A phytoestrogen secoisolariciresinol diglucoside induces browning of white adipose tissue and activates non-shivering thermogenesis through AMPK pathway.

Secoisolariciresinol diglucoside (SDG) is the main phytoestrogen component of flaxseed known as an antioxidant. Current study focused on the effect of SDG in white adipose tissue (WAT) browning. Browning of WAT is considered as a promising treatment strategy for metabolic diseases. To demonstrate the effect of SDG as an inducer of browning, brown adipocyte markers were investigated in inguinal WAT (iWAT) of high fat diet-fed obese mice and genetically obese db/db mice after SDG administration. SDG increased thermogenic factors such as uncoupling protein 1, peroxisome proliferator-activated receptor gamma coactivator 1 alpha and PR domain containing 16 in iWAT and brown adipose tissue (BAT) of mice. Similar results were shown in beige-induced 3T3-L1 adipocytes and primary cultured brown adipocytes. Furthermore, SDG increased factors of mitochondrial biogenesis and activation. We also observed SDG-induced alteration of AMP-activated protein kinase α (AMPKα). As AMPKα is closely related in the regulation of adipogenesis and thermogenesis, we then evaluated the effect of SDG in AMPKα-inhibited conditions. Genetic or chemical inhibition of AMPKα demonstrated that the role of SDG on browning and thermogenesis was dependent on AMPKα signaling. In conclusion, our data suggest SDG as a potential candidate for improvement of obesity and other metabolic disorders.

Moderating AKT signaling with baicalein protects against weight loss by preventing muscle atrophy in a cachexia model caused by CT26 colon cancer.

Cancer cachexia is a type of energy-wasting syndrome characterized by fatigue, anorexia, muscle weakness, fat loss, and systemic inflammation. Baicalein, a flavonoid with bioactive properties, has demonstrated the ability to mitigate cardiac and skeletal muscle atrophy in different experimental settings. This effect is achieved through the inhibition of muscle proteolysis, suggesting its potential in preserving skeletal muscle homeostasis. In this study, we investigated the anti-cancer cachexia effects of baicalein in the regulation of muscle and fat wasting, both in vivo and in vitro. Baicalein attenuated body weight loss, including skeletal muscle and white adipose tissue (WAT), in CT26-induced cachectic mice. Moreover, baicalein increased muscle fiber thickness and suppressed the muscle-specific ubiquitin-protease system, including F-box only protein 32 and muscle RING-finger protein-1, by activating AKT phosphorylation both in vivo and in vitro. The use of LY294002, a particular inhibitor of AKT, eliminated the observed impact of baicalein on the improvement of muscle atrophy. In conclusion, baicalein inhibits muscle proteolysis and enhances AKT phosphorylation, indicating its potential role in cancer cachexia-associated muscle atrophy.

Epigallocatechin gallate protects against fat and muscle atrophy in B16BL6 melanoma-bearing mice on a high-fat diet.

AIMS: Epidemiological evidence indicates that there is a substantial association between body mass index (BMI) and at least ten forms of cancer, including melanoma, and BMI imbalance contributes to the poor survival rate of cancer patients before and after therapy. Nevertheless, few pharmacological studies on models of obesity and cancer have been reported. In this study, we administered epigallocatechin gallate (EGCG) to B16BL6 tumor-bearing mice that received a high-fat diet (HFD) to examine its impact. METHODS: B16BL6 tumor-bearing mice were fed a HFD. Body weight and food intake were documented every week. We conducted a Western blot analysis to examine the protein levels in the tumor, gastrocnemius (GAS), and tibialis anterior (TA) muscles, as well as the inguinal and epididymal white adipose tissues (iWAT and eWAT). KEY FINDINGS: EGCG has been shown to have anti-cancer effects equivalent to those of cisplatin, a chemotherapy drug. Furthermore, EGCG protected against the loss of epidydimal white adipose tissue by regulating protein levels of lipolysis factors of adipose triglyceride lipase and hormone-sensitive lipase as well as WAT browning factors of uncoupling protein 1, as opposed to cisplatin. EGCG was shown to reduce the protein levels of muscular atrophy factors of muscle RING-finger protein-1, whereas cisplatin did not contribute to rescuing the atrophy of TA and GAS muscles. CONCLUSION: Taken together, our findings indicate that EGCG has a preventive effect against cachexia symptoms and has anti-cancer effects similar to those of cisplatin in tumor-bearing mice fed a high-fat diet.

Panax ginseng C.A. meyer alleviates benign prostatic hyperplasia while preventing finasteride-induced side effects.

Panax ginseng C.A. Meyer, a widely used traditional medicine in East Asia, shows many beneficial effects on immune function, male erectile dysfunction, cancer, excessive oxidants, and aging issues. However, its effect on benign prostatic hyperplasia (BPH) and its potential in the treatment of side effects related to finasteride (Fi), an FDA-approved drug for BPH, are less known. This study aimed to verify the therapeutic effects of a water extract of P. ginseng (PGWE) on BPH in testosterone propionate (TP)-induced BPH rats and TP-treated RWPE-1 human epithelial cells, and the inhibitory potential on the Fi-induced side effects is also explored. In the TP-induced BPH rat model, PGWE alleviated the pathological markers of BPH such as weight and epithelial thickness of the prostate, and the serum level of dihydrotestosterone. PGWE downregulated androgen-related BPH factors such as 5α-reductase 2 and androgen receptor. PGWE also showed prostatic cell apoptosis accompanied by increased expression of Bax and decreased expression of Bcl-xL and cleaved-caspase 3, respectively, in addition to increasing mitochondrial dynamics in both in vivo and in vitro BPH models. Notably, reduced sperm count, one of the serious side effects of Fi, in the epididymis of BPH rats was recovered with PGWE treatment, suggesting less toxicity to sperm development by PGWE. PGWE also protected against Fi-induced sperm loss when PGWE was administered in combination with Fi without compromising the therapeutic effects of Fi on BPH. Based on these findings, we propose that PGWE could be an alternative therapeutic agent for BPH.

Ellagic acid improves benign prostate hyperplasia by regulating androgen signaling and STAT3.

Benign prostate hyperplasia (BPH) is an age-related disease in men characterized by the growth of prostate cells and hyperproliferation of prostate tissue. This condition is closely related to chronic inflammation. In this study, we highlight the therapeutic efficacy of ellagic acid (EA) for BPH by focusing on the AR signaling axis and STAT3. To investigate the effect of EA on BPH, we used EA, a phytochemical abundant in fruits and vegetables, to treat testosterone propionate (TP)-induced BPH rats and RWPE-1 human prostate epithelial cells. The EA treatment reduced prostate weight, prostate epithelial thickness, and serum DHT levels in the TP-induced BPH rat model. In addition, EA improved testicular injury by increasing antioxidant enzymes in testis of the BPH rats. EA reduced the protein levels of AR, 5AR2, and PSA. It also induced apoptosis by regulating Bax, Bcl_xL, cytochrome c, caspase 9, and caspase 3 with increasing mitochondrial dynamics. Furthermore, EA reduced the expression of IL-6, TNF-α, and NF-κB, as well as phosphorylation of STAT3 and IκBα. These findings were also confirmed in TP-treated RWPE-1 cells. Overall, our data provide evidence of the role of EA in improving BPH through inhibition of AR and the STAT3 pathway.

PEX13 is required for thermogenesis of white adipose tissue in cold-exposed mice.

Non-shivering thermogenesis (NST) is a heat generating process controlled by the mitochondria of brown adipose tissue (BAT). In the recent decade, 'functionally' acting brown adipocytes in white adipose tissue (WAT) has been identified as well: the so-called process of the 'browning' of WAT. While the importance of uncoupling protein 1 (UCP1)-oriented mitochondrial activation has been intensely studied, the role of peroxisomes during the browning of white adipocytes is poorly understood. Here, we assess the change in peroxisomal membrane proteins, or peroxins (PEXs), during cold stimulation and importantly, the role of PEX13 in the cold-induced remodeling of white adipocytes. PEX13, a protein that originally functions as a docking factor and is involved in protein import into peroxisome matrix, was highly increased during cold-induced recruitment of beige adipocytes within the inguinal WAT of C57BL/6 mice. Moreover, beige-induced 3 T3-L1 adipocytes and stromal vascular fraction (SVF) cells by exposure to the peroxisome proliferator-activated receptor gamma (PPARγ) agonist rosiglitazone showed a significant increase in mitochondrial thermogenic factors along with peroxisomal proteins including PEX13, and these were confirmed in SVF cells with the beta 3 adrenergic receptor (ß3AR)-selective agonist CL316,243. To verify the relevance of PEX13, we used the RNA silencing method targeting the Pex13 gene and evaluated the subsequent beige development in SVF cells. Interestingly, siPex13 treatment suppressed expression of thermogenic proteins such as UCP1 and PPARγ coactivator 1 alpha (PGC1α). Overall, our data provide evidence supporting the role of peroxisomal proteins, in particular PEX13, during beige remodeling of white adipocytes.

Anmyungambi Decoction Ameliorates Obesity through Activation of Non-Shivering Thermogenesis in Brown and White Adipose Tissues.

Obesity is a burden to global health. Non-shivering thermogenesis of brown adipose tissue (BAT) and white adipose tissue (WAT) is a novel strategy for obesity treatment. Anmyungambi (AMGB) decoction is a multi-herb decoction with clinical anti-obesity effects. Here, we show the effects of AMGB decoction using high-fat diet (HFD)-fed C57BL6/J mice. All four versions of AMGB decoction (100 mg/kg/day, oral gavage for 28 days) suppressed body weight gain and obesity-related blood parameters in the HFD-fed obese mice. They also inhibited adipogenesis and induced lipolysis in inguinal WAT (iWAT). Especially, the AMGB-4 with 2:1:3:3 composition was the most effective; thus, further studies were performed with the AMGB-4 decoction. The AMGB-4 decoction displayed a dose-dependent body weight gain suppression. Serum triglyceride, total cholesterol, and blood glucose decreased as well. In epididymal WAT, iWAT, and BAT, the AMGB-4 decoction increased lipolysis markers. Additionally, the AMGB-4 decoction-fed mice showed an increased non-shivering thermogenic program in BAT and iWAT. Excessive reactive oxygen species (ROS) and suppressed antioxidative factors induced by the HFD feeding were also altered to normal levels by the AMGB-4 decoction treatment. Overall, our study supports the clinical use of AMGB decoction for obesity treatment by studying its mechanisms. AMGB decoction alleviates obesity through the activation of the lipolysis-thermogenesis program and the elimination of pathological ROS in thermogenic adipose tissues.

Raphani Semen (Raphanus sativus L.) Ameliorates Alcoholic Fatty Liver Disease by Regulating De Novo Lipogenesis.

In this study, we investigated the pharmacological effect of a water extract of Raphani Semen (RSWE) on alcoholic fatty liver disease (AFLD) using ethanol-induced AFLD mice (the NIAAA model) and palmitic acid (PA)-induced steatosis HepG2 cells. An RSWE supplement improved serum and hepatic triglyceride (TG) levels of AFLD mice, as well as their liver histological structure. To explore the molecular action of RSWE in the improvement of AFLD, we investigated the effect of RSWE on four major pathways for lipid homeostasis in the liver: free fatty acid transport, lipogenesis, lipolysis, and ß-oxidation. Importantly, RSWE decreased the mRNA expression of de novo lipogenesis-related genes, such as Srebf1, Cebpa, Pparg, and Lpin1, as well as the protein levels of these factors, in the liver of AFLD mice. That these actions of RSWE affect lipogenesis was confirmed using PA-induced steatosis HepG2 cells. Overall, our findings suggest that RSWE has the potential for improvement of AFLD by inhibiting de novo lipogenesis.

Fruit of Gardenia jasminoides Induces Mitochondrial Activation and Non-Shivering Thermogenesis through Regulation of PPARγ.

The extract of the Gardenia jasminoides fruit (GJFE) can been consumed as an herbal tea or used as a yellow dye. Recently, studies report that GFJE exerts inhibitory effects on lipid accumulation and adipogenesis in white adipocytes. We evaluated the thermogenic actions of GJFE by focusing on mitochondrial activation and studying the underlying mechanisms. To investigate the role of GJFE on thermogenesis in mice, we used an acute cold exposure model. After 2 weeks of feeding, the cold tolerance of GJFE-fed mice was notably increased compared to PBS-fed mice. This was due to an increase in thermogenic proteins in the inguinal white adipose tissue of the cold-exposed mice. Moreover, GJFE significantly increased thermogenic factors such as peroxisome proliferator-activated receptor gamma (PPARγ), uncoupling protein 1 (UCP1), and PPARγ coactivator 1 alpha (PGC1α) in vitro as well. Factors related to mitochondrial abundance and functions were also induced by GJFE in white and beige adipocytes. However, the treatment of PPARγ inhibitor abolished the GJFE-induced changes, indicating that activation of PPARγ is critical for the thermogenic effect of GJFE. In conclusion, GJFE induces thermogenic action by activating mitochondrial function via PPARγ activation. Through these findings, we suggest GJFE as a potential anti-obesity agent with a novel mechanism involving thermogenic action in white adipocytes.

Fruit of Hovenia dulcis Thunb. Induces Nonshivering Thermogenesis through Mitochondrial Biogenesis and Activation by SIRT1 in High-Fat Diet-Fed Obese Mice and Primary Cultured Brown Adipocytes.

Brown adipocytes, which contain abundant mitochondria, use stored energy as fuel during a process named nonshivering thermogenesis. Thus, the pharmacological activation of thermogenesis in brown adipose tissue (BAT) has become a promising target for treating obesity. We investigated the effect of fruit of Hovenial dulcis Thunb. (FHD), a frequently used herbal treatment for liver diseases, on thermogenesis and its mechanism using primary cultured brown adipocytes and BAT of high-fat-diet (HFD)-induced obese mice. Thermogenesis-related factors including UCP1 and PGC1α increased with FHD treatment. FHD also increased mitochondrial biogenesis and activation factors such as nuclear respiratory factor (NRF)1 and oxidative phosphorylation (OXPHOS) complex. Furthermore, FHD increased the intercellular nicotinamide adenine dinucleotide (NAD+) level and sirtuin 1 (SIRT1) activity, which may be responsible for the activation of the thermogenic reaction. Overall, our results suggest that FHD can be a novel option for obesity treatment due to its thermogenic action through mitochondrial biogenesis and activation.

Corrigendum: Berberine Improves Benign Prostatic Hyperplasia via Suppression of 5 Alpha Reductase and Extracellular Signal-Regulated Kinase in Vivo and in Vitro.

[This corrects the article DOI: 10.3389/fphar.2018.00773.].

Berberine Improves Benign Prostatic Hyperplasia via Suppression of 5 Alpha Reductase and Extracellular Signal-Regulated Kinase in Vivo and in Vitro.

Benign prostate hyperplasia (BPH) is a common disease in elderly men, characterized by proliferated prostate and urinary tract symptoms. The hormonal cascade starting by the action of 5-alpha-reductase (5AR) is known to be one of the pathways responsible for the pathogenesis of BPH. Present investigation evaluated the capacity of berberine (BBR), a nature-derived compound abundant in Coptis japonica, in testosterone-induced BPH rats. Experimental BPH was induced by inguinal injection with testosterone propionate (TP) for 4 weeks. BBR or finasteride, a 5AR inhibitor as positive control, was treated for 4 weeks during BPH. BPH induced by TP evoked weight gaining and histological changes of prostate and BBR treatment improved all the detrimental effects not only weight reduction and histological changes but also suppression of prostate-specific antigen (PSA), which is elevated during BPH. Additionally, BBR suppressed TP-associated increase of 5AR, androgen receptor (AR) and steroid coactivator-1 (SRC-1), the key factors in the pathogenesis of BPH. To evaluate the underlying molecular mechanisms responsible for beneficial effects of BBR, we investigated whether these effects were associated with the mitogen-activated protein kinase pathway. BPH induced by TP showed increased phosphorylation of extracellular signal-regulated kinase (ERK), whereas this was suppressed by BBR treatment. On the other hand, c-jun-N-terminal kinase (JNK) and p38 mitogen-activated protein kinase was not changed in BPH rats. In in vitro study using RWPE-1 cells, a human prostate epithelial cell line. TP increased cell proliferation and BPH-related key factors such as PSA, AR, and 5AR in RWPE-1 cells, and those factors were significantly decreased in the presence of BBR. Furthermore, these proliferative effects in RWPE-1cells were attenuated by treatment with U0126, an ERK inhibitor, confirming BBR can relieve overgrowth of prostate via ERK-dependent signaling. The cotreatment of U0126 and BBR did not affect the change of 5AR nor proliferation compared with U0126 alone, suggesting that the effect of BBR was dependent on the action of ERK. In conclusion, this study shows that BBR can be used as a therapeutic agent for BPH by controlling hyperplasia of prostate through suppression of ERK mechanism.

Secoisolariciresinol diglucoside inhibits adipogenesis through the AMPK pathway.

Flaxseeds are used to treat metabolic diseases such as type 2 diabetes, fatty liver, hyperlipidemia and obesity. Secoisolariciresinol diglucoside (SDG) is a main substance of lignan which belongs to the phytoestrogen family and exists abundantly in flaxseeds. In this study, SDG reduced the body weight and size of adipose tissue, and decreased protein expressions of peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT-enhancer-binding protein α (C/EBPα) in the high fat diet-fed-induced obese mice model. In the vitro study, we examined the anti-adipogenic effect of SDG during differentiation of 3T3-L1 cells into adipocytes. 3T3-L1 preadipocytes were differentiated and treated with various concentrations of SDG. Oil Red O staining was done to measure the quantity of lipid contents. As a result, SDG reduced lipid accumulation and decreased the expressions of adipogenic-related genes such as adipocyte fatty-acid-binding protein 2, adiponectin, and resistin. SDG also decreased the mRNA and protein levels of PPARγ and C/EBPα. Furthermore, phosphorylation levels of AMP-activated protein kinase α (AMPK α) and its upstream activator, liver kinase B1, were significantly increased by SDG in 3T3-L1 cells. These results suggest that SDG inhibits adipogenesis by activating AMPKα, suggesting it could be an attractive therapeutic candidate for the treatment of obesity.