BACKGROUND This study was conducted to verify the ability to plan using a short experiment based on the metacognitive model of executive functions proposed by Borkowski and Burke. The research questions were: (1) Are there differences among patients in metacognitive level and executive capacity as measured by visual planning tasks? (2) Does visual planning ability in alcohol-dependent individuals change after metacognitive activation? MATERIAL AND METHODS One hundred twenty-two alcohol-dependent men were examined as part of a neuropsychological clinical trial using a visual planning task (Porteus Maze Test). RESULTS Multivariate mixed-model MANCOVA revealed a significant interaction effect between activation (specific knowledge) and visual planning (P<0.05) in the analyzed group. Patients who confirmed - likely more impulsively - that knowledge about their skills was helpful were characterized by higher alcohol use disorder severity (heavy drinkers) compared with patients who responded less definitively but improved their visual planning on the second trial (light drinkers). Pairwise comparisons showed that patients with planning difficulties made more errors in visual planning before metacognitive activation, but their performance significantly improved afterward (P<0.05). Metacognitive activation type did not result in a significant difference (P>0.05). CONCLUSIONS Patients who responded with more reflection to the question regarding specific knowledge improved their visual planning in the second trial (light drinkers) compared with patients who gave less reflective responses (heavy drinkers). The effect of metacognitive activation was substantial among patients with difficulties in visual planning (light and heavy drinkers), but not among patients with intact planning abilities.
Steatotic liver disease (SLD) comprises a heterogeneous group of liver diseases defined by pathological hepatic lipid accumulation with varying degrees of steatohepatitis and progressive fibrosis, which may culminate in cirrhosis and/or hepatocellular carcinoma. SLD encompasses metabolic dysfunction-associated steatotic liver disease (MASLD), formerly called non-alcoholic fatty liver disease (NAFLD); MetALD, describing patients with MASLD consuming moderately high amounts of alcohol; and alcohol-associated/related liver disease (ALD). In addition, SLD encompasses less common aetiologies, including drug-induced and monogenic causes, as well as cryptogenic disease, which lacks metabolic risk factors or an identifiable cause. As the leading cause of chronic liver disease worldwide, MASLD, including metabolic dysfunction-associated steatohepatitis (MASH), is a complex multisystem disorder associated with extrahepatic organ dysfunction. Consequently, MASLD has become a major focus of multidisciplinary research, driving innovation across hepatology, immunology, cardiometabolism, addiction medicine, nutrition, prevention, and beyond. Over the past two decades, a broad array of in vivo, in vitro, and ex vivo experimental models have been developed to recapitulate diverse aspects of SLD pathophysiology, genetics, inflammation, treatment response, and multi-organ crosstalk, substantially advancing mechanistic understanding and therapeutic development. However, the rapid expansion and heterogeneity of available models have also highlighted the need for improved categorisation, standardisation, and harmonisation in line with evolving disease definitions and clinical concepts. In this EASL position paper, we critically review and classify currently available experimental SLD models and propose key criteria required for their appropriate use across distinct SLD subtypes. These criteria encompass systemic and hepatic metabolism, cardiometabolic comorbidities, histopathology, immunopathology, and molecular features relevant to disease stage and aetiology. This position paper aims to guide informed model selection, promote consistent nomenclature, and enhance rigour and translational relevance in preclinical and experimental SLD research.
For the current noninvasive lung cancer screening methods based on volatile organic compounds (VOCs) using electronic noses (e-noses), existing approaches still face limitations in modeling the long-range dependencies of sensor responses, the cross-channel global correlations, and the long-term trend features during the steady-state phase. Moreover, the associated deep learning models are often structurally complex and rely heavily on manual feature engineering, which restricts the engineering application and clinical translation of e-nose systems. To address these issues, this study proposes a lightweight global-local feature fusion framework for complex VOC sensing tasks and designs an efficient, lightweight feature extraction module (LFE) to achieve high-efficiency gas classification. For quantitative analysis of gas components, a GBDT-GRU Joint Prediction Model (JGPM) is introduced, effectively modeling the temporal evolution characteristics of sensor response signals. The above models were systematically validated using an e-nose experimental platform with synthetic gases of acetone, ethanol, isopropanol, and their mixtures at the ppm level as a proof-of-concept (PoC) study. The experimental results show that the proposed models outperform the comparative methods in both gas classification accuracy and concentration prediction performance, while maintaining low model complexity. Although current validation is at the preclinical stage, this framework provides a robust algorithmic foundation for future intelligent gas sensing and clinical breath-based disease screening.
Cytoreductive surgery (CRS) with heated intraperitoneal chemotherapy (HIPEC) is a treatment for peritonitis carcinomatosa. These procedures often involve significant blood and fluid loss, leading to hyperdynamic circulation and vasodilation, necessitating intraoperative fluids and vasoconstrictors such as catecholamines. Excessive fluid administration to counteract vasodilation can cause intraoperative fluid overload, which is linked to increased postoperative complications. Vasopressin has emerged as a potential alternative to catecholamines, restoring vascular tone via non-adrenergic pathways and supporting perfusion pressure, potentially reducing the need for compensatory fluids solely administered to compensate for vasodilation. We hypothesise that compared with norepinephrine, vasopressin reduces cumulative intraoperative fluid administration during CRS-HIPEC within a goal-directed fluid therapy (GDFT) protocol, ultimately leading to a lowering of postoperative complications. HiPress is a two-centre, two-arm randomised clinical trial with blinding of both patients and outcome assessors. A total of 70 adult patients undergoing CRS-HIPEC will be included. Patients will be randomised to receive either continuous low-dose argipressin or continuous low-dose norepinephrine. Both groups will receive standardised GDFT during the procedure. The primary endpoint is cumulative intraoperative fluid administration (mL). Secondary endpoints include direct fluid-related outcomes (eg, cumulative intraoperative fluid (ml/kg/hour), postoperative fluid balance until day five and ultrasound-assessed pulmonary oedema and venous congestion) and indirect fluid-associated outcomes (eg, quality of recovery, surgical and abdominal complications, acute kidney injury (AKI), pulmonary complications, length of ICU and hospital stay and 30-day mortality). The study is enrolling patients since February 2025. The trial is approved by the Medical Research Ethics Committee (hereinafter: MREC) NedMec, The Netherlands (Ref: D-25-500202). Results of the trial will be published in an international peer-reviewed journal and announced at national and international scientific meetings. Clinical Trials Information System (CTIS): European Union clinical trials register (EUCT) number: 2024-5 13 598-33-00.
Background/Objectives: A 90-day randomized double-blind and placebo-controlled study was conducted to assess the effect of carob (Ceratonia siliqua L.) on glucose metabolism in subjects with confirmed prediabetes. Methods: The carob liquid concentrate containing inositols of the carob fruit (D-pinitol, myo-inositol, D-chiro inositol) was administered at a daily dose of 6.66 g, divided into two doses of 3.33 g each. Study variables included glucose- and insulin-related parameters obtained at fasting conditions and during a standard 2 h oral glucose tolerance test (OGTT) at baseline and after 45 and 90 days of administration of the study products. Results: The study population included 52 subjects (25 in the experimental group, 27 in the placebo group), 27 men and 25 women, with a mean age of 45.6 ± 13.9 years. Subjects who consumed the active product showed improvements in glycated hemoglobin (HbA1c) and glucose levels as compared with placebo (p < 0.001 of the time × group interaction). Fasting serum insulin showed within-group significant decreases in the experimental group, with insulin indexes (HOMA-IR and QUICKI) improving significantly in the experimental group only. In the OGTT, there were significant improvements in the AUC of glucose and insulin, as well as glucose peak in the experimental group only. The product was well tolerated and no adverse effects were recorded. Conclusions: The use of a specific carob-based liquid concentrate decreased HbA1c and glucose levels in subjects with prediabetes, which may suggest its potential clinical relevance in the prevention of the transition from prediabetes to overt type 2 diabetes.
Gastrodia elata Blume (TM), a renowned traditional Chinese medicinal herb, has long been clinically used for the treatment of dizziness, stroke and other cerebrovascular diseases. Modern pharmacological investigations have confirmed that its neuroprotective effects are closely associated with the amelioration of neuroinflammation. Nevertheless, the underlying anti-neuroinflammatory mechanisms and quality markers (Q-marker) of TM remain to be further elucidated. To identify the Q-marker and mechanisms of TM anti-neuroinflammation based on network pharmacology and experimental verification. Integrated chemical composition analysis and network pharmacology predict Q-Marker and mechanisms of TM in alleviating neuroinflammation, verified by in vivo and in vitro experiments. Gastrodin (GAS) and p-hydroxybenzyl alcohol (HBA) were identified as the efficacy Q-marker of TM for ameliorating neuroinflammation. The in vitro and in vivo experimental results demonstrated that TM, GAS and HBA all could regulate the polarization shift of microglia from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, inhibit the release of TNF-α, IL-6 and IL-1β, reduce neuronal apoptosis, and alleviate inflammatory injuries in BALB/c mice and BV2 microglial cells. Furthermore, Western blot assay confirmed that the underlying molecular mechanism of the anti-neuroinflammatory efficacy exerted by TM, GAS and HBA might be mediated by inhibiting the Src/NF-κB signaling pathway. GAS and HBA as the key Q-marker responsible for the anti-neuroinflammatory activity of TM, primarily by inhibiting of the Src/NF-κB signaling pathway.
To evaluate flexural strength (FS) and flexural modulus (FM) of experimental composites containing bioactive glass (BG) 45S5 (C-series) or a customized low-sodium, fluoride-containing BG (F-series) after aggressive artificial aging. A Bis-GMA/TEGDMA (60:40) resin was filled to 70 wt% total filler, comprising 5-40 wt% of either BG type, with the remaining filler fraction consisting of silanized barium glass and silica (2:1). Specimens (2 × 2 × 16 mm; NIST 4877) were artificially aged by immersion for 30 or 90 days in simulated body fluid (SBF; pH 7.4), lactic acid (pH 4.0), 75% ethanol or NaOH (pH 13.0), and by thermocycling (10,000 cycles; 5-55°C). FS and FM were measured by three-point bending test. Sample size was n = 20 per experimental group, and data were analyzed using three-way ANOVA with additional one-way ANOVAs at an overall significance level of α = 0.05. The C-series showed a BG dose-dependent decline in flexural properties at baseline and after artificial aging, while the F-series, particularly F-20, maintained higher FS and FM than the C-series under all aging conditions. At baseline, FS decreased from 139.6 to 23.9 MPa across the C-series (5-40 wt% BG), while the F-series maintained values between 147.7 and 176.6 MPa. After 90 days, F-20 retained FS of 133.6-134.8 MPa compared with 41.2-47.2 MPa for C-20, and FM remained substantially higher in the F-series (9.5 vs. 3.7 GPa in SBF). The effects of artificial aging media varied in both severity and time-dependent pattern of change; SBF and lactic acid produced moderate degradation, ethanol induced a marked reduction that leveled off between 30 and 90 days, and NaOH produced the most extensive deterioration over the 90-day observation period. Thermocycling showed intermediate effects and maintained comparable differences between composites. Reduced BG solubility improved tolerance to higher BG fractions under neutral and moderately acidic aqueous aging, whereas extreme ethanol and alkaline challenges primarily reflected matrix and interface vulnerability. Customized low-sodium BG improved flexural property retention under clinically relevant aqueous challenges compared with BG 45S5, while extreme chemical aging reduced differences between the materials by shifting degradation toward matrix and filler/matrix interface. The improved flexural stability of composites containing customized low-sodium BG suggests their potential for use in restorations with higher functional filler loadings.
This study aimed to clarify the pharmacodynamic effects of YaJieShaBa (YJSB) against alcoholic hepatic fibrosis (HF) and elucidate its mechanism in regulating the transforming growth factor-β1 (TGF-β1)/Smad pathway. Induce the alcoholic HF model in rats using 56% ethanol (10 mL/kg). The pharmacological efficacy of YJSB in combating liver fibrosis was evaluated through comprehensive assessments of key indicators: body weight, liver mass and index, biochemical liver function parameters (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]), liver fibrosis biomarkers (type Ⅲ procollagen amino-terminal propeptide [PⅢNP], type-Ⅳ collagen (COL-Ⅳ), laminin (LN), and hyaluronic acid [HA]), serum hydroxyproline (Hyp) and TGF-β1 levels, hepatocyte homogenate levels of COL-I, COL-Ⅲ, and α-smooth muscle actin (α-SMA), along with histopathological changes observed in liver tissue via hematoxylin and eosin (H&E) staining, Ag staining, and Masson staining. Pathway-focused qPCR array analysis was used to detect the expression of 72 genes related to signaling pathways such as TGF-β1, Keap1-Nrf2, and TLR4/MyD88 in liver tissue from the control group, model group, and YJSB group, identifying differentially expressed genes (DEGs) and key signaling pathways between the model group and the YJSB treatment group. Finally, based on the results of the pathway-focused qPCR array, the mechanism of action of YJSB against HF was validated using ELISA, WB, and immunofluorescence methods. Concurrently, TGF-β1 receptor inhibitors were employed in vitro experiments to determine whether YJSB could still provide additional protective effects when the TGF-β1/Smad pathway was maximally blocked. Furthermore, after confirming that YJSB could inhibit TGF-β1-induced activation, a rescue experiment was conducted by adding exogenous TGF-β1 to observe whether it could reverse the inhibitory effects of YJSB. YJSB administration significantly increased body mass and decreased liver index in alcoholic HF rats. Serum levels of AST, ALT, PⅢNP, COL-Ⅳ, LN, HA, Hyp, and TGF-β1 were significantly reduced, as were the levels of COL-I, Ⅲ, and α-SMA in liver homogenates. Histological analyses, including H&E, Ag, and Masson staining, revealed a significant reduction in liver damage. Pathway-focused qPCR array results showed that, compared with the blank group, 65 genes were upregulated and seven genes were downregulated in the model group, among which the relative expression levels of 40 genes were statistically significant (expression change factor ≥ 1 and p  < 0.05). Compared with the model group, 68 genes were downregulated, and four genes were upregulated in the YJSB group, with 34 genes showing statistically significant relative expression levels (fold change [FC] ≥ 2 and p  < 0.05). The DEGs were primarily enriched in the TGF-β1 signaling pathway. Additionally, YJSB reduced the levels of inflammatory factors IL-1β, TNF-α, IL-6, and IL-8 in liver tissue homogenates while increasing SOD, GSH-Px, and catalase (CAT) levels and decreasing MDA and ROS levels. Western blotting results showed that YJSB downregulated the expression levels of TGF-β1, Smad2, Smad3, P-Smad2, and P-Smad3 in the liver. Immunofluorescence results indicated that YJSB downregulated the expression levels of Smad4 in hepatocyte nuclei. In vitro experiments demonstrated that the mechanism of YJSB involves primarily inhibiting TGF-βR1 receptor activation, effectively downregulating P-Smad2/3 protein levels, as validated by the TGF-βR1 inhibitor LY2157299. Concurrently, in rescue experiments, the inhibitory effect of YJSB on P-Smad2/3 protein was partially reversed by exogenous TGF-β1, indicating that YJSB's antifibrotic action is highly correlated with the TGF-β1/Smad pathway. YJSB effectively inhibits the inflammatory and oxidative stress-related cascade by regulating the TGF-β1/Smad signaling pathway (TSSP), thus suppressing the progression of alcoholic HF. This demonstrates that YJSB possesses potential for combating alcoholic HF in animal models, providing experimental evidence for its subsequent research and clinical application.
Metabolic dysfunction-associated steatotic liver disease (MASLD) constitutes a chronic inflammatory condition within the spectrum of metabolic liver diseases, characterized by the accumulation of hepatic lipids in the absence of significant alcohol consumption, however, the contribution of PANoptosis to its pathobiology remains largely undefined. We retrieved MASLD transcriptomic datasets from the Gene Expression Omnibus (GEO). Shared genes were first defined by intersecting differentially expressed genes (DEGs) with modules identified by weighted gene co-expression network analysis (WGCNA). To identify the PANoptosis-related hub genes, a comprehensive approach was adopted, integrating three distinct machine-learning algorithms: least absolute shrinkage and selection operator (LASSO) regression, random forest (RF), and support-vector machine recursive feature elimination (SVM-RFE). Receiver operating characteristic (ROC) curves were constructed to quantify the diagnostic performance of each candidate gene. Immune-infiltration landscapes were delineated with CIBERSORT. Finally, the expression of the hub gene was corroborated in vitro, in vivo and in human biopsies. The PANoptosis-related gene SIK1 exhibited robust association with MASLD and significant diagnostic value. Immune-infiltration profiling revealed a marked increase in gamma delta T cells and resting mast cells in MASLD tissues relative to controls. Experimental validation further confirmed that SIK1 expression was significantly down-regulated in MASLD samples. Our findings illuminate novel aspects of PANoptosis in MASLD, thereby paving the way for future research into its underlying pathogenesis and the development of targeted therapeutic strategies.
Craving is a diagnostic criterion and predictor of relapse in patients with alcohol dependence (AD) and is induced in cue exposure therapy (CET) to prepare patients for real-life risk situations. The benefits of virtual reality (VR) as an innovative tool within treatment for this highly prevalent disorder include increased practicability, standardization, and personalization of CET. Accurate measurement of craving is essential to develop effective virtual reality cue exposure (VR-CE) scenarios. Despite being relevant for diagnostics and therapy, the psychophysiological reaction to alcohol cues and its relationship to subjective craving has not been sufficiently examined. This study aimed to investigate the induction of subjective craving, its physiological correlates, and their relationship in patients with AD during an innovative VR-CE paradigm, including 2 alcohol-associated risk scenarios (bar and living room) and a neutral baseline scenario. Craving was analyzed by measuring physiological reactions (electrodermal activity, including nonspecific skin conductance responses [NS-SCR] and skin conductance level [SCL]; heart rate [variability] [HR(V)]; brightness-corrected pupil diameter [BCPD]; and respiration rate [RR]) and subjective craving (visual analog scale) in 61 patients with AD. Linear mixed-effects models were conducted to estimate the effects of VR-CE. Correlations between subjective and physiological craving parameters were analyzed using Spearman correlations. Results showed that alcohol-associated VR scenarios had significant effects on subjective craving (β values between 9.48, 95% CI 6.02-12.95 and 15.93, 95% CI 12.47-19.40, with moderate effect sizes between d=0.56 and d=0.72) and on NS-SCR frequency (β values between 0.97, 95% CI 0.14-1.80 and 3.06, 95% CI 2.23-3.89, with small-to-large effect sizes between d=0.31 and d=0.91), BCPD (β values between 0.03, 95% CI 0.01-0.06 and 0.05, 95% CI 0.02-0.07, with small effect sizes between d=0.21 and d=0.29), and RR (β values between 0.67, 95% CI 0.06-1.28 and 1.66, 95% CI 1.05-2.26, with small effect sizes between d=0.22 and d=0.45), but not on SCL and HR(V). Correlation analyses showed significant but weak correlations between subjective craving and electrodermal activity (SCL: r=0.20, P=.04; NS-SCR frequency: r=0.21, P=.03). This study showed that subjective and physiological craving (NS-SCR, BCPD, and RR but not SCL and HR[V]) can be successfully induced by VR-CE in patients with AD. These outcomes add to research on the induction of craving using a wide range of psychophysiological and subjective parameters. Furthermore, this study expands the still-limited research on the relationship between subjective and psychophysiological craving in patients with AD. In the long term, this study informs the development of effective VR-CET, which could, by further building on psychophysiological parameters, lead to biofeedback VR-CET as an innovative treatment option for patients with AD.
Gualou Xiebai Banxia decoction (GXB) is a classic formula originated from "Synopsis of the Golden Chamber", with efficacy in activating cardiac "yang", resolving phlegm, and promoting blood circulation. Nearly 2000 years of clinical practice have demonstrated the efficacy of GXB in managing myocardial ischemia (MI). Nevertheless, its regulatory effects on metabolic disturbances associated with MI and the underlying mechanisms remain obscure. This study aims to evaluate the therapeutic effects of GXB against MI, characterize the metabolomic and lipidomic alterations related to GXB treatment, and investigate the potential mechanisms of action. UHPLC-Q-Orbitrap HRMS combined with network pharmacology were implemented to explore the active ingredients and potential targets of GXB in the treatment of MI. Subsequently, an isoprenaline (ISO)-induced rat model of MI was established to assess the cardioprotective effects of GXB using echocardiography, biochemical indicators, and histopathological analysis. Comprehensive metabolomics and lipidomics were conducted to characterize endogenous metabolic alterations following GXB intervention. A components-targets-differential metabolites network was constructed through integrated analysis. Further molecular biology experiment verification was performed in ISO-induced rat model and H9c2 cell injury model. Notably, inhibitors were used in H9c2 cells to validate the role of PLA2 and PKC in GXB's protective effects. The levels of key proteins, oxidative stress markers and inflammatory cytokines were detected. A total of 123 constituents were identified in GXB, with 18 detected in plasma. The "constituents-targets-disease" interaction network was constructed based on absorbed components. GXB improved cardiac function, alleviated cardiac injury, reduced oxidative stress and inflammation in MI rats. Metabolomic and lipidomic analyses revealed 19 differential metabolites and 122 lipids associated with GXB treatment, primarily involved in lipid metabolism, amino acid metabolism, and energy metabolism. Conjoint analysis identified four key targets, including PLA2G2A, PLA2G4A, PRKCA, and PRKCE, which were mainly linked to lipid metabolism. GXB treatment decreased the expressions of these four proteins, reduced oxidative stress and inflammation. In vitro functional experiments confirmed that inhibition of PLA2 and PKC proteins mimicked the protective effects of GXB. This study demonstrates that GXB protects against MI by regulating lipid metabolism and attenuating inflammation via inhibiting the PLA2/PKC-NOX signaling axis, providing evidence for its clinical application.
Psidium guajava (guava) is an important medicinal plant used for gastrointestinal disorders, diabetes, and inflammation, primarily due to its bioactive compounds including flavonoids and tannins. To ensure safety for human use, rigorous preclinical toxicity assessments are essential. The purpose of this study was to assess the safety of ethanol extract of Psidium guajava (EEPG) by acute and subacute toxicity tests. Organization for Economic Co-operation and Development (OECD) 425 recommendations were used for the acute toxicity investigation in mice, while OECD 407 guidelines were used for the sub-acute toxicity study in mice. Mice were given oral doses of 2000 mg/kg/ body weight in the acute toxicity trial. They were then monitored individually for the first four hours, then for 24 hours, then at least once a day for 14 days. Ethanol extract of Psidium guajava (EEPG) was administered orally to male and female mice for 28 days at dosages of 250 mg/kg, 500 mg/kg, and 1000 mg/kg /body weight, respectively, in the subacute toxicity tests. Over the course of the experiment, general behavior, negative impacts, and mortality were noted. Hematological and biochemical markers, body weight, organ weight, and histopathological alterations were assessed. in acute toxicity during the observation period, the mice examined showed no evidence of acute toxicity or mortality at the limit dosages of 2000 mg/kg/body weight. The findings of sub-acute toxicity testing revealed no anomalies associated with treatment in terms of biochemical, hematological and histopathology markers at the maximum dose of 1000 mg/kg /body weight. the substance showed a favorable safety profile, with no acute and subacute toxicity or mortality at 2000 mg/kg and no treatment-related adverse effects at 1000 mg/kg/body weight/day in mice.
Subarachnoid hemorrhage (SAH) from ruptured intracranial aneurysms is a severe stroke subtype with a high mortality rate. Statins, noted for cholesterol-independent benefits, are being studied as potential treatments, but their effectiveness is debated. This study assesses the impact of pre-admission statin therapy on aneurysmal SAH outcomes. This was a multicenter, observational, real-world study from May 2012 to May 2023 at four Chinese tertiary medical centers. Patients were divided into statin and control groups based on pre-admission statin use. The primary outcome was favorable outcome at 30 days, defined as a modified Rankin Scale (mRS) score of 0-2. Propensity score matching (PSM) was applied to balance baseline characteristics. The trial was registered with Chinese Clinical Trial Registry (ChiCTR2300079305). Out of 1,431 patients, 821 met the inclusion criteria (statin group: 367; control group: 454). After PSM, each group comprised 220 patients. Pre-admission statin was associated with a higher likelihood of favorable outcome at 30 days (before PSM: odds ratio [OR] 3.67, 95% confidence interval [CI] 2.46-5.47, p < 0.001; after PSM: OR 5.00, 95% CI 3.00-8.32, p < 0.001). Subgroup analysis of the primary outcome revealed significant interactions between pre-admission statin and low-density lipoprotein cholesterol (LDL-C) and alcohol consumption (Both P for interaction < 0.05). The benefit of statin at 30 days was more pronounced in patients with LDL-C < 3.4 mmol/L and non-drinkers. Pre-admission statin therapy was associated with improved prognosis at 30 days in patients with aneurysmal SAH, however this benefit could not extend to 90 days. The effect of statin appeared to vary according to baseline LDL-C levels and alcohol consumption. Further multicenter, international randomized controlled trials are warranted to confirm these findings.
Ethanol affects lipid metabolism through multiple pathways, leading to fatty liver development in most alcohol-related liver disease (ALD) patients. Recent studies have highlighted the role of calpain, a calcium-dependent protease, in liver inflammation and fibrosis. Calpain activity is regulated by its essential subunit, Capns1 (calpain-4), which stabilizes and modulates the activity of its catalytic isoforms, calpain-1 and calpain-2. This study investigated calpain's impact on lipid metabolism in ALD. Six-week-old C57Bl6/J mice were injected with rAAV8 vectors encoding Capns1 shRNA or control vectors. After 4 weeks, mice underwent a 10-day period of ad libitum ethanol consumption, followed by a single gavaged ethanol administration on day 11. Capns1 knockdown attenuated ethanol-induced microvesicular steatosis. Hepatic triglyceride and free fatty acid levels were not significantly altered, whereas cholesterol levels were significantly reduced in the ethanol group with Capns1 knockdown. Cpt1a expression increased significantly in the ethanol group with Capns1 knockdown. Western blot analysis revealed increased Cleaved-3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) to Pro-HMGCR ratio in Capns1-knockdown mice, suggesting reduced HMGCR activity and suppressed cholesterol biosynthesis. LXRα expression was mainly increased in the cytoplasm in the ethanol group, and following Capns1 knockdown, it was relocalized to the nucleus via its activation. In addition, RNA sequencing analysis indicated that Capns1 knockdown contributes to the reprogramming of ethanol-induced disruptions in metabolic pathways, primarily those involving cholesterol metabolism. Further investigation into the relationship between Capns1 and cholesterol biosynthesis proteins may provide insights into using calpain inhibitors as a therapeutic approach for alcohol-related liver disease.
Spinal cord injury is a critical issue in neurosurgery, lacking established clinical methods for functional restoration. This study reports the effects of a fusogen sealant, composed of polyethylene glycol and chitosan, in an experimental model of complete spinal cord transection in pigs. To evaluate the functional and morphological recovery of the spinal cord in an animal model of complete transection following treatment with a polyethylene glycol-chitosan conjugate. Hungarian Mangalica pigs (m = 20.0 ± 2.0 kg, N = 5) underwent complete transection of the thoracic spinal cord, followed by an extended laminectomy and transpedicular fixation. In the experimental group (N = 3), a synthesized gel based on a polyethylene glycol-chitosan conjugate was applied to the spinal gap; the other group (N = 2) served as a control. The postoperative period lasted 60 days and included multi-component rehabilitation. Clinical-functional status was assessed using established neurological scales. In vivo retrograde tracing of the spinal cord was performed using hydroxystilbamidine (FluoroGold). Following the experiment, immunofluorescent histology was conducted using primary antibodies to neurofilament (NF-200), a fluorochrome-conjugated secondary antibody, and the nuclear dye 4',6-diamidino-2-phenylindole (DAPI). The resulting morphology was examined via fluorescence and light microscopy. Control animals maintained lower paraplegia, anesthesia, and pelvic dysfunction throughout the experiment. In contrast, the experimental group showed positive changes, including the return of sensation from day two. By the end of the study, all animals in this group could assume an upright posture and ambulate on all limbs. These outcomes were statistically significant. Microscopy revealed axons traversing the injury site in the experimental group, whereas control samples showed degenerative post-traumatic changes. This study demonstrates that a fusogen sealant based on a polyethylene glycol-chitosan conjugate promotes significant morpho-functional recovery after complete spinal cord transection, supporting its therapeutic potential.
MicroRNAs (miRNAs) and the NAD+-dependent deacetylase SIRT1 are critical regulators of hepatic metabolism, inflammation, and stress responses. Growing evidence suggests that miRNA-SIRT1 interactions are frequently disrupted during the pathogenesis of liver diseases, including Metabolism-Associated Steatotic Liver Disease (MASLD), Alcohol-Associated Liver Disease, Drug-Induced Liver Injury (DILI), fibrosis, and hepatocellular carcinoma (HCC).In the context of metabolic liver diseases, specific miRNAs, such as miR-122, miR-93, miR-132, miR-34a, and miR-141, regulate lipid and energy metabolism by modulating SIRT1 and its downstream targets, notably AMPK and PGC-1α. Furthermore, miRNAs can suppress SIRT1 activity during liver injury, exacerbating oxidative stress, mitochondrial dysfunction, and inflammation. In HCC, the role of SIRT1 is context-dependent; influenced by the stage of differentiation and genetic factors such as p53, SIRT1 may exert either tumor-suppressive or tumor-promoting effects. While preclinical studies demonstrate the therapeutic potential of targeting the miRNA-SIRT1 pathway, current evidence remains largely experimental. Pharmacological modulation, via SIRT1 activators, small-molecule compounds, or RNA-based therapeutics, has shown promise in experimental models. However, significant hurdles impede clinical translation, including poor bioavailability, off-target effects, and, most critically, the complex, context-specific biological role of SIRT1 within the liver. Ultimately, while the miRNA-SIRT1 axis appears to be a central regulatory pathway in liver disease, its translational potential and safety in humans require further mechanistic and clinical investigation.
Endometriosis is a chronic inflammatory disease presenting with debilitating symptoms strongly impacting patients' quality of life (QoL). Assessing QoL is crucial for understanding the full patient experience beyond clinical symptoms. This narrative systematic review specifically aimed to identify and describe non-pharmacological and non-surgical factors associated with QoL in women with endometriosis as reported in the literature. Following PRISMA guidelines, we systematically searched PubMed, MEDLINE, Web of Science, and Embase up to January 15, 2025, for case-control, cohort, randomized controlled trials, and cross-sectional studies. This study was registered in PROSPERO (registration number: CRD42023438457) Eligible studies assessed socio-demographic characteristics, lifestyle factors, symptoms, comorbidities, or coping strategies in relation to QoL among women with endometriosis. Twenty-one studies with a low risk of bias were included. A better QoL was related to favorable socioeconomic profiles (n = 3), high care satisfaction (n = 2), partner involvement (n = 1), healthier lifestyle habits (n = 1), and the use of coping therapeutic strategies. Poor QoL was associated with poor health (n = 5), more severe symptoms (n = 5), unhealthy lifestyle habits (n = 2), and ineffective use of coping strategies (n = 2). This review highlights a broad range of non-medical determinants of QoL, underscoring that clinical measures alone fail to capture the full patient experience. By consolidating evidence across diverse study designs, it offers a comprehensive overview of modifiable factors that could inform holistic, patient-centered approaches to endometriosis care. Further prospective and interventional studies are needed to clarify causal pathways and evaluate the effectiveness of targeted strategies to improve QoL. Endometriosis is a chronic disease affecting around 10% of women of reproductive age, associated with pain, infertility, and significant impacts on daily life. Because clinical measures alone fail to capture the full patient experience, assessing QoL is essential to understand the real burden of the disease. This review examined non-pharmacological and non-surgical factors that may be associated with QoL, such as lifestyle habits, socioeconomic conditions, health status, and coping strategies. Across 21 studies, we found that a better QoL was linked to good healthcare access, healthy habits, and effective coping mechanisms. Conversely, severe symptoms, poor health, and unhealthy lifestyles (smoking and alcohol use) were associated with worse QoL. The findings highlight the need for a more holistic approach to endometriosis care, combining psychological support, lifestyle guidance, and improved access to quality healthcare. Future research should use standardized QoL tools and robust study designs to develop evidence-based strategies that can meaningfully enhance patient well-being.
Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine-metabolic disorder in which reproductive dysfunction coexists with insulin resistance, chronic low-grade inflammation, and heightened oxidative stress (OS). Increasing evidence indicates that these abnormalities are not independent phenomena but components of a self-perpetuating redox-endocrine network that sustains hyperandrogenism, anovulation, and metabolic impairment. This review critically synthesizes experimental, translational, and clinical data to examine whether vitamin D, myo-inositol, and melatonin, three widely used but often studied in isolation bioactives, can act synergistically as a mechanistically coherent 'bioactive cocktail' in PCOS. Vitamin D modulates inflammatory tone and steroidogenic signaling through vitamin D receptor-dependent transcription and immune-metabolic crosstalk; myo-inositol restores insulin signaling via inositolphosphoglycan second-messenger pathways, thereby attenuating hyperinsulinemia-driven androgen excess; and melatonin exerts pleiotropic effects on mitochondrial function, circadian regulation, and redox balance. Therefore, these agents converge on shared molecular hubs, including NF-κB, Nrf2, PI3K/Akt, and AMPK, linking OS reduction with endocrine and metabolic recalibration. The review further integrates emerging insights into gut microbiota-adipokineinteractions, highlighting how dysbiosis and altered adipokine profiles amplify oxidative and hormonal disturbances, and how these bioactives may counteract such system-level disruptions. While existing clinical trials report improvements in ovulatory function, insulin resistance indices, and OS biomarkers, outcomes remain heterogeneous due to differences in dosing, duration, and phenotype stratification. We propose a redox-guided, phenotype-aware framework for future trials, emphasizing biomarker-anchored outcomes and systems-level integration. If validated, combined vitamin D, myo-inositol, and melatonin supplementation may represent a precision nutraceutical strategy that targets the pathogenic core of PCOS rather than its isolated clinical manifestations.
This study investigates the phytochemical composition and biological activities of Heliotropium indicum and Caesalpinia bonduc, two medicinal plants widely used in traditional medicine in Benin. In ethnomedicinal practice, H. indicum is commonly prepared as decoctions or infusions of the aerial parts and administered orally or topically to treat inflammatory conditions, wounds, fever, and infections, whereas C. bonduc roots are typically used in decoction for the management of urinary tract infections, pain, diabetes, and reproductive disorders. The present research aims to generate preliminary scientific data supporting these traditional applications. Aqueous and hydroethanolic (70% ethanol) extracts were prepared from the aerial parts of H. indicum and the roots of C. bonduc. Preliminary phytochemical screening was performed using standard qualitative colorimetric and precipitation reactions. The antimicrobial activities were evaluated against multiresistant uropathogenic strains using the agar disk diffusion method and broth microdilution for determination of minimum inhibitory concentrations (MICs). Antibiofilm activity was assessed using a crystal violet colorimetric assay. Analgesic and diuretic activities were evaluated in vivo in Wistar rats using hydroethanolic extracts. Acute oral toxicity was assessed following a limit test at 2000 mg/kg in rats. Phytochemical analysis revealed the presence of alkaloids, flavonoids, glycosides, saponins, and tannins in both plant species. Among the tested samples, only the hydroethanolic extract of C. bonduc exhibited antibacterial activity against the tested uropathogenic strains, with inhibition zones ranging from 14.6 to 16.6 mm and MIC values between 6 and 6.5 mg/mL. The aqueous extract of C. bonduc and both extracts of H. indicum did not exhibit detectable antibacterial activity under the experimental conditions. However, all extracts demonstrated antibiofilm activity, inhibiting biofilm formation in Escherichia coli and Staphylococcus spp. strains by 40.52%-71.93%. Hydroethanolic extracts of both plants showed significant analgesic activity (p < 0.05) in the acetic acid-induced writhing test and exhibited measurable diuretic effects in rats. In the acute toxicity study, no mortality or clinical signs of toxicity were observed at 2000 mg/kg during the 14-day observation period. Hematological and biochemical parameters remained within normal ranges, and histopathological examination of the liver and kidneys revealed no treatment-related alterations. These findings provide preliminary experimental support for some of the traditional uses of H. indicum and C. bonduc and suggest that hydroethanolic extracts of these plants warrant further investigation for the isolation and characterization of bioactive compounds.
Neuropsychiatric disorders represent a significant global health burden. Despite decades of research, current treatments typically provide only symptomatic relief, rather than addressing the underlying mechanisms of these conditions. Historically, research focused on the dopaminergic and serotonergic systems, which are deeply involved in the pathophysiology of many mental health disorders, including depression, schizophrenia, anxiety, autism spectrum disorder (ASD), and different substance use disorders, including alcohol use disorder (AUD). However, therapies targeting these systems have limitations, often only producing partial symptom relief plus compliance-limiting side effects. This highlights the need for improved treatments that may emerge from a broader understanding of the neurobiological bases of these conditions, especially neurochemical systems beyond dopamine and serotonin. Additional monoamines (e.g., histamine, acetylcholine, norepinephrine), neurolipid systems (e.g., endocannabinoids), and diverse signaling molecules such as neuropeptides, trace amines, and cytokines are increasingly recognized as key players in the dysfunction of neural circuits. In this review, which originated from the International Society for Neurochemistry (ISN)/Journal of Neurochemistry 5th Flagship School in October 2024 held in Naxos, Greece, we describe the importance of these neuromodulatory systems in the pathophysiology of select neuropsychiatric disorders, discuss their potential as targets for therapeutic intervention, exploring how they may offer more effective, mechanism-based treatments. We also highlight recent clinical trials, underscoring the progress in advancing towards clinical application, as well as sex-specific neurobiological differences, a historically overlooked, yet fundamental determinant of the pathophysiology of neuropsychiatric disorders. We propose that expanding our focus beyond traditional monoamines offers a promising avenue for the development of new, disease-modifying treatments that can more effectively address the underlying causes of neuropsychiatric disorders. By targeting these pathways, we believe it may be possible to develop therapies that restore balance to dysregulated brain circuits and improve long-term outcomes for patients.