TRMT13 inhibits the growth of papillary thyroid cancer by targeting ANAPC4.

The recently discovered gene TRMT13 encodes a type of RNA methylase and is a member of the CCDC family (also called CCDC76). Here, we delineate its role in papillary thyroid cancer (PTC). Bioinformatics analysis shows significant TRMT13 and ANAPC4 downregulation in PTC and reveals that the expression levels of both genes are linearly correlated. Subsequent analyses confirm that both TRMT13 and ANAPC4 expressions are downregulated in PTC tissues and that this change in expression has a significant impact on cancer diagnosis. We conduct assays on PTC cells subjected to TRMT13 and ANAPC4 silencing or overexpression to assess the biological effects of these genes. We also perform rescue experiments to validate the regulatory effects of TRMT13 on ANAPC4. A nude mouse tumor model is used to evaluate the effects of TRMT13 and ANAPC4 on PTC tumorigenesis. TRMT13 expression is decreased in PTC tissues and cell lines and is positively correlated with that of ANAPC4. Cell assays reveal that TRMT13/ANAPC4 attenuates the malignancy of PTC cells by restraining cell proliferation, migration and invasion, while rescue experiments corroborate that ANAPC4 is a downstream target of TRMT13. In the nude mouse xenograft model, both TRMT13 and ANAPC4 inhibit tumor growth, and TRMT13 and ANAPC4 expression levels are significantly associated with survival. Taken together, these findings lead to the conclusion that TRMT13 inhibits PTC growth via ANAPC4, indicating a new role of TRMT13 and providing insights into the tRNA methyltransferase and coiled-coil domain-containing protein families.

CircGPR137B/miR-4739/FTO feedback loop suppresses tumorigenesis and metastasis of hepatocellular carcinoma.

BACKGROUND: Emerging evidence indicates that circular RNAs (circRNAs) and m6A RNA methylation participate in the pathogenesis and metastasis of multiple malignancies including hepatocellular carcinoma (HCC). However, it remains undocumented how circRNAs form a feedback loop with the m6A modification contributing to HCC. METHODS: A novel hsa_circ_0017114 (circGPR137B) was identified from three pairs of primary HCC and adjacent normal tissues by circRNA expression profiling. The association of circGPR137B and miR-4739 with clinicopathological parameters and prognosis in patients with HCC was analyzed by RT-qPCR, fluorescence in situ hybridization and TCGA cohorts. The role of circGPR137B in HCC was estimated in vitro and in vivo. RT-qPCR, western blot, m6A dot blot, RIP, MeRIP and dual-luciferase reporter assays were used to validate the reciprocal regulation of the feedback loop among circGPR137B, miR-4739 and m6A demethylase FTO. Meanwhile, the expression, function and prognosis of FTO in HCC were investigated by RT-qPCR, western blot, TCGA and rescue experiments. RESULTS: We identified a new dramatically downregulated circGPR137B in HCC tissues, and found that downregulation of circGPR137B or upregulation of miR-4739 was associated with poor prognosis in patients with HCC. Ectopic expression of circGPR137B strikingly repressed the proliferation, colony formation and invasion, whereas knockdown of circGPR137B harbored the opposite effects. Moreover, restored expression of circGPR137B inhibited tumor growth and lung metastasis in vivo. Further investigations showed that circGPR137B, co-localized with miR-4739 in the cytoplasm, acted as a sponge for miR-4739 to upregulate its target FTO, which mediated m6A demethylation of circGPR137B and promoted its expression. Thus, a feedback loop comprising circGPR137B/miR-4739/FTO axis was formed. FTO suppressed cell growth and indicated favorable survival in patients with HCC. CONCLUSION: Our results demonstrate that circGPR137B inhibits HCC tumorigenesis and metastasis through the circGPR137B/miR-4739/FTO feedback loop. This positive feedback mechanism executed by functional coupling between a circRNA sponge and an m6A modification event suggests a model for epigenetics.

Existing bitter medicines for fighting 2019-nCoV-associated infectious diseases.

The sudden outbreak of COVID-19 has led to more than seven thousand deaths. Unfortunately, there are no specific drugs available to cure this disease. Type 2 taste receptors (TAS2Rs) may play an important role in host defense mechanisms. Based on the idea of host-directed therapy (HDT), we performed a negative co-expression analysis using big data of 60 000 Affymetrix expression arrays and 5000 TCGA data sets to determine the functions of TAS2R10, which can be activated by numerous bitter substances. Excitingly, we found that the main functions of TAS2R10 involved controlling infectious diseases caused by bacteria, viruses, and parasites, suggesting that TAS2R10 is a key trigger of host defense pathways. To quickly guide the clinical treatment of 2019-nCoV, we searched currently available drugs that are agonists of TAS2Rs. We identified many cheap, available, and safe medicines, such as diphenidol, quinine, chloroquine, artemisinin, chlorpheniramine, yohimbine, and dextromethorphan, which may target the most common symptoms caused by 2019-nCoV. We suggest that a cocktail-like recipe of existing bitter drugs may help doctors to fight this catastrophic disease and that the general public may drink or eat bitter substances, such as coffee, tea, or bitter vegetables, to reduce the risk of infection.

Effect of resistance exercise on peripheral neuropathy in Type 2 diabetes mellitus. / 抗阻力运动对2åž‹ç³–å°¿ç— å‘¨å›´ç¥žç»ç— å˜çš„å½±å“.

OBJECTIVES: To explore the improvement of neurological symptoms in patients with Type 2 diabetic peripheral neuropathy via resistance exercise. METHODS: A total of 100 patients with Type 2 diabetic peripheral neuropathy were selected as the research objects, and they were randomly divided into an observation group who performed resistance exercise (n=50) and a control group who did not performed resistance exercise (n=50). Resistance exercise was performed on the bioDensity™ resistance exercise instrument. The study graded the severity of diabetic peripheral neuropathy by the Toronto clinical scoring system (TCSS), and the improvement of diabetic peripheral neuropathy (DPN) was evaluated by the decline of the TCSS score. The observation group was treated with resistance exercise for 6 months. The changes of body mass index (BMI), waist circumference, hip circumference, systolic blood pressure, diastolic blood pressure, fasting blood glucose (FBG), fasting insulin (FINS), glycosylated hemoglobin (HbA1C), total cholesterol (TC), glycerin trilaurate (TG), low density lipoprotein (LDL), high density lipoprotein (HDL), and TCSS score were compared between baseline and 3, 6 months of exercise. At the same time, the differences in sensory test scores, nerve reflex scores, and neurological symptom scores were compared between the baseline, 3 and 6 months, in the observation group. Except for resistance exercise, the other treatments in the control group were the same as those in the observation group. RESULTS: Compared with the control group, there was statistically difference in the TCSS scores in the observation group at 3 months (P<0.05); there were also statistically difference in the HbA1C and TCSS scores in the observation group at 6 months (both P<0.05). The changes of TCSS scores, FBG, HbA1C in the observation group at 3 months and 6 months were significantly lower than those in the baseline, with significant differences (all P<0.05); but there were no significant differences in BMI, waist circumference, hip circumference, systolic blood pressure, diastolic blood pressure and TC, TG, LDL, HDL (all P>0.05). In the TCSS scores, the neurosymptom score, sensory test score were all reduced compared with the baseline, with significant differences (both P<0.05); but there was no significant difference in the neuroreflex score (P>0.05). In the control group, the TG and TC at 3 and 6 months were decreased compared with the baseline, and there was significant difference (both P<0.05), while there was no significant difference in the other indicators (all P>0.05). CONCLUSIONS: After the intervention of resistance exercise, the blood glucose and DPN can be improved in a certain extent, and which can be popularized in Type 2 diabetes patients.

Expression of sweet taste receptor and gut hormone secretion in modelled type 2 diabetes.

Sweet taste receptors (STRs) are expressed in L cells which secret glucagon-like peptide-1 (GLP-1) in the gut. The STR blocker lactisole reduces GLP-1 secretion and increases blood glucose levels. Therefore, we investigated the expression of sweet taste molecules in the proximal and distal small intestine, and gut hormone secretion, in healthy control and type 2 diabetic rats. Two groups of rats (Sprague Dawley (SD), and Zucker diabetic fatty (ZDF)) were involved in the study. Each group (n=10) received an intragastric glucose infusion (50% glucose solution, 2g/kg body weight). Blood samples were taken for measurement of blood glucose, plasma insulin, and GLP-1 concentrations. One week later, we obtained small intestinal tissue and detected the expression of STRs and glucose transporters (GTs) by real time polymerase chain reaction (Real Time-PCR). Sweet taste molecules of T1R2, T1R3, α-gustducin and TRPM5 in ileum were dramatically higher than those in duodenum (P<0.01 for each). T1R3, α-gustducin and TRPM5 expression were less in the ileum of ZDF than those in SD (P<0.05 for each), while expression of glucose transporter 2 (GLUT-2) in ileum was significantly higher in ZDF rats. Plasma GLP-1 levels were higher in ZDF rats than SD rats at t=0, 15, 30, 60 and 120min (P<0.01). In conclusion, transcript levels of ileal T1R3 and GLUT-2 are disordered in ZDF rats suggesting that intestinal sweet taste receptor expression is associated with altered glucose metabolism. The mechanism needs further investigation, but might provide a potential therapy in the treatment of type 2 diabetes.

CHIP promotes thyroid cancer proliferation via activation of the MAPK and AKT pathways.

The carboxyl terminus of Hsp70-interacting protein (CHIP) is a U box-type ubiquitin ligase that plays crucial roles in various biological processes, including tumor progression. To date, the functional mechanism of CHIP in thyroid cancer remains unknown. Here, we obtained evidence of upregulation of CHIP in thyroid cancer tissues and cell lines. CHIP overexpression markedly enhanced thyroid cancer cell viability and colony formation in vitro and accelerated tumor growth in vivo. Conversely, CHIP knockdown impaired cell proliferation and tumor growth. Notably, CHIP promoted cell growth through activation of MAPK and AKT pathways, subsequently decreasing p27 and increasing cyclin D1 and p-FOXO3a expression. Our findings collectively indicate that CHIP functions as an oncogene in thyroid cancer, and is therefore a potential therapeutic target for this disease.

MiR-204-5p suppresses cell proliferation by inhibiting IGFBP5 in papillary thyroid carcinoma.

microRNAs (miRNAs) are frequently dysregulated in human malignancies. It was recently shown that miR-204-5p is downregulated in papillary thyroid carcinoma (PTC); however, the functional significance of this observation is not known. This study investigated the role of miR-204-5p in PTC. Overexpressing miR-204-5p suppressed PTC cell proliferation and induced cell cycle arrest and apoptosis. The results of a luciferase reporter assay showed that miR-204-5p can directly bind to the 3' untranslated region (UTR) of insulin-like growth factor-binding protein 5 (IGFBP5) mRNA, and IGFBP5 overexpression partially reversed the growth-inhibitory effects of miR-204-5p. These results indicate that miR-204-5p acts as a tumor suppressor in PTC by regulating IGFBP5 expression and that miR-204-5p can potentially serve as an antitumorigenic agent in the treatment of PTC.

Emerging roles for PIWI proteins in cancer.

It is generally accepted that PIWI proteins are predominately expressed in the germline but absent in somatic tissues. Their best-characterized role is to suppress transposon expression, which ensures genomic stability in the germline. However, increasing evidence has suggested that PIWI proteins are linked to the hallmarks of cancer defined by Weinberg and Hanahan, such as cell proliferation, anti-apoptosis, genomic instability, invasion and metastasis. This provides new possibilities for anticancer therapies through the targeting of PIWI proteins, which may have fewer side effects due to their potential classification as a CTA (cancer/testis antigen). Furthermore, PIWI has been proposed to act as a diagnostic and prognostic marker for many types of cancer, and even to differentiate early- and late-stage cancers. We herein summarize the latest progress in this exciting field, hoping to encourage new investigations of PIWIs in cancer biology that will help to develop new therapeutics for clinical application.

miR-182 targets CHL1 and controls tumor growth and invasion in papillary thyroid carcinoma.

In this study, we investigated the role and underlying mechanism of action of miR-182 in papillary thyroid carcinoma (PTC). Bioinformatics analysis revealed close homolog of LI (CHL1) as a potential target of miR-182. Upregulation of miR-182 was significantly correlated with CHL1 downregulation in human PTC tissues and cell lines. miR-182 suppressed the expression of CHL1 mRNA through direct targeting of the 3'-untranslated region (3'-UTR). Downregulation of miR-182 suppressed growth and invasion of PTC cells. Silencing of CHL1 counteracted the effects of miR-182 suppression, while its overexpression mimicked these effects. Our data collectively indicate that miR-182 in PTC promotes cell proliferation and invasion through direct suppression of CHL1, supporting the potential utility of miR-182 inhibition as a novel therapeutic strategy against PTC.

PIWIL1 Promotes Malignant Progression of Papillary Thyroid Carcinoma by Inducing EVA1A Expression.

INTRODUCTION: Papillary thyroid carcinoma (PTC) is the most common subtype of thyroid cancer. Previous studies have reported on the ectopic expression of P-element-induced wimpy testis ligand 1 (PIWIL1) in various human cancers, but its role in PTC progression has not been investigated. METHODS: In this study, we measured the expression levels of PIWIL1 and Eva-1 homolog A (EVA1A) in PTC using qPCR and WB. We performed a viability assay to evaluate PTC cell proliferation and used flow cytometry to investigate apoptosis. Moreover, we conducted a Transwell invasion assay to quantify cell invasion and assessed PTC growth in vivo using xenograft tumor models. RESULTS: Our findings showed PIWIL1 to be highly expressed in PTC and promote cell proliferation, cell cycle activity, and cell invasion, while suppressing apoptosis. Additionally, PIWIL1 accelerated tumor growth in PTC xenografts by modulating the EVA1A expression. CONCLUSION: Our study suggests that PIWIL1 contributes to the progression of PTC through EVA1A signaling, indicating its potential role as a therapeutic target for PTC. These results provide valuable insights into PIWIL1 function and may lead to more effective treatments for PTC.

Correlation Between Mean Amplitude of Glycemic Excursion and Bone Turnover Markers in Patients with Type 2 Diabetes: A Cross-Sectional Study.

Objective: The present study explores the relationship between glycemic excursion and bone turnover markers. Methods: A total of 250 patients with type 2 diabetes mellitus (T2DM) (142 female and 108 male patients) were enrolled in this study. All participants underwent 72 hours of continuous glycemic monitoring to evaluate the mean amplitude of glycemic excursions (MAGE) of each person. Bone turnover markers and other biochemical data were measured for each patient. Linear regression was performed to explore the relationship between bone turnover markers and glycemic excursion. A value of P < 0.05 was considered statistically significant. Results: MAGE was negatively correlated to N-terminal propeptide of type 1 collagen (P1NP) female: [odds ratios (95% confidence interval) (OR (95% CI)), -2.516 (-5.389, 0.356)]; male: [-2.895, (-6.521, -0.731)] and C-terminal telopeptide fragments of type-I collagen (ß-CTX) female [-0.025, (-0.036, 0.005)]; male [-0.043, (-0.082, 0.003)]. MAGE was still negatively correlated with ß-CTX female [-0.036, (-0.198, -0.030)]; male [-0.048, (-0.089, -0.007)] after adjusting for clinical data and biochemical indices. Conclusion: An independent negative relationship between glycemic excursion and bone turnover markers in patients with T2DM was identified in this study.

Potential of ATP5MG to Treat Metabolic Syndrome-Associated Cardiovascular Diseases.

Introduction: Metabolic syndrome-associated cardiovascular disease (MetS-CVD) is a cluster of metabolism-immunity highly integrated diseases. Emerging evidence hints that mitochondrial energy metabolism may be involved in MetS-CVD development. The physiopathological role of ATP5MG, a subunit of the F0 ATPase complex, has not been fully elucidated. Methods: In this study, we selected ATP5MG to identify the immunity-mediated pathway and mine drugs targeting this pathway for treating MetS-CVD. Using big data from public databases, we dissected co-expressed RNA (coRNA), competing endogenous RNA (ceRNA), and interacting RNA (interRNA) genes for ATP5MG. Results: It was identified that ATP5MG may form ceRNA with COX5A through hsa-miR-142-5p and interplay with NDUFB8, SOD1, and MDH2 through RNA-RNA interaction under the immune pathway. We dug out 251 chemicals that may target this network and identified some of them as clinical drugs. We proposed five medicines for treating MetS-CVD. Interestingly, six drugs are being tested to treat COVID-19, which unexpectedly offers a new potential host-targeting antiviral strategy. Conclusion: Collectively, we revealed the potential significance of the ATP5MG-centered network for developing drugs to treat MetS-CVD, which offers insights into the epigenetic regulation for metabolism-immunity highly integrated diseases.

Undercarboxylated Osteocalcin and Its Associations With Bone Mineral Density, Bone Turnover Markers, and Prevalence of Osteopenia and Osteoporosis in Chinese Population: A Cross-Sectional Study.

Objective: Undercarboxylated osteocalcin (ucOC) is one form of osteocalcin lacking full carboxylation, which plays an important role in bone homeostasis, glucose homeostasis, and energy metabolism. Our aim is to obtain the profile of serum ucOC level according to gender and age and explore its associations with bone mineral density (BMD), bone turnover markers (BTMs), and prevalence of osteopenia and osteoporosis in the Chinese population. Methods: This is a cross-sectional study with 900 subjects, composed of 431 men and 469 women. Clinical information was collected, and BMD values of the lumbar spine (L1-4), left femoral neck, and total hip were scanned. Biochemical markers including hepatic and renal function, serum calcium, serum phosphorus, procollagen type 1 N-propeptide (P1NP) ß-CrossLaps of type I collagen-containing cross-linked C-telopeptide (ß-CTX) intact parathyroid hormone (PTH), 25-hydroxyvitamin D (25OHD), and ucOC were measured. Results: We found that the median ucOC level was higher in men than women [men, 2.6 ng/ml; women, 1.6 ng/ml; p < 0.001]. The profile according to age showed that ucOC levels were the lowest at the age of 40-49 years in both men [2.55 ng/ml (95% CI = 1.96-3.13 ng/ml)] and women [1.57 ng/ml (95% CI = 1.12-2.03 ng/ml)]; in patients younger than 49 years, they decreased with age; then over 50 years, they quickly increased. Furthermore, we found that a higher ucOC level was correlated with lower BMD values at the lumbar spine (men, r = -0.128, p = 0.013; women, r = -0.321, p < 0.001), femoral neck (men, r = -0.095, p = 0.062; women, r = -0.260, p < 0.001), and total hip (men, r = -0.123, p = 0.015; women, r = -0.209, p < 0.001) and higher P1NP (men, r = 0.307, p < 0.001; women, r = 0.239, p < 0.001) and ß-CTX (men, r = 0.169, p = 0.001; women, r = 0.354, p < 0.001) levels in both men and women. Furthermore, we also showed that a 1 - SD increase in ucOC was associated with an odds ratio (OR) of 1.63 and 1.70 for having osteopenia or osteoporosis in men and women, respectively (men, 95% CI = 1.25-2.13, p = 0.004; women, 95% CI = 1.19-2.42, p = 0.004). Conclusions: We first revealed the profile of serum ucOC levels according to gender and age in the Chinese population and demonstrated the associations of ucOC with BMD and BTMs and the risk of prevalent osteopenia or osteoporosis. Our findings provide a clue to elucidate the function of ucOC in bone metabolism.

Effect of Hedan Tablets on Body Weight and Insulin Resistance in Patients with Metabolic Syndrome.

INTRODUCTION: Apart from their recognized lipid-lowering effect, Hedan tablets, a mixture of Chinese herbal medicines, have demonstrated a certain weight-loss effect in clinical practice. The aim of this randomized, double-blind, placebo-controlled study was to verify the effect of Hedan tablets on body weight (BW) and insulin resistance (IR) in patients with metabolic syndrome (MetS). METHODS: A total of 62 eligible patients with MetS were divided into two groups: the treatment group (Hedan tablets at 4.38 g/day tid) and the control group (placebo treatment). Both groups attended follow-ups at 8, 16, and 24 weeks during the process. The parameters of the assessment include lipid level, BW, triglyceride (TG) to high-density lipoprotein cholesterol (HDLc) ratio (TG/HDLc), homeostasis model assessment for IR (HOMA-IR) index, and adiponectin. RESULTS: Patients in the treatment group showed a significant decrease in BW compared to those in the control group (-4.47 vs. 0.06 kg) after 8 weeks of treatment. A significant decrease in body mass index (BMI) was also observed in the treatment group after 16 weeks of treatment (-1.79 vs. -0.03 kg/m2). In the treatment group, 20 out of 31 (64.5%) patients lost 5-10% BW and 4 out of 31 (12.9%) patients lost over 10% BW after 24 weeks of treatment. Although there were no significant changes in the patients' HOMA-IR, the treatment group showed a significant reduction in TG/HDLc (-0.98 vs. -0.19) after 8 weeks of treatment and a significant increase in adiponectin (6.87 vs. -0.43) after 16 weeks of treatment. DISCUSSION/CONCLUSION: The Hedan tablets significantly improve BW, BMI, TG/HDLc, and adiponectin in patients with MetS. Thus, Hedan tablets may be used as an adjunct to existing MetS management methods.