia and Sierra Leone (r = 0.2-0.4) and strong correlations with particulate carbon across most regions (r = 0.6-0.8). Chlorophyll fluorescence correlations were generally low (r = 0.2), except for higher correlations in the Senegal-Gabon and Côte d'Ivoire-Ghana stretches, indicating that localized factors influence bloom dynamics. Molecular docking results predict that polycarbonate microplastics have the strongest binding affinities with algal proteins, particularly flagellin (-11.3 kcal/mol), suggesting significant retention potential within bloom matrices. In contrast, ethylene plastics displayed weaker interactions (up to -2.2 kcal/mol) and a high dissociation constant (Kd = 0.079 M), indicating minimal retention potential. The low Kd values for polycarbonateprotein interactions (e.g., 5.15e09 M for flagellin) predict a concerning scenario where microplastics become increasingly integrated into algal biomass, increasing exposure risks for marine life. Warm, nutrient-rich conditions along the West African coast, especially from southwest Nigeria to Togo and Côte d'Ivoire to Sierra Leone, are expected to increase the frequency and severity of algal blooms. This proliferation disrupts biodiversity and water quality while straining local fisheries by altering marine food webs. To mitigate microplastic entrapment from algal blooms and protect vulnerable marine ecosystems, targeted monitoring and intervention strategies are essential.

Thiophene and pyrrole units are extensively utilized in light-responsive materials and have significantly advanced the field of organic photovoltaics (OPV). This progress has inspired our exploration of photosensitizers (PS) for photodynamic therapy (PDT). Currently, traditional PS face limitations in clinical application, including a restricted variety and narrow applicability. Drawing upon molecular design concepts from OPV, we aim to transcend these limitations in PDT. Given the abundance of candidate molecules, effective screening is crucial. Theoretical calculations and electronic structure analyses serve as precise and practical screening methods. In this study, we adopted strategies successfully employed in OPV molecular design, focusing on donor-acceptor (D-A) and acceptor-donor-acceptor (A-D-A) structures. Using density functional theory (DFT) and time-dependent density functional theory (TDDFT), we systematically designed combinations of promising organic fragments. These fragments include polythiophene and polypyrrole-dominated donor structures, paired with five electron acceptors: indene (Ind), diketopyrrole (DPP), naphthalimide (Ni), benzothiazole (Btd), and dithiazolyl diketopyrrole (Tbo). Through meticulous calculations, we obtained electronic structures and spectral properties for all candidate molecules, facilitating an efficient screening process. Our findings highlight that those combinations of polypyrrole-based frameworks with DPP, Ni, and Btd show significant promise for PS applications. Approximately 13% of candidates were selected through comprehensive comparison, markedly reducing molecular design time and experimental costs. This interdisciplinary approach holds potential to pave the way for more targeted and successful PS designs.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignant tumor characterized by a complex tumor microenvironment (TME) with significant heterogeneity, posing immense challenges for devising effective therapeutic strategies. This study aims to elucidate the dynamic changes in the TME during PDAC progression and develop a prognostic model using single-cell RNA sequencing (scRNA-seq) data. We utilized a previously published comprehensive dataset comprising 31 samples (including 8 PDAC I, 9 PDAC II, 6 PDAC III, and 8 PDAC IV) to characterize the changes in TME composition with PDAC progression through advanced scRNA-seq analysis. We found that as cancer progresses, immune cells gradually become a predominant component in late-stage PDAC. We defined a novel Treg and exhausted T cell signature gene, TNFRSF4. Additionally, we identified a prognostic gene set (RPS10, MIF, MT-ATP6, CSTB, IFI30, NPC2, BTG1, CTSD, FCGR2A, SEC61G, IER3, HSPB1, HMOX1, and ZFP36L1) and differentiated high-risk from low-risk PDAC patients based on median risk score threshold. Based on these findings, we developed a novel prognostic model that identifies poorer prognosis in high-risk groups. Furthermore, our analysis revealed significant interactions between cells at different stages of PDAC and identified three promising therapeutic agents (XR-11576, Ixabepilone, and AMONAFIDE) based on correlated genes. Finally, molecular docking studies validated their potential by confirming stable binding with key protein targets. This study not only provides insights into the evolving TME of PDAC but also offers a new prognostic model and potential therapeutic strategies, contributing to improved management and treatment of this aggressive cancer.

At present, although some studies have offered certain insights into the genetic factors related to unruptured intracranial aneurysms (uIAs), the potential genetic targets associated with uIAs remain largely unknown. Thus, this research adopted Mendelian randomization (MR) analysis to study two genome-wide association studies on uIAs, aiming to determine the reliable genetic susceptibility and potential therapeutic targets for uIAs.

This study summarizes the data of expression quantitative trait loci (eQTL) as exposure data. The outcome data of uIAs were derived from the study by Bakker et al. and the FinnGen Biobank (version R10). The reliable genetic susceptibility and potential therapeutic targets of uIAs were identified by means of Mendelian randomization (MR) methods, with the inverse variance weighting (IVW) method as the primary analytical approach. Simultaneously, sensitivity and pleiotropy analyses were carried out, and the results were visualized. Subsequently, drug predictions and molecular docking were conducted for the potential gene targets to verify their reliability.

The MR analysis of the training cohort identified 100 targets related to uIAs. Then, these 100 gene targets and eQTL data were verified by MR Analysis again with the testing cohort. Finally, 7 gene targets were selected, namely MTMR3, SERINC1, CITED2, NKX3-1, ATOX1, MYADM and SLC20A1-DT.GO/KEGG enrichment analysis confirmed that the 7 gene targets mainly participate in the process Biological functions and pathways such as art development, cellular response to hypoxia, male Gonad development, RNA polymerase II specific DNA binding transcription factor binding, DNA binding transcription factor binding, Mineral absorption, Inositol phase metabolism, Photoshatidylinositol signaling system, etc.The protein-protein interaction（PPI） network describes the interactions between seven gene targets and related proteins.The molecular docking diagram shows good binding between candidate drugs and proteins related to gene targets.

The study identified 7 reliable gene susceptibility and potential therapeutic targets associated with uIAs, offering new insights for clinical diagnosis and treatment of uIAs, and suggesting novel research directions for understanding the etiology and molecular mechanisms of uIAs.

The pathological levels of reactive oxygen species (ROS) and oxidative stress has been recognized as a critical driver for inflammatory disorders. Apoptosis signal-regulating kinase 1 (ASK1) has been reported to be activated by intracellular ROS and its inhibition leads to a down regulation of p38-and JNK-dependent signaling. ASK1 inhibitors are reported to have the potential to treat clinically important inflammatory pathologies including liver, pulmonary and renal disorders. In view of its biological and pathological significance, inhibition of ASK1 with small molecules has been pursued as an attractive strategy to combat human diseases such as non-alcoholic steatohepatitis (NASH). Despite several ASK1 inhibitors being developed, the failure in Phase 3 clinical trials of most advanced candidate selonsertib's, underscores to discover therapeutic agents with diverse chemical moiety. Here, by using structural pharmacophore and enumeration strategy on mining co-crystals of ASK1, different scaffolds were generated to enhance the chemical diversity keeping the critical molecular interaction in the catalytic site intact. A total of 15,772 compounds were generated from diverse chemical scaffolds and were evaluated using a virtual screening pipeline. Based on docking and MM-GBSA scores, a lead candidate, S3C-1-D424 was identified from top hits. A comparative molecular dynamics simulations (MD) of APO, Selonsertib and shortlisted potential candidates combined with pharmacokinetics profiling and thermodynamic analysis, demonstrating their suitability as potential ASK1 inhibitors to explore further for establishment towards hit-to-lead campaign.Communicated by Ramaswamy H. Sarma.

XRCC1 is involved in repair of single-strand breaks generated by mutagenic exposure. Polymorphisms within XRCC1 affect its ability to efficiently repair DNA damage. Polycyclic aromatic hydrocarbons or PAHs are genotoxic compounds which form bulky DNA adducts that are linked with infertility. Few reports suggest combined role of XRCC1 polymorphisms and PAHs in infertility. Present study investigates association of three XRCC1 polymorphisms (p.Arg194Trp, p.Arg280His, p.Arg399Gln) with male and female infertility in a North-West Indian population using case-control approach. Additionally, in silico approach has been used to predict whether XRCC1 polymorphisms effect interaction of XRCC1 with different PAHs. For case-control study, XRCC1 polymorphisms were screened in peripheral blood samples of age- and gender-matched 201 infertile cases (♂-100, ♀-101) and 201 fertile controls (♂-100, ♀-101) using PCR-RFLP method. For in silico study, AutoDock v4.2.6 was used for molecular docking of B[a]P, BPDE-I, ( ±)-anti-BPDE, DB[a,l]P, 1-N, 2-N, 1-OHP, 2-OHF with XRCC1 and assess effect of XRCC1 polymorphisms on their interaction. In case-control study, statistical analysis showed association of XRCC1 p.Arg280His GA genotype (p = 0.027), A allele (p = 0.019) with reduced risk of male infertility. XRCC1 p.Arg399Gln AA genotype (p = 0.021), A allele (p = 0.014) were associated with reduced risk for female primary infertility. XRCC1 p.Arg194Trp T allele was associated with increased risk for female infertility (p = 0.035). In silico analysis showed XRCC1-PAH interaction with non-significant effect of XRCC1 polymorphisms on predicted binding. Therefore, present study concludes that XRCC1 polymorphism-modified risk for male and female infertility in North-West Indians without significant effect on predicted XRCC1-PAH interactions. This is the first report on XRCC1 in female infertility.

Hepatocellular carcinoma (HCC) is the most prevalent type of liver cancer. Dosage suppressor of NNF1 (DSN1), a component of the MIS12 kinetochore complex, encodes a kinetochore protein crucial for proper mitotic assembly. The role of DSN1 in HCC remains to be elucidated. In this study, we utilized The Cancer Genome Atlas, the Hepatocellular carcinoma Cell Database, and other databases to analyze DSN1 expression and prognosis in samples from patients with HCC. We investigated the signaling pathways regulated by DSN1 and their implications in HCC. Additionally, we engineered siRNA/shRNA and overexpression vectors for DSN1 and assessed the specific mechanisms of regulatory pathways of DSN1 in hepatoma cell lines and subcutaneous tumor xenograft model. Our findings revealed that DSN1 expression was significantly upregulated in patients with HCC, correlating with decreased survival rates. Elevated DSN1 expression led to the overproduction of cell cycle-related proteins through direct interaction with Centromere Protein T. This interaction contributes to chromosomal instability in patients with HCC, resulting in an aberrant cell cycle and fostering the development and progression of HCC. Increased DSN1 expression is pivotal in HCC initiation and progression. Investigating DSN1 offers valuable insights into the pathogenesis, treatment, and prevention of HCC.

Ginkgolide B (GB) is a bioactive constituent found in Ginkgo biloba leaves that has been long recognized as a protective agent against many neurological disorders. Our study aimed to examine the effect of GB in an in vitro Parkinson's disease (PD) model and to investigate its neuroprotective mechanism as a primary objective. SK-N-SH cells were challenged with 1-methyl-4-phenylpyridinium (MPP+) to act as a PD-like model of neuronal damage. CCK-8 method, flow cytometry assay, and fluorescent probe JC-1 respectively measured cell viability, apoptosis, and mitochondrial membrane potential (MMP). Oxidative stress parameters were examined with assay kits. Nicotinamide adenine dinucleotide phosphate level and adenosine triphosphate (ATP) synthesis were also appraised. RT-qPCR examined mitochondrial DNA (mtDNA) release. Western blotting analyzed the proteins implicated in apoptosis and the histone deacetylase 4 (HDAC4)/Jun N-terminal kinase (JNK) pathway. GB concentration-dependently alleviated MPP+-stimulated viability loss, apoptosis, oxidative stress, and mitochondrial dysfunction in SK-N-SH cells. GB docked with HDAC4 and downregulated the HDAC4/JNK pathway. HDAC4 overexpression further reduced the viability and aggravated apoptosis, oxidative stress, and mitochondrial dysfunction in GB-treated SK-N-SH cells challenged with MPP+. Altogether, GB might inactivate the HDAC4/JNK pathway to protect against MPP+-triggered neuronal damage in PD.

Serpins (serine protease inhibitors) constitute a superfamily of proteins with functional diversity and unusual conformational flexibility. In insects, serpins act as multiple inhibitors, by forming inactive acyl-enzyme complexes, in regulating Spätzles activation, phenoloxidases (POs) activity, and other cytokines. In this study, we present the cloning and characterization of Octodonta nipae serpin2 (OnSPN2), a 415 residues protein homologous to Tenebrio molitor 42Dd-like. Notably, OnSPN2 features an arginine residue (R364) at the P1 position, and additional arginine residues (R362, R367) at the P3 and P3' positions, respectively which is crucial for protease inhibition. Immunohistochemistry (IHC) and Western blot analyses revealed that OnSPN2 is primarily synthesized in plasmatocytes and then released into the plasma to exert its function. RNA interference results indicated that OnSPN2 knockdown may depress serine protease in melanization and remarkably increase the transcript level of Attacin in hemolymph, but its messenger RNA levels were not changed upon immune induction. Reciprocal co-immunoprecipitation assay results confirmed that OnSPN2 binds to OnPPAF1 and OnSP8, indicating its role as a negative regulator in the PO and AMP pathway. Intriguingly, several cathepsin-L isoforms were identified in the OnSPN2 immunoprecipitated samples. The cathepsin-L inhibition assays and protein-protein docking results, identified cathepsin-L as a potential target of OnSPN2. These results indicate that OnSPN2 is produced as an intracellular resident and additionally is associated with the PO and AMP pathway. OnSPN2 represents a multiple defense tool that may provide multiple antiproteolytic functions.

Vitiligo is a complex autoimmune disease characterized by the loss of melanocytes, leading to skin depigmentation. Despite advances in understanding its genetic and molecular basis, the precise mechanisms driving vitiligo remain elusive. Integrating multiple layers of omics data can provide a comprehensive view of disease pathogenesis and identify potential therapeutic targets. The study aims to delineate the genetic and molecular mechanisms of vitiligo pathogenesis using an integrative multiomics strategy. We focus on exploring the regulatory influence of the JAK/STAT pathway on Cathepsin S, a potential therapeutic target in vitiligo. Our GWAS-meta analysis pinpointed five druggable genes: ERBB3, RHOH, CDK10, MC1R, and NDUFAF3, and underwent drug target exploration and molecular docking. SMR analysis linked CTSS, CTSH, STX8, KIR2DL3, and GRHPR to vitiligo through pQTL and eQTL associations. Microarray and single-cell RNA-seq data showed differential expression of CTSS and STAT1/3 in vitiligo patients' blood and skin lesions. Our study offers novel perspectives on vitiligo's genetic and molecular basis, highlighting the JAK/STAT pathway's role in regulating CTSS for antigen processing in melanocytes. Further research is needed to confirm these results and assess the therapeutic potential of CTSS and related genes.

Gamma-interferon-induced lysosomal thiol reductase (GILT), known for catalyzing disulfide bond reduction, is involved in various physiological processes. While the involvement of GILT in the development of various tumors has been demonstrated, the mechanisms underlying its regulation in prostate cancer (PCa) are not fully understood. In the present study, we confirmed that GILT was significantly upregulated in PCa and facilitated tumor metastasis. Mechanistically, GILT stabilized the cofilin protein by competitively binding to cofilin with Src family tyrosine kinase (SRC), inhibiting SRC-mediated tyrosine phosphorylation of cofilin, thereby suppressing the ubiquitination pathway degradation of cofilin. GILT overexpression stabilized and increased the protein level of cofilin in PCa cells and promoted the metastasis of PCa cells by accelerating actin dynamics through cofilin-mediated actin severing. Our findings reveal a novel mechanism of GILT in PCa and provide a new potential target for the diagnosis and treatment of PCa patients.