Fumarate-1 Mediates the Regulation of Mitochondrial Homeostasis by PGC-1α to Promote Cell Pyroptosis and Inhibit the Progression of Thyroid Cancer.

BACKGROUND: Thyroid cancer is a rare but increasingly prevalent form of cancer worldwide. The development and progression of thyroid cancer are associated with mitochondrial instability, which refers to alterations in the structure, function, and energy status of mitochondria. These alterations lead to an imbalance in mitochondrial metabolism, causing cellular damage and apoptosis. However, the molecular mechanisms underlying mitochondrial instability and thyroid cancer remain poorly understood. OBJECTIVE: This study aimed to explore the molecular mechanism of delaying the progression of thyroid cancer by regulating mitochondrial homeostasis through fumarate 1-mediated PGC-1α in vitro. METHODS: Human papillary thyroid carcinoma cell lines (TPC-1 and K-1) and a normal thyroid cell line (Nthy-ori 3-1) were cultured in this study. TPC-1 cells and K-1 cells were separately transfected with oveRNA-FH1 and oveRNA-NC, designated as the oveRNA-FH1 group, oveRNA- NC group, TPC-1 group, and Nthy-ori 3-1 group. Various assays were performed to assess cell viability, proliferation capacity, invasion and migration abilities, as well as mitochondrial morphology changes and the expression of relevant factors. qRT-PCR and Western blot analysis were carried out to analyze the expression changes of PGC-1α, mitochondrial dynamics-related factors, and pyroptosis genes. The goal of these experiments was to evaluate the impact of FH1 on mitochondrial instability and elucidate the specific mechanisms underlying thyroid cancer and mitochondrial instability. RESULTS: The results of this study demonstrated that FH1 expression was significantly downregulated in thyroid papillary carcinoma cell lines compared to the normal thyroid cell line. Overexpression of FH1 reduced cell viability and inhibited cell proliferation rate in TPC-1 cells. Furthermore, FH1 overexpression suppressed cell invasion and migration abilities. Abnormal mitochondrial morphological changes were observed in TPC-1 and K-1 cells, whereas FH1 overexpression resulted in relatively normal mitochondria. FH1 overexpression also affected the expression of fusion and fission genes, promoting fission and inhibiting fusion in thyroid cancer cells. Moreover, FH1 overexpression led to increased inflammation and pyroptosis. These conclusions were further verified by in vitro tumor formation experiments. CONCLUSION: FH1 promoted thyroid cancer progression by regulating mitochondrial homeostasis via the PGC-1α-dependent pathway, which affected pyroptosis and apoptosis.

ZFPM2-AS1 transcriptionally mediated by STAT1 regulates thyroid cancer cell growth, migration and invasion via miR-515-5p/TUSC3.

Objective: Our purpose was to study the roles and molecular mechanisms of long non-coding RNA (lncRNA) ZFPM2 Antisense RNA 1 (ZFPM2-AS1) in thyroid cancer. Methods: Firstly, the expression of ZFPM2-AS1, miR-515-5p and TUSC3 was detected in thyroid cancer tissues and cells. Secondary, their biological functions (proliferation, apoptosis, migration and invasion) were analyzed by a serious of functional experiments including cell counting kit-8 (CCK-8), clone formation, 5-Ethynyl-2'-deoxyuridine (EdU), enzyme-linked immunosorbent assay (ELISA), wound healing and Transwell assays. Thirdly, the mechanisms of STAT1/ZFPM2-AS1 and ZFPM2-AS1/miR-515-5p/TUSC were validated using chromatin immunoprecipitation (CHIP), pull-down and luciferase reporter assays. Results: ZFPM2-AS1 and TUSC were both highly expressed and miR-515-5p was down-regulated in thyroid cancer tissues as well as cells. Their knockdown weakened thyroid cancer cell growth, migration, and invasion. ZFPM2-AS1 was mainly distributed in the nucleus and cytoplasm of thyroid cancer cells. Mechanistically, up-regulation of ZFPM2-AS1 was induced by transcription factor STAT1 in line with CHIP and luciferase reporter assays. Furthermore, as a sponge of miR-515-5p, ZFPM2-AS1 decreased the ability of miR-515-5p to inhibit TUSC3 expression by pull-down, luciferase reporter and gain-and-loss assays, thereby promoting malignant progression of thyroid cancer. Conclusion: ZFPM2-AS1 acted as an oncogene in thyroid cancer, which was transcriptionally mediated by STAT1. Furthermore, ZFPM2-AS1 weakened the inhibitory effect of miR-515-5p on TUSC3. Thus, ZFPM2-AS1 could be an underlying biomarker for thyroid cancer.

Efficacy of synchronous stereotactic radiotherapy with temozolomide combined with whole brain radiotherapy in treating brain metastases originating from non-small cell lung cancer.

PURPOSE: To investigate the efficacy and safety of synchronous stereotactic radiotherapy (SRT) with temozolomide (TMZ) combined with whole brain radiotherapy (WBRT) in treating brain metastases originating from non-small cell lung cancer (NSCLC). METHODS: The clinical data of 128 patients with brain metastases originating from NSCLC treated in the hospital from August 2015 to August 2017 were retrospectively analyzed. Among these patients, 64 received synchronous SRT with TMZ+WBRT (TMZ group), and 64 underwent SRT+WBRT (radiotherapy group). The clinical data of all patients were collected, and the short-term responses and adverse reactions after treatment were compared between the two groups. Additionally, the patients were followed up to record the overall survival (OS) and progression-free survival (PFS), and the factors probably affecting the prognosis of patients were analyzed. RESULTS: The incidence rate of nausea & vomiting was overtly higher in the TMZ group than that in the radiotherapy group (67.2% vs. 43.8%, p=0.008), while the incidence rate of other treatment-related adverse reactions showed no remarkable difference between the two groups (p>0.05). The follow-up results revealed that the median OS and PFS were (13.1±4.6) and (11.2±4.2) months in the TMZ group and (10.6±3.8) and (8.3±3.4) months in the radiotherapy group, respectively. According to log-rank test, the OS and PFS of patients in the TMZ group were evidently better than those in the radiotherapy group (p=0.041, p=0.025). Univariate and multivariate regression analyses suggested that the absence of extracranial metastasis, recursive partitioning analysis (RPA) class I, mini mental status examination (MMSE) score ≥27 points before radiotherapy, and treatment with TMZ were protective factors affecting the prognosis of patients. CONCLUSIONS: Synchronous SRT with TMZ combined with WBRT is effective in treating patients with brain metastases originating from NSCLC, which can effectively improve the survival of patients and has tolerable adverse reactions. The absence of extracranial metastases, RPA class I, MMSE score ≥27 points before radiotherapy and treatment with TMZ are protective factors affecting the prognosis of patients.

Morphological changes of blocklets during the gelatinization process of tapioca starch.

After combined hydrolysis by α-amylase and ß-amylase at room temperature, spherical blocklets in diameters of 27-60nm were observed on the surface of tapioca starch granules by scanning electron micrography (SEM). Tapioca starch (1%, w/w, db, distilled water) was heated by using a rapid visco analyzer (RVA) in four different programs, then the samples were settled and freeze dried, respectively. The SEM images showed that the blocklets swelled at 52°C; the swollen blocklets deformed to olive shape, and linked by molecular chains, formed bead-like structure at 62°C; they started to merge at 72°C (pasting temperature); then the blocklets fused together and their shapes disappeared completely, and the gel network formed at 95°C. Furthermore, the morphological changes of the blocklets were not simultaneously.

A 3-year follow-up study of ß-cell function in patients with early-onset type 2 diabetes.

Insulin resistance and reduced ß-cell glucose sensitivity are present in patients with type 2 diabetes. In the present study, we investigated the changes in ß-cell function in patients with type 2 diabetes during a 3-year follow-up study. A total of 48 patients with early-onset type 2 diabetes (EOD) and 55 patients with late-onset type 2 diabetes (LOD) were enrolled. Weight, height, waist circumference, hip circumference, blood pressure and plasma levels of lipids, glucose, fasting serum C-peptide (CPR0) and serum C-peptide 6 min after glucagon stimulation (CPR6) were measured. In addition, islet ß-cell secretory activity was detected. Subjects with EOD had lower Systolic blood pressure (SBP), diastolic blood pressure (DBP), body mass index (BMI), fasting CPR0, CPR6 and greater glycated hemoglobin A1c (HbA1c), triglyceride (TG) compared with subjects with LOD. CPR0, CPR6 and TG were decreased in both EOD and LOD groups 3 years later. The ratio of ß-cell function failure was 29.17 and 10.91% in the EOD and LOD groups, respectively, and there was significant difference between the two groups. A positive correlation was identified between the CPR0 and waist-hip ratio, HbA1c in the EOD group. A similar positive correlation was observed between CPR0 and BMI in the LOD group. Collectively, islet ß-cell function has declined in patients with EOD, and this change may be more evident when compared with those with LOD.

Radiotherapy for urinary bladder pheochromocytoma with invasion of the prostate: A case report and literature review.

Malignant pheochromocytoma is a rare tumor, for which there is currently no effective therapy. Cytoreductive surgery is recommended to reduce tumor burden and relieve the symptoms of catecholamine excess, although complete eradication of the lesions is often not feasible. In patients with advanced disease, for whom surgical resection is not an option, systemic chemotherapy, radiotherapy and treatment with iodine-131-meta-iodobenzylguanidine may be used to achieve symptomatic relief. Although malignant pheochromocytoma is considered to be unresponsive to radiotherapy, a limited number of case reports, although not large patient samples, have been published on the effectiveness of radiotherapy for the treatment of this disease. This is the case report of a 23-year-old male patient with bladder pheochromocytoma invading the prostate, who refused to undergo surgery. The tumor shrank following radiotherapy and had not increased in size 1.5 years after treatment. Similarly, the blood pressure of the patient remained within normal limits without antihypertensive medication; the levels of catecholamines and their metabolites also remained normal. Our case demonstrated that radiotherapy was effective for malignant pheochromocytoma to a certain extent and, therefore, it may be selected when surgery is not feasible.

Association between thyroid hormones and body fat in euthyroid subjects.

OBJECTIVE: Thyroid hormones disorders are associated with changes of body composition. However, the relationship between thyroid hormones and body fat in a euthyroid population is unclear. The aim of this study was to explore the association between thyroid hormones and body fat in a euthyriod population. SUBJECTS: A total of 865 euthyroid individuals were recruited in this study. Subjects with thyroid diseases or diabetes and who were taking medications that could influence thyroid hormones, weight or glucose metabolism were excluded. MEASUREMENTS: FT3, FT4, lipid parameters, fasting insulin (FINS) and blood glucose were determined, and homeostasis model assessment for insulin resistance (HOMA-IR) was calculated. Anthropometric measurements were taken, and body fat parameters were assessed. RESULTS: Serum FT3 was slightly higher in body mass index (BMI) ≥25 kg/m(2) group than that in BMI <25 kg/m(2) group (P < 0·05). However, the difference was too small to have clinical significance. FT4 levels were not significantly different between the two groups. Body weight, BMI, waist circumference, hip circumference, waist-to-hip ratio (WHR), percentage of body fat (PBF), waist-fat-to-hip-fat ratio, FINS and HOMA-IR increased linearly with the elevation of FT3 adjusted for age and gender. A multivariate linear regression analysis revealed that fat mass, PBF, HOMA-IR and FT4 contributed significantly to FT3 levels. CONCLUSION: Grouped according to BMI, overweight and obese subjects have similar thyroid hormones compared to those with normal weight. Body composition parameters increase with the elevation of FT3, and FT3 is associated with body fat parameters in euthyroid subjects.

Chronic ethanol consumption increases the levels of chemerin in the serum and adipose tissue of humans and rats.

AIM: Chemerin is a new adipokine involved in adipogenesis and insulin resistance. Since ethanol affects the insulin sensitivity that is closely associated with adipokines. The aim of this study was to investigate the effects of ethanol on chemerin in humans and rats. METHODS: In the human study, 148 men who consumed alcohol for more than 3 years and 55 men who abstained from alcohol were included. Based on ethanol consumption per day, the drinkers were classified into 3 groups: low-dose (<15 g/d), middle-dose (15-47.9 g/d) and high-dose (≥48 g/d). Anthropometric measurements and serum parameters were collected. In the rat study, 27 male Wistar rats were randomly divided into 4 groups administered water or ethanol (0.5, 2.5, or 5 g·kg(-1)·d(-1)) for 22 weeks. The chemerin levels in the sera, visceral adipose tissue (VAT) and liver were measured using ELISA. RESULTS: In the high-dose group of humans and middle- and high-dose groups of rats, chronic ethanol consumption significantly increased the serum chemerin level. Both the middle- and high-dose ethanol significantly increased the chemerin level in the VAT of rats. In humans, triglyceride, fasting glucose, insulin and HOMA-IR were independently associated with chemerin. In rats, the serum chemerin level was positively correlated with chemerin in the VAT after adjustments for the liver chemerin (r=+0.768). High-dose ethanol significantly increased the body fat in humans and the VAT in rats. CONCLUSION: Chronic ethanol consumption dose-dependently increases the chemerin levels in the serum and VAT. The serum chemerin level is associated with metabolic parameters in humans. The increased serum chemerin level is mainly attributed to an elevation of chemerin in the VAT after the ethanol treatment.