BACKGROUND MiRNAs play important roles in regulating many fundamental biological processes. Deregulation of miRNAs is involved in the initiation and progression of cancer. MiR-193b is regarded as tumor suppressor in many types of cancers. However, the role of miR-193b in ovarian cancer is poorly understood. MATERIAL AND METHODS The expression level of miR-193b in ovarian cancer cell lines and ovarian cancer samples was evaluated using quantitative real-time reverse transcription-PCR (qRT-PCR). The ovarian cancer patients were categorized into a high miR-193b expression group and a low miR-193b expression group according to the median miR-193b expression level. The correlation between tissue miR-193b expression and the patients' clinicopathological factors, as well as survival, was also analyzed. RESULTS The results showed that the miR-193b expression was significantly down-regulated in ovarian cancer cell lines and tumor tissues compared with normal controls. In addition, tissue miR-193b expression was positively correlated with FIGO stage (P=0.001), histological grade (P=0.032), ascites (P=0.019), lymph node metastasis (P=0.003), and tumor size (P=0.041). Among 116 patients with ovarian cancer examined, the 5-year overall survival (OS) rates were 62.5% and 22.01% in patients with high and low miR-193b expression, respectively (P=0.003). Multivariate analysis showed that tissue miR-193b is an independent prognostic factor in patients with ovarian cancer (HR=4.219; P=0.015). CONCLUSIONS Reduction of miR-193b was found in ovarian cancer and its lower expression was associated with poorer prognosis. Tissue miR-193b showed potential as novel biomarker for ovarian cancer.

Second generation antipsychotics (SGAs), like olanzapine, exhibit acute metabolic side effects leading to metabolic inflexibility, hyperglycemia, adiposity and diabetes. Understanding how SGAs affect the skeletal muscle transcriptome could elucidate approaches for mitigating these side effects. Male Sprague-Dawley rats were infused intravenously with vehicle or olanzapine for 24h using a dose leading to a mild hyperglycemia. RNA-Seq was performed on gastrocnemius muscle, followed by alignment of the data with the Rat Genome Assembly 5.0. Olanzapine altered expression of 1347 out of 26407 genes. Genes encoding skeletal muscle fiber-type specific sarcomeric, ion channel, glycolytic, O2- and Ca2+-handling, TCA cycle, vascularization and lipid oxidation proteins and pathways, along with NADH shuttles and LDH isoforms were affected. Bioinformatics analyses indicate that olanzapine decreased the expression of slower and more oxidative fiber type genes (e.g., type 1), while up regulating those for the most glycolytic and least metabolically flexible, fast twitch fiber type, IIb. Protein turnover genes, necessary to bring about transition, were also up regulated. Potential upstream regulators were also identified. Olanzapine appears to be rapidly affecting the muscle transcriptome to bring about a change to a fast-glycolytic fiber type. Such fiber types are more susceptible than slow muscle to atrophy, and such transitions are observed in chronic metabolic diseases. Thus these effects could contribute to the altered body composition and metabolic disease olanzapine causes. A potential interventional strategy is implicated because aerobic exercise, in contrast to resistance exercise, can oppose such slow to fast fiber transitions.

To date, eleven genome-wide significant (GWS) loci (P < 5×10-8) for polycystic ovary syndrome (PCOS) have been identified through genome-wide association studies (GWAS). Some of the risk loci have been selected for replications and validated in multiple ethnicities, however, few previous studies investigated all loci. Scanning all the GWAS variants would demonstrate a more informative profile of variance they explained. Thus, we analyzed all the 17 single nucleotide polymorphisms (SNPs) mapping to the 11 GWAS loci in an independent sample set of 800 Chinese subjects with PCOS and 1110 healthy controls systematically. Variants of rs3802457 in C9orf3 locus (P = 5.99×10-4) and rs13405728 in LHCGR locus (P = 3.73×10-4) were significantly associated with PCOS after the strict Bonferroni correction in our data set. The further haplotype analysis indicated that in the block of C9orf3 gene (rs4385527 and rs3802457), GA haplotype played a protective role in PCOS (8.7 vs 5.0, P = 9.85×10-6, OR = 0.548, 95%CI = 0.418-0.717), while GG haplotype was found suffering from an extraordinarily increased risk of PCOS (73.6% vs79.2%, P = 3.41×10-5, OR = 1.394, 95%CI = 1.191-1.632). Moreover, the directions of effects for all SNPs were consistent with previous GWAS reports (P = 1.53×10-5). Polygenic score analysis demonstrated that these 17 SNPs have a significant capacity on predicting case-control status in our samples (P = 7.17×10-9), meanwhile all these gathered 17 SNPs explained about 2.40% of variance. Our findings supported that C9orf3 and LHCGR loci variants were vital susceptibility of PCOS.

Polycystic ovary syndrome (PCOS) is an endocrine and metabolic heterogeneous disorder. The incidence of which reaches 5% to 10% among reproductive-age women. Abnormal folliculogenesis is considered to be a common characteristic of PCOS, but the cause of this disorder and its pathogenesis still remain uncertain. Previous studies had proved that dysregulation of microRNAs is related to the pathogenesis of PCOS. In this study, we investigated the effect of miR-323-3p on the human cumulus cells (CCs). We also investigated the underlying mechanisms of miR-323-3p on human granulosa-like tumor cell line (KGN) or primary human CCs by stimulating with Dihydrotestosterone (DHT). Our findings suggested that the level of miR-323-3p in human CCs of women with PCOS was down-regulated, compared with that of the control group. Moreover, the inhibition of the level of miR-323-3p could up-regulate of the steroidogenesis and promote the apoptosis in KGN cells. In addition, our data confirmed that the Insulin-like growth factor 1 (IGF-1) gene was the direct target of miR-323-3p. Furthermore, the mimic of miR-323-3p inhibited the expression of IGF-1, which down-regulated the levels of AR, AMHR-II, CYP19A, EGFR, and GATA-4. In conclusion, miR-323-3p targeting IGF-1 regulates the steroidogenesis and the activity of CCs, which plays an important role in the occurrence and development of PCOS. Our results have shown that miR-323-3p is a novel and promising molecular target for the improvement of the dysfunction of CCs in PCOS.

Circulating branched-chain amino acids (BCAAs) are elevated in obesity and this has been linked to obesity comorbidities. However it is unclear how obesity affects alloisoleucine, a BCAA and pathognomonic marker of branched-chain keto acid dehydrogenase complex (BCKDC) disorders. It has been previously established that obese Zucker rats exhibit BCKDC impairments in fat and other tissues, whereas BCKDC impairments in adipose tissue of DIO rats are compensated by increased hepatic BCKDC activity. Therefore, alloisoleucine was investigated in these two obesity models.

Six new casbane diterpenoids, named as sinularcasbanes A-F (1-6), along with six known analogues 7-12, were isolated from a South China Sea soft coral, Sinularia sp. The structures of the new compounds were elucidated by extensive spectroscopic analysis and by comparison with data reported in the literature. All compounds were evaluated for their cytotoxicity against selected cancer cell lines and the inhibition of lipopolysaccharide (LPS)-induced nitric oxide (NO) production in mouse peritoneal macrophages.

Glucagon-like peptide-1 receptor (GLP-1R) is a kind of G protein coupled receptor which regulates the insulin secretion and serves as potential target in the diagnosis of functional pancreas neuroendocrine tumor. The aim of this study was to evaluate the feasibility of GLP-1R targeted tracer [68Ga]Ga-NOTA-MAL-Cys39-exendin-4 in the detection of insulinoma.

Adults with childhood-onset growth hormone deficiency (CO AGHD) have prominently impaired volumetric bone density (vBMD) and bone microarchitecture. Effects of recombinant human growth hormone (rhGH) on bone microarchitecture in CO AGHD were insufficiently evaluated. The objective of this study is to assess the effects of rhGH on bone microarchitecture and vBMD in CO AGHD patients.

To realize the diagnosis of HER2-positive gastric cancer via PET imaging, herein, a new kind of 18F-labeled HER2 affibody probe was created; the bifunctional maleimide derivative 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA-MAL) was first coupled to a polypeptide, and the resulting compound was subsequently labeled with the 18FAl complex. The binding characteristics of the probe were assessed using both in vitro studies and in vivo microPET imaging and biodistribution experiments. Immunohistochemical staining was performed to confirm the expression level of HER2 in the studied cell lines and tumors. The probe was successfully produced with the radiochemical purity of more than 95%. The NCI N87 cell-associated radioactivity was 19.31 ± 1.01% AD, and it decreased to 0.83 ± 0.04% AD per 106 cells after blocking HER2 as early as 15 minutes post-incubation (p < 0.05). A competition binding assay between radiolabeled and non-radioactive affibody molecules with NCI N87 indicated that the IC50 was 8.10 nM. The microPET imaging and biodistribution of human gastric cancer xenografts demonstrated that the probe could specifically accumulate in tumors at early time points. Protein detection confirmed a strong HER2 expression in NCIN87 and a weak HER2 expression in SGC7901. In conclusion, 18FAl-NOTA-MAL-Cys-GGGRDN(M0)-ZHER2:342 was successfully prepared via a one-step method. The favorable preclinical data showed specific and effective tumor targeting capacity of the proposed probe; this revealed that the probe proposed herein might have potential application in gastric cancer imaging.

The axonemal dynein arms (outer (ODA) and inner dynein arms (IDAs)) are multiprotein structures organized by light, intermediate, light intermediate (LIC), and heavy chain proteins. They hydrolyze ATP to promote ciliary and flagellar movement. Till now, a variety of dynein protein deficiencies have been linked with asthenospermia (ASZ), highlighting the significance of these structures in human sperm motility. Herein, we detected bi-allelic DNALI1 mutations [c.663_666del (p.Glu221fs)], in an ASZ patient, which resulted in the complete loss of the DNALI1 in the patient's sperm. We identified loss of sperm DNAH1 and DNAH7 rather than DNAH10 in both DNALI1663_666del patient and Dnali1-/- mice, demonstrating that mammalian DNALI1 is a LIC protein of a partial IDA subspecies. More importantly, we revealed that DNALI1 loss contributed to asymmetries in the most fibrous sheath (FS) of the sperm flagellum in both species. Immunoprecipitation revealed that DNALI1 might interact with the cytoplasmic dynein complex proteins in the testes. Furthermore, DNALI1 loss severely disrupted the transport and assembly of the FS proteins, especially AKAP3 and AKAP4, during flagellogenesis. Hence, DNALI1 may possess a non-classical molecular function, whereby it regulates the cytoplasmic dynein complex that assembles the flagella. We conclude that a DNALI deficiency-induced IDAs injury and an asymmetric FS-driven tail rigid structure alteration may simultaneously cause flagellum immotility. Finally, intracytoplasmic sperm injection (ICSI) can effectively resolve patient infertility. Collectively, we demonstrate that DNALI1 is a newly causative gene for AZS in both humans and mice, which possesses multiple crucial roles in modulating flagellar assembly and motility.

Primary hypertrophic osteoarthropathy (PHO) is a rare genetic multi-organic disease characterized by digital clubbing, periostosis and pachydermia. Two genes, HPGD and SLCO2A1, which encodes 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and prostaglandin transporter (PGT), respectively, have been reported to be related to PHO. Deficiency of aforementioned two genes leads to failure of prostaglandin E2 (PGE2) degradation and thereby elevated levels of PGE2. PGE2 plays an important role in tumorigenesis. Studies revealed a tumor suppressor activity of 15-PGDH in tumors, such as lung, bladder and breast cancers. However, to date, no HPGD-mutated PHO patients presenting concomitant tumor has been documented. In the present study, we reported the first case of HPGD-mutated PHO patient with soft tissue giant tumors at lower legs and evaluated the efficacy of selective COX-2 inhibitor (etoricoxib) treatment in the patient.

Positron emission tomography (PET) has the potential for visualization and quantification of gastric emptying (GE). The traditional Chinese medicine (TCM) has been recognized promising for constipation. This study aimed to establish a PET imaging method for noninvasive GE measurement and to evaluate the efficacy of a TCM on delayed GE caused by constipation using PET imaging.

Positron emission tomography (PET) has great benefits for developing therapeutics and quantifying pathological markers in neuropsychiatric disorders. This study aimed to firstly demonstrate the feasibility of PET imaging for glucagon-like peptide-1 receptor (GLP-1R) in Alzheimer's disease (AD) and evaluate the GLP-1R expression. Besides, microglial activation, dopamine D2 receptor (D2R) expression, and glucose metabolism in the brain of APP/PS1/tau transgenic model of AD (3×Tg-AD) were also investigated by PET. [18F]FBEM-Cys39-exendin-4, [18F]DPA-714, [18F]fallypride, and [18F]FDG were prepared and PET imaging acquisitions for 3×Tg-AD mice and wild-type (WT) mice were performed at 15, 30, and 60 min post-injection. Fifteen regions of interest (ROIs) were selected and %ID/g was calculated. The results showed that the uptake of [18F]FBEM-Cys39-exendin-4 in 10 ROIs of 3×Tg-AD mice at 60 min post-injection was significantly lower than that of WT mice (p < 0.05). Besides, 3×Tg-AD mice showed significantly higher [18F]DPA-714 uptake in 7 ROIs and lower [18F]fallypride uptake in 4 ROIs compared to WT mice. [18F]FDG PET showed no significant differences in any ROIs between the two groups. A positive correlation between the uptake of [18F]fallypride and [18F]FBEM-Cys39-exendin-4 could be found in the whole brain. In summary, these results validated the feasibility of GLP-1R PET in AD and demonstrated the reduced GLP-1R and D2R expression as well as increased microglial activation caused by AD.

The purpose of this study was to investigate the potential effect of oxymatrine in monocrotaline-induced pulmonary hypertension and its possible influence on the NG,NG-dimethyl-L-arginine (ADMA) metabolism pathway. Pulmonary hypertension was induced in rats by a single-dose injection of monocrotaline (60 mg/kg). Daily oral administration of oxymatrine (25, 50 and 100 mg/kg) was started on the day following the monocrotaline injection for 28 days. Oxymatrine (50 and 100 mg/kg) significantly attenuated monocrotaline-induced lung and right ventricular hypertrophy, right ventricular systolic pressure elevation, and right ventricular dysfunction. Oxymatrine also reduced the thickening of monocrotaline-induced pulmonary arterial medial wall. Meanwhile, oxymatrine normalized the level of pulmonary asymmetric ADMA and attenuated the upregulated expression of protein arginine methyltransferase 1 (PRMT1). Oxymatrine had no effect on the expression of protein arginine methyltransferase 2 (PRMT2) and NG,NG-Dimethylarginine dimethylaminohydrolase 1 (DDAH1), which were upregulated in monocrotaline-induced pulmonary arterial hypertensive rats. However, the expression of the protein NG,NG-Dimethylarginine dimethylaminohydrolase 2 (DDAH2) did not differ among all groups (all P﹥0.05). These results suggest that oxymatrine may offer protective effects on the development of pulmonary hypertension by ameliorating pulmonary remodeling and modulating the ADMA metabolism pathway.

Dapper antagonist of catenin-1 (DACT1) plays an important role in embryogenesis and organogenesis of the female reproductive tract in mouse models. The aim of this study was to investigate the association between DACT1 mutations and human Müllerian duct anomalies (MDA). One hundred clinically well-defined Chinese Han patients with MDA and 200 healthy controls were recruited in this study. All four exons coding for DACT1 were amplified and sequenced. A missense mutation (c.G1084A, p.V362M) was identified in a patient who had a didelphic uterus and was absent from the control group. This variant changed the hydrophilicity of the amino acid residue and was predicted to be deleterious to the structure and function of DACT1 protein. The data indicate that the p.V362M mutation of DACT1 may be an underlying cause of MDA.

FSHR is an appealing target for cancer theranostics. Radiolabeled FSH1 and its derivatives have shown potential to in vivo detect FSHR expression. However, moderate labeling yields (~50% nondecay-corrected) may partially limit their wide use. 68Ga is an excellent PET nuclide due to availability, nearly quantitative reaction, and short physical half-life. In this study, 68Ga labeled FSH1 peptide was developed for imaging of FSHR in cancers. In vitro studies and MicroPET imaging were performed in PC-3 prostate tumor model. [68Ga] Ga-NOTA-MAL-FSH1 can be produced within 20 min with 93.2 ± 2.1% yield and the radiochemical purity was greater than 95%. It showed that [68Ga] Ga-NOTA-MAL-FSH1 possessed FSHR binding affinities. The tracer was stable in PBS and human serum for at least 2 hours. MicroPET imaging revealed that the PC-3 xenografts were clearly visualized and the tumor uptakes were 1.87 ± 0.10, 1.26 ± 0.06, and 0.71 ± 0.10% ID/g at 0.5, 1 h, and 2 h postinjection. The corresponding tumor to blood and tumor to muscle ratios were 1.77 ± 0.70, 7.94 ± 1.35, and 10.37 ± 1.16 and 7.42 ± 0.46, 26.13 ± 2.99, and 36.40 ± 2.54, respectively. FSHR binding specificity was also demonstrated by reduced tumor uptake of [68Ga] Ga-NOTA-MAL-FSH1 after coinjecting excess unlabeled FSH1 peptide. The favorable characters of [68Ga] Ga-NOTA-MAL-FSH1 such as convenient synthesis and specific tumor uptake warrant its further investigation for FSHR expression imaging.

The basic leucine zipper (bZIP) proteins family is one of the largest and most diverse transcription factors, widely distributed in eukaryotes. However, no information is available regarding the bZIP gene family in Coniothyrium minitans, an important biocontrol agent of the plant pathogen Sclerotinia sclerotiorum. In this study, we identified 34 bZIP genes from the C. minitans genome, which were classified into 8 groups based on their phylogenetic relationships. Intron analysis showed that 28 CmbZIP genes harbored a variable number of introns, and 15 of them shared a feature that intron inserted into the bZIP domain. The intron position in bZIP domain was highly conserved, which was related to recognize the arginine (R) and could be treated as a genomic imprinting. Expression analysis of the CmbZIP genes in response to abiotic stresses indicated that they might play distinct roles in abiotic stress responses. Results showed that 22 CmbZIP genes were upregulated during the later stage of conidial development. Furthermore, transcriptome analysis indicated that CmbZIP genes are involved in different stages of mycoparasitism. Among deletion mutants of four CmbZIPs (CmbZIP07, -09, -13, and -16), only ΔCmbZIP16 mutants significantly reduced its tolerance to the oxidative stress. The other mutants exhibited no significant effects on colony morphology, mycelial growth, conidiation, and mycoparasitism. Taken together, our results suggested that CmbZIP genes play important roles in the abiotic stress responses, conidial development, and mycoparasitism. These results provide comprehensive information of the CmbZIP gene family and lay the foundation for further research on the bZIP gene family regarding their biological functions and evolutionary history.

Light therapy has been accepted as a promising therapeutic choice for depression. Positron emission tomography (PET) combined with specific radiotracers has great benefits for revealing pathogenesis and developing therapeutics. This study aimed to investigate the influences of light therapy on microglial activation and glucagon-like peptide-1 receptor (GLP-1R) expression in the brain of depressive rats using [18F]DPA-714 and [18F]exendin-4 PET. The results showed that chronic unpredictable mild stress (CUMS)-induced depressive rats had poorer performance in behavioral tests compared to normal rats (p < 0.05) and the depressive-like behavior could be ameliorated by light therapy. Besides, depressive rats had significantly higher [18F]DPA-714 uptake and lower [18F]FDG uptake compare to normal rats in 11 and 9 regions of interest (ROIs) of the brain, respectively (p < 0.05). After 5 weeks of light therapy, higher [18F]FDG and [18F]exendin-4 uptake was observed in most ROIs of light therapy-treated depressive rats compared to untreated depressive rats (p < 0.05) and no significant differences existed in [18F]DPA-714 uptake between the two groups. This study demonstrated that light therapy can ameliorate depressive-like behavior, improve glucose metabolism, and halt the decline of brain GLP-1R expression of depressive rats, but have no effects on microglial activation caused by CUMS. Besides, this study validated that [18F]DPA-714 and [18F]exendin-4 PET have the potential for noninvasive evaluation of microglial activation and GLP-1R expression in the brain of depression.

Immune dysregulation is one of the mechanisms to promote endometriosis (EMS). Various T cell subpopulations have been reported to play different roles in the development of EMS. The mucosa-associated invariant T cell (MAIT) is an important T cell subset in the pathogenesis of various autoimmune diseases. Evidence has indicated that there are three functionally distinct MAIT subsets: CD4+, CD8+ and CD4/CD8-/- (double negative, DN) MAIT cells. Till now, the associations between endometriosis and MAIT have not been studied. Our research investigates different MAIT subpopulations in peripheral blood (PB) and peritoneal fluid (PF) from EMS patients.

Coniothyrium minitans (Cm) is a mycoparasitic fungus of Sclerotinia sclerotiorum (Ss), the causal agent of Sclerotinia stem rot of oilseed rape. Ss can produce oxalic acid (OA) as a phytotoxin, whereas Cm can degrade OA, thereby nullifying the toxic effect of OA. Two oxalate decarboxylase (OxDC)-coding genes, CmOxdc1 and CmOxdc2, were cloned, and only CmOxdc1 was found to be partially responsible for OA degradation, implying that other OA-degrading genes may exist in Cm. This study cloned a novel OxDC gene (CmOxdc3) in Cm and its OA-degrading function was characterized by disruption and complementation of CmOxdc3. Sequence analysis indicated that, unlike CmOxdc1, CmOxdc3 does not have the signal peptide sequence, implying that CmOxDC3 may have no secretory capability. Quantitative RT-PCR showed that CmOxdc3 was up-regulated in the presence of OA, malonic acid and hydrochloric acid. Deletion of CmOxdc3 resulted in reduced capability to parasitize sclerotia of Ss. The polypeptide (CmOxDC3) encoded by CmOxdc3 was localized in cytoplasm and gathered in vacuoles in response to the extracellular OA. Taken together, our results demonstrated that CmOxdc3 is a novel gene responsible for OA degradation, which may work in a synergistic manner with CmOxdc1.