Bioactive peptide apelin rescues acute kidney injury by protecting the function of renal tubular mitochondria.

Mitochondrial dysfunction in proximal tubular epithelial cells is a key event in acute kidney injury (AKI), which is a risk factor for the development of chronic kidney disease (CKD). Apelin is a bioactive peptide that protects against AKI by alleviating inflammation, inhibiting apoptosis, and preventing lipid oxidation, but its role in protecting against mitochondrial damage remains unknown. Herein, we examined the protective effects of apelin on mitochondria in cisplatin-stimulated human renal proximal tubular epithelial cells and evaluated its therapeutic efficacy in cisplatin-induced AKI mice. In vitro, apelin inhibited the cisplatin-induced mitochondrial fission factor (MFF) upregulation and the fusion-promoting protein optic atrophy 1 (OPA1) downregulation. Apelin co-treatment reversed the decreased levels of the deacetylase, Sirt3, and the increased levels of protein acetylation in mitochondria of cisplatin-stimulated cells. Overall, apelin improved the mitochondrial morphology and membrane potential in vitro. In the AKI model, apelin administration significantly attenuated mitochondrial damage, as evidenced by longer mitochondrial profiles and increased ATP levels in the renal cortex. Suppression of MFF expression, and maintenance of Sirt3 and OPA1 expression in apelin-treated AKI mice was also observed. Finally, exogenous administration of apelin normalized the serum level of creatinine and urea nitrogen and the urine levels of NGAL and Kim-1. We also confirmed a regulatory pathway that drives mitochondrial homeostasis including PGC-1α, ERRα and Sirt3. In conclusion, we demonstrated that apelin ameliorates renal functions by protecting tubular mitochondria through Sirt3 upregulation, which is a novel protective mechanism of apelin in AKI. These results suggest that apelin has potential renoprotective effects and may be an effective agent for AKI treatment to significantly retard CKD progression.

The Value of Peripheral Blood Cell Ratios in Primary Membranous Nephropathy: A Single Center Retrospective Study.

Background: Primary membranous nephropathy (PMN) is a common cause of nephrotic syndrome in adults. Forty percent of the patients continue to progress and eventually develop into chronic renal failure. Although phospholipase A2 receptor (PLA2R) is the major antigen of PMN, the clinical features do not often parallel with the antibody titers. Therefore, it is significant to find relative credible markers to predict the treatment response. Methods: One hundred and eighteen PMN patients were recruited. The response to treatment was defined as ALB≥30g/L at 6 months and complete remission (CR) or not at the end of the follow-up. Renal outcome endpoint was defined as 50% or more Cr increase at the end. Results: The patients with poor treatment effects had numerically higher platelet-lymphocytes ratio (PLR). For patients with CR or not, the difference was near to statistic significant (P=0.095). When analyzing CR or not, the fitting of the binary logistic regression model including both PLA2R Ab titer and PLR (Hosmer-Lemeshow test: χ 2=8.328, P = 0.402; OR (PLA2R Ab titer) = 1.002 (95% CI 1.000-1.004, P = 0.042); OR (PLR) = 1.006 (95% CI 0.999-1.013, P = 0.098)) was markedly better than that with only PLA2R Ab titer (Hosmer-Lemeshow test: χ 2=13.885, P = 0.016). The patients with renal function deterioration showed significantly higher monocyte-lymphocyte ratio (MLR) (0.26 (0.22-0.31) vs 0.18 (0.13-0.22), P = 0.012). Conclusion: PMN patients with poor treatment response tended to have higher PLR at the time of renal biopsy, and a higher MLR was associated with poor renal outcomes. Our findings suggested that PLR and MLR might be used to predict treatment efficacy and prognosis for PMN patients, respectively.

Nirmatrelvir/ritonavir use in patients with COVID-19 on hemodialysis: a case series.

Patients undergoing hemodialysis (HD) are particularly vulnerable to coronavirus disease 2019 (COVID-19) and are at increased risk of developing severe infection. However, given the exclusion of such patients from clinical trials, there are limited data regarding the effectiveness of the antiviral drug nirmatrelvir/ritonavir (N/R) in patients on HD. We prescribed N/R to 4 patients on HD with COVID-19 after obtaining informed consent. Their clinical symptoms were improved at approximately 3 days after N/R administration. The viral load was reduced after approximately 10 days. The main adverse effects were nausea and vomiting. Rational dosage adjustment obtained good tolerance but did not influence the efficacy. These results suggest that N/R may be a promising agent for patients on HD with COVID-19.

Stanniocalcin 2 Is Upregulated by Calcium-Sensing Receptor and Protects Human Vascular Smooth Muscle Cells from High-Phosphate-Induced Apoptosis.

INTRODUCTION: Apoptosis of vascular smooth muscle cells induced by hyperphosphatemia is a critical mechanism of chronic kidney disease-related vascular disorders. The present study investigated whether extracellular calcium-sensing receptor (CaSR) regulates stanniocalcin 2 (STC2) expression in HAoSMCs and subsequently protects HAoSMCs from high-phosphate-induced apoptosis. METHODS: HAoSMCs were cultured, and STC2 expression was determined by qPCR. A calcimimetic (NPS R-568) or calcilytic (NPS-2143) was applied to HAoSMCs. STC2 mRNA and protein levels were measured by qPCR and Western blot, respectively, and confocal microscopy was employed to investigate subcellular localization. STC2 overexpression and silencing were induced to assess the effects of STC2 on high-phosphate-induced apoptosis, which was determined by caspase-3 levels and TUNEL staining. The anti-apoptotic effect of CaSR-induced STC2 was confirmed by interfering with STC2 expression in the presence of NPS R-568. RESULTS: The constitutive expression of STC2 was confirmed. STC2 mRNA and protein levels were increased by NPS R-568 with or without high phosphate. NPS-2143 resulted in decreased STC2 mRNA levels, but decreased STC2 protein levels were only found under the high-phosphate condition. Confocal microscopy demonstrated the colocalization of STC2 and plasma membrane or endoplasmic reticulum markers. STC2 overexpression reduced HAoSMCs apoptosis, which were reversed with STC2 silencing. NPS R-568 treatment reduced HAoSMCs apoptosis, but STC2 silencing abolished the protective effect. CONCLUSION: This is the first evidence that STC2 is regulated by CaSR in HAoSMCs. CaSR activation-induced STC2 has putative anti-apoptotic effects against high phosphate. Calcimimetics are promising agents to treat uremic vascular injury.

Clinical Efficacy Evaluation of 1-Year Subcutaneous Immunotherapy for Artemisia sieversiana Pollen Allergic Rhinitis by Serum Metabolomics.

Subcutaneous immunotherapy is the only treatment that improves the natural progression of allergic rhinitis and maintains long-term outcomes after discontinuation of the drug. Metabolomics is increasingly applied in the study of allergic diseases, including allergic rhinitis. However, little is known about the discovery of metabolites that can evaluate clinical efficacy and possible mechanisms of Artemisia sieversiana pollen subcutaneous immunotherapy. Thirty-three patients with Artemisia sieversiana pollen allergic rhinitis significantly improved after 1-year subcutaneous immunotherapy treatment, while ten patients were ineffective. Pre- and post-treatment serum samples from these patients were analyzed by metabolomics based on the combined detection of liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry. As a result, L-Tyrosine can be a potential biomarker because of its opposite trend in effective patients and ineffective patients. And mechanism of immunotherapy may be closely related to NO and nitric oxide synthase. The discovery of potential biomarkers and metabolic pathways has contributed to the in-depth study of mechanisms of subcutaneous immunotherapy treatment of Artemisia sieversiana pollen allergic rhinitis.

[Infiltration of CD(4)(+)CD(25)(+) T cells into the allergic asthmatic airways caused by house dust mite antigen administration.].

OBJECTIVE: To investigate whether house dust mite (HDM) could induce CD(4)(+) CD(25)(+) T cells infiltration into asthmatic airways in patients vivo. METHODS: Ten subjects with asthma underwent initial bronchoscopy during which normal saline and HDM were administered to two sublobar segments separately. The second bronchoscopy were carried out and bronchoal lavage fluid from HDM-challenged sites and saline-challenged sites were separately taken 24 h later. The differential cell counts were determined, and the absolute number of each type was calculated. At the same time, CD(3)(+), CD(4)(+) and CD(4)(+) CD(25)(+) T cells were determined by flow-cytometric analysis. We compared cellular counts in airways without and after topical instillation of HDM. RESULTS: Eosinophile granulocyte cells of broncho-alveolar fluid in the HDM-challenged sites (1.4 +/- 0.1) x 10(6)/ml are more than it in control sites (0.3 +/- 0.1) x 10(6)/ml, P < 0.003. Lymphocyte cells of BALF in the HDM-challenged sites (2.2 +/- 0.3) x 10(6)/ml are more than it in control sites (0.3 +/- 0.1) x 10(6)/ml, P < 0.001; CD(4)(+) CD(25)(+)T cells of BALF in the HDM-challenged sites (784.0 +/- 281.3) cell/microl are more than it in control sites (7.7 +/- 3.6) cell/microl, P < 0.001. CONCLUSIONS: Our findings suggest that HDM is capable of inducing CD(4)(+) CD(25)(+) T cells recruitment into non-acute mild allergic asthmatic airways.

Polymorphism of XRCC1 and the frequency of mutation in codon 249 of the p53 gene in hepatocellular carcinoma among Guangxi population, China.

In hepatocellular carcinoma (HCC), hotspot mutation in codon 249 of the p53 gene has been associated with exposure to aflatoxin B1 (AFB1). While the polymorphism of DNA repair gene X-ray repair cross-complementary group 1 (XRCC1) Arg399Gln may be related with AFB1-DNA adducts and gene mutations. Five hundred one HCCs were included in this study to investigate the role of the XRCC1 codon 399 polymorphism on hotspot mutation in codon 249 of the p53 gene. The genotypes of XRCC1 codon 399 and p53 codon 249 were examined by PCR-RFLP. The HCC patients with XRCC1 genotypes with 399 Gln (namely: XRCC1-AG/GG) exhibited a significantly higher frequency of the p53 hotspot mutations in codon 249 than those with the wild-type homozygote of XRCC1 [namely: XRCC1-AA, adjusted odds ratio (OR) = 6.77, 95% confidence interval (CI) = 4.34-10.57]. Compared with those individuals who did express XRCC1-AA as reference (OR = 1), moreover, individuals featuring XRCC1-AG/GG and AFB1-DNA adducts did experience a significantly greater frequency of the hotspot mutation in codon 249 of the p53 gene (adjusted OR = 28.37, 95% CI = 13.19-61.02, P < 0.01). This study suggests that the XRCC1 Arg399Gln polymorphism and AFB1-DNA adducts are associated with the increased frequency of the p53 mutations in codon 249.

Diagnostic and prognostic potential of serum microRNA-4651 for patients with hepatocellular carcinoma related to aflatoxin B1.

BACKGROUND: The serum microRNAs have been reported as potential biomarkers for hepatitis virus-related hepatocellular carcinoma (HCC); however, their role in aflatoxin B1 (AFB1)-related HCC to has not yet been evaluated. MATERIALS AND METHODS: We conducted a case-control study, including 366 HCC cases and 662 controls without any evidence of tumors, to identify and assess diagnostic and prognostic potential of serum microRNAs for AFB1-related HCC. The sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) were used to elucidate diagnostic performance, and to compare the microRNAs with α-fetoprotein (AFP) at a cutoff of 20 ng/mL (AFP20) and 400 ng/mL (AFP400). RESULTS: We found 8 differentially expressed microRNAs via the microRNA array analysis; however, only microRNA-4651 was further identified to detect AFB1-positive HCC but not AFB1-negative HCC. For AFB1-positive HCC, microRNA-4651 showed higher accuracy and sensitivity than AFP400 (AUC, 0.85 vs. 0.72; Sensitivity, 78.1% vs. 43.0%). Compared to AFP20, microRNA-4651 exhibited higher potential in identifying small-size (0.68 vs. 0.84 for AUC and 36.7% vs. 75.5% for sensitivity, respectively) and early-stage HCC (0.69 vs. 0.84 for AUC and 38.7% vs. 75.7% for sensitivity, respectively). Additionally, miR-4651 was also associated with HCC prognosis (hazard risk value, 2.67 for overall survival and 3.62 for tumor recurrence analysis). CONCLUSIONS: These data suggest that serum microRNA-4651 may be a useful marker for HCC diagnosis and prognosis, especially AFB1-positive cases.

XPC codon 939 polymorphism is associated with susceptibility to DNA damage induced by aflatoxin B1 exposure.

Aflatoxin B1 (AFB1), resulting in the formation of AFB1-DNA adducts, is a known human carcinogen. AFB1-exposure individuals with inherited susceptible carcinogen-repairing genotypes may experience an increased risk of genotoxicity. This study was aimed to investigate whether DNA repair gene xerodermapigmentosum complementation group C codon 939 polymorphism (rs2228001) affected the levels of AFB1-DNA adducts in Guangxi Population (n = 2558), from an AFB1-exposure area. AFB1-DNA adducts were measured by ELISA, and XPC codon 939 genotypes were identified by TaqMan-PCR. We found that longer AFB1-exposure years significantly increased XPC genotypes with codon 939 Gln alleles (namely, XPC-LG and -GG, odds ratios [95% confidence intervals] were 1.37 (1.15-1.63) and 1.99 (1.55-2.55), respectively) was significantly associated with higher levels of AFB1-DNA adducts. Furthermore, there was a positive joint effect between XPC genotypes and long-year AFB1 exposure in the formation of AFB1-DNA adducts. These results suggest that individuals with susceptible genotypes XPC-LG and -GG may experience an increased risk of DNA damage elicited by AFB1 exposure.

MicroRNA-429 Modulates Hepatocellular Carcinoma Prognosis and Tumorigenesis.

MicroRNA-429 (miR-429) may modify the development and progression of cancers; however, the role of this microRNA in the hepatocellular carcinoma (HCC) has not been well elaborated. Here, we tested miR-429 expression in 138 pathology-diagnosed HCC cases and SMMC-7721 cells. We found that miR-429 was upregulated in HCC tumor tissues and that the high expression of miR-429 was significantly correlated with larger tumor size (odd ratio (OR), 2.70; 95% confidence interval (CI), 1.28-5.56) and higher aflatoxin B1-DNA adducts (OR = 3.13, 95% CI = 1.47-6.67). Furthermore, this microRNA overexpression modified the recurrence-free survival and overall survival of HCC patients. Functionally, miR-429 overexpression progressed tumor cells proliferation and inhibited cell apoptosis. These results indicate for the first time that miR-429 may modify HCC prognosis and tumorigenesis and may be a potential tumor therapeutic target.