Tricellulin, a key tricellular tight junction (TJ) protein, is essential for maintaining the barrier integrity of acinar epithelia against macromolecular passage in salivary glands. This study aims to explore the role and regulatory mechanism of tricellulin in the development of salivary gland hypofunction in Sjögren's syndrome (SS). Employing a multifaceted approach involving patient biopsies, non-obese diabetic (NOD) mice as a SS model, salivary gland acinar cell-specific tricellulin conditional knockout (Tric^CKO) mice, and IFN-γ-stimulated salivary gland epithelial cells, we investigated the role of tricellulin in SS-related hyposalivation. Our data revealed diminished levels of tricellulin in salivary glands of SS patients. Similarly, NOD mice displayed a reduction in tricellulin expression from the onset of the disease, concomitant with hyposecretion and an increase in salivary albumin content. Consistent with these findings, Tric^CKO mice exhibited both hyposecretion and leakage of macromolecular tracers when compared to control animals. Mechanistically, the JAK/STAT1/miR-145 axis was identified as mediating the IFN-γ-induced downregulation of tricellulin. Treatment with AT1001, a TJ sealer, ameliorated epithelial barrier dysfunction, restored tricellulin expression, and consequently alleviated hyposalivation in NOD mice. Importantly, treatment with miR-145 antagomir to specifically recover the expression of tricellulin in NOD mice significantly alleviated hyposalivation and macromolecular leakage. Collectively, we identified that tricellulin deficiency in salivary glands contributed to hyposalivation in SS. Our findings highlight tricellulin as a potential therapeutic target for hyposecretion, particularly in the context of reinforcing epithelial barrier function through preventing leakage of macromolecules in salivary glands.
Sjogren's Syndrome/complications* ; Animals ; Xerostomia/etiology* ; Mice ; Mice, Inbred NOD ; MARVEL Domain Containing 2 Protein/metabolism* ; Humans ; Mice, Knockout ; Disease Models, Animal ; Interferon-gamma ; Salivary Glands/metabolism* ; Tight Junctions/metabolism* ; MicroRNAs/metabolism* ; Female

Aim To investigate the correlation between serum remnant lipoprotein cholesterol(RLP-C),triglyc-eride levels(TG)and coronary heart disease(CHD)in middle-aged people.Methods A total of 439 middle-aged in-dividuals who were hospitalized in the Department of Cardiology of Liuzhou People's Hospital from January 2015 to Decem-ber 2022 and underwent coronary angiography were selected as the research subjects.They were divided into CHD group(190 cases)and control group(249 cases)according to the results of coronary angiography.The general clinical data and laboratory tests of the subjects were collected,and RLP-C was calculated based on blood lipid profile.Bivariate Spearman correlation,multivariate Logistic regression,and restricted cubic spline graph were used to analyze the correlation between RLP-C,TG,and CHD in these middle-aged participants.Receiver operating characteristic(ROC)curve was used to evaluate the value of RLP-C and TG in predicting CHD.Results The age in CHD group was older than that in control group,proportion of male,proportion of smoking history,incidence of hypertension,incidence of diabetes,inci-dence of hyperlipidemia,body mass index(BMI),systolic blood pressure(SBP),fasting blood glucose(FBG),glycosy-lated hemoglobin(HbA1c),TG,low density lipoprotein cholesterol(LDLC),RLP-C were higher than those in control group,while high density lipoprotein cholesterol(HDLC)was lower than that in control group(P＜0.05).The Spearman correlation analysis results showed positive correlation between RLP-C,TG,LDLC and CHD(r=0.227,0.279,and 0.105,respectively,P＜0.05),and negative correlation between HDLC and CHD(r=-0.340,P＜0.001)in these stud-ied population.Multivariate Logistic regression analysis showed that whether as continuous or categorical variables,RLP-C and TG were independent risk factors for CHD(P＜0.05),HDLC was independent protective factor for CHD(P＜0.05).Compared with lowest quartile group,The OR(95％CI)of CHD incidence in 3rd and 4th quartile group of RLP-C were 2.648(1.364～5.144)and 2.847(1.468-5.520)respectively;The OR(95％CI)of CHD incidence in 3rd and 4th quartile group of TG were 3.043(1.520-6.092)and 3.520(1.811～6.842)respectively.The restricted cubic spline graph revealed that RLP-C,TG were positively nonlinearly correlated with CHD(P for overall＜0.001,P for nonlin-ear=0.002,0.001,respectively).Subgroup analysis showed that the relationship between RLP-C,TG and CHD was more significant in females than in males.ROC curve analysis showed that the areas under the curve(95％CI)of RLP-C,TG in predicting CHD were 0.632(0.580-0.685)(P＜0.001)and 0.663(0.612-0.713)(P＜0.001)in general,meanwhile,0.735(0.659-0.811)(P＜0.001)and 0.740(0.666-0.813)(P＜0.001)in females.Conclusion RLP-C and TG are independent risk factors for CHD in middle-aged people,and their correlation with CHD are greater than that of LDLC.They may become the main targets for the prevention and treatment of CHD,and should be given clinical attention.

Objective To construct a predictive model for septic shock based on the propensity score matching (PSM) method and validate its effectiveness. Methods A total of 114 patients with sepsis were enrolled as study objects, and were divided into septic shock group (40 patients) and sepsis group (74 patients) according to whether they developed septic shock. PSM was performed with a ratio of septic shock to sepsis of 1∶2, resulting in the inclusion of 30 patients in the septic shock group and 60 patients in the sepsis group after matching. The levels of C-reactive protein (CRP), procalcitonin (PCT), interleukin-6 (IL-6), serum amyloid A (SAA), soluble endothelial protein C receptor (sEPCR), endothelial cell-specific molecule 1 (ESM-1), clusterin (CLU), and the Acute Physiology and Chronic Health Evaluation Ⅱ (APACHE Ⅱ) score and Sequential Organ Failure Assessment (SOFA) score at admission were compared between the two groups. Cox proportional hazards regression analysis was used to identify the factors influencing septic shock, and a predictive model for septic shock was constructed and internally validated using the receiver operating characteristic (ROC) curve. Kaplan-Meier survival curves were plotted to analyze the differences in survival prognosis among patients with different expression levels of the indicators. Results After matching, there were no statistically significant differences in general information between the two groups (P>0.05). At admission, the septic shock group had higher levels of serum PCT, CRP, SAA, IL-6, sEPCR, ESM-1, and higher APACHE Ⅱ and SOFA scores, as well as a lower level of serum CLU compared with the sepsis group (P < 0.05). Cox regression analysis showed that PCT, CRP, SAA, IL-6, sEPCR, ESM-1, APACHE Ⅱ score, and SOFA score were independent risk factors for septic shock (P < 0.05), while CLU was an independent protective factor (P < 0.05). The predictive model for septic shock, constructed based on these factors, showed an internal validation accuracy of 94.44%, an area under the curve of 0.950, a sensitivity of 93.33%, and a specificity of 96.67%. Dead patients had higher levels of PCT, CRP, SAA, IL-6, sEPCR, ESM-1, and higher APACHE Ⅱ and SOFA scores, as well as a lower level of CLU at admission compared with survivors (P < 0.05). Compared with patients with low expression levels or low scores, patients with high expression levels of PCT, CRP, SAA, IL-6, sEPCR, ESM-1, and high APACHE Ⅱ and SOFA scores had higher fatality rates, while patients with high CLU expression levels had a lower fatality rate (P < 0.05). Conclusion The serum biomarkers including PCT, CRP, SAA, IL-6, sEPCR, ESM-1, CLU, and the APACHE Ⅱ and SOFA scores in sepsis patients are closely related to the occurrence of septic shock and survival prognosis. The predictive model constructed by combining these indicators can accurately predict the occurrence of septic shock.

Purpose: Little is known about the role of gut microbiota in the pathogenesis of erectile dysfunction (ED). We performed a study to compare taxonomic profiles of gut microbiota of ED and healthy males. Materials and Methods: A total of 43 ED patients and 16 healthy controls were enrolled in the study. The 5-item version of the International Index of Erectile Function (IIEF-5) with a cutoff value of 21 was used to evaluate erectile function. All participants underwent nocturnal penile tumescence and rigidity test. Samples of stool were sequenced to determine the gut microbiota. Results: We identified a distinct beta diversity of gut microbiome in ED patients by unweighted UniFrac analysis (R2=0.026, p=0.036). Linear discriminant analysis effect size (LEfse) analysis showed Actinomyces was significantly enriched, whereas Coprococcus_1, Lachnospiraceae_FCS020_group, Lactococcus, Ruminiclostridium_5, and Ruminococcaceae_UCG_002 were depleted in ED patients. Actinomyces showed a significant negative correlation with the duration of qualified erection, average maximum rigidity of tip, average maximum rigidity of base, tip tumescence activated unit (TAU), and base TAU. Coprococcus_1, Lachnospiraceae_FCS020_group, Ruminiclostridium_5, and Ruminococcaceae_UCG_002 were significantly correlated with the IIEF-5 score. Ruminiclostridium_5 and Ruminococcaceae_UCG_002 were positively related with average maximum rigidity of tip, average maximum rigidity of base, ΔTumescence of tip, and Tip TAU. Further, a random forest classifier based on the relative abundance of taxa showed good diagnostic efficacy with an area under curve of 0.72. Conclusions This pilot study identified evident alterations in the gut microbiome composition of ED patients and found Actinomyces was negatively correlated with erectile function, which may be a key pathogenic bacteria.

【Objective】 To investigate the mechanism of Yishen Tonglong Decoction (益肾通癃汤, YSTLD) inhibiting the toll-like receptor 4/p38 mitogen activated protein kinases/nuclear factor kappa-B (TLR4/p38 MAPK/NF-κB) signaling pathway against prostate cancer by up-regulating miR-145-5p. 【Methods】 miRNA microarray technology was used to detect the changes of miRNA expression profile in prostate cancer PC-3 cells treated with YSTLD, and miRNAs with marked differences in miRNA microarray results were screened and validated by real-time polymerase chain reaction (qRT-PCR). Lentiviral transfection of miR-145-5p into prostate cancer PC-3 cells, Cell Counting Kit-8 (CCK8) assay, and scratch assay were adopted to detect the effects of miR-145-5p on prostate cancer PC-3 cell proliferation and migration. qRT-PCR and Western blot were employed to detect the effects of miR-145-5p on TLR4/p38 MAPK/NF-κB signaling pathway and the expression levels of apoptosis-related genes caspase3, tumor necrosis factor-α (TNF-α), Bax, and Bcl-2. qRT-PCR and Western blot were used to detect the effects of serum containing YSTLD on miR-145-5p, TLR4/p38 MAPK/NF-κB signaling pathway, and the expression levels of apoptosis-related genes caspase3, TNF-α, Bax, and Bcl-2. 【Results】 The expression levels of 35 miRNAs in prostate cancer PC-3 cells treated with YSTLD were significantly different from those in the control group, with miR-145-5p being the most significantly different; qRT-PCR validation revealed that the miR-145-5p levels in prostate cancer PC-3 cells treated with YSTLD were significantly higher than those in the DMSO control group (P < 0.05). After lentiviral transfection of miR-145-5p into prostate cancer PC-3 cells, miR-145-5p was found to inhibit the proliferation and migration of prostate cancer PC-3 cells. Overexpression of miR-145-5p up-regulated expression levels of caspase3, TNF-α, and Bax mRNA, and down-regulated expression levels of p38 MAPK, p65 NF-κB, and Bcl-2 mRNA in prostate cancer PC-3 cells (P < 0.05), while up-regulated caspase3 protein expression levels in prostate cancer PC-3 cells and down-regulated expression levels of TLR4, p38 MAPK, and p65 NF-κB protein (P < 0.05). Serum containing YSTLD could up-regulate the expression levels of caspase3, TNF-α, and Bax mRNA, and down-regulate the mRNA expression levels of p38 MAPK, p65 NF-κB, Bcl-2, and TNF receptor-associated factor 1 (TRAF1) in prostate cancer PC-3 cells after intervening prostate cancer PC-3 cells (P < 0.05). Simultaneously, it up-regulated the expression levels of caspase3 protein and down-regulated the protein expression levels of TLR4, p38 MARK, p65 NF-κB, and TRAF1 in prostate cancer PC-3 cells (P < 0.05). 【Conclusion】 YSTLD can promote apoptosis of prostate cancer PC-3 cells by up-regulating the expression level of miR-145-5p and inhibiting TLR4/p38 MAPK/NF-κB signaling pathway, which may be an important mechanism of YSTLD against prostate cancer.

Objective:To explore the clinical features and risk factors of systemic lupus erythematosus(SLE) concomitant with interstitial lung disease(ILD) in children.Methods:A retrospective analysis was performed.A total of 111 hospitalized children diagnosed with SLE in the Department of Rheumatology and Immunology, Children′s Hospital of Soochow University from February 2016 to November 2018 were selected as the research subjects and divided into the SLE-ILD group(18 cases) and the SLE-non-ILD group(93 cases)according to the lung high-resolution CT manifestations. T-test and Wilcoxon rank sum test were used to compare and analyze the general situation, clinical manifestations and laboratory results.Multivariate Logistic regression was used to analyze the risk factors of SLE-ILD. Results:The prevalence of SLE-ILD was 16.2%(18/111 cases). There were significant differences between the SLE-ILD group and the SLE-non-ILD group in the course of disease [14.00 (12.00-24.25) months vs.1.00(1.00-2.00) months], the incidence of serositis [55.6%(10/18 cases) vs.8.6%(8/93 cases)], post-activity shortness of breath [83.3%(15/18 cases) vs.25.8%(24/93 cases)], nervous system damage [27.8%(5/18 cases) vs.6.5%(6/93 cases)], cardiovascular system damage [38.9%(7/18 cases) vs.9.7%(9/93 cases)], the occu-rrence of increased erythrocyte sedimentation rate [66.7%(12/18 cases) vs.31.2%(29/93 cases)], the decreased C 3[88.9%(16/18 cases) vs.62.4%(58/93 cases)], positive anti neutrophil cytoplasmic antibody (ANCA) [88.9%(16/18 cases) vs.18.3%(17/93 cases)], positive anti-Sm antibody [61.1%(11/18 cases) vs.15.1%(14/93 cases)] and anti ribonucleoprotein antibody (anti RNP antibody)[66.7%(12/18 cases) vs.16.1%(15/93 cases)](all P<0.05). Logistic regression analysis demonstrated that serositis( OR=30.535, 95% CI: 2.167-430.336, P=0.011), shortness of breath after exercise( OR=55.115, 95% CI: 1.117-2 579.852, P=0.041), positive ANCA( OR=65.090, 95% CI: 4.488-944.071, P=0.002) and positive anti-RNP antibody( OR=10.007, 95% CI: 1.362-73.500, P=0.024) were risk factors for SLE-ILD. Conclusions:The longer the course of SLE, the higher the incidence of ILD; serositis, shortness of breath after exercise, positive ANCA and positive anti RNP antibody may be risk factors for SLE-ILD.

To analyze the clinical characteristics of patients with antisynthetase syndrome (ASS) and positive anti-Ro52 antibody. The clinical data of 203 ASS patients admitted to the First Affiliated Hospital of Zhengzhou University from 2017 to 2020 were analyzed retrospectively. Demographics, clinical manifestations, laboratory results, treatment and outcome were collected including data of 18 patients with rapidly progressive interstitial lung disease (RP-ILD). In total, the majority were women (148,72.9%). The average onset age was (51.9±13.3) years. There were 163 (80.3%) patients with positive anti-Ro52 antibody. The positivity in women (77.3% vs. 55.0%, P=0.004) was higher, and the median time from disease onset to diagnosis [4.5 (2.0, 24.0) months vs. 2.0 (1.0, 12.0) months, P=0.024] was longer in patients with positive anti-Ro52 antibody than those negative. Compared with negative patients, patients with positive anti-Ro52 antibody had a higher incidence of interstitial lung disease (ILD) (96.9% vs. 65.0%, P<0.001), arthritis (33.7% vs. 17.5%, P=0.046), and arthralgia (39.3% vs. 20.0%, P=0.022). Higher rate of positve antinuclear antibody (ANA) (85.3% vs. 55.0%, P<0.001), lower rate of positive anti-Jo-1 antibody (32.5% vs. 50.0%, P=0.039), lower albumin level [(34.6±5.2) g/L vs. (37.3±4.7) g/L, P=0.004] and lower lymphocyte counts [(1.4±0.8) ×10 9/L vs. (1.8±0.8) ×10 9/L, P=0.014] were more common in patients with positive anti-Ro52 antibody. The presence of anti-Ro52 antibody is associated with a particular phenotype of ASS, leading to common ILD, involvement of joints, high ANA positivity, low albumin and low lymphocyte counts.

BACKGROUND: Anlotinib is a newly developed small molecule multiple receptor tyrosine kinase (RTK) inhibitor that was approved for the treatment of patients with lung cancer in China. We aim to report 3 cases of rare complication of anlotinib-bronchial fistula (BF) during the treatment of lung cancer patients and summarize the possible causes. METHODS: We collected three patients who developed BF due to anlotinib treatment, and conducted a search of Medline and PubMed for medical literature published between 2018 and 2020 using the following search terms: "anlotinib," "lung cancer," and "fistula." RESULTS: Our literature search produced two case reports (three patients) which, in addition to our three patients. We collated the patients' clinical characteristics including demographic information, cancer type, imaging features, treatment received, risk factors for anlotinib related BF, and treatment-related outcomes. The six patients shared some common characteristics: advanced age, male, concurrent infection symptoms, diabetes mellitus (DM), advanced squamous cell and small cell lung cancers, centrally located tumors, tumor measuring ≥5 cm in longest diameter, and newly formed tumor cavitation after multi-line treatment especially after receiving radiotherapy. Fistula types included broncho-pericardial fistula, broncho-pleural fistula, and esophago-tracheobronchial fistula. Six patients all died within 6 months. CONCLUSIONS Although anlotinib is relatively safe, it is still necessary to pay attention to the occurrence of BF, a rare treatment side effect that threatens the quality of life and overall survival of patients. Anlotinib, therefore, requires selective use and close observation of high-risk patients.

Objective: To investigate the prevalence of hyperuricemia and its correlation among adolescents aged 13-16 in Hanjiang district of Yangzhou city. Methods: Five hundred and nine adolescents aged 13-16 years in Hangjiang district of Yangzhou city were recruited. Their fasting serum uric acid level were measured by Benecheck premium UA monitoring system. The demographic imformation, family history, eating and living habits of the respondents were collected by questionnaires. Results: The average serum uric acid level of 509 adolescents in Hangjiang district of Yangzhou city was (374±98) μmol/L, and (420±103) μmol/L in males, higher than that of females [(329±70) μmol/L](t=11.69, P<0.05). The overall prevalence of HUA was 36.9%(188/509), and 43.2%(108/250) in males, higher than in females 30.8%(80/259)(χ²=4.16, P<0.05). Multivariate Logistic regression analysis showed that male [OR=1.70, 95%CI(1.18, 2.45)], obese [OR=8.99, 95%CI(4.58, 17.63)], high-salt oily diet [OR=1.67, 95%CI(1.05, 2.61)], soy products [OR=2.66, 95%CI(1.45, 4.88)], animal offal [OR=7.81, 95%CI(3.42, 17.83)], seafood [OR=4.80, 95%CI(2.83, 8.12)], sugary drinks [OR=6.49, 95%CI(3.08, 13.64)] and time spent on electronic products [OR=1.98, 95%CI(1.07, 3.65)] might be risk factors for hyperuricemia (P<0.05), while fruit [OR=0.52, 95%CI(0.32, 0.85)] and outdoor activities [OR=0.55, 95%CI(0.33, 0.92)] might be protective factors for HUA (P<0.05). Conclusion There is a high prevalence of hyperuricemia among adolescents aged 13-16 in Hangjiang district of Yangzhou city. The level of serum uric acid in adolescents significantly increased. Male, obesity, high salt and oily diets, soy products, animal offal, seafood, and sugary drinks may be risk factors for HUA. Fruits and outdoor activities may be protective factors for HUA. Relevant disciplines can take corresponding measures to prevent adolescent HUA.

Objective To identify the pathogenesis gene mutation of a pedigree with Cockayne syndrome.Methods The peripheral blood samples of the patient and his family members were collected and the genomic DNA was then extracted.Whole exome sequencing(WES)was performed for proband′s DNA.The disease-causing mutations were identified by bioinformatics analysis and pedigree analysis. Meanwhile,the mutations were confirmed by Sanger sequencing.Results Two novel mutations in ERCC8 gene,including c.400-2A >G and c.394_398delATGTA(p.L132fs)were identified in proband.The splicing mutation originated from his father and changed the splice acceptor site AG to GG, thus possibly caused alternative splicing.The c.394_398delATGTA(p.L132fs)frameshifting mutation was inherited from his mother.The proband′s sister also carried the same compound heterozygous mutation and had the same phenotype as proband.Conclusion The pathogenesis ERCC8 gene mutation of this pedigree with Cockayne syndrome was identified by using whole exome sequencing.