Leonuride protects diabetic nephropathy by activating SREBPs pathway.

Diabetic nephropathy (DN), a micro vascular complication of diabetes, is the main cause of end-stage renal disease, with a morbidity over 40% of diabetes. High glucose and lipid metabolism dysfunction are the leading cause of the development of DN. Previous study demonstrated that increased expression or activation of SREBPs in models of DN. Leonuride (LE), as an active constituent of Leonurus japonicus Houttuyn, has multiple biological activities, including antioxidant and anti-inflammatory effects. Previous studies showed that increasing the degradation of mature SREBPs is a robust way of lowering lipids and improve lipid metabolism dysfunction. However, effective regulation method of SREBPs degradation are still lacking. Herein, this study indicated that LE can effectively improve glucose and lipid metabolism disorders. In addition, the kidney function was also improved by inhibition of SREBPs activities in streptozocin (STZ)-induced type II diabetic mice. To our knowledge, this is the first time to describe the detailed mechanism of LE on the inhibition of precursor SREBPs, which would present a new direction for diabetic nephropathy treatment.

Correlations of Acute Cerebral Hemorrhage Complicated with Stress Ulcer Bleeding with Acute Physiology and Chronic Health Evaluation (APACHE) II Score, Endothelin (ET), Tumor Necrosis Factor-alpha (TNF-α), and Blood Lipids.

BACKGROUND This study investigated the correlations between acute cerebral hemorrhage complicated with stress ulcer bleeding and corresponding indexes, including the Acute Physiology and Chronic Health Evaluation (APACHE) II score, vascular endothelin-1 (ET-1), tumor necrosis factor-alpha (TNF-α), and blood lipid factors. MATERIAL AND METHODS A total of 53 patients with acute cerebral hemorrhage complicated with stress ulcer bleeding were selected as the observation group and 50 patients with simple acute cerebral hemorrhage were selected as the control group. The APACHE II score and the levels of ET-1, TNF-α, and blood lipid factors, including total cholesterol (TC), triglyceride (TG), high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), and malondialdehyde (MDA), were detected and the correlations of were analyzed between the 2 groups of patients. RESULTS The blood lipid index TG, APACHE II score, ET-1, TNF-a, renal function indexes [blood urea nitrogen (BUN) and creatinine (Cr)], mortality rate, hemoglobin, and MDA in the observation group were significantly higher than those in the control group, while HDL-C in the observation group was obviously lower than in the control group (p<0.05). The APACHEII score had positive correlations with TG and TNF-α (r=0.8960, r=0.8563, respectively), while it was negatively correlated with TC, HDL-C, LDL-C, and ET-1 (r=-0.909, r=-0.9292, r=-0.8543, and r=-0.8899, respectively) (p<0.001 in all comparisons). APACHEII score, BUN, and Cr were all risk factors. CONCLUSIONS Stress ulcer in patients with acute cerebral hemorrhage is associated with blood lipid changes and inflammation, which provides clues for the diagnosis and treatment of acute cerebral hemorrhage.

Identification of miRNA-mRNA Network Associated with Acute Myeloid Leukemia Survival.

BACKGROUND Acute myeloid leukemia (AML) is a common hematologic malignancy of adults. The pathophysiological mechanism of AML is not well understood. The purpose of this study was to examine the crucial miRNAs and mRNAs associated with AML survival. MATERIAL AND METHODS The full clinical dataset of miRNA and mRNA expression profiling of AML patients was downloaded from The Cancer Genome Atlas database. Univariate Cox regression analysis was performed to obtain those miRNAs and mRNAs associated with AML survival. A miRNA-mRNA interaction network was constructed. The underlying functions of mRNAs were predicted through Kyoto Encyclopedia of Genes and Genomes (KEEG) pathway enrichment. The expression levels of miRNAs and mRNAs were detected by quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS Fourteen miRNAs and 830 mRNAs associated with AML survival were identified. Of the 14 miRNAs, hsa-mir-425, hsa-mir-1201, and hsa-mir-1978 were identified as risk factors and the other 11 miRNAs were identified as protective factors of AML survival. For target-genes of miRNAs, GTSF1, RTN4R, and CD44 were the top risk factor target-genes associated with AML survival. An interaction network was constructed that including 607 miRNA-target gene pairs associated with AML survival. Target-genes associated with AML survival were significantly enriched in several pathways including pancreatic secretion, calcium signaling pathway, natural killer cell mediated cytotoxicity, and Alzheimer's disease. The qRT-PCR results were consistent with our bioinformatics analyses. CONCLUSIONS The miRNA hsa-mir-425 was identified as the top risk factor miRNA of AML survival and CD44 was identified as one of the top three risk factor target-genes associated with AML survival. Both hsa-mir-425 and CD44 may play key roles in progression and development of AML through calcium signaling pathway and natural killer cell mediated cytotoxicity.

MiR-150 Inhibits Cell Growth In Vitro and In Vivo by Restraining the RAB11A/WNT/ß-Catenin Pathway in Thyroid Cancer.

BACKGROUND Emerging evidence has shown that downregulation or upregulation of microRNAs (miRNAs) plays an important role in the development and progression of thyroid cancer (TC). However, the potential role of miR-150 and its biological function in TC remains largely unclear. MATERIAL AND METHODS Real-time polymerase chain reaction (RT-qPCR) was employed to detect the expression level of miR-150 and RAB11A in human TC tissue and human normal thyroid tissue. MTT assay, colony formation assay, flow cytometry cell cycle, and apoptosis assay were used to investigate the role of miR-150 and RAB11A on the malignant phenotypes in vitro. Nude mouse xenograft assay and western blot assay was used to verify the function of miR-150 in vivo. Western blot assay and immunofluorescence assay were used to detect the activation of WNT/ß-catenin pathway mediated by miR-150 and RAB11A. EGFP reporter assay, RT-qPCR assay, and western blot assay were used to validate the regulation relationship. RESULTS This study demonstrated that miR-150 expression in human TC tissues was markedly downregulated. Moreover, overexpression of miR-150 markedly inhibited cell proliferation via inducing the cell cycle arrest and promoting cell apoptosis by directly targeting RAB11A in vitro and suppressing tumor growth in vivo. However, overexpression of RAB11A promoted cell malignant phenotypes. In addition, miR-150 restrained the RAB11A mediated WNT/ß-catenin activation in TC cells. CONCLUSIONS miR-150 may function as a suppressor gene in TC cells by inhibiting the RAB11A/WNT/ß-catenin pathway.

LncRNA CASC15 promotes the proliferation of papillary thyroid carcinoma cells by regulating the miR-7151-5p/WNT7A axis.

Long noncoding RNAs (lncRNAs) play crucial roles in the regulation of human thyroid cancer (TC), including papillary thyroid carcinoma (PTC); PTC is the most common pathological subtype of TC. To date, the expression, function, and mechanism of the lncRNA CASC15 in PTC remain unclear. The present study results showed that CASC15 was overexpressed in PTC tissues compared with normal tissues and acted as a potent oncogene to promote the proliferation and tumorigenesis of PTC cells both in vitro and in vivo. Mechanistic studies demonstrated that CASC15 could serve as an endogenous miRNA sponge to absorb and downregulate miR-7151-5p, thereby preventing the inhibition of WNT7A during PTC progression. Furthermore, the study demonstrated that CASC15 activated the WNT/ß­catenin signaling pathway by upregulating WNT7A in PTC. Taken together, our findings identified CASC15 as a potential diagnostic marker or therapeutic target for PTC progression. DATA AVAILABILITY: Please contact the corresponding author for a data request.

Oxidative stress is important in the pathogenesis of stress-related mucosal disease.

Stress-related mucosal disease (SRMD) is a common complication in patients in the intensive care unit (ICU). The aim of the present study was to investigate the possible mechanisms for the pathogenesis of SRMD. In total, 38 patients with SRMD were enrolled from an ICU, as well as 15 healthy volunteers. The disease severity of patients in ICU was evaluated using the Acute Physiology and Chronic Health Evaluation (APACHE) II score. Gastric mucosa with the most severe lesions were biopsied for hematoxylin and eosin staining and then assessed by pathological damage scoring. The serum levels of malondialdehyde (MDA), superoxide dismutase (SOD) and ischemic modified albumin (IMA) were also detected. In addition, claudin-3 and inducible nitric oxide (NO) synthase (iNOS) in the gastric mucosa were assessed by western blotting and immunohistochemistry. The average APACHE II score of the patients with SRMD was significantly higher compared with the controls. Moreover, the levels of MDA (4.74±2.89 nmol/ml) and IMA (93.61±10.78 U/ml) in patients with SRMD were significantly higher compared with the controls (P<0.001), while those of SOD (89.66±12.85 U/ml) in the patients with SRMD were significantly lower compared with the controls (P<0.001). Furthermore, compared with the control, iNOS expression was significantly higher (P=0.034), while the expression of claudin-3 was significantly lower in patients with SRMD (P<0.001). The results indicated that APACHE II score was positively correlated with pathological damage score (r=0.639, P<0.001) and levels of MDA (r=0.743, P<0.001), but negatively correlated with the level of SOD (r=-0.392, P=0.015). In addition, MDA was positively correlated with IMA (r=0.380, P=0.018), but negatively correlated with claudin-3 (r=-0.377, P=0.020). Therefore, it was speculated that oxidative stress may play an important role in the pathogenesis of SRMD, and NO levels and cell membrane permeability are altered during this process.

An experimental study of exenatide effects on renal injury in diabetic rats1.

PURPOSE: To investigate the effects of exenatide on renal injury in streptozotocin-induced diabetic rats. METHODS: Fifty SD rats were randomly divided into normal control, model, exenatide-1, exenatide-2 and exenatide-3 groups, 10 rats in each group. The diabetic nephropathy model was constructed in later 4 groups. Then, the later 3 groups were treated with 2, 4 and 8 µg/kg exenatide for 8 weeks, respectively. The serum and urine biochemical indexes and oxidative stress and inflammatory indexes in renal tissue were determined. RESULTS: Compared to the model group, in exenatide-3 group the serum fasting plasma glucose and hemoglobin A1c levels were significantly decreased, the fasting insulin level was significantly increased, the renal index and blood urea nitrogen, serum creatinine and 24 h urine protein levels were significantly decreased, the renal tissue superoxide dismutase and glutathione peroxidase levels were significantly increased, the malondialdehyde level was significantly decreased, and the renal tissue tumor necrosis factor alpha, interleukin 6, hypersensitive C-reactive protein and chemokine (C-C motif) ligand 5 levels were significantly decreased P<0.05). CONCLUSIONS: Exenatide can mitigate the renal injury in diabetic rats. The mechanisms may be related to its resistance of oxidative stress and inflammatory response in renal tissue.

Efficacy and safety of tacrolimus-based treatment for nephrotic idiopathic membranous nephropathy in young adults: A retrospective study.

In China, the prevalence of idiopathic membranous nephropathy (IMN) is increasing with a younger age of onset. From January 2012 to October 2018, biopsy-proven nephrotic IMN patients aged between 15 and 40 in Taian City Central Hospital treated with tacrolimus (TAC) were retrospectively analyzed. Twelve-month follow-up data were collected. A total of 86 patients were enrolled in this study. Forty patients in the TAC group received TAC monotherapy with an initial dose of 0.05 to 0.1 mg/kg/day. Forty-six patients in the TAC + Pred group received TAC combined with oral prednisone (0.5 mg/kg/day initially). Remission rate, relapse rate, and adverse events in the two groups were assessed. Total remission (TR) rates at the end of the 3rd, 6th, and 12th month were 15%, 35%, and 77.5% (TAC group) and 28.3%, 56.5%, and 80.4% (TAC + Pred group), respectively. Compared with the TAC group, the TAC + Pred group had higher complete remission rates at the end of the 6th and 12th month, and TR rate at the 6th month was significantly higher. Twenty-four-hour urinary protein excretion, serum albumin and estimated glomerular filtration rate between the two groups were comparable during the follow-up. Decrease in proteinuria was significantly greater in the TAC + Pred group. No significant difference of relapse rate was found between the two groups. Adverse effects in the two groups were mild and controllable. Both TAC monotherapy and TAC combined with medium-dose prednisone are effective and safe for young adults with nephrotic IMN, while TAC + Pred regimen brings more benefits.

An experimental study of exenatide effects on renal injury in diabetic rats

Abstract Purpose: To investigate the effects of exenatide on renal injury in streptozotocin-induced diabetic rats. Methods: Fifty SD rats were randomly divided into normal control, model, exenatide-1, exenatide-2 and exenatide-3 groups, 10 rats in each group. The diabetic nephropathy model was constructed in later 4 groups. Then, the later 3 groups were treated with 2, 4 and 8 μg/kg exenatide for 8 weeks, respectively. The serum and urine biochemical indexes and oxidative stress and inflammatory indexes in renal tissue were determined. Results: Compared to the model group, in exenatide-3 group the serum fasting plasma glucose and hemoglobin A1c levels were significantly decreased, the fasting insulin level was significantly increased, the renal index and blood urea nitrogen, serum creatinine and 24 h urine protein levels were significantly decreased, the renal tissue superoxide dismutase and glutathione peroxidase levels were significantly increased, the malondialdehyde level was significantly decreased, and the renal tissue tumor necrosis factor alpha, interleukin 6, hypersensitive C-reactive protein and chemokine (C-C motif) ligand 5 levels were significantly decreased P<0.05). Conclusions: Exenatide can mitigate the renal injury in diabetic rats. The mechanisms may be related to its resistance of oxidative stress and inflammatory response in renal tissue.