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.

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.

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.

Asymptomatic Transmissibility Calls for Implementing a Zero-COVID Strategy to End the Current Global Crisis.

The coronavirus disease 2019 (COVID-19) pandemic has led to unprecedented global challenges. A zero-COVID strategy is needed to end the crisis, but there is a lack of biological evidence. In the present study, we collected available data on SARS, MERS, and COVID-19 to perform a comprehensive comparative analysis and visualization. The study results revealed that the fatality rate of COVID-19 is low, whereas its death toll is high compared to SARS and MERS. Moreover, COVID-19 had a higher asymptomatic rate. In particular, COVID-19 exhibited unique asymptomatic transmissibility. Further, we developed a foolproof operating software in Python language to simulate COVID-19 spread in Wuhan, showing that the cumulative cases of existing asymptomatic spread would be over 100 times higher than that of only symptomatic spread. This confirmed the essential role of asymptomatic transmissibility in the uncontrolled global spread of COVID-19, which enables the necessity of implementing the zero-COVID policy. In conclusion, we revealed the triggering role of the asymptomatic transmissibility of COVID-19 in this unprecedented global crisis, which offers support to the zero-COVID strategy against the recurring COVID-19 spread.

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.

The rs1634330 Polymorphisms in the SOST Gene Are Associated with Body Composition in Chinese Nuclear Families with Male Offspring.

OBJECTIVE: The purpose of this study was to explore the effect of the SOST gene polymorphisms on body composition in Chinese nuclear families with male offspring. METHODS: 1,016 individuals were recruited from 335 Chinese nuclear families with male offspring. The nuclear families consist of at least one male offspring aged 18 to 44. We genotyped the 10 tagged single-nucleotide polymorphisms (SNPs) in SOST gene (rs7220711, rs865429, rs851057, rs1708635, rs2023794, rs1234612, rs74252774, rs1634330, rs851058, and rs1513670) in all the above people. We used dual-energy X-ray absorptiometry to measure the composition of the human body. The quantitative transmission disequilibrium test (QTDT) was used to analyze the associations of the SNPs with the body composition. RESULTS: QTDT analysis showed that rs1634330 was significantly associated with trunk LM (P < 0.05). However, haplotypes were not found to be significantly associated with the body composition in the within-family association. The 1000 permutations were consistent with these within-family association results. CONCLUSIONS: Our results showed that the genetic variation in the SOST gene may contribute to variations in the body composition of Chinese male offspring.

Rediscovery of Caffeine: An Excellent Drug for Improving Patient Outcomes while Fighting WARS.

The COVID-19 (here specifically called Worldwide Acute Respiratory Syndrome, WARS) pandemic is surging worldwide. Unfortunately, no specific drug meets the urgent need to fight this pandemic, leading to thousands of deaths. The theory of host-directed therapies (HDTs) is viewed as the ideal means to rephrase the treatment of infectious diseases. However, related drugs based on this theory have not been identified. Previously, we realized that caffeine is the ligand of type 2 taste receptors (TAS2Rs), which play a critical role in host defense. Here, we gathered data on caffeine acting as an immunomodulator. Unexpectedly, we found that caffeine can fight WARS by acting on multiple organs, which may prevent the virus from entering the cell, stimulate the phagocytosis of macrophages, enhance breathing, and inhibit the cytokine storm. Thus, the immunoprotective effects of caffeine can improve the therapeutic outcomes in patients infected with coronavirus. Collectively, we report that caffeine, an FDA-approved, highly safe, inexpensive, and widely available drug, could be an excellent HDT for battling WARS.

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.

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.

Clinical and Molecular Characterization and Discovery of Novel Genetic Mutations of Chinese Patients with COL2A1-related Dysplasia.

COL2A1-related disorders represent a heterogeneous group of skeletal dysplasias with a wide phenotypic spectrum. Our aim is to characterize the clinical and molecular phenotypes of Chinese patients with COL2A1-related dysplasia and to explore their phenotype-genotype relations. Clinical data were collected, physical examinations were conducted, and X-ray radiography and genetic analyses were performed in ten families involving 29 patients with COL2A1-related dysplasia. Nine mutations were identified in COL2A1, including five novel (c.816+6C>T, p.Gly246Arg, p.Gly678Glu, p.Gly1014Val and p.Ter1488Gln) and four reported previously (p.Gly204Val, p.Arg275Cys, p.Gly504Ser and p.Arg719Cys). Based on clinical features and molecular mutations, the ten families were classified into five definite COL2A1-related disorders: four families with spondyloepiphyseal dysplasia congenita (SEDC), three with osteoarthritis with mild chondrodysplasia (OSCPD), one with Czech dysplasia, one with Kniest dysplasia, and one with epiphyseal dysplasia, multiple, with myopia and deafness (EDMMD). Based on genetic testing results, prenatal diagnosis and genetic counseling were accomplished for one female proband with OSCDP. Chinese patients with OSCDP, Czech dysplasia and EDMMD caused by COL2A1 mutations were first reported, expanding the spectrum of COL2A1 mutations and the phenotype of COL2A1-related disorders and providing further evidence for the phenotype-genotype relations, which may help improve procreative management of COL2A1-related disorders.

Systematic prediction of the biological functions of TAS2R10 using positive co-expression analysis.

Type 2 taste receptor 10 (TAS2R10), belonging to the TAS2R family of bitter receptors, is widely expressed in extra-oral tissues. However, its biological roles beyond bitterness sensing in the tongue have remained largely elusive. The present study aimed to perform a positive co-expression analysis using 60,000 Affymetrix expression arrays and 5,000 The Cancer Genome Atlas datasets to uncover such roles. Based on the functional enrichment analysis, it was indicated that in the Gene Ontology (GO) category biological process, TAS2R10 was mostly involved in 'cellular protein metabolic process', 'protein modification process', 'cellular protein modification process' and 'cellular component assembly'. In the GO category cellular component, the co-expressed genes were accumulated in 'Spt-Ada-Gcn5 acetyltransferase (SAGA)-type complex' and 'SAGA complex', and in the category molecular function, they were concentrated in 'hexosaminidase activity', 'cytoskeletal adaptor activity', 'cyclin binding' and 'ß-N-acetylhexosaminidase activity'. Of note, it was indicated that TAS2R10 may be involved in 'ubiquitin-mediated proteolysis', which may provide a starting point to fully investigate the detailed functions of TAS2R10 in the future. TAS2R10 was also indicated to be associated with human diseases, i.e. 'Salmonella infection'. Overall, the present study was the first to perform a comprehensive bioinformatics analysis of the functions of TAS2R10 and provide insight regarding the notion that this gene may have crucial roles beyond bitterness sensing.