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.

The role of hydrogen sulphide signalling in macrophage activation.

Hydrogen sulphide (H2 S) is the latest identified small gaseous mediator enabled by its lipophilic nature to freely permeate the biological membranes. Initially, H2 S was recognized by its roles in neuronal activity and vascular relaxation, which makes it an important molecule involved in paracrine signalling pathways. Recently, the immune regulatory function of gasotransmitters, H2 S in particular, is increasingly being appreciated. Endogenous H2 S level has been linked to macrophage activation, polarization and inflammasome formation. Mechanistically, H2 S-induced protein S-sulphydration suppresses several inflammatory pathways including NF-κB and JNK signalling. Moreover, H2 S serves as a potent cellular redox regulator to modulate epigenetic alterations and to promote mitochondrial biogenesis in macrophages. Here in this review, we intend to summarize the recent advancements of H2 S studies in macrophages, and to discuss with focus on the therapeutic potential of H2 S donors by targeting macrophages. The feasibility of H2 S signalling component as a macrophage biomarker under disease conditions would be also discussed.

Arginine metabolism regulates the pathogenesis of inflammatory bowel disease.

The pathogenesis of inflammatory bowel disease (IBD) is related to genetic susceptibility, enteric dysbiosis, and uncontrolled, chronic inflammatory responses that lead to colonic tissue damage and impaired intestinal absorption. As a consequence, patients with IBD are prone to nutrition deficits after each episode of disease resurgence. Nutritional supplementation, especially for protein components, is often implemented during the remission phase of IBD. Notably, ingested nutrients could affect the progression of IBD and the prognostic outcome of patients; therefore, they should be cautiously evaluated prior to being used for IBD intervention. Arginine (Arg) is a semi-essential amino acid required for protein synthesis and intimately associated with gut pathophysiology. To help optimize arginine-based nutritional intervention strategies, the present work summarizes that during the process of IBD, patients manifest colonic Arg deficiency and the turbulence of Arg metabolic pathways. The roles of Arg-nitric oxide (catalyzed by inducible nitric oxide synthase) and Arg-urea (catalyzed by arginases) pathways in IBD are debatable; the Arg-polyamine and Arg-creatine pathways are mainly protective. Overall, supplementation with Arg is a promising therapeutic strategy for IBD; however, the dosage of Arg may need to be carefully tailored for different individuals at different disease stages. Additionally, the combination of Arg supplementation with inhibitors of Arg metabolic pathways as well as other treatment options is worthy of further exploration.

[Removal Performance and Mechanism of Potassium Permanganate Modified Coconut Shell Biochar for Cd(â ¡) and Ni(â ¡) in Aquatic Environment].

In this study, coconut shell biochar modified by KMnO4 (MCBC) was used as the adsorbent, and its removal performance and mechanism for Cd(Ⅱ) and Ni(Ⅱ) were discussed. When the initial pH and MCBC dosage were separately 5 and 3.0 g·L-1, respectively, the removal efficiencies of Cd(Ⅱ) and Ni(Ⅱ) were both higher than 99%. The removal of Cd(Ⅱ) and Ni(Ⅱ) was more in line with the pseudo-second-order kinetic model, indicating that their removal was dominated by chemisorption. The rate-controlling step for Cd(Ⅱ) and Ni(Ⅱ) removal was the fast removal stage, for which the rate depended on the liquid film diffusion and intraparticle diffusion (surface diffusion). Cd(Ⅱ) and Ni(Ⅱ) were mainly attached to the MCBC via surface adsorption and pore filling, in which the contribution of surface adsorption was greater. The maximum adsorption amounts of Cd(Ⅱ) and Ni(Ⅱ) by MCBC were individually 57.18 mg·g-1 and 23.29 mg·g-1, which were approximately 5.74 and 6.97 times that of the precursor (coconut shell biochar), respectively. The removal of Cd(Ⅱ) and Zn(Ⅱ) was spontaneous and endothermic and had obvious thermodynamic characteristics of chemisorption. Cd(Ⅱ) was attached to MCBC through ion exchange, co-precipitation, complexation reaction, and cation-π interaction, whereas Ni(Ⅱ) was removed by MCBC via ion exchange, co-precipitation, complexation reaction, and redox. Among them, co-precipitation and complexation were the main modes of surface adsorption of Cd(Ⅱ) and Ni(Ⅱ). Additionally, the proportion of amorphous Mn-O-Cd or Mn-O-Ni in the complex may have been higher. These research results will provide important technical support and theoretical basis for the practical application of commercial biochar in the treatment of heavy metal wastewater.

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.

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.

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.

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.

SUMOylation of PDPK1 Is required to maintain glycolysis-dependent CD4 T-cell homeostasis.

The immune system is finely tuned to fight against infections, eradicate neoplasms, and prevent autoimmunity. Protein posttranslational modification (PTM) constitutes a molecular layer of regulation to guarantee the proper intensity of immune response. Herein, we report that UBC9-mediated protein SUMOylation plays an essential role in peripheral CD4 T-cell proliferation, but without a perceptible impact on T-cell polarization. Both conventional T-cell (Tcon) and regulatory T-cell (Treg) maintenance are differentially affected, which was likely caused by a shared deficit in cell glycolytic metabolism. Mechanistically, PDPK1 (3-phosphoinositide-dependent protein-kinase 1) was identified as a novel SUMOylation substrate, which occurred predominantly at lysine 299 (K299) located within the protein-kinase domain. Loss of PDPK1 SUMOylation impeded its autophosphorylation at serine 241 (S241), thereby leading to hypoactivation of downstream mTORC1 signaling coupled with incompetence of cell proliferation. Altogether, our results revealed a novel regulatory mechanism in peripheral CD4 T-cell homeostatic proliferation, which involves SUMOylation regulation of PDPK1-mTORC1 signaling-mediated glycolytic process.

Revisiting the Antigen-Presenting Function of ß Cells in T1D Pathogenesis.

Type 1 diabetes (T1D) is characterized by the unresolved autoimmune inflammation and islet ß cell destruction. The islet resident antigen-presenting cells (APCs) including dendritic cells and macrophages uptake and process the ß cell-derived antigens to prime the autoreactive diabetogenic T cells. Upon activation, those autoreactive T cells produce copious amount of IFN-γ, TNF-α and IL-1ß to induce ß cell stress and death. Autoimmune attack and ß cell damage intertwine together to push forward this self-destructive program, leading to T1D onset. However, ß cells are far beyond a passive participant during the course of T1D development. Herein in this review, we summarized how ß cells are actively involved in the initiation of autoimmune responses in T1D setting. Specifically, ß cells produce modified neoantigens under stressed condition, which is coupled with upregulated expression of MHC I/II and co-stimulatory molecules as well as other immune modules, that are essential properties normally exhibited by the professional APCs. At the cellular level, this subset of APC-like ß cells dynamically interacts with plasmacytoid dendritic cells (pDCs) and manifests potency to activate autoreactive CD4 and CD8 T cells, by which ß cells initiate early autoimmune responses predisposing to T1D development. Overall, the antigen-presenting function of ß cells helps to explain the tissue specificity of T1D and highlights the active roles of structural cells played in the pathogenesis of various immune related disorders.

The MAPK dual specific phosphatase (DUSP) proteins: A versatile wrestler in T cell functionality.

The functional state of T cells is diverse and under dynamic control for adapting to the changes of microenvironment. Reversible protein phosphorylation represents an important post-translational modification that not only involves in the immediate early response of T cells, but also affects their functionality in the long run. Perturbation of global phosphorylation profile and/or phosphorylation of specific signaling nodes result in aberrant T cell activity. Dual specific phosphatases (DUSPs), which target MAPKs and beyond, have increasingly been emerged as a versatile regulator in T cell biology. Herein in this mini review, we sought to summarize and discuss the impact of DUSP proteins on the regulation of effector T cell activity, T cell polarization, regulatory T cell development and T cell senescence/exhaustion. Given the distinctive engagement of each DUSP member under various disease settings such as chronic infection, autoimmune disorders, cancer and age-related diseases, DUSP proteins likely hold the promise to become a druggable target other than the existing therapeutics that are predominantly by manipulating protein kinase activity.

Waterproof-breathable PTFE nano- and Microfiber Membrane as High Efficiency PM2.5 Filter.

This study shows the feasibility of using electrospinning technique to prepare polytetrafluoroethylene/poly (vinyl alcohol) (PTFE/PVA) nanofibers on PTFE microfiber membrane as substrate. Then, PVA in the fiber membrane was removed by thermal treatment at about 350 °C. Compared to PTFE microfiber substrates, the composite PTFE fiber membranes (CPFMs) have improved filtration efficiency by 70% and water contact angle by 23°. Experimental test data showed that the water contact angle of the sample increased from about 107° to 130°, the filtration efficiency of PM2.5 increased from 44.778% to 98.905%, and the filtration efficiency of PM7.25 increased from 66.655% to 100% due to the electrospun PTFE nanofiber layer. This work demonstrates the potential of CPFMs as a filter for the production of indoor or outdoor dust removal and industrially relevant gas filtration.

Electrospinning of Carboxymethyl Chitosan/Polyoxyethylene Oxide Nanofibers for Fruit Fresh-Keeping.

Electrospinning provides an effective method for generating nanofibers from solution of carboxymethyl chitosan/polyoxyethylene oxide (CMCS/PEO). The goal of this work is to explore the potential application of electrospun CMCS/PEO nanofiber membrane in fruit fresh-keeping. The microstructure, antibacterial activity, hydrophilia, and air permeability of the nanofiber membrane have been tested. For comparison, the fresh-keeping effects of commercial cling wrap and CMCS/PEO nanofiber membranes on strawberries' rotting rate and weight loss rate have been studied. The results indicate that the electrospun CMCS/PEO membrane could effectively avoid water loss in strawberries and has a remarkable effect to prolong strawberries' shelf life due to its breathability and antibacterial activity. In addition, the composite CMCS/PEO, nanofiber membrane is non-poisonous and edible, which can be used in food industry.