Ischemia-reperfusion (I/R)-induced retinal ganglion cells (RGCs) death involves multiple types of regulated cell death. Ferroptosis plays an active role in retinal I/R injury. Primaquine, a classical antimalarial drug, has unique pharmacological properties that suggest it may inhibit ferroptosis. We employed an acute high intraocular pressure (aHIOP) mouse model and oxygen-glucose deprivation/reoxygenation (OGD/R) injury in R28 cells to investigate the effects of primaquine on retinal I/R injury. Transcriptomic sequencing at both the animal and cellular levels identified glutathione S-transferase alpha 1 (GSTA1) as a potential key target of primaquine. In vitro, primaquine treatment inhibited cell death induced by OGD/R, Erastin, and RSL3. It suppressed the accumulation of ROS and Fe²⁺, ameliorated mitochondrial morphological damage, and promoted the increased expression of SLC7A11 and GPX4. Primaquine administration reduced RGC layer cell loss, increased retinal thickness, and upregulated SLC7A11 and GPX4 protein levels in the retina. Knocking down GSTA1 expression reversed the protective effects of primaquine against ferroptosis induced by OGD/R, Erastin, or RSL3. Our study offers new insights into the critical function of primaquine in inhibiting ferroptosis via modulating GSTA1 activity in retinal neuron induced by OGD/R, Erastin, or RSL3, a mechanism that has not been previously explored.

Introduction Emerging evidence suggests that a novel inflammatory programmed cell death pathway, PANoptosis-entailing the co-activation of apoptosis, pyroptosis, and necroptosis-may contribute to renal ischemic injury. While growing research implicates PANoptosis in the pathogenesis of diverse ischemic conditions, its specific role in AKI has not been thoroughly elucidated. Methods To test whether PANoptosis exists in renal ischemia diseases, we screened renal ischemia injury involving apoptosis, pyroptosis, and necroptosis as the research model and analyzed the data. Meanwhile, we detected the expression of several marker proteins (cleaved caspase-3, p-MLKL, NLRP3, and GSDMD) in HK-2 cells following ischemic injury. Results The bibliometric results indicate that there is a large number of studies on apoptosis, pyroptosis, and necroptosis in cell and animal models simulating renal ischemia-reperfusion injury. Meanwhile, the experimental results show that in the ischemia-reperfusion injury model of HK-2 cells, the expression levels of key molecules involved in apoptosis, pyroptosis, and necroptosis change. Discussion Our results demonstrate the involvement of PANoptosis in renal ischemic injury, offering a basis for targeted therapies against renal ischemia-related diseases and supporting the development of PANoptosis inhibitors. Conclusion Collectively, our findings indicate that a PANoptosis-like cell death process occurs in renal ischemic injury.

Chronic methamphetamine (Meth) exposure has been recognized as a critical risk factor for male reproductive dysfunction, yet its mechanistic underpinnings remain elusive. This study elucidates the molecular pathways through which Meth compromises spermatogenesis in a murine model. Male mice subjected to 15 days of chronic Meth administration presented severe testicular atrophy, characterized by seminiferous epithelial disorganization and diminished sperm reserves in both the testes and epididymides. Quantitative assessments revealed marked reductions in sperm motility and increased tail abnormalities. Transcriptomic profiling revealed significant down-regulation of methyltransferase-like 21C ( Mettl21c ), an undifferentiated spermatogonial-enriched methyltransferase, within pathways governing germ cell differentiation. Immunofluorescence analysis revealed predominant Mettl21c colocalization with undifferentiated spermatogonial marker ubiquitin carboxyl-terminal hydrolase L1 (Uchl1), with minimal overlap in tyrosine-protein kinase Kit (Kit) positive differentiated populations. In vitro suppression of Mettl21c in C18-4 lines triggered proliferation arrest and increased apoptosis. These findings establish Mettl21c as a pivotal mediator of Meth-induced spermatogenic failure through spermatogonial maintenance pathways. Our work provides novel insights into the epigenetic regulation of drug-associated male infertility and identifies Mettl21c as a potential therapeutic target for preserving fertility in substance abuse cases.

Retinal ischemia-reperfusion (I/R) injury is an important pathological mechanism of glaucoma. The role of peroxiredoxin 5 (PRDX5) in this process remains unclear. An acute high intraocular pressure (aHIOP) mouse model was used, and oxygen and glucose deprivation and reoxygenation (OGD/R) injury in R28 cells was used to investigate the role of PRDX5 in retinal I/R injury. The role of PRDX5 was assessed by hematoxylin-eosin (HE) staining, TUNEL staining, and Western blotting (WB) in vivo. Cell viability, lactate dehydrogenase (LDH) release, propidium iodide (PI) staining, reactive oxygen species (ROS), mitochondrial membrane potential assay, and WB analyses were conducted to validate the effect of PRDX5 in vitro. The effects of PRDX5 acetylation were analyzed using nicotinamide and nicotinamide riboside chloride (NRC) in the OGD/R model. Knocking down PRDX5 expression exacerbated OGD/R-induced apoptosis and oxidative stress. Overexpressing PRDX5 reduced OGD/R-induced apoptosis and oxidative stress. Overexpressing PRDX5 significantly attenuated retinal tissue damage and neuronal apoptosis after I/R in vivo. OGD/R increased PRDX5 acetylation in R28 cells. NAM treatment increased PRDX5 acetylation induced by OGD/R, concomitant with increased ROS levels and apoptosis in R28 cells. NRC treatment reduced OGD/R-induced PRDX5 acetylation, concomitantly decreasing ROS production and attenuating apoptosis. Notably, inhibiting deacetylation abolished the protective effect of PRDX5 overexpression. Our study suggested that PRDX5 plays a vital role in protecting against oxidative stress and apoptosis in retinal I/R injury. The acetylation of PRDX5 inhibits its antioxidant and anti-apoptotic functions.

B cell malfunction is implicated in the pathogenesis of systemic lupus erythematosus (SLE) through the release of proinflammatory cytokines and the production of autoreactive antibodies. RNA N6-methyladenosine (m6A) is the predominant post-transcriptional RNA modification that has been reported to control various biological processes. Whether RNA m6A alteration and m6A reader protein YTHDF1 contribute to B cell activation and terminal B cell differentiation in SLE has not been fully demonstrated. Here we observed that SLE peripheral B cell subsets, activated B cells and differentiated plasma cells (PCs) had abnormally elevated levels of YTHDF1, the deficit of which attenuated PC differentiation both in vitro and in mouse models that have been immunized with keyhole limpet hemocyanin (KLH) or N-propionyl polysialic acid (NP–KLH). Utilizing RNA sequencing, RNA immunoprecipitation, m6A immunoprecipitation and other functional experiments, we have identified and described a PC-promoting role of YTHDF1. YTHDF1 binds to the m6A-marked 3′ untranslated region of transcription factor IRF4 messenger RNA to enhance its stability, thereby facilitating PC differentiation. Depletion of YTHDF1 hindered the differentiation of PCs, reduced the generation of autoantibodies and ameliorated the lupus-like phenotypes in an imiquimod-treated mouse model. Overall, this study highlights a distinct role of YTHDF1 in promoting PC differentiation through the direct regulation of IRF4 in an m6A-dependent manner and identifies YTHDF1 as a potential target for the treatment of SLE. Systemic lupus erythematosus (SLE) is a complex autoimmune disease in which the immune system attacks the body’s own tissues. Researchers have been exploring ways to manage SLE by targeting specific immune cells called B cells. This study investigates a protein called YTHDF1, which is involved in the regulation of B cells. They found that YTHDF1 levels are higher in certain B cells of patients with SLE. They conducted experiments using both human cells and mice to understand how YTHDF1 affects B cell behavior. They used techniques such as gene editing and RNA analysis to study the effects of removing YTHDF1 from B cells. This study showed that without YTHDF1, B cells had trouble developing into plasma cells, which are crucial for producing antibodies. The results suggest that YTHDF1 helps to stabilize a key molecule called IRF4, which is important for plasma cell development. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

Hantaan virus (HTNV) infection causes severe hemorrhagic fever with renal syndrome (HFRS) in humans and the infectious process can be regulated by autophagy. The phosphatase and tensin homolog (PTEN) protein has antiviral effects and plays a critical role in the autophagy pathway. However, the relationship between PTEN and HTNV infection is not clear and whether PTEN-regulated autophagy involves in HTNV replication is unknown. Here, we identified that HTNV infection inhibits PTEN expression in vitro and in vivo. The HTNV glycoprotein Gc promotes PTEN ubiquitination and degradation through 26S-proteasome pathway via the E3 ubiquitin ligase NEDD4. In addition, knockdown of PTEN prevents autophagy and increases HTNV production, while overexpression of PTEN induces autophagosome formation which can wrap HTNV particles, thus leading to restrain the production of progeny viruses. Altogether, our findings reveal the role of PTEN in HTNV infection by autophagy, highlighting the potential importance of PTEN and autophagy in the treatment of HFRS diseases.

BACKGROUND AND AIMS:Atherosclerosis (AS) is a continuously low-grade inflammatory disease, and monocyte-derived macrophages play a vital role in AS pathogenesis. Regulatory factor X1 (RFX1) has been reported to participate in differentiation of various cells. Our previous report showed that RFX1 expression in CD14+ monocytes from AS patients was decreased and closely related to AS development. Macrophages mostly derive from monocytes and play an important role in AS plaque formation and stability. However, the functions of RFX1 in the formation of macrophage-derived foam cells and consequent AS development are unclear.METHODS:We explored the effects of RFX1 on oxidation low lipoprotein (ox-LDL)-stimulated foam cell formation and CD36 expression by increasing or silencing Rfx1 expression in mouse peritoneal macrophages (PMAs). The ApoE-/-Rfx1f/f or ApoE-/-Rfx1f/f Lyz2-Cre mice fed a high-fat diet for 24 weeks were used to further examine the effect of RFX1 on AS pathogenesis. We then performed dual luciferase reporter assays to study the regulation of RFX1 for CD36 transcription.RESULTS:Our results demonstrate that RFX1 expression was significantly reduced in ox-LDL induced foam cells and negatively correlated with lipid uptake in macrophages. Besides, Rfx1 deficiency in myeloid cells aggravated atherosclerotic lesions in ApoE-/- mice. Mechanistically, RFX1 inhibited CD36 expression by directly regulating CD36 transcription in macrophages.CONCLUSIONS:The reduction of RFX1 expression in macrophages is a vital determinant for foam cell formation and the initiation of AS, proving a potential novel approach for the treatment of AS disease.

INTRODUCTION:Methamphetamine (METH) is a synthetic drug widely abused globally and can result in hyperthermia (HT) and psychiatric symptoms. Our previous studies showed that heat shock protein 90 alpha (HSP90α) plays a vital role in METH/HT-elicited neuronal necroptosis; however, the detailed mechanism of HSP90α regulation remained obscure. METHODS:Herein, we demonstrated a function of the suppressor of G-two allele of SKP1 (Sgt1) in METH/HT-induced necroptosis. Sgt1 was mainly expressed in neurons, co-located with HSP90α, and increased in rat striatum after METH treatment. METH/HT injury triggered necroptosis and increased Sgt1 expression in PC-12 cells. RESULTS:Data from computer simulations indicated that Sgt1 might interact with HSP90α. Geldanamycin (GA), the specific inhibitor of HSP90α, attenuated the interaction between Sgt1 and HSP90α. Knockdown of Sgt1 expression did not affect the expression level of HSP90α. Still, it inhibited the expression of receptor-interacting protein 3 (RIP3), mixed lineage kinase domain-like protein (MLKL), p-RIP3, and p-MLKL, as well as necroptosis induced by METH/HT injury. CONCLUSION:In conclusion, Sgt1 may regulate the expression of RIP3, p-RIP3, MLKL, and p-MLKL by assisting HSP90α in affecting the METH/HT-induced necroptotic cell death.

Introduction Methamphetamine (METH) is an illicit psychoactive substance that can damage various organs in the body, especially the nervous system. We hypothesized that expression of homocysteine-inducible endoplasmic reticulum-resident with ubiquitin-like domain member 1 (Herpud1) protein would alleviate the induction of apoptosis following METH administration.Methods To test this hypothesis, we analysed the changes in Herpud1 expression and apoptosis in PC12 cells under different concentrations and exposure times of METH. Moreover, we examined the effects of Herpud1 knockdown on METH-induced neuronal apoptosis. Flow cytometry and Western blot analyses were used to evaluate apoptosis levels and the expression of apoptotic markers (cleaved caspase-3) in PC12 cells following Herpud1 knockdown by synthetic small interfering RNA (siRNA).Results Our results showed that Herpud1 expression was upregulated in PC12 cells following METH treatment, while endoplasmic reticulum stress (ERS) and apoptosis were also increased. Conversely, Herpud1 knockdown reduced METH-induced ERS and apoptosis levels in vitro.Conclusion These results suggest that Herpud1 plays an essential role in METH-induced neuronal ERS and apoptosis and may represent a potential therapeutic gene target in METH-induced neurotoxicity.

Skin diseases are global health issues caused by multiple pathogenic factors, in which epigenetics plays an invaluable role. Post-transcriptional RNA modifications are important epigenetic mechanism that regulate gene expression at the genome-wide level. N6-methyladenosine (m6A) is the most prevalent modification that occurs in the messenger RNAs (mRNA) of most eukaryotes, which is installed by methyltransferases called “writers”, removed by demethylases called “erasers”, and recognised by RNA-binding proteins called “readers”. To date, m6A is emerging to play essential part in both physiological processes and pathological progression, including skin diseases. However, a systematic summary of m6A in skin disease has not yet been reported. This review starts by illustrating each m6A-related modifier specifically and their roles in RNA processing, and then focus on the existing research advances of m6A in immune homeostasis and skin diseases.

Systemic lupus erythematosus (SLE) is an autoimmune disorder in which excessive CD4+ T-cell activation and imbalanced effector T-cell differentiation play critical roles. Recent studies have implied a potential association between posttranscriptional N6-methyladenosine (m6A) modification and CD4+ T-cell-mediated humoral immunity. However, how this biological process contributes to lupus is not well understood. In this work, we investigated the role of the m6A methyltransferase like 3 (METTL3) in CD4+ T-cell activation, differentiation, and SLE pathogenesis both in vitro and in vivo. The expression of METTL3 was knocked down and METTL3 enzyme activity was inhibited using siRNA and catalytic inhibitor, respectively. In vivo evaluation of METTL3 inhibition on CD4+ T-cell activation, effector T-cell differentiation, and SLE pathogenesis was achieved using a sheep red blood cell (SRBC)-immunized mouse model and a chronic graft versus host disease (cGVHD) mouse model. RNA-seq was performed to identify pathways and gene signatures targeted by METTL3. m6A RNA-immunoprecipitation qPCR was applied to confirm the m6A modification of METTL3 targets. METTL3 was defective in the CD4+ T cells of SLE patients. METTL3 expression varied following CD4+ T-cell activation and effector T-cell differentiation in vitro. Pharmacological inhibition of METTL3 promoted the activation of CD4+ T cells and influenced the differentiation of effector T cells, predominantly Treg cells, in vivo. Moreover, METTL3 inhibition increased antibody production and aggravated the lupus-like phenotype in cGVHD mice. Further investigation revealed that catalytic inhibition of METTL3 reduced Foxp3 expression by enhancing Foxp3 mRNA decay in a m6A-dependent manner, hence suppressing Treg cell differentiation. In summary, our findings demonstrated that METTL3 was required for stabilizing Foxp3 mRNA via m6A modification to maintain the Treg differentiation program. METTL3 inhibition contributed to the pathogenesis of SLE by participating in the activation of CD4+ T cells and imbalance of effector T-cell differentiation, which could serve as a potential target for therapeutic intervention in SLE.

Objective:The integration of training in theory and practice across the medical education spectrum is being encouraged to increase student understanding and skills in the sciences.This study aimed to determine the deciding factors that drive students'perceived advantages in class to improve precision education and the teaching model.Methods:A mixed strategy of an existing flipped classroom(FC)and a case-based learning(CBL)model was conducted in a medical morphology curriculum for 575 postgraduate students.The subjective learning evaluation of the individuals(learning time,engagement,study interest and concentration,and professional integration)was collected and analyzed after FC-CBL model learning.Results:The results from the general evaluation showed promising results of the medical morphology in the FC-CBL model.Students felt more engaged by instructors in person and benefited in terms of time-saving,flexible arrangements,and professional improvement.Our study contributed to the FC-CBL model in Research Design in postgraduate training in 4 categories:1)advancing a guideline of precision teaching according to individual characteristics;2)revealing whether a learning background is needed for a Research Design course to guide setting up a preliminary course;3)understanding the perceived advantages and their interfaces;and 4)barriers and/or improvement to implement the FC-CBL model in the Research Design class,such as a richer description of e-learning and hands-on practice.Conclusion:Undertaking a FC-CBL combined model could be a useful addition to pedagogy for medical morphology learning in postgraduate training.

Although KMT2D, also known as MLL2, is known to play an essential role in development, differentiation, and tumor suppression, its role in pancreatic cancer development is not well understood. Here, we discovered a novel signaling axis mediated by KMT2D, which links TGF-β to the activin A pathway. We found that TGF-β upregulates a microRNA, miR-147b, which in turn leads to post-transcriptional silencing of KMT2D. Loss of KMT2D induces the expression and secretion of activin A, which activates a non-canonical p38 MAPK-mediated pathway to modulate cancer cell plasticity, promote a mesenchymal phenotype, and enhance tumor invasion and metastasis in mice. We observed a decreased KMT2D expression in human primary and metastatic pancreatic cancer. Furthermore, inhibition or knockdown of activin A reversed the pro-tumoral role of KMT2D. These findings reveal a tumor-suppressive role of KMT2D and identify miR-147b and activin A as novel therapeutic targets in pancreatic cancer.

Background: Inhibiting Tfh cell overexpansion prevents autoimmune responses and disease flares in systemic lupus erythematosus (SLE). miR-21 is highly expressed in SLE CD4(+) T cells, but whether inhibiting miR-21 can reduce Tfh cell expansion and alleviate the disease progression of lupus is unclear. Aim of the study: To address the role and molecular mechanism of miR-21 in regulating Tfh cell expansion and its therapeutic effect on SLE. Methods: We treated 12-week-old MRL/lpr mice with Antagomir-21, which specifically inhibited miR-21 in vivo. After 12 weeks of treatment, we examined the proportions of Tfh cells and germinal center (GC) B cells and serum levels of autoantibodies and evaluated disease severity by histological scoring and albuminuria. We determined the level of intracellular free iron in CD4+ T cells by PGSK probe and examined the expression of the Fth and Tfrc genes by qPCR. Immunohistochemistry (IHC) was used to assess the 5-hmC level in the draining lymph nodes (dLNs) and spleen. Results and Conclusions: Inhibiting miR-21 significantly reduced the expansion of Tfh cells and GC B cells. Furthermore, Antagomir-21 highly improved skin lesions and nephritis in MRL/lpr mice. Inhibiting miR-21 reduced intracellular iron accumulation and DNA hydroxymethylation in T cells. In conclusion, inhibiting miR-21 in vivo improves intracellular iron homeostasis and inhibits Tfh cell overexpansion, contributing to reduced autoimmune responses and the remission of disease symptoms in murine lupus.

Trace element iron affects T cell biology, but the knowledge about the role of iron in regulating Treg cell expansion is limited. Treg cells play an important role in keeping peripheral T cell tolerance, increasing Treg cell expansion is a promising therapeutic method for SLE. Here we showed that iron deficiency promotes Treg cell expansion by reducing ROS accumulation, improving the disease progression of pristane-induced lupus. Increased oxidative stress inhibits Treg cell differentiation by inducing cell apoptosis. Our data suggest that altering iron metabolism promotes Treg cell expansion by preventing oxidation-induced cell death, which may provide a potential therapeutic strategy for SLE.

Pancreatic ductal adenocarcinoma (PDAC) is highly resistant to chemoradiation and immune therapies, which is at least in part driven by its immunosuppressive tumor microenvironment (TME) consisting of dense cancer-associated fibroblasts (CAF) and highly suppressed immune cells. Lysine methyltransferase 2D (KMT2D), also known as MLL4 in mice, has been identified as one of the most frequently altered epigenetic regulators in PDAC. Most importantly, KMT2D mutation was found in more than 80% of neoadjuvant-treated PDAC, suggesting that KMT2D loss may be associated with treatment resistance. In human PDAC, low KMT2D protein level is correlated with worse survival. However, it is unknown whether KMT2D loss in PDAC cells modulates the TME. This project aimed to elucidate the role of KMT2D in remodeling the immune and stromal environment in PDAC. We first screened for changes in the immune cell population by performing immunohistochemistry (IHC) stains with human PDAC samples. We found that primary human tumors with low KMT2D expression had increased immunosuppressive tumor-associated neutrophils. xCell digital dissection analysis with The Cancer Genome Atlas (TCGA) data revealed that KMT2D-low PDAC had decreased effector T cell signature and enriched immunosuppressive Treg cell signature. Single-cell RNA sequencing analysis showed that KMT2D-low PDAC had increased suppressive myeloid cells and decreased CD8 T cells. We then generated Ptf1a-Cre; LSL-KrasG12D; Mll4+/+ (KCM+/+) and Ptf1a-Cre; LSL-KrasG12D; Mll4f/f (KCMf/f) mice to model pancreas-specific loss of Mll4 in the background of Kras mutation, a classic PDAC genetic mouse model. All KCM+/+ mice younger than 12 weeks had normal pancreas or low-grade pancreatic intraepithelial neoplasia (PanIN). In contrast, 66% of KCMf/f mice developed high-grade PanIN lesions or PDAC by 12 weeks. Immunohistochemistry staining showed that infiltration of immunosuppressive myeloid cells (tumor-associated macrophages and neutrophils) increased, whereas the presence of CD8+ T cells decreased in Mll4-deficient pancreata. Additionally, myofibroblastic CAFs, defined as PDPN+aSMA+ CAFs, decreased in KCMf/f mice pancreata compared to KCM+/+ pancreata. Mechanistically, we found that KMT2D loss in PDAC cells upregulates the interferon and inflammatory response pathways, including many cytokines and chemokines. These results suggest that KMT2D is a critical tumor suppressor, partly by promoting an immunogenic and tumor-suppressive TME. Cytokines in the interferon and inflammatory response pathways may serve as potential therapeutic targets, especially for treatment-resistant PDACs and KMT2D-deficient PDACs. Citation Format: Hong S. Kim, Jing Yang, Shuang Lu, Marina Pasca di Magliano, Kai Ge, Jiaqi Shi. KMT2D loss in pancreatic cancer cells leads to an immunosuppressive tumor microenvironment by upregulating the interferon and inflammatory response pathways [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C037.

Some scholars have recently developed the concept of PANoptosis in the study of infectious diseases where pyroptosis, apoptosis and necroptosis act in consort in a multimeric protein complex, PANoptosome. This allows all the components of PANoptosis to be regulated simultaneously. PANoptosis provides a new way to study the regulation of cell death, in that different types of cell death may be regulated at the same time. To test whether PANoptosis exists in diseases other than infectious diseases, we chose cerebral ischemia/reperfusion injury as the research model, collected articles researching cerebral ischemia/reperfusion from three major databases, obtained the original research data from these articles by bibliometrics, data mining and other methods, then integrated and analyzed these data. We selected papers that investigated at least two of the components of PANoptosis to check its occurrence in ischemia/reperfusion. In the cell model simulating ischemic brain injury, pyroptosis, apoptosis and necroptosis occur together and this phenomenon exists widely in different passage cell lines or primary neurons. Pyroptosis, apoptosis and necroptosis also occurred in rat and mouse models of ischemia/reperfusion injury. This confirms that PANoptosis is observed in ischemic brain injury and indicates that PANoptosis can be a target in the regulation of various central nervous system diseases.

Skin inflammation and photosensitivity are common in lupus erythematosus (LE) patients, and ultraviolet (UV) light is a known trigger of skin and possibly systemic inflammation in systemic lupus erythematosus (SLE) and discoid lupus erythematosus (DLE) patients. Type I interferons (IFN) are upregulated in LE skin after UV exposure; however, the mechanisms to explain UVB-induced inflammation remain unclear. Here, we demonstrated that UVB irradiation-induced activation of human endogenous retroviruses (HERVs) plays a major role in the immune response. UVB-induced HERV-associated dsRNA transcription and subsequent activation of the innate antiviral RIG-I/MDA5/IRF7 pathway led to downstream transcription of interferon-stimulated genes, which promotes UVB-induced apoptosis and proliferation inhibition in keratinocytes through RIG-I and MDA5 pathways. Our findings indicate that UVB irradiation induces HERV-dsRNA overexpression, and the dsRNA-sensing innate immunity pathway promotes type I IFN production, which may be a potential mechanism of skin inflammatory response and skin lesion of SLE/DLE.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that affects various organs or systems. We performed metabolomic and lipidomic profiles analyses of 133 SLE patients and 30 HCs. Differential metabolites and lipids were integrated, and then the biomarker panel was identified using binary logistic regression. We found that a combination of four metabolites or lipids could distinguish SLE from HC with an AUC of 0.998. Three lipids were combined to differentiate inactive SLE and active SLE. The AUC was 0.767. In addition, we also identified the biomarkers for different organ phenotypes of SLE. The AUCs for diagnosing SLE patients with only kidney involvement, skin involvement, blood system involvement, and multisystem involvement were 0.766, 0.718, 0.951, and 0.909, respectively. Our study succeeded in identifying biomarkers associated with different clinical phenotypes in SLE patients, which could facilitate a more precise diagnosis and assessment of disease progression in SLE.

Background: Sulforaphane, which is found in cruciferous vegetables, has been reported to have anti-inflammatory, antioxidant, and antitumour activities. However, whether sulforaphane has therapeutic effects on inflammatory or autoimmune skin diseases, including psoriasis and systemic lupus erythematosus (SLE), is unclear. Methods: The therapeutic effects of sulforaphane were analyzed in Imiquimod (IMQ)-induced psoriasis-like mice and lupus-prone MRL/lpr mice. In IMQ-induced psoriasis-like mice treated with sulforaphane (55.3 and 110.6 μmol/kg) or vehicle control, the pathological phenotypes were assessed by the psoriasis area and severity index (PASI) score, haematoxylin-eosin staining (H&E) and quantifying of acanthosis and dermal inflammatory cell infiltration. The proportions of T cell subsets in draining lymph nodes (dLNs) and spleens were examined by flow cytometry. In MRL/lpr mice treated with sulforaphane (82.9 μmol/kg) or vehicle control, mortality and proteinuria were observed, and the glomerular pathology was examined by H&E staining. C3 and IgG depositions in kidney sections were examined by immunofluorescence staining. The proportions of plasma cells, follicular helper T (Tfh) cells, neutrophils and dendritic cells in the dLNs and spleens were examined by flow cytometry. Finally, we examined the Malondialdehyde (MDA) concentration by thiobarbituric acid reactive substance assay and the expression of Prdx1, Nqo1, Hmox1, and Gss by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Results: Sulforaphane ameliorated the skin lesions in IMQ-induced psoriasis-like mice and the renal damage in lupus-prone MRL/lpr mice. In IMQ-induced psoriasis-like mice, sulforaphane reduced the proportions of Th1 and Th17 cells and increased the expression of antioxidant gene Prdx1. In lupus-prone MRL/lpr mice, sulforaphane increased the lifespan and the expression of Prdx1, and decreased the proportions of plasma cells, Tfh cells, neutrophils, and dendritic cells in the dLNs and spleens and the concentration of MDA. Conclusion: Sulforaphane has significant therapeutic effects on IMQ-induced psoriasis-like mice and lupus-like MRL/Lpr mice by reducing inflammatory and autoimmune-related cells and oxidative stress. These findings provide new evidence for developing natural products to treat inflammatory and autoimmune diseases.