Search

Over the past ten years, the incidence rate of papillary thyroid carcinoma (PTC) worldwide has been increasing rapidly year by year, with the incidence rate increasing 6% annually. PTC has become the malignant tumor with the highest growth rate in the world that fourteen PTC-related mutant genes have been identified. Whether the BRAFA total of 9,908 papillary thyroid carcinoma patients with average 74.6% BRAFThe following variables were associated with an increased risk of BRAFOur systematic review identified the following significant risk factors of BRAF

Maternal high-fat (HF) diet negatively affects maternal metabolism and placental function. This study aimed to determine whether gestational exercise prevents the effect of HF diet on placental amino acid transporter expression and nutrient-sensing signaling and the fetal response. Pregnant Sprague-Dawley rats were either fed with a CHOW (13.5% fat) or HF (60% fat) diet during gestation and further divided into two subgroups: voluntary exercised and sedentary. Placentae were collected on gestational day (GD) 14 and GD20, and male placentae were used in this study. We found that gestational exercise ameliorated the detrimental effects of HF diet on dams’ adiposity, plasma leptin, and insulin concentrations. Maternal exercise did not influence fetoplacental growth but affected male fetal hypothalamic Leprb, Stat3, Insr, Agrp, and Pomc expressions on GD20. Maternal HF diet decreased placental labyrinth thickness and increased system A amino acid transporter SNAT2 expression, while these changes were normalized by exercise. The activation of placental mechanistic target of rapamycin complex 1/4E-BP1 and LepRb/STAT3 signaling might contribute to the increased placental SNAT2 expression in HF-fed dams, which were reversed by exercise on GD20. These data highlight that gestational exercise reverses HF-diet-induced placental alterations during late gestation without influencing fetal growth. However, maternal exercise altered fetal hypothalamic gene expression, which may affect long-term offspring health.

Nicotinamide N-methyltransferase (NNMT) is a novel regulator, shown recently to regulate adipose tissue energy expenditure partly through changing NAD + content, which is essential for mitochondrial. We determine whether NNMT plays important role in energy metabolism during the beige adipogenesis in vivo and in vitro. Male C57BL/6 mice at 8 weeks old were exposed to 4 ℃ for 1, 2, 3, 4, and 5 days, respectively. Interscapular brown adipose tissue (iBAT), inguinal subcutaneous WAT (sWAT), and epididymal WAT (eWAT) were harvested for gene and protein expression analysis and the correlation analysis. In addition, cultured primary mice brown adipocyte (BA) and white adipocyte (WA) treated with or without β3-adrenoceptor agonist (CL316, 243) were also harvested for these analyses. A combination of NNMT and its related genetic (Nmnat1, Nampt, Cyp2e1, Nrk1, Cd38) and proteic analyses and also the NAD + levels demonstrated the dynamical and depot-specific remodeling of NAD metabolism in different adipose tissues in response to cold exposure. While upon CL316, 243 treatment, gene expression of Nnmt, Nampt, Cyp2e1, and Nrk1 was all significantly decreased in WA but not in BA. The increased NAD + amount in BA and WA during the beige adipogenesis was observed. Besides, it is demonstrated that the expression of NNMT both in sWAT and WA showed significant negative correlation with browning markers UCP-1 and PGC-1α at protein levels. Above all, NNMT was induced in WAT during the 'cold remodeling' phase and correlated negatively with the process of browning in sWAT and WA, indicating the specific role of NNMT in the regulation of energy homeostasis during the process of beige adipogenesis.

Anaemia is the most common complication of myeloma and is associated with worse clinical outcomes. Although marrow replacement with myeloma cells is widely considered a mechanistic rationale for anaemia, the exact process has not been fully understood. Our large cohort of 1363 myeloma patients had more than 50% of patients with moderate or severe anaemia at the time of diagnosis. Anaemia positively correlated with myeloma cell infiltration in the bone marrow (BM) and worse patient outcomes. The quantity and erythroid differentiation of HSPCs were affected by myeloma cell infiltration in the BM. The master regulators of erythropoiesis, GATA1 and KLF1, were obviously downregulated in myeloma HSPCs. However, the gene encoding the chemokine CCL3 showed significantly upregulated expression. Elevated CCL3 in the BM plasma of myeloma further inhibited the erythropoiesis of HSPCs via activation of CCL3/CCR1/p38 signalling and suppressed GATA1 expression. Treatment with a CCR1 antagonist effectively recovered GATA1 expression and rescued erythropoiesis in HSPCs. Myeloma cell infiltration causes elevated expression of CCL3 in BM, which suppresses the erythropoiesis of HSPCs and results in anaemia by downregulating the level of GATA1 in HSPCs. Thus, our study indicates that targeting CCL3 would be a potential strategy against anaemia and improve the survival of myeloma patients.

Stress-induced phosphoprotein 1 (STIP1) plays an important role in cancer tumorigenesis and progression. However, the role of STIP1 in colorectal cancer (CRC) remains unclear. This study aimed to explore clinical significance, biological function and potential molecular mechanism of STIP1 in CRC. Immunohistochemistry (IHC) and Western bolt were performed to detect STIP1 protein level in CRC and adjacent normal tissues. DLD1 and HCT116 cell lines were treated with shSTIP1, cell proliferation was detected by CCK8 and colony formation assays, and cell migration and invasion were detected by wound healing and transwell assays. Moreover, western blot and immunofluorescence assays were performed to explore the potential molecular mechanism of STIP1 in the progression of CRC. We found that STIP1 expression in CRC tissues was significantly higher than in adjacent normal tissues. High STIP1 expression was associated with poor overall survival (OS) in CRC patients. Furthermore, secreted STIP1 promoted CRC cell proliferation and invasion through STAT3 signaling pathway, while STIP1 knockdown inhibited the proliferation, migration and invasion of CRC cells. Mechanistically, STIP1 knockdown suppressed the activation of STAT3 signaling pathway in CRC. In conclusion, STIP1 knockdown suppresses CRC cell proliferation, migration and invasion by inhibiting the activation of STAT3 signaling, and STIP1 is a potential target for CRC therapy.

OBJECTIVE: To investigate the time-sequential expression of a novel long non-coding RNA, lnc AK079912, in metabolically related tissues and during adipose tissue development and browning in mice. METHODS: The interscapular brown adipose tissue (iBAT), subcutaneous white adipose tissue (sWAT), epididymal white adipose tissue (eWAT), liver tissues and muscular tissues were collected from 8-week-old C57BL/6J mice. The iBAT, sWAT and eWAT were also collected from the mice during development (0 day, 21 days, 8 weeks and 6 months after birth) and from 8- to 10-week- mice with cold exposure (4 ℃) and intraperitoneal injections of CL316, 243 (1 μg/g body weight) for 1 to 5 days. Trizol was used to extract the total RNA from the tissues, and RT-qPCR was performed to detect the expressions of lnc AK079912. Isolated mouse preadipocytes in primary culture were induced for adipogenic differentiation for 9 days and then treated with CL316, 243 (2 μmol/L) for different durations (no longer than 24 h); the expression of lnc AK079912 in the cells was detected using RT-qPCR at different time points of the treatment. RESULTS: Lnc AK079912 was highly expressed in mouse adipose tissues, the highest in iBAT, followed by the muscular tissue, but was hardly detected in the liver tissue. The expression level of lnc AK079912 increased progressively in iBAT and sWAT during development of the mice, while its expression in eWAT showed an initial increase followed by a reduction at 8 weeks (P < 0.001). No significant difference was found in the expression of lnc AK079912 in the iBAT, sWAT or eWAT in mice with cold stimulation for 1 to 5 days (P > 0.05). The expression of lnc AK079912 was significantly decreased in iBAT and eWAT (P < 0.05) but increased in eWAT from mice with intraperitoneal injection of CL316, 243 for 1 to 5 days (P < 0.05). The expression level in the adipocytes in primary culture was significantly increased in response to treatment with CL316, 243 (P < 0.05). CONCLUSION: Lnc AK079912 is highly expressed in mouse adipose tissue, and its expression gradually increases with the development of adipose tissue but with a depot-specific difference. Lnc AK079912 is significantly elevated in the early stage of adipose tissue browning, indicating its important role in the development and browning of adipose tissue.

Perinatal high-fat diet (HFD) increases risk of metabolic disorders in offspring. Adipose tissue remodeling is associated with metabolic syndrome. The current study characterizes the profile of maternal HFD-induced changes in adipose tissue remodeling and adipokines expression in mice offspring.Female C57BL/6 mice are fed with CHOW or HFD for 2 weeks before mating, throughout gestation and lactation. At weaning, pups are randomly fed with CHOW or HFD, resulting in eight groups according to sex and maternal diet: Male CHOW-CHOW (MCC), Male CHOW-HFD (MCH), Male HFD-CHOW (MHC), Male HFD-HFD (MHH), Female CHOW-CHOW (FCC), Female CHOW-HFD (FCH), Female HFD-CHOW (FHC), and Female HFD-HFD (FHH). Increased body weight, impaired glucose tolerance, increased adipose tissue mass and hypertrophy, and decreased circulating asprosin level are only observed in male offspring exposure to maternal HFD. Serum asprosin level negatively correlates with fasting blood glucose, serum cholesterol (CHO), and high-density lipoprotein (HDL) levels, while positively correlates with serum low-density lipoprotein (LDL) and glutamate-oxaloacetate transaminase (GOT) levels in male offspring. A combination of genetic and biochemical analyses of adipokines shows the depot- and sex-specific changes in response to maternal and/or post-weaning HFD.This study's results reveal the differential metabolic changes in response to maternal and/or post-weaning HFD in male and female offspring. The effect of maternal HFD on metabolic phonotype is more obvious in male offspring, supporting the notion that males are more susceptible to HFD-induced metabolic disorders.

To characterize the timeliness of β3 adrenergic receptor agonist CL316,243-induced browning of white adipose tissues in mice. Methods: Male C57BL/6J mice at 10 weeks of age were housed in conventional cages and given sterile saline for the control group or CL316,243 (1 μg/g) for the experimental group via intraperitoneal injection for 1, 3, and 5 days. Food intake and body weight were measured daily. Interscapular brown adipose tissue (iBAT), inguinal subcutaneous white adipose (sWAT) and epididymal white adipose tissue (eWAT) were harvested for histological and gene expression analysis. Results: Compared with the control group, intraperitoneal injection of CL316,243 reduced the weight of eWAT on the first day. Meanwhile, CL316,243 continuously promoted the mRNA and protein expression of uncoupling protein-1 (UCP-1) in sWAT and eWAT. Furthermore, CL316,243 injection significantly decreased the food intake and weight gain of the mice, and reduced the diameter of adipocyte and accumulation of small lipid droplets in adipose tissues. Conclusion: CL316,243 can induce the brown-like remodeling in adipose tissues of mice in vivo, which show different time-dependent manners in different adipose tissues.目的：研究β3肾上腺素能受体激动剂CL316,243在体诱导小鼠各部位脂肪组织棕色化的时效性，明确其潜在的分子调控机制。方法：以10周龄C57BL/6J小鼠为研究对象，实验组分别腹腔注射CL316,243(1 μg/g)1，3及 5 d，对照组注射无菌生理盐水溶剂。通过免疫组织化学法和基因表达分析等，观察不同作用时间下小鼠各部位脂肪组织的棕色化改变及产热相关基因及蛋白质的表达水平。结果：与对照组相比，在腹腔注射CL316,243第1天时附睾周围白色脂肪组织(epididymal white adipose tissue，eWAT)的重量就明显减轻，并且随着给药时间的延长，腹股沟皮下白色脂肪组织(inguinal subcutaneous white adipose tissue，sWAT)和eWAT中解偶联蛋白UCP-1 mRNA和蛋白质表达升高；而持续注射5 d能显著抑制小鼠的摄食及体重增加，并诱导小鼠肩胛部棕色脂肪(interscapular brown adipose tissue，iBAT)、sWAT及eWAT中细胞直径的缩小及小脂滴的聚集。结论：β3肾上腺素能受体激动剂CL316,243能在体诱导小鼠脂肪组织的棕色化，并且在不同脂肪组织中表现出不同的时效性特点。.

The nicotinamide adenine dinucleotide (NAD

Non-nutritive sweeteners have been considered to promote diet healthfulness by delivering a pleasant sweet taste without calories. We investigated the effects of long term supplementation with drinks containing saccharin on body weight and possible mechanisms of the effects in post-weanling rats. Our results showed that saccharin solution intake increased food intake and energy intake in male rats. In males, saccharin solution intake increased TIR3 mRNA expression in the taste buds and ghrelin receptor mRNA expression both in the taste buds and hypothalamus, whereas no effects were observed in females. These results suggest the effects of saccharin solution exposure on food intake and body weight gain may be different in developmental males and females. In males, peripheral sweet taste receptors and both peripheral and central ghrelin receptors may be involved in the effect of saccharin solution intake to promote food intake and weight gain.

Ghrelin is a potent orexigenic hormone that acts in the central nervous system to stimulate food intake via the growth hormone secretagogue receptor (GHSR) that is abundantly expressed in the ventral tegmental area (VTA). Not only does ghrelin modulate feeding behavior via a homeostatic mechanism, but numerous studies have identified ghrelin as a key regulator of reward-based hedonic feeding behaviors. Nutritional states influence ghrelin and GHSR expression as well as the behavioral sensitivity to reward-inducing stimuli. In the current study, we examined the role of ghrelin at the VTA level in food intake in two different nutritional states, satiety and hunger, by using a restricted feeding model. In this model, rats were conditioned to a daily 3-h (h) feeding session on standard chow for 10days and a high-fat diet (HFD) was supplied either in the third hour after 2h of chow diet intake, or at the beginning of a daily meal on the test day. We found that intra-VTA microinjection of 1, 2, and 4μg of ghrelin, induced a dose-related increase of 1h of reward-based feeding on HFD in sated rats, as well as a 24-h body weight gain. The overconsumption stimulated by ghrelin could be attenuated by 10μg of direct infusion of the ghrelin receptor antagonist D-Lys3-GHRP-6 into the VTA. Moreover, our data showed that the injection of 1, 2, and 4μg of ghrelin in the VTA, enhanced fasting-induced hyperphagia on HFD in a dose-related manner following a 21-h food restriction as well as a 24-h body weight gain. Conversely, hyperphagia on HFD that is potentiated by ghrelin could be blocked by pretreatment with a 10-μg D-Lys3-GHRP-6 intra-VTA microinjection. Collectively, these data demonstrate that ghrelin signaling at the VTA level mediates both reward-based eating and fasting-induced hyperphagia and provides a primary target for the control of the intake of rewarding food.

Nicotinamide N-methyltransferase (Nnmt) methylates nicotinamide, a form of vitamin B3, to produce N(1)-methylnicotinamide (MNAM). Nnmt has emerged as a metabolic regulator in adipocytes, but its role in the liver, the tissue with the strongest Nnmt expression, is not known. In spite of its overall high expression, here we find that hepatic expression of Nnmt is highly variable and correlates with multiple metabolic parameters in mice and humans. Further, we find that suppression of hepatic Nnmt expression in vivo alters glucose and cholesterol metabolism and that the metabolic effects of Nnmt in the liver are mediated by its product MNAM. Supplementation of high-fat diet with MNAM decreases serum and liver cholesterol and liver triglycerides levels in mice. Mechanistically, increasing Nnmt expression or MNAM levels stabilizes sirtuin 1 protein, an effect that is required for their metabolic benefits. In summary, we describe here a novel regulatory pathway for vitamin B3 that could provide a new opportunity for metabolic disease therapy.

Opioid mechanisms are involved in the control of water and NaCl intake and opioid receptors (ORs) are present in the central nucleus of the amygdala (CeA), a site of important facilitatory mechanisms related to the control of sodium appetite. Therefore, in the present study we investigated the effects of the activation of μ-ORs in the CeA on 0.3 M NaCl and water intake in rats. Male Sprague–Dawley rats with stainless steel cannulas implanted bilaterally in the CeA were used. In rats submitted to water deprivation–partial rehydration, bilateral injections of the selective μ-OR agonist [D-Ala 2 , N-Me-Phe 4 , Gly 5 -ol]-enkephalin (DAMGO) in the doses of 1, 2, and 4 nmol into the CeA induced a dose-related increase of 0.3 M NaCl intake and water intake, and bilateral injections of the selective μ-OR antagonist D-Phe-Cys-Trp-Arg-Thr-Pen-Thr-NH 2 (CTAP) in the doses of 0.5, 1, and 2 nmol into the CeA produced a dose-related decrease of 0.3 M NaCl and water intake induced by DAMGO 2 nmol into the same site. In rats treated with the diuretic furosemide (10 mg/kg b.w.) combined with the angiotensin-converting enzyme inhibitor captopril (5 mg/kg b.w.) injected subcutaneously, bilateral injections of DAMGO 2 nmol into the CeA increased 0.3 M NaCl intake and water intake and the blockade of μ-ORs with CTAP 1 nmol injected into the CeA reduced the increase in 0.3 M NaCl intake and water intake induced by DAMGO 2 nmol into the same site. Bilateral injections of DAMGO into the CeA did not change urinary volume, sodium urinary excretion and mean arterial pressure, but increased activity. Thus stimulating μ-ORs in the CeA increases hypertonic sodium intake, whereas antagonizing these sites inhibits hypertonic sodium intake. Together, our results implicate μ-ORs in the CeA in a positive regulation of sodium intake.

To investigate the role of N-Methyl-D-aspartic acid (NMDA)-type glutamate receptors in the central nucleus of the amygdale (CeA) in food and water intake.Male Sprague-Dawley rats with stainless steel cannulae implanted unilaterally into the CeA were used. The prototypic NMDA receptor agonist NMDA, or the selective NMDA receptor antagonist D(-)-2-amino-5-phosphonopentanoic acid (D-AP-5) was microinjected into the CeA of satiated and euhydrated rats.Intra-CeA injection of 8.50, 17.00, or 34.00 nmol NMDA did not alter food intake but significantly increased water intake 0-1 h after the injection (F(3,32)=3.191, P=0.037) independent of food intake. Without affecting the food intake, injection of 6.34, 12.70, or 25.40 nmol D-AP-5 into the CeA significantly decreased water intake 0-1 h after the injection (F(3,28)=3.118, P=0.042) independent of food intake.NMDA receptors in the CeA may participate in the control of water intake rather than food intake.