Vitiligo: An immune disease and its emerging mesenchymal stem cell therapy paradigm.

Melanocyte damage, innate immune response, adaptive immune response, and immune inflammatory microenvironment disorders are involved in the development of the immunological pathogenic mechanism of vitiligo. Mesenchymal stem cells are considered an ideal type of cells for the treatment of vitiligo owing to their low immunogenicity, lower rates of transplant rejection, and ability to secrete numerous growth factors, exosomes, and cytokines in vivo. The regulation of signaling pathways related to oxidative stress and immune imbalance in the immunological pathogenesis of vitiligo can improve the immune microenvironment of tissue injury sites. In addition, co-transplantation with melanocytes can reverse the progression of vitiligo. Therefore, continuous in-depth research on the immunopathogenic mechanism involved in this disease and mesenchymal stem cell-based therapy is warranted for the treatment of vitiligo in the future.

Research progress of phenolic compounds regulating IL-6 to exert antitumor effects.

Cytokine therapy, which activates the host immune system, has become an important and novel therapeutic approach to treat various cancers. Recent studies have shown that IL-6 is an important cytokine that regulates the homeostasis in vivo. However, excessive IL-6 plays a pathological role in a variety of acute and chronic inflammatory diseases, especially in cancer. IL-6 can transmit signals through JAK/STAT, RAS /MAPK, PI3K/ Akt, NF-κB, and other pathways to promote cancer progression. Phenolic compounds can effectively regulate the level of IL-6 in tumor cells and improve the tumor microenvironment. This article focuses on the phenolic compounds through the regulation of IL-6, participate in the prevention of cancer, inhibit the proliferation of cancer cells, reduce angiogenesis, improve therapeutic efficacy, and reduce side effects and other aspects. This will help to further advance research on cytokine therapy to reduce the burden of cancer and improve patient prognosis. However, current studies are mostly limited to animal and cellular experiments, and high-quality clinical studies are needed to further determine their antitumor efficacy in humans.

Remodeling the Epigenetic Landscape of Cancer-Application Potential of Flavonoids in the Prevention and Treatment of Cancer.

Epigenetics, including DNA methylation, histone modification, and noncoding RNA regulation, are physiological regulatory changes that affect gene expression without modifying the DNA sequence. Although epigenetic disorders are considered a sign of cell carcinogenesis and malignant events that affect tumor progression and drug resistance, in view of the reversible nature of epigenetic modifications, clinicians believe that associated mechanisms can be a key target for cancer prevention and treatment. In contrast, epidemiological and preclinical studies indicated that the epigenome is constantly reprogrammed by intake of natural organic compounds and the environment, suggesting the possibility of utilizing natural compounds to influence epigenetics in cancer therapy. Flavonoids, although not synthesized in the human body, can be consumed daily and are common in medicinal plants, vegetables, fruits, and tea. Recently, numerous reports provided evidence for the regulation of cancer epigenetics by flavonoids. Considering their origin in natural and food sources, few side effects, and remarkable biological activity, the epigenetic antitumor effects of flavonoids warrant further investigation. In this article, we summarized and analyzed the multi-dimensional epigenetic effects of all 6 subtypes of flavonoids (including flavonols, flavones, isoflavones, flavanones, flavanols, and anthocyanidin) in different cancer types. Additionally, our report also provides new insights and a promising direction for future research and development of flavonoids in tumor prevention and treatment via epigenetic modification, in order to realize their potential as cancer therapeutic agents.

Brachybacterium subflavum sp. nov., a novel actinobacterium isolated from the foregut of grass carp.

A novel actinobacterium, designated CFH 10395T, was isolated from the foregut of grass carp (Ctenopharyngodon idella), which had been fed with ginseng extract supplement. The taxonomic position was investigated by a polyphasic approach. Cells of CFH 10395T were Gram-staining-positive, aerobic, ovoid-shaped, non-spore-forming and non-motile. On the basis of the results of 16S rRNA gene sequence analysis, CFH 10395T was most closely related to Brachybacterium endophyticum KCTC 49087T, Brachybacterium squillarum JCM 16464T and Brachybacterium paraconglomeratum JCM 17781T (97.85%, 97.51 and 97.29% similarity, respectively). CFH 10395T grew at 4-37 °C, pH 5.0-9.0 and in the presence of up to 10.0 % NaCl (w/v). The dominant menaquinone was MK-7. The whole-cell sugars were rhamnose, glucose, mannose and galactose. meso-diaminopimelic acid was the diagnostic diamino acid in the cell-wall peptidoglycan. The major fatty acids were anteiso-C15 : 0, anteiso-C17 : 0 and iso-C16 : 0. The genome size was 3.99 Mbp with a DNA G+C content of 71.9 mol%. On the basis of the results of phylogenetic analysis, physiological properties, chemotaxonomic characteristics, low average nucleotide identity (ANI) and digital DDH (dDDH) results [ANI calculated using MUMmer (ANIm) <87 %, ANI calculated using blast (ANIb) <83 % and dDDH <23 %], it is concluded that CFH 10395T represents a novel species of the genus Brachybacterium, for which the name Brachybacterium subflavum sp. nov., is proposed. The type strain is CFH 10395T (=CGMCC 1.13804T=KCTC 49235T).

An invasive plant experiences greater benefits of root morphology from enhancing nutrient competition associated with arbuscular mycorrhizae in karst soil than a native plant.

The Eupatorium adenophorum have widespread invaded the karst ecosystem of southwest China and threatened the regional native community stability. Arbuscular mycorrhizae (AM) plays an important role in promoting growth for host plants via root external mycelia. However, whether AM regulates plant root traits underlying competition between invasive and native species via mycorrhizal networks in karst habitats, remains unclear. An experiment was conducted in a microcosm composed of two planting compartments flanking a competition compartment. The invasive E. adenophorum and native Artemisia annua were each placed in one of the two planting compartments with or without Glomus etunicatum fungus. The nutrient access treatments included the competitive utilization (Cu), single utilization (Su) and non-utilization (Nu) by using different nylon meshes allowed or prevented mycelium passing to acquire nutrients from the competition compartment. Root traits and nutrients of the two species were analyzed. The results showed that AM fungi had differential effects on root traits and nutrients of E. adenophorum and A. annua seedlings, which increased dry weight, length, surface area, volume, tips and branching points in roots, specific root length and volume, root nitrogen (N) and phosphorus (P) contents under Cu, Su and Nu treatments. AM fungus was also associated with decreases in the average diameter for both species. Under the Cu treatment, E. adenophorum had significantly greater length, surface area, volume, tips and branching points of roots, specific root traits, and root N and P than A. annua. AM fungi changed root phenotypes and nutrient uptake for both invasive and native plant species via interconnected mycorrhizal networks. Overall, our results suggest that through mycorrhizal networks, the invasive plant experiences greater benefits than the native plant in the nutrient competition, which fosters root morphological developments in karst soil.

Astragalus Polysaccharide Promotes Adriamycin-Induced Apoptosis in Gastric Cancer Cells.

PURPOSE: Astragalus polysaccharide (APS), a common Chinese herbal compound extracted from Astragalus membranaceus, has been proposed to increase the tumour response of and stabilize chemotherapy drugs while reducing their toxicity. Here, we examined the effects of APS on apoptosis in gastric cancer (GC) cells in the presence or absence of adriamycin (0.1 µg/mL). METHODS: GC cells cultured in the presence or absence of adriamycin (0.1 µg/mL) were administered APS (50-200 µg/mL) for 24-72 h and subjected to an MTT assay to examine cell viability. Active caspase-3 expression and DNA fragmentation were assessed to evaluate apoptosis, and real-time PCR was used to analyse the expression levels of multidrug resistance (MDR1) genes and tumour suppressor genes. Western blot analysis was applied to detect cleaved caspase-3 and phosphorylated AMPK (p-AMPK). RESULTS: Cellular viability was profoundly reduced by APS, and GC cell apoptosis was strongly increased by APS in a time- and dose-dependent manner; these changes may be linked to an increase in p-AMPK levels because the AMPK inhibitor compound C blocked the effects of APS. Similarly, adriamycin-induced decreases in cellular viability and apoptosis of GC cells were enhanced by APS administration. The expression of tumour suppressor genes (SEMA3F, P21WAF1/CIP1, FBXW7), but not of MDR1, was increased by APS compared to the control, and p-AMPK levels were lower in adriamycin-resistant GC cells than in either adriamycin-sensitive GC cells or an immortalized human gastric epithelial cell line. CONCLUSION: APS induces apoptosis independently and strengthens the proapoptotic effect of adriamycin on GC cells, suggesting that APS may act as a chemotherapeutic sensitizer.

Effect and mechanism of ethanol extracts of muxiang (Radix Aucklandiae) on gastric ulcers in rats.

OBJECTIVE: To investigate the effect of ethanol extracts of Muxiang (Radix Aucklandiae) (RA) on gastric ulcers in rats and explore the potential mechanisms. METHODS: A model was established by ethanol (0.75 mL/kg). According to body weight, rats were pretreated with RA extracts (2.5 or 5 g/kg). The rats were administered 95% ethanol orally after 1 h. The effects of ethanol were evaluated by measuring the gastric secretion volume, pH, pepsin activity, and ulcer area. Histological analysis and immunohistochemistry were also conducted. Furthermore, the effect of the ethanol extract of RA on transiting activity of the gastrointestinal tract was observed in mice. RESULTS: Intragastric administration of RA extracts protected the gastric mucosa from ethanol-induced gastric ulcers, while reducing submucosal edema and preventing hemorrhagic damage. Moreover, the extracts increased the production of gastric mucus, upregulated Bcl-2, and downregulated Bax expression. Importantly, pretreated rats exhibited no significant change in the gastric secretion volume, gastric juice acidity, or pepsin. Furthermore, pretreatment prominently (P < 0.05) enhanced propulsive movement of the gastrointestinal tract in normal mice and mice with gastrointestinal motility disorders. CONCLUSION: Ethanol extracts of RA ameliorated gastric lesions in the gastric ulcer rat model. The mechanisms of action were related to improvement of gastrointestinal dynamics, maintenance of mucus integrity, and inhibition of apoptosis by downregulating proapoptotic Bax protein and upregulating anti-apoptotic Bcl-2 protein.

An ATF4-ATG5 signaling in hypothalamic POMC neurons regulates obesity.

ATF4 (activating transcription factor 4) is an important transcription factor that has many biological functions, while its role in hypothalamic POMC (pro-opiomelanocortin-α) neurons in the regulation of energy homeostasis has not been explored. We recently discovered that mice with an Atf4 deletion specific to POMC neurons (PAKO mice) are lean and have higher energy expenditure. Furthermore, these mice are resistant to high-fat diet (HFD)-induced obesity and obesity-related metabolic disorders. Mechanistically, we found the expression of ATG5 (autophagy-related 5) is upregulated in POMC neurons of PAKO mice, and ATF4 regulates ATG5 expression by binding directly to its promoter. Mice with Atf4 and Atg5 double knockout in POMC neurons have reduced energy expenditure and gain more fat mass compared with PAKO mice under a HFD. Finally, the effect of Atf4 knockout in POMC neurons is possibly mediated by enhanced ATG5-dependent macroautophagy/autophagy and α-melanocyte-stimulating hormone (α-MSH) production in the hypothalamus. Together, this work not only identifies a beneficial role for ATF4 in hypothalamic POMC neurons in the regulation of obesity, but also provides a new potential therapeutic target for obesity and obesity-related metabolic diseases.

ATF4/ATG5 Signaling in Hypothalamic Proopiomelanocortin Neurons Regulates Fat Mass via Affecting Energy Expenditure.

Although many biological functions of activating transcription factor 4 (ATF4) have been identified, a role of hypothalamic ATF4 in the regulation of energy homeostasis is poorly understood. In this study, we showed that hypothalamic proopiomelanocortin (POMC) neuron-specific ATF4 knockout (PAKO) mice are lean and have higher energy expenditure. Furthermore, PAKO mice were resistant to high-fat diet-induced obesity, glucose intolerance, and leptin resistance. Moreover, the expression of autophagy protein 5 (ATG5) was increased or decreased by ATF4 knockdown or overexpression, respectively, and ATF4 inhibited the transcription of ATG5 by binding to the basic zipper-containing protein sites on its promoter. Importantly, mice with double knockout of ATF4 and ATG5 in POMC neurons gained more fat mass and reduced energy expenditure compared with PAKO mice under a high-fat diet. Finally, the effect of ATF4 deletion in POMC neurons was possibly mediated via enhanced ATG5-dependent autophagy and α-melanocyte-stimulating hormone production in the hypothalamus. Taken together, these results identify the beneficial role of hypothalamic ATF4/ATG5 axis in the regulation of energy expenditure, obesity, and obesity-related metabolic disorders, which suggests that ATF4/ATG5 axis in the hypothalamus may be a new potential therapeutic target for treating obesity and obesity-related metabolic diseases.

Knockout of inositol-requiring enzyme 1α in pro-opiomelanocortin neurons decreases fat mass via increasing energy expenditure.

Although numerous functions of inositol-requiring enzyme 1α (IRE1α) have been identified, a role of IRE1α in pro-opiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus is largely unknown. Here, we showed that mice lacking IRE1α specifically in POMC neurons (PIKO) are lean and resistant to high-fat diet-induced obesity and obesity-related insulin resistance, liver steatosis and leptin resistance. Furthermore, PIKO mice had higher energy expenditure, probably due to increased thermogenesis in brown adipose tissue. Additionally, α-melanocyte-stimulating hormone production was increased in the hypothalamus of PIKO mice. These results demonstrate that IRE1α in POMC neurons plays a critical role in the regulation of obesity and obesity-related metabolic disorders. Our results also suggest that IRE1α is not only an endoplasmic reticulum stress sensor, but also a new potential therapeutic target for obesity and obesity-related metabolic diseases.

Enhanced LL-37 expression following vitamin D supplementation in patients with cirrhosis and spontaneous bacterial peritonitis.

BACKGROUND & AIMS: The morbidity and mortality of spontaneous bacterial peritonitis (SBP) are high among patients with cirrhosis; however, the mechanisms of SBP pathogenesis are poorly understood. This study aimed to determine the role of the vitamin D-LL-37 pathway in the pathogenesis and treatment in patients with cirrhosis and SBP. METHODS: Serum 25-hydroxyvitamin D concentrations of 119 patients with chronic liver diseases were tested. Vitamin D receptor (VDR) and LL-37 in peritoneal leucocytes of cirrhotic and ascitic patients with SBP were detected and compared with those without SBP. Then the peritoneal macrophages of non-infected patients were cultured and activated by lipopolysaccharide (LPS) to analyse the changes of VDR and LL-37 expressions after incubation with vitamin D. RESULTS: Vitamin D deficiency or insufficiency was found in all of patients with cirrhosis. LPS inhibited VDR and LL-37 expression in peritoneal macrophages [1.3-fold decrease (P = 0.003) and 20-fold decrease (P = 0.010) respectively]. However, vitamin D could reverse the inhibition of both VDR and LL-37 [1.5-fold increase (P = 0.001) and 2000-fold increase (P < 0.001) respectively]. The effect of the incubation time following vitamin D supplementation was significant for LL-37 expression, with a peak expression found at 36 h (P < 0.001). CONCLUSIONS: When vitamin D levels were low, bacteria inhibited VDR and LL-37 responses in peritoneal macrophages as a mechanism to evade antibacterial defence. Vitamin D supplementation could up-regulate peritoneal macrophage VDR and LL-37 expressions, which resulted in an enhanced immunological defence against SBP in patients with cirrhosis and ascites.

The natural compound celastrol inhibits necroptosis and alleviates ulcerative colitis in mice.

Ulcerative colitis (UC) is a chronic intestinal inflammatory disease. Necroptosis plays an important role in the pathogenesis of UC. Celastrol, a triterpene from the root bark of the Chinese medicinal plant Tripterygium wilfordii, has been reported to have anti-oxidant and anti-inflammatory activities in colitis. It is not known, however, how celastrol exerts its beneficial effects. The aim of this study is to investigate the effects and possible mechanism of celastrol in UC. Colitis was induced in mice by administration of 5% dextran sulfate sodium (DSS) in drinking water for 4days. Celastrol was administered intraperitoneally (1mg/kg) for 7days after colitis was induced. Our results showed that celastrol treatment ameliorated the severity of colitis, decreased the level of interleukin (IL)-1ß, IL-6 and myeloperoxidase (MPO) and upregulated the level of E-cadherin in colitis mice. Moreover, the TUNEL staining and cleaved caspase-3 immunohistochemistry staining proved decreased necrotic cell death after celastrol treatment. On the mechanism, decreased level of necroptosis factors RIP3 and MLKL, and increased level of active caspase-8 were detected after celastrol treatment. Taken together, our results demonstrated that celastrol exerted beneficial effects in colitis treatment via suppressing the RIP3/MLKL necroptosis pathway.

Central prolactin receptors (PRLRs) regulate hepatic insulin sensitivity in mice via signal transducer and activator of transcription 5 (STAT5) and the vagus nerve.

AIMS/HYPOTHESIS: Recent studies have revealed the crucial role of the central nervous system (CNS), especially the hypothalamus, in the regulation of insulin sensitivity in peripheral tissues. The aim of our current study was to investigate the possible involvement of hypothalamic prolactin receptors (PRLRs) in the regulation of hepatic insulin sensitivity. METHODS: We employed overexpression of PRLRs in mouse hypothalamus via intracerebroventricular injection of adenovirus expressing PRLR and inhibition of PRLRs via adenovirus expressing short-hairpin RNA (shRNA) specific for PRLRs in vivo. Selective hepatic vagotomy was employed to verify the important role of the vagus nerve in mediating signals from the brain to peripheral organs. In addition, a genetic insulin-resistant animal model, the db/db mouse, was used in our study to investigate the role of hypothalamic PRLRs in regulating whole-body insulin sensitivity. RESULTS: Overexpression of PRLRs in the hypothalamus improved hepatic insulin sensitivity in mice and inhibition of hypothalamic PRLRs had the opposite effect. In addition, we demonstrated that hypothalamic PRLR-improved insulin sensitivity was significantly attenuated by inhibiting the activity of signal transducer and activator of transcription 5 (STAT5) in the CNS and by selective hepatic vagotomy. Finally, overexpression of PRLRs significantly ameliorated insulin resistance in db/db mice. CONCLUSIONS/INTERPRETATION: Our study identifies a novel central pathway involved in the regulation of hepatic insulin sensitivity, mediated by hypothalamic PRLR/STAT5 signalling and the vagus nerve, thus demonstrating an important role for hypothalamic PRLRs under conditions of insulin resistance.

Leptin signaling is required for leucine deprivation-enhanced energy expenditure.

Leptin signaling in the hypothalamus is crucial in energy homeostasis. We have previously shown that dietary deprivation of the essential amino acid leucine in mice stimulates fat loss by increasing energy expenditure. The involvement of leptin signaling in this regulation, however, has not been reported. Here, we show that leucine deprivation promotes leptin signaling in mice maintained on an otherwise normal diet and restores leptin responses in mice maintained on a high fat diet, a regimen known to induce leptin resistance. In addition, we found that leucine deprivation stimulated energy expenditure, and fat loss was largely blocked in db/db mice homozygous for a mutation in leptin receptor and a knock-in mouse line Y3F with abrogation of leptin receptor Tyr(1138)-mediated signal transducer and activator transcript 3 signaling. Overall, our studies describe a novel link between hypothalamic leptin signaling and stimulation of energy expenditure under leucine deprivation.

Central activating transcription factor 4 (ATF4) regulates hepatic insulin resistance in mice via S6K1 signaling and the vagus nerve.

Recent studies have revealed that the central nervous system, particularly the hypothalamus, is critical for regulating insulin sensitivity in peripheral tissues. The aim of our current study is to investigate the possible involvement of hypothalamic activating transcription factor 4 (ATF4) in the regulation of insulin sensitivity in the liver. Here, we show that overexpression of ATF4 in the hypothalamus resulting from intracerebroventricular injection of adenovirus expressing ATF4 induces hepatic insulin resistance in mice and that inhibition of hypothalamic ATF4 by intracerebroventricular adenovirus expressing a dominant-negative ATF4 variant has the opposite effect. We also show that hypothalamic ATF4-induced insulin resistance is significantly blocked by selective hepatic vagotomy or by inhibiting activity of the mammalian target of rapamycin (mTOR) downstream target S6K1. Finally, we show that inhibition of hypothalamic ATF4 reverses hepatic insulin resistance induced by acute brain endoplasmic reticulum (ER) stress. Taken together, our study describes a novel central pathway regulating hepatic insulin sensitivity that is mediated by hypothalamic ATF4/mTOR/S6K1 signaling and the vagus nerve and demonstrates an important role for hypothalamic ATF4 in brain ER stress-induced hepatic insulin resistance. These results may lead to the identification of novel therapeutic targets for treating insulin resistance and associated metabolic diseases.

S6K1 in the central nervous system regulates energy expenditure via MC4R/CRH pathways in response to deprivation of an essential amino acid.

It is well established that the central nervous system (CNS), especially the hypothalamus, plays an important role in regulating energy homeostasis and lipid metabolism. We have previously shown that hypothalamic corticotropin-releasing hormone (CRH) is critical for stimulating fat loss in response to dietary leucine deprivation. The molecular mechanisms underlying the CNS regulation of leucine deprivation-stimulated fat loss are, however, still largely unknown. Here, we used intracerebroventricular injection of adenoviral vectors to identify a novel role for hypothalamic p70 S6 kinase 1 (S6K1), a major downstream effector of the kinase mammalian target of rapamycin, in leucine deprivation stimulation of energy expenditure. Furthermore, we show that the effect of hypothalamic S6K1 is mediated by modulation of Crh expression in a melanocortin-4 receptor-dependent manner. Taken together, our studies provide a new perspective for understanding the regulation of energy expenditure by the CNS and the importance of cross-talk between nutritional control and regulation of endocrine signals.

Leucine deprivation stimulates fat loss via increasing CRH expression in the hypothalamus and activating the sympathetic nervous system.

We previously showed that leucine deprivation decreases abdominal fat mass largely by increasing energy expenditure, as demonstrated by increased lipolysis in white adipose tissue (WAT) and uncoupling protein 1 (UCP1) expression in brown adipose tissue (BAT). The goal of the present study was to investigate the possible involvement of central nervous system (CNS) in this regulation and elucidate underlying molecular mechanisms. For this purpose, levels of genes and proteins related to lipolysis in WAT and UCP1 expression in BAT were analyzed in wild-type mice after intracerebroventricular administration of leucine or corticotrophin-releasing hormone antibodies, or in mice deleted for three ß-adrenergic receptors, after being maintained on a leucine-deficient diet for 7 d. Here, we show that intracerebroventricular administration of leucine significantly attenuates abdominal fat loss and blocks activation of hormone sensitive lipase in WAT and induction of UCP1 in BAT in leucine-deprived mice. Furthermore, we provide evidence that leucine deprivation stimulates fat loss by increasing expression of corticotrophin-releasing hormone in the hypothalamus via activation of stimulatory G protein/cAMP/protein kinase A/cAMP response element-binding protein pathway. Finally, we show that the effect of leucine deprivation on fat loss is mediated by activation of the sympathetic nervous system. These results suggest that CNS plays an important role in regulating fat loss under leucine deprivation and thereby provide novel and important insights concerning the importance of CNS leucine in the regulation of energy homeostasis.