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Cdc42, a member of the Rho GTPases family, is involved in the regulation of several cellular functions including cell cycle progression, survival, transcription, actin cytoskeleton organization and membrane trafficking. Diabetes is a chronic and metabolic disease, characterized as glycometabolism disorder induced by insulin deficiency related to β cell dysfunction and peripheral insulin resistance (IR). Diabetes could cause many complications including diabetic nephropathy (DN), diabetic retinopathy and diabetic foot. Furthermore, hyperglycemia can promote tumor progression and increase the risk of malignant cancers. In this review, we summarized the regulation of Cdc42 in insulin secretion and diabetes-associated diseases. Organized researches indicate that Cdc42 is a crucial member during the progression of diabetes, and Cdc42 not only participates in the process of insulin synthesis but also regulates the insulin granule mobilization and cell membrane exocytosis via activating a series of downstream factors. Besides, several studies have demonstrated Cdc42 as participating in the pathogenesis of IR and DN and even contributing to promote cancer cell proliferation, survival, invasion, migration, and metastasis under hyperglycemia. Through the current review, we hope to cast light on the mechanism of Cdc42 in diabetes and associated diseases and provide new ideas for clinical diagnosis, treatment, and prevention.

Allergic diseases, which include asthma, allergic rhinitis (AR), chronic rhinosinusitis (CRS), atopic dermatitis (AD), food allergy (FA), allergic keratoconjunctivitis, seriously affect the quality of life of people all over the world. Recently, interleukin-33 (IL-33) has been found to play an important role in these refractory disorders, mainly by inducing T helper (Th) 2 immune responses. This article reviews the mobilization and biological function of IL-33 in allergic disorders, providing novel insights for addressing these hypersensitive conditions.

Lung cancer is one of the most malignant cancers around the world, with high morbidity and mortality. Metastasis is the leading cause of lung cancer deaths and treatment failure. MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs), two groups of small non-coding RNAs (nc-RNAs), are confirmed to be lung cancer oncogenes or suppressors. Transforming growth factor-β (TGF-β) critically regulates lung cancer metastasis. In this review, we summarize the dual roles of miRNAs and lncRNAs in TGF-β signaling-regulated lung cancer epithelial-mesenchymal transition (EMT), invasion, migration, stemness, and metastasis. In addition, lncRNAs, competing endogenous RNAs (ceRNAs), and circular RNAs (circRNAs) can act as miRNA sponges to suppress miRNAs, thereby mediating TGF-β signaling-regulated lung cancer invasion, migration, and metastasis. Through this review, we hope to cast light on the regulatory mechanisms of miRNAs and lncRNAs in TGF-β signaling-regulated lung cancer metastasis and provide new insights for lung cancer treatment.

Background Variated anti-cancer therapies are combined with immune checkpoint blockades (ICBs) for improving ICB therapeutic efficacy. Occurrence of tissue damage is common that triggers multiple inflammatory cytokine generation. Gastrointestinal organs are the commonly affected. We investigated the impact of acute colitis on tumor infiltration of antigen-specific CD8 + cytotoxic T lymphocytes (CTLs) for controlling tumor growth and responding to antibody against PD-1 (anti-PD-1). Methods Several tumor cell lines were inoculated into syngeneic mice subcutaneously or intra-hepatically. When tumor mass formed, activated CTLs were intravenously transferred into the tumor-bearing mice, that were given the drinking water containing 2% dextran sulfate sodium (DSS) for acute colitis induction. Tumor growth, infiltration of two exhausted CTL subsets, and the CTL interaction with tumor vascular endothelium were examined. Results Acute colitis dampened CTL-mediated antitumor effects, correlating with IL-17A elevation in the inflamed intestine. In the tumor bed, stem-like exhausted CTLs, which were defined as PD-1 + Slamf6 + Tim3 − , expressed higher IL-17A receptor heterodimers and lower leukocyte function-associated antigen-1 (LFA-1) than terminally exhausted CTLs did, that were defined as PD-1 + Slamf6 − Tim3 + . IL-17A stimulation reduced LFA-1 surface expression on stem-like exhausted CTLs and the counterpart ICAM-1 (intracellular adhesion molecule-1) on tumor vascular endothelium. IL-17A stimulation suppressed the extravasation across tumor vascular endothelium and self-renewal of stem-like, not the terminally exhausted CTLs. Administration of anti-IL-17A neutralizing antibody to the colitis mice restored the CTL tumor infiltration and enhanced anti-PD-1 treatment efficacy against tumors. In 33 hepatocellular carcinoma patients being treated with anti-PD-1 plus antibody against vascular endothelial growth factor, disease progression of 15 patients, that exhibited serum IL-17A increase 24 h post-therapy as compared to pre-therapy level, was poorer than that of 18 patients that exhibited serum IL-17A no-increase. Conclusions Abnormal generation of IL-17A mainly repressed tumor infiltration of stem-like exhausted CTLs. ICB-based immunotherapeutic efficacy could be upgraded with administration of anti-IL-17A, when treatment-related IL-17A elevation occurred due to tissue damage, such as acute colitis.

In this article, we distinguish the contributions of the positive parity and negative parity Ω c states, study the masses and pole residues of the 1S, 1P, 2S and 2P Ω c states with the spin J = 1 2 and 3 2 using the QCD sum rules in a consistent way, and we revisit the assignments of the new narrow excited Ω c 0 states. The predictions support assigning Ω c ( 3000 ) to the 1P Ω c state with J P = 1 2 - , assigning Ω c ( 3090 ) to the 1P Ω c state with J P = 3 2 - or the 2S Ω c state with J P = 1 2 + , and assigning Ω c ( 3119 ) to the 2S Ω c state with J P = 3 2 + .

BackgroundTherapeutic efficacy of carcinoembryonic antigen (CEA)-specific chimeric antigen receptor (CAR) T cells against colorectal cancer (CRC) remains limited due to the unique characteristics and distinct microenvironments of tumor tissues. We modified CEA-specific CAR-T cells, aiming to stimulate endogenous CD8+ T cell responses against neoantigens that were derived from CEA-positive tumors destroyed by the CAR T cells.MethodsIn a conventional CEA CAR (reg-CAR), we modified it to express lymphotactin XCL1 and interleukin (IL)-7 genes, constructing a modified 7XCL1-CAR. By generating the CEA-specific 7XCL1-CAR T cells, we assessed their antitumor efficacy against CRC cells with varying levels of CEA expression, both in cell-cultures and in two strains of tumor-bearing syngeneic mice.ResultsFollowing retroviral transduction, 7XCL1-CAR T cells and reg-CAR T cells exhibited similar positive proportions of CEA-CAR and CD4:CD8 ratios. In co-culture system with CEA-negative CT26 cells, no differences in cytotoxicity were observed between 7XCL1-CAR and reg-CAR T cells. However, in co-culture with CT26.CEAhigh and CT26.CEAint cells, 7XCL1-CAR T cells displayed higher cytotoxicity than that reg-CAR T cells after 60 hours. On interaction with CT26.CEA-positive cells, 7XCL1-CAR T cells secreted higher levels of XCL1 and IL-7, effectively recruited the most potent cross-presenting cDC1s (type-I conventional dendritic cells), and sustained the antitumor activity of CAR-T cells. In treating mice that carried tumors derived from universally CEA-positive cells, 7XCL1-CAR T cells exhibited no difference compared with reg-CAR T cells. However, in treating mice with tumors containing both CEA-positive and CEA-negative cells, 7XCL1-CAR T cells displayed greater inhibition than that of reg-CAR-T cells. After treatment of 7XCL1-CAR T cells, tumor-bearing mice exhibited enhanced infiltration of cDC1s, maintained CAR-T activity, and generation of endogenous neoantigen-specific T cells. Consequently, 7XCL1-CAR T cell-treated mice demonstrated resistance to challenge with CEA-negative CT26 cells.ConclusionTreatment with CEA-specific, XCL1-secreting CAR-T cells for CEA-positive tumors promoted the generation of CD8+ T cells against tumor neoantigens, mediating a long-term antitumor immunity against heterogeneous CRCs.

DNA methylation is a common feature of epigenetic regulation and is associated with various biological processes. Anthocyanins are among the secondary metabolites that contribute to fruit colour, which is a key appearance and nutrition quality attribute of apple fruit. Although few studies reported that DNA methylation in the promoter of MYB transcription factor was associated with fruit skin color, there is a general lack of understanding of the dynamics of global and genic DNA methylation in apple fruit. Here, whole-genome bisulfite sequencing was carried out in fruit skin of apple (Malus domestica Borkh.) cv. ‘Red Delicious’ (G0) and its four-generation bud sport mutants, including ‘Starking Red’ (G1), ‘Starkrimson’ (G2), ‘Campbell Redchief’ (G3) and ‘Vallee spur’ (G4) at color break stage. Correlation and linear-regression analysis between DNA methylation level and anthocyanin content, as well as the transcription levels of genes related to anthocyanin biosynthesis were carried out. The results showed that the number of differentially methylated regions (DMRs) and differentially methylated genes (DMGs) was considerably increased from G1 to G4 versus the number observed in G0. The mCHH context was dominant in apple, but the levels of mCG and mCHG of DMGs were significantly higher than that of the mCHH. Genetic variation of bud sport mutants from ‘Red Delicious’ was associated with differential DNA methylation. Additionally, hypomethylation of mCG and mCHG contexts in flavonoid biosynthesis pathway genes (PAL, 4CL, CYP98A, PER, CCOAOMT, CHS, and F3'H), mCHG context in MYB10 at upstream, led to transcriptional activation and was conductive to anthocyanin accumulation. However, hypermethylation of mCG context in bHLH74 at upstream led to transcriptional inhibition, inhibiting anthocyanin accumulation.

To investigate the association between polycystic ovary syndrome (PCOS) and inflammatory proteins, and to identify and quantify the role of serum metabolites as potential mediators. Utilizing summary-level data from a genome-wide association study (GWAS), we conducted a two-sample Mendelian Randomization (MR) analysis, a genetic approach that uses genetic variants as instrumental variables to assess the causal relationships between risk factors and outcomes. This analysis involved genetically predicted PCOS (1,639 cases and 218,970 controls) and inflammatory proteins (14,824 participants of primarily European descent). Additionally, a two-step MR analysis was performed to quantify the proportion of the effect of serum metabolites-mediated inflammatory proteins on PCOS. The Inverse Variance Weighted (IVW) method, a statistical technique used within MR to combine data from multiple genetic variants, was used to estimate the causal effects. The IVW method revealed that the inflammatory proteins IFN-γ ( -value = 0.037, OR = 1.396, 95% CI = 1.020-1.910) and CCL7 ( -value = 0.033, OR = 1.294, 95% CI = 1.021-1.641) were associated with an increased risk of PCOS, while IL-6 ( -value = 0.015, OR = 0.678, 95% CI = 0.495-0.929) and MMP-10 ( -value = 0.025, OR = 0.753, 95% CI = 0.587-0.967) were associated with a decreased risk. No significant evidence suggested an effect of genetically predicted PCOS on inflammatory proteins. The serum metabolite X-11444 was found to mediate 5.44% (95% CI: 10.8-0.0383%) of the effect of MMP-10 on PCOS. This study not only introduces novel causal associations between inflammatory proteins and PCOS but also highlights the mediating role of serum metabolites in these associations. By applying MR, we were able to minimize confounding and reverse causality, offering robust insights into the biological mechanisms underlying PCOS. These findings advance the understanding of PCOS pathogenesis, particularly in relation to inflammatory pathways and serum metabolite interactions, and suggest potential therapeutic targets that could inform future clinical interventions aimed at mitigating inflammation-related PCOS risks.

Breast cancer is the most common malignant tumors in females. Although the conventional treatment has demonstrated a certain effect, some limitations still exist. The Rho guanosine triphosphatase (GTPase) Cdc42 (Cell division control protein 42 homolog) is often upregulated by some cell surface receptors and oncogenes in breast cancer. Cdc42 switches from inactive guanosine diphosphate (GDP)-bound to active GTP-bound though guanine-nucleotide-exchange factors (GEFs), results in activation of signaling cascades that regulate various cellular processes such as cytoskeletal changes, proliferation and polarity establishment. Targeting Cdc42 also provides a strategy for precise breast cancer therapy. In addition, Cdc42 is a potential target for several types of non-coding RNAs including microRNAs and lncRNAs. These non-coding RNAs is extensively involved in Cdc42-induced tumor processes, while many of them are aberrantly expressed. Here, we focus on the role of Cdc42 in cell morphogenesis, proliferation, motility, angiogenesis and survival, introduce the Cdc42-targeted non-coding RNAs, as well as present current development of effective Cdc42-targeted inhibitors in breast cancer.

It is widely recognized that hypertension is one of the major risk factor for disease severity and mortality in patients with coronavirus disease 2019 (COVID‐19). However, type 2 diabetes mellitus (T2DM) and hypertension are frequent comorbid conditions, complicating the assessment of hypertension's individual contribution to the risk. The aims of this study were to evaluate the contributions of hypertension alone, T2DM alone, or their combination to the risk of death, acute respiratory distress syndrome (ARDS)/respiratory failure, and severe COVID‐19 infection. Additionally, we assessed risks associated with elevated blood pressure and fasting blood glucose on the same three clinical outcomes. Multivariate logistic models were used for these analyses. Among the 3400 patients, 3327(97.9%) survived and 73(2.1%) died. Compared to patients having neither hypertension nor T2DM (n = 1392), the risk of mortality was significantly higher in patients with T2DM alone (n = 226, OR 5.26 [95% CI: 2.39–11.58]) or with T2DM in combination with hypertension (n = 507, OR 3.02, [95% CI: 1.48–6.15]). Similarly, T2DM was a risk factor for development of ARDS/respiratory failure and severe infection. Hypertension alone (n = 1275) only conferred additional risk for the development of severe infection (OR 1.22 [95% CI: 1.00–1.51]). In conclusion, neither hypertension nor elevated blood pressure was independent risk factors for death or ARDS/respiratory failure but hypertension marginally increased the risk of severe COVID‐19 infection. The risk associated with hypertension is accentuated through its confounding effect on T2DM.