IGF2 deficiency promotes liver aging through mitochondrial dysfunction and upregulated CEBPB signaling in D-galactose-induced aging mice.

BACKGROUND: Liver aging, marked by cellular senescence and low-grade inflammation, heightens susceptibility to chronic liver disease and worsens its prognosis. Insulin-like growth factor 2 (IGF2) has been implicated in numerous aging-related diseases. Nevertheless, its role and underlying molecular mechanisms in liver aging remain largely unexplored. METHODS: The expression of IGF2 was examined in the liver of young (2-4 months), middle-aged (9-12 months), and old (24-26 months) C57BL/6 mice. In vivo, we used transgenic IGF2f/f; Alb-Cre mice and D-galactose-induced aging model to explore the role of IGF2 in liver aging. In vitro, we used specific short hairpin RNA against IGF2 to knock down IGF2 in AML12 cells. D-galactose and hydrogen peroxide treatment were used to induce AML12 cell senescence. RESULTS: We observed a significant reduction of IGF2 levels in the livers of aged mice. Subsequently, we demonstrated that IGF2 deficiency promoted senescence phenotypes and senescence-associated secretory phenotypes (SASPs), both in vitro and in vivo aging models. Moreover, IGF2 deficiency impaired mitochondrial function, reducing mitochondrial respiratory capacity, mitochondrial membrane potential, and nicotinamide adenine dinucleotide (NAD)+/NADH ratio, increasing intracellular and mitochondrial reactive oxygen species levels, and disrupting mitochondrial membrane structure. Additionally, IGF2 deficiency markedly upregulated CCAAT/enhancer-binding protein beta (CEBPB). Notably, inhibiting CEBPB reversed the senescence phenotypes and reduced SASPs induced by IGF2 deficiency. CONCLUSIONS: In summary, our findings strongly suggest that IGF2 deficiency promotes liver aging through mitochondrial dysfunction and upregulated CEBPB signaling. These results provide compelling evidence for considering IGF2 as a potential target for interventions aimed at slowing down the process of liver aging.

UHPLC-MS/MS-based central carbon metabolism unveils the biomarkers related to colon cancer.

Even though colon cancer ranks among the leading causes of cancer mortality, early detection dramatically increases survival rates. Many studies have been conducted to determine whether altered metabolite levels may serve as a potential biomarker of cancer that affects key metabolic pathways. The goal of the study was to detect metabolic biomarkers in patients with colon cancer using liquid chromatography-mass spectrometry (LC-MS). This study consisted of 30 patients with colon cancer. An analysis of the metabolomes of cancer samples and para-carcinoma tissues was conducted. We identified a series of important metabolic changes in colon cancer by analyzing metabolites in cancerous tissues compared to their normal counterparts. They are mainly involved in the pentose phosphate pathway, the TCA cycle, glycolysis, galactose metabolism, and butanoate metabolism. As well, we observed dysregulation of AMP, dTMP, fructose, and D-glucose in colon cancer. Additionally, the AUCs for AMP, dTMP, fructose, and D-glucose were greater than 0.7 for the diagnosis of colon cancer. In conclusion, AMP, dTMP, fructose, and D-glucose showed excellent diagnostic performance and could serve as novel disease biomarkers for colon cancer diagnosis.

Clinical and genetic analysis of pseudohypoparathyroidism complicated by hypokalemia: a case report and review of the literature.

BACKGROUND: Pseudohypoparathyroidism (PHP) encompasses a highly heterogenous group of disorders, characterized by parathyroid hormone (PTH) resistance caused by mutations in the GNAS gene or other upstream targets. Here, we investigate the characteristics of a female patient diagnosed with PHP complicated with hypokalemia, and her family members. CASE PRESENTATION AND GENE ANALYSIS: A 27-year-old female patient occasionally exhibited asymptomatic hypocalcemia and hypokalemia during her pregnancy 1 year ago. Seven months after delivery, she experienced tetany and dysphonia with diarrhea. Tetany symptoms were relieved after intravenous calcium gluconate supplementation and she was then transferred to our Hospital. Laboratory assessments of the patient revealed hypokalemia, hypocalcemia and hyperphosphatemia despite elevated PTH levels. CT scanning of the brain revealed globus pallidus calcification. Possible mutations in GNAS and hypokalemia related genes were identified using WES, exon copies of STX16 were analized by MLPA and the methylation status of GNAS in three differential methylated regions (DMRs) was analyzed by methylation-specific polymerase chain reaction, followed by confirmation with gene sequencing. The patient was clinically diagnosed with PHP-1b. Loss of methylation in the A/B region and hypermethylation in the NESP55 region were detected. No other mutations in GNAS or hypokalemia related genes and no deletions of STX16 exons were detected. A negative family history and abnormal DMRs in GNAS led to a diagnosis of sporadic PHP-1b of the patient. CONCLUSIONS: Hypokalemia is a rare disorder associated with PHP-1b. Analysis of genetic and epigenetic mutations can aid in the diagnosis and accurate subtyping of PHP.

Maternal undernutrition modulates hepatic MicroRNAs expression in the early life of offspring.

Emerging studies revealed that a poor intrauterine environment elicited by maternal nutrient restriction (MNR) is associated with an increased risk of metabolic diseases in adulthood. Previous research has shown that microRNAs (miRNAs) exert pivotal roles in modulating molecular pathways involved in disease pathogenesis and progression. In this respect, we herein examined miRNA profiles in samples of liver from offspring whose mothers were fed either with a 50% food-restricted diet or standard laboratory chow during pregnancy. Our findings enumerated that miR-181a, involved in lipid metabolism, was found to be downregulated in the liver of MNR offspring at 1 day of age when compared to that of control offspring. We also noted that overexpression of miR-181a reduced the lipid droplets after treatment with oleic acid for 48 h, which suppressed the expressions levels of SIRT1, FOXO1, KLF6 and PPARγ in BRL-3A cells, while the opposite results were observed with decreased expression of miR-181a. Furthermore, the luciferase reporter assay confirmed the direct interactions between miR-181a with KLF6 and SIRT1. In adults, the MNR offspring elucidated increased TG content, decreased expression of miR-181a, and increased expressions levels of SIRT1, FOXO1, KLF6, and PPARγ in liver tissues. Collectively, these findings provided novel evidence that MNR could regulate miRNAs expression, which might be related to lipid metabolism in MNR offspring.

Transthyretin contributes to insulin resistance and diminishes exercise-induced insulin sensitivity in obese mice by inhibiting AMPK activity in skeletal muscle.

Exercise improves obesity-induced insulin resistance and metabolic disorders via mechanisms that remain unclear. Here, we show that the levels of the hepatokine transthyretin (TTR) in circulation are elevated in insulin-resistant individuals including high-fat diet (HFD)-induced obese mice, db/db mice, and patients with metabolic syndrome. Liver Ttr mRNA and circulating TTR levels were reduced in mice by treadmill training, as was the TTR levels in quadriceps femoris muscle; however, AMP-activated protein kinase (AMPK) signaling activity was enhanced. Transgenic overexpression of TTR or injection of purified TTR triggered insulin resistance in mice fed on regular chow (RC). Furthermore, TTR overexpression reduced the beneficial effects of exercise on insulin sensitivity in HFD-fed mice. TTR was internalized by muscle cells via the membrane receptor Grp78 and the internalization into the quadriceps femoris was reduced by treadmill training. The TTR/Grp78 combination in C2C12 cells was increased, whereas the AMPK activity of C2C12 cells was decreased as the TTR concentration rose. In addition, Grp78 silencing prevented the TTR internalization and reversed its inhibitory effect on AMPK activity in C2C12 cells. Our study suggests that elevated circulating TTR may contribute to insulin resistance and counteract the exercise-induced insulin sensitivity improvement; the TTR suppression might be an adaptive response to exercise through enhancing AMPK activity in skeletal muscles.NEW & NOTEWORTHY Exercise improves obesity-induced insulin resistance via mechanisms that remain unclear. The novel findings of the study are that circulating TTR (a hepatokine) level is decreased by exercise, and the elevated circulating TTR, as was the elevated transthyretin internalization mediated by Grp78, counteracts the exercise-induced insulin sensitivity by downregulating AMPK activity in skeletal muscle of obese mice. These data suggest that TTR suppression might be an adaptive response to exercise through the crosstalk between liver and muscle.

IGF2 deficiency causes mitochondrial defects in skeletal muscle.

Exercise training improves muscle fitness in many aspects, including induction of mitochondrial biogenesis and maintenance of mitochondrial dynamics. The insulin-like growth factors were recently proposed as key regulators of myogenic factors to regulate muscle development. The present study aimed to investigate the physical exercise impact on insulin-like growth factor 2 (IGF2) and analyzed its functions on skeletal muscle cells in vitro. Using online databases, we stated that IGF2 was relatively highly expressed in skeletal muscle cells and increased after exercise training. Then, IGF2 deficiency in myotubes from C2C12 and primary skeletal muscle cells (PMSCs) led to impaired mitochondrial function, reduced mitochondria-related protein content, and decreased mitochondrial biogenesis. Furthermore, we explored the possible regulatory pathway and found that mitochondrial regulation in skeletal muscle cells might occur through IGF2-Sirtuin 1 (SIRT1)-peroxisome proliferator-activated receptor-γ co-activator-1α (PGC1α) signaling pathway. Therefore, the present study first demonstrated the relationship between IGF2 and mitochondria in skeletal muscle.

Knock-down of circular RNA H19 induces human adipose-derived stem cells adipogenic differentiation via a mechanism involving the polypyrimidine tract-binding protein 1.

PURPOSE: The metabolic syndrome (MetS) is characterized of a cluster of medical disorders. Altered function of adipose tissue has a significant impact on whole-body metabolism and represents a key driver for MetS. In this study, we aim to explore the function of human circular RNA H19 (hsa_circH19) in human adipose-derived stem cells (hADSCs). METHODS: The blood samples from MetS patients and normal subjects were used to determine the expression level of the hsa_circH19. After knock-down of hsa_circH19 in hADSCs, we measured the expression of adipogenic genes. Oil red O, Nile red staining assay and triglyceride assessment were performed to examine the role of hsa_circH19 in hADSCs differentiation. Then, RNA Pull-down and RIP assays were conducted to explore the related RNA binding protein of hsa_circH19. IF was performed to determine the potential molecular regulatory mechanism. RESULTS: After accounting for confounding factors, high levels of hsa_circH19 remained an independent risk factor for MetS. Furthermore, the knockdown of hsa_circH19 significantly increased the expression of adipogenic genes and the formation of lipid droplets. Bioinformatics analyses revealed that has_circH19 shared multiple binding sites with polypyrimidine tract-binding protein 1 (PTBP1) and their interaction was validated by circRNA pull-down and RIP assays. Mechanistically, depletion of hsa_circH19 triggered translocation of sterol-regulatory element binding proteins (SREBP1) from cytoplasm to nucleus in the presence of PTBP1. CONCLUSION: Our experiments suggest that knockdown of hsa_circH19 promotes hADCSs adipogenic differentiation via targeting of PTBP1. In consequence, the expression of hsa_circH19 might correlated to lipid metabolism in adipose tissue from MetS.

LncRNAH19 improves insulin resistance in skeletal muscle by regulating heterogeneous nuclear ribonucleoprotein A1.

BACKGROUND: Skeletal muscle is essential for glucose and lipid metabolism. Growing evidence reveals the importance of long non-coding RNAs (LncRNAs) in metabolism. This study aimed to investigate the function of LncRNA H19 (H19) in lipid metabolism of skeletal muscle and its potential mechanisms. METHODS: Glucose tolerance, serum insulin and lipid content in serum and skeletal muscle were determined in control and H19-overexpressed db/db mice. Lipid metabolism was evaluated in H19-overexpressed or H19-silencing muscle cells by detecting lipid contents and mitochondria related functions. The underlying mechanisms were explored by RNA pull-down, mass spectrometry and RNA immunoprecipitation (RIP). RESULTS: H19 was downregulated in skeletal muscle of db/db mice. H19 overexpression in db/db mice inhibited lipid ectopic deposition in skeletal muscle, meanwhile improved glucose intolerance and insulin resistance as compared with control db/db mice treated with ad-GFP. Furthermore, overexpression of H19 reversed FFA-induced lipid accumulation and increased cellular respiration in muscle cells, while H19 knockdown exhibited opposite effects in muscle cells. Mechanistically, H19 interacted with heterogeneous nuclear ribonucleoprotein (hnRNPA1) which was validated by RNA pulldown and RIP analysis, which increased translation of fatty acid oxidation closely related genes PGC1a and CPT1b. CONCLUSION: Our data suggest that overexpression of H19 ameliorates insulin resistance by reducing ectopic lipid accumulation in skeletal muscle. The possible underlying mechanisms are that overexpression of lncRNAH19 promotes fatty acids oxidation via targeting of hnRNPA1. Video abstract.

[A novel mutation W257R in GCK gene discovered from a Chinese patient with maturity onset diabetes of the young].

Maturity onset diabetes of the young (MODY) is a monogenic autosomal dominant inherited disease. Its clinical manifestations are asymptomatic with slightly elevated fasting blood glucose and few complications. This paper reports a novel mutation W257R in glucokinase (GCK) gene from a Chinese patient with MODY. Heterozygous mutation c.769T>C (p.W257R) in exon 7 of GCK gene (Chr744187343) was found in the proband, her father and brother. This W257R mutation was first reported in Chinese population.

A novel compound heterozygous variant of the SLC12A3 gene in Gitelman syndrome pedigree.

BACKGROUND: Gitelman syndrome (GS) is an autosomal recessive disorder caused by genic mutations of SLC12A3 (Solute carrier family 12 member 3), which encodes the Na-Cl cotransporter (NCC), and presents with characteristic metabolic abnormalities, including hypokalemia, metabolic alkalosis, hypomagnesemia, and hypocalciuria. In this study, we report a case of a GS pedigree, including analysis of GS-associated gene mutations. METHODS: We performed next-generation sequencing analysis and Sanger sequencing to explore the SLC12A3 mutations in a GS pedigree that included a 35-year-old female patient with GS and five family members within three generations. Furthermore, we summarized their clinical manifestations and analyzed laboratory parameters related to GS. RESULTS: The female proband (the patient with GS) presented with intermittent fatigue and transient periods of tetany, along with significant hypokalemia, hypomagnesemia, and hypocalciuria. All other members of the pedigree had normal laboratory results without obvious GS-related symptoms. Genetic analysis of the SLC12A3 gene identified two novel missense mutations (c.1919A > G, p.N640S in exon 15; c.2522A > G, p.D841G in exon 21) in the patient with GS. Moreover, we demonstrated that her mother, younger maternal uncle, and cousin were carriers of one mutation (c.1919A > G), and her father was the carrier of the other (c.2522A > G). CONCLUSION: This is the first report of these two novel pathogenic variants of SLC12A3 and their contribution to GS. Further functional studies are particularly warranted to explore the underlying molecular mechanisms.

Recurrence of diet-treated gestational diabetes in primiparous women in northern Zhejiang, China: Epidemiology, risk factors and implications.

AIM: This study sought to determine the rate of recurrence of gestational diabetes mellitus (GDM) recurrence during the second pregnancies of women who were diagnosed with GDM during their first pregnancies, to identify risk factors associated with the probability of such recurrence and to evaluate the influence of GDM recurrence on pregnancy outcomes in north Zhejiang, China, after the recent adjustment to the nation's childbirth policy. METHODS: A retrospective longitudinal study was performed in north Zhejiang, China (at Jiaxing Maternal and Child Health Hospital). A total of 128 women who delivered two sequential live singleton infants and were diagnosed with diet-treated GDM during their first pregnancies were included. RESULTS: According to the 2013 World Health Organization diagnostic criteria for diabetes during pregnancy, the prevalence of gestational diabetes was 11.02% in northern Zhejiang. The recurrence rate of GDM in northern Zhejiang was 43.75% (56/128). The age at second pregnancy, weight gain during pregnancy, interpregnancy interval and macrosomia during the index pregnancy were risk factors for GDM recurrence. Among those women with recurrent GDM, GDM developed earlier and caesarean section was more frequently required during the second pregnancy; in addition, the second pregnancy was associated with more premature and low birthweight infants but less macrosomia. CONCLUSION: The recurrence rate of GDM is high in northern Zhejiang. Glucose monitoring and management are needed during subsequent pregnancies for patients who previously presented with GDM to improve maternal and fetal outcomes.

PTBP1 induces ADAR1 p110 isoform expression through IRES-like dependent translation control and influences cell proliferation in gliomas.

Internal ribosomal entry site (IRES)-mediated translation initiation is constitutively activated during stress conditions such as tumorigenesis and hypoxia. The RNA editing enzyme ADAR1 plays an important role in physiology and pathology. Initially, we found that the ADAR1 p150 or p110 transcript levels were decreased in glioma cells compared with normal astrocyte cells. In contrast, protein levels of ADAR1 p110 were significantly upregulated in glioma tissues and cells. This expression pattern indicated translationally controlled regulation. We identified an 885-nt sequence that was located between AUG1 and AUG2 within the ADAR1 mRNA that exhibited IRES-like activity. Furthermore, we confirmed that the translational mode of ADAR1 p110 was mediated by PTBP1 in glioma cells. The protein levels of PTBP1 and ADAR1 were cooperatively expressed in glioma tissues and cells. Knocking down ADAR1 p110 significantly decreased cell proliferation in three types of glioma cells (T98G, U87MG and A172). The removal of a minimal IRES-like sequence in a p150-overexpression construct could effectively abolish p110 induction and resulted in the slight suppression of cell proliferation compared with ADAR1-p150 overexpression in siPTBP1-treated T98G cells. In summary, our study revealed a mechanism whereby ADAR1 p110 can be activated by PTBP1 through an IRES-like element in glioma cells, and ADAR1 is essential for the maintenance of gliomagenesis.

[Correlation between serum free fatty acid level and estimated glomerular filtration rate in type 2 diabetic patients].

OBJECTIVE: To investigate the relationship between serum free fatty acid (FFA) level and glomerular filtration rate (GFR) in patients with type 2 diabetes mellitus (T2DM). METHODS: A total of 442 T2DM patients treated in Sir Run Run Shaw Hospital from January 2013 to June 2015 were retrospectively analyzed and divided into three groups according to estimated glomerular filtration rate (eGFR) levels using modified modification of diet in renal disease (MDRD) formula: eGFR≥90 ml·min(-1)·1.73 m(-2)group (group A, 227 cases), 60 ml·min(-1)·1.73 m(-2)≤eGFR<90 ml·min(-1)·1.73 m(-2)group (group B, 118 cases), and eGFR<60 ml·min(-1)·1.73 m(-2)group (group C, 97 cases). In addition, 50 body mass index (BMI)-matched non-diabetic subjects were selected as control group. Fasting serum FFA level was measured in each group, and its relationship with eGFR was analyzed. RESULTS: FFA level in group C[(450±203)µmol/L]was significantly higher than that in group A[(326±167)µmol/L], group B[(394±184)µmol/L]and control group[(320±90)µmol/L](all P<0.05). Meanwhile, FFA level in group B was higher compared with that in group A (P<0.05). However, no statistical difference was found in FFA level between group A and Control group (P>0.05). Multiple linear regression analysis using eGFR as the dependent variable demonstrated that uric acid (UA), FFA, triglyceride (TG), total cholesterol (TC), albuminuria, hypertension, smoking and duration of diabetes were all independent risk factors for decreased eGFR (all P<0.05). CONCLUSION: The present results suggest that increased FFA level might be involved in the development of diabetic nephropathy.

Comparison of Incidence of Metabolic Syndrome and Five Obesity- and Lipid-Linked Indicators for Predicting Metabolic Syndrome Among Normal-Weight and Overweight Adults.

Purpose: Metabolic syndrome (MetS) is an increasingly prevalent issue in China's public health landscape. Few studies have investigated the metabolic syndrome (MetS) in overweight people. We proposed to analyze and contrast the occurrence of MetS in normal-weight and overweight individuals and identify potential indicators for forecasting MetS in adults in Zhejiang Province. Methods: This cohort study included 359 adults aged 40-65 years and followed up for five years in Zhejiang Province. The study assessed the predictive capabilities of five indicators linked to obesity and lipid levels, namely body mass index (BMI), waist-to-height ratio (WHtR), triglyceride-glucose index (TyGi), and their combined indices (TyG-BMI, TyG-WHtR). The evaluation was done employing the area under the Receiver Operating Characteristic (ROC) Curve (AUC). DeLong test was applied to compare area under different ROC curves.We evaluated the relationships between five variables and MetS using multivariate logistic regression. Results: In normal-weight individuals, the five-year cumulative incidence of MetS was 21.85%, but in overweight people, it was 60.33%. After adjusting for confounding factors, BMI, WHtR, TyGi, TyG-BMI, and TyG-WHtR were independently linked to MetS in normal-weight individuals, while BMI, TyGi, TyG-BMI, and TyG-WHtR were independently linked to MetS in overweight individuals. In normal-weight individuals, the WHtR (AUC=0.738 and optimal threshold value =0.469) and TyG-WHtR (AUC=0.731 and optimal threshold value =4.121) had the larger AUC, which was significantly greater than that of the different three indicators. The TyG-BMI (AUC=0.769 and optimal threshold value = 211.099) was the best predictor of MetS in overweight individuals. Conclusion: The five-year cumulative incidence of MetS in overweight people was approximately triple that of normal-weight people in Zhejiang Province. In the overweight population, the TyG-BMI performed better than the other indices in predicting MetS. WHtR and TyG-WHtR outperformed BMI, TyGi, and TyG-BMI in anticipating MetS in a normal-weight population.

Regulation mechanism and pathogenic role of lncRNA plasmacytoma variant translocation 1 (PVT1) in human diseases.

Plasmacytoma variant translocation 1 (PVT1) is a long non-coding RNA (lncRNA) gene identified as a recurrent breakpoint of Burkitt's lymphomas. Human PVT1 gene is located on region 8q24.21, a well-known cancer risk region, and encodes at least 26 linear ncRNA isoforms and 26 circular RNA isoforms, as well as 6 microRNAs. Several PVT1 functioning models have been reported recently such as competing endogenous RNA (ceRNA) activity and regulating protein stability of oncogenes, especially MYC oncogene. The promoter of PVT1 gene is a boundary element of tumor-suppressor DNA. CircPVT1 derived from PVT1 gene is also a critical non-coding oncogenic RNA. Although substantial advancements have been made in understanding the roles of PVT1 in cancer recently, the detailed mechanisms underlying its functions remain unclear. Herein, we summarize the recent progressions on the mechanisms underlying PVT1 regulated gene expression at different levels. We also discuss the interaction between lncRNA and protein, RNA and DNA, as well as the potential cancer therapy strategy by targeting these networks.

7-Ketocholesterol accelerates pancreatic ß-cell senescence by inhibiting the SIRT1/CDK4-Rb-E2F1 signaling pathway.

Pancreatic ß-cell dysfunction is a key factor in the development of type 2 diabetes. Pancreatic ß-cell senescence accelerates abnormal glucose metabolism, which decreases insulin secretion and cell regeneration ability, eventually leading to diabetes. A cholesterol oxidation product, 7-ketocholesterol (7-KC) can affect pancreatic ß-cell function. However, its role in pancreatic ß-cell senescence has not been reported. We investigated the role of 7-KC in pancreatic ß-cell senescence and its underlying molecular mechanism in MIN6 cells. MIN6 cells were treated with 25 µmol/L 7-KC for 24 h and the proportion of senescent cells was detected based on senescence-associated ß-galactosidase (SA-ß-gal) activity. The cell cycle, DNA damage, and the senescence-associate secretory phenotype (SASP) and protein expression were detected by flow cytometry, immunofluorescence, and western blotting, respectively. 7-KC can significantly increase SA-ß-gal activity, promoted G0/G1 arrest, DNA damage, and interleukin-1ß expression in MIN6 cells and significantly inhibited insulin synthesis. Further studies indicated that 7-KC induced ß-cell senescence by inhibiting the SIRT1/CDK4-Rb - E2F1 signaling pathway.

Transthyretin knockdown recapitulates the insulin-sensitizing effects of exercise and promotes skeletal muscle adaptation to exercise endurance.

Liver transthyretin (TTR) synthesis and release are exacerbated in insulin-resistant states but are decreased by exercise training, in relation to the insulin-sensitizing effects of exercise. We hypothesized that TTR knockdown (TTR-KD) may mimic this exercise-induced metabolic improvement and skeletal muscle remodeling. Adeno-associated virus-mediated TTR-KD and control mice were trained for 8 weeks on treadmills. Their metabolism status and exercise capacity were investigated and then compared with sedentary controls. After treadmill training, the mice showed improved glucose and insulin tolerance, hepatic steatosis, and exercise endurance. Sedentary TTR-KD mice displayed metabolic improvements comparable to the improvements in trained mice. Both exercise training and TTR-KD promoted the oxidative myofiber compositions of MyHC I and MyHC IIa in the quadriceps and gastrocnemius skeletal muscles. Furthermore, training and TTR-KD had an additive effect on running performance, accompanied by substantial increases in oxidative myofiber composition, Ca2+-dependent Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity, and the downstream expression of PGC1α as well as the unfolded protein response (UPR) segment of PERK-p-eIF2a pathway activity. Consistent with these findings, electrical pulse stimulation of an in vitro model of chronic exercise (with differentiated C2C12 myoblasts) showed that exogenous TTR protein was internalized and localized in the endoplasmic reticulum, where it disrupted Ca2+ dynamics; this led to decreases in intracellular Ca2+ concentration and downstream pathway activity. TTR-KD may function as an exercise/Ca2+-dependent CaMKII-PGC1α-UPR regulator that upregulates the oxidative myofiber composition of fast-type muscles; it appears to mimic the effect of exercise training on insulin sensitivity-related metabolic improvement and endurance capacity.

Drug-induced hypersensitivity syndrome induced by propylthiouracil: case report and literature review.

BACKGROUND: Drug-induced hypersensitivity syndrome (DIHS) is a rare, potentially life-threatening systemic drug reaction. Antithyroid drugs (ATDs) causing DIHS have seldom been reported before. CASE PRESENTATION: We present a case of propylthiouracil (PTU)-induced DIHS, which included fever, skin rash, lymphadenopathy, hepatosplenomegaly, serious liver and kidney dysfunction, peripheral blood eosinophilia, and atypical lymphocytosis. Following supportive therapy, intravenous immunoglobulin (IVIG), and systemic corticosteroid, the patient experienced a resolution of fever and rash combined with progressive normalization of hematological index and organ function. These clinical features, and the skin lesion biopsy confirmed DIHS diagnosis. CONCLUSIONS: To our knowledge, this is the second reported case of PTU-induced DIHS worldwide and the first human leukocyte antigen (HLA) typing of PTU-induced DIHS. Clinicians should cautiously distinguish hyperthyroidism etiology and identify the indication of ATDs. Timely recognition and formal DIHS treatment are required in patients with ATDs.

The Different Effects of Skeletal Muscle and Fat Mass on Height Increment in Children and Adolescents Aged 6-11 Years: A Cohort Study From China.

Objective: This study aimed to investigate the contribution of body composition including skeletal muscle mass (SMM) and body fat mass (BFM) to longitudinal growth among children and adolescents aged 6-11 years old. Methods: This cohort study was conducted from the annual health examination between 2019 and 2020. Annual height gain and weight gain and changes in SMM and BFM were calculated and compared between sexes, different nutritional status, and growth curve shifting mode. Spearman analyses and multiple linear regression analysis were performed to identify the impact of SMM, BFM, or body mass index (BMI) on height gain. Results: Of the 584 subjects, the annual height gains of boys (4.76 cm in the 6-9-year group and 4.63 cm in the 10-11-year group) were significantly lower than those of girls (5.48 and 5.74 cm, respectively). Spearman analysis showed that SMM gain and height gain were positively and significantly correlated in each examination of all children (r = 0.535 for boys and 0.734 for girls, p < 0.001). Conversely, BFM and height gains were negatively (r = -0.5240 for boys and -0.232 for girls, p < 0.001) correlated. Multiple linear regression analysis identified SMM gain as an independent predictor (95% CI: 1.20,1.44) of height gain after adjusting for age, gender, BMI, BFM gain, and percentage of body fat (PBF). Conclusion: SMM gains, rather than BFM gains, were associated with height gains in children and adolescents aged 6-11 years. Monitoring SMM changes in routine healthcare might motivate children and adolescents to achieve dietary and exercise recommendations, thereby growing taller without gaining excessive weight.

Obesity: Epidemiology, Pathophysiology, and Therapeutics.

Obesity is a complex multifactorial disease that accumulated excess body fat leads to negative effects on health. Obesity continues to accelerate resulting in an unprecedented epidemic that shows no significant signs of slowing down any time soon. Raised body mass index (BMI) is a risk factor for noncommunicable diseases such as diabetes, cardiovascular diseases, and musculoskeletal disorders, resulting in dramatic decrease of life quality and expectancy. The main cause of obesity is long-term energy imbalance between consumed calories and expended calories. Here, we explore the biological mechanisms of obesity with the aim of providing actionable treatment strategies to achieve a healthy body weight from nature to nurture. This review summarizes the global trends in obesity with a special focus on the pathogenesis of obesity from genetic factors to epigenetic factors, from social environmental factors to microenvironment factors. Against this background, we discuss several possible intervention strategies to minimize BMI.