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BACKGROUND: As inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), statins can reduce the synthesis of low-density lipoptrotein cholesterol (LDL-C), and are clinically used as first-line lipid-lowering drugs to prevent cardiovascular diseases. However, the effect of statins on sepsis is controversial. Therefore, we intend to explore the effects of statins on sepsis and inflammatory factors through Mendelian randomization (MR). METHOD: We obtained sepsis, inflammatory factors, and LDL-C data from open and free genome-wide association study (GWAS) for subsequent analysis. Inverse-variance weighted (IVW) was the main method, MR-Egger, MR-PRESSO and Cochrane's Q-test were used as sensitive analysis to evaluate the robustness of MR results. RESULTS: Statins were associated with a reduced risk of sepsis under 75 (sepsis in individuals under 75 years old) (OR: .716, 95% CI: .572-.896, p = .003), elevated circulating IL-18 (OR: .762, 95% CI: .643-.903, p = .002) and elevated circulating CCL2 (OR: .416, 95% CI: .279-.620, p = 1.685e-5). CONCLUSION: Statins may have a protective effect on sepsis and this may provide a new idea for the treatment of sepsis.
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Inhibidores de Hidroximetilglutaril-CoA Reductasas , Sepsis , Humanos , Anciano , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , LDL-Colesterol , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Sepsis/tratamiento farmacológico , Sepsis/genéticaRESUMEN
OBJECTIVES: To explore the role of endothelial-mesenchymal transition (EndMT) mediated by the TGF-ß/SMAD signalling pathway in the pathogenesis of ankylosing spondylitis (AS). METHODS: Serum levels of TGF-ß1 were measured by enzyme-linked immunosorbent assay (ELISA) in 48 patients with AS and 15 healthy subjects. The expression levels of TGF-ß1, SMAD7, CTGF, CD34 and EndMT-related markers (α-SMA, vimentin, FSP-1, VE-cadherin) in the sacroiliac joint (SIJ) of three AS patients were detected by immunohistochemistry, and three non-spondyloarthritis (SpA) autopsy samples were used as controls. RESULTS: Serum TGF-ß1 level of AS patients was significantly higher than that of healthy controls (22971 ± 7667 pg/ml vs. 14837±4653 pg/ml, p<0.01). Compared with the non-SpA control group, the microvascular density (MVD) at the pannus formation site of SIJ in AS patients was significantly increased, accompanied by respectively increased expressions of TGF-ß1, CTGF, α-SMA, vimentin, and FSP-1 (all p<0.05), whereas respectively decreased expressions of VE-cadherin and SMAD7 (p<0.01). The expression level of FSP-1 was positively correlated with levels of TGF-ß1 and MVD, and negatively correlated with SMAD7. CONCLUSIONS: Our findings show that EndMT is involved in the promotion of pannus formation by TGF-ß/SMAD signalling pathway activation in AS.
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The controversy regarding the causal relationship between circulating glutamine and cancer risk remains unresolved. Here, we aim to assess the causal impact of glutamine on the risk of six prevalent cancer types and their respective subtypes including breast, lung, ovarian, thyroid, prostate, and endometrial cancers. A Mendelian randomization (MR) analysis was conducted to evaluate the causal effect of circulating glutamine on cancers risk. Data on circulating glutamine were extracted from the UK Biobank (UKB), comprising 114,750 European patients. To ensure the validity of our findings, we employed several analytical approaches, such as inverse variance weighting, weighted median, weighted mode test, MR-Egger regression, and MR-PRESSO method. Both univariable and multivariable MR analyses were conducted. Additionally, we employed a large-scale summary-level study on circulating glutamine involving 24,925 European participants for validation purposes. Our MR analysis reveals a causal association between circulating glutamine and thyroid cancer in both the UKB cohort (IVW: OR = 0.667, 95% CI [0.541-0.822], P = 1.52×10-4) and the validated cohort (IVW: OR = 0.577, 95% CI [0.421-0.790], P = 6.14×10-4). Sensitivity analysis, including multivariable MR analyses, consistently supports this finding (P < 0.05), affirming the reliability and robustness of our study. Our findings indicate an inverse correlation between circulating glutamine and the incidence of thyroid cancer in European populations. However, further research encompassing diverse ancestries is necessary to validate this causal relationship.
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BACKGROUND: Studies investigating the association between single nucleotide polymorphisms (SNPs) of tumor necrosis factor-alpha (TNFα) and the efficacy of adalimumab (ADA) in ankylosing spondylitis (AS) therapy have reported conflicting results. We aimed to investigate the value of SNP typing of TNFα in predicting the efficacy of ADA in AS. MATERIALS AND METHODS: Eighty patients with active AS who received ADA treatment were followed up for 24 weeks. Six known SNPs of TNFα (+489G/A, -238G/A, -308G/A, -857C/T, -863C/A, and -1031C/T) were subjected to the SNaPshot SNP typing method, which has been proven to be a reliable, efficient, and cost-effective method for detecting SNPs. The relationship between each SNP genotype and the therapeutic efficacy of ADA was analyzed. RESULTS: At the end of the 24-week follow-up, 58.8% of the patients with AS achieved Assessment of SpondyloArthritis International Society (ASAS) partial remission (PR), 67.5% of the patients achieved the criteria of an ASAS40 response (40% improvement on indices), and 53.8% of the patients achieved Ankylosing Spondylitis Disease Activity Score (ASDAS) major improvement (MI). The univariate analysis showed that patients with AS carrying the TNFα +489 A allele were more likely to achieve ASAS-PR, ASAS40 response criteria, and ASDAS-MI after ADA treatment. In the multivariate regression analysis, the TNFα +489 A allele was an independent factor influencing the efficacy of ADA in treating AS (ASAS-PR odds ratio (OR) = 2.66, 95% confidence interval (CI) = 1.01-7.01; ASAS40 OR = 4.56, 95% CI = 1.39-15.00; ASDAS-MI OR = 3.31, 95% CI = 1.02-10.69). CONCLUSIONS: The patients carrying the TNFα +489 A allele may be more likely to experience better therapeutic efficacy and achieve the treatment target (ASAS-PR, ASAS40 response, or ASDAS-MI) after receiving ADA treatment. Detection of TNFα +489 G/A may predict the therapeutic efficacy of ADA, which can be used in clinical practice to tailor treatment for individual patients with AS. Further studies with larger sample sizes and longer follow-up periods with imaging evaluation are needed to verify our findings.
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BACKGROUND: Axial spondyloarthritis (axSpA) is a chronic inflammatory rheumatic disease predominantly affecting the axial skeleton. We aimed to describe the clinical characteristics of patients with non-radiographic axSpA (nr-axSpA) in China and compare the differences between adult- and juvenile-onset cases. METHODS: A cross-sectional study was conducted using data from 776 patients with nr-axSpA in the Clinical Characteristic and Outcome in Chinese Axial Spondyloarthritis (COCAS) study cohort. Patients were divided into two groups including the adult-onset group (n = 662) and the juvenile-onset group (n = 114) according to age at disease onset. Baseline demographics and clinical characteristics were compared between patients with adult-onset and juvenile-onset nr-axSpA. RESULTS: Overall, the male-to-female ratio was 1.26:1, the prevalence of HLA-B27 positivity was 72.2%, and the median age at disease onset of nr-axSpA was 22 years. Nearly 75% of nr-axSpA patients had peripheral arthritis in the disease course, and the prevalence of extra-articular manifestations was 10.4%. The juvenile-onset group contained a higher proportion of men (66.7% vs. 53.9%, P = 0.011) and a longer baseline disease duration (4.0 [4.0] vs. 1.6 [3.5], P < 0.001) than the adult-onset group. A family history of spondyloarthritis was more frequent in the juvenile-onset group than in the adult-onset group (23.7% vs. 15.4%, P = 0.028), but no significant difference in the prevalence of HLA-B27 positivity was observed between the two groups (P = 0.537). Regarding initial symptoms, peripheral arthritis occurred more often in patients with juvenile-onset nr-axSpA, whereas patients with adult-onset nr-axSpA presented more frequently with axial involvement. The prevalence of inflammatory back pain (IBP) was higher in the adult-onset group than in the juvenile-onset group (85.0% vs. 75.4%, P = 0.010), whereas the juvenile-onset group showed a higher prevalence of peripheral arthritis and enthesitis than the adult-onset group (67.5% vs. 48.5%, P < 0.001; 35.1% vs. 23.3%, P = 0.007, respectively). CONCLUSIONS: Compared with adult-onset nr-axSpA, juvenile-onset nr-axSpA was more common in men and those with a family history of spondyloarthritis. Juvenile-onset nr-axSpA presents with a "peripheral predominant" mode at disease onset and a higher frequency of peripheral arthritis and enthesitis during the disease course.
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Espondiloartritis Axial no Radiográfica , Espondiloartritis , Espondilitis Anquilosante , Adulto , Femenino , Humanos , Masculino , Adulto Joven , Estudios Transversales , Progresión de la Enfermedad , Pueblos del Este de Asia , Antígeno HLA-B27/genética , Espondiloartritis Axial no Radiográfica/diagnóstico , Espondiloartritis Axial no Radiográfica/epidemiología , Dolor , Espondiloartritis/epidemiología , Espondiloartritis/diagnóstico , Espondilitis Anquilosante/diagnóstico , Espondilitis Anquilosante/epidemiologíaRESUMEN
Homocysteine (Hcy) is associated with nonalcoholic fatty liver disease (NAFLD). orphan nuclear receptor subfamily 4 group A member 1 (NR4A1) is involved in hepatic lipid metabolism. However, the potential role of NR4A1 in Hcy-associated NAFLD remains elusive. We aimed to elucidate the regulation of NR4A1 and its significance in Hcy-induced NAFLD. Hcy induced steatosis and elevated the expression of CD36 and FATP2 in HepG2 cells. Furthermore, Hcy enhanced p300 and decreased HDAC7 recruitment to the NR4A1 promoter, resulting in histone H3K27 hyperacetylation and NR4A1 upregulation. Moreover, NR4A1 depletion not only mimicked but also exaggerated the effects of Hcy on steatosis, whereas NR4A1 agonist Cytosporone B (CsnB) blocked Hcy-induced steatosis. In hyperhomocysteinemia (HHcy) mice, CsnB attenuated HHcy-induced hepatic steatosis. Thus, Hcy transiently and rapidly induces NR4A1 expression to reduce Hcy-induced steatosis.
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Hígado Graso/metabolismo , Hiperhomocisteinemia/complicaciones , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , Animales , Hígado Graso/etiología , Hígado Graso/genética , Hígado Graso/prevención & control , Regulación de la Expresión Génica , Células Hep G2 , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genéticaRESUMEN
OBJECTIVE: The aim of the study was to examine whether the cannabinoid agonist WIN55212-2 could attenuate ischemic spinal cord injury (SCI) in rats through inhibition of GAPDH/Siah1 signaling. METHODS: Male Sprague-Dawley rats were distributed randomly into 5 groups: (1) sham group that received no aortic occlusion and injected intraperitoneally (i.p.) with vehicle control after reperfusion; (2) control group that received a 12-minute aortic occlusion and injected i.p. with vehicle control after reperfusion; (3) WIN55212-2 group (WIN) that received the aortic occlusion and injected i.p. with 1 mg/kg of WIN55212-2 after reperfusion; and (4) WIN55212-2 plus AM251 group and (5) WIN55212-2 plus AM630 group that received the same surgical operation as the WIN group, except that 1 mg/kg of AM251 or AM630 was injected i.p. 30 min before each dose of WIN55212-2 injection, respectively. Neurologic function was assessed 48 hours after reperfusion. Histopathologic examination was performed to determine the number of normal neurons in anterior spinal cord. Protein expression of active caspase-3, total caspase-3, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), inducible nitric oxide synthase (iNOS), nuclear factor kappa light chain enhancer of activated B cells (NF-κB), Siah1, tumor necrosis factor α, and interleukin 1ß were determined with Western blot and enzyme-linked immunosorbent assay; coimmunoprecipitation assays were also used to determine GAPDH/Siah1 complexing. Finally, terminal deoxynucleotidyl transferase dUTP nick end labeling staining was used to determine neuronal apoptosis in the lumbar spinal cord. RESULTS: The nuclear translocation of GAPDH and Siah1 in the spinal cord was initiated after ischemic spinal cord injury (SCI) along with the increased formation of GAPDH/Siah1 complexes. However, the activation of GAPDH/Siah1 was blocked by WIN. In addition, the treatment of WIN55212-2 promoted neuronal survival in the spinal cord, reduced apoptosis and inflammation, and improved neurologic scores. Furthermore, these beneficial effects of WIN55212-2 were abolished by the combined treatment of the CB2 antagonist AM630, but not the CB1 antagonist AM251. CONCLUSIONS: Our findings reveal GAPDH/Siah1 signaling cascades as a novel therapeutic target for ischemic SCI and identify WIN55212-2 with the potential to treat ischemic SCI by targeting this pathway.
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Benzoxazinas/farmacología , Agonistas de Receptores de Cannabinoides/farmacología , Morfolinas/farmacología , Naftalenos/farmacología , Transducción de Señal/efectos de los fármacos , Isquemia de la Médula Espinal , Médula Espinal , Animales , Apoptosis/efectos de los fármacos , Gliceraldehído-3-Fosfato Deshidrogenasa (Fosforilante)/metabolismo , Inflamación/metabolismo , Masculino , Neuronas/citología , Neuronas/efectos de los fármacos , Proteínas Nucleares/metabolismo , Ratas , Ratas Sprague-Dawley , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismo , Isquemia de la Médula Espinal/tratamiento farmacológico , Isquemia de la Médula Espinal/prevención & control , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
This study aimed to clarify changes in the prevalence of rheumatic diseases in Shantou, China, in the past 3 decades and validate whether stair-climbing is a risk factor for knee pain and knee osteoarthritis (KOA). The World Health Organization-International League Against Rheumatism Community Oriented Program for Control of Rheumatic Diseases (COPCORD) protocol was implemented. In all, 2337 adults living in buildings without elevators and 1719 adults living in buildings with elevators were surveyed. The prevalence of rheumatic pain at any site and in the knee was 15.7% and 10.2%, respectively; both types of pain had a significantly higher incidence in residents of buildings without elevators than was reported by people who lived in buildings with elevators (14.9% vs. 10.6% and 11.32% vs. 8.82%, respectively) (both P < 0.0001). The prevalence of rheumatic pain in the neck, lumbar spine, shoulder, elbow, and foot was 5.6%, 4.5%, 3.1%, 1.4%, and 1.8%, respectively; these findings were similar to the data from the 1987 rural survey, but were somewhat lower than data reported in the urban and suburban surveys of the 1990s, with the exception of neck and lumbar pain. The prevalence of KOA, gout, and fibromyalgia was 7.10%, 1.08%, and 0.07%, respectively, and their prevalence increased significantly compared with those in previous studies from the 20th century. There were no significant differences in the prevalence of rheumatoid arthritis (RA) (0.35%) or ankylosing spondylitis (AS) (0.31%) compared to that reported in prior surveys. The prevalence of KOA was higher in for residents of buildings without elevators than that in those who had access to elevators (16-64 years, 5.89% vs. 3.95%, P = 0.004; 16->85 years, 7.64% vs. 6.26%, P = 0.162). The prevalence of RA and AS remained stable, whereas that of KOA, gout, and fibromyalgia has increased significantly in Shantou, China, during the past 3 decades. Stair-climbing might be an important risk factor for knee pain and KOA.