Zhankui Jia

HMGB1 Is Involved in the Protective Effect of the PPARα Agonist Fenofibrate against Cardiac Hypertrophy

High mobility group box 1 (HMGB1) is a ubiquitous nuclear DNA-binding protein whose function is dependent on its cellular location. Extracellular HMGB1 is regarded as a delayed mediator of proinflammatory cytokines for initiating and amplifying inflammatory responses, whereas nuclear HMGB1 has been found to prevent cardiac hypertrophy and heart failure. Because fenofibrate, a peroxisome proliferator-activated receptor α (PPARα) agonist, has shown both protective effects against cardiac hypertrophy and inhibitory effects against inflammation, the potential modulation of HMGB1 expression and secretion by fenofibrate is of great interest. We herein provide evidence that fenofibrate modulates basal and LPS-stimulated HMGB1 expression and localization in addition to secretion of HMGB1 in cardiomyocytes. In addition, administration of fenofibrate to mice prevented the development of cardiac hypertrophy induced by thoracic transverse aortic constriction (TAC) while increasing levels of nuclear HMGB1. Altogether, these data suggest that fenofibrate may inhibit the development of cardiac hypertrophy by regulating HMGB1 expression, which provides a new potential strategy to treat cardiac hypertrophy.

Adjuvant therapy for locally advanced renal cell carcinoma: A meta-analysis and systematic review

OBJECTIVES Many adjuvant therapies have been widely used in an attempt to reduce the local recurrence or distant metastasis of locally advanced renal cell carcinoma (RCC) after surgical resection. However, the benefits of adjuvant therapy remain controversial. Thus, we performed this study to analyze the role and safety of adjuvant therapy in renal cancer setting. METHODS AND METHODS We comprehensively searched PubMed, EMBASE, Web of Science, and the Cochrane Library for published randomized controlled trials comparing adjuvant therapy (chemotherapy, vaccine therapy, immune therapy, and targeted therapy) versus no active treatment after surgery among patients with locoregional RCC. Outcomes of interest were disease-free survival, overall survival, and severe toxicities. Different kinds of adjuvant therapy were evaluated separately. RESULTS Twelve studies (5,936 patients) were included in the present analysis. Adjuvant therapy did not contribute to overall survival (HR = 1.04; 95% CI: 0.95-1.15; P = 0.395; I2 = 0%) or disease-free survival (HR = 1.00; 95% CI: 0.92-1.08; P = 0.971; I2 = 35%) when compared to placebo or observation. No survival benefit was observed according to subgroup analyses (targeted therapy, vaccine therapy, and immune therapy). Moreover, adjuvant therapy increased obviously the risk of toxicities. CONCLUSIONS The addition of adjuvant therapy provided no survival benefit but increased the rates of adverse events for locally advanced RCC patients.

Additive effect of prostaglandin E2 and adenosine in mouse experimental autoimmune encephalomyelitis

Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS), which is a T cell-mediated autoimmune disease of the central nervous system (CNS). Emerging evidence indicates that both prostaglandin E (PGE) and adenosine play important roles in immune inflammation although the mechanism remains unclear. In the study, we examined individual and combined effect of PGE and adenosine during EAE development. The results showed that both PGE and adenosine could inhibit EAE progression and they in combination showed substantially higher inhibition than each modality used alone. On the other hand, using specific agonists or antagonists for PGE and adenosine receptors indicated that the suppression of EAE development was mainly mediated by EP4 and A receptors. Furthermore, combined PGE and adenosine treatment significantly suppressed the production of IFN-γ and IL-17 via EP4 and A receptors. Taken together, PGE and adenosine in combination could protect EAE mouse from serious EAE through limiting the over-reactive effects of T cells via EP4 and A receptors.

MicroRNA-212 inhibits the proliferation, migration and invasion of renal cell carcinoma by targeting X-linked inhibitor of apoptosis protein (XIAP)

MicroRNAs have been found to be critical regulator of cancer cell biology. MicroRNA-212 (miR-212) was identified to be a critical cancer-associated microRNA playing either oncogenic functions or tumor suppressive roles in different types of human cancers. In this study, we found that the level of miR-212 in renal cell carcinoma (RCC) tissues was significantly lower than that in adjacent non-tumor tissues. Decreased level of miR-212 was associated with advanced T stage and TNM stage of RCC. The expression of miR-212 was decreased in RCC cell lines as compared with the HK-2 cell line. Overexpression of miR-212 inhibited cell viability, proliferation, migration and invasion of CAKI-2 cells. Knockdown of miR-212 increased cell viability and proliferation, migration and invasion of ACHN cells. In vivo experiments showed that miR-212 inhibited the proliferation and promoted the apoptosis of ACHN cells in nude mice and thus inhibited the in vivo tumor growth of CAKI-2 cells. Furthermore, we confirmed that X-linked inhibitor of apoptosis protein (XIAP) was the downstream target of miR-212. The expression level of miR-212 was negatively correlated with XIAP expression in RCC tissues. Moreover, XIAP mediated the tumor suppressive roles of miR-212 in RCC. Finally, we demonstrated that the aberrant expression of miR-212 and XIAP was evidently correlated with poor prognosis of RCC patients. In all, miR-212 can act as a prognostic biomarker for RCC patients and inhibits the growth and metastasis of RCC cells by inhibiting XIAP.

Consumption of fruits and vegetables and risk of renal cell carcinoma: a meta-analysis of observational studies

Background There have been inconsistent results about the association between consumption of fruits and vegetables and renal cell carcinoma (RCC) risk. We conducted a meta-analysis of the published observational studies to explore this association. Results Nineteen observational studies (4 cohort, 1 pooled and 14 case-control studies), involving 10,215 subjects with RCC were part of this meta-analysis. The SRR for the highest vs. the lowest intake of vegetables was 0.73 (95% CI: 0.63–0.85; Pheterogeneity = 0.004, I2 = 53.5%), whereas for fruits it was 0.86 (95% CI: 0.75–0.98; Pheterogeneity = 0.012, I2 = 47.4%). Linear dose-response analysis also showed similar results, e.g., for per 1 serving/day increment of vegetables, the SRR was 0.90 (95% CI: 0.84–0.96) and for fruits it was 0.97 (95% CI: 0.93–1.01). Nonlinear association was only observed for vegetables (Pnonlinearity = 0.001), but not for fruits (Pnonlinearity = 0.221). Materials and Methods Eligible studies up to August 31, 2016 were identified and retrieved by searching MEDLINE and EMBASE databases along with manual review of the reference list from the retrieved studies. Quality of included studies was evaluated using Newcastle-Ottawa Quality Assessment Scale (NOS). Random-effects model was used to calculate summary relative risk (SRR) and corresponding 95% confidence interval (CI). Conclusions This meta-analysis indicated a protective effect of consumption of vegetables and fruits on RCC risk. Further studies are warranted with prospective designs that use validated questionnaires and control for important confounders.

Involvement of interstitial cells of Cajal in bladder dysfunction in mice with experimental autoimmune encephalomyelitis

BackgroundBladder dysfunction is an important symptom of experimental autoimmune encephalomyelitis (EAE). Our previous study showed that EAE-induced upregulation of the E-prostanoid receptor 3 (EP3) and E-prostanoid receptor 4 (EP4) in the bladder was accompanied by bladder dysfunction. Although many other studies have evaluated the lower urinary tract symptoms in multiple sclerosis, the mechanism remains unclear.ObjectivesTo investigate the effects of interstitial cells of Cajal (ICC) on bladder dysfunction in a novel neurogenic bladder model induced by experimental autoimmune encephalomyelitis.Materials and methodsThe EAE model was induced by a previously established method, and bladder functions in mice were evaluated. Bladders were harvested for the analysis of ICCs and the genes associated with bladder mechanosensation including pannexin 1 (Panx1) and Gja1 (encoding connexin43) by immunofluorescence and western blotting. The stem cell factor cytokine (SCF) was intraperitoneally injected at the beginning of EAE onset.ResultsEAE mice developed profound bladder dysfunction characterized by significant urine retention, increased micturition and decreased urine output per micturition. EAE induced a significant decrease in c-Kit expression and ICCs number. EAE also induced a significant increase in pannexin 1 and connexin43. SCF treatment could ameliorate all of these pathological changes.ConclusionsICCs and stem cell factor play an important role in EAE-induced bladder dysfunction, which may be used as therapeutic options in treating patients with multiple sclerosis-related bladder dysfunction.

Effects of PGE2 EP3/EP4 receptors on bladder dysfunction in mice with experimental autoimmune encephalomyelitis

To investigate the expression of four subtypes of PGE2 E-prostanoid (EP) receptors (EP1-EP4) and the effects of EP3/EP4 on bladder dysfunction in a new neurogenic bladder model induced by experimental autoimmune encephalomyelitis (EAE), the mouse model of EAE was induced using a previously established method, and bladder function in mice with different defined levels of neurological impairment was then examined, including micturition frequencies and voiding weight. Bladders were then harvested for analysis of EP receptor expression by Western blot. Activities of agonists/antagonists of EP3 and EP4 receptors as well as PGE2 were also evaluated at different stages of EAE. The results showed that EAE mice developed profound bladder dysfunction characterized by significantly increased micturition and significantly decreased urine output per micturition. EAE-induced upregulation of EP3 and EP4 receptors in the bladder was accompanied by bladder dysfunction. However, EAE had no significant effect on EP1 and EP2 receptors. Moreover, PGE2 and agonists/antagonists of EP3 and EP4 receptors significantly affected bladder dysfunction in EAE mice. Thus, we believe that EAE mice are useful for investigations of the neurogenic bladder. In addition, EP3 and EP4 receptors play a role in EAE-induced bladder dysfunction, providing us with a new target for the treatment of neurogenic bladders.

Acetyl-CoA synthetase 2 enhances tumorigenesis and is indicative of a poor prognosis for patients with renal cell carcinoma

BACKGROUND Acetyl-CoA synthetase 2 (ACSS2) is highly expressed in various cancers, whereas ACSS2 expression and function in renal cell carcinoma (RCC) are unknown. METHODS We investigated ACSS2 expression in 198 human RCC tissues using immunohistochemistry, and analyzed its clinicopathological correlation and prognostic relevance. Overexpression and knockdown of ACSS2 were used to investigate the proliferation, migration and invasion of human RCC 786-O, 769-P, and ACHN cell lines. RESULTS High-ACSS2 expression was associated with advanced T stage (P = 0.008), advanced tumor-node-metastasis stage (P = 0.015) and high University of California, Los Angeles, Integrated Staging System score category (P = 0.009). Multivariate analysis identified high-ACSS2 expression as a poor prognostic factor for recurrence-free survival (hazard ratio [HR] = 1.83, P = 0.038) and overall survival (HR = 1.60, P = 0.043). Cell-based functional assays showed that ACSS2 knockdown inhibited RCC cell growth, migration, and invasion, whereas overexpression of ACSS2 enhanced these effects. ACSS2 silencing inhibited PI3K/AKT signaling pathway. CONCLUSION ACSS2 may increase tumor progression and aggressive behavior and be an independent prognostic factor in RCC.

Single-plane retroperitoneoscopic adrenalectomy: a new operative procedure for benign adrenal disease

To evaluate the therapeutic effect of single-plane retroperitoneoscopic adrenalectomy. From February 2014 to March 2017, 251 patients underwent single-plane retroperitoneoscopic adrenalectomy, and their operative outcomes were compared with those of 98 patients who underwent anatomical three-plane retroperitoneoscopic adrenalectomy. Among 35 patients with a body mass index (BMI) of ≥30 kg/m2, their operative outcomes were compared between two operative procedures. The demographic data and perioperative outcomes of the patients were statistically analysed. The single-plane and three-plane groups were comparable in terms of estimated blood loss, time to oral intake, hospital stay, and incidence of complications among patients with similar baseline demographics. The single-plane group had a significantly shorter operation time (46.9 ± 5.8 vs 54.8 ± 7.0 mins, P < 0.0001) and lower analgesia requirement (56/251 vs 33/98, p = 0.03). For obese patients with a BMI of ≥30 kg/m2, single-plane adrenalectomy was also associated with a significantly shorter operation time(48.1 ± 6.2 vs 64.1 ± 5.1 mins, p < 0.0001). Single-plane retroperitoneoscopic adrenalectomy is feasible, safe, and effective in the treatment of adrenal masses <5 cm in size and provides a shorter operation time and better pain control than anatomical retroperitoneal adrenalectomy, especially in obese patients.

Down-regulation of miR-210-3p encourages chemotherapy resistance of renal cell carcinoma via modulating ABCC1

BackgroundATP-binding cassette transporter super-family including ABCC1 and MDR-1 were involved in multi-drug resistance (MDR) of renal cell carcinoma (RCC) patients. Several miRNAs were confirmed to promote the MDR and the survival of tumor cells.MethodsThe RCC cell lines Caki-2 with vinblastine-resistant (Caki-2/VBL) or doxorubicin-resistant (Caki-2/DOX) were constructed, respectively. The expressions of miR-210-3p, ABCC1 and MDR-1 protein were determined by qRT-PCR and Western blot assays. The viability of RCC cells was assessed by MTT assay. The regulatory relationship between miR-210-3p and ABCC1 was analyzed by Dual Luciferase assay. The effect of miR-210-3p in vivo was investigated with a tumor xenograft model in mice.ResultsMiR-210-3p expression was observed to significantly decrease in Caki-2/VBL and Caki-2/DOX cells. Meanwhile, ABCC1 and MDR-1 were significantly increased in Caki-2/VBL and Caki-2/DOX cells. ABCC1 was a novel target of miR-210-3p and negatively regulated by miR-210-3p. And miR-210-3p improved drug-sensitivity of RCC cells. Down-regulation of ABCC1 could reverse the effect of miR-210-3p knockdown on the drug-resistance and the level of MDR-1 in drug-sensitive RCC cells.ConclusionWe confirmed that down-regulation of miR-210-3p increased ABCC1 expression, thereby enhancing the MRP-1-mediated multidrug resistance of RCC cells.