The prevalence of metabolic diseases, including type 2 diabetes, obesity, and cardiovascular disease, has rapidly increased, yet the molecular mechanisms underlying the metabolic syndrome, a primary risk factor, remain incompletely understood. The small, gaseous molecule carbon monoxide (CO) has well-known anti-inflammatory, antiproliferative, and antiapoptotic effects in a variety of cellular- and tissue-injury models, whereas its potential effects on the complex pathways of metabolic disease remain unknown. We demonstrate here that CO can alleviate metabolic dysfunction in vivo and in vitro. We show that CO increased the expression and section of the fibroblast growth factor 21 (FGF21) in hepatocytes and liver. CO-stimulated PERK activation and enhanced the levels of FGF21 via the eIF2α–ATF4 signaling pathway. The induction of FGF21 by CO attenuated endoreticulum stress- or diet-induced, obesity-dependent hepatic steatosis. Moreover, CO inhalation lowered blood glucose levels, enhanced insulin sensitivity, and promoted energy expenditure by stimulating the emergence of beige adipose cells from white adipose cells. In conclusion, we suggest that CO acts as a potent inducer of FGF21 expression and that CO critically depends on FGF21 to regulate metabolic homeostasis.—Joe, Y., Kim, S., Kim, H. J., Park, J., Chen, Y., Park, H.-J., Jekal, S.-J., Ryter, S. W., Kim, U. H., Chung, H. T. FGF21 induced by carbon monoxide mediates metabolic homeostasis via the PERK/ATF4 pathway.

The protective effects of baicalin (BA), a major flavone from Scutellaria radix, on acetaminophen (AP)-induced hepatotoxicity and the possible mechanism(s) of its protective action were investigated in mice. Treatment with BA (300 mg/kg, p.o.) 0.5 h after AP administration significantly prevented an increase in plasma alanine aminotransferase and aspartate aminotransferase activities and AP-induced hepatic necrosis, and also reduced AP-induced mortality from 43% to 0%. In addition, oral treatment with BA significantly prevented AP-induced depletion of glutathione (GSH) contents. However, BA treatment, by itself, did not affect hepatic GSH contents. The effect of BA on the cytochrome P450 2E1 (CYP2E1), the major isozyme involved in AP bioactivation, was investigated. Oral treatment of mice with BA resulted in a significant decrease in AP-induced CYP2E1 activity together with its inhibition of AP-induced CYP2EI expression. These results show that the hepatoprotective effects of BA against AP overdose may be due to its ability to block the bioactivation of AP by inhibiting CYP2E1 expression.

Pterostilbene, a dimethyl ester analog of resveratrol, has anti-inflammatory and antioxidative effects and alters cell proliferation. Tristetraprolin (TTP) promotes the degradation of proinflammatory mediators via binding to adenosine and uridine- (AU-) rich elements (ARE) located in the 3′-untranslated regions of mRNAs. Here, we utilized pterostilbene 4′-β-glucoside (4-PG), a compound derived from pterostilbene, to investigate whether it has anti-inflammatory effects on dextran sulfate sodium- (DSS-) induced colitis via TTP enhancement. TTP expression was increased in 4-PG dose- and time-dependent manners in RAW264.7 cells. The production of proinflammatory cytokine, such as TNF-α, was reduced by 4-PG in vitro. To investigate the role of TTP in the anti-inflammatory effects of 4-PG, we used DSS–induced colitis in TTP WT and KO mice as models. The expression levels of TTP and proinflammatory cytokines were determined in serum and colon tissue. 4-PG increased the expression of TTP while suppressing proinflammatory cytokines both in vitro and in vivo. These findings suggest that treatment with 4-PG mediates the anti-inflammatory effects of 4-PG on DSS-induced colitis via enhancing TTP expression.

Purpose: To determine the effects of 630 nm light emitting diode (LED) on full-thickness wound healing. Methods: Twelve male Sprague-Dawley rats were randomly divided into LED (n= 6) and control group (n= 6). Two 19.63 mm 2 wounds were created on the mid dorsum. LED group received a 630 nm LED irradiation with 3.67 mW/cm 2 for 30 minutes (6.60 J/cm 2) for 7 days, while control group received sham LED irradiation. Epithelial gap, collagen density, α-SMA fibroblast and PCNA keratinocyte were measured on histochemical and immunohistochemical staining using image analysis system. An independent t-test was conducted to compare the difference between groups. Results: The wound closure rate, collagen density, α-SMA fibroblast number, epithelial gap and PCNA keratinocyte number have shown no significant difference between LED and control group at day 3 after the treatment. At day 7 after the treatment, the wound closure rate in LED group was increased when compared with control group (p< 0.05). The collagen density (p< 0.05) and α-SMA immunoreactive fibroblast number (p< 0.001) were increased when compared with control group at day 7. The epithelial gap in LED group was significantly shorten than control group at day 7 (p< 0.01). The PCNA positive cell number in LED group was higher than control group at day 7 (p< 0.01). Conclusion: 630 nm LED with 3.67 mW/cm 2 , 6.60 J/cm 2 accelerate collagen deposition by stimulating fibroblasts, and enhance wound contraction by differentiating myofibroblasts in the dermis, and accelerate keratinocyte proliferation by facilitating DNA synthesis in the epidermis. It may promote the healing process in proliferation stage of wound healing.

Atopic dermatitis (AD) is a chronic inflammatory skin disease. It is characterized by eczematous lesions, skin dryness, and pruritus. The existing treatment drugs for AD have side effects, especially if the drugs are taken for extended periods. Therefore, new alternative therapies are necessary. The aim of this study was to investigate the combined effects of curcumin administration and LED irradiation on AD. AD-like lesions were induced in BALB/c mice by repeated application of 1-chloro-2,4-dinitrobenzene (DNCB) to the shaved skin of the ear and neck. Thirty male BALB/c mice were divided into five groups: vehicle, DNCB, curcumin, LED, and curcumin+LED groups. Curcumin (0.1 g/kg/day) was administrated repeatedly during a period of 14 days (experimental period) and 630 nm LED irradiation (5 J/cm 2 /day) was performed in the acryl box once a day for 10 days, after inducing AD-like lesions via DNCB application. The severity of AD-like lesions was evaluated during the experimental period, using a modified SCORAD index. Both ear and neck skin tissues were examined histologically for epidermal thickness, mast cell, eosinophil counting, and dermal collagen density. Epidermal cell proliferation and apoptosis were detected using immunohistochemistry and TUNEL, respectively. These were all reduced in SCORAD index, epidermal thickness, collagen density, number of mast cell and eosinophil in dermis, and number of proliferating cell and apoptotic cell in epidermis by curcumin administration and 630 nm LED irradiation. Moreover, all parameters were significantly lower in the curcumin+LED group compared with the curcumin group and LED group. These results suggest that the combined therapy of curcumin and LED is more effective than a single treatment. We recommend that this can be a feasible alternative therapy to manage AD.

PURPOSE: The purpose of this study was to evaluate whether light-emitting diodes (LED) irradiation could be effective in a noninvasive, therapeutic device for the treatment of osteoarthritis(OA). METHODS: Twenty-four male Sprague-Dawley rats were divided into four groups: Vehicle control (saline); monosodium iodoacetate-injection (MIA); LED irradiation after MIA injection (MIA-LED); indomethacin-treatment after MIA injection (MIA-IMT). OA was induced by intra-articular injection of 3 ㎎ MIA through the patellar ligament of the right knee. Vehicle control rats were injected with an equivalent volume of saline. The LED was irradiated for 15 min/day for a week after 7 days of MIA treatment. To

This study was performed to evaluate the cytotoxicity of aluminum chloride (AlCl3), and the protective effect of Lonicerae flos (LF) extract on AlCl3-induced cytotoxicity in the cultured C6 glioma cells. Here, the cell viability and antioxidative effects, such as DPPH-radical scavenging activity, superoxide anion scavenging activity, and lipid peroxidation (LP), were assessed. AlCl3 significantly decreased the cell viability in a dose-dependent manner; the XTT50 value was measured at 128.8 M of AlCl3. The cytotoxicity of AlCl3 was determined as highly toxic the y Borenfreund and Puerner's toxic criteria. The butylated hydroxytoluene (BHT) and antioxidant both significantly increased the cell viability, which was damaged by AlCl3-induced cytotoxicity in these cultures. In the protective effect of LF extract on AlCl3-induced cytotoxicity, the LF extract significantly increased the superoxide anion scavenging activity and inhibitory activity of LP, as well as the DPPH-radical scavenging activity. From these results, it is suggested that the oxidative stress may have been involved in the cytotoxicity of AlCl3, and LP extract effectively protected AlCl3-induced cytotoxicity through the antioxidative effects. Conclusively, the natural resources, like LP extract, may be a putative therapeutic agent for the treatment of dementia induced by allergen like aluminum correlated with the oxidative stress.

We have generated the transgenic Tabaco plants expressing multiple monoclonal antibody (mAb) CO7-1A × BR55 by cross-pollinating with mAb CO17-1A and mAb BR55. We have demonstrated the anti-cancer effect of plant-derived multiple mAb CO17-1A × BR55. We find that co-treatment of colorectal mAbs (anti-epithelial cellular adhesion molecule (EpCAM), plant-derived monoclonal antibody (mAbP) CO17-1A and mAbP CO17-1A × BR55) with RAW264.7 cells significantly inhibited the cell growth in SW620 cancer cells. In particular, multi mAbP CO17-1A × BR55 significantly and efficiently suppressed the growth of SW620 cancer cells compared to another mAbs. Apoptotic death-positive cells were significantly increased in the mAbP CO17-1A × BR55-treated. The mAbP CO17-1A × BR55 treatment significantly decreased the expression of B-Cell lymphoma-2 (BCl-2), but the expression of Bcl-2-associated X protein (Bax), and cleaved caspase-3 were markedly increased. In vivo, the mAbP CO17-1A × BR55 significantly and efficiently inhibited the growth of colon tumors compared to another mAbs. The apoptotic cell death and inhibition of pro-apoptotic proteins expression were highest by treatment with mAbP CO17-1A × BR55. In addition, the mAbP CO17-1A × BR55 significantly inhibited the extracellular signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation in cancer cells and tumors. Therefore, this study results suggest that multiple mAbP CO17-1A × BR55 has a significant effect on apoptosis-mediated anticancer by suppression of ERK1/2 phosphorylation in colon cancer compared to another mAbs. In light of these results, further clinical investigation should be conducted on mAbP CO17-1A × BR55 to determine its possible chemopreventive and/or therapeutic efficacy against human colon cancer.