PCDHA9 as a candidate gene for amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. To identify additional genetic factors, we analyzed exome sequences in a large cohort of Chinese ALS patients and found a homozygous variant (p.L700P) in PCDHA9 in three unrelated patients. We generated Pcdhα9 mutant mice harboring either orthologous point mutation or deletion mutation. These mice develop progressive spinal motor loss, muscle atrophy, and structural/functional abnormalities of the neuromuscular junction, leading to paralysis and early lethality. TDP-43 pathology is detected in the spinal motor neurons of aged mutant mice. Mechanistically, we demonstrate that Pcdha9 mutation causes aberrant activation of FAK and PYK2 in aging spinal cord, and dramatically reduced NKA-α1 expression in motor neurons. Our single nucleus multi-omics analysis reveals disturbed signaling involved in cell adhesion, ion transport, synapse organization, and neuronal survival in aged mutant mice. Together, our results present PCDHA9 as a potential ALS gene and provide insights into its pathogenesis.

Clinical characteristics, treatments, and outcomes of interferon-beta-induced thrombotic microangiopathy: a literature-based retrospective analysis.

Background: Thrombotic microangiopathy (TMA) is a rare side effect of interferon-beta (IFN-ß) therapy. The clinical characteristics of IFN-ß-induced TMA are unknown. Objectives: To explore the clinical characteristics of IFN-ß-induced TMA and provide reference for the prevention of TMA. Design: Articles on IFN-ß-induced TMA were collected by searching the literature in relevant Chinese and English databases from inception to 31 July 2023. Methods: Data in the articles were extracted and analyzed retrospectively. Results: Forty-seven patients, with a median age of 41 years (range 22, 66), were included in the analysis. The median time to the diagnosis of IFN-ß-induced TMA was 8 years (range 0.1-30) after administration. The main clinical symptoms were neurological symptoms (51.1%), hypertension (78.7%), dyspnea (19.1%), edema (19.1%), asthenia/fatigue (19.1%), and digestive symptoms (17.0%). Most patients presented with hemolytic anemia (76.6%), thrombocytopenia (63.8%), and acute kidney injury (70.2%). All patients stopped IFN-ß and received plasma exchange therapy (53.2%), systemic steroids (46.8%), antihypertensive therapy (46.8%), eculizumab (12.8%), and rituximab (12.8%). Kidney damage was not completely reversible; 40.4% of patients achieved renal function and hematology remission, 27.7% developed chronic kidney disease, 25.5% developed end-stage renal disease, and 2.1% died. Conclusion: IFN-ß-induced TMA is a rare but serious complication that can be life-threatening. It may occur after many years of IFN-ß therapy, and patients taking IFN-ß should be monitored for symptoms such as headache and hypertension.

Clinical and HLA genotype analysis of immune checkpoint inhibitor-associated diabetes mellitus: a single-center case series from China.

Objective: To investigate the clinical characteristics and HLA genotypes of patients with immune checkpoint inhibitor-associated diabetes mellitus (ICI-DM) in China. Methods: We enrolled 23 patients with ICI-DM and 51 patients with type 1 diabetes (T1D). Clinical characteristics of the patients were collected. HLA-DRB1, HLA-DQA1, and HLA-DQB1 genotyping was conducted via next-generation sequencing. Results: The ICI-DM patients had a male predominance (70.6%), a mean body mass index (BMI) of 21.2 ± 3.5 kg/m2, and a mean onset of ICI-DM in 5 (IQR, 3-9) cycles after ICI therapy. Most (78.3%) ICI-DM patients were treated with anti-PD-1, 78.3% presented with diabetic ketoacidosis, and all had low C-peptide levels and received multiple insulin injections. Compared to T1D patients, ICI-DM patients were significantly older (57.2 ± 12.4 vs 34.1 ± 15.7 years) and had higher blood glucose but lower HbA1c levels (P<0.05). Only two (8.7%) ICI-DM patients were positive for islet autoantibodies, which was lower than that in T1D patients (66.7%, P<0.001). A total of 59.1% (13/22) of ICI-DM patients were heterozygous for an HLA T1D risk haplotype, and DRB1*0901-DQA1*03-DQB1*0303 (DR9) and DRB1*0405-DQA1*03-DQB1*0401 were the major susceptible haplotypes. Compared to T1D, the susceptible DR3-DQA1*0501-DQB1*0201 (DR3) and DR9 haplotypes were less frequent (17.7% vs 2.3%; P=0.011 and 34.4% vs 15.9%; P=0.025), whereas the protective haplotypes (DRB1*1101-DQA1*05-DQB1*0301 and DRB1*1202-DQA1*0601-DQB1*0301) were more frequent in ICI-DM patients (2.1% vs 13.6%; P=0.006 and 4.2% vs 15.9%; P=0.017). None of the ICI-DM patients had T1D-associated high-risk genotypes DR3/DR3, DR3/DR9, and DR9/DR9. Among the 23 ICI-DM patients, 7 (30.4%) presented with ICI-associated fulminant type 1 diabetes (IFD), and 16 (69.6%) presented with ICI-associated type 1 diabetes (IT1D). Compared to IT1D patients, IFD patients exhibited marked hyperglycemia and low C-peptide and HbA1c levels (P<0.05). Up to 66.7% (4/6) of IFD patients were heterozygous for reported fulminant type 1 diabetes susceptibility HLA haplotypes (DRB1*0405-DQB1*0401 or DRB1*0901-DQB1*0303). Conclusion: ICI-DM shares similar clinical features with T1D, such as acute onset, poor islet function and insulin dependence. However, the lack of islet autoantibodies, the low frequencies of T1D susceptibility and high frequencies of protective HLA haplotypes indicate that ICI-DM represents a new model distinct from classical T1D.

S1PR1 attenuates pulmonary fibrosis by inhibiting EndMT and improving endothelial barrier function.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic fatal disease of unknown etiology. Its pathological manifestations include excessive proliferation and activation of fibroblasts and deposition of extracellular matrix. Endothelial cell-mesenchymal transformation (EndMT), a novel mechanism that generates fibroblast during IPF, is responsible for fibroblast-like phenotypic changes and activation of fibroblasts into hypersecretory cells. However, the exact mechanism behind EndMT-derived fibroblasts and activation is uncertain. Here, we investigated the role of sphingosine 1-phosphate receptor 1 (S1PR1) in EndMT-driven pulmonary fibrosis. METHODS: We treated C57BL/6 mice with bleomycin (BLM) in vivo and pulmonary microvascular endothelial cells with TGF-ß1 in vitro. Western blot, flow cytometry, and immunofluorescence were used to detect the expression of S1PR1 in endothelial cells. To evaluate the effect of S1PR1 on EndMT and endothelial barrier and its role in lung fibrosis and related signaling pathways, S1PR1 agonist and antagonist were used in vitro and in vivo. RESULTS: Endothelial S1PR1 protein expression was downregulated in both in vitro and in vivo models of pulmonary fibrosis induced by TGF-ß1 and BLM, respectively. Downregulation of S1PR1 resulted in EndMT, indicated by decreased expression of endothelial markers CD31 and VE-cadherin, increased expression of mesenchymal markers α-SMA and nuclear transcription factor Snail, and disruption of the endothelial barrier. Further mechanistic studies found that stimulation of S1PR1 inhibited TGF-ß1-mediated activation of the Smad2/3 and RhoA/ROCK1 pathways. Moreover, stimulation of S1PR1 attenuated Smad2/3 and RhoA/ROCK1 pathway-mediated damage to endothelial barrier function. CONCLUSIONS: Endothelial S1PR1 provides protection against pulmonary fibrosis by inhibiting EndMT and attenuating endothelial barrier damage. Accordingly, S1PR1 may be a potential therapeutic target in progressive IPF.

S1PR2/Wnt3a/RhoA/ROCK1/ß-catenin signaling pathway promotes diabetic nephropathy by inducting endothelial mesenchymal transition and impairing endothelial barrier function.

AIMS: Hyperglycemia and hyperlipidemia are key factors in the pathogenesis of diabetic nephropathy (DN), and renal fibrosis is the most common pathway leading to the disease. Endothelial mesenchymal transition (EndMT) is a crucial mechanism for the production of myofibroblasts, and impaired endothelial barrier function is one of the mechanisms for the generation of microalbuminuria in DN. However, the specific mechanisms behind these are not yet clear. MAIN METHODS: Protein expression was detected by immunofluorescence, immunohistochemistry and Western blot. Knocking down or pharmacological inhibition of S1PR2 were used to inhibit Wnt3a, RhoA, ROCK1, ß-catenin, and Snail signaling. Changes in cell function were analyzed by CCK-8 method, cell scratching assay, FITC-dextran permeability assay, and Evans blue staining. KEY FINDINGS: Consistent with increased gene expression of S1PR2 in DN patients and mice with kidney fibrosis disease, S1PR2 expression was significantly increased in glomerular endothelial cells of DN mice and HUVEC cells treated with glucolipids. Knocking down or pharmacological inhibition of S1PR2 significantly decreased the expression of Wnt3a, RhoA, ROCK1, and ß-catenin in endothelial cells. Furthermore, inhibition of S1PR2 in vivo reversed EndMT and endothelial barrier dysfunction in glomerular endothelial cells. Inhibition of S1PR2 and ROCK1 in vitro also reversed EndMT and endothelial barrier dysfunction in endothelial cells. SIGNIFICANCE: Our results suggest that the S1PR2/Wnt3a/RhoA/ROCK1/ß-catenin signaling pathway is involved in the pathogenesis of DN by inducing EndMT and endothelial barrier dysfunction.

A bibliometric analysis and visualization of nonalcoholic fatty liver disease from 2012 to 2021.

As a common chronic liver disease, nonalcoholic fatty liver disease (NAFLD) has attracted increasing attention in the past decade. Nevertheless, there are few bibliometric analyses that systematically study this field as a whole. This paper explores the latest research progress and future research trends of NAFLD through the method of bibliometric analysis. The articles related to NAFLD, published from 2012 to 2021 in the Web of Science Core Collections, were searched on February 21, 2022, using relevant keywords. Two different scientometrics software tools were used to conduct the knowledge maps of NAFLD research field. A total of 7975 articles on NAFLD research were included. From 2012 to 2021, the publications related to NAFLD increased by year. China ranked on the top of the list with 2043 publications, and the University of California System emerged as the premier institution in this field. PLOs One, Journal of Hepatology and Scientific Reports became the prolific journals in this research field. Co-cited reference analysis revealed the landmark literature in this research field. In terms of potential hotspots, the burst keywords analysis revealed that liver fibrosis stage, sarcopenia, and autophagy will become the focus of future NAFLD research. The annual output of the global publications in the field of NAFLD research showed a strong upward trend. Research in the field of NAFLD in China and America is more mature than in other countries. Classic literature lays the foundation for research, and multi-field studies provide the new development directions. And besides, fibrosis stage, sarcopenia and autophagy research are the hot spots and frontiers of this field.

Clinical features, diagnosis, and management of pembrolizumab-induced myasthenia gravis.

Myasthenia gravis (MG) is a rare but life-threatening adverse event with pembrolizumab. What is known about pembrolizumab-induced MG is largely based on case reports. This analysis collected pembrolizumab-induced MG cases from Chinese and English databases published from September 1, 2014, to June 30, 2022. Demographic and clinical information of the patients, management, and outcome data were collected and analyzed. Sixty-five patients with a median age of 73 years (range 30-86), including 43 male patients (66.2%), were included. Eight patients (12.3%) with prior MG experienced worsening symptoms after receiving pembrolizumab. The median time to the onset of MG was four weeks (range 0.7-27). The most common symptoms were ptosis (81.5%, 53 patients), diplopia (50.8%, 33 patients), dyspnea (44.6%, 29 patients), trunk or peripheral weakness (43.1%, 28 patients), and dysphagia (30.8%, 20 patients). Concurrent myositis and myocarditis occurred in 13 (20.0%) and 17 patients (26.2%). Pembrolizumab was discontinued in 63 patients (96.9%). Forty-four patients (67.7%) received combination therapies based on steroids (intravenous immune globulin, plasmapheresis, or immunosuppressants). Twenty-seven patients (41.5%) had symptoms completely recovered. Fourteen patients (21.5%) died from immunotoxicity or primary cancers. Clinicians should consider the possibility of pembrolizumab-induced MG, especially during the first eight weeks of therapy. Patients should be treated as early as possible, regardless of the severity of the initial symptoms.

Identifying myoglobin as a mediator of diabetic kidney disease: a machine learning-based cross-sectional study.

In view of the alarming increase in the burden of diabetes mellitus (DM) today, a rising number of patients with diabetic kidney disease (DKD) is forecasted. Current DKD predictive models often lack reliable biomarkers and perform poorly. In this regard, serum myoglobin (Mb) identified by machine learning (ML) may become a potential DKD indicator. We aimed to elucidate the significance of serum Mb in the pathogenesis of DKD. Electronic health record data from a total of 728 hospitalized patients with DM (286 DKD vs. 442 non-DKD) were used. We developed DKD ML models incorporating serum Mb and metabolic syndrome (MetS) components (insulin resistance and ß-cell function, glucose, lipid) while using SHapley Additive exPlanation (SHAP) to interpret features. Restricted cubic spline (RCS) models were applied to evaluate the relationship between serum Mb and DKD. Serum Mb-mediated renal function impairment induced by MetS components was verified by causal mediation effect analysis. The area under the receiver operating characteristic curve of the DKD machine learning models incorporating serum Mb and MetS components reached 0.85. Feature importance analysis and SHAP showed that serum Mb and MetS components were important features. Further RCS models of DKD showed that the odds ratio was greater than 1 when serum Mb was > 80. Serum Mb showed a significant indirect effect in renal function impairment when using MetS components such as HOMA-IR, HGI and HDL-C/TC as a reason. Moderately elevated serum Mb is associated with the risk of DKD. Serum Mb may mediate MetS component-caused renal function impairment.

Clinical features, diagnosis and management of amoxicillin-induced Kounis syndrome.

Background: The available evidence suggests that amoxicillin is often associated with the occurrence of Kounis syndrome (KS). The purpose of this study is to explore the clinical characteristics of KS induced by amoxicillin. Methods: We searched for case reports of amoxicillin-induced KS through Chinese and English databases from 1972 to May 2022. Results: A total of 33 patients with KS were included, including 16 patients (48.5%) receiving amoxicillin treatment and 17 patients (51.5%) receiving amoxicillin-clavulanate. The median age was 58 years (range 13-82), 75.8% were from Europe and 81.8% were male. Nearly 70% of KS patients develop symptoms within 30 min after administration. Chest pain (63.6%) and allergic reaction (75.8%) were the most common clinical manifestations. Diagnostic evaluation revealed elevated troponin (72.7%), ST-segment elevation (81.2%) and coronary artery stenosis with thrombosis (53.6%). Thirty-two (97.0%) patients recovered completely after discontinuation of amoxicillin and treatments such as steroids and antihistamines. Conclusion: KS is a rare adverse reaction of amoxicillin. Amoxicillin-induced KS should be considered when chest pain accompanied by allergic symptoms, electrocardiogram changes and or elevated levels of myocardial injury markers. Therapeutic management of KS requires simultaneous treatment of cardiac and allergic symptoms. Epinephrine should be used with caution in patients with suspected KS.

Trimethylamine oxide induces pyroptosis of vascular endothelial cells through ALDH2/ROS/NLRP3/GSDMD pathway. / 氧化三甲胺通过ALDH2/ROS/NLRP3/GSDMDé€šè·¯è¯±å¯¼è¡€ç®¡å† çš®ç»†èƒžç„¦äº¡ï¼ˆè‹±æ–‡ï¼‰.

OBJECTIVES: Trimethylamine oxide (TMAO) is a metabolite of intestinal flora and is known to promote the progression of atherosclerotic plaques. However, how TMAO works, including its effect on vascular endothelial cells, is not fully understood. This study aims to explore the biological role of TMAO in human umbilical vein endothelial cells (HUVECs) and the underlying mechanism. METHODS: Cell pyroptosis and the loss of plasma membrane integrity were induced under TMAO stimulation in HUVECs. The plasma membrane integrity of the cells was measured by Hoechst 33342/propidium iodide (PI) staining and lactate dehydrogenase leakage assay, and the changes in cell morphology were observed by atomic force microscope. The expression of proteins related to pyroptosis was determined by Western blotting or immunofluorescence. Mitochondrial acetaldehyde dehydrogenase 2 (ALDH2) activity in HUVECs was measured by the ALDH2 activity assay kit, and the level of reactive oxygen species (ROS) was detected by fluorescent probe DCFH-DA. RESULTS: TMAO induced pyroptotic cell death, manifesting by the presence of propidium iodide-positive cells, the leakage of lactate dehydrogenase, the production of N-terminal gasdermin D (GSDMD-N), and the formation of plasma membrane pores. Moreover, TMAO induced elevated expression of inflammasome components, nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3), apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC), and caspase-1 in cells. TMAO significantly inhibited ALDH2 activity and increased intracellular ROS production. However, the activation of ALDH2 by pharmacological manipulation attenuated TMAO-induced inflammasome activation and GSDMD-N production. CONCLUSIONS: TMAO induces pyroptosis of vascular endothelial cells through the ALDH2/ROS/NLRP3/GSDMD signaling pathway, which may be a potential therapeutic target for improving the treatment of atherosclerosis.

Diagnosis and Management of Fingolimod-Associated Macular Edema.

Objective: To investigate the clinical features, treatment, and prognosis of fingolimod-associated macular edema (FAME) and to provide a reference for its rational management. Methods: FAME-related case reports were included in a pooled analysis by searching Chinese and English databases from 2010 to November 31, 2021. Results: The median age of 41 patients was 50 years (range, 21, 67 years), of whom 32 were women. The median time to onset of FAME was 3 m (range.03, 120), and blurred vision (17 cases) and decreased vision (13 cases) were the most common complaints. A total of 55 eyes were involved in FAME, including the left eye (14 cases), right eye (10 cases), and both eyes (15 cases), of which 46 eyes had best-corrected visual acuity close to normal (20/12-20/60) and 8 eyes had moderate to severe visual impairment (20/80-20/500). Fundus examination in 23 patients showed macular edema (11 cases). Optical coherence tomography (OCT) in 39 patients mainly showed perifoveal cysts (24 cases), ME (23 cases), and foveal thickening (19 cases). Fundus fluorescein angiography (FFA) in 18 patients showed vascular leakage (11 cases). Complete resolution of ME occurred in 50 eyes and recovery of visual acuity occurred in 45 eyes at a median time of 2 m (range 0.25, 24) after discontinuation of fingolimod or administration of topical therapy. Conclusions: Macular edema is a known complication of fingolimod. All patients using fingolimod require regular eye exams, especially those with a history of diabetes and uveitis and those undergoing cataract surgery.

Glucolipotoxicity induces endothelial cell dysfunction by activating autophagy and inhibiting autophagic flow.

OBJECTIVES: This study aims to determine the role and mechanism of autophagy in endothelial cell dysfunction by glucolipotoxicity. METHODS: Human umbilical vein endothelial cells (HUVECs) were treated with high glucose and high palmitic acid. The number of autophagosomes was evaluated by monodansylcadaverine (MDC) staining and transmission electron microscopy (TEM). The expression of autophagy-related proteins (LC3 and P62) was assessed by Western blotting. Capillary tube-like formation was evaluated on Matrigel. Reactive oxygen species (ROS) production was detected by DCFH-DA. Cell apoptosis was measured by Hoechst 33258 staining and flow cytometry. Phosphorylation of AMPK, mTOR, and ULK1 was also analyzed by Western blotting. RESULTS: We found that glucolipotoxicity induced autophagy initiation and hindered autophagosomes degradation. Moreover, glucolipotoxicity increased the production of intracellular ROS, decreased the ability of tubular formation, and increased cell apoptosis. However, endothelial cell dysfunction was alleviated by 3-methyladenine, an early-stage autophagy inhibitor. Additionally, glucolipotoxicity promoted the phosphorylation of AMPK and ULK1 and inhibited the phosphorylation of mTOR. CONCLUSIONS: Glucolipotoxicity initiates autophagy through the AMPK/mTOR/ULK1 signaling pathway and inhibits autophagic flow, leading to the accumulation of autophagosomes, thereby inducing apoptosis and impairing endothelial cell function.

S1PR2/RhoA/ROCK1 pathway promotes inflammatory bowel disease by inducing intestinal vascular endothelial barrier damage and M1 macrophage polarization.

Vascular and immune dysfunctions are thought to be related to the pathogenesis of inflammatory bowel disease (IBD), but behind this, the exact mechanism of mucosal vascular endothelial barrier dysfunction and macrophage phenotypic transition is not fully understood. Here, we explored the mechanistic role of sphingosine 1-phosphate receptor 2 (S1PR2) and its downstream G protein RhoA/Rho kinase 1 (ROCK1) signaling pathway in the intestinal endothelial barrier damage and M1 macrophage polarization in IBD. We found that the expression of S1PR2 in intestinal mucosal vascular endothelial cells and macrophages of IBD patients and DSS-induced colitis mice as well as vascular endothelial cells and macrophages treated with LPS in vitro was significantly increased. Knocking down or pharmacologically inhibiting S1PR2 significantly downregulated the expression of RhoA and ROCK1 in vascular endothelial cells and macrophages. Furthermore, inhibition of S1PR2 and ROCK1 reversed the impaired vascular barrier function and M1 macrophage polarization in vivo and in vitro, while reducing ER stress in vascular endothelial cells and glycolysis in macrophages. In addition, inhibition of ER stress or glycolysis reversed LPS-induced impairment of vascular endothelial cell barrier function and M1 macrophage polarization. Collectively, our results indicate that the S1PR2/RhoA/ROCK1 signaling pathway may participate in the pathogenesis of IBD by regulating vascular endothelial barrier function and M1 macrophage polarization.

Evolutionarily conservative and non-conservative regulatory networks during primate interneuron development revealed by single-cell RNA and ATAC sequencing.

The differences in size and function between primate and rodent brains, and the association of disturbed excitatory/inhibitory balance with many neurodevelopmental disorders highlight the importance to study primate ganglionic eminences (GEs) development. Here we used single-cell RNA and ATAC sequencing to characterize the emergence of cell diversity in monkey and human GEs where most striatal and cortical interneurons are generated. We identified regional and temporal diversity among progenitor cells which give rise to a variety of interneurons. These cells are specified within the primate GEs by well conserved gene regulatory networks, similar to those identified in mice. However, we detected, in human, several novel regulatory pathways or factors involved in the specification and migration of interneurons. Importantly, comparison of progenitors between our human and published mouse GE datasets led to the discovery and confirmation of outer radial glial cells in GEs in human cortex. Our findings reveal both evolutionarily conservative and nonconservative regulatory networks in primate GEs, which may contribute to their larger brain sizes and more complex neural networks compared with mouse.

[Clinical and genetic analysis of a child with 2q37 deletion syndrome resulting from a translocation involving chromosome satellite].

OBJECTIVE: To carry out cyto- and molecular genetic testing for a child featuring facial dysmorphism and attention deficit and hyperactive disorder. METHODS: The child was subjected to routine peripheral blood lymphocyte chromosomal karyotyping, fluorescence in situ hybridization (FISH) and single nucleotide polymorphism array (SNP-array) analyses. RESULTS: The child's facial dysmorphism included low-set ears, curly ear auricle, protuberance of eyebrow arch, nostril notch, short and flat philtrum and thin upper lip. SNP-array revealed that he has carried a 4.883 Mb deletion at 2q37. His chromosomal karyotype was ultimately determined as 45, XY, der(2;21) (2pter→ 2q37.3::21p13→ 21p10::20p10→ 20pter), der(20) (21qter→ 21q10::20q10→ 20qter). CONCLUSION: A rare case of 2q37 deletion syndrome involving three chromosomes was discovered. Combined use of various cyto- and molecular genetic techniques is crucial for the diagnosis of chromosomal abnormalities with complex structures.

Cbl Proto-Oncogene B (CBLB) c.197A>T Mutation Induces Mild Metabolic Dysfunction in Partial Type I Multiple Symmetric Lipomatosis (MSL).

BACKGROUND: Multiple symmetric lipomatosis (MSL) is a rare disease showing chronic progression of multiple, symmetrical, and non-encapsulated subcutaneous lipoma. The cause of the disease remains unknown. PATIENTS AND METHODS: This study reported and summarized 13 sporadic cases of Type I MSL patients in terms of histopathology and cellular and molecular biology and assessed the CBLB c.197A>T mutation in the IRS1-PI3K-Akt pathway. RESULTS: The clinical data showed that these 13 Type I patients were all male with a mean age of 57.0 ± 6.6 years old and consumed alcohol heavily. The laboratory tests revealed that most of the patients had hyperuricemia, diabetes, hyperinsulinemia, or insulin resistance; however, their blood lipid levels were close to a normal range. The imaging data exhibited lipomas that only occurred subcutaneously but not viscerally, ie, Types Ia (15.4%), Ib (30.8%), and Ic (53.8%). The molecular analyses of adipocytes of isoprenaline stimulated human adipose tissue-derived mesenchymal stromal cells (hADSCs) isolated from the adipose tissue lipoma-like masses (ATLLM) demonstrated that these adipocytes did not express UCP-1. The Cbl proto-oncogene B (CBLB), an E3 ubiquitin-protein ligase, was associated with insulin resistance and obesity and was mutated (ie, CBLB c.197A>T) in four MSL patients after the whole genome and Sanger sequencing of the blood samples. Furthermore, the CBLB c.197A>T mutation induced hADSC resistance to insulin by inactivation of the IRS-1-PI3K-AKT pathway. CONCLUSION: This study analyzed clinical, histopathological, and cellular and molecular biological characterizations of 13 Type I MSL patients and identified the CBLB c.197A>T heterozygous mutation that could be responsible for MSL metabolic dysfunction or even MSL development.

Treatment-induced neuropathy in diabetes: A report of 2 cases and literature review. / ç³–å°¿ç— æ²»ç–—è¯±å¯¼çš„ç¥žç»ç— å˜2ä¾‹å¹¶æ–‡çŒ®å¤ä¹ .

Treatment-induced neuropathy is an distinct, acute form of neuropathic pain which often occur shortly after initiation of intensive glycemic control and is characterized by excruciating neuropathic pain. It is a rare form of diabetic neuropathy and easy to be misdiagnosed. Clinical characteristics were analyzed based on two cases of treatment-induced neuropathy in diabetes accepted by the Third Xiangya Hospital of Central South University. It is proposed that strict glycemic control may lead to the occurrence of the disease. At Present, the pathogenesis is still unclear. Besides, the morbidity is much higher than we expected. It is important to improve the doctors awareness of this disease and avoid the the disease through carful glycemic control.

Predictive Model of Type 2 Diabetes Remission after Metabolic Surgery in Chinese Patients.

INTRODUCTION: Metabolic surgery is an effective treatment for type 2 diabetes (T2D). At present, there is no authoritative standard for predicting postoperative T2D remission in clinical use. In general, East Asian patients with T2D have a lower body mass index and worse islet function than westerners. We aimed to look for clinical predictors of T2D remission after metabolic surgery in Chinese patients, which may provide insights for patient selection. METHODS: Patients with T2D who underwent metabolic surgery at the Third Xiangya Hospital between October 2008 and March 2017 were enrolled. T2D remission was defined as an HbA1c level below 6.5% and an FPG concentration below 7.1 mmol/L for at least one year in the absence of antidiabetic medications. RESULTS: (1) Independent predictors of short-term T2D remission (1-2 years) were age and C-peptide area under the curve (C-peptide AUC); independent predictors of long-term T2D remission (4-6 years) were C-peptide AUC and fasting plasma glucose (FPG). (2) The optimal cutoff value for C-peptide AUC in predicting T2D remission was 30.93 ng/ml, with a specificity of 67.3% and sensitivity of 75.8% in the short term and with a specificity of 61.9% and sensitivity of 81.5% in the long term, respectively. The areas under the ROC curves are 0.674 and 0.623 in the short term and long term, respectively. (3) We used three variables (age, C-peptide AUC, and FPG) to construct a remission prediction score (ACF), a multidimensional 9-point scale, along which greater scores indicate a better chance of T2D remission. We compared our scoring system with other reported models (ABCD, DiaRem, and IMS). The ACF scoring system had the best distribution of patients and prognostic significance according to the ROC curves. CONCLUSION: Presurgery age, C-peptide AUC, and FPG are independent predictors of T2D remission after metabolic surgery. Among these, C-peptide AUC plays a decisive role in both short- and long-term remission prediction, and the optimal cutoff value for C-peptide AUC in predicting T2D remission was 30.93 ng/ml, with moderate predictive values. The ACF score is a simple reliable system that can predict T2D remission among Chinese patients.

S1PR2 antagonist ameliorate high glucose-induced fission and dysfunction of mitochondria in HRGECs via regulating ROCK1.

AIMS: Sphingosine-1-phosphate receptor 2 (S1PR2) is a G-protein-coupled receptor that regulates sphingosine-1-phosphate-triggered cellular response. However, the role of S1PR2 in diabetes-induced glomerular endothelial cell dysfunction remains unclear. This study aims to investigate the effect of S1PR2 blockade on the morphology and function of mitochondria in human renal glomerular endothelial cells (HRGECs). METHODS: HRGECs were pretreated with a S1PR2 antagonist (JTE-013) or a Rho-associated coiled coil-containing protein kinase 1 (ROCK1) inhibitor (Y27632) for 30 min and then cultured with normal glucose (5.5 mM) or high glucose (30 mM) for 72 h. The protein expression levels of RhoA, ROCK1, and Dynmin-related protein-1(Drp1) were evaluated by immunoblotting; mitochondrial morphology was observed by electron microscopy; intracellular levels of ATP, ROS, and Ca2+ were measured by ATPlite, DCF-DA, and Rhod-2 AM assays, respectively. Additionally, the permeability, apoptosis, and migration of cells were determined to evaluate the effects of S1PR2 and ROCK1 inhibition on high glucose-induced endothelial dysfunction. RESULTS: High glucose induced mitochondrial fission and dysfunction, indicated by increased mitochondrial fragmentation, ROS generation, and calcium overload but decreased ATP production. High glucose also induced endothelial cell dysfunction, indicated by increased permeability and apoptosis but decreased migration. However, inhibition of either S1PR2 or ROCK1 almost completely blocked these high glucose-mediated cellular responses. Furthermore, inhibiting S1PR2 resulted in the deceased expression of RhoA, ROCK1, and Drp1 while inhibiting ROCK1 led to the downregulated expression of Drp1. CONCLUSIONS: S1PR2 antagonist modulates the morphology and function of mitochondria in HRGECs via the positive regulation of the RhoA/ROCK1/Drp1 signaling pathway, suggesting that the S1PR2/ROCK1 pathway may play a crucial role in high glucose milieu.