PDIA3 orchestrates effector T cell program by serving as a chaperone to facilitate the non-canonical nuclear import of STAT1 and PKM2.

Dysregulated T cell activation underpins the immunopathology of rheumatoid arthritis (RA), yet the machineries that orchestrate T cell effector program remain incompletely understood. Herein, we leveraged bulk and single-cell RNA sequencing data from RA patients and validated protein disulfide-isomerase A3 (PDIA3) as a potential therapeutic target. PDIA3 is remarkably upregulated in pathogenic CD4 T cells derived from RA patients and positively correlates with C-reactive protein (CRP) level and disease activity score 28 (DAS28). Pharmacological inhibition or genetic ablation of PDIA3 alleviates RA-associated articular pathology and autoimmune responses. Mechanistically, T cell receptor (TCR) signaling triggers intracellular calcium flux to activate NFAT1, a process that is further potentiated by Wnt5a under RA settings. Activated NFAT1 then directly binds to the Pdia3 promoter to enhance the expression of PDIA3, which complexes with STAT1 or PKM2 to facilitate their nuclear import for transcribing Th1 and Th17 lineage-related genes, respectively. This non-canonical regulatory mechanism likely occurs under pathological conditions as PDIA3 could only be highly induced following aberrant external stimuli. Together, our data support that targeting PDIA3 is a vital strategy to mitigate autoimmune diseases, such as RA, in clinical settings.

Expression and significance of SIRT6 in human peritoneal dialysis effluents and peritoneal mesothelial cells.

Sirtuin 6 (SIRT6) can inhibit the fibrosis of many organs. However, the relationship between SIRT6 and peritoneal fibrosis (PF) in peritoneal dialysis (PD) remains unclear. We collected 110 PD patients with a duration of PD for more than 3 months and studied the influence of PD duration and history of peritonitis on SIRT6 levels in PD effluents (PDEs). We also analyzed the relationship between SIRT6 levels in PDEs and transforming growth factor beta 1 (TGF-ß1), IL-6, PD duration, peritoneal function, PD ultrafiltration (UF), and glucose exposure. We extracted human peritoneal mesothelial cells (HPMCs) from PDEs and measured the protein and gene expression levels of SIRT6, E-cadherin, vimentin, and TGF-ß1 in these cells. Based on the clinical results, we used human peritoneal mesothelial cells lines (HMrSV5) to observe the changes in SIRT6 levels and mesothelial-to-mesenchymal transition (MMT) after intervention with PD fluid. By overexpressing and knocking down SIRT6 expression, we investigated the effect of SIRT6 expression on E-cadherin, vimentin, and TGF-ß1 expression to elucidate the role of SIRT6 in mesothelial-to-epithelial transition in PMCs. Results: (1) With the extension of PD duration, the influence of infection on SIRT6 levels in PDEs increased. Patients with the PD duration of more than 5 years and a history of peritonitis had the lowest SIRT6 levels. (2) SIRT6 levels in PDEs were negatively correlated with PD duration, total glucose exposure, TGF-ß1, IL-6 levels, and the dialysate-to-plasma ratio of creatinine (Cr4hD/P), but positively correlated with UF. This indicates that SIRT6 has a protective effect on the peritoneum. (3) The short-term group (PD ≤ 1 year) had higher SIRT6 and E-cadherin gene and protein levels than the mid-term group (1 year < PD ≤ 5 years) and long-term group (PD > 5 years) in PMCs, while vimentin and TGF-ß1 levels were lower in the mid-term group and long-term group. Patients with a history of peritonitis had lower SIRT6 and E-cadherin levels than those without such a history. (4) After 4.25% PD fluid intervention for HPMCs, longer intervention time resulted in lower SIRT6 levels. (5) Overexpressing SIRT6 can lead to increased E-cadherin expression and decreased vimentin and TGF-ß1 expression in HPMCs. Knocking down SIRT6 expression resulted in decreased E-cadherin expression and increased vimentin and TGF-ß1 expression in HPMCs. This indicates that SIRT6 expression can inhibit MMT in HPMCs, alleviate PF associated with PD, and have a protective effect on the peritoneum.

Lysosomal control of dendritic cell function.

Lysosomal compartments undergo extensive remodeling during dendritic cell (DC) activation to meet the dynamic functional requirements of DCs. Instead of being regarded as stationary and digestive organelles, recent studies have increasingly appreciated the versatile roles of lysosomes in regulating key aspects of DC biology. Lysosomes actively control DC motility by linking calcium efflux to the actomyosin contraction, while enhanced DC lysosomal membrane permeability contributes to the inflammasome activation. Besides, lysosomes provide a platform for the transduction of innate immune signaling and the intricate host-pathogen interplay. Lysosomes and lysosome-associated structures are also critically engaged in antigen presentation and cross-presentation processes, which are pivotal for the induction of antigen-specific adaptive immune response. Through the current review, we emphasize that lysosome targeting strategies serve as vital DC-based immunotherapies in fighting against tumor, infectious diseases, and autoinflammatory disorders.

Pancreatic draining lymph nodes (PLNs) serve as a pathogenic hub contributing to the development of type 1 diabetes.

Type 1 diabetes (T1D) is a chronic, progressive autoinflammatory disorder resulting from the breakdown of self-tolerance and unrestrained ß cell-reactive immune response. Activation of immune cells is initiated in islet and amplified in lymphoid tissues, especially those pancreatic draining lymph nodes (PLNs). The knowledge of PLNs as the hub of aberrant immune response is continuously being replenished and renewed. Here we provide a PLN-centered view of T1D pathogenesis and emphasize that PLNs integrate signal inputs from the pancreas, gut, viral infection or peripheral circulation, undergo immune remodeling within the local microenvironment and export effector cell components into pancreas to affect T1D progression. In accordance, we suggest that T1D intervention can be implemented by three major ways: cutting off the signal inputs into PLNs (reduce inflammatory ß cell damage, enhance gut integrity and control pathogenic viral infections), modulating the immune activation status of PLNs and blocking the outputs of PLNs towards pancreatic islets. Given the dynamic and complex nature of T1D etiology, the corresponding intervention strategy is thus required to be comprehensive to ensure optimal therapeutic efficacy.

Identification and validation of a m7G-related lncRNA signature for predicting the prognosis and therapy response in hepatocellular carcinoma.

BACKGROUND: N7-methylguanosine (m7G) is one of the most common RNA posttranscriptional modifications; however, its potential role in hepatocellular carcinoma (HCC) remains unknown. We developed a prediction signature based on m7G-related long noncoding RNAs (lncRNAs) to predict HCC prognosis and provide a reference for immunotherapy and chemotherapy. METHODS: RNA-seq data from The Cancer Genome Atlas (TCGA) database and relevant clinical data were used. Univariate and multivariate Cox regression analyses were conducted to identify m7G-related lncRNAs with prognostic value to build a predictive signature. We evaluated the prognostic value and clinical relevance of this signature and explored the correlation between the predictive signature and the chemotherapy treatment response of HCC. Moreover, an in vitro study to validate the function of CASC19 was performed. RESULTS: Six m7G-related lncRNAs were identified to create a signature. This signature was considered an independent risk factor for the prognosis of patients with HCC. TIDE analyses showed that the high-risk group might be more sensitive to immunotherapy. ssGSEA indicated that the predictive signature was strongly related to the immune activities of HCC. HCC in high-risk patients was more sensitive to the common chemotherapy drugs bleomycin, doxorubicin, gemcitabine, and lenalidomide. In vitro knockdown of CASC19 inhibited the proliferation, migration and invasion of HCC cells. CONCLUSION: We established a 6 m7G-related lncRNA signature that may assist in predicting the prognosis and response to chemotherapy and immunotherapy of HCC.

Integrated Analysis of Single-Cell RNA-Seq and Bulk RNA-Seq Combined with Multiple Machine Learning Identified a Novel Immune Signature in Diabetic Nephropathy.

Background: Increasing evidence suggests that immune modulation contributes to the pathogenesis and progression of diabetic nephropathy (DN). However, the role of immune modulation in DN has not been elucidated. The purpose of this study was to search for potential immune-related therapeutic targets and molecular mechanisms of DN. Methods: Gene expression datasets were obtained from the Gene Expression Omnibus (GEO) database. A total of 1793 immune-related genes were acquired from the Immunology Database and Analysis Portal (ImmPort). Weighted gene co-expression network analysis (WGCNA) was performed for GSE142025, and the red and turquoise co-expression modules were found to be key for DN progression. We utilized four machine learning algorithms, namely, random forest (RF), support vector machine (SVM), adaptive boosting (AdaBoost), and k-nearest neighbor (KNN), to evaluate the diagnostic value of hub genes. Immune infiltration patterns were analyzed using the CIBERSORT algorithm, and the correlation between immune cell type abundance and hub gene expression was also investigated. Results: A total of 77 immune-related genes of advanced DN were selected for subsequent analyzes. Functional enrichment analysis showed that the regulation of cytokine-cytokine receptor interactions and immune cell function play a corresponding role in the progression of DN. The final 10 hub genes were identified through multiple datasets. In addition, the expression levels of the identified hub genes were corroborated through a rat model. The RF model exhibited the highest AUC. CIBERSORT analysis and single-cell sequencing analysis revealed changes in immune infiltration patterns between control subjects and DN patients. Several potential drugs to reverse the altered hub genes were identified through the Drug-Gene Interaction database (DGIdb). Conclusion: This pioneering work provided a novel immunological perspective on the progression of DN, identifying key immune-related genes and potential drug targets, thus stimulating future mechanistic research and therapeutic target identification for DN.

Comparative analysis of pre- and postmenopausal endometrial cancer in 216 patients.

Background: Endometrial carcinoma (EC) is one of the most common gynecological malignancies and has become more prevalent in recent decades. The clinical manifestations and characteristics of EC in premenopausal and postmenopausal women differ and present with distinct pathological stages and subtypes of EC. Surgery remains the principal therapeutic approach, but the postoperative prognosis is largely affected by the pathological state. Methods: A retrospective study was conducted on 216 patients with EC who were hospitalized from August 2008 to August 2019 in Wuhan Union Hospital. The patients were divided into 2 groups based on the pre- or postmenopausal occurrence of EC. The general clinical characteristics, intraoperative situation, clinicopathological data, and postoperative outcomes of the 2 groups were compared. Results: Patients with premenopausal EC had earlier menarche, a higher incidence of primary infertility and anemia, and fewer pregnancies and deliveries. Patients with postmenopausal EC were older and often had hyperlipidemia and diabetes. Additionally, patients who were postmenopausal had worse tumor pathological gradings, more severe muscular invasion, and a higher rate of lymphatic metastasis. These factors led to a higher demand for postoperative radiotherapy in patients but a lower survival rate. Conclusions: Generally, premenopausal EC differs from postmenopausal EC: the latter is more malignant and has a worse prognosis.

Ghrelin attenuates inflammation in diabetic lung disease by TLR4 pathway in vivo and in vitro.

INTRODUCTION: Diabetic lung disease is already known as one of the diabetes complications, but report on its therapeutic strategy is rare. The present study aimed to add novel therapeutic strategy for diabetic lung disease, to reveal the protective effect of ghrelin on diabetic lung disease both in vivo and in vitro, and to discuss its probable molecular mechanism. RESEARCH DESIGN AND METHODS: Diabetic mice and 16HBE cells were our research objects. We surveyed the effect of ghrelin on streptozotocin-induced lung tissue morphology changes by H&E staining. Furthermore, the changes of proinflammatory cytokines (interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α)) were detected by ELISA. To expound the molecular mechanism, we detected critical proteins of TLR4 pathway and observed their changes by immunohistochemistry (IHC), real-time PCR and western blot analysis in vivo and in vitro, respectively. RESULTS: The results of H&E staining showed that pathological alterations of the lung induced by hyperglycemia were ameliorated by ghrelin. The results of ELISA demonstrated that the elevated levels of IL-1ß and TNF-α induced by hyperglycemia turned to decrease in the lung after ghrelin treatment. In the results of IHC, real-time PCR and western blot analysis, we found that the TLR4 pathway was elevated by hyperglycemia or high glucose and is remarkably inhibited by the treatment of ghrelin both in vivo and in vitro. CONCLUSIONS: Ghrelin could inhibit inflammation of diabetic lung disease by regulating the TLR4 pathway. This study might affect research on diabetic lung disease, and the therapeutic potential of ghrelin for diabetic lung disease is worth considering.

Construction and validation of a prognostic signature based on necroptosis-related genes in hepatocellular carcinoma.

BACKGROUND: Necroptosis is a necrotic programmed cell death with potent immunogenicity. Due to the dual effects of necroptosis on tumor growth, metastasis and immunosuppression, we evaluated the prognostic value of necroptosis-related genes (NRGs) in hepatocellular carcinoma (HCC). METHODS: We first analyzed RNA sequencing and clinical HCC patient data obtained to develop an NRG prognostic signature based on the TCGA dataset. Differentially expressed NRGs were further evaluated by GO and KEGG pathway analyses. Next, we conducted univariate and multivariate Cox regression analyses to build a prognostic model. We also used the dataset obtained from the International Cancer Genome Consortium (ICGC) database to verify the signature. The Tumor Immune Dysfunction and Exclusion (TIDE) algorithm was used to investigate the immunotherapy response. Furthermore, we investigated the relationship between the prediction signature and chemotherapy treatment response in HCC. RESULTS: We first identified 36 differentially expressed genes out of 159 NRGs in hepatocellular carcinoma. Enrichment analysis showed that they were mainly enriched in the necroptosis pathway. Four NRGs were screened by Cox regression analysis to establish a prognostic model. The survival analysis revealed that the overall survival of patients with high-risk scores was significantly shorter than that of patients with low-risk scores. The nomogram demonstrated satisfactory discrimination and calibration. The calibration curves validated a fine concordance between the nomogram prediction and actual observation. The efficacy of the necroptosis-related signature was also validated by an independent dataset and immunohistochemistry experiments. TIDE analysis revealed that patients in the high-risk group were possibly more susceptible to immunotherapy. Furthermore, high-risk patients were found to be more sensitive to conventional chemotherapeutic medicines such as bleomycin, bortezomib, and imatinib. CONCLUSION: We identified 4 necroptosis-related genes and established a prognostic risk model that could potentially predict prognosis and response to chemotherapy and immunotherapy in HCC patients in the future.

UBC9 deficiency enhances immunostimulatory macrophage activation and subsequent antitumor T cell response in prostate cancer.

The role of tumor-associated macrophages (TAMs), along with the regulatory mechanisms underlying distinct macrophage activation states, remains poorly understood in prostate cancer (PCa). Herein, we report that PCa growth in mice with macrophage-specific Ubc9 deficiency is substantially suppressed compared with that in wild-type littermates, an effect partially ascribed to the augmented CD8+ T cell response. Biochemical and molecular analyses revealed that signal transducer and activator of transcription 4 (STAT4) is a crucial UBC9-mediated SUMOylation target, with lysine residue 350 (K350) as the major modification site. Site-directed mutation of STAT4 (K350R) enhanced its nuclear translocation and stability, thereby facilitating the proinflammatory activation of macrophages. Importantly, administration of the UBC9 inhibitor 2-D08 promoted the antitumor effect of TAMs and increased the expression of PD-1 on CD8+ T cells, supporting a synergistic antitumor efficacy once it combined with the immune checkpoint blockade therapy. Together, our results demonstrate that ablation of UBC9 could reverse the immunosuppressive phenotype of TAMs by promoting STAT4-mediated macrophage activation and macrophage-CD8+ T cell crosstalk, which provides valuable insights to halt the pathogenic process of tumorigenesis.

Management of an emergency sample collection team under the setting of whole-community severe acute respiratory syndrome coronavirus 2 nucleic acid testing.

BACKGROUND: During the coronavirus disease 2019 pandemic, a nucleic acid test is frequently conducted to identify positive cases. Compared with a hospital-based strategy, whole-community nucleic acid testing displays a unique advantage in rapid screening of a massive population. Yet a management plan to ensure ample and contamination-free sample collection is lacking.The objective of the current study was to establish an efficient operational mode of whole-community nucleic acid testing by management of a sample collection team and to provide a reference for joint prevention work to contain the spread of severe acute respiratory syndrome coronavirus 2. METHODS: The efficient operation of nucleic acid testing within the community was implemented by urgent setting up of sample collection teams, efficient allocation of medical supplies, optimization of management procedures and coordination among multiple working departments. RESULTS: A total of 21 585 nucleic acid samples were collected within 3 d, while no one was missed or experienced a cross infection. No falls, heatstroke, disputes or other adverse events occurred. CONCLUSIONS: Under the emergency setting of nucleic acid testing of a large population, a management system with orderly organization, clear division of responsibilities and standardized operational procedures should be formulated.

Analysis of prognostic factors of extranodal NK/T-cell lymphoma treated with pegaspargase/L-asparaginase: a multicenter retrospective study / 中华血液学杂志

Objective: To explore the prognostic factors of extracellular NK/T cell lymphoma (ENKTL) treated with pegaspargase/L-asparaginase. Methods: The clinical data of 656 ENKTL patients diagnosed at 11 medical centers in the Huaihai Lymphoma Working Group from March 2014 to April 2021 were retrospectively analyzed. The patients were randomly divided into two groups: a training set (460 cases) and a validation set (196 cases) at 7∶3, and the prognostic factors of the patients were analyzed. A prognostic scoring system was established, and the predictive performance of different models was compared. Results: Patients' median age was 46 (34, 57) years, with 456 males (69.5% ) and 561 nasal involvement (85.5% ). 203 patients (30.9% ) received a chemotherapy regimen based on L-asparaginase combined with anthracyclines, and the 5-year overall survival rate of patients treated with P-GEMOX regimen (pegaspargase+gemcitabine+oxaliplatin) was better than those treated with SMILE regimen (methotrexate+dexamethasone+cyclophosphamide+L-asparaginase+etoposide) (85.9% vs 63.8% ; P=0.004). The results of multivariate analysis showed that gender, CA stage, the Eastern Cooperative Oncology Group performance status (ECOG PS) score, HGB, and EB virus DNA were independent influencing factors for the prognosis of ENKTL patients (P<0.05). In this study, the predictive performance of the prognostic factors is superior to the international prognostic index, Korean prognostic index, and prognostic index of natural killer lymphoma. Conclusion: Gender, CA stage, ECOG PS score, HGB, and EB virus DNA are prognostic factors for ENKTL patients treated with pegaspargase/L-asparaginase.

Efficacy and safety of various doses of hybutimibe monotherapy or in combination with atorvastatin for primary hypercholesterolemia: a multicenter, randomized, double-blind, double-dummy, parallel-controlled phase Ⅲ clinical trial / 中华心血管病杂志

Objective: To evaluate the efficacy and safety of hybutimibe monotherapy or in combination with atorvastatin in the treatment of primary hypercholesterolemia. Methods: This was a multicenter, randomized, double-blind, double-dummy, parallel-controlled phase Ⅲ clinical trial of patients with untreated primary hypercholesterolemia from 41 centers in China between August 2015 and April 2019. Patients were randomly assigned, at a ratio of 1∶1∶1∶1∶1∶1, to the atorvastatin 10 mg group (group A), hybutimibe 20 mg group (group B), hybutimibe 20 mg plus atorvastatin 10 mg group (group C), hybutimibe 10 mg group (group D), hybutimibe 10 mg plus atorvastatin 10 mg group (group E), and placebo group (group F). After a dietary run-in period for at least 4 weeks, all patients were administered orally once a day according to their groups. The treatment period was 12 weeks after the first dose of the study drug, and efficacy and safety were evaluated at weeks 2, 4, 8, and 12. After the treatment period, patients voluntarily entered the long-term safety evaluation period and continued the assigned treatment (those in group F were randomly assigned to group B or D), with 40 weeks' observation. The primary endpoint was the percent change in low density lipoprotein cholesterol (LDL-C) from baseline at week 12. Secondary endpoints included the percent changes in high density lipoprotein cholesterol (HDL-C), triglyceride (TG), apolipoprotein B (Apo B) at week 12 and changes of the four above-mentioned lipid indicators at weeks 18, 24, 38, and 52. Safety was evaluated during the whole treatment period. Results: Totally, 727 patients were included in the treatment period with a mean age of (55.0±9.3) years old, including 253 males. No statistical differences were observed among the groups in demographics, comorbidities, and baseline blood lipid levels. At week 12, the percent changes in LDL-C were significantly different among groups A to F (all P<0.01). Compared to atorvastatin alone, hybutimibe combined with atorvastatin could further improve LDL-C, TG, and Apo B (all P<0.05). Furthermore, there was no significant difference in percent changes in LDL-C at week 12 between group C and group E (P=0.991 7). During the long-term evaluation period, there were intergroup statistical differences in changes of LDL-C, TG and Apo B at 18, 24, 38, and 52 weeks from baseline among the statins group (group A), hybutimibe group (groups B, D, and F), and combination group (groups C and E) (all P<0.01), with the best effect observed in the combination group. The incidence of adverse events was 64.2% in the statins group, 61.7% in the hybutimibe group, and 71.0% in the combination group during the long-term evaluation period. No treatment-related serious adverse events or adverse events leading to death occurred during the 52-week study period. Conclusions: Hybutimibe combined with atorvastatin showed confirmatory efficacy in patients with untreated primary hypercholesterolemia, which could further enhance the efficacy on the basis of atorvastatin monotherapy, with a good overall safety profile.

Leucine-rich repeat kinase 2 is protective during acute kidney injury through its activation of autophagy in podocytes.

Leucine-rich repeat kinase 2 (LRRK2) is a known regulator of autophagy in a range of cell types. Here, we investigated the role of LRRK2-associated autophagy during acute kidney injury (AKI) and its underlying mechanism(s) of action. Male mice aged 8-weeks were treated with the LRRK2 inhibitor MLi-2 and exposed to lipopolysaccharide (LPS) through intraperitoneal injection or ischemia-reperfusion (IR) surgery. Mice were sacrificed 12 or 24 h post-LPS injection or IR operation and blood was collected for serum creatinine measurements. Kidney cortical tissues were collected for western blot analysis of podocyte-specific markers and autophagy-associated proteins. Renal histopathology was observed through hematoxylin-eosin staining. For cell-based assays, immortalized mouse podocytes were silenced for LRRK2 through siRNA transfection and exposed to LPS or cobalt chloride. Changes in cell viability were investigated using cell counting kit-8, flow cytometry and MTT assays. Expression of podocyte-specific markers and autophagy-associated proteins were analyzed by western blotting. We observed an increase in LRRK2 expression at 12 h post-LPS injection and IR surgery that was accompanied by enhanced autophagy. At 24 h post-treatment, both LRRK2 expression and autophagy declined. Kidney injury was most pronounced in mice treated with MLi-2. Podocytes silenced for LRRK2 showed a loss of cell viability, decreased levels of podocyte-specific protein expression and a suppression of autophagy. Together, these data reveal the protective effects of LRRK2 during AKI through enhanced podocyte autophagy and cell viability.

The Essential Role of FoxO1 in the Regulation of Macrophage Function.

Macrophages are widely distributed in various tissues and organs. They not only participate in the regulation of innate and adaptive immune response, but also play an important role in tissue homeostasis. Dysregulation of macrophage function is closely related to the initiation, development and prognosis of multiple diseases, including infection and tumorigenesis. Forkhead box transcription factor O1 (FoxO1) is an important member among the forkhead box transcription factor family. Through directly binding to the promoter regions of downstream target genes, FoxO1 is implicated in cell proliferation, apoptosis, metabolic activities and other biological processes. In this review, we summarized the regulatory role of FoxO1 in macrophage phagocytosis, migration, differentiation and inflammatory activation. We also emphasized that macrophage reciprocally modulated FoxO1 activity via a post-translational modification (PTM) dominant manner.

The interferon regulatory factors, a double-edged sword, in the pathogenesis of type 1 diabetes.

Type 1 diabetes (T1D) is an autoimmune disease resulted from the unrestrained inflammatory attack towards the insulin-producing islet ß cells. Although the exact etiology underlying T1D remains elusive, viral infections, especially those specific strains of enterovirus, are acknowledged as a critical environmental cue involved in the early phase of disease initiation. Viral infections could either directly impede ß cell function, or elicit pathological autoinflammatory reactions for ß cell killing. Autoimmune responses are bolstered by a massive body of virus-derived exogenous pathogen-associated molecular patterns (PAMPs) and the presence of ß cell-derived damage-associated molecular patterns (DAMPs). In particular, the nucleic acid components and the downstream nucleic acid sensing pathways serve as the major effector mechanism. The endogenous retroviral RNA, mitochondrial DNA (mtDNA) and genomic fragments generated by stressed or dying ß cells induce host responses reminiscent of viral infection, a phenomenon termed as viral mimicry during the early stage of T1D development. Given that the interferon regulatory factors (IRFs) are considered as hub transcription factors to modulate immune responses relevant to viral infection, we thus sought to summarize the critical role of IRFs in T1D pathogenesis. We discuss with focus for the impact of IRFs on the sensitivity of ß cells to cytokine stimulation, the vulnerability of ß cells to viral infection/mimicry, and the intensity of immune response. Together, targeting certain IRF members, alone or together with other therapeutics, could be a promising strategy against T1D.

Capsaicin induces ferroptosis of NSCLC by regulating SLC7A11/GPX4 signaling in vitro.

NSCLC is the first cause of cancer-related deaths in China and threatens life expectancy of the people. Novel drugs and treatment strategies are urgently required. Capsaicin is noticed as a potential new drug for lots of tumors due to its anti-proliferative effect on cancer cells. Our study evaluated the roles of capsaicin in NSCLC cells (A549 and NCI-H23) and further explored its underlying mechanisms. Effect of capsaicin treatment on cell viability was determined by MTT assay and IC50 values for A549 and NCI-H23 cells were ascertained. The iron kit detected the total iron levels and the ferric divalent ions levels in A549 and NCI-H23 cells. GSH kit was used to detect the expression of GSH in A549 and NCI-H23 cells. Additionally, mRNA and protein levels of SLC7A11 and GPX4 were analyzed by real-time PCR and western blot analysis. Through MTT assay, we found that 200 µM capsaicin in cultured A549 cells for 48 h could reach the IC50 value, and the condition was 100 µM and 48 h for NCI-H23 cells. Capsaicin increased total iron levels and ferrous ion levels in A549 and NCI-H23 cells in contrast with the control group, whereas the levels of GSH was reduced in contrast with the control group. Besides, mRNA and protein levels of SLC7A11 and GPX4 were decreased significantly in A549 and NCI-H23 cells treated with capsaicin in contrast with the control group. Our study indicated that capsaicin inhibited the proliferation of A549 and NCI-H23 cells and induced ferroptosis by inactivating SLC7A11/GPX4 signaling. Capsaicin could be used as a potential anticancer agent in the treatment of NSCLC.

Blockage of TIM-3 relieves lupus nephritis by expanding Treg cells and promoting their suppressive capacity in MRL/lpr mice.

T Cell Immunoglobulin and Mucin Containing Protein-3 (TIM-3) is an important immune checkpoint protein that is expressed in Tregs and affects their function. However, the expression and role of TIM-3 in modulating regulatory T cells (Tregs) in lupus nephritis (LN) are still unknown. In this study, we found that the percentage of TIM-3+ cells among spleen lymphocytes, CD4+ T cells and Tregs was higher in MRL/lpr mice than in MpJ mice. TIM-3high CD4+ T cells and TIM-3high Tregs were mainly responsible for the increase. The percentage of Tregs in TIM-3high CD4+ T cells was lower than that in TIM-3low CD4+ T cells, and the expression of CTLA-4 and IL-10 was lower in TIM-3high Tregs than in the TIM-3low Tregs in MRL/lpr mice. Blockade of TIM-3 in vivo significantly increased the Treg population and the expression of CTLA-4 and IL-10 in Tregs, thus relieving the LN symptoms and pathology in MRL/lpr mice. Additionally, bioinformatics analysis indicated that TIM-3 regulates Treg cells in LN mainly through cytokine-cytokine receptor interactions, the PI3K-Akt signaling pathway, the T cell receptor signaling pathway, Th17 cell differentiation and the FoxO signaling pathway. Together, our study has demonstrated that TIM-3 regulates Tregs in LN and that overexpression of TIM-3 in CD4+ T cells and Tregs leads to Treg quantity and quality deficiency in MRL/lpr mice. Blockade of TIM-3 protects against LN by expanding Tregs and enhancing their suppressive capacity. Finally, TIM-3 might be a potential therapeutic target for the treatment of LN.

Lymphotoxins Serve as a Novel Orchestrator in T1D Pathogenesis.

Type 1 diabetes (T1D) stems from pancreatic ß cell destruction by islet reactive immune cells. Similar as other autoimmune disorders, there is no curative remedy for T1D thus far. Chronic insulitis is the hallmark of T1D, which creates a local inflammatory microenvironment that impairs ß cell function and ultimately leads to ß cell death. Immune regulation shows promise in T1D treatment by providing a time window for ß cell recovery. However, due to the complex nature of T1D pathogenesis, the therapeutic effect of immune regulation is often short-lasting and unsatisfying in monotherapies. Lymphotoxins (LTs) were first identified in 1960s as the lymphocyte-producing cytokine that can kill other cell types. As a biological cousin of tumor necrosis factor alpha (TNFα), LTs play unique roles in T1D development. Herein in this review, we summarized the advancements of LTs in T1D pathogenesis. We particularly highlighted their effect on the formation of peri-islet tertiary lymphoid organs (TLOs), and discussed their synergistic effect with other cytokines on ß cell toxicity and autoimmune progression. Given the complex and dynamic crosstalk between immune cells and ß cells in T1D setting, blockade of lymphotoxin signaling applied to the existing therapies could be an efficient approach to delay or even reverse the established T1D.

Aloperine Ameliorates IMQ-Induced Psoriasis by Attenuating Th17 Differentiation and Facilitating Their Conversion to Treg.

Aloperine is an anti-inflammatory compound isolated from the Chinese herb Sophora alopecuroides L. Previously, our group has reported that the generation of induced Treg was promoted by aloperine treatment in a mouse colitis model. However, the effect of aloperine on effector T cell subsets remains unclear. We therefore carefully examined the effect of aloperine on the differentiation of major subsets of T helper cells. Based on our results, psoriasis, a Th17 dominant skin disease, is selected to explore the potential therapeutic effect of aloperine in vivo. Herein, we demonstrated that topical application of aloperine suppressed epidermal proliferation, erythema, and infiltration of inflammatory cells in skin lesions. Mechanistic studies revealed that aloperine suppressed the differentiation of Th17 cells directly through inhibiting the phosphorylation of STAT3 or indirectly through impairing the secretion of Th17-promoting cytokines by dendritic cells. Moreover, aloperine enhanced the conversion of Th17 into Treg via altering the pSTAT3/pSTAT5 ratio. Collectively, our study supported that aloperine possesses the capacity to affect Th17 differentiation and modulates Th17/Treg balance, thereby alleviating imiquimod (IMQ)-induced psoriasis in mice.