Renal cell carcinoma in an adult-onset ESRD patient with nephronophthisis harboring NPHP3 deletion: A case report.

Background: Nephronophthisis (NPHP) is a rare autosomal recessive inherited tubulointerstitial nephropathy, the most prevalent genetic cause of end-stage renal disease (ESRD) in children. Convincing evidence indicated that the overall prevalence of NPHP in adult-onset ESRD is very likely to be an underestimation. Therefore, understanding the genetic background and clinicopathologic features of adult-onset NPHP is warranted. Case presentation: we reported one intriguing case with concurrent NPHP3 c.2694-2_2694-1delAG (splicing) variant and c.1082C > G (p.S361C) variant. A 48-year-old male was admitted to our hospital, complained about renal dysfunction for 10 years, and found right renal space-occupying lesion for 1 week. One of the most interesting clinical features is adult-onset ESRD, which differs from previous cases. Another discovery of this study is that the NPHP harboring NPHP3 deletion may be associated with clear cell renal cell carcinoma. Conclusion: In conclusion, we report two mutations in the NPHP3 gene that cause NPHP with adult-onset ESRD and renal clear cell carcinoma in a Chinese family, enriching the clinical features of NPHP.

The functional role of cellular senescence during vascular calcification in chronic kidney disease.

Vascular calcification (VC) has emerged as a key predictor of cardiovascular events in patients with chronic kidney disease (CKD). In recent years, an expanding body of research has put forth the concept of accelerated vascular aging among CKD patients, highlighting the significance of vascular cells senescence in the process of VC. Within the milieu of uremia, senescent vascular endothelial cells (VECs) release extracellular microvesicles (MV) that promote vascular smooth muscle cells (VSMCs) senescence, thereby triggering the subsequent osteogenic phenotypic switch and ultimately contributing to the VC process. In addition, senescent vascular progenitor or stem cells with diminished ability to differentiate into VECs and VSMCS, compromise the repair of vascular integrity, on the other hand, release a cascade of molecules associated with senescence, collectively known as the senescence-associated secretory phenotype (SASP), perpetuating the senescence phenomenon. Furthermore, SASP triggers the recruitment of monocytes and macrophages, as well as adjacent VECs and VSMCs into a pro-adhesive and pro-inflammatory senescent state. This pro-inflammatory microenvironment niche not only impacts the functionality of immune cells but also influences the differentiation of myeloid immune cells, thereby amplifying the reduced ability to effectively clear senescent cells of senescent macrophages, promoted calcification of VSMCs. The objective of this paper is to provide a comprehensive review of the contribution of vascular cell senescence to the emergence and advancement of VC. Gaining a comprehensive understanding of the involvement of cellular senescence within the vessel wall is pivotal, especially when it comes to its intersection with VC. This knowledge is essential for advancing groundbreaking anti-aging therapies, aiming to effectively mitigate cardiovascular diseases.

Measurement of urinary exosomal phospholipase A2 receptor is a sensitive method for diagnosis of PLA2R-associated membranous nephropathy.

Background: The discovery of phospholipase A2 receptor (PLA2R) and its antibody (aPLA2Rab) has paved the way for diagnosing PLA2R-associated membranous nephropathy (PLA2R-MN) with a high specificity of 98%. However, the sensitivity was only 40% to 83.9%, and there is ongoing discussion around determining the optimal threshold for diagnosis. Recent advancements in the use of exosomes, a novel form of "liquid biopsy," have shown great promise in identifying markers for various medical conditions. Methods: Protein mass spectrometry and western blot were applied to verify the existence of PLA2R antigen in the urine exosome. We then evaluated the efficacy of urinary exosomal PLA2R antigen alone or combined with serum aPLA2Rab level to diagnose PLA2R-MN. Results: The urinary exosomes contained a high abundance of PLA2R antigen as evidenced by protein mass spectrometry and western blot in 85 PLA2R-MN patients vs the disease controls (14 secondary MN patients, 22 non-MN patients and 4 PLA2R-negative MN patients) and 20 healthy controls. Of note, urinary exosomal PLA2R antigen abundance also had a good consistency with the PLA2R antigen level in the renal specimens of PLA2R-MN patients. The sensitivity of urinary exosomal PLA2R for diagnosing PLA2R-MN reached 95.4%, whereas the specificity was 63.3%. Combining detection of the urinary exosomal PLA2R and serum aPLA2Rab could develop a more sensitive diagnostic method for PLA2R-MN, especially for patients with serum aPLA2Rab ranging from 2 to 20 RU/mL. Conclusions: Measurement of urinary exosomal PLA2R could be a sensitive method for the diagnosis of PLA2R-MN.

Multiple test procedures of disease prevalence based on stratified partially validated series in the presence of a gold standard.

This paper discusses the problem of disease prevalence in clinical studies, focusing on multiple comparisons based on stratified partially validated series in the presence of a gold standard. Five test statistics, including two Wald-type test statistics, the inverse hyperbolic tangent transformation test statistic, likelihood ratio test statistic, and score test statistic, are proposed to conduct multiple comparisons. To control the overall type I error rate, several adjustment procedures are developed, namely the Bonferroni, Single-step adjusted MaxT, Single-step adjusted MinP, Holm's Step-down, and Hochberg's step-up procedures, based on these test statistics. The performance of the proposed methods is evaluated through simulation studies in terms of the empirical type I error rate and empirical power. Simulation results show that the Single-step adjusted MaxT procedure and Single-step adjusted MinP procedure generally outperform the other three procedures, and these two test procedures based on all test statistics have satisfactory performance. Notably, the Single-step adjusted MinP procedure tends to exhibit higher empirical power than the Single-step adjusted MaxT procedure. Furthermore, the Step-down and Step-up procedures show greater power compared to the Bonferroni method. The study also observes that as the validated ratio increases, the empirical type I errors of all test procedures approach the nominal level while maintaining higher power. Two real examples are presented to illustrate the proposed methods.

Computed tomography-determined skeletal muscle density predicts 3-year mortality in initial-dialysis patients in China.

BACKGROUND: Skeletal muscle mass and quality assessed by computed tomography (CT) images of the third lumbar vertebra (L3) level have been established as risk factors for poor clinical outcomes in several illnesses, but the relevance for dialysis patients is unclear. A few studies have suggested a correlation between CT-determined skeletal muscle mass and quality at the first lumbar vertebra (L1) level and adverse outcomes. Generally, chest CT does not reach beyond L1. We aimed to determine whether opportunistic CT scan (chest CT)-determined skeletal muscle mass and quality at L1 are associated with mortality in initial-dialysis patients. METHODS: This 3-year multicentric retrospective study included initial-dialysis patients from four centres between 2014 and 2017 in China. Unenhanced CT images of the L1 and L3 levels were obtained to assess skeletal muscle mass [by skeletal muscle index, (SMI), cm2 /m2 ] and quality [by skeletal muscle density (SMD), HU]. Skeletal muscle measures at L1 were compared with those at L3. The sex-specific optimal cutoff values of L1 SMI and L1 SMD were determined in relation to all-cause mortality. The outcomes were all-cause death and cardiac death. Cox regression models were applied to investigate the risk factors for death. RESULTS: A total of 485 patients were enrolled, of whom 257 had both L1 and L3 images. Pearson's correlation coefficient between L1 and L3 SMI was 0.84 (P < 0.001), and that between L1 and L3 SMD was 0.90 (P < 0.001). No significant association between L1 SMI and mortality was observed (P > 0.05). Low L1 SMD (n = 280, 57.73%) was diagnosed based on the optimal cutoff value (<39.56 HU for males and <33.06 HU for females). Multivariate regression analysis revealed that the low L1 SMD group had higher risks of all-cause death (hazard ratio 1.80; 95% confidence interval 1.05-3.11, P = 0.034) and cardiac death (hazard ratio 3.74; 95% confidence interval 1.43-9.79, P = 0.007). CONCLUSIONS: In initial-dialysis patients, there is high agreement between the L1 and L3 measures for SMI and SMD. Low SMD measured at L1, but not low SMI, is an independent predictor of both all-cause death and cardiac death.

Genomic Evidence for the Nonpathogenic State in HIV-1-Infected Northern Pig-Tailed Macaques.

HIV-1 is a highly host-specific retrovirus that infects humans but not most nonhuman primates. Thus, the lack of a suitable primate model that can be directly infected with HIV-1 hinders HIV-1/AIDS research. In the previous study, we have found that the northern pig-tailed macaques (NPMs) are susceptible to HIV-1 infection but show a nonpathogenic state. In this study, to understand this macaque-HIV-1 interaction, we assembled a de novo genome and longitudinal transcriptome for this species during the course of HIV-1 infection. Using comparative genomic analysis, a positively selected gene, Toll-like receptor 8, was identified with a weak ability to induce an inflammatory response in this macaque. In addition, an interferon-stimulated gene, interferon alpha inducible protein 27, was upregulated in acute HIV-1 infection and acquired an enhanced ability to inhibit HIV-1 replication compared with its human ortholog. These findings coincide with the observation of persistently downregulated immune activation and low viral replication and can partially explain the AIDS-free state in this macaque following HIV-1 infection. This study identified a number of unexplored host genes that may hamper HIV-1 replication and pathogenicity in NPMs and provided new insights into the host defense mechanisms in cross-species infection of HIV-1. This work will facilitate the adoption of NPM as a feasible animal model for HIV-1/AIDS research.

Ultrasound-assessed diaphragm dysfunction predicts clinical outcomes in hemodialysis patients.

Skeletal muscle atrophy is prevalent and remarkably increases the risk of cardiovascular (CV) events and mortality in hemodialysis (HD) patients. However, whether diaphragm dysfunction predicts clinical outcomes in HD patients is unknown. This was a prospective cohort study of 103 HD patients. After assessment of diaphragm function by ultrasonography and collection of other baseline data, a 36-month follow-up was then initiated. Participants were divided into diaphragm dysfunction (DD+) group and normal diaphragm function (DD-) group, according to cutoff value of thickening ratio (i.e. the change ratio of diaphragm thickness) at force respiration. The primary endpoint was the first nonfatal CV event or all-cause mortality. A secondary endpoint was less serious CV events (LSCEs, a composite of heart failure readmission, cardiac arrhythmia or myocardial ischemia needed pharmacological intervention in hospital). 98 patients were eligible to analysis and 57 (58.16%) were men. 28 of 44 patients(63.64%) in DD+ group and 23 of 54 patients (42.59%) in DD- group had at least one nonfatal CV event or death (p = 0.038). Compared to DD- group, DD+ group had significantly higher incidence of LSCEs (21 vs.14, p = 0.025) and shorter survival time (22.02 ± 12.98 months vs. 26.74 ± 12.59 months, p = 0.046). Kaplan-Meier analysis revealed significantly higher risks of primary endpoint (p = 0.039), and LSCEs (p = 0.040) in DD+ group. Multivariate hazard analysis showed that DD+ group had significantly higher risk of primary endpoint [hazard ratio (HR) 1.59; 95% confident interval (CI) 1.54-1.63], and LSCEs (HR 1.47; 95%CI 1.40-1.55). Ultrasound-assessed diaphragm dysfunction predicts clinical outcomes in HD patients.Trial registration: This study was registered with Chinese Clinical Trials Registry ( www.chictr.org.cn ) as ChiCTR1800016500 on Jun 05, 2018.

Effects of Sacubitril/Valsartan on resistant hypertension and myocardial work in hemodialysis patients.

Growing evidences have confirmed the effect of Sacubitril/Valsartan (SV) on antihypertension and cardiac protection in general population. However, there was no prospective study about the effect and safety of SV on resistant hypertension and myocardial work in hemodialysis patients. In this single-center, prospective, before-after study, enrolled patients were endured with resistant hypertension for more than 6 months. Participants were initially instructed to take SV 50 mg twice daily, and the dosage was gradually increased up to 100 mg twice daily. The primary outcomes were blood pressure (BP) control, N-terminal pro-B-type natriuretic peptide (NT-proBNP), myocardial work (MW), fatigue and life quality. In addition, the adverse events were also recorded in this cohort. A total of 18 patients (34-64 years old) was finally enrolled and completed in this study. The SV-based regimen provided significantly mean sitting systolic BP (msSBP) and mean sitting diastolic BP (msDBP) reductions from baseline (-20.7/-8.3 mm Hg), respectively. The cardiac remodeling parameters were partially improved. Compared to the baseline, NT-proBNP was significantly reduced at week 4 (8119.50 [3710.75, 29300] pg/ml to 7216.50 [4124.75, 17455.00] pg/ml, p = .046), which was much lower at week 12 (3130.50 [2244.50, 9565.70] pg/ml, p = .037). Global MW index was higher at week 12 compared to the baseline (p = .026). MW efficiency was also improved accordingly compared to the baseline, even though the statistical difference was not significant (p = .226). Life quality and fatigue were improved at week 12 compared to the baseline (all p = .000). There was no serious adverse events were observed. SV safely and effectively controlled resistant hypertension and improved MW as well as life quality in hemodialysis patients.

Combination of a Novel Genetic Variant in CFB Gene and a Pathogenic Variant in COL4A5 Gene in a Sibling Renal Disease: A Case Report.

Complement factor B (CFB) variants have been described to play a causative role in auto-immune associated C3 glomerulopathy (C3G) and/or atypical hemolytic uremic syndrome (aHUS) by affecting the dysregulations of alternative pathway activation. However, CFB variant concomitant with COL4A5 variant is scarce. Here, we depict two intriguing cases with concurrent novel heterozygosity for CFB c.2054_2057del (p.Ser687Profs∗16) variant and a previous reported COL4A5 c.2999G > T (p.Gly1000Val) variant in a pair of siblings. The clinical feature of either paternal CFB variant or maternal COL4A5 variant is just mild microscopic hematuria. Interestingly, their two children with paternal CFB c.2054_2057del (p.Ser687Profs∗16) variant and maternal COL4A5 c.2999G > T (p.Gly1000Val) variant presented with massive proteinuria, hematuria, and progressive renal failure with poor treatment response. Moreover, complement pathway activation in renal tissue further supports and strengthens the pathogenic role of CFB variant in the development of renal injury in the presence of COL4A5 variant. In conclusion, the rare sibling cases highlight that the extension of genetic analyses in the proband is helpful for the diagnosis and understanding of some family cluster renal diseases.

An Alu Element Insertion in Intron 1 Results in Aberrant Alternative Splicing of APOBEC3G Pre-mRNA in Northern Pig-Tailed Macaques (Macaca leonina) That May Reduce APOBEC3G-Mediated Hypermutation Pressure on HIV-1.

APOBEC3 family members, particularly APOBEC3F and APOBEC3G, inhibit the replication and spread of various retroviruses by inducing hypermutation in newly synthesized viral DNA. Viral hypermutation by APOBEC3 is associated with viral evolution, viral transmission, and disease progression. In recent years, increasing attention has been paid to targeting APOBEC3G for AIDS therapy. Thus, a controllable model system using species such as macaques, which provide a relatively ideal in vivo system, is needed for the study of APOBEC3-related issues. To appropriately utilize this animal model for biomedical research, important differences between human and macaque APOBEC3s must be considered. In this study, we found that the ratio of APOBEC3G-mediated/APOBEC3-mediated HIV-1 hypermutation footprints was much lower in peripheral blood mononuclear cells (PBMCs) from northern pig-tailed macaques than in PBMCs from humans. Next, we identified a novel and conserved APOBEC3G pre-mRNA alternative splicing pattern in macaques, which differed from that in humans and resulted from an Alu element insertion into macaque APOBEC3G gene intron 1. This alternative splicing pattern generating an aberrant APOBEC3G mRNA isoform may significantly dilute full-length APOBEC3G and reduce APOBEC3G-mediated hypermutation pressure on HIV-1 in northern pig-tailed macaques, which was supported by the elimination of other possibilities accounting for this hypermutation difference between the two hosts.IMPORTANCE APOBEC3 family members, particularly APOBEC3F and APOBEC3G, are important cellular antiviral factors. Recently, more attention has been paid to targeting APOBEC3G for AIDS therapy. To appropriately utilize macaque animal models for the study of APOBEC3-related issues, it is important that the differences between human and macaque APOBEC3s are clarified. In this study, we identified a novel and conserved APOBEC3G pre-mRNA alternative splicing pattern in macaques, which differed from that in humans and which may reduce the APOBEC3G-mediated hypermutation pressure on HIV-1 in northern pig-tailed macaques (NPMs). Our work provides important information for the proper application of macaque animal models for APOBEC3-related issues in AIDS research and a better understanding of the biological functions of APOBEC3 proteins.

Facile synthesis of graphene oxide/palygorskite composites for Pb(II) rapid removal from aqueous solutions.

As a kind of earth-abundant and cheap natural clay mineral, palygorskite (Pal) was facilely modified by grafting with graphene oxide (GO) to fabricate GO/Pal composites for rapid removal of Pb(II) from aqueous solutions. The results of characterization confirmed that the GO/Pal composites were successfully grafted between GO sheets and Pal nanorods. The effects of pH, adsorbent dosage, adsorption time, initial Pb(II) concentration and temperature on the adsorption of Pb(II) onto the GO/Pal composites as adsorbents were systematically investigated. The maximum adsorption capacity over 106.6 mg/g was obtained within a short adsorption time of less than 1 h even at 298.15 K. The adsorption of Pb(II) was a fast process that more accurately followed the pseudo-second-order kinetic equation. This process also could be described better with the Langmuir equation model than the Freundlich model. The negative values of ΔG° and the positive values of ΔH° and ΔS° indicated that it was a spontaneous, endothermic and entropy-increasing adsorption process. Compared with pristine Pal and GO powders, such the GO/Pal composites as a cost-efficient and eco-friendly adsorbents could significantly improve the adsorption properties of Pb(II) and would have potential application in the industrial wastewater treatment for rapid removal of Pb(II).

Cinacalcet attenuated bone loss via inhibiting parathyroid hormone-induced endothelial-to-adipocyte transition in chronic kidney disease rats.

BACKGROUND: Recently, cinacalcet (CINA) has been shown to be effective for attenuating bone loss in the treatment of secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD), which might be associated with the reduction in serum parathyroid hormone (PTH) levels. However, the exact mechanism is largely unclear. Emerging studies have revealed that an increased number of bone marrow adipocytes (BMAs) are involved in bone loss and the endothelial-to-adipocyte transition via the endothelial-to-mesenchymal transition (EndMT) might play a key role in this pathological process. Here, we assessed whether CINA could attenuate bone loss via inhibiting endothelial-to-adipocyte transition in CKD rats. METHODS: A rat model of CKD was induced by adenine and a high phosphorus diet. CINA was orally administrated to CKD animals (10 mg/kg once a day). Dual energy X-ray absorptiometry, micro-computed tomography, bone histomorphometry, and bone mechanical tests were used to determine the skeletal changes. The bone marrow expression of EndMT markers was also examined. The effect of elevated PTH levels on the endothelial-to-adipocyte transition was studied in endothelial cells (ECs). RESULTS: Elevation of serum PTH levels, remarkable bone loss and increased numbers of BMAs were observed in rats with CKD compared with the controls, and these changes were attenuated after treatment with CINA. Furthermore, the CINA treatment abolished the upregulation of mesenchymal markers (FSP1 and α-SMA) and the downregulation of an endothelial marker (CD31) in bone tissues from rats with CKD. The serum PTH concentrations were correlated with the bone marrow protein levels of these EndMT-related proteins. An in vitro treatment in ECs demonstrated that PTH induced the EndMT in a concentration- and time-dependent manner. Accordingly, ECs treated with PTH exhibited adipogenic potential following growth in adipogenic culture medium. CONCLUSIONS: Our study indicated CINA treatment attenuated bone loss in CKD rats, which might be associated with inhibiting PTH-induced endothelial-to-adipocyte transition in CKD rats.

The profibrotic effects of MK-8617 on tubulointerstitial fibrosis mediated by the KLF5 regulating pathway.

The discovery of hypoxia-inducible factor (HIF)-prolyl hydroxylase inhibitor (PHI) has revolutionized the treatment strategy for renal anemia. However, the presence of multiple transcription targets of HIF raises safety concerns regarding HIF-PHI. Here, we explored the dose-dependent effect of MK-8617 (MK), a kind of HIF-PHI, on renal fibrosis. MK was administered by oral gavage to mice for 12 wk at doses of 1.5, 5, and 12.5 mg/kg. In vitro, the human proximal tubule epithelial cell line HK-2 was treated with increasing doses of MK administration. Transcriptome profiling was performed, and fibrogenesis was evaluated. The dose-dependent biphasic effects of MK on tubulointerstitial fibrosis (TIF) were observed in chronic kidney disease mice. Accordingly, high-dose MK treatment could significantly enhance TIF. Using RNA-sequencing, combined with in vivo and in vitro experiments, we found that Krüppel-like factor 5 (KLF5) expression level was significantly increased in the proximal tubular cells, which could be transcriptionally regulated by HIF-1α with high-dose MK treatment but not low-dose MK. Furthermore, our study clarified that HIF-1α-KLF5-TGF-ß1 signaling activation is the potential mechanism of high-dose MK-induced TIF, as knockdown of KLF5 reduced TIF in vivo. Collectively, our study demonstrates that high-dose MK treatment initiates TIF by activating HIF-1α-KLF5-TGF-ß1 signaling. These findings provide novel insights into TIF induction by high-dose MK (HIF-PHI), suggesting that the safety dosage window needs to be emphasized in future clinical applications.-Li, Z.-L., Lv, L.-L., Wang, B., Tang, T.-T., Feng, Y., Cao, J.-Y., Jiang, L.-Q., Sun, Y.-B., Liu, H., Zhang, X.-L., Ma, K.-L., Tang, R.-N., Liu, B.-C. The profibrotic effects of MK-8617 on tubulointerstitial fibrosis mediated by the KLF5 regulating pathway.

FK506 prevented bone loss in streptozotocin-induced diabetic rats via enhancing osteogenesis and inhibiting adipogenesis.

BACKGROUND: Type 1 diabetes mellitus (DM) is associated with severe osteoporosis, which is still a great challenge in the clinic. This work aimed to investigate the skeletal effects of FK506 in a rat model of streptozocin induced type 1 DM. METHODS: Rats were divided into three groups: control (CTL), DM rats and DM rats treated with FK506. Dual energy X-ray absorption, micro-computed tomography, bone mechanics and bone histology were used for skeletal analysis. Bone marrow adipocytes infiltrations were detected by oil red O stain and H&E stain. In addition, the protein expression of adipocyte-specific makers (PPAR-γ, C/EBP-αß), osteoblast-specific markers (Runx2, Osterix) and nuclear translocation of ß-catenin in femurs were determined by western blot. RESULTS: In the study, bone mineral density of femurs and lumbar vertebras in diabetic rats were increased after FK506 administration. FK506 treatment resulted in higher cancellous bone volume but had no significant effect on cortical bones in diabetic rats. The ultimate force and work to failure were increased in DM+FK506 group, while they were reduced in the DM group. Compared with the CTL, the infiltration of bone marrow adipocytes was significantly increased in the DM group, which was reduced after the treatment of FK506. Besides, the expression levels of Runx2 and Osterix were up-regulated, and that of PPAR-γ and C/EBP-α were down-regulated in diabetic rats after FK506 treatment. In addition, the nuclear translocation of ß-catenin protein levels were increased in diabetic rats after the treatment of FK506. CONCLUSIONS: Our study indicated that FK506 could alleviate bone loss in diabetic rats. This effects could be due to the results of enhancing osteogenesis and inhibiting adipogenesis, which might be regulated by activation the nuclear translocation of ß-catenin.

MicroRNA-155 Promotes Heat Stress-Induced Inflammation via Targeting Liver X Receptor α in Microglia.

Background: The neuroinflammatory responses of microglial cells play an important role in the process of brain dysfunction caused by heat stroke. MicroRNAs are reportedly involved in a complex signaling network and have been identified as neuroinflammatory regulators. In this study, we determined the biological roles of microRNA-155 in the inflammatory responses in heat-stressed microglia and explored the underlying mechanisms. Methods: MicroRNA-155 mimic and inhibitor were used to separately upregulate or downregulate microRNA-155 expression. The activation state of BV-2 microglial cells (BV-2 cells) was assessed via immunoreactions using the microglial marker CD11b and CD68. Levels of induced interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were measured using real-time reverse transcription polymerase chain reaction (RT-PCR) and enzyme linked immunosorbent assays (ELISAs). The activation of nuclear factor kappa B (NF-κB) signaling proteins was evaluated by Western blotting for inhibitory kappa B alpha (IκBα) and NF-κB p65 phosphorylation and indirect immunofluorescence analysis using a p65 phosphorylation antibody. A luciferase reporter assay was used to verify liver X receptor α (LXRα) as a target gene of microRNA-155. Results: Heat stress significantly induced IL-1ß, IL-6, and TNF-α release and increased the expression of CD11b and CD68. In addition, IκBα and NF-κB p65 phosphorylation were dramatically increased by heat stress, and microRNA-155 expression was also elevated. High expression of microRNA-155 in heat-stressed microglial cells was inversely correlated with LXRα expression. We then determined the role of microRNA-155 in the heat stress-induced inflammatory responses. The results revealed that by targeting LXRα, microRNA-155 enhanced NF-κB signaling activation and facilitated immune inflammation in heat stress-treated BV-2 cells. Conclusion: MicroRNA-155 promotes heat stress-induced inflammatory responses in microglia. The underlying mechanisms may include facilitating inflammatory factors expression by increasing NF-κB pathway activation via targeting LXRα.

The Release of Monocyte-Derived Tissue Factor-Positive Microparticles Contributes to a Hypercoagulable State in Idiopathic Membranous Nephropathy.

AIM: Idiopathic membranous nephropathy (IMN) is an immune-mediated inflammatory disease characterized by a high risk of thromboembolic complications. Microparticles (MPs), a type of extracellular vesicles, have procoagulant properties, especially when they display tissue factor (TF). This study aimed to investigate whether circulating TF-positive MPs contributed to the hypercoagulable state in patients with IMN. METHODS: Twenty adult IMN patients and fourteen healthy subjects were included in the study. The basic indexes of a routine biochemical examination and coagulative function were determined. The plasma levels of MPs were detected by flow cytometry, and TF activity of MPs was examined using an assay kit. The plasma levels of lipopolysaccharide (LPS) were measured by an enzyme-linked immunosorbent assay. RESULTS: Total circulating MPs were not increased in patients with IMN compared with healthy controls. Circulating CD14＋/TF＋MPs were significantly increased in IMN patients, but this achieved significance was not observed in CD41＋/TF＋MPs between the two groups. Interestingly, the circulating TF-positive MPs were increased significantly. Plasma MPs TF assays revealed high procoagulant activity, which was positively associated with the D-dimer level in IMN. In addition, circulating LPS in IMN patients were significantly higher than those in the controls. Furthermore, after two hours' incubation with healthy whole blood, LPS enhanced the release of circulating TF-positive MPs and the TF activity of MPs. CONCLUSION: Increased circulating LPS may mediate the release of monocyte-derived TF-positive MPs, which further contributes to the hypercoagulable state in IMN patients. These findings provide an additional mechanism by which patients with IMN have a higher risk of thromboembolic complication.

Association of lipoprotein(a) and coronary artery disease in 1003 patients with stage 3-5 chronic kidney disease undergoing coronary angiography.

AIM: Lipoprotein(a) [Lp(a)] is considered a risk factor for cardiovascular disease. However, the role of Lp(a) in chronic kidney disease (CKD) patients is not well understood. The aim of this study was to evaluate the association between Lp(a) levels and the presence of coronary artery disease (CAD) and the severity of coronary artery stenosis (CAS) in patients with stage 3-5 CKD. PATIENTS AND METHODS: We retrospectively studied patients who were diagnosed with stage 3-5 CKD and underwent coronary artery angiography in Zhongda Hospital. The Gensini scoring system was used to assess the severity of coronary stenosis. RESULTS: A total of 1003 patients were enrolled in this cross-sectional study, and 776 of these patients were diagnosed with CAD. The Lp(a) levels were significantly higher in the CAD group than the non-CAD group [271.50 (168.00-459.25) vs. 195.00 (131.00-347.00) mg/l, P<0.001]. Multivariate logistic regression analysis showed that the Lp(a) tertiles were associated independently with the presence of CAD [tertile 2 vs. tertile 1 [adjusted odds ratio (OR)=2.063, 95% confidence interval (CI): 1.394-3.053, P<0.001] and tertile 3 vs. tertile 1 (adjusted OR=2.022, 95% CI: 1.345-3.040, P=0.001)]. After adjusting for potential confounders, the Lp(a) levels were associated independently with severe CAS [tertile 2 vs. tertile 1 (adjusted OR=1.603, 95% CI: 1.040-2.472, P=0.033); tertile 3 vs. tertile 1 (adjusted OR=1.743, 95% CI: 1.128-2.693, P=0.012)]. CONCLUSION: Higher Lp(a) levels were associated the presence of CAD and the severe CAS among patients with stage 3-5 CKD independently.

Host Restriction Factors APOBEC3G/3F and Other Interferon-Related Gene Expressions Affect Early HIV-1 Infection in Northern Pig-Tailed Macaque (Macaca leonina).

The northern pig-tailed macaques (NPMs) lack TRIM5α, an antiviral restriction factor, and instead have TRIM5-CypA. In our previous study, we demonstrated that HIV-1NL4-3 successfully infected NPMs and formed a long-term viral reservoir in vivo. However, the HIV-1-infected NPMs showed relatively high viremia in the first 6 weeks of infection, which declined thereafter suggesting that HIV-1 NL4-3 infection in these animals was only partly permissive. To optimize HIV-1 infection in NPMs therefore, we generated HIV-1NL4-R3A and stHIV-1sv, and infected NPMs with these viruses. HIV-1NL4-R3A and stHIV-1sv can replicate persistently in NPMs during 41 weeks of acute infection stage. Compared to the HIV-1NL4-R3A, stHIV-1sv showed a notably higher level of replication, and the NPMs infected with the latter induced a more robust neutralizing antibody but a weaker cellular immune response. In addition, IFN-I signaling was significantly up-regulated with the viral replication, and was higher in the stHIV-1sv infected macaques. Consequently, the sequences of pro-viral env showed fewer G-A hyper-mutations in stHIV-1sv, suggesting that vif gene of SIV could antagonize the antiviral effects of APOBEC3 proteins in NPMs. Taken together, NPMs infected with HIV-1NL4-R3A and stHIV-1sv show distinct virological and immunological features. Furthermore, interferon-related gene expression might play a role in controlling primary HIV-1NL4-R3A and stHIV-1sv replication in NPMs. This result suggests NPM is a potential HIV/AIDS animal model.