Molecular and Cellular Biochemistry最新文献

Esophageal squamous cell carcinoma (ESCC) is a common and aggressive subtype of esophageal cancer. This research investigates the functions of cancer-associated fibroblasts (CAFs) in the malignant phenotype of ESCC and probes the underpinning mechanism. Key CAF-associated proteins in ESCC were identified using bioinformatics analyses. ESCC cell lines were co-cultured with CAFs, followed by the addition of neutralizing antibodies against WNT family member 5A (WNT5A) (Anti-WNT5A; AW) and frizzled class receptor 5 (FZD5) (Anti-FZD5; AF), or a human recombinant protein of WNT5A (rWNT5A; rW). The effects of CAF stimulation and the neutralizing or recombinant proteins on the growth and dissemination of ESCC cells were investigated. In addition, ESCC cells were transplanted into nude mice for in vivo assessment of tumor growth and metastasis. WNT5A was identified as a CAF-associated protein linked to poor prognosis in ESCC. Co-culturing with CAFs augmented proliferation, mobility, and apoptosis resistance of ESCC cells. These effects were negated by the AW or AF but restored by rW. WNT5A interacted with FZD5 to activate the WNT signaling in ESCC cells. The rW treatment also enhanced tumorigenesis and metastasis of xenograft tumors in nude mice, with these effects diminished by AW or AF treatment. This study suggests that CAFs promote growth and dissemination of ESCC cell primarily through the secretion of WNT5A.

MicroRNAs (miRNAs) have emerged as promising tools for diagnosis and treatment in numerous pathophysiological processes, including cardiovascular diseases (CVD). In this context, acute myocardial infarction (AMI) is one of the leading causes of death by CVD worldwide. In this sense, physical exercise (PE) is considered a non-pharmacological strategy to reduce the complex alterations in AMI. This study is an integrative review of the literature to explore the effects of PE on the cardiomyocyte post-AMI, including an understanding of the mechanisms by which the PE acts on the miRNAs expression. A review was performed on PubMed, Scopus, and Web of Science. After the searches, all records were imported into the Mendeley software, and duplicate articles were removed. The year of publication of the papers was not limited. 19 studies were performed on animal models, 10 in experimental models using rats, and 08 in models with mice and only one study was carried out on patients with AMI. The results showed the potential use of miRNAs as diagnostic tools and attractive biomarkers for treating AMI. In addition, PE can regulate miRNAs expression in the myocardial cell, promotes apoptosis resistance, autophagy regulation, lower cardiac fibrosis and cardiac hypertrophy, and higher angiogenesis through the signaling of miRNAs. The main microRNAs mitigating the deleterious effects of AMI and modulated by PE were miRNA-222, miRNA-1192, miRNA-146, and miRNA-126. PE modulates the expression of specific miRNAs that support cardiac function, promoting cardioprotective effects or facilitating cardiac recovery post-AMI.

Studies have shown that decorin is a potent pan-cancer tumor suppressor that is under-expressed in most cancers. Decorin interacts with receptor tyrosine kinases and functions as a pan-receptor tyrosine kinase inhibitor, thereby suppressing oncogenic signals. Decorin deficiency promotes epithelial-to-mesenchymal transition and enhances cancer dissemination and metastasis. According to recent GLOBOCAN estimates, the most common cancers worldwide are breast, lung, prostate, colorectal, skin (non-melanoma), and stomach. Considering the burden of rising cancer incidence and the importance of discovering novel molecular markers and potential therapeutic agents for cancer management, we have outlined the possible expressional and clinicopathological significance of decorin in major cancers based on available pre-clinical and clinical studies. Measuring plasma decorin is a minimally invasive technique, and human studies have shown that it is useful in predicting clinical outcomes in cancer though it needs further validation. Oncolytic virus-mediated decorin gene transfer has shown significant anti-tumorigenic effects in pre-clinical studies, though its implication in human subjects is yet to be understood. Exogenous decorin delivery in experimental studies has been shown to mitigate cancer growth, but its therapeutic efficacy and safety are poorly understood. Future research is required to translate the tumor-suppressive action of decorin observed in preclinical experiments to therapeutic interventions in human subjects.

Cancer-associated fibroblasts (CAFs) secrete and synthesize fibroblast activation protein (FAP), which could promote proliferation and immunosuppression of multiple cancers including esophageal squamous cell carcinoma (ESCC). CXCL12/CXCR4 signaling could be revitalized by CAFs in cancer cells. Nevertheless, the significance of this interaction in ESCC has yet to be elucidated. Herein, we investigated whether FAP⁺ CAF cells could promote ESCC cells proliferation, migration and regulate immunity through the CXCL12/CXCR4 pathway in vitro and in vivo. The protein expression level of FSP1, FAP, CD8+ and Ki-67 in different sample was estimated by IHC and western blot. qPCR was used to quantify the mRNA level of FSP1, FAP, CD8+ and Ki-67 in different sample. The cell viability, proliferation, migration and invasion of different sample were evaluated by CCK-8, EdU staining, wound healing assay and Transwell assay, respectively. The ELISA was carried out to measure the protein level of IFN-γ, TNF-α, GZMB and IL-2. ESCC xenograft mice model was established to assess the impact of FAP+ CAF. FSP1, FAP, CD8+ and Ki-67 are greatly up-regulated in hESCC tissues. Through CXCL12/CXCR4 axis, FAP-positive CAF was capable of promoting the cell proliferation, migration and invasion of ESCC tumor cells and preventing the CD8+ T cells from secreting cytokine. Blocking this signaling with selective CXCR4 antagonist could counteract the effects caused by high-expression of FAP. FAP+ CAFs could inhibit the occurrence and development of tumors. These results indicated that FAP-positive CAF have an impact on cell proliferation migration and immunoregulation of ESCC through the CXCL12/CXCR4 axis.

Diabetic cardiomyopathy (DCM) is a cardiac complication specific to individuals with diabetes. It is defined as abnormalities of myocardial structure and function in diabetic patients who do not exhibit any obvious coronary artery disease, hypertensive heart disease, valvular heart disease, or inherited cardiomyopathy. A significant cardiovascular protective factor identified recently is angiotensin-converting enzyme 2 (ACE2), which is a rising star in the renin angiotensin system (RAS) and is responsible for the onset and progression of DCM. Nonetheless, there is not a comprehensive review outlining ACE2's effect on DCM. From the perspective of the pathogenesis of DCM, this review summarizes the myocardial protective role of ACE2 in the aspects of alleviating myocardial structure and dysfunction, correcting energy metabolism disorders, and restoring vascular function. Concurrently, we propose the connections between ACE2 and underlying signaling pathways, including ADAM17, Apelin/APJ, and Nrf2. Additionally, we highlight ACE2-related pharmaceutical treatment options and clinical application prospects for preventing and managing DCM. Further and underlying research is extensively required to completely comprehend the principal pathophysiological mechanism of DCM and the distinctive function of ACE2, switching experimental findings into clinical practice and identifying efficient therapeutic approaches.

Cancer evades therapy by multiple mechanisms, leading to uncontrolled cell growth and metastasis. Targeted therapies have shown promise in treating cancer by focusing on pathways within cancer cells. The PEAK family, comprising PEAK1 (SgK269), PEAK2 (SgK223/Pragmin), and the latest addition, PEAK3 (C19orf35), plays a crucial role in modulating cellular processes. Dysregulation and hyperactivity of these proteins, through overexpression or mutations, are associated with a wide range of cancers. This review delves into the different roles of the PEAK family members in regulating cell signaling pathways and highlights their potential in cancer therapy.

Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease worldwide, and its exact pathogenesis has not been fully studied. Hydrogen sulfide (H₂S) is the third gas signaling molecule discovered in mammals, following nitric oxide and carbon monoxide. It has the effects of anti-inflammation, anti-apoptosis, and so on, thereby playing an important role in many diseases. However, the role and mechanism of exogenous H₂S in NAFLD are not fully understood. In this study, we constructed in vitro and in vivo NAFLD models by feeding mice a high-fat diet and stimulating hepatocytes with palmitic acid, respectively, to investigate the improvement effect and mechanism of exogenous H₂S on NAFLD. The results showed that NaHS (a donor of H₂S) treatment alleviated lipid accumulation, inflammation, apoptosis and pyroptosis, and downregulated endoplasmic reticulum (ER) stress and nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NRRP3) inflammasome in NAFLD. The activation of NLRP3 inflammasome weakened NaHS improvement of NAFLD, indicating that exogenous H₂S ameliorated NAFLD by inhibiting NLRP3 inflammasome-mediated lipid synthesis, inflammation, apoptosis and pyroptosis. Similarly, the activation of ER stress weakened NaHS improvement of NAFLD and NaHS inhibition of NLRP3 inflammasome, indicating that exogenous H₂S suppressed NLRP3 inflammasome by downregulating ER stress, thus improving NAFLD. Additionally, the protein expressions of NLRP3 and cleaved caspase-1 were downregulated after inhibiting the reactive oxygen species (ROS)/extracellular signal-regulated kinases (ERK) and ROS/thioredoxin-interacting protein (TXNIP) pathways, indicating that ER stress activated NLRP3 inflammasome through the ROS/ERK and ROS/TXNIP pathways. In conclusion, our results indicated that exogenous H₂S inhibited NLRP3 inflammasome-mediated hepatocytes inflammation, lipid synthesis, apoptosis and pyroptosis by downregulating ER stress, thereby improving NAFLD; Furthermore, ER stress activated NLRP3 inflammasome through the ROS/ERK and ROS/TXNIP pathways in NAFLD. ER stress/NLRP3 inflammasome is expected to become a new target of H₂S for treating NAFLD.

Myotubularin-related protein 7 (MTMR7) represses proliferation in several cell types. However, the role of MTMR7 in pulmonary arterial smooth muscle cells (PASMCs) and pulmonary hypertension (PH) is unknown. The present study aimed to explore the role of MTMR7 in PH, as well as in the proliferation and migration of PASMCs. A monocrotaline (MCT)-induced PH mouse model was established. Mtmr7-transgenic (Mtmr7-Tg) mice and an adenovirus carrying the Mtmr7 vector (Ad-Mtmr7) were used to achieve MTMR7 overexpression in vivo and in vitro, respectively. Ultrasound and morphological analyses were used to evaluate the severity of PH. Cell counting kit-8 (CCK-8) and Ki-67 immunofluorescence staining were used to assess the proliferation of PASMCs. Wound-healing and transwell assays were used to assess cell migration. MTMR7 was upregulated in hypoxia-stimulated PASMCs and pulmonary arteries of MCT-treated mice. When compared with wild-type mice, PH-associated symptoms were significantly ameliorated in Mtmr7-Tg mice after MCT treatment when compared to wild-type mice. MTMR7 overexpression suppressed the proliferation and migration of PASMCs induced by hypoxia. Further experiments revealed that MTMR7 inhibited the phosphorylation levels of ERK1/2 and STAT3 both in vivo and in vitro. Restoring either ERK1/2 or STAT3 eliminated the protective role of MTMR7 against PH. Additionally, restoring ERK1/2 also reversed MTMR7-mediated STAT3 dephosphorylation. Our study highlights the inhibitory role of MTMR7 in PH and in the proliferation and migration of PASMCs and thus provides a novel potent therapeutic strategy for treating PH.

Myocardial ischemia/reperfusion (I/R) injury has high morbidity and mortality rates, posing a significant burden on society. There is an urgent need to understand its pathogenesis and develop effective treatments. Reactive oxygen species (ROS) are crucial for the development of myocardial I/R injury, and inhibiting ROS overproduction is one of the most critical ways to delay myocardial I/R injury. Sirtuins are a group of nicotinic adenine dinucleotide ( +)-dependent histone deacetylases whose members can regulate ROS by modulating various biological processes. Numerous studies have shown that Sirtuins play an essential role in the progression of myocardial I/R injury by regulating ROS. This study focuses on the relationship between myocardial I/R injury and ROS, Sirtuins and ROS, discusses the role of Sirtuins in regulating ROS in myocardial I/R, and summarizes the therapeutic modalities aimed at targeting Sirtuins to modulate ROS in myocardial I/R injury, thereby guiding future research endeavors.