EZH2 G553C significantly increases the risk of brain metastasis from lung cancer due to salt bridge instability.

BACKGROUND: The incidence and mortality of lung cancer is the highest in China and the world. Brain is the most common distant metastasis site of lung cancer. Its transfer mechanism and predictive biomarkers are still unclear. EZH2 participates in the catalysis of transcriptional inhibition complex, mediates chromatin compactness, leads to the silencing of its downstream target genes, participates in the silencing of multiple tumor suppressor genes, and is related to cell proliferation, apoptosis and cycle regulation. In physiology, EZH2 has high activity in stem cells or progenitor cells, inhibits genes related to cell cycle arrest and promotes self-renewal. To detect the expression and mutation of EZH2 gene in patients with brain metastasis of lung cancer, and provide further theoretical basis for exploring the pathogenesis of brain metastasis of lung cancer and finding reliable biomarkers to predict brain metastasis of lung cancer. METHODS: This study investigated susceptible genes for brain metastasis of lung cancer. The second-generation sequencing technology was applied to screen the differential genes of paired samples (brain metastasis tissues, lung cancer tissues and adjacent tissues) of lung cancer patients with brain metastasi. RESULTS: It revealed that there was a significant difference in the G553C genotype of EZH2 between lung cancer brain metastasis tissues and lung cancer tissues (p = 0.045). The risk of lung cancer brain metastasis in G allele carriers was 2.124 times higher than that in C allele carriers. Immunohistochemistry showed that compared with lung cancer patients and lung cancer patients with brain metastasis, the expression level of EZH2 in lung cancer tissues of lung cancer patients was significantly higher than that in adjacent lung tissues (p < 0.0001), and higher than that in brain metastasis tissues (p = 0.0309). RNA in situ immunohybridization showed that EZH2 mRNA expression was gradually high in lung cancer adjacent tissues, lung cancer tissues and lung cancer brain metastasis tissues. CONCLUSIONS: EZH2 G553C polymorphism contributes to the prediction of brain metastasis of lung cancer, in which G allele carriers are more prone to brain metastasis.

Factors associated with antiretroviral treatment adherence among people living with HIV in Guangdong Province, China: a cross sectional analysis.

BACKGROUND: Understanding factors associated with antiretroviral treatment (ART) adherence is crucial for ART success among people living with HIV (PLHIV) in the "test and treat" era. Multiple psychosocial factors tend to coexist and have a syndemic effect on ART adherence. We aimed to explore factors associated with ART adherence and the syndemic effect of multiple psychosocial factors on ART adherence among PLHIV newly starting ART in Guangdong Province, China. METHODS: Newly diagnosed PLHIV from six cities in Guangdong Province were recruited between May 2018 and June 2019, and then followed up from May 2019 to August 2020. Baseline and follow-up data were collected from a questionnaire and the national HIV surveillance system, the follow-up data of which were analyzed in this study. A Center for Adherence Support Evaluation (CASE) index > 10 points was defined as optimal ART adherence, which was measured via participants' self-reported adherence during follow-up survey. Multivariable logistic regression was used to identify factors associated with ART adherence. Exploratory factor analysis (EFA) and multi-order latent variable structural equation modeling (SEM) were performed to explore the syndemic effect of multiple psychosocial factors on ART adherence. RESULTS: A total of 734 (68.53%) follow-up participants were finally included in this study among the 1071 baseline participants, of whom 91.28% (670/734) had self-reported optimal ART adherence. Unemployment (aOR = 1.75, 95%CI: 1.01-3.02), no medication reminder (aOR = 2.28, 95%CI: 1.09-4.74), low medication self-efficacy (aOR = 2.28, 95%CI: 1.27-4.10), low social cohesion (aOR = 1.82, 95%CI: 1.03-3.19), no social participation (aOR = 5.65, 95%CI: 1.71-18.63), and ART side effects (aOR = 0.46, 95%CI: 0.26-0.81) were barriers to optimal ART adherence. The EFA and second-order latent variable SEM showed a linear relationship (standardized coefficient = 0.43, P < 0.001) between ART adherence and the latent psychosocial (syndemic) factor, which consisted of the three latent factors of medication beliefs and self-efficacy (standardized coefficient = 0.65, P < 0.001), supportive environment (standardized coefficient = 0.50, P < 0.001), and negative emotions (standardized coefficient=-0.38, P < 0.01). The latent factors of medication beliefs and self-efficacy, supportive environment, and negative emotions explained 42.3%, 25.3%, and 14.1% of the variance in the latent psychosocial factor, respectively. CONCLUSIONS: About nine out of ten PLHIV on ART in Guangdong Province self-reported optimal ART adherence. However, more efforts should be made to address barriers to optimal ART adherence.

Selective deficiency of UCP-1 and adropin may lead to different subtypes of anti-neutrophil cytoplasmic antibody-associated vasculitis.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a systemic autoimmune disease that is prone to respiratory and renal failures. Its major target antigens are serine protease 3 (PR3) and myeloperoxidase (MPO), but the determinants of PR3 and MPO subtypes are still unclear. Uncoupling protein-1 (UCP-1) and adropin (Adr) regulate mutually and play an important role in endothelial cell injury. In this study, adropin and UCP-1 knockout (AdrKO and UCP-1-KO) models were established on the basis of C57BL/6 J mice. The results showed that UCP-1-KO and AdrKO mice similar to AAV: significant inflammatory cell infiltration, vascular wall damage, and erythrocyte extravasation. The pathological basis of AdrKO was that endothelial cells adhered and activated neutrophils to release MPO, and the core gene was peroxisome proliferator-activated receptor gamma (PPARG). However, UCP-1-KO induced PR3 release, and the accumulation and expression of tissue factor on the vascular wall, and the core gene was peroxisome proliferator-activated receptor delta (PPARD). The present study verified that the subtypes of AAV may be genetically different diseases and it also provide novel experimental evidence for clinical differentiation of the two subtypes.

Analysis of serum metabolome of laborers exposure to welding fume.

OBJECTIVE: Welding fume exposure is inevitable of welding workers and poses a severe hazard to their health since welding is a necessary industrial process. Thus, preclinical diagnostic symptoms of worker exposure are of great importance. The aim of this study was to screen serum differential metabolites of welding fume exposure based on UPLC-QTOF-MS/MS. METHODS: In 2019, 49 participants were recruited at a machinery manufacturing factory. The non-target metabolomics technique was used to clarify serum metabolic signatures in people exposed to welding fume. Differential metabolites were screened by OPLS-DA analysis and Student's t-test. The receiver operating characteristic curve evaluated the discriminatory power of differential metabolites. And the correlations between differential metabolites and metal concentrations in urine and whole blood were analyzed utilizing Pearson correlation analysis. RESULTS: Thirty metabolites were increased significantly, and 5 metabolites were decreased. The differential metabolites are mainly enriched in the metabolism of arachidonic acid, glycero phospholipid, linoleic acid, and thiamine. These results observed that lysophosphatidylcholine (20:1/0:0) and phosphatidylglycerol(PGF1α/16:0) had a tremendous anticipating power with relatively increased AUC values (AUC > 0.9), and they also presented a significant correlation of Mo concentrations in whole blood and Cu concentrations in urine, respectively. CONCLUSION: The serum metabolism was changed significantly after exposure to welding fume. Lysophosphatidylcholine (20:1/0:0) and phosphatidylglycerol (PGF1α/16:0) may be a potential biological mediator and biomarker for laborers exposure to welding fume.

Immune disguise: the mechanisms of Neu5Gc inducing autoimmune and transplant rejection.

Organ (stem cell) transplantation is the most effective treatment for advanced organ failure. Neu5Gc (N-hydroxyacetylneuraminic acid) is a pathogenic non-human sialic acid, which is very similar to the molecular structure of Neu5Ac (N-acetylneuraminic acid) in human body. Neu5Gc has the function of "immune disguise", which is the main obstacle to transplantation. Gene knockout such as cytidine monophosphate-N-acetylneuraminidase (CMAH) reduces donor antigenicity, making xenotransplantation from fiction to reality. Exploring the immune disguise event in this emerging field has become a hot topic in the research of transplantation immune tolerance mechanism.

Synthesis, biological evaluation, pharmacokinetic studies and molecular docking of 4'''-acetyl-delicaflavone as antitumor agents.

Structural modification of natural products is the effective option to improve their pharmacological effects and drug properties. DLF is a lead compound of antitumor drug, which is a broad-spectrum, low toxic and high-efficient component isolated from Selaginella doederleinii Hieron by our research group. Here, we report the structural modification method of this component, and find that the acetylated product of C4'''- OH (C4'''-acetyl-delicaflavone, 4'''ADLF) has better inhibitory effect on the selected cancer cell lines, including, lung, liver, colon and cervical cancer cell lines. Since the increased water solubility of 4'''ADLF may lead to higher absorption rate and activity, we evaluate the pharmacodynamics in vitro and in vivo, and the pharmacokinetic of 4'''ADLF. It shows that 4'''ADLF inhibit the proliferation and induce cycle arrest in tumor cells, and had better anticancer activity and bioavailability than DLF.

Limb-Bud and Heart (LBH) Upregulation in Cardiomyocytes under Hypoxia Promotes the Activation of Cardiac Fibroblasts via Exosome Secretion.

The activation of cardiac fibroblasts (CFs) after myocardial infarction (MI) is essential for post-MI infarct healing, during which the regulation of transforming growth factor beta1 (TGF-ß1) signaling is predominant. We have demonstrated that TGF-ß1-mediated upregulation of LBH contributes to post-MI CF activation via modulating αB-crystallin (CRYAB), after being upregulated by TGF-ß1. In this study, the effect of LBH-CRYAB signaling on the cardiac microenvironment via exosome communication and the corresponding mechanisms were investigated. The upregulation of LBH and CRYAB was verified in both cardiomyocytes (CMs) and CFs in hypoxic, post-MI peri-infarct tissues. CM-derived exosomes were isolated and identified, and LBH distribution was elevated in exosomes derived from LBH-upregulated CMs under hypoxia. Treatment with LBH+ exosomes promoted cellular proliferation, differentiation, and epithelial-mesenchymal transition-like processes in CFs. Additionally, in primary LBHKO CFs, western blotting showed that LBH knockout partially inhibited TGF-ß1-induced CF activation, while LBH-CRYAB signaling affected TGF-ß1 expression and secretion through a positive feedback loop. The administration of a Smad3 phosphorylation inhibitor to LBHKO CFs under TGF-ß1 stimulation indicated that Smad3 phosphorylation partially accounted for TGF-ß1-induced LBH upregulation. In conclusion, LBH upregulation in CMs in post-MI peri-infarct areas correlated with a hypoxic cardiac microenvironment and led to elevated exosomal LBH levels, promoting the activation of recipient CFs, which brings new insights into the studies and therapeutic strategies of post-MI cardiac repair.

Limb-bud and Heart (LBH) mediates proliferation, fibroblast-to-myofibroblast transition and EMT-like processes in cardiac fibroblasts.

Cardiac fibrosis is an important pathological change after myocardial infarction (MI). Its progression is essential for post-MI infarct healing, during which transforming growth factor beta1 (TGF-ß1) plays a critical role. Limb-bud and Heart (LBH), a newly discovered target gene of TGF-ß1, was shown to promote normal cardiogenesis. αB-crystallin (CRYAB), an LBH-interacting protein, was demonstrated to be involved in TGF-ß1-induced fibrosis. The roles and molecular mechanisms of LBH and CRYAB during cardiac fibrosis remain largely unexplored. In this study, we investigated the alterations of LBH and CRYAB expression in mouse cardiac tissue after MI. LBH and CRYAB were upregulated in activated cardiac fibroblasts (CFs), while in vitro TGF-ß1 stimulation induced the upregulation of LBH, CRYAB, and fibrogenic genes in primary CFs of neonatal rats. The results of the ectopic expression of LBH proved that LBH accelerated CF proliferation under hypoxia, mediated the expression of CRYAB and fibrogenic genes, and promoted epithelial-mesenchymal transition (EMT)-like processes in rat CFs, while subsequent CRYAB silencing reversed the effects induced by elevated LBH expression. We also verified the protein-protein interaction (PPI) between LBH and CRYAB in fibroblasts. In summary, our work demonstrated that LBH promotes the proliferation of CFs, mediates TGF-ß1-induced fibroblast-to-myofibroblast transition and EMT-like processes through CRYAB upregulation, jointly functioning in post-MI infarct healing. These findings suggest that LBH could be a promising potential target for the study of cardiac repair and cardiac fibrosis.

Upregulated lnc-HZ02 and miR-hz02 inhibited migration and invasion by downregulating the FAK/SRC/PI3K/AKT pathway in BPDE-treated trophoblast cells.

BPDE (benzo(a)pyren-7,8-dihydrodiol-9,10-epoxide), a metabolite of environmental carcinogenic BaP, weakens the migration and invasion of human villous trophoblast cells and may further induce miscarriage. However, the underlying mechanisms remain largely unknown. In this study, we identified that in trophoblast Swan 71 and HTR-8/SVneo cells, miR-hz02 upregulates the level of lnc-HZ02, which inhibits the expression of an RNA-binding protein HuR. HuR could interact with FAK mRNA and promote its mRNA stability, thus upregulating the FAK level and the FAK/SRC/PI3K/AKT pathway, and finally maintaining the normal migration and invasion of trophoblast cells. If trophoblast cells are exposed to BPDE, both miR-hz02 and lnc-HZ02 are upregulated, which reduce the level of HuR, weaken the interactions of HuR with FAK mRNA, downregulate FAK level and the FAK/SRC/PI3K/AKT pathway, and finally inhibit cell migration and invasion. This study provides a novel scientific understanding of the dysfunctions of human trophoblast cells.

Timing considerations for removal of early cumulus cells in short-term insemination strategies.

Context The timing of early cumulus cell removal (ECCR) can be changed within a range. The change has an effect on the multiple pronuclei (MPN) rate and the exposure time of oocytes to sperm waste products. The timing of ECCR effects the outcomes of assisted reproductive technology, however, it is still unclear what time is best for ECCR. Aims To find the best time for ECCR based on clinical outcomes in order to increase the success rate of assisted reproductive technology. Methods A retrospective study was performed. Cycles were categorised into six groups according to the timing of ECCR. The clinical outcomes of these six groups were compared by Kruskal-Wallis test and Pearson X 2 test. Key results The timing of ECCR had a significant effect on the MPN rate, 0PN without cleavage rate and grade 1-2 embryo rate at Day3. Among our six time groups of ECCR, the cumulus cell removal ≤4h post-insemination group had the highest MPN rate and grade 1-2 embryo rate at Day3, and the 5.5h

Platelet Antibodies in Infertility Patients.

BACKGROUND: Platelet antigens can stimulate the body to produce platelet alloimmune antibodies through blood transfusion, pregnancy, and autoimmunity. In the blood of pregnant women, anti-platelet antibodies can cause embryo implantation failure, abortion, etc. if they are present. METHODS: The platelet antibody was screened in 326 infertile patients (282 primary infertility and 44 secondary infertility) and 522 healthy controls in the physical examination center of our hospital by solid phase agglutination of red blood cells. RESULTS: The positive rate of anti-platelet antibody was 9.51% in the infertility group and 2.30% in the healthy control group. There was a significant difference between them (χ2 = 4.51, p < 0.05). The positive rate of anti-platelet antibody in the infertility group was significantly higher than that in the control group. The positive rate of anti-platelet antibody in the secondary infertility patients was significantly higher than that in the primary infertility patients (χ2 = 1.62, p < 0.05), and the positive rate of serum anti-platelet antibody increased gradually with the increase of infertility years. CONCLUSIONS: The positive rate of anti-platelet antibody is closely related to infertility and gradually increases with the age of infertility.

Effects of Environmental Endocrine-Disrupting Chemicals on Female Reproductive Health.

Environmental endocrine-disrupting chemicals (EDCs) are xenobiotic compounds that are frequently contacted in daily life. With the species and quantity of substances created and utilized by human beings significantly surpassing the self-purification capacity of nature, a large number of hazardous substances are enriched in the human body through the respiratory tract, digestive tract, and skin. Some of these compounds cause many problems endangering female reproductive health by simulating/antagonizing endogenous hormones or affecting the synthesis, metabolism, and bioavailability of endogenous hormones, including reproductive disorders, fetal birth defects, fetal developmental abnormalities, endocrine and metabolic disorders, and even gynecological malignancies. Therefore, the study of the relationship between environmental EDCs and female reproductive diseases and related mechanisms is of considerable significance to women, children health care, and improve the quality of the population.

Tissue-specific splicing of a ubiquitously expressed transcription factor is essential for muscle differentiation.

Alternate splicing contributes extensively to cellular complexity by generating protein isoforms with divergent functions. However, the role of alternate isoforms in development remains poorly understood. Mef2 transcription factors are essential transducers of cell signaling that modulate differentiation of many cell types. Among Mef2 family members, Mef2D is unique, as it undergoes tissue-specific splicing to generate a muscle-specific isoform. Since the ubiquitously expressed (Mef2Dα1) and muscle-specific (Mef2Dα2) isoforms of Mef2D are both expressed in muscle, we examined the relative contribution of each Mef2D isoform to differentiation. Using both in vitro and in vivo models, we demonstrate that Mef2D isoforms act antagonistically to modulate differentiation. While chromatin immunoprecipitation (ChIP) sequencing analysis shows that the Mef2D isoforms bind an overlapping set of genes, only Mef2Dα2 activates late muscle transcription. Mechanistically, the differential ability of Mef2D isoforms to activate transcription depends on their susceptibility to phosphorylation by protein kinase A (PKA). Phosphorylation of Mef2Dα1 by PKA provokes its association with corepressors. Conversely, exon switching allows Mef2Dα2 to escape this inhibitory phosphorylation, permitting recruitment of Ash2L for transactivation of muscle genes. Thus, our results reveal a novel mechanism in which a tissue-specific alternate splicing event has evolved that permits a ubiquitously expressed transcription factor to escape inhibitory signaling for temporal regulation of gene expression.

GNAI1 and GNAI3 Reduce Colitis-Associated Tumorigenesis in Mice by Blocking IL6 Signaling and Down-regulating Expression of GNAI2.

BACKGROUND & AIMS: Interleukin 6 (IL6) and tumor necrosis factor contribute to the development of colitis-associated cancer (CAC). We investigated these signaling pathways and the involvement of G protein subunit alpha i1 (GNAI1), GNAI2, and GNAI3 in the development of CAC in mice and humans. METHODS: B6;129 wild-type (control) or mice with disruption of Gnai1, Gnai2, and/or Gnai3 or conditional disruption of Gnai2 in CD11c+ or epithelial cells were given dextran sulfate sodium (DSS) to induce colitis followed by azoxymethane (AOM) to induce carcinogenesis; some mice were given an antibody against IL6. Feces were collected from mice, and the compositions of microbiomes were analyzed by polymerase chain reactions. Dendritic cells (DCs) and myeloid-derived suppressor cells (MDSCs) isolated from spleen and colon tissues were analyzed by flow cytometry. We performed immunoprecipitation and immunoblot analyses of colon tumor tissues, MDSCs, and mouse embryonic fibroblasts to study the expression levels of GNAI1, GNAI2, and GNAI3 and the interactions of GNAI1 and GNAI3 with proteins in the IL6 signaling pathway. We analyzed the expression of Gnai2 messenger RNA by CD11c+ cells in the colonic lamina propria by PrimeFlow, expression of IL6 in DCs by flow cytometry, and secretion of cytokines in sera and colon tissues by enzyme-linked immunosorbent assay. We obtained colon tumor and matched nontumor tissues from 83 patients with colorectal cancer having surgery in China and 35 patients with CAC in the United States. Mouse and human colon tissues were analyzed by histology, immunoblot, immunohistochemistry, and/or RNA-sequencing analyses. RESULTS: GNAI1 and GNAI3 (GNAI1;3) double-knockout (DKO) mice developed more severe colitis after administration of DSS and significantly more colonic tumors than control mice after administration of AOM plus DSS. Development of increased tumors in DKO mice was not associated with changes in fecal microbiomes but was associated with activation of nuclear factor (NF) κB and signal transducer and activator of transcription (STAT) 3; increased levels of GNAI2, nitric oxide synthase 2, and IL6; increased numbers of CD4+ DCs and MDSCs; and decreased numbers of CD8+ DCs. IL6 was mainly produced by CD4+/CD11b+, but not CD8+, DCs in DKO mice. Injection of DKO mice with a blocking antibody against IL6 reduced the expansion of MDSCs and the number of tumors that developed after CAC induction. Incubation of MDSCs or mouse embryonic fibroblasts with IL6 induced activation of either NF-κB by a JAK2-TRAF6-TAK1-CHUK/IKKB signaling pathway or STAT3 by JAK2. This activation resulted in expression of GNAI2, IL6 signal transducer (IL6ST, also called GP130) and nitric oxide synthase 2, and expansion of MDSCs; the expression levels of these proteins and expansion of MDSCs were further increased by the absence of GNAI1;3 in cells and mice. Conditional disruption of Gnai2 in CD11c+ cells of DKO mice prevented activation of NF-κB and STAT3 and changes in numbers of DCs and MDSCs. Colon tumor tissues from patients with CAC had reduced levels of GNAI1 and GNAI3 and increased levels of GNAI2 compared with normal tissues. Further analysis of a public human colorectal tumor DNA microarray database (GSE39582) showed that low Gani1 and Gnai3 messenger RNA expression and high Gnai2 messenger RNA expression were significantly associated with decreased relapse-free survival. CONCLUSIONS: GNAI1;3 suppresses DSS-plus-AOM-induced colon tumor development in mice, whereas expression of GNAI2 in CD11c+ cells and IL6 in CD4+/CD11b+ DCs appears to promote these effects. Strategies to induce GNAI1;3, or block GNAI2 and IL6, might be developed for the prevention or therapy of CAC in patients.

Gut microbe-derived metabolite trimethylamine N-oxide induces cardiac hypertrophy and fibrosis.

Trimethylamine N-oxide (TMAO), a gut microbe-derived metabolite of dietary choline and other trimethylamine-containing nutrients, has been linked to increased cardiovascular disease risk. It is unknown whether TMAO plays a role in the development of cardiac hypertrophy. Transverse aortic constriction (TAC) was performed to induce cardiac hypertrophy in Sprague-Dawley (SD) rats. We observed that TMAO levels were significantly elevated in SD rats after 6 weeks of TAC, suggesting the potential role of TMAO in regulating cardiac hypertrophy. In cultured cardiomyocytes, TMAO treatment stimulated cardiac hypertrophy, as indicated by increased cell area of cardiomyocytes and expression of hypertrophic markers including atrial natriuretic peptide (ANP) and beta-myosin heavy chain (ß-MHC). Additionally, TMAO treatment induced cardiac hypertrophy and cardiac fibrosis in SD rats. Reducing TMAO synthesis by antibiotics (Abs) attenuated TAC-induced cardiac hypertrophy and fibrosis. Furthermore, pharmacological inhibition of Smad3 by SIS3 significantly reduced the expression of ANP and ß-MHC, and cardiomyocyte cell size in TMAO-treated group. These data for the first time demonstrate that gut microbe-derived metabolite TMAO induces cardiac hypertrophy and fibrosis involving Smad3 signaling, suggesting that inhibition of gut microbes or generation of TMAO may become a potential target for the prevention and treatment of cardiac hypertrophy.

PRSS1 mutation: a possible pathomechanism of pancreatic carcinogenesis and pancreatic cancer.

BACKGROUND: Previous studies revealed somatic mutations of the cationic trypsinogen gene (PRSS1) in patients with chronic pancreatitis and pancreatic cancer. However, whether PRSS1 mutations trigger pancreatic cancer and/or promote malignant proliferation and metastasis in pancreatic cancer remains largely unclear, as well as the potential underlying mechanisms. METHODS: In the present study, whole-exome sequencing was applied for screening, and the R116C mutation was validated by Sanger sequencing. Phosphorylation antibody array, RNA-Seq, and RT-qPCR were adopted to screen and validate that R116C mutation promoted pancreatic cancer progression via the JAK1-STAT5 pathway. RESULTS: It showed that migration and invasion were significantly increased in R116C-bearing PANC-1 cells compared with wild type counterparts. In a transgenic mouse model of iZEG-PRSS1_R116C, primary pancreatic intraepithelial neoplasia (PanINs) was observed in the pancreatic duct. CONCLUSIONS: These findings suggested a novel pathway mediating pancreatic cancer development, with PRSS1 mutation and overexpression playing an "inside job" role in pancreatic carcinogenesis and tumor development.

A Promising Therapeutic Target for Metabolic Diseases: Neuropeptide Y Receptors in Humans.

Human neuropeptide Y (hNPY) is one of the most widely expressed neurotransmitters in the human central and peripheral nervous systems. It consists of 36 highly conserved amino acid residues, and was first isolated from the porcine hypothalamus in 1982. While it is the most recently discovered member of the pancreatic polypeptide family (which includes neuropeptide Y, gut-derived hormone peptide YY, and pancreatic polypeptide), NPY is the most abundant peptide found in the mammalian brain. In order to exert particular functions, NPY needs to bind to the NPY receptor to activate specific signaling pathways. NPY receptors belong to the class A or rhodopsin-like G-protein coupled receptor (GPCR) family and signal via cell-surface receptors. By binding to GPCRs, NPY plays a crucial role in various biological processes, including cortical excitability, stress response, food intake, circadian rhythms, and cardiovascular function. Abnormal regulation of NPY is involved in the development of a wide range of diseases, including obesity, hypertension, atherosclerosis, epilepsy, metabolic disorders, and many cancers. Thus far, five receptors have been cloned from mammals (Y1, Y2, Y4, Y5, and y6), but only four of these (hY1, hY2, hY4, and hY5) are functional in humans. In this review, we summarize the structural characteristics of human NPY receptors and their role in metabolic diseases.

Three-phase solvent bar liquid-phase microextraction combined with high-performance liquid chromatography to determine sarcosine in human urine.

Sarcosine is a potential prostate cancer marker. In this study, we developed a method of three-phase solvent bar liquid-phase microextraction combined with high-performance liquid chromatography to determine sarcosine after derivatization with 4-dimethylarminoazobenzene-4-sulfonyl chloride from human urine. The effects of different extraction conditions on extraction efficiency were investigated and optimized. Under optimum experimental conditions, a calibration graph exhibited linearity over the range of 0.05-25 µmol/L with a correlation coefficient (r2 ) of 0.9990. The enrichment factor was 168, and the detection limit was 0.02 µmol/L. The method was successfully used to analyze sarcosine in human urine and non-invasive detection, and good spiked recoveries ranging from 90.5 to 93.6% were obtained. The proposed method exhibited high sensitivity, high enrichment factor, good precision, and a simple setup. It may contribute to the early accurate diagnosis and the progression monitoring of prostatic carcinoma.

Resveratrol Ameliorates Cardiac Dysfunction by Inhibiting Apoptosis via the PI3K/Akt/FoxO3a Pathway in a Rat Model of Diabetic Cardiomyopathy.

The aim of this study was to explore the effect and mechanism of action of resveratrol (RSV) on cardiac function in diabetic cardiomyopathy (DCM). Hyperglycemia-induced apoptosis contributes to the pathogenic changes in DCM. RSV treatment inhibited high glucose-induced apoptosis of neonatal rat ventricular myocytes. Additionally, high glucose decreased cell viability, prevented serine-threonine kinase (Akt) and FoxO3a phosphorylation, and suppressed cytoplasmic translocation of FoxO3a. However, these effects of apoptosis were reversed by 10 µM of RSV. The PI3K inhibitor LY294002 abolished the RSV protective effect in vitro. RSV (5 or 50 mg·kg·d orally for 8 weeks) prevented the deterioration of cardiac function and structural cardiomyopathy in a streptozotocin-induced rat model of diabetes and reduced apoptosis in diabetic myocardium. Furthermore, it restored streptozotocin-impaired phosphorylation of Akt and FoxO3a (p-Akt and p-FoxO3a) and suppressed nuclear translocation of FoxO3a in vivo. Together, these data indicate that RSV has therapeutic potential against DCM by inhibiting apoptosis via the PI3K/Akt/FoxO3a pathway.

Human epididymis protein 4 expression positively correlated with miR-21 and served as a prognostic indicator in ovarian cancer.

Ovarian cancer is the most common cause of gynecological malignancy-related mortality. Human epididymis protein 4 (HE4) is a useful biomarker for ovarian cancer when either used alone or in combination with carbohydrate antigen 125 (CA125). What is more, aberrant expression of microRNA-21 (miR-21) has been shown to be involved in oncogenesis, but the relationship between miR-21 and HE4 in ovarian cancer is not clear. Tumor and adjacent tumor tissues from 43 patients with ovarian cancer were examined. Real-time polymerase chain reaction (RT-PCR) was used to detect the expression of HE4 in the carcinoma and adjacent tissues. The associations between HE4 and tumor biological characters were discussed. TaqMan(®) MicroRNA (miRNA) assays were employed to detect the expression of miR-21 in the ovarian carcinoma. In ovarian cancer, the expression of HE4 messenger RNA (mRNA) in cancer tissues was higher than adjacent tumor tissues (P < 0.0001), which was 1.299-fold of adjacent tumor tissues. And, the expression of miR-21 was also up-regulated which was significantly different in the ovarian cancer (the positive rate was 76.74 %). There was a significantly positive correlation between miR-21 and HE4 expression (r = 0.283 and P = 0.066 for HE4 mRNA, r = 0.663 and P < 0.0001 for serum HE4). There was also a significant correlation between miR-21 and tumor grade (r = 0.608, P < 0.0001). Significantly, patients with recent recurrence (less than 6 months, n = 17) have a higher miR-21 expression than those with no recent recurrence. Therefore, HE4 and miR-21 may play an important role in the development and progression of ovarian cancer and they may serve as prognostic indicators in ovarian cancer.