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Fascial adipocytes are recently identified as a unique population of adipose cells, which have different developmental origins, anatomical locations, cytological and functional characteristics compared with subcutaneous or visceral adipocytes. Superficial fascia in rats (also in pigs but not obviously in mice) contains numbers of lineage committed preadipocytes which possess adipogenic potential in vivo. The present study aimed to investigate the physiological factors that contribute to fascial adipogenesis in rats. We detected that mast cells, adipose progenitor cells, and mature adipocytes distributed in certain fascia areas were closely associated with each other, and numerous heparin-loaded granules released from mast cells were distributed around fascial preadipocytes. The culture supernatants of rat peritoneal mast cells and RBL-2H3 mast cells contained 20–30 μg/ml of heparin, effectively activated PPAR-responsive luciferase activity, promoted mRNA and protein expressions of key adipogenic genes, and hence increased adipogenic differentiation of fascia- or epididymal adipose-derived stromal cells. Adipogenic effects of mast cell supernatants were mimicked by heparin but not by histamine or 5-hydroxytryptamine, and were antagonized by protamine sulfate. In rats, local administration of heparin-loaded microspheres for 30 days induced adipogenesis in local areas of superficial fascia. This adipogenic effects of heparin might be related by chain length of glucosamine units, because heparin stimulated stronger adipogenesis than dalteparin and enoxaparin with relatively short chains. Our findings suggested that mast cell and its granule heparin could serve as the endogenous physiological factors to initiate and accelerate local adipogenesis in superficial fascia, or in adipose tissue with the fascia naturally embedded inside.

The dermal adipocytes, superficial fascia and subcutaneous adipose tissue (SAT) exist in the interspaces between the dermis and muscular fascia. They are adjacent to each other and traditionally recognized as one SAT. Recently, the dermal adipocyte was redefined as a unique population independent from the SAT. Also, we identified a novel type of adipogenic progenitors in rat superficial fascia. This study aimed to examine cytological and functional characteristics of fascial adipocytes in rats. Superficial fascia had no adipocytes in neonatal rats but gradually appeared numbers of adipocytes in growing rats. Adipogenic progenitors were found to reside in fascia and had strong ability in spontaneous and induced adipogenic differentiation in vitro. Differentiated fascial adipocytes versus subcutaneous or visceral adipocytes expressed increased adipose triglyceride lipase but decreased beta-adrenoreceptor, perilipin-1 and hormone-sensitive lipase (HSL), thus having high basal lipolysis but low lipolysis response to catecholamines. Phosphorylation of perilipin-1 and HSL and translocation of HSL to lipid droplets were attenuated in response to catecholamines rather than post-adrenoreceptoral lipolytic stimulators. The results suggested that superficial fascia was an origin of adipocytes with distinct developmental, cytological and functional characteristics. We proposed that fascial adipocytes could be considered as a unique population of adipocytes in the body. The fascia origin of adipocytes as an adipogenic model might logically explain fat neogenesis occurred at anatomical locations where originally exist no adipose tissues and thereby no adipose-derived stromal precursors. Also, the special histoanatomical relations and overlaps between the dermis, superficial fascia, SAT, and their adipocytes were discussed.

Triptolide, an active ingredient extracted from the Chinese herb Tripterygium wilfordii Hook f., has multiple pharmacological properties, including anti-inflammatory, immune-modulatory, and anti-proliferative activities. However, the hepatotoxicity of triptolide always limits its clinical applications.Farnesoid X receptor (FXR) is a ligand-activated transcription factor that plays a key role in hepatoprotection through the maintenance of liver metabolism homeostasis. This study explored the role of FXR in triptolide-induced cytotoxicity and investigated whether activation of FXR can protect against triptolide-induced liver injury.The role of FXR in triptolide-induced cytotoxicity was investigated in HepG2 cells. In addition, the protective effect of the selective FXR agonist GW4064 on triptolide-induced hepatotoxicity was explored in BALB/c mice.HepG2 cells were transient transfected with FXR expression plasmid or FXR-siRNA. The cytotoxicity was compared using the MTT assay. The extent of liver injury was assessed by histopathology and serum aminotransferases. The expression of FXR and its target genes were detected by Western blot and qRT-PCR.The transient overexpression of FXR protected against triptolide-induced cell death, whereas FXR knockdown with a specific small interfering RNA resulted in increased cytotoxicity. In BALB/c mice, treatment with the FXR agonist GW4064 attenuated triptolide-induced liver dysfunction, structural damage, glutathione depletion and lipid peroxidation. Moreover, the livers of GW4064-treated mice showed increased expression of FXR and several related target genes involved in phase II and phase III xenobiotic metabolism.Taken together, these results indicate that activation of FXR attenuates triptolide-induced hepatotoxicity and provide direct implications for the development of novel therapeutic strategies against triptolide-induced hepatotoxicity.

Cisplatin is a potent anti-cancer agent for various types of tumors. However, the clinical use of cisplatin is often limited by its nephrotoxicity. This study reports that WZ tablet (WZ, a preparation of an ethanol extract of Schisandra sphenanthera) mitigates cisplatin-induced toxicity in renal epithelial HK-2 cells and in mice. Pretreatment of HK-2 cells with WZ ameliorated cisplatin-induced cytotoxicity caused by oxidative stress, as was demonstrated by reductions in the levels of reactive oxygen species (ROS) and increased levels of glutathione (GSH). WZ facilitated the nuclear accumulation of the transcription factor NF-E2-related factor 2 (Nrf2) and the subsequent expression of its target genes such as NAD(P)H:quinine oxidoreductase 1 (NQO1), heme oxygenase-1 (HO-1) and glutamate cysteine ligase (GCL). Protective effects of WZ on cisplatin-induced nephrotoxicity were also observed in mice. WZ attenuated cisplatin-induced renal dysfunction, structural damage and oxidative stress. The nuclear accumulation of Nrf2 and its target genes were increased by WZ treatment. Taken together, these findings demonstrated WZ have a protective effect against cisplatin-induced nephrotoxicity by activation of the Nrf2 mediated defense response, which is of significant importance for therapeutic intervention in cisplatin induced renal injury.

Background Tanshinone IIA (Tan), the main active component of Salvia miltiorrhiza, has been demonstrated to have antioxidant activity. Acetaminophen (APAP), a widely used antipyretic and analgesic, can cause severe hepatotoxicity and liver failure when taken overdose. Oxidative stress has been reported to be involved in APAP-induced liver failure. Purpose This study aimed to investigate the effect of Tan on APAP-induced hepatotoxicity and the underlying mechanisms involved. Study Design C57BL/6 J mice were divided into six groups: (1) control, (2) APAP group, (3) APAP + Tan (30 mg/kg) group, (4) Tan (30 mg/kg) group, (5) APAP + Tan (10 mg/kg) group, (6) Tan (10 mg/kg) group. Mice in group 3 and 5 were pre-treated with specified dose of Tan by gavage and subsequently injected with an overdose of APAP intraperitoneally (i.p., 300 mg/kg). The effect of Tan on Nrf2 pathway was investigated in HepG2 cells and mice. Methods Plasma aspartate transaminase (ALT), aspartate transaminase (AST), lactate dehydrogenase (LDH), liver glutathione (GSH), glutathione transferase (GST), glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (CAT) levels were determined after mice were sacrificed. Lipid peroxidation and histological examination were performed. The effect of Tan on the Nrf2 pathway was detected by western blotting and qRT-PCR. Results Tan pretreatment reduced APAP-induced liver injury. Tan was able to activate Nrf2 and increase the expression levels of Nrf2 target genes, including glutamate-cysteine ligase catalytic subunit (GCLC), NAD(P)H:quinine oxidoreductase 1 (NQO1) and hemeoxygenase-1 (HO-1), in a dose-dependent manner in HepG2 cells. Consistent with our observations in HepG2 cells, Tan increased nuclear Nrf2 accumulation and upregulated mRNA and protein levels of the Nrf2 target genes GCLC, NQO1 and HO-1 in C57BL/6 J mice compared with mice treated with APAP alone. Conclusions Our results demonstrate that Tan pretreatment could protect the liver from APAP-induced hepatic injury by activating the Nrf2 pathway. Tan may provide a new strategy for the protection against APAP-induced liver injury.

Diammonium glycyrrhizinate (DG), an active compound extracted and purified from liquorices root, has been reported to exhibit antioxidant and anti-inflammatory properties. The aim of this study was to investigate the effect and underlying mechanisms of DG on the hepatotoxicity induced by valproic acid (VPA). DG at the dose of 60mg/kg was orally administered with VPA (100mg/kg) to mice once daily for 14 consecutive days. DG treatment attenuated VPA-induced liver dysfunction, structural damage, glutathione depletion and decrease in antioxidant enzymes in BALB/C mice. DG prevented VPA-induced depletion of cytosolic nuclear factor E2-related factor 2 (Nrf2) and suppression of nuclear translocation of Nrf2, which, in turn, up-regulated phase II/antioxidant enzyme activities. The effects of VPA and DG on Nrf2 expression in HepG2 cells were in consistent with that of mice. Furthermore, an increase in the nuclear levels of nuclear factor-kappaB (NF-κB) was observed in the livers of VPA-treated mice that coincided with induction of inflammatory cytokines. In contrast, DG inhibited NF-κB translocation and that subsequently decreased inflammatory cytokines. Taken together, these results demonstrate that DG attenuates VPA-induced liver injury through increasing the expression of Nrf2 mediated phase II/antioxidant enzymes and simultaneously decreasing the expression of inflammatory mediators.

Triptolide, the major active component of Tripterygium wilfordii Hook f. (TWHF), has a wide range of pharmacological activities. However, the toxicities of triptolide, particularly the hepatotoxicity, limit its clinical application. The hepatotoxicity of triptolide has not been well characterized yet. The aim of this study was to investigate the role of NF-E2-related factor 2 (Nrf2) in triptolide-induced toxicity and whether activation of Nrf2 could protect against triptolide-induced hepatotoxicity. The results showed that triptolide caused oxidative stress and cell damage in HepG2 cells, and these toxic effects could be aggravated by Nrf2 knockdown or be counteracted by overexpression of Nrf2. Treatment with a typical Nrf2 agonist, sulforaphane (SFN), attenuated triptolide-induced liver dysfunction, structural damage, glutathione depletion and decrease in antioxidant enzymes in BALB/C mice. Moreover, the hepatoprotective effect of SFN on triptolide-induced liver injury was associated with the activation of Nrf2 and its downstream targets. Collectively, these results indicate that Nrf2 activation protects against triptolide-induced hepatotoxicity.