Takumi Yamane

The hypocholesterolemic activity of Momordica charantia fruit is mediated by the altered cholesterol- and bile acid–regulating gene expression in rat liver

Although many studies have demonstrated the hypocholesterolemic activity of Momordica charantia, also called bitter gourd fruit (BGF), the relative hypocholesterolemic mechanism is not fully understood. In the present study, we hypothesized that BGF alters hepatic gene expression of cholesterol- and bile acid-regulating proteins to improve blood cholesterol profiles. To clarify the mechanism, we fed 7-week-old male Wistar rats a high-cholesterol (HC) diet containing 5% BGF for 4 weeks and determined the cholesterol levels in the serum, liver and feces, concentrations of the fecal total bile acid, and the expression level of cholesterol- and bile acid-regulating genes. The HC diet with BGF supplementation showed a significant serum hypocholesterolemic activity compared with the HC diet without BGF. BGF intake also significantly increased the levels of fecal total bile acid, suggesting that BGF inhibited the reabsorption of bile acids into the intestine. Hepatic messenger RNA (mRNA) levels of small heterodimer partner (SHP) and liver receptor homolog-1, which are both involved in cholesterol 7α-hydroxylase (CYP7A1) regulation, were significantly decreased and increased, respectively, by BGF intake. In addition, BGF tended to increase the hepatic CYP7A1 mRNA level. Taken together, these results suggest that BGF not only decreases the reabsorption of bile acids into the intestine but also increases the conversion of cholesterol to bile acids by CYP7A1 up-regulation through the down-regulation of the hepatic farnesoid X receptor/SHP pathway.

Adiponectin promotes hyaluronan synthesis along with increases in hyaluronan synthase 2 transcripts through an AMP-activated protein kinase/peroxisome proliferator-activated receptor-α-dependent pathway in human dermal fibroblasts

Although adipocytokines affect the functions of skin, little information is available on the effect of adiponectin on the skin. In this study, we investigated the effect of adiponectin on hyaluronan synthesis and its regulatory mechanisms in human dermal fibroblasts. Adiponectin promoted hyaluronan synthesis along with an increase in the mRNA levels of hyaluronan synthase 2 (HAS2), which plays a primary role in hyaluronan synthesis. Adiponectin also increased the phosphorylation of AMP-activated protein kinase (AMPK). A pharmacological activator of AMPK, 5-aminoimidazole-4-carboxamide-1β-ribofuranoside (AICAR), increased mRNA levels of peroxisome proliferator-activated receptor-α (PPARα), which enhances the expression of HAS2 mRNA. In addition, AICAR increased the mRNA levels of HAS2. Adiponectin-induced HAS2 mRNA expression was blocked by GW6471, a PPARα antagonist, in a concentration-dependent manner. These results show that adiponectin promotes hyaluronan synthesis along with increases in HAS2 transcripts through an AMPK/PPARα-dependent pathway in human dermal fibroblasts. Thus, our study suggests that adiponectin may be beneficial for retaining moisture in the skin, anti-inflammatory activity, and the treatment of a variety of cutaneous diseases.

A high-fat diet reduces ceramide synthesis by decreasing adiponectin levels and decreases lipid content by modulating HMG-CoA reductase and CPT-1 mRNA expression in the skin.

SCOPE Molecules involved in skin function are greatly affected by nutritional conditions. However, the mechanism linking high-fat (HF) diets with these alterations is not well understood. This study aimed to investigate the molecular changes in skin function that result from HF diets. METHODS AND RESULTS Sprague-Dawley rats were fed HF diets for 28 days. The skin levels of ceramide, lipids and mRNAs involved in lipid metabolism were evaluated using TLC, oil red O staining and quantitative PCR, respectively. The serum adiponectin concentration was determined by ELISA. HF diets led to reduced ceramide levels and lowered skin lipid content. They also decreased mRNA levels of serine palmitoyltransferase (SPT) and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase in the skin and those of peroxisome proliferator-activated receptor-α -PPAR-α), which upregulates SPT and HMG-CoA reductase expression. The HF diets reduced the serum concentration of adiponectin, which acts upstream of PPAR-α. Finally, these diets led to increased mRNA levels of carnitine palmitoyltransferase-1, the rate-limiting enzyme that acts in β-oxidation. CONCLUSION Our study suggests that HF diets reduce ceramide and lipid synthesis in the skin by reducing levels of SPT and HMG-CoA reductase through lowered adiponectin and PPAR-α activity. Additionally, they decrease lipid content by enhancing β-oxidation.

High-fat diet reduces levels of type I tropocollagen and hyaluronan in rat skin.

Although it is known that nutritional conditions affect the skin function, little information is available on the effect of a high-fat (HF) diet on skin. In this study, Sprague-Dawley rats were fed HF diets for 28 days, and we investigated the effect of this diet on type I tropocollagen and hyaluronan in rat skin. The HF diets reduced the levels of type I tropocollagen, COL1A1 mRNA, hyaluronan, and rat hyaluronan synthase (rhas)2 mRNA, which play a primary role in hyaluronan synthase in the dermis. However, rhas3 mRNA level in the skin was increased. The HF diets also decreased the skin mRNA expression of transforming growth factor (TGF)-beta1, which enhances the expression of COL1A1 and rhas2 mRNA and decreases rhas3 mRNA expression, and decreased the hepatic mRNA expression of insulin-like growth factor (IGF)-I, which enhances COL1A1, rhas2, and TGF-beta1 mRNA expression. The serum level of adiponectin, which promotes the syntheses of type I collagen and hyaluronan, was decreased in the HF diet groups. These findings suggest that an HF diet reduces the levels of type I tropocollagen and hyaluronan in the skin by suppressing the action of TGF-beta1, IGF-I and adiponectin, and these effects are deleterious for skin function.

Hydrocellular foam dressing promotes wound healing along with increases in hyaluronan synthase 3 and PPARα gene expression in epidermis.

Background Hydrocellular foam dressing, modern wound dressing, induces moist wound environment and promotes wound healing: however, the regulatory mechanisms responsible for these effects are poorly understood. This study was aimed to reveal the effect of hydrocellular foam dressing on hyaluronan, which has been shown to have positive effects on wound healing, and examined its regulatory mechanisms in rat skin. Methodology/Principal Findings We created two full-thickness wounds on the dorsolateral skin of rats. Each wound was covered with either a hydrocellular foam dressing or a film dressing and hyaluronan levels in the periwound skin was measured. We also investigated the mechanism by which the hydrocellular foam dressing regulates hyaluronan production by measuring the gene expression of hyaluronan synthase 3 (Has3), peroxisome proliferator-activated receptor α (PPARα), and CD44. Hydrocellular foam dressing promoted wound healing and upregulated hyaluronan synthesis, along with an increase in the mRNA levels of Has3, which plays a primary role in hyaluronan synthesis in epidermis. In addition, hydrocellular foam dressing enhanced the mRNA levels of PPARα, which upregulates Has3 gene expression, and the major hyaluronan receptor CD44. Conclusions/Significance These findings suggests that hydrocellular foam dressing may be beneficial for wound healing along with increases in hyaluronan synthase 3 and PPARα gene expression in epidermis. We believe that the present study would contribute to the elucidation of the mechanisms underlying the effects of hydrocellular foam dressing-induced moist environment on wound healing and practice evidence-based wound care.

Hydrocellular foam dressings promote wound healing associated with decrease in inflammation in rat periwound skin and granulation tissue, compared with hydrocolloid dressings

The effects of modern dressings on inflammation, which represent the earliest phase of wound healing, are poorly understood. We investigated the effects of modern hydrocellular foam dressings (HCFs) on wound healing and on the gene expression levels of the inflammatory markers—interleukin (IL)-1β, IL-6, and IL-10—in rat periwound skin and granulation tissue by quantitative reverse transcription-polymerase chain reaction. HCF absorbed significantly higher volume of water than hydrocolloid dressing (HCD) and increased the contraction of wounds. Polymorphonuclear neutrophils were massively infiltrated to the wound edge and boarded between granulation and dermis in the HCD group. IL-1β, IL-6, and IL-10 mRNA levels were significantly decreased in the periwound skin around the wounds and granulation tissue covered with HCF. These findings suggest that HCF may promote wound healing along with decrease in inflammation by reducing gene expression levels of IL-1β, IL-6, and IL-10. Graphic·Abstract HCF promotes wound healing along with decreases in inflammation by reducing gene expression levels of IL-1β, IL-6 and IL-10 in rat periwound skin and granulation tissue.

Ultraviolet B Irradiation Reduces the Expression of Adiponectin in Ovarial Adipose Tissues through Endocrine Actions of Calcitonin Gene-Related Peptide-Induced Serum Amyloid A

Ultraviolet (UV) B irradiation decreases blood adiponectin levels, but the mechanism is not well understood. This study investigated how UVB irradiation reduces adiponectin expression in ovarial adipose tissues. Female Hos:HR-1 hairless mice were exposed to UVB (1.6 J/cm2) irradiation and were killed 24 h later. UVB irradiation decreased the adiponectin protein level in the serum and the adiponectin mRNA level in ovarial adipose tissues. UVB irradiation also decreased the mRNA levels of peroxisome proliferator-activated receptor (PPAR) γ, CCAAT/enhancer binding protein (C/EBP) α, C/EBPβ, and fatty acid binding protein 4 (aP2) in ovarial adipose tissues. In contrast, UVB irradiation increased the mRNA levels of interleukin (IL)-6 and monocyte chemoattractant protein (MCP)-1 in ovarial adipose tissues. In the serum and liver, the levels of serum amyloid A (SAA), involved in PPARγ, C/EBPα, C/EBPβ, aP2, IL-6, and MCP-1 regulation, increased after UVB irradiation. The SAA gene is regulated by IL-1β, IL-6, and tumor necrosis factor-α, but only IL-6 expression increased in the liver after UVB irradiation. Additionally, in the liver, hypothalamus, and epidermis, UVB irradiation increased the expression of calcitonin gene-related peptide (CGRP), which upregulates SAA in the liver. Collectively, our results suggest that the CGRP signal induced by skin exposure to UVB transfers to the liver, possibly through the brain, and increases SAA production via IL-6 in the liver. In turn, serum SAA acts in an endocrine manner to decreases the serum adiponectin level by downregulating factors that regulate adiponectin expression in adipose tissues.

Perfluorooctanoic acid binds to peroxisome proliferator-activated receptor γ and promotes adipocyte differentiation in 3T3-L1 adipocytes

We examined the effect of perfluorooctanoic acid (PFOA) on adipose cells using 3T3-L1 adipocytes and found that PFOA increased adipocyte differentiation, triglyceride accumulation, and the mRNA level of factors related to adipocyte differentiation. In addition, PFOA bound to peroxisome proliferator-activated receptor γ (PPAR γ). These results suggest that PFOA promotes adipocyte differentiation as a PPAR γ ligand.

Hydrocellular foam dressing increases the leptin level in wound fluid

Hydrocellular foam dressing (HCF) absorbs excessive wound fluid, which contains various cytokines and growth factors, and ensures a moist environment to promote wound healing. However, the molecular mechanisms underlying the wound fluid component changes induced by HCF are poorly understood. In the present study, we examined the effect of HCF on wound healing and the associated regulatory mechanisms in relation to variations in cytokine levels in the wound fluid. We created full‐thickness wounds on the dorsolateral skin of rats and collected the resulting wound fluid samples. HCF was immersed in a plate containing the wound fluids. HCF was then removed and the excess wound fluid remaining in the plate was examined by cytokine array and enzyme‐linked immunosorbent assay. We also used a rat model and human dermal fibroblast cultures to examine the effect of wound fluid component changes during the wound healing process. Upon treatment with HCF, leptin levels were upregulated in the wound fluid. Fibroblast proliferation was enhanced and the effect was suppressed in the presence of leptin antagonist. In our in vivo model, HCF increased wound contraction compared with film dressings and this positive effect of HCF was suppressed by addition of leptin antagonist. Our results suggest that dermal fibroblast proliferation is upregulated by HCF due to increased leptin level at the wound surface, and these effects promote wound healing. We believe that the present study contributes to furthering the understanding of the mechanisms underlying the effects of HCF‐induced wound healing.

Calcitonin gene-related peptide regulates mitogen-activated protein kinase pathway to decrease transforming growth factor β1-induced hepatic plasminogen activator inhibitor-1 mRNA expression in HepG2 cells.

Transforming growth factor (TGF) β1-induced plasminogen activator inhibitor (PAI)-1 is one of factors associated with the development of hepatic fibrosis. Calcitonin gene-related peptide (CGRP) shows hepatoprotective effect during hepatic injuries, including fibrosis. However, the effects of CGRP on PAI-1 expression induced by TGFβ1 are unknown. In this study, we investigated the effect of CGRP on TGFβ1-induced PAI-1 expression and its regulatory mechanisms in HepG2 cells. CGRP inhibited TGFβ1-induced PAI-1 expression. H89, a protein kinase A inhibitor, abolished the inhibition of TGFβ1-induced PAI-1 expression by CGRP. TGFβ1 activated mitogen-activated protein kinase (MAPK), including extracellular signal-regulated kinase, c-jun NH2-terminal kinase, and p38, and this activation was abolished by CGRP. These results show that the CGRP-induced cAMP/PKA activation suppresses activation of MAPK induced by TGFβ1, leading to decreased PAI-1 expression in HepG2 cells. Graphical Abstract The action of CGRP suppresses TGF-β1-induced expression of PAI-1 by decreasing the phosphorylation status of the MAPK pathways through activating the cAMP/PKA pathway in HepG2 cells.