Cell death in atherosclerosis.

A complex and evolutionary process that involves the buildup of lipids in the arterial wall and the invasion of inflammatory cells results in atherosclerosis. Cell death is a fundamental biological process that is essential to the growth and dynamic equilibrium of all living things. Serious cell damage can cause a number of metabolic processes to stop, cell structure to be destroyed, or other irreversible changes that result in cell death. It is important to note that studies have shown that the two types of programmed cell death, apoptosis and autophagy, influence the onset and progression of atherosclerosis by controlling these cells. This could serve as a foundation for the creation of fresh atherosclerosis prevention and treatment strategies. Therefore, in this review, we summarized the molecular mechanisms of cell death, including apoptosis, pyroptosis, autophagy, necroptosis, ferroptosis and necrosis, and discussed their effects on endothelial cells, vascular smooth muscle cells and macrophages in the process of atherosclerosis, so as to provide reference for the next step to reveal the mechanism of atherosclerosis.

Emerging Therapeutic Approaches Targeting Ferroptosis in Cancer: Focus on Immunotherapy and Nanotechnology.

Ferroptosis is a newly discovered form of programmed cell death characterized by iron overload, ROS accumulation, and lipid peroxidation. It is distinguished by unique morphological, biochemical, and genetic features and stands apart from other known regulated cell death mechanisms. Studies have demonstrated a close association between ferroptosis and various cancers, including liver cancer, lung cancer, renal cell carcinoma, colorectal cancer, pancreatic cancer, and ovarian cancer. Inducing ferroptosis has shown promising results in inhibiting tumor growth and reversing tumor progression. However, the challenge lies in regulating ferroptosis in vivo due to the scarcity of potent compounds that can activate it. Integrating emerging biomedical discoveries and technological innovations with conventional therapies is imperative. Notably, considerable progress has been made in cancer treatment by leveraging immunotherapy and nanotechnology to trigger ferroptosis. This review explores the relationship between ferroptosis and emerging immunotherapies and nanotechnologies, along with their potential underlying mechanisms, offering valuable insights for developing novel cancer treatment strategies.

The Roles of Autophagy in the Genesis and Development of Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is a common and frequent disease and always leads endocrine and metabolic disorder among women in reproductive age. Ovary is the main organ involved in polycystic ovary syndrome, and its function impairment will lead to reproductive dysfunction. Some recent studies have demonstrated that autophagy plays an important role in the pathogenesis of PCOS, and there are many different mechanisms that affect autophagy and the occurrence of PCOS, and they provide a new direction for us to predict the mechanism of PCOS. In this review, we discuss the role of autophagy in different ovarian cells: granulosa cells, oocytes, and theca cells, and introduce the important role that they play in the progress of PCOS. The main purpose of this review is to provide the research background and some relevant suggestions for our future work in autophagy and help us better explore the pathogenesis and autophagy mechanisms of PCOS. Furthermore, it will help us gain a new insight of the pathophysiology and treatment of PCOS.

Androgen increases klotho expression via the androgen receptor-mediated pathway to induce GCs apoptosis.

BACKGROUND: Many epidemiological studies have shown that anovulatory polycystic ovary syndrome (PCOS) is accompanied by hyperandrogenism. However, the exact mechanism of hyperandrogen-induced anovulation remains to be elucidated. In this study, we aimed to investigate the potential mechanism of anovulation in PCOS. To investigate the role of klotho as a key factor in the androgen receptor (AR)-mediated development of PCOS, we investigated the effects of testosterone on ovarian klotho expression in vivo and in vitro. RESULTS: Testosterone propionate (TP)-induced rats showed cycle irregularity, hyperandrogenism, polycystic ovarian changes, dyslipidemia. However, inhibition of AR expression could relieve PCOS traits. We also found that AR and klotho showed relatively high expression in PCOS rat ovarian tissue and in TP-induced granulosa cells (GCs), which was inhibited by the addition of flutamide. TP-induced GCs apoptosis was suppressed by AR antagonist, as well as silencing klotho expression in human GCs. Chromatin immunoprecipitation assay demonstrated that AR indirectly binds to the klotho promoter. CONCLUSIONS: Our results demonstrated TP mediates the expression of klotho via androgen receptor and klotho alterations could be a reason for ovarian dysfunction in PCOS.

The Key Roles of Makorin RING Finger Protein 3 (MKRN3) During the Development of Pubertal Initiation and Central Precocious Puberty (CPP).

Puberty is initiated from the continuous and growing pulsatile secretion of gonadotropin-releasing hormone (GnRH) in the hypothalamus and then the activation of the hypothalamic-pituitary-gonadal (HPG) axis. Numerous factors involve pubertal initiation, whose abnormality may come from the dysfunction of these regulators. Makorin RING finger protein 3 (MKRN3) inhibits the secretion of GnRH and plays indispensable roles during the development of pubertal onset, and mutations of MKRN3 showed the commonest genetic cause of central precocious puberty (CPP). Recently, growing studies have revealed the functional mechanisms of MKRN3 in the pubertal initiation and the occurrence of CPP. In this review, we mainly summarized the research advances on the roles of MKRN3 in the development of pubertal onset and their underpinning mechanisms, contributing to a better understanding of the precise mechanisms of pubertal initiation and the pathogenesis of CPP.

Effect of CPP-related genes on GnRH secretion and Notch signaling pathway during puberty.

Puberty is a complex biological process of sexual development, influenced by genetic, metabolic-nutritional, environmental and socioeconomic factors, characterized by the development of secondary sexual characteristics, maturation of the gonads, leading to the acquisition of reproductive capacity. The onset of central precocious puberty (CPP) is mainly associated with the early activation of the hypothalamic-pituitary-gonadal (HPG) axis and increased secretion of gonadotropin-releasing hormone (GnRH), leading to increased pituitary secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and activation of gonadal function. Due to the expense and invasiveness of current diagnostic testing and drug therapies for CPP, it would be helpful to find serum and genetic markers to facilitate diagnosis. In this paper, we summarized the related factors that may affect the expression of GnRH1 gene and the secretion and action pathway of GnRH and related sex hormones, and found several potential targets, such as MKRN3, DLK1 and KISS1. Although, the specific mechanism still needs to be further studied, we would be encouraged if the insights from this review could provide new insights for future research and clinical diagnosis and treatment of CPP.

Role of Neurite Outgrowth Inhibitor B Receptor in hepatic steatosis.

Hepatic steatosis, characterized by excessive lipid accumulation, is one of the common liver diseases. Neurite Outgrowth Inhibitor B Receptor (NgBR) regulates the lipid metabolism, cholesterol efflux, and protein glycosylation. Recently, it has been demonstrated that NgBR deficiency leads to hepatic steatosis. In this review we summarize the current knowledge about the structure of NgBR, the role and molecular mechanism of NgBR in the occurrence and development of hepatic steatosis.

The regulatory role of NLRX1 in innate immunity and human disease.

Nucleotide binding and oligomerization domain (NOD)-like receptor (NLR) initially appeared in the public view as a cytoplasmic pathogen recognition receptor (PRR) that plays an important role in innate immunity. NLRX1 is currently the only NLR known to be located in mitochondria through a mechanism presumed to be associated with its special N-terminal domain, and it establishes a novel connection between mitochondrial function and disease pathophysiology. NLRX1 functions as a negative regulator of the body's inflammatory response. Concurrently, the role of NLRX1 in regulating mitochondrial autophagy and metabolism has also been confirmed. Based on accumulating evidence, NLRX1 is involved in the occurrence and development of various diseases, including autoimmune diseases and inflammatory diseases. Research on the roles of NLRX1 in cancer, nervous system diseases and metabolic diseases has also undergone qualitative advances. However, according to current research, the function of NLRX1 is controversial, and the opposite effect has even been observed. This new study suggests that this phenomenon may be related to the specific localization of NLRX1 in cells. To date, the biological function of NLRX1 has not been comprehensively explored, but studies have introduced some new directions. For example, some recent studies have shown that NLRX1 affects pyroptosis. In this review, we summarize existing research results on NLRX1, facilitating explorations of the potential mechanism of NLRX1 and the development of new treatment strategies.

MiR-26a-5p regulates proliferation, apoptosis, migration and invasion via inhibiting hydroxysteroid dehydrogenase like-2 in cervical cancer cell.

BACKGROUND: Evidences have indicated that miR-26a-5p regulates the malignant properties of various tumor cells. However, the influences of miR-26a-5p on proliferation, apoptosis and invasion are still vague in the cervical cancer (CC) cells. METHODS: The miRNA microarray and real-time quantitative PCR (RT-qPCR) analysis were utilized to detect the expression of miR-26a-5p in the patients with CC. Kaplan-Meier plotter was performed to evaluate the overall survival (OS) of the patients with CC. The CCK-8, flow cytometry, transwell and wound healing analyses were respectively used to analyze proliferation, migration and invasion in the CC cells. RT-qPCR, western blot and IHC analysis were executed to measure the expression of hydroxysteroid dehydrogenase like-2 (HSDL2) in the patients with CC. Bioinformatics and luciferase reporter assay were carried out to verify the relationship of miR-26a-5p and HSDL2. RESULTS: The expression of miR-26a-5p was downregulated and low expression of miR-26a-5p indicated a poor OS in patients with CC. Overexpression of miR-26a-5p significantly inhibited proliferation, migration and invasion, accelerated apoptosis in the Hela and C33A cells. The expression of HSDL2 was upregulated, and negatively correlated with miR-26a-5p in the patients with CC. HSDL2 was directly targeted by miR-26a-5p and rescue experiments displayed that HSDL2 partially abolished proliferation, apoptosis, migration, and invasion induced by miR-26a-5p in CC cells. CONCLUSIONS: MiR-26a-5p alleviated progression of CC by suppressing proliferation, migration and invasion, promoting apoptosis through downregulating HSDL2.

Identification of key genes associated with polycystic ovary syndrome (PCOS) and ovarian cancer using an integrated bioinformatics analysis.

BACKGROUND: Accumulating evidence suggests a strong association between polycystic ovary syndrome (PCOS) and ovarian cancer (OC), but the potential molecular mechanism remains unclear. In this study, we identified previously unrecognized genes that are significantly correlated with PCOS and OC via bioinformatics. MATERIALS AND METHODS: Multiple bioinformatic analyses, such as differential expression analysis, univariate Cox analysis, functional and pathway enrichment analysis, protein-protein interaction (PPI) network construction, survival analysis, and immune infiltration analysis, were utilized. We further evaluated the effect of OGN on FSHR expression via immunofluorescence. RESULTS: TCGA-OC, GSE140082 (for OC) and GSE34526 (for PCOS) datasets were downloaded. Twelve genes, including RNF144B, LPAR3, CRISPLD2, JCHAIN, OR7E14P, IL27RA, PTPRD, STAT1, NR4A1, OGN, GALNT6 and CXCL11, were identified as signature genes. Drug sensitivity analysis showed that OGN might represent a hub gene in the progression of PCOS and OC. Experimental analysis found that OGN could increase FSHR expression, indicating that OGN could regulate the hormonal response in PCOS and OC. Furthermore, correlation analysis indicated that OGN function might be closely related to m6A and ferroptosis. CONCLUSIONS: Our study identified a 12-gene signature that might be involved in the prognostic significance of OC. Furthermore, the hub gene OGN represent a significant gene involved in OC and PCOS progression by regulating the hormonal response.

Dendrobium nobile Lindl polysaccharides improve testicular spermatogenic function in streptozotocin-induced diabetic rats.

Dendrobium nobile Lindl polysaccharides (DNLP) exhibited various biological functions. This study aimed to investigate the protective effects of DNLP on testicular spermatogenic function in streptozotocin (STZ)-induced diabetic rats in comparison with metformin. The blood glucose level was significantly increased and the homeostatic model assessment for insulin resistance (HOMA-IR) aggravated markedly in diabetic rats. The weight of testis and epididymis, and the sperm number and motility were decreased in the diabetic rats. The pathologic changes occurred in the spermatogenic tubules along with the decreased number of spermatogenic cells, downregulated proliferating cell nuclear antigen (PCNA) and Sirtuin 1 (SIRT1) expression and increased cell apoptosis in the testes. Compared with the model group, DNLP and metformin treatment significantly decreased the level of blood glucose, improved the HOMA-IR, and increased the weight of testis and epididymis, as well as the sperm number and sperm motility. Furthermore, the pathologic changes in the spermatogenic tubules improved significantly with increased number of spermatogenic cells, the upregulation of PCNA and SIRT1 and suppression of cell apoptosis in the testes. Collectively, our study for the first time examined the effects of DNLP on the male reproductive system of STZ-induced diabetic rats, and indicated that DNLP was protective against diabetes mellitus-induced testis injury via increasing the proliferation, inhibiting cell apoptosis and upregulating SIRT1 expression in testicular spermatogenic cells.

Dietary Interventions: A Promising Treatment for Polycystic Ovary Syndrome.

BACKGROUND: Dietary interventions as a first-line treatment for patients with polycystic ovary syndrome (PCOS) have been evaluated, but the optimal diet has not been determined. Proper diet and the maintenance of adequate nutritional status are of great importance in the prevention of this disorder, and therapeutics and dietary habits play an important role in the recovery of patients with PCOS. SUMMARY: A range of dietary patterns have been shown to impact weight loss and insulin resistance (IR) and improve reproductive function, including the Mediterranean diet, the ketogenic diet, Dietary Approaches to Stop Hypertension, and other dietary patterns. Key Messages: Diets that can reduce rates of obesity and IR are beneficial to women with PCOS, the status of obesity and IR should be determined at the early stage of the disease, so as to develop individualized and sustainable dietary intervention. The long-term efficacy, safety, and health benefits of diet management in patients with PCOS need to be tested by further researches.

Recent insights into atherosclerotic plaque cell autophagy.

Cardiovascular and cerebrovascular diseases, such as coronary heart disease and stroke, caused by atherosclerosis have become the "number one killer", seriously endangering human health in developing and developed countries. Atherosclerosis mainly occurs in large and medium-sized arteries and involves intimal thickening, accumulation of foam cells, and formation of atheromatous plaques. Autophagy is a cellular catabolic process that has evolved to defend cells from the turnover of intracellular molecules. Autophagy is thought to play an important role in the development of plaques. This review focuses on studies on autophagy in cells involved in the formation of atherosclerotic plaques, such as monocytes, macrophages, endothelial cells, dendritic cells, and vascular smooth muscle cells, indicating that autophagy plays an important role in plaque development. We mainly discuss the roles of autophagy in these cells in maintaining the stability of atherosclerotic plaques, providing a reference for the next steps to unravel the mechanisms of atherogenesis.

Progress on the role of extrachromosomal DNA in tumor pathogenesis and evolution.

The amplification of oncogenes on extrachromosomal DNA (ecDNA) provides a new mechanism for cancer cells to adapt to the changes in the tumor microenvironment and accelerate tumor evolution. These extrachromosomal elements contain oncogenes, and their chromatin structures are more open than linear chromosomes and therefore have stronger oncogene transcriptional activity. ecDNA always contains enhancer elements, and genes on ecDNA can be reintegrated into the linear genome to regulate the selective expression of genes. ecDNA lacks centromeres, and the inheritance from the parent cell to the daughter cell is uneven. This non-Mendelian genetic mechanism results in the increase of tumor heterogeneity with daughter cells that can gain a competitive advantage through a large number of copies of oncogenes. ecDNA promotes tumor invasiveness and provides a mechanism for drug resistance associated with poorer survival outcomes. Recent studies have demonstrated that the overall proportion of ecDNA in tumors is approximately 40%. In this review, we summarize the current knowledge of ecDNA in the field of tumorigenesis and development.

The Role of the PI3K/AKT/mTOR Signalling Pathway in Male Reproduction.

Male fertility is closely related to the normal function of the hypothalamicpituitary- testicular axis. The testis is an important male reproductive organ that secretes androgen and produces sperm through spermatogenesis. Spermatogenesis refers to the process by which spermatogonial stem cells (SSCs) produce highly differentiated spermatozoa and is divided into three stages: mitosis, meiosis and spermiogenesis. Spermatogenesis requires SSCs to strike a proper balance between self-renewal and differentiation and the commitment of spermatocytes to meiosis, which involves many molecules and signalling pathways. Abnormal gene expression or signal transduction in the hypothalamus and pituitary, but particularly in the testis, may lead to spermatogenic disorders and male infertility. The phosphoinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signalling pathway is involved in many stages of male reproduction, including the regulation of the hypothalamus-pituitarygonad (HPG) axis during spermatogenesis, the proliferation and differentiation of spermatogonia and somatic cells, and the regulation of sperm autophagy and testicular endocrine function in the presence of environmental pollutants, particularly endocrinedisrupting chemicals (EDCs). In the PI3K/AKT/mTOR signalling pathway, mTOR is considered the central integrator of several signals, regulating metabolism, cell growth and proliferation. In particular, mTOR plays an important role in the maintenance and differentiation of SSCs, as well as in regulating the redox balance and metabolic activity of Sertoli cells, which play an important role in nutritional support during spermatogenesis.

Lnc-ATG9B-4 aggravates progress of hepatocellular carcinoma through cell proliferation and migration by upregulating CDK5.

Long noncoding RNAs play an important role in the occurrence, invasion, as well as metastasis of various human cancers, including hepatocellular carcinoma. Long noncoding RNAs can affect the biological functions of hepatocellular carcinoma cells by regulating various genes; however, only a small fraction of molecular mechanisms of long noncoding RNAs have been elucidated. In the present study, lnc AC010973.1 (lnc-ATG9B-4) was first identified by microarray analysis from 8 patients with hepatocellular carcinoma and confirmed by quantitative PCR in 176 patients with hepatocellular carcinoma. We demonstrated that lnc-ATG9B-4 was tightly relative to the tumorous size, TNM stages, portal vein tumor thrombus (PVTT), the tumor capsule, metastasis, degree of differentiation, and poor prognosis of hepatocellular carcinoma according to long-term follow-up data. In hepatocellular carcinoma cells, overexpression of lnc-ATG9B-4 promoted proliferation, invasion, as well as migration, while inhibiting lnc-ATG9B-4 by siRNA significantly attenuated the proliferation, invasion, as well as migration. Interestingly, lnc-ATG9B-4 increased the expression of cyclin-dependent kinase 5 (CDK5), which was closely related to the development and chemotherapy sensitivity of hepatocellular carcinoma. In summary, our results revealed that lnc-ATG9B-4 suggests an unfavorable prognosis of hepatocellular carcinoma and facilitates the proliferation, invasion, as well as migration of hepatocellular carcinoma cells by upregulating CDK5. This research suggests that lnc-ATG9B-4 may be a new biomarker for predicting the prognosis of hepatocellular carcinoma; meanwhile, targeting lnc-ATG9B-4 might serve as a potential strategy for the treatment hepatocellular carcinoma.

Multiple pathophysiological roles of midkine in human disease.

Midkine (MK) is a low molecular-weight protein that was first identified as the product of a retinoic acid-responsive gene involved in embryonic development. Recent studies have indicated that MK levels are related to various diseases, including cardiovascular disease (CVD), renal disease and autoimmune disease. MK is a growth factor involved in multiple pathophysiological processes, such as inflammation, the repair of damaged tissues and cancer. The pathophysiological roles of MK are diverse. MK enhances the recruitment and migration of inflammatory cells upon inflammation directly and also through induction of chemokines, and contributes to tissue damage. In lung endothelial cells, oxidative stress increased the expression of MK, which induced angiotensin-converting enzyme (ACE) expression and the consequent conversion from Ang I to Ang II, leading to further oxidative stress. MK inhibited cholesterol efflux from macrophages by reducing ATP-binding cassette transporter A1 (ABCA1) expression, which is involved in lipid metabolism, suggesting that MK is an important positive factor involved in inflammation, oxidative stress and lipid metabolism. Furthermore, MK can regulate the expansion, differentiation and activation of T cells as well as B-cell survival; mediate angiogenic and antibacterial activity; and possess anti-apoptotic activity. In this paper, we summarize the pathophysiological roles of MK in human disease.

Apelin/Apelin receptor: A new therapeutic target in Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is an endocrinopathy, and it accounts for 75% of non-ovulatory infertile in women of childbearing age. It is clear that obesity, insulin resistance, dyslipidaemia coexist in PCOS. Apelin, as an endogenous ligand of the previously orphan receptor, is an adipokine that secreted by adipose tissue. Apelin and apelin receptors are expressed in many tissues and organ to regulate their physiological functions. Studies have shown that Apelin/apelin-receptor also expressed in ovary such as follicles, granulosa cells. Furthermore, Apelin/apelin-receptor play roles in vascular establishment and hormone metabolism in ovary. These indicate that the Apelin/apelin-receptor play an important role in the development of follicle. Apelin/apelin-receptor are increased in ovary of PCOS, which are associated with abnormal ovarian hormones and function. These are important causes of menstrual cycle disorders and anovulation. Moreover, apelin now appears clearly as a new player in energy metabolism. Apelin can regulate glucose and lipid metabolism but also modulate insulin secretion. And plasma apelin concentrations are elevated in obesity and type 2 diabetes patients. Interestedly, obesity and type 2 diabetes are also companied with polycystic ovary syndrome patients. We speculate apelin/apelin-receptor may play a vital role in pathogenesis of polycystic ovary syndrome, but the underlying mechanisms remain under exploration. Here, we review apelin/apelin-receptor, as a new therapeutic target, have effects on ovarian function and energy metabolism in polycystic ovary syndrome.

Mechanisms of immune escape in the cancer immune cycle.

Cancer is a critical issue globally with high incidence and mortality, imposing great burden on the society. Although great progress has been made in immunotherapy based on immune checkpoint, only a subset of patients responds to this treatment, suggesting that cancer immune evasion is still a major barrier in current immunotherapy. There are a series of factors contributing to immune evasion despite in an immunocompetent environment. Given that these factors are involved in different steps of the cancer immune cycle. In this review, we discuss the mechanisms of immune escape in each step of the cancer immune cycle and then present therapeutic strategies for overcoming immune escape, with the potential to better understand the determinants of immune escape and make anti-tumor immunity more effective.

Lycium barbarum Polysaccharides Improve Testicular Spermatogenic Function in Streptozotocin-Induced Diabetic Rats.

The objective of this study was to investigate the protective effects of Lycium barbarum polysaccharides (LBP) on testicular spermatogenic function in streptozotocin (STZ)-induced diabetic rats. Compared to the control group, blood glucose levels were significantly increased and the insulin resistance was markedly aggravated in STZ-induced diabetic rats. Further, the weight of testis and epididymis and the sperm number and motility were decreased in diabetic rats. Pathological changes were also observed in the spermatogenic tubules, along with a decreased number of spermatogenic cells, downregulated proliferating cell nuclear antigen (PCNA) expression, and increased cell apoptosis in the testes. Compared to the saline-treated diabetic rat group, metformin and LBP treatment significantly decreased the level of blood glucose and improved insulin resistance and testicular function. After treatment with metformin and LBP, the pathological changes in the spermatogenic tubules improved significantly, with an increase in the number of spermatogenic cells, upregulation of PCNA, and suppression of apoptosis in the testes. The expressions of sirtuin 1 (SIRT1) and hypoxia-inducible factor 1-alpha (HIF-1α) in diabetic testes were also upregulated by metformin or LBP treatment. In summary, LBP exerted protective effects by increasing cell proliferation, inhibiting cell apoptosis, and regulating SIRT1/HIF-1α expression in the testes of diabetic rats.