Recently, β‐arrestin1 has been indicated as a prostate cancer promoter through promoting cell proliferation and epithelial to mesenchymal transition, but its underlying mechanism remains unclear. ...Here, our data revealed that β‐arrestin1 could promote cell growth through inhibiting the transcriptional activity and expression of FOXO3a in prostate cancer cells in vitro and in vivo. We found that β‐arrestin1 could promote the cell and tumor growth of prostate cancer, and β‐arrestin1 expression represented a negative correlation with FOXO3a expression but not FOXO1 expression in prostate cancer cell lines and tissues. In addition, forced expression of β‐arrestin1 induced a significant decrease of FOXO3a expression but had no clear effect on FOXO1 expression. Mechanistically, β‐arrestin1 could interact with FOXO3a and MDM2, respectively, and promote the interaction between FOXO3a and MDM2, whereas it had no obvious interaction with FOXO1. Furthermore, β‐arrestin1 could inhibit the transcriptional activity of FOXO3a via Akt and ERK1/2 pathways. Together, our results revealed a novel mechanism for β‐arrestin1 in the regulation of the prostate cancer procession through inhibiting FOXO3a.
Our results demonstrated for the first time that β‐arrestin1 could promote prostate cancer cell growth via inhibiting the activity and expression of FOXO3a, rather than FOXO1, in vitro and in vivo, thus representing a novel mechanism of β‐arrestin1 in the regulation of cell growth via FOXO3a in prostate process.
Hyperoxaluria-induced oxidative injury of renal tubular epithelial cell is a casual and essential factor in kidney calcium oxalate (CaOx) stone formation. Autophagy has been shown to be critical for ...the regulation of oxidative stress-induced renal tubular injury; however, little is known about its role in kidney CaOx stone formation. In the present study, we found that the autophagy antagonist chloroquine could significantly attenuate oxalate-induced autophagy activation, oxidative injury and mitochondrial damage of renal tubular cells in vitro and in vivo, as well as hyperoxaluria-induced CaOx crystals depositions in rat kidney, whereas the autophagy agonist rapamycin exerted contrasting effects. In addition, oxalate-induced p38 phosphorylation was significantly attenuated by chloroquine pretreatment but was markedly enhanced by rapamycin pretreatment, whereas the protective effect of chloroquine on rat renal tubular cell oxidative injury was partly reversed by a p38 protein kinase activator anisomycin. Furthermore, the knockdown of Beclin1 represented similar effects to chloroquine on oxalate-induced cell oxidative injury and p38 phosphorylation in vitro. Taken together, our results revealed that autophagy inhibition could attenuate oxalate-induced oxidative injury of renal tubular cell and CaOx crystal depositions in the rat kidney via, at least in part, inhibiting the activation of p38 signaling pathway, thus representing a novel role of autophagy in the regulation of oxalate-induced renal oxidative injury and CaOx crystal depositions for the first time.
•Oxalate stimulation could induce autophagy activation in a time- and dose-depended manner in renal tubular epithelial cells.•Chloroquine-mediated autophagy inhibition attenuated oxalate-induced renal oxidative injury and CaOx crystal depositions.•The protective effect of chloroquine or Beclin1 siRNA on oxalate-induced oxidative injury of renal tubular epithelial cells is mediated, at least in part, by p38 signaling.
Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive malignant tumor with a poor prognosis. This study aimed to establish a novel clinical-radiomics model for predicting the prognosis of ICC ...after radical hepatectomy.
A clinical-radiomics model was established for 82 cases of ICC treated with radical hepatectomy in our hospital from May 2011 to December 2020. Radiomics features were extracted from venous-phase and arterial-phase images of computed tomography. Kaplan-Meier survival analysis was generated to compare overall survival (OS) between different groups. The independent factors were identified by univariate and multivariate Cox regression analyses. Nomogram performance was evaluated regarding discrimination, calibration, and clinical utility. C-index and area under the curve (AUC) were utilized to compare the predictive performance between the clinical-radiomics model and conventional staging systems.
The radiomics model included five features. The AUC of the radiomics model was 0.817 in the training cohort, and 0.684 in the validation cohort. The clinical-radiomics model included psoas muscle index, radiomics score, hepatolithiasis, carcinoembryonic antigen, and neutrophil/lymphocyte ratio. The reliable C-index of the model was 0.768, which was higher than that of other models. The AUC of the model for predicting OS at 1, and 3 years was 0.809 and 0.886, which was significantly higher than that of the American Joint Committee on Cancer 8
staging system (0.594 and 0.619), radiomics model (0.743 and 0.770), and tumor differentiation (0.645 and 0.628). After stratification according to the constructed model, the median OS was 59.8 months for low-risk ICC patients and 10.1 months for high-risk patients (
0.0001).
The clinical-radiomics model integrating sarcopenia, clinical features, and radiomics score was accurate for prognostic prediction for mass-forming ICC patients. It provided an individualized prognostic evaluation in patients with mass-forming ICC and could helped surgeons with clinical decision-making.
Epicardial fat is a unique adipose tissue located between the myocardium and the visceral layer of pericardium. This tissue is characterized by highly active fatty acid metabolism and highly ...expressed thermogenic genes. Epicardial fat and the underlying myocardium share the same microcirculation, suggesting a close and strong interaction between these two structures. Under physiological conditions, epicardial fat protects and supports the heart to exert its normal function. Many clinical studies have shown significant associations between increased amounts of epicardial fat and coronary artery disease (CAD). In patients with CAD, increased epicardial fat becomes inflammatory and may promote plaque development through secretion of proinflammatory cytokines and other mechanisms. Therefore, epicardial fat is a biomarker of cardiovascular risk and a potential therapeutic target for cardiovascular disease. Weight loss and pharmaceuticals can reduce epicardial fat and improve its protective physiological functions.
Accumulation and activation of immunocytes in adipose tissues are essential to obesity-induced inflammation and insulin resistance. Chemokines are pivotal for the recruitment of immunocytes in ...adipose tissue during obesity. Chemokine (C-C motif) ligand 5 (CCL5) plays a vital role in the recruitment of immunocytes to sites of inflammation. CCL5 expression level is increased in obese adipose tissue from humans and mice. However, the role of CCL5 in obesity-induced adipose inflammation remains unclear. Our study found that the CCL5 expression level was increased in the epididymal white adipose tissue (eWAT) of obese mice, particularly in CD8
T cells. CCL5 knockout (KO) mice exhibited better glucose tolerance than wild-type (WT) mice under lean conditions. In contrast, CCL5 KO mice were more insulin resistant and had severe hepatic steatosis than WT mice under obese conditions. Increased T cells in adipose tissue heaven adipose inflammation in obese CCL5 KO mice. The compensatory increased T cell-associated chemokines may account for increased T cell content in the eWAT of obese CCL5 KO mice. These findings imply that CCL5 deficiency exacerbates adipose inflammation and impairs insulin sensitivity in the metabolic tissues of obese mice.
Th1 cell activation is considered a key mediator of the pathogenesis of type 1 diabetes. Targeting IL-12-induced Th1 cell differentiation seems to be an effective way to block the development of type ...1 diabetes. However, given the critical function of Th1 in the immune system, the potential side effects hinder the application of anti-Th1 therapy in the treatment of type 1 diabetes. To identify safe anti-Th1 treatment(s), we screened the FDA-approved tyrosine kinase inhibitor (TKI) drug library using an IL-12-induced Th1 differentiation cell model. We found that among the TKIs with little effect on T cell viability, sorafenib is the top contender for the inhibition of Th1 differentiation. Treatment of NOD mice with sorafenib significantly impeded the development of type 1 diabetes and ameliorated insulitis, which coincided with a specifically decreased accumulation of Th1 cell population in the pancreas but not in peripheral immune organs. Mechanistically, sorafenib indirectly inhibited janus kinase 2 (JAK2) activity and blocked IL-12-induced phosphorylations of JAK2 and signal transducer and activator of transcription 4 (STAT4). Since sorafenib is classified as an FDA-approved drug, it serves as a preliminary lead point for additional experimentation and may be a promising therapy for type 1 diabetes in humans.
Surgical resection is the only widely accepted curative method for intrahepatic cholangiocarcinoma (ICC). However, little is known about the efficacy of laparoscopic liver resection for ICC, ...especially in patients with early-stage disease. The aim of this study was to compare the short-term and long-term effects of laparoscopy and open surgery for the treatment of ICC.
Data from 1,084 patients treated at three hospitals from January 2011 to December 2018 were selected and analyzed. Propensity score matching was performed to compare the long-term outcomes (overall survival and recurrence-free survival) and short-term outcomes (perioperative outcomes) of all-stage and early-stage patients.
After matching, 244 patients (122
122) in the all-stage group and 65 patients (27
38) in the early-stage group were included. The baseline of the two groups was balanced, and no significant differences were found in sex or age. The short-term results of the laparoscopic group were better than those of the open group, including less blood loss blood loss ≥400 ml 27 (22.1%)
6 (4.92%), p<0.001 for all-stage, 12 (31.6%)
2 (7.41%), p=0.042 for early stage), shorter surgery 200 (141; 249) min
125 (115; 222) min, p=0.025 for early stage and shorter hospital stay 11.0 (9.00; 16.0) days
9.00 (7.00; 12.0) days, p=0.001 for all stage, 11.0 (8.50; 17.8) days
9.00 (6.50; 11.0) days, p=0.011 for early stage. Regarding long-term outcomes, no significant differences were found for all-stage patients, while there were significant differences observed for the early-stage group (p=0.013 for OS, p=0.014 for RFS). For the early-stage patients, the 1-, 3-, and 5-year OS rates of the OLR group were 84.2, 65.8, and 41.1%, respectively, and those of the LLR group were 100, 90.9, and 90.9%, respectively. The RFS rates of the OLR group were 84.2, 66.7, and 41.7%, respectively, and those of the LLR group were and 92.3, 92.3, and 92.3%, respectively.
Patients treated with laparoscopy seemed to have better short-term outcomes, such as less blood loss, shorter operation duration, and shorter hospital stay, than patients undergoing open surgery. Based on the long-term results, laparoscopic treatment for early ICC may have certain advantages.
Background Inflammatory bowel disease (IBD) is a group of diseases characterized by chronic and recurrent inflammation of the gastrointestinal tract. The etiology of IBD remains multifaceted and ...poorly understood, resulting in limited treatment options that primarily target disease induction and remission maintenance. Thus, the exploration of novel therapeutic options for IBD among existing medications is advantageous. Mendelian randomization analysis (MR) serves as a valuable tool in investigating the relationship between drugs and diseases. In this study, MR analysis was employed to investigate the potential causal relationship between 23 approved drugs for the treatment of various diseases and IBD. Method We performed a two-sample MR analysis using publicly available genome-wide association study (GWAS) statistics. The inverse variance weighting (IVW) method was used as the main analysis method, supplemented by the remaining four methods (weighted median, MR Egger regression, simple and weighted models), and Meta-analysis was performed to expand the sample size to obtain a more reliable composite causal effect. Finally, Cochran’s Q statistic and the MR-Egger test for directed pleiotropy were applied to determine whether significant heterogeneity or directed pleiotropy existed. Results In the main MR analysis (IVW), drugs with a negative causal association with the risk of IBD were immunosuppressant {OR (95% CI) = 0.7389 0.6311–0.8651, p = 0.0046} and diabetes drugs {OR (95% CI) = 0.9266 0.8876–0.9674, p = 0.0058}. A positive causal association with the risk of IBD was found for salicylic acid and derivatives {OR (95% CI) = 1.2737 1.0778–1.5053, p = 0.0345}. Negative causal associations with UC risk were identified for immunosuppressants {OR (95% CI) = 0.6660 0.5133–0.8640, p = 0.0169} and diabetes medications {OR (95% CI) = 0.9020 0.8508–0.9551, p = 0.0046}; positive causal associations with UC risk were found for β-receptor blockers {OR (95% CI) = 1.1893 1.0823–1.3070, p = 0.0046}. A negative causal association with the risk of CD was found for immunosuppressants {OR (95% CI) = 0.6957 0.5803–0.8341, p = 0.0023}. There was no statistically significant association between the remaining 19 drugs and IBD and subtypes. Conclusion This MR study provides evidence suggesting that immunosuppressants have a mitigating effect on the risk of IBD and demonstrate consistent efficacy in subtypes of ulcerative colitis (UC) and Crohn’s disease (CD). Additionally, diabetes medications show potential in reducing the risk of IBD, particularly in cases of UC, while β-blockers may elevate the risk of UC. Conversely, salicylic acid and its derivatives may increase the risk of IBD, although this effect is not consistently observed in the subtypes of the disease. These findings offer new insights into the prevention and management of IBD.
Immunomodulation is considered a potential therapeutic approach for chronic kidney disease (CKD). Although it has been previously reported that CD4
T cells contribute to the development of renal ...fibrosis, the role of MHC class II (MHCII) in the development of renal fibrosis remains largely unknown. The present study reports that the expression of MHCII molecules in renal cortical tubules is upregulated in mouse renal fibrosis models generated by unilateral ureter obstruction (UUO) and folic acid (FA). Proximal tubule epithelial cells (PTECs) are functional antigen-presenting cells that promote the proliferation of CD4
T cells in an MHCII-dependent manner. PTECs from mice with renal fibrosis had a stronger ability to induce T cell proliferation and cytokine production than control cells. Global or renal tubule-specific ablation of H2-Ab1 significantly alleviated renal fibrosis following UUO or FA treatment. Renal expression of profibrotic genes showed a consistent reduction in H2-Ab1 gene-deficient mouse lines. Moreover, there was a marked increase in renal tissue CD4
T cells after UUO or FA treatment and a significant decrease following renal tubule-specific ablation of H2-Ab1. Furthermore, renal tubule-specific H2-Ab1 gene knockout mice exhibited higher proportions of regulatory T cells (Tregs) and lower proportions of Th2 cells in the UUO- or FA-treated kidneys. Finally, Immunohistochemistry (IHC) studies showed increased renal expression of MHCII and the profibrotic gene α smooth muscle actin (α-SMA) in CKD patients. Together, our human and mouse data demonstrate that renal tubular MHCII plays an important role in the pathogenesis of renal fibrosis.
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