IGF2BP3 modified GLI2 transcriptionally regulates SYVN1 and facilitates sepsis liver injury through autophagy.

Autophagy enhancement in septic liver injury can play a protective role. Nerveless, the mechanism of autophagy-mediated septic liver injury needs further investigation. Our study demonstrated that in septic condition, GLI Family Zinc Finger 2 (GLI2) was elevated, whereas peroxisome-proliferator-activated receptor α (PPARα) was downregulated. Suppressing GLI2 or synovialapoptosis inhibitor 1 (SYVN1) in LPS-exposed cells increased PPARα levels, enhanced cell viability and autophagy, while inhibiting apoptosis. LPS enhanced the GLI2-SYVN1 promoter binding. SYVN1 fostered ubiquitin-mediated degradation of PPARα. IGF2BP3 stabilized GLI2 mRNA by targeting its m6A site. Silencing IGF2BP3 led to decreased GLI2 and SYVN1 but increased PPARα levels, promoting cell survival and autophagy, while repressing apoptosis. This was counteracted by SYVN1 overexpression. In cecal ligation and puncture mice, IGF2BP3, SYVN1, or GLI2 knockdown ameliorated liver damage and augmented autophagy. In summary, IGF2BP3 enhanced GLI2 stability, overexpressed GLI2 subsequent promoted SYVN1 levels by interacting with its promoter, leading to ubiquitinated degradation of PPARα, thereby inhibiting PPARα-mediated autophagy and then exacerbating liver injury in sepsis.

PPARG-mediated autophagy activation alleviates inflammation in rheumatoid arthritis.

INTRODUCTION: Rheumatoid arthritis (RA) is a systemic inflammatory autoimmune disease characterized by joint inflammation and bone damage, that not only restricts patient activity but also tends to be accompanied by a series of complications, seriously affecting patient prognosis. Peroxisome proliferator-activated receptor gamma (PPARG), a receptor that controls cellular metabolism, regulates the function of immune cells and stromal cells. Previous studies have shown that PPARG is closely related to the regulation of inflammation. However, the role of PPARG in regulating the pathological processes of RA is poorly understood. MATERIALS AND METHODS: PPARG expression was examined in the synovial tissues and peripheral blood mononuclear cells (PBMCs) from RA patients and the paw of collagen-induced arthritis (CIA) model rats. Molecular biology experiments were designed to examine the effect of PPARG and cannabidiol (CBD) on RAW264.7 cells and CIA rats. RESULTS: The results reveal that PPARG accelerates reactive oxygen species (ROS) clearance by promoting autophagy, thereby inhibiting ROS-mediated macrophage polarization and NLRP3 inflammasome activation. Notably, CBD may be a promising candidate for understanding the mechanism by which PPARG regulates autophagy-mediated inflammation. CONCLUSIONS: Taken together, these findings indicate that PPARG may have a role for distinguishing between RA patients and healthy control, and for distinguishing RA activity; moreover, PPARG could be a novel pharmacological target for alleviating RA through the mediation of autophagy. CBD can act as a PPARG agonist that alleviates the inflammatory progression of RA.

Immunomodulatory effects of curcumin on macrophage polarization in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by synovial inflammation, cartilage destruction, pannus formation and bone erosion. Various immune cells, including macrophages, are involved in RA pathogenesis. The heterogeneity and plasticity of macrophages render them pivotal regulators of both the induction and resolution of the inflammatory response. Predominantly, two different phenotypes of macrophages have been identified: classically activated M1 macrophages exacerbate inflammation via the production of cytokines, chemokines and other inflammatory mediators, while alternatively activated M2 macrophages inhibit inflammation and facilitate tissue repair. An imbalance in the M1/M2 macrophage ratio is critical during the initiation and progression of RA. Macrophage polarization is modulated by various transcription factors, epigenetic elements and metabolic reprogramming. Curcumin, an active component of turmeric, exhibits potent immunomodulatory effects and is administered in the treatment of multiple autoimmune diseases, including RA. The regulation of macrophage polarization and subsequent cytokine production as well as macrophage migration is involved in the mechanisms underlying the therapeutic effect of curcumin on RA. In this review, we summarize the underlying mechanisms by which curcumin modulates macrophage function and polarization in the context of RA to provide evidence for the clinical application of curcumin in RA treatment.

Dihydroartemisinin alleviates erosive bone destruction by modifying local Treg cells in inflamed joints: A novel role in the treatment of rheumatoid arthritis.

Treg cell-based therapy has exhibited promising efficacy in combatting rheumatoid arthritis (RA). Dihydroartemisinin (DHA) exerts broad immunomodulatory effects across various diseases, with its recent spotlight on T-cell regulation in autoimmune conditions. The modulation of DHA on Treg cells and its therapeutic role in RA has yet to be fully elucidated. This study seeks to unveil the influence of DHA on Treg cells in RA and furnish innovative substantiation for the potential of DHA to ameliorate RA. To this end, we initially scrutinized the impact of DHA-modulated Treg cells on osteoclast (OC) formation in vitro using Treg cell-bone marrow-derived monocyte (BMM) coculture systems. Subsequently, employing the collagen-induced arthritis (CIA) rat model, we validated the efficacy of DHA and probed its influence on Treg cells in the spleen and popliteal lymph nodes (PLN). Finally, leveraging deep proteomic analysis with data-independent acquisition (DIA) and parallel accumulation-serial fragmentation (PASEF) technology, we found the alterations in the Treg cell proteome in PLN by proteomic analysis. Our findings indicate that DHA augmented suppressive Treg cells, thereby impeding OC formation in vitro. Consistently, DHA mitigated erosive joint destruction and osteoclastogenesis by replenishing splenic and joint-draining lymph node Treg cells in CIA rats. Notably, DHA induced alterations in the Treg cell proteome in PLN, manifesting distinct upregulation of alloantigen Col2a1 (Type II collagen alfa 1 chain) and CD8a (T-cell surface glycoprotein CD8 alpha chain) in Treg cells, signifying DHA's targeted modulation of Treg cells, rendering them more adept at sustaining immune tolerance and impeding bone erosion. These results unveil a novel facet of DHA in the treatment of RA.

Broadband lens and graphene/silicon photodiode for wide spectral imaging.

We designed a broadband lens along with a graphene/silicon photodiode for wide spectral imaging ranging from ultraviolet to near-infrared wavelengths. By using five spherical glass lenses, the broadband lens, with the modulation transfer function of 0.38 at 100 lp/mm, corrects aberrations ranging from 340 to 1700 nm. Our design also includes a broadband graphene/silicon Schottky photodiode with the highest responsivity of 0.63 A/W ranging from ultraviolet to near-infrared. By using the proposed broadband lens and the broadband graphene/silicon photodiode, several single-pixel imaging designs in ultraviolet, visible, and near-infrared wavelengths are demonstrated. Experimental results show the advantages of integrating the lens with the photodiode and the potential to realize broadband imaging with a single set of lens and a detector.

m6A methylation: a process reshaping the tumour immune microenvironment and regulating immune evasion.

N6-methyladenosine (m6A) methylation is the most universal internal modification in eukaryotic mRNA. With elaborate functions executed by m6A writers, erasers, and readers, m6A modulation is involved in myriad physiological and pathological processes. Extensive studies have demonstrated m6A modulation in diverse tumours, with effects on tumorigenesis, metastasis, and resistance. Recent evidence has revealed an emerging role of m6A modulation in tumour immunoregulation, and divergent m6A methylation patterns have been revealed in the tumour microenvironment. To depict the regulatory role of m6A methylation in the tumour immune microenvironment (TIME) and its effect on immune evasion, this review focuses on the TIME, which is characterized by hypoxia, metabolic reprogramming, acidity, and immunosuppression, and outlines the m6A-regulated TIME and immune evasion under divergent stimuli. Furthermore, m6A modulation patterns in anti-tumour immune cells are summarized.

Flexible Large-Area Graphene Films of 50-600 nm Thickness with High Carrier Mobility.

Bulk graphene nanofilms feature fast electronic and phonon transport in combination with strong light-matter interaction and thus have great potential for versatile applications, spanning from photonic, electronic, and optoelectronic devices to charge-stripping and electromagnetic shielding, etc. However, large-area flexible close-stacked graphene nanofilms with a wide thickness range have yet to be reported. Here, we report a polyacrylonitrile-assisted 'substrate replacement' strategy to fabricate large-area free-standing graphene oxide/polyacrylonitrile nanofilms (lateral size ~ 20 cm). Linear polyacrylonitrile chains-derived nanochannels promote the escape of gases and enable macro-assembled graphene nanofilms (nMAGs) of 50-600 nm thickness following heat treatment at 3,000 °C. The uniform nMAGs exhibit 802-1,540 cm2 V-1 s-1 carrier mobility, 4.3-4.7 ps carrier lifetime, and > 1,581 W m-1 K-1 thermal conductivity (nMAG-assembled 10 µm-thick films, mMAGs). nMAGs are highly flexible and show no structure damage even after 1.0 × 105 cycles of folding-unfolding. Furthermore, nMAGs broaden the detection region of graphene/silicon heterojunction from near-infrared to mid-infrared and demonstrate higher absolute electromagnetic interference (EMI) shielding effectiveness than state-of-the-art EMI materials of the same thickness. These results are expected to lead to the broad applications of such bulk nanofilms, especially as micro/nanoelectronic and optoelectronic platforms.

KW2449 ameliorates collagen-induced arthritis by inhibiting RIPK1-dependent necroptosis.

Objective: Necroptosis has recently been found to be associated with the pathogenesis of many autoimmune diseases, including rheumatoid arthritis (RA). This study was undertaken to explore the role of RIPK1-dependent necroptosis in the pathogenesis of RA and the potential new treatment options. Methods: The plasma levels of receptor-interacting protein kinase 1 (RIPK1) and mixed lineage kinase domain-like pseudokinase (MLKL) in 23 controls and 42 RA patients were detected by ELISA. Collagen-induced arthritis (CIA) rats were treated with KW2449 by gavage for 28 days. Arthritis index score, H&E staining, and Micro-CT analysis were used to evaluate joint inflammation. The levels of RIPK1-dependent necroptosis related proteins and inflammatory cytokines were detected by qRT-PCR, ELISA and Western blot, and the cell death morphology was detected by flow cytometry analysis and high-content imaging analysis. Results: The plasma levels of RIPK1 and MLKL in RA patients were higher than those in healthy people, and were positively correlated with the severity of RA. KW2449 could reduce joint swelling, joint bone destruction, tissue damage, and the plasma levels of inflammatory cytokines in CIA rats. Lipopolysaccharide combined with zVAD (LZ) could induce necroptosis in RAW 264.7 cells, which could be reduced by KW2449. RIPK1-dependent necroptosis related proteins and inflammatory factors increased after LZ induction and decreased after KW2449 treatment or knockdown of RIPK1. Conclusion: These findings suggest that the overexpression of RIPK1 is positively correlated with the severity of RA. KW2449, as a small molecule inhibitor targeting RIPK1, has the potential to be a therapeutic strategy for RA treatment by inhibiting RIPK1-dependent necroptosis.

Mechanisms by which kidney-tonifying Chinese herbs inhibit osteoclastogenesis: Emphasis on immune cells.

The immune system plays a crucial role in regulating osteoclast formation and function and has significance for the occurrence and development of immune-mediated bone diseases. Kidney-tonifying Chinese herbs, based on the theory of traditional Chinese medicine (TCM) to unify the kidney and strengthen the bone, have been widely used in the prevention and treatment of bone diseases. The common botanical drugs are tonifying kidney-yang and nourishing kidney-yin herbs, which are divided into two parts: one is the compound prescription of TCM, and the other is the single preparation of TCM and its active ingredients. These botanical drugs regulate osteoclastogenesis directly and indirectly by immune cells, however, we have limited information on the differences between the two botanical drugs in osteoimmunology. In this review, the mechanism by which kidney-tonifying Chinese herbs inhibiting osteoclastogenesis was investigated, emphasizing the immune response. The differences in the mechanism of action between tonifying kidney-yang herbs and nourishing kidney-yin herbs were analysed, and the therapeutic value for immune-mediated bone diseases was evaluated.

Potential medicinal value of N6-methyladenosine in autoimmune diseases and tumours.

Autoimmune diseases (ADs) are closely related to malignant tumours. On the one hand, ADs can increase the incidence of tumours; on the other hand, malignant tumours can cause rheumatic disease-like manifestations. With the increasing depth of analysis into the mechanism of N6 -methyladenosine (m6A) modification, it has been found that changes in m6A-related modification enzymes are closely related to the occurrence and development of ADs and malignant tumours. In this review, we explore the pathogenesis of ADs and tumours based on m6A modification. According to systematic assessment of the similarities between ADs and tumours, m6A may represent a common target of both diseases. At present, most of the drugs targeting m6A are in the research and development stage, not in clinical trials. Therefore, advancing the development of drugs targeting m6A is of great significance for both the combined treatment of ADs and malignant tumours and improving the quality of life and prognosis of patients.

Diagnostic gene signatures and aberrant pathway activation based on m6A methylation regulators in rheumatoid arthritis.

Purpose: Rheumatoid arthritis (RA) is a chronic autoimmune disease (AD) characterized by persistent synovial inflammation, bone erosion and progressive joint destruction. This research aimed to elucidate the potential roles and molecular mechanisms of N6-methyladenosine (m6A) methylation regulators in RA. Methods: An array of tissues from 233 RA and 126 control samples was profiled and integrated for mRNA expression analysis. Following quality control and normalization, the cohort was split into training and validation sets. Five distinct machine learning feature selection methods were applied to the training set and validated in validation sets. Results: Among the six models, the LASSO_λ-1se model not only performed better in the validation sets but also exhibited more stringent performance. Two m6A methylation regulators were identified as significant biomarkers by consensus feature selection from all four methods. IGF2BP3 and YTHDC2, which are differentially expressed in patients with RA and controls, were used to predict RA diagnosis with high accuracy. In addition, IGF2BP3 showed higher importance, which can regulate the G2/M transition to promote RA-FLS proliferation and affect M1 macrophage polarization. Conclusion: This consensus of multiple machine learning approaches identified two m6A methylation regulators that could distinguish patients with RA from controls. These m6A methylation regulators and their target genes may provide insight into RA pathogenesis and reveal novel disease regulators and putative drug targets.

The Role of Reactive Oxygen Species in the Rheumatoid Arthritis-Associated Synovial Microenvironment.

Rheumatoid arthritis (RA) is an inflammatory disease that begins with a loss of tolerance to modified self-antigens and immune system abnormalities, eventually leading to synovitis and bone and cartilage degradation. Reactive oxygen species (ROS) are commonly used as destructive or modifying agents of cellular components or they act as signaling molecules in the immune system. During the development of RA, a hypoxic and inflammatory situation in the synovium maintains ROS generation, which can be sustained by increased DNA damage and malfunctioning mitochondria in a feedback loop. Oxidative stress caused by abundant ROS production has also been shown to be associated with synovitis in RA. The goal of this review is to examine the functions of ROS and related molecular mechanisms in diverse cells in the synovial microenvironment of RA. The strategies relying on regulating ROS to treat RA are also reviewed.

Polycyclic Aromatic Hydrocarbons Affect Rheumatoid Arthritis Pathogenesis via Aryl Hydrocarbon Receptor.

Rheumatoid arthritis (RA), the most common autoimmune disease, is characterized by symmetrical synovial inflammation of multiple joints with the infiltration of pro-inflammatory immune cells and increased cytokines (CKs) levels. In the past few years, numerous studies have indicated that several factors could affect RA, such as mutations in susceptibility genes, epigenetic modifications, age, and race. Recently, environmental factors, particularly polycyclic aromatic hydrocarbons (PAHs), have attracted increasing attention in RA pathogenesis. Therefore, exploring the specific mechanisms of PAHs in RA is vitally critical. In this review, we summarize the recent progress in understanding the mechanisms of PAHs and aryl hydrocarbon receptors (AHRs) in RA. Additionally, the development of therapeutic drugs that target AHR is also reviewed. Finally, we discuss the challenges and perspectives on AHR application in the future.

Polycyclic aromatic hydrocarbons in bone homeostasis.

Prolonged exposure to polycyclic aromatic hydrocarbons (PAHs) may result in autoimmune diseases, such as rheumatoid arthritis (RA) and osteoporosis (OP), which are based on an imbalance in bone homeostasis. These diseases are characterized by bone erosion and even a disruption in homeostasis, including in osteoblasts and osteoclasts. Current evidence indicates that multiple factors affect the progression of bone homeostasis, such as genetic susceptibility and epigenetic modifications. However, environmental factors, especially PAHs from various sources, have been shown to play an increasingly prominent role in the progression of bone homeostasis. Hence, it is essential to investigate the effects and pathogenesis of PAHs in bone homeostasis. In this review, recent progress is summarized concerning the effects and mechanisms of PAHs and their ligands and receptors in bone homeostasis. Moreover, strategies based on the effects and mechanisms of PAHs in the regulation of the bone balance and alleviation of bone destruction are also reviewed. We further discuss the future challenges and perspectives regarding the roles of PAHs in autoimmune diseases based on bone homeostasis.

Multifunctional Macroassembled Graphene Nanofilms with High Crystallinity.

A "cooling-contraction" method to separate large-area (up to 4.2 cm in lateral size) graphene oxide (GO)-assembled films (of nanoscale thickness) from substrates is reported. Heat treatment at 3000 °C of such free-standing macroscale films yields highly crystalline "macroassembled graphene nanofilms" (nMAGs) with 16-48 nm thickness. These nMAGs present tensile strength of 5.5-11.3 GPa (with ≈3 µm gauge length), electrical conductivity of 1.8-2.1 MS m-1 , thermal conductivity of 2027-2820 W m-1 K-1 , and carrier relaxation time up to ≈23 ps. As a demonstration application, an nMAG-based sound-generator shows a 30 µs response and sound pressure level of 89 dB at 1 W cm-2 . A THz metasurface fabricated from nMAG has a light response of 8.2% for 0.159 W mm-2 and can detect down to 0.01 ppm of glucose. The approach provides a straightforward way to form highly crystallized graphene nanofilms from low-cost GO sheets.

Synthesis and In Vitro Evaluation of Caffeoylquinic Acid Derivatives as Potential Hypolipidemic Agents.

A series of novel caffeoylquinic acid derivatives of chlorogenic acid have been designed and synthesized. Biological evaluation indicated that several synthesized derivatives exhibited moderate to good lipid-lowering effects on oleic acid-elicited lipid accumulation in HepG2 liver cells. Particularly, derivatives 3d, 3g, 4c and 4d exhibited more potential lipid-lowering effect than the positive control simvastatin and chlorogenic acid. Further studies on the mechanism of 3d, 3g, 4c and 4d revealed that the lipid-lowering effects were related to their regulation of TG levels and merit further investigation.

Cordycepin promotes browning of white adipose tissue through an AMP-activated protein kinase (AMPK)-dependent pathway.

Obesity is a worldwide epidemic. Promoting browning of white adipose tissue (WAT) contributes to increased energy expenditure and hence counteracts obesity. Here we show that cordycepin (Cpn), a natural derivative of adenosine, increases energy expenditure, inhibits weight gain, improves metabolic profile and glucose tolerance, decreases WAT mass and adipocyte size, and enhances cold tolerance in normal and high-fat diet-fed mice. Cpn markedly increases the surface temperature around the inguinal WAT and turns the inguinal fat browner. Further investigations show that Cpn induces the development of brown-like adipocytes in inguinal and, to a less degree, epididymal WAT depots. Cpn also increases the expression of uncoupling protein 1 (UCP1) and other thermogenic genes in WAT and 3T3-L1 differentiated adipocytes, in which AMP-activated protein kinase (AMPK) plays an important role. Our results provide novel insights into the function of Cpn in regulating energy balance, and suggest a potential utility of Cpn in the treatment of obesity.

Asperlin Stimulates Energy Expenditure and Modulates Gut Microbiota in HFD-Fed Mice.

Asperlin is a marine-derived, natural product with antifungal, anti-inflammatory and anti-atherosclerotic activities. In the present study, we showed that asperlin effectively prevented the development of obesity in high-fat diet (HFD)-fed mice. Oral administration of asperlin for 12 weeks significantly suppressed HFD-induced body weight gain and fat deposition without inhibiting food intake. Hyperlipidemia and liver steatosis were also substantially ameliorated. A respiratory metabolism monitor showed that asperlin efficiently increased energy expenditure and enhanced thermogenic gene expression in adipose tissue. Accordingly, asperlin-treated mice showed higher body temperature and were more tolerant of cold stress. Meanwhile, asperlin also increased the diversity and shifted the structure of gut microbiota. Oral administration of asperlin markedly increased the relative abundance of Bacteroidetes, leading to a higher Bacteroidetes-to-Fimicutes ratio. The HFD-induced abnormalities at both phylum and genus levels were all remarkably recovered by asperlin. These results demonstrated that asperlin is effective in preventing HFD-induced obesity and modulating gut microbiota. Its anti-obesity properties may be attributed to its effect on promoting energy expenditure.

The caffeic acid moiety plays an essential role in attenuating lipid accumulation by chlorogenic acid and its analogues.

Chlorogenic acid (5-caffeoylquinic, CA) possesses distinct hypolipidemic properties in vivo and in vitro, yet the structure-activity relationship (SAR) of CA on lipid metabolism remains unknown. To achieve this aim, we designed and synthesized two sets of CA analogues and evaluated their efficacies to prevent oleic acid (OA)-elicited lipid accumulation in HepG2 cells. Blockage of all hydroxyl and carboxyl groups on the quinic acid moiety did not deteriorate the hypolipidemic effect of CA while blockage of all phenolic hydroxyl groups on the caffeic acid moiety abolished the activity of CA. Further replacement of the quinic acid moiety with cyclohexane and modification of individual phenolic hydroxyl groups on the caffeic acid moiety showed that the phenolic-hydroxyl-reserved analogues displayed a more potent hypolipidemic effect than CA, whereas the analogue with no phenolic hydroxyl displayed little effect on the OA-elicited lipid accumulation. In accordance, the modulating effects of CA on the transcription of the lipogenic gene sterol-regulatory element binding protein (SREBP)1c/1a, acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS) and peroxisome proliferator-activated receptor α (PPARα) were also abolished when the phenolic hydroxyl groups on the caffeic acid moiety were blocked. Our results suggest that the phenolic hydroxyl on the caffeic acid moiety is vital for the lipid-lowering activity of CA.

Cordycepin stimulates autophagy in macrophages and prevents atherosclerotic plaque formation in ApoE-/- mice.

Autophagy in macrophages plays a key role in the pathogenesis and progression of atherosclerosis and has become a potential therapeutic target. Here we show that cordycepin (Cpn), a natural derivative of adenosine, markedly reduced atherosclerotic plaque and ameliorated associated symptoms such as dyslipidemia, hyperglycemia and inflammation in ApoE-/- mice. Supplementation of Cpn dose-dependently inhibited oxLDL-elicited foam cell formation and modulated intracellular cholesterol homeostasis by inhibiting cholesterol uptake and promoting cholesterol efflux in RAW264.7 macrophages. Notably, Cpn exhibited significant stimulating effect on macrophage autophagy, as estimated by western blotting, immunofluorescent staining and autophagic vacuoles observation by transmission electron microscopy. The inhibitive effects of Cpn on foam cell formation were dramatically deteriorated in the presence of various autophagy inhibitors, suggesting that autophagy participate, at least in part, in the atheroprotective role of Cpn. Further investigations using different autophagy inhibitors and specific siRNAs for AMP-activated protein kinase (AMPK) gamma1 subunit indicated that Cpn may stimulate macrophage autophagy through AMPK-mTOR pathway. Together, our results demonstrated Cpn as a potential therapeutic agent for the prevention and treatment of atherosclerosis, and the autophagic activity presents a novel mechanism for Cpn-mediated atheroprotection.