Search Results (1,910)

Objective: Visceral leishmaniasis (VL), a Neglected Tropical Disease caused by Leishmania donovani, remains insufficiently addressed by current therapies due to high toxicity, poor efficacy, and immunosuppressive complications. This study aimed to identify and characterize repurposed drugs that simultaneously target parasite-encoded and host-associated mechanisms essential for VL pathogenesis. Methods: Two complementary in silico drug repurposing strategies were employed. The first method utilized electron–ion interaction potential (EIIP) screening followed by molecular docking and molecular dynamics (MD) simulations targeting two L. donovani proteins: Rab5a and pteridine reductase 1 (PTR1). The second approach employed network-based drug repurposing using the Drugst.One platform, prioritizing candidates via STAT3-associated gene networks. Predicted drug–target complexes were validated by 100 ns MD simulations, and pharmacokinetic parameters were assessed via ADMET profiling using QikProp v7.0 and SwissADME web server. Results: Entecavir and valganciclovir showed strong binding to Rab5a and PTR1, respectively, with Glide Scores of −9.36 and −9.10 kcal/mol, and corresponding MM-GBSA ΔG_bind values of −14.00 and −13.25 kcal/mol, confirming their stable interactions and repurposing potential. Network-based analysis identified nifuroxazide as the top candidate targeting the host JAK2/TYK2–STAT3 axis, with high stability confirmed in MD simulations. Nifuroxazide also displayed the most favorable ADMET profile, including oral bioavailability, membrane permeability, and absence of PAINS alerts. Conclusions: This study highlights the potential of guanine analogs such as entecavir and valganciclovir, and the nitrofuran derivative nifuroxazide, as promising multi-target drug repurposing candidates for VL. Their mechanisms support a dual strategy targeting both parasite biology and host immunoregulation, warranting further preclinical investigation. Full article

Allicin (ALC), a naturally occurring organosulfur compound derived from garlic (Allium sativum), exhibits potential neuroprotective properties. Parkinson’s disease (PD) is a progressive neurodegenerative disease characterized by degeneration of dopaminergic neurons and motor dysfunction. This study utilized bioinformatics and network pharmacology methods to predict the anti-PD mechanism of ALC and established in vivo and in vitro PD models using 6-hydroxydopamine (6-OHDA) for experimental verification. Network pharmacological analysis indicates that apoptosis regulation and the PKA/p-CREB/BDNF signaling pathway are closely related to the anti-PD effect of ALC, and protein kinase A (PKA) and dopamine transporter (DAT) are key molecular targets. The experimental results show that ALC administration can alleviate the cytotoxicity of SH-SY5Y induced by 6-OHDA and simultaneously improve the motor dysfunction and dopaminergic neuron loss in PD mice. In addition, ALC can also activate the PKA/p-CREB/BDNF signaling pathway and increase the DAT level in brain tissue, regulate the expression of BAX and Bcl-2, and reduce neuronal apoptosis. These results indicate that ALC can exert anti-PD effects by up-regulating the PKA/p-CREB/BDNF/DAT signaling pathway and inhibiting neuronal apoptosis, providing theoretical support for the application of ALC in PD. Full article

Background: Huntington’s Disease (HD) is a monogenic neurodegenerative disease resulting in a CAG repeat expansion in the HTT gene. Despite this genetic simplicity, its molecular mechanisms remain highly complex. Methods: In this study, untargeted serum proteomics, bioinformatics analysis, biomarker filtering and ELISA validation were implemented to characterize the proteomic landscape across the three HD stages—asymptomatic, early symptomatic and symptomatic advanced—alongside gender/age-matched controls. Results: We identified 84 over-expressed and 118 under-expressed differentially expressed proteins. Enrichment analysis revealed dysregulation in pathways including the complement cascade, LXR/RXR activation and RHOGDI signaling. Biomarker analysis highlighted key proteins with diagnostic potential, including CAP1 (AUC = 0.809), CAPZB (AUC = 0.861), TAGLN2 (AUC = 0.886), THBS1 (AUC = 0.883) and CFH (AUC = 0.948). CAP1 and CAPZB demonstrated robust diagnostic potential in linear mixed-effects models. CAP1 decreased in the asymptomatic stage, suggesting early cytoskeletal disruption, while CAPZB was consistently increased across HD stages. Conclusions: Our findings illuminate the dynamic proteomic and molecular landscape of HD. Future studies should validate these candidates in larger, more diverse cohorts and explore their mechanistic roles in HD pathology and progression. Full article

Oxidative stress is a defining and pervasive driver of neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). As a molecular accelerant, reactive oxygen species (ROS) and reactive nitrogen species (RNS) compromise mitochondrial function, amplify lipid peroxidation, induce protein misfolding, and promote chronic neuroinflammation, creating a positive feedback loop of neuronal damage and cognitive decline. Despite its centrality in promoting disease progression, attempts to neutralize oxidative stress with monotherapeutic antioxidants have largely failed owing to the multifactorial redox imbalance affecting each patient and their corresponding variation. We are now at the threshold of precision redox medicine, driven by advances in syndromic multi-omics integration, Artificial Intelligence biomarker identification, and the precision of patient-specific therapeutic interventions. This paper will aim to reveal a mechanistically deep assessment of oxidative stress and its contribution to diseases of neurodegeneration, with an emphasis on oxidatively modified proteins (e.g., carbonylated tau, nitrated α-synuclein), lipid peroxidation biomarkers (F2-isoprostanes, 4-HNE), and DNA damage (8-OHdG) as significant biomarkers of disease progression. We will critically examine the majority of clinical trial studies investigating mitochondria-targeted antioxidants (e.g., MitoQ, SS-31), Nrf2 activators (e.g., dimethyl fumarate, sulforaphane), and epigenetic reprogramming schemes aiming to re-establish antioxidant defenses and repair redox damage at the molecular level of biology. Emerging solutions that involve nanoparticles (e.g., antioxidant delivery systems) and CRISPR (e.g., correction of mutations in SOD1 and GPx1) have the potential to transform therapeutic approaches to treatment for these diseases by cutting the time required to realize meaningful impacts and meaningful treatment. This paper will argue that with the connection between molecular biology and progress in clinical hyperbole, dynamic multi-targeted interventions will define the treatment of neurodegenerative diseases in the transition from disease amelioration to disease modification or perhaps reversal. With these innovations at our doorstep, the future offers remarkable possibilities in translating network-based biomarker discovery, AI-powered patient stratification, and adaptive combination therapies into individualized/long-lasting neuroprotection. The question is no longer if we will neutralize oxidative stress; it is how likely we will achieve success in the new frontier of neurodegenerative disease therapies. Full article

Powdery mildew (PM), caused by Sphaerotheca phaseoli, severely threatens mungbean (Vigna radiata) productivity and quality, yet the molecular basis of resistance remains poorly defined. This study employed transcriptome profiling to compare defense responses in a resistant genotype, SUPER5, and a susceptible variety, CN84-1, following pathogen infection. A total of 1755 differentially expressed genes (DEGs) were identified, with SUPER5 exhibiting strong upregulation of genes encoding pathogenesis-related (PR) proteins, disease resistance proteins, and key transcription factors. Notably, genes involved in phenylpropanoid and flavonoid biosynthesis, pathways associated with antimicrobial compound and lignin production, were markedly induced in SUPER5. In contrast, CN84-1 showed limited activation of defense genes and downregulation of essential regulators such as MYB14. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses highlighted the involvement of plant–pathogen interaction pathways, MAPK signaling, and reactive oxygen species (ROS) detoxification in the resistant response. Quantitative real-time PCR validated 11 candidate genes, including PAL3, PR2, GSO1, MLO12, and P21, which function in pathogen recognition, signaling, the biosynthesis of antimicrobial metabolites, the production of defense proteins, defense regulation, and the reinforcement of the cell wall. Co-expression network analysis revealed three major gene modules linked to flavonoid metabolism, chitinase activity, and responses to both abiotic and biotic stresses. These findings offer valuable molecular insights for breeding PM-resistant mungbean varieties. Full article

Mycoplasma bovis is an important pathogen that is associated with respiratory diseases, mastitis, and arthritis in cattle, leading to significant economic losses in the global cattle industry. Most notably in this study, we pioneer the discovery that its secreted effector ENO1 (α-enolase) directly targets host cytoskeletal proteins for metabolic–immune regulation. Using an innovative GST pull-down/mass spectrometry approach, we made the seminal discovery of β-actin (ACTB) as the primary host target of ENO1—the first reported bacterial effector–cytoskeleton interaction mediating metabolic reprogramming. ENO1–ACTB binding depends on a hydrogen bond network involving ACTB’s 117Glu and 372Arg residues. This interaction triggers (1) glycolytic activation via Glut1 upregulation, establishing Warburg effect characteristics (lactic acid accumulation/ATP inhibition), and (2) ROS-mediated activation of dual inflammatory axes (HIF-1α/IL-1β and IL-6/TNF-α). This work establishes three groundbreaking concepts: (1) the first evidence of a pathogen effector hijacking host ACTB for metabolic manipulation, (2) a novel ‘glycolysis–ACTB–ROS-inflammation’ axis, and (3) the first demonstration of bacterial proteins coordinating a Warburg effect with cytokine storms. These findings provide new targets for anti-infection therapies against Mycoplasma bovis. Full article

Background: Melanoma metastasis, driven by tumor microenvironment (TME)-mediated crosstalk facilitated by extracellular vesicles (EVs), remains a major therapeutic challenge. A critical barrier to clinical translation is the overlap in protein cargo between tumor-derived and healthy cell EVs. Objective: To address this, we developed Scaffold-free Functional Deconvolution (SFD), a novel computational approach that leverages a comprehensive healthy cell EV protein database to deconvolute non-oncogenic background signals. Methods: Beginning with 1915 proteins (identified by MS/MS analysis on an Orbitrap Fusion Lumos Mass Spectrometer using the IonStar workflow) from melanoma EVs isolated using REIUS, SFD applies four sequential filters: exclusion of normal melanocyte EV proteins, prioritization of metastasis-linked entries (HCMDB), refinement via melanocyte-specific databases, and validation against TCGA survival data. Results: This workflow identified 21 high-confidence targets implicated in metabolic-associated acidification, immune modulation, and oncogenesis, and were analyzed for reduced disease-free and overall survival. SFD’s versatility was further demonstrated by surfaceome profiling, confirming enrichment of H7-B3 (CD276), ICAM1, and MIC-1 (GDF-15) in metastatic melanoma EV via Western blot and flow cytometry. Meta-analysis using Vesiclepedia and STRING categorized these targets into metabolic, immune, and oncogenic drivers, revealing a dense interaction network. Conclusions: Our results highlight SFD as a powerful tool for identifying clinically relevant biomarkers and therapeutic targets within melanoma EVs, with potential applications in drug development and personalized medicine. Full article

Background: The metabolic dysfunction-associated steatotic liver disease (MASLD) represents an escalating global health concern, with effective treatments still lacking. Given its complex pathogenesis, multi-targeted strategies are highly desirable. Methods: This study reports the isolation of four flavone C-glycosides (FCGs) from Dianthus superbus L. and explores their potential in treating MASLD. The bioactivity and underlying mechanisms of FCGs were systematically evaluated by integrating network pharmacology, molecular docking, and zebrafish model validation. Results: Network pharmacology analysis revealed that FCGs may modulate multiple MASLD-related pathways, including lipid metabolism, insulin signaling, inflammation, and apoptosis. Molecular docking further confirmed strong binding affinities between FCGs and key protein targets involved in these pathways. In the zebrafish model of MASLD induced by egg yolk powder, FCGs administration markedly attenuated obesity, hepatic lipid accumulation, and liver tissue damage. Furthermore, FCGs improved lipid metabolism and restored locomotor function. Molecular analyses confirmed that FCGs upregulated PPARγ expression to promote lipid metabolism, restored insulin signaling by enhancing INSR, PI3K, and AKT expression, and suppressed inflammation by downregulating TNF, IL-6 and NF-κB. Additionally, FCGs inhibited hepatocyte apoptosis by elevating the BCL-2/BAX ratio. Conclusions: These findings highlight the multi-pathway regulatory effects of FCGs in MASLD, underscoring its potential as a novel therapeutic candidate for further preclinical development. Full article

Alzheimer’s disease (AD) is a neurodegenerative disease with a multifaceted pathogenesis, which remains elusive, seriously affecting the quality of life of elderly patients and placing a heavy burden on affected individuals, their families, and society. As third-party synapses in brain networks, astrocytes play an important role in maintaining the normal function of neural networks, which contribute to the abnormal function of networks in AD. In recent years, numerous studies have shown that clusterin, a protein expressed by astrocytes, can participate in the progression of AD. Clusterin plays a significant role in many pathological processes of AD, such as lipid metabolism, AD pathological features, the imbalance in neural circuit excitatory inhibition, and neuroinflammation. Therefore, delving deeper into the association between clusterin and AD will help us to understand the mechanisms of disease better and provide a theoretical basis for early diagnosis and the development of treatment strategies for AD. Full article

Codonopsis pilosula polysaccharides have demonstrated multiple biological activities including immune regulation, antitumor, and antioxidant properties. The rapid development and integrated application of multi-omics can facilitate the unraveling of the complex network of immune system regulation. In this study, C. pilosula alkali-extracted polysaccharide (CPAP) were prepared, and their effects on gut microbiota compositions, metabolic pathways, and protein expressions in peripheral blood and solid tumors in mice were further evaluated. The 16S rDNA sequencing results showed that CPAP could effectively promote the enrichment of intestinal Lactobacillus in tumor-bearing mice. In addition, it could be inferred from peripheral blood and solid tumor proteomics results that CPAP might activate T cell-mediated antitumor immune functions by regulating purine metabolism and alleviate tumor-caused inflammation by promoting neutrophil degranulation, finally inducing apoptosis in tumor cells by increasing oxidative stress. These results will provide a theoretical foundation and data support for the further development of CPAP as dietary adjuvants targeting immune deficiency-related diseases. Full article

Background: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive disease that easily develops into cirrhosis and hepatocellular carcinoma, but its pathogenesis is not clear, and most therapeutic drugs have obvious limitations. However, Babao Dan (BBD) has a good therapeutic effect on liver disease, but its treatment mechanism is still to be studied. Therefore, we further investigated the mechanism of BBD in treating MASH. Methods: We predicted BBD-related targets through network pharmacology and further verified the binding ability of BBD-related targets through molecular docking. We also detected relevant indicators before and after model treatment, as well as metabolomics analysis and identification of the mechanism of action of BBD on MASH. Results: Through network pharmacology methods, 158 key cross targets and the top 10 core targets were identified, and it was determined that the PI3K-AKT signaling pathway plays an important regulatory role in the treatment of MASH with BBD. The molecular docking results indicate that the representative compounds quercetin and 17 Beta Estradiol have good binding activity with five core targets. Metabolomics has identified four metabolic biomarkers, such as Piceid, and it is determined that the key pathway for BBD treatment of MASH is the bile secretion pathway. Conclusions: BBD effectively treats MASH by modulating Piceid and other biomarkers, targeting ESR1 and other core proteins via quercetin and 17-beta-estradiol, and regulating the PI3K-AKT and bile secretion pathways to alleviate liver injury. Full article

Background/Objectives: Sepsis-induced cardiomyopathy (SIC) is a serious clinical disorder with a high death rate. Qifu decoction (QFD) is a renowned traditional Chinese medicine with documented pharmacological actions, such as anti-inflammatory, anti-oxidant and anti-apoptosis activities, and it has good therapeutic effects on cardiovascular diseases. This study aimed to reveal the cardioprotective effects and underlying mechanisms of QFD against SIC. Methods: Electrocardiography, histopathological examination, and biochemical indicator determination were carried out to investigate the cardioprotective effects of QFD in the treatment of LPS-induced SIC mice. Metabolomics and network pharmacology strategies were employed to preliminarily analyze and predict the mechanisms of QFD against SIC. Molecular docking and Western blot were further applied to validate the core targets and potential pathways for the treatment of SIC in in vitro and in vivo models. Results: It was found that QFD considerably enhanced cardiac function; attenuated myocardial injury; and reduced the serum levels of LDH, CK-MB, IL-1β, and TNF-α by 28.7%, 32.3%, 38.6%, and 36.7%, respectively. Metabolomic analysis showed that QFD could regulate seven metabolic pathways, namely, glutathione metabolism; alanine, aspartate, and glutamate metabolism; arachidonic acid metabolism; glycerophospholipid metabolism; purine metabolism; sphingolipid metabolism; and fatty acid metabolism. Network pharmacology suggested that the anti-SIC effect of QFD may be mediated through the TNF, toll-like receptor, NOD-like receptor, NF-κB, and PPAR signaling pathways. Additionally, 26 core targets were obtained. Molecular docking revealed that active ingredients such as formononetin, kaempferol, quercetin, and (R)-norcoclaurine in QFD had a high affinity for binding to PPARα and TLR4. Further Western blot validation indicated that QFD could regulate the protein levels of NLRP3, TLR4, NF-κB, IL-6, TNF-α, COX2, sPLA2, PPARα, CPT1B, and CPT2. Conclusions: This study demonstrates that QFD can alleviate SIC by suppressing the TLR4/NF-κB/NLRP3 inflammatory pathway and modulating impaired FAO through the activation of the PPARα/CPT pathway, highlighting QFD as a promising candidate drug for SIC treatment. Full article

Proto-oncogenes in the RAS superfamily play dual roles in maintaining cellular homeostasis, such as regulating growth signals and contributing to cancer development through proliferation and deregulation. Activating proto-oncogenes in vitro transforms cells, underscoring their centrality in gene regulation and cellular networks. Despite decades of research, poor outcomes in advanced cancers reveal gaps in understanding Ras-driven mechanisms or therapeutic strategies. This narrative review examines RAS genes and Ras proteins in both housekeeping functions, such as cell growth, apoptosis, and protein trafficking, as well as in tumorigenesis, integrating insights from human (HRAS, KRAS, NRAS), mouse (Hras, Kras, Nras), and Drosophila melanogaster (ras) models. While RAS mutations are tightly linked to human tumors, the interplay between their standard and oncogenic functions remains complex. Even within the same tissue, distinct cancer pathways—such as the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways—can drive varied disease courses, complicating treatment. Advanced-stage cancers add further challenges, including heterogeneity, protective microenvironments, drug resistance, and adaptive progression. This synthesis organizes current knowledge of RAS gene regulation and Ras protein function from genomic alterations and intracellular signaling to membrane dynamics and extracellular interactions, offering a layered perspective on the Ras pathway’s role in both housekeeping and tumorigenic contexts. Full article

Xerostomia, the subjective complaint of a dry mouth, is frequently associated with salivary flow reduction and/or salivary gland hypofunction. This condition significantly impacts an individual’s quality of life and oral health, including difficulties in speaking, chewing, and swallowing. Xerostomia may be caused by autoimmune diseases, xerogenic medications, and radiation therapy. Our objective was to identify differentially expressed proteins in the saliva of patients with medication and autoimmune disease-associated xerostomia compared to non-xerostomic control subjects. Two groups of individuals (N = 45 total) were recruited: non-xerostomic subjects (NX-group; n = 18) and xerostomic patients (XP-group; n = 27). Dried saliva spot samples were collected from major salivary glands, i.e., parotid (left and right) and submandibular glands. Proteomic analysis was performed by deep nanoLC-MS/MS. Differential protein expression in the XP-group relative to the NX-group was determined by the Mann–Whitney U-test with FDR Benjamini–Hochberg correction (p_adj < 0.05). The Search Tool for Recurring Instances of Neighboring Genes (STRING_v12.0) was used to generate interaction networks and perform pathway analysis. A total of 1407 proteins were detected. Of these, 86 from the left parotid gland, 112 from the right parotid gland, and 73 from the submandibular gland were differentially expressed proteins (DEPs). Using STRING analysis, we identified, for the first time, several neurodegenerative disease-associated networks, primarily involving the downregulation of the 20S proteasome core complex and glyoxalase proteins across salivary glands. In this study, we determined neuronal dysregulation and impaired methylglyoxal (MGO) detoxification, possibly through reduced protein expression of glyoxalase Parkinson’s Disease (PD) Protein 7 (encoded by the PARK7 gene) in major salivary glands of xerostomic patients. Indeed, impaired MGO detoxification has been previously shown to cause salivary gland dysfunction in a mouse model of type 2 diabetes. Based on other DEPs associated with neurodegenerative disorders, our results also suggest a possible deficiency in the parasympathetic nervous system innervation of salivary glands, warranting further investigation. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become the leading cause of chronic liver disease worldwide, affecting approximately 25–30% of the global adult population and highlighting the urgent need for effective therapeutics and prevention strategies. MASLD is characterized by excessive hepatic lipid accumulation and can progress, in a subset of patients, to metabolic dysfunction-associated steatohepatitis (MASH), a pro-inflammatory and pro-fibrotic condition associated with increased risk of liver cirrhosis and hepatocellular carcinoma. Although the molecular drivers of MASLD progression remain incompletely understood, several key metabolic pathways—such as triglyceride handling, cholesterol catabolism, bile acid metabolism, mitochondrial function, and autophagy—are consistently dysregulated in MASLD livers. This narrative review summarizes primary literature and highlights insights from recent reviews on the multifaceted role of the mRNA-binding protein Human antigen R (HuR) in the post-transcriptional regulation of critical cellular processes, including nutrient metabolism, cell survival, and stress responses. Emerging evidence underscores HuR’s essential role in maintaining liver homeostasis, particularly under metabolic stress conditions characteristic of MASLD, with hepatocyte-specific HuR depletion associated with exacerbated disease severity. Moreover, comorbid conditions such as obesity, type 2 diabetes mellitus, and cardiovascular disease not only exacerbate MASLD progression but also involve HuR dysregulation in extrahepatic tissues, further contributing to liver dysfunction. A deeper understanding of HuR-regulated post-transcriptional networks across metabolic organs may enable the development of targeted therapies aimed at halting or reversing MASLD progression. Full article