The objective of this completed, randomized, open-label trial across 11 hemodialysis centers in Shanghai, China, was to evaluate whether hemoadsorption combined with hemodialysis (HAHD) reduces mortality compared to hemodialysis (HD) alone in end-stage kidney disease patients (maintenance HD ≥ 3 months, Kt/V ≥ 1.2). We randomized 1362 patients 1:1 to receive HAHD (n = 683) or HD alone (n = 679; mainly low-flux HD plus intermittent HDF). All 1362 randomized patients were analyzed. The primary outcome was all-cause mortality, while secondary outcomes included cardiovascular mortality and major cardiovascular events. Over a median follow-up of 39.5 months, all-cause mortality occurred in 117 (17.1%) of HAHD patients compared to 144 (21.2%) of HD patients (hazard ratio [HR]: 0.778, 95% confidence interval [CI]: 0.609-0.994; P = 0.045). HAHD also significantly reduced cardiovascular mortality (HR: 0.659, 95% CI: 0.481-0.901; P = 0.009) and major cardiovascular events (HR: 0.772, 95% CI: 0.621-0.959; P = 0.019). Important adverse events, primarily infections and abnormal blood pressure, were comparable between the two groups. Adding hemoadsorption significantly reduced all-cause mortality, cardiovascular mortality, and major cardiovascular events compared to HD alone (mainly low-flux HD plus intermittent HDF). Trial Registration: ClinicalTrials.gov NCT03227770.

Objective:To investigate the predictive value of red blood cell distribution width (RDW) for late thrombosis in arteriovenous fistula (AVF). Methods:A retrospective analysis was conducted on data from 50 patients with late AVF thrombosis admitted to Yangpu Hospital between June 2017 and May 2022 were collected. 60 patients with AVF but without thrombosis were recruited from the same institution during the same study period were selected as the control group. The correlation between RDW and other data was analyzed. Statistically significant risk factors were analyzed by multivariate logistic regression. The ROC curve was used to evaluate the value of RDW in predicting late AVF thrombosis. Results:The values of RDW and leukocyte count in the thrombosis group were higher than those in the control group (P < 0.01). The levels of CRP, PLR, NLR, and neutrophils in the thrombosis group were higher than those in the control group (P < 0.05). Pearson correlation analysis showed that RDW was positively correlated with CRP, red blood cell count, PLR, NLR, and blood phosphorus. Multivariate logistic regression analysis showed that RDW (OR = 1.774, 95% CI: 1.055-2.983, P< 0.05) was an independent risk factor for late AVF thrombosis. ROC curve analysis displayed that the area under the curve (AUC) for RDW was 0.702 (95% CI: 0.59 6-0.808, P<0.001). The optimal predictive cutoff value for RDW, calculated according to the Youden index, is 15.30%. Using RDW ≥ 15.30% to predict late AVF thrombosis yielded a sensitivity of 60.00% and a specificity of 98.30%. Conclusion:RDW exhibits distinct expression patterns in late AVF thrombosis and demonstrates significant diagnostic potential. Incorporating this marker into existing diagnostic algorithms may enhance early risk prediction. However, further validation in large-scale, prospective multicenter studies is required to establish its clinical utility in routine practice.

BACKGROUND:Colony-stimulating factor 1 receptor (CSF1R) is a promising imaging biomarker for neuroinflammation and tumor-associated macrophages. However, existing positron emission tomography (PET) tracers for CSF1R imaging often suffer from limited specificity or sensitivity. RESULTS:We have performed 11C-labeled radiosynthesis of compound FJRD (3-((2-amino-5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)ethynyl)-N-(4-methoxyphenyl)-4-methylbenzamide), which exhibits excellent affinity for CSF1R, and evaluated its in vivo and in vitro binding properties. PET images of [11C]FJRD show low brain uptake and specific binding in the living organs, except the kidneys in both normal mice and rats. In vitro autoradiographs demonstrate high levels of specific binding in all investigated organs, including the brain, spleen, liver, kidneys and lungs, when self-blocking was used. The addition of CPPC partially blocked in vitro [11C]FJRD binding in these organs, with blocking effects ranging from 9 to 67%. In contrast, the other two CSF1R inhibitors, GW2580 and BLZ945, showed minimal blocking effects, suggesting unignorable off-target binding in these organs. Furthermore, specific binding of [11C]CPPC and [11C]GW2580 was faint in the mouse organs, with [11C]CPPC demonstrating detectable binding only in the spleen. CONCLUSIONS:These results suggest that [11C]FJRD is a potential CSF1R-PET tracer for more sensitive detection of CSF1R, compared to [11C]CPPC and [11C]GW2580. However, the high level off-target binding necessitates further improvements in specificity for CSF1R imaging.

BACKGROUND:Emerging evidence suggests that renal inflammation, characterized by the activation of renal macrophages, plays a critical role in the pathogenesis of kidney diseases, including acute kidney injury (AKI). However, reliable research methods for visualizing renal macrophages remain limited. In this study, we utilized positron emission tomography (PET) imaging combined with a radiolabeled ligand targeting colony-stimulating factor 1 receptor (CSF1R) to assess the potential of CSF1R-PET as a non-invasive tool for examining renal inflammation. METHODS:Single-cell RNA sequencing analysis was performed to identify imaging biomarkers for activated macrophages in an ischemia-reperfusion (I/R)-induced AKI (I/R-AKI) model. We employed PET and in-vitro autoradiography with 11C-CPPC, a CSF1R-specific radioligand, in mouse models of I/R-AKI and renal/perinephric abscesses (RA). Immunohistochemical analysis was performed to assess renal pathologies, macrophage activation, and CSF1R expression. RESULTS:Single-cell RNA sequencing analysis of publicly available data revealed a dramatic upregulation of CSF1R, primarily expressed in M2 macrophages, in response to I/R-AKI. PET and in-vitro autoradiography showed that retention of 11C-CPPC was markedly increased in ischemic renal regions and RA-affected areas compared to normal kidney regions. Immunohistochemical analysis confirmed substantial increases in CSF1R expression and the accumulation of activated macrophages in the medullary region of I/R-AKI mice and RA-affected renal regions, supporting the in-vivo and in-vitro imaging results. CONCLUSION:Our findings provide the first evidence supporting the utility of 11C-CPPC-PET as a clinically-available tool for non-invasive detection of activated renal macrophages, predominantly of the M2 phenotype.

Acute oxalate nephropathy is a rare but potentially underrecognized cause of acute kidney injury (AKI). The reports of secondary oxalate nephropathy induced by high doses of vitamin C, portulaca oleracea, Peanut were described, but the cause as yellow wine consumption are rare. We report a 63-year-old man with acute kidney injury due to yellow rice wine. The patient has drunk yellow rice wine 500 mL/day for the past 10 years. He underwent an ultrasound-guided renal biopsy, which showed acute tubular injury and birefringent crystals were observed in the renal tubules under a polarizing microscope. The 24-hour urinary oxalate excretion established and the baseline serum creatinine of 407 µmol/L. Following 3 months therapy, subsequent laboratory evaluation demonstrated significant reduction in urinary oxalate excretion excretion and serum creatinine normal. Acute secondary oxalate nephropathy due to excessive dietary intake of oxalate may lead to AKI. Kidney biopsies in unknown cause AKI patients is important and attention should be payed to food behaviors when reasons for AKI are explored.

Breast cancer is the most common cancer among females. Dachshund Homolog 1 (DACH1) gene is regarded as an important tumor suppressor gene in breast cancer which plays an important regulatory role in the development disease progression, particularly in carcinomas. Circular RNAs (circRNAs) and microRNA (miRNA), regarded as a novel group of noncoding RNAs, are always involved in regulating gene expression. In this work, hsa_circ_0047604 expressed lower in breast cancer tissue and played the role of sponge of miR-548o. By this way, hsa_circ_0047604 could upregulate DACH1 to inhibit breast cancer. In conclusion, this study revealed that hsa_circ_0047604 acted as a tumor suppressor and regulated breast cancer progression via hsa_circ_0047604-miR-548o-DACH1 axis, which might provide a therapeutic method for breast cancer.

Lead (Pb) intoxication is known to damage the proximal tubules of kidney. Autophagy and apoptosis have been shown to be involved in a variety of renal injuries, but the underlying mechanisms remain largely unknown. In this study, we constructed a mice model of Pb intoxication and validated it against lead concentrations in blood and urine. Electron microscopy revealed that Pb promoted the accumulation of autophagosomes. Subsequent immunofluorescence and western blotting revealed that Pb intoxication suppressed the autophagic flux. Next, exosomes were isolated and extracted through ultracentrifugation, and were further identified by diameter analysis and marker detection. We also demonstrated that autophagy and apoptosis were enhanced in renal cells with exosomes of Pb expose. Furthermore, the specific mechanisms were explored by RNA sequencing and it was found that several targeted genes regulated by differential exosomal miRNAs and lncRNAs. Target genes accumulated in several signaling pathways, especially the adenosine 5'-monophosphate-activated protein kinase (AMPK) signaling. We found that Pb intoxication-induced exosomes activated the AMPK signaling in renal proximal tubule cells. Furthermore, autophagy and apoptosis assays showed that GSK-690693, an AMPK inhibitor, significantly alleviated exosome-induced renal injuries by Pb intoxication. In conclusion, Pb-mediated exosome-induced autophagy and apoptosis via activating the AMPK signaling contributing to Pb-induced nephrotoxicity in renal cells.

Epidemiology studies have indicated that environmental cadmium exposure, even at low levels, will result in chronic cadmium accumulation in the kidney with profound adverse consequences and that the diabetic population is more susceptible. However, the underlying mechanisms are yet not fully understood. In the present study, we applied an animal model to study chronic cadmium exposure-induced renal injury and performed whole transcriptome profiling studies. Repetitive CdCl2 exposure resulted in cadmium accumulation and remarkable renal injuries in the animals. The diabetic ob/ob mice manifested increased severity of renal injury compared with the wild type C57BL/6 J littermate controls. RNA-Seq data showed that cadmium treatment induced dramatic gene expression changes in a dose-dependent manner. Among the differentially expressed genes include the apoptosis hallmark genes which significantly demarcated the treatment effects. Pathway enrichment and network analyses revealed biological oxidation (mainly glucuronidation) as one of the major stress responses induced by cadmium treatment. We next implemented a deep learning algorithm in conjunction with cloud computing and discovered a gene signature that can predict the degree of renal injury induced by cadmium treatment. The present study provided, for the first time, a comprehensive mechanistic understanding of chronic cadmium-induced nephrotoxicity in normal and diabetic populations at the whole genome level.

Alzheimer's disease (AD) is the most common type of dementia, pathologically characterized by the accumulation of senile plaques and neurofibrillary tangles. Chronic kidney disease (CKD) is highly prevalent in the elderly population closely associated with the occurrence of dementia. Recent epidemiological and experimental studies suggest a potential association of CKD with AD. Both diseases share a panel of identical risk factors, such as type 2 diabetes and hypertension. However, the relationship between CKD and AD is unclear. Lower clearance of a panel of uremic toxin including cystatin- C, guanidine, and adiponectin due to CKD is implied to contribute to AD pathogenesis. In this review, we summarize the current evidence from epidemiological, experimental, and clinical studies on the potential contribution of uremic toxins to AD pathogenesis. We describe outstanding questions and propose an outlook on the link between uremic toxins and AD.

Objective: To investigate the occurrence and influencing factors of fatigue and sleep disturbance in Maintenance Hemodialysis (MHD) patients. Methods: A total of 170 patients with end-stage renal disease who underwent MHD treatment in the hemodialysis room of Shaanxi Provincial Hospital of Traditional Chinese Medicine from October 2021 to March 2022 were selected as the research subjects. The basic information and laboratory indicators of the patients were collected by cross-sectional survey. The survey methods were evaluated by the revised Piper Fatigue Scale and the Pittsburgh Sleep Quality Rating Scale and the incidence and influencing factors of fatigue and sleep disturbance in MHD patients were analyzed. Results: Fatigue occurred in 135 cases, the incidence rate was 79.41%; sleep disturbance occurred in 124 cases and the incidence rate was 72.94%. After one-way analysis of variance, factors such as exercise, Albumin (ALB, serum Creatinine(CRE), Phosphorus(P) and Hemoglobin(HGB) in MHD patients can affect fatigue; while age, gender, exercise, primary disease, dialysis frequency, Phosphorus(P), Hemoglobin(HGB) and high-sensitivity C-Reactive Protein (hs-CRP) factors can affect sleep. A multiple linear regression model was constructed for the factors affecting fatigue (F = 81.110, p < 0.001), and it showed that 70.3% of fatigue (adjusted R2 = 0.703) was related to albumin (ALB), serum creatinine(CRE), and hemoglobin(HGB) (all p < 0.05); A multiple linear regression model was constructed based on the factors of 58% (F = 26.933, p < 0.001), which showed that 58% of sleep disorders (adjusted R2 = 0.580) were significantly related to age, gender, exercise or not, phosphorus(P), high-sensitivity C-reactive protein(hs-CRP) (all p < 0.05) related. Pearson correlation analysis was used to analyze sleep disturbance and fatigue in MHD patients and the results showed that there was a positive correlation between the two (r = 0.478, p < 0.001). Conclusion: The proportion of fatigue and sleep disturbance in MHD patients is relatively high, mainly mild to moderate and the two influence each other. Exercise intervention and nutritional support can effectively improve the occurrence of fatigue and sleep disturbance in MHD patients.

Objective: To investigate the effects of chronic non-occupational exposure to cadmium(Cd) on renal injury in residents living in the urban areas of China. Methods: In this cross-sectional study, we recruited 1000 participants in Shanghai from August 2015 to August 2017 and collected data on their socio-demographic characteristics, lifetime occupation, and lifestyle factors. The urinary Cd, urinary albumin, urinary creatinine, serum creatinine, urea, and uric acid levels were tested, and 683 participants completed those measurements. Results: The median urinary Cd concentration of this study population was 0.77 mu g/g. The urinary Cd concentration was significantly higher in the female, older, and lower body mass index populations. There were 148 participants with dominant albuminuria who had higher urinary Cd levels than those without dominant albuminuria (0.98 vs. 0.72 mu g/g; P < 0.001). Among participants without dominant albuminuria, there were 134 participants with lowgrade albuminuria (13.84 <= ACR < 30 mg/g) and 401 participants who had normal urinary albumin excretion (ACR < 13.84 mg/g). Compared with those who had normal urinary albumin excretion, those with low-grade albuminuria had significantly higher urinary Cd levels (0.83 vs. 0.69 mu g/g; P < 0.001). Among those without dominant albuminuria, participants in the highest quartile of urinary Cd were more likely to have low-grade albuminuria than those in the lowest quartile (Odd's ratio= 2.98; P < 0.001). Further adjustment for age, sex, andBMI or other potential confounding factors did not change the magnitudes of the associations. Moreover, we conducted multivariable stepwise linear regression analysis within 134 low-grade albuminuria participants and demonstrated that urinary Cd concentration (P < 0.001) were independent determinants of urine albumin after adjusting for relevant confounders. Conclusion: The urinary Cd levels observed in Chinese urban adults are substantial and associated with an increased risk of low-grade albuminuria. Our findings suggest that potential sources of environmental Cd exposure should be explored, and the associated renal toxicity should be studied in more detail in future.

Osteoporosis bears an imbalance between bone formation and resorption, which is strongly related to oxidative stress. The function of leonurine on bone marrow-derived mesenchymal stem cells (BMSCs) under oxidative stress is still unclear. Therefore, this study was aimed at identifying the protective effect of leonurine on H2O2 stimulated rat BMSCs. We found that leonurine can alleviate cell apoptosis and promote the differentiation ability of rat BMSCs induced by oxidative stress at an appropriate concentration at 10 μM. Meanwhile, the intracellular ROS level and the level of the COX2 and NOX4 mRNA decreased after leonurine treatment in vitro. The ATP level and mitochondrial membrane potential were upregulated after leonurine treatment. The protein level of PINK1 and Parkin showed the same trend. The mitophage in rat BMSCs blocked by 3-MA was partially rescued by leonurine. Bioinformatics analysis and leonurine-protein coupling provides a strong direct combination between leonurine and the PI3K protein at the position of Asp841, Glu880, Val882. In conclusion, leonurine protects the proliferation and differentiation of BMSCs from oxidative stress by activating mitophagy, which depends on the PI3K/Akt/mTOR pathway. The results showed that leonurine may have potential usage in osteoporosis and bone defect repair in osteoporosis patients.

Object: The aims of the study were to explore the protective effects of S-propargyl-cysteine (SPRC) on periodontitis and to determine the underlying mechanisms.Methods: A rat periodontitis model was constructed by injecting LPS and SPRC (0, 25, and 50 mg/kg/d) was administered intraperitoneally. H2S and CSE level were detected. The alveolar bone level was evaluated by micro-CT, HE staining and methylene blue staining analysis. Inflammation-related factors, Treg and Th17 cells were detected by immunohistochemistry, RT-PCR, immunofluorescence, Western blot and flow cytometry. Phosphorylation levels of ERK1/2 and CREB were analysed.Results: The administration of SPRC significantly increased the expression of CSE in the gingival tissue and the concentration of endogenous H2S in the peripheral blood. Simultaneously, SPRC significantly inhibited the resorption of alveolar bone based on the H&E staining, micro-CT and methylene blue staining analysis. Compared with the periodontitis group, the levels of IL-17A, IL-10 were downregulated and IL-6,TGF-β1 were upregulated in the SPRC groups. In the SPRC group, the percentage of TH17 cells and the expression of ROR-γt were downregulated, while the percentage of Tregs and the expression of Foxp3 were upregulated accompanied with inhibition of phosphorylation ERK1/2 and CREB.Conclusion: SPRC can prevent the progression of periodontitis by regulating the Th17/Treg balance by inhibition of the ERK/CREB signalling pathway.

Neuroinflammation play an important role in Alzheimer’s disease pathogenesis. Advances in molecular imaging using positron emission tomography have provided insights into the time course of neuroinflammation and its relation with Alzheimer’s disease central pathologies in patients and in animal disease models. Recent single-cell sequencing and transcriptomics indicate dynamic disease-associated microglia and astrocyte profiles in Alzheimer’s disease. Mitochondrial 18-kDa translocator protein is the most widely investigated target for neuroinflammation imaging. New generation of translocator protein tracers with improved performance have been developed and evaluated along with tau and amyloid imaging for assessing the disease progression in Alzheimer’s disease continuum. Given that translocator protein is not exclusively expressed in glia, alternative targets are under rapid development, such as monoamine oxidase B, matrix metalloproteinases, colony-stimulating factor 1 receptor, imidazoline-2 binding sites, cyclooxygenase, cannabinoid-2 receptor, purinergic P2X7 receptor, P2Y12 receptor, the fractalkine receptor, triggering receptor expressed on myeloid cells 2, and receptor for advanced glycation end products. Promising targets should demonstrate a higher specificity for cellular locations with exclusive expression in microglia or astrocyte and activation status (pro- or anti-inflammatory) with highly specific ligand to enable in vivo brain imaging. In this review, we summarised recent advances in the development of neuroinflammation imaging tracers and provided an outlook for promising targets in the future.

BackgroundLeonurine, a major bioactive component from Herba leonuri, has been shown to exhibit anti-inflammatory and antioxidant effects. The aim of this study was to investigate the effect of leonurine on bone marrow-derived mesenchymal stem cells (BMSCs) as a therapeutic approach for treating osteoporosis.Materials and MethodsRat bone marrow-derived mesenchymal stem cells (rBMSCs) were isolated from 4-weeks-old Sprague–Dawley rats. The cytocompatibility of leonurine on rBMSCs was tested via CCK-8 assays and flow cytometric analyses. The effects of leonurine on rBMSC osteogenic differentiation were analyzed via ALP staining, Alizarin red staining, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blot. Additionally, autophagy-related markers were examined via qRT-PCR and Western blot analyses of rBMSCs during osteogenic differentiation with leonurine and with or without 3-methyladenine (3-MA) as an autophagic inhibitor. Finally, the PI3K/Akt/mTOR signaling pathway was evaluated during rBMSC osteogenesis.ResultsLeonurine at 2–100 μM promoted the proliferation of rBMSCs. ALP and Alizarin red staining results showed that 10 μM leonurine promoted rBMSC osteoblastic differentiation, which was consistent with the qRT-PCR and Western blot results. Compared with those of the control group, the mRNA and protein levels of Atg5, Atg7, and LC3 were upregulated in the rBMSCs upon leonurine treatment. Furthermore, leonurine rescued rBMSC autophagy after inhibition by 3-MA. Additionally, the PI3K/AKT/mTOR pathway was activated in rBMSCs upon leonurine treatment.ConclusionLeonurine promotes the osteoblast differentiation of rBMSCs by activating autophagy, which depends on the PI3K/Akt/mTOR pathway. Our results suggest that leonurine may be a potential treatment for osteoporosis.

Lipopolysaccharide (LPS) from oral pathogenic bacteria is an important factor leading to alveolar bone absorption and the implant failure. The present study aimed to evaluate the modulation of berberine hydrochloride (BBR) on the LPS-mediated osteogenesis and adipogenesis imbalance in rat bone marrow-derived mesenchymal stem cells (BMSCs). Cell viability, osteoblastic and adipogenic differentiation levels were measured using the Cell Counting Kit-8 assay, alkaline phosphatase (ALP) staining and content assay, and oil red O staining, respectively. Reverse transcription-quantitative PCR and immunoblotting were used to detect the related gene and protein expression levels. In undifferentiated cells, BBR increased the mRNA expression levels of the osteoblastic genes (Alp, RUNX family transcription factor 2, osteocalcin and secreted phosphoprotein 1) but not the adipogenic genes (fatty acid binding protein 4, Adipsin and peroxisome proliferator-activated receptorγ). LPS-induced osteoblastic gene downregulation, adipogenic gene enhancement and NF-κB activation were reversed by BBR treatment. In osteoblastic differentiated cells, decreased ALP production by LPS treatment was recovered with BBR co-incubation. In adipogenic differentiated cells, LPS-mediated lipid accumulation was decreased by BBR administration. The mRNA expression levels of the pro-inflammatory factors (MCP-1, TNF-α, IL-6 and IL-1β) were increased by LPS under both adipogenic and osteoblastic conditions, which were effectively ameliorated by BBR. The actions of BBR were attenuated by compound C, suggesting that the role of BBR may be partly due to AMP-activated protein kinase activation. The results demonstrated notable pro-osteogenic and anti-adipogenic actions of BBR in a LPS-stimulated inflammatory environment. This indicated a potential role of BBR for bacterial infected-related peri-implantitis medication.