scholarly journals Dihydromyricetin Ameliorates Inflammation-Induced Insulin Resistance via Phospholipase C-CaMKK-AMPK Signal Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-18
Author(s):  
Lianjie Hou ◽  
Fangyi Jiang ◽  
Bo Huang ◽  
Weijie Zheng ◽  
Yufei Jiang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Phospholipase C ◽  
Public Health Problem ◽  
Signal Pathway ◽  
Target Protein ◽  
Inflammatory Factors ◽  
The Metabolic Syndrome

Patients with metabolic syndrome have a higher risk of type II diabetes and cardiovascular disease. The metabolic syndrome has become an urgent public health problem. Insulin resistance is the common pathophysiological basis of metabolic syndrome. The higher incidence of insulin resistance in obese groups is due to increased levels of inflammatory factors during obesity. Therefore, developing a therapeutic strategy for insulin resistance has great significance for the treatment of the metabolic syndrome. Dihydromyricetin, as a bioactive polyphenol, has been used for anti-inflammatory, antitumor, and improving insulin sensitivity. However, the target of DHM and molecular mechanism of DHM for preventing inflammation-induced insulin resistance is still unclear. In this study, we first confirmed the role of dihydromyricetin in inflammation-induced insulin resistance in vivo and in vitro. Then, we demonstrated that dihydromyricetin resisted inflammation-induced insulin resistance by activating Ca2+-CaMKK-AMPK using signal pathway blockers, Ca2+ probes, and immunofluorescence. Finally, we clarified that dihydromyricetin activated Ca2+-CaMKK-AMPK signaling pathway by interacting with the phospholipase C (PLC), its target protein, using drug affinity responsive target stability (DARTS) assay. Our results not only demonstrated that dihydromyricetin resisted inflammation-induced insulin resistance via the PLC-CaMKK-AMPK signal pathway but also discovered that the target protein of dihydromyricetin is the PLC. Our results provided experimental data for the development of dihydromyricetin as a functional food and new therapeutic strategies for treating or preventing PLC.

scholarly journals Dihydromyricetin Ameliorates Inflammation-Induced Insulin Resistance via Phospholipase C-CaMKK-AMPK Signal Pathway

2021 ◽  
Author(s):  
Lianjie Hou ◽  
Fangyi Jiang ◽  
Bo Huang ◽  
Weijie Zheng ◽  
Yufei Jiang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Phospholipase C ◽  
Therapeutic Strategy ◽  
Public Health Problem ◽  
Signal Pathway ◽  
Target Protein ◽  
Inflammatory Factors ◽  
Oral Glucose ◽  
The Metabolic Syndrome

Abstract Background Metabolic syndrome is associated with obesity, inflammation, and insulin resistance. Patients with metabolic syndrome have a higher risk of turning into type II diabetes and cardiovascular disease. The metabolic syndrome has become an urgent public health problem. Insulin resistance in obesity is the common pathophysiological basis of metabolic syndrome. The insulin resistance is induced by the increasing levels of inflammatory factors during obesity. Therefore, developing a therapeutic strategy for preventing inflammation-induced insulin resistance has great significance for the treatment of metabolic syndrome. Dihydromyricetin, as a bioactive polyphenol, has been used for anti-inflammatory, anti-tumor, and improving insulin sensitivity. However, the target of DHM and the molecular mechanism of DHM in preventing inflammation-induced insulin resistance are still unclear. Methods In this study, we first confirmed the role of dihydromyricetin in inflammation-induced insulin resistance through ELISA, oral glucose tolerance test and glucose uptake test. Then, we demonstrated the pathway of dihydromyricetin ameliorated inflammation-induced insulin resistance by using signal pathway blockers, Ca2 + probes, and immunofluorescence. Finally, we clarified the target protein of dihydromyricetin by using drug affinity responsive target stability (DARTS) assay, qPCR, and western blotting. Results In this study, we first confirmed that dihydromyricetin ameliorated inflammation-induced insulin resistance in vivo and in vitro. Then, we demonstrated that dihydromyricetin ameliorated inflammation-induced insulin resistance by activating Ca2+-CaMKK-AMPK signal pathway. Finally, we clarified that dihydromyricetin activated Ca2+-CaMKK-AMPK signaling pathway by interacting with phospholipase C (PLC), its target protein. Conclusions Our results not only demonstrated that dihydromyricetin ameliorated inflammation-induced insulin resistance via the PLC-CaMKK-AMPK signal pathway but also discovered that the target protein of dihydromyricetin is PLC. Our results provided experimental data for the development of dihydromyricetin as a functional food additive and a new therapeutic strategy for treating or preventing insulin resistance and metabolic syndrome.

scholarly journals Dihydromyricetin Ameliorates Inflammation-induced Insulin Resistance via Phospholipase C-CaMKK-AMPK Signal Pathway

2020 ◽  
Author(s):  
Lianjie Hou ◽  
Fangyi Jiang ◽  
Bo Huang ◽  
Weijie Zheng ◽  
Yufei Jiang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Phospholipase C ◽  
Therapeutic Strategy ◽  
Public Health Problem ◽  
Signal Pathway ◽  
Target Protein ◽  
Inflammatory Factors ◽  
Oral Glucose ◽  
The Metabolic Syndrome

Abstract Background: Metabolic syndrome is associated with obesity, inflammation, and insulin resistance. Patients with metabolic syndrome have a higher risk of turning into type II diabetes and cardiovascular disease. The metabolic syndrome has become an urgent public health problem. Insulin resistance in obesity is the common pathophysiological basis of metabolic syndrome. The insulin resistance is induced by the increasing levels of inflammatory factors during obesity. Therefore, developing a therapeutic strategy for preventing inflammation-induced insulin resistance has great significance for the treatment of metabolic syndrome. Dihydromyricetin, as a bioactive polyphenol, has been used for anti-inflammatory, anti-tumor, and improving insulin sensitivity. However, the target of DHM and the molecular mechanism of DHM in preventing inflammation-induced insulin resistance are still unclear.Methods: In this study, we first confirmed the role of dihydromyricetin in inflammation-induced insulin resistance through ELISA, oral glucose tolerance test and glucose uptake test. Then, we demonstrated the pathway of dihydromyricetin ameliorated inflammation-induced insulin resistance by using signal pathway blockers, Ca2+ probes, and immunofluorescence. Finally, we clarified the target protein of dihydromyricetin by using drug affinity responsive target stability (DARTS) assay, qPCR, and western blotting.Results: In this study, we first confirmed that dihydromyricetin ameliorated inflammation-induced insulin resistance in vivo and in vitro. Then, we demonstrated that dihydromyricetin ameliorated inflammation-induced insulin resistance by activating Ca2+-CaMKK-AMPK signal pathway. Finally, we clarified that dihydromyricetin activated Ca2+-CaMKK-AMPK signaling pathway by interacting with phospholipase C (PLC), its target protein.Conclusions: Our results not only demonstrated that dihydromyricetin ameliorated inflammation-induced insulin resistance via the PLC-CaMKK-AMPK signal pathway but also discovered that the target protein of dihydromyricetin is PLC. Our results provided experimental data for the development of dihydromyricetin as a functional food additive and a new therapeutic strategy for treating or preventing insulin resistance and metabolic syndrome.

scholarly journals Enhanced phosphorylation of Na+–Cl− co-transporter in experimental metabolic syndrome: role of insulin

2012 ◽  
Vol 123 (11) ◽  
pp. 635-647 ◽  
Author(s):  
Radko Komers ◽  
Shaunessy Rogers ◽  
Terry T. Oyama ◽  
Bei Xu ◽  
Chao-Ling Yang ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Time Course ◽  
Kinase Inhibitor ◽  
Endogenous Expression ◽  
The Metabolic Syndrome ◽  
Mammalian Cell Lines ◽  
Phosphoinositide 3 Kinase

In the present study, we investigated the activity of the thiazide-sensitive NCC (Na+–Cl− co-transporter) in experimental metabolic syndrome and the role of insulin in NCC activation. Renal responses to the NCC inhibitor HCTZ (hydrochlorothiazide), as a measure of NCC activity in vivo, were studied in 12-week-old ZO (Zucker obese) rats, a model of the metabolic syndrome, and in ZL (Zucker lean) control animals, together with renal NCC expression and molecular markers of NCC activity, such as localization and phosphorylation. Effects of insulin were studied further in mammalian cell lines with inducible and endogenous expression of this molecule. ZO rats displayed marked hyperinsulinaemia, but no differences in plasma aldosterone, compared with ZL rats. In ZO rats, natriuretic and diuretic responses to NCC inhibition with HCTZ were enhanced compared with ZL rats, and were associated with a decrease in BP (blood pressure). ZO rats displayed enhanced Thr53 NCC phosphorylation and predominant membrane localization of both total and phosphorylated NCC, together with a different profile in expression of SPAK (Ste20-related proline/alanine-rich kinase) isoforms, and lower expression of WNK4. In vitro, insulin induced NCC phosphorylation, which was blocked by a PI3K (phosphoinositide 3-kinase) inhibitor. Insulin-induced reduction in WNK4 expression was also observed, but delayed compared with the time course of NCC phosphorylation. In summary, we report increased NCC activity in hyperinsulinaemic rodents in conjunction with the SPAK expression profile consistent with NCC activation and reduced WNK4, as well as an ability of insulin to induce NCC stimulatory phosphorylation in vitro. Together, these findings indicate that hyperinsulinaemia is an important driving force of NCC activity in the metabolic syndrome with possible consequences for BP regulation.

scholarly journals ADAM19: A Novel Target for Metabolic Syndrome in Humans and Mice

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Lakshini Weerasekera ◽  
Caroline Rudnicka ◽  
Qing-Xiang Sang ◽  
Joanne E. Curran ◽  
Matthew P. Johnson ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Adipose Tissue ◽  
Mouse Model ◽  
White Adipose Tissue ◽  
Mononuclear Cells ◽  
Western World ◽  
Diet Induced Obesity ◽  
The Metabolic Syndrome

Obesity is one of the most prevalent metabolic diseases in the Western world and correlates directly with insulin resistance, which may ultimately culminate in type 2 diabetes (T2D). We sought to ascertain whether the human metalloproteinase A Disintegrin and Metalloproteinase 19 (ADAM19) correlates with parameters of the metabolic syndrome in humans and mice. To determine the potential novel role of ADAM19 in the metabolic syndrome, we first conducted microarray studies on peripheral blood mononuclear cells from a well-characterised human cohort. Secondly, we examined the expression of ADAM19 in liver and gonadal white adipose tissue using an in vivo diet induced obesity mouse model. Finally, we investigated the effect of neutralising ADAM19 on diet induced weight gain, insulin resistance in vivo, and liver TNF-α levels. Significantly, we show that, in humans, ADAM19 strongly correlates with parameters of the metabolic syndrome, particularly BMI, relative fat, HOMA-IR, and triglycerides. Furthermore, we identified that ADAM19 expression was markedly increased in the liver and gonadal white adipose tissue of obese and T2D mice. Excitingly, we demonstrate in our diet induced obesity mouse model that neutralising ADAM19 therapy results in weight loss, improves insulin sensitivity, and reduces liver TNF-α levels. Our novel data suggest that ADAM19 is pro-obesogenic and enhances insulin resistance. Therefore, neutralisation of ADAM19 may be a potential therapeutic approach to treat obesity and T2D.

scholarly journals C-Type Natriuretic Peptide Plays an Anti-Inflammatory Role in Rat Epididymitis Induced by UPEC

2021 ◽  
Vol 11 ◽  
Author(s):  
Chunlei Mei ◽  
Yafei Kang ◽  
Chenlu Zhang ◽  
Chunyu He ◽  
Aihua Liao ◽  
...  
Keyword(s):  
Natriuretic Peptide ◽  
Signal Pathway ◽  
Expression Level ◽  
Inflammatory Factors ◽  
Signal Pathways ◽  
Inflammatory Damage ◽  
Cgmp Analog ◽  
Acute Epididymitis

Human epididymitis is mainly caused by retrograde urinary tract infection with uropathogenic Escherichia coli (UPEC). This disease is an important factor (accounting for 20–30%) causing male infertility. C-type natriuretic peptide (CNP), a protein composed of 22 amino acids, is proved to play an immunoregulatory role in respiratory and cardiovascular systems. CNP is expressed extremely high in the epididymis, but whether CNP plays the same role in acute epididymitis is unclear. At first, we established an acute caput epididymitis model in rats with UPEC and treated them with CNP to measure inflammatory damage. Then RNA-seq transcriptome technology was used to reveal potential signal pathways. Secondly, the turbidity and activity of UPEC were assessed using a microplate reader and the amount of UPEC by agar plates after incubation with CNP. Thirdly, macrophages in caput epididymis were tested by immunohistochemistry (IHC). Meanwhile, lipopolysaccharide (LPS) with or without CNP was used to stimulate the macrophage (RAW264.7) in vitro and to detect the expression level of pro-inflammatory factors. Finally, the macrophage (RAW264.7) was treated with CNP, 8-Br-cGMP [cyclic guanosinc monophosphate (cGMP) analog] and KT5823 [protein kinase G (PKG) inhibitor], and the expression level of nuclear factor-k-gene binding (NF-kB) signal pathway was examined. The results showed that the damage of epididymis induced by UPEC as well as the pro-inflammatory factors could be alleviated significantly with CNP treatment. CNP could inhibit the activity and numbers of bacteria in both in vivo and in vitro experiments. Moreover, CNP repressed the invasion, and the expression of pro-inflammatory factors (such as NF-kB, IL-1β, IL-6, TNF-α) in macrophages and its effect could be inhibited by KT5823. Therefore, we drew a conclusion from the above experiments that CNP alleviates the acute epididymitis injury induced by UPEC. On one hand, CNP could inhibit the growth of UPEC. On the other hand, CNP could decrease invasion and inflammatory reaction of macrophages; the mechanism was involved in inhibiting NF-kB signal pathway through the cGMP/PKG in macrophages. This research would open up the possibility of using CNP as a potential treatment for epididymitis.

Latest advances in hydrogel-based drug delivery systems for optimization of metabolic syndrome treatment

2021 ◽  
Vol 28 ◽  
Author(s):  
Diego Arauna ◽  
Sekar Vijayakumar ◽  
Esteban Durán-Lara
Keyword(s):  
Drug Delivery ◽  
Metabolic Syndrome ◽  
Controlled Release ◽  
Therapeutic Efficacy ◽  
Drug Delivery Systems ◽  
Epigallocatechin Gallate ◽  
Delivery Systems ◽  
The Metabolic Syndrome

Background: Drug delivery systems such as hydrogels have become relevant in cardiovascular and metabolic therapies due to their sustained and controlled release properties of drugs, versatile polymer structures, safety and biodegradability. Results: The literature presented demonstrates that a hydrogel-based controlled release system increases the therapeutic efficacy in different components of the metabolic syndrome. Hypertension has been the most explored component with advances in vitro and murine models. However, clinical evidence in humans is scarce, and more translational studies are needed. Hydrogel-based systems for diabetes, obesity, and dyslipidemia have been little explored. Observations mainly demonstrated an increase in therapeutic efficacy, in vitro and in vivo, for the use of insulin, leptin, and natural components, such as epigallocatechin gallate. In all cases, the hydrogel systems achieve better plasma levels of the loaded compound, higher bioavailability, and low cytotoxicity; compared to conventional systems. Also, the evidence existing suggests that the development of an injectable hydrogel system for controlled release of drugs or therapeutic compounds is presented as an attractive option for MeS treatment, due to the possibility of sustained pharmacological release, no need for repeated doses, and a safe administration route. Conclusion: The following review aims to evaluate the use of the hydrogel systems in the therapy of diabetes, obesity, hypertension, and dyslipidemia, which are the main components of metabolic syndrome.

The impact of EPA and DHA on ceramide lipotoxicity in the metabolic syndrome

2020 ◽  
pp. 1-13
Author(s):  
Chelsey Walchuk ◽  
Yidi Wang ◽  
Miyoung Suh
Keyword(s):  
Metabolic Syndrome ◽  
High Fat Diet ◽  
Animal Studies ◽  
Sphingolipid Metabolism ◽  
Current Evidence ◽  
The Metabolic Syndrome ◽  
Epa And Dha ◽  
The Impact

Abstract The metabolic syndrome (MetS) is a cluster of cardiovascular risk factors including obesity, insulin resistance (IR) and dyslipidaemia. Consumption of a high-fat diet (HFD) enriched in SFA leads to the accumulation of ceramide (Cer), the central molecule in sphingolipid metabolism. Elevations in plasma and tissue Cer are found in obese individuals, and there is evidence to suggest that Cer lipotoxicity contributes to the MetS. EPA and DHA have shown to improve MetS parameters including IR, inflammation and hypertriacylglycerolaemia; however, whether these improvements are related to Cer is currently unknown. This review examines the potential of EPA and DHA to improve Cer lipotoxicity and MetS parameters including IR, inflammation and dyslipidaemia in vitro and in vivo. Current evidence from cell culture and animal studies indicates that EPA and DHA attenuate palmitate- or HFD-induced Cer lipotoxicity and IR, whereas evidence in humans is greatly lacking. Overall, there is intriguing potential for EPA and DHA to improve Cer lipotoxicity and related MetS parameters, but more research is warranted.

scholarly journals Flavonoids and Insulin-Resistance: From Molecular Evidences to Clinical Trials

2019 ◽  
Vol 20 (9) ◽  
pp. 2061 ◽  
Author(s):  
Benedetta Russo ◽  
Fabiana Picconi ◽  
Ilaria Malandrucco ◽  
Simona Frontoni
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Clinical Trials ◽  
Insulin Sensitivity ◽  
Insulin Signaling ◽  
Molecular Mechanisms ◽  
Food Sources ◽  
Main Factors

Insulin-resistance is one of the main factors responsible for the onset and progression of Metabolic Syndrome (MetS). Among all polyphenols, the effects of flavonoids and their main food sources on insulin sensitivity have been widely evaluated in molecular and clinical studies. The aim of this review is to analyse the data observed in vitro, in vivo and in clinical trials concerning the effects of flavonoids on insulin resistance and to determine the molecular mechanisms with which flavonoids interact with insulin signaling.

Mouse models of PPAR-γ deficiency: dissecting PPAR-γ's role in metabolic homoeostasis

2005 ◽  
Vol 33 (5) ◽  
pp. 1053-1058 ◽  
Author(s):  
S.L. Gray ◽  
E. Dalla Nora ◽  
A.J. Vidal-Puig
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Adipose Tissue ◽  
Mouse Models ◽  
Murine Models ◽  
Metabolic Processes ◽  
Glucose Homoeostasis ◽  
Ppar Γ ◽  
The Metabolic Syndrome

The identification of humans with mutations in PPAR-γ (peroxisome-proliferator-activated receptor-γ) has underlined its importance in the pathogenesis of the metabolic syndrome. Genetically modified mice provide powerful tools to dissect the mechanisms by which PPAR-γ regulates metabolic processes. Ablation of PPAR-γ in vivo is lethal and thus dissection of PPAR-γ function using mouse models has relied on the development of tissue and isoform-specific ablation and mouse models of human mutations. These models exhibit phenotypes of partial PPAR-γ impairment and are useful to elucidate how PPAR-γ regulates specific metabolic processes. These murine models have confirmed the involvement of PPAR-γ in adipose tissue development, maintenance and distribution. The mechanism involved in PPAR-γ regulation of glucose homoeostasis is obscure as both agonism and partial impairment of PPAR-γ increase insulin sensitivity. While adipose tissue is likely to be the primary target for the insulin-sensitizing effects of PPAR-γ, some murine models suggest PPAR-γ expressed outside adipose tissue may also contribute actively to maintain glucose homoeostasis. Interestingly, mutations in PPAR-γ that cause severe insulin resistance in humans when expressed in mice do not result in insulin insensitivity. However, these murine models can recapitulate the effects in fuel partitioning, post-prandial lipid handling and vasculature dysfunction observed in humans. In summary, these murine models of PPAR-γ have provided useful in vivo systems to dissect the function of PPAR-γ, but additionally have revealed a picture of complexity. These models have confirmed a key role for PPAR-γ in the metabolic syndrome; however, they challenge the concept that insulin resistance is the main factor linking the clinical manifestations of the metabolic syndrome.

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