BACKGROUND: Hypertension is associated with an increased risk of calcific aortic valve stenosis (CAVS). However, the directionality of causation between blood pressure traits and aortic stenosis is unclear, as is the benefit of antihypertensive drugs for CAVS. METHODS: Using genome-wide association studies (GWAS) summary statistics, we performed bidirectional two-sample univariable mendelian randomization (UVMR) to assess the causal associations of systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP) with CAVS. Multivariable mendelian randomization (MVMR) was conducted to evaluate the direct effect of hypertension on CAVS, adjusting for confounders. Drug target mendelian randomization (MR) and summary-level MR (SMR) were used to estimate the effects of 12 classes of antihypertensive drugs and their target genes on CAVS risk. Inverse variance weighting was the primary MR method, with sensitivity analyses to validate results. RESULTS: UVMR showed SBP, DBP, and PP have causal effects on CAVS, with no significant reverse causality. MVMR confirmed the causality between hypertension and CAVS after adjusting for confounders. Drug-target MR analyses indicated that calcium channel blockers (CCBs), loop diuretics, and thiazide diuretics via SBP lowering exerted protective effects on CAVS risk. SMR analysis showed that the CCBs target gene CACNA2D2 and ARBs target gene AGTR1 were positively associated with CAVS risk, while diuretics target genes SLC12A5 and SLC12A1 were negatively associated with aortic stenosis risk. CONCLUSIONS Hypertension has a causal relationship with CAVS. Managing SBP in hypertensive patients with CCBs may prevent CAVS. ARBs might exert protective effects on CAVS independent of blood pressure reduction. The relationship between diuretics and CAVS is complex, with opposite effects through different mechanisms.

Objective To analyze the efficacy and safety of different minimally invasive operations[endoscopic re-trogradebiliary drainage(ERBD)、endoscopic nasobiliary drainage(ENBD)、percutaneous transhepatic cholangial drainage(PTCD)] for choledocholithiasis complicated with acute cholangitis to provide reference for clinical treatment retrospectively. Methods A total of 151 patients with choledocholithiasis complicated with acute cholangitis at Department of Emergency Surgery in our hospital from January 2019 to December 2020 were included and divided into four groups based on the four treatment strategies, including non-surgical treatment. Changes in leukocyte count, bilirubin levels, and liver function before and after treatment, as well as postoperative recovery, complication rates, length of hospital stay, and prognosis were compared among patients who underwent different surgical treatments. Results There were significant improvements in leukocyte count, percentage of neutrophils, and liver function of the patients underwent ENBD or ERBD operation (P<0.05). The total bilirubin and direct bilirubin were significantly reduced after ERBD, ENBD, and PTCD operations (P<0.05). Patients undergoing ERBD, ENBD, or PTCD demonstrated faster recovery times, fewer complications, shorter hospital stays, and lower mortality rates compared to those managed conservatively. Conclusions ERBD and ENBD as minimally invasive therapeutic modalities for the management of choledocholithiasis complicated with acute cholangitis, exhibit remarkable clinical efficacy, coupled with a high degree of safety and reliability. These techniques significantly enhance the long-term minimally invasive cure rate, thereby establishing them as the preferred treatment strategies. Tailored to the patient's specific clinical conditions, such as the severity of infection, stone dimensions, and the use of oral anticoagulant therapy, clinicians can formulate individualized minimally invasive treatment strategies, facilitating the optimal attainment of therapeutic objectives.

Head and neck squamous cell carcinoma(HNSCC)is a highly prevalent malignancy with poor prognosis.Treatment strategies to date have achieved limited success in significantly improving overall survival rates.γδ T cells,a unique subset of immune cells in the tumor microenvironment,can link adaptive and innate immune functions.While γδ T cells can effectively recognize and eliminate HNSCC tumor cells,certain subsets of these cells can secrete interleukin-17,contributing to tumor progression.Nevertheless,due to their remarkable cyto-toxic activity,γδ T cells have been identified as promising candidates for antitumor immunotherapy.This article reviews the biological back-ground of γδ T cells,their role in tumor immunity in HNSCC,and recent advances in γδ T cell immunotherapy,aiming to provide new in-sights into HNSCC diagnosis and treatment.

Periodontitis is a common oral disease characterized by progressive alveolar bone resorption and inflammation of the periodontal tissues. Dimethyl fumarate (DMF) has been used in the treatment of various immune-inflammatory diseases due to its excellent anti-inflammatory and antioxidant functions. Here, we investigated for the first time the therapeutic effect of DMF on periodontitis. In vivo studies showed that DMF significantly inhibited periodontal destruction, enhanced mitophagy, and decreased the M1/M2 macrophage ratio. In vitro studies showed that DMF inhibited macrophage polarization toward M1 macrophages and promoted polarization toward M2 macrophages, with improved mitochondrial function, inhibited oxidative stress, and increased mitophagy in RAW 264.7 cells. Furthermore, DMF increased intracellular mitochondrial Tu translation elongation factor (TUFM) levels to maintain mitochondrial homeostasis, promoted mitophagy, and modulated macrophage polarization, whereas TUFM knockdown decreased the protective effect of DMF. Finally, mechanistic studies showed that DMF increased intracellular TUFM levels by protecting TUFM from degradation via the ubiquitin-proteasomal degradation pathway. Our results demonstrate for the first time that DMF protects mitochondrial function and inhibits oxidative stress through TUFM-mediated mitophagy in macrophages, resulting in a shift in the balance of macrophage polarization, thereby attenuating periodontitis. Importantly, this study provides new insights into the prevention of periodontitis.
Dimethyl Fumarate/pharmacology* ; Mitophagy/drug effects* ; Animals ; Mice ; Macrophages/metabolism* ; Periodontitis/prevention & control* ; RAW 264.7 Cells ; Oxidative Stress/drug effects* ; Peptide Elongation Factor Tu/metabolism* ; Mice, Inbred C57BL ; Male ; Mitochondria/drug effects*

OBJECTIVE: To elucidate the role and mechanism of microRNA-145-5p (miR-145-5p) in hypoxia-induced pyroptosis of human alveolar epithelial cells. METHODS: In vitro, human alveolar epithelial cell line BEAS-2B was cultured. Cells in the logarithmic growth phase were cultured to 80% confluence and then used for the experiment. (1) BEAS-2B cells were cultured under 1% O₂ hypoxic condition, with a normoxic control group. Western blotting was employed to detect the expressions of pyroptosis marker proteins [NOD-like receptor protein 3 (NLRP3), Gasdermin D N-terminal domain (GSDMD-N), and caspase-1] in cells cultured for 24 hours. Real-time fluorescent quantitative reverse transcription-polymerase chain reaction (RT-PCR) was used to detect the expression of miR-145-5p in cells cultured for 6 hours and 12 hours. (2) Cells were transfected with 30 nmol/L miR-145-5p mimic to overexpress miR-145-5p expression under normoxic condition or 30 nmol/L miR-145-5p inhibitor to suppress miR-145-5p expression under hypoxic condition. Control group and negative control group were respectively set up. After 24 hours of cell culture, Western blotting was used to detect the expressions of pyroptosis marker proteins and nuclear factor-E2-related factor 2 (Nrf2) in cells. Flow cytometry was applied to detect the level of reactive oxygen species (ROS) in cells. The target genes of miR-145-5p were predicted by miR target gene prediction software miRWalk and verified by Western blotting. (3) Under hypoxic condition, cells were transfected with 6.94 ng/μL silent information regulator 5 (Sirt5) overexpression plasmid or pretreated with 12.5 mmol/L N-acetyl-L-cysteine (NAC) as an ROS inhibitor. The empty plasmid group and control group were set up. After 24 hours of cell culture, Western blotting was used to detect the expressions of Sirt5, Nrf2, and pyroptosis marker proteins in cells. Flow cytometry was used to detect the level of ROS in cells. RESULTS: (1) Compared with the normoxic control group, the expression levels of pyroptosis marker proteins in the 24-hour hypoxia group was significantly increased, indicating that hypoxia could induce pyroptosis in BEAS-2B cells. The expression level of miR-145-5p in cells gradually increased with the extension of hypoxia induction time, indicating that hypoxia could cause the increase of miR-145-5p expression level. (2) The expression levels of pyroptosis marker proteins in cells of miR-145-5p mimic group significantly increased under normoxic condition as compared with the control and negative control groups [NLRP3 protein (NLRP3/β-actin): 1.58±0.07 vs. 1.00±0.01, 0.98±0.07, GSDMD-N protein (GSDMD-N/β-actin): 1.71±0.03 vs. 1.01±0.01, 0.85±0.03, caspase-1 protein (caspase-1/β-actin): 2.33±0.04 vs. 1.01±0.01, 1.05±0.04, all P < 0.05], Nrf2 protein expression level was significantly decreased (Nrf2/β-actin: 0.79±0.03 vs. 1.00±0.01, 1.03±0.04, both P < 0.05), ROS level was significantly up-regulated (fluorescence intensity: 1.74±0.03 vs. 1.00±0.01, 0.92±0.03, both P < 0.05). Under hypoxia condition, compared with control group and negative control group, the expression levels of pyroptosis marker proteins in miR-145-5p inhibitor group were significantly decreased [NLRP3 protein (NLRP3/β-actin): 0.21±0.04 vs. 1.70±0.02, 1.63±0.04; GSDMD-N protein (GSDMD-N/β-actin): 1.32±0.02 vs. 2.51±0.02, 2.72±0.03; caspase-1 protein (caspase-1/β-actin): 0.56±0.01 vs. 2.77±0.02, 3.12±0.03; all P < 0.05], Nrf2 protein expression level was significantly increased (Nrf2/β-actin: 1.57±0.04 vs. 1.22±0.01, 1.28±0.04, both P < 0.05), ROS level was significantly down-regulated (fluorescence intensity: 0.64±0.05 vs. 1.87±0.04, 1.70±0.07, both P < 0.05). The results indicated that miR-145-5p could promote cell pyrodeath. The predictive result of miRWalk showed that the 3' untranslated region (3'UTR) of Sirt5 had complementary base binding sites with miR-145-5p. The expression level of Sirt5 protein in cells of miR-145-5p mimic group was significantly lower than that of control group and negative control group under normoxic condition (Sirt5/β-actin: 0.59±0.03 vs. 1.00±0.01, 1.01±0.03, both P < 0.05), which verified that Sirt5 was the target gene of miR-145-5p. (3) The occurrence of pyrodeath could be partially reversed by transfection with Sirt5 overexpression plasmid or adding ROS inhibitor NAC into cells, and Sirt5 overexpression could also up-regulate Nrf2 expression and eliminate intracellular ROS. CONCLUSION In human alveolar epithelial cells, miR-145-5p can down-regulate Nrf2 by targeting Sirt5, thereby increasing ROS expression and inducing pyrodeath.
Humans ; MicroRNAs ; Pyroptosis ; Cell Hypoxia ; Alveolar Epithelial Cells/cytology* ; Cell Line ; NLR Family, Pyrin Domain-Containing 3 Protein ; Caspase 1/metabolism* ; Epithelial Cells/metabolism* ; Gasdermins ; Phosphate-Binding Proteins

OBJECTIVE: To investigate the relationship between physical activity and genetic risk and their combined effects on the risk of developing chronic obstructive pulmonary disease. METHODS: This prospective cohort study included 318,085 biobank participants from the UK. Physical activity was assessed using the short form of the International Physical Activity Questionnaire. The participants were stratified into low-, intermediate-, and high-genetic-risk groups based on their polygenic risk scores. Multivariate Cox regression models and multiplicative interaction analyses were used. RESULTS: During a median follow-up period of 13 years, 9,209 participants were diagnosed with chronic obstructive pulmonary disease. For low genetic risk, compared to low physical activity, the hazard ratios ( HRs) for moderate and high physical activity were 0.853 (95% confidence interval [ CI]: 0.748-0.972) and 0.831 (95% CI: 0.727-0.950), respectively. For intermediate genetic risk, the HRs were 0.829 (95% CI: 0.758-0.905) and 0.835 (95% CI: 0.764-0.914), respectively. For participants with high genetic risk, the HRs were 0.809 (95% CI: 0.746-0.877) and 0.818 (95% CI: 0.754-0.888), respectively. A significant interaction was observed between genetic risk and physical activity. CONCLUSION Moderate or high levels of physical activity were associated with a lower risk of developing chronic obstructive pulmonary disease across all genetic risk groups, highlighting the need to tailor activity interventions for genetically susceptible individuals.
Humans ; Pulmonary Disease, Chronic Obstructive/epidemiology* ; Exercise ; Male ; Female ; Middle Aged ; Prospective Studies ; Aged ; Genetic Predisposition to Disease ; Risk Factors ; United Kingdom/epidemiology* ; Incidence ; Adult

Head and neck squamous cell carcinoma(HNSCC)is a highly prevalent malignancy with poor prognosis.Treatment strategies to date have achieved limited success in significantly improving overall survival rates.γδ T cells,a unique subset of immune cells in the tumor microenvironment,can link adaptive and innate immune functions.While γδ T cells can effectively recognize and eliminate HNSCC tumor cells,certain subsets of these cells can secrete interleukin-17,contributing to tumor progression.Nevertheless,due to their remarkable cyto-toxic activity,γδ T cells have been identified as promising candidates for antitumor immunotherapy.This article reviews the biological back-ground of γδ T cells,their role in tumor immunity in HNSCC,and recent advances in γδ T cell immunotherapy,aiming to provide new in-sights into HNSCC diagnosis and treatment.

Aim To explore the mechanism of Jiawei Shaofu Zhuyu decoction in antagonizing endometriosis fibrosis by regulating mitophagy.Methods After the animal model was constructed,the syndrome was evalu-ated by general condition,organ water content and ther-mal imaging.The curative effect was evaluated by the weight of ectopic focus and the degree of adhesion.The pathological changes were compared using HE stai-ning,transmission electron microscopy,Masson and Sir-ius red staining.The expression of PINK1 and Parkin was detected by immunohistochemistry.The expression of mRNA and protein was determined by qPCR and Western blot,and the level of serum ROS was detected by ELISA.Results The autonomic activity of model mice was weakened,the water content of organs rose,and the temperature of limbs and lower abdomen was reduced by thermal imaging.HE staining showed obvi-ous hyperplasia of ectopic epithelium and glands.Transmission electron microscopy showed mitochondrial and endoplasmic reticulum structure damage,and nor-mal autophagy structure disappeared.Masson and Siri-us red staining showed increased collagen deposition;immunohistochemistry showed decreased expression of PINK1 and Parkin in ectopic foci.qPCR and Western blot showed that the expression of PINK1,Parkin,Bec-lin1,LC3 mRNA and protein in ectopic foci of model mice decreased,the expression of p62 mRNA and pro-tein increased,and serum ROS increased.The syn-drome performance of model mice was improved after the intervention of Jiawei Shaofu Zhuyu decoction;the inflammatory infiltration of ectopic foci was relieved,the morphology of mitochondria and endoplasmic retic-ulum was restored,and normal autophagy structure ap-peared.The degree of collagen deposition and fibrosis was reduced;the mRNA and protein expression of PINK1,Parkin,Beclin1 and LC3 increased.The ex-pression of p62 mRNA and protein decreased,and the level of ROS decreased.Conclusions Jiawei Shaofu Zhuyu decoction can improve the fibrosis of ectopic le-sions in mice with endometriosis of cold-dampness sta-sis syndrome,which may be related to the regulation of mitophagy.

Objective To observe the clinical efficacy of Fangxiang Wentong Powder(composed of Salviae Miltiorrhizae Radix et Rhizoma,Chuanxiong Rhizoma,Alpiniae Officinarum Rhizoma,Piper Longum,and Corydalis Rhizoma)acupoint application combined with Kuanxiong Aerosol in treating female patients with coronary slow flow(CSF)associated angina.Methods After sample size estimation,119 female inpatients diagnosed as CSF associated angina and differentiated as chest-qi obstruction with yang deficiency and cold accumulation syndrome of traditional Chinese medicine(TCM)were collected from the cardiovascular departments of the Third People's Hospital of Fujian University of Traditional Chinese Medicine,the Second Affiliated Hospital of Guangzhou University of Chinese Medicine(Guangdong Provincial Hospital of Chinese Medicine),Zhanjiang First Traditional Chinese Medicine Hospital,and Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine from November 2023 to March 2024.Using a table of random numbers,the patients were divided into a treatment group(84 cases)and a control group(35 cases)in a ratio of 5∶2.The control group was treated with Isosorbide Monomitrate Sustained-Release Capsules,while the treatment group was treated with application of Fangxiang Wentong Powder on acupoints of Danzhong(CV17),Gaohuang(BL43),and Xinshu(BL15),together with sublingual administration of Kuanxiong Aerosol.The treatment course for both groups covered 7 days.Before and after treatment,the changes in the simplified Seattle Angina Questionnaire(SAQ-7)scores,Chinese Quality of Life Questionnaire for Cardiovascular Patients(CQQC)scores,6-minute walking distance(6MWD),serum C-reactive protein(CRP)level,and white blood cell-to-mean platelet volume ratio(WMR)were observed.The TCM symptom efficacy was compared between the two groups,and adverse reactions were monitored.Results(1)There were 8 patients withdrew in the treatment group for failing in completing the questionnaires,and 2 patients withdrew in the control group for suffering headaches after taking nitrates.Eventually,109 patients completed the trial,including 76 in the treatment group and 33 in the control group.(2)After 7 days of treatment,the total effective rate for TCM symptom efficacy in the treatment group was 86.84%(66/76),and that in the control group was 72.73%(24/33).The intergroup comparison(tested by the chi-square test)showed that the TCM symptom efficacy in the treatment group was significantly superior to that in the control group.(3)After treatment,both groups showed improvements in the scores of activity limitation and angina frequency items of SAQ-7,and the treatment group also showed improvements in the scores of subjective satisfaction item of SAQ-7(P＜0.05).The treatment group's improvements in the scores of activity limitation,angina frequency,and subjective satisfaction items of SAQ-7 were significantly superior to those of the control group(P＜0.05).(4)After treatment,the CQQC scores in the treatment group was significantly improved(P＜0.05),while no significant improvement was observed in the control group(P＞0.05).The improvement of CQQC scores in the treatment group was significantly superior to that in the control group(P＜0.05).(5)After treatment,both groups showed improvements in 6MWD(P＜0.05),and the improvement in the treatment group was significantly superior to that in the control group(P＜0.05).(6)After treatment,the serum levels of inflammatory indicators of CRP and WMR in the treatment group were significantly improved(P＜0.05),while no significant improvements were presented in the control group(P＞0.05).The improvements in serum CRP level and WMR value in the treatment group were significantly superior to those in the control group(P＜0.05).(7)No adverse reactions were found in the treatment group,indicating high safety.Conclusion Fangxiang Wentong Powder acupoint application combined with Kuanxiong Aerosol is more effective than Isosorbide Monomitrate Sustained-Release Capsules,improving exercise tolerance,decreasing inflammatory factor levels,and improving the quality of life to some extent during the treatment of female patients with CSF.

OBJECTIVE To explore the intervention mechanism of Shangke Lengtongtie on cold hyperalgesia in KOA mice based on the HMGB1/CXCL12/CXCR4 signaling axis.METHODS Monosodium iodoacetate(MIA)was used for the intra-articular injec-tion into the knee joint to establish mice model of knee osteoarthritis(KOA).Peripheral blood monocytes were extracted from mice,cultured,and then reinfused into the tail vein of the mice.Subsequently,in vivo animal imaging was used to observe the recruitment sites of these monocytes.The cold hyperalgesia threshold was measured at various time points in each group of mice.Hematoxylin and eosin(HE)staining was used to evaluate the level of synovial pathological changes.ELISA was employed to detect the expression of in-flammatory factors IL-1β,TNF-α,and pain mediators CGRP and Substance P in mouse serum.Western blot and qPCR methods were used to detect the protein and gene expression of cold hyperalgesia-related indicators such as TRPA1,TRPM8,HMGB1,CXCL12,CXCR4,Collagen Ⅰ,and Netrin-1 in synovial tissue,as well as DCC in dorsal root ganglia(DRG)tissue.RESULTS In vivo ima-ging showed that after the monocytes were reinfused into KOA mice,they were recruited to the knee joint area,with the HMGB1 group exhibiting a greater recruitment of circulating monocytes at the knee joint.Additionally,compared to the control group,the KOA group and HMGB1 group showed inflammatory pathological changes in the synovium,increased expression of serum inflammatory factors and pain mediators,reduced cold hyperalgesia threshold,and upregulated protein and gene expression of cold hyperalgesia-related indica-tors in synovial and DRG tissues.The changes were more significant in the HMGB1 group compared to the KOA group(P<0.05).Af-ter treatment with Shangke Lengtongtie or GL intervention,synovial inflammation was alleviated,serum inflammatory factors and pain mediators decreased,cold hyperalgesia threshold increased,and the upregulation of cold hyperalgesia-related indicator protein and gene expression levels was significantly reversed(P<0.05).CONCLUSION Shangke Lengtongtie exerts a beneficial effect on the mitigation of synovitis and cold hyperalgesia in KOA mice,a therapeutic mechanism that possibly mediated through the inhibition of the HMGB1/CXCL12/CXCR4 signaling axis.