Gasdermin D deficiency aborts myeloid calcium influx to drive granulopoiesis in lupus nephritis.

Gasdermin D (GSDMD) is emerging as an important player in autoimmune diseases, but its exact role in lupus nephritis (LN) remains controversial. Here, we identified markedly elevated GSDMD in human and mouse LN kidneys, predominantly in CD11b+ myeloid cells. Global or myeloid-conditional deletion of GSDMD was shown to exacerbate systemic autoimmunity and renal injury in lupus mice with both chronic graft-versus-host (cGVH) disease and nephrotoxic serum (NTS) nephritis. Interestingly, RNA sequencing and flow cytometry revealed that myeloid GSDMD deficiency enhanced granulopoiesis at the hematopoietic sites in LN mice, exhibiting remarkable enrichment of neutrophil-related genes, significant increases in total and immature neutrophils as well as granulocyte/macrophage progenitors (GMPs). GSDMD-deficient GMPs and all-trans-retinoic acid (ATRA)-stimulated human promyelocytes NB4 were further demonstrated to possess enhanced clonogenic and differentiation abilities compared with controls. Mechanistically, GSDMD knockdown promoted self-renewal and granulocyte differentiation by restricting calcium influx, contributing to granulopoiesis. Functionally, GSDMD deficiency led to increased pathogenic neutrophil extracellular traps (NETs) in lupus peripheral blood and bone marrow-derived neutrophils. Taken together, our data establish that GSDMD deletion accelerates LN development by promoting granulopoiesis in a calcium influx-regulated manner, unraveling its unrecognized critical role in LN pathogenesis.

Up-to-date advance in the relationship between OSA and stroke: a narrative review.

PURPOSE: Obstructive sleep apnea (OSA) and stroke affect each other. In this review, we summarized the effect of OSA on the onset and recurrence of stroke, the prognosis, and the treatment of poststroke patients with OSA. METHODS: Pubmed/MEDLINE were searched through May 2023 to explore the relationship between OSA and stroke. The relevant papers included OSA and stroke, OSA and recurrent stroke, and the prognosis and treatment of poststroke patients with OSA. RESULTS: The results showed that OSA can promote the onset and recurrence of stroke and that OSA may adversely affect the prognosis of poststroke patients. The application of continuous positive airway pressure (CPAP) and other treatments may benefit poststroke patients with OSA, though the long term effects of treatment are not well documented. CONCLUSION: Both the onset and recurrence of stroke closely correlated with OSA, but the specific mechanisms remain unclear. Further studies should be carried out to explore effective treatments in patients with stroke and OSA.

The effect of traditional Chinese medicine soaking method on the healing of diabetic foot ulcers: A meta-analysis.

Foot infections, sores or deep tissue damage from diabetes can be a serious psychological and physical injury. This paper aims at making meta-analyses on the therapeutic effects of traditional Chinese medicine (TCM) on diabetic foot ulcers. The Chinese National Knowledge Infrastructure, VIP Database, Wanfang Database and so on, has conducted a randomized controlled trial to evaluate the clinical effect of TCM soaking method for diabetes patients with diabetes. Literature has been determined to be included by computer search and by hand rough checks. The search period was from the creation of the database to October 2023. Review Manager 5.3 was used to analyse the meta data and evaluate it systematically. Altogether, 479 research was conducted in China's data base and 20 of them were eventually collected for the final statistical analysis. In all, 1361 patients were enrolled in the trials. The results indicated that TCM immersion in diabetic foot resulted in significantly improved obvious wound healing (OR, 3.2; 95% CI, 2.5, 4.09, p < 0.0001); results showed that TCM immersion therapy significantly increased the efficiency of effective wound healing (OR, 4.55; 95% CI, 3.25, 6.37, p < 0.001). Statistical significance was found. Using Egger's approach to detect publishing bias suggests that there is no risk of publishing bias in terms of marked wound healing and effective healing. Traditional Chinese drug immersion can increase obviously the recovery ratio and the effective recovery ratio of diabetic foot.

Elevated Serum Trimethylamine N-Oxide Levels Are Associated with Mortality in Male Patients on Peritoneal Dialysis.

BACKGROUND: Elevated levels of serum trimethylamine N-oxide (TMAO) have been previously linked to adverse cardiovascular (CV) and all-cause mortality in hemodialysis patients. However, the clinical significance of serum TMAO levels in patients treated with peritoneal dialysis (PD) is unclear. METHODS: A total of 1,032 PD patients with stored serum samples at baseline were enrolled in this prospective study. Serum concentrations of TMAO were quantified by ultra-performance liquid chromatography-tandem mass spectrometry. Cox proportional hazards and competing-risk regression models were performed to examine the association of TMAO levels with all-cause and CV mortality. RESULTS: The median level of serum TMAO in our study population was 34.5 (interquartile range (IQR), 19.8-61.0) µM. During a median follow-up of 63.7 months (IQR, 43.9-87.2), 245 (24%) patients died, with 129 (53%) deaths resulting from CV disease. In the entire cohort, we observed an association between elevated serum TMAO levels and all-cause mortality (adjusted subdistributional hazard ratio [SHR], 1.22; 95% confidence interval [95% CI], 1.01-1.48; p = 0.039) but not CV mortality. Further analysis revealed such association differed by sex; the elevation of serum TMAO levels was independently associated with increased risk of both all-cause (SHR, 1.37; 95% CI, 1.07-1.76; p = 0.013) and CV mortality (SHR, 1.41; 95% CI, 1.02-1.94; p = 0.038) in men but not in women. CONCLUSIONS: Higher serum TMAO levels were independently associated with all-cause and CV mortality in male patients treated with PD.

Association of left ventricular systolic dysfunction with mortality in incident peritoneal dialysis patients.

AIM: Cardiovascular disease is associated with morbidity and mortality in peritoneal dialysis patients but the relationship between left ventricular ejection fraction (LVEF) and outcomes is unclear. This study aimed to explore the association between LVEF and mortality in incident continuous ambulatory peritoneal dialysis (CAPD) patients. METHODS: The patients were divided into three groups according to LVEF levels (>0.6, 0.5 to 0.6, and <0.5). Kaplan-Meier analysis and the Cox proportional hazards models were used to evaluate association of LVEF with mortality. RESULTS: Among the 594 patients, LVEF levels of >0.6, 0.5 to 0.6, and <0.5 were detected in 428 (72.0%), 127 (21.4%) and 39 (6.6%) patients, respectively. During a median follow-up of 39.6 months, 127 (21.4%) patients died, of the deaths, 57.5% were attributable to cardiovascular causes. Patients with LVEF <0.5 had worst overall rates of survival and cardiovascular death-free survival among groups. Compared with LVEF >0.6, adjusted all-cause mortality hazard ratio (HR) and 95% confidence interval (CI) for patients with LVEF 0.5 to 0.6 and <0.5 were 1.62 (1.09-2.43) and 1.93 (1.06-3.52), respectively. The corresponding adjusted cardiovascular mortality HR were 1.60 (0.94-2.47) and 2.16 (1.04-4.74), respectively. CONCLUSION: Reduced LVEF is significantly associated with increased all-cause and cardiovascular mortality in incident CAPD patients.

Association of baseline, longitudinal serum high-sensitive C-reactive protein and its change with mortality in peritoneal dialysis patients.

BACKGROUND: The prognostic values of baseline, longitudinal high-sensitivity C-reactive protein (hs-CRP) and its change over time on mortality in patients undergoing continuous ambulatory peritoneal dialysis (CAPD) remain uncertain. METHODS: We retrospectively studied 1228 consecutive CAPD patients from 2007 to 2012, and followed up through December 2014. Cox regression models were performed to assess the association of hs-CRP on outcomes using serum hs-CRP levels as: (1) stratified by tertile of baseline or longitudinal hs-CRP levels; (2) baseline or longitudinal hs-CRP levels as continuous variables; and (3) categorized by tertile of slopes of hs-CRP change per year for each subject. RESULTS: Higher baseline hs-CRP levels were not associated with clinical outcomes after adjustment for potential confounders. However, patients with the upper tertile of longitudinal hs-CRP had a nearly twice-fold increased risk of both all-cause and cardiovascular mortality [adjusted hazard ratio (HR) 1.77; (95% CI 1.16-2.70) and 2.08 (1.17-3.71), respectively], as compared with those with lower tertile. Results were similar when baseline or longitudinal hs-CRP was assessed as continuous variable. Additionally, the risk of all-cause and cardiovascular mortality in patients with increased trend in serum hs-CRP levels over time (tertile 3) was significantly higher [adjusted HR 2.48 (1.58-3.87) and 1.99 (1.11-3.56), respectively] when compared to those with relatively stable hs-CRP levels during follow-up period. These associations persisted after excluding subjects with less than 1-year follow up. CONCLUSIONS: Higher longitudinal serum hs-CRP levels and its elevated trend over time, but not baseline levels were predictive of worse prognosis among CAPD patients.

The Arg399Gln polymorphism in the XRCC1 gene is associated with increased risk of hematological malignancies.

The associations between the Arg399Gln polymorphism in X-ray repair cross-complementing gene 1 (XRCC1) gene and the risk of hematological malignancies have been extensively investigated. However, the results were inconsistent. The objective of the current study is to investigate the association by meta-analysis. We searched PubMed database, Embase database, CNKI database, Wanfang database, and Weipu database, covering all studies until August 7, 2013. Statistical analysis was performed by using the Revman4.2 software and the Stata10.0 software. A total of 27 case-control studies concerning the Arg399Gln polymorphism were included from 26 articles. The results suggested that the Arg399Gln polymorphism was not associated with an increased/decreased risk of hematological malignancies in total analysis (OR = 1.15, 95 % confidence interval (CI) = 0.97-1.35, P = 0.10 for Arg/Gln + Gln/Gln vs. Arg/Arg). In the subgroup analysis by ethnicity and cancer types, significant association was found in Asians (OR = 1.35, 95 % CI = 1.04-1.75, P = 0.03) but not in Europeans (OR = 1.07, 95 % CI = 0.86-1.33, P = 0.56), and in leukemia (OR = 1.25, 95 % CI = 1.02-1.54, P = 0.03) but not in lymphoma (OR = 0.98, 95 % CI = 0.80-1.20, P = 0.84) or myeloma (OR = 1.13, 95 % CI = 0.23-5.69, P = 0.88). The current meta-analysis indicated that the Arg399Gln polymorphism in the XRCC1 gene might be a risk factor for hematological malignancies in Asians or for leukemia. In future, more large-scale case-control studies are needed to validate these results.

The Three-Dimensional Techniques in the Objective Measurement of Breast Aesthetics.

UNLABELLED: Breast symmetry, size, and shape are key components of aesthetic outcomes of augmentation mammoplasty, reduction, and reconstruction. Many have claimed that the 3D scanning technique, which measures breast volumes directly and assesses the asymmetry of the chest and breast on a 3D model, is superior to anthropometric measuring in accuracy, precision, and reproducibility. The documented methods of 3D body surface imaging include laser scanning, stereo photography and so on. To achieve ideal aesthetic results, individualized surgery planning based on a reliable virtual model of the prospective surgery outcome could be of considerable value in decision making and assisting in guidance for the surgery procedure. Additionally, the 3D scanning technique is applicable in postoperative monitoring of morphological change, notably, in a dynamic way. Another distinguishing feature is that it enables virtual division of breast volume, thus surgeons could virtually divide the breast volumes into portions using 3D scanning during the programming and evaluation of surgery plans. However, because 3D surface scanning cannot look through the breast substances and reach the interspace between the chest and posterior border of the breast/dorsal limit of the breast, the inframammary fold in larger breasts cannot be correctly imaged, leaving the preoperative inframammary fold reference lacking. Therefore, 3D scanning is thought to be inaccurate in large and/or ptotic breasts. Another fact that prevents 3D scanning from wide application is its high cost and lack of access. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

The association between the Arg280His polymorphism in the XRCC1 gene and the risk of hematological malignancies.

The associations between the Arg280His polymorphism in X-ray repair cross-complementing gene 1 (XRCC1 gene) and hematological malignancies have been extensively investigated. However, the results were inconsistent. The objective of the current study was to investigate the associations between the Arg280His polymorphism in XRCC1 gene and the risk of hematological malignancies by meta-analysis. We searched PubMed, Embase, CNKI, Wanfang, and Weipu databases, covering all studies until 07 Aug 2013. Statistical analysis was performed by using the Revman4.2 software and the Stata10.0 software. A total of 2,650 cases and 3,856 controls in 12 case-control studies concerning the Arg280His polymorphism were included. The results suggested that the Arg280His polymorphism might not be associated with risk of hematological malignancies (OR = 1.08, 95%CI = 0.86-1.35, P = 0.50). In the subgroup analyses by cancer types and ethnicity, no significant associations were found among different cancers or different ethnicities. The current meta-analysis indicated that the Arg280His polymorphism in the XRCC1 gene might not be a risk factor for hematological malignancies. In future, more large-scale case-control studies are needed to validate these results.

The Glu298Asp polymorphism in the NOS3 gene and the risk of prostate cancer.

The Glu298Asp polymorphism in the NOS3 gene has been implicated as a risk factor for prostate cancer. To date, several studies have evaluated the associations between the Glu298Asp polymorphism and prostate cancer risk; however, the results were inconclusive. The aim of the current study was to perform a meta-analysis to investigate the association between the polymorphism and the risk of prostate cancer. A total of 3,206 cases and 3,880 controls from eight case-control studies were included for data synthesis. The overall results suggested no significant association between the polymorphism and the risk of prostate cancer (OR=1.01, 95% CI=0.92-1.11, p = 0.83 for Asp/Asp+Glu/Asp vs. Glu/Glu). In the stratified analysis according to ethnicity, no significant associations were observed in Asians and Europeans. The current meta-analysis suggested that the Glu298Asp polymorphism of the NOS3 gene might not contribute to the risk of prostate cancer.

The Thr241Met polymorphism in the XRCC3 gene is associated with increased risk of cancer in Chinese mainland populations.

The Thr241Met polymorphism in XRCC3 gene may affect the DNA repair pathways and be associated with the risk of cancer. However, the results of previous studies are inconsistent in Chinese mainland populations. The objective of this study is to investigate the association between the Thr241Met polymorphism in XRCC3 gene and risk of cancer for the Chinese Mainland populations by meta-analysis. We searched PubMed database, Embase database, CNKI database, and Wanfang database, and the last search was updated on July 24, 2013. Statistical analysis was performed using RevMan4.2 and Stata10.0 software. Finally, a total of 23 case-control studies in 23 articles were included. The results suggested a significant association between the Thr241Met polymorphism in XRCC3 gene and cancer risk in Chinese mainland populations (Met/Met + Thr/Met vs. Thr/Thr: OR = 1.25, 95 % CI = 1.02-1.54, P = 0.04). In the subgroup analyses by cancer types, significant associations were found in cervical cancer and nasopharyngeal cancer. The current meta-analysis suggested that the Thr241Met polymorphism in the XRCC3 gene may be a risk factor for cancer in Chinese mainland populations. In the future, more case-control studies are needed to validate these results.

Study on the association between the Arg194Trp polymorphism in the XRCC1 gene and the risk of hematological malignancies.

The association between the Arg194Trp polymorphism in the XRCC1 gene and the risk of hematological malignancies has been extensively investigated. However, the results were inconsistent. The objective of the current study is to investigate the association by meta-analysis. We searched the PubMed, Embase, CNKI, Wanfang, and Weipu databases, covering all studies until Aug. 7, 2013. Statistical analysis was performed by using the RevMan4.2 software and the Stata10.0 software. A total of 20 case-control studies concerning the Arg194Trp polymorphism were indentified from 19 articles. In total analysis, our results suggested that the Arg194Trp polymorphism was not associated with an increased/decreased risk of hematological malignancies (odds ratio (OR) = 1.01, 95 % confidence interval (CI) = 0.85-1.22, P = 0.87 for Arg/Trp+Trp/Trp vs. Arg/Arg). In the subgroup analysis by ethnicity, no significant association was found either among Asians (OR = 1.04, 95% CI = 0.84-1.29, P = 0.72) or among Europeans (OR = 1.04, 95% CI = 0.72-1.49, P = 0.83); in the subgroup analyses by cancer types, no significant association was found either among leukemia (OR = 1.10, 95% CI = 0.89-1.35, P = 0.39) or in lymphoma (OR = 0.83, 95% CI = 0.57-1.22, P = 0.35). The current meta-analysis indicated that the Arg194Trp polymorphism in the XRCC1 gene might be not a risk factor for hematological malignancies. In the future, more large-scale case-control studies are needed to validate these results.

Acetylcholinesterase overexpression mediated by oncolytic adenovirus exhibited potent anti-tumor effect.

BACKGROUND: Acetylcholinesterase (AChE) mainly functions as an efficient terminator for acetylcholine signaling transmission. Here, we reported the effect of AChE on gastric cancer therapy. METHODS: The expression of AChE in gastric cancerous tissues and adjacent non-cancerous tissues was examined by immunohistochemistry. Gastric cancer cells were treated with AChE delivered by replication-deficient adenoviral vector (Ad.AChE) or oncolytic adenoviral vector (ZD55-AChE), respectively, followed by measurement of cell viability and apoptosis by MTT assay and apoptosis detection assays. In vivo, the tumor growth of gastric cancer xenografts in mice treated with Ad.AChE or ZD55-AChE (1 × 10(9) PFU) were measured. In addition, the cell viability of gastric cancer stem cells treated with Ad.AChE or ZD55-AChE were evaluated by MTT assay. RESULTS: A positive correlation was found between higher level of AChE expression in gastric cancer patient samples and longer survival time of the patients. Ad.AChE and ZD55-AChE inhibited gastric cancer cell growth, and low dose of ZD55-AChE induced mitochondrial pathway of apoptosis in cells. ZD55-AChE repressed tumor growth in vivo, and the anti-tumor efficacy is greater than Ad.AChE. Moreover, ZD55-AChE suppressed the growth of gastric cancer stem cells. CONCLUSION: ZD55-AChE represented potential therapeutic effect for human gastric cancer.

A tablet-based multi-dimensional drawing system can effectively distinguish patients with amnestic MCI from healthy individuals.

The population with dementia is expected to rise to 152 million in 2050 due to the aging population worldwide. Therefore, it is significant to identify and intervene in the early stage of dementia. The Rey-Osterreth complex figure (ROCF) test is a visuospatial test scale. Its scoring methods are numerous, time-consuming, and inconsistent, which is unsuitable for wide application as required by the high number of people at risk. Therefore, there is an urgent need for a rapid, objective, and sensitive digital scoring method to detect cognitive dysfunction in the early stage accurately. This study aims to clarify the organizational strategy of aMCI patients to draw complex figures through a multi-dimensional digital evaluation system. At the same time, a rapid, objective, and sensitive digital scoring method is established to replace traditional scoring. The data of 64 subjects (38 aMCI patients and 26 NC individuals) were analyzed in this study. All subjects completed the tablet's Geriatric Complex Figure (GCF) test, including copying, 3-min recall, and 20-min delayed recall, and also underwent a standardized neuropsychological test battery and classic ROCF test. Digital GCF (dGCF) variables and conventional GCF (cGCF) scores were input into the forward stepwise logistic regression model to construct classification models. Finally, ROC curves were made to visualize the difference in the diagnostic value of dGCF variables vs. cGCF scores in categorizing the diagnostic groups. In 20-min delayed recall, aMCI patients' time in air and pause time were longer than NC individuals. Patients with aMCI had more short strokes and poorer ability of detail integration (all p < 0.05). The diagnostic sensitivity of dGCF variables for aMCI patients was 89.47%, slightly higher than cGCF scores (sensitivity: 84.21%). The diagnostic accuracy of both was comparable (dGCF: 70.3%; cGCF: 73.4%). Moreover, combining dGCF variables and cGCF scores could significantly improve the diagnostic accuracy and specificity (accuracy: 78.1%, specificity: 84.62%). At the same time, we construct the regression equations of the two models. Our study shows that dGCF equipment can quantitatively evaluate drawing performance, and its performance is comparable to the time-consuming cGCF score. The regression equation of the model we constructed can well identify patients with aMCI in clinical application. We believe this new technique can be a highly effective screening tool for patients with MCI.

A Novel Murine Model for Lupus-Like Ocular Chronic Graft-Versus-Host Disease.

Purpose: Lupus-like chronic graft-versus-host disease (cGVHD) has been previously described, but the ocular findings have not been elucidated. Recipient mice in a lupus-like cGVHD model manifested notable and persistent ocular surface phenotypes. Herein, we further explored immunopathogenic mechanisms underlying these ocular phenotypes. Methods: A previously described lupus-like cGVHD model was established by intraperitoneal injection of splenocytes from bm12 mice into C57BL/6J mice. Systemic findings were evaluated for the presence of splenomegaly, proteinuria, and autoantibodies. Comprehensive evaluations were conducted on ocular manifestations and immunopathological features in this model. Results: The lupus-like cGVHD model was successfully constructed 2 weeks post-transplantation. The recipient mice developed lupus-like phenotypes, including splenomegaly, proteinuria, and increased autoantibodies, and their ocular presentations included corneal epithelial defects and decreased tear secretion. Histological analysis revealed a reduction in corneal nerve fiber density and corneal endothelial cells, along with conjunctival fibrosis and loss of goblet cells. Moreover, cGVHD induced progressive aggravation of immune cell infiltration and fibrosis in the lacrimal glands. RNA-Sequencing (RNA-seq) results of the lacrimal glands demonstrated that the differentially expressed genes (DEGs) between the control and cGVHD groups were associated with GVHD pathways. Immune infiltration analysis using RNA-seq and flow cytometry confirmed that CD8+ T lymphocytes predominantly constituted the inflammatory infiltrating cells within the lacrimal glands. Conclusions: This lupus-like cGVHD model (bm12→C57BL/6J) exhibited persistent ocular surface manifestations, characterized by immune infiltration of CD8+ T lymphocytes in the lacrimal glands. Thus, this ocular cGVHD model may be used to explore the underlying mechanisms and discover novel therapeutic interventions.

Knockout of integrin αvß6 protects against renal inflammation in chronic kidney disease by reduction of pro-inflammatory macrophages.

Integrin αvß6 holds promise as a therapeutic target for organ fibrosis, yet targeted therapies are hampered by concerns over inflammatory-related side effects. The role of αvß6 in renal inflammation remains unknown, and clarifying this issue is crucial for αvß6-targeted treatment of chronic kidney disease (CKD). Here, we revealed a remarkable positive correlation between overexpressed αvß6 in proximal tubule cells (PTCs) and renal inflammation in CKD patients and mouse models. Notably, knockout of αvß6 not only significantly alleviated renal fibrosis but also reduced inflammatory responses in mice, especially the infiltration of pro-inflammatory macrophages. Furthermore, conditional knockout of αvß6 in PTCs in vivo and co-culture of PTCs with macrophages in vitro showed that depleting αvß6 in PTCs suppressed the migration and pro-inflammatory differentiation of macrophages. Screening of macrophage activators showed that αvß6 in PTCs activates macrophages via secreting IL-34. IL-34 produced by PTCs was significantly diminished by αvß6 silencing, and reintroduction of IL-34 restored macrophage activities, while anti-IL-34 antibody restrained macrophage activities enhanced by αvß6 overexpression. Moreover, RNA-sequencing of PTCs and verification experiments demonstrated that silencing αvß6 in PTCs blocked hypoxia-stimulated IL-34 upregulation and secretion by inhibiting YAP expression, dephosphorylation, and nuclear translocation, which resulted in the activation of Hippo signaling. While application of a YAP agonist effectively recurred IL-34 production by PTCs, enhancing the subsequent macrophage migration and activation. Besides, reduced IL-34 expression and YAP activation were also observed in global or PTCs-specific αvß6-deficient injured kidneys. Collectively, our research elucidates the pro-inflammatory function and YAP/IL-34/macrophage axis-mediated mechanism of αvß6 in renal inflammation, providing a solid rationale for the use of αvß6 inhibition to treat kidney inflammation and fibrosis.

A Natural Small Molecule Mitigates Kidney Fibrosis by Targeting Cdc42-mediated GSK-3ß/ß-catenin Signaling.

Kidney fibrosis is a common fate of chronic kidney diseases (CKDs), eventually leading to renal dysfunction. Yet, no effective treatment for this pathological process has been achieved. During the bioassay-guided chemical investigation of the medicinal plant Wikstroemia chamaedaphne, a daphne diterpenoid, daphnepedunin A (DA), is characterized as a promising anti-renal fibrotic lead. DA shows significant anti-kidney fibrosis effects in cultured renal fibroblasts and unilateral ureteral obstructed mice, being more potent than the clinical trial drug pirfenidone. Leveraging the thermal proteome profiling strategy, cell division cycle 42 (Cdc42) is identified as the direct target of DA. Mechanistically, DA targets to reduce Cdc42 activity and down-regulates its downstream phospho-protein kinase Cζ(p-PKCζ)/phospho-glycogen synthase kinase-3ß (p-GSK-3ß), thereby promoting ß-catenin Ser33/37/Thr41 phosphorylation and ubiquitin-dependent proteolysis to block classical pro-fibrotic ß-catenin signaling. These findings suggest that Cdc42 is a promising therapeutic target for kidney fibrosis, and highlight DA as a potent Cdc42 inhibitor for combating CKDs.

FAAH served a key membrane-anchoring and stabilizing role for NLRP3 protein independently of the endocannabinoid system.

NLRP3, the sensor protein of the NLRP3 inflammasome, plays central roles in innate immunity. Over-activation of NLRP3 inflammasome contributes to the pathogenesis of a variety of inflammatory diseases, while gain-of-function mutations of NLRP3 cause cryopyrin-associated periodic syndromes (CAPS). NLRP3 inhibitors, particularly those that inhibit inflammasome assembly and activation, are being intensively pursued, but alternative approaches for targeting NLRP3 would be highly desirable. During priming NLRP3 protein is synthesized on demand and becomes attached to the membranes of ER and mitochondria. Here, we show that fatty acid amide hydrolase (FAAH), the key integral membrane enzyme in the endocannabinoid system, unexpectedly served the critical membrane-anchoring and stabilizing role for NLRP3. The specific interaction between NLRP3 and FAAH, mediated by the NACHT and LRR domains of NLRP3 and the amidase signature sequence of FAAH, was essential for preventing CHIP- and NBR1-mediated selective autophagy of NLRP3. Heterozygous knockout of FAAH, resulting in ~50% reduction in both FAAH and NLRP3 expression, was sufficient to substantially inhibit the auto-inflammatory phenotypes of the NLRP3-R258W knock-in mice, while homozygous FAAH loss almost completely abrogates these phenotypes. Interestingly, select FAAH inhibitors, in particular URB597 and PF-04457845, disrupted NLRP3-FAAH interaction and induced autophagic NLRP3 degradation, leading to diminished inflammasome activation in mouse macrophage cells as well as in peripheral blood mononuclear cells isolated from CAPS patients. Our results unraveled a novel NLRP3-stabilizing mechanism and pinpointed NLRP3-FAAH interaction as a potential drug target for CAPS and other NLRP3-driven diseases.

Group 3 Innate Lymphoid Cells Exacerbate Lupus Nephritis by Promoting B Cell Activation in Kidney Ectopic Lymphoid Structures.

Group 3 innate lymphoid cells (ILC3s) represent a new population in immune regulation, yet their role in lupus nephritis (LN) remains elusive. In the present work, systemic increases in ILC3s, particularly in the kidney, are observed to correlate strongly with disease severity in both human and murine LN. Using MRL/lpr lupus mice and a nephrotoxic serum-induced LN model, this study demonstrates that ILC3s accumulated in the kidney migrate predominantly from the intestine. Furthermore, intestinal ILC3s accelerate LN progression, manifested by exacerbated autoimmunity and kidney injuries. In LN kidneys, ILC3s are located adjacent to B cells within ectopic lymphoid structures (ELS), directly activating B cell differentiation into plasma cells and antibody production in a Delta-like1 (DLL1)/Notch-dependent manner. Blocking DLL1 attenuates ILC3s' effects and protects against LN. Altogether, these findings reveal a novel pathogenic role of ILC3s in B cell activation, renal ELS formation and autoimmune injuries during LN, shedding light on the therapeutic value of targeting ILC3s for LN.

Higher serum phosphorus predicts residual renal function loss in male but not female incident peritoneal dialysis patients.

BACKGROUND: Elevated serum phosphorus level is a risk factor for progression of chronic kidney disease in non-dialysis patients. However, the association of serum phosphorus level with residual renal function (RRF) loss among incident continuous ambulatory peritoneal dialysis (CAPD) patients remains unclear. METHODS: We performed a retrospective analysis of prospectively collected cohort of 1245 incident CAPD patients from January 2006 to December 2015 and followed up until December 2017. Patients were stratified into tertiles according to baseline serum phosphorus levels. RRF loss was defined as residual glomerular filtration rate (mL/min/1.73 m2) reaching zero or estimated urine output less than 200 mL/day on two successive clinic visits. Propensity-score matched Cox's proportional hazards and competing risk models were performed to examine the association of serum phosphorus with RRF loss. RESULTS: A total of 421 (33.82%) patients had loss of RRF over a median follow-up of 26.23 months. In the entire cohort, elevated serum phosphorus was associated with increased risk for RRF loss after adjustment. In the propensity-score matched cohort, patients in the 3rd tertile of serum phosphorus had a 51% higher risk of RRF loss than those in the combination of the 1st and 2nd tertiles. Furthermore, the association of serum phosphorus level with RRF loss differed by sex (interaction P = 0.018). The adjusted HRs per 1 mg/dL increase in serum phosphorus level of RRF loss were 1.32 (95% CI 1.15-1.50, P < 0.001) for male and 1.03 (95% CI 0.87-1.21, P = 0.750) for female, respectively. These findings persisted in competing risk analysis. CONCLUSION: Higher serum phosphorus levels independently predicts RRF loss in men treated with CAPD.