Therapeutic effects of orexin-A in sepsis-associated encephalopathy in mice.

BACKGROUND: Sepsis-associated encephalopathy (SAE) causes acute and long-term cognitive deficits. However, information on the prevention and treatment of cognitive dysfunction after sepsis is limited. The neuropeptide orexin-A (OXA) has been shown to play a protective role against neurological diseases by modulating the inflammatory response through the activation of OXR1 and OXR2 receptors. However, the role of OXA in mediating the neuroprotective effects of SAE has not yet been reported. METHODS: A mouse model of SAE was induced using cecal ligation perforation (CLP) and treated via intranasal administration of exogenous OXA after surgery. Mouse survival, in addition to cognitive and anxiety behaviors, were assessed. Changes in neurons, cerebral edema, blood-brain barrier (BBB) permeability, and brain ultrastructure were monitored. Levels of pro-inflammatory factors (IL-1ß, TNF-α) and microglial activation were also measured. The underlying molecular mechanisms were investigated by proteomics analysis and western blotting. RESULTS: Intranasal OXA treatment reduced mortality, ameliorated cognitive and emotional deficits, and attenuated cerebral edema, BBB disruption, and ultrastructural brain damage in mice. In addition, OXA significantly reduced the expression of the pro-inflammatory factors IL-1ß and TNF-α, and inhibited microglial activation. In addition, OXA downregulated the expression of the Rras and RAS proteins, and reduced the phosphorylation of P-38 and JNK, thus inhibiting activation of the MAPK pathway. JNJ-10,397,049 (an OXR2 blocker) reversed the effect of OXA, whereas SB-334,867 (an OXR1 blocker) did not. CONCLUSION: This study demonstrated that the intranasal administration of moderate amounts of OXA protects the BBB and inhibits the activation of the OXR2/RAS/MAPK pathway to attenuate the outcome of SAE, suggesting that OXA may be a promising therapeutic approach for the management of SAE.

Internal fistula stenosis with true pseudoaneurysm formation in a patient on maintenance hemodialysis: A case report.

BACKGROUND: Arteriovenous fistula stenosis can directly lead to the formation of autologous arteriovenous fistula aneurysms (AVFAs), but the coexistence of true and pseudoaneurysms is relatively rare. The coexistence of true and pseudoaneurysms increases the risk of rupture of the arteriovenous fistula and complicates subsequent surgical intervention, potentially posing a threat to the patient's life, and thus requires significant attention. CASE PRESENTATION: The patient presented with arteriovenous fistula (AVF) after hemodialysis 6 years ago. 2 years ago, the patient presented with a mass that had formed near the left forearm arteriovenous fistula and gradually increased in size. Preoperatively, the AVF stenosis was identified as the cause of the mass formation, and the patient was operated on. First, the blood flow was controlled to reduce the pressure at the aneurysm, and then the incision was enlarged to separate the AVF anastomosis from the mass area. The stenotic segment of the true and pseudo aneurysms and cephalic vein was removed and the over-dilated proximal cephalic vein was locally narrowed and subsequently anastomosed with the proximal radial artery to create AVF. The patient was dialyzed with an internal fistula the next day and showed no clinical manifestations related to end-limb ischemia. CONCLUSION: We removed a true pseudoaneurysm in AVF and secured the patient's vascular access. This report provides an effective strategy to manage this condition.

Human pluripotent stem cell-derived kidney organoids: Current progress and challenges.

Human pluripotent stem cell (hPSC)-derived kidney organoids share similarities with the fetal kidney. However, the current hPSC-derived kidney organoids have some limitations, including the inability to perform nephrogenesis and lack of a corticomedullary definition, uniform vascular system, and coordinated exit pathway for urinary filtrate. Therefore, further studies are required to produce hPSC-derived kidney organoids that accurately mimic human kidneys to facilitate research on kidney development, regeneration, disease modeling, and drug screening. In this review, we discussed recent advances in the generation of hPSC-derived kidney organoids, how these organoids contribute to the understanding of human kidney development and research in disease modeling. Additionally, the limitations, future research focus, and applications of hPSC-derived kidney organoids were highlighted.

Diffusion Tensor and Kurtosis MRI-Based Radiomics Analysis of Kidney Injury in Type 2 Diabetes.

BACKGROUND: Diffusion tensor imaging (DTI) and diffusion kurtosis imaging (DKI) can provide quantitative parameters that show promise for evaluation of diabetic kidney disease (DKD). The combination of radiomics with DTI and DKI may hold potential clinical value in detecting DKD. PURPOSE: To investigate radiomics models of DKI and DTI for predicting DKD in type 2 diabetes mellitus (T2DM) and evaluate their performance in automated renal parenchyma segmentation. STUDY TYPE: Prospective. POPULATION: One hundred and sixty-three T2DM patients (87 DKD; 63 females; 27-80 years), randomly divided into training cohort (N = 114) and validation cohort (N = 49). FIELD STRENGTH/SEQUENCE: 1.5-T, diffusion spectrum imaging (DSI) with 9 different b-values. ASSESSMENT: The images of DSI were processed to generate DKI and DTI parameter maps, including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD). The Swin UNETR model was trained with 5-fold cross-validation using 100 samples for renal parenchyma segmentation. Subsequently, radiomics features were automatically extracted from each parameter map. The performance of the radiomics models on the validation cohort was evaluated by utilizing the receiver operating characteristic (ROC) curve. STATISTICAL TESTS: Mann-Whitney U test, Chi-squared test, Pearson correlation coefficient, least absolute shrinkage and selection operator (LASSO), dice similarity coefficient (DSC), decision curve analysis (DCA), area under the curve (AUC), and DeLong's test. The threshold for statistical significance was set at P < 0.05. RESULTS: The DKI_MD achieved the best segmentation performance (DSC, 0.925 ± 0.011). A combined radiomics model (DTI_FA, DTI_MD, DKI_FA, DKI_MD, and DKI_RD) showed the best performance (AUC, 0.918; 95% confidence interval [CI]: 0.820-0.991). When the threshold probability was greater than 20%, the combined model provided the greatest net benefit. Among the single parameter maps, the DTI_FA exhibited superior diagnostic performance (AUC, 887; 95% CI: 0.779-0.972). DATA CONCLUSION: The radiomics signature constructed based on DKI and DTI may be used as an accurate and non-invasive tool to identify T2DM and DKD. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

[High mobility group nucleosome binding protein 1 (HMGN1) induces activation of mouse BV2 microglia and upregulates their pro-inflammatory mediator expression by activating TLR4/MyD88/NF-κB p65/IKK-ß signal pathway].

Objective To explore the effects and mechanism of high-mobility group nucleosome-binding protein 1 (HMGN1) on the inflammatory response of mouse BV2 microglia. Methods BV2 cells were incubated with recombinant HMGN1 at different concentrations (0, 100, 200, 500, 1000, 2000 ng/mL) for 6 hours, and the morphological changes were observed under a microscope. The mRNA levels of tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), interleukin-1ß (IL-1ß) and monocyte chemotactic protein 1 (MCP-1) were detected by real time quantitative PCR. Microglial cells were then randomly divided into a control group, model group, inhibitor group and antagonist group. The cells in the model group were treated with 500 ng/mL HMGN1, while the antagonist group was treated with 500 ng/mL TAK-242 (resatorvid), a Toll-like receptor 4 (TLR4) antagonist, in addition to HMGN1. Real time quantitative PCR and immunofluorescence were used to detect the expression of M1/M2 markers in the four groups, and Western blot analysis was used to measure the protein expression levels of inducible nitric-oxide synthase (iNOS), TLR4, myeloid differentiation factor88 (MyD88), nuclear factor κB p65 (NF-κB p65) and inhibitor of NF-κB(IκB)kinase ß(IKK-ß). Results After the treatment of HMGN1, the morphology of BV2 cells changed significantly, showing an amoeba-like appearance. The mRNA levels of TNF-α, IL-6, IL-1ß and MCP-1 increased with the HMGN1 concentration, with a statistically significant difference compared to the 0 ng/mL HMGN1 group. At the same time, the mRNA level of iNOS, a M1 phenotype marker, increased with the HMGN1 concentration, while the level of CD206, a M2 phenotype marker, decreased with HMGN1 concentration, showing a statistically significant difference compared to the 0 ng/mL HMGN1 group. Compared with the model group, the mRNA level of M1 phenotypic marker iNOS in the antagonist group was significantly lower, and the level of M2 phenotypic marker CD206 was significantly higher. The results of immunofluorescence cytochemistry also showed that the expression of M1 phenotypic marker iNOS in the antagonist group was lower. The results of Western blot suggested that the protein expression levels of iNOS, TLR4, MyD88, NF-κB p65 and IKK-ß decreased significantly in the antagonist group. Conclusion HMGN1 may induce the activation of BV2 microglial cells by upregulating pro-inflammatory mediators through activating the TLR4/MyD88/NF-κB p65/IKK-ß signaling pathway.

Causal effects of gut microbiota on sepsis and sepsis-related death: insights from genome-wide Mendelian randomization, single-cell RNA, bulk RNA sequencing, and network pharmacology.

BACKGROUND: Gut microbiota alterations have been implicated in sepsis and related infectious diseases, but the causal relationship and underlying mechanisms remain unclear. METHODS: We evaluated the association between gut microbiota composition and sepsis using two-sample Mendelian randomization (MR) analysis based on published genome-wide association study (GWAS) summary statistics. Sensitivity analyses were conducted to validate the robustness of the results. Reverse MR analysis and integration of GWAS and expression quantitative trait loci (eQTL) data were performed to identify potential genes and therapeutic targets. RESULTS: Our analysis identified 11 causal bacterial taxa associated with sepsis, with increased abundance of six taxa showing positive causal relationships. Ten taxa had causal effects on the 28-day survival outcome of septic patients, with increased abundance of six taxa showing positive associations. Sensitivity analyses confirmed the robustness of these associations. Reverse MR analysis did not provide evidence of reverse causality. Integration of GWAS and eQTL data revealed 76 genes passing the summary data-based Mendelian randomization (SMR) test. Differential expression of these genes was observed between sepsis patients and healthy individuals. These genes represent potential therapeutic targets for sepsis. Molecular docking analysis predicted potential drug-target interactions, further supporting their therapeutic potential. CONCLUSION: Our study provides insights for the development of personalized treatment strategies for sepsis and offers preliminary candidate targets and drugs for future drug development.

Central administration of Dapagliflozin alleviates a hypothalamic neuroinflammatory signature and changing tubular lipid metabolism in type 2 diabetic nephropathy by upregulating MCPIP1.

BACKGROUND: Hypothalamic neuroinflammation is associated with disorders of lipid metabolism. Considering the anti-neuroinflammation effects of sodium-glucose cotransporter 2(SGLT2) inhibitors, a central administration of Dapagliflozin is postulated to provide hypothalamic protection and change lipid metabolism in kidney against diabetic kidney disease (DKD). METHODS: Blood samples of DKD patients were collected. Male Sprague-Dawley (SD) rats with 30 mg/kg streptozotocin and a high-fat diet, db/db mice and palmitic acid (PA)-stimulated BV2 microglia were used for study models. 0.28 mg/3ul dapagliflozin was injected into the lateral ventricle in db/db mice. Genes and protein expression levels were determined by qPCR, western blotting, immunofluorescence, and immunohistochemistry staining. Secreted IL-1ß and IL-6 were quantified by ELISA. Oil red O staining, lipidomic, and non-targeted metabolomics were performed to evaluate abnormal lipid metabolism in kidney. RESULTS: The decrease of serum MCPIP1 was an independent risk factor for renal progression in DKD patients (OR=1.22, 95 %CI: 1.02-1.45, P = 0.033). Higher microglia marker IBA1 and lower MCPIP1 in the hypothalamus, as well as lipid droplet deposition increasing in the kidney were observed in DKD rats. Central dapagliflozin could reduce the blood sugar, hypothalamic inflammatory cytokines, lipid droplet deposition in renal tubular. Lipidomics and metabolomics results showed that dapagliflozin changed 37 lipids and 19 metabolites considered on promoting lipolysis. These lipid metabolism changes were attributed to dapagliflozin by upregulating MCPIP1, and inhibiting cytokines in the microglia induced by PA. CONCLUSIONS: Central administrated Dapagliflozin elicits an anti-inflammatory effect by upregulating MCPIP1 levels in microglia and changes lipid metabolism in kidney of DKD.

The association of left ventricular fraction shortening with cardiovascular events in peritoneal dialysis patients.

BACKGROUND: Peritoneal dialysis (PD) patients have a high incidence of cardiovascular events (CVEs). Left ventricular fraction shortening (LVFS), one of the echocardiographic parameters, is an independent risk factor for mortality in previous studies. The aim of this study was to evaluate associations between LVFS and CVEs in PD patients. METHODS: This was a single-center observational cohort study. Seven hundred and eighty-four PD patients were enrolled from 1 January 2012 to 1 June 2021 and followed until 1 June 2022. The primary outcome was the incidence of CVEs. PD patients were categorized into three groups according to the tertiles of LVFS levels (tertile 1-tertile 3). Kaplan-Meier method, Cox proportional hazard models and competing risk regression models were used for survival analysis. The areas under the curve (AUC) of receiver-operating characteristic analysis was used to determine the predictive values of LVFS for CVEs. A preplanned subgroup analysis was assessed according to age, gender, and the presence of hypertension and dyslipidemia, etc. RESULTS: During a median follow-up period of 42.3 months (interquartile range 24.0-79.0 months), 259 CVEs occurred. Compared to the other two groups respectively, patients in tertile 3 group had the lowest incidence of CVEs (24.5% vs 31.6% vs 43.0%, respectively, p < 0.05). After multiple adjustments, the tertile 3 group was associated with the 45.1% decrease in the CVEs hazard compared to that of the tertile1 group (SHR = 0.549, 95%CI: 0.395-0.762, p < 0.001). Subgroup analysis demonstrated that tertile 1 group as the reference, the association between LVFS and CVEs in tertile 3 group was robust among female patients (HR = 0.506, 95%CI: 0.309-0.829, p = 0.007), aged < 45 years (HR = 0.496, 95%CI: 0.331-0.744, p = 0.001), history of hypertension (HR = 0.586, 95%CI: 0.349-0.872, p = 0.008) and combined with dyslipidemia (HR = 0.464, 95%CI: 0.269-0.799, p = 0.006). CONCLUSIONS: This study suggests that LVFS is independently associated with the increased risk of CVEs in PD patients, especially those with aged < 45 years, female, with hypertension and dyslipidemia.

One-year change in sarcopenia was associated with cognitive impairment among haemodialysis patients.

BACKGROUND: Our study aimed to evaluate change in sarcopenia, its defining components over 1 year follow-up and investigate associations with subsequent cognitive decline, incident mild cognitive impairment (MCI) and dementia among patients undergoing haemodialysis (HD). METHODS: In the multicentre, longitudinal study, 1117 HD patients aged 56.8 ± 14.3 years (654 men; and 463 women) from 17 dialysis centres in Guizhou Province, China, were recruited in 2019 and followed up for 1 year in 2020. Sarcopenia was diagnosed with Asian Working Group for Sarcopenia criteria using appendicular skeletal muscle mass index (ASMI) and handgrip strength (HGS). Body composition was measured using body composition monitor; body water, weight, and height were corrected to calculate ASMI. HGS was measured by mechanical handgrip dynamometer. Cognitive function was measured with Mini Mental State Examination. Multivariate linear, logistic regression models and subgroup analyses were employed to examine the associations of changes in sarcopenia, ASMI, and HGS with Mini Mental State Examination score change, and incident MCI, dementia. RESULTS: Four hundred fourteen (37.1%) patients had sarcopenia at baseline; during 1 year follow-up, 257 (23.0%) developed MCI and 143 (12.8%) developed dementia. According to changes in sarcopenia, patients were stratified into four groups: non-sarcopenia; non-sarcopenia to sarcopenia; sarcopenia; and sarcopenia to non-sarcopenia. HD patients in sarcopenia and non-sarcopenia to sarcopenia groups had higher risk of MCI (34.8%, 32.0%, vs. 17.4%) and dementia (20.6%, 19.8%, vs. 8.7%), compared non-sarcopenia group (P < 0.001). Multivariate linear regression analyses showed that sarcopenia [regression coefficients (ß) -1.098, 95% confidence interval (CI) -1.872, -0.324, P = 0.005] and non-sarcopenia to sarcopenia (ß -1.826, -2.441, -1.212, P < 0.001) were associated with faster cognitive decline compared to non-sarcopenia. HGS decline (ß 0.046, 0.027-0.064, P < 0.001) and ASMI decline (ß 0.236, 0.109-0.362, P < 0.001) were both positively associated with cognitive decline. Multivariate logistic regression analyses demonstrated that patients with sarcopenia and non-sarcopenia to sarcopenia were both at increased risk of developing MCI [odds ratio (OR) 1.788, 95% CI 1.115-2.870, P = 0.016 and OR 1.589, 95% CI 1.087-2.324, P = 0.017, respectively], but only non-sarcopenia to sarcopenia was at increased risk of dementia (OR 1.792, 95% CI 1.108-2.879, P = 0.017). Both greater change of ASMI and HGS had lower risk of MCI with adjusted ORs of 0.857 (0.778-0.945, P = 0.002) and 0.976 (0.963-0.989, P < 0.001). Robust associations were found among female individuals, aged >60 years, and with low educational level. CONCLUSIONS: Longitudinal associations were observed between new-onset, persistent sarcopenia, and cognitive impairment. Early detection and intervention should be implemented to delay the onset of sarcopenia and improve cognitive health among HD patients.

Multiplex lateral flow test strip for detection of carbapenemase genes using barcoded tetrahedral DNA capture probe-based biosensing interface.

Carbapenem-resistant Enterobacterales pose significant global health challenges due to their rapid spread and ability to hydrolyse various beta-lactam antibiotics. Rapid tests for these carbapenemase genes are crucial to ensure appropriate prescription administration and infection control. In this study, we developed a rapid visual nanodiagnostic platform for multiplexed detection of carbapenemase genes using a lateral flow strip. The nanodiagnostic strip was designed with separate barcoded DNA tetrahedrons for the blaKPC and blaNDM genes. These tetrahedrons were distributed on a nitrocellulose membrane at two different test lines as capture probes. When tested against a panel of carbapenemase genes, the tetrahedral probes captured single-stranded amplicons of asymmetric PCR via strand hybridisation. The amplicons acted as bridging elements, binding the DNA-modified gold nanoparticles to the test line of the strip, resulting in clear visual readouts specific to the blaKPC and blaNDM genes. By employing barcoded tetrahedrons and asymmetric PCR in conjunction with the lateral flow strip, a single diagnostic test enabled the detection of multiple carbapenemase genes. The test yielded results as low as 0.12 fM for blaKPC and 0.05 fM for blaNDM within 75 min. Furthermore, the strip effectively identified specific carbapenemase genes in clinical isolates using real-time PCR, antibody-based lateral flow systems for carbapenemase detection, and carbapenemase phenotype experiments. Thus, the strip develop has a high potential for testing blaKPC and blaNDM genes in practice.

Dendrobium officinale Kimura & Migo polysaccharide inhibits hyperglycaemia-induced kidney fibrosis via the miRNA-34a-5p/SIRT1 signalling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Fibrosis is a fundamental change occurring in impaired renal function and plays an important role in the progression of diabetic kidney disease (DKD). Dendrobium officinale Kimura & Migo polysaccharide (DOP), a primary active component of Dendrobium officinale Kimura & Migo, is reported to act on reducing blood glucose, suppressing inflammation. However, the anti-fibrosis effect of DOP in the treatment of DKD is still unclear. AIM OF THE STUDY: To explore the therapeutic effect of DOP on renal fibrosis in DKD. MATERIALS AND METHODS: We used db/db mice as a DKD model and administered DOP by oral gavage. The expression of miRNA-34a-5p, SIRT1, and fibrosis molecules (TGF-ß, CTGF, and a-SMA) were detected in renal tissue. Human renal tubular epithelium cells (HK-2) were cultured with 5.5 mM glucose (LG) or 25 mM glucose (HG), and intervened with 100-400 µg/ml DOP. The changes of the above indicators were observed in vitro. RESULTS: MiRNA-34a-5p was mainly localised in the nucleus and increased expression in the DKD mice. Inhibition or excitation of miRNA-34a-5p is involved in renal fibrosis by regulating SIRT1. DOP could depress the miRNA-34a-5p/SIRT1 signalling pathway to relieve renal fibrosis. Moreover, DOP has outstanding results in the treatment of DKD through hypoglycaemic action and weight reduction. CONCLUSIONS: DOP plays a protective role in arresting or slowing the progression of fibrosis, which may provide a novel clinical treatment strategy for DKD.

Glycolytic regulatory enzyme PFKFB3 as a prognostic and tumor microenvironment biomarker in human cancers.

The 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFK-2/FBPase-2, PFKFB3) is a glycolysis regulatory enzyme and plays a key role in oncogenesis of several cancers. However, the systematic study of crosstalk between PFKFB3 and Tumor microenvironment (TME) in pan-cancer has less been examined. In this study, we conducted a comprehensive analysis of the relationship between PFKFB3 expression, patient prognostic, Tumor mutational burden (TMB), Microsatellite instability (MSI), DNA mismatch repair (MMR), and especially TME, including immune infiltration, immune regulator, and immune checkpoint, across 33 types of tumors using datasets of The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). We found that PFKFB3 expression was significantly correlated with patient prognostic and TME factors in various tumors. Moreover, we confirmed that PFKFB3 was an independent prognostic factor for kidney renal papillary cell carcinoma (KIRP), and established a risk prognostic model based on the expression of PFKFB3 as a clinical risk factor, which has a good predictive ability. Our study indicated that PFKFB3 is a potent regulatory factor for TME and has the potential to be a valuable prognostic biomarker in human tumor therapy.

[C21 inhibits cytokine secretion in rat renal tubular epithelial cells stimulated by advanced glycation end products].

Objective To investigate the effect and mechanism of compound 21(C21), an agonist of angiotensin II-2 receptor (AT2R) on the cytokine levels of NRK-52E cells stimulated by advanced glycation end products bovine serum albumin (AGE-BSA). Methods NRK-52E cells were divided into control and (25, 50, 100, 200)mg/L AGE-BSA groups and cultured for 48 hours. The mRNA and protein expression levels of leukin-6 (IL-6) and tumor necrosis factor α (TNF-α) were detected by real-time quantitative PCR and ELISA. The NRK-52E cells stimulated by AGE-BSA(25 mg/L) for 48 hours were then treated with (0.01, 0.05, 0.1)mmol/L C21 for 24 hours. The mRNA and protein expression levels of protein kinase C (PKC), nuclear factor κB p65 (NF-κB p65) and transforming growth factor ß1 (TGF-ß1) were detected by qRT-PCR and Western blot analysis. Results The mRNA expression levels of IL-6 and TNF-α significantly increased in NRK-52E cells stimulated by AGE-BSA at different doses, with the greatest increase in the 25 mg/L AGE-BSA group. The mRNA and protein expression levels of PKC, NF-κB p65 and TGF-ß1 in AGE-BSA-induced NRK-52E cells significantly decreased by (0.01, 0.05, 0.1)mmol/L C21. Conclusion AGE-BSA promotes the expression of IL-6, TNF-α, PKC, NF-κB p65 and TGF-ß1 in NRK-52E cells, while C21 inhibits the effect of AGE-BSA on NRK-52E cells.

Acteoside alleviates UUO-induced inflammation and fibrosis by regulating the HMGN1/TLR4/TREM1 signaling pathway.

Purpose: Acteoside (Act), a phenylethanoid compound that was first isolated from mullein, has been widely used for the investigation of anti-inflammatory and anti-fibrotic effect. However, the mechanism of Act against unilateral ureteral obstruction (UUO)-mediated renal injury is largely unknown. Therefore, this study aimed to explore the effects of Act on UUO rats and possible mechanisms. Methods: A total of 20 Sprague-Dawley (SD) rats were divided randomly into three groups (n ≥ 6): (i) sham-operated group (Sham); (ii) UUO group (UUO+Saline); and (iii) UUO + Act 40 mg/kg/day, (UUO+Act); Continuous gavage administration for 2 weeks postoperatively, while the rats in Sham and UUO+saline groups were given equal amounts of saline. All rats were sacrificed after 14 days, the urine and blood samples were collected for biochemical analysis, the renal tissues were collected for pathological staining and immunohistochemistry. Correlations between individual proteins were analyzed by Pearson correlation analysis. Results: The results of renal function indexes and histopathological staining showed that Act could improve renal function by reducing serum creatinine, blood urea nitrogen and urine protein at the same time, Act could alleviate renal inflammation and fibrosis. In addition, the results of immunohistochemistry showed that Act could reduce the expression of inflammation and kidney injury-related proteins F4/80, Mcp-1, KIM-1 proteins, as well as the expression of fibrosis-related protein α-SMA and ß-catenin. More importantly, Act can also reduce the expression of HMGN1, TLR4 and TREM-1 proteins. Conclusion: These data demonstrate that Act can ameliorate UUO-induced renal inflammation and fibrosis in rats probably through triggering HMGN1/TLR4/TREM-1 pathway.

The Impact of Malnutrition, Inflammation on Cognitive Impairment in Hemodialysis Patients: A Multicenter Study.

INTRODUCTION: Cognitive impairment is prevalent in patients undergoing hemodialysis (HD), which is related to the nutritional and inflammatory status of this population. Malnutrition-inflammation score (MIS) has been identified as a useful tool to evaluate nutrition and inflammation status. The aim of this study is to investigate the association between MIS and cognitive impairment in HD patients. METHODS: This was a multicenter observational cohort study with 1,591 patients undergoing HD. Nutritional and inflammatory status was evaluated with MIS, anthropometric measurements, and body composition assessments. Cognitive function was evaluated with the Mini Mental State Examination (MMSE). The associations between MIS and cognitive impairment were analyzed by multivariable logistic regression models. RESULTS: Among 1,591 HD patients, the mean MIS was 6.0 ± 2.6. Patients with higher MIS had significantly lower MMSE scores. 311 patients had cognitive impairment. After adjusting clinical confounders, higher MIS was independently associated with increased rate of cognitive impairment both as a categorized variable (OR, 1.358; 95% CI, 1.010-1.825; p = 0.045) and as a continuous variable (OR, 1.113; 95% CI, 1.053-1.178; p < 0.001). Subgroup analysis showed a stronger association between MIS and cognitive impairment in males, the population with age 41-60 years, and 61-80 years, no smoker, living by oneself, HD combined with or without hemoperfusion as dialysis modality. ROC curve analysis of MIS showed 60.1% sensitivity and 52.0% specificity in predicting cognitive impairment (AUC 0.604; 95% CI 0.567-0.640, p < 0.001). CONCLUSIONS: MIS was independently associated with cognitive impairment in HD patients.

Hyperhomocysteinemia exacerbates acute kidney injury via increased mitochondrial damage.

Acute kidney injury (AKI) is a complex and common set of multifactorial clinical syndromes, and associated with increased in-hospital mortality. There is increasing evidence that Hyperhomocysteinemia (HHcy) is highly associated with the development of a variety of kidney diseases, including AKI. However, the pathogenesis of HHcy in AKI remains unclear. In this study, we investigated the effect and mechanism of HHcy on cisplatin-induced AKI in mice and NRK-52E cells cultured with HHcy. We confirmed that mice with HHcy had higher serum levels of creatinine and more severe renal tubule injury after cisplatin injection. We found that HHcy aggravated renal mitochondrial damage, mainly manifested as decreased ATP ß, significantly increased cytoplasmic Cyt C expression and the ADP/ATP ratio, and a significantly decreased mitochondrial DNA (mtDNA) copy number. In addition, we found that HHcy accelerated cisplatin-induced renal DNA damage; culturing NRK-52E cells with homocysteine (Hcy) could significantly increase apoptosis and mitochondrial damage. Interestingly, we found that Mdivi-1 reduced Hcy-induced mitochondrial damage, thereby reducing the level of apoptosis. In conclusion, these results suggest that HHcy might aggravate the development of AKI by increasing mitochondrial damage and that reducing Hcy levels or inhibiting mitochondrial damage may be a potential therapeutic strategy to delay the development of AKI.

Single-cell RNA sequencing data analysis suggests the cell-cell interaction patterns of the pituitary-kidney axis.

Kidney functions, including electrolyte and water reabsorption and secretion, could be influenced by circulating hormones. The pituitary gland produces a variety of hormones and cytokines; however, the influence of these factors on the kidney has not been well explained and explored. To provide more in-depth information and insights to support the pituitary-kidney axis connection, we used mouse pituitary and kidney single-cell transcriptomics data from the GEO database for further analysis. Based on a ligand-receptor pair analysis, cell-cell interaction patterns between the pituitary and kidney cell types were described. Key ligand-receptor pairs, such as GH-GHR, PTN-SDC2, PTN-SDC4, and DLK1-NOTCH3, were relatively active in the pituitary-kidney axis. These ligand-receptor pairs mainly target proximal tubule cells, principal cells, the loop of Henle, intercalated cells, pericytes, mesangial cells, and fibroblasts, and these cells are related to physiological processes, such as substance reabsorption, angiogenesis, and tissue repair. Our results suggested that the pituitary gland might directly regulate kidney function by secreting multiple hormones or cytokines and indicated that the above ligand-receptor pairs might represent a new research focus for studies on kidney function or kidney disease.

Renal tubule ectopic lipid deposition in diabetic kidney disease rat model and in vitro mechanism of leptin intervention

Diabetic kidney disease (DKD) is a major health burden closely related to lipid metabolism disorders. Leptin has lipid-lowering efficacy, but the specific mechanism of its local effects on kidney is still unclear. This study aims to investigate the role of ectopic lipid deposition (ELD) in DKD and evaluate the lipid-lowering efficacy of leptin in the palmitic acid (PA)-induced renal tubular epithelial cells (NRK-52E). DKD model was established in Sprague–Dawley (SD) rats by giving single intraperitoneal injection of streptozotocin (STZ, 30 mg/kg) after high-fat diet for 8 weeks. Then, the expression changes of lipid metabolism-related markers were observed. At week 12, the protein expression level of lipid-deposited marker adipose differentiation-related protein (ADRP) was significantly increased. Besides, the lipid synthesis marker sterol regulatory element-binding protein 1c (SREBP 1c) was highly expressed while the expression of insulin-induced gene 1 (Insig-1), a key molecular of inhibiting SREBP 1c, was decreased. Leptin and compound c were incubated with the PA-induced NRK-52E cells to investigate the lipid-lowering effects and whether this effect was mediated by the AMPK/Insig-1/SREBP 1c signaling pathways. mRNA and protein of ADRP and SREBP 1c were reduced after leptin treatment, while Insig-1 and phosphorylated AMP-activated protein kinase (AMPK) were increased. Conversely, inhibition of AMPK phosphorylation by compound c mostly eliminated lipid-lowering efficacy of leptin in PA-induced cells. Collectively, these results suggested that there was ELD of renal tubular epithelial cells in DKD rats. Leptin upregulated the expression level of Insig-1 by activating AMPK to attenuate ELD in PA-induced NRK-52E cells. (AU)

Renal tubule ectopic lipid deposition in diabetic kidney disease rat model and in vitro mechanism of leptin intervention.

Diabetic kidney disease (DKD) is a major health burden closely related to lipid metabolism disorders. Leptin has lipid-lowering efficacy, but the specific mechanism of its local effects on kidney is still unclear. This study aims to investigate the role of ectopic lipid deposition (ELD) in DKD and evaluate the lipid-lowering efficacy of leptin in the palmitic acid (PA)-induced renal tubular epithelial cells (NRK-52E). DKD model was established in Sprague-Dawley (SD) rats by giving single intraperitoneal injection of streptozotocin (STZ, 30 mg/kg) after high-fat diet for 8 weeks. Then, the expression changes of lipid metabolism-related markers were observed. At week 12, the protein expression level of lipid-deposited marker adipose differentiation-related protein (ADRP) was significantly increased. Besides, the lipid synthesis marker sterol regulatory element-binding protein 1c (SREBP 1c) was highly expressed while the expression of insulin-induced gene 1 (Insig-1), a key molecular of inhibiting SREBP 1c, was decreased. Leptin and compound c were incubated with the PA-induced NRK-52E cells to investigate the lipid-lowering effects and whether this effect was mediated by the AMPK/Insig-1/SREBP 1c signaling pathways. mRNA and protein of ADRP and SREBP 1c were reduced after leptin treatment, while Insig-1 and phosphorylated AMP-activated protein kinase (AMPK) were increased. Conversely, inhibition of AMPK phosphorylation by compound c mostly eliminated lipid-lowering efficacy of leptin in PA-induced cells. Collectively, these results suggested that there was ELD of renal tubular epithelial cells in DKD rats. Leptin upregulated the expression level of Insig-1 by activating AMPK to attenuate ELD in PA-induced NRK-52E cells.

Roxadustat (FG-4592) protects against ischaemia/reperfusion-induced acute kidney injury through inhibiting the mitochondrial damage pathway in mice.

Ischaemia-reperfusion (I/R) is one of the main factors of acute kidney injury (AKI). mitochondrial damage pathway are important features of I/R induced-acute kidney injury (IRI-AKI). Hypoxia-inducible factor (HIF) expression in renal tubule segments is up-regulated during AKI. Herein, we investigated the role of FG-4592 in a mouse model of IRI-AKI to confirm whether FG-4592 is beneficial in AKI. We found that pretreatment with FG-4592 significantly ameliorated renal function and renal histological damage in mice after IRI. Furthermore, these results suggest that pretreatment with FG-4592 significantly reduced the tubular cells apoptosis (decreased TUNEL-positive cells, Bax, caspase12 levels), attenuated mitochondrial damage (increased ATPß, PPARγ, mitochondrial DNA copy number, and decreased cytoplasmic cytochrome C), and alleviated DNA damage after IRI. In conclusion, pretreatment with FG-4592 may effectively prevent kidney from IRI possibly by via diminishing tubular cells injuries and protection of mitochondrial damage pathway. These results further validate that FG-4592 may be an effective drug in the clinical treatment of IRI-AKI.