Ovarian cancer (OC) exhibits significant ethnic and geographic disparities, with rising incidence in Asia contrasting global declines. While non-modifiable risk factors (e.g., genetics) are well-established, evidence for the role of modifiable factors like physical activity remains inconsistent, especially in Asian populations. This study systematically evaluates the association between physical activity, sedentary behavior, and OC risk in Asia. We conducted a meta-analysis of seven studies (156,910 participants, 1,585 OC cases) from Japan, Korea, and China. Physical activity and sedentary behavior were assessed via self-reports. Meta-analysis was performed to pool RR estimates together with their 95

Parkinson's disease (PD) is a neurodegenerative disorder of the central nervous system (CNS) that predominantly affects middle-aged and elderly populations, characterized by the progressive loss of dopaminergic neurons in the substantia nigra and the abnormal aggregation of α-synuclein (α-Syn) as its core pathological features. Its pathogenesis is complex, and the crosstalk among genetic factors, microenvironmental factors and neuroinflammation has emerged as a central research focus at present. Triggering receptor expressed on myeloid cells 2 (TREM2), a key regulator of microglial function, is deeply implicated in the pathophysiological processes of PD by mediating multiple biological events, including phagocytic clearance, inflammatory homeostasis, autophagy regulation and neuronal repair. In recent years, Advances in genomics, cell biology and model animal technologies, the genetic association between TREM2 gene variants and PD, the regulatory role of the TREM2 signaling pathway in α-Syn pathological propagation, and its dual effects in neuroinflammation and dopaminergic neuron protection have been gradually elucidated. This review systematically summarizes the molecular structure and signal transduction mechanisms of TREM2, with a focus on elaborating the multidimensional roles of the TREM2 signaling pathway in the regulation of α-Syn metabolism, microglial polarization, dopaminergic neuron survival and non-motor symptoms in PD. We also conduct an in-depth analysis of the pathological significance of TREM2 gene variants and their interactive effects with microenvironmental factors, and discuss therapeutic strategies and research progress for PD targeting the TREM2 signaling pathway. Finally, we summarize the current research controversies and future directions, aiming to provide new insights into the mechanistic investigation and precision therapy of PD.

The role of endogenous hydrogen sulfide (H2S) in the pathophysiological mechanisms of various organ tumors has been extensively studied; however, its relevance to cervical cancer remains unexplored. This study aimed to examine the effect of endogenous H2S and its main synthetic enzyme, cystathionine-γ-lyase (CSE), in regulating the growth behavior in cervical cancer cells. The proliferation, migration, and invasion of C33A and HeLa cervical cancer cells were investigated, followed by molecular, biochemical, and immunocytochemical analyses. The results indicated that CSE is highly expressed in C33A and HeLa cells and modulates the levels of endogenous H2S. CSE knockdown suppressed the proliferation, migration, and invasion of cervical cancer cells. The CSE-mediated growth patterns involved epithelial-mesenchymal transition (EMT), mitochondrial apoptosis, pyroptosis, reactive oxygen species (ROS) production, and the PI3K/AKT/mTOR signaling pathway. Additionally, CSE knockdown inhibited the growth of xenograft tumors in vivo. Similarly, CSE overexpression was performed for reverse verification. In brief, inhibition of CSE reduced cervical cancer growth, while overexpression of CSE promoted it. These findings indicated that CSE may serve as a potential target for early diagnosis, prognosis assessment, and therapeutic intervention in cervical cancer.

Hepatocellular carcinoma (HCC) and colorectal cancer (CRC) are among the most common cancers across the world. Therefore, identifying the potential molecular mechanisms that promote HCC and CRC progression and metastasis are urgently needed. Spermidine/spermine N1-acetyltransferase (SSAT) is a catabolic enzyme that acetylates the high-order polyamines spermine and spermidine, thus decreasing the cellular content of polyamines. Several publications have suggested that depletion of intracellular polyamines inhibited tumor progression and metastasis in various cancer cells. However, whether and how SSAT regulates cell growth, migration and invasion in hepatocellular and colorectal carcinoma cells remains unclear. In this study, depletion of polyamines mediated by SSAT not only attenuated the tumor cell proliferation but also dramatically inhibited cell migration and invasion in hepatocellular and colorectal carcinoma cells. Subsequent investigations revealed introduction of SSAT into HepG2, SMMC7721 hepatocellular carcinoma cells and HCT116 colorectal carcinoma cells significantly suppressed p-AKT, p-GSK3β expression as well as β-catenin nuclear translocation, while inhibition of GSK3β activity or exogenous polyamines could restore SSAT-induced decreases in the protein expression of p-AKT, p-GSK3β and β-catenin. Conversely, knockdown of SSAT in Bel7402 hepatocellular carcinoma cells and HT-29 colorectal carcinoma cells which expressed high levels of SSAT endogenously significantly promoted the expression of p-AKT, p-GSK3β as well as β-catenin nuclear translocation. Taken together, our results indicated depletion of polyamines by SSAT significantly inhibited cell proliferation, migration and invasion through AKT/GSK3β/β-catenin signaling pathway in hepatocellular carcinoma and colorectal cancer cells.

Lysosome-dependent cell death (LCD) plays a significant role in overcoming cancer apoptosis and drug resistance. However, the relationship between LCD-associated genes (LCDGs) and glioma, including glioblastoma (GBM) and low-grade glioma (LGG), remains unclear. In this study, an LCDGs risk signature was constructed for glioma patients by utilizing 4 algorithms (Extreme Gradient Boosting, Support Vector Machine, Random Forest, and Generalized Linear Models) to identify core LCDGs. Their correlation with clinical features and the immune microenvironment was also determined in glioma, GBM, and LGG. Additionally, the role of hub LCDGs in various cancers was elucidated via pan-cancer analyses. Validation of the core gene in glioma was performed using qRT-qPCR and immunofluorescence staining analysis. The results showed that the LCDGs risk signature was strongly associated with the prognosis, cancer grades, histological types, and primary therapy outcomes of glioma patients. Furthermore, it was closely linked to the overall survival of LGG patients. Mechanistic analyses revealed a significant association between the risk signature and the immune microenvironment in glioma. Based on differential expression analysis, receiver operating characteristic analysis, and interacted model algorithms, LAPTM4A was identified as a hub LCDG in glioma. It exhibited significant upregulation in glioma, GBM, and LGG samples. Moreover, LAPTM4A expression correlated with the prognosis of glioma and LGG patients, as well as age, grades, histological types, and primary therapy outcomes in glioma. Pan-cancer analysis confirmed that LAPTM4A expression was modulated in the majority of cancers and was associated with the prognosis of various cancers. Mechanistic analyses suggested a strong relationship between LAPTM4A and immune cell infiltration, as well as several drug sensitivities. In conclusion, our findings suggest that LAPTM4A may serve as a potential oncogene associated with LCD in pan-cancer, particularly in glioma, GBM, and LGG. These findings provide important insights for individualized treatment of glioma.

AIM:To determine whether limb remote ischemic post-conditioning (LRIC) protects against high-intraocular-pressure (IOP)-induced retinal injury, and to identify underlying molecular mechanisms.METHODS:In mice, IOP was increased to 110 mm Hg for 50min and LRIC applied to the unilateral leg for three occlusion cycles (5min/release). Three animal groups (control, high IOP, and high IOP+LRIC) were arranged in this study. Plasma was collected from LRIC treated mice. Retinal histology, oxidative stress were determined by histological section staining and chemical kit. C/EBP homologous protein (CHOP), and Iba-1 parameters were evaluated by immunofluorescent staining and Western blot.RESULTS:The data showed that LRIC treatment alleviated the retinal histological disorganization and ganglion cell loss induced by high IOP. The CHOP, Iba-1 expression and oxidative stress marker also were inhibited by LRIC treatment. To further explore underlying mechanisms, plasma from LRIC treated animals was intravenously transfused into high-IOP animals. The results showed plasma injection decreased caspase 9 expression and DHE staining signals compared with that in high IOP retinas.CONCLUSION:These data suggest that LRIC treatments exert retinal protective effects against high-IOP injury. Endogenous humoral factors release into the circulation by LRIC may contribute to homeostatic protection by reducing monocyte infiltration and/or microglia activation.

With the growing diversity and complexity of diet, animals and humans are at risk of exposure to aflatoxin B1 (AFB1), which is a well-known contaminant in the food chain that causes various toxicological effects. The in-testine acts as the first barrier against external contaminants, but the effect of AFB1 on intestinal barrier has not been determined. This study aimed to evaluate AFB1 on the intestinal barrier function in vitro and in vivo. In vitro, porcine jejunal epithelial cells (IPEC-J2) were treated with increasing concentrations of AFB1 (10-60 mg/L). In vivo, Kunming (KM) mice were used as controls or gavaged with 1% dimethyl sulfoxide (110 mg/kg b.w.) and AFB1 (0.3 mg/kg b.w.) for 28 days. In IPEC-J2 cells, the cell viability decreased with increasing mycotoxin concentrations, and the viability of IPEC-J2 cells decreased significantly (P < 0.05) when the AFB1 concentra-tions were greater than 30 mg/L. In addition, quantitative real-time PCR, Western blot analysis, and immuno-fluorescence results show that AFB1 can downregulate the tight junction proteins and increase the expression levels of Caspase-3 and the ratio of Bax/Bcl-2, suggesting that AFB1 was cytotoxic to IPEC-J2. In vivo, the ratio of villus height to crypt depth, the intestinal wall thickness, the number of intestinal villus per 1000 mu m in the jejunum, the expression levels of ZO-1, Claudin-3, Occludin, MUC2, and Caspase-3, and the ratio of Bax/Bcl-2 were significantly affected in mice exposed to AFB1. In vitro and in vivo results showed that the effects of exposure to AFB1 on the intestinal function in the jejunum of KM mice and in the IPEC-J2 was similar, suggesting that AFB1 may adversely affect animal intestine.

Abstract Hibernation/torpor enables certain mammals to survive under extreme environmental conditions. However, pharmacological induction of hibernation-like or torpor state in most mammals remains a huge challenge. Here we show that a natural product P57 promptly induces hypothermia and decreases energy expenditure in rodents. Mechanistically, P57 inhibits the kinase activity of pyridoxal kinase (PDXK), a key metabolic enzyme of vitamin B6 catalyzing phosphorylation of pyridoxal (PL), resulting in the accumulation of PL in hypothalamus to cause hypothermia. The hypothermia induced by P57 is significantly recuperated in the mice with knockout of PDXK in medial preoptic area (MPA). We further found that P57 and PL have consistent effects on gene expression regulation in hypothalamus, and both directly activate MPA neurons to induce hypothermia. Taken together, our findings demonstrate that P57 has a potential application in therapeutic hypothermia through regulation of vitamin B6 metabolism and PDXK serves as a previously unknown target of P57 in thermoregulation. In addition, P57 may serve as a chemical probe for exploring the neuron circuitry related to hibernation-like state in rodents.

The retina, owing to its cellular anatomy and physical location, is susceptible to generating reactive oxygen species (ROS), which are associated with several major retinal diseases. When ROS exceeds the body’s natural antioxidants, the retina is in a state of oxidative stress, which is recognized as the pathogenesis of retinal diseases. The early stage of the pathogenic process is an adaptive change in which oxidative stress and endogenous defense mechanisms occur. If no treatment is applied, the retinal diseases will progress to the pathological stage with neuronal and vascular dysfunction or damage and even blindness. This review summarizes the role of oxidative stress in several common retinal diseases, including retinitis pigmentosa, age-related macular degeneration, diabetic retinopathy, glaucoma, and retinopathy of prematurity. In addition, we discuss the early intervention strategies for these diseases. An outline is provided to identify potential intervention targets for further research. Early intervention for retinal diseases is necessary and urgent and may offer hope to improve patients’ quality of life through functional vision.

Myocardial infarction (MI) is identified as the myocardial necrosis due to myocardial ischemia/reperfusion (I/R) injury and remains a leading cause of mortality. C1q/TNF-related protein 13 (CTRP13) is a member of CTRP family that has been found to be involved in coronary artery disease (CAD). However, the role of CTRP13 in MI remains unclear. We aimed to explore the functional role of CTRP13 in H9c2 cells exposed to hypoxia/reoxygenation (H/R). Our results demonstrated that H/R stimulation significantly decreased the expression of CTRP13 in H9c2 cells. H/R-induced an increase in ROS production and reductions in activities of SOD and CAT were prevented by CTRP13 overexpression but were aggravated by CTRP13 silencing. Moreover, CTRP13 overexpression could reverse the inductive effect of H/R on caspase-3 activity and bax expression, as well as the inhibitory effect of H/R on bcl-2 expression in H9c2 cells. However, CTRP13 silencing presented opposite effects with CTRP13 overexpression. Furthermore, CTRP13 overexpression enhanced the H/R-stimulated the expression levels of p-AMPK and nuclear Nrf2, and Nrf2 transcriptional activity. However, inhibition of AMPK reversed the CTRP13-mediated activation of Nrf2/ARE signaling and the cardiac-protective effect in H/R-exposed H9c2 cells. Additionally, silencing of Nrf2 reversed the protective effects of CTRP13 against H/R-stimulated oxidative stress and apoptosis in H9c2 cells. Finally, recombinant CTRP13 protein attenuated myocardial I/R-induced injury in rats. Taken together, these findings indicated that CTRP13 protected H9c2 cells from H/R-stimulated oxidative stress and apoptosis via regulating the AMPK/Nrf2/ARE signaling pathway. Our results provided evidence for the therapeutic potential of CTRP13 in myocardial I/R injury.

缺血处理(ischemic conditioning)是一种能够对重要器官/组织缺血损伤发挥保护作用的非药物干预措施,主要包括缺血预处理和后处理等,早在1986年被Murry等[1]首次发现.后来发展为远离重要目标器官/组织,间歇阻断远处相对比较耐受缺血的器官(如肢体等)的血供,进行缺血干预调节,被称为远程缺血处理(remote ischemic conditioning,RIC).

体外循环技术目前已广泛应用于心脏外科手术,低温缺血导致的心肌缺血再灌注损伤(MIRI)是影响术后心功能恢复的重要因素.该文介绍硫化氢(H2S)在MIRI中的作用和机制.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths. Peptide V3 has shown anti-angiogenic and anti-tumor effects on S180 and H22 xenografts in nude mice. However, the detailed mechanism of action of peptide V3 has not yet been fully elucidated. In the present study, the effects of peptide V3 on the growth of human HCC cells were examined both in vitro and in vivo. Our results showed that peptide V3 inhibited the proliferation, viability, migration, and invasion of human HCC cells. However, no obvious effect was observed in HL-7702 cells. Peptide V3 increased the apoptosis and decreased the protein levels of H-RAS, phospho (p)-RAF, p-MEK, and p-extracellular signal-regulated protein kinase (ERK) in human HCC cells. Peptide V3 suppressed the growth of human HCC xenografts by down-regulating angiogenesis and up-regulating apoptosis. In conclusion, peptide V3 could inhibit the growth of human HCC by inhibiting the Ras/Raf/MEK/ERK signaling pathway. Novel peptides and modification strategies could be designed and applied for the treatment of different types of cancer.

Autophagy can regulate cell growth, proliferation, and stability of cell environment. Its dysfunction can be involved in a variety of diseases. Hydrogen sulfide (H2S) is an important signaling molecule that regulates many physiological and pathological processes. Recent studies indicate that H2S plays an important protective role in many diseases through influencing autophagy, but its mechanism is not fully understood. This article reviewed the progress about the effect of H2S on autophagy in diseases in recent years in order to provide theoretical basis for the further research on the interaction of H2S and autophagy and the mechanisms involved.

Oxidative stress and blood-retinal barrier (BRB) damage induced by hyperglycemia are the principal processes involved in the early stages of diabetic retinopathy (DR). CXC chemokine receptor 3 (CXCR3)-mediated inflammatory infiltration exists in many disease models. The main objective of the present study was to determine whether AMG487, a CXCR3 antagonist, can ameliorate BRB disruption and reactive oxygen species generation in the DR model. The retinal endothelial cell and ganglion cell ultrastructures were observed using a transmission electron microscope. The pericyte marker PDGFR-β, tight junction occludin, and leaking albumin were evaluated. The oxidative stress level, CCAAT-enhancer-binding protein homologous protein (CHOP), and p-p38 expression were also investigated in vivo and in vitro. The results indicated that AMG487 application might alleviate PDGFR-β and occludin loss, and decreased the residual content of retinal albumin in the streptozocin-induced DR mouse model via the inhibition of oxidative and endoplasmic reticulum stress, in which p38 activation was also involved. Thus, CXCR3 inhibition might be a target to prevent the early stage of DR injury.

The aim of this study is to investigate whether exogenous hydrogen sulfide (H2S) could mitigate lipopolysaccharide (LPS) + Adenosine Triphosphate (ATP)-induced inflammation by inhibiting nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) inflammasome activation and promoting autophagy in L02 cells. We stimulated L02 cells with different concentrations of LPS, then the cell viability, cell apoptosis, and the protein level of NLRP3 inflammasome were detected by MTT and western blot to determine the appropriate LPS concentration used in this study. The cells were divided into 4 group: the cells in control group were cultured with RPMI-1640 for 23.5 h; the cells in LPS + ATP group were cultured with RPMI-1640 for 0.5 h, then were stimulated with 100 ng/ml LPS for 18 h followed by stimulation with 5 mM ATP for 5 h; the cells in Sodium hydrosulfide (NaHS) + LPS + ATP group were pretreated with NaHS for 0.5 h before exposure to LPS for 18 h and ATP for 5 h; the cells in NaHS group were treated with NaHS for 0.5 h, then were cultured with RPMI-1640 for 23 h. Subsequently, the cells in each group were collected, the protein levels of NLRP3, pro-caspase-1, cleaved caspase-1, P62, toll-like receptor 4 (TLR4), nuclear factor-kappa B (NF-κB), LC3, Beclin-1, and interleukin (IL)-1 beta (β) were detected by western blot and enzyme-linked immunosorbent assay. Our results showed that exogenous H2S reduced the protein levels of NLRP3, cleaved caspase-1, TLR4, NF-κB, P62, and IL-1β induced by LPS + ATP and increased the ratio of LC3-II/I and the protein levels of Beclin 1 suppressed by LPS + ATP. This study demonstrated that H2S might suppress LPS + ATP-induced inflammation by inhibiting NLRP3 inflammasome and promoting autophagy. In conclusion, H2S might have potential applications in the treatment of aseptic hepatitis.

Medullary thyroid cancer (MTC) is a relatively rare thyroid cancer responsible for a substantial fraction of thyroid cancer mortality. More effective therapeutic drugs with low toxicity for MTC are urgently needed. Orphan nuclear receptor 4A1 (NR4A1) plays a pivotal role in regulating the proliferation and apoptosis of a variety of tumor cells. Based on the NR4A1 protein structure, 2-imino-6-methoxy-2H-chromene-3-carbothioamide (IMCA) was identified from the Specs compounds database using the protein structure-guided virtual screening approach. Computationally-based molecular modeling studies suggested that IMCA has a high affinity for the ligand binding pocket of NR4A1. MTT [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide] and apoptosis assays demonstrated that IMCA resulted in significant thyroid cancer cell death. Immunofluorescence assays showed that IMCA induced NR4A1 translocation from the nucleus to the cytoplasm in thyroid cancer cell lines, which may be involved in the cell apoptotic process. In this study, the quantitative polymerase chain reaction results showed that the IMCA-induced upregulation of sestrin1 and sestrin2 was dose-dependent in thyroid cancer cell lines. Western blot showed that IMCA increased phosphorylation of adenosine 5′-monophosphate-activated protein kinase (AMPK) and decreased phosphorylation of ribosomal protein S6 kinase (p70S6K), which is the key enzyme in the mammalian target of rapamycin (mTOR) pathway. The experimental results suggest that IMCA is a drug candidate for MTC therapy and may work by increasing the nuclear export of NR4A1 to the cytoplasm and the tumor protein 53 (p53)-sestrins-AMPK-mTOR signaling pathway.

Vincristine is one of the most common anticancer drugs clinically employed in the treatment of various malignancies. A major side effect associated with vincristine is the development of neuropathic pain, which is not readily relieved by available analgesics. Although efforts have been made to identify the pathogenesis of vincristine-induced neuropathic pain, the mechanisms underlying its pathogenesis have not been fully elucidated. In the present study, a neuropathic pain model was established in Sprague-Dawley rats by intraperitoneal injection of vincristine sulfate. The results demonstrated that vincristine administration induced the upregulation of transient receptor potential cation channel subfamily V member 1 (TRPV1) protein expression and current density in dorsal root ganglion (DRG) nociceptive neurons. Consistently, inhibition of TRPV1 with capsazepine alleviated vincristine-induced mechanical allodynia and thermal hyperalgesia in rats. Furthermore, vincristine administration induced the upregulation of tumor necrosis factor (TNF)-α production in DRGs, and inhibition of TNF-α synthesis with thalidomide in vivo reversed TRPV1 protein expression, as well as pain hypersensitivity induced by vincristine in rats. The present results suggested that TNF-α could sensitize TRPV1 by promoting its expression, thus leading to mechanical allodynia and thermal hyperalgesia in vincristine-treated rats. Taken together, these findings may enhance our understanding of the pathophysiological mechanisms underlying vincristine-induced pain.

The mechanisms regarding the retinal protective and anti-inflammatory effects of capsaicin (CAP) remain unclear. Somatostatin is contained in CAP-sensitive sensory neurons, including nerve terminals, from which it can be released by capsaicin. The present study provides a novel neurohumoral regulatory mechanism for CAP-induced-endogenous somatostatin in a retinal ischaemia-reperfusion (I/R) mouse model. CAP (0.5 mg/kg) was injected subcutaneously 5 minutes after I/R. A selective somatostatin-depleting agent, cysteamine, was applied subcutaneously 4 hours before the experiment to examine the effects of endogenous somatostatin. Ischaemia and oxidative stress-induced inflammatory factors (CXCL10, CXCR3 and NF-κB p65) were also examined in the present study. The morphometric evaluation showed that the retinal thickness was increased 24 hours after I/R injury and attenuated 7 days after I/R injury. The number of ganglion cells was reduced 7 days after I/R injury. The application of CAP significantly prevented retinal I/R damage. Cysteamine pretreatment reversed the effects of CAP. Inhibition of CXCL10/CXCR3 and NF-κB (especially in astrocytes and microglia/macrophage) was involved in capsaicin-induced retinal protection through endogenous somatostatin. CAP has anti-inflammatory and neuroprotective effects in ischaemia-induced retinal injuries through endogenous somatostatin. Novel therapeutic remedies for inflammation or neuronal injuries were developed based on the systemic humoral effects related to CAP.

Occludin is a tight junction protein that forms the permeability barrier, which is typically disturbed in ischemic associated diseases. The aim of the present study was to determine whether somatostatin receptor 2 (SSTR2) in RF/6A cells is involved in the modulation of the downregulation of occludin induced by high glucose, and to evaluate the implicated molecules. RF/6A cells were maintained in Dulbecco's modified Eagle medium and treated with 0 or 30 mM D-glucose. SSTR2 agonist octreotide (OCT), OCT with SSTR2 antagonist cycle-somatostatin (c-SOM) and neuropilin 1 (NRP1) inhibitor ATWLPPR, respectively, were administered to RF/6A cells under high glucose conditions. Cell apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick-end labeling. Western blot analysis was used to detect the protein expression level of SSTR2, occludin, vascular endothelial growth factor (VEGF), protein kinase B (Akt), phosphorylated Akt (p-Akt), extracellular signal-related kinases (ERK) and p-ERK proteins. The amount of VEGF released was determined by ELISA. Notably, the level of occludin reduced significantly under high glucose conditions. The results indicated that the administration of OCT prevented the reduction of occludin induced by high glucose, and co-administration with c-SOM reversed the effect of OCT. Increased VEGF secretion and expression of VEGF, p-Akt and p-ERK in RF/6A cells induced by high glucose were inhibited by OCT. ATWLPPR also prevented the downregulation of occludin, but did not inhibit p-Akt and p-ERK levels under high glucose conditions. The current study concluded that the activation of SSTR2 prevents high glucose-induced occludin downregulation in RF/6A cells, and VEGF, NRP1, p-Akt and p-ERK were implicated in this process. The pharmacological effects of SSTR2 targeting to endothelium may be used to assess the role of resistance of permeability and anti-inflammation.