Molecular and Cellular Biochemistry最新文献

Doxorubicin (DOX) is limited in clinical application because of its cardiotoxicity. One of the key elements of DOX-induced cardiotoxicity is pyroptosis, a kind of programmed cell death brought on by immunity and followed by inflammatory response. Growth differentiation factor (GDF) 11 plays an significant role in oxidative stress and inflammation. The purpose of this work was to determine if GDF11 inhibits oxidative stress and pyroptosis in order to lessen the cardiotoxicity caused by DOX. SD rats were used to establish an in vivo model by intraperitoneal injection of DOX and induction of GDF11 overexpression in the heart using adeno-associated virus type 9 (AAV9). Human cardiomyocytes (AC16) were used to create the in-vitro model. By measuring the degree of cardiac function, cardiac fibrosis, inflammation, and oxidative stress; using transmission electron microscopy to examine the rat heart's microstructure; analyzing the expression of proteins of pyroptosis and oxidative stress-associated nuclear factor E2-related factor (Nrf-2)/heme oxygenase-1 (HO-1) pathway, the protective mechanism of GDF11 against DOX-induced cardiotoxicity was explored. GDF11 decreased the expression level of cardiac function, oxidative stress and inflammation-related indexes, attenuated the degree of DOX-induced cardiac fibrosis, and had some protective effects against damage to the rat heart's microstructures. Besides, GDF11 decreased the level of oxidative stress and restored the levels of anti-oxidative stress and other proteins, including Nrf-2, while also reduced the expression of DOX-induced pyroptosis-related proteins. GDF11 attenuates DOX-induced cardiotoxicity by inhibiting pyroptosis and oxidative stress, which provides new ideas for clinical improvement of DOX-induced myocardial injury.

Gastric cancer (GC) remains a primary contributor to cancer-associated deaths worldwide, especially in East Asia. We investigated the function of nuclear-localized full-length FOXP3 (FOXP3FL) as an oncosuppressive factor in GC. Total FOXP3 was markedly reduced in GC tissues versus adjacent normal mucosa, with distinct cytoplasmic and nuclear patterns. Functional assays revealed that nuclear overexpression of FOXP3FL suppresses proliferation, migration, and invasion of GC cells in vitro and in vivo and promotes cellular senescence in vivo. Mechanistically, FOXP3FL directly represses MYC transcription and induces CDKN1A, thereby restraining proliferation and metastasis. These transcriptional changes, together with concomitant PTEN upregulation and PI3K-P110α downregulation, collectively attenuate PI3K/AKT signaling and impair epithelial-mesenchymal transition (EMT) in FOXP3FL-expressing GC cells. The forkhead (FKH) domain is essential: its deletion yields cytoplasmic FOXP3ΔFKH, which loses transcriptional control and antitumor activity. Our findings underscore nuclear-localized FOXP3FL as a tumor suppressor whose FKH domain is integral to its suppressive function.

The aim of this study was to examine the potential antioxidant activity of curcumin in therapeutic and preventive condition and its potential role as adjuvant to conventional drug methotrexate in treatment of rheumatoid arthritis (RA). The study included 104 female Wistar albino rats, 6 weeks old, body weight of 200-250 g, which were divided into 8 groups (n=13 in each group): 1. CTRL: negative control, 2. CUR: positive control 1 (curcumin 200 mg/kg three times a week for 4 weeks per os), 3. MTX: positive control 2 (methotrexate 0,75 mg/kg i.p. two times a week for 4 weeks), 4. RA: positive control 3 (induced RA), 5. RA+pCUR: rats with induced RA + preventive administration of curcumin (curcumin 200 mg/kg three times a week for 4 weeks per os before the induction of RA), 6. RA+tCUR: rats with induced RA + curcumin therapy, 7. RA+MTX+pCUR; rats with induced RA + preventive administration of curcumin + methotrexate 0.75 mg/kg i.p. twice weekly for 4 weeks, 8. RA+MTX+tCUR: rats with induced RA + therapeutic administration of curcumin + methotrexate 0.75 mg/kg i.p. twice weekly for 4 weeks. Potential therapeutic effect of curcumin (200 mg/kg three times a week for 4 weeks orally) and RA induction were initiated on the same day; for preventive protocol, curcumin was administered 4 weeks before the start of RA induction at a dose of 200 mg/kg orally three times a week. Rheumatoid arthritis was triggered by administering 0.1 ml of Complete Freund's Adjuvant (CFA) subcutaneously at the base of the rat tail. Rats were sacrificed 28 days after immunization. During the experimental period, we collected data for arthritis score, radiography testing, and blood sample collecting for specific biochemical analysis for prooxidative and antioxidative parameters (superoxide anion radical, hydrogen peroxide, nitric oxide, index of lipid peroxidation, superoxide dismutase, catalase, and reduced glutathione). Our experimental study confirmed that the therapeutic administration of curcumin reduced disease activity and significantly increased the activities of antioxidative enzymes and reduced prooxidants. Also, preventive administration, especially in combination with methotrexate, offers superior protection by limiting the onset and development of oxidative stress. These findings support the claim that curcumin as turmeric can effectively inhibit inflammatory reactions and reduces symptoms through changing the redox status. Future large randomized controlled trials on the effects of turmeric substance are needed.

The tumor microenvironment (TME) is a complex ecosystem containing various cells and secreted molecules that play critical roles in the progression of tumorigenesis. In recent years, antitumor strategies aimed at reshaping the TME have attracted much attention. Tumor-associated macrophages (TAMs) are the most abundant immune cells infiltrating the TME, contributing more than 50% of the tumor mass. In a variety of cancers, TAMs participate in the processes of tumor formation, migration, and invasion and are significantly related to a poor prognosis. Furthermore, TAMs play crucial roles in the regulation of the TME, chemoresistance, and immunotherapy resistance, and are potential targets in tumor therapy. TAMs are supposed to be carriers of ligands of immune checkpoint inhibitors (ICIs). Therefore, it is expected that TAMs can regulate T cell immune function through providing costimulatory/coinhibitory signals and may significantly influence the immune response related to ICIs. B7/CD28 family members are the best studied immune checkpoint receptors and ligands. Several studies have demonstrated that these B7/CD28 family members are highly expressed on TAMs, eliminating the inhibitory signal of T cell activation. However, the role of TAMs and B7/CD28 family members in ICI-induced immunotherapy is complicated and need to be illustrated. This study aims to review the crosstalk between TAMs and the B7/CD28 family, highlight the role of TAM-mediated tumor immune escape in ICI immunotherapy, explore the application prospects of TAMs in reversing ICI resistance.

Irisin, a myokine secreted by the skeletal muscles during exercise, exerts atheroprotective effects. However, the precise molecular mechanisms that underlie these effects remain incompletely elucidated. This study aimed to investigate the effect of irisin on atherosclerosis and vascular smooth muscle cell (VSMC) migration, and to explore the role of cofilin-mediated cytoskeletal remodeling in the atheroprotective effect of irisin. In vivo, irisin was administered to high-fat diet-fed ApoE^-/- mice. Dyslipidemia in these mice was alleviated by irisin treatment. Atherosclerotic lesion assessment via Oil Red O staining, Masson's trichrome staining, and alpha-smooth muscle actin (a-SMA) immunofluorescence staining revealed that irisin significantly attenuated atherosclerotic plaque burden, necrotic core size, and VSMC area within the aortic tissue of ApoE^-/- mice. However, the atheroprotective effect of irisin was partially reversed when ApoE^-/- mice were cotreated with an integrin αVβ5 inhibitor. In vitro, irisin supplementation decreased platelet-derived growth factor (PDGF)-induced VSMC migration, determined by wound healing assay and transwell migration assay. Furthermore, irisin treatment reversed the elevated expression of p-PI3K and p-Akt as well as the decreased expression of p-cofilin observed both in the aorta of ApoE^-/- mice and in PDGF-stimulated VSMCs. The effects of irisin on p-PI3K, p-Akt, and p-cofilin expression were partially blocked by cotreatment with an integrin αVβ5 inhibitor or PI3K activator. The decreased expression of p-cofilin in PDGF-stimulated VSMCs was partially blocked by PI3K inhibitor. Systemic irisin administration confers protection against atherosclerosis in ApoE^-/- mice. Mechanistically, this beneficial effect involves suppression of the PI3K-Akt signaling pathway, which modulates cofilin-mediated cytoskeletal remodeling to regulate VSMC migration.

In this study, we discussed the impact of CIITA on the occurrence and development of gastric cancer, as well as its potential mechanisms. In this study, N87-C and AGS were used as in vitro research subjects. After knocking down and overexpressing CIITA, CCK8, ELISA, reactive oxygen species (ROS), JC-1, immunofluorescence and western blot were used to assess the effect of CIITA on ferroptosis. To further validate the potential mechanism of CIITA, we continued to transfect lentiviruses cloned with ACSL4 knockdown into cells and repeated the above experiment. In addition, we constructed a subcutaneous transplant tumor model to validate the results of in vitro experiments. In vitro experiments showed that overexpressed CIITA promoted ferroptosis in gastric cancer cells, manifested as the decreased cell viability, increased ROS production, decreased mitochondrial membrane potential, and changes in the expression of ferroptosis-related proteins and secreted factors. After knocking down CIITA, the above results were reversed, inhibiting ferroptosis. In addition, we confirmed that the effect of CIITA on ferroptosis was related to ACSL4. In vitro experiments also confirmed that CIITA overexpression promoted ferroptosis and inhibited tumor growth, while low CIITA had the opposite effect. Overexpressed CIITA promoted ferroptosis and inhibited gastric cancer growth by upregulating ACSL4. CIITA may be a potential therapeutic target for gastric cancer and may have certain predictive value in future clinical applications.

RNA binding proteins (RBPs) play a pivotal role in the posttranscriptional regulation of inflammatory processes. Transformer-2 (Tra2) is an evolutionarily conserved RBP that regulates mRNA alternative splicing, encoding two homologous proteins in vertebrates, Tra2α and Tra2β. Dysregulation of Tra2α or Tra2β may lead to the development of several inflammatory diseases. However, the roles of Tra2α and Tra2β in inflammation remain unclear. In the current research, the expression levels of Tra2α and Tra2β were upregulated in RAW264.7 macrophage cells stimulated by lipopolysaccharide (LPS). Downregulation of Tra2α or Tra2β inhibited the expression of inflammatory factors induced by LPS. Notably, combined suppression of Tra2α and Tra2β cooperatively reduced LPS-activated inflammation and suppressed the activation of NFκB and MAPK pathways. Myeloid differentiation primary response gene 88 (MyD88), a crucial adaptor in the TLR4 pathway, expresses splicing variants MyD88-L and MyD88-S, which exert pro-inflammatory and anti-inflammatory effects, respectively. We found that Tra2α and Tra2β proteins interacted with MyD88 mRNA. Moreover, downregulation of Tra2α and Tra2β promoted the expression of MyD88-S mRNA variants, thereby modulating the inflammatory response. Therefore, our findings demonstrated that Tra2α and Tra2β cooperatively regulated inflammation by modulating the alternative splicing of MyD88 in LPS-stimulated macrophages. These mechanistic insights into Tra2-mediated regulation of macrophage inflammation may provide novel therapeutic targets for treating inflammatory diseases.

Obesity is a multifactorial metabolic disorder characterized by excessive fat accumulation and associated with numerous health risks, including insulin resistance, cardiovascular disease, and metabolic syndrome. Adipose tissue, particularly subcutaneous (SAT) and visceral (VAT) fat, plays a central role in metabolic regulation, yet its biochemical properties and functions differ significantly. While metabolomics offers a promising approach to studying adipose tissue at a molecular level, significant methodological limitations and inconsistencies in study design undermine the reliability of current findings. Although VAT is frequently characterized by a pro-inflammatory and lipolytic metabolic profile, whereas SAT is more involved in lipid storage and insulin, these generalizations overlook important depot-specific variations and fail to address the heterogeneity within adipose tissue. This critical review evaluates existing metabolomic studies, identifying key discrepancies in lipid metabolism, energy homeostasis, and inflammation-related pathways across VAT and SAT. It highlights the need for improved standardization in metabolomic analyses, greater inclusion of diverse populations, and more robust longitudinal studies. By addressing these issues, future research can provide more precise insights into adipose tissue's role in obesity-related metabolic dysfunction and better inform clinical strategies for obesity management.

Keratin 15 (KRT15) promotes tumor progression in several cancers, but its engagement in breast cancer is seldom uncovered. This study aimed to explore the impact of KRT15 modification on breast cancer growth, mobility, radiosensitivity, ferroptosis, and Wnt/β-catenin signaling pathway. A lentiviral vector containing short hairpin RNA or complementary DNA targeting KRT15 was transfected into MDA-MB-231 and MCF-7 cells in vitro. The transfected MCF-7 cells were further proposed to irradiation treatment. In vivo, female BALB/c nude mice were used to establish xenograft model with KRT15-overexpressed MDA-MB-231 cells and treated by irradiation. KRT15 overexpression promoted cell proliferation, migration, invasion, colony number, epithelial-mesenchymal transition (EMT, reflected by E-Cadherin, N-Cadherin, and Vimentin expressions), and S-stage cell cycle arrest in MDA-MB-231 and MCF-7 cells, but repressed cell apoptosis and ferroptosis (reflected by DMT1, SLC7A11, FTH1, and GPX4 expressions); while KRT15 knockdown exhibited the opposite effects. Importantly, KRT15 overexpression enhanced irradiation resistance in MCF-7 cells reflected by cell proliferation, migration, invasion, colony number, cell cycle, and cell apoptosis detections. Besides, KRT15 overexpression increased EMT and activated Wnt/β-catenin signaling pathway (reflected by β-catenin, TCF-1, c-Myc, CCND1, MMP7 expressions) in MCF-7 cells with or without irradiation. In vivo experiments further validated that KRT15 overexpression promoted tumor growth, EMT, Wnt/β-catenin signaling pathway, and irradiation resistance, but repressed the ferroptosis. Collectively, KRT15 may facilitate tumor growth, invasion, EMT, and radioresistance but represses ferroptosis in a Wnt/β-catenin signaling-related way, suggesting its potency as a treatment target for breast cancer management.