KSHV vIL-6 promotes SIRT3-induced deacetylation of SERBP1 to inhibit ferroptosis and enhance cellular transformation by inducing lipoyltransferase 2 mRNA degradation.

Ferroptosis, a defensive strategy commonly employed by the host cells to restrict pathogenic infections, has been implicated in the development and therapeutic responses of various types of cancer. However, the role of ferroptosis in oncogenic Kaposi's sarcoma-associated herpesvirus (KSHV)-induced cancers remains elusive. While a growing number of non-histone proteins have been identified as acetylation targets, the functions of these modifications have yet to be revealed. Here, we show KSHV reprogramming of host acetylation proteomics following cellular transformation of rat primary mesenchymal precursor. Among them, SERPINE1 mRNA binding protein 1 (SERBP1) deacetylation is increased and required for KSHV-induced cellular transformation. Mechanistically, KSHV-encoded viral interleukin-6 (vIL-6) promotes SIRT3 deacetylation of SERBP1, preventing its binding to and protection of lipoyltransferase 2 (Lipt2) mRNA from mRNA degradation resulting in ferroptosis. Consequently, a SIRT3-specific inhibitor, 3-TYP, suppresses KSHV-induced cellular transformation by inducing ferroptosis. Our findings unveil novel roles of vIL-6 and SERBP1 deacetylation in regulating ferroptosis and KSHV-induced cellular transformation, and establish the vIL-6-SIRT3-SERBP1-ferroptosis pathways as a potential new therapeutic target for KSHV-associated cancers.

Carboxymethyl potato starch hydrogels encapsulated cyclodextrin metal-organic frameworks for enantioselective loading of S-naproxen and its programmed release.

A natural polysaccharide-based vehicle is facilely prepared for enantioselective loading of S-naproxen (S-NPX) and its programmed release. Cyclodextrin metal-organic frameworks (CD-MOF) are synthesized through the coordination of K+ with γ-cyclodextrin (γ-CD). Compared with R-NPX, the CD-MOF preferably combines with S-NPX, which can be confirmed by the thermodynamic calculations. The S-NPX loaded CD-MOF (CD-MOF-S-NPX) is grafted with disulfide bond (-S-S-) to improve its hydrophobicity, and the loaded S-NPX is further encapsulated in the chiral cavity of γ-CD by carboxymethyl potato starch (CPS) hydrogels. The intermolecular hydrogen bonding of the CPS hydrogels is prone to be destroyed in mildly basic media (∼pH 8.0), resulting in the swelling of the hydrogels; the -S-S- linkage in the vehicle can be cleaved in the presence of glutathione (GSH), leading to the collapse of the CD-MOF. Therefore, the programmed release of S-NPX can be achieved. Also in this work, the release kinetics is investigated, and the results indicate that the release of S-NPX is controlled by the Higuchi model.

Enhanced STAT3/PIK3R1/mTOR signaling triggers tubular cell inflammation and apoptosis in septic-induced acute kidney injury: implications for therapeutic intervention.

Septic acute kidney injury (AKI) is a severe form of renal dysfunction associated with high morbidity and mortality rates. However, the pathophysiological mechanisms underlying septic AKI remain incompletely understood. Herein, we investigated the signaling pathways involved in septic AKI using the mouse models of lipopolysaccharide (LPS) treatment and cecal ligation and puncture (CLP). In these models, renal inflammation and tubular cell apoptosis were accompanied by the aberrant activation of the mechanistic target of rapamycin (mTOR) and the signal transducer and activator of transcription 3 (STAT3) signaling pathways. Pharmacological inhibition of either mTOR or STAT3 significantly improved renal function and reduced apoptosis and inflammation. Interestingly, inhibition of STAT3 with pharmacological inhibitors or small interfering RNA blocked LPS-induced mTOR activation in renal tubular cells, indicating a role of STAT3 in mTOR activation. Moreover, knockdown of STAT3 reduced the expression of the phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1/p85α), a key subunit of the phosphatidylinositol 3-kinase for AKT and mTOR activation. Chromatin immunoprecipitation assay also proved the binding of STAT3 to PIK3R1 gene promoter in LPS-treated kidney tubular cells. In addition, knockdown of PIK3R1 suppressed mTOR activation during LPS treatment. These findings highlight the dysregulation of mTOR and STAT3 pathways as critical mechanisms underlying the inflammatory and apoptotic phenotypes observed in renal tubular cells during septic AKI, suggesting the STAT3/ PIK3R1/mTOR pathway as a therapeutic target of septic AKI.

Rituximab Combined with Steroid and Tacrolimus Treats Proliferative Glomerulonephritis with Monoclonal IgG Deposits: A Case Report and Review of the Literature.

INTRODUCTION: Due to the confounding heterogeneity, the therapeutic strategy for proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) remains to be defined. CASE REPRESENTATION: We report a 38-year-old man with recurrent swelling of the eyelids and lower limbs, undergoing rituximab combined with steroid and tacrolimus treatment, who achieved an improved renal outcome. Underlying solid malignant tumours were excluded from the diagnosis. DISCUSSION: We treated patients with rituximab along with steroids and tacrolimus. Improvements in proteinuria and renal function were observed. We also reviewed the current literature to assess the efficacy of rituximab in the treatment of PGNMID. CONCLUSION: However, a larger pool of patients and a longer follow-up period are required to establish the role of rituximab and steroids in the treatment of PGNMID.

Voriconazole plus flucytosine is not superior to amphotericin B deoxycholate plus flucytosine as an induction regimen for cryptococcal meningitis treatment.

BACKGROUND: The efficacy and side effects of voriconazole plus 5-flucytosine (Vori + 5-FC) versus amphotericin B deoxycholate plus 5-flucytosine (AmBd + 5-FC) as an induction treatment for cryptococcal meningitis are unknown. METHODS: Forty-seven patients treated with Vori + 5-FC and 92 patients treated with AmBd + 5-FC were included in the current study after propensity score matching (PSM) at a ratio of 1:2. Two-week laboratory test results and 90-day mortality were compared between the two groups. RESULTS: After 2 weeks of induction treatment, the CSF Cryptococcus sterile culture rate was 57.1% in the Vori + 5-FC group and 76.5% in the AmBd + 5-FC group (p = .026). No difference was found in the normalization of CSF indicators (glucose, total protein, intracranial pressure and India ink sterile rate) between the two groups. Both the Vori + 5FC regimen and AmBd + 5-FC regimen obviously decreased haemoglobin concentrations, platelet counts and serum potassium levels (all p ≤ .010). Notably, the Vori + 5FC regimen did not influence serum creatinine levels (p = .263), while AmBd + 5FC increased serum creatinine levels (p = .019) after 2-week induction treatment. The Vori + 5-FC group and AmBd + 5-FC group had similar 90-day cumulative survival rates (89.9% vs. 87.8%, p = .926). CONCLUSION: The Vori + 5-FC regimen was associated with low 2-week CSF sterile culture and was not superior to AmBd + 5-FC as induction therapy in terms of the 90-day cumulative survival rate of CM patients.

Conformal Fabrication of Thick Film Platinum Strain Gauge Via Error Regulation Strategies for In Situ High-Temperature Strain Detection.

Monitoring high-temperature strain on curved components in harsh environments is a challenge for a wide range of applications, including in aircraft engines, gas turbines, and hypersonic vehicles. Although there are significant improvements in the preparation of high-temperature piezoresistive film on planar surfaces using 3D printing methods, there are still difficulties with poor surface compatibility and high-temperature strain testing on curved surfaces. Herein, a conformal direct ink writing (CDIW) system coupled with an error feedback regulation strategy was used to fabricate high-precision, thick films on curved surfaces. This strategy enabled the maximum amount of error in the distance between the needle and the substrate on a curved surface to be regulated from 155 to 4 µm. A conformal Pt thick-film strain gauge (CPTFSG) with a room-temperature strain coefficient of 1.7 was created on a curved metallic substrate for the first time. The resistance drift rate at 800 °C for 1 h was 1.1%, which demonstrated the excellent stability and oxidation resistance of the CPTFSG. High-temperature dynamic strain tests up to 769 °C revealed that the sensor had excellent high-temperature strain test performance. Furthermore, the CPTFSG was conformally deposited on an aero-engine turbine blade to perform in situ tensile and compressive strain testing at room temperature. High-temperature strain tests were conducted at 100 and 200 °C for 600 and 580 µÎµ, respectively, demonstrating a high steady-state response consistent with the commercial high-temperature strain transducer. In addition, steady-state strain tests at high temperatures up to 496 °C were tested. The CDIW error modulation strategy provides a highly promising approach for the high-precision fabrication of Pt thick films on complex surfaces and driving in situ sensing of high-temperature parameters on curved components toward practical applications.

Rapid laser fabrication of indium tin oxide and polymer-derived ceramic composite thin films for high-temperature sensors.

Thin-film sensors are essential for real-time monitoring of components in high-temperature environments. Traditional fabrication methods often involve complicated fabrication steps or require prolonged high-temperature annealing, limiting their practical applicability. Here, we present an approach using direct ink writing and laser scanning (DIW-LS) to fabricate high-temperature functional thin films. An indium tin oxide (ITO)/preceramic polymer (PP) ink suitable for DIW was developed. Under LS, the ITO/PP thin film shrank in volume. Meanwhile, the rapid pyrolysis of PP into amorphous precursor-derived ceramic (PDC) facilitated the faster sintering of ITO nanoparticles and improved the densification of the thin film. This process realized the formation of a conductive network of interconnected ITO nanoparticles. The results show that the ITO/PDC thin film exhibits excellent stability, with a drift rate of 4.7 % at 1000 °C for 25 h, and withstands temperatures up to 1250 °C in the ambient atmosphere. It is also sensitive to strain, with a maximum gauge factor of -6.0. As a proof of concept, we have used DIW-LS technology to fabricate a thin-film heat flux sensor on the surface of the turbine blade, capable of measuring heat flux densities over 1 MW/m2. This DIW-LS process provides a viable approach for the integrated, rapid, and flexible fabrication of thin film sensors for harsh environments.

EIF2α/ATF4 pathway enhances proliferation of mesangial cell via cyclin D1 during endoplasmic reticulum stress in IgA nephropathy.

IgA nephropathy (IgAN) is an essential cause of kidney failure and end-stage kidney disease worldwide. Mesangial hypercellularity is an important characteristic of IgAN, but the underlying mechanism remains unclear. Endoplasmic reticulum (ER) stress is a series of stress responses to restore the function of endoplasmic reticulum. We aimed to explore how ER stress functioned in kidneys of IgAN. We first examined ER stress in IgAN kidneys in vivo and in vitro, by testing the levels of ER stress associated proteins (BIP, p-eIF2α and ATF4). Our results showed that ER stress was activated in IgAN patients, mice and cell model. ER stress activation was related to the distribution of IgA deposition and the degree of mesangial proliferation. To determine the role of ER stress in mesangial cell (MC) proliferation of IgAN, we then tested the levels of ER stress and MC proliferation (cyclin D1, cell viability and cell cycle) through inhibiting ER stress associated proteins. After inhibiting ER stress associated proteins, ER stress was inactivated and cell proliferation was inhibited in MCs. We also explored the correlation between ER stress in the glomerulus and the clinical outcomes of IgAN patients in a prospective study. Patients with lower expression of p-eIF2α or ATF4 had higher rates of hematuria remission, proteinuria remission and clinical remission. In summary, our work outlines that in IgAN, ER stress mediated by eIF2α/ATF4 pathway promotes MC proliferation via up-regulating the expression of cyclin D1. Furthermore, p-eIF2α and ATF4 in the glomerulus negatively correlate with the clinical remission of IgAN patients.

All-Three-Dimensionally-Printed AgPd Thick-Film Strain Gauge with a Glass-Ceramic Protective Layer for High-Temperature Applications.

A high-temperature thin/thick-film strain gauge (TFSG) shows development prospects for in situ strain monitoring of hot-end components due to their small perturbations, no damage, and fast response. Direct ink writing (DIW) 3D printing is an emerging and facile approach for the rapid fabrication of TFSG. However, TFSGs prepared based on 3D printing with both high thermal stability and low temperature coefficient of resistance (TCR) over a wide temperature range remain a great challenge. Here, we report a AgPd TFSG with a glass-ceramic protective layer based on DIW. By encapsulating the AgPd sensitive layer and regulating the Pd content, the AgPd TFSG demonstrated a low TCR (191.6 ppm/°C) from 50 to 800 °C and ultrahigh stability (with a resistance drift rate of 0.14%/h at 800 °C). Meanwhile, the achieved specifications for strain detection included a strain sensing range of ±500 µÎµ, fast response time of 153 ms, gauge factor of 0.75 at 800 °C, and high durability of >8000 cyclic loading tests. The AgPd TFSG effectively monitors strain in superalloys and can be directly deposited onto cylindrical surfaces, demonstrating the scalability of the presented approach. This work provides a strategy to develop TFSGs for in situ sensing of complex curved surfaces in harsh environments.

Cost-effectiveness of Trastuzumab Deruxtecan for HER2-low Advanced Breast Cancer in the United States.

PURPOSE: Trastuzumab deruxtecan has been shown to be effective for advanced breast cancer with low levels of human epidermal growth factor receptor 2. To optimize the allocation of limited health care resources, this study evaluated the cost-effectiveness of trastuzumab deruxtecan from the US payer perspective. METHODS: A partitioned survival model was developed to project the disease course of advanced breast cancer. Clinical efficacy, treatment utilization, safety, and cost data were gathered from the DESTINY-Breast04 (Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer) trial and the Centers for Medicare & Medicaid Services. Transition probabilities were obtained from the reported survival probabilities per DESTINY-Breast04 group. The incremental cost-effectiveness ratio (ICER), the incremental monetary benefit, and the incremental net health benefit were measured. One-way sensitivity analysis, probabilistic sensitivity analysis, and subgroup analysis were performed to explore the uncertainty of the model. FINDINGS: Trastuzumab deruxtecan had an ICER of $307,751 per quality-adjusted life-year (QALY) gained, with an incremental net health benefit of -0.317 QALY and an incremental monetary benefit of -$63,313 compared with the physician's choice of alternative chemotherapy agents. Subgroup analysis indicated that trastuzumab deruxtecan had an ICER of $383,776 per QALY gained for the hormone receptor-positive subgroup and an ICER of $194,424 per QALY for the hormone receptor-negative subgroup. One-way sensitivity analysis showed that the cost of trastuzumab deruxtecan had the most impact on model outcomes. The cost-effectiveness acceptability curve projected that the probability of trastuzumab deruxtecan being cost-effective was 5% in the overall population, 2% in the hormone receptor-positive subgroup, and 56% in the hormone receptor-negative subgroup at the willingness-to-pay threshold of $200,000 per QALY. IMPLICATIONS: Trastuzumab deruxtecan may be a cost-effective option for hormone receptor-negative patients with advanced breast cancer with low levels of human epidermal growth factor receptor 2.

Glucocorticoid regulation of the mTORC1 pathway modulates CD4+ T cell responses during infection.

Objectives: Conventional glucocorticoid (GC) treatment poses significant risks for opportunistic infections due to its suppressive impact on CD4+ T cells. This study aimed to explore the mechanisms by which GCs modulate the functionality of CD4+ T cells during infection. Methods: We consistently measured FOXP3, inflammatory cytokines and phospho-S6 ribosomal protein levels in CD4+ T cells from patients undergoing conventional GC treatment. Using Foxp3EGFP animals, we investigated the dynamic activation of the mechanistic target of rapamycin complex 1 (mTORC1) pathway and its correlation with the immunoregulatory function of CD4+ T cells under the influence of GCs. Results: GCs dynamically altered the expression pattern of FOXP3 in CD4+ T cells, promoting their acquisition of an active T regulatory (Treg) cell phenotype upon stimulation. Mechanistically, GCs undermined the kinetics of the mTORC1 pathway, which was closely correlated with phenotype conversion and functional properties of CD4+ T cells. Dynamic activation of the mTORC1 signaling modified the GC-dampened immunoregulatory capacity of CD4+ T cells by phenotypically and functionally bolstering the FOXP3+ Treg cells. Interventions targeting the mTORC1 pathway effectively modulated the GC-dampened immunoregulatory capacity of CD4+ T cells. Conclusion: These findings highlight a novel mTORC1-mediated mechanism underlying CD4+ T cell immunity in the context of conventional GC treatment.

Efficacy of protein A immunoadsorption and therapeutic plasma exchange in ANCA-associated vasculitis with severe renal involvement: a retrospective study.

BACKGROUND: Severe renal impairment is a common complication of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and is associated with poor prognosis and shorter survival. It is urgent to find effective treatments to improve the prognosis of AAV patients. This study was designed to assess the efficacy and safety of protein A immunoadsorption (PAIA) and therapeutic plasma exchange (TPE) for AAV with severe renal involvement. METHODS: A total of 48 AAV patients with renal involvement admitted to the Second Xiangya Hospital from January 2018 to February 2021 were selected. Clinical data, myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA), remission at 6 months, and outcomes were evaluated. The primary outcomes of interest were death and renal survival as defined by the occurrence of end-stage renal disease (ESRD). RESULTS: PAIA was effective in the removal of MPO-ANCA and IgG, and showed superior over TPE in the clearance of MPO-ANCA within 1 month after treatment. After a median follow-up of 14.5 months, PAIA therapy showed an advantage in reducing mortality over TPE. There was no difference in the development of ESRD between the two groups. Multivariate Cox regression analysis indicated that higher serum creatinine (SCr) and lower haemoglobin level were independent risks of ESRD. Age > 60, lower serum albumin (ALB), and failure to achieve remission at 6 months were independent risks of death. CONCLUSIONS: PAIA treatment reduces MPO-ANCA and IgG as well as mortality in AAV patients, and may be beneficial for severe AAV in clinical practice. Higher SCr, lower serum ALB or haemoglobin levels, age > 60, and failure to achieve remission at 6 months independently predict the ESRD or death of AAV patients with severe renal involvement.KEY MESSAGESCompared with therapeutic plasma exchange, protein A immunoadsorption treatment eliminates myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA) and IgG better and reduces mortality in ANCA-associated vasculitis (AAV) patients with severe renal involvement.Higher serum creatinine, lower serum albumin or haemoglobin levels, age > 60, and failure to achieve remission at 6 months independently predict the end-stage renal disease (ESRD) or death of AAV patients with severe renal involvement.

The kinetics of mTORC1 activation associates with FOXP3 expression pattern of CD4+ T cells and outcome of steroid-sensitive minimal change disease.

Minimal change disease (MCD) usually responds to glucocorticoids (GCs) but relapses in most cases. Relapse pathogenesis after complete remission (CR) remains unclear. We hypothesized that FOXP3+ T regulatory cell (Treg) dysregulation may drive early relapses (ER). In this study, a cohort of 23 MCD patients were treated with a conventional GC regimen for the initial onset of nephrotic syndrome. Upon GC withdrawal, seven patients suffered from ER, while 16 patients sustained remission (SR) during the 12-month follow-up. Patients with ER had reduced FOXP3+ Treg proportions compared with healthy controls. Treg reduction, accompanied by IL-10 impairment, was ascribed to a proportional decline of FOXP3medium rather than FOXP3high cells. GC-induced CR was marked by a rise in the proportions of FOXP3+ and FOXP3medium cells compared to baseline levels. These increases declined in patients with ER. The expression level of phosphorylated ribosomal protein S6 was used to track the dynamic shifts in mTORC1 activity within CD4+ T cells of MCD patients at various stages of treatment. Baseline mTORC1 activity was inversely correlated with FOXP3+ and FOXP3medium Treg proportion. The mTORC1 activity in CD4+ T cells served as a reliable indicator for ER and demonstrated improved performance when paired with FOXP3 expression. Mechanically, targeting mTORC1 intervention by siRNAs sufficiently altered the conversion pattern of CD4+ T cell to FOXP3+ Treg. Taken together, the activity of mTORC1 in CD4+ T cells can act as a credible predictor for ER in MCD, especially when combined with FOXP3 expression, and may offer a potential therapeutic avenue for the treatment of podocytopathies.

The STAT1/HMGB1/NF-κB pathway in chronic inflammation and kidney injury after cisplatin exposure.

Rationale: Cisplatin, a potent chemotherapeutic drug, induces side effects in normal tissues including the kidney. To reduce the side effects, repeated low-dose cisplatin (RLDC) is commonly used in clinical setting. While RLDC reduces acute nephrotoxicity to certain extents, a significant portion of patients later develop chronic kidney problems, underscoring the need for novel therapeutics to alleviate the long-term sequelae of RLDC therapy. Methods: In vivo, the role of HMGB1 was examined by testing HMGB1 neutralizing antibodies in RLDC mice. In vitro, the effects of HMGB1 knockdown on RLDC-induced nuclear factor-κB (NF-κB) activation and fibrotic phenotype changes were tested in proximal tubular cells. To study signal transducer and activator of transcription 1 (STAT1), siRNA knockdown and its pharmacological inhibitor Fludarabine were used. We also searched the Gene Expression Omnibus (GEO) database for transcriptional expression profiles and evaluated kidney biopsy samples from CKD patients to verify the STAT1/HMGB1/NF-κB signaling axis. Results: We found that RLDC induced kidney tubule damage, interstitial inflammation, and fibrosis in mice, accompanied by up-regulation of HMGB1. Blockage of HMGB1with neutralizing antibodies and Glycyrrhizin suppressed NF-κB activation and associated production of pro-inflammatory cytokines, reduced tubular injury and renal fibrosis, and improved renal function after RLDC treatment. Consistently, knockdown of HMGB1 decreased NF-κB activation and prevented the fibrotic phenotype in RLDC-treated renal tubular cells. At the upstream, knockdown of STAT1 suppressed HMGB1 transcription and cytoplasmic accumulation in renal tubular cells, suggesting a critical role of STAT1 in HMGB1 activation. Upregulation of STAT1/HMGB1/NF-κB along with inflammatory cytokines was also verified in kidney tissues of CKD patients. Conclusion: These results unravel the STAT1/HMGB1/NF-κB pathway that contributes to persistent inflammation and chronic kidney problems after cisplatin nephrotoxicity, suggesting new therapeutic targets for kidney protection in cancer patients receiving cisplatin chemotherapy.

T-cell immunoglobulin and mucin-domain containing-3 (TIM-3): Solving a key puzzle in autoimmune diseases.

Dysfunctional immune cells participate in the pathogenesis of a variety of autoimmune diseases, although the specific mechanisms remain elusive and effective clinical interventions are lacking. Recent research on immune checkpoint molecules has revealed significant expression of T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) on the surfaces of various immune cells. These include different subsets of T cells, macrophages, dendritic cells, natural killer cells, and mast cells. Further investigation into its protein structure, ligands, and intracellular signaling pathway activation mechanisms has found that TIM-3, by binding with different ligands, is involved in the regulation of crucial biological processes such as proliferation, apoptosis, phenotypic transformation, effector protein synthesis, and cellular interactions of various immune cells. The TIM-3-ligand axis plays a pivotal role in the pathogenesis of numerous conditions, including autoimmune diseases, infections, cancers, transplant rejection, and chronic inflammation. This article primarily focuses on the research findings of TIM-3 in the field of autoimmune diseases, with a special emphasis on the structure and signaling pathways of TIM-3, its types of ligands, and the potential mechanisms implicated in systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, as well as other autoimmune diseases and chronic inflammation. The latest research results in the field of immunology suggest that TIM-3 dysfunction affects various immune cells and participates in the pathogenesis of diseases. Monitoring the activity of its receptor-ligand axis can serve as a novel biological marker for disease clinical diagnosis and prognosis evaluation. More importantly, the TIM-3-ligand axis and the downstream signaling pathway molecules may become key targets for targeted intervention treatment of autoimmune-related diseases.

Activation of CD3 + TIM3 + T cells contributes to excessive inflammatory response during glucocorticoid treatment.

Glucocorticoids (GCs) are widely used to treat autoimmune and inflammatory diseases, but recent research has challenged the notion that GCs are universally anti-inflammatory. In this study, we investigated the effects of long-term GC exposure on circulating T cells in a retrospective cohort of 5,476 patients with primary glomerular diseases. Our results revealed that GCs altered the composition pattern of circulating leukocytes and the correlation between circulating lymphocytes and serum cytokines in response to infections, as well as the subsets of CD4 + T cells. Specifically, GCs promoted the loss of CD4 + T cells and increased the proportions of CD3 + TIM3 + T cells in response to infections, which correlated with the expression of serum inflammatory cytokines, such as IFNG and IL-10. Using animal models of cecal ligation and puncture, we demonstrated that long-term GC exposure exacerbated apoptosis of CD4 + T cells and cytokine storm during sepsis, which was mechanistically linked to the increase of CD3 + TIM3 + T cells. Notably, we found that CD3 + TIM3 + T cells expressed high levels of multiple cytokine genes during infections, suggesting a potent role of TIM3 in the regulation of T cell biology. In vitro studies further showed that engagement of anti-TIM3 treatment enhanced the inflammatory activity of CD3 + T cells. Our findings suggest a causal relationship between chronic exposure to GCs and an excessive inflammatory response mediated by T cells during infections, which is, at least partly, driven by dysregulation of CD3 + TIM3 + T cells.

Network Pharmacology and Experimental Validation to Explore That Celastrol Targeting PTEN is the Potential Mechanism of Tripterygium wilfordii (Lév.) Hutch Against IgA Nephropathy.

Purpose: Accumulating clinical evidence showed that Tripterygium hypoglaucum (Lév.) Hutch (THH) is effective against IgA nephropathy (IgAN), but the mechanism is still unclear. This study is to evaluate the renal protective effect and molecular mechanism of THH against IgAN via network pharmacology, molecular docking strategy and experimental validation. Methods: Several databases were used for obtaining the active ingredients of THH, the corresponding targets, as well as the IgAN-related genes. The critical active ingredients, functional pathways, and potential for the combination of the hub genes and their corresponding active components were determined through bioinformatics analysis and molecular docking. The IgAN mouse model was treated with celastrol (1 mg/kg/d) for 21 days, and the aggregated IgA1-induced human mesangial cell (HMC) was treated with various concentrations of celastrol (25, 50 or 75 nM) for 48 h. The immunohistochemistry and Western blot techniques were applied to evaluate the protein expression of the predicted target. The cell counting kit 8 (CCK8) was used to detect HMC proliferation. Results: A total of 17 active ingredients from THH were screened, covering 165 IgAN-related targets. The PPI network identified ten hub targets, including PTEN. The binding affinity between the celastrol and PTEN was the highest (-8.69 kJ/mol). The immunohistochemistry showed that celastrol promoted the expression of PTEN in the glomerulus of IgAN mice. Furthermore, the Western blot techniques showed that celastrol significantly elevated the expression of PTEN and inhibited PCNA and Cyclin D1 in vitro and in vivo. The CCK8 assay determined that celastrol decreased HMC proliferation in a concentration-dependent manner. Conclusion: This study suggests that activating PTEN by celastrol may play a pivotal role in THH alleviating IgAN renal injury.

Long-term glucocorticoid exposure persistently impairs CD4+ T cell biology by epigenetically modulating the mTORC1 pathway.

Conventional glucocorticoid (GC) treatment has a long-term influence on T-cell immunity, resulting in an increased risk of opportunistic infection after drug withdrawal. The underlying mechanisms remain ambiguous. This study demonstrated that long-term GC treatment induced persistent lymphopenia in patients with primary glomerular disease. GCs continuously suppressed the proportion of CD4+ T cells even after the daily dose was tapered down to the physiologic equivalences, leading to a significant decline of the CD4/CD8 ratio. Meanwhile, GCs impaired CD4+ T cell biology, leading to enhanced apoptotic cell death, reduced proliferative capacity, downregulated pro-inflammatory genes, and upregulated immunoregulatory genes. Specifically, GCs altered FOXP3 expression pattern in CD4+ T cells and favored their acquisition of an active T regulatory (Treg) cell phenotype with enhanced IL-10 production upon stimulation. Mechanistically, GCs tampered with the transcriptional regulation of mechanistic target of rapamycin complex 1 (mTORC1) pathway, resulting in an inhibitory impact on the signaling activity. Targeting mTORC1 signaling by siRNAs could sufficiently modify the viability of GC-exposed CD4+ T cells. By high-throughput sequencing of genome-wide DNA methylation and mRNA, we further uncovered a causal relationship between the altered DNA methylation level and transcription activity in a subset of mTORC1 pathway genes in long-term GC exposure. Taken together, this study reveals a novel regulation of mTORC1 signaling, which might dominate the long-term influence of GC on CD4+ T cell biology in a dose-independent manner.

Rapid Printing of High-Temperature Polymer-Derived Ceramic Composite Thin-Film Thermistor with Laser Pyrolysis.

Polymer-derived ceramic (PDC)-based high-temperature thin-film sensors (HTTFSs) exhibit promising applications in the condition monitoring of critical components in aerospace. However, fabricating PDC-based HTTFS integrated with high-efficiency, high-temperature anti-oxidation, and customized patterns remains challenging. In this work, we introduce a rapid and flexible selecting laser pyrolysis combined with a direct ink writing process to print double-layer high-temperature antioxidant PDC composite thin-film thermistors under ambient conditions. The sensitive layer (SL) was directly written on an insulating substrate with excellent conductivity by laser-induced graphitization. Then, the antioxidant layer (AOL) was written on the surface of the SL to realize the integrated manufacturing of double-functional layers. Through characterization analysis, it was shown that B2O3 and SiO2 glass phases generated by the PDC composite AOL could effectively prevent oxygen intrusion. Therefore, the fabricated PDC composite thermistors exhibited a negative temperature coefficient in the temperature range from 100 to 1100 °C and high repeatability below 800 °C. Meanwhile, it has excellent high-temperature stability at 800 °C with a resistance change of only 2.4% in 2 h. Furthermore, the high-temperature electrical behavior of the thermistor was analyzed. The temperature dependence of the conductivity for this thermistor has shown an agreement with the Mott's variable range hopping mechanism. Additionally, the thermistor was fabricated on the surface of an aero-engine blade to verify its feasibility below 800 °C, showing the great potential of this work for state sensing on the surface of high-temperature components, especially for customized requirements.