Luteolin, a flavone ingredient: Anticancer mechanisms, combined medication strategy, pharmacokinetics, clinical trials, and pharmaceutical researches.

Current pharmaceutical research is energetically excavating the pharmacotherapeutic role of herb-derived ingredients in multiple malignancies' targeting. Luteolin is one of the major phytochemical components that exist in various traditional Chinese medicine or medical herbs. Mounting evidence reveals that this phytoconstituent endows prominent therapeutic actions on diverse malignancies, with the underlying mechanisms, combined medication strategy, and pharmacokinetics elusive. Additionally, the clinical trial and pharmaceutical investigation of luteolin remain to be systematically delineated. The present review aimed to comprehensively summarize the updated information with regard to the anticancer mechanism, combined medication strategies, pharmacokinetics, clinical trials, and pharmaceutical researches of luteolin. The survey corroborates that luteolin executes multiple anticancer effects mainly by dampening proliferation and invasion, spurring apoptosis, intercepting cell cycle, regulating autophagy and immune, inhibiting inflammatory response, inducing ferroptosis, and pyroptosis, as well as epigenetic modification, and so on. Luteolin can be applied in combination with numerous clinical anticarcinogens and natural ingredients to synergistically enhance the therapeutic efficacy of malignancies while reducing adverse reactions. For pharmacokinetics, luteolin has an unfavorable oral bioavailability, it mainly persists in plasma as glucuronides and sulfate-conjugates after being metabolized, and is regarded as potent inhibitors of OATP1B1 and OATP2B1, which may be messed with the pharmacokinetic interactions of miscellaneous bioactive substances in vivo. Besides, pharmaceutical innovation of luteolin with leading-edge drug delivery systems such as host-guest complexes, nanoparticles, liposomes, nanoemulsion, microspheres, and hydrogels are beneficial to the exploitation of luteolin-based products. Moreover, some registered clinical trials on luteolin are being carried out, yet clinical research on anticancer effects should be continuously promoted.

Topical treatment of tea saponin stabilized silybin nanocrystal gel reduced oxidative stress in UV-induced skin damage.

UV-induced peroxidation is a significant factor in skin damage. Some natural products have been utilized to protect the skin. However, most of them suffer from issues such as poor bioavailability. A promising strategy is to prepare them as safe and convenient gels. In this study, we constructed Silybin Nanocrystal Gel (SIL-NG). Tea saponin, a spatial stabilizer that we have previously reported, was used to prepare SIL-NS and subsequently combined with xanthan gum to prepare SIL-NG with an excellent safety profile. This nanogel with a natural stabilizer has a suitable ductility and shows a good safety profile in vitro and in vivo. In L929 cells, SIL-NG was able to reduce H2O2-induced ROS levels. In addition, SIL-NG exhibited better antioxidant activity compared to SIL-NS. SIL-NG was able to reduce UVB irradiation-induced oxidative damage in mice, significantly increase SOD activity, and reduce MDA levels. In conclusion, our work gives a new perspective on the treatment of UV skin damage using natural ingredients.

Polysaccharide-Based Stimulus-Responsive Nanomedicines for Combination Cancer Immunotherapy.

Cancer immunotherapy is a promising antitumor approach, whereas nontherapeutic side effects, tumor microenvironment (TME) intricacy, and low tumor immunogenicity limit its therapeutic efficacy. In recent years, combination immunotherapy with other therapies has been proven to considerably increase antitumor efficacy. However, achieving codelivery of the drugs to the tumor site remains a major challenge. Stimulus-responsive nanodelivery systems show controlled drug delivery and precise drug release. Polysaccharides, a family of potential biomaterials, are widely used in the development of stimulus-responsive nanomedicines due to their unique physicochemical properties, biocompatibility, and modifiability. Here, the antitumor activity of polysaccharides and several combined immunotherapy strategies (e.g., immunotherapy combined with chemotherapy, photodynamic therapy, or photothermal therapy) are summarized. More importantly, the recent progress of polysaccharide-based stimulus-responsive nanomedicines for combination cancer immunotherapy is discussed, with the focus on construction of nanomedicine, targeted delivery, drug release, and enhanced antitumor effects. Finally, the limitations and application prospects of this new field are discussed.

Hypericin as a promising natural bioactive naphthodianthrone: A review of its pharmacology, pharmacokinetics, toxicity, and safety.

Hypericin can be derived from St. John's wort, which is widely spread around the world. As a natural product, it has been put into clinical practice such as wound healing and depression for a long time. In this article, we review the pharmacology, pharmacokinetics, and safety of hypericin, aiming to introduce the research advances and provide a full evaluation of it. Turns out hypericin, as a natural photosensitizer, exhibits an excellent capacity for anticancer, neuroprotection, and elimination of microorganisms, especially when activated by light, potent anticancer and antimicrobial effects are obtained after photodynamic therapy. The mechanisms of its therapeutic effects involve the induction of cell death, inhibition of cell cycle progression, inhibition of the reuptake of amines, and inhibition of virus replication. The pharmacokinetics properties indicate that hypericin has poor water solubility and bioavailability. The distribution and excretion are fast, and it is metabolized in bile. The toxicity of hypericin is rarely reported and the conventional use of it rarely causes adverse effects except for photosensitization. Therefore, we may conclude that hypericin can be used safely and effectively against a variety of diseases. We hope to provide researchers with detailed guidance and enlighten the development of it.

Galanin peptide family regulation of glucose metabolism.

Recent preclinical and clinical studies have indicated that the galanin peptide family may regulate glucose metabolism and alleviate insulin resistance, which diminishes the probability of type 2 diabetes mellitus. The galanin was discovered in 1983 as a gut-derived peptide hormone. Subsequently, galanin peptide family was found to exert a series of metabolic effects, including the regulation of gut motility, body weight and glucose metabolism. The galanin peptide family in modulating glucose metabolism received recently increasing recognition because pharmacological activiation of galanin signaling might be of therapeutic value to improve insuin resistance and type 2 diabetes mellitus. To date, however, few papers have summarized the role of the galanin peptide family in modulating glucose metabolism and insulin resistance. In this review we summarize the metabolic effect of galanin peptide family and highlight its glucoregulatory action and discuss the pharmacological value of galanin pathway activiation for the treatment of glucose intolerance and type 2 diabetes mellitus.

Effect of Baicalein on GLUT4 Translocation in Adipocytes of Diet-Induced Obese Mice.

BACKGROUND/AIMS: Although baicalein has been shown to increase insulin sensitivity in liver of mice, there is no literature available about the effect of baicalein on glucose transporter 4 (GLUT4) translocation from intracellular membrane pools to plasma membranes in adipocytes of diet-induced obese mice. METHODS: In the present study, the obese model was induced in mice fed a high fat diet (20% carbohydrates, 21% protein and 59% fat) for 16 weeks. The diet-induced obese mice were given 20mg/kg baicalein intraperitoneally (i.p.) once a day for 21 days. The plasma insulin was measured by enzyme-linked immunosorbent assay. Fasting blood glucose and insulin resistance indexes were measured by glucose tolerance test (GTT). The expression levels of PGC-1α, UCP1, GLUT4, PPARγ, pP38MAPK, pERK and pAKT in adipocytes were determined by quantitative real-time polymerase chain reaction and western blotting. RESULTS: The present findings showed that administration of baicalein decreased pP38MAPK, pERK and PPARγ levels, but enhanced pAKT, PGC-1α and UCP1 contents as well as GLUT4 expression in adipocytes, and reversed high fat diet-induced glucose intolerance, hyperglycemia and insulin resistance in diet-induced obese mice. Moreover, baicalein treatment increased GLUT4 concentration in plasma membranes of adipocytes, i.e. baicalein may prevent insulin resistance through the GLUT4 translocation from intracellular membrane compartments to plasma membranes in adipocytes. CONCLUSION: These results suggest that baicalein is a powerful and promising agent for treatment of obesity and insulin resistance via Akt/GLUT4 pathway.

Akt2-Dependent Beneficial Effect of Galanin on Insulin-Induced Glucose Uptake in Adipocytes of Diabetic Rats.

BACKGROUND/AIMS: Glucose uptake occurs via the activation of an insulin-signaling cascade, resulting in the translocation of glucose transporter 4 (GLUT4) to the plasma membrane of adipocytes and myocytes. Recent research found that galanin could boost insulin-induced glucose uptake. This study aimed to explore whether activation of Akt2 mediates the beneficial effects of galanin on insulin-induced glucose uptake in the adipocytes of diabetic rats. METHOD: In this experiment, insulin, galanin and MK-2206, an Akt inhibitor, were injected individually or in combination into diabetic rats once a day for ten days. Then, glucose uptake and pAkt2 and its downstream proteins were examined in adipocytes. RESULTS: Administration of galanin significantly enhanced insulin-induced 2-Deoxy-D-[3H]glucose uptake; GLUT4 and vesicle-associated membrane protein 2 contents in plasma membranes; and pAkt2Thr308/Ser473 and Akt2 mRNA expression levels in adipocytes. In addition, Akt2 downstream proteins including phosphorylated AS160 were increased, but the levels of phosphorylated forkhead box O1 and glycogen synthase kinase-3ß were reduced. Treatment with MK-2206 may block the beneficial effects of galanin on these insulin-induced events. CONCLUSIONS: The results of this study suggest that phosphorylation of Akt2 mediates the beneficial effects of galanin on insulin-induced glucose uptake in the adipocytes of diabetic rats.

Beneficial effects of neuropeptide galanin on reinstatement of exercise-induced somatic and psychological trauma.

Galanin is a versatile neuropeptide that is distinctly upregulated by exercise in exercise-related tissues. Although benefits from exercise-induced upregulation of this peptide have been identified, many issues require additional exploration. This Review summarizes the information currently available on the relationship between galanin and exercise-induced physical and psychological damage. On the one hand, body movement, exercise damage, and exercise-induced stress and pain significantly increase local and circulatory galanin levels. On the other hand, galanin plays an exercise-protective role to inhibit the flexor reflex and prevent excessive movement of skeletal muscles through enhancing response threshold and reducing acetylcholine release. Additionally, elevated galanin levels can boost repair of the exercise-induced damage in exercise-related tissues, including peripheral nerve, skeletal muscle, blood vessel, skin, bone, articulation, and ligament. Moreover, elevated galanin levels may serve as effective signals to buffer sport-induced stress and pain via inhibiting nociceptive signal transmission and enhancing pain threshold. This Review deepens our understanding of the profitable roles of galanin in exercise protection, exercise injury repair, and exercise-induced stress and pain. Galanin and its agonists may be used to develop a novel preventive and therapeutic strategy to prevent and treat exercise-induced somatic and psychological trauma. © 2016 Wiley Periodicals, Inc.

Bacterial community in the metal(loid)-contaminated marine vertical sediments of Jinzhou Bay: Impacts and adaptations.

Metal(loid) discharge has led to severe coastal contamination; however, there remains a significant knowledge gap regarding its impact on sediment profiles and depth-resolved bacterial communities. In this study, geochemical measurements (pH, nutrient elements, total and bioavailable metal(loid) content) consistently revealed decreasing nitrogen, phosphorus, and metal(loid) levels with sediment depth, accompanied by reduced alpha diversity. Principal coordinate analysis indicated distinct community compositions with varying sediment depths, suggesting a geochemical influence on diversity. Ecological niche width expanded with depth, favoring specialists over generalists, but both groups decreased in abundance. Taxonomic shifts emerged, particularly in phyla and families, correlated with sediment depth. Microbe-microbe interactions displayed intricate dynamics, with keystone taxa varying by sediment layer. Zinc and arsenic emerged as key factors impacting community diversity and composition using random forest, network analysis, and Mantel tests. Functional predictions revealed shifts in potential phenotypes related to mobile elements, biofilm formation, pathogenicity, N/P/S cycles, and metal(loid) resistance along sediment profiles. Neutral and null models demonstrated a transition from deterministic to stochastic processes with sediment layers. This study provides insights into the interplay between sediment geochemistry and bacterial communities across sediment depths, illuminating the factors shaping these ecosystems.

Promising Nanomedicines of Shikonin for Cancer Therapy.

Malignant tumor, the leading cause of death worldwide, poses a serious threat to human health. For decades, natural product has been proven to be an essential source for novel anticancer drug discovery. Shikonin (SHK), a natural molecule separated from the root of Lithospermum erythrorhizon, shows great potential in anticancer therapy. However, its further clinical application is significantly restricted by poor bioavailability, adverse effects, and non-selective toxicity. With the development of nanotechnology, nano drug delivery systems have emerged as promising strategies to improve bioavailability and enhance the therapeutic efficacy of drugs. To overcome the shortcoming of SHK, various nano drug delivery systems such as liposomes, polymeric micelles, nanoparticles, nanogels, and nanoemulsions, were developed to achieve efficient delivery for enhanced antitumor effects. Herein, this review summarizes the anticancer pharmacological activities and pharmacokinetics of SHK. Additionally, the latest progress of SHK nanomedicines in cancer therapy is outlined, focusing on long circulation, tumor targeting ability, tumor microenvironment responsive drug release, and nanosystem-mediated combination therapy. Finally, the challenges and prospects of SHK nanomedicines in the future clinical application are spotlighted.

Galanin peptide family as a modulating target for contribution to metabolic syndrome.

Metabolic syndrome (MetS) is defined as abdominal central obesity, atherogenic dyslipidemia, insulin resistance, glucose intolerance and hypertension. The rapid increasing prevalence of MetS and the consequent diseases, such as type 2 diabetes mellitus and cardiovascular disorder, are becoming a global epidemic health problem. Despite considerable research into the etiology of this complex disease, the precise mechanism underlying MetS and the association of this complex disease with the development of type 2 diabetes mellitus and increased cardiovascular disease remains elusive. Therefore, researchers continue to actively search for new MetS treatments. Recent animal studies have indicated that the galanin peptide family of peptides may increase food intake, glucose intolerance, fat preference and the risk for obesity and dyslipidemia while decreasing insulin resistance and blood pressure, which diminishes the probability of type 2 diabetes mellitus and hypertension. To date, however, few papers have summarized the role of the galanin peptide family in modulating MetS. Through a summary of available papers and our recent studies, this study reviews the updated evidences of the effect that the galanin peptide family has on the clustering of MetS components, including obesity, dyslipidemia, insulin resistance and hypertension. This line of research will further deepen our understanding of the relationship between the galanin peptide family and the mechanisms underlying MetS, which will help develop new therapeutic strategies for this complex disease.

Heavy Metal Pollution and Health Risk Assessment of Vegetable-Soil Systems of Facilities Irrigated with Wastewater in Northern China.

Soil pollution by heavy metals is a major concern in China and has received much attention in recent years. Aiming to investigate the status of heavy metal pollution and the safety of vegetables in the soil of wastewater-irrigated facilities, this study investigated the distribution and migration characteristics of heavy metals in vegetable−soil systems of facilities in a typical sewage irrigation area of the Xi River, Shenyang City, northern China. Health risks due to the fact of exposure to heavy metals in the vegetable soil of facilities and ingrown vegetables through different exposure pathways were evaluated. Spatial interpolation and a potential ecological risk assessment were applied to evaluate the soil quality. Bioaccumulation factors (BCFs) were used to analyze the absorption and transportation capacity of Cd, Cu, Pb, and Zn by different parts of different vegetables. The results showed that the average concentration of Cd exceeded the standard values by 1.82 times and accumulated by 11 times, suggesting that Cd poses the most severe pollution among the four metals in the soil of facilities in the Xi River sewage irrigation area. In the city, a significant accumulation of Cd in the soil was identified with different spatial distributions. Cd also contributed the most in terms of the estimated potential ecological risk index, while the impacts of the other three metals were relatively small. The concentrations of heavy metals were mostly lower than the limit set by the corresponding Chinese standards. Various BCFs were observed for the four metals in the order Cd > Zn > Cu > Pb. Vegetables also demonstrated different BCFs in the order of leaf vegetables > Rhizome vegetable > Solanaceae vegetable. The magnitude of the noncarcinogenic risk for all four heavy metals was less than one for all three exposure routes and did not cause significant noncarcinogenic health effects in humans. However, the carcinogenic risk of Cd from some vegetables via dietary intake was considered higher. Protection measures should be taken to implement better pollution control and land use planning.

Galanin antagonist increases insulin resistance by reducing glucose transporter 4 effect in adipocytes of rats.

Seeing that galanin increases animal body weight on the conditions of inhibiting insulin secretion and animals with metabolic disorder of galanin easily suffer from diabetes, we postulate that endogenous galanin is necessary to reduce insulin resistance in adipocytes. To test this hypothesis, we compared four groups of rats to examine whether an increase in galanin secretion stimulated by swimming may reduce insulin resistance. The rats from sedentary and trained drug groups were injected by M35, a galanin antagonist. The rats from trained control and trained drug groups swam after each injection for four weeks. We found that exercise significantly elevated plasma galanin contents and glucose transporter 4 (GLUT4) mRNA levels in adipocytes. Meanwhile, M35 treatment reduced GLUT4 and GLUT4 mRNA levels, and glucose infusing rates in euglycemic-hyperinsulinemic clamp tests. The ratios of GLUT4 concentrations at plasma membranes to total cell membranes in both drug groups were lower compared with each control group, respectively. These observations suggest that endogenous galanin reduces insulin resistance by increasing GLUT4 contents and promoting GLUT4 transportation from intracellular membranes to plasma membranes in adipocytes. Galanin is an important hormone to reduce insulin resistance in rats.

Therapeutic potential of catalpol and geniposide in Alzheimer's and Parkinson's diseases: A snapshot of their underlying mechanisms.

Rehmannia glutinosa, the fresh or dried root of Rehmannia glutinosa (Gaertn.) Libosch. ex Fisch. & Mey., and Gardenia, the fruit of Gardenia jasminoides Ellis from Rubiaceae, both are famous traditional Chinese medicines that have been traditionally used in China. Catalpol and geniposide, as two kinds of iridoid glycosides with high activities, are the main bioactive components in Rehmannia glutinosa and Gardenia jasminoides Ellis, respectively. Over the past few decades, catalpol and geniposide have been widely studied for their therapeutic effects. The preclinical experiments demonstrated that they possessed significant neuroprotective activities against Alzheimer's disease, Parkinson's disease, stroke, and depression, etc. In this paper, the pharmacological effects and mechanisms of catalpol and geniposide on Alzheimer's disease and Parkinson's disease from 2005 to now were systematically summarized and comprehensively analyzed. At the same time, the pharmacokinetic characteristics of the analyzed compounds were also described, hoping to provide some enlightenment for the design, research, and development of iridoid glycosides.

Baicalin and its aglycone: a novel approach for treatment of metabolic disorders.

BACKGROUND: The current strategies for prevention and treatment of insulin resistance and type 2 diabetes are not fully effective and frequently accompanied by many negative effects. Therefore, novel ways to prevent insulin resistance and type 2 diabetes are urgently needed. The roots of Scutellaria radix are commonly used in traditional Chinese medicines for prevention and treatment of type 2 diabetes, atherosclerosis, hypertension, hyperlipidemia, dysentery, and other respiratory disorders. Baicalin and baicalein are the major and active ingredient extracts from Scutellaria baicalensis. METHODS: A comprehensive and systematic review of literature on baicalin and baicalein was carried out. RESULTS: Emerging evidence indicated that baicalin and baicalein possessed hepatoprotective, anti-oxidative, anti-dyslipidemic, anti-lipogenic, anti-obese, anti-inflammatory, and anti-diabetic effects, being effective for treating obesity, insulin resistance, non-alcoholic fatty liver, and dyslipidemia. Besides, baicalin and baicalein are almost non-toxic to epithelial, peripheral, and myeloid cells. CONCLUSION: The purpose of this study is to focus on the therapeutic applications and accompanying molecular mechanisms of baicalin and baicalein against hyperglycemia, insulin resistance, type 2 diabetes, hyperlipidemia, obesity, and non-alcoholic fatty liver, and trying to establish a novel anti-obese and anti-diabetic strategy.

San-Huang-Tang protects obesity/diabetes induced NAFLD by upregulating PGC-1α/PEPCK signaling in obese and galr1 knockout mice models.

ETHNOPHARMACOLOGICAL RELEVANCE: San-Huang-Tang (ST), a classic prescription, has been clinically used to cure diabetes and diabetes-associated metabolic disorders. Established studies have reported that ST can alleviate inflammation, obesity, hyperglycemia and insulin resistance. AIM OF THE STUDY: To the best of our knowledge, here, we reported for the first time the underlying mechanistic therapeutic efficacy of the ST against nonalcoholic fatty liver disease (NAFLD) in high-fat induced obese and galr1-deficient diabetic mice. MATERIALS AND METHODS: The obese and galr1-deficient mice were treated with ST at a dose of 10 g/kg every day for three weeks. Then food intake, body weight and insulin resistance indexes were measured. Western blotting, qRT-PCR, and plasma biochemical analyses were applied. RESULTS: ST reduced food intake, body weight, blood glucose level and insulin resistance, improved glucose tolerance in obese and galr1-deficient mice. Mechanistically, we confirmed that ST protected against NAFLD through activation of PGC-1α and its downstream signaling pathways as shown by the attenuated hepatic adipogenesis and lipid accumulation, increased hepatic fatty acid oxidation, regulated plasma lipid parameters, and increased energy expenditure and metabolic function in fat and muscle. CONCLUSIONS: Reduction in food intake produced by ST may contribute to the observed metabolic effects. Our findings strongly suggest that ST might be a potential novel therapeutic drug against obesity/diabetes-induced NAFLD and other metabolic disorders.

Baicalin ameliorates hepatic insulin resistance and gluconeogenic activity through inhibition of p38 MAPK/PGC-1α pathway.

BACKGROUND: Although the results of our and other studies show that baicalin can enhance glucose uptake and insulin sensitivity in skeletal muscle and adipocytes of mice, the specific metabolic contribution of baicalin on hepatic insulin resistance and gluconeogenic activity is still unclear. PURPOSE: The aim of this study is to investigate whether baicalin is involved in regulation of hepatic insulin resistance and gluconeogenic activity and its underlying mechanisms. STUDY DESIGN/METHODS: In the present study, high-fat diet-induced obese mice were given 50 mg/kg baicalin intraperitoneally (i.p.) once a day for 21 consecutive days, and hepatocytes were treated with baicalin (100 µM) or metformin (100 µM) in the presence of glucagon (200 nM) for 12 h. Then insulin resistance indexes and genes related to gluconeogenesis were examined in liver tissues. RESULTS: The present findings showed that baicalin decreased body weight, HOMA-IR, and alleviated high fat diet-induced glucose intolerance, hyperglycemia and insulin resistance in diet-induced obese mice. Furthermore, baicalin markedly suppressed p-p38 MAPK, p-CREB, FoxO1, PGC-1α, PEPCK and G6Pase expression in liver of obese mice and hepatocytes. Moreover, inhibition of gluconeogenic genes by baicalin was also strengthened by p38MAPK inhibitor in hepatocytes. CONCLUSION: Baicalin suppressed expression of PGC-1α and gluconeogenic genes, and reduced glucose production in high-fat diet-induced obese mice. Baicalin ameliorated hepatic insulin resistance and gluconeogenic activity mainly through inhibition of p38 MAPK/PGC-1α signal pathway. This study provides a possibility of using baicalin to treat hyperglycemia and hepatic insulin resistance in clinic.

Treatment with celastrol protects against obesity through suppression of galanin-induced fat intake and activation of PGC-1α/GLUT4 axis-mediated glucose consumption.

Overweight and obesity may cause several metabolic complications, including type 2 diabetes mellitus and hyperlipidemia. Despite years of progress in medicine, there are no highly effective pharmacological treatments for obesity. The natural compound celastrol, a pentacyclic triterpene extracted from the roots of Tripterygium Wilfordi (thunder god vine) plant, exerts various bioactivities including anti-diabetic and anti-obese effects. Although celastrol could decrease food intake and obesity, the detailed mechanism for celastrol is still unclear as yet. Herein, we intended to determine the effect of celastrol on obesity and the underlying mechanisms. In the present study, diet-induced obese mice were treated with 100 µg/kg/d celastrol for the last 21 days, and 3T3-L1 cells were treated with celastrol for 6 h. The present findings showed that celastrol suppresses fat intake, and leads to weight loss by inhibiting galanin and its receptor expression in the hypothalamus of mice fed a high-fat diet. More importantly, in addition to these direct anti-obesity activities, celastrol augmented the PGC-1α and GLUT4 expression in adipocytes and skeletal muscles to increase glucose uptake through AKT and P38 MAPK activation. Celastrol also inhibited gluconeogenic activity through a CREB/PGC-1α pathway. In conclusion, the weight-lowering effects of celastrol are driven by decreased galanin-induced food consumption. Thus, this study contributes to our understanding of the anti-obese role of celastrol, and provides a possibility of using celastrol to treat obesity in clinic.

The decline of whole-body glucose metabolism in ovariectomized rats.

Age is a major risk factor for developing chronic diseases, including type 2 diabetes and osteoporosis. Emerging evidences suggest that the disorder of bone metabolism in osteoporosis is involved in the pathogenesis of glucose intolerance, insulin resistance and type 2 diabetes. However, their etiology and relative regulatory factors still remain elusive to clinicians and researchers. In this study, rats were divided into two groups: normal sham surgery control and ovariectomized (OVX) groups. We evaluated the global bone parameters, glucose metabolism, protein and gene expressions in both skeletal muscle and adipocytes. The present findings showed that the bone mineral density (BMD) and compression load of bone were markedly reduced in OVX rats as revealed by micro-CT, dual energy X-ray absorptiometry and bone biomechanics analysis. Besides, plasma estrogen, total alkaline phosphatase (TALP) and osteocalcin levels were significantly decreased in the OVX rats, but body weight, fat mass and plasma tartrate-resistant acid phosphatase (TRAP) and chemerin levels were significantly increased in the OVX rats. More interestingly, we found that p-AKT, p-P38MAPK, glucose transporter 4 (GLUT4) and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) contents as well as GLUT4 and PGC-1α mRNA expression were significantly decreased in skeletal muscle and adipocytes of OVX rats. In conclusion, our results indicated that whole-body glucose metabolism and glucose intolerance in OVX rats was degressive, suggesting there was a novel link between osteoporosis and whole body glucose homeostasis, which are controlled by the P38MAPK/PGC-1α/GLUT4 signaling pathway.

Central galanin receptor 2 mediates galanin action to promote systemic glucose metabolism of type 2 diabetic rats.

Although recent results of our and other studies have showed that galanin (GAL) is an antidiabetic and anti-inflammatory neuropeptide, the molecular mechanism how central GAL regulates energy homeostasis and insulin sensitivity is still not fully understood. The aim of this study was to investigate whether central type 2 of GAL receptors (GALR2) are involved in the regulation of systemic glucose metabolism and its underlying mechanisms. In the present study, type 2 diabetic rats were intracerebroventricularly (i.c.v.) given 100 nM/kg/d GALR2 agonist M1145 or GALR2 antagonist M871 in 5 µl artificial cerebrospinal fluid once a day for consecutive 21 days. Then insulin resistance indexes, inflammatory factor and many genes associated with the function of glucose metabolism were examined in peripheral tissues. The present findings showed that the intracerebroventricular injection of M1145 or M871 respectively increased or decreased glucose infusion rates in hyperinsulinemic euglycemic clamp tests, but attenuated or enhanced the plasma inflammatory factors and glucose concentration in type 2 diabetic rats. Moreover, administration of M1145 markedly increased PGC-1α and GLUT4 expression in skeletal muscles and adipocytes of type 2 diabetic rats. In conclusion, activation of central GALR2 promotes glucose metabolism and ameliorates insulin resistance mainly through the PGC-1α/GLUT4 pathways. The central GALR2 is crucial to whole-body insulin sensitivity and energy homeostasis.