Search Results (823)

Glaucoma is a leading cause of irreversible vision loss characterized by the progressive degeneration of retinal ganglion cells (RGCs) and structural and biochemical remodeling of the optic nerve head. Although lowering intraocular pressure remains the primary clinical intervention, neurodegeneration often persists, highlighting the complexity and multiple mechanisms involved in the disease’s pathophysiology. In the healthy retina, astrocytes and Müller cells maintain structural integrity, homeostatic balance, and metabolic support. However, sustained pathological stress triggers reactive gliosis, a phenomenon with a dichotomous phenotype. Initially, the macroglial response is adaptive and neuroprotective. Persistent biomechanical and ischemic insults shift this profile into a typically deleterious one, characterized by extracellular matrix remodeling, complement system activation, and heightened neuroinflammation, factors that intensify RGC death. Mechanosensitive pathways, notably Piezo1 and various transient receptor potential (TRP) channels, emerge as critical sensors translating physical stress into these reactive cascades within interconnected multicellular networks. This review examines the crucial role of astrocytes and Müller cells in the dynamic modulation of the retinal microenvironment during glaucomatous progression. Finally, it discusses the therapeutic potential of macroglia-directed pharmacological or gene therapies to reprogram the retinal environment. Full article

Isoflurane remains a cornerstone of clinical anaesthesia, valued for its robust pharmacological profile. However, its long-term neurological impact, specifically its potential to trigger cognitive impairment, remains a subject of intense debate. As a highly lipophilic agent that readily penetrates the blood–brain barrier, isoflurane exerts complex modulatory effects on various neurotransmitter systems and signaling cascades. While traditional paradigms have predominantly focused on isoflurane-induced neurotoxicity, characterised by neuronal apoptosis, oxidative stress and neuroinflammation, emerging evidence reveals a more nuanced, “Janus-faced” reality. Intriguingly, exposure to low doses during specific developmental stages has been shown to enhance cognitive function and consolidate memory. This suggests that a unidimensional toxicity model fails to capture the drug’s full biological spectrum. In this review, we propose a “dose–age-effect” model, a novel two-dimensional framework designed to reconcile these divergent findings. By categorising isoflurane’s impact across distinct developmental and mature neurobiological stages, we systematically synthesise high-quality evidence ranging from molecular signaling to behavioural phenotypes. We also examine the underlying mechanistic landscape and evaluate potential intervention strategies. This integrated perspective advances our theoretical understanding of anaesthetic–brain interactions and provides a roadmap for optimising clinical protocols and mitigating the risk of adverse postoperative cognitive outcomes. Full article

Cancer-related fatigue (CRF) remains difficult to manage, and the impact of metal ion-regulated cell death on peripheral fatigue during anticancer therapy is unclear. Here, we investigated whether ferroptosis inducers (FINs) potentiate copper ionophore (CIN)-triggered cuproptosis in skeletal muscle and aggravate lung cancer-related fatigue (LCaRF), and evaluated redox-based interventions. LCaRF cellular models were established using C2C12 exposed to LLC/M109 tumor-conditioned supernatants and treated with FINs (sorafenib/erastin) plus CIN + CuCl₂ (CIN–Cu + FINs). Cell viability, lipid peroxidation, DLAT aggregation (cuproptosis hallmark), copper/glutathione (GSH), mitochondrial function, and FKBP5/Nrf2–HO-1 signaling were assessed with pharmacologic and genetic modulation. An orthotopic lung cancer mouse model underwent wheel-running, tail suspension, and open-field testing with tetrathiomolybdate (TTM) or hydrogen as interventions. FINs sensitized C2C12 cells to CIN–Cu cytotoxicity and increased DLAT aggregation; copper chelation with TTM attenuated these effects. FINs depleted GSH and amplified mitochondrial dysfunction/ROS; exogenous GSH or hydrogen reduced DLAT aggregation and restored mitochondrial indices. FKBP5 was markedly upregulated by CIN–Cu + FINs and linked to suppressed antioxidant defense (Nrf2/HO-1). In vivo, CIN–Cu + FIN treatment exacerbated fatigue-like behaviors, while TTM or hydrogen partially improved performance. FIN–CIN combinations may aggravate skeletal muscle injury and fatigue-like phenotypes in LCaRF models by promoting cuproptosis via GSH depletion and FKBP5/Nrf2-HO-1 dysregulation. Full article

Background/Objectives: Venous thromboembolism (VTE) is a common and potentially preventable complication after hemorrhagic stroke, yet the optimal timing of pharmacologic prophylaxis remains uncertain because of concern for hematoma expansion or rebleeding. Repeat neuroimaging is frequently used to assess hemorrhage stability before initiating deep vein thrombosis (DVT) chemoprophylaxis, although the value of radiographic stability alone remains unclear. This review evaluates the evidence supporting imaging-guided initiation of prophylaxis after intracerebral hemorrhage (ICH) and aneurysmal subarachnoid hemorrhage (aSAH). Methods: A narrative review of the literature was performed focusing on hemorrhage expansion, thrombotic risk, repeat neuroimaging, and timing of pharmacologic prophylaxis in spontaneous ICH and aSAH. Observational studies, limited randomized data, and current guideline recommendations were assessed. Results: In spontaneous ICH, hematoma expansion risk is greatest within the first 24 h, whereas thrombotic risk increases over subsequent days because of immobility and systemic inflammation. Available evidence suggests that early low-dose anticoagulant prophylaxis may be safe in selected patients with stable hemorrhage, although definitions of stability vary and no prospective study has validated repeat imaging as an independent decision trigger. In aSAH, rebleeding risk depends more heavily on aneurysm securement and procedural factors than on imaging appearance alone. Conclusions: Repeat neuroimaging provides important reassurance after hemorrhagic stroke but does not fully capture ongoing biological risks. Current evidence supports a cautious, individualized approach in which radiographic stability informs, but does not independently determine, the timing of pharmacologic VTE prophylaxis. Full article

Background: Microplastics (MPs) and cadmium (Cd) are widespread environmental pollutants posing significant health risks, but their combined hepatotoxic effects and underlying mechanisms remain poorly understood. Methods: Using in vivo and in vitro co-exposure models, we systematically investigated the impact of MPs on Cd-induced hepatotoxicity. The study assessed hepatic injury, oxidative stress, and inflammatory responses through transcriptomic analysis, histopathological examination, immunofluorescence, and quantitative real-time PCR. Pharmacological inhibition of endoplasmic reticulum stress with 4-phenylbutyric acid and selective blockade of IRE1α with MKC3946 were employed to dissect the signaling pathway. Results: Co-exposure to MPs and Cd significantly aggravated Cd-induced hepatic pathological damage, inflammation, and oxidative stress. Transcriptomic profiling revealed marked activation of the endoplasmic reticulum stress pathway and upregulation of pyroptosis-associated genes. Mechanistically, endoplasmic reticulum stress triggered pyroptosis via the IRE1α/TXNIP/NLRP3 signaling axis. Notably, inhibition of endoplasmic reticulum stress with 4-phenylbutyric acid, or selective blockade of IRE1α with MKC3946, effectively attenuated TXNIP/NLRP3 activation and the downstream pyroptotic response. Conclusions: MPs intensify Cd-induced hepatotoxicity by activating the IRE1α/TXNIP/NLRP3 pathway, leading to endoplasmic reticulum stress-driven pyroptosis. These findings provide a mechanistic framework for understanding the combined toxicity of microplastics and heavy metals, with important implications for environmental health risk assessment in animals and humans. Full article

The high-pathogenicity island (HPI) is a major virulence determinant in pathogenic Escherichia coli (E. coli), contributing to severe inflammation and tissue damage. Autophagy plays a critical role in clearing intracellular pathogens and modulating inflammation, but whether HPI manipulates this process remains unknown. Here, using a swine-pathogenic E. coli strain and its HPI-deficient mutant (Δirp2) generated by CRISPR/Cas9, we investigated the interplay between HPI and autophagy in RAW264.7 macrophages and a mouse intestinal infection model. We found that HPI⁺ infection induced autophagic activation, as evidenced by increased LC3 puncta (immunofluorescence), upregulated Beclin-1 and autophagy-related gene mRNA levels (qPCR), and downregulated phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) expression at both mRNA (qPCR) and protein (immunohistochemistry) levels. In a mouse model, HPI⁺ infection upregulated intestinal Microfold (M) cell markers and secretory Immunoglobulin A (IgA), triggered robust production of pro-inflammatory cytokines, and induced more severe tissue pathology than the HPI-deficient mutant. Pharmacological activation of autophagy with rapamycin alleviated HPI-induced inflammation and injury, whereas inhibition of autophagy by 3-methyladenine (3-MA) or Beclin-1 silencing exacerbated damage. These findings suggest that HPI induces autophagy, but the endogenous autophagic response is insufficient to counteract HPI-induced pathology; pharmacological enhancement of autophagy partially alleviated this insufficiency and reduced tissue damage. Notably, Beclin-1 knockdown blunted HPI-induced upregulation of PI3K and autophagy-related genes, suggesting a role for Beclin-1 in the transcriptional regulation of these responses. In conclusion, HPI simultaneously exerts direct pro-inflammatory effects and induces Beclin-1-dependent autophagy. Enhancing this autophagic response pharmacologically, rather than relying on the endogenous level triggered by HPI alone, limits excessive tissue damage. Thus, boosting autophagy may represent a promising therapeutic strategy against HPI-bearing pathogenic E. coli infections. Full article

Background: P97 regulates diverse cellular processes, including proteostasis, metabolism and pluripotency. Pharmacological inhibitors of P97 protein have shown antitumor activity in various cancers. However, the downstream pathways and effectors remain poorly characterized, limiting clinical translation. Methods: We performed a quantitative proteomic analysis using liquid chromatography–mass spectrometry (LC–MS) to identify differentially expressed proteins (DEPs) (fold change > 1.5, p < 0.05) and pathway alterations in gastric cancer AGS cells following treatment with two distinct P97 inhibitors, Eeyarestatin I (EerI) and NMS873. Results: Proteomic analysis revealed that both inhibitors significantly perturbed multiple signaling pathways. The endoplasmic reticulum (ER) proteostasis network was markedly disrupted, evidenced by activation of the unfolded protein response (UPR) and upregulation of ER-associated degradation (ERAD) components. Pathway enrichment further indicated that cell death processes, particularly ferroptosis, were prominently affected (p < 0.05). Key ferroptosis regulators showed altered expression, which was validated by Western blotting. Functional assays demonstrated that P97 inhibition suppressed cell proliferation and increased the accumulation of ferroptosis-associated lipid hydroperoxides in vitro, suggesting execution of ferroptotic cell death. In vivo, using a xenograft mouse model established by subcutaneous injection of AGS cells into nude mice, P97 inhibition significantly reduced tumor growth, confirming its antitumor efficacy. Conclusions: This integrated proteomic and functional study delineates that pharmacological P97 inhibitors disrupt ER proteostasis and simultaneously trigger ferroptosis in gastric cancer cells. These findings identify ferroptosis as a key downstream mechanism of P97 inhibition and provide molecular mechanisms for developing P97-targeted therapies in gastric cancer. Full article

Lung cancer represents a substantial global oncology burden, exhibiting mortality rates that surpass those of prostate, pancreatic, and breast cancers. Extensive research has established a correlation between exposure to polycyclic aromatic hydrocarbon mixtures—particularly those containing benzo(a)pyrene (BaP)—and elevated risks of pulmonary and dermal malignancies across various species, including humans. Hesperidin (HSP), a prominent bioactive flavonoid found in citrus fruits and medicinal herbs such as Hypericum perforatum, is recognized for its diverse pharmacological properties. The present study aimed to elucidate the antioxidant and anti-inflammatory efficacy of HSP against BaP-induced toxicity in the A549 non-small cell lung cancer (NSCLC) cell line. Following the determination of application concentrations via MTT assay, the modulatory effects of HSP on cellular proliferation, oxidative stress markers (TAS, TOS, and OSI), and key pro-inflammatory cytokines (TNF−α, IL−1β, and TGF−β) were systematically evaluated. Isolated exposure to BaP predominantly triggered a targeted upregulation of IL-1β; however, hesperidin demonstrated unexpected pro-oxidant dynamics, characterized by a substantial drop in TAS alongside a concurrent elevation in both TOS and OSI profiles, especially at maximum-dose concentrations. Notably, combining BaP with this heightened hesperidin regimen manifested the most severe oxidative distress phenotype, implying a synergistic pro-oxidant cascade between the two agents. On the contrary, minimized concentrations of hesperidin exerted explicit cytoprotective mitigation against the BaP-induced surge in IL-1β, thereby confirming a highly delicate and narrow therapeutic index for this flavonoid. Full article

Ulcerative colitis (UC) is a chronic, relapsing inflammatory bowel disease characterized by mucosal inflammation and epithelial barrier disruption. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, the principal cytosolic DNA-sensing axis, has emerged as a critical node in UC pathogenesis. This review elucidates the cGAS/STING signaling network in UC, from its upstream activation triggered by exogenous stimuli and leaked endogenous DNA to its downstream effects. We discuss how this pathway modulates distinct lines of intestinal defense, including the mechanical, chemical, and immunological barriers, while integrating its bidirectional crosstalk with the microbial barrier. Rather than exerting purely detrimental effects, cGAS/STING functions as a double-edged sword that coordinates both barrier homeostasis and inflammatory pathogenesis. Crucially, we summarize current pharmacological interventions, highlighting synthetic small molecules and bioactive natural products that target and modulate this axis to restore intestinal equilibrium. This framework provides a theoretical foundation for future precision therapies in UC. Full article

Objectives: This study aimed to investigate the effects of nature-based immersive virtual reality (IVR) applied during dry needling (DN) on pain experienced during the procedure and on immediate and short-term post-intervention outcomes, compared with traditional DN, with a primary focus on immediate post-intervention pain intensity. Methods: In this single-blinded randomized controlled trial, participants were randomly assigned to the control (DN) or experimental (DN + IVR) group. Eligible participants were healthy individuals with identifiable latent myofascial trigger points (MTPs) in the quadriceps muscles. The primary outcome was pain intensity, measured using a numerical rating scale (NRS), immediately after the intervention. Secondary outcomes included pressure pain threshold (PPT) and pain intensity at follow-up time points (1, 6, and 24 h). Linear mixed-effects models were used to analyze the effects of group, time, and their interactions. Results: A total of 40 participants (control group, n = 21, 21.7 ± 3.1 years, 15 males; experimental group, n = 19, 22.4 ± 3.7 years, 11 males) were included. The DN + IVR group showed significantly lower pain intensity immediately after the intervention than the DN group (p = 0.032). Pain intensity decreased over time in both groups (p < 0.001), with no significant intergroup differences at later time points (all p > 0.05). For PPT, a significant effect of time was observed (p < 0.001), but no significant group × time interaction was observed. Conclusions: Nature-based IVR may reduce immediate procedural pain associated with dry needling, although these effects are not sustained over time. IVR may be a useful non-pharmacological strategy for pain relief during invasive physiotherapy procedures. Full article

Cerebellar climbing fiber–Purkinje cell (CF–PC) long-term depression (LTD) plays a critical role in motor learning and is modulated by locus coeruleus (LC) noradrenergic afferents via distinct adrenergic receptor (AR) subtypes. Nevertheless, the mechanisms underlying LC noradrenergic neuron-mediated regulation of CF–PC LTD remain poorly understood. Here, we investigated the effects of chemogenetic activation of LC noradrenergic afferents on CF–PC LTD in cerebellar slices from dopamine β-hydroxylase (DBH)-Cre mice using electrophysiology, glutamate sensor imaging, immunofluorescence and pharmacological approaches. Tetanic stimulation (5 Hz) of CFs induced CF–PC LTD under control conditions, and this LTD was enhanced by chemogenetic activation of LC noradrenergic afferents. Blockade of group I metabotropic glutamate receptors (mGluR1) abolished LTD under control conditions, whereas chemogenetic activation of LC noradrenergic afferents triggered a novel form of CF–PC LTD accompanied by an increased N2/N1 ratio. With mGluR1 blocked, chemogenetic activation of LC noradrenergic afferents failed to trigger the novel CF–PC LTD following blockade of α₂-AR or α₂A-AR, but not α₂B-AR or α₂C-AR. Importantly, chemogenetic activation of LC noradrenergic afferents triggered LTD of glutamate fluorescence at CF terminals, which was abolished by blockade of α_2-AR or α₂A-AR, but not α₂B-AR or α₂C-AR. Notably, inhibition of either cyclin-dependent kinase 5 (CDK5) or presynaptic, but not postsynaptic, protein kinase A (PKA) completely abolished the CF–PC LTD triggered by chemogenetic activation of LC noradrenergic afferents in mouse cerebellar slices. Immunofluorescence results showed robust α₂A-AR expression throughout the cerebellar molecular layer, with intense signals along PC dendrites and clear colocalization with vesicular glutamate transporter 2 (vGluT2) at cerebellar CF terminals. These results indicate that activation of LC noradrenergic afferents potentiates CF–PC LTD by triggering Glu-LTD at CF terminals through the α₂A-AR/CDK5/PKA signaling cascade in the mouse cerebellar cortex. Full article

Chronic pain acts as a potent driver of progressive cognitive impairment. Although microglial hyperactivation serves as a pivotal mechanistic bridge in this comorbidity, the intracellular molecular cascades coupling persistent nociception to cognitive decline remain largely elusive. Here, we identify a previously unrecognized microglial secretome remodeling axis, governed by CX3CL1-CX3CR1 signaling, that drives pain-associated cognitive impairment. Clinically, elevated cerebrospinal fluid (CSF) CX3CL1 correlates strongly with cognitive impairment in chronic pain patients. In murine models, pharmacological blockade of the microglial CX3CL1-CX3CR1 signaling attenuated chronic pain-induced memory deficits. Mechanistically, aberrant CX3CL1-CX3CR1 activation triggers a sequential p38 MAPK-NF-κB cascade to upregulate the kinesin motor KIFC2. This KIFC2 surge fundamentally reprograms microglial vesicular trafficking, driving the massive release of IL-17-enriched small exosomes (<100 nm) that subsequently induce synaptic deterioration and neuronal apoptosis manifested by PSD95 degradation, caspase-3 cleavage, and compromised cell viability. Crucially, this microglial p38 MAPK-NF-κB-KIFC2 cascade hyperactivation was validated in situ within the hippocampal slices of chronic pain models. Collectively, our findings delineate a comprehensive cascade spanning from receptor hyperactivation to KIFC2-dependent exosomal remodeling, elucidating a novel mechanism of microglia-mediated neurotoxicity. Targeting this CX3CL1-KIFC2 exosomal axis offers a potential therapeutic strategy to uncouple chronic pain from its debilitating cognitive comorbidities. Full article

Background/Objectives: Since redox balance is critical to colorectal cancer cell survival, and estradiol, a potent antioxidant, correlates with reduced disease incidence, understanding the redox basis of cellular responsiveness to estradiol is essential for advancing therapeutic insight. This study evaluates the adaptive and maladaptive redox responses of colorectal carcinoma cells to estradiol treatment by defining the basal redox set-point as the intracellular balance between pro-oxidants and antioxidants. Methods: Human colorectal cancer cell lines HCT-116 and SW-480 were treated for 24 h with pregnancy-range and pharmacological-range concentrations of estradiol. Redox biomarkers (superoxide anion/O₂^.−, hydrogen peroxide/H₂O₂, nitric oxide/NO, reduced glutathione/GSH and oxidized glutathione/GSSG), cell viability, and basal migration were analyzed. Correlation, network topology, PCA, and Jaccard similarity analyses were applied to characterize basal redox set-points and quantify estradiol-induced changes in redox profiles in the two cell lines. Results: HCT-116 cells exhibited an O₂^.−-centered redox set-point associated with NO and GSH. SW-480 cells displayed a H₂O₂-centered redox set-point associated with NO and GSH. In HCT-116 cells, estradiol triggered a maladaptive response associated with antioxidant activation and reduced proliferation. Conversely, SW-480 cells exhibited an adaptive response characterized by modulation of NO levels and the GSH pool and associated with increased proliferation. Conclusions: These findings identify redox set-point organization as a potential determinant of estradiol responsiveness in colorectal cancer cells. From a clinical perspective, characterizing basal redox set-points in patient-derived tumor cells may enable stratification of colorectal cancer patients by predicted responsiveness to redox-modulating therapies, informing personalized treatment. Full article

The tree shrew (Tupaia belangeri) is increasingly recognized as an important experimental model for studying human diseases due to its close phylogenetic relationship with humans. Because the basilar artery’s response to endogenous vasoactive mediators varies among species, we investigated the effects of vasoactive substances on isolated tupaia basilar arteries to determine whether this species is suitable as a human model. 5-Hydroxytryptamine (5-HT) and histamine (His) induced contraction, while bradykinin (BK) and acetylcholine (ACh) produced concentration-dependent relaxation. Pharmacological analysis revealed that contractions triggered by 5-HT were regulated through 5-H₁ and 5-HT₂ receptors, while His-induced responses were mediated by H₁ receptors. BK-induced relaxation was inhibited by the B₂ antagonist HOE140 and N^ω-nitro-L-arginine (L-NA), but not by B₁ antagonists or indomethacin, suggesting a B₂ receptor-mediated nitric oxide (NO) pathway. ACh-induced relaxation was markedly reduced in the presence of L-NA and the M₃ antagonist pFHHSiD, indicating M₃ receptor-mediated NO release. At basal tone, L-NA evoked a contractile response, while indomethacin led to relaxation, suggesting basal regulation by NO and prostanoids. These findings demonstrate that 5-HT₁/5-HT₂ and H₁ receptors mediate contraction, while B₂ and M₃ receptors mediate relaxation in the tupaia basilar artery. This study highlights species-specific cerebrovascular regulation and supports the tupaia as a relevant model for investigating human cerebrovascular physiology and pathophysiology. Full article

While altered lipid metabolism is a hallmark of cancer, specific phospholipid dependencies remain poorly defined. Here, we identify phosphatidylserine synthase 1 (PTDSS1) as a targetable metabolic vulnerability in esophageal squamous cell carcinoma (ESCC) and glioblastoma (GBM). Pharmacological inhibition of PTDSS1 selectively and potently suppresses tumor growth both in vitro and in vivo. Mechanistically, PTDSS1 blockade triggers a rapid collapse of cellular phosphatidylserine (PS) and phosphatidylethanolamine (PE) pools, fundamentally disrupting endoplasmic reticulum (ER) homeostasis. This targeted lipid depletion activates a PERK-mediated autophagic response that ultimately yields to apoptosis. Clinically, pan-cancer transcriptomic analysis links elevated PTDSS1 expression to reduced overall survival across diverse malignancies. Collectively, we establish PTDSS1 as an essential maintainer of ER integrity and highlight PS biosynthesis as a viable therapeutic target for exploiting tumor-specific metabolic dependencies. Full article