Green Tea Polyphenols Alleviate Kidney Injury Induced by Di(2-Ethylhexyl) Phthalate in Mice.

INTRODUCTION: Di(2-ethylhexyl) phthalate (DEHP) is a common plasticizer. Studies have revealed that DEHP exposure can cause kidney damage. Green tea is among the most popular beverages in China. Green tea polyphenols (GTPs) have been proven to have therapeutic effects on organ damage induced by heavy metal exposure. However, few studies have reported on GTP-relieving DEHP-induced kidney damage. METHODS: C57BL/6J male mice aged 6-8 weeks were treated with distilled water (control group), 1,500 mg/kg/d DEHP + corn oil (model group), 1,500 mg/kg/d DEHP + corn oil + 70 mg/kg GTP (treatment group), corn oil (oil group), and 70 mg/kg GTP (GTP group) by gavage for 8 weeks, respectively. The renal function of mice and renal tissue histopathology of each group were evaluated. The renal tissues of mice in the model, treatment, and control groups were analyzed using high-throughput sequencing. We calculated the differentially expressed microRNAs (miRNAs) and messenger RNAs (mRNAs) using the limma R package, the CIBERSORT algorithm was used to predict immune infiltration, the starBase database was used to screen the miRNA-mRNA regulatory axis, and immunohistochemical analyses were performed to verify protein expression. RESULTS: GTP alleviated the deterioration of renal function, renal inflammation and fibrosis, and mitochondrial and endoplasmic reticulum lesions induced by DEHP in mice. Differential immune infiltrations of plasma, dendritic, T, and B cells were noted between the model and treatment groups. We found that three differentially expressed miRNAs (mmu-miR-383-5p, mmu-miR-152-3p, and mmu-miR-144-3p), three differentially expressed mRNAs (Ddit4, Dusp1, and Snx18), and three differentially expressed proteins (Ddit4, Dusp1, and Snx18) played crucial roles in the miRNA-mRNA-protein regulatory axes when GTPs mitigate DEHP-induced kidney damage in mice. CONCLUSION: GTP can alleviate DEHP-induced kidney damage and regulate immune cell infiltration. We screened four important miRNA-mRNA-protein regulatory axes of GTP, mitigating DEHP-induced kidney damage in mice.

Integrated Network Pharmacology and Cellular Assay to Explore the Mechanisms of Selenized Tripterine Phytosomes (Se@Tri-PTs) Alleviating Podocyte Injury in Diabetic Nephropathy.

AIM: This work aimed to elucidate the mechanisms of Se@Tri-PTs in alleviating podocyte injury via network pharmacology and in vitro cellular assay. BACKGROUND: Selenized tripterine phytosomes (Se@Tri-PTs) have been confirmed to undertake synergistic and sensitized effects on inflammation, which may be curatively promising for diabetic nephropathy (DN). However, the mechanisms of Se@Tri-PTs in alleviating podocyte injury, a major contributor to DN, still remain unclear. OBJECTIVE: The objective of the study was to find out the underlying mechanisms of Se@Tri-PTs in alleviating podocyte injury in diabetic nephropathy. METHODS: The key components and targets of Tripterygium wilfordii (TW) significant for DN as well as the signaling pathways involved have been identified. A high glucose-induced podocyte injury model was established and verified by western blot. The protective concentration of Se@Tri-PTs was screened by CCK-8 assay. Podocytes cultured with high glucose were treated with Se@Tri-PTs under protective levels. The expression of key protective proteins, nephrin and desmin, in podocytes, was assayed by western blot. Further, autophagy- related proteins and factors, like NLRP3, Beclin-1, LC3II/LC3, P62, and SIRT1, were analyzed, which was followed by apoptosis detection. RESULTS: Network pharmacology revealed that several monomeric components of TW, especially Tri, act on DN through multiple targets and pathways, including the NLRP3-mediated inflammatory pathway. Se@Tri-PTs improved the viability of podocytes and alleviated their injury induced by high glucose at 5 µg/L or above. High-glucose induction promoted the expression of NLRP3 in podocytes, while a low concentration of Se@Tri-PTs suppressed the expression. A long-term exposure of high glucose significantly inhibited the autophagic activity of podocytes, as manifested by decreased Beclin-1 level, lower ratio of LC3 II/LC3 I, and up- regulation of P62. This abnormality was efficiently reversed by Se@Tri-PTs. Importantly, the expression of SIRT1 was up-regulated and podocyte apoptosis was reduced. CONCLUSION: Se@Tri-PTs can alleviate podocyte injury associated with DN by modulating NLRP3 expression through the pathway of SIRT1-mediated autophagy.

The Activation of cGAS-STING in Acute Kidney Injury.

The activation of the cGAS-STING pathway is associated with many sterile inflammatory and inflammatory conditions, including acute kidney injury. As a cytoplasmic DNA sensor, sensitization of the cGAS-STING pathway can ignite the innate immune response in vivo and trigger a series of biological effects. In recent years, there is increasing evidence showing that the cGAS-STING pathway plays a vital role in acute kidney injury, a non-inflammatory disease induced by activation of innate immune cells, and closely related to intracellular reactive oxygen species, mitochondrial DNA, and the cGAS-STING pathway. This review provides a prospect of the cGAS-STING pathway and its relationship to acute kidney injury.

Green tea polyphenols alleviate di-(2-ethylhexyl) phthalate-induced liver injury in mice.

BACKGROUND: Di (2-ethylhexyl) phthalate (DEHP) is a common plasticizer known to cause liver injury. Green tea is reported to exert therapeutic effects on heavy metal exposure-induced organ damage. However, limited studies have examined the therapeutic effects of green tea polyphenols (GTPs) on DEHP-induced liver damage. AIM: To evaluate the molecular mechanism underlying the therapeutic effects of GTPs on DEHP-induced liver damage. METHODS: C57BL/6J mice were divided into the following five groups: Control, model [DEHP (1500 mg/kg bodyweight)], treatment [DEHP (1500 mg/kg bodyweight) + GTP (70 mg/kg bodyweight), oil, and GTP (70 mg/kg bodyweight)] groups. After 8 wk, the liver function, blood lipid profile, and liver histopathology were examined. Differentially expressed micro RNAs (miRNAs) and mRNAs in the liver tissues were examined using high-throughput sequencing. Additionally, functional enrichment analysis and immune infiltration prediction were performed. The miRNA-mRNA regulatory axis was elucidated using the starBase database. Protein expression was evaluated using immunohistochemistry. RESULTS: GTPs alleviated DHEP-induced liver dysfunction, blood lipid dysregulation, fatty liver disease, liver fibrosis, and mitochondrial and endoplasmic reticulum lesions in mice. The infiltration of macrophages, mast cells, and natural killer cells varied between the model and treatment groups. mmu-miR-141-3p (a differentially expressed miRNA), Zcchc24 (a differentially expressed mRNA), and Zcchc24 (a differentially expressed protein) constituted the miRNA-mRNA-protein regulatory axis involved in mediating the therapeutic effects of GTPs on DEHP-induced liver damage in mice. CONCLUSION: This study demonstrated that GTPs mitigate DEHP-induced liver dysfunction, blood lipid dysregulation, fatty liver disease, and partial liver fibrosis, and regulate immune cell infiltration. Additionally, an important miRNA-mRNA-protein molecular regulatory axis involved in mediating the therapeutic effects of GTPs on DEHP-induced liver damage was elucidated.

miR-29c Inhibits Renal Interstitial Fibrotic Proliferative Properties through PI3K-AKT Pathway.

Renal fibrosis, in particular tubulointerstitial fibrosis, which is characterized by an increased extracellular matrix (ECM) formation and development in the interstitium, is the common end pathway for nearly all progressive kidney disorders. One of the sources for this matrix is the epithelial to mesenchymal transition (EMT) from the tabular epithelium. The driving force behind it is some profibrotic growth factors such as transforming growth factor-ß (TGF-ß) which is responsible for the formation of collagen in renal fibrosis. miR-29c, which is an antifibrotic microRNA, downregulates renal interstitial fibrosis by downregulating the TGF-ß and collagen. However, it is not known whether miR-29c mediates the TGF-ß1-driven PI3K-Akt pathway and Col-1 triggering within NRK-52E cultures. The main objective of this investigation was to examine the influence of miR-29c on the downregulation of the TGF-ß1-driven PI3K-Akt pathway and Col-1 triggering in NRK-52E cultures. This study revealed that miR-29c inhibited TGF-ß1 expression in NRK-52E cell cultures. Overexpression of miR-29c significantly inhibits NRK-52E culture proliferation mediated by TGF-ß1. miR-29c inhibited the expression of Col-1 and decreased PI3K/Akt phosphorylation. These findings revealed a novel mechanism by which miR29c inhibits the proliferation of renal interstitial fibrotic cultures by downregulating the PI3k-Akt pathway, which is controlled by TGF-ß1.

Effects of vitamin E and vitamin C on male infertility: a meta-analysis.

PURPOSE: The efficacy of the antioxidants vitamin E (VitE) and vitamin C (VitC) on male infertility is uncertain. Therefore, this research systematically assessed the influences of VitE and VitC on male infertility. METHODS: We did a meta-analysis of randomized controlled trials (RCTs) to analyze semen parameters, pregnancy rate, and adverse effects (AEs) between VitE and VitC groups and control groups by searching Cochrane Library, Excerpta Medica Database (Embase), PubMed, China Biology Medicine disc (CBMdisc), and Web of Science up to June 2020. RESULTS: We screened 11 studies (832 patients) that met the inclusion criteria. The evidence quality ranged from moderate to low. The pregnancy rate was obviously better in the VitE group than in the control group (relative risk (RR) 1.86, 95% confidence interval (CI) 1.02-3.41). Compared with the control group, VitE and VitC significantly improved progressive motility (standardized mean difference (SMD) 0.38, 95% CI 0.22-0.55), sperm concentration (SMD 0.21, 95% CI 0.09-0.34), sperm morphology (SMD 0.32, 95% CI 0.09-0.55), and total sperm number (SMD 0.28, 95% CI 0.12-0.43) without AEs. CONCLUSION: This study suggests that VitC and VitE can improve the spousal pregnancy rate and semen parameters in infertile men without AEs.

Effects of Lycium barbarum glycopeptide on renal and testicular injury induced by di(2-ethylhexyl) phthalate.

Di(2-ethylhexyl) phthalate (DEHP) is a common environmental pollutant with renal and reproductive toxicity. Lycium barbarum glycopeptide (LbGp) is the main active component of Lycium barbarum, which can protect the kidney and promote reproduction. Autophagy and apoptosis are the regulatory mechanisms of cell adaptation to external stress. This study investigated whether DEHP and LbGp affect kidney and testis by regulating autophagy and apoptosis. DEHP induced apoptosis in human embryonic kidney-293 (HEK-293) cells and human kidney-2 (HK-2) cells, as well as glomerular enlargement, enhanced renal autophagy and inflammation, decreased testicular germ cells, and enhanced testicular autophagy. LbGp reduced apoptosis in HEK-293 cells and HK-2 cells, reduced glomerular enlargement and renal inflammation, enhanced renal autophagy, increased testicular germ cells, and alleviated testicular autophagy. These results suggested that DEHP induced inflammation to cause kidney injury, mildly enhanced renal autophagy, and also induced excessive autophagy, leading to testicular injury. LbGp reduced inflammation and appropriately enhanced autophagy to alleviate renal injury and also reduced excessive autophagy to alleviate testicular injury. Silent information regulator 1 (SIRT1)/forkhead box O3a (FoxO3a)-mediated autophagy and p38 mitogen-activated protein kinase (p38 MAPK)-mediated inflammation played important roles.

An Efficient Signature Based on Necroptosis-Related Genes for Prognosis of Patients With Pancreatic Cancer.

Pancreatic cancer (PCa) is a highly lethal and aggressive disease, characterized by high mortality rates. Although necroptosis plays a vital role in tumor progression, cancer metastasis, prognosis of cancer patients, necroptosis-related gene (NRG) sets have rarely been analyzed in PCa. Therefore, definition of novel necroptosis-related prognostic markers for PCa patients is urgently needed. Here, we screened 159 NRGs and identified 132 differentially expressed NRGs in The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) cohorts. Next, we employed univariate and multivariate Cox proportional regression models to establish a prognostic-related NRG signature comprising five NRGs that could stratify patients into high-risk and low-risk groups. Results from survival analysis showed that patients in the high-risk had dramatically shorter overall survival (OS) rates compared with their low-risk counterparts. Results from univariate and multivariate Cox regression analysis further confirmed the independent prognostic value of the established necroptosis-related signature, and the area under receiver (AUC) of the operating curve (ROC) for 1-, 3-, 5-years was 0.72, 0.74, and 0.75, respectively. Finally, we validated the signature efficacy using an independent cohort from the Gene Expression Omnibus (GEO) database. The ROC curve confirmed the predictive capacity of the five-gene signature. Furthermore, we validated expression of the signature proteins using the Human Protein Atlas (HPA) database. In conclusion, we successfully constructed a novel necroptosis-related signature for prognosis of patients with pancreatic cancer.

Dipeptidyl peptidase-4 inhibitor and insulin combination treatment in type 2 diabetes and chronic kidney disease: A meta-analysis.

AIMS/INTRODUCTION: The union of dipeptidyl peptidase-4 inhibitors and insulin in patients with type 2 diabetes and chronic kidney disease provides satisfactory glucose management without increasing adverse events (AEs). This research appraised the therapeutic effect and safety of combination therapy in patients with type 2 diabetes and chronic kidney disease. MATERIALS AND METHODS: We carried out a meta-analysis of randomized controlled trials to analyze AEs, hypoglycemia, serious AEs, severe hypoglycemia, estimated glomerular filtration rate, fasting plasma glucose, glycated hemoglobin, insulin dose, low-density lipoprotein cholesterol, uric acid and weight between combination treatment groups and control groups by searching the Cochrane Library, Excerpta Medica Database (Embase), PubMed and Web of Science databanks until October 2020. RESULTS: Five studies (6 trials, 1,278 participants) met the inclusion criteria. The evidence quality ranged from moderate to high. Glycated hemoglobin (standardized mean difference -0.29, 95% confidence interval -0.44 to -0.14) and insulin dose (standardized mean difference -0.16, 95% confidence interval -0.29 to -0.02) were obviously smaller in the combination cure patients than in the control patients. Compared with the control groups, combination treatment did not increase AEs, hypoglycemia, serious AEs or severe hypoglycemia. CONCLUSIONS: This study showed the effectiveness and safety of dipeptidyl peptidase-4 inhibitors bonded with insulin in patients with type 2 diabetes and chronic kidney disease, but the protective actions of this cure on kidney and cardiovascular outcomes, as well as the functions of other dipeptidyl peptidase-4 inhibitors, need to be affirmed by more good-quality randomized controlled trials.

Selenium-deposited tripterine phytosomes ameliorate the antiarthritic efficacy of the phytomedicine via a synergistic sensitization.

Arthritis remains the notion of a hard-to-treat disease that raises an area of unmet clinical need. The phytomedicine tripterine (Tri) and trace element selenium (Se) have been shown to be of anti-inflammatory activity. This study was devoted to develop nanomedicine containing Tri and Se used for fighting against arthritis via a coordination mechanism. Se-deposited Tri phytosomes (Se@Tri-PTs) were prepared by a melting-hydration/in situ reduction technique and characterized by particle size, ζ potential, morphology, and entrapment efficiency (EE). The resultant Se@Tri-PTs were 126 nm around in particle size with an EE of 98.85%. Se@Tri-PTs exhibited a sustained drug release both in 0.1 M HCl and pH 6.8 PBS compared with Se-free phytosomes (Tri-PTs). The in vivo antiarthritic test demonstrated that Se@Tri-PTs could result in significant resolution of arthritis and decline of inflammatory factors. Phytosomes primely facilitated the transepithelial transport of Tri, while Se enhanced the antiarthritic efficacy of the phytomedicine synergistically. The present work provides a proof-of-concept for the combined therapy of arthritis using Tri and Se in the form of nanoparticles.

Lycium barbarum polysaccharide alleviates nonylphenol exposure induced testicular injury in juvenile zebrafish.

Nonylphenol is an endocrine disrupting chemicals that can disrupt the organisms' reproductive system, and exists widely in rivers and lakes. Lycium barbarum polysaccharide (LBP) is the main active constituent (about 10%) in Lycium barbarum, which is used to protect reproductive health. In this study, we investigated whether LBP can alleviate nonylphenol exposure induced testicular injury in juvenile zebrafish. We detected histological alteration, anti-oxidant enzyme profile and P450 gene transcription to assess LBP effect on testicular development. The GSI reduced significantly due to nonylphenol exposure, while LBP can improve the GSI. The densities of sperms increased and non-celluar zone decreased after LBP treatment. Meanwhile, Cyp11b gene was up regulated to NP group, and cyp19a gene was down regulated to NP group. In sum, the LBP could repair the testicular injury in zebrafish. This findings provide a basis research to remit the estrogen effect of artificial endocrine disruptor.

[Effects of total flavonoids in Drynaria fortunei on osteoblasts differentiation and the expression of ERK1/2 and p38 MAPK after treatment by high glucose in vitro].

OBJECTIVE: To observe the effects of Total Flavonoids in Drynaria fortunei (TFDF) on osteoblasts differentiation activity after treatment by high glucose and observe the effects on p38MAPK and ERK1/2 signaling protein in osteoblasts. METHODS: Primary osteoblasts of newborn SD rats was extracted and cultured and its biological characteristics was observed. MTT method was used to observe osteoblasts' cytotoxicity,and to choose a suitable concentration of TFDF in the culture medium. pNPP,ELISA,Alizarin dyeing were used to test ALP,Type I collagen,osteocalcin and mineralization of osteoblasts after treatment by different concentration of glucose respectively and after treatment by TFDF and high glucose. Western-blot was used to detect p38MAPK and ERK1/2 protein phosphorylation after treatment by TFDF and high glucose. RESULTS: Primary osteoblasts of newborn SD rats could be used well in this experiment. According to the toxicity of TFDF on OB, 25, 50, 100 mg/L of TFDF were selected for the experimental concentration gradient. ALP, Type I collagen,osteocalcin and mineralization of osteoblasts after treatment with glucose (25, 50 mmol/L) were less than those of control group respectively. TFDF could increase ALP, Type I collagen, osteocalcin activity and mineralization of osteoblasts in a dose-dependent manner after treatment by high glucose (25 mmol/L). TFDF(50 mg/L) could increase protein phosphorylation of p38MAPK and ERK1/2 of osteoblasts after treatment by high glucose (25 mmol/L). CONCLUSION: High glucose can decrease differentiation and mineralization of osteoblasts. TFDF can increase differentiation and mineralization of osteoblasts in a dose-dependent manner after treatment by high glucose. The role of TFDF in the promotion of osteoblasts differentiation is related to protein phosphorylation of p38MAPK and ERK1/2.

Improvement of lipid profile and reduction of body weight by shan he jian fei granules in high fat diet-induced obese rats.

BACKGROUND: The goal was to study lipid profiles (TG, TC, LDL, HDL), effects on serum leptin, and fat tissue adiponectin, and resistin as well as body weight effects of Shan He Jian Fei Granules (SHJFG) in rats on a high fat diet. METHODS: Rats were randomly divided into five groups: normal control group fed with normal fat diet, rats on high fat diet receiving low dosage, middle dosage, high dosage of Shan He Jian Fei Granules (SHJFG) as well as a high fat diet group receiving placebo. Rats were treated for 8 weeks. Body weight and naso-anal length of each rat were recorded and Lee's index was calculated. Serum TG, TC, LDL, HDL and leptin concentrations were analyzed. The gene expressions of adiponectin and resistin in adipose tissues were tested by RT-PCR. RESULTS: Compared to the high-fat diet group, body weights, Lee's indexes, weight of fat tissues and serum TG, TC, LDL and leptin of SHJFG groups significantly decreased (p < 0.05), whereas mRNA expressions of adiponectin and resistin of SHJFG groups significantly increased (p < 0.05). CONCLUSIONS: SHJFG could significantly lower body weight and serum TG, TC, and LDL of obese rats. The effects of SHJFG in lowering leptin synthesis and raising mRNA expression of adiponectin and resistin in fat tissues may act as part of the mechanisms in lowering body weight of obese rats. Further studies are needed to demonstrate whether SHJFG may also reduce overall cardiovascular morbidity and mortality like other lipid lowering drugs.

Preparation and development of equine hyperimmune globulin F(ab')2 against severe acute respiratory syndrome coronavirus.

AIM: The resurgence of severe acute respiratory syndrome (SARS) is still a threat because the causative agent remaining in animal reservoirs is not fully understood, and sporadic cases continue to be reported. Developing high titers of anti-SARS hyperimmune globulin to provide an alternative pathway for emergent future prevention and treatment of SARS. METHODS: SARS coronavirus (CoV)F69 (AY313906) and Z2-Y3 (AY394989) were isolated and identified from 2 different Cantonese onset SARS patients. Immunogen was prepared from SARS-CoV F69 strain. Six health horses were immunized 4 times and serum was collected periodically to measure the profile of specific IgG and neutralizing antibodies using indirect enzyme-linked immunosorbent assay and a microneutralization test. Sera were collected in large amounts at the peak, where IgG was precipitated using ammonium sulphate and subsequently digested with pepsin. The product was then purified using anion-exchange chromatography to obtain F(ab')2 fragments. RESULTS: The specific IgG and neutralizing antibody titers peaked at approximately week 7 after the first immunization, with a maximum value of 1:14210. The sera collected at the peak were then purified. Fragment of approximately 15 g F(ab')2 was obtained from 1litre antiserum and the purity was above 90% with the titer of 1:5120, which could neutralize the other strain (SARS-CoV Z2-Y3) as well. CONCLUSION: This research provides a viable strategy for the prevention and treatment of SARS coronavirus infection with equine hyperimmune globulin, with the purpose of combating any resurgence of SARS.

[Clinical observation of the therapeutic effect of valsartan for renal hypertension in 64 cases].

OBJECTIVE: To observe the therapeutic effects of valsartan on hypertension secondary to chronic renal diseases. METHODS: Sixty-four patients with renal hypertension were examined for plasma K(+), Na(+), Cl(-), 24-hour urine protein, blood urea nitrogen (BUN), serum creatinine (SCr), erythropoietin (EPO) before and 8 weeks after of valsartan therapy. RESULTS: After valsartan therapy for 8 weeks, no significant changes took place in plasma K(+), Na(+), Cl(-), BUN, SCr, EPO, but 24-hour urine protein was significantly reduced. CONCLUSION: Valsartan significantly reduce 24-hour urine protein without significantly affecting plasma K(+), Na(+), Cl(-), BUN, SCr, and EPO in patients with hypertension secondary to chronic renal diseases.