RÉSUMÉ
Glucagon-like peptide 1 (GLP1), which is mainly processed and cleaved from proglucagon in enteroendocrine cells (EECs) of the intestinal tract, acts on the GLP1 receptor in pancreatic cells to stimulate insulin secretion and to inhibit glucagon secretion. However, GLP1 processing is not fully understood. Here, we show that reticulon 4B (Nogo-B), an endoplasmic reticulum (ER)-resident protein, interacts with the major proglucagon fragment of proglucagon to retain proglucagon on the ER, thereby inhibiting PCSK1-mediated cleavage of proglucagon in the Golgi. Intestinal Nogo-B knockout in male type 2 diabetes mellitus (T2DM) mice increases GLP1 and insulin levels and decreases glucagon levels, thereby alleviating pancreatic injury and insulin resistance. Finally, we identify aberrantly elevated Nogo-B expression and inhibited proglucagon cleavage in EECs from diabetic patients. Our study reveals the subcellular regulatory processes involving Nogo-B during GLP1 production and suggests intestinal Nogo-B as a potential therapeutic target for T2DM.
Sujet(s)
Diabète de type 2 , Réticulum endoplasmique , Glucagon-like peptide 1 , Protéines Nogo , Proglucagon , Proprotein convertase 1 , Animaux , Humains , Mâle , Souris , Diabète de type 2/métabolisme , Diabète de type 2/génétique , Réticulum endoplasmique/métabolisme , Cellules entéroendocrines/métabolisme , Glucagon-like peptide 1/métabolisme , Appareil de Golgi/métabolisme , Cellules HEK293 , Insuline/métabolisme , Insulinorésistance , Intestins/anatomopathologie , Souris de lignée C57BL , Souris knockout , Protéines Nogo/métabolisme , Protéines Nogo/génétique , Proglucagon/métabolisme , Proglucagon/génétique , Proprotein convertase 1/métabolisme , Proprotein convertase 1/génétique , Liaison aux protéines , ProtéolyseRÉSUMÉ
Thrombo-inflammation is closely associated with a few severe cardiovascular and infectious diseases. Factor XIIa (FXIIa) in the intrinsic coagulation pathway plays a pivotal role in the development of thrombo-inflammation and its inhibition has emerged as a potential therapeutic approach for thrombo-inflammatory disorders. Nonetheless, as of now, few small-molecule FXIIa inhibitors have demonstrated notable effectiveness against thrombo-inflammation, with none progressing into clinical stages. Herein, we present potent, covalent, reversible, and selective small-molecule FXIIa inhibitors such as 4a and 4j obtained through structure-based drug design. Compounds 4a and 4j showed significant anticoagulation and substantial anti-inflammatory effects in vitro, coupled with exceptional plasma stability. Furthermore, in carrageenan-induced thrombosis models, 4a and 4j demonstrated remarkable dual antithrombotic and anti-inflammatory activity when administered orally. Compound 4j exhibited a favorable safety profile without obvious tissue toxicity in mice, suggesting its potential as an oral therapeutic option for thrombo-inflammation.
Sujet(s)
Facteur XIIa , Thrombose , Animaux , Thrombose/traitement médicamenteux , Souris , Humains , Facteur XIIa/antagonistes et inhibiteurs , Facteur XIIa/métabolisme , Administration par voie orale , Anti-inflammatoires/pharmacologie , Anti-inflammatoires/usage thérapeutique , Anti-inflammatoires/composition chimique , Anti-inflammatoires/pharmacocinétique , Relation structure-activité , Carragénane , Découverte de médicament , Inflammation/traitement médicamenteux , Mâle , Anticoagulants/pharmacologie , Anticoagulants/usage thérapeutique , Anticoagulants/composition chimique , Fibrinolytiques/pharmacologie , Fibrinolytiques/usage thérapeutique , Fibrinolytiques/composition chimique , BiodisponibilitéRÉSUMÉ
Type 2 diabetes (T2D) is a chronic, burdensome disease that is characterized by disordered insulin sensitivity and disturbed glucose/lipid homeostasis. Berberine (BBR) has multiple therapeutic actions on T2D, including regulation of glucose and lipid metabolism, improvement of insulin sensitivity and energy expenditure. Recently, the function of BBR on fibroblast growth factor 21 (FGF21) has been identified. However, if BBR ameliorates T2D through FGF21, the underlying mechanisms remain unknown. Herein, we used T2D wild type (WT) and FGF21 global knockout (FKO) mice [mouse T2D model: established by high-fat diet (HFD) feeding plus streptozotocin (STZ) injection], and hepatocyte-specific peroxisome proliferator activated receptor γ (PPARγ) deficient (PPARγHepKO) mice, and cultured human liver carcinoma cells line, HepG2 cells, to characterize the role of BBR in glucose/lipid metabolism and insulin sensitivity. We found that BBR activated FGF21 expression by up-regulating PPARγ expression at the cellular level. Meanwhile, BBR ameliorated glucosamine hydrochloride (Glcn)-induced insulin resistance and increased glucose transporter 2 (GLUT2) expression in a PPARγ/FGF21-dependent manner. In T2D mice, BBR up-regulated the expression of PPARγ, FGF21 and GLUT2 in the liver, and GLUT2 in the pancreas. BBR also reversed T2D-induced insulin resistance, liver lipid accumulation, and damage in liver and pancreas. However, FGF21 deficiency diminished these effects of BBR on diabetic mice. Altogether, our study demonstrates that the therapeutic effects of BBR on T2D were partly accomplished by activating PPARγ-FGF21-GLUT2 signaling pathway. The discovery of this new pathway provides a deeper understanding of the mechanism of BBR for T2D treatment.
Sujet(s)
Berbérine , Diabète expérimental , Diabète de type 2 , Insulinorésistance , Souris , Humains , Animaux , Insulinorésistance/physiologie , Glucose/métabolisme , Diabète de type 2/traitement médicamenteux , Diabète de type 2/génétique , Diabète de type 2/métabolisme , Récepteur PPAR gamma/génétique , Récepteur PPAR gamma/métabolisme , Berbérine/pharmacologie , Berbérine/usage thérapeutique , Diabète expérimental/traitement médicamenteux , Diabète expérimental/métabolisme , Foie/métabolisme , Homéostasie , LipidesRÉSUMÉ
Licorice is a traditional and versatile herbal medicine and food. Glabridin (Gla) is a kind of isoflavone extracted from the licorice root, which has anti-obesity, anti-atherosclerotic, and antioxidative effects. Alcoholic liver disease (ALD) is a widespread liver disease induced by chronic alcohol consumption. However, studies demonstrating the effect of Gla on ALD are rare. The research explored the positive effect of Gla in C57BL/6J mice fed by the Lieber-DeCarli ethanol mice diet and HepG2 cells treated with ethanol. Gla alleviated ethanol-induced liver injury, including reducing liver vacuolation and lipid accumulation. The serum levels of inflammatory cytokines were decreased in the Gla-treated mice. The reactive oxygen species and apoptosis levels were attenuated and antioxidant enzyme activity levels were restored in ethanol-induced mice by Gla treatment. In vitro, Gla reduced ethanol-induced cytotoxicity, nuclear factor kappa B (NF-κB) nuclear translocation, and enhanced nuclear factor (erythroid-derived 2)-like 2 (Nrf2) nuclear translocation. Anisomycin (an agonist of p38 MAPK) eliminated the positive role of Gla on ethanol-caused oxidative stress and inflammation. On the whole, Gla can alleviate alcoholic liver damage via the p38 MAPK/Nrf2/NF-κB pathway and may be used as a novel health product or drug to potentially alleviate ALD.
Sujet(s)
Inflammation , Maladies alcooliques du foie , Stress oxydatif , Transduction du signal , Animaux , Femelle , Humains , Souris , Apoptose/effets des médicaments et des substances chimiques , Lignée cellulaire tumorale , Éthanol/toxicité , Inflammation/traitement médicamenteux , Maladies alcooliques du foie/métabolisme , Souris de lignée C57BL , Facteur de transcription NF-kappa B/métabolisme , Stress oxydatif/effets des médicaments et des substances chimiques , p38 Mitogen-Activated Protein Kinases/métabolisme , Transduction du signal/effets des médicaments et des substances chimiquesRÉSUMÉ
Parkinson's disease (PD) is a progressive neurodegenerative disorder with a complex etiology. Neuroinflammation and oxidative stress are important factors driving the progression of PD. It has been reported that 1,3,4-oxadiazole and flavone derivatives have numerous biological functions, especially in the aspect of anti-inflammatory and antioxidant. Based on the strategy of pharmacodynamic combination, we introduced 1,3,4-oxadiazole moiety into the flavonoid backbone, designed and synthesized a series of novel flavonoid 1,3,4-oxadiazole derivatives. Further, we evaluated their toxicity, anti-inflammatory and antioxidant activities using BV2 microglia. Following a comprehensive analysis, compound F12 showed the best pharmacological activity. In vivo, we induced the classical PD animal model by intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into C57/BL6J mice. Our results showed that compound F12 ameliorated MPTP-induced dysfunction in mice. Further, compound F12 reduced oxidative stress by promoting the nucleation of nuclear factor erythroid 2-related factor 2 (Nrf2) and decreased the inflammatory response by inhibiting the nuclear translocation of nuclear factor-κB (NF-κB) in vivo and in vitro. Meanwhile, compound F12 inhibited the mitochondrial apoptotic pathway to rescue microglia inflammation-mediated loss of dopaminergic neurons. In conclusion, compound F12 reduced oxidative stress and inflammation and could be as a potential agent for PD treatment.
Sujet(s)
Neuroprotecteurs , Maladie de Parkinson , Souris , Animaux , Maladie de Parkinson/traitement médicamenteux , Maladie de Parkinson/métabolisme , Facteur de transcription NF-kappa B/métabolisme , Facteur-2 apparenté à NF-E2/métabolisme , Antioxydants/pharmacologie , Flavonoïdes/pharmacologie , Flavonoïdes/usage thérapeutique , 1-Méthyl-4-phényl-1,2,3,6-tétrahydropyridine/pharmacologie , Neuroprotecteurs/pharmacologie , Neuroprotecteurs/usage thérapeutique , Transduction du signal , Inflammation/traitement médicamenteux , Anti-inflammatoires/pharmacologie , Modèles animaux de maladie humaine , Souris de lignée C57BLRÉSUMÉ
Heart failure is the leading cause of death worldwide. Compound Danshen Dripping Pill (CDDP) or CDDP combined with simvastatin has been widely used to treat patients with myocardial infarction and other cardiovascular diseases in China. However, the effect of CDDP on hypercholesterolemia/atherosclerosis-induced heart failure is unknown. We constructed a new model of heart failure induced by hypercholesterolemia/atherosclerosis in apolipoprotein E (ApoE) and LDL receptor (LDLR) dual deficient (ApoE-/-LDLR-/-) mice and investigated the effect of CDDP or CDDP plus a low dose of simvastatin on the heart failure. CDDP or CDDP plus a low dose of simvastatin inhibited heart injury by multiple actions including anti-myocardial dysfunction and anti-fibrosis. Mechanistically, both Wnt and lysine-specific demethylase 4A (KDM4A) pathways were significantly activated in mice with heart injury. Conversely, CDDP or CDDP plus a low dose of simvastatin inhibited Wnt pathway by markedly up-regulating expression of Wnt inhibitors. While the anti-inflammation and anti-oxidative stress by CDDP were achieved by inhibiting KDM4A expression and activity. In addition, CDDP attenuated simvastatin-induced myolysis in skeletal muscle. Taken together, our study suggests that CDDP or CDDP plus a low dose of simvastatin can be an effective therapy to reduce hypercholesterolemia/atherosclerosis-induced heart failure.
RÉSUMÉ
Sensitization of central pain and inflammatory pathways play essential roles in migraine, a primary neurobiological headache disorder. Since hypoxia-inducible factor-1α (HIF-1α) is implicated in neuroprotection and inflammation inhibition, herein we investigated the role of HIF-1α in migraine. A chronic migraine model was established in mice by repeated injection of nitroglycerin (10 mg/kg, i.p.) every other day for 5 total injections. In the prevention and acute experiments, roxadustat, a HIF-1α stabilizer, was orally administered starting before or after nitroglycerin injection, respectively. Pressure application measurement, and tail flick and light-aversive behaviour tests were performed to determine the pressure pain threshold, thermal nociceptive sensitivity and migraine-related light sensitivity. At the end of experiments, mouse serum samples and brain tissues were collected for analyses. We showed that roxadustat administration significantly attenuated nitroglycerin-induced basal hypersensitivity and acute hyperalgesia by improving central sensitization. Roxadustat administration also decreased inflammatory cytokine levels in serum and trigeminal nucleus caudalis (TNC) through NF-κB pathway. Consistent with the in vivo results showing that roxadustat inhibited microglia activation, roxadustat (2, 10, and 20 µM) dose-dependently reduced ROS generation and inflammation in LPS-stimulated BV-2 cells, a mouse microglia cell line, by inhibiting HIF-1α/NF-κB pathway. Taken together, this study demonstrates that roxadustat administration ameliorates migraine-like behaviours and inhibits central pain sensitization in nitroglycerin-injected mice, which is mainly mediated by HIF-1α/NF-κB/inflammation pathway, suggesting the potential of HIF-1α activators as therapeutics for migraine.
Sujet(s)
Migraines , Facteur de transcription NF-kappa B , Souris , Animaux , Facteur de transcription NF-kappa B/métabolisme , Nitroglycérine/effets indésirables , Sous-unité alpha du facteur-1 induit par l'hypoxie , Seuil nociceptif , Migraines/induit chimiquement , Migraines/traitement médicamenteux , Migraines/métabolisme , Inflammation/induit chimiquement , Inflammation/traitement médicamenteuxRÉSUMÉ
The pharmaceutical application of fungal polysaccharides has been extensively studied based on their multiple biological activities. However, the effect of Morchella esculenta polysaccharides on the development of atherosclerosis remains unknown. This study aims to investigate the anti-atherosclerotic effect of a novel polysaccharide (MCP) extracted from Morchella esculenta. The average molecular weight of MCP is 1.69 × 105 Da, and it is composed of glucose, mannose and galactose in the molar ratio of 1 : 1.9 : 0.51. LDLR-deficient (LDLR-/-) mice were fed high-fat diet (HFD) and administered intragastrically (i.g.) with saline or MCP dissolved in saline for 15 weeks. We found that MCP inhibited en face and sinus lesions. Moreover, serum levels of total and low-density lipoprotein cholesterol and triglyceride were decreased by MCP. The HFD-induced hepatic lipid accumulation was also attenuated by MCP. The underlying molecular mechanisms of anti-atherogenic and lipogenic effects of MCP might be attributed to reduced cholesterol synthesis by activating AMPKα signaling pathway and inhibiting SREBP2 expression. In addition, MCP-decreased serum triglyceride level is related to inhibiting LXRα expression. Taken together, these results indicate that MCP markedly alleviates atherosclerosis and M. esculenta can be used as a functional food additive to benefit patients with atherosclerosis.
Sujet(s)
Ascomycota/composition chimique , Athérosclérose/traitement médicamenteux , Polysaccharides fongiques/pharmacologie , AMP-Activated Protein Kinases/métabolisme , Animaux , Aorte/effets des médicaments et des substances chimiques , Athérosclérose/métabolisme , Cholestérol LDL/sang , Alimentation riche en graisse , Femelle , Additifs alimentaires , Polysaccharides fongiques/composition chimique , Foie/métabolisme , Souris , Souris de lignée C57BL , Souris knockout , Plaque d'athérosclérose/traitement médicamenteux , Plaque d'athérosclérose/métabolisme , Transduction du signal/effets des médicaments et des substances chimiques , Protéine-2 de liaison à l'élément de régulation des stérols/métabolisme , Triglycéride/sangRÉSUMÉ
Cholestasis can induce liver fibrosis and cirrhosis. Apigenin has anti-oxidant and anti-inflammatory effects. Herein, we determined whether apigenin can protect mice against cholestasis. In vitro, apigenin protected TFK-1 cells (a human bile duct cancer cell line) against H2O2-induced ROS generation and inhibited transforming growth factor-ß-activated collagen type 1 alpha 1 and α-smooth muscle actin in LX2 cells (a human hepatic stellate cell line). In vivo, cholestatic mice induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) were treated with apigenin. Apigenin potently blocked DDC-induced gallbladder atrophy and associated liver injury, fibrosis and collagen accumulation. Moreover, apigenin relieved the DDC-caused abnormality of bile acid metabolism and restored the balance between bile secretion and excretion by regulating the farnesoid X receptor signaling pathway. Furthermore, apigenin reduced inflammation or oxidative stress in the liver by blocking the DDC-activated Toll-like receptor 4, nuclear factor κB and tumor necrosis factor α, or DDC-suppressed superoxidase dismutase 1/2, catalase and glutathione peroxidase. Taken together, apigenin improves DDC-induced cholestasis by reducing inflammation and oxidative damage and improving bile acid metabolism, indicating its potential application for cholestasis treatment.
Sujet(s)
Apigénine/pharmacologie , Cholestase , Agents protecteurs/pharmacologie , Pyridines/effets indésirables , Animaux , Acides et sels biliaires/métabolisme , Lignée cellulaire tumorale , Cholestase/induit chimiquement , Cholestase/métabolisme , Humains , Foie/effets des médicaments et des substances chimiques , Cirrhose du foie/métabolisme , Mâle , Souris , Souris de lignée C57BL , Stress oxydatif/effets des médicaments et des substances chimiques , Transduction du signal/effets des médicaments et des substances chimiquesRÉSUMÉ
Salvia miltiorrhiza, a traditional Chinese medicine, also named Danshen in China, is widely used for the treatment of cardiovascular disease. It demonstrates multiple biological functions, such as anti-oxidative stress, anti-inflammation and anti-thrombosis. Diabetic angiopathy is one of the diabetic complications with macro- and microangiopathy. Macroangiopathy mainly occurs in arteries, while the microangiopathy mainly includes diabetic retinopathy and nephropathy. Many factors associated with diabetes, such as metabolic abnormalities and oxidative stress, can induce vascular lesions. These factors promote the accumulation of lipids as well as inflammatory cytokines, increase the production of extracellular cell-matrix, and impair endothelium functions, thereby leading to vascular dysfunction. This review attempts to summarize the progress of the studies of Salvia miltiorrhiza on diabetic angiopathy, including improving endothelial function, anti- oxidative stress, reducing the risk of vascular blockage, inhibiting inflammation as well as regulating lipid metabolism. We also summarize the pharmacological activity of bioactive components in Salvia miltiorrhiza and the delivery systems. We made the conclusion that Salvia miltiorrhiza can be used as a potential auxiliary drug for the treatment of diabetic angiopathy.
Sujet(s)
Maladies cardiovasculaires , Diabète , Angiopathies diabétiques , Salvia miltiorrhiza , Maladies cardiovasculaires/métabolisme , Diabète/traitement médicamenteux , Stress oxydatifRÉSUMÉ
Alzheimer's disease (AD) is the most common neurodegenerative disease in aging population. Neuroinflammation, hyperphosphorylated Tau (p-Tau) and the imbalance between production and clearance of ß-amyloid peptide (Aß) are the major causes for AD development. NaoXinTong Capsule (NXT), a traditional Chinese medicine, is wildly used for treatment of cardiovascular and cerebrovascular diseases. Hence, we used the double transgenic mice expressing chimeric human amyloid precursor protein and mutant human presenilin 1 (APP/PS1) and HT-22 cells to determine the neuroprotective effects of NXT in AD development and the involved mechanisms. The 3-month-old APP/PS1 mice were randomly divided into 3 groups and received following treatment: Control group, mice were fed normal chow; NXT groups, mice were fed normal chow containing NXT at a normal and a high dose, respectively. While the age-matched C57BL/6J mice fed normal chow were used as the normal control. The NXT treatment was lasted for 5 months. We found that NXT treatment improved spatial memory impairment and cognitive decline in APP/PS1 mice by decreasing p-Tau levels and Aß accumulation in the brain. Mechanistically, we observed that NXT inhibited neuron atrophy and apoptosis by downregulating inflammatory cytokines, interleukin 1ß (IL-1ß), IL-6 and tumor necrosis factor α (TNF-α), and inflammation mediators, nuclear factor κB (NF-κB) and toll-like receptor 4 (TLR4) in the brain. Consistently, NXT blocked l-glutamic acid-induced reactive oxygen species production, inflammation and apoptosis in HT-22 cells partially by inhibiting TLR4/NF-κB/IL-1ß signaling pathway. Our study demonstrates that NXT ameliorates AD by reducing p-Tau, Aß accumulation, inflammation and neuron apoptosis via regulation of TLR4-mediated inflammatory system. It also suggests the potential application of NXT for AD treatment.
Sujet(s)
Anti-inflammatoires/pharmacologie , Comportement animal/effets des médicaments et des substances chimiques , Encéphale/effets des médicaments et des substances chimiques , Cytokines/métabolisme , Médicaments issus de plantes chinoises/pharmacologie , Médiateurs de l'inflammation/métabolisme , Troubles de la mémoire/prévention et contrôle , Mémoire/effets des médicaments et des substances chimiques , Nootropiques/pharmacologie , Peptides bêta-amyloïdes/métabolisme , Animaux , Apoptose/effets des médicaments et des substances chimiques , Encéphale/métabolisme , Encéphale/anatomopathologie , Capsules , Lignée cellulaire , Cognition/effets des médicaments et des substances chimiques , Modèles animaux de maladie humaine , Mâle , Troubles de la mémoire/métabolisme , Troubles de la mémoire/anatomopathologie , Troubles de la mémoire/psychologie , Souris de lignée C57BL , Souris transgéniques , Phosphorylation , Plaque amyloïde , Espèces réactives de l'oxygène/métabolisme , Transduction du signal , Protéines tau/métabolismeRÉSUMÉ
Alzheimer's disease (AD) is the most common form of dementia in the elderly. It may be caused by oxidative stress, inflammation, and cerebrovascular dysfunctions in the brain. LongShengZhi Capsule (LSZ), a traditional Chinese medicine, has been approved by the China Food and Drug Administration for treatment of patients with cardiovascular/cerebrovascular disease. LSZ contains several neuroprotective ingredients, including Hirudo, Astmgali Radix, Carthami Flos (Honghua), Persicae Semen (Taoren), Acori Tatarinowii Rhizoma (Shichangpu), and Acanthopanax Senticosus (Ciwujia). In this study, we aimed to determine the effect of LSZ on the AD process. Double transgenic mice expressing the amyloid-ß precursor protein and mutant human presenilin 1 (APP/PS1) to model AD were treated with LSZ for 7 months starting at 2 months of age. LSZ significantly improved the cognition of the mice without adverse effects, indicating its high degree of safety and efficacy after a long-term treatment. LSZ reduced AD biomarker Aß plaque accumulation by inhibiting ß-secretase and γ-secretase gene expression. LSZ also reduced p-Tau expression, cell death, and inflammation in the brain. Consistently, in vitro, LSZ ethanol extract enhanced neuronal viability by reducing L-glutamic acid-induced oxidative stress and inflammation in HT-22 cells. LSZ exerted antioxidative effects by enhancing superoxide dismutase and glutathione peroxidase expression, reduced Aß accumulation by inhibiting ß-secretase and γ-secretase mRNA expression, and decreased p-Tau level by inhibiting NF-κB-mediated inflammation. It also demonstrated neuroprotective effects by regulating the Fas cell surface death receptor/B-cell lymphoma 2/p53 pathway. Taken together, our study demonstrates the antioxidative stress, anti-inflammatory, and neuroprotective effects of LSZ in the AD-like pathological process and suggests it could be a potential medicine for AD treatment.
RÉSUMÉ
Natural trans-1,4-polyisoprene (TPI) as a functional biomaterial has aroused great interest for rubber industrial product use. Here, we proposed a method that enables simultaneous analysis of the content and molecular-weight distribution (MWD) of natural TPI by gel permeation chromatography (GPC). The natural TPIs were collected from leaves, fruit coatings and bark of Eucommia ulmoides Oliver (E. ulmoides) through toluene extraction followed by ethanol purification. The results of TPI contents from leaves and fruit coatings were shown ca. 3.5% and 13.8%, respectively. Accordingly, limits of detection (LODs) of TPI were 0.58mg/mL from leaves and 0.47mg/mL from fruit coatings. The MWDs of TPI demonstrated a bimodal distribution from leaves, a unimodal distribution from bark, and a unimodal distribution with a tiny peak shoulder from fruit coatings. In real-life E. ulmoides analysis, the results from three independent methods (GPC, gravimetric method, and infrared spectroscopy) were obtained with good consistency.