Molecular and Cellular Biochemistry最新文献

Mesenchymal stem cells (MSCs) may play a pivotal role in shaping the tumor microenvironment (TME), influencing tumor growth. Nonetheless, conflicting evidence exists regarding the distinct impacts of MSCs on tumor progression, with some studies suggesting promotion while others indicate suppression of tumor cell growth. Considering that oxidative stress is implicated in the dynamic interaction between components of the TME and tumor cells, we investigated the contribution of exosomes released by hydrogen peroxide (H₂O₂)-treated MSCs to murine mammary tumor growth and progression. Additionally, we aimed to identify the underlying mechanism through which MSC-derived exosomes affect breast tumor growth and angiogenesis. Our findings demonstrated that exosomes released by H₂O₂-treated, stress-induced MSCs (St-MSC Exo) promoted breast cancer cell progression by inducing the expression of vascular endothelial growth factor (VEGF) and markers associated with epithelial-to-mesenchymal transition. Further clarification revealed that the promoting effect of St-MSC Exo on VEGF expression may, in part, depend on activating STAT3 signaling in BC cells. In contrast, exosomes derived from untreated MSCs retarded JAK1/STAT3 phosphorylation and reduced VEGF expression. Additionally, our observations revealed that the activation of the transcription factor NF-κB in BC cells, stimulated with St-MSC Exo, occurs concurrently with an increase in intracellular ROS production. Moreover, we observed that the increase in VEGF secretion into the conditioned media of 4T1 BC, mediated by St-MSC Exo, positively influenced endothelial cell proliferation, migration, and vascular behavior in vitro. In turn, our in vivo studies confirmed that St-MSC Exo, but not exosomes derived from untreated MSCs, exhibited a significant promoting effect on breast tumorigenicity. Collectively, our findings provide new insights into how MSCs may contribute to modulating the TME. We propose a novel mechanism through which exosomes derived from oxidative stress-induced MSCs may contribute to tumor progression and angiogenesis.

Hypertension is a major harbinger of cardiovascular morbidity and mortality. It predisposes to higher rates of myocardial infarction, chronic kidney failure, stroke, and heart failure than most other risk factors. By 2025, the prevalence of hypertension is projected to reach 1.5 billion people. The pathophysiology of this disease is multifaceted, as it involves nitric oxide and endothelin dysregulation, reactive oxygen species, vascular smooth muscle proliferation, and vessel wall calcification, among others. With the advent of new biomolecular techniques, various studies have elucidated a gaping hole in the etiology and mechanisms of hypertension. Indeed, epigenetics, DNA methylation, histone modification, and microRNA-mediated translational silencing appear to play crucial roles in altering the molecular phenotype into a hypertensive profile. Here, we critically review the experimentally determined associations between microRNA (miRNA) molecules and hypertension pharmacotherapy. Particular attention is given to the epigenetic mechanisms underlying the physiological responses to antihypertensive drugs like candesartan, and other relevant drugs like clopidogrel, aspirin, and statins among others. Furthermore, how miRNA affects the pharmaco-epigenetics of hypertension is especially highlighted.

Atherosclerosis (AS) is a pivotal pathological basis of cardiovascular and cerebrovascular diseases, and circular RNAs (circRNAs) has been disclosed to exert a vital part in the progression of AS. However, the functions of circ_0004872 in the progression of AS is indistinct. In this context, we aimed to elucidate the role of circ_0004872 and the potential mechanism in AS. The level of circ_0004872, miR-424-5p and fibroblast growth factor receptor substrate 2 (FRS2) was detected using quantitative real-time polymerase chain reaction (qRT-PCR). Cell proliferation was monitored by Cell Counting Kit-8 and 5-ethynyl-2'-deoxyuridine (EDU) assays. The invasion and migration capabilities of VSMCs were tested by transwell assays and wound-healing assay, respectively. Western blot was adopted to check the protein levels of CyclinD1, Vimentin and FRS2. Dual-luciferase reporter and RNA immunoprecipitation assay were executed to manifest the interaction between miR-424-5p and circ_0004872 or FRS2. The level of circ_0004872 was increased in the serum samples of AS patients and ox-LDL-exposed VSMCs. Ox-LDL exposure triggered cell proliferation, invasion and migration ability of VSMCs. depletion of circ_0004872 partly weakened ox-LDL-mediated effects in VSMCs. Mechanistically, circ_0004872 functioned as a sponge of miR-424-5p, and miR-424-5p inhibition partly alleviated circ_0004872 deficiency-mediated influences in VSMCs. Additionally, miR-424-5p interacted with FRS2, and miR-424-5p constrained dysfunction in ox-LDL-stimulated VSMCs via reducing FRS2 level. Notably, circ_0004872 functioned as a sponge of miR-424-5p to elevate FRS2 expression. Circ_0004872 accelerated ox-LDL-induced damage via mediating miR-424-5p/FRS2 axis.

Ferroptosis is a newly recognized type of regulated cell death that is characterized by the accumulation of iron and lipid peroxides in cells. Studies have shown that ferroptosis plays a significant role in the pathogenesis of various diseases, including cardiovascular diseases. In cardiovascular disease, ferroptosis is associated with ischemia-reperfusion injury, myocardial infarction, heart failure, and atherosclerosis. The molecular mechanisms underlying ferroptosis include the iron-dependent accumulation of lipid peroxidation products, glutathione depletion, and dysregulation of lipid metabolism, among others. This review aims to summarize the current knowledge of the molecular mechanisms of ferroptosis in cardiovascular disease and discuss the potential therapeutic strategies targeting ferroptosis as a treatment for cardiovascular disease.

Bone marrow adipose tissue (BMAT) exhibits a multitude of biological functionalities and influences hematopoiesis. The adiposity status of the bone marrow may play a role in the decline of hematopoietic function. Mesenchymal stem cells (MSCs) constitute crucial regulators within the bone marrow microenvironment; however, their precise role in modulating BMAT and the subsequent implications for hematopoiesis remain poorly understood. We conducted in vivo studies to observe the effects of human umbilical cord mesenchymal stem cells (hucMSCs) on BMAT accumulation and restoration of hematopoietic function in mice with drug-induced hematopoietic impairment. Concurrently, in vitro co-culture experiments were used to investigate the impact of hucMSCs on preadipocytes and mature adipocytes, and the potential subsequent consequences for hematopoietic cells. Moreover, we explored the potential mechanisms underlying these interactions. Our findings reveal that hucMSCs concomitantly mitigate BMAT accumulation and facilitate the recovery of hematopoietic function in mouse models with drug-induced hematopoietic impairment. In vitro, hucMSCs potentially impede adipogenic differentiation of 3T3-L1 preadipocytes through interference with the JAK2/STAT3 signaling pathway and affect the functionality of mature adipocytes, thus mitigating the detrimental effects of adipocytes on hematopoietic stem cells (HSCs). Furthermore, we demonstrate that hucMSCs may protect hematopoietic cells from adipocyte-induced damage by protecting antioxidative mechanisms. These results suggest that hucMSCs exhibit an inhibitory effect on the excessive expansion of adipose tissue and modulate adipose tissue function, which may potentially contribute to the regulation of the bone marrow microenvironment and favorably influence hematopoietic function improvement.

Tumor-associated macrophages (TAMs) are a type of highly plastic immune cells in the tumor microenvironment (TME), which can be classified into two main phenotypes: classical activated M1 macrophages and alternatively activated M2 macrophages. As previously reported, M2-polarized TAMs play critical role in promoting the progression of non-small cell lung cancer (NSCLC) via secreting exosomes, but the detailed mechanisms are still largely unknown. In the present study, the THP-1 monocytes were sequentially induced into M0 and M2-polarized macrophages, and the exosomes were obtained from M0 (M0-exos) and M2 (M2-exos) polarized macrophages, respectively, and co-cultured with NSCLC cells (H1299 and A549) to establish the exosomes-cell co-culture system in vitro. As it was determined by MTT assay, RT-qPCR and Transwell assay, in contrast with the M0-exos, M2-exos significantly promoted cell proliferation, migration and epithelial-mesenchymal transition (EMT) process in NSCLC cells. Next, through screening the contents in the exosomes, it was verified that miR-155-5p was especially enriched in the M2-exos, and M2-exos enhanced cancer aggressiveness and tumorigenesis in in vitro NSCLC cells and in vivo xenograft tumor-bearing mice models via delivering miR-155-5p. The detailed molecular mechanisms were subsequently elucidated, and it was found that miR-155-5p bound with HuR to increase the stability and expression levels of VEGFR2, which further activated the tumor-promoting PI3K/Akt/mTOR signal pathway, and M2-exos-enhanced cancer progression in NSCLC cells were apparently suppressed by downregulating VEGFR2 and PI3K inhibitor LY294002 co-treatment. Taken together, M2-polarized TAMs secreted miR-155-5p-containing exosomes to enhanced cancer aggressiveness of NSCLC by activating the VEGFR2/PI3K/Akt/mTOR pathway in a HuR-dependent manner.

Coronary artery disease, atherosclerosis, and its life-threatening sequels impose the hugest burden on the healthcare systems throughout the world. The intricate process of atherosclerosis is considered as an inflammatory-based disorder, and therefore, the components of the immune system are involved in different stages from formation of coronary plaques to its development. One of the major effectors in this way are the antibody producing entities, the B cells. These cells, which play a significant and unique role in responding to different stress, injuries, and infections, contribute differently to the development of atherosclerosis, either inhibitory or promoting, depending on the type of subsets. B cells implicate in both systemic and local immune responses of an atherosclerotic artery by cell-cell contact, cytokine production, and antigen presentation. In particular, natural antibodies bind to oxidized lipoproteins and cellular debris, which are abundant during plaque growth. Logically, any defects in B cells and consequent impairment in antibody production may greatly affect the shaping of the plaque and its clinical outcome. In this comprehensive review, we scrutinize the role of B cells and different classes of antibodies in atherosclerosis progression besides current novel B-cell-based therapeutic approaches that aim to resolve this affliction of mankind.

Epithelial-mesenchymal transition (EMT) plays critical roles in cancer progression and metastasis. Thus, the exploration of the molecular mechanism regulating EMT would provide potential opportunities for the therapy of metastatic ovarian cancer (OC). Herein, we investigated the putative role of KMT2A in modulating EMT and metastasis in OC. The expression of KMT2A in OC was detected by Western blot and immunohistochemistry and its relationship with clinicopathological factors was analyzed. The effect of KMT2A on the biological behavior of OC cells was examined. Moreover, the expressions of EMT-associated proteins were detected in vivo and vitro by Western blot, immunofluorescence, and immunohistochemistry. KMT2A was highly expressed in OC cell lines and tissues and was positively correlated with advanced International Federation of Gynecology and Obstetrics (FIGO) stage, pathological grade, and metastasis. KMT2A overexpression was correlated with poor prognosis. Suppression of KMT2A inhibited OC cells proliferation, migration, and invasion and induced their apoptosis in vitro and vivo. In contrast, the ectopic expression of KMT2A had the opposite effects. Furthermore, KMT2A knockdown inhibited TGF-β-induced EMT in OC and reduced the phosphorylation levels of Smad2. Taken together, these observations demonstrate that KMT2A could promote the malignant behavior of OC by activating TGF-β/Smad signaling pathway and may be a potential prognostic biomarker and therapeutic target for OC.

Oxaliplatin (L-OHP) and 5-fluorouracil (5-FU) are used to treat colon cancer; however, resistance contributes to poor prognosis. Epithelial-mesenchymal transition (EMT) has been induced in tumor tissues after administration of anticancer drugs and may be involved in drug resistance. We investigated the mechanism of EMT induction in colon cancer cells treated with 5-FU and L-OHP. We found that L-OHP and 5-FU at clinical steady-state concentrations induced EMT in LoVo and DLD-1 cells (KRAS G13D-mutated), but not in HT-29 and Caco-2 cells (KRAS wild type). L-OHP and 5-FU elevated vimentin, N-cadherin, Twist, Slug, and Snail and decreased E-cadherin expressions. Moreover, 5-FU- and L-OHP -induced EMT cells showed increased cell migration and decreased sensitivity to 5-FU and L-OHP. L-OHP and 5-FU treatment promoted KRAS, ERK1/2, and NF-κB activation. Combined administration with KRAS siRNA, MEK1/2 inhibitor trametinib, and NF-κB inhibitor dimethyl fumarate (DMF), suppressed L-OHP- and 5-FU-induced EMT. These results suggest that KRAS/ERK/NF-κB pathway activation is important for EMT induction by L-OHP and 5-FU treatment. Thus, MEK1/2 and NF-κB inhibitors may facilitate the resistance acquisition to L-OHP and 5-FU therapy in KRAS G13D-mutated colon cancer.

Carotid artery stenosis is the main cause of cerebral watershed infarction (CWI). In recent years, increasing attention has been given to treating this condition. The present study aimed to investigate how Verteporfin-eluting stent (VPES) modulates the YAP signaling pathway to inhibit restenosis of the carotid artery and alleviate CWI. Through transcriptome sequencing and functional experiments, it was found that VP could regulate the Yes-associated protein (YAP) signaling pathway and effectively suppress the proliferation and migration of smooth muscle cells (SMCs). Further investigation revealed that VPES could inhibit carotid artery restenosis through the YAP signaling pathway in a rabbit model, reducing the occurrence of CWI.