European Journal of Pharmacology

IntroductionIntestinal constipation (IC) is a common and early non-motor symptom in Parkinsons disease (PD), impacting patients quality of life. In this context, the Mediterranean diet plays a fundamental role in managing IC. This study aimed to evaluate the effects of a nutritional education program based on the principles of the Mediterranean diet on IC in individuals with PD. MethodsThis is a randomized, controlled, single-center, parallel-group, single-blind clinical study to evaluate the effectiveness of a nutritional education program based on the Mediterranean diet for three months, with a delayed-start design, in people with PD and IC. Participants were randomly allocated (1:1 ratio) to two groups: early-start (intervention from baseline to the third month) and delayed-start (intervention from the third to the sixth month) nutritional counseling, with an initial in-person assessment and monthly remote assessments. Bowel habits, adherence to the Mediterranean diet, and clinical variables were analyzed. ResultsAfter six months, a significant increase in the frequency of weekly bowel movements was observed (Early-start: 2.91 to 4.14; Delayed-start: 2.68 to 4.18 bowel movements/week; p < 0.001), along with changes in stool consistency and improved adherence to the Mediterranean diet over time. However, no significant differences were detected between the groups. ConclusionA nutritional education program based on the principles of the Mediterranean diet was associated with improved bowel habits and dietary adherence over time. These results support that locally adapted, low-cost dietary counseling may represent a complementary approach to the treatment of IC in individuals with PD in non-Mediterranean settings.

Inflammation and oxidative stress (OS) are key to Parkinsons disease (PD). We performed a cross-dataset integrative transcriptomic analysis to identify OS- and inflammation-related hub genes persistently dysregulated in PD and to evaluate their response to nutrigenomic interventions using publicly available datasets. Four GEO datasets (GSE7621, GSE20141, GSE20146, GSE49036) were analysed to identify differentially expressed genes (DEGs), which were intersected with GeneCards OS-inflammation gene sets. Functional enrichment analyses, including gene ontology (GO), pathway over-representation analysis (ORA), and protein-protein interaction (PPI) analysis, were used to identify key pathways and hub genes. Gene-food bioactive compound (FBC) association was explored by integrating PD signatures with nutrigenomic profiles from NutriGenomeDB. We identified 183 DEGs in PD, enriched in synaptic, dopaminergic, OS, and inflammatory pathways. Intersection analysis yielded 26 OS-inflammation-related genes and 10 central regulators, including TH, DDC, SNCA, LRRK2, HSPB1, and HSPA1B. revealed opposing transcriptional patterns, with several FBCs suppressing stress-related genes and upregulating dopaminergic markers such as TH, GCH1, and DDC. Overall, this integrative analysis highlights OS-inflammation gene networks in PD and identifies candidate diet-gene interactions that warrant further experimental validation

Inflammatory bowel disease (IBD) is characterised by chronic pain, a debilitating symptom for which effective treatments are few and far between. IBD pathogenesis includes the prevalence of a variety of pro-inflammatory cytokines, including the Interleukin-6 (IL-6) family members Il-6 and Oncostatin M (OSM). Previous research has shown disruption of OSM signaling can modulate nociceptor sensitization and activation, however the downstream signalling pathway is unknown. When an in silico analysis of murine colonic sensory neuronal populations was undertaken for receptor expression for OSM and other factors necessary for intracellular signaling, we can find diverse expression indicative of functional signaling. We were able to observe that hyper Il-6 (Il-6 bound to the soluble Il-6 receptor) and OSM can elicit activation of a subset of murine sensory neurons by finding an increase in calcium mobilization following superfusion. This could then be attenuated by the pharmacologic inhibition of all janus kinases or interestingly, TYK2 alone. Furthermore, inhibition of transient receptor potential vanilloid 1 or transient receptor potential ankyrin 1 ion channels, which are known to be sensitized by OSM in other sensory neurons also reduced the proportion of OSM-responsive neurons. This further understanding of OSM signaling in sensory neurons creates avenues for more extensive research into the molecular mechanisms occurring as well as the potential to exploit these therapeutically to induce analgesia in a subset of neurons.

The Na+/K+-ATPase (NKA) regulates ion balance in the kidney and influences cellular processes like proliferation and apoptosis through its signal transduction. The endogenous ligand 20-Hydroxyeicosatetraenoic acid (20-HETE) contributes to inflammation and fibrosis in chronic kidney disease (CKD) and inhibits NKA activity in renal tubules. However, the molecular mechanism of this interaction remains unclear. In this study, we used in-silico approach to investigate the potential interaction between 20-HETE and NKA. Various ligands, including known NKA ligands such as cardiotonic steroids (CTS), 20-HETE, and negative controls, were docked using rigid and Induced Fit Docking to predict the affinity of the ligands toward NKA. Binding free energy calculations with the Prime Molecular mechanics with generalized Born and surface area (Prime MM/GBSA) tools were used to confirm the involvement of key amino acids in ligand-receptor interactions. The docking analyses revealed that 20-HETE exhibited a binding affinity comparable to negative control, with some differences between rigid and induced fit docking. Binding free energy data highlighted key amino acids in the 20-HETE and NKA interaction. Interaction fingerprint and mutations such as Ala330Gly and Val329Ala significantly reduced binding free energy, while Thr804Ala showed a notable decrease, underscoring the potential importance of these amino acids in ligand stabilization. These findings provide computational evidence supporting potential direct interaction between 20-HETE and NKA and identify candidate residues for future experimental validation.

Introduction Stroke is a leading cause of disability and death in adults with type 2 diabetes (T2D). We evaluated the comparative stroke risk in Veterans with T2D initiated on either of two glucose-lowering medications: GLP-1 receptor agonists (GLP-1RA) or SGLT-2 inhibitors (SGLT2i). Patients and Methods We conducted a retrospective cohort study on diabetic Veterans aged 40 and older with no prior history of stroke or transient ischemic attack, who started on a GLP-1RA or SGLT2i between 2014 and 2021. Patients with contraindications or prior exposure to medication were excluded. Using national Veteran health data, we identified 195,072 [SS1.1]eligible individuals and followed them from treatment initiation until stroke, death, loss to follow up, or end of follow up, whichever came first. Primary outcome was incident stroke, and secondary outcomes included ischemic and hemorrhagic stroke. We applied Kaplan-Meier methods and Cox proportional hazards models. Adjusted associations were estimated using inverse probability weighting. Results Both unadjusted and adjusted analyses suggest GLP-1RA users have reduced stroke incidence compared SGLT-2i users[HS2.1] (HR = 0.[HS3.1]67, 95% CI 0.64-0.69; HR = 0.72, 95% CI 0.69-0.75). Similar results were found in secondary outcome and stratified analyses, with GLP-1RA users having reduced stroke risk compared to SGLT2i users for all age groups, chronic kidney disease stages, and hemoglobin A1c levels. Discussion and Conclusion GLP-1RA treatment was associated with a lower risk of stroke compared with SGLT2i treatment in Veterans with T2D. These findings were consistent for ischemic and hemorrhagic strokes, suggesting potential differences in stroke risk between the treatments.

BACKGROUNGBisphenol A (BPA) has been linked to hypertension and disturbances in lipid metabolism; however, limited evidence is available regarding its association with hypertensive intracerebral hemorrhage (ICH). METHODSA multicenter, retrospective case-control study was conducted involving 129 participants, including individuals from an ICH group and healthy controls. Standard assays were employed to assess serum thyroid function, lipid profiles, serum fatty acid-binding [x]protein 4 (FABP4), oxidative stress markers, gap junction proteins, Wnt/{beta}-catenin signaling pathway activity, and expression changes of S100A8-mediated inflammatory cytokines involved in gut-brain interactions. Correlation analyses using Pearson and Spearman methods revealed that both BPA exposure and low T3 levels were significantly associated with elevated diastolic blood pressure, altered lipid metabolism, gut microbiota composition, and microglial activation. RESULTSGender-based disparities in lipid metabolism were identified. Changes in {beta}3-adrenergic receptor and neuromodulin-1 expression appear to influence fat regulation and attenuate oxidative stress responses. Subsequently, increased expression of gap junction proteins and activation of the Wnt/{beta}-catenin signaling pathway contribute to metabolic reprogramming and alterations in biochemical kinetics. Gut microbiota analysis demonstrated that, compared to controls, the ICH group exhibited significant dysbiosis and reduced alpha diversity. Further correlation analyses indicated that BPA levels were positively associated with FABP4 and oxidative stress markers, while S100A8 showed a strong dependence on microglial expression. CONCLUSIONThe interplay between lipid metabolism dysfunction and pro-inflammatory cytokines enhances vascular vulnerability. Collectively, BPA exposure, oxidative stress, and microglia-mediated neuroinflammation are significantly associated with an elevated risk of hypertensive ICH. China Clinical Trial Registry registration noticeFrom: China Clinical Trials Registry <chictr@vip.qq.com>+To:guopingwang60a<guopingwang60a@163.com> yunyanshuangfei <yunyanshuangfei@126.com> FUNDINGThis work was supported by the Natural Science Foundation of Shanxi Province (grant no. 201701D121177) Key informationGender-specific differences were observed in lipid metabolism and oxidative stress parameters; BPA exposure was shown to induce lipid metabolic disturbances, promote excessive production of oxidative stress byproducts, and consequently elevate oxidative stress responses; BPA was associated with stress-induced alterations in thyroid hormone function, further exacerbating dysregulation of lipid metabolism and oxidative stress; Fatty acid binding protein 4 (FABP4), a key adipokine implicated in metabolic disorders and adipose tissue inflammation, exhibited a significant positive correlation with serum BPA levels, whereas low levels of triiodothyronine (T3) were negatively correlated with FABP4. These findings suggest that serum FABP4 may serve as a biochemical marker for chronic low-grade adipose tissue inflammation and metabolic dysfunction; Gap junction proteins and the Wnt/{beta}-catenin signaling pathway may contribute to microglial activation and mediate neuroinflammatory responses, nerve injury, and secondary pathological processes in obesity-related cerebral hemorrhage.

AimsPercutaneous coronary intervention has improved survival following myocardial infarction, yet strategies to further reduce infarct size are limited. This study investigates the role of cytotoxic {gamma}{delta}-T cells in ischemic cardiomyocyte death and potential therapeutic interventions to reduce infarct size. MethodsGenetic and pharmacological approaches were used to delete {gamma}{delta}-T cells and their specific proteins to assess their involvement in cardiomyocyte death using mouse models of permanent ligation (PL) and ischemia/reperfusion (IR). Results{gamma}{delta}-T cells accumulated in infarct zones within 6h post-PL, expressing IFN-{gamma}, TNF-, granzyme B, and perforin. Their deletion reduced infarct size by 73% (PL) and 64% (IR). They induced cardiomyocyte death via apoptosis, gasdermin E-dependent pyroptosis, and MLKL-dependent necroptosis; {gamma}{delta}-T cell depletion reduced apoptosis by 80% and pyroptosis by 38%, with perforin deletion yielding similar effects. Necroptosis, attributed to combined IFN-{gamma}/TNF- cytotoxicity, decreased by 67%. Cytoplasmic DNA (cDNA) in stressed cardiomyocytes activated the cGAS/STING pathway, inducing expression of chemoattractant MCP-1 and death signal RAE-1. These signals recruited and activated {gamma}{delta}-T cells, which then triggered the death of the stressed cardiomyocytes. STING inhibition suppressed these expressions, reducing {gamma}{delta}-T cell accumulation and infarct size. NKG2D-deficient {gamma}{delta}-T cells prevented activation and reduced infarct size. Administration of an anti-IFNAR antibody at PL onset markedly reduced infarct size. ConclusionEarly activation of cytotoxic {gamma}{delta}-T cells via cardiomyocyte stress signals contributes significantly to immunogenic cardiomyocyte death. Targeting the STING pathway and type I interferon signalling presents a promising therapeutic avenue to mitigate infarct size and improve outcomes.

The activation of thermogenesis in brown adipose tissue (BAT) represents a pivotal target for ameliorating disorders of glucose and lipid metabolism. This study sought to elucidate the regulatory effects of quercetin on thermogenesis and glucose-lipid metabolism within brown adipocytes, alongside its underlying molecular mechanisms. The findings demonstrated that quercetin markedly upregulated the expression of uncoupling protein 1 (UCP1), a critical thermogenic protein in brown adipocytes, thereby enhancing cellular thermogenic capacity and effectively mitigating glucose and lipid metabolism disorders. Subsequent mechanistic investigations confirmed that quercetin activated the COX2-PGE2-EP4-UCP1 signaling axis by augmenting the stability of cyclooxygenase 2 (COX2) protein, thus mediating its thermogenic-promoting and metabolism-improving effects. This study identifies quercetin as a potential therapeutic agent for the improvement of glucose and lipid metabolism disorders, uncovers a novel molecular mechanism through which quercetin regulates brown adipocyte thermogenesis, and provides a theoretical and experimental foundation for the application of quercetin in the prevention and treatment of obesity and related metabolic diseases.

In both preclinical and clinical studies, transfusions of plasma from young individuals have been reported to ameliorate aspects of neurodegeneration. This study was designed as a preliminary test of the hypothesis that plasma transfusions from young donors might benefit Parkinson's patients. 19 patients were allocated to receive either 2-liters of plasma from young donors, in two doses spaced two days apart, or two doses of placebo. For the next 24 weeks, this double-blind study evaluated changes on a modified MDS-UPDRS scale, along with blood tests and other observations. Adverse events possibly related to transfusion were mild rise in blood pressure and urticaria. A t-test on the changes in the sum of UPDRS subscales 1-3 showed that the plasma patients did better than the placebo patients (p = 0.03*). For patients given yFFP (young Fresh Frozen Plasma), the estimated decrease in the sum of scales 1-3 was 7.1 (95% conf. interval 4.3 to 9.9). Our results give a preliminary indication that young plasma transfusions reduce Parkinson's symptoms and have a place in treatment of these patients. (NCT 04202757).

Multipotent mesenchymal stem cells (MSCs) including bone marrow stromal cells (BMSCs) have shown analgesic efficacy in recent years. Studies suggested that the therapeutic effect of MSCs was mediated by their secreted small extracellular vesicles (sEVs) mainly exosomes. The present study evaluated the antihyperalgesic effect of BMSC-related sEVs in a mouse model of neuropathic pain involving chronic constriction injury of the infraorbital nerve (CCI-ION). Our separation protocol generated EV particles mostly sized in the range of exosomes (30-170 nm) and express exosome marker proteins CD9, CD81, and Tsg101, suggesting their endosome origin. We show that intravenous injection of BMSC-related sEVs attenuated pain hypersensitivity induced by CCI-ION as indicated by decreased mechanical hypersensitivity (von Frey test) and reduced aversion to noxious stimulation (conditioned place avoidance test). The antihyperalgesic effect of sEVs was observed in both female and male animals, and the effect was dose-dependent. sEVs from NAIVE serum-treated BMSC cultures produced short-lasting antihyperalgesia in male but not female mice, suggesting a subtle sex difference. The antihyperalgesia of sEVs from BMSC culture was blocked by the pretreatment of the culture with GM4869, the antagonist of exosome secretion, suggesting that the effect was not related to other co-isolated soluble mediators but mediated by MSC-derived exosomes. Interestingly, the prior injury condition in which sEVs were isolated favors the pain-relieving effect of sEVs. sEVs isolated from the serum of BMSC-treated animals receiving tendon ligation (TL) injury attenuated hyperalgesia for 24 h, while sEVs from the serum of BMSC-treated NAIVE animals only attenuated hyperalgesia at 3 h after injection. sEVs from the BMSC culture treated with the serum of TL rats were antihyperalgesic, but sEVs from the BMSC culture treated with the serum of naive animals were ineffective. Our results indicate that BMSC-related sEVs produced antihyperalgesia similar to that produced by BMSCs. The results suggest that the interactions between BMSCs and injury conditions are crucially important for producing efficacious sEVs/exosomes and support that the effect of sEVs could be optimized by priming BMSCs with injury-related conditions.

Background: Pediatric dilated cardiomyopathy (DCM) is a leading cause of heart failure and transplantation, with variable prognosis and high early mortality. This study developed and validated a nomogram predicting short-term mortality risk to guide clinical decisions. Methods: The data were sourced from the Pediatric Cardiomyopathy Database at Shandong Provincial Hospital. Cox regression analysis was conducted to determine outcome-associated factors, and a nomogram was developed to estimate 1, 3, and 5year mortality risks for children with DCM. Model effectiveness was assessed through the concordance index (C-index) and area under the receiver operating characteristic curve (AUC). Additionally, calibration curves and decision curve analysis (DCA) were employed to evaluate the model's predictive accuracy and clinical relevance. Results: A cohort of 106 children diagnosed with primary DCM and who underwent genetic analysis was studied, with a median diagnostic age of 10 months (ranging from 5 to 84 months), comprising 50 girls (47.2%). The rate of detecting genetic mutations was 28.3%, uncovering 14 gene variants linked to DCM, with TTN mutations being the most common. Both univariate and multivariate Cox regression analyses indicated that both sex and NT-proBNP levels had a significant impact on survival rates among pediatric DCM patients.The model exhibited strong discriminative performance, calibration, and clinical net benefit, as assessed by the C-index, calibration plots, and decision curve analysis (DCA). Conclusions: The prediction model created in this research shows strong accuracy in forecasting survival rates at 1, 3, and 5 years for children with DCM, highlighting its significant relevance in clinical settings.

TRPA1 is a non-selective cation channel that plays a crucial role in several pain and inflammatory conditions. Agents reducing membrane cholesterol decrease TRPA1 activation, but it remains unclear how cholesterol-lowering medications affect TRPA1 function. Given that TRPA1 is activated by a wide variety of chemicals, we explored whether statins have acute effects on this channel. We found that five commonly used statins activate human and mouse TRPA1 in a reversible and concentration-dependent manner. The effective concentrations were above the micromolar range, in the order: simvastatin {approx} lovastatin < fluvastatin < atorvastatin < pravastatin. Statin-induced activation was not correlated to changes in membrane order, nor mediated by N-terminal cysteine residues contributing to electrophilic compound agonism. Molecular docking calculations and the functional characterization of single-point mutants revealed two separate putative binding sites, one situated close to the kink of transmembrane segment 5 (TM5) and the other at the interface between TM4 and TM5. The mTRPA1 inhibitor A-967079 largely abrogated the response to the electrophilic agonist allyl isothiocyanate, but had weaker and varied effects across different statins and menthol. Mutation T877L strongly altered the effect of A-967079, also in an agonist-dependent manner, suggesting competitive binding between this antagonist and the non-electrophilic agonists. The identification of two distinct agonist binding sites may help explaining how TRPA1 is able to respond to a large variety of non-electrophilic compounds, while the finding of competitive interactions at one of these sites may help guide the development of agonist-specific antagonists of therapeutic relevance.

Opioid withdrawal is associated with heightened pain sensitivity, including allodynia. Although opioid-induced allodynia is well-documented in humans and animal models, the relationship between the severity of opioid withdrawal-induced allodynia and individual addiction-like behaviors remains poorly understood. To address this gap, Heterogeneous Stock rats underwent long access (12 hours/day) intravenous oxycodone self-administration, followed by measurement of mechanical sensitivity at six timepoints across three weeks of abstinence. Rats were stratified by an Addiction Index derived from individual differences in the escalation of oxycodone intake, motivation to consume oxycodone, tolerance to oxycodones analgesic effects, and acute withdrawal-induced mechanical pain sensitivity. Here, we show that oxycodone withdrawal induces significant and prolonged allodynia for up to three weeks, with High Addiction Index rats exhibiting greater intensity and longer duration of pain sensitivity than Low Addiction Index rats. Results remained consistent even when excluding allodynia from the Addiction Index, highlighting the robustness of the association between addiction-like severity and protracted allodynia. Linear regression associations revealed that self-administration behaviors, particularly oxycodone intake escalation and motivation to seek oxycodone, predicted subsequent withdrawal-induced allodynia severity. These findings demonstrate that greater addiction-like severity is associated with more intense and prolonged withdrawal-induced pain, supporting mechanical allodynia as a marker of addiction severity. These results motivate future work to define the mechanisms linking addiction severity to protracted opioid withdrawal-induced pain, with the goal of informing targeted clinical interventions for individuals most susceptible to severe abstinence-related allodynia.

BackgroundNeuropathic pain is a major source of disability and distress with few pharmacological options for treatment. Opioid drugs can be effective, but high doses are needed, leading to unwanted effects. BMS-986122 is a positive allosteric modulator of the mu opioid receptor that potentiates acute opioid antinociception without increasing opioid-induced constipation, reward, or respiratory depression. Therefore, we asked if BMS-986122 could increase the effects of low-dose opioid analgesics in chronic neuropathic pain. MethodsWe employed the spared nerve injury and tibial neuroma models in rats and assessed the tactile hypersensitivity of the hind paw and site of neuroma, respectively. ResultsAdministration of low doses of (R)-methadone, morphine, or buprenorphine slightly reduced the tactile hypersensitivity of the hind paw the in spared nerve injury model. Pretreatment with BMS-986122 significantly enhanced the reversal of hypersensitivity, reaching the effect of high-dose gabapentin, a standard of care in neuropathic pain. Pretreatment with BMS-986122 similarly increased the anti-allodynic effects of low dose (R)-methadone on neuroma pain. A similar effect of (R)-methadone in the absence of BMS-986122 was only observed at a dose where respiratory distress was seen. ConclusionsThese findings show that allosteric modulators of the mu opioid receptor such as BMS-986122 can enhance opioid activity that could translate to a safe and effective treatment for chronic neuropathic pain.

OBJECTIVEThis study aimed to explore the role and underlying mechanism of microRNA-128 (miR-128) in regulating vascular remodeling in spontaneously hypertensive rats (SHRs), focusing on its targeting of peroxisome proliferator-activated receptor {gamma} (PPAR-{gamma}) and modulation of the Toll-like receptor 4/nuclear factor-{kappa}B (TLR4/NF-{kappa}B) inflammatory pathway. METHODSAll experimental procedures were approved by the Animal Care and Use Committee of Fujian Medical University. In vivo, ten-week-old male SHRs were randomly assigned to three groups: renal denervation (RDN, n=6), sacubitril/valsartan (Sac/Val, n=6), and Sham (n=6). Age-matched Wistar-Kyoto (WKY) rats served as normotensive controls (n=6).Eight weeks after intervention, mesenteric arteries were harvested for histological, functional, and molecular analyses. Serum miR-128 levels were measured by quantitative real-time polymerase chain reaction (qRT-PCR). The expression levels of key proteins in the vascular wall were assessed via immunofluorescence (IF), immunohistochemistry (IHC), and Western blotting (WB). Bioinformatics analysis and RNA sequencing (RNA-seq) were employed to identify core genes and signaling pathways associated with hypertension-induced pathological inflammation. RESULTSIn vivo, in the SHR sham-operated group, elevated blood pressure, severe vascular remodeling, and impaired vasodilatory function were observed, accompanied by downregulated miR-128 expression and upregulated TLR4/NF-{kappa}B signaling activity (all p < 0.0001).RDN postoperative, miR-128 expression was significantly restored, which in turn inhibited the TLR4/NF-{kappa}B pathway, reduced the production of pro-inflammatory cytokines (including IL-1{beta}, IL-6, and TNF-), and ameliorated vascular dilation dysfunction in SHRs (all p < 0.0001). Mechanistically, miR-128 negatively regulated the TLR4/NF-{kappa}B signaling pathway while upregulating the expression of PPAR-{gamma} (p < 0.05). CONCLUSIONRDN not only exerts a hypotensive effect but also improves hypertensive vascular remodeling. miR-128 inhibits excessive inflammation in vascular smooth muscle cells and alleviates vascular remodeling in SHRs via the PPAR-{gamma}/TLR4/NF-{kappa}B axis. These findings identify miR-128 as a potential therapeutic target for RDN in the treatment of hypertension, providing a novel regulatory strategy for the precision management of cardiovascular diseases.

BackgroundRecent studies have established an association between traumatic brain injury (TBI) and cardiometabolic diseases (CMDs). However, the influence of TBI on the sequential progression from a healthy state to CMD, subsequent to cardiometabolic multimorbidity (CMM), and ultimately to mortality remains unclear. MethodsA total of 366,616 participants free of CMD at baseline were derived from the UK Biobank (UKB). CMM was defined as the co-occurrence of [&ge;]2 CMD, including diabetes mellitus (DM), ischemic heart disease (IHD), and stroke. Cox proportional hazards models and multi-state models were utilized to evaluate the association of TBI with disease transitions from a healthy state to CMM and subsequent mortality. ResultsDuring a median follow-up of 16.91 years, 54,224 participants developed at least one CMD, among whom 7,562 progressed to CMM. Furthermore, 32,785 cases of mortality were documented. In multi-state models, the hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) for transitions from a healthy state to IHD, DM, stroke, and mortality were 1.91(95% CI: 1.77-2.05), 1.89 (95% CI: 1.71-2.09), and 4.73 (95% CI: 4.39-5.09), respectively. For sequential transitions from IHD, DM, and stroke to CMM, the HRs (95% CIs) were 2.67 (95% CI: 2.34-3.04), 3.29 (95% CI: 2.78-3.89), and 1.41 (95% CI: 1.15-1.72), respectively. Additionally, in Cox proportional hazards models, the HRs (95% CIs) for incident CMM and mortality among individuals with TBI were 3.98 (95% CI: 3.63-4.36) and 2.57 (95% CI: 2.44-2.71), respectively. ConclusionThis study found that TBI was associated with increased risk of progression from a healthy state to CMD, and subsequently to CMM and mortality, highlighting the importance of comprehensive management of TBI in cardiometabolic health. What is Known; What the Study AddsO_ST_ABSWhat is KnownC_ST_ABSTraumatic brain injury (TBI) is associated with an elevated risk of developing multiple cardiometabolic diseases (CMDs). What the Study AddsThis study performed a systematic analysis of the relationships between TBI and multiple CMDs, providing valuable clinical references for the prevention and management of the onset and progression of cardiometabolic diseases and cardiometabolic multimorbidity (CMM) among patients with TBI.

We investigated whether people with Parkinson's disease who are dual GBA1+LRRK2 carriers have a milder, LRRK2-like phenotype as previously reported. This was accomplished by comparing clinical features and alpha-synuclein seed amplification assay (SAA) positivity rates between dual GBA1+LRRK2-PD(n=13), GBA1-PD(n=169) and LRRK2-PD(n=175) carriers in a cross-sectional retrospective study of Parkinson's Progression Markers Initiative (PPMI) data. Our results show that GBA1+LRRK2-PD rate(83%) is closer to GBA1-PD rate(87%) rather than LRRK2-PD rate (62%mp-value>0.05). GBA1+LRRK2-PD have both non-motor and motor phenotypic similarity of GBA1-PD(p-value>0.05). This small PPMI cohort indicates that dual GBA1+LRRK2-PD carriers' SAA positivity and phenotype are aligned with GBA1-PD.

Crush syndrome (CS) is a serious medical condition characterized by damage to the muscle cells due to pressure and is associated with high mortality, even in patients receiving fluid therapy. We focused on adrenaline (Adr), a standard medication administered by medical teams dispatched during disasters. Adr is readily available for use in disaster scenarios owing to its inclusion in standard emergency kits. The effectiveness of Adr in the treatment of CS remains a subject of ongoing debate. This study aimed to evaluate the impact of Adr on acute complications, such as heart failure, shock, and renal failure, and explore whether its influence on inflammatory pathways is correlated with improved survival in rats with CS. The CS model involved subjecting anesthetized rats to bilateral hindlimb compression using a rubber tourniquet for 5 h. Subsequently, the rats were randomly divided into eight groups. Under continuous monitoring and recording of the arterial blood pressure, blood and tissue samples were collected for biochemical analyses at designated time points before and after reperfusion. The survival rate, vital signs, and blood gas parameters were higher in the CS group than in the sham group. They were improved in the Adr-treated group (0.01 or 0.01 mg/kg), which was not significantly different from that in the CS group, despite the improvement in shock and kidney dysfunction. In conclusion, intramuscular Adr provides immediate hemodynamic stabilization and renal protection during the early stages of CS. However, its use requires careful dose titration; low doses may promote the systemic release of lethal toxins, whereas high doses may worsen metabolic acidosis. These findings highlight the importance of combining Adr with other therapies, such as fluid resuscitation, to manage systemic toxemia inherent in CS.

Spinal cord injury (SCI) is a devastating neurological condition with limited regenerative capacity. Stem cell-based approaches have emerged as promising strategies due to their neuroprotective and immunomodulatory properties, largely mediated by small extracellular vesicles (sEVs) and their molecular cargo, including miRNAs. In this study, we aimed to evaluate the neuroprotective and anti-apoptotic potential of sEVs derived from SPC-01 and iMR-90 neural stem cell sources using an in vitro rat model of SCI. sEVs were isolated from conditioned media and characterized by multi-angle dynamic light scattering and Western blot analysis. Organotypic spinal cord slices (SCS) were used as an in vitro SCI model, with injury induced at 18-20 days, followed by immediate sEV application. After 72 h, tissue samples were collected and tissue was analyzed for markers of apoptosis, cytoskeletal integrity, and survival-related signaling pathways. Results show that SCI induced cytoskeletal disruption and increased apoptotic markers. Treatment with sEVs mitigated these changes, reducing injury-associated protein levels toward baseline. Both SPC-01- and iMR-90-derived sEVs exerted comparable neuroprotective effects, accompanied by decreased PTEN expression, enhanced STAT3 phosphorylation, and increased levels of the anti-apoptotic protein Bcl-xL. In parallel, reduced Nogo-A expression and normalization of RhoA suggested improved cytoskeletal stability and attenuation of inhibitory signaling. Together, these findings demonstrate that neural stem cell-derived sEVs promote early neuroprotective responses in vitro by modulating key signaling pathways, reducing apoptosis, and stabilizing cytoskeletal dynamics, supporting their potential as a cell-free therapeutic strategy for SCI.

Syntaxin-binding protein 1 (STXBP1) mutations lead to severe epilepsy, intellectual disability, developmental delay, and movement disorder. Effective treatments for these conditions do not exist. Recent studies in Munc18-1 (STXBP1) C. elegans models demonstrate that 4-phenylbutyrate (4-PBA) or related pharmacological chaperones stabilize Munc18-1 protein levels and rescue locomotion deficits. These studies suggest a novel treatment strategy for these patients. Here, we used a stxbp1a zebrafish model with a profound movement disorder to screen 4-PBA and alternative structural analogs identified using artificial intelligence (AI)-based screening. Automated locomotion assays conducted on larval stxbp1a mutant zebrafish at 5 days post-fertilization (dpf) confirm and extend the movement disorder endophenotype. Drug treatment (4-PBA or 16 identified candidates) failed to rescue the stxbp1a mutant zebrafish locomotion deficit. Electrophysiology studies in a stxbp1b zebrafish model characterized by spontaneous seizure activity (i.e., epilepsy) failed to detect a reduction in ictal-like events with 4-PBA treatment. Taken together, our results suggest caution in repurposing 4-PBA or related compounds for treatment of STXBP1 disorders.