Prevalence and molecular characteristics of ceftazidime-avibactam resistance among carbapenem-resistant Pseudomonas aeruginosa clinical isolates.

OBJECTIVES: Resistance against ceftazidime-avibactam (CZA) in carbapenem-resistant Pseudomonas aeruginosa (CRPA) is emerging. This study was aimed at detecting the prevalence and molecular characteristics of CZA-resistant CRPA clinical isolates in Guangdong Province, China. METHODS: The antimicrobial susceptibility profile of these strains was determined. A subset of 16 CZA-resistant CRPA isolates was analysed by whole-genome sequencing (WGS). Genetic surroundings of carbapenem resistance genes and pan-genome-wide association analysis were further studied. RESULTS: Of the 250 CRPA isolates, CZA resistance rate was 6.4% (16/250). The minimum inhibitory concentration (MIC) of CZA range was from 0.25 to >256 mg/L. MIC50 and MIC90 were 2/4 and 8/4 mg/L, respectively. Among the 16 CZA-resistant CRPA strains, 31.3% (5/16) of them carried class B carbapenem resistance genes, including blaIMP-4, blaIMP-45, and blaVIM-2, located on IncP-2 megaplasmids or chromosomes, respectively. Pan-genome-wide association analysis of accessory genes for CZA-susceptible or -resistant CRPA isolates showed that PA1874, a hypothetical protein containing BapA prefix-like domain, was enriched in CZA-resistant group significantly. CONCLUSIONS: Class B carbapenem resistance genes play important roles in CZA resistance. Meanwhile, the PA1874 gene may be a novel mechanism involving in CZA resistance. It is necessary to continually monitor CZA-resistant CRPA isolates.

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.

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.

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.

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.

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.

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.

A peptide that binds specifically to the ß-amyloid of Alzheimer's disease: selection and assessment of anti-ß-amyloid neurotoxic effects.

The accumulation of the amyloid-ß peptide (Aß) into amyloid plaques, an essential event in Alzheimer's disease (AD) pathogenesis, has caused researchers to seek compounds that physiologically bind Aß and modulate its aggregation and neurotoxicity. In order to develop new Aß-specific peptides for AD, a randomized 12-mer peptide library with Aß1₋10 as the target was used to identify peptides in the present study. After three rounds of selection, specific phages were screened, and their binding affinities to Aß1₋10 were found to be highly specific. Finally, a special peptide was synthesized according to the sequences of the selected phages. In addition, the effects of the special peptide on Aß aggregation and Aß-mediated neurotoxicity in vitro and in vivo were assessed. The results show that the special peptide not only inhibited the aggregation of Aß into plaques, but it also alleviated Aß-induced PC12 cell viability and apoptosis at appropriate concentrations as assessed by the cell counting kit-8 assay and propidium iodide staining. Moreover, the special peptide exhibited a protective effect against Aß-induced learning and memory deficits in rats, as determined by the Morris water maze task. In conclusion, we selected a peptide that specifically binds Aß1₋10 and can modulate Aß aggregation and Aß-induced neuronal damage. This opens up possibilities for the development of a novel therapeutic approach for the treatment of AD.