Oridonin attenuates diabetes­induced renal fibrosis via the inhibition of TXNIP/NLRP3 and NF­κB pathways by activating PPARγ in rats.

INTRODUCTION: Oridonin possesses remarkable anti-inflammatory, immunoregulatory properties. However, the renoprotective effects of Oridonin and the underlying molecular mechanisms have not been explored in Diabetic Nephropathy (DN). We hypothesized that Oridonin could ameliorate diabetes­induced renal fibrosis. METHODS: We used streptozocin (STZ)-induced diabetic rats combined high-fat diet to establish a type 2 diabetes mellitus (T2DM) animal model, and then treated with Oridonin (10,20mg/kg/day) for two weeks. Kidney function and renal fibrosis were assessed. We also treated high glucose-induced human renal proximal tubule epithelial cells (HK-2) with Oridonin. In addition, the expression of inflammatory factors and fibrotic markers were analyzed. RESULTS: Oridonin treatment preserved kidney function and markedly limited the renal fibrosis size in diabetic rats. The renal fibrotic markers were inhibited in the 10mg/kg/day group and 20mg/kg/day group compared to the T2DM group. Moreover, the expression levels of TXNIP/NLRP3 and NF­κB pathway were decreased and the level of PPARγ were increased in the Oridonin treatment group compared to non-treated group. In vitro, intervention of PPARγ could significantly regulate the effect of Oridonin on the high glucose-induced inflammatory changes in HK-2. CONCLUSION: Oridonin reduces renal fibrosis and preserves kidney function via the inhibition of TXNIP/NLRP3 and NF­κB pathway by activating PPARγ in T2DM rat model, which indicates potential therapeutic effect of Oridonin on DN.

Research Progress of Pyroptosis in Fatty Liver Disease.

Fatty liver disease (FLD) is a clinical and pathological syndrome characterized by excessive fat deposition and even steatosis in hepatocytes. It has been proven that liver inflammation induced by fat and its derivatives are involved in the pathogenesis of FLD, while the precise mechanism still remains poorly understood. Pyroptosis is programmed inflammatory cell death driving cell swelling and membrane rupture. Pyroptosis is initiated by the activation of inflammasomes and caspases, which further cleaves and activates various gasdermins, leading to pores forming on the cell membrane and the release of pro-inflammatory factors such as interleukin (IL)-1ß and IL-18. Recent studies demonstrate that pyroptosis occurs in hepatocytes, and inhibiting pyroptosis could effectively reduce fat deposition in the liver and could ameliorate inflammation from FLD, attracting our prime focus on the role of pyroptosis in FLD. In this manuscript, we reviewed the current understanding of pyroptosis in FLD development, aiming to provide new insights and potential research targets for the clinical diagnosis and intervention of FLD.

Phase separation of DDX21 promotes colorectal cancer metastasis via MCM5-dependent EMT pathway.

RNA binding proteins (RBPs) contributes to cancer progression, but the underlying mechanism reminds unclear. Here, we find that DDX21, a representative RBP, is highly expressed in colorectal cancer (CRC), which leads to CRC cell migration and invasion in vitro, and CRC to liver metastasis and lung metastasis in vivo. This effect of DDX21 on CRC metastasis is correlated to the activation of Epithelial-mesenchymal transition (EMT) pathway. Moreover, we reveal that DDX21 protein is phase separated in vitro and in CRC cells, which controls CRC metastasis. Phase-separated DDX21 highly binds on MCM5 gene locus, which is markedly reduced when phase separation is disrupted by mutations on its intrinsically disordered region (IDR). The impaired metastatic ability of CRC upon DDX21 loss is restored by ectopic expression of MCM5, indicating MCM5 is a key downstream target of DDX21 for CRC metastasis. Furthermore, co-higher expressions of DDX21 and MCM5 is significantly correlated with poor survival outcomes of stage III and IV CRC patients, indicating the importance of this mechanism in CRC late and metastatic stage. Altogether, our results elucidate a new model of DDX21 in regulating CRC metastasis via phase separation.

An accurate prediction of the origin for bone metastatic cancer using deep learning on digital pathological images.

BACKGROUND: Determining the origin of bone metastatic cancer (OBMC) is of great significance to clinical therapeutics. It is challenging for pathologists to determine the OBMC with limited clinical information and bone biopsy. METHODS: We designed a regional multiple-instance learning algorithm to predict the OBMC based on hematoxylin-eosin (H&E) staining slides alone. We collected 1041 cases from eight different hospitals and labeled 26,431 regions of interest to train the model. The performance of the model was assessed by ten-fold cross validation and external validation. Under the guidance of top3 predictions, we conducted an IHC test on 175 cases of unknown origins to compare the consistency of the results predicted by the model and indicated by the IHC markers. We also applied the model to identify whether there was tumor or not in a region, as well as distinguishing squamous cell carcinoma, adenocarcinoma, and neuroendocrine tumor. FINDINGS: In the within-cohort, our model achieved a top1-accuracy of 91.35% and a top3-accuracy of 97.75%. In the external cohort, our model displayed a good generalizability with a top3-accuracy of 97.44%. The top1 consistency between the results of the model and the immunohistochemistry markers was 83.90% and the top3 consistency was 94.33%. The model obtained an accuracy of 98.98% to identify whether there was tumor or not and an accuracy of 93.85% to differentiate three types of cancers. INTERPRETATION: Our model demonstrated good performance to predict the OBMC from routine histology and had great potential for assisting pathologists with determining the OBMC accurately. FUNDING: National Science Foundation of China (61875102 and 61975089), Natural Science Foundation of Guangdong province (2021A15-15012379 and 2022A1515 012550), Science and Technology Research Program of Shenzhen City (JCYJ20200109110606054 and WDZC20200821141349001), and Tsinghua University Spring Breeze Fund (2020Z99CFZ023).

Pyroptosis and Insulin Resistance in Metabolic Organs.

Skeletal muscle serves as the optimal effective organ to balance glucose homeostasis, but insulin resistance (IR) in skeletal muscle breaks this balance by impeding glucose uptake and causes metabolic disorders. IR in skeletal muscle is caused by multiple factors, and it has been reported that systemic low-grade inflammation is related to skeletal muscle IR, though its molecular mechanisms need to be ulteriorly studied. Pyroptosis is a novel inflammatory-mediated type of cell death. It has recently been reported that pyroptosis is associated with a decline in insulin sensitivity in skeletal muscle. The appropriate occurrence of pyroptosis positively eliminates pathogenic factors, whereas its excessive activation may aggravate inflammatory responses and expedite disease progression. The relationship between pyroptosis and IR in skeletal muscle and its underlined mechanism need to be further illustrated. The role of pyroptosis during the process of IR alleviation induced by non-drug interventions, such as exercise, also needs to be clarified. In this paper, we review and describe the molecular mechanisms of pyroptosis and further comb the roles of its relevant key factors in skeletal muscle IR, aiming to propose a novel theoretical basis for the relationship between pyroptosis and muscle IR and provide new research targets for the improvement of IR-related diseases.

Podocyte-specific deletion of miR-146a increases podocyte injury and diabetic kidney disease.

Diabetic glomerular injury is a major complication of diabetes mellitus and is the leading cause of end stage renal disease (ESRD). Healthy podocytes are essential for glomerular function and health. Injury or loss of these cells results in increased proteinuria and kidney dysfunction and is a common finding in various glomerulopathies. Thus, mechanistic understanding of pathways that protect podocytes from damage are essential for development of future therapeutics. MicroRNA-146a (miR-146a) is a negative regulator of inflammation and is highly expressed in myeloid cells and podocytes. We previously reported that miR-146a levels are significantly reduced in the glomeruli of patients with diabetic nephropathy (DN). Here we report generation of mice with selective deletion of miR-146a in podocytes and use of these mice in models of glomerular injury. Induction of glomerular injury in C57BL/6 wildtype mice (WT) and podocyte-specific miR-146a knockout (Pod-miR146a-/-) animals via administration of low-dose lipopolysaccharide (LPS) or nephrotoxic serum (NTS) resulted in increased proteinuria in the knockout mice, suggesting that podocyte-expressed miR-146a protects these cells, and thus glomeruli, from damage. Furthermore, induction of hyperglycemia using streptozotocin (STZ) also resulted in an accelerated development of glomerulopathy and a rapid increase in proteinuria in the knockout animals, as compared to the WT animals, further confirming the protective role of podocyte-expressed miR-146a. We also confirmed that the direct miR-146a target, ErbB4, was significantly upregulated in the diseased glomeruli and erlotinib, an ErbB4 and EGFR inhibitor, reducedits upregulation and the proteinuria in treated animals. Primary miR146-/- podocytes from these animals also showed a basally upregulated TGFß-Smad3 signaling in vitro. Taken together, this study shows that podocyte-specific miR-146a is imperative for protecting podocytes from glomerular damage, via modulation of ErbB4/EGFR, TGFß, and linked downstream signaling.

ShenKang Injection Attenuates Renal Fibrosis by Inhibiting EMT and Regulating the Wnt/ß-Catenin Pathway.

Shenkang Injection (SKI) is a traditional Chinese medicine injection commonly used in the clinical treatment of chronic kidney disease. Although it has been confirmed that SKI has anti-kidney fibrosis effects, the underlying mechanism remains unclear. To investigate the effects of SKI on epithelial-mesenchymal transition (EMT) and Wnt/ß-catenin pathway and explore its potential anti-fibrosis mechanism. A unilateral ureteral obstruction (UUO) model was induced by ligating the left ureter of male SD rats. A total of 24 rats were randomly divided into the following four groups: sham group, model group, SKI group, and benazepril group. The rats in each group were treated for 28 days, and renal function was evaluated by blood urea nitrogen (BUN) and serum creatinine (Scr). The degree of renal fibrosis was assessed by hematoxylin and eosin (HE) and Masson staining. Extracellular matrix (ECM) deposition was evaluated by immunohistochemistry. Real-time fluorescent quantitative PCR (RT-qPCR) and western blotting were used to detect the expression of genes and proteins in the Wnt/ß-catenin signaling pathway. Further studies were performed in vitro using HK-2 cells treated with TGF-ß1. At 28 days postoperation, the levels of BUN and Scr expression were significantly increased in the UUO group. SKI and benazepril reduced the levels of BUN and Scr, which displayed protective renal effects. Pathological staining showed that compared with the sham operation group, the renal parenchymal structure was severely damaged, the number of glomeruli was reduced, and a large amount of collagen was deposited in the kidney tissue of the UUO group. SKI treatment reduced morphological changes. Immunohistochemistry showed that compared with the sham operation group, the content of collagen I and FN in the kidney tissue of the UUO group were significantly increased, whereas the SKI content was decreased. In addition, compared with the UUO group, the levels of Wnt1, active ß-catenin, Snail1, and PAI-1 expression were reduced in the SKI group, suggesting that SKI may reduce renal fibrosis by mediating the Wnt/ß-catenin pathway. Further in vitro studies showed that collagen I, FN, and α-SMA levels in HK-2 cells were significantly increased following stimulation with TGF-ß1. SKI could significantly reduce the expression of collagen I, FN, and α-SMA. A scratch test showed that SKI could reduce HK-2 migration. In addition, by stimulating TGF-ß1, the levels of Wnt1, active ß-catenin, snail1, and PAI-1 were significantly upregulated. SKI treatment could inhibit the activity of the Wnt/ß-catenin signaling pathway in HK-2 cells. SKI improves kidney function by inhibiting renal fibrosis. The anti-fibrotic effects may be mediated by regulation of the Wnt/ß-catenin pathway and EMT inhibition.

Surgical Correction of Kyphosis in Patients With Camptocormia Associated With Parkinson's Disease: A Case Report and Review of the Literature.

Background: Camptocormia is a postural deformity that is characterized by a markedly flexed lumbar spine, with symptoms that worsen with walking and standing. Here, we report a case of camptocormia associated with Parkinson's disease. Case description: A 70-year-old man with a 7-year history of Parkinson's disease presented with a fall injury that caused lower back pain for 3 months and was aggravated for 2 months. He had been diagnosed with a compression fracture after the fall and had undergone percutaneous kyphoplasty at a local hospital. MRI showed non-union of the L1 vertebra and compression fracture of L2. The patient underwent posterior osteotomy, canal decompression, and internal fixation of the T10-L3 intervertebral plate with bone graft fusion. Postoperative examination showed that the lumbar lordosis was corrected and sensation was restored in both lower extremities. However, after 1 month, the fixation was loosened and a correction surgery was performed at our hospital. At the most recent follow-up at 1.5 years, the patient was found to be in good general health and did not complain of lower back discomfort. He was also actively exercising according to the rehabilitation regimen and had resumed social life. Conclusion: This is a rare case of camptocormia in a Parkinson's patient that highlights the need for careful evaluation of whether internal spinal fixation surgery is beneficial in such patients.

Clinicopathologic and molecular features of vascular tumors in a series of 118 cases.

AIMS: Vascular tumors are composed of benign, intermediate, and malignant lesions. The diagnosis is challenging because some entities demonstrate overlapping morphologies and harbor the same genetic alterations. We describe herein a cohort of vascular tumors with clinicopathologic, immunohistochemical, and molecular features. METHODS AND RESULTS: 118 vascular tumors including 56 angiosarcomas, 18 epithelioid haemangioendotheliomas (EHE), 25 epithelioid haemangiomas (EH), 8 pseudomyogenic haemangioendotheliomas (PHE), 1 papillary intralymphatic angioendothelioma (PILA), 2 kaposiform haemangioendotheliomas (KHE), 3 Kaposi sarcomas, 2 retiform haemangioendotheliomas (RHE), and 3 anastomosing haemangiomas were assessed. FOSB, c-Fos, CAMTA1, and TFE3 expression and gene rearrangements were analyzed by immunohistochemical staining and FISH, respectively. Our results showed that FOSB expression was diffusely positive in all 8 PHEs, focally or sparsely in 12 EHs, and in 2 angiosarcomas. C-FOS expression was sparsely to diffusely positive in 15 EHs, focally or sparsely in 17 angiosarcomas, 1 EHE, 1 Kaposi sarcoma, and 1 PHE. CAMTA1 expression was positive in only 12 EHEs. TFE3 expression was focally or sparsely positive in all 8 PHEs, 22 angiosarcomas, 6 EHEs, 3 EHs, 2 Kaposi sarcomas, and 2 AHs. FOSB rearrangement was found in 5 PHEs, FOS rearrangement only in 1 EH, CAMTA1 rearrangement in 4 EHEs. CONCLUSIONS: FOSB and CAMTA1 are useful diagnostic markers for PHE and EHE, respectively. FOSB and FOS fusion represent a subset of epithelioid haemangioma. TFE3 is not a diagnostically meaningful marker in a majority of vascular tumors. The combined utility of these markers will facilitate the differential diagnosis in vascular tumors with morphologic overlap.

Performance of Multiparametric Models in Patients With Brugada Syndrome: A Systematic Review and Meta-Analysis.

Background: Multiparametric models have shown better risk stratification in Brugada syndrome. Recently, these models have been validated in different populations. Aims: To perform a systematic review and meta-analysis of the predictive performance of three validated multiparametric models (Delise model, Sieria model, and Shanghai score). Methods: We searched PubMed, Embase, MEDLINE, Web of Science, and Ovid for studies validating the risk multiparametric model. A Sieria score > 2 and Shanghai score ≥ 4 were considered to indicate higher risk. Performance estimates were summarized using a random-effects model. Results: Seven studies were included, with sample sizes of 111-1,613. The follow-up duration was 3.3-10.18 years. The Sieria model had a pooled area under the curve (AUC), sensitivity, and specificity of 0.71 [95% confidence interval (CI): 0.67-0.75], 57% (95% CI: 35-76), and 71% (95% CI: 62-79), respectively. The Shanghai score had an AUC of 0.63-0.71, 68.97-90.67% sensitivity, and 43.53-63.43% specificity. The AUC of the Delise model was 0.77-0.87; however, the optimal cut-off was not identified. Conclusions: The three models exhibited moderate discriminatory ability for Brugada syndrome. The Sieria model has poor sensitivity and moderate specificity, whereas the Shanghai score has poor specificity and moderate sensitivity.

Exercise Affects the Formation and Recovery of Alcoholic Liver Disease through the IL-6-p47phox Oxidative-Stress Axis.

(1) Background: To explore the effect of exercise on the formation and recovery of alcoholic liver disease (ALD) and whether the IL-6−p47phox oxidative−stress axis is involved in that process. (2) Methods: Firstly, 23 six-week-old male C57BL/6J mice were randomly divided into the Con group, ALD group, ALD + NOXI group, ALD + Ex group, and ALD + Ex + NOXI group. The Liber−DeCarli alcoholic liquid diet was used for 6 weeks to establish the ALD mice model, and the Con group was given the TP4030C control diet. The remaining groups were fed with the TP4030B alcoholic diet, and exercise intervention was started after the ALD model establishment and lasted for another 6 weeks, with or without administration of the NOX inhibitor apocynin by intraperitoneal injection on every exercise training day. Secondly, 28 mice were randomly divided into the Sed group, Eth group, Eth + Ex group and Eth + Ex + NOXI group. The Sed group was given the TP4030C control diet. The remaining groups were fed with the TP4030B alcoholic diet and exercise intervention was started synchronously combined with or without administration of intraperitoneal apocynin injections on every exercise training day for 5 weeks. After each individual experiment was accomplished, physiological assessment and biochemical analysis of blood and tissue samples were examined. (3) Results: The levels of TG in serum and IL-6 protein content in liver tissue in the ALD group were significantly increased compared to the Con group (p < 0.05); compared with ALD, p47phox expression in muscle was increased significantly in the ALD + NOXI group (p < 0.05), and TG in serum decreased in the ALD + Ex group (p < 0.05). TG in serum, AST/ALT ratio, and IL-6 content in both liver and muscle decreased (p < 0.05) in the ALD + Ex + NOXI group with MDA in muscle significantly increased (p < 0.01). The AST/ALT ratio, TG in serum, SOD in liver, and p47phox in both liver and muscle in the ALD + Ex + NOXI group were significantly decreased compared with the ALD + NOXI group (p < 0.01). Compared with the ALD + Ex group, the liver index and HDL-C levels in serum were decreased (p < 0.05) in the ALD + Ex + NOXI group. The degree of hepatocyte steatosis and inflammatory infiltration were ameliorated after exercise intervention. In the Eth group, the relative epididymal fat content, HDL-C level, and AST/ALT ratio were significantly decreased, and TG and gp91phox in liver were significantly higher than in the Sed group (p < 0.05, p < 0.01). Compared with the Eth group, the AST/ALT ratio, MDA in the liver, and NOX4 and p47phox protein expression in the liver were significantly increased, and body weight decreased significantly in the Eth + Ex group (p < 0.05, p < 0.01), as did TG in the liver and MDA in muscle. In the th + Ex + NOXI group, gp91phox expression in the liver and body weight were significantly decreased (p < 0.05, p < 0.01). In the Eth + Ex + NOXI group, the ratio of AST/ALT and MDA in muscle were increased when compared with the Eth + Ex group, and the protein expression of gp91phox and p47phox were much lower (p < 0.01). (4) Conclusions: 6 weeks of exercise intervention during the recovery phase of ALD ameliorates hepatocyte damage and dyslipidemia through the IL-6−p47phox oxidative−stress axis, and applying a NOX inhibitor in combination could optimize this. However, drinking alcohol during exercise exacerbates dyslipidemia and oxidative stress, with hepatocyte IL-6−p47phox downregulated.

Emerging role of TWEAK-Fn14 axis in lupus, a disease related to autoimmunity and fibrosis.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder. Lupus nephritis (LN) is one of the severe clinical implications in SLE, and this was relates to fibrosis in the kidney. As an important marker in the tumor necrosis factor (TNF) superfamily, TNF-like weak inducer of apoptosis (TWEAK) has been given much attention with respect to its role in regulating pro-inflammatory immune response. Fibroblast growth factor-inducible 14 (Fn14), the sole receptor for TWEAK, has been found expressed in different immune and non-immune cells. TWEAK binds to Fn14, and then regulates inflammatory components production via downstream signaling pathways. To date, dysregulated expression of TWEAK, Fn14 has been reported in SLE, LN patients, and in vivo, in vitro studies have discussed the significant role of TWEAK-Fn14 axis in SLE, LN pathogenesis, partly through mediating the fibrosis process. In this review, we will discuss the association of TWEAK-Fn14 axis in lupus. Understanding the relationship will better realize the potential for making TWEAK-Fn14 as a marker for the diseases, and will help to give many clues for targeting them in treatment of lupus in the future.

[Effects of different tillage and sowing practices on root growth, soil moisture, and soil nitrate nitrogen content of wheat after rice]. / è€•ä½œæ’­ç§æ–¹å¼å¯¹ç¨»èŒ¬å°éº¦æ ¹ç³»å‘è‚²ã€åœŸå£¤æ°´åˆ†å’Œç¡æ€æ°®å«é‡çš„å½±å“.

With deep rotary tillage before sowing (DRT) as control, the effects of shallow rotary tillage with simultaneous sowing (SRT) and strip tillage under no tillage conditions along with sowing (NT) on root growth, soil moisture, and soil nitrate content of wheat (Triticum aestivum) after rice (Oryza sativa) were examined from 2016 to 2018. Compared with DRT, NT and SRT resulted in higher soil water content, and lower soil nitrate content in the plow layer before booting. There was no significant difference in root weight density and root surface area density among the treatments at jointing and anthesis stages. No significant difference was found in grain yield and aboveground plant nitrogen uptake among the treatments in the growing season of 2016-2017. In the growing season of 2017-2018, NT and SRT resulted in 10.9% and 10.5% higher grain yield and 17.5% and 12.0% higher aboveground plant nitrogen uptake than DRT, respectively. Compared with DRT and SRT, NT resulted in better work efficiency and lower seedling missing rate. In conclusion, NT could effectively improve sowing quality, enhance soil water storage ability, reduce the risk of soil nitrogen leaching, and ultimately enhance wheat yield and environmental benefits in the growing stage of wheat plantation after rice.

[Effects of tillage and sowing practices on plant growth, soil nutrient uptake and utilization of wheat after rice]. / è€•ä½œæ’­ç§æ–¹å¼å¯¹ç¨»èŒ¬å°éº¦ç”Ÿé•¿å’Œå »åˆ†å¸æ”¶åˆ©ç”¨çš„å½±å“.

From 2016 to 2018, a field trial on three tillage and sowing practices, deep rotary tillage before sowing (DRT), shallow rotary tillage with simultaneous sowing (SRT), and strip tillage under no tillage conditions along with sowing (NT), was conducted to evaluate shoot growth, soil nutrient uptake, and utilization of wheat (Triticum aestivum) after rice (Oryza sativa) in Guanghan, Sichuan Province, China. Compared with DRT, both SRT and NT improved tillering capacity and fertile shoot rate. In 2016-2017, grain yield did not differ among the treatments, whereas in 2017-2018, NT had significantly higher grain yield (10.9%) than DRT. Furthermore, the diffe-rence in dry matter accumulation among the treatments mainly occurred prior to wheat jointing. Total nitrogen uptake of plants was higher by 9.9% in NT than in DRT, whereas nitrogen harvest index was higher in DRT than in NT. Total phosphorus uptake was not different among the treatments. Total potassium uptake was higher in NT plants than in DRT plants. Overall, the results showed that compared with the traditional tillage practice (i.e., DRT), strip tillage practice along with sowing (i.e., NT) is an effective method for increasing grain yield and soil nutrient uptake for wheat after rice.

Association of FcγRIIA-R/H131 polymorphism and systemic lupus erythematosus lupus nephritis risk: A meta-analysis.

AIM: Previous studies have discussed association of FcγRIIA-R/H131 polymorphism and systemic lupus erythematosus (SLE), lupus nephritis (LN) risk. However, conclusions were inconsistent. METHODS: A meta-analysis was performed in this study with allelic contrast (allele R vs H), additive model (genotype RR vs HH), recessive model (genotype RR vs RH + HH), and dominant model (genotype RR + RH vs HH). RESULTS: A total of 33 studies discussed the correlation between FcγRIIA-R/H131 polymorphism and SLE, involving 5652 SLE patients and 6322 controls. Allele R was significantly related to SLE in the overall population (odds ratio [OR] = 1.238, P < .001), Asian (OR = 1.237, P < .001) and European population (OR = 1.212, P = .012). Additive, recessive and dominant models were correlating with SLE in the overall population (OR = 1.448, P < .001; OR = 1.303, P < .001; OR = 1.310, P < .001), Asian population (OR = 1.640, P = .001; OR = 1.437, P < .001; OR = 1.344, P = .005), respectively. In addition, 22 studies evaluated relation of FcγRIIA-R/H131 polymorphism with LN, involving 2065 patients with LN, and 2023 patients without LN. Results showed that allele R and the other 3 models related to LN susceptibility in the overall population when discussing differences of polymorphism between patients with/without LN. We further compared differences of polymorphism between patients with LN and controls, showing that additive and recessive models related to LN risk in the overall population, Asian, European and North American populations. CONCLUSION: In summary, FcγRIIA-R/H131 polymorphism is associated with SLE and LN.

Parkin regulates NF-κB by mediating site-specific ubiquitination of RIPK1.

Parkin (Park2), a RING-between-RING-type E3 ubiquitin ligase, has been implicated in regulating NF-κB. Mutations in Parkin are associated with Parkinson's disease. Here we investigated the interaction of Parkin with Receptor-interacting protein kinase 1 (RIPK1) kinase, a key mediator of multiple signaling pathways activated by TNFR1 including NF-κB pathway. We report that Parkin interacts with RIPK1 and mediates K63 ubiquitination of RIPK1 on K376 in TNFR1-signaling pathway. The expression of Parkin promotes the recruitment of transforming growth factor ß (TGF-ß)-activated kinase 1 (TAK1), nuclear factor-κB (NF-κB) essential molecule (NEMO), Sharpin and A20 in complex I associated with TNFR1 upon TNFα stimulation. Ubiquitination of RIPK1 by Parkin increases the activation of NF-κB and mitogen-activated protein kinases (MAPKs) by promoting the phosphorylation of inhibitor of kappa B kinase (IKK)α/ß and IκBα and nuclear translocation of p65. Thus, we conclude that Parkin modulates the K63 ubiquitination status of RIPK1 to promote the activation of NF-κB and MAPKs.

PELI1 functions as a dual modulator of necroptosis and apoptosis by regulating ubiquitination of RIPK1 and mRNA levels of c-FLIP.

Apoptosis and necroptosis are two distinct cell death mechanisms that may be activated in cells on stimulation by TNFα. It is still unclear, however, how apoptosis and necroptosis may be differentially regulated. Here we screened for E3 ubiquitin ligases that could mediate necroptosis. We found that deficiency of Pellino 1 (PELI1), an E3 ubiquitin ligase, blocked necroptosis. We show that PELI1 mediates K63 ubiquitination on K115 of RIPK1 in a kinase-dependent manner during necroptosis. Ubiquitination of RIPK1 by PELI1 promotes the formation of necrosome and execution of necroptosis. Although PELI1 is not directly involved in mediating the activation of RIPK1, it is indispensable for promoting the binding of activated RIPK1 with its downstream mediator RIPK3 to promote the activation of RIPK3 and MLKL. Inhibition of RIPK1 kinase activity blocks PELI1-mediated ubiquitination of RIPK1 in necroptosis. However, we show that PELI1 deficiency sensitizes cells to both RIPK1-dependent and RIPK1-independent apoptosis as a result of down-regulated expression of c-FLIP, an inhibitor of caspase-8. Finally, we show that Peli1-/- mice are sensitized to TNFα-induced apoptosis. Thus, PELI1 is a key modulator of RIPK1 that differentially controls the activation of necroptosis and apoptosis.

Cytotoxic necrotizing factor 1 promotes prostate cancer progression through activating the Cdc42-PAK1 axis.

Uropathogenic Escherichia coli (UPEC) is the leading cause of urinary tract infections and plays a role in prostatic carcinogenesis and prostate cancer (PCa) progression. However, the mechanisms through which UPEC promotes PCa development and progression are unclear. Cytotoxic necrotizing factor 1 (CNF1) is one of the most important UPEC toxins and its role in PCa progression has never been studied. We found that UPEC-secreted CNF1 promoted the migration and invasion of PCa cells and PCa metastasis. In vitro studies showed that CNF1 promotes pro-migratory and pro-invasive activity through entering PCa cells and activating Cdc42, which subsequently induced PAK1 phosphorylation and up-regulation of MMP-9 expression. CNF1 also promoted pulmonary metastasis in a xenograft mouse model through these mechanisms. PAK1 phosphorylation correlated with advanced grades of PCa in human clinical PCa tissues. These results suggest that CNF1 derived from UPEC plays an important role in PCa progression through activating a Cdc42-PAK1 signal axis and up-regulating the expression of MMP-9. Therefore, surveillance for and treatment of cnf1-carrying UPEC strains may diminish PCa progression and thus have an important clinical therapeutic impact. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

CD47 promotes ovarian cancer progression by inhibiting macrophage phagocytosis.

Targeting CD47 efficiently enhances macrophage phagocytosis in both physiological and pathological conditions. Anti-CD47 antibodies have been shown to inhibit the progression of several types of cancer. However, the mechanism of anti-CD47 monoclonal antibody (mAb) treatment remains controversial. In this study, we confirmed that CD47 protein is highly expressed in ovarian cancer, and is correlated with poor clinical characteristics and prognosis. CD47 knockdown in the ovarian cancer cell line, SK-OV-3, promoted phagocytosis by macrophages in vitro and inhibited tumor growth in vivo. These data combined suggest that CD47 inhibition is a potential strategy for cancer treatment. Using an anti-CD47 mAb, we found that CD47 inhibition in both SK-OV-3 cells and primary cancer cells was able to recapitulate our knockdown results and led to an increase in the number of infiltrating macrophages. In addition, the CD133+ tumor initiating cells expressed a high level of CD47, and anti-CD47 mAb treatment was able to trigger the phagocytosis of this cell population. In conclusion, our results indicate that CD47 inhibits macrophage phagocytosis of ovarian cancer cells, and down-regulation of CD47 or inhibiting CD47 by mAb was able to reverse the negative effect. Thus, CD47 antibody therapy may be a promising strategy to treat ovarian cancer.

Functions of PARylation in DNA Damage Repair Pathways.

Protein poly ADP-ribosylation (PARylation) is a widespread post-translational modification at DNA lesions, which is catalyzed by poly(ADP-ribose) polymerases (PARPs). This modification regulates a number of biological processes including chromatin reorganization, DNA damage response (DDR), transcriptional regulation, apoptosis, and mitosis. PARP1, functioning as a DNA damage sensor, can be activated by DNA lesions, forming PAR chains that serve as a docking platform for DNA repair factors with high biochemical complexity. Here, we highlight molecular insights into PARylation recognition, the expanding role of PARylation in DDR pathways, and the functional interaction between PARylation and ubiquitination, which will offer us a better understanding of the biological roles of this unique post-translational modification.