Emodin improves renal fibrosis in chronic kidney disease by regulating mitochondrial homeostasis through the mediation of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α).

Chronic kidney disease (CKD) is a leading public health issue associated with high morbidity worldwide. However, there are only a few effective therapeutic strategies for CKD. Emodin, an anthraquinone compound from rhubarb, can inhibit fibrosis in tissues and cells. Our study aims to investigate the antifibrotic effect of emodin and the underlying molecular mechanism. A unilateral ureteral obstruction (UUO)-induced rat model was established to evaluate the effect of emodin on renal fibrosis development. Hematoxylin and eosin staining, Masson's trichrome staining, and immunohistochemistry staining were performed to analyze histopathological changes and fibrotic features after emodin treatment. Subsequently, a transforming growth factor-beta 1 (TGF-ß1)-induced cell model was used to assess the inhibition of emodin on cell fibrosis in vitro. Furthermore, Western blot analysis and real-time quantitative reverse transcription-polymerase chain reaction were performed to validate the regulatory mechanism of emodin on renal fibrosis progression. As a result, emodin significantly improved histopathological abnormalities in rats with UUO. The expression of fibrosis biomarkers and mitochondrial biogenesis-related proteins also decreased after emodin treatment. Moreover, emodin blocked TGF-ß1-induced fibrotic phenotype, lipid accumulation, and mitochondrial homeostasis in NRK-52E cells. Conversely, peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α) silencing significantly reversed these features in emodin-treated cells. Collectively, emodin plays an important role in regulating PGC-1α-mediated mitochondria function and energy homeostasis. This indicates that emodin exhibits great inhibition against renal fibrosis and acts as a promising inhibitor of CKD.

Nomogram for the prediction of crescent formation in IgA nephropathy patients: a retrospective study.

BACKGROUND: The 2017 Oxford classification of immunoglobulin A nephropathy (IgAN) recently reported that crescents could predict a worse renal outcome. Early prediction of crescent formation can help physicians determine the appropriate intervention, and thus, improve the outcomes. Therefore, we aimed to establish a nomogram model for the prediction of crescent formation in IgA nephropathy patients. METHODS: We retrospectively analyzed 200 cases of biopsy-proven IgAN patients. Least absolute shrinkage and selection operator(LASSO) regression and multivariate logistic regression was applied to screen for influencing factors of crescent formation in IgAN patients. The performance of the proposed nomogram was evaluated based on Harrell's concordance index (C-index), calibration plot, and decision curve analysis. RESULTS: Multivariate logistic analysis showed that urinary protein ≥ 1 g (OR = 3.129, 95%CI = 1.454-6.732), urinary red blood cell (URBC) counts ≥ 30/ul (OR = 3.190, 95%CI = 1.590-6.402), mALBU ≥ 1500 mg/L(OR = 2.330, 95%CI = 1.008-5.386), eGFR < 60ml/min/1.73m2(OR = 2.295, 95%CI = 1.016-5.187), Serum IgA/C3 ratio ≥ 2.59 (OR = 2.505, 95%CI = 1.241-5.057), were independent risk factors for crescent formation. Incorporating these factors, our model achieved well-fitted calibration curves and a good C-index of 0.776 (95%CI [0.711-0.840]) in predicting crescent formation. CONCLUSIONS: Our nomogram showed good calibration and was effective in predicting crescent formation risk in IgAN patients.

Indoleamine 2, 3-dioxygenase 1 aggravates acetaminophen-induced acute liver failure by triggering excess nitroxidative stress and iron accumulation.

Acetaminophen (APAP) is the leading cause of acute liver failure (ALF), which is characterized by GSH depletion, oxidative stress and mitochondrial dysfunction. However, the specific mechanism of APAP-induced ALF remains to be clarified. In this study, we demonstrated that indoleamine 2,3-dioxygenase 1 (IDO1) aggravated APAP-induced ALF associated with excess lipid peroxidation, which was reversed by lipid peroxidation inhibitor (ferrostatin-1). Meanwhile, IDO1 deficiency effectively decreased the accumulation of reactive nitrogen species. Additionally, IDO1 deficiency prevented against APAP-induced liver injury through suppressing the activation of macrophages, thereby reduced their iron uptake and export, eventually reduced iron accumulation in hepatocytes through transferrin and transferrin receptor axis. In summary, our study confirmed that APAP-induced IDO1 aggravated ALF by triggering excess oxidative and nitrative stress and iron accumulation in liver. These results offer new insights for the clinical treatment of ALF or iron-dysregulated liver diseases in the future.

Ginsenoside Rb1 Alleviates Alcohol-Induced Liver Injury by Inhibiting Steatosis, Oxidative Stress, and Inflammation.

Alcoholic liver disease (ALD) has become a heavy burden on health worldwide. Ginsenoside Rb1 (GRb1), extracted from Panax quinquefolium L., has protective effects on many diseases, but the effect and mechanisms of GRb1 on ALD remain unknown. This study aimed to investigate the protective effects of GRb1 on ALD and to discover the potential mechanisms. Zebrafish larvae were exposed to 350 mM ethanol for 32 h to establish a model of acute alcoholic liver injury, and the larvae were then treated with 6.25, 12.5, or 25 µM GRb1 for 48 h. The human hepatocyte cell line was stimulated by 100 mM ethanol and meanwhile incubated with 6.25, 12.5, and 25 µM GRb1 for 24 h. The lipid changes were detected by Oil Red O staining, Nile Red staining, and triglyceride determination. The antioxidant capacity was assessed by fluorescent probes in vivo, and the expression levels of inflammatory cytokines were detected by immunohistochemistry, immunofluorescence, and quantitative real-time PCR. The results showed that GRb1 alleviated lipid deposition in hepatocytes at an optimal concentration of 12.5 µM in vivo. GRb1 reversed the reactive oxygen species accumulation caused by alcohol consumption and partially restored the level of glutathione. Furthermore, GRb1 ameliorated liver inflammation by inhibiting neutrophil infiltration in the liver parenchyma and downregulating the expression of nuclear factor-kappa B pathway-associated proinflammatory cytokines, including tumor necrosis factor-α and interleukin-1ß. This study revealed that GRb1 has a protective effect on alcohol-induced liver injury due to its resistance to lipid deposition as well as antioxidant and anti-inflammatory actions. These findings suggest that GRb1 may be a promising candidate against ALD.

Limonin Alleviates Non-alcoholic Fatty Liver Disease by Reducing Lipid Accumulation, Suppressing Inflammation and Oxidative Stress.

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and continues to rise in the worldwide. Limonin is a triterpenoid compound widely found in the fruits of citrus plants with a wide range of pharmacological effects, including anti-cancer, anti-inflammation, anti-viral, anti-oxidation and liver protection properties. However, the potential molecular mechanism of limonin on NAFLD in zebrafish remains unknown. In this study, zebrafish larvae were exposed to thioacetamide to establish an NAFLD model and the larvae were treated with limonin for 72 h simultaneously. The human liver cell line was stimulated with lipid mixture and meanwhile incubated with limonin for 24 h. The results showed that Limonin significantly reduced the accumulation of lipid droplets in the liver and down-regulated the levels of lipogenic transcription factors FASN and SREBP1 in NAFLD. Limonin suppressed macrophages infiltration and the down-regulated the relative expression levels of the pro-inflammatory factors IL-6, IL-1ß and TNF-α secreted by macrophages. Besides, limonin could reversed the reduction of glutathione and the accumulation of reactive oxygen species through up-regulating NRF2/HO-1 signaling pathway in the liver. In conclusion, this study revealed that limonin has a protective effect on NAFLD due to its resistance to lipid deposition as well as antioxidant and anti-inflammatory actions.

A Chinese and Western medication adherence scale in patients with Chronic Kidney Disease.

OBJECTIVE: The self-reported scale is a widely used method to assess patients' medication adherence in clinical practice, but there is still a lack of medicine adherence measurement scale for patients with Chronic Kidney Disease (CKD). Therefore, this study aimed to develop a medication adherence measurement scale of traditional Chinese medicine and Western medicine, providing a tool for evaluating medicine adherence of CKD patients. METHODS: In the preliminary stage, we formed the prediction scale after three rounds Delphi method and it was filled by 20 patients, who were selected randomly. After pre-investigation and language adaption, we adjusted the prediction measurement scale which included 31 items based on Knowledge-Attitude-Belief Theory. Then, 222 CKD patients in Guangdong Hospital of traditional Chinese Medicine were investigated by this 31-item scale. We screened 31 items by Items analysis theory, including critical ratio, item correlation analysis, internal consistency analysis, principal component analysis and other methods. The left 26 items made up a formal scale. We collected and analyzed data of the 26-item scale and Chinese version of MGL scale, and took their scores correlation analysis as the criterion validity of the 26-item scale. At the same time, we evaluated content validity, Cronbach alpha coefficient and retest reliability of the 26-item scale. RESULTS: We developed a scale with 26 items and 5 dimensions finally. In the validation analysis, the scale had good construct validity and content validity. The Pearson relation index between respective scores of the scale and Chinese version of MGL scale was 0.426, P<0.01. The scale also had good reliability as its 0.915 in Cronbach alpha, 0.753 in retest reliability and P<0.01. CONCLUSION: The scale revealed great reliability and validity, which could be used as a measurement tool to evaluate the medication adherence of patients with CKD.

Therapeutic effects and associated adverse events of multikinase inhibitors in metastatic renal cell carcinoma: A meta-analysis.

This study aimed to compare the therapeutic effects and adverse events of the multikinase inhibitors sorafenib, sunitinib, pazopanib and axitinib in advanced renal cell carcinoma (RCC). A meta-analysis of randomized controlled trials was performed to assess the effects of multikinase inhibitors among patients with advanced RCC. The data of median progression-free survival (PFS), median overall survival (OS), progressive disease rate (PDR), objective response rate (ORR) and grade 3/4 adverse events were extracted to assess therapeutic effects and toxicity, respectively. It was found that multikinase inhibitors are more effective in extending PFS [hazard ratio (HR)=0.58; 95% confidence interval (CI): 0.45-0.74; P<0.0001), controlling tumor progression [relative risk (RR)=0.67; 95% CI: 0.55-0.83; P=0.0002) and ORR (RR=2.93; 95% CI: 1.40-6.14; P=0.004) compared with placebo or interferon-α. Patients treated with multikinase inhibitors had significantly higher rates of grade 3 or 4 hypertension (RR=6.00; 95% CI: 3.36-10.69; P<0.00001), diarrhea (RR=5.84; 95% CI: 3.06-11.16; P<0.00001), nausea (RR=2.30; 95% CI: 1.16-4.54; P=0.02), vomiting (RR=1.84; 95% CI: 1.00-3.41; P=0.05) and hand-foot skin reaction (RR=11.78; 95% CI: 5.16-26.93; P<0.00001). Multikinase inhibitors can significantly control disease progress and improve the ORR. However, they are also associated with a higher risk of grade 3 and 4 hypertension and gastrointestinal events. Proper management of these events is necessary to improve patient quality of life.

High expression of heparanase-2 is an independent prognostic parameter for favorable survival in gastric cancer patients.

AIM: Heparanase-2 expression has been suggested to up-regulate in several types of human cancers. However, the expression patterns of heparanase-2 in gastric cancer and its effect on prognosis of gastric cancer patients are unclear. METHODS: In this study, the methods of tissue microarray, immunohistochemistry (IHC), and western blot were used to investigate heparanase-2 expression in gastric cancer and the adjacent non-cancerous tissues. Heparanase-2 expression was analyzed by immunohistochemistry in 95 clinicopathologically characterized gastric cancer cases. In addition Fisher's exact test, Kaplan-Meier plots and Cox proportional hazards regression model were used to analyze the results. RESULTS: High expression of cytoplasmic heparanase-2 was observed in 70.5% (67/95) of gastric cancer, when compared with its normal counterpart. Overexpression of heparanase-2 was correlated with tumor size and differentiation (P<0.05). Further analysis showed that a significant correlation between high expression of heparanase-2 and favorable prognosis (P<0.05). In multivariate analysis, high expression of heparanase-2 was evaluated as an independent prognostic factor in gastric cancer (P<0.05). CONCLUSIONS: Our data suggest for the first time that the high expression of heparanase-2 is associated significantly with tumor growth and differentiation. Importantly, heparanase-2 may be a potential molecular marker for predicting prognosis of gastric cancer.