Identification of A Novel Gene Signature Combining Ferroptosis- and Immunity-Related Genes for Prognostic Prediction, Immunotherapy and Potential Therapeutic Targets in Gastric Cancer.

Gastric cancer (GC) is one of the most prevalent cancers worldwide. Ferroptosis and the immune status of tumor tissue play vital roles in the initiation and progression of GC. However, the role and functional mechanisms of ferroptosis- and immunity-related genes (FIRGs) in GC pathogenesis and their correlations with GC prognosis have not been elucidated. We aim to establish a prognostic prediction model based on the FIRGs signature for GC patients. Differentially expressed genes were screened from the Cancer Genome Atlas (TCGA) GC cohorts. The least absolute shrinkage and selection operator (LASSO) regression was performed to establish a FIRGs-based risk model. This gene signature with 7 FIRGs was identified as an independent prognostic factor. A nomogram incorporating clinical parameters and the FIRG signature was constructed to individualize outcome predictions. Finally, we provided in vivo and in vitro evidence to verify the reliability of FIRG signature for GC prognosis, and validate the expression and function of FIRGs contributing to the development and progression of GC. Herein, our work represents great therapeutic and prognostic potentials for GC.

Mitochondrial-derived peptides in cardiovascular disease: Novel insights and therapeutic opportunities.

BACKGROUND: Mitochondria-derived peptides (MDPs) represent a recently discovered family of peptides encoded by short open reading frames (ORFs) found within mitochondrial genes. This group includes notable members including humanin (HN), mitochondrial ORF of the 12S rDNA type-c (MOTS-c), and small humanin-like peptides 1-6 (SHLP1-6). MDPs assume pivotal roles in the regulation of diverse cellular processes, encompassing apoptosis, inflammation, and oxidative stress, which are all essential for sustaining cellular viability and normal physiological functions. Their emerging significance extends beyond this, prompting a deeper exploration into their multifaceted roles and potential applications. AIM OF REVIEW: This review aims to comprehensively explore the biogenesis, various types, and diverse functions of MDPs. It seeks to elucidate the central roles and underlying mechanisms by which MDPs participate in the onset and development of cardiovascular diseases (CVDs), bridging the connections between cell apoptosis, inflammation, and oxidative stress. Furthermore, the review highlights recent advancements in clinical research related to the utilization of MDPs in CVD diagnosis and treatment. KEY SCIENTIFIC CONCEPTS OF REVIEW: MDPs levels are diminished with aging and in the presence of CVDs, rendering them potential new indicators for the diagnosis of CVDs. Also, MDPs may represent a novel and promising strategy for CVD therapy. In this review, we delve into the biogenesis, various types, and diverse functions of MDPs. We aim to shed light on the pivotal roles and the underlying mechanisms through which MDPs contribute to the onset and advancement of CVDs connecting cell apoptosis, inflammation, and oxidative stress. We also provide insights into the current advancements in clinical research related to the utilization of MDPs in the treatment of CVDs. This review may provide valuable information with MDPs for CVD diagnosis and treatment.

Aberrant hyper-expression of the RNA binding protein GIGYF2 in endothelial cells modulates vascular aging and function.

Vascular endothelial cells (ECs) senescence plays a crucial role in vascular aging that promotes the initiation and progression of cardiovascular disease. The mutation of Grb10-interacting GYF protein 2 (GIGYF2) is strongly associated with the pathogenesis of aging-related diseases, whereas its role in regulating ECs senescence and dysfunction still remains elusive. In this study, we found aberrant hyperexpression of GIGYF2 in senescent human ECs and aortas of old mice. Silencing GIGYF2 in senescent ECs suppressed eNOS-uncoupling, senescence, and endothelial dysfunction. Conversely, in nonsenescent cells, overexpressing GIGYF2 promoted eNOS-uncoupling, cellular senescence, endothelial dysfunction, and activation of the mTORC1-SK61 pathway, which were ablated by rapamycin or antioxidant N-Acetyl-l-cysteine (NAC). Transcriptome analysis revealed that staufen double-stranded RNA binding protein 1 (STAU1) is remarkably downregulated in the GIGYF2-depleted ECs. STAU1 depletion significantly attenuated GIGYF2-induced cellular senescence, dysfunction, and inflammation in young ECs. Furthermore, we disclosed that GIGYF2 acting as an RNA binding protein (RBP) enhances STAU1 mRNA stability, and that the intron region of the late endosomal/lysosomal adaptor MAPK and mTOR activator 4 (LAMTOR4) could bind to STAU1 protein to upregulate LAMTOR4 expression. Immunofluorescence staining showed that GIGYF2 overexpression promoted the translocation of mTORC1 to lysosome. In the mice model, GIGYF2flox/flox Cdh-Cre+ mice protected aged mice from aging-associated vascular endothelium-dependent relaxation and arterial stiffness. Our work discloses that GIGYF2 serving as an RBP enhances the mRNA stability of STAU1 that upregulates LAMTOR4 expression through binding with its intron region, which activates the mTORC1-S6K1 signaling via recruitment of mTORC1 to the lysosomal membrane, ultimately leading to ECs senescence, dysfunction, and vascular aging. Disrupting the GIGYF2-STAU1-mTORC1 signaling cascade may represent a promising therapeutic approach against vascular aging and aging-related cardiovascular diseases.

Arginase: Biological and Therapeutic Implications in Diabetes Mellitus and Its Complications.

Arginase is a ubiquitous enzyme in the urea cycle (UC) that hydrolyzes L-arginine to urea and L-ornithine. Two mammalian arginase isoforms, arginase1 (ARG1) and arginase2 (ARG2), play a vital role in the regulation of ß-cell functions, insulin resistance (IR), and vascular complications via modulating L-arginine metabolism, nitric oxide (NO) production, and inflammatory responses as well as oxidative stress. Basic and clinical studies reveal that abnormal alterations of arginase expression and activity are strongly associated with the onset and development of diabetes mellitus (DM) and its complications. As a result, targeting arginase may be a novel and promising approach for DM treatment. An increasing number of arginase inhibitors, including chemical and natural inhibitors, have been developed and shown to protect against the development of DM and its complications. In this review, we discuss the fundamental features of arginase. Next, the regulatory roles and underlying mechanisms of arginase in the pathogenesis and progression of DM and its complications are explored. Furthermore, we review the development and discuss the challenges of arginase inhibitors in treating DM and its related pathologies.

Arginase: shedding light on the mechanisms and opportunities in cardiovascular diseases.

Arginase, a binuclear manganese metalloenzyme in the urea, catalyzes the hydrolysis of L-arginine to urea and L-ornithine. Both isoforms, arginase 1 and arginase 2 perform significant roles in the regulation of cellular functions in cardiovascular system, such as senescence, apoptosis, proliferation, inflammation, and autophagy, via a variety of mechanisms, including regulating L-arginine metabolism and activating multiple signal pathways. Furthermore, abnormal arginase activity contributes to the initiation and progression of a variety of CVDs. Therefore, targeting arginase may be a novel and promising approach for CVDs treatment. In this review, we give a comprehensive overview of the physiological and biological roles of arginase in a variety of CVDs, revealing the underlying mechanisms of arginase mediating vascular and cardiac function, as well as shedding light on the novel and promising therapeutic approaches for CVDs therapy in individuals.

Arginase: An emerging and promising therapeutic target for cancer treatment.

Arginase is a key hydrolase in the urea cycle that hydrolyses L-arginine to urea and L-ornithine. Increasing number of studies in recent years demonstrate that two mammalian arginase isoforms, arginase 1 (ARG1) and arginase 2 (ARG2), were aberrantly upregulated in various types of cancers, and played crucial roles in the regulation of tumor growth and metastasis through various mechanisms such as regulating L-arginine metabolism, influencing tumor immune microenvironment, etc. Thus, arginase receives increasing focus as an attractive target for cancer therapy. In this review, we provide a comprehensive overview of the physiological and biological roles of arginase in a variety of cancers, and shed light on the underlying mechanisms of arginase mediating cancer cells growth and development, as well as summarize the recent clinical research advances of targeting arginase for cancer therapy.

Arginase 2 negatively regulates sorafenib-induced cell death by mediating ferroptosis in melanoma.

Ferroptosis, a newly defined and iron-dependent cell death, morphologically and biochemically differs from other cell deaths. Melanoma is a serious type of skin cancer, and the poor efficacy of current therapies causes a major increase in mortality. Sorafenib, a multiple kinase inhibitor, has been evaluated in clinical phase trials of melanoma patients, which shows modest efficacy. Emerging evidence has demonstrated that arginase 2 (Arg2), type 2 of arginase, is elevated in various types of cancers including melanoma. To investigate the role and underlying mechanism of Arg2 in sorafenib-induced ferroptosis in melanoma, reverse transcriptase-quantitative polymerase chain reaction, western blot analysis, adenovirus and lentivirus transduction, and in vivo tumor homograft model experiments were conducted. In this study, we show that sorafenib treatment leads to melanoma cell death and a decrease in Arg2 at both the mRNA and protein levels. Knockdown of Arg2 increases lipid peroxidation, which contributes to ferroptosis, and decreases the phosphorylation of Akt. In contrast, overexpression of Arg2 rescues sorafenib-induced ferroptosis, which is prevented by an Akt inhibitor. In addition, genetic and pharmacological suppression of Arg2 is able to ameliorate the anticancer activity of sorafenib in melanoma cells in vitro and in tumor homograft models. We also show that Arg2 suppresses ferroptosis by activating the Akt/GPX4 signaling pathway, negatively regulating sorafenib-induced cell death in melanoma cells. Our study not only uncovers a novel mechanism of ferroptosis in melanoma but also provides a new strategy for the clinical applications of sorafenib in melanoma treatment.