Muscle Strength, but Not Muscle Mass, Is Associated with Left Ventricular Diastolic Function during Aging in Chinese.

Sarcopenia, a progressive and systemic skeletal muscle disorder, is closely related with the incidence of cardiovascular disease (CVD) and CVD-related mortality, but its association with cardiac structure and function during aging remains unclear, particularly in the absence of serious cardiovascular diseases. This study aimed to investigate the correlation of muscle mass and muscle strength, the main components of sarcopenia, with left ventricular mass and function in Chinese subjects.A total of 265 men and 70 women (aged 25-95 years) without serious diseases that could have pronounced impact on muscle and/or cardiovascular system were included. Left ventricular mass and function were assessed by echocardiography and muscle mass and grip strength were evaluated by dual-energy X-ray absorptiometry and a Jamar hand dynamometer, respectively.Grip strength and left ventricular diastolic function, rather than left ventricular mass, demonstrated age-dependent decline in both genders. Muscle mass in males and left ventricular systolic function in females declined with age. In the multivariate-adjusted model, grip strength rather than the relative appendicular skeletal muscle mass (RASM) was positively associated with E/A ratio (r = 0.154, P = 0.019) and e´-av (r = 0.175, P = 0.008), but was negatively correlated with E/e´-av ratio (r = -0.136, P = 0.038). No significant correlation was observed between RASM, grip strength and left ventricular mass, left ventricular ejection fraction or left ventricular fractional shortening. Higher grip strength is independently associated with better left ventricular diastolic function in Chinese during aging.

Age-Related Changes in Trabecular Bone Score and Bone Mineral Density in Chinese Men: A Cross-Sectional and Longitudinal Study.

Purpose: This study was designed to explore age-related changes in trabecular bone score (TBS) and bone mineral density (BMD) in Chinese men through cross-sectional and longitudinal studies. Patients and Methods: We included adult men who had at least twice TBS and BMD examinations in our hospital between January 2013 and December 2020. All men were divided into an age subgroup per 10 years, comparing differences in baseline lumbar spine (LS) TBS and BMD at various parts between each age group and analyzing age-related changes in TBS and BMD during follow-up. Results: Baseline data showed that in men aged 36 to 85 years, BMD in the hip region showed a decreasing trend with age (P for trend < 0.01). However, TBS reached a high value around the age of 50, after which it decreased with age (P for trend = 0.03). During a mean follow-up of 3 years, the average annual change rate at TBS was -0.17% in men aged 36 to 85 years, with the fastest decrease rate -1.08% at 66 to 75 years (P < 0.05). The mean annual rate of change in LS BMD in different age subgroups increased with age (P for trend = 0.001). There was no significant decrease in mean annual change in BMD in hip regions. Conclusion: In men aged 36~85 years, the trend of TBS was inconsistent with BMD. Men experience a high value of LS TBS around age 50, later than the commonly believed age of peak BMD, which may reflect developmental differences between bone microstructure and bone minerals. The TBS may be used as a better indicator of changes in bone strength than BMD in adult men at short-term follow-up. The rapid loss of TBS at age 66 to 75 may have implications for the prevention and medication of osteoporosis in men.

Correlation of sarcopenia and depressive mood in older community dwellers: a cross-sectional observational study in China.

OBJECTIVE: Whether sarcopenia is detrimental to depression is still controversial, which may be due to the three components of the sarcopenia. Our objective was to define the correlation between depression and sarcopenia in older Chinese community dwellers. DESIGN: The study has a cross-sectional design. SETTING: The study was conducted in Jiangsu, China. PARTICIPANTS: A total of 101 men and 149 women aged 60 years or older were recruited. OUTCOME MEASURES: Lean tissue mass was measured by dual-energy X-ray absorptiometry. Muscle strength in the upper and lower limbs was measured by a handheld dynamometer and a chair stand test, respectively. Physical performance was assessed by gait speed and standing balance tests. Depressive mood was assessed using the Geriatric Depression Scale-30 (range 0-30). RESULTS: Participants in the sarcopenia group had a higher mean depression score than the normal group (p=0.002). Pearson's correlation analysis showed that depression was negatively associated with muscle strength (handgrip strength: R=-0.170, p=0.028 for women, R=-0.196, p=0.048 for men; chair stand test performance: R=0.252, p=0.002 for women, R=0.311, p=0.001 for men) and physical performance (gait speed: R=-0.200, p=0.009, standing balance test performance: R=-0.224, p=0.006, Short Physical Performance Battery (SPPB): R=-0.218, p=0.007 for women; SPPB: R=-0.252, p=0.01 for men). Multiple linear regression models revealed that depressive mood was inversely associated with chair stand test (ß=0.325, p<0.001), gait speed (ß=-0.009, p=0.041) and standing balance test (ß=-0.24, p=0.016) after adjusting for confounding factors, while no significant correlation was observed between depressive mood and muscle mass. CONCLUSION: The diagnostic components of sarcopenia-strength of the leg muscles (chair stand test) and physical performance (gait speed and standing balance test)-were associated with depressive mood.

Core Outcome Set for Clinical Trials on Coronavirus Disease 2019 (COS-COVID).

Since its outbreak in December 2019, a series of clinical trials on coronavirus disease 2019 (COVID-19) have been registered or carried out. However, the significant heterogeneity and less critical outcomes of such trials may be leading to a waste of research resources. This study aimed to develop a core outcome set (COS) for clinical trials on COVID-19 in order to tackle the outcome issues. The study was conducted according to the Core Outcome Measures in Effectiveness Trials (COMET) Handbook: Version 1.0, a guideline for COS development. A research group was set up that included experts in respiratory and critical medicine, traditional Chinese medicine (TCM), evidence-based medicine, clinical pharmacology, and statistics, in addition to medical journal editors. Clinical trial registry websites (www.chictr.org.cn and clinicaltrials.gov) were searched to retrieve clinical trial protocols and outcomes in order to form an outcome pool. A total of 78 clinical trial protocols on COVID-19 were included and 259 outcomes were collected. After standardization, 132 outcomes were identified within seven different categories, of which 58 were selected to develop a preliminary outcome list for further consensus. After two rounds of Delphi survey and one consensus meeting, the most important outcomes for the different clinical classifications of COVID-19 were identified and determined to constitute the COS for clinical trials on COVID-19 (COS-COVID). The COS-COVID includes one outcome for the mild type (time to 2019 novel coronavirus (2019-nCoV) reverse transcription-polymerase chain reaction (RT-PCR) negativity), four outcomes for the ordinary type (length of hospital stay, composite events, score of clinical symptoms, and time to 2019-nCoV RT-PCR negativity), five outcomes for the severe type (composite events, length of hospital stay, arterial oxygen partial pressure (PaO2)/fraction of inspired oxygen (FiO2), duration of mechanical ventilation, and time to 2019-nCoV RT-PCR negativity), one outcome for critical type (all-cause mortality), and one outcome for rehabilitation period (pulmonary function). The COS-COVID is currently the most valuable and practical clinical outcome set for the evaluation of intervention effect, and is useful for evidence assessment and decision-making. With a deepening understanding of COVID-19 and application feedback, the COS-COVID should be continuously updated.

Bone mineral density and trabecular bone score in Chinese subjects with sarcopenia.

BACKGROUND: As the general population is aging worldwide, the incidence of sarcopenia and osteoporosis is also rapidly increasing. Studies have found the link between sarcopenia and osteoporosis, but the relationship between sarcopenia and osteoporosis, especially bone microarchitecture, remains unclear. AIMS: To investigate the relationship between components of sarcopenia (muscle mass, handgrip strength, and gait speed) and components of osteoporosis [bone mass measured by bone mineral density (BMD) and bone microarchitecture measured by trabecular bone score (TBS)] in Chinese subjects. METHODS: 318 Chinese men and 203 Chinese women were included in our study. Muscle mass and BMD were measured by dual-energy X-ray absorptiometry (DXA). TBS iNsight® software was used for TBS. Jamar hydraulic hand dynamometer was used to assess muscle strength, and gait speed was used to assess physical performance. RESULTS: We found that the relative appendicular skeletal muscle mass (RASM) in both genders and handgrip strength in women correlated positively with TBS, RASM in men and handgrip strength in women correlated positively with BMDs. In the multiple linear regression model, RASM was positively associated with TBS in both genders, but no significant association was observed between RASM and BMDs. Interestingly, handgrip strength showed positive association with all evaluated BMDs and TBS in women, but not in men. Women with sarcopenia had lower TBS and BMDs at all evaluated sites. Men with sarcopenia had lower BMDs only at femur neck and total hip. CONCLUSIONS: The reduction of muscle mass and strength was significantly associated with decreased bone mass and deteriorated bone microarchitecture. More importantly, low muscle mass is an independent risk factor for bone microarchitecture in Chinese subjects.

The correlation of muscle thickness and pennation angle assessed by ultrasound with sarcopenia in elderly Chinese community dwellers.

Background: Sarcopenia is typically defined as the loss of muscle mass, strength and low physical performance with aging. Ultrasound is a safe and easy method for evaluating muscle mass and quality by muscle thickness (MT) and pennation angle (PA), respectively. Although the positive correlations between MT and muscle mass and handgrip strength were observed, the relationship between MT, PA and physical performance remains unclear. Purpose: This study aimed to investigate the correlation of aforementioned ultrasound parameters with muscle mass, muscle strength and physical performance and explore the utility of ultrasound in predicting sarcopenia. Patients and methods: A total of 265 elderly Chinese community dwellers were included. MT of both forearm and lower leg as well as PA of gastrocnemius was assessed by ultrasound. Muscle mass was assessed by dual-energy X-ray absorptiometry. Muscle strength was measured by a Jamar hand dynamometer. Physical performance was assessed by the Short Physical Performance Battery (SPPB). Results: Anterior radial MT in men and regional MTs except posterior fibula in women were negatively correlated with the age. No significant correlation was observed between PA and the age in both genders. Posterior tibial MT and posterior fibula MT were positively correlated with the relative appendicular skeletal muscle mass in men and women, respectively. Anterior ulnar MT was positively correlated with grip strength in both genders. Moreover, gastrocnemius medialis PA showed a positive association with gait speed and SPPB in women but not in men. Conclusion: A combination of posterior fibula MT, anterior ulnar MT and gastrocnemius medialis PA measured by muscle ultrasound is helpful for the assessment of sarcopenia in Chinese elderly women. In addition, a combination of posterior tibial MT and anterior ulnar MT measured by muscle ultrasound is helpful for the assessment of sarcopenia in Chinese elderly men.

Association of thyroid function with sarcopenia in elderly Chinese euthyroid subjects.

OBJECTIVES: With the increase in aging population worldwide, the incidence of sarcopenia is also increasing. Thyroid hormones are important regulators that can affect body composition and physical function. The association between thyroid hormone levels and sarcopenia in susceptible elderly euthyroid subjects remains unclear. In this study, we investigated the effect of thyroid hormone concentrations on body muscle mass, muscle strength and physical function related to sarcopenia in elderly Chinese euthyroid subjects. METHODS: A total of 94 elderly Chinese euthyroid subjects (73 men, 21 women) without medications or diseases which obviously affected muscle metabolism or thyroid function were included in our study. Concentrations of free triiodothyronine (FT3), free thyroxine (FT4) and thyroid-stimulating hormone (TSH) were determined by immunoassays. Appendicular skeletal muscle mass (ASM) was assessed by dual-energy X-ray absorptiometry. Handgrip strength was measured using a Jamar hand dynamometer, and physical function was assessed by the Short Physical Performance Battery (SPPB). RESULTS: Muscle function, both handgrip strength and SPPB, was negatively associated with age, and FT3 demonstrated age-dependent decline. Pearson's correlation analysis showed positive associations of FT3 with ASM, handgrip strength and SPPB. Neither FT4 nor TSH was associated with these parameters of sarcopenia in euthyroid subjects. Significantly positive correlations between FT3 and ASM, handgrip strength and SPPB were also observed in multiple linear regression analysis adjusted for age, gender and BMI, while no significant correlations were found between FT4 or TSH and aforementioned four parameters of sarcopenia. Subjects with sarcopenia had lower level of FT3. CONCLUSIONS: Higher FT3 concentration within normal range was correlated to muscle mass and muscle function in elderly subjects.

Age-associated changes of resting energy expenditure, body composition and fat distribution in Chinese Han males.

Age-related alterations in whole body composition, particularly, reduced fat free mass (FFM) and increased fat mass (FM), lead to a progressive decline in resting energy expenditure (REE). Similarly, regional body composition and fat distribution changes with age might also contribute to an overall lower REE. This study investigated the influence of age on REE, regional body composition and fat distribution, including subcutaneous fat (SF) and visceral fat (VF), in a Chinese Han population as well as their contributions to age-related changes in REE. One hundred and two males aged 31-83 years old underwent dual-energy X-ray absorptiometry (DXA) which measured whole body and regional FM and FFM. SF and VF were measured by magnetic resonance imaging (MRI) and REE by indirect calorimetry. Age was significantly negatively correlated with REE (r = -0.37), total FFM (r = -0.25), upper limbs FFM (r = -0.32), lower limbs FFM (r = -0.34) and showed positive association with trunk FFM (ß=0.926). FM, SF and VF decreased in older age groups after an initial rise up to 55-65 years. REE correlated positively to FM, FFM, SF, VF and showed significant association with age (ß = -0.254) independent of age-associated changes in body composition. The regional alterations in body composition with age were explained by changes in trunk FFM (ß = 0.926). Age-related decline in REE were not solely due to alterations in FM and FFM. Therefore, the changes in regional body composition, fat distribution and REE which occur during aging could be explained by disparities in race, ethnicity, diet, physical activity, and lower specific metabolic rates of FFM components.

11ß-hydroxysteroid dehydrogenase type 1 inhibitor attenuates high-fat diet induced cardiomyopathy.

BACKGROUND: High-fat diet (HFD) induces cardiac hypertrophy; however, the underlying cellular and molecular mechanisms are yet unclear. In the present study, we investigated the roles of 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1), an amplifier of local glucocorticoid activity, in the pathogenesis of cardiac dysfunction. METHODS: Male Wistar rats were fed normal chow diet (NC) or HFD and examined the cardiac remolding and functional alteration by echocardiography and histology. Primary neonatal rat ventricular cardiomyocytes (NRCMs) treated with palmitic acid (PA) or infected by lentivirus were used for identifying the role by 11ß-HSD1 in cardiac hypertrophy. Genome microarray of NRCMs was performed to further reveal the mechanism underlying cardiac dysfunction. RESULTS: Palmitic acid induced hypertrophy in NRCMs that upregulated 11ß-HSD1 expression in cardiomyocytes, which led to a significant enlargement in the cell size and expression of cardiac hypertrophy-specific genes. Conversely, a remarkable decrease in cardiomyocytes size was detected in either BVT.2733 (a selective inhibitor of 11ß-HSD1)-treated or 11ß-HSD1-deficient NRCMs. Furthermore, both glucocorticoid receptor (GR) antagonist RU486 and mineralocorticoid receptor (MR) antagonist spironolactone markedly attenuated the 11ß-HSD1-induced cardiomyocytes hypertrophy. Genome microarray revealed that cAMP and calcium signaling pathways are potential downstream signaling pathways regulated by 11ß-HSD1 in cardiomyocytes hypertrophy. Similar to in vitro results, BVT.2733 strikingly attenuated cardiac hypertrophy and improved cardiac function in HFD-fed rats. CONCLUSION: 11ß-HSD1 acts as an important regulator that controls the cardiac remolding via both GR and MR and the pharmacological inhibition of 11ß-HSD1 could be a new therapeutic approach in preventing HFD-induced cardiac hypertrophy.

MiR-27b-3p Regulation in Browning of Human Visceral Adipose Related to Central Obesity.

OBJECTIVE: Given the rising prevalence of central obesity and the discovery that beige cells appear within white adipose tissue, strategies to enhance these energy-expending adipocytes or "browning" within white adipose depots have become of therapeutic interest to combat obesity and its associated disorders. This study focused on, the role of microRNA (miRNA)-27b-3p in human visceral adipose tissue (VAT) browning. METHODS: Expression of miR-27b-3p and UCP1 in VAT and serum of humans was measured. MiR-27b-3p was overexpressed or suppressed in human visceral stromal fraction cells to analyze the potential role of miR-27b-3p. RESULTS: UCP1 expression in human VAT decreased with elevated BMI and waist-hip ratio, whereas expression of miR-27b-3p was found to correlate positively with BMI and waist-hip ratio. High expression of miR-27b-3p was associated with reduced browning ability of human visceral adipocytes. Antagonism of miR-27b-3p led to the enhancement of browning ability in human visceral adipocytes. CONCLUSIONS: These findings highlight the decreased browning ability of VAT from humans with obesity and the role of miR-27b-3p in regulating browning of human visceral adipocytes. They suggest that miR-27b-3p should be further explored as a potential target for the treatment of central obesity.

Opposing effects on cardiac function by calorie restriction in different-aged mice.

Calorie restriction (CR) increases average and maximum lifespan and exhibits an apparent beneficial impact on age-related diseases. Several studies have shown that CR initiated either in middle or old age could improve ischemic tolerance and rejuvenate the aging heart; however, the data are not uniform when initiated in young. The accurate time to initiate CR providing maximum benefits for cardiac remodeling and function during aging remains unclear. Thus, whether a similar degree of CR initiated in mice of different ages could exert a similar effect on myocardial protection was investigated in this study. C57BL/6 mice were subjected to a calorically restricted diet (40% less than the ad libitum diet) for 3 months initiated in 3, 12, and 19 months. It was found that CR significantly reversed the aging phenotypes of middle-aged and old mice including cardiac remodeling (cardiomyocyte hypertrophy and cardiac fibrosis), inflammation, mitochondrial damage, telomere shortening, as well as senescence-associated markers but accelerated in young mice. Furthermore, whole-genome microarray demonstrated that the AMP-activated protein kinase (AMPK)-Forkhead box subgroup 'O' (FOXO) pathway might be a major contributor to contrasting regulation by CR initiated in different ages; thus, increased autophagy was seen in middle-aged and old mice but decreased in young mice. Together, the findings demonstrated promising myocardial protection by 40% CR should be initiated in middle or old age that may have vital implications for the practical nutritional regimen.

Assessment of Fat distribution and Bone quality with Trabecular Bone Score (TBS) in Healthy Chinese Men.

Whether fat is beneficial or detrimental to bones is still controversial, which may be due to inequivalence of the fat mass. Our objective is to define the effect of body fat and its distribution on bone quality in healthy Chinese men. A total of 228 men, aged from 38 to 89 years, were recruited. BMD, trabecular bone score (TBS), and body fat distribution were measured by dual-energy X-ray absorptiometry. Subcutaneous and visceral fat were assessed by MRI. In the Pearson correlation analysis, lumbar spine BMD exhibited positive associations with total and all regional fat depots, regardless of the fat distribution. However, the correlation disappeared with adjusted covariables of age, BMI, HDL-C, and HbA1c%. TBS was negatively correlated with fat mass. In multiple linear regression models, android fat (and not gynoid, trunk, or limbs fat) showed significant inverse association with TBS (ß = -0.611, P < 0.001). Furthermore, visceral fat was described as a pathogenic fat harmful to TBS, even after adjusting for age and BMI (ß = -0.280, P = 0.017). Our findings suggested that body fat mass, especially android fat and visceral fat, may have negative effects on bone microstructure; whereas body fat mass contributes to BMD through mechanical loading.

Determination of UCP1 expression in subcutaneous and perirenal adipose tissues of patients with hypertension.

The objective of this study is to determine the property of human perirenal adipose tissue (PAT) and assess the adipose property of PAT in hypertension. Ninety-four patients, including 64 normotensive patients (T-NP) and 30 hypertensive patients (HP), who underwent renal surgery were included. Expression analysis was performed using quantitative real-time polymerase chain reaction, Western blot, and immunohistochemistry in PAT and back subcutaneous adipose tissue (bSAT) depots. Compared with bSAT, PAT adipocytes were smaller, and the expressions of uncoupling protein-1 (UCP1) mRNA and protein were markedly higher, while the mRNA expressions of markers for classic beige and white adipocytes were lower in PAT. Immunohistochemistry analysis showed more multilocular UCP1-positive adipocytes in PAT than in bSAT. UCP1 expressions were lower in PAT in HP than in the T-NP or age- and body mass index-matched NP groups. Bigger unilocular adipocytes with less UCP1 staining in PAT were detected in HP than in NP group, although no such difference was observed in bSAT. PAT acts as a brown-like fat. UCP1 expression of PAT was lower in HP than in normotensive patients. UCP1 expression of PAT may serve as a protective indicator for hypertension.

Glucocorticoids transcriptionally regulate miR-27b expression promoting body fat accumulation via suppressing the browning of white adipose tissue.

Long-term glucocorticoid (GC) treatment induces central fat accumulation and metabolic dysfunction. We demonstrate that microRNA-27b (miR-27b) plays a central role in the pathogenesis of GC-induced central fat accumulation. Overexpression of miR-27b had the same effects as dexamethasone (DEX) treatment on the inhibition of brown adipose differentiation and the energy expenditure of primary adipocytes. Conversely, antagonizing miR-27b function prevented DEX suppression of the expression of brown adipose tissue-specific genes. GCs transcriptionally regulate miR-27b expression through a GC receptor-mediated direct DNA-binding mechanism, and miR-27b suppresses browning of white adipose tissue (WAT) by targeting the three prime untranslated region of Prdm16. In vivo, antagonizing miR-27b function in DEX-treated mice resulted in the efficient induction of brown adipocytes within WAT and improved GC-induced central fat accumulation. Collectively, these results indicate that miR-27b functions as a central target of GC and as an upstream regulator of Prdm16 to control browning of WAT and, consequently, may represent a potential target in preventing obesity.

Single-molecule conductance of dipyridines binding to Ag electrodes measured by electrochemical scanning tunneling microscopy break junction.

We have measured the conductance of three pyridyl-terminated molecules binding to Ag electrodes by using electrochemical jump-to-contact scanning tunneling microscopy break junction approach (ECSTM-BJ). Three molecules, including 4,4'-bipyridine (BPY), 1,2-di(pyridin-4-yl)ethene (BPY-EE), and 1,2-di(pyridin-4-yl)ethane (BPY-EA), contacting with Ag electrodes show three sets of conductance values, which follow the order of BPY > BPY-EE > BPY-EA. These values are smaller than those of molecules with Au electrodes, but larger than those of molecules with Cu electrodes. The difference may attribute to the different electronic coupling efficiencies between the molecules and electrodes. Moreover, the influence of the electrochemical potential on the Fermi level of electrodes is also discussed.

11ß-Hydroxysteroid dehydrogenase type 1 selective inhibitor BVT.2733 protects osteoblasts against endogenous glucocorticoid induced dysfunction.

Pharmacologic glucocorticoids (GCs) inhibit osteoblast function and induce osteoporosis. 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) may play a role in osteoporosis as it regulates GC action at a pre-receptor level by converting inactive GC to its active form. Further, 11ß-HSD1 was found increasingly expressed in bone with age. In spite of these observations, its function in senile osteoporosis remains uncertain. In this study we constructed a lentiviral vector overexpressing mouse 11ß-HSD1 and then MC3T3-E1 preosteoblast cells were infected by the negative control lentivirus and 11ß-HSD1-overexpressing lentivirus, respectively. The mRNA and protein levels of 11ß-HSD1 were significantly increased in MC3T3-E1 cells that were infected by 11ß-HSD1-overexpressing lentivirus compared to the cells infected by the negative control lentivirus. The osteogenic differentiation of MC3T3-E1 preosteoblast cells was dramatically suppressed by 11ß-HSD1 overexpression under the reductase substrate dehydrocorticosterone (DHC). The inhibition effect was similar to the inhibition of osteogenesis by over-dose GCs, including ALP activity, the ultimate calcium nodus formation as well as the expression of the osteogenic genes such as ALP, BSP, OPN and OCN. However, with addition of BVT.2733, a selective inhibitor of 11ß-HSD1, all of the above osteogenic repression effects by 11ß-HSD1 overexpression were reversed. Furthermore, a GC receptor antagonist RU486 also showed the similar effect, preventing inhibition of osteogenesis by 11ß-HSD1 overexpression. These results demonstrated that the specific 11ß-HSD1 inhibitor BVT.2733 can reverse the suppression effect towards osteogenic differentiation in 11ß-HSD1 overexpressed MC3T3-E1 cells. Inhibition of 11ß-HSD1 can be a new therapeutic strategy for senile osteoporosis.

Essential roles of 11ß-HSD1 in regulating brown adipocyte function.

Brown adipose tissue (BAT) increases energy expenditure and is an attractive therapeutic target for obesity. 11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1), an amplifier of local glucocorticoid activity, has been shown to modulate white adipose tissue (WAT) metabolism and function. In this study, we investigated the roles of 11ß-HSD1 in regulating BAT function. We observed a significant increase in the expression of BAT-specific genes, including UCP1, Cidea, Cox7a1, and Cox8b, in BVT.2733 (a selective inhibitor of 11ß-HSD1)-treated and 11ß-HSD1-deficient primary brown adipocytes of mice. By contrast, a remarkable decrease in BAT-specific gene expression was detected in brown adipocytes when 11ß-HSD1 was overexpressed, which effect was reversed by BVT.2733 treatment. Consistent with the in vitro results, expression of a range of genes related to brown fat function in high-fat diet-fed mice treated with BVT.2733. Our results indicate that 11ß-HSD1 acts as a vital regulator that controls the expression of genes related to brown fat function and as such may become a potential target in preventing obesity.

BVT.2733, a selective 11ß-hydroxysteroid dehydrogenase type 1 inhibitor, attenuates obesity and inflammation in diet-induced obese mice.

BACKGROUND: Inhibition of 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) is being pursued as a new therapeutic approach for the treatment of obesity and metabolic syndrome. Therefore, there is an urgent need to determine the effect of 11ß-HSD1 inhibitor, which suppresses glucocorticoid action, on adipose tissue inflammation. The purpose of the present study was to examine the effect of BVT.2733, a selective 11ß-HSD1 inhibitor, on expression of pro-inflammatory mediators and macrophage infiltration in adipose tissue in C57BL/6J mice. METHODOLOGY/PRINCIPAL FINDINGS: C57BL/6J mice were fed with a normal chow diet (NC) or high fat diet (HFD). HFD treated mice were then administrated with BVT.2733 (HFD+BVT) or vehicle (HFD) for four weeks. Mice receiving BVT.2733 treatment exhibited decreased body weight and enhanced glucose tolerance and insulin sensitivity compared to control mice. BVT.2733 also down-regulated the expression of inflammation-related genes including monocyte chemoattractant protein 1 (MCP-1), tumor necrosis factor alpha (TNF-α) and the number of infiltrated macrophages within the adipose tissue in vivo. Pharmacological inhibition of 11ß-HSD1 and RNA interference against 11ß-HSD1 reduced the mRNA levels of MCP-1 and interleukin-6 (IL-6) in cultured J774A.1 macrophages and 3T3-L1 preadipocyte in vitro. CONCLUSIONS/SIGNIFICANCE: These results suggest that BVT.2733 treatment could not only decrease body weight and improve metabolic homeostasis, but also suppress the inflammation of adipose tissue in diet-induced obese mice. 11ß-HSD1 may be a very promising therapeutic target for obesity and associated disease.

Adipose tissue-targeted 11ß-hydroxysteroid dehydrogenase type 1 inhibitor protects against diet-induced obesity.

Current pharmacological treatments for obesity and metabolic syndrome have various limitations. Recently, adipose tissue 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) has been proposed as a novel therapeutic target for the treatment of obesity and metabolic syndrome. Nevertheless, there is no adipose tissue-targeted 11ß-HSD1 inhibitor available now. We sought to develop a new 11ß-HSD1 pharmacological inhibitor that homes specifically to the white adipose tissue and aimed to investigate whether adipose tissue-targeted 11ß-HSD1 inhibitor might decrease body weight gain and improve glucose tolerance in diet-induced obesity mice. BVT.2733, an 11ß-HSD1 selective inhibitor was connected with a peptide CKGGRAKDC that homes to white fat vasculature. CKGGRAKDC-BVT.2733 (T-BVT) or an equimolar mixture of CKGGRAKDC and BVT.2733 (NT-BVT) was given to diet-induced obesity mice for two weeks through subcutaneous injection. T-BVT decreased body weight gain, improved glucose tolerance and decreased adipocyte size compared with vehicle treated mice. In adipose tissue T-BVT administration significantly increased adiponectin, vaspin mRNA levels; In liver T-BVT administration decreased the mRNA level of phosphoenolpyruvate carboxykinase (PEPCK), increased the mRNA levels of mitochondrial carnitine palmi-toyltransferase-I (mCPT-I) and peroxisome proliferator-activated receptorα(PPARα). No significant differences in adipocyte size and hepatic gene expression were observed after treatment with NT-BVT compared with vehicle treated mice, though NT-BVT also decreased body weight gain, improved glucose tolerance, and increased uncoupling protein-2 (UCP-2) mRNA levels in muscle. These results suggest that an adipose tissue-targeted pharmacological inhibitor of 11ß-HSD1 may prove to be a new approach for the treatment of obesity and metabolic syndrome.

Association of polymorphism of DNA repair gene XRCC1 with sporadic late-onset Alzheimer's disease and age of onset in elderly Han Chinese.

Alzheimer's disease (AD) is characterized by the presence of beta-amyloid plaques, neurofibrillary tangles and extensive neuronal loss. There is evidence indicating that the increased DNA damages may contribute to neuronal loss in AD. Recently, it has been shown that the capacity of some types of DNA repair is impaired in the neurons of AD patients. A functional polymorphism (Arg194Trp) of X-ray repair cross-complementing group 1 (XRCC1) gene may be associated with the repair efficiency of DNA damage which may have a role in AD. Therefore, XRCC1 Arg194Trp polymorphism may be a good candidate for genetic risk analysis in AD. A case-control study from Turkey found that XRCC1 194Trp was associated with late-onset AD (LOAD). In order to determine whether the XRCC1 gene Arg194Trp polymorphism contributes to the risk for LOAD in elderly Han Chinese, we have investigated it in 212 sporadic LOAD patients and 203 healthy controls from Chinese. No significantly increased risk of LOAD in the carriers of XRCC1 194Trp allele (OR=1.04, 95% CI 0.70-1.52, P=0.860) was observed. As expected, Apolipoprotein (APOE) epsilon4 allele significantly increased the risk of LOAD (OR=2.95, 95% CI 1.90-4.58, P<0.001), while APOE epsilon2 allele significantly decreased the risk of LOAD (OR=0.13, 95% CI 0.08-0.24, P<0.001). After stratifying by APOE epsilon4 status, no increased LOAD risks associated with the XRCC1 194Trp allele carriers were observed. Our findings suggest that it is unlikely that the XRCC1 Arg194Trp polymorphism plays a major role in the pathogenesis of LOAD in elderly Han Chinese and does not support the previous findings that 194Trp allele confers an increased risk for LOAD.