The phytochemical hyperforin triggers thermogenesis in adipose tissue via a Dlat-AMPK signaling axis to curb obesity.

Stimulation of adipose tissue thermogenesis is regarded as a promising avenue in the treatment of obesity. However, pharmacologic engagement of this process has proven difficult. Using the Connectivity Map (CMap) approach, we identified the phytochemical hyperforin (HPF) as an anti-obesity agent. We found that HPF efficiently promoted thermogenesis by stimulating AMPK and PGC-1α via a Ucp1-dependent pathway. Using LiP-SMap (limited proteolysis-mass spectrometry) combined with a microscale thermophoresis assay and molecular docking analysis, we confirmed dihydrolipoamide S-acetyltransferase (Dlat) as a direct molecular target of HPF. Ablation of Dlat significantly attenuated HPF-mediated adipose tissue browning both in vitro and in vivo. Furthermore, genome-wide association study analysis indicated that a variation in DLAT is significantly associated with obesity in humans. These findings suggest that HPF is a promising lead compound in the pursuit of a pharmacological approach to promote energy expenditure in the treatment of obesity.

The efficacy and safety of cold atmospheric plasma as a novel therapy for diabetic wound in vitro and in vivo.

Cold atmospheric plasma (CAP) is a group of various chemical active species, such as ozone and nitric oxide, generated by working gas. CAP was demonstrated to have an effect on tissue regeneration and wound healing. We conducted this study to evaluate the efficacy and safety of CAP as a novel therapy for diabetic wounds in vitro and in vivo. The plasma consists of ionised helium gas that is produced by a high-voltage and high-frequency power supply. Eight-week-old male db/db mice and C57BL mice were treated with helium gas (control group), 90s' CAP (low-dose group), and 180s' CAP (high-dose group). Mice were treated and observed for 2 weeks. Skin samples from around the wound and blood samples were collected. Our in vitro analysis included scratch wound-healing assays by using human HaCaT immortalised human epidermal cells. After 14 days of treatment, CAP could obviously promote diabetic wound healing. Wound closure rates were significantly higher in the low-dose group and high-dose groups compared with the control group. Meanwhile, compared with the control group, the protein expression of IL-6, tumour necrosis factor-α, inducible nitric oxide synthase, and superoxide dismutase in two CAP groups significantly decreased, while the protein expression of vascular endothelial growth factor and transforming growth factor-ß in two CAP groups significantly increased (all P < .05); these data show good agreement with the change in mRNA level (all P < .05). In vitro, scratch wound-healing assays showed that plasma treatment could effectively ensure healing within 3 minutes of exposure (all P < .05). In addition, no difference was found in histological observations of normal skin and the level of serum alanine transaminase, aspartate aminotransferase, blood urea nitrogen, creatinine, and white blood cells among the CAP groups and control group. CAP treatment for 3 minutes every day improves wound healing in diabetic mice by suppressing inflammation, reducing oxidative stress, and enhancing angiogenesis, involving several proteins signalling, and it is safe for the liver and kidney.

Yin Yang 1 protein ameliorates diabetic nephropathy pathology through transcriptional repression of TGFß1.

Transforming growth factor-ß1 (TGFß1) has been identified as a major pathogenic factor underlying the development of diabetic nephropathy (DN). However, the current strategy of antagonizing TGFß1 has failed to demonstrate favorable outcomes in clinical trials. To identify a different therapeutic approach, we designed a mass spectrometry-based DNA-protein interaction screen to find transcriptional repressors that bind to the TGFB1 promoter and identified Yin Yang 1 (YY1) as a potent repressor of TGFB1. YY1 bound directly to TGFB1 promoter regions and repressed TGFB1 transcription in human renal mesangial cells. In mouse models, YY1 was elevated in mesangial cells during early diabetic renal lesions and decreased in later stages, and knockdown of renal YY1 aggravated, whereas overexpression of YY1 attenuated glomerulosclerosis. In addition, although their duration of diabetic course was comparable, patients with higher YY1 expression developed diabetic nephropathy more slowly compared to those who presented with lower YY1 expression. We found that a small molecule, eudesmin, suppressed TGFß1 and other profibrotic factors by increasing YY1 expression in human renal mesangial cells and attenuated diabetic renal lesions in DN mouse models by increasing YY1 expression. These results suggest that YY1 is a potent transcriptional repressor of TGFB1 during the development of DN in diabetic mice and that small molecules targeting YY1 may serve as promising therapies for treating DN.

Beneficial effects of an 8-week, very low carbohydrate diet intervention on obese subjects.

Aim. To investigate the effects of weight loss during an 8-week very low carbohydrate diet (VLCD) on improvement of metabolic parameters, adipose distribution and body composition, and insulin resistance and sensitivity in Chinese obese subjects. Methods. Fifty-three healthy obese volunteers were given an 8-week VLCD. The outcomes were changes in anthropometry, body composition, metabolic profile, abdominal fat distribution, liver fat percent (LFP), and insulin resistance and sensitivity. Results. A total of 46 (86.8%) obese subjects completed the study. The VLCD caused a weight loss of -8.7 ± 0.6 kg (mean ± standard error (SE), P < 0.0001) combined with a significant improvement of metabolic profile. In both male and female, nonesterified fatty acid (NEFA) significantly decreased (-166.2 ± 47.6 µ mol/L, P = 0.001) and ß -hydroxybutyric acid (BHA) increased (0.15 ± 0.06 mmol/L, P = 0.004) after eight weeks of VLCD intervention. The significant reductions in subcutaneous fat area (SFA), visceral fat area (VFA), and LFP were -66.5 ± 7.9 cm(2), -35.3 ± 3.9 cm(2), and -16.4 ± 2.4%, respectively (all P values P < 0.0001). HOMA IR and HOMA ß significantly decreased while whole body insulin sensitivity index (WBISI) increased (all P values P < 0.001). Conclusion. Eight weeks of VLCD was an effective intervention in obese subjects. These beneficial effects may be associated with enhanced hepatic and whole-body lipolysis and oxidation.

Oral supplementation with cholecalciferol 800 IU ameliorates albuminuria in Chinese type 2 diabetic patients with nephropathy.

BACKGROUND: Low vitamin D levels can be associated with albuminuria, and vitamin D analogs are effective anti-proteinuric agents. The aim of this study was to investigate differences in vitamin D levels between those with micro- and those with macroalbuminuria, and to determine whether low dose cholecalciferol increases vitamin D levels and ameliorates albuminuria. METHODS: Two studies were performed in which 25-OH vitamin D(3) (25(OH)D(3)) concentrations were determined by electrochemiluminescence immunoassay: 1) a cross-sectional study of patients with type 2 diabetes mellitus (T2DM) (n = 481) and healthy controls (n = 78); and 2) a longitudinal study of T2DM patients with albuminuria treated with conventional doses, 800 IU, of cholecalciferol for 6 months (n = 22), and a control group (n = 24). RESULTS: 1) Cross-sectional study: Compared to controls and T2DM patients with normoalbuminuria, serum 25(OH)D(3) concentrations were significantly lower in patients with macro-albuminuria, but not in those with micro-albuminuria. Serum 25(OH)D(3) levels were independently correlated with microalbuminuria. 2) Longitudinal study: Cholecalciferol significantly decreased microalbuminuria in the early stages of treatment, in conjunction with an increase in serum 25(OH)D(3) levels. CONCLUSIONS: Low vitamin D levels are common in type 2 diabetic patients with albuminuria, particularly in patients with macroalbuminuria, but not in those with microalbuminuria. Conventional doses of cholecalciferol may have antiproteinuric effects on Chinese type 2 diabetic patients with nephropathy.