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Luteolin enhances insulin sensitivity via activation of PPARΓ transcriptional activity in adipocytes
Abstract
Obesity and insulin resistance have been linked to a low-grade chronic inflammatory response characterized by increased macrophage infiltration, altered cytokine production and activation of inflammatory signaling pathway in adipose tissue. Pharmacological agents and natural products that are capable of reducing inflammatory activity possess anti-diabetic properties. Luteolin, a naturally occurring flavonoid, has been demonstrated to inhibit lipopolysaccharide-induced tumor necrosis factor-α (TNFα) release and activation of NF-κB pathway in macrophages. However, little is known about the mechanism and effect of luteolin on inflammation-related insulin resistance in adipocytes. In this study, we investigated the effect of luteolin on insulin action in 3T3-L1 adipocytes and primary adipose cells. Here we showed that luteolin treatment for 24 h increased the response of glucose uptake to insulin stimulation in 3T3-L1 adipocytes. Our results also demonstrated that luteolin enhanced Akt2 phosphorylation in an insulin-stimulated state. Furthermore, luteolin treatment decreased mRNA levels of TNFα, interleukin-6 and MCP-1, while it increased the gene expression of adiponectin and leptin in 3T3-L1 adipocytes and primary mouse adipose cells. Most interestingly, we found that treatment of luteolin markedly enhanced peroxisome proliferator-activated receptor γ (PPARγ) transcriptional activity in 3T3-L1 adipocytes, and luteolin-increased expression of adiponectin and leptin was blocked by GW9662, a PPARγ antagonist. Thus, our data suggest that luteolin influences insulin action and production of adipokines/cytokines in adipocytes by activating the PPARγ pathway.
... 41 In this regard, an in vitro study 42 has shown an up-regulating role of chamomile extract on PPAR and glucose transporter (GLUT)-4 gene expression, which raises insulin sensitivity as well as decreases peripheral glucose levels, respectively. 42 Additionally, αglucosidase is an important carbohydrate digestive enzyme in the enterocyte brush border 39 which might be suppressed by quercetin and esculetin, two main components of chamomile, and thus reduce circulating glucose levels dramatically. 43 Additionally, prolonged exposure to hyperglycemia is accompanied by high levels of reducing sugars which react with lipids and proteins and has a deteriorative effects on endogenous antioxidant capacity. ...
... 51 Studies have shown that luteolin, one of the active components of chamomile, leads to an increase in the expression of the adiponectin gene. 42 Besides, the chamazulene carboxylic acid constituent of chamomile structurally shows similarities to profens and acts as a selective inhibitor of cyclooxygenase-2 and thereby may help to improve inflammatory responses. 46,52 Due to high amounts of chamomile antioxidants, it has been assumed that this herbal medicine extract can ameliorate oxidative stress and chronic inflammation in people suffering from DM. 25 The biological activities of chamomile on dyslipidemia have attracted a great deal of attention. ...
... 60 Therefore, due to the antioxidant properties of chamomile, it is recommended to investigate the effects of chamomile on the factors involved in the AMPK signaling pathway. Studies have shown that adiponectin, by binding to its receptor, leads to activating the AMPK pathway, 51 and considering the effect of luteolin, one of the active components of chamomile on increasing the expression of adiponectin gene, 42 it is recommended that future studies evaluate the effect of chamomile on the levels and expression of adiponectin gene expression. ...
Chamomile, as a rich source of phenolic compounds and terpenoids, seems to be an effective approach in the management of chronic conditions such as diabetes mellitus. The aim of this systematic review was to evaluate evidence from animal and human studies of the effects of chamomile on metabolic risk markers and complications of diabetes mellitus. The literature search was conducted in PubMed, SCOPUS, Embase, ProQuest and Google Scholar electronic and were considered the articles published on April 2019. Original studies that investigated the effect of chamomile in diabetes mellitus which met the inclusion criteria were eligible. After screening 208 citations, 15 studies were included. The results of these studies demonstrated a significant effect of chamomile administration on metabolic profiles. All 12 studies that examined the impact of chamomile sup-plementation on glycemic control indicated this feature. Four of the five studies appraising the impact of cha-momile on lipid profiles showed that it improved dyslipidemia. Six studies showed that chamomile markedly decreased oxidative stress particularly malondialdehyde. Altogether, four chamomile studies evaluating diabetes complications, including renal and hepatic profiles, found significant decreases compared to controls. These findings extend the novel functions of chamomile in the improvement of glycemic and lipid profiles and oxi-dative stress indicators in diabetes mellitus and related complications. In-depth studies focusing on underlying mechanisms are warranted to make useful conclusions.
... Luteolin did not change the adipocyte formation or cellular lipid content in differentiated 3T3-L1 cells. In previous studies, luteolin resulted in contradictory results in intracellular lipid accumulation (Ding, Jin and Chen, 2010;Mosqueda-Solís et al., 2017;Park et al., 2009). Luteolin (from 10 μM) showed a lipid accumulation inhibiting effect on differentiated 3T3-L1 cells treated with IBMX, dexamethasone, and insulin at the early stage of differentiation (Park et al., 2009). ...
... Multiple dietary polyphenols such as apigenin, esculetin, and cyclocarioside have shown anti-adipogenic effects via AMPK inhibition (Guru et al., 2020). Luteolin showed AMPK activation effects that may attenuate the expression of PPARγ and C/EBPs to inhibit adipogenesis, but also can induce PPARγ activation (Ding et al., 2010;Zhang et al., 2016). The AMPK activating and the PPARγ partial agonism effects of luteolin may result in different adipogenic and lipogenic profiles when combined with ROSI and the POP mixture. ...
... Besides impacts on PPARγ, luteolin and luteolin-7-O-glucoside have shown inhibitory effects on glucose uptake via the glucose transporter (GLUT) 4 (Nagai et al., 2016;Nishina et al., 2015). In differentiated 3T3-L1 cells, luteolin promoted PPARγ expression and PPARγ DNA binding activity, and enhanced glucose uptake via glucose transporter (GLUT) 4 (Ding et al., 2010). Recently, the adipogenic and lipogenic effects of selected plastic extracts were elucidated, and showed chemicals extracted from plastic products increased adipocyte formation and lipid accumulation without the activation of PPARγ or glucocorticoid receptor pathways (Völker et al., 2022). ...
Human exposure to persistent organic pollutants (POPs) may contribute to obesogenic effects. We have previously shown that POP mixtures modelled on blood levels relevant to the Scandinavian population induces adipogenic effects in the mouse 3T3-L1 cell line. Luteolin is a flavone that has shown anti-lipogenic and anti-adipogenic effects on adipogenesis in in vitro models. In this study, luteolin has been applied to inhibit adipocyte formation and intracellular lipid content increase induced by a human relevant mixture of POPs. 3T3-L1 cells were exposed to a POP mixture consisting of 29 chemicals, including amongst others polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), it perfluoroalkylated acids (PFAAs), and polybrominated diphenyl ethers (PBDEs). Rosiglitazone was applied as a positive lipogenic control. Luteolin was tested between 0.5 and 10 μM. High content analysis was used to assess changes in adipocyte formation and intracellular lipid content in the 3T3-L1 cell line. Luteolin significantly reduced POP-induced adipocyte formation at 2, 5 and 10 μM, and lipid accumulation at 10 μM. Interestingly, luteolin did not affect rosiglitazone induced adipo- and lipogenic effects, suggesting differences in mechanisms of action. In conclusion, this in vitro study shows that dietary polyphenols such as luteolin may protect against POP induced adipo- and lipogenic effects.
... In addition, it was previously shown that luteolin facilitates insulin action in adipocytes by activating the peroxisome proliferator-activated receptor (PPAR-γ) pathway [22]. Luteolin treatment for 24 h reportedly increases the response of glucose uptake to insulin stimulation in 3T3-L1 adipocytes enhancing Akt2 phosphorylation in an insulin-stimulated state [22]. Herein, we show that insulin resistance in GK rats is significantly reduced by luteolin treatment, high- ...
... It was previously reported that luteolin was able to reduce hepatic steatosis and insulin resistance [15][16][17] in mice with diet-induced obesity [16]. In addition, it was previously shown that luteolin facilitates insulin action in adipocytes by activating the peroxisome proliferator-activated receptor (PPAR-γ) pathway [22]. Luteolin treatment for 24 h reportedly increases the response of glucose uptake to insulin stimulation in 3T3-L1 adipocytes enhancing Akt2 phosphorylation in an insulin-stimulated state [22]. ...
... In addition, it was previously shown that luteolin facilitates insulin action in adipocytes by activating the peroxisome proliferator-activated receptor (PPAR-γ) pathway [22]. Luteolin treatment for 24 h reportedly increases the response of glucose uptake to insulin stimulation in 3T3-L1 adipocytes enhancing Akt2 phosphorylation in an insulin-stimulated state [22]. Herein, we show that insulin resistance in GK rats is significantly reduced by luteolin treatment, highlighting the major role of this flavone in controlling insulin sensitivity. ...
We investigated the effects of luteolin on metabolism, vascular reactivity, and perivascular adipose tissue (PVAT) in nonobese type 2 diabetes mellitus animal model, Goto-Kakizaki (GK) rats.
Methods:
Wistar and GK rats were divided in two groups: (1) control groups treated with vehicle; (2) groups treated with luteolin (10 mg/kg/day, for 2 months). Several metabolic parameters such as adiposity index, lipid profile, fasting glucose levels, glucose and insulin tolerance tests were determined. Endothelial function and contraction studies were performed in aortas with (PVAT+) or without (PVAT-) periaortic adipose tissue. We also studied vascular oxidative stress, glycation and assessed CRP, CCL2, and nitrotyrosine levels in PVAT.
Results:
Endothelial function was impaired in diabetic GK rats (47% (GK - PVAT) and 65% (GK + PVAT) inhibition of maximal endothelial dependent relaxation) and significantly improved by luteolin treatment (29% (GK - PVAT) and 22% (GK + PVAT) inhibition of maximal endothelial dependent relaxation, p < 0.01). Vascular oxidative stress and advanced glycation end-products' levels were increased in aortic rings (~2-fold, p < 0.05) of diabetic rats and significantly improved by luteolin treatment (to levels not significantly different from controls). Periaortic adipose tissue anti-contractile action was significantly rescued with luteolin administration (p < 0.001). In addition, luteolin treatment significantly recovered proinflammatory and pro-oxidant PVAT phenotype, and improved systemic and metabolic parameters in GK rats.
Conclusions:
Luteolin ameliorates endothelial dysfunction in type 2 diabetes and exhibits therapeutic potential for the treatment of vascular complications associated with type 2 diabetes.
... Like apigenin, luteolin is a yellow flavonoid and is an active ingredient of chamomile flowers (Ding et al., 2010). Pharmacological effects of luteolin include antioxidant, antitumor, anti-inflammatory and antimicrobial actions (Lopez-Lazaro, 2009). ...
... Pharmacological effects of luteolin include antioxidant, antitumor, anti-inflammatory and antimicrobial actions (Lopez-Lazaro, 2009). Beneficial effects of luteolin in obesity and insulin resistance have also been reported (Ding et al., 2010;Liu et al., 2014;Bumke-Vogt et al., 2014). Luteolin was found to intensify transcriptional activity of PPARγ in 3T3-L1 adipocytes and increase their insulin sensitivity by up-regulation of the expression of insulindependent glucose transporter (GLUT-4) receptors (Ding et al., 2010). ...
... Beneficial effects of luteolin in obesity and insulin resistance have also been reported (Ding et al., 2010;Liu et al., 2014;Bumke-Vogt et al., 2014). Luteolin was found to intensify transcriptional activity of PPARγ in 3T3-L1 adipocytes and increase their insulin sensitivity by up-regulation of the expression of insulindependent glucose transporter (GLUT-4) receptors (Ding et al., 2010). Luteolin also enhanced expression of the adiponectin gene, which is one of the PPARγ targets and involved in regulation of glucose levels and fatty acid breakdown (Ding et al., 2010). ...
Obesity is an increasing health concern related to many metabolic disorders, including metabolic syndrome, diabetes type 2 and cardiovascular diseases. Many studies suggest that herbal products can be useful dietary supplements for weight management due to the presence of numerous biologically active compounds, including antioxidant polyphenols that can counteract obesity-related oxidative stress. In this review we focus on Matricaria chamomilla, commonly known as chamomile, and one of the most popular medicinal plants in the world. Thanks to a high content of phenolic compounds and essential oils, preparations from chamomile flowers demonstrate a number of pharmacological effects, including antioxidant, anti-inflammatory, antimicrobial and sedative actions as well as improving gastrointestinal function. Several recent studies have shown certain positive effects of chamomile preparations in the prevention of obesity and complications of diabetes. These effects were associated with modulation of signaling pathways involving the AMP-activated protein kinase, NF-κB, Nrf2 and PPARγ transcription factors. However, the potential of chamomile in the management of obesity seems to be underestimated. This review summarizes current data on the use of chamomile and its individual components (apigenin, luteolin, essential oils) to treat obesity and related metabolic disorders in cell and animal models and in human studies. Special attention is paid to molecular mechanisms that can be involved in the anti-obesity effects of chamomile preparations. Limitation of chamomile usage is also analyzed.
... 2,31 Furthermore, the flavonoids present in the PS pulp, the flavones isoorientin, orientin and hesperetin, 17 and the metabolites (epi)catechin O-glucuronide, (iso)orientinsulphate and hydroxy-luteolin O-glucuronide found in the plasma of participants after 14 days of consumption exert antiinflammatory and anti-diabetic properties. 6,[31][32][33][34] Isoorientin has been shown to reverse insulin resistance in adipocytes, stimulating adequate phosphorylation of the IRS in the insulin signaling pathway. The effect of this flavone in improving insulin sensitivity was similar to that of rosiglitazone, commonly used for this purpose, but it has side effects such as the development of osteoporosis and reduced liver regeneration. ...
... 32 Predictive analyses performed in silico suggested high affinity for binding of the sulfated metabolite of isoorientin to the IRS substrate and to Akt, a key protein kinase in the insulin signaling cascade, 6 revealing a relevant molecular mechanism underlying the health properties of this polyphenol-rich food. Luteolin, in turn, is a flavonoid capable of increasing Akt phosphorylation, 33 inhibiting insulinemia and insulin resistance. 34 We also observed that PS reduced IL-6 to basal levels, whereas with PB, its levels increased. ...
Passiflora setacea (PS) is a species of wild Brazilian passion fruit, rich in bioactive compounds. Studies suggested that a diet rich in bioactive compounds can positively modulate inflammation and oxidative...
... Luteolin is a flavonoid derivative found in many Moroccan antidiabetic medicinal plants. Scientific reports highlighted the in vitro and in vivo antidiabetic effects of this substance (Choi, Islam et al., 2014;Choi, Kang, Lee, and Kim et al., 2014;Deqiu et al., 2011;Ding et al., 2010Ding et al., , 2014Kim et al., 2000;Matsui et al., 2002b;Yan et al., 2014;Zang et al., 2016;Zarzuelo et al., 1996;Zhang et al., 2016b). An in vitro study was carried out by Kim et al. (2000) on the inhibitory effect of luteolin onα-amylase and α-glucosidase. ...
... Luteolin exhibited an antidiabetic phenotype in the in vitro cell culture model. In 3T3-L1 cell lines, luteolin increased the response of glucose uptake to insulin stimulation in 3T3-L1 adipocytes, enhanced Akt2 phosphorylation in an insulin-stimulated state, decreased mRNA levels of TNFα and interleukin-6, and enhanced PPARγ transcriptional activity in 3T3-L1 adipocytes (Ding et al., 2010). In another study, Deqiu et al. (2011) showed that luteolin increased insulin-mediated endothelium-dependent relaxation in rat aorta, and reduced gene over-expressions (TNF-α and IL-6), restored insulin signaling cascades, elevated insulin-dependent production of nitric oxide in endothelial cells cultivated in vitro (Deqiu et al., 2011). ...
Background
Moroccan flora is rich with medicinal plants that are widely used in traditional medicine for the treatment of various diseases including diabetes. These plants possess several classes of bioactive molecules, which belong to different chemical families such as phenolic acids, flavonoids, terpenoids and alkaloids.
Scope and approach
This review highlights the published reports on the antidiabetic properties of Moroccan medicinal plants. The mechanism of action of these plants and their secondary metabolites were discussed in detail. Clinical trials on the antidiabetic active constituents were summarized demonstrating the potential application of these natural treasures to be developed as potent antidiabetic agents.
Key findings and conclusions
were reported to be used in the treatment of diabetes in Morocco. Among these medicinal plants, the antidiabetic activity was evaluated for 15 species in vitro and 30 species in vivo. The in vitro studies showed significant inhibition of enzymes involved in the intestinal metabolism of carbohydrates. The in vivo reports revealed that the extracts and essential oils of these plants exhibited several antidiabetic effects such as a decrease of blood glucose and an increase of insulin secretion. Phytochemical analysis of the active plants revealed the presence of 148 secondary metabolites. These compounds belong to different chemical classes such as terpenoids, flavonoids, alkaloids, phenolic acids, and fatty acids. Among the identified compounds, 95 were evaluated for their antidiabetic activity. The results showed that these compounds manage diabetes by several mechanisms such as enzymatic inhibition, interference with glucose and lipid metabolism signaling pathways, and the inhibition and/or the activation of gene expression involved in glucose homeostasis. Eighteen active compounds reached clinical trials and showed impressive results in controlling diabetes and its manifestations.
... 3 The amyloid hypothesis was proposed as a consequence of the discovery that genetic mutations can result in the deposition of amyloid-beta (Aβ) and the formation of neurotoxic Aβ plaques. The amyloid hypothesis remains a commonly accepted hypothesis, and an Alzheimer'slike animal model can be created by Aβ (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35), , or infusion into the CA1 region of the hippocampus of rats. 4,5 However, despite the neurotoxic effects of high concentrations of Aβ, decreasing the content of Aβ in the brain by using monoclonal antibody therapy 6 or β-secretase inhibitors 7 has been unsuccessful. ...
... 30,31 Luteolin is reported to mitigate the impairment of these pathways to increase fat utilization and contributes to protection against obesity and hepatic steatosis. [30][31][32] Luteolin decreases free fatty acids in the bloodstream to reduce hepatic insulin resistance by elevating PPAR-γ protein expression in adipose tissues to enhance fatty acid uptake, lipogenesis, and fatty acid utilization. Therefore, luteolin acts as a modulator of the liver and adipose tissue cross-talk. ...
Luteolin is a widely distributed flavone herbs and vegetables. It has anti-oxidant and anti-inflammatory activities and improves glucose metabolism by potentiating insulin sensitivity and improving β-cell function and mass. Alzheimer's disease (AD) is induced by the deposition of amyloid-beta (Aβ) in the hippocampus and the formation of neurotoxic Aβ plaques. The Aβ deposition is associated with increased formation of Aβ from amyloid precursor protein by up-regulation of β-secretase and β-site amyloid precursor protein-cleaving enzyme 1 (BACE1). Furthermore, Aβ accumulation is increased by brain insulin resistance. The impairment of insulin/IGF-1 signaling mainly in the hippocampus and brain insulin resistance is connected to signals originating in the liver and gut microbiota, known as the gut microbiota-liver-brain axis. This indicates that the changes in the production of short-chain fatty acids by the gut microbiota and pro-inflammatory cytokines can alter insulin resistance in the liver and brain. Luteolin is detected in the brain tissues after passing through the blood-brain barrier, where it can directly influence neuroinflammation and brain insulin resistance and modulate Aβ deposition. Luteolin (10-70 mg/kg bw for rodents) can modulate the systemic and brain insulin resistance, and it suppresses AD development directly, and it influences Aβ deposition by activation of the gut microbiota-liver-brain axis. In this review, we evaluate the potential of luteolin to mitigate two potential causes of AD, neuroinflammatory processes, and disruption of glucose metabolism in the brain. This review suggests that luteolin intake can enhance brain insulin resistance and neuroinflammation, directly and indirectly, to protect against the development of Alzheimer's-like disease, and the gut microbiota-liver-brain axis is mainly involved in the indirect pathway. However, most studies have been conducted in animal studies, and human clinical trials are needed.
... Among the putative compounds, luteolin, and apigenin, both under the flavone class of flavonoids, were previously identified as compounds present in A. sessilis varieties of other countries. Several studies have already presented the antidiabetic activity of luteolin through inhibition of α-amylase and α-glucosidase activities (Zhang et al., 2017;Kim, Kwon, Son, 2000), including improvement of insulin sensitivity in adipocytes by increasing glucose uptake and reducing mRNA levels of cytokines linked to insulin resistance, such as TNF-α, interleukin-6, and MCP-1 (Zang, Igarashi, Li, 2016;Ding, Jin, Chen, 2010). Continuous oral feeding of 200 mg/kg dose of luteolin in streptozotocin-induced diabetic rats for 8 weeks demonstrated a significant fall in blood glucose levels compared to baseline values. ...
... 36 compounds belonged to the active group with their values of EC50≤30 μM. The nonactive group included 18 inactive compounds (the EC50 values>30 μM) 20 and 288 decoys obtained from ZINC15 database through using Decoy Finder 2.0. ...
... Likewise, luteolin was able to prevent hepatic and adipocyte fibrosis and IR via the toll-like receptor (TLR) signaling pathway (Kwon & Choi, 2018). By directly stimulating the PPARγ pathway or regulating the insulin signaling cascades, luteolin may also improve the function of insulin in adipocytes (Ding, Jin & Chen, 2010). ...
Insulin resistance (IR) is a main etiology of various metabolic diseases such as type 2 diabetes mellitus (T2DM), hypertension, hyperlipidemia and coronary heart disease. IR is a multi-factorial etiology disease regulated by various mechanisms. Obesity, a significant public health problem worldwide, is considered as a high-risk factor to induce IR and T2DM. Thus, inhibiting obesity-induced IR is one of the key therapeutic strategies to improve T2DM. Natural products from herbs and nutraceuticals have shown promising efficacy on obesity-induced IR and T2DM owing to its multi-component and multi-target characteristics. However, the active constituents and the action mechanisms are still not yet well elucidated. In this review, the natural constituents with protective capacities against IR were summarized. The active constituents include crude extracts such as polyphenols, saponins, alkaloids, terpenoids, phenylpropanoids, as well as monomeric compounds such as curcumin, berberine, capsaicin, naringenin, quercetin, betaine and isoliquiritigenin. The action mechanisms of these active constituents could be mainly divided into 4 categories: ameliorating metabolic abnormality, inhibiting inflammation, reversing gut microbiota dysbiosis, regulating micro RNAs (miRNAs). Their precise roles in regulating PI3K/AKT, AMPK, PPARs, SIRT1 and NF-κB pathways, brown adipose tissue activity and white adipose tissue browning, NLRP3 inflammasome activity, gut microbiota structure and composition and miRNA expression were discussed. The sources, chemical structures, experimental models, pharmacological effects and action targets of these active constituents were also summarized. This review provides new active constituents, therapeutic targets and reasoning for the clinical application of herbs and nutraceuticals in the treatment of IR and T2DM.
... However,GLUT-4 expression was markedly low in the diabetic group [43]. GLUT-4, which is specifically distributed on the cell membrane of adipose cells, is majorly responsible for basal glucose transport and regulates the transport of insulin and glucose through translocation and activation, facilitated by the PI3K/phosphorylated protein kinase B (p-Akt) pathway [44]. GLUT-4 knockout in mouse models confirmed that the extensive metabolic and tissue-specific regulation of the GLUT-4 gene has a significant effect on insulin-induced glucose clearance. ...
Reduced activity of glucose transporter type 4 isoform (GLUT-4), an insulin-sensitive glucose transporter distributed on the adipocytes, is associated with impaired insulin signaling. Insulin resistance resulting from alteration in glucose transport is responsible for exacerbating the emergence of metabolic abnormalities. The present study aimed to investigate the effects of the antidote gallic acid (GA) on expression-related changes in GLUT-4 and insulin receptor substrate-1 (IRS-1) in the visceral adipose tissue and on the subsequent development of insulin resistance in a high-fat diet (HFD)–induced obesity animal model. Methods: Twenty-four female Swiss albino mice were used and separated into the following four groups (six animals in each group): control group (standard pellet diet), HFD group, (60% HFD), HFD + GA group (60% HFD and GA 50 mg/kg body weight for 60 days), and GA group (GA 50 mg/kg body weight for 60 days). The effect of HFD on serum glucose, total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL), low-density lipoprotein (LDL) cholesterol, and insulin was evaluated. Additionally, homeostasis model assessment for insulin resistance (HOMA-IR) and glucose tolerance test (GTT) was performed. The serum antioxidative profile, which comprises oxidative parameters (superoxide dismutase [SOD], catalase [CAT], and glutathione peroxidase [GPx]) was measured. The effectiveness of GA against HFD-induced alteration in GLUT-4 and IRS-1 expression was also evaluated. Results: The experimental group that fed on GA + HFD had improved levels of serum triglycerides (p˂0.001), cholesterol (p˂0.05), and LDL cholesterol. GA administration also significantly improved hyperinsulinemia and HOMA-IR index (p˂0.001) in HFD mice. GA improved GTT results (p˂0.05); activity of SOD, CAT, and GPx (p˂0.05); and upregulated mRNA expression of GLUT-4 and IRS-1(p˂0.05) in the visceral adipose tissue in the HFD + GA experimental group. Conclusion: A link exists between insulin resistance, GLUT-4, and IRS-1 expression in the adipose tissue, and the initiation of metabolic syndrome, a condition characterized by obesity. GA may promote insulin signaling, glucose uptake, and lipid metabolism in the adipose tissues by mitigating oxidative stress. GA can also be used to manage obesity-related comorbidities including type 2 diabetes and dyslipidemia.
... It was reported that some flavonoid compounds, such as hispidulin and luteolin, which both exhibit similar structures to pectolinarigenin, targeted peroxisome proliferators-activated receptor γ (PPARγ) and induced PPARγ activation [23,24]. PPARγ is a key transcription factor involved in lipid metabolism, PPARγ activation induces decreased lipid biosynthesis and increased lipid metabolism [25]. ...
A comparative study was conducted to determine whether hesperetin and pectolinarigenin could lower total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL), and high-density lipoprotein cholesterol (HDL) in a high-fat diet (HFD)-induced high lipid model in Golden Syrian hamsters. 48 Golden Syrian hamsters (8 weeks old) were fed with a HFD for 15 days. HFD induced significant increases in plasma TC, TG, LDL, and HDL. Then, these high lipid hamsters were divided into four groups and were administered with 0.5% sodium carboxymethyl cellulose (CMC-Na), hesperetin (100 mg/kg/day), pectolinarigenin (100 mg/kg/day) or atorvastatin (1.0 mg/kg/day), for 7 weeks. It was found that pectolinarigenin treatment resulted in significant reductions in body weight, adiposity index, serum levels of TC, TG and hepatic TC, TG and free fatty acid compared to those in control hamsters with hyperlipidemia (P<0.05). However, hesperetin treatment only caused reductions in plasma TC and hepatic TG levels. Besides, the hamsters treated with pectolinarigenin showed a relatively normal hepatic architecture compared to the hepatic steatosis shown in the control group. Moreover, the expressions of fatty-acid synthase (Fasn) and solute carrier family 27 member 1 (Slc27a1) involved in lipid biosynthesis, were suppressed in the pectolinarigenin-treated groups, and the expression of carnitine palmitoyltransferase 1A (Cpt1a) involved in fatty acid oxidation was increased in the pectolinarigenin-treated group. Taken together, these results suggest pectolinarigenin exerts stronger protective effects against hyperlipidemia and hepatic steatosis than hesperetin, which may involve the inhibition of lipid uptake and biosynthesis.
... Indeed, in mouse 3T3-L1 adipocytes exposed to glucose, luteolin reduced the levels of inflammatory cytokines TNF-α, IL-6 and MCP-1 (Ding, Jin, and Chen 2010); the reduction is associated with increased expression and activation of PPARγ, leading to upregulation of the adipokines, leptin and adiponectin. Moreover, luteolin enhanced the response of mouse 3T3-L1 adipocytes to insulin, resulting in enhanced glucose uptake and increased activation of Akt2 phosphorylation (Ding, Jin, and Chen 2010). A lowering of insulin resistance by luteolin was also observed in spontaneous type-2 diabetic KK-A y mice (which develop obesity and hyperglycemia at 7 or 8 weeks old), coupled with reduced fasting blood glucose level, serum HbA 1C level and insulin level when compared with KK-A y mice not treated with luteolin (Zang, Igarashi, and Li 2016). ...
Diabetes, being the most widespread illness, poses a serious threat to global public health. It seems that inflammation plays a critical role in the pathophysiology of diabetes. This review aims to demonstrate a probable link between type 2 diabetes mellitus (T2DM) and chronic inflammation during its development. Additionally, the current review examined the bioactivity of natural flavones and the possible molecular mechanisms by which they influence diabetes and inflammation. While natural flavones possess remarkable anti-diabetic and anti-inflammatory bioactivities, their therapeutic use is limited by the low oral bioavailability. Several factors contribute to the low bioavailability, including poor water solubility, food interaction, and unsatisfied metabolic behaviors, while the diseases (diabetes, inflammation, etc.) causing even less bioavailability. Throughout the years, different strategies have been developed to boost flavones' bioavailability, including structural alteration, biological transformation, and innovative drug delivery system design. This review addresses current advancements in improving the bioavailability of flavonoids in general, and flavones in particular. Clinical trials were also analyzed to provide insight into the potential application of flavonoids in diabetes and inflammatory therapies.
... Lutein (Figure 4) is abundant in celery, parsley, broccoli, onion leaves, and chrysanthemum blooms, among other vegetables and fruits [87]. In 3T3-L1 adipocytes and primary mouse adipose cells, luteolin potentiates insulin action and enhances peroxisome proliferator-activated receptor (PPAR) expression and transcriptional activity, and the expression of PPAR target genes such as adiponectin, leptin, and GLUT4, and a PPAR antagonist inhibits this induction [88]. e decrease in circulation levels of inflammatory mediators such as monocyte chemoattractant protein 1 (MCP-1) and resistin, as well as the increase in adiponectin levels in obese mice, is likely to be managed by luteolin's beneficial effects on metabolic pathways implicated in insulin resistance and DM pathogenesis [89]. ...
Diabetes mellitus (DM) is a fatal metabolic disorder, and its prevalence has escalated in recent decades to a greater extent. Since the incidence and severity of the disease are constantly increasing, plenty of therapeutic approaches are being considered as a promising solution. Many dietary polyphenols have been reported to be effective against diabetes along with its accompanying vascular consequences by targeting multiple therapeutic targets. Additionally, the biocompatibility of these polyphenols raises questions about their use as pharmacological mediators. Nevertheless, the pharmacokinetic and biopharmaceutical properties of these polyphenols limit their clinical bene t as therapeutics. Pharmaceutical industries have attempted to improve compliance and therapeutic effects. However, nanotechnological approaches to overcome the pharmacokinetic and biopharmaceutical barriers associated with polyphenols as antidiabetic medications have been shown to be effective to improve clinical compliance and efficacy. Therefore, this review highlighted a comprehensive and up-to-date assessment of polyphenol nanoformulations in the treatment of diabetes and vascular consequences.
... The effective anti-inflammatory activity of luteolin has also been suggested to contribute to its protective effect against insulin resistance (Daily et al., 2021). Indeed, luteolin has been shown to improve insulin sensitivity in many cell types, including adipocytes and endothelial cells (Ding et al., 2010;Deqiu et al., 2011). In agreement, a diet supplemented with luteolin has been demonstrated to ameliorate obesity and insulin resistance in mice . ...
Alzheimer’s disease (AD) is a chronic, complex neurodegenerative disorder mainly characterized by the irreversible loss of memory and cognitive functions. Different hypotheses have been proposed thus far to explain the etiology of this devastating disorder, including those centered on the Amyloid-β (Aβ) peptide aggregation, Tau hyperphosphorylation, neuroinflammation and oxidative stress. Nonetheless, the therapeutic strategies conceived thus far to treat AD neurodegeneration have proven unsuccessful, probably due to the use of single-target drugs unable to arrest the progressive deterioration of brain functions. For this reason, the theoretical description of the AD etiology has recently switched from over-emphasizing a single deleterious process to considering AD neurodegeneration as the result of different pathogenic mechanisms and their interplay. Moreover, much relevance has recently been conferred to several comorbidities inducing insulin resistance and brain energy hypometabolism, including diabetes and obesity. As consequence, much interest is currently accorded in AD treatment to a multi-target approach interfering with different pathways at the same time, and to life-style interventions aimed at preventing the modifiable risk-factors strictly associated with aging. In this context, phytochemical compounds are emerging as an enormous source to draw on in the search for multi-target agents completing or assisting the traditional pharmacological medicine. Intriguingly, many plant-derived compounds have proven their efficacy in counteracting several pathogenic processes such as the Aβ aggregation, neuroinflammation, oxidative stress and insulin resistance. Many strategies have also been conceived to overcome the limitations of some promising phytochemicals related to their poor pharmacokinetic profiles, including nanotechnology and synthetic routes. Considering the emerging therapeutic potential of natural medicine, the aim of the present review is therefore to highlight the most promising phytochemical compounds belonging to two major classes, polyphenols and monoterpenes, and to report the main findings about their mechanisms of action relating to the AD pathogenesis.
... Activation of JNK and hindering of translocation of NF-κB (p65) is responsible for its anticancer property [55]. Zang et al. [56] evaluated the anticancer potential of luteolin and confirmed its activity in KK-A(y) mice by suppressing the glucose levels. Luteolin decreases insulin resistance and improves insulin production and action through activation of the PPARγ pathway [57]. ...
Cancer is a major health problem across the globe, and is expeditiously growing at a faster rate worldwide. The endoplasmic reticulum (ER) is a membranous cell organelle having inextricable links in cellular homeostasis. Altering ER homeostasis initiates various signaling events known as the unfolded protein response (UPR). The basic purpose of the UPR is to reinstate the homeostasis; however, a continuous UPR can stimulate pathways of cell death, such as apoptosis. As a result, there is great perturbation to target particular signaling pathways of ER stress. Flavonoids have gained significant interest as a potential anticancer agent because of their considerable role in causing cytotoxicity of the cancerous cells. Luteolin, a flavonoid isolated from natural products, is a promising phytochemical used in the treatment of cancer. The current study is designed to review the different endoplasmic reticulum stress pathways involved in the cancer, mechanistic insights of luteolin as an anticancer agent in modulating ER stress, and the available luteolin patent formulations were also highlighted. The patents were selected on the basis of pre-clinical and/or clinical trials, and established antitumor effects using patent databases of FPO IP and Espacenet. The patented formulation of luteolin studied so far has shown promising anticancer potential against different cancer cell lines. However, further research is still required to determine the molecular targets of such bioactive molecules so that they can be used as anticancer drugs. View Full-Text
... Bars marked with different letters are significantly (p < 0.05) different. sensitivity in adipocytes through the activation of PPARγ transcriptional activity has been described as one of the main mechanisms responsible for the hypoglycemic effect of luteolin (Ding, Jin, & Chen, 2010). The lipid-lowering property of luteolin was in turn attributed to its inhibitory effect on inflammatory pathways, while the cholesterollowering property was ascribed to its ability to hinder cholesterol synthesis (Santos, Bueno, & Mota, 2018). ...
... Another study by [77] showed that chlorogenic acid and caffeic acid found in T. officinale has been explored for their antihyperglycemic properties, where caffeic acid, in particular, has been reported to decrease blood glucose in test animals. In another study done by [20], luteolin has been found to increase insulin action, besides decreasing the expression of a particular gene responsible for inflammation of cytokines, as well as inducing the gene and protein expression Glucose Transporter type 4 (GLUT4) which assist glucose uptake by the cells. Certain compounds extracted from M. charantia such as charantin, oleanolic acid, oleanolic acid 3-O-glucuronide, polypeptide-p, momordin and 3-O-monodesmoside have hypoglycemic activity [58]. ...
Type 2 Diabetes Mellitus accounts for 90% of most diabetes cases. Many commercial drugs used to treat this disease come with adverse side effects and eventually fail to restore glucose homeostasis. Therefore, an effective, economical and safe antidiabetic remedy from dietary source is considered. Taraxacum officinale (L.) Weber ex F.H.Wigg and Momordica charantia L. were chosen since both are used for centuries as traditional medicine to treat various ailments and diseases. In this study, the antidiabetic properties of a polyherbal combination of T. officinale and M. charantia ethanol extracts are evaluated. The bioactive solvent extracts of the samples selected from in vitro antidiabetic assays; α-amylase, α-glucosidase, and dipeptidyl peptidase-4 (DPP-4) inhibition, and glucose-uptake in L6 muscle cells were combined (1:1) to form the polyherbal combination. The antidiabetic efficacy of polyherbal combination was evaluated employing the above stated in vitro antidiabetic assays and in vivo oral glucose tolerance test and streptozotocin-nicotinamide (STZ-NA) induced diabetic rat model. A quadrupole time-of-flight liquid chromatography-mass spectrometry (Q-TOF LCMS) analysis was done to identify active compounds. The polyherbal combination exerted improved antidiabetic properties; increased DPP-4, α-amylase, and α-glucosidase inhibition. The polyherbal combination tested in vivo on diabetic rats showed optimum blood glucose-lowering activity comparable to that of Glibenclamide and Metformin. This study confirms the polyherbal combination of T. officinale and M. charantia to be rich in various bioactive compounds, which exhibited antidiabetic properties. Therefore, this polyherbal combination has the potential to be further developed as complex phytotherapeutic remedy for the treatment of Type 2 Diabetes Mellitus.
... Therefore, the muscle uptake of glucose is reduced and shows high glucose levels in the blood (Mohammad et al., 2006). The activation and translocation of GLUT2 and GLUT4 stimulated by insulin help to transport glucose mainly via the PI3K/p-Akt pathway (Ding et al., 2010;Jing et al., 2008). ...
Ethnopharmacological relevance
Demand for plant-based medications and therapeutics is increasing worldwide as of its potential effects and no toxic. Traditionally, so many medicinal plants are used to treat diabetes. Subsequently, investigation on medicinal plants was enduring to discover potential antidiabetic drugs. A. tetracantha is used traditionally to cure diabetes mellitus, cough, dropsy, chronic diarrhea, rheumatism, phthisis and smallpox. Scientifically, A. tetracantha has been reported as an antidiabetic agent. Friedelin, the isolated compound has been reported as hypolipidemic, antioxidant, scavenging of free radicals, antiulcer, anti-inflammatory, analgesic and antipyretic agent.
... Adipose tissue plays an important role in the regulation of glucose metabolism throughout the body. It is reported that many kinds of synthetic [23,24] and natural [25,26] PPARγ agonists increase the number of insulin-sensitive small adipocytes by promoting adipocyte differentiation. On the other hand, it has been reported that heterozygous knockout of PPARγ or moderate suppression of PPARγ activity also contribute to enhancement of insulin sensitivity without increasing adipocyte mass [8][9][10]. ...
Obesity is a major risk factor for some metabolic disorders including type 2 diabetes. Enhancement of peroxisome proliferator-activated receptor (PPAR) γ, a master regulator of adipocyte differentiation, is known to increase insulin-sensitive small adipocytes. In contrast, decreased PPARγ activity is also reported to improve insulin resistance. We have previously identified erucic acid as a novel natural component suppressing PPARγ transcriptional activity. In this study, we investigated the effect of erucic acid-rich yellow mustard oil (YMO) on obese/diabetic KK-Ay mice. An in vitro luciferase reporter assay and mesenchymal stem cell (MSC) differentiation assay revealed that 25 µg/mL YMO significantly inhibited PPARγ transcriptional activity and differentiation of MSCs into adipocytes but promoted their differentiation into osteoblasts. In KK-Ay mice, dietary intake of 7.0% (w/w) YMO significantly decreased the surrogate indexes for insulin resistance and the infiltration of macrophages into adipose tissue. Furthermore, 7.0% YMO increased bone mineral density. These results suggest that YMO can ameliorate obesity-induced metabolic disorders.
... Use of Luteolin by patients of type1 diabetes alleviates their heart related complications due to neutralization of reactive oxygen species (Wang et al. 2012). Use of Luteolin by Type2 diabetic patients minimizes insulin resistance by stimulating adipocytes to release specific cytokines called adipokines that act through peroxisome proliferator activated receptor gamma (PPAR-γ) to improve sensibility for insulin (Ding et al. 2010). ...
Honey comes with a legendary history of being used as an indigenous medicine to cure a number of diseases. Honey is an essential source of phenolic molecules such as flavonoids and phenolic acids. The most abundant flavonoids present in honey include flavones, flavanones, and flavonols. Flavonoids show diverse activities such as non-inflammatory, antiallergenic, antiviral, antimalignant, antimicrobial, however, the antioxidant activity has been studied widely. Honey also possess a diverse molecules of phenolic acids including p-coumaric, ferulic, caffeic acid, acetophenones, phenylacetic acids, syringic, vanillic, gallic acid, and so on which endow it with the therapeutic activities against pathogens, inflammation while at the same time shows antioxidant and healing properties. The phenolic compounds owing to their medical properties make honey a very critical and attractive prophylactic entity for the prevention of chronic diseases associated with oxidative stress including cancer, cardiovascular disease, diabetes, respiratory disease, hypertension, neurodegenerative diseases etc. In this chapter, a discussion has been made on classification, structure, and medicinal and health benefits of phenolic compounds.
... Luteolin, a flavonoid, was shown to reduce hyperglycaemia by raising insulin secretion in a diabetic animal model [139]. The process of activation of peroxisome proliferator-activated receptor gamma (PPAR-γ) [140] also prevented insulin resistance in T2DM patients by the formation of adipokines, which implies that honey may be helpful in modulating adiponectin mediated by PPAR-γ [116], thus alleviating insulin resistance. ...
Despite the availability of various antidiabetic drugs, diabetes mellitus (DM) remains one of the world's most prevalent chronic diseases and is a global burden. Hyperglycaemia, a characteristic of type 2 diabetes mellitus (T2DM), substantially leads to the generation of reactive oxygen species (ROS), triggering oxidative stress as well as numerous cellular and molecular modifications such as mitochondrial dysfunction affecting normal physiological functions in the body. In mitochondrial-mediated processes, oxidative pathways play an important role, although the responsible molecular mechanisms remain unclear. The impaired mitochondrial function is evidenced by insulin insensitivity in various cell types. In addition, the roles of master antioxidant pathway nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1)/antioxidant response elements (ARE) are being deciphered to explain various molecular pathways involved in diabetes. Dietary factors are known to influence diabetes, and many natural dietary factors have been studied to improve diabetes. Honey is primarily rich in carbohydrates and is also abundant in flavonoids and phenolic acids; thus, it is a promising therapeutic antioxidant for various disorders. Various research has indicated that honey has strong wound-healing properties and has antibacterial, anti-inflammatory, antifungal, and antiviral effects; thus, it is a promising antidiabetic agent. The potential antidiabetic mechanisms of honey were proposed based on its major constituents. This review focuses on the various prospects of using honey as an antidiabetic agent and the potential insights. © 2020 Visweswara Rao Pasupuleti et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
... Luteolin has the most potential targets, followed by Tanshinone IIA. According to reports, luteolin can not only increase insulin-mediated glucose uptake and enhance insulin sensitivity [ 23 ], but also inhibit high glucose-induced vascular endothelial growth factor (VEGF) [ 24 ], reducing reactive oxygen species (ROS) generation, and reducing lipid accumulation To predict the mechanism underlying the therapeutic effect of SM against DN, we performed GO enrichment analysis of 64 potential targets. As shown in Figure 5A, the rst 20 terms of BP are mainly related to cytokines, apoptosis, reactive oxygen species, and in ammation regulation. ...
Background
The mechanisms underlying the therapeutic effect of Salvia Miltiorrhiza (SM) against diabetic nephropathy (DN) using systematic network pharmacology and molecular docking methods were examined.MethodsTCMSP database was used to screen the active ingredients of SM. Gene targets were obtained using Swiss Target Prediction and TCMSP databases. Related targets of DN were retrieved from the Genecards and DisGeNET databases. Next, a PPI network was constructed using the common targets of SM-DN in the STRING database. The Metascape platform was used for GO function analysis and Cytoscape plug-in ClueGO was used for KEGG pathway enrichment analysis. Molecular docking was performed using iGEMDOCK and AutoDock Vina software. Pymol and LigPlos were used for mapping the network. ResultsSixty-six active ingredients and 189 targets were screened from SM. Among them, 64 targets overlapped with DN targets. The PPI network diagram revealed that AKT1, VEGFA , IL6 , TNF , MAPK1 , TP53 , EGFR , STAT3 , MAPK14 , and JUN were the top 10 relevant targets. GO and KEGG analyses mainly focused on advanced glycation end products, oxidative stress, inflammatory response, and immune regulation. Molecular docking revealed that the potential target genes closely related to DN, including TNF , NOS2 , and AKT1 , were more stable in combination with salvianolic acid B, and their stability was better than that of tanshinone IIA.Conclusion
This study reveals the active components and potential molecular mechanisms involved in the therapeutic effect of SM against DN and provides a reference for the wide application of SM in clinically managing DN.
... Moreover, it has been reported that the luteolin stimulates the insulin action and the production of adipokines/cytokines in adipocytes by activating the PPARγ pathway (Ding, Jin, & Chen, 2010). While in cyanidin-3-glucoside plus a gut microbiota-derived metabolite, the protocatechuic acid seems to promote cholesterol efflux and HDL formation via the activation of liver X receptor (LXR) and/or the regulation of lipid transporters, including ABCA1 and ABCG1 (Millar, Duclos, & Blesso, 2017). ...
Metabolic Syndrome (MetS) is a complex condition associated with cardiovascular risk factors and diabetes. The weight gain, especially the accumulation of central adipose tissue, may be the first leading cause of the MetS. It is important to highlight that the lifestyle choices considered as modifiable risk factors contribute to the increase in the incidence of the MetS in the population, such as sedentarism and food intake. There is evidence in the literature concerning the benefits associated with the Mediterranean diet, which is rich in polyphenols. Therefore, the flavonoids are a class of non-nutrient that can be extensively studied mainly to elucidate the mechanisms related to the action of these compounds in the modulation of the microbiota, DNA methylation and health improvement. Thus, this review summarized evidence linking flavonoid intake to obesity, insulin resistance, T2DM and cardiovascular diseases.
Obesity presents a major health challenge that increases the risk of several non-communicable illnesses, such as but not limited to diabetes, hypertension, cardiovascular diseases, musculoskeletal and neurological disorders, sleep disorders, and cancers. Accounting for nearly 8% of global deaths (4.7 million) in 2017, obesity leads to diminishing quality of life and a higher premature mortality rate among affected individuals. Although essentially dubbed as a modifiable and preventable health concern, prevention, and treatment strategies against obesity, such as calorie intake restriction and increasing calorie burning, have gained little long-term success. In this manuscript, we detail the pathophysiology of obesity as a multifactorial, oxidative stress-dependent inflammatory disease. Current anti-obesity treatment strategies, and the effect of flavonoid-based therapeutic interventions on digestion and absorption, macronutrient metabolism, inflammation and oxidative stress and gut microbiota has been evaluated. The use of several naturally occurring flavonoids to prevent and treat obesity with a long-term efficacy, is also described.
Flavonoids are ubiquitous compounds in nature and are found in many Chinese herbal medicines. Due to their biological activity, flavonoids show potential for decreasing insulin resistance (IR), thereby delaying the progression of diabetes and accompanying metabolic syndromes. This review focuses on the mechanisms of flavonoids decreasing IR: (1) the interaction between flavonoids and target proteins of the insulin signalling pathway; (2) bioactivities of flavonoids, such as anti-inflammatory, lipid-lowering and antioxidant. Meanwhile, we summarise the structural characteristics, structure activity relationships and biological activity of flavonoids, providing evidence for their potential in the treatment of IR. Here, we also analyse the potential and limitations of their therapeutic use.
Scope:
Serotonin (5-HT)-induced visceral adipocyte lipolysis is essential for the development of obesity-related complications. Diet supplementation of luteolin prevents high-fat diet (HFD)-fed mice against obesity and associated fatty liver. However, independent of the body weight loss, whether dietary luteolin can substantially reduce hepatic steatosis remains unclear.
Methods and results:
In differentiated 3T3-L1 cells, 5-HT treatment promotes adipocyte lipolysis, while luteolin significantly inhibits 5-HT-induced lipolysis, Ca2+ -PKG cascade, and SIRT1/FoxO1/AMPKα signaling through binding to 5-HT receptor HTR2B. Further, 5-week-old mice are fed with an HFD for 16 weeks. At the 6th, 8th, or 10th weeks of HFD feeding, some mice are switched to a luteolin-containing HFD, respectively. In all HFD-fed mice, body weight gain and body component are unaffected by dietary luteolin. However, diet supplementation of luteolin at the 6th or 8th, rather than at the 10th weeks, alleviates hepatic steatosis. Meanwhile, dietary luteolin reduces epididymal adipose tissue (EAT) lipolysis, and represses the level of lipolytic enzyme, the expression of Htr2b, and the activation of PKG and SIRT1/FoxO1/AMPKα signaling in EAT.
Conclusions:
Diet supplementation of luteolin before the formation of fatty liver protects HFD-fed mice against ectopic lipid deposition in liver by inhibiting visceral adipocyte lipolysis. This article is protected by copyright. All rights reserved.
With the rapid development of industrialization, the problem of air pollution is becoming more and more serious all around the world, and PM2.5 pollution is one of the unsafe factors that seriously endanger human health. PM2.5 can damage the lungs in many ways, but there are not many effective treatments available for PM2.5-induced lung injury, and there is not much research in this area. Natural active compounds extracted from plants, microorganisms and so on have various physiological activities and can be used as possible preventive measures for lung injury. This study introduces the basic properties of PM2.5 and its injury mechanisms involved in lung damage. Then, the physiological functions of flavonoids, polyphenols and alkaloids are introduced, and the possible mechanism of their alleviating PM2.5-induced lung injury is discussed in order to provide new thinking and reference for natural active components in alleviating lung injury and maintaining health.
Pectolinarigenin is the main flavonoid compound and presents in Linaria vulgaris and Cirsium chanroenicum. In this study, RNA sequencing (RNA‐seq) was applied to dissect the effect of pectolinarigenin on the transcriptome changes in the high lipid Huh‐7 cells induced by oleic acid. RNA‐seq results revealed that 15 pathways enriched by downregulated genes are associated with cell metabolism including cholesterol metabolism, glycerophospholipid metabolism, steroid biosynthesis, steroid hormone biosynthesis, fatty acid biosynthesis, etc. Moreover, 13 key genes related to lipid metabolism were selected. Among them, PPARG coactivator 1 beta (PPARGC1B) and carnitine palmitoyltransferase 1A (CPT1A) were found to be upregulated, solute carrier family 27 member 1(SLC27A1), acetyl‐CoA carboxylase alpha (ACACA), fatty‐acid synthase (FASN), 3‐Hydroxy‐3‐Methylglutaryl‐CoA Reductase (HMGCR), etc. were found to be downregulated. Glycolysis/gluconeogenesis, steroid hormone biosynthesis, and fatty acid biosynthesis were all significantly downregulated, according to gene set variation analysis and gene set enrichment analysis. Besides, protein levels of FASN, ACACA, and SLC27A1 were all decreased, whereas PPARγ and CPT1A were increased. Docking models showed that PPARγ may be a target for pectolinarigenin. Furthermore, pectolinarigenin reduced serum TG and hepatic TG, and improved insulin sensitivity in vivo. Our findings suggest that pectolinarigenin may target PPARγ and prevent fatty acid biosynthesis.
Evidence for the anti‐diabetic actions of camellia and herbal tea in diabetic patients has not been summarized. Several data sources were searched for randomized trials assessing the effect of different teas on cardiometabolic risk factors in T2D subjects. Two independent reviewers extracted relevant data and assessed the risk of bias. Results were summarized using mean differences (MDs) based on a random model. Sixteen studies (19 trials, N = 832) fulfilled the eligibility criteria. Mean differences were measured for body weight, body mass index, fasting blood glucose, glycosylated hemoglobin, a homeostatic model for insulin resistance, high and low‐density lipoproteins, triglycerides, and systolic and diastolic blood pressure. No effects on total cholesterol and waist circumference were observed when either camellia or herbal tea was consumed. Tea produced moderate regulatory effects on adipose, glycemic control, lipid profiles, and blood pressure. In terms of efficacy, camellia and herbal teas yield different benefits in regulating metabolism. This discovery has some implications for clinical research and drug development. However, more high‐quality trials are needed to improve the certainty of our estimates.
Shen Qi Wan (SQW) prescription has been used to treat type 2 diabetes mellitus (T2DM) for thousands of years, but its pharmacological mechanism is still unclear. The network pharmacology method was used to reveal the potential pharmacological mechanism of SQW in the treatment of T2DM in this study. Nine core targets were identified through protein-protein interaction (PPI) network analysis and KEGG pathway enrichment analysis, which were AKT1, INSR, SLC2A1, EGFR, PPARG, PPARA, GCK, NOS3, and PTPN1. Besides, this study found that SQW treated the T2DM through insulin resistance (has04931), insulin signaling pathway (has04910), adipocytokine signaling pathway (has04920), AMPK signaling pathway (has04152) and FoxO signaling pathway (has04068) via ingredient-hub target-pathway network analysis. Finally, molecular docking was used to verify the drug-target interaction network in this research. This study provides a certain explanation for treating T2DM by SQW prescription, and provides a certain angle and method for researchers to study the mechanism of TCM in the treatment of complex diseases.
Supplementary information:
The online version contains supplementary material available at 10.1007/s40203-022-00124-2.
Insulin resistance is an elemental facet of the etiology of diabetes mellitus and the principal relating factor between obesity and diabetes. Oxidative stress, lipotoxicity, inflammation and receptor dysfunction are the underlying determinants of insulin resistance commencement in metabolic illnesses. ppar-γ is a nuclear transcription factor whose activation or inhibition directly influences insulin resistance and controls glucose and lipid homeostasis by modulating gene expression. Synthetic ligands of ppar-γ are therapeutically employed to counter the hyper-glycaemia associated with obesity and type 2 diabetes, but they possess severe side effects. In the modern era, bioactive phytochemicals have been employed in the drug development process and a considerable investigation has recently been initiated to analyze the ppar-γ activating ability of diverse phytochemicals. In this review, we outlined the role of phytochemicals in insulin resistance treatment through ppar-γ activation.
Irinotecan (CPT-11) is one of the main agents used to treat colorectal cancer; unfortunately, it is associated with increased intestinal mucositis developing. Luteolin has been shown to prevent damage induced by this chemotherapeutic in mice; thus, in this research, we have investigated luteolin's action mechanism in human intestinal epithelial cells. The potential of luteolin in reducing inflammation and oxidative stress induced by irinotecan in Caco-2 cells was evaluated by PCR through mRNA expression of inflammatory and oxidative genes and by ELISA at the protein level. To assess whether luteolin's ability to control irinotecan-induced damage occurs in a PPARγ dependent manner, experiments were performed on PPARγ downregulated cells. Irinotecan downregulated PPARγ expression and upregulated inflammatory and oxidative genes, while luteolin upregulated PPARγ, HO-1, SOD and decreased expression of IL-1β and iNOS. Interestingly, when the cells were co-stimulated with luteolin and irinotecan, the flavonoid reversed the inflammation and oxidative imbalance evoked by the chemotherapeutic. However, when these experiments were performed in cells downregulated for PPARγ, luteolin lost the capacity to increase PPARγ and reverse the effect of irinotecan in all tested genes, except by IL-1β. The present study showed that the protective effect of luteolin against irinotecan is PPARγ dependent.
Management of diabetes mellitus is a challenge for clinicians. Uncontrolled hyperglycemia increases the risk of microvascular and macrovascular complications, damaging the body systems. Although a number of antidiabetic drugs are available for therapeutic intervention, toxicity, loss of efficacy in chronic use and high cost of treatment have necessitated the search for new molecules to manage diabetes. Safety and cost are the main prerequisite for the new antidiabetic molecules. Medicinal plants and their purified phytochemicals have shown promising antidiabetic potential in the past few years. The flavonoids can be widely classified into different categories like anthocyanins, catechins, flavanols, flavones, flavanones etc. Some flavonoids have hypoglycemic properties. They may improve al-tered glucose and oxidative metabolisms of diabetic states. The hypoglycemic effect of some herbal extracts has been confirmed in human and animal models of type 2 diabetes mellitus (T2DM). Some of the important phytoconstituents from the classes of flavonoid have been discussed here. The current review summarizes the antidiabetic activity of flavonoids, the mechanism-based action of flavonoids that target the various metabolic pathways in humans. Keywords: Diabetes mellitus, Flavonoids, Medicinal plants, mechanisms of action, T2DM
Ethnopharmacological relevance
Demand for plant-based medications and therapeutics is increasing worldwide as of its potential effects and no toxic. Traditionally, so many medicinal plants are used to treat diabetes. Subsequently, investigation on medicinal plants was enduring to discover potential antidiabetic drugs. A. tetracantha is used traditionally to cure diabetes mellitus, cough, dropsy, chronic diarrhea, rheumatism, phthisis and smallpox. Scientifically, A. tetracantha has been reported as an antidiabetic agent. Friedelin, the isolated compound has been reported as hypolipidemic, antioxidant, scavenging of free radicals, antiulcer, anti-inflammatory, analgesic and antipyretic agent.
Aim of the study
To scrutinize the mechanism of antidiabetic activity of friedelin isolated from the leaves of A. tetracantha.
Materials and methods
A. tetracantha leaves powder (5 kg) was soaked in hexane (15 L) to obtain hexane extract. Using column chromatography, the hexane extract was fractionated using a combination of solvents like hexane and ethyl acetate. 25 fractions were obtained and the fractions 13 and 14 yielded the compound, friedelin. Friedelin at the doses of 20 and 40 mg/kg was used to treated STZ -induced diabetic rats for 28 days. Later 28 days of treatment, the bodyweight changes, levels of blood glucose, insulin, SGOT, SGPT, SALP, liver glycogen and total protein were assessed.
Results
Friedelin significantly brought these altered levels to near normal. Moreover, friedelin also enhanced the translocation as well as activation of GLUT2 and GLUT4 through PI3K/p-Akt signaling cascade in skeletal muscles and liver on diabetic rats.
Conclusion
This finding proved that friedelin has an anti-diabetic effect through insulin-dependent signaling cascade mechanism, thus it may lead to establishing a drug to treat type 2 diabetes mellitus.
Transient receptor potential (TRP) channels are non-selective cation channels that are implicated in analgesia, bowel motility, wound healing, thermoregulation, vasodilation and voiding dysfunction. Many natural products have been reported to affect the activity of TRP channels. We hypothesize that numerous traditional herbal medicines (THMs) might exert their pharmacological activity through modulating the activity of TRP channels. The present study aimed to evaluate the effects of flavonoid aglycones and their glycosides, which are the main components of many THMs, on the TRP channel subtypes. A Ca2+ influx assay was performed using recombinant human TRPA1, TRPV1, TRPV4 and TRPM8 cell lines. Our findings showed that flavonoid aglycones and glycycoumarin activated TRPA1. In particular, isoflavone and chalcone compounds displayed potent TRPA1 agonistic activity. Furthermore, flavone aglycones showed concomitant potent TRPM8 inhibiting activity. Indeed, flavone, isoflavone aglycones, non-prenylated chalcones and glycycoumarin were found to be TRPM8 inhibitors. Hence, flavonoid aglycones metabolized by lactase-phlorizin hydrolase and β-glucosidase in the small intestine or gut microbiota of the large intestine could generate TRPA1 agonists and TRPM8 antagonists.
The mechanisms underlying the therapeutic effect of Salvia miltiorrhiza (SM) on diabetic nephropathy (DN) were examined using a systematic network pharmacology approach and molecular docking. The Traditional Chinese Medicine Systems Pharmacology (TCMSP) database was used to screen active ingredients of SM. Targets were obtained using the SwissTargetPrediction and TCMSP databases. Proteins related to DN were retrieved from the GeneCards and DisGeNET databases. A protein–protein interaction (PPI) network was constructed using common SM/DN targets in the STRING database. The Metascape platform was used for GO function analysis, and the Cytoscape plug-in ClueGO was used for KEGG pathway enrichment analysis. Molecular docking was performed using iGEMDOCK and AutoDock Vina software. Pymol and LigPlos were used for network mapping. Sixty-six active ingredients and 189 targets of SM were found. Sixty-four targets overlapped with DN-related proteins. The PPI network revealed that AKT1, VEGFA, IL6, TNF, MAPK1, TP53, EGFR, STAT3, MAPK14, and JUN were the 10 most relevant targets. Go and KEGG analyses revealed that the common targets of DN and SM were mainly involved in advanced glycation end products, oxidative stress, inflammatory response, and immune regulation. Molecular docking revealed that potential DN-related targets, includingTNF, NOS2, and AKT1, more stably bound with salvianolic acid B than with tanshinone IIA. In conclusion, this study revealed the active components and potential molecular therapeutic mechanisms of SM in DN and provides a reference for the wide application of SM in clinically managing DN.
Commonly flavonoids are the natural components found in vegetables, spices and colored fruits. Flavonoids include a large group of polyphenolic compounds, namely flavones, flavanols, flavonols, flavanones, isoflavones and anthocyanidins, which have been proposed as effective supplements for the management of diabetes and associated disorders. The aim of present review was to highlight various classes of flavonoids, their structure – activity relationships, bioavailability, and mechanisms involved in the management of diabetes and associated complications. The relevant research and review articles were collected from online (Pubmed, Sciencedirect, Scopus, Google, andWeb of science) and offline sources (books and journals from library). A total of 245 articles published between 1996 to 2018 were reviewed, and 232 articles were included in present review. Article being related with flavonoids and diabetes is the major criterion for inclusion in this compilation. Flavonoids regulate the redox status and prevent damage caused by oxidative stress and possess anti-oxidant activity. Flavonoids are a wide group of compounds including quercetin, kaempferol, luteolin, apigenin, genistein, glycitein, eriodictyol, hesperidin, catechin, gallocatechin, pelargonidin, and cyanidin. Type 2 diabetes mellitus is associated with insulin resistance, β-cell dysfunction, inflammation, altered lipid metabolism and increased oxidative stress. It can affect many metabolic processes may cause serious complications such as retinopathy, cardiovascular disease and nephropathy. Flavonoids produce antidiabetic effect through suppressing α-amylase activities, attenuating insulin resistance and promoting pancreatic β-cells proliferation. Several reports including in-vitro and in-vivo studies on flavonoids confirmed their major role in maintaining metabolic pathways during type 2 diabetes mellitus treatment.
Luteolin, a flavone subclass of flavonoids, is commonly found in food plants and has multiple biological activities. Recently, evidence is growing with regard to the potential of luteolin intake to beneficially affect glycolipid metabolism disorders (GLMDs), particularly insulin resistance, diabetes, and obesity. The aim of this contribution is to provide an overview of recent advances in identifying and understanding the pharmacokinetic properties (absorption, metabolism, and bioavailability) of luteolin, its regulatory effects on glycolipid metabolism, and the underlying mechanisms of action of luteolin in the brain, liver, adipose tissues, and other tissues/organs. Collectively, luteolin or its principal metabolites may contribute to counteracting GLMDs, especially for human obesity and diabetes.
Around the world, the prevalence of obesity and diabetes are high raising multiple severe diseases. Some of the common disorders associated with obesity are diabetes, heart diseases, and hypertension. These disorders have a tremendous effect on social lifestyles of every individual. However, another lifestyle disorder is diabetes, which can also be called hyperglycemia. Uncontrolled diabetes has the potential to cause serious complications in the body including kidney disease, loss of vision, and cardiovascular disease, which contribute towards morbidity and mortality. Though various allopathic drugs are available in the market, the herbal products and their derivatives have enough potential to treat such diseases with little or no side effects. This chapter is concerned and focuses on the application of herbal drugs along with proven mechanisms of action.
Currently, researchers are oriented to the use of several natural products as alternatives in curing various ailments. Among natural products, honey occupies a great position as a sweetening agent as well as a magic remedy for a large list of diseases. Several studies had been conducted on different types of honeys. At first, most of the studies were focused on the use of honey as a natural antimicrobial. Afterwards, many pharmaceutical applications have been knocked. The well-known anti-inflammatory, antioxidant, and antimicrobial characteristics of honey suggest its use to promote wound healing, relief oxidative stress in case of cardiovascular diseases and cure several infectious and inflammatory diseases. Honey has proved its effectiveness in eradication of multidrug resistant pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), controlling blood sugar in diabetic patients, accelerating healing of wounds and chronic ulcers, improving cough and asthma, treatment of different types of cancers, and reducing symptoms associated with periodontal diseases.
Background:
For thousands of years, natural food products have been a medicine for diseases that affect the human body, including diabetes mellitus. Lately, several investigations have studied the flavonoids derivatives of plant origins and their biological activity. Given our need to know more mechanisms for treating this disease,
Methods:
we will do a thorough research review on treating diabetes mellitus based on flavonoids, its therapeutic potential, and biological action.
Results:
Flavonoids reduces complications in addition to its vital role as effective supplements for preventing diabetes mellitus by regulating glucose metabolism, lipid profile, liver enzyme activity, a protein kinase inhibitor, PPAR, AMPK with NF-κB
Conclusion:
Articles that we reviewed showed the positive role of flavonoids, which at a certain way reduce diabetes, but its side effects are still missing, this review focus on the different type of dietary flavonoids along with their mechanism in reducing blood glucose and enhance insulin sensitivity as well as some side effects
Oxidative stress has emerged as one of the targets in several medical conditions and in several types of clinical researches. Growing evidences from research on diverse diseases show that oxidative stress is conjoined with the pathogenesis of diabetes and its complications. This review has examined the role of oxidative stress in the pathogenesis of insulin resistance and beta-cell dysfunction. A vast variety of medicinal plants and products have been utilized for the prevention of diabetes and its related complications. Natural products such as phenolic acids and flavonoids construct one of the most ubiquitous groups of plant phenolics. At present, the effect of dietary phenolics is of extreme concern due to their antioxidant, free radical scavenging, and as quenchers of singlet oxygen formation. Reactive oxygen species (ROS) as well as reactive nitrogen species play either harmful or beneficial roles in biological systems depending on pathophysiological conditions. This review extends on the fundamental aspect of ROS in biological processes and diseases and how natural bioactive compounds of fruits and vegetables regulate their health improving properties. Flavonoids and phenolics acids are the most important groups of secondary metabolites and bioactive compounds in plants. Diverse phytochemical agents have become the backbone in pharmacotherapy of diabetes by virtue of their antioxidant properties along with their other pharmacological actions. Consequently, accession to obstruction the generation of reactive free radicals or abduct the reactive free radical may yield direct and casual approach for the medication of diabetes and its complications.
Diabetes Mellitus is one of the major healthcare problems faced by the society today and has become alarmingly epidemic in many parts of the world. Despite enormous knowledge and technology advancement, available diabetes therapeutics only provide symptomatic relief by reducing blood glucose level, thereby, just slows down development and progression of diabetes and its associated complications. Thus, the need of the day is to develop alternate strategies that can not only prevent the progression but also reverse already “set-in” diabetic complications. Many flavonoids are reported, traditionally as well as experimentally, to be beneficial in averting diabetes and lowering risk of its accompanying complications. In the present chapter we have convened different flavonoids beneficial in diabetes and comorbid complications and discussed their mechanisms of action. Further, we conclude that coupling current therapeutics with flavonoids might provide exceptional advantage in the management of diabetes and its complications.
Nutrients can act as signalling molecules to initiate or mediate signalling transduction that regulates cell function and homeostasis. As such, altered nutrient status has been linked to dysregulated transcripts and protein expression, which affects mitochondrial function, autophagy, inflammation, metabolism and even gut microbiota. This book disseminates the cutting-edge knowledge pertaining to nutritional signalling activities in metabolism and metabolic derangements (e.g., obesity and diabetes), which covers the regulatory mechanisms and dietary interventions for disease prevention.
This book represents current nutritional and metabolic research. From the basic (molecular science) perspective, it covers metabolomics, proteomics, nutrigenomics, nuclear receptors and transcription factors, inflammatory pathways, autophagy, mitochondrial health and gut microbiota. From the clinical (translational science) perspective, this book covers clinical trials, precision nutrition, maternal nutrition and transgenerational health, and allometric scaling of dietary bioactives in translational metabolic research. It brings to the reader in-depth understanding of the nutritional aspect, cellular and molecular biology, as well as pathophysiology of obesity and diabetes. In addition, each chapter in this book includes a component of future direction or intervention perspective, making the new knowledge transformative and translational. Aimed at researchers and professionals interested in nutrition, dietetics and metabolic disorders, this book will also appeal to health science researchers.
Ethnopharmacological relevance
Tecoma stans (L.) Juss. ex Kunth (Bignoniaceae) is an attractive evergreen plant known as kusi urakame, koyawari, Palo amarillo, tronadora, yellow-elder, yellow trumpet bush, trumpet-flower, yellow-bells, trumpet bush, ginger-Thomas, esperanza, and timboco. It is widely used in traditional Mexican medicine, to treat hyperglycemia, gastrointestinal and urinary tract disorders, jaundice, toothaches, headaches, colds, skin infections, and scorpion, snake, and rat bites. Current research focusses on evaluating its bioactive components and therapeutic potential.
Aim of the study
The current article reviewed the information available on Tecoma stans ethnopharmacology, geographical distribution, chemical composition, phytochemistry, therapeutic effects, and toxicology.
Material and methods
Information of botanical description, distribution, traditional uses, chemical composition, bioactive components, and therapeutic investigations was gathered from a comprehensive literature search of electronic databases such as Science Direct, PubMed, Web of Science, Wiley, ACS, Springer, Taylor and Francis, Google Scholar, and SCOPUS until 2020 for publications (peer-reviewed articles, eBooks, short communications, reports from international organizations, and case letters). Information was also included from books, conference proceedings, and thesis. Primary keywords for data collection were “Tecoma stans,” and “Ethnopharmacology,” followed by secondary keywords such as “Constituents,” “Therapeutic effect,” and “Toxicity.” Results: An exhaustive comparative study of the accessible sources of Tecoma stans confirmed its origin, ethnopharmacological and therapeutic uses. More than 120 chemical compounds have been isolated, and the main active principles are alkaloids, phenolic acids, flavonoids, and fatty acids. The plant possesses vast therapeutic benefits, such as lowering elevated blood sugar levels, anti-inflammatory, anti-cancer, anti-bacterial, anti-fungal, anti-oxidant, hepatoprotective, and wound healing actions.
Conclusions
Comprehensive literature analysis exhibits that many populations have utilized Tecoma stans around the globe with specific reference to different parts of Mexico. The above information shows that the plant holds many hidden potentials and can, therefore, be studied extensively for its phytoconstituents and therapeutic effects. However, while going through the literature, it was observed that incomplete data is reported on in vivo trials, especially concerning its dosage, positive and negative control groups, intervention time, and toxicity studies. Additionally, there is a lack of information on its complete nutritional and phytochemical profiling. We trust that this review will help lay the groundwork for encouraging pharmacological and pharmaceutical studies. It will also direct us to understand the clinical relevance and applications of bioactive compounds from Tecoma stans in the prevention and treatment of diseases.
Artichoke floral stems (AFS) food waste by-products were examined for their phytochemical constituents and their in vitro and in vivo biological activities. Although that the highest total phenol content and total flavonoid content were found in ethyl acetate extract, methanol extract possessed the strongest DPPH and ABTS radical scavenging activity, and showed the highest reducing ferric antioxidant power (FRAP). The anti-acetylcholinesterase activity was higher in butanol extract, whereas the ethyl acetate extract had the highest inhibitory effect on heat-induced protein denaturation. In alloxan-induced diabetic mice, the AFS methanol extract (AFSE) rich in caffeoylquinic acids and flavones reduced blood glucose, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, creatinine, and improved liver, and renal antioxidative status. Administration of AFSE to diabetic mice reduced total cholesterol, triglycerides, LDL-cholesterol, and the atherogenic index of plasma (AIP) suggesting its hypolipidemic action. Overall, AFS could be considered as attractive source of health-promoting ingredients.
Background
Corn silk is the elongated stigma of the female flower of Zea mays and traditionally used to treat diabetes mellitus (DM).
Objective
To investigate the beneficial effects of corn silk extract (CSE) on HFD/STZ-induced diabetic C56BL/6J mice.
Method
Establishment of a T2DM model through feeding HFD combined with STZ. T2DM were randomly divided into 5 groups: diabetic control mice treated with vehicle (model group, n=10), metformin-treated group (metformin: 150 mg/kg.d, n=10), three CS-treated groups (CS: 300, 600 and 1200 mg/kg.d, n=10). After four weeks of CS treatment, the body weight, FBG, IR, TC, TG, LDL-C, MDA and SOD levels of mice were measured. In addition, the liver tissue was histomorphologically analyzed by HE stain followed a light microscopy observation.
Results
4-week CSE treatment significantly reduced FBG and enhanced the glucose tolerance; improved IR indicated by decreased HOMA-IR and elevated ISI; alleviated hyperlipidemia indicated by decreased TC, TG, LDL-C, and increased HDL-C; reduced oxidative stress by decreased MDA and elevated SOD activity; decreased hepatic lipid accumulation and prevented liver tissue morphological change in T2DM. In addition, CSE treatments effectively prevent the weight gain loss of diabetic mice.
Conclusion
These results confirmed the traditionally claimed benefits of corn silk on DM, which suggested that the corn silk possessed the anti-diabetic potential and could be further developed as a cheap and plant-derived agent for the treatment of type 2 diabetes mellitus.
Murine 3T3-L1 fibroblasts enter a differentiation program subsequent to prolonged maintenance in the confluent state and develop into adipocytes. The hormone sensitivity of adenylate cyclase and the physiological responsiveness to insulin were compared in 3T3-L1 preadipocytes and adipocytes. The following observations, comprising several distinct categories of hormone responsiveness, were made. (a) (2.5 micronM) isoproterenol stimulated adenylate cyclase 15-fold in adipocyte homogenates, but only 2.5-fold in preadipocyte preparations, suggesting a considerable magnification in beta-adrenergic responsiveness during development. (b) A totally new control element, adrenocorticotropic hormone responsiveness, was incorporated into the adenylate cyclase system of the adipocytes. (c) Sensitivity to prostaglandin E1 was observed in both preadipocytes and adipocytes, but no change in responsiveness could be detected in the differentiated cells. (d) Glucagon-sensitive adenylate cyclase could not be detected in either preadipocytes or adipocytes. (e) Both preadipocytes and adipocytes possess considerable insulin binding activity, but near physiological levels of insulin stimulate the conversion of glucose to CO2 and lipid only in the differentiated cells.
Tumor necrosis factor-α (TNF-α) is an important mediator of insulin resistance in obesity and diabetes through its ability
to decrease the tyrosine kinase activity of the insulin receptor (IR). Treatment of cultured murine adipocytes with TNF-α
was shown to induce serine phosphorylation of insulin receptor substrate 1 (IRS-1) and convert IRS-1 into an inhibitor of
the IR tyrosine kinase activity in vitro. Myeloid 32D cells, which lack endogenous IRS-1, were resistant to TNF-α-mediated
inhibition of IR signaling, whereas transfected 32D cells that express IRS-1 were very sensitive to this effect of TNF-α.
An inhibitory form of IRS-1 was observed in muscle and fat tissues from obese rats. These results indicate that TNF-α induces
insulin resistance through an unexpected action of IRS-1 to attenuate insulin receptor signaling.
Genistein is a dietary-derived plant product that inhibits the activity of protein-tyrosine kinases. We show here that it is a potent inhibitor of the mammalian facilitative hexose transporter GLUT1. In human HL-60 cells, which express GLUT1, genistein inhibited the transport of dehydroascorbic acid, deoxyglucose, and methylglucose in a dose-dependent manner. Transport was not affected by daidzein, an inactive genistein analog that does not inhibit protein-tyrosine kinase activity, or by the general protein kinase inhibitor staurosporine. Genistein inhibited the uptake of deoxyglucose and dehydroascorbic acid in Chinese hamster ovary (CHO) cells overexpressing GLUT1 in a similar dose-dependent manner. Genistein also inhibited the uptake of deoxyglucose in human erythrocytes indicating that its effect on glucose transporter function is cell-independent. The inhibitory action of genistein on transport was instantaneous, with no additional effect observed in cells preincubated with it for various periods of time. Genistein did not alter the uptake of leucine by HL-60 cells, indicating that its inhibitory effect was specific for the glucose transporters. The inhibitory effect of genistein was of the competitive type, with a Ki of approximately 12 microM for inhibition of the transport of both methylglucose and deoxyglucose. Binding studies showed that genistein inhibited glucose-displaceable binding of cytochalasin B to GLUT1 in erythrocyte ghosts in a competitive manner, with a Ki of 7 microM. These data indicate that genistein inhibits the transport of dehydroascorbic acid and hexoses by directly interacting with the hexose transporter GLUT1 and interfering with its transport activity, rather than as a consequence of its known ability to inhibit protein-tyrosine kinases. These observations indicate that some of the many effects of genistein on cellular physiology may be related to its ability to disrupt the normal cellular flux of substrates through GLUT1, a hexose transporter universally expressed in cells, and is responsible for the basal uptake of glucose.
A number of studies have demonstrated that tumor necrosis factor-alpha (TNF-alpha) is associated with profound insulin resistance in adipocytes and may also play a critical role in the insulin resistance of obesity and non-insulin-dependent diabetes mellitus. Reports on the mechanism of TNF-alpha action have been somewhat contradictory. GLUT4 down-regulation has been implicated as a possible cause of insulin resistance as has been the reduced kinase function of the insulin receptor. Here we examine the effects of tumor necrosis factor on the protein components thought to be involved in insulin-stimulated glucose transport in adipocytes, namely the insulin receptor, its major substrate IRS-1, and the insulin responsive glucose transporter GLUT4. Prolonged exposure (72-96 h) of 3T3-L1 adipocytes to TNF-alpha causes a substantial reduction (>80%) in IRS-1 and GLUT4 mRNA and protein as well as a lesser reduction (>50%) in the amount of the insulin receptor. Nevertheless, the remaining proteins appear to be biochemically indistinguishable from those in untreated adipocytes. Both the insulin receptor and IRS-1 are tyrosine-phosphorylated to the same extent in response to acute insulin stimulation following cellular TNF-alpha exposure. Furthermore, the ability of the insulin receptor to phosphorylate exogenous substrate in the test tube is also normal following its isolation from TNF-alpha-treated cells. These results are confirmed by the reduced but obvious level of insulin-dependent glucose transport and GLUT4 translocation observed in TNF-alpha-treated adipocytes. We conclude that the insulin resistance of glucose transport in 3T3-L1 adipocytes exposed to TNF-alpha for 72-96 h results from a reduced amount in requisite proteins involved in insulin action. These results are consistent with earlier studies indicating that TNF-alpha reduces the transcriptional activity of the GLUT4 gene in murine adipocytes, and reduced mRNA transcription of a number of relevant genes may be the general mechanism by which TNF-alpha causes insulin resistance in adipocytes.
The ob gene product, leptin, is a major hormonal regulator of appetite and fat cell mass. Recent work has suggested that the antidiabetic
agents, the thiazolidinediones (TZ), which are also high affinity ligands of peroxisome proliferator-activated receptor-γ
(PPARγ), inhibit leptin expression in rodents. To examine the effects of this class of drug on the leptin gene in adipocytes
we performed Northern analysis on primary rat adipocytes cultured in the presence or absence of TZ. TZ reduced leptin mRNA
levels by 75%. To determine whether this effect was mediated at the transcriptional level, we isolated 6510 base pairs of
5′-flanking sequence of the leptin promoter and studied reporter constructs in primary rat adipocytes and CV-1 cells. Sequence
analysis demonstrated the presence of a consensus direct repeat with a 1-base-pair gap site between −3951 and −3939 as well
as a consensus CCAAT/enhancer binding protein (C/EBP) site between −55 and −47. Our functional analysis in transfected primary
rat adipocytes demonstrates that, despite the presence of a canonical direct repeat with a 1-base-pair gap site, TZ alone
decreases reporter gene expression of leptin promoter constructs ranging from −6510 to +9 to −65 to +9. In CV-1 cells, which
contain endogenous PPARγ, TZ treatment alone had little effect on these constructs. However, TZ treatment did inhibit C/EBPα-mediated
transactivation of the leptin promoter. This down-regulation of leptin reporter constructs mapped to a −65 to +9 promoter
fragment which binds C/EBPα in gel-mobility shift assays but does not bind PPARγ2 alone or as a heterodimer with 9-cis-retinoic acid receptor. Conversely, the promoter (−5400 to +24 base pairs) of the aP2 gene, another adipocyte-specific gene,
was induced 7.3-fold by TZ. Co-transfection with C/EBPα minimally stimulated the aP2 promoter from basal levels but notably
blocked activation by TZ. These data indicate that PPARγ and C/EBPα can functionally antagonize each other on at least two
separate promoters and that this mechanism may explain the down-regulation of leptin expression by thiazolidinediones.
Tumor necrosis factor-α (TNFα) has been implicated as a contributing mediator of insulin resistance observed in pathophysiological conditions such as obesity, cancer-induced cachexia, and bacterial infections. Previous studies have demonstrated that TNFα confers insulin resistance by promoting phosphorylation of serine residues on insulin receptor substrate 1 (IRS-1), thereby diminishing subsequent insulin-induced tyrosine phosphorylation of IRS-1. However, little is known about which signaling molecules are involved in this process in adipocytes and about the temporal sequence of events that ultimately leads to TNFα-stimulated IRS-1 serine phosphorylation. In this study, we demonstrate that specific inhibitors of the MAP kinase kinase (MEK)1/2-p42/44 mitogen-activated protein (MAP) kinase pathway restore insulin signaling to normal levels despite the presence of TNFα. Additional experiments show that MEK1/2 activity is required for TNFα-induced IRS-1 serine phosphorylation, thereby suggesting a mechanism by which these inhibitors restore insulin signaling.
We observe that TNFα requires 2.5–4 h to markedly reduce insulin-triggered tyrosine phosphorylation of IRS-1 in 3T3-L1 adipocytes. Although TNFα activates p42/44 MAP kinase, maximal stimulation is observed within 10–30 min. To our surprise, p42/44 activity returns to basal levels well before IRS-1 serine phosphorylation and insulin resistance are observed. These activation kinetics suggest a mechanism of p42/44 action more complicated than a direct phosphorylation of IRS-1 triggered by the early spike of TNFα-induced p42/44 activity.
Chronic TNFα treatment (≫ 72 h) causes adipocyte dedifferentiation, as evidenced by the loss of triglycerides and down-regulation of adipocyte-specific markers. We observe that this longer term TNFα-mediated dedifferentiation effect utilizes alternative, p42/44 MAP kinase-independent intracellular pathways.
This study suggests that TNFα-mediated insulin resistance, but not adipocyte dedifferentiation, is mediated by the MEK1/2-p42/44 MAP kinase pathway.
Flavonoids are nearly ubiquitous in plants and are recognized as the pigments responsible for the colors of leaves, especially in autumn. They are rich in seeds, citrus fruits, olive oil, tea, and red wine. They are low molecular weight compounds composed of a three-ring structure with various substitutions. This basic structure is shared by tocopherols (vitamin E). Flavonoids can be subdivided according to the presence of an oxy group at position 4, a double bond between carbon atoms 2 and 3, or a hydroxyl group in position 3 of the C (middle) ring. These characteristics appear to also be required for best activity, especially antioxidant and antiproliferative, in the systems studied. The particular hydroxylation pattern of the B ring of the flavonoles increases their activities, especially in inhibition of mast cell secretion. Certain plants and spices containing flavonoids have been used for thousands of years in traditional Eastern medicine. In spite of the voluminous literature available, however, Western medicine has not yet used flavonoids therapeutically, even though their safety record is exceptional. Suggestions are made where such possibilities may be worth pursuing.
Flavonoids are naturally occurring polyphenolic compounds with a wide distribution throughout the plant kingdom. In the present study, we compared the ability of several flavonoids to modulate the production of proinflammatory molecules from lipopolysaccharide (LPS)-stimulated macrophages and investigated their mechanism(s) of action. Pretreatment of RAW 264.7 with luteolin, luteolin-7-glucoside, quercetin, and the isoflavonoid genistein inhibited both the LPS-stimulated TNF-alpha and interleukin-6 release, whereas eriodictyol and hesperetin only inhibited TNF-alpha release. From the compounds tested luteolin and quercetin were the most potent in inhibiting cytokine production with an IC(50) of less than 1 and 5 microM for TNF-alpha release, respectively. To determine the mechanisms by which flavonoids inhibit LPS signaling, we used luteolin and determined its ability to interfere with total protein tyrosine phosphorylation as well as Akt phosphorylation and nuclear factor-kappaB activation. Pretreatment of the cells with luteolin attenuated LPS-induced tyrosine phosphorylation of many discrete proteins. Moreover, luteolin inhibited LPS-induced phosphorylation of Akt. Treatment of macrophages with LPS resulted in increased IkappaB-alpha phosphorylation and reduced the levels of IkappaB-alpha. Pretreatment of cells with luteolin abolished the effects of LPS on IkappaB-alpha. To determine the functional relevance of the phosphorylation events observed with IkappaB-alpha, macrophages were transfected either with a control vector or a vector coding for the luciferase reporter gene under the control of kappaB cis-acting elements. Incubation of transfected RAW 264.7 cells with LPS increased luciferase activity in a luteolin-sensitive manner. We conclude that luteolin inhibits protein tyrosine phosphorylation, nuclear factor-kappaB-mediated gene expression and proinflammatory cytokine production in murine macrophages.
Peroxisome proliferator-activated receptor-gamma (PPARgamma) has been shown to play an important role in the regulation of expression of a subclass of adipocyte genes and to serve as the molecular target of the thiazolidinedione (TZD) and certain non-TZD antidiabetic agents. Hypercorticosteroidism leads to insulin resistance, a variety of metabolic dysfunctions typically seen in diabetes, and hypertrophy of visceral adipose tissue. In adipocytes, the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1) converts inactive cortisone into the active glucocorticoid cortisol and thereby plays an important role in regulating the actions of corticosteroids in adipose tissue. Here, we show that both TZD and non-TZD PPARgamma agonists markedly reduced 11beta-HSD-1 gene expression in 3T3-L1 adipocytes. This diminution correlated with a significant decrease in the ability of the adipocytes to convert cortisone to cortisol. The half-maximal inhibition of 11beta-HSD-1 mRNA expression by the TZD, rosiglitazone, occurred at a concentration that was similar to its K(d) for binding PPARgamma and EC(50) for inducing adipocyte differentiation thereby indicating that this action was PPARgamma-dependent. The time required for the inhibitory action of the TZD was markedly greater for 11beta-HSD-1 gene expression than for leptin, suggesting that these genes may be down-regulated by different molecular mechanisms. Furthermore, whereas regulation of PPARgamma-inducible genes such as phosphoenolpyruvate carboxykinase was maintained when cellular protein synthesis was abrogated, PPARgamma agonist inhibition of 11beta-HSD-1 and leptin gene expression was ablated, thereby supporting the conclusion that PPARgamma affects the down-regulation of 11beta-HSD-1 indirectly. Finally, treatment of diabetic db/db mice with rosiglitazone inhibited expression of 11beta-HSD-1 in adipose tissue. This decrease in enzyme expression correlated with a significant decline in plasma corticosterone levels. In sum, these data indicate that some of the beneficial effects of PPARgamma antidiabetic agents may result, at least in part, from the down-regulation of 11beta-HSD-1 expression in adipose tissue.
Peroxisome proliferator-activated receptor (PPAR) gamma is a ligand-activated transcription factor and a member of the nuclear hormone receptor superfamily that is thought to be the master regulator of fat storage; however, the relationship between PPARgamma and insulin sensitivity is highly controversial. We show here that supraphysiological activation of PPARgamma by PPARgamma agonist thiazolidinediones (TZD) markedly increases triglyceride (TG) content of white adipose tissue (WAT), thereby decreasing TG content of liver and muscle, leading to amelioration of insulin resistance at the expense of obesity. Moderate reduction of PPARgamma activity by heterozygous PPARgamma deficiency decreases TG content of WAT, skeletal muscle, and liver due to increased leptin expression and increase in fatty acid combustion and decrease in lipogenesis, thereby ameliorating high fat diet-induced obesity and insulin resistance. Moreover, although heterozygous PPARgamma deficiency and TZD have opposite effects on total WAT mass, heterozygous PPARgamma deficiency decreases lipogenesis in WAT, whereas TZD stimulate adipocyte differentiation and apoptosis, thereby both preventing adipocyte hypertrophy, which is associated with alleviation of insulin resistance presumably due to decreases in free fatty acids, and tumor necrosis factor alpha, and up-regulation of adiponectin, at least in part. We conclude that, although by different mechanisms, both heterozygous PPARgamma deficiency and PPARgamma agonist improve insulin resistance, which is associated with decreased TG content of muscle/liver and prevention of adipocyte hypertrophy.
Adiponectin is a fat-derived hormone with antidiabetic and antiatherogenic properties. Hypoadiponectinemia seen in obesity is associated with insulin-resistant diabetes and atherosclerosis. Thiazolidinediones, peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists, have been shown to increase plasma adiponectin levels by the transcriptional induction in adipose tissues. However, the precise mechanism of such action is unknown. In this study, we have identified a functional PPAR-responsive element (PPRE) in human adiponectin promoter. PPAR-gamma/retinoid X receptor (RXR) heterodimer directly bound to the PPRE and increased the promoter activity in cells. In adipocytes, point mutation of the PPRE markedly reduced the basal transcriptional activity and completely blocked thiazolidinedione-induced transactivation of adiponectin promoter. We have also identified a responsive element of another orphan nuclear receptor, liver receptor homolog-1 (LRH-1), in adiponectin promoter. LRH-1 was expressed in 3T3-L1 cells and rat adipocytes. LRH-1 bound specifically to the identified responsive element (LRH-RE). LRH-1 augmented PPAR-gamma-induced transactivation of adiponectin promoter, and point mutation of the LRH-RE significantly decreased the basal and thiazolidinedione-induced activities of adiponectin promoter. Our results indicate that PPAR-gamma and LRH-1 play significant roles in the transcriptional activation of adiponectin gene via the PPRE and the LRH-RE in its promoter.
Whereas thiazolidinediones (TZDs) are known to rapidly improve insulin action in animals, short durations of TZD therapy have never been studied in humans. Among the many known actions of TZDs, increased circulating levels of the high molecular weight (HMW) multimer of adiponectin may be an important insulin-sensitizing mechanism. We examined the effects of only 21 days of 45 mg of pioglitazone (P+) versus placebo (P-) in nine subjects with type 2 diabetes (HbA(1c), 10.9 +/- 0.6%; BMI, 31.9 +/- 1.5 kg/m(2)). Total adiponectin levels increased by approximately twofold in P+ in association with increased adipose tissue gene expression. However, plasma free fatty acid and glucose levels were unchanged, and there were only minimal changes in other "adipokines." Glucose fluxes ([3-(3)H]glucose infusion) were measured during 6-h euglycemic (5 mmol/l) "pancreatic clamp" studies (somatostatin/glucagon/growth hormone) with stepped insulin levels. Pioglitazone induced marked decreases in endogenous glucose production (P+ = 0.9 +/- 0.1 vs. P- = 1.7 +/- 0.3 mg. kg(-1). min(-1); P < 0.05) at physiologic hyperinsulinemia ( approximately 50 microU/ml), which was highly correlated with an increased ratio of HMW adiponectin/total levels (r(2) = 0.90). Maximal insulin stimulation ( approximately 400 microU/ml) revealed pioglitazone-associated increases in glucose uptake (P+ = 10.5 +/- 0.9 vs. P- = 8.9 +/- 0.8 mg. kg(-1). min(-1); P < 0.05), which did not correlate with HMW or total adiponectin levels. Thus, only 21 days of pioglitazone therapy improved insulin action in humans with type 2 diabetes. Increased abundance of the HMW adiponectin multimer may contribute to the hepatic insulin-sensitizing effects of these agents.
The facilitative glucose transporter, GLUT4, mediates insulin-stimulated glucose uptake in adipocytes and muscles, and the participation of GLUT4 in the pathogenesis of various clinical conditions associated with obesity, visceral fat accumulation and insulin resistance has been proposed. Glucose uptake by some members of the GLUT family, mainly GLUT1, is inhibited by flavonoids, the natural polyphenols present in fruits, vegetables and wine. Therefore it is of interest to establish if these polyphenolic compounds present in the diet, known to be effective antioxidants but also endowed with several other biological activities such as protein-tyrosine kinase inhibition, interfere with GLUT4 function. In the present study, we show that three flavonoids, quercetin, myricetin and catechin-gallate, inhibit the uptake of methylglucose by adipocytes over the concentration range of 10-100 microM. These three flavonoids show a competitive pattern of inhibition, with K(i)=16, 33.5 and 90 microM respectively. In contrast, neither catechin nor gallic acid inhibit methylglucose uptake. To obtain a better understanding of the interaction among GLUT4 and flavonoids, we have derived a GLUT4 three-dimensional molecular comparative model, using structural co-ordinates from a GLUT3 comparative model and a mechanosensitive ion channel [PDB (Protein Data Bank) code 1MSL] solved by X-ray diffraction. On the whole, the experimental evidence and computer simulation data favour a transport inhibition mechanism in which flavonoids and GLUT4 interact directly, rather than by a mechanism related to protein-tyrosine kinase and insulin signalling inhibition. Furthermore, the results suggest that GLUT transporters are involved in flavonoid incorporation into cells.
We characterised insulin resistance, metabolic defects and endocrine dysfunction in cultured adipose cells and examined the autocrine or paracrine roles of cytokines/adipokines in the progression of insulin resistance.
Rat primary adipose cells were prepared and cultured for 24 and 48 h. Insulin resistance and gene expression were examined by glucose uptake assay, cDNA microarray and real-time RT-PCR.
After 24 h in culture, the fold increase of insulin-stimulated glucose uptake in adipose cells was markedly reduced; after 48 h the response of the cells to insulin decreased. cDNA microarray analysis showed that the expression of 514 genes was altered in adipose cells after 24 h in culture. The dysregulated genes included those involved in the citric acid cycle and in fatty acid and pyruvate metabolism. Specifically, the following genes were all downregulated: genes encoding lipolytic and lipogenic enzymes; uncoupling protein 1 and 2 genes; peroxisome proliferator-activated receptor gamma, coactivator 1 alpha gene. This indicates that lipolytic and lipogenic activity, as well as mitochondria capacity decline in adipose cells cultured for 24 h. The mRNAs encoding 40 adipokines were also dysregulated in cultured cells. Strikingly, the dysregulated adipokines in cultured cells and in freshly isolated adipose cells from insulin-resistant Zucker fa/fa rats displayed a similar pattern with regard to protein functions. Also striking was the fact that progression of insulin resistance was promoted by the adipokines secreted from insulin-resistant adipose tissue or cells.
Our data demonstrate that the impairment of metabolism and endocrine dysfunction in cultured adipose cells mimics the insulin resistance occurring in vivo. Cytokines and adipokines appear to play a critical role in the progression of insulin resistance in adipose cells.
Peroxisome proliferator-activated receptor-gamma (PPARgamma) regulates adipocyte genes involved in adipogenesis and lipid metabolism and is the molecular target for thiazolidinedione (TZD) antidiabetic agents. Adipose triglyceride lipase (ATGL) is a recently described triglyceride-specific lipase that is induced during adipogenesis and remains highly expressed in mature adipocytes. This study evaluates the ability of PPARgamma to directly regulate ATGL expression in adipocytes in vitro and in vivo. In fully differentiated 3T3-L1 adipocytes, ATGL mRNA and protein are increased by TZD and non-TZD PPARgamma agonists in a dose- and time-dependent manner. Rosiglitazone-mediated induction of ATGL mRNA is rapid and is not inhibited by the protein synthesis inhibitor cycloheximide, indicating that intervening protein synthesis is not required for this effect. Rosiglitazone-mediated induction of ATGL mRNA and protein is inhibited by the PPARgamma-specific antagonist GW-9662 and is also significantly reduced following siRNA-mediated knockdown of PPARgamma, supporting the direct transcriptional regulation of ATGL by PPARgamma. In vivo, ATGL mRNA and protein are increased by rosiglitazone treatment in white and brown adipose tissue of mice with and without obesity due to high-fat diet or leptin deficiency. Thus, PPARgamma positively regulates ATGL mRNA and protein expression in mature adipocytes in vitro and in adipose tissue in vivo, suggesting a role for ATGL in mediating PPARgamma's effects on lipid metabolism.
The adipocyte-derived secretory protein adiponectin functions as an insulin-sensitizing agent. In plasma, adiponectin exists as low, medium, and high molecular weight oligomers. Treatment with trans-10, cis-12 conjugated linoleic acid (t-10, c-12 CLA) reduces levels of adiponectin as well as triglyceride (TG) in mice and adipocyte cell culture models. The aim of this study was to determine whether the effects of t-10, c-12 CLA on adiponectin and TG are mediated through modulation of the transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma). 3T3-L1 cells were treated either during or after differentiation into adipocytes with 100 microM t-10, c-12 CLA with or without 10 microM troglitazone, a PPARgamma agonist, or 1 microM GW9662, a PPARgamma antagonist, and adiponectin and TG levels were analyzed. Treatment with t-10, c-12 CLA reduced TG as well as cellular and secreted adiponectin levels and impaired the assembly of adiponectin oligomers. These changes were accompanied by decreases in PPARgamma mass. Troglitazone was able to reverse the t-10, c-12 CLA-mediated decrease in TG levels and restore the assembly of adiponectin oligomers but was unable to restore adiponectin synthesis. Conversely, treatment with GW9662 decreased TG mass and impaired adiponectin oligomer assembly but did not decrease total adiponectin mass. In a reporter assay, t-10, c-12 CLA appeared to be a partial PPARgamma agonist and prevented the stimulation of reporter activity by troglitazone. Therefore, the t-10, c-12 CLA isomer appears to alter adipocyte adiponectin metabolism through PPARgamma-dependent and PPARgamma-independent mechanisms.
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear receptor superfamily PPARα is highly expressed in liver, skeletal muscle, kidney, heart and the vascular wall. PPARγ is predominantly detected in adipose tissue, intestine and macrophages. PPARs are activated by fatty-acid derivatives and pharmacological agents such as fibrates and glitazones which are specific for PPARα and PPARγ respectively. PPARs regulate lipid and lipoprotein metabolism, glucose homeostasis, cell proliferation and differentiation, and apoptosis. PPARα controls intra- and extracellular lipid metabolisms whereas PPARγ triggers adipocyte differentiation and promotes lipid storage. In addition. PPARs also modulate the inflammatory response. PPAR activators have been shown to exert antiinflammatory activities in various cell types by inhibiting the expression of proinflammatory genes such as cytokines, metalloproteases and acute-phase proteins. PPARs negatively regulate the transcription of inflammatory response genes by antagonizing the AP-1, nuclear factor-KB (NF-κB), signal transducer and activator of transcription and nuclear factor of activated T-cells signalling pathways and by stimulating the catabolism of proinflammatory eicosanoids. These recent findings indicate a modulatory role for PPARs in inflammation with potential therapeutical applications in chronic inflammatory diseases.
Several herbal medicines improve hyperlipidemia, diabetes and cardiovascular diseases. However, the molecular mechanism underlying this improvement has not yet been clarified. In this study, we found that several isoprenols, common components of herbal plants, activate human peroxisome proliferator-activated receptors (PPARs) as determined using the novel GAL4 ligand-binding domain chimera assay system with coactivator coexpression. Farnesol and geranylgeraniol that are typical isoprenols in herbs and fruits activated not only PPARγ but also PPARα as determined using the chimera assay system. These compounds also activated full-length human PPARγ and PPARα in CV1 cells. Moreover, these isoprenols upregulated the expression of some lipid metabolic target genes of PPARγ and PPARα in 3T3-L1 adipocytes and HepG2 hepatocytes, respectively. These results suggest that herbal medicines containing isoprenols with dual action on both PPARγ and PPARα can be of interest for the amelioration of lipid metabolic disorders associated with diabetes.
Insulin resistance and its dreaded consequence, type 2 diabetes, are major causes of atherosclerosis. Adiponectin is an adipose-specific plasma protein that possesses anti-atherogenic properties, such as the suppression of adhesion molecule expression in vascular endothelial cells and cytokine production from macrophages. Plasma adiponectin concentrations are decreased in obese and type 2 diabetic subjects with insulin resistance. A regimen that normalizes or increases the plasma adiponectin might prevent atherosclerosis in patients with insulin resistance. In this study, we demonstrate the inducing effects of thiazolidinediones (TZDs), which are synthetic PPARgamma ligands, on the expression and secretion of adiponectin in humans and rodents in vivo and in vitro. The administration of TZDs significantly increased the plasma adiponectin concentrations in insulin resistant humans and rodents without affecting their body weight. Adiponectin mRNA expression was normalized or increased by TZDs in the adipose tissues of obese mice. In cultured 3T3-L1 adipocytes, TZD derivatives enhanced the mRNA expression and secretion of adiponectin in a dose- and time-dependent manner. Furthermore, these effects were mediated through the activation of the promoter by the TZDs. On the other hand, TNF-alpha, which is produced more in an insulin-resistant condition, dose-dependently reduced the expression of adiponectin in adipocytes by suppressing its promoter activity. TZDs restored this inhibitory effect by TNF-alpha. TZDs might prevent atherosclerotic vascular disease in insulin-resistant patients by inducing the production of adiponectin through direct effect on its promoter and antagonizing the effect of TNF-alpha on the adiponectin promoter.
Luteolin, 3',4',5,7-tetrahydroxyflavone, is a common flavonoid that exists in many types of plants including fruits, vegetables, and medicinal herbs. Plants rich in luteolin have been used in Chinese traditional medicine for treating various diseases such as hypertension, inflammatory disorders, and cancer. Having multiple biological effects such as anti-inflammation, anti-allergy and anticancer, luteolin functions as either an antioxidant or a pro-oxidant biochemically. The biological effects of luteolin could be functionally related to each other. For instance, the anti-inflammatory activity may be linked to its anticancer property. Luteolin's anticancer property is associated with the induction of apoptosis, and inhibition of cell proliferation, metastasis and angiogenesis. Furthermore, luteolin sensitizes cancer cells to therapeutic-induced cytotoxicity through suppressing cell survival pathways such as phosphatidylinositol 3'-kinase (PI3K)/Akt, nuclear factor kappa B (NF-kappaB), and X-linked inhibitor of apoptosis protein (XIAP), and stimulating apoptosis pathways including those that induce the tumor suppressor p53. These observations suggest that luteolin could be an anticancer agent for various cancers. Furthermore, recent epidemiological studies have attributed a cancer prevention property to luteolin. In this review, we summarize the progress of recent research on luteolin, with a particular focus on its anticancer role and molecular mechanisms underlying this property of luteolin.
In light of the pivotal role that PPARgamma2 plays in the expression of fat specific genes (e.g., A-FABP), we have examined the hypothesis that a rise in PPARgamma2 protein is required for the expression of A-FABP, and that the acceleration of fat cell differentiation by the thiazolidinedione agent, pioglitazone (PIOG), reflects an increase in the abundance of PPARgamma2 mRNA and protein. Western analyses surprisingly revealed that undifferentiated 3T3-L1 fibroblasts contained significant levels of PPARgamma2 protein; that the amount of total cellular PPARgamma2 only increased 2-fold during differentiation; and that the levels of PPARgamma2 protein and mRNA were not increased by PIOG even though fat cell differentiation was accelerated by PIOG as revealed by a 20-fold increase in A-FABP expression. Cell fractionation studies revealed that PPARgamma2 was evenly distributed between the cytosolic and nuclear compartments in both undifferentiated and differentiating 3T3-L1 cells. Immunocytochemical studies with a PPARgamma2-specific antibody indicated that PPARgamma2 was diffusely distributed throughout the cytosol of undifferentiated 3T3-L1 cells, but as the differentiation progressed, the PPARgamma2 became focused around the developing lipid droplets. In contrast to PPARgamma2, undifferentiated 3T3-L1 cells contained no measurable quantities of RXRalpha, but once fat cell differentiation was initiated by treatment with IBMX and dexamethasone, the cellular content of RXRalpha increased several fold. The rise in RXRalpha content paralleled the induction of A-FABP, but the expression of RXRalpha was not enhanced by PIOG. Although the amount of PPARgamma2 and RXRalpha was unaffected by PIOG, gel shift assays revealed that PIOG stimulated PPARgamma2/RXRalpha binding to the adipose response element of A-FABP by 5-fold in less than 12 h. Apparently, RXRalpha rather than PPARgamma2 is the pivotal trans-factor essential for the initiation of terminal fat cell differentiation. However, the high cytsolic content of PPARgamma2 and its association with the lipid droplet of differentiating 3T3-L1 cells suggests PPARgamma2 may possess a cytosolic function in the developing fat cell.
Flavonoids are a group of polyphenolic compounds ubiquitously found in plants including fruits, and vegetables. Broad ranges of the biological activities of flavonoids have been reported using in vitro studies. I report that several natural flavonoids blocked glucose uptake in myelocytic U937 cells. Although there were some variations in the blocking activity of individual flavonoids, approximately half of the glucose uptake was blocked by flavonoids at the concentrations of 8-50 microM. The decreasing order of the blocking activity was fisetin >/= myricetin >/= quercetin >/= apigenin > genistein > cyanidin > daidzein >/= hesperetin > naringenin > catechin. Fisetin showed approximately 50% inhibition of glucose uptake at a concentration of 8 microM. Similar patterns of the inhibition were observed in lymphocytic Jurkat cells. Fisetin and quercetin inhibited glucose transport in a competitive manner. K(i) values for fisetin and quercetin were proximately 9 and 12 microM, respectively. This study showed that some types of natural flavonoids block glucose uptake in U937 cells and that natural flavonoids could be used as alternative blockers of glucose uptake in vitro.
The facilitative hexose transporter GLUT1 is a multifunctional protein that transports hexoses and dehydroascorbic acid, the oxidized form of vitamin C, and interacts with several molecules structurally unrelated to the transported substrates. Here we analyzed in detail the interaction of GLUT1 with a group of tyrosine kinase inhibitors that include natural products of the family of flavones and isoflavones and synthetic compounds such as the tyrphostins. These compounds inhibited, in a dose-dependent manner, the transport of hexoses and dehydroascorbic acid in human myeloid HL-60 cells, in transfected Chinese hamster ovary cells overexpressing GLUT1, and in normal human erythrocytes, and blocked the glucose-displaceable binding of cytochalasin B to GLUT1 in erythrocyte ghosts. Kinetic analysis of transport data indicated that only tyrosine kinase inhibitors with specificity for ATP binding sites inhibited the transport activity of GLUT1 in a competitive manner. In contrast, those inhibitors that are competitive with tyrosine but not with ATP failed to inhibit hexose uptake or did so in a noncompetitive manner. These results, together with recent evidence demonstrating that GLUT1 is a nucleotide binding protein, support the concept that the inhibitory effect on transport is related to the direct interaction of the inhibitors with GLUT1. We conclude that predicted nucleotide-binding motifs present in GLUT1 are important for the interaction of the tyrosine kinase inhibitors with the transporter and may participate directly in the binding transport of substrates by GLUT1.
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear receptor superfamily. PPARalpha is highly expressed in liver, skeletal muscle, kidney, heart and the vascular wall. PPARgamma is predominantly detected in adipose tissue, intestine and macrophages. PPARs are activated by fatty-acid derivatives and pharmacological agents such as fibrates and glitazones which are specific for PPARalpha and PPARgamma respectively. PPARs regulate lipid and lipoprotein metabolism, glucose homeostasis, cell proliferation and differentiation, and apoptosis. PPARalpha controls intra- and extracellular lipid metabolisms whereas PPARgamma triggers adipocyte differentiation and promotes lipid storage. In addition, PPARs also modulate the inflammatory response. PPAR activators have been shown to exert anti-inflammatory activities in various cell types by inhibiting the expression of proinflammatory genes such as cytokines, metalloproteases and acute-phase proteins. PPARs negatively regulate the transcription of inflammatory response genes by antagonizing the AP-1, nuclear factor-kappaB (NF-kappaB), signal transducer and activator of transcription and nuclear factor of activated T-cells signalling pathways and by stimulating the catabolism of proinflammatory eicosanoids. These recent findings indicate a modulatory role for PPARs in inflammation with potential therapeutical applications in chronic inflammatory diseases.
Several herbal medicines improve hyperlipidemia, diabetes and cardiovascular diseases. However, the molecular mechanism underlying this improvement has not yet been clarified. In this study, we found that several isoprenols, common components of herbal plants, activate human peroxisome proliferator-activated receptors (PPARs) as determined using the novel GAL4 ligand-binding domain chimera assay system with coactivator coexpression. Farnesol and geranylgeraniol that are typical isoprenols in herbs and fruits activated not only PPARgamma but also PPARalpha as determined using the chimera assay system. These compounds also activated full-length human PPARgamma and PPARalpha in CV1 cells. Moreover, these isoprenols upregulated the expression of some lipid metabolic target genes of PPARgamma and PPARalpha in 3T3-L1 adipocytes and HepG2 hepatocytes, respectively. These results suggest that herbal medicines containing isoprenols with dual action on both PPARgamma and PPARalpha can be of interest for the amelioration of lipid metabolic disorders associated with diabetes.
In the course of a high throughput screen to search for ligands of peroxisome proliferator activated receptor-gamma (PPARgamma), we identified GW9662 using a competition binding assay against the human ligand binding domain. GW9662 had nanomolar IC(50) versus PPARgamma and was 10- and 600-fold less potent in binding experiments using PPARalpha and PPARdelta, respectively. Pretreatment of all three PPARs with GW9662 resulted in the irreversible loss of ligand binding as assessed by scintillation proximity assay. Incubation of PPAR with GW9662 resulted in a change in the absorbance spectra of the receptors consistent with covalent modification. Mass spectrometric analysis of the PPARgamma ligand binding domain treated with GW9662 established Cys(285) as the site of covalent modification. This cysteine is conserved among all three PPARs. In cell-based reporter assays, GW9662 was a potent and selective antagonist of full-length PPARgamma. The functional activity of GW9662 as an antagonist of PPARgamma was confirmed in an assay of adipocyte differentiation. GW9662 showed essentially no effect on transcription when tested using both full-length PPARdelta and PPARalpha. Time-resolved fluorescence assays of ligand-modulated receptor heterodimerization, coactivator binding, and corepressor binding were consistent with the effects observed in the reporter gene assays. Control activators increased PPAR:RXR heterodimer formation and coactivator binding to both PPARgamma and PPARdelta. Corepressor binding was decreased. In the case of PPARalpha, GW9662 treatment did not significantly increase heterodimerization and coactivator binding or decrease corepressor binding. The experimental data indicate that GW9662 modification of each of the three PPARs results in different functional consequences. The selective and irreversible nature of GW9662 treatment, and the observation that activity is maintained in cell culture experiments, suggests that this compound may be a useful tool for elucidation of the role of PPARgamma in biological processes.
We have previously shown that the flavonoid luteolin inhibits the expression of pro-inflammatory molecules induced by LPS. In the present study we tested the ability of luteolin to block signalling pathways implicated in LPS-induced inflammatory gene expression in macrophages.
Exposure of the murine macrophage cell line RAW 264.7 to LPS increased phosphorylation of the mitogen-activated protein kinase family members ERK1/2, p38 and JNK1/2 in a time-dependent manner. Pretreatment of RAW 264.7 with luteolin inhibited the LPS-induced ERK1/2 and p38, but not JNK1/2, phosphorylation, and blocked the LPS-induced TNF-α release.
To investigate which of these pathways contribute to the inhibitory effects of luteolin on TNF-α release, cells were pretreated with pharmacological inhibitors of these pathways; PD98059 and SB203580 when used alone failed to inhibit TNF-α release, whereas pretreatment with both agents attenuated TNF-α release.
We have previously shown that luteolin blocks Akt phosphorylation in response to LPS in RAW 264.7 macrophages. To determine the role of Akt in TNF-α release, cells were transiently transfected with a dominant negative form of Akt (K179M). Overexpression of K179M Akt did not alter LPS-induced TNF-α release, suggesting that inhibition of this kinase does not mediate the inhibitory action of luteolin.
In addition, DRB (a pharmacological inhibitor of CK2) blocked TNF-α release in a concentration-dependent manner, whereas co-treatment of cells with luteolin and DRB did not have an additive effect.
We conclude that luteolin interferes with LPS signalling by reducing the activation of several MAPK family members and that its inhibitory action on TNF-α release correlates with inhibition of ERK, p38 and CK2 activation.
British Journal of Pharmacology (2002) 136, 1058–1064. doi:10.1038/sj.bjp.0704803
The thiazolidinedione (TZD) class of antidiabetic drugs has been shown to inhibit the formation of bone-resorbing osteoclasts in vitro and to decrease bone resorption markers in vivo. These drugs also inhibit the expression of leptin in adipocytes. Less leptin can be associated with higher bone mass, based on analyses of mice deficient in leptin action. Effects of 1-year treatment with troglitazone, a member of the TZDs, on bone mineral density (BMD) and bone metabolism were examined in 25 Japanese type 2 diabetic patients. Glucose metabolism was improved, whereas body mass index and percent body fat did not change throughout the study. The percent change of BMD was negatively correlated with that of serum leptin, whereas it was not associated with changes of bone metabolic markers, type I collagen N-telopeptide (NTx), bone alkaline phosphatase (ALP), body mass index, or HbA1c. Serum leptin decreased in 68% of subjects (responders) after 1-month treatment and was consistently lower than the basal level throughout the treatment. Percent changes of BMD were significantly higher in the responders than in the nonresponders and in nondiabetic subjects at 6 and 12 months. NTx and bone ALP decreased at 1 month but increased thereafter in either group of patients. Thus, it is suggested that the decrease in serum leptin with no reduction in body fat mass by troglitazone is associated with preventing bone loss in type 2 diabetic patients. Hence, TZDs may have an advantage for diabetic patients who have risk factors for osteoporosis.
Abietic acid is one of the terpenoids, which are multifunctional natural compounds. It has been reported that abietic acid suppresses effects on inflammation. However, the mechanism underlying the anti-inflammatory effects remains unclear. The present work indicates that abietic acid suppresses the protein expression of tumor necrosis factor-alpha and cyclooxygenase 2, which are involved in inflammation, in lipopolysaccharide-stimulated macrophages. Moreover, this effect resembles that of thiazolidinedione, a synthetic peroxisome proliferator-activated receptor-gamma (PPARgamma) ligand. Indeed, abietic acid activates PPARgamma in luciferase reporter assays. The activity of abietic acid induces PPARgamma target gene expression in RAW264.7 macrophages and 3T3-L1 adipocytes. These data indicate that abietic acid is a PPARgamma ligand and that its anti-inflammatory effect is partly due to the activation of PPARgamma in stimulated macrophages. The present work suggests a novel possibility that abietic acid, a naturally occurring compound, can be used not only for anti-inflammation but also for regulating lipid metabolism and atherosclerosis.
Insulin resistance is a pivotal feature in the pathogenesis of type 2 diabetes, and it may be detected 10-20 y before the clinical onset of hyperglycemia. Insulin resistance is due to the reduced ability of peripheral target tissues to respond properly to insulin stimulation. In particular, impaired insulin-stimulated muscle glycogen synthesis plays a significant role in insulin resistance. Glucose transport (GLUT4), phosphorylation (hexokinase) and storage (glycogen synthase) are the three potential rate-controlling steps regulating insulin-stimulated muscle glucose metabolism, and all three have been implicated as being the major defects responsible for causing insulin resistance in patients with type 2 diabetes. Using (13)C/(31)P magnetic resonance spectroscopy (MRS), we demonstrate that a defect in insulin-stimulated muscle glucose transport activity is the rate-controlling defect. Using a similar (13)C/(31)P MRS approach, we have also demonstrated that fatty acids cause insulin resistance in humans due to a decrease in insulin-stimulated muscle glucose transport activity, which could be attributed to reduced insulin-stimulated IRS-1-associated phosphatidylinositol 3-kinase activity, a required step in insulin-stimulated glucose transport into muscle. Furthermore, we have recently proposed that this defect in insulin-stimulated muscle glucose transport activity may be due to the activation of a serine kinase cascade involving protein kinase C theta and IKK-beta, which are key downstream mediators of tissue inflammation. Finally, we propose that any perturbation that leads to an increase in intramyocellular lipid (fatty acid metabolites) content such as acquired or inherited defects in mitochondrial fatty acid oxidation, defects in adipocyte fat metabolism or simply increased fat delivery to muscle/liver due to increased energy intake will lead to insulin resistance through this final common pathway. Understanding these key cellular mechanisms of insulin resistance should help elucidate new targets for treating type 2 diabetes.