Search Results (3,059)

The cerebellar cortex presents a repetitive structure, but the main projecting neurons of this tissue, the Purkinje cells, are not identical and behave differently to various types of injury. Common patterns of neurodegeneration exist, where certain Purkinje cells die earlier than others. By contrast, lobe X of the cerebellum is a particularly resistant structure, independently of the cerebellar disease or damage. However, the mechanisms underlying the survival capability of these especially resistant Purkinje cells are still unknown. In this work, we have used the Purkinje Cell Degeneration (PCD) mouse, a model of severe cerebellar degeneration that also reproduces the human disease called childhood-onset neurodegeneration with cerebellar atrophy, to study Purkinje cell resistance. After an exhaustive immunochemical analysis of the different subpopulations of Purkinje cells, the Heat Shock Protein 25 (HSP25) and its phosphorylated version HSP25-P-Ser15 were found to be especially induced in lobe X of PCD mice. As this protein has neuroprotective properties, it may be responsible for resistance against cerebellar neurodegeneration. Taking into account the constant resistance of lobe X, the use of HSP25 may lead to new possibilities for achieving natural protection both in cerebellum and in other brain structures, or even for developing future neuroprotective therapies. Full article

Osmotic stress affects ion transport and cell hydration, potentially disrupting redox homeostasis through altered proteostasis and mitochondrial metabolism. However, how immune hemocytes coordinate volume regulation with these stress-linked processes, particularly oxidative stress and antioxidant responses, remains unclear in crustaceans. This study integrated quantitative cytology, RNA sequencing, and network analysis to profile hemocyte volume plasticity in the euryhaline shrimp Penaeus monodon across a salinity gradient. Hemocytes were incubated for 24 h in hypoosmotic, isosmotic, and hyperosmotic media, with significant volume shifts observed while maintaining membrane integrity and morphology. The permeability of solutes (urea and sorbitol) suggested that volume adjustment is coupled with solute transport. Transcriptomic analyses identified key salinity-responsive pathways, including oxidative phosphorylation, MAPK signaling, ribosome biogenesis, and antioxidant defense mechanisms, underscoring the activation of redox-regulatory systems under osmotic stress. Weighted gene co-expression network analysis highlighted ribosomal proteins as central hubs in a salinity-responsive module, with qRT-PCR confirming the co-regulation of these hubs alongside representative osmoregulatory and antioxidant genes (AQP4, Na⁺/K⁺-ATPase, HSP70, CHOP, and antioxidant enzymes). These findings reveal how hemocyte volume dynamics are coupled to redox regulation, providing a mechanistic framework for understanding osmotic stress–redox coupling in crustacean immune cells. Full article

Autonomous drone swarms are increasingly deployed in critical domains such as infrastructure inspection, environmental monitoring, and emergency response. While their distributed operation enables scalability and resilience, it also introduces new vulnerabilities, particularly in authentication and trust establishment. Conventional cryptographic solutions, including public key infrastructures (PKI) and symmetric key protocols, impose computational and connectivity requirements unsuited to resource-constrained and external infrastructure-free swarm deployments. In this paper, we present a decentralized authentication scheme rooted in hardware security primitives (HSPs); specifically, Physical Unclonable Functions (PUFs) and True Random Number Generators (TRNGs). The protocol leverages master-initiated token broadcasting, iterative HSP seed evolution, randomized response delays, and statistical trust evaluation to detect cloning, replay, and impersonation attacks without reliance on centralized authorities or pre-distributed keys. Simulation studies demonstrate that the scheme achieves lightweight operation, rapid anomaly detection, and robustness against wireless interference, making it well-suited for real-time swarm systems. Full article

Natural compounds, as honey-derived flavonoids and phenolic compounds, are increasingly investigated for their potential to mitigate skin aging and prevent oxidative stress-induced cellular damages. In this context, a dynamic cell culture model was employed to assess the protective influence of honey pre-treatment on stem cell–associated genes and the Wingless-related integration site (Wnt) signaling pathway following ultraviolet (UV)-induced aging. Using a bioreactor, skin stem cells (SSCs) derived from healthy skin biopsies and human skin fibroblasts (HFF1) were pre-treated with 1% honey for 48 h and then exposed to UV. Real-time quantitative polymerase chain reaction (RT-qPCR) analyses were performed on Wnt signaling and anti-aging molecular responses. Honey pre-treatment enhanced the expression of pluripotency markers (Octamer-binding transcription factor 4 (Oct4); SRY-box transcription factor 2 (Sox2)) and reduced senescence-related cell cycle regulators (cyclin-dependent kinase inhibitor 2A (p16); cyclin-dependent kinase inhibitor 1A (p21); tumor protein 53 (p53)) in SSCs. In UV-damaged SSCs, honey also significantly increased Wnt3a expression. In fibroblasts, honey pre-treatment upregulated Heat shock protein 70 (Hsp70) and Hyaluronan synthase 2 (HAS2) expression, while downregulating caspase-8 (CASP8), indicating a protective role against UV-mediated cellular stress. We also analyzed nitric oxide release and the total antioxidant capacity of cells after treatment. Collectively, these findings suggest that honey may safeguard skin stem cells from UV-induced aging by modulating pluripotency and senescence-associated genes and regulating differentiation through alterations in Wnt signaling. Furthermore, Hsp70 upregulation in fibroblasts appears to strengthen cellular stress responses and support homeostatic stability. Full article

Prostate cancer (PCa) metastasis is reliant on the activity of proteases, such as matrix metalloproteinase-2 (MMP-2). While increased extracellular heat shock protein 90α (eHSP90α) has been linked to increased MMP-2 activity, this has not been examined in the context of cellular stress. We examined stress-induced eHSP90α in human prostate cell lines by immunoblot. Fluorometric gelatin dequenching and zymography assays measured MMP activity. Wound healing and Matrigel drop invasion assays were used to quantify cell motility. HSP90α knockout (KO) cells were established with CRISPR/Cas9. Proteases were profiled with molecular inhibitors and protein arrays and validated by siRNA knockdown, immunoblot, and motility assays. Stress increased eHSP90 in four out of four human prostate cell lines examined. Surprisingly, it concurrently decreased MMP-2 activity. The functional relevance of this was demonstrated when conditioned media from stressed cells decreased the motility of non-stressed cells. Screening for protease inhibitors that would rescue stress-induced decreases in MMP-2 activity identified a single serine protease inhibitor: aprotinin. Yet rescue with aprotinin was lost in HSP90α KO cells. A protease array identified stress-induced increases in kallikrein-related peptidase 6 (KLK6). Knockdown of KLK6 rescued stress-induced MMP-2 activity and cell motility. In conclusion, we identify a novel stress-induced extracellular network that regulates MMP-2 activity and cell motility. We identified KLK6 as a stress-induced extracellular protease leading to decreased MMP-2 activity and cellular invasion, while eHSP90α is required for the rescue of MMP-2 activity once KLK6 is neutralized. Full article

Hylocereus undatus growth is limited by long-term heat stress, and heat shock protein 70 (Hsp70) is crucial in the plant’s heat stress (HS) response. In a previous study, transcriptomic data revealed that Hsp70 family members in pitaya seedlings respond to temperature changes. This study identified 27 HuHsp70 genes in pitaya, analyzed their physicochemical properties (such as molecular weight and isoelectric point), and divided them into five subfamilies with conserved gene structures, motifs (short conserved sequence patterns), and cis-acting elements (regulatory DNA sequences). The Ks value (synonymous substitution rate) ranged from 0.93~3.54, and gene duplication events occurred between 71.17 and 272.19 million years ago (Mya). Under HS, eight and nine differentially expressed genes (DEGs) were detected at 24 h and 48 h, respectively. Quantitative real-time PCR (qRT-PCR, a method for measuring gene expression) verified the expression trends, with HuHsp70-11 expression increasing with heat shock duration, indicating that HuHsp70-11 is a key candidate. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed that HuHsp70s, especially HuHsp70-11, play key roles in responding to high temperatures (HT) in H. undatus seedlings. A potential model by which HuHsp70-11 removes excess reactive oxygen species (ROS) and enhances cell membrane permeability was constructed. These results provide new perspectives for exploring the HS response mechanisms and adaptability of H. undatus plants to heat stress. Full article

HIV/AIDS continues to pose a significant global public health concern, with Sub-Saharan Africa having the highest number of people living with HIV (PLHIV). Traditional medicines have been increasingly essential in treating and managing PLHIV. Product Nkabinde (PN), a polyherbal formulation derived from traditional medicinal plants, has recently demonstrated significant potential in the treatment of HIV. This study aims to elucidate the molecular mechanisms underlying the therapeutic effects of phytochemicals identified from PN in HIV treatment, utilizing network pharmacology and molecular docking. The intersecting (common) genes of the 27 phytochemicals of PN and HIV were computed on a Venn diagram, while the protein–protein interaction (PPI) network of the intersecting genes was plotted using STRING. The hub (10) genes were computed and analyzed for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment pathways using ShinyGO. Molecular docking and protein–ligand interaction analysis of the 27 phytochemicals with each of the 10 hub genes were performed using the Maestro Schrodinger suite. The KEGG analysis reveals an important network with lower False Discovery Rate (FDR) values and higher fold enrichment. The pathway enrichments reveal that the 10 hub genes regulated by PN focus on immune regulation, metabolic modulation, viral comorbidity, carcinogenesis, and inflammation. GO analysis further reveals that PN plays key roles in transcription regulation, such as miRNA, responses to hormones and endogenous stimuli, oxidative stress regulation, and apoptotic signalling, kinase binding, protein kinase binding, transcription factor binding, and ubiquitin ligase binding enriched pathways. Consequently, molecular docking unveils complexes with higher binding energies, such as rutin-HSP90AA1 (−10.578), catechin-JUN (−9.512), quercetin-3-O-arabinoside-AKT1 (−9.874), rutin-EGFR (−8.127), aloin-ESR1 (−8.585), and quercetin-3-0-β-D-(6′-galloyl)-glucopyranoside-BCL2 (−7.021 kcal/mol). Overall, the results reveal pathways associated with HIV pathology and possible anti-HIV mechanisms of PN. Therefore, further in silico, in vitro, and in vivo validations are required to substantiate these findings. Full article

We present a computational study that precedes the potential interactions between SARS-CoV-2 helicase (NSP13) and selected host proteins implicated in chaperone-assisted folding and polyamine metabolism. Using structure-based modelling and protein–protein docking (BioLuminate v4.6), followed by all-atom molecular dynamics (MD) simulations (GROMACS v2018.6), and comparative MM-GBSA scoring (HawkDock v2), we evaluated the stability and interface properties of NSP13 complexes with cytosolic heat shock proteins; heat shock protein 40 (HSP40), heat shock protein 70 (HSP70), heat shock protein 90 (HSP90) and the polyamine biosynthesis enzyme ornithine decarboxylase (ODC). Docking, MD, and interface analyses indicate distinct complex behaviours: HSP70-NSP13 complexes sampled compact conformations, HSP90-NSP13 ensembles displayed greater conformational heterogeneity but more favourable comparative MM-GBSA estimates, and ODC-NSP13 interfaces were comparatively well packed. Per-residue contact mapping identified a small set of recurrent NSP13 residues, Lys22 and Asn51, as putative interaction hotspots. The reported findings herein generate testable hypotheses about NSP13 recruitment of host chaperones and modulation of polyamine metabolism that may inform downstream experimental studies. Full article

Background: β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors demonstrated amyloid-lowering efficacy but failed in phase II/III clinical trials due to adverse effects and limited disease-modifying outcomes. This study employed an integrated network pharmacology and molecular docking approach to quantitatively elucidate the multitarget mechanisms of 4 (phase II/III) discontinued BACE1 inhibitors (Verubecestat, Lanabecestat, Elenbecestat, and Umibecestat) and the preclinical compound AM-6494 in Alzheimer’s disease (AD). Methods: Drug-associated targets were intersected with AD-related genes to construct a protein–protein interaction (PPI) network, followed by topological analysis to identify hub proteins. Gene Ontology (GO) and KEGG pathway enrichment analyses were performed using statistically significant thresholds (p < 0.05, FDR-adjusted). Molecular docking was conducted using AutoDock Vina to quantify binding affinities and interaction modes between the selected compounds and the identified hub proteins. Results: Network analysis identified 10 hub proteins (CASP3, STAT3, BCL2, AKT1, MTOR, BCL2L1, HSP90AA1, HSP90AB1, TNF, and MDM2). GO enrichment highlighted key biological processes, including the negative regulation of autophagy, regulation of apoptotic signalling, protein folding, and inflammatory responses. KEGG pathway analysis revealed significant enrichment in the PI3K–AKT–MTOR signalling, apoptosis, and TNF signalling pathways. Molecular docking demonstrated strong multitarget binding, with binding affinities ranging from approximately −6.6 to −11.4 kcal/mol across the hub proteins. Umibecestat exhibited the strongest binding toward AKT1 (−11.4 kcal/mol), HSP90AB1 (−9.5 kcal/mol), STAT3 (−8.9 kcal/mol), HSP90AA1 (−8.5 kcal/mol), and MTOR (−8.3 kcal/mol), while Lanabecestat showed high affinity for AKT1 (−10.6 kcal/mol), HSP90AA1 (−9.9 kcal/mol), BCL2L1 (−9.2 kcal/mol), and CASP3 (−8.5 kcal/mol), respectively. These interactions were stabilized by conserved hydrogen bonding, hydrophobic contacts, and π–alkyl interactions within key regulatory domains of the target proteins, supporting their multitarget engagement beyond BACE1 inhibition. Conclusions: This study demonstrates that clinically failed BACE1 inhibitors engage multiple non-structural regulatory proteins that are central to AD pathogenesis, particularly those governing autophagy, apoptosis, proteostasis, and neuroinflammation. The identified ligand–hub protein complexes provide a mechanistic rationale for repurposing and optimization strategies targeting network-level dysregulation in Alzheimer’s disease, warranting further in silico refinement and experimental validation. Full article

Chronic stress (CS) contributes to male infertility, reduced testosterone levels, and impaired semen quality. CS models induced by glucocorticoids, such as dexamethasone (DEX), negatively affect sperm parameters and testicular health, notably by promoting testicular apoptosis. While individual plant extracts have been studied for their ability to mitigate stress-induced reproductive dysfunction, the preventive effect of the Tri Garn Pis (TGP) polyherbal extract in DEX-induced CS (DexCS) has not previously been investigated. This study evaluated the effects of TGP extract on testicular function, sexual behavior, and sperm quality in DexCS male mice. Seventy-two ICR mice were randomly divided into six groups: control, DexCS, TGP (50, 100, and 200) + DexCS, and TGP200. Mice received TGP (50, 100, 200 mg/kgBW) for 14 days before DEX co-treatment for 28 days. Behavioral and reproductive assessments included depression-like behavior tests, sexual behavior, sperm quality, testicular histopathology, steroidogenesis proteins (AR, CYP11A1, StAR), and apoptosis markers (Hsp70, caspase-3, caspase-9). TGP extract—which is rich in phenolics and flavonoids with antioxidant activity—improved depressive behavior, sexual performance, testicular histology, and low sperm quality. TGP also upregulated testicular StAR expression while reducing caspase-3 and caspase-9 levels. TGP prevents testicular apoptosis, sexual dysfunction, and poor sperm motility induced by DexCS. Full article

White Spot Syndrome Virus (WSSV) remains one of the most devastating pathogens in global shrimp aquaculture, causing massive economic losses annually. This study employed comparative transcriptomics to elucidate the molecular basis of the differential resistance to WSSV between the highly susceptible Pacific white shrimp (Litopenaeus vannamei) and the remarkably resistant oriental river prawn (Macrobrachium nipponense). Our analysis of gill, hepatopancreas, and muscle tissues at 24 h post-infection revealed fundamentally distinct defense strategies. The resistant M. nipponense employs a unique “proactive homeostatic reinforcement” strategy, characterized by significant enrichment of pathways central to cellular homeostasis, including signal transduction, cellular processes, and transport/catabolism. This approach, supported by coordinated up-regulation of heat shock proteins and structural genes, enables effective viral control without triggering excessive immune activation. In contrast, susceptible L. vannamei displays either widespread metabolic dysregulation leading to systemic collapse in moribund individuals or dependency on specific immune pathways (Toll-like receptor signaling and apoptosis) in survivors. Through comparative KEGG analysis, we identified heat shock protein 70 kDa (HSP70, K03283) as a key conserved gene and functionally validated its critical role in antiviral defense using RNA interference. Knockdown of HSP70 in M. nipponense significantly increased cumulative mortality and viral load, confirming its essential protective function. These findings provide novel insights into crustacean antiviral immunity and identify promising genetic targets for breeding WSSV-resistant shrimp strains, offering sustainable solutions for disease management in aquaculture. Full article

Aging-associated facial hyperpigmentation is driven not only by enhanced melanogenesis but also by dermal senescence and deterioration of the dermal–epidermal junction. The purpose of this study was to evaluate whether monopolar radiofrequency (MRF) monotherapy can improve aging-related facial hyperpigmentation by simultaneously suppressing melanogenic signaling and restoring senescence-associated dermal alterations. We assumed that deep dermal heating induced by MRF would modulate fibroblast senescence and basement membrane integrity, thereby indirectly regulating melanocyte activity. In a retrospective review of 26 Asian women, MRF treatment significantly decreased multiple pigmentation parameters, including melanin level, hyperconcentration, and Hemi Melasma Area and Severity Index (hemi-MASI) scores, while concurrently reducing wrinkles, pores, and enhanced overall skin texture without inducing inflammation. Complementary ex vivo experiments using ultraviolet B (UVB)-irradiated human skin demonstrated that MRF markedly reduced pro-melanogenic markers (α-MSH, MC1R, MITF, TYR, TRP1/2), restored collagen type IV expression at the basement membrane, decreased senescence-associated genes (p16, p21), and upregulated protective heat shock proteins (HSP70/47). Together, these findings suggest that MRF improves aging-associated hyperpigmentation by both suppressing melanogenesis and rejuvenating the senescent dermal microenvironment. MRF may serve as an effective non-invasive treatment option for pigmentation disorders in aging skin. Full article

Background: Adrenocortical carcinoma (ACC) is a rare, aggressive malignancy where endogenous steroid excess may foster immune evasion. However, whether this hormonal axis directly modulates the antigen presentation machinery remains unclear. Methods: We applied an immunoinformatics approach to the TCGA-ACC cohort (n = 79) to investigate relationships among steroid phenotype, HLA expression, tumor microenvironment (TME), and patient outcome. Key findings were assessed in an independent validation cohort (ENSAT-ACC, n = 44) using C1A/C1B molecular subtypes corresponding to the steroid phenotypes. Results: Stratification by steroid phenotype revealed two distinct immunological profiles. The high steroid production (HSP) phenotype was associated with suppressed HLA expression and a lymphocyte-depleted “cold” TME. In contrast, the low steroid production (LSP) phenotype displayed elevated HLA expression, enriched T-cell infiltration, and upregulation of immune checkpoints (e.g., PDCD1, CTLA4), consistent with an inflamed but exhausted TME. The core signature of HLA downregulation in the HSP-like phenotype (C1A) and the significant survival advantage of the LSP-like phenotype (C1B) were confirmed in the validation cohort, demonstrating biological robustness despite platform and sample size differences. Conclusions: These findings identify the steroid phenotype as a critical regulator of immune escape in ACC. Our results support incorporating this stratification as a biomarker for patient selection, identifying LSP tumors as the subgroup most likely to benefit from immune checkpoint blockade due to their “hot” yet exhausted microenvironment. Full article

Coxsackievirus B3 (CVB3) is a picornavirus that causes systemic inflammatory diseases including myocarditis, pericarditis, pancreatitis, and meningoencephalitis. We have previously reported that CVB3 induces mitochondrial fission and mitophagy while inhibiting lysosomal degradation by blocking autophagosome-lysosome fusion. This promotes the release of virus-laden mitophagosomes from host cells as infectious extracellular vesicles (EVs), enabling non-lytic viral egress. Transient receptor potential vanilloid 1 (TRPV1), a heat and capsaicin-sensitive cation channel, regulates mitochondrial dynamics by inducing mitochondrial membrane depolarization and fission. In this study, we found that TRPV1 activation by capsaicin dramatically enhances CVB3 egress from host cells via EVs. Released EVs revealed increased levels of viral capsid protein VP1, mitochondrial protein TOM70, and fission protein phospho-DRP1. Moreover, these EVs were enriched in heat shock protein HSP70, suggesting its role in facilitating infectious EV release from cells. Furthermore, TRPV1 inhibition with capsazepine and SB-366791 significantly reduced viral infection in vitro. Our in vivo studies also found that SB-366791 significantly mitigates pancreatic damage and reduces viral titers in a mouse model of CVB3 pancreatitis. Given the lack of understanding regarding factors that contribute to diverse clinical manifestations of CVB3, our study highlights capsaicin and TRPV1 as potential exacerbating factors that facilitate CVB3 dissemination via mitophagy-derived EVs. Full article

Objectives: Contrast-induced acute kidney injury (CIAKI) is a major cause of hospital-acquired renal injury, and strategies for its treatment are currently lacking. This study aimed to investigate the amelioration effect and mechanism of purpurin, a natural antioxidant, against CIAKI via an integrated analysis of network pharmacology, bioinformatics, molecular docking, and animal experiments. Methods: Network pharmacology approaches were used to predict key targets of purpurin against CIAKI. The differential expression of these key targets was further investigated using bioinformatics analysis and molecular binding with purpurin by molecular docking. A CIAKI model was established in SD rats via iohexol administration, and they were treated with 2.5 mg/kg or 5 mg/kg purpurin. Related physiological and pathological indexes were detected to explore the intervention mechanism. Results: Key gene targets were screened from protein–protein interaction networks, of which Pik3c2a, Esr1, Aktip, HSP90AA1, Bcl2, Caspase3, and SRC in the CIAKI group of GSE189881 were significantly differentially expressed compared to the control group. Molecular docking results show that PI3K, ESR1, HSP90, CASP3, AKTI, and SRC had the highest level of connectivity with purpurin. In vivo experiments demonstrated that the Scr and BUN increased in CIAKI rats, the pathological morphology of renal tissue deteriorated, the levels of TNF-α, IL-1β, and IL-6 increased, the contents of MOD and NO in oxidative stress increased, and the activity of SOD and GSH-PX decreased. After administration of purpurin, the above indexes improved in a dose-dependent manner (<0.05). Western blotting showed that purpurin inhibited the Beclin1/Bcl-2/caspase-3 apoptotic cascade and induced the P62/LC3 autophagy pathway. Conclusions: This study provides experimental evidence supporting purpurin as a potential therapeutic agent for CIAKI and further explores its antioxidant mechanisms. Full article