搜索结果：Journal of experimental pharmacology

The 2023 iteration of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) estimated prevalence, incidence, and health burden for 375 diseases and injuries, including 12 mental disorders. We assess past, current, and emerging trends in the prevalence and burden of mental disorders across sexes and age groups, for 21 regions, 204 countries and territories, and by Socio-demographic Index (SDI) quintile, from 1990 to 2023. Mental disorders included in GBD 2023 were anxiety disorders, major depressive disorder, dysthymia, bipolar disorder, schizophrenia, autism spectrum disorders, conduct disorder, attention-deficit hyperactivity disorder, anorexia nervosa, bulimia nervosa, idiopathic developmental intellectual disability, and a residual category of other mental disorders. A literature review identified epidemiological data for each disorder. These were analysed via a Bayesian meta-regression to estimate prevalence by disorder, sex, age, location, and year. Disorder-specific prevalence was multiplied by disability weights representing the severity of health loss associated with each disorder to estimate years lived with disability (YLDs). Deaths due to anorexia nervosa were assessed with a Cause of Death Ensemble modelling strategy to estimate deaths by sex, age, location, and year, and then multiplied by the standard life expectancy at age of death to estimate years of life lost (YLLs). YLDs equalled disability-adjusted life-years (DALYs) for all mental disorders except anorexia nervosa (the only mental disorder considered as an underlying cause of death in GBD), for which DALYs represented the sum of YLDs and YLLs. We presented prevalence, deaths, YLDs, YLLs, and DALYs as counts, age-specific rates per 100 000 population, and age-standardised rates per 100 000 population. We estimated 1·17 billion (95% uncertainty interval 1·06-1·31) prevalent cases of mental disorders globally in 2023, equivalent to an age-standardised prevalence rate of 14 210·7 cases (12 849·5-15 940·1) per 100 000 population. These estimates represented a 95·5% (75·0-121·2) increase in prevalent cases and 24·2% (11·4-41·4) increase in age-standardised prevalence rate between 1990 and 2023. All mental disorders showed increases in prevalent cases between 1990 and 2023, while notable increases were seen in age-standardised prevalence rates for anxiety disorders, major depressive disorder, dysthymia, anorexia nervosa, bulimia nervosa, schizophrenia, and conduct disorder. There were an estimated 171 million (127-228) DALYs due to mental disorders globally across sex and age in 2023, equivalent to an age-standardised DALY rate of 2070·5 DALYs (1519·1-2750·5) per 100 000 population. Mental disorders contributed to 6·1% (4·8-7·6) of all-cause DALYs in 2023, making them the fifth leading cause of global DALYs (up from 12th in 1990). DALYs were almost entirely composed of YLDs. Mental disorders were the leading cause of YLDs in 2023 (up from second in 1990), explaining 17·3% (14·8-20·6) of all-cause global YLDs. Leading causes of mental disorder DALYs were anxiety disorders (ranked 11th among the 304 diseases and injuries at Level 4 of the GBD cause hierarchy), major depressive disorder (15th), and schizophrenia (41st). Globally in 2023, mental disorder age-standardised DALY rates were higher among females (2239·6 [1643·7-3014·1] per 100 000) than among males (1900·2 [1399·8-2510·8] per 100 000), and peaked in the 15-19 years age group (2617·3 [1850·6-3696·8] per 100 000). All locations showed increased mental disorder DALY rates in 2023 compared with 1990, ranging across countries and territories from 1302·4 (952·7-1683·7) per 100 000 in Viet Nam to 3555·8 (2661·9-4715·0) per 100 000 in the Netherlands. Across SDI quintiles, DALY rates ranged from 1853·0 (1352·1-2469·3) per 100 000 for middle SDI to 2184·1 (1606·1-2890·3) per 100 000 for high SDI. A significant health burden was imposed by mental disorders in all countries and territories in 2023, irrespective of the health resources available. In some instances, this burden has increased over time and is unevenly distributed across populations. Stronger surveillance systems, particularly in low-income and middle-income countries, are required. Additionally, we need more coordinated and inclusive policies to reduce the burden through early treatment and prevention, tailored to sex and age differences across locations. Responding to the mental health needs of our global population, especially those most vulnerable, is an obligation, not a choice. Gates Foundation, Queensland Health, and University of Queensland.

Inflammation is associated with metabolic alterations that can lead to the release of volatile organic compounds (VOCs) reflecting cellular biochemical activity. Profiling these volatile metabolites may provide insight into cellular responses to inflammatory stimuli, although their characterization in skin-derived cells remains limited. In this exploratory proof-of-concept study, we investigated the volatile metabolite profiles of human skin fibroblasts exposed to different inflammatory stimuli. Fibroblast cell lines were stimulated with polyinosinic:polycytidylic acid (Poly I:C), tumor necrosis factor-alpha (TNF-α), and lipopolysaccharide (LPS) to model viral-, cytokine-, and bacterial-associated stress conditions. Headspace solid-phase microextraction coupled with comprehensive two-dimensional gas chromatography and time-of-flight mass spectrometry (HS-SPME-GC×GC-TOFMS) was applied to analyze volatile metabolites released from the cell cultures, enabling exploratory profiling of the fibroblast volatilome. A data-processing workflow including pairwise comparisons between experimental groups and statistical filtering was implemented to identify volatile features associated with the different conditions. Several VOCs were tentatively identified, mainly belonging to alcohol, ester, and hydrocarbon classes, and showed differential abundance patterns between stimulated and control samples. Multivariate analysis indicated a separation between stimulated and non-stimulated groups, suggesting stimulus-associated differences in the volatile profiles of fibroblast cultures. While these observations may reflect metabolic responses occurring under inflammatory stimulation, the chemical identity and biochemical origins of several detected features remain to be confirmed. All in all, this study demonstrates the feasibility of applying HS-SPME-GC×GC-TOFMS-based volatilome profiling to investigate stimulus-associated changes in fibroblast cultures. The detected VOC patterns should therefore be considered preliminary observations requiring further chemical characterization and independent validation. Future studies including larger sample numbers, complementary biological verification of the inflammatory response, and more physiologically relevant experimental models will be necessary to further assess the robustness and potential relevance of these volatile signatures in the context of inflammatory processes.

This study aimed to systematically investigate the active components, potential targets, and molecular mechanisms of jujube against alcoholic liver disease (ALD) using an integrated approach combining serum pharmacochemistry, network pharmacology, and molecular docking, with validation through in vitro experiments. Using UPLC-Q-TOF-MS/MS, 78 chemical components were identified from jujube extract, and 24 blood-absorbed components were detected in rat serum, among which kaempferol, luteolin, and betulonic acid were identified as key active compounds. Network pharmacology analysis revealed 255 common targets, with core targets including AKT, TNF, and EGFR. KEGG enrichment analysis indicated that jujube exerts its interventive effects mainly through the PI3K-Akt signaling pathway, HIF-1 signaling pathway, and lipid and atherosclerosis, among others. Molecular docking revealed binding energies lower than -6 kcal/mol between core targets and active components, demonstrating strong affinity. In vitro experiments confirmed that jujube extract significantly upregulated the expression of AKT, supporting the findings from network pharmacology. The results suggested that jujube might exert therapeutic effects on ALD by modulating the AKT, providing a scientific basis for the development and application of jujube and laying a foundation for research on natural medicines.

During the cultivation of Ziziphus jujuba Mill. var. spinosa trees, two varieties exhibiting floral sterility were identified. Their flowers are often discarded, resulting in resource wastage. Therefore, non-targeted metabolomics technology was employed to characterize the chemical composition of Z. jujuba Mill. var. spinosa flowers. Network pharmacology was then utilized to explore their medicinal active components and mechanisms of action, which were validated through molecular docking and in vitro anti-inflammatory experiments. Results revealed that 3851 metabolites were identified in Z. jujuba Mill. var. spinosa flowers, with 23 potential compounds screened. Among these, 212 targets were directly involved in inflammatory responses. KEGG enrichment analysis suggested that Z. jujuba Mill. var. spinosa flowers may exert anti-inflammatory effects through the TNF signaling pathway, Toll-like receptor signaling pathway, Th17 cell differentiation, and hypoxia-inducible factor-1 pathway. Molecular docking results indicated that active components in Z. jujuba Mill. var. spinosa flowers exhibit good binding affinity with key inflammatory targets. In vitro anti-inflammatory assays validated that the ethanol extract of Z. jujuba Mill. var. spinosa flowers reduces the expression of TNF-α, IL-1β, and IL-6, thereby alleviating inflammation. This study preliminarily demonstrates that Z. jujuba Mill. var. spinosa flowers contain anti-inflammatory active components, and the associated bioactive substances hold potential for development into anti-inflammatory drugs.

Male infertility contributes to nearly half of all infertility cases worldwide and is closely linked to oxidative stress, inflammation, endocrine imbalance, and environmental toxicant exposure, all of which impair spermatogenesis and sperm function. Interest in naturally derived bioactive compounds has increased due to their potential multitarget therapeutic effects and relatively favorable safety profiles. Acetyl-eugenol, a structural derivative of eugenol found in Syzygium aromaticum and other aromatic plants, has demonstrated antioxidant, anti-inflammatory, and cytoprotective activities in experimental studies. This review critically evaluates the potential role of acetyl-eugenol in male reproductive health, focusing on its pharmacological properties and proposed mechanisms of action. Available preclinical evidence suggests that acetyl-eugenol may reduce oxidative stress by scavenging reactive oxygen species, enhancing endogenous antioxidant defenses, and modulating inflammatory pathways such as NF-κB signaling. It may also contribute to the preservation of testicular structure and function, including protection of Sertoli and Leydig cells. However, current evidence remains limited and is derived predominantly from in vitro and animal studies, with very limited direct evidence in humans. Many proposed reproductive benefits are inferred from studies involving eugenol or related compounds rather than acetyl-eugenol specifically. In addition, conflicting findings regarding dose-dependent toxicity, insufficient pharmacokinetic data, and the absence of standardized clinical studies limit definitive conclusions regarding efficacy and safety. Overall, acetyl-eugenol represents a promising candidate for mitigating oxidative stress-associated male reproductive dysfunction, but its therapeutic potential remains preliminary. Further well-designed experimental and clinical studies are necessary to clarify its mechanisms, safety profile, and translational relevance in male infertility management.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease, is one of the most prevalent liver diseases globally, contributing to both economic and health-related challenges. We aimed to evaluate the global, regional, and national burden of MASLD from 1990 to 2023, quantify the contribution of identified modifiable risk factors, and project future prevalence up to the year 2050. Estimates of MASLD prevalence and disability-adjusted life-years (DALYs) were produced by age, sex, region, Socio-demographic Index (SDI), and Healthcare Access and Quality (HAQ) index across 204 countries and territories from 1990 to 2023 as part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023. The MASLD burden attributable to three risk factors (smoking, high BMI, and high fasting plasma glucose) was assessed as part of the GBD comparative risk assessment. As a secondary analysis, we used these estimates to forecast MASLD prevalence up to 2050 using fasting plasma glucose and mean BMI as predictors. Furthermore, to examine the relative contributions of population ageing, population growth, and changes in MASLD prevalence rate to the forecasted changes in case counts from 2023 to 2050, we conducted a decomposition analysis. In 2023, approximately 1·3 billion (95% uncertainty interval [UI] 1·2 to 1·4) individuals were estimated to be living with MASLD (ie, 16·1% of the global population), with an age-standardised prevalence rate of 14 429·3 (95% UI 13 268·3 to 15 990·6) per 100 000 population, representing a percentage increase of 142·7% (95% UI 139·2 to 146·7) in crude numbers from 1990 (0·5 billion [0·5 to 0·6]) and of 28·6% (27·8 to 29·5) in the rate (11 217·2 [10 276·8 to 12 467·0] per 100 000 in 1990). An estimated 3·6 million (2·8 to 4·5) total DALYs were attributable to MASLD worldwide in 2023, corresponding to an age-standardised DALY rate of 39·6 (31·2 to 49·9) per 100 000 population. Despite a 116·3% (93·3 to 139·4) increase in crude DALYs (from 1·7 million [1·3 to 2·1] in 1990), its age-standardised estimate remained consistent (1·8% [-8·6 to 12·8]) from 1990 (38·9 [30·1 to 49·8] per 100 000) to 2023. There was substantial variation in age-standardised estimates across regions. North Africa and the Middle East had the highest prevalence rate (29 246·1 [26 848·3 to 32 048·7] per 100 000) and Andean Latin America showed the highest DALY rate (152·3 [114·1 to 194·7] per 100 000). By contrast, the high-income Asia Pacific region had the lowest prevalence rate (8653·5 [7923·7 to 9592·8] per 100 000) and east Asia had the lowest DALY rate (16·3 [13·5 to 19·9] per 100 000) among all GBD regions. North Africa and the Middle East showed disproportionately higher prevalence rates relative to other regions with similar SDIs. Lower SDIs and HAQs were associated with higher age-standardised DALY rates. The age-standardised prevalence rate was consistently higher in males (15 616·4 [14 349·2 to 17 263·3] per 100 000 people in 2023) than in females (13 245·2 [12 132·0 to 14 692·6] per 100 000 people), and peaked at age 80-84 years in both sexes. The number of MASLD prevalent cases was the highest in younger adults, peaking at age 35-39 years for males and age 55-59 years for females. Among the risk factors for MASLD, high fasting plasma glucose presented the largest contribution to the age-standardised DALY rate of total MASLD in 2023 (2·2 [95% UI 1·6 to 3·1] per 100 000 people), followed by high BMI (1·4 [0·6 to 2·4] per 100 000 people) and smoking (1·0 [0·3 to 1·8] per 100 000 people). Our forecasting model estimates that 1·8 billion (95% UI 1·6 to 2·0) individuals are likely to have MASLD by 2050, representing a 42·0% increase from 2023. The age-standardised prevalence rate is expected to increase to 15 774·9 (95% UI 14 613·9 to 17 336·2) per 100 000 people in 2050, representing an average annual percentage change of 0·3% (95% UI 0·3-0·3). According to our decomposition analysis, this change will be primarily due to population growth, particularly in sub-Saharan Africa and North Africa and Middle East, and less by population ageing or epidemiological change. With a global prevalence of 16·1% and approximately 1·3 billion people already living with MASLD in 2023, the condition has and will continue to have substantial health and economic impacts worldwide. An inverse association between the HAQ Index and age-standardised DALY rates suggests that countries with lower health-care access and quality might be less well positioned to manage the growing MASLD burden, underscoring the need for strengthened health-system capacity in these settings. Gates Foundation.

Hypertrophic cardiomyopathy (HCM) is a heritable cardiac disorder characterized by increased left ventricular (LV) wall thickness, often leading to heart failure (HF). The role of cardiovascular magnetic resonance (CMR) imaging in predicting new onset of HF symptoms in patients with HCM remains unknown. This study aimed to identify CMR predictors of new-onset HF symptoms in individuals with HCM. This study was a single-centre retrospective cohort study of HCM patients treated at a tertiary referral centre in the USA who underwent CMR examination between 1998 and 2018, had no HF symptoms at baseline CMR, and at least 1 year of follow-up. Clinical data were collected by review of electronic medical records, and CMR images were analyzed by a blinded expert cardiac radiologis. The primary outcome was new onset of HF symptoms, defined as New York Heart Association (NYHA) class ≥ II at follow-up. Kaplan-Meier analyses and Cox proportional hazard analyses were performed. Of 1462 patients diagnosed with HCM who had at least 1 CMR, 276 HCM patients without HF symptoms (average age 52.7 years, 33.3% female),median maximum left ventricular (LV) wall thickness was 19 mm ([IQR] 17-22) with a and median LV ejection fraction of 71% (IQR 66-77). Late gadolinium enhancement was detected in 56.2%) patients (60.7% had mild; 30.7% moderate; 8.6% severe). During a median follow-up period of 6.3 years, 93 patients developed HF symptoms (NYHA class II in 56 (60.2%); class III in 31 (33.3%); and class IV in 6 (6.5%). Multivariable analysis adjusted for age showed that LA enlargement (HR 1.626; 95% CI 1.01-2.62; P = .045) and LV mass index (HR 1.014; 95% CI 1.007-1.022; P≤ .001) and sex (HR 1.7; 95% CI 1.074-2.691; P = .023) were independent predictors of new onset of HF symptoms in patients with HCM. Nearly half of the patients with HCM developed HF symptoms within 6.3 years. Left atrial enlargement, LV mass index, and sex were independent predictors of new onset of HF symptoms in HCM patients. These findings emphasize the value of CMR in HF risk stratification.

Cisplatin is a key treatment for head and neck squamous cell carcinoma (HNSCC), but the development of resistance severely limits its effectiveness. The molecular determinants underlying cisplatin resistance in HNSCC remain unclear. Multiple databases were used to screen the core genes related to cisplatin resistance in HNSCC patients. Tumor tissue samples from HNSCC patients were collected and the expression of FOXA2 was verified through various pathological tests to establish the correlation between FOXA2 expression and the clinical characteristics of the patients. The in vitro and patient-derived organoids (PDOs) models were used to verify the regulatory effect of FOXA2 on the cisplatin resistance of HNSCC. Transcriptome sequencing combined with multi-omics analysis demonstrated that LAMC2 is a downstream target of FOXA2 in regulating cisplatin resistance. Bioinformatic screening of cisplatin-resistant cohorts revealed that FOXA2 was the only gene significantly associated with poor survival outcomes in TCGA-HNSCC patients. Transcriptomic profiling and pathway enrichment analyses revealed the activation of the PI3K/AKT signaling cascade. We identified LAMC2 as a direct transcriptional target of FOXA2. Chromatin immunoprecipitation and luciferase reporter assays confirmed FOXA2 binding to the LAMC2 promoter, resulting in transcriptional activation. FOXA2-mediated upregulation of LAMC2 increased PI3K and AKT phosphorylation, and LAMC2 overexpression reversed the impaired malignant phenotypes caused by FOXA2 silencing. In xenograft models and PDO systems, FOXA2 overexpression reduced responsiveness to cisplatin, whereas FOXA2 inhibition significantly increased therapeutic sensitivity. Our research has identified a previously unrecognized regulatory axis involving FOXA2, LAMC2, and PI3K/AKT, which plays a crucial role in the progression and resistance to cisplatin in HNSCC. Therefore, targeting the FOXA2-LAMC2 axis may represent a novel therapeutic strategy to overcome cisplatin resistance in HNSCC.

CARD11 is a scaffold protein expressed primarily in hematopoietic tissues, shaping key processes in B and T cells via regulation of Ag-linked signaling pathways, including NF-κB, mTOR, JNK, and AKT. Heterozygous, gain-of-function (GOF) variants in its encoding gene, CARD11, are implicated in a human disorder characterized by frequent upper respiratory infections, poor responses to polysaccharide vaccines, vulnerability to certain opportunistic viruses, and polyclonal B-cell expansion, likely predisposing these patients to lymphoma. Over the past decade, several studies have elucidated some of the B-cell functional defects that likely underlie the patients' infectious phenotype. However, the potential contributions of CARD11 GOF variants to subpopulations of T cells have not been explored in detail. Therefore, our study sought to investigate the effect of increased CARD11 activity on the development, maturation, activation, differentiation, and effector function of adaptive lymphocytes from a cohort of five individuals harboring monoallelic CARD11 GOF variants through detailed ex vivo immunophenotyping and in vitro analyses. Our findings revealed intrinsic requirements for CARD11 in activation, differentiation, and effector function of human naïve B cells. Contrary to previous reports, intact CARD11 activity is also required for multiple aspects of CD4+ T-cell homeostasis alongside its notable role in the humoral immune response. Overall, these results shed light on mechanisms underlying disease pathogenesis due to not only CARD11 GOF variants but also LOF variants and reveal opportunities to consider targeted therapies in CARD11 GOF patients.

Following the publication of the above paper, it was drawn to the Editor's attention by a concerned reader that, regarding the western blot analyses shown in Fig. 2A and B on p. 179, the control β‑actin blots in Fig. 2A were very similar to a section of the control blots in Fig. 2B, albeit with some horizontal and vertical resizing of the bands in question, even though the affected lanes of the gel highlighted different experimental treatments. The authors were contacted by the Editorial Office to offer an explanation for this apparent anomaly in the presentation of the data in this paper, and we are awaiting their response. Owing to the fact that the Editorial Office has been made aware of potential issues surrounding the scientific integrity of this paper, we are issuing an Expression of Concern to notify readers of this potential problem while the Editorial Office continues to investigate this matter further. [International Journal of Oncology 32: 177‑184, 2008; DOI: 10.3892/ijo.32.1.177].

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.

To evaluate whether systemic supplementation with L. rhamnosus LR-04 and L. acidophilus LA-14 modulates the expression of TLR4, hBD-2, and hBD-3 in a rat model of experimental apical periodontitis (AP), and to assess potential histopathological alterations in the liver. Twenty-four male Wistar rats were randomly allocated into three groups (n=8): control (AP + water), AP + L. rhamnosus LR-04, and AP + L. acidophilus LA-14. AP was induced by exposing the pulp chambers of the first mandibular molars for 30 days. From the day of induction, probiotics (109 CFU/day via oral gavage) or water (control) were administered daily. After 30 days, the rats were euthanized. Mandibles were processed for immunohistochemical analysis of hBD-2, hBD-3, and TLR4 expression, which was assessed semi-quantitatively. Liver samples were collected, fixed, and stained with hematoxylin-eosin for histopathological evaluation of lobular inflammation, necrosis, portal inflammation, and fibrosis. Data were analyzed using the nonparametric Kruskal-Wallis test at a 5% significance level. No hepatic histopathological alterations were observed in any group. Probiotic supplementation resulted in significantly greater hBD-2 immunoreactivity in periapical tissues compared to the control group (P<0.05). hBD-3 expression was significantly higher in the L. acidophilus LA-14 group than in both the control and L. rhamnosus LR-04 groups (P<0.05). TLR4 expression in periapical lesions was increased in both probiotic groups relative to control (P<0.05). Systemic supplementation with L. rhamnosus LR-04 and L. acidophilus LA-14 enhanced the local immune response in apical periodontitis, as evidenced by upregulation of TLR4, hBD-2, and hBD-3, without inducing detectable hepatic histopathological alterations.

Allergic rhinitis is a chronic non-communicable disease that adversely affects respiratory health and quality of life. Ginger-based formulations, owing to their anti-inflammatory and immunomodulatory properties, may offer a promising alternative therapeutic option. To systematically review and meta-analyze evidence from animal studies and human randomized controlled trials assessing the efficacy of ginger-based formulations in allergic rhinitis. A systematic search of the Cochrane Library, Embase, PubMed, and Scopus (April 2025) identified studies comparing ginger-based formulations with control interventions. Outcomes included clinical symptoms and relevant biomarkers. Risk of bias was assessed using the SYRCLE tool for animal studies and RoB2 for human studies. Meta-analyses were conducted using random-effects models, with results expressed as standardized mean difference (SMD) and 95% confidence intervals (CIs). Twenty-one studies (6 animal and 15 human studies) were included. In rodents, ginger-based formulations significantly reduced nasal rubbing (SMD&#x2009;=&#x2009;-1.99; 95%CI, -3.15 to -0.83), sneezing (SMD&#x2009;=&#x2009;-1.99; 95%CI, -2.78 to -1.20), and biomarkers (IL-4, IL-5, and OVA-specific IgE). In humans, ginger-based formulations significantly improved itching (SMD&#x2009;=&#x2009;-0.51; 95%CI, -0.79 to -0.24), runny nose (SMD&#x2009;=&#x2009;-0.59; 95%CI, -0.87 to -0.30), sneezing (SMD&#x2009;=&#x2009;-0.56; 95%CI, -0.75 to -0.37), total nasal symptom scores (SMD&#x2009;=&#x2009;-0.63; 95%CI, -1.00 to -0.26), and quality of life (SMD&#x2009;=&#x2009;-0.56; 95%CI, -0.87 to -0.24), and eosinophil levels. Ginger-based formulations improve symptoms and biomarkers of allergic rhinitis in both animal and human studies. As many interventions are multi-component, the observed effects are more appropriately attributed to the overall formulations rather than ginger alone. Further research is needed to explore mechanisms and clarify clinical applications.

This study aimed to investigate the histopathological and functional effects of pirfenidone in a rat model of frozen shoulder (adhesive capsulitis). Thirty-two male Wistar Albino rats were randomly divided into four groups (n&#x2009;=&#x2009;8 each): control, frozen shoulder (FS), pirfenidone-treated (FS&#x2009;+&#x2009;PFD), and dexamethasone-treated (FS&#x2009;+&#x2009;DEX). The FS model was induced by immobilizing the shoulder joint with plaster for 4 weeks. Treatment groups received oral pirfenidone (30&#x2009;mg/kg/day) or prednisolone (3&#x2009;mg/kg/day) for 30 days. Histopathological changes in the synovial membrane and fibrous capsule were evaluated with hematoxylin-eosin and Masson's trichrome staining, while shoulder joint range of motion (ROM) was measured. The FS group showed significant pathological alterations, including synovial epithelial atrophy, loss of synovial folds, hyperemia, edema, and severe capsular fibrosis. Both pirfenidone and dexamethasone treatments reduced these abnormalities. Pirfenidone was more effective in preserving collagen fiber organization and synovial fold integrity. ROM was markedly reduced in the FS group, but partial recovery occurred in both treatment groups. Pirfenidone provided greater functional improvement compared with dexamethasone. Inflammation scores did not differ significantly between groups, consistent with evaluation during the fibrotic phase. Pirfenidone attenuates fibrotic changes and improves joint mobility in an experimental frozen shoulder model. Pirfenidone improved histological fibrosis scores and ROM in this experimental model. Comparative effectiveness versus corticosteroids requires confirmation in larger, appropriately powered studies. These results emphasize the antifibrotic potential of pirfenidone and support further long-term and clinical studies to clarify its role in adhesive capsulitis management.

While epilepsy research has largely focused on medical management and clinical outcomes, less attention has been given to the unmet psychosocial and everyday needs of people with epilepsy (PWE), particularly in low- and middle-income countries. The Global Epilepsy Needs Study (GENS) aims to explore these needs, which are integral to the quality of life, by capturing both shared and context-specific experiences. The GENS employed a patient-centered approach and mixed-methods design, integrating a cross-sectional survey and semi-structured interviews in 15 countries. The survey, available in 12 languages, captured experiences across 10 life domains (n&#x2009;=&#x2009;5296 participants). Interviews were analyzed thematically using a phenomenological approach and Colaizzi's method, exploring lived experiences in depth (n&#x2009;=&#x2009;75 participants). To ensure meaningful involvement and diverse representation, national patient associations, healthcare professionals, researchers, and people with lived experience guided each stage of the research process, from study design to manuscript development. Quantitative and qualitative data were integrated using a joint display method. This analysis generated five Generalized Themes across all life domains: (1) managing uncertainty and redefining daily life; (2) living with risk, social exclusion, and misunderstanding; (3) challenges in navigating inaccessible systems; (4) consequences of inaccessible or inadequate information; and (5) complex epilepsy needs demand more than standard approaches. This first-of-its-kind global study offers a comprehensive picture of the psychosocial and everyday challenges faced by PWE. It establishes a critical evidence base for epilepsy organizations, highlights the need for healthcare systems to adopt holistic, multidisciplinary approaches, and calls on policymakers to invest in systemic reforms that safeguard dignity, inclusion, and life opportunities. Future research should explore the needs of underserved groups, including caregivers, individuals with complex epilepsy, women, and those in low-income or rural settings. This study examined the everyday challenges faced by people with epilepsy in different parts of the world. It showed that many people struggle with fear, stigma, poor access to services, and a lack of clear information and support. Women, people in rural areas, and those in low-income settings often face the greatest challenges. The study calls for better education, more support for caregivers, and improvements across health, work, school, and transport systems. It also shows the need for more research to understand and respond to the real-life needs of people most impacted by epilepsy.

Maternal sleep deprivation (MSD) is a common but usually unnoticed issue during pregnancy, and in recent years, it has been increasingly recognised as an important prenatal stressor that may adversely influence maternal physiology, placental function, and fetal neurodevelopment. Sleep disturbances during pregnancy, including reduced sleep duration, fragmented sleep, poor sleep quality, circadian disruption, and rapid eye movement sleep restriction, have been associated with altered hypothalamic-pituitary-adrenal axis activity, systemic inflammation, oxidative stress, and impaired circadian regulation. Emerging evidence from clinical and preclinical studies suggests that these alterations may affect fetal neurogenesis, synaptic development, neuroimmune signaling, and maturation of brain circuits involved in cognition and emotional regulations. Within the framework of the Developmental Origins of Health and Disease, maternal sleep disturbances may contribute to epigenetic modifications, mitochondrial dysfunction, microglial activation, and altered neuroplasticity-related pathways, which are increasingly implicated in long-term neurological vulnerability. Experimental findings further indicate that prenatal sleep disruption may impair offspring cognitive performance, emotional behavior, and stress responsiveness, while potentially influencing biological pathways associated with brain aging-related processes. However, the extent to which MSD directly contributes to pathological brain aging in humans remains incompletely understood. Factors such as timing and duration of exposure, sex-specific responses, and postnatal environmental conditions may further influence offspring outcomes. Therefore, this narrative review critically summarizes current evidence regarding MSD and examines the molecular, cellular, and neurodevelopmental mechanisms through which prenatal sleep disturbances may influence long-term neurological health and vulnerability to brain aging-associated alterations in offspring.This graphical abstract illustrates the mechanistic framework connecting maternal sleep deprivation to the developmental programming of brain aging in offspring. [ MSD: maternal sleep deprivation; DOHaD: Developmental Origins of Health and Disease; 11&#x3b2; HSD2: 11&#x3b2; hydroxysteroid dehydrogenase type 2; ROS: reactive oxygen species; REM: rapid eye movement; HPA axis: hypothalamic pituitary adrenal axis; BDNF: brain derived neurotrophic factor].

Idiopathic pulmonary fibrosis (IPF) is a devastating chronic lung disorder with limited treatment options. Macropinocytosis is one of the key cellular processes involved in nutrient consumption from the extracellular environment under stress conditions. Here, we studied the role of macropinocytosis in experimental pulmonary fibrosis models. We found that macropinocytosis is increased in human lung fibroblasts (HLFs) derived from patients with IPF. The inhibition of macropinocytosis with 5-(n-ethyl-n-isopropyl)-amiloride (EIPA) inhibited profibrotic responses in IPF-derived and TGF-&#x3b2;1-stimulated HLFs and reduced pulmonary fibrosis in bleomycin-injured (Bleo-injured) mice. EIPA exerted its antifibrotic effects by regulating amino acid uptake, mammalian target of rapamycin complex 1 (mTORC1) activation and mesenchyme homeobox1 (MEOX1) expression in activated HLFs. Fittingly, genetic inhibition of macropinocytosis also ameliorated lung fibroblast activation and pulmonary fibrosis in mice. Using IPF-derived precision cut lung slices (PCLSs), we observed robust repression of profibrotic gene expression programs in EIPA-treated PCLSs across different fibroblast subpopulations. Finally, we found that imipramine (Imi), a tricyclic antidepressant approved by the FDA, effectively inhibited macropinocytosis and ameliorated profibrotic responses in lung fibroblasts, Bleo-injured mice, and IPF-derived PCLSs. Taken together, our results suggest that macropinocytosis inhibition can be considered as a potential therapeutic strategy to treat pulmonary fibrosis.

Lung adenocarcinoma is a common malignancy that requires new treatments. Arsenic trioxide (ATO) exerts antitumor activity in various cancers; however, its mechanisms of action in lung adenocarcinoma remain unclear. The 24-h half-maximal inhibitory concentration (IC50) of ATO on human lung adenocarcinoma A549 cells was determined using the Cell Counting Kit-8 assay. Cells were treated with the IC50 concentration in the experimental group, and untreated cells served as the control group. A comparative assessment of cell proliferation, apoptosis, invasion, and migration was performed. Transcriptome sequencing followed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were conducted to identify differentially expressed genes and enriched pathways. Candidate pathway proteins were validated by western blot analysis. The 24-h IC50 of ATO was 99.12 &#x3bc;mol/L. The ATO-treated group exhibited reduced proliferation, increased apoptosis, and decreased invasion and migration ( P < 0.05) compared with that in the control group. Transcriptome analysis revealed 4,522 upregulated and 4,045 downregulated genes, with enrichment in the mammalian target of rapamycin (mTOR) signaling pathway, base excision repair (BER), and apoptosis pathways. At the protein level, total mTOR expression did not significantly change, whereas phosphorylated mTOR (p-mTOR), APE-1, Bcl-2, and Bcl-XL were downregulated, and cleaved caspase-8 and cleaved caspase-9 were upregulated ( P < 0.05). These results indicate that ATO suppresses the malignant phenotype of A549 cells by inhibiting mTOR phosphorylation, downregulating key BER components, and activating the extrinsic and intrinsic apoptotic pathways, providing experimental evidence for further studies of ATO in lung adenocarcinoma therapy.

Network pharmacology and molecular docking are widely applied in drug discovery, yet fragmented workflows and inconsistent operations frequently undermine result reproducibility. Here, a standardized protocol integrating these approaches into a reproducible framework for drug screening and mechanism exploration is described, with the workflow organized into three sequential phases: data preparation, computational analysis, and validation. In the preparation phase, compound libraries from public databases are filtered via Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) criteria, including oral bioavailability, drug-likeness, and toxicity prediction, while potential therapeutic targets are obtained through target prediction and integration of disease-related databases to comprehensively identify drug-disease interaction candidates. In the computational analysis phase, overlapping targets undergo Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses and protein-protein interaction network topological analysis to identify core targets; molecular docking is configured with two standardized optional strategies with distinct advantages. The two-step progressive strategy employs AutoDock Vina for high-throughput preliminary screening of the compound library, followed by precise re-docking with YASARA, which eliminates false positives from high-throughput screening and generates protein-ligand complexes natively compatible with subsequent YASARA molecular dynamics (MD) simulations to avoid structural deviations caused by cross-software format conversion. The one-step strategy completes the full docking process via YASARA alone, which simplifies the operation workflow, improves experimental efficiency, and is fully applicable for specific research goals. In the validation phase, standardized MD simulations evaluate ligand-protein complex stability via core metrics of root mean square deviation (RMSD) and root mean square fluctuation (RMSF). This unified, reproducible pipeline enhances the reliability of network pharmacology and docking studies and facilitates cross-study comparisons in computational drug discovery.