A GITRL-mTORC1-GM-CSF positive loop promotes pathogenic Th17 response in exacerbating Primary Sjögren's Syndrome.

OBJECTIVES: Glucocorticoid-induced Tumor-Necrosis-Factor-Receptor Family-related Protein (GITR), with its ligand (GITRL), plays an important role in CD4+T-cell-mediated autoimmunity. This study aimed to investigate the underlying mechanisms of GITRL in primary Sjögren's Syndrome (pSS). METHODS: pSS patients and healthy controls were recruited. Serum GITRL and Th17-related cytokines were determinated. RNA-Sequencing was performed to decipher key signal pathways. Non Obese Diabetes (NOD) mice was adopted as experimental Sjögren models and recombinant adeno-associated virus (rAAV) transduction was conducted to verify the therapeutic potentials of targeting GITRL in vivo. RESULTS: Serum GITRL was significantly higher in pSS patients and showed a positive correlation with leukopenia, thrombocytopenia, autoantibodies, lung involvement and disease activity. Serum GITRL was correlated with Th17-related cytokines. GITRL promoted expansion of Th17 and Th17.1 cells. Expansion of granulocyte-macrophage-colony-stimulating-factor (GM-CSF+)CD4+T cells induced by GITRL could be inhibited by blockade of GITRL. Moreover, GM-CSF could stimulate GITRL expression on monocytes. RNA-Sequencing revealed mammalian target of rapamycin complexes 1 (mTORC1) might be the key modulator. The increased phosphorylation of S6 and STAT3 and expansion of Th17 and Th17.1 cells induced by GITRL were effectively inhibited by rapamycin, suggesting a GITRL/mTORC1/GM-CSF positive loop in pathogenic Th17 response in pSS. Administration of rAAV vector expressing shRNA targeting GITRL alleviated disease progression in NOD mice. CONCLUSIONS: Our results identified the pathogenic role of GITRL in exacerbating disease activity and promoting pathogenic Th17 response in pSS through a GITRL/mTORC1/GM-CSF positive loop. These findings suggest GITRL might be a promising therapeutic target in the treatment of pSS.

Human embryonic stem cell-derived mesenchymal stromal cells suppress inflammation in mouse models of rheumatoid arthritis and lung fibrosis by regulating T-cell function.

BACKGROUND AIMS: Rheumatoid arthritis (RA) is characterized by an overactive immune system, with limited treatment options beyond immunosuppressive drugs or biological response modifiers. Human embryonic stem cell-derived mesenchymal stromal cells (hESC-MSCs) represent a novel alternative, possessing diverse immunomodulatory effects. In this study, we aimed to elucidate the therapeutic effects and underlying mechanisms of hESC-MSCs in treating RA. METHODS: MSC-like cells were differentiated from hESC (hESC-MSCs) and cultured in vitro. Cell proliferation was assessed using Cell Counting Kit-8 assay and Ki-67 staining. Flow cytometry was used to analyze cell surface markers, T-cell proliferation and immune cell infiltration. The collagen-induced arthritis (CIA) mouse model and bleomycin-induced model of lung fibrosis (BLE) were established and treated with hESC-MSCs intravenously for in vivo assessment. Pathological analyses, reverse transcription-quantitative polymerase chain reaction and Western blotting were conducted to evaluate the efficacy of hESC-MSCs treatment. RESULTS: Intravenous transplantation of hESC-MSCs effectively reduced inflammation in CIA mice in this study. Furthermore, hESC-MSC administration enhanced regulatory T cell infiltration and activation. Additional findings suggest that hESC-MSCs may reduce lung fibrosis in BLE mouse models, indicating their potential to mitigate complications associated with RA progression. In vitro experiments revealed a significant inhibition of T-cell activation and proliferation during co-culture with hESC-MSCs. In addition, hESC-MSCs demonstrated enhanced proliferative capacity compared with traditional primary MSCs. CONCLUSIONS: Transplantation of hESC-MSCs represents a promising therapeutic strategy for RA, potentially regulating T-cell proliferation and differentiation.

Ion channel TRPV2 is critical in enhancing B cell activation and function.

The function of transient receptor potential vanilloid (TRPV) cation channels governing B cell activation remains to be explored. We present evidence that TRPV2 is highly expressed in B cells and plays a crucial role in the formation of the B cell immunological synapse and B cell activation. Physiologically, TRPV2 expression level is positively correlated to influenza-specific antibody production and is low in newborns and seniors. Pathologically, a positive correlation is established between TRPV2 expression and the clinical manifestations of systemic lupus erythematosus (SLE) in adult and child SLE patients. Correspondingly, mice with deficient TRPV2 in B cells display impaired antibody responses following immunization. Mechanistically, the pore and N-terminal domains of TRPV2 are crucial for gating cation permeation and executing mechanosensation in B cells upon antigen stimulation. These processes synergistically contribute to membrane potential depolarization and cytoskeleton remodeling within the B cell immunological synapse, fostering efficient B cell activation. Thus, TRPV2 is critical in augmenting B cell activation and function.

Rice PIFs: Critical regulators in rice development and stress response.

Phytochrome-interacting factors (PIFs) belong to a subfamily of the basic helix-loop-helix (bHLH) family of transcription factors, which serve as a "hub" for development and growth of plants. They have the capability to regulate the expression of many downstream genes, integrate multiple signaling pathways, and act as a signaling center within the cell. In rice (Oryza sativa), the PIF family genes, known as OsPILs, play a crucial part in many different aspects. OsPILs play a crucial role in regulating various aspects of photomorphogenesis, skotomorphogenesis, plant growth, and development in rice. These vital processes include chlorophyll synthesis, plant gravitropism, plant height, flowering, and response to abiotic stress factors such as low temperature, drought, and high salt. Additionally, OsPILs are involved in controlling several important agronomic traits in rice. Some OsPILs members coordinate with each other to function. This review summarizes and prospects the latest research progress on the biological functions of OsPILs transcription factors and provides a reference for further exploring the functions and mechanism of OsPILs.

Anti-Toxoplasma gondii antibodies as a risk factor for the prevalence and severity of systemic lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease characterized by the presence of numerous autoantibodies. The interaction of infectious agents (viruses, bacteria and parasites) and a genetically susceptible host may be a key mechanism for SLE. Toxoplasma gondii is a widespread intracellular parasite that has been implicated in the pathogenesis of autoimmune diseases. However, the relationship between T. gondii infection and the increased risk of SLE in Chinese populations remains unclear. METHODS: The seroprevalence of T. gondii infection was assessed in 1771 serum samples collected from Chinese individuals (908 healthy controls and 863 SLE patients) from different regions of China using an enzyme-linked immunosorbent assay. Serum autoantibodies and clinical information were obtained and analysed. RESULTS: Our observations revealed a higher prevalence of anti-T. gondii antibodies (ATxA) immunoglobulin G (IgG) in serum samples from SLE patients (144/863, 16.7%) than in those from the healthy controls (53/917, 5.8%; P < 0.0001), indicating a 2.48-fold increased risk of SLE in the ATxA-IgG+ population, after adjustment for age and sex (95% confidence interval [CI] 1.70-3.62, P < 0.0001). ATxA-IgG+ SLE patients also showed a 1.75-fold higher risk of developing moderate and severe lupus symptoms (95% CI 1.14-2.70, P = 0.011) compared to ATxA-IgG- patients. Relative to ATxA-IgG- patients, ATxA-IgG+ patients were more likely to develop specific clinical symptoms, including discoid rash, oral ulcer, myalgia and alopecia. Seven antibodies, namely anti-ribosomal RNA protein (rRNP), anti-double stranded DNA (dsDNA), anti-cell membrane DNA (cmDNA), anti-scleroderma-70 (Scl-70), anti-cardiolipin (CL), anti-beta2-glycoprotein-I (B2GPI) and rheumatoid factor (RF), occurred more frequently in ATxA-IgG+ patients. When combined with anti-dsDNA and RF/anti-rRNP/anti-cmDNA/ESR, ATxA-IgG significantly increased the risk for severe lupus. CONCLUSIONS: Our results suggest that ATxA-IgG may be a significant risk factor for SLE prevalence and severity in Chinese populations.

Artemisinins: Promising drug candidates for the treatment of autoimmune diseases.

Autoimmune diseases are characterized by the immune system's attack on one's own tissues which are highly diverse and diseases differ in severity, causing damage in virtually all human systems including connective tissue (e.g., rheumatoid arthritis), neurological system (e.g., multiple sclerosis) and digestive system (e.g., inflammatory bowel disease). Historically, treatments normally include pain-killing medication, anti-inflammatory drugs, corticosteroids, and immunosuppressant drugs. However, given the above characteristics, treatment of autoimmune diseases has always been a challenge. Artemisinin is a natural sesquiterpene lactone initially extracted and separated from Chinese medicine Artemisia annua L., which has a long history of curing malaria. Artemisinin's derivatives such as artesunate, dihydroartemisinin, artemether, artemisitene, and so forth, are a family of artemisinins with antimalarial activity. Over the past decades, accumulating evidence have indicated the promising therapeutic potential of artemisinins in autoimmune diseases. Herein, we systematically summarized the research regarding the immunoregulatory properties of artemisinins including artemisinin and its derivatives, discussing their potential therapeutic viability toward major autoimmune diseases and the underlying mechanisms. This review will provide new directions for basic research and clinical translational medicine of artemisinins.

In-situ growth of electrically conductive MOFs in wood cellulose scaffold for flexible, robust and hydrophobic membranes with improved electrochemical performance.

Electrically conductive metal-organic frameworks (EC-MOFs) have attracted great attentions in electrochemical fields, but their practical application is limited by their hard-to-shape powder form. The aims was to integrate continuously nucleated EC-MOFs on natural wood cellulose scaffold to develop biobased EC-MOFs membrane with robust flexibility and improved electrochemical performance for wearable supercapacitors. EC-MOF materials (NiCAT or CuCAT) were successfully incorporated onto porous tempo-oxidized wood (TOW) scaffold to create ultrathin membranes through electrostatic force-mediated interfacial growth and simple room-temperature densification. The studies demonstrated the uniform and continuous EC-MOFs nanolayer on TOW scaffold and the interfacial bonding between EC-MOF and TOW. The densification of EC-MOF@TOW bulk yielded highly flexible ultrathin membranes (about 0.3 mm) with high tensile stress exceeding 180 MPa. Moreover, the 50 %-NiCAT@TOW membrane demonstrated high electrical conductivity (4.227 S·m-1) and hydrophobicity (contact angle exceeding 130°). Notably, these properties remained stable even after twisting or bending deformation. Furthermore, the electrochemical performance of EC-MOF@TOW membrane with hierarchical pores outperformed the EC-MOF powder electrode. This study innovatively anchored EC-MOFs onto wood through facile process, yielding highly flexible membranes with exceptional performance that outperforms most of reported conductive wood-based membranes. These findings would provide some references for flexible and functional EC-MOF/wood membranes for wearable devices.

A B-box transcription factor OsBBX17 regulates saline-alkaline tolerance through the MAPK cascade pathway in rice.

Rice OsBBX17 encodes a B-box zinc finger transcription factor in which the N-terminal B-box structural domain interacts with OsMPK1. In addition, it directly binds to the G-box of OsHAK2 and OsHAK7 promoters and represses their transcription. Under saline-alkaline conditions, the expression of OsBBX17 was inhibited. Meanwhile, activation of the OsMPK1-mediated mitogen-activated protein kinase cascade pathway caused OsMPK1 to interact with OsBBX17 and phosphorylate OsBBX17 at the Thr-95 site. It reduced OsBBX17 DNA-binding activity and enhanced saline-alkaline tolerance by deregulating transcriptional repression of OsHAK2 and OsHAK7. Genetic assays showed that the osbbx17-KO had an excellent saline-alkaline tolerance, whereas the opposite was in OsBBX17-OE. In addition, overexpression of OsMPK1 significantly improved saline-alkaline tolerance, but knockout of OsMPK1 caused an increased sensitivity. Further overexpression of OsBBX17 in the osmpk1-KO caused extreme saline-alkaline sensitivity, even a quick death. OsBBX17 was validated in saline-alkaline tolerance from two independent aspects, transcriptional level and post-translational protein modification, unveiling a mechanistic framework by which OsMPK1-mediated phosphorylation of OsBBX17 regulates the transcription of OsHAK2 and OsHAK7 to enhance the Na+ /K+ homeostasis, which partially explains light on the molecular mechanisms of rice responds to saline-alkaline stress via B-box transcription factors for the genetic engineering of saline-alkaline tolerant crops.

A Comparative Study of Antitumor Immunity Induced by Radiofrequency Microwave and Cryoablation in Hepatocellular Carcinoma.

PURPOSE: This study aimed to compare the immune responses induced by microwave ablation (MWA), radiofrequency ablation (RFA), and cryoablation (CRYO) in hepatocellular carcinoma (HCC) and identify differences in immune responses and the timing of immune changes. MATERIALS AND METHODS: A bilateral subcutaneous model was established in C57 mice, and the successfully modeled mice were divided into the microwave (n = 15), radiofrequency (n = 15), CRYO (n = 15), control (n = 9), and blank groups (n = 3). Mice in the control group were dissected before ablation, whereas mice in the three ablation groups underwent ultrasound-guided ablation of one axillary tumor. Three mice were sacrificed and dissected at 1-4 weeks after ablation. After tissue processing, flow cytometry was used to detect the levels of CD8 + T and regulatory T (Treg) cells in the tissue, and western blotting was used to assess the level of programmed cell death ligand 1 (PD-L1) protein in the tumor tissue. RESULTS: The pattern of immune changes after the three types of ablation was consistent, with immune changes occurring at 3-4 weeks. CRYO induced the most significant increase in the percentage of CD8 + T cells. There were no significant differences in the levels of Treg cells and the level of PD-L1 protein among the three types of ablation (p > 0.05), but the decline in Treg cells and PD-L1 protein level caused by CRYO was the most pronounced. CONCLUSION: In the HCC mouse model, the immune changes following the three types of ablation were consistent, with immune changes occurring at 3-4 weeks. Among them, CRYO elicited the strongest adaptive immune response, and RFA outperformed MWA.

Sesamol serves as a p53 stabilizer to relieve rheumatoid arthritis progression and inhibits the growth of synovial organoids.

BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease known as a leading cause of disability with considerable mortality. Developing alternative drugs and targets for RA treatment is an urgent issue. Sesamol is a phenolic compound isolated from natural food sesame (Sesamum indicum L.) with various biological activities. PURPOSE: The current research intended to illuminate the bioactivity and mechanisms of sesamol in RA fibroblast-like synoviocytes (FLS), and aimed to estimate the potential clinical application value of sesamol in RA treatment. METHODS: CCK-8, EdU, and flow cytometry assays, as well as transwell tests were applied to observe the effects of sesamol on the abnormal functions of RA-FLS. Moreover, synovial organoids and a collagen-induced arthritis (CIA) mouse model were constructed to further explore the therapeutic capacity of sesamol on RA. Furthermore, RNA sequencing combined with quantitative real-time PCR assay, Western blot as well as co-immunoprecipitation were employed to clarify the mechanism of sesamol in regulating RA progression. RESULTS: Sesamol suppressed the proliferation through inhibiting DNA replication, triggering cell cycle arrest and apoptosis of RA-FLS. Besides, sesamol impaired RA-FLS migration and invasion. Interestingly, sesamol inhibited the growth of constructed synovial organoids and alleviated RA symptoms in CIA mice. Moreover, RNA sequencing further implicated p53 signaling as a downstream pathway of sesamol. Furthermore, sesamol was shown to decrease p53 ubiquitination and degradation, thereby activating p53 signaling. Finally, bioinformatics analyses also highlighted the importance of sesamol-regulated networks in the progression of RA. CONCLUSIONS: Our investigation demonstrated that sesamol served as a novel p53 stabilizer to attenuate the abnormal functions of RA-FLS via facilitating the activation of p53 signaling. Moreover, our study highlighted that sesamol might be an effective lead compound or candidate drug and p53 could be a promising target for the therapy of RA.

Arecoline hydrobromide suppresses PI3K/AKT pathway in rheumatoid arthritis synovial fibroblasts and relieves collagen-induced arthritis in mice.

OBJECTIVE: This study investigated the effectiveness of arecoline hydrobromide (AH) on the functions of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs) and collagen-induced arthritis (CIA) mice. METHODS: Immunofluorescence was used to identify RA-FLSs. Cell Counting Kit-8 (CCK-8) was used to determine the viability of RA-FLSs and the half maximal inhibitory concentration (IC50) of AH. The 5-ethynyl-2'-deoxyuridine (EdU) assay was used to detect DNA replication in RA-FLSs. Cell cycle and apoptosis were examined by flow cytometry. Migration and invasion, as well as wound healing assays, were employed to determine cell migration and invasion ability. Proteins and mRNA expression levels were investigated using Western blot, quantitative real-time PCR (RT-qPCR), and immunofluorescence. The CIA mice model was used to assess the effect of AH in vivo. RNA-sequencing (RNA-seq) was used to find the potential signaling pathways of AH against RA, and Western blot was used to verify the key signaling pathway of AH on RA-FLSs. Network pharmacology and molecular docking were used to predict drug targets. RESULTS: AH inhibited the proliferation and DNA replication of RA-FLSs, promoted cell cycle arrest by reducing the levels of cyclin-dependent kinase 1 (CDK1), cyclin A2, and cyclin B1, promoted apoptosis by suppressing B-cell lymphoma-2 (Bcl-2) expression, and suppressed migration and invasion by inhibiting vimentin expression in RA-FLSs. AH was also effective in relieving arthritis in vivo. RNA sequencing analyses suggested that AH inhibited the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway in RA-FLSs, which was also confirmed in Western blot analysis. Furthermore, network pharmacology and molecular docking suggested that F2, MAPK14, SRC, AKT1, and CTSK might be the direct targets of AH. CONCLUSION: AH can modulate the pathological process of RA-FLSs by blocking the PI3K/AKT pathway and relieve CIA in mice, making it a potential new small molecule candidate.

Preparation of degradable chemically cross-linked polylactic acid films and its application on disposable straws.

The semi-rigidity of the polylactic acid (PLA) molecular chain makes it brittle, poor impact resistance and barrier properties, which severely limits its practical applications. In this paper, a bio-based reactive plasticizer epoxy soybean oil (ESO) was used to improve the mechanical and barrier properties of maleic anhydride grafted polylactic acid (MAPLA) by the chemical reaction between the epoxy and anhydride group. Firstly, the optimum curing conditions were 93.5 °C, 100 °C, and 110.8 °C for 2 h. The effects of different mass fractions of ESO on the properties of MAPLA-ESO (ME) films were systematically investigated. It was found that when the content of ESO was 10 wt%, the tensile properties of the resulting ME films were the best, with a tensile strength of 35.2 MPa. And it had an elongation at break of 20.0 % and toughness of 5.4 MJ/m3, which increased to 690 % and 675 %, respectively, compared with pure MAPLA films. The chemically crosslinked ME films also displayed excellent water resistance, well degradation, low migration properties, and better performance than that of commercial paper straws and PLA straws, exhibiting great application potential as degradable disposable straws. Therefore, this work provides an effective way to develop high-performance, green, and degradable PLA films and products.

Superparamagnetic Composite Nanobeads Anchored with Molecular Glues for Ultrasensitive Label-free Proteomics.

Mass spectrometry has emerged as a mainstream technique for label-free proteomics. However, proteomic coverage for trace samples is constrained by adsorption loss during repeated elution at sample pretreatment. Here, we demonstrated superparamagnetic composite nanoparticles functionalized with molecular glues (MGs) to enrich proteins in trace human biofluid. We showed high protein binding (>95 %) and recovery (≈90 %) rates by anchor-nanoparticles. We further proposed a Streamlined Workflow based on Anchor-nanoparticles for Proteomics (SWAP) method that enabled unbiased protein capture, protein digestion and pure peptides elution in one single tube. We demonstrated SWAP to quantify over 2500 protein groups with 100 HEK 293T cells. We adopted SWAP to profile proteomics with trace aqueous humor samples from cataract (n=15) and wet age-related macular degeneration (n=8) patients, and quantified ≈1400 proteins from 5 µL aqueous humor. SWAP simplifies sample preparation steps, minimizes adsorption loss and improves protein coverage for label-free proteomics with previous trace samples.

Testicular ischemia associated with IgA vasculitis in a child: a case report and literature review.

Testicular necrosis is a rare and severe complication of immunoglobulin A (IgA) vasculitis (IgAV). Herein, We report a case of a 10-year-old boy who was admitted to the hospital due to skin purpura and intermittent abdominal pain for 10 days and bilateral testicular pain for 2 days. Scrotal ultrasonography indicated right testicle ischemia, right epididymo-orchitis, and bilateral hydrocele of the testis. Scrotal surgical exploration revealed significant swelling and darkening of the right testicle. Conservative treatment led to improvement in his condition, and he was discharged. During 3 months of follow-up, there was no recurrence of skin purpura or pain, and the urine tests were normal. Color ultrasound indicated only partial blood flow signal to the right testicle tissue, which was slightly smaller than the left testicle. This case highlights the need for continuous attention from clinicians to the signs and symptoms of the reproductive system during the diagnosis and treatment of IgAV. Continuous monitoring with ultrasound can aid in early detection, diagnosis, and treatment of reproductive system lesions of IgA vasculitis.

Discovery of Pyrazolone Carbothioamide Derivatives as Inhibitors of the Pdr1-KIX Interaction for Combinational Treatment of Azole-Resistant Candidiasis.

Candida glabrata has emerged as an important opportunistic pathogen of invasive candidiasis due to increasing drug resistance. Targeting Pdr1-KIX interactions with small molecules represents a potential strategy for treating drug-resistant candidiasis. However, effective Pdr1-KIX inhibitors are rather limited, hindering the validation of target druggability. Here, new Pdr1-KIX inhibitors were designed and assayed. Particularly, compound B8 possessed a new chemical scaffold and exhibited potent KIX binding affinity, leading to enhanced synergistic efficacy with fluconazole to treat resistant C. glabrata infection (FICI = 0.28). Compound B8 acted by inhibiting the efflux pump and down-regulating resistance-associated genes through blocking the Pdr1-KIX interaction. Compound B8 exhibited excellent in vitro and in vivo antifungal potency in combination with fluconazole against azole-resistant C. glabrata. It also had direct antifungal effect to treat C. glabrata infection, suggesting new mechanisms of action independent of Pdr1-KIX inhibition. Therefore, compound B8 represents a promising lead compound for antifungal drug development.

Label-Free Detection of Single Living Bacteria: Single-Entity Electrochemistry Targeting Metabolic Products.

This study presents a novel approach employing single-entity electrochemistry for the label-free detection of living Escherichia coli. By examination of the collision signals generated from the reduction of hydrogen peroxide, a metabolic product of E. coli that accumulates on the cell surface, the concentration of living bacteria can be determined. Within a broad concentration range from 3.0 × 107 to 1.0 × 109 cells/mL, cell aggregation was not observed. Cell migration in the solution was primarily governed by diffusion, exhibiting a diffusion coefficient of 6.8 × 10-9 cm2/s. The collision frequency exhibits a linear relationship with the cell concentration, aligning well with theoretical predictions. Through statistical analysis of each collision signal's integrated charge quantity, the metabolic activity of single cells can be assessed. This method was applied to a cytotoxicity assay, where it monitored the decline in living cell numbers and metabolic activities in addition to identifying potential cell damage during antibiotic treatment.

Transcriptomic and metabolite analyses provided a new sight of 1-MCP on organic acid metabolism in peach during storage.

In this study, "Xiahui 6" peaches were treated with 10 µL/L 1-methylcyclopropene (1-MCP) for 12 h and then stored at 20°C for 9 days; the regulation of 1-MCP on organic acids during storage was investigated through transcriptomic and metabolite analyses. Results showed that 1-MCP maintained higher gene expression of malate synthesis (PpPEPC1, PpPEPC2, and PpNAD-cytMDH) at the end of storage but extremely inhibited the gene expression of malate degradation (PpNADP-cytME) during storage, resulting that malate content in treated peaches was twice that of control group at day 7. Besides, the increasement of citrate synthesis and degradation-related genes (PpmitCS, PpcytACO, PpNAD-mitIDH, and PpNADP-cytIDH) at days 3 and 5 was postponed by 1-MCP treatment, accompanied by 0.5 times higher citrate content at day 7. Our results suggested that 1-MCP has inhibitory effects on both the synthesis and degradation of organic acids; however, the inhibitory effect of 1-MCP on organic acid degradation may be greater than that on organic acid synthesis. Practical Application: This study provides a theoretical basis for the application of 1-methylcyclopropene (1-MCP) in fruit preservation.

[Characteristics of Organic Matter Composition and Oxidation Potential in Road Dust in Winter in Xi'an].

Roads are the main places where urban people are exposed to atmospheric particulate matter from outdoor activities, and certain oxidatively active substances contained in road particulate matter are important components that induce the generation of reactive oxygen species (ROS), which in turn endanger human health. Here, we explored the characteristics of organic matter composition in water-soluble (WSM) and methanol-soluble fractions (MSM) of road dust in Xi'an and its oxidation potential (OP). Additionally, we investigated the organic fractions and their distribution based on parallel factor analysis (PARAFAC) and analyzed the correlation between organic matter types and OP. The results showed that the water-insoluble fraction of road dust in Xi'an contained more chromophoric organic matter with an average total concentration of (4.71±1.27)×104 R.U., which was 12 times higher than that of WSM[(3.96±1.10)×103 R.U.], of which low-oxidizing humic-like substances (HULIS) were the main organic matter (34.8%-43.7% of the total organic matter). The results of cluster analysis showed that the important sources of organic matter in road dust in Xi'an were fuel combustion and industrial production. The mean value of dust oxidative toxicity was (0.34±0.08) pmol·(min·µg)-1, with the water-insoluble fraction providing 70% of the total oxidative toxicity of dust particles, which was 2.4 times higher than the water-soluble fraction. The main precursors of oxidative toxicity of dust particles were metal elements, and special types of organic substances were also one of the important oxidative toxicity precursors, among which chromophore organic matter was the main cause of OP production in the WSM fraction (r=0.35, P<0.01), and protein-like organic matter and highly oxidized HULIS in WSM may have been the main two types of organic substances for OP production. However, there was no significant correlation between organic matter concentration in MSM and water-insoluble OP (OPTotal-OPWSM) (r=-0.04, P>0.1), so the oxidative toxicity of the water-insoluble particulate matter fraction was mainly generated from non-organic matter.

CT2-3 induces cell cycle arrest and apoptosis in rheumatoid arthritis fibroblast-like synoviocytes through regulating PI3K/AKT pathway.

Rheumatoid arthritis (RA) is a kind of chronic autoimmune disease. The existing therapies encountered several challenges. Therefore, continued novel anti-RA drug discovery remains necessary for RA therapy. Recently, our group reported a novel compound named CT2-3, which could be realized as a hybrid of the natural product magnolol and phthalimide and exhibited anti-lung cancer activity. However, the effect of CT2-3 on RA is unclear. Here, we aim to explore the effect and potential mechanism of CT2-3 on the abnormal functions of RA-fibroblast-like synoviocytes (RA-FLSs). In this study, we identified the important role of the dysregulated cell cycle and apoptosis of RA-FLSs in RA progression. Interestingly, we found that CT2-3 inhibited the proliferation and DNA replication of primary RA-FLSs and immortalized RA-FLSs namely MH7A. In addition, CT2-3 downregulated the mRNA and protein expression of cyclin-dependent kinase 2 (CDK2), cyclin A2, and cyclin B1, resulting in cell cycle arrest of primary RA-FLSs and MH7A cells. Also, CT2-3 downregulated the level of B-cell lymphoma-2 (Bcl-2), and increased the level of Bcl-2 associated X (Bax), contributing to apoptosis of primary RA-FLSs and MH7A cells. Furthermore, differential analyses of RNA-sequencing, Western blot, and network pharmacological analysis confirmed that CT2-3 inhibited phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway of primary RA-FLSs and MH7A cells. In conclusion, CT2-3 induces cell cycle arrest and apoptosis in RA-FLSs through modulating PI3K/AKT pathway, which may serve as a potential lead compound for further novel small molecule anti-RA drug development.