Objective To investigate the influencing factors associated with the comorbidity of inflammatory bowel disease (IBD) and depression. Methods A case-control study was conducted based on the ^“Healthcare Big Data Platform^” of a tertiary class-A comprehensive hospital in Shandong Province. IBD comorbid with depression was served as the case group and IBD without depression was served as the control group. Propensity score matching (PSM) was performed by matching the case group with the control group in a ratio of 1:2 according to the age and gender of the patients. Conditional logistic regression model was used to explore the influencing factors associated with the comorbidity of IBD and depression. Results A total of 405 patients with IBD were enrolled in this study, including 270 patients without depression and 135 patients comorbid with depression. The results of conditional logistic regression showed that the use of immunosuppressants (OR=2.84, 95% CI: 1.00-8.07) and glucocorticoids (OR=2.05, 95% CI: 1.17-3.58), dementia (OR=5.20, 95% CI:1.59-17.05), cardiovascular disease (OR=3.58, 95% CI: 1.84-6.98) and cancer (OR=2.63, 95% CI: 1.16-5.95) were associated with the comorbidity of depression and IBD. Conclusion Attention should be paid to the use of immunosuppressants and glucocorticoids in the population of IBD comorbid with depression, and the coexistence of physical diseases such as dementia, cardiovascular disease and cancer. Early prevention and targeted treatment measures should be taken for high-risk populations to reduce their risk of depression and improve their quality of life and health.

Objective To identify long non-coding RNA (lncRNA) associated with rheumatoid arthritis-associated interstitial lung disease (RA-ILD) and investigate their mechanisms. Methods Peripheral blood samples were collected from RA-ILD patients (n＝3), RA patients without lung involvement (n＝3), and healthy controls (n＝3). Next-generation sequencing was performed to screen differentially expressed lncRNA. A human fibrotic lung cell model was established by inducing the MRC-5 cell line with transforming growth factor-β (TGF-β). Following siRNA-mediated knockdown of target genes, changes in inflammatory and oxidative stress-related genes were analyzed via real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR). Western blotting and dual-luciferase reporter (DLR) assays were used to validate protein expression, ubiquitination levels, and nuclear translocation of oxidative stress regulators, and antioxidant response element (ARE) transcriptional activity. Rescue experiments were conducted to confirm the role of target lncRNA in oxidative stress and inflammation in fibrotic lung cells. Results High-throughput sequencing revealed significant downregulation of LINC00638 in RA-ILD patients. Knockdown of LINC00638 markedly reduced transcriptional levels of interleukin (IL)-4, nuclear factor erythroid-2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and superoxide dismutase 2 (SOD2), while increasing IL-6, IL-1β, interferon-γ (IFN-γ), and reactive oxygen species (ROS) levels. Furthermore, LINC00638 knockdown decreased Nrf2 protein expression, increased its ubiquitination, reduced nuclear translocation, and suppressed ARE transcriptional activity. In MRC-5 cells, LINC00638 knockdown combined with N-acetylcysteine treatment restored Nrf2 and HO-1 levels while reducing IL-6 expression. Conclusions LINC00638 suppresses inflammatory responses in RA-ILD by activating the Nrf2/ARE antioxidant signaling pathway, suggesting its potential as a therapeutic target for diagnosis and treatment.

Objective To analyze the efficacy of different intracavitary operations for calyceal diverticulum calculi,so as to provide reference for the diagnosis and treatment of such disease.Methods A retrospective analysis of the data of 21 patients with calyceal diverticulum calculi was conducted during Jan.2015 and Dec.2021.The patients were divided into the retrograde intrarenal surgery(RIRS,n=14)group and percutaneous nephrolithotomy(PCNL,n=7)group.The perioperative data were compared.Results There was no significant difference in stone load between the RIRS group and PCNL group[(11.56±4.79)mm vs.(13.06±6.27)mm,P=0.609].There were significant differences in the thickness of renal parenchyma at the top of the diverticulum[(10.08±4.81)mm vs.(5.24±2.23)mm,P=0.005],operation time[(58.57±19.23)min vs.(88.29±25.28)min,P=0.007],hospitalization time[3(1,5)vs.12(5,7),P=0.023]days.After operation,there were no significant differences in stone-clearance rate,decrease of hemoglobin,and postoperative complications between the two groups(P＞0.05).Conclusion Both RIRS and PCNL are viable options for treating renal calyceal diverticulum calculi.RIRS has advantages of shorter operation time and hospital stay.PCNL can be an alternative treatment when RIRS is unsuccessful.

Objective To investigate the effect of asiaticoside on blood pressure and relaxation of thoracic aorta in rats and explore the underlying mechanism.Methods SD rats treated with 50 and 100 mg/kg asiaticoside by daily gavage for 2 weeks were monitored for systolic blood pressure changes,and histological changes of the thoracic aorta were evaluated using HE staining.In isolated rat endothelium-intact and endothelium-denuded thoracic aorta rings,the effects of asiaticoside on relaxation of the aortic rings were tested at baseline and following norepinephrine(NE)-and KCl-induced constriction.The vascular relaxation effect of asiaticoside was further observed in NE-stimulated endothelium-intact rat aortic rings pretreated with L-nitroarginine methyl ester,indomethacin,zinc protoporphyrin Ⅸ,tetraethyl ammonium chloride,glibenclamide,barium chloride,Iberiotoxin,4-aminopyridine,or TASK-1-IN-1.The aortic rings were treated with KCl and NE followed by increasing concentrations of CaCl2 to investigate the effect of asiaticoside on vasoconstriction induced by external calcium influx and internal calcium release.Results Asiaticoside at 50 and 100 mg/kg significantly lowered systolic blood pressure in rats without affecting the thoracic aorta histomorphology.While not obviously affecting resting aortic rings with intact endothelium,asiaticoside at 100 mg/kg induced significant relaxation of the rings constricted by KCl and NE,but its effects differed between endothelium-intact and endothelium-denuded rings.In endothelium-intact aortic rings pretreated with indomethacin,ZnPP Ⅸ,barium chloride,glyburide,TASK-1-IN-1 and 4-aminopyridine,asiaticoside did not produce significant effect on NE-induced vasoconstriction,and tetraethylammonium,Iberiotoxin and L-nitroarginine methyl ester all inhibited the relaxation effect of asiaticoside.In KCl-and NE-treated rings,asiaticoside obviously inhibited CaCl2-induced vascular contraction.Conclusion Asiaticoside induces thoracic aorta relaxation by mediating high-conductance calcium-activated potassium channel opening,promoting nitric oxide release from endothelial cells and regulating Ca2+ influx and outflow,thereby reducing systolic blood pressure in rats.

OBJECTIVE To investigate the effect of Huangqi-Ezhu-Chonglou combination on macrophage polarization and its mechanism of inhibiting colorectal cancer(CRC)cells proliferation and migration.METHODS THP-1 cells were stimulated with phorbol 12-myristate 13-acetate(PMA)and interleukin-4(IL-4)to establish M2 macrophage polarization model.The experiment was divided into M0 group(PMA treatment),M2 group(PMA+IL-4 treatment),and M2+ Huangqi-Ezhu-Chonglou combination group(PMA+IL-4+Huangqi-Ezhu-Chonglou combination treatment).The effect of Huangqi-Ezhu-Chonglou combination freeze-dried powder on the viability of macrophage was detected by CCK-8 method.The expression of macrophage polarization markers,glu-taminase(GLS)mRNA and protein was detected by qPCR and Western blot.The levels of interleukin-10(IL-10),transforming growth factor-β(TGF-β)and tumor necrosis factor-α(TNF-α)in cell supernatant were detected by ELISA.CCK-8 method and Tr-answell assays were used to detect the proliferation and migration of HCT116 cells intervened by the supernatant of macrophage culture treated with Huangqi-Ezhu-Chonglou combination,namely conditioned medium(CM).RESULTS Compared with the M0 group,the expression levels of IL-10,mannose receptor(CD206),arginase 1(ARG1),and GLS mRNA and protein in the M2 group were significantly increased(P<0.01,P<0.001),the levels of IL-10 and TGF-β secreted by macrophages were significantly increased(P<0.01,P<0.001);compared with the M2 group,the M2+ Huangqi-Ezhu-Chonglou combination group had significantly reduced IL-10,CD206,ARG1,and GLS mRNA and protein expression(P<0.05,P<0.01),the mRNA and protein levels of TNF-α and in-ducible nitric oxide synthase(iNOS)were significantly increased(P<0.05,P<0.01,P<0.001),the interleukin-1β(Interleukin-1β,IL-1β)mRNA expression significantly increased(P<0.01),and the contents of IL-10 and TGF-β in the cell supernatant sig-nificantly decreased(P<0.05,P<0.01),while TNF-α content significantly increased(P<0.01).CCK-8 and Transwell results showed that compared with the M0-CM group,the M2-CM promoted the proliferation and migration of HCT116 cells(P<0.01,P<0.001),the M2+ Huangqi-Ezhu-Chonglou-CM group significantly inhibited HCT116 cell proliferation and reduced cell migration compared to the M2-CM group(P<0.01,P<0.001).CONCLUSION Huangqi-Ezhu-Chonglou combination can inhibit colorectal cancer cells proliferation and migration by regulating macrophage polarization,and its mechanism may be related to the changes in the expression of GLS,a key enzyme in glutamine metabolism.

Objective To investigate the effect of asiaticoside on blood pressure and relaxation of thoracic aorta in rats and explore the underlying mechanism.Methods SD rats treated with 50 and 100 mg/kg asiaticoside by daily gavage for 2 weeks were monitored for systolic blood pressure changes,and histological changes of the thoracic aorta were evaluated using HE staining.In isolated rat endothelium-intact and endothelium-denuded thoracic aorta rings,the effects of asiaticoside on relaxation of the aortic rings were tested at baseline and following norepinephrine(NE)-and KCl-induced constriction.The vascular relaxation effect of asiaticoside was further observed in NE-stimulated endothelium-intact rat aortic rings pretreated with L-nitroarginine methyl ester,indomethacin,zinc protoporphyrin Ⅸ,tetraethyl ammonium chloride,glibenclamide,barium chloride,Iberiotoxin,4-aminopyridine,or TASK-1-IN-1.The aortic rings were treated with KCl and NE followed by increasing concentrations of CaCl2 to investigate the effect of asiaticoside on vasoconstriction induced by external calcium influx and internal calcium release.Results Asiaticoside at 50 and 100 mg/kg significantly lowered systolic blood pressure in rats without affecting the thoracic aorta histomorphology.While not obviously affecting resting aortic rings with intact endothelium,asiaticoside at 100 mg/kg induced significant relaxation of the rings constricted by KCl and NE,but its effects differed between endothelium-intact and endothelium-denuded rings.In endothelium-intact aortic rings pretreated with indomethacin,ZnPP Ⅸ,barium chloride,glyburide,TASK-1-IN-1 and 4-aminopyridine,asiaticoside did not produce significant effect on NE-induced vasoconstriction,and tetraethylammonium,Iberiotoxin and L-nitroarginine methyl ester all inhibited the relaxation effect of asiaticoside.In KCl-and NE-treated rings,asiaticoside obviously inhibited CaCl2-induced vascular contraction.Conclusion Asiaticoside induces thoracic aorta relaxation by mediating high-conductance calcium-activated potassium channel opening,promoting nitric oxide release from endothelial cells and regulating Ca2+ influx and outflow,thereby reducing systolic blood pressure in rats.

Excessive N-acetyl-p-benzoquinone imine(NAPQI)formation is a starting event that triggers oxidative stress and subsequent hepatocyte necrosis in acetaminophen(APAP)overdose caused acute liver failure(ALF).S-glutathionylation is a reversible redox post-translational modification and a prospective mechanism of APAP hepatotoxicity.Glutaredoxin-1(Glrx1),a glutathione-specific thioltransferase,is a primary enzyme to catalyze deglutathionylation.The objective of this study was to explored whether and how Glrx1 is associated with the development of ALF induced by APAP.The Glrx1 knockout mice(Glrx1-/-)and liver-specific overexpression of Glrx1(AAV8-Glrx1)mice were produced and underwent APAP-induced ALF.Pirfenidone(PFD),a potential inducer of Glrx1,was administrated preceding APAP to assess its protective effects.Our results revealed that the hepatic total protein S-glutathionylation(PSSG)increased and the Glrx1 level reduced in mice after APAP toxicity.Glrx1-/- mice were more sensitive to APAP overdose,with higher oxidative stress and more toxic metabolites of APAP.This was attributed to Glrx1 deficiency increasing the total hepatic PSSG and the S-glutathionylation of cytochrome p450 3a 11(Cyp3a11),which likely increased the activity of Cyp3a11.Conversely,AAV8-Glrx1 mice were defended against liver damage caused by APAP overdose by inhibiting the S-glutathionylation and activity of Cyp3a11,which reduced the toxic metabolites of APAP and oxidative stress.PFD precede administration upregulated Glrx1 expression and alleviated APAP-induced ALF by decreasing oxidative stress.We have identified the function of Glrx1 mediated PSSG in liver injury caused by APAP overdose.Increasing Glrx1 expression may be investigated for the medical treatment of APAP-caused hepatic injury.

[This corrects the article DOI: 10.1016/j.apsb.2021.09.017.].

Pulmonary endothelial barrier dysfunction is a hallmark of clinical pulmonary edema and contributes to the development of acute lung injury (ALI). Here we reported that ruscogenin (RUS), an effective steroidal sapogenin of Radix Ophiopogon japonicus, attenuated lipopolysaccharides (LPS)-induced pulmonary endothelial barrier disruption through mediating non-muscle myosin heavy chain IIA (NMMHC IIA)‒Toll-like receptor 4 (TLR4) interactions. By in vivo and in vitro experiments, we observed that RUS administration significantly ameliorated LPS-triggered pulmonary endothelial barrier dysfunction and ALI. Moreover, we identified that RUS directly targeted NMMHC IIA on its N-terminal and head domain by serial affinity chromatography, molecular docking, biolayer interferometry, and microscale thermophoresis analyses. Downregulation of endothelial NMMHC IIA expression in vivo and in vitro abolished the protective effect of RUS. It was also observed that NMMHC IIA was dissociated from TLR4 and then activating TLR4 downstream Src/vascular endothelial cadherin (VE-cadherin) signaling in pulmonary vascular endothelial cells after LPS treatment, which could be restored by RUS. Collectively, these findings provide pharmacological evidence showing that RUS attenuates LPS-induced pulmonary endothelial barrier dysfunction by inhibiting TLR4/Src/VE-cadherin pathway through targeting NMMHC IIA and mediating NMMHC IIA‒TLR4 interactions.

Objective To investigate the relationship between the expression of ITGAV and the radiosensitivity of NSCLC cells. Methods The expression of ITGAV in NSCLC and its relationship to the prognosis of patients who received radiotherapy were analyzed using bioinformatics methods. Differences in radiosensitivity between radio-resistant cells and parent cells were verified by clone formation experiment, and the protein expression of ITGAV was detected by Western blot. The transfection efficiency of si-ITGAV was determined by Western blot and qRT-PCR analyses. The best ITGAV interference sequence was selected to transfect A549R and H1299R cells. Clone formation experiment and flow cytometry were used to detect clone formation, apoptosis and cell cycle of A549R and H1299R cells. Results The expression of ITGAV in NSCLC tissues was significantly higher than that in normal tissues (P<0.05), and NSCLC patients with high ITGAV expression had poor prognosis. The clonogenic ability of the si-ITGAV group was significantly lower than that of the negative control group at 4, 6, 8Gy irradiation (all P<0.05). After 6 Gy irradiation, the apoptosis of the si-ITGAV group was increased (P_H1299R<0.0001, P_A549R=0.0002), the proportion of G₂/M phase cells to A549-siITGAV and H1299R-siITGAV cells was higher than that in the negative control group (P_H1299R<0.0001, P_A549R=0.0007). Conclusion Interfering with ITGAV expression can increase the radiosensitivity of NSCLC.