Background::Whether functional gastrointestinal disorders (FGIDs) are associated with the long-term risk of chronic kidney disease (CKD) remains unclear. We aimed to investigate the prospective association of FGIDs with CKD and examine whether mental health mediated the association.Methods::About 416,258 participants without a prior CKD diagnosis enrolled in the UK Biobank between 2006 and 2010 were included. Participants with FGIDs (including irritable bowel syndrome [IBS], dyspepsia, and other functional intestinal disorders [FIDs; mainly composed of constipation]) were the exposure group, and non-FGID participants were the non-exposure group. The primary outcome was incident CKD, ascertained from hospital admission and death registry records. A Cox proportional hazard regression model was used to investigate the association between FGIDs and CKD, and the mediation analysis was performed to investigate the mediation proportions of mental health.Results::At baseline, 33,156 (8.0%) participants were diagnosed with FGIDs, including 21,060 (5.1%), 8262 (2.0%), and 6437 (1.6%) cases of IBS, dyspepsia, and other FIDs, respectively. During a mean follow-up period of 12.1 years, 11,001 (2.6%) participants developed CKD. FGIDs were significantly associated with a higher risk of incident CKD compared to the absence of FGIDs (hazard ratio [HR], 1.36; 95% confidence interval [CI], 1.28–1.44). Similar results were observed for IBS (HR, 1.27; 95% CI, 1.17–1.38), dyspepsia (HR, 1.30; 95% CI, 1.17–1.44), and other FIDs (HR, 1.60; 95% CI, 1.43–1.79). Mediation analyses suggested that the mental health score significantly mediated 9.05% of the association of FGIDs with incident CKD and 5.63–13.97% of the associations of FGID subtypes with CKD. Specifically, the positive associations of FGIDs and FGID subtypes with CKD were more pronounced in participants with a high genetic risk of CKD.Conclusion::Participants with FGIDs had a higher risk of incident CKD, which was partly explained by mental health scores and was more pronounced in those with high genetic susceptibility to CKD.

OBJECTIVE: To investigate the potential mechanisms that mediate the inhibitory effect of porcine recombinant NKlysin (prNK-lysin) against liver cancer cell metastasis. METHODS: HPLC-tandem mass spectrometry was used to identify the differentially expressed proteins in prNK-lysin-treated hepatocellular carcinoma SMMOL/LC-7721 cells in comparison with the control and PBS-treated cells. GO functional annotation and KEGG pathway analysis of the differentially expressed proteins were performed using GO and KEGG databases. RT-qPCR was used to determine the mRNA expression levels of polypeptide-N-acetylgalactosaminotransferase 13 (GALNT13), transmembrane protein 51 (TMEM51) and FKBP prolyl isomerase 3 (FKBP3) in the cells, and the protein expression of FKBP3 was verified using Western blotting. RESULTS: Proteomic analysis identified 1989 differentially expressed proteins in prNK-lysin-treated cells compared with the control cells, and 2753 compared with PBS-treated cells. Fifteen proteins were differentially expressed between PBS-treated and the control cells, and 1909 were differentially expressed in prNK- lysin group compared with both PBS and control groups. These differentially expressed proteins were involved mainly in the viral process, translational initiation and RNA binding and were enriched mainly in ribosome, protein process in endoplasmic reticulum, and RNA transport pathways. RT-qPCR showed that compared with the control group, prNK-lysin treatment significantly increased the mRNA expressions of GALNT13 (P < 0.05) and TMEM51 (P < 0.01) and lowered FKBP3 mRNA expression (P < 0.05). Western blotting also showed a significantly decreased expression of FKBP3 protein in prNK-lysin-treated cells (P < 0.001). CONCLUSION Treatment with prNK-lysin causes significant changes in protein expression profile of SMMOL/LC-7721 cells and inhibits hepatocellular carcinoma metastasis by downregulating FKBP3 protein and affecting the cellular oxidative phosphorylation and glycolysis pathways.
Animals ; Swine ; Carcinoma, Hepatocellular/pathology* ; Liver Neoplasms/pathology* ; Oxidative Phosphorylation ; Proteomics ; Glycolysis ; RNA, Messenger

Objective The intervention effect of Huoxue Jiedu Huayu Recipe on the pyroptosis of vascular smooth muscle cells(VSMC)on the contralateral renal vessel of 6-month unilateral ureteral obstruction(UUO)rat model was observed,and part of the treatment mechanism of Huoxue Jiedu Huayu Recipe on chronic kidney disease(CKD)was investigated.Methods Forty male wistar rats were randomly divided into 4 groups:the sham operation(Sham)group,the unilateral ureteral obstruction(UUO)group,the eplerenone treatment(EPL)group and the Huoxue Jiedu Huayu Recipe intervention(HJHR)group,10 rats in each group.The EPL group was given eplerenone and the HJHR group was given traditional Chinese medicine.The right kidney was collected after 6 months.Pathological changes were assessed by HE staining and Masson staining.The expressions of Cysteinyl aspartate specific proteinase1(Caspase-1),Interleukin-1β(IL-1β),Serum and glucocorticoid-induced kinase 1(SGK1)and nuclear factor κappa-B(NF-κB)were detected by immunohistochemistry.The DNA damage in renal VSMC was examined by TUNEL staining.Rat VSMCs were used for in vitro experiments.The cells were divided into 4 groups using the random number method:the control(CON)group,the aldosterone(ALD)group,the aldosterone plus eplerenone treatment(EPL)group and the aldosterone plus Huoxue Jiedu Huayu Recipe treatment(HJHR)group.The ALD group was given aldosterone stimulation for 24 h.The EPL group and the HJHR group were given eplerenone and rat serum containing 10%Huoxue Jiedu Huayu Recipe pretreatment before aldosterone stimulation,respectively.The apoptosis rate was detected by flow cytometry.Perforation of gasdermin D(GSDMD)and nuclear translocation of NR3C2(Encode MR)in cell membranes were examined by immunofluorescence.The protein expression of inflammation and pyroptosis-related signaling molecules were examined by western blotting.The mRNA expression of pyroptosis signaling pathway were detected by qRT-PCR.Results Compared with the Sham group,DNA damage of renal blood vessels and VSMCs was increased in UUO group,and expressions of Caspase-1,IL-1β,SGK1 and NF-κB were increased.Compared with the UUO group,the DNA damage of renal blood vessels and VSMCs in EPL and HJHR groups was reduced,and the expressions of Caspase-1,IL-1β,SGK1 and NF-κB were decreased.Compared with the CON group,the ALD group showed pyroptosis and DNA damage of rat VSMC.The expression of NR3C2,NLRP3,Caspase-1,GSDMD,IL-1β,SGK1 and NF-κB was up-regulated.Compared with the ALD group,the pyroptosis and DNA damage were alleviated,and the expression of NR3C2,NLRP3,Caspase-1,GSDMD,IL-1β,SGK1 and NF-κB was decreased in EPL and HJHR groups.Conclusion Huoxue Jiedu Huayu Recipe reduce the vascular damage of the contralateral kidneys of UUO by inhibiting the activation of the MR/NLRP3 inflammasome pathway and inhibiting the pyroptosis of VSMC.

We aimed to investigate the relationship of dietary zinc intake with new-onset hypertension among Chinese adults. A total of 12,177 participants who were free of hypertension at baseline from the China Health and Nutrition Survey were included. Dietary intake was assessed by three consecutive 24-h dietary recalls combined with a household food inventory. Participants with systolic blood pressure ≽ 140 mmHg or diastolic blood pressure ≽ 90 mmHg or diagnosed by a physician or under antihypertensive treatment during the follow-up were defined as having new-onset hypertension. During a median follow-up duration of 6.1 years, 4269 participants developed new-onset hypertension. Overall, the association between dietary zinc intake and new-onset hypertension followed a J-shape (P for non-linearity < 0.001). The risk of new-onset hypertension significantly decreased with the increment of dietary zinc intake (per mg/day: hazard ratio (HR) 0.93; 95% confidence interval (CI) 0.88-0.98) in participants with zinc intake < 10.9 mg/day, and increased with the increment of zinc intake (per mg/day: HR 1.14; 95% CI 1.11-1.16) in participants with zinc intake ≽ 10.9 mg/day. In conclusion, there was a J-shaped association between dietary zinc intake and new-onset hypertension in general Chinese adults, with an inflection point at about 10.9 mg/day.
Adult ; Humans ; Cohort Studies ; Zinc ; Diet ; Hypertension/epidemiology* ; Eating ; China/epidemiology*

Objective:To seek specific response points on the body surface of patients with primary dysmenorrhea(PD)by observing blood perfusion unit(PU)at different points of the three Yin meridians of foot using laser speckle contrast imaging(LSCI). Methods:Eighty PD patients were recruited as a PD group,and 80 healthy female undergraduates were taken as a normal group.During one menstrual cycle(before menstruation,during menstruation,and 3 d after menstruation),each participant was examined using the LSCI system to determine PU at bilateral Taixi(KI3),Taibai(SP3),Taichong(LR3),Shuiquan(KI5),Diji(SP8),Zhongdu(LR6),Sanyinjiao(SP6),and Xuehai(SP10)and non-acupuncture points.The researchers in charge of point location,operation,and statistical analysis were not aware of grouping.PU at the detection spots was taken as the outcome measure. Results:Compared with the normal group,the PD group showed increases in PU at right Taixi(KI3)before menstruation(P<0.05)and at bilateral Zhongdu(LR6)and right Diji(SP8)during menstruation(P<0.05).At the other time points,significance was not found between the two groups in comparing PU at the detected spots. Conclusion:Compared with healthy participants,PD patients present specific changes in PU at Taixi(KI3),Diji(SP8),and Zhongdu(LR6)at specific time points during the menstrual cycle,which provides a reference for acupuncture-moxibustion treatment of PD in clinical settings.

Alcoholic liver disease(ALD)is the most frequent liver disease worldwide,resulting in severe harm to personal health and posing a serious burden to public health.Based on the reported antioxidant and anti-inflammatory capacities of scutellarin(SCU),this study investigated its protective role in male BALB/c mice with acute alcoholic liver injury after oral administration(10,25,and 50 mg/kg).The results indicated that SCU could lessen serum alanine aminotransferase(ALT)and aspartate aminotransferase(AST)levels and improve the histopathological changes in acute alcoholic liver;it reduced alcohol-induced malondialdehyde(MDA)content and increased glutathione peroxidase(GSH-Px),catalase(CAT),and superoxide dismutase(SOD)activity.Furthermore,SCU decreased tumor necrosis factor-α(TNF-α),interleukin-6(IL-6),and IL-1β messenger RNA(mRNA)expression levels,weakened inducible nitric oxide synthase(iNOS)activity,and inhibited nucleotide-binding oligomerization domain(NOD)-like receptor protein 3(NLRP3)inflammasome activation.Mechanistically,SCU suppressed cytochrome P450 family 2 subfamily E member 1(CYP2E1)upregulation triggered by alcohol,increased the expression of oxidative stress-related nuclear factor erythroid 2-related factor 2(Nrf2)and heme oxygenase-1(HO-1)pathways,and suppressed the inflammation-related degradation of inhibitor of nuclear factor-κB(NF-κB)-α(IκBα)as well as activation of NF-κB by mediating the protein kinase B(AKT)and p38 mitogen-activated protein kinase(MAPK)pathways.These findings demonstrate that SCU protects against acute alcoholic liver injury via inhibiting oxidative stress by regulating the Nrf2/HO-1 pathway and suppressing inflammation by regulating the AKT,p38 MAPK/NF-κB pathways.

Objective:To retrospectively analyze the efficacy and safety of dupilumab in the treatment of bullous pemphigoid (BP) .Methods:Clinical data were collected from BP patients who received injections of dupilumab at an initial dose of 600 mg followed by an every-2-week regimen at a dose of 300 mg (the frequency of injections could be increased if necessary) in Department of Dermatology, Peking University First Hospital from October 2020 to October 2021, and their clinical manifestations and changes in laboratory indices were analyzed.Results:A total of 21 BP patients treated with dupilumab were included in this study. Nineteen (90.5%) patients achieved complete or marked disease control after 2-week treatment with dupilumab; 12 patients were followed up for 16 weeks, and all maintained complete disease control at 16 weeks. All patients had a bullous pemphigoid disease area index (BPDAI) score of 122.5 ± 51.1 points at baseline, which decreased to 30.6 ± 27.4 points after 2-week treatment with dupilumab ( t = 8.53, P < 0.001) , and continued to decrease to 12.7 ± 9.1 points after 4-week treatment ( t = 9.73, P < 0.001) . Pruritus was markedly relieved in all the 21 patients within 4-week treatment with dupilumab. Among 10 patients with elevated eosinophil counts at baseline, the eosinophil counts markedly decreased in 9 after treatment. The serum IgE level was elevated in 7 patients at baseline, which markedly decreased in 6 after treatment. Viral conjunctivitis occurred in 1 (4.8%) patient, and no adverse reactions were observed in other patients. Conclusion:Dupilumab is effective in the control of BP and relief of pruritus, with a favorable safety profile.

Drinking culture has high significance in both China and the world, whether in the entertainment sector or in social occasions; according to the World Health Organization's 2018 Global Alcohol and Health Report, about 3 million people died from excessive drinking in 2016, accounting for 5.3% of the total global deaths that year. Oxidative stress and inflammation are the most common pathological phenomena caused by alcohol abuse (Snyder et al., 2017). Scutellarin, a kind of flavonoid, is one of the main active ingredients extracted from breviscapine. It exerts anti-inflammatory, antioxidant, and vasodilation effects, and has been used to treat cardiovascular diseases and alcoholic liver injury. Although scutellarin can effectively alleviate multi-target organ injury induced by different forms of stimulation, its protective effect on alcoholic brain injury has not been well-defined. Therefore, the present study established an acute alcohol mice brain injury model to explore the effect of scutellarin on acute alcoholic brain injury. The study was carried out based on the targets of oxidative stress and inflammation, which is of great significance for the targeted therapy of clinical alcohol diseases.
Animals ; Apigenin/therapeutic use* ; Brain Injuries/drug therapy* ; Glucuronates/therapeutic use* ; Humans ; Mice ; Oxidative Stress

Objective:To investigate the relationship between serum vascular endothelial growth factor (VEGF) levels and white matter high signal and non-dementia vascular cognitive dysfunction in patients with cerebral small vascular disease (CSVD).Methods:Total 106 patients with CSVD who were admitted to the Department of Neurology of the First Affiliated Hospital of Xinxiang Medical College from April 2019 to December 2020 were enrolled.They were divided into vascular cognitive impairment no dementia group (VCIND group, n=47) and no vascular cognitive impairment group (N-VCI group, n=59)according to mini-mental assessment scale (MMSE), Montreal cognitive assessment (MoCA) scale and activity of daily living scale (ADL). Serum VEGF levels were detected by enzyme-linked immunosorbent assay (ELISA). The baseline data, serum VEGF levels, MoCA score and Fazekas score were compared between the two groups.The correlation between serum VEGF level and white matter high signal and cognitive function was analyzed.SPSS 19.0 software was used for data processing.The statistical methods were t-test, Chi square test, nonparametric test, Logistic regression analysis, Pearson correlation analysis and Spearman correlation analysis. Results:There were significant differences in serum VEGF level((464.18±114.58)pg/mL, (414.17±45.80)pg/mL, F=22.880), MoCA score((13.07±6.48), (20.17±4.06), F=17.920) and Fazekas score (4(3, 5), 3(1, 3), Z=-4.189)between the two groups (all P<0.05). The level of VEGF( β=0.008, OR=1.008, 95% CI=1.001-1.015, P<0.05) was the influencing factor of cognitive function in patients with CSVD .The level of VEGF was negatively correlated with the total score of MoCA, attention and calculation power, and orientation ability ( r=-0.345, -0.373, -0.445, all P<0.05) and it was positively correlated with the total Fazekas score and the Fazekas score of paraventricular and deep white matter ( r=0.392, 0.495, 0.302, all P<0.05). There was a linear trend between the high signal grade of paraventricular and deep white matter and VCIND (both P<0.05). Conclusion:Serum VEGF level is correlated with cognitive function and white matter hyperintensity in patients with CSVD.The increase of VEGF level may be a factor reflecting cognitive dysfunction.In addition, with the increase of white matter hyperintensity level, the risk of VCIND in CSVD is increased.

Acetaminophen (APAP) overdose is the leading cause of drug-induced liver injury, and its prognosis depends on the balance between hepatocyte death and regeneration. Sirtuin 6 (SIRT6) has been reported to protect against oxidative stress-associated DNA damage. But whether SIRT6 regulates APAP-induced hepatotoxicity remains unclear. In this study, the protein expression of nuclear and total SIRT6 was up-regulated in mice liver at 6 and 48 h following APAP treatment, respectively.