Coronary Artery Disease And Melatonin: The Mechanisms and Therapeutic Applications.

Background: Delaying the formation of atherosclerosis and reducing cardiac ischemia-reperfusion injury remain pressing issues. Melatonin (MLT) possesses anti-inflammatory and antioxidant properties, rendering it a promising candidate for clinical application in coronary artery disease (CAD) patients. While numerous in vivo experiments have elucidated the regulatory mechanisms of MLT in animal models and clinical trials have preliminarily demonstrated the excellent therapeutic potential of MLT in CAD, several key questions remain unanswered. In this review, the authors elucidate the mechanisms underlying CAD's occurrence, progression, and prognosis; delineate the pathways through which MLT exerts its effects; and present compelling evidence supporting its efficacy in CAD. In addition, the authors also describe unresolved issues in the treatment of CAD with MLT, thus providing scholars with directions for future research.

Cytokine receptor-like factor 1 (CRLF1) promotes cardiac fibrosis via ERK1/2 signaling pathway. / ç»†èƒžå› å­å—ä½“æ ·å› å­1(CRLF1)通过ERK1/2信号通路促进心脏纤维化.

Cardiac fibrosis is a cause of morbidity and mortality in people with heart disease. Anti-fibrosis treatment is a significant therapy for heart disease, but there is still no thorough understanding of fibrotic mechanisms. This study was carried out to ascertain the functions of cytokine receptor-like factor 1 (CRLF1) in cardiac fibrosis and clarify its regulatory mechanisms. We found that CRLF1 was expressed predominantly in cardiac fibroblasts. Its expression was up-regulated not only in a mouse heart fibrotic model induced by myocardial infarction, but also in mouse and human cardiac fibroblasts provoked by transforming growth factor-|ß1 (TGF|-|ß1). Gain- and loss-of-function experiments of CRLF1 were carried out in neonatal mice cardiac fibroblasts (NMCFs) with or without TGF-|ß1 stimulation. CRLF1 overexpression increased cell viability, collagen production, cell proliferation capacity, and myofibroblast transformation of NMCFs with or without TGF|-|ß1 stimulation, while silencing of CRLF1 had the opposite effects. An inhibitor of the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway and different inhibitors of TGF-|ß1 signaling cascades, comprising mothers against decapentaplegic homolog (SMAD)|-dependent and SMAD-independent pathways, were applied to investigate the mechanisms involved. CRLF1 exerted its functions by activating the ERK1/2 signaling pathway. Furthermore, the SMAD-dependent pathway, not the SMAD-independent pathway, was responsible for CRLF1 up-regulation in NMCFs treated with TGF-|ß1. In summary, activation of the TGF-|ß1/SMAD signaling pathway in cardiac fibrosis increased CRLF1 expression. CRLF1 then aggravated cardiac fibrosis by activating the ERK1/2 signaling pathway. CRLF1 could become a novel potential target for intervention and remedy of cardiac fibrosis.

Insulin-Like Growth Factor 1 and Risk of Cardiovascular Disease: Results From the UK Biobank Cohort Study.

CONTEXT: Relationships between insulin-like growth factor 1 (IGF-1) levels and cardiovascular disease (CVD) in the general population remain unclear. OBJECTIVE: This study aims to investigate the association of circulating IGF-1 concentrations with CVD from a population-based cohort study. METHODS: A total of 394 082 participants without CVD and cancer at baseline from UK Biobank were included with measurements of serum IGF-1 at baseline. Main outcomes were incidence of CVD, including CVD mortality, coronary heart disease (CHD), myocardial infarction (MI), heart failure (HF), and stroke. RESULTS: Over a median 11.6 years of follow-up, UK Biobank documented 35 803 incident CVD cases, including 4231 from CVD-related death, 27 051 from CHD, 10 014 from MI, 7661 from HF, and 6802 from stroke. Dose-response analysis showed a U-shaped relationship between IGF-1 levels and cardiovascular events. Compared with the third quintile of IGF-1, the lowest category of IGF-1 was associated with increased risk of CVD (hazard ratio 1.128; 95% CI, 1.093 to 1.164), CVD mortality (1.294; 1.181 to 1.418), CHD (1.118; 1.078 to 1.159), MI (1.071; 1.008 to 1.139), HF (1.185; 1.107 to 1.268), and stroke (1.149, 1.070 to 1.235); also, the highest category was associated with increased risk of CVD (1.056; 1.020 to 1.094), CVD mortality (1.111; 1.000 to 1.236), CHD (1.070; 1.028 to 1.114), MI (1.111; 1.041 to 1.187) and HF (1.098; 1.015 to 1.188) after multivariable adjustment. CONCLUSION: This study indicates that both low and high levels of circulating IGF-1 are associated with increased risk of CVD in general population. These results highlight the importance of monitoring IGF-1 status on cardiovascular health.

Innovative color jet 3D printing of levetiracetam personalized paediatric preparations.

3D printing is a promising technology used in the fabrication of complex oral dosage delivery pharmaceuticals. This study first reports an innovative color jet 3D printing (CJ-3DP) technology to produce colorful cartoon levetiracetam pediatric preparations with high accuracy and reproducibility. For this study, the ideal printing ink consisted of 40% (v/v) isopropanol aqueous solution containing 0.05% (w/w) polyvinylpyrrolidone and 4% (w/w) glycerin, which was satisfied with scale-up of the production. The external and internal spatial structures of the tablets were designed to control the appearance and release, and cartoon tablets with admirable appearances and immediate release characteristics were printed. The dosage model showed a good linear relationship between the model volume and the tablet strength (r > 0.999), which proved the potential of personalized administration. The surface roughness indicated that the appearance of the CJ-3DP tablets was significantly better than the first listed 3D printed drug (SpritamⓇ). Moreover, the scanning electron microscopy and porosity results further showed that the tablets have a structure of loose interior and tight exterior, which could ensure good mechanical properties and rapid dispersion characteristics simultaneously. In conclusion, the innovative CJ-3DP technology can be used to fabricate personalized pediatric preparations for improved compliance. Due to the stable formulation and fabrication process, this technology has the potential in scale-up production.

Protective effects of dihydromyricetin on primary hippocampal astrocytes from cytotoxicity induced by comorbid diabetic neuropathic pain and depression.

Activated astrocytes play a key role in diabetic neuropathic pain and depression. We aimed to assess the protective effects of dihydromyricetin (DHM) on primary hippocampal astrocytes cultured with high glucose (HG), substance P (SP), and corticosterone (CORT). Culturing with HG + SP + CORT resulted in damage to primary hippocampal astrocytes, which simulates the clinical damage caused by comorbidity of diabetic neuropathic pain and depression. Western blot, qPCR, and immunofluorescence analyses revealed that HG + SP + CORT increased P2X7 receptor expression in primary hippocampal astrocytes, which was reversed by DHM treatment. Further, HG + SP + CORT elevated TNF-α, IL-1ß, free Ca2+, and ERK1/2 phosphorylation levels, which was inhibited by DHM or P2X7 shRNA treatment. Moreover, DHM significantly reduced the P2X7 agonist-activated currents in HEK293 cells transfected with the P2X7 receptor. These findings suggest that DHM can protect primary hippocampal astrocytes cultured with HG + SP + CORT from P2X7 receptor-mediated damage. Culturing cells with HG + SP + CORT might be a viable cell model for cellular injury exploration of diabetic comorbid pain and depression.

MicroRNA-96-5p Facilitates the Viability, Migration, and Invasion and Suppresses the Apoptosis of Cervical Cancer Cells byNegatively Modulating SFRP4.

PURPOSE: The current study was intended to research the functional role and regulatory mechanism of microRNA-96-5p in the progression of cervical cancer. METHODS: MicroRNA-96-5p expression in cervical cancer tissues was assessed by quantitative real-time polymerase chain reaction. The association between microRNA-96-5p expression and clinicopathological features of patients with cervical cancer was analyzed. MTT, flow cytometry, wound healing, and transwell assay were performed to evaluate the viability, apoptosis, migration, and invasion of Hela and SiHa cells. Targetscan, dual-luciferase reporter gene assay, and RNA pull-down analysis were constructed to evaluate the target relationship between microRNA-96-5p and secreted frizzled-related protein 4. RESULTS: MicroRNA-96-5p was overexpressed in cervical cancer tissues, and microRNA-96-5p expression was markedly associated with the clinical stage and lymph node metastasis of patients with cervical cancer. Overexpressed microRNA-96-5p facilitated the viability, migration, invasion, and inhibited the apoptosis of Hela and SiHa cells, whereas suppression of microRNA-96-5p exerted the opposite trend. Secreted frizzled-related protein 4 was proved to be a target of microRNA-96-5p. Silencing of secreted frizzled-related protein 4 eliminated the anti-tumor effect of microRNA-96-5p on cervical cancer cells. CONCLUSIONS: MicroRNA-96-5p facilitated the viability, migration, and invasion and inhibited the apoptosis of cervical cancer cells via negatively regulating secreted frizzled-related protein 4.

MicorRNA-148b inhibits cell proliferation and facilitates cell apoptosis by regulating DNA Methyltransferase 1 in endometrial cancer.

BACKGROUND: MicroRNA (miR)-148b has been shown to be dysregulated in a number of cancers; however, studies on the role of miR-148b in the gynaecologic malignancy endometrial cancer (EC) are rare. The purpose of this study was to explore the role of miR-148b in EC and the underlying molecular mechanism. METHODS: The expression levels of miR-148b and DNA methyltransferase 1 (DNMT1) were determined by quantitative real-time PCR (qRT-PCR) in both EC tissues and cell lines (HEC-1A and HEC-1B). These EC cell lines were then transfected with either an miR-148b inhibitor or miR-148b mimics, and cell proliferation, colony, and apoptosis and the cell cycle were measured by the cell counting kit-8, colony formation assay, and flow cytometry assays, respectively. In addition, the expression levels of p16, cyclin-dependent kinase 4 (CDK4), cyclin D1, caspase-3, B-cell lymphoma 2 (Bcl-2), and Bcl-2-associated X (Bax) were assessed by western blotting. Dual luciferase reporter and RNA pull-down assays were performed to investigate the target genes of miR-148b and validate their relationship. RESULTS: miR-148b expression was down-regulated in both EC tissues and HEC-1A and HEC-1B cells, whereas DNMT1 was highly expressed. Moreover, transfection of miR-148b mimics inhibited cell proliferation and cell cycle progression, but induced cell apoptosis. Western blotting showed that transfection of miR-148b mimics markedly increased caspase-3 and cyclin D1 expression, whereas transfection of miR-148b inhibitor dramatically decreased the expression of caspase-3 and cyclin D1. Importantly, we determined that DNMT1 is a target gene of miR-148b in EC cells, and silencing of DNMT1 reversed the effects of miR-148b inhibitor on cell proliferation, cell cycle progression, and apoptosis in EC. CONCLUSIONS: miR-148b inhibits cell proliferation and facilitates cell apoptosis in EC by regulating DNMT1.

Effects of L-carnitine on follicular survival and graft function following autotransplantation of cryopreserved-thawed ovarian tissues.

The aim of this study was to investigate the effects of L-carnitine (LC) on follicular survival and ovarian function following cryopreservation-thawing and autotransplantation of ovarian tissues. ICR mice were divided into three groups: control; saline group (cryopreservation+autograft+saline); and LC group (cryopreservation+autograft+L-carnitine). The ovarian tissues from control group, saline group, and LC group were histological assessed. There were no significant differences in the percentage of morphologically normal primordial follicles between the LC group and the saline group. After 28 days of autotransplantation, apoptosis rates, plasma malondialdehyde (MDA), progesterone (P4) and estradiol (E2) concentrations, and follicular densities of grafts were evaluated. Apoptosis rate and the concentration of MDA in the LC group were significantly lower than those in the saline group. The concentration of E2 and follicular densities of grafts in LC group were significantly higher than that in saline group. LC inhibits follicle apoptosis and increases follicular survival and function of ovarian graft.

Endoplasmic reticulum stress inhibition is a valid therapeutic strategy in vitrifying oocytes.

The aim of this study is to determine the link between oocyte cryopreservation and endoplasmic reticulum (ER) stress; whether ER stress inhibition improves the efficiency of oocyte vitrification is also explored. Oocytes from mice were exposure to tauroursodeoxycholic acid (TUDCA, an ER stress inhibitor) or TM (tunicamycin, an ER stress inducer) with or without vitrification. The expressions of X-box binding protein-1 (XBP-1) protein and caspase-12 protein, viability of vitrified-warmed oocytes, and their subsequent embryo competence were measured. The levels of XBP-1 protein and caspase-12 protein expression in vitrified-warmed oocytes were significantly higher than those of fresh control oocytes. TUDCA improved the viability of vitrified-warmed oocytes and their subsequent embryo competence. Mouse oocyte cryopreservation is associated with ER stress, and ER stress inhibition improves the efficiency of oocyte vitrification.