scholarly journals Buyang Huanwu Decoction Enhances Revascularization via Akt/GSK3β/NRF2 Pathway in Diabetic Hindlimb Ischemia

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Xiao-Yi Bao ◽  
Li-Hui Deng ◽  
Zi-Jun Huang ◽  
Abdirizak S. Daror ◽  
Zi-Hao Wang ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Femoral Artery ◽  
Lower Extremities ◽  
Adenovirus Vector ◽  
Lower Limbs ◽  
Heme Oxygenase 1 ◽  
Hindlimb Ischemia ◽  
Buyang Huanwu Decoction ◽  
Nrf2 Pathway ◽  
Tnf Α

Background. Peripheral arterial disease (PAD) is a typical disease of atherosclerosis, most commonly influencing the lower extremities. In patients with PAD, revascularization remains a preferred treatment strategy. Buyang Huanwu decoction (BHD) is a popular Chinese herbal prescription which has showed effects of cardiovascular protection through conducting antioxidant, antiapoptotic, and anti-inflammatory effects. Here, we intend to study the effect of BHD on promoting revascularization via the Akt/GSK3β/NRF2 pathway in diabetic hindlimb ischemia (HLI) model of mice. Materials and Methods. All db/db mice ( n = 60 ) were randomly divided into 6 groups by table of random number. (1) Sham group ( N = 10 ): 7-0 suture thread passed through the underneath of the femoral artery and vein without occlusion. The remaining 5 groups were treated differently on the basis of the HLI (the femoral artery and vein from the inguinal ligament to the knee joint were transected and the vascular stump was ligated with 7-0 silk sutures) model: (2) HLI+NS group ( N = 15 ): 0.2 ml NS was gavaged daily for 3 days before modeling and 14 days after occlusion; (3) HLI+BHD group ( N = 15 ): 0.2 ml BHD (20 g/kg/day) was gavaged daily for 3 days before modeling and 14 days after occlusion; (4) HLI+BHD+sh-NC group ( N = 8 ): local injection of adenovirus vector carrying the nonsense shRNA (Ad-GFP) in the hindlimbs of mice before treatment; (5) HLI+BHD+sh-NRF2 group ( N = 8 ): knockdown of NRF2 in the hindlimbs of mice by local intramuscular injection of adenovirus vector carrying NRF2 shRNA (Ad-NRF2-shRNA) before treatment; and (6) HLI+BHD+LY294002 group ( N = 4 ): intravenous injection of LY294002 (1.5 mg/kg) once a day for 14 days on the basis of the HLI+BHD group. Laser Doppler examination, vascular cast, and immunofluorescence staining were applied to detect the revascularization of lower limbs in mice. Western blot analysis was used to detect the expression of vascular endothelial growth factor (VEGF), interleukin-1beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor- (TNF-) α, heme oxygenase-1 (HO-1), NAD(P)H dehydrogenase quinone-1 (NQO-1), catalase (CAT), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), phosphorylated protein kinase B (p-AKT), and phosphorylated glycogen synthase kinase-3 beta (p-GSK3β). HE staining was used to assess the level of muscle tissue damage and inflammation in the lower extremities. Local multipoint injection of Ad-NRF2-shRNA was used to knock down NRF2, and qPCR was applied to detect the mRNA level of NRF2. The blood glucose, triglyceride, cholesterol, MDA, and SOD levels of mice were tested using corresponding kits. The SPSS 20.0 software and GraphPad Prism 6.05 were used to do all statistics. Values of P < 0.05 were considered as statistically significant. Results and Conclusions. BHD could enhance the revascularization of lower limbs in HLI mice, while BHD has no effect on blood glucose and lipid level in db/db mice ( P > 0.05 ). BHD could elevate the protein expression of VEGF, HO-1, NQO-1, and CAT ( P < 0.05 ) and decrease the expression of IL-1β, IL-6, and TNF-α ( P < 0.05 ) in HLI mice. Meanwhile, BHD could activate NRF2 and promote the phosphorylation of AKT/GSK3β during revascularization ( P < 0.05 ). In contrast, knockdown of NRF2 impaired the protective effects of BHD on HLI ( P < 0.05 ). LY294002 inhibited the upregulation of NRF2 activated by BHD through inhibiting the phosphorylation of the AKT/GSK3β pathway ( P < 0.05 ). The present study demonstrated that BHD could promote revascularization on db/db mice with HLI through targeting antioxidation, anti-inflammation, and angiogenesis via the AKT/GSK3β/NRF2 pathway.

Network Pharmacology Approach uncovering Pathways involved in targeting Hsp90 through Curcumin and Epigallocatechin to control Inflammation.

2019 ◽  
Vol 16 ◽  
Author(s):  
Umme Hani ◽  
Shivananda Kandagalla ◽  
B.S. Sharath ◽  
K Jyothsna. ◽  
H Manjunatha.
Keyword(s):  
Gene Ontology ◽  
Molecular Chaperones ◽  
Curcuma Longa ◽  
Interaction Network ◽  
Network Pharmacology ◽  
Heme Oxygenase 1 ◽  
Nrf2 Pathway ◽  
Functional Behavior ◽  
Inflammatory Proteins ◽  
Prime Target

: Hsp90 are molecular chaperones of chronic inflammatory proteins and have emerged as prime target for treatment of inflammation. Principal components from Curcuma longa and Camellia sinensis, Curcumin and EGC respectively possesses anti-inflammatory properties inhibiting cytokines responsible for inflammation. Both act on common pathways in upregulation of heme oxygenase 1 through Pkcδ-Nrf2 pathway and downregulation of Tlr4, which in turn suppress expression of Hsp90. Curcumin and EGC were also found to bind -N and -C terminal domain of Hsp90 respectively. Based on this, work was designed with network pharmacological approach. Hsp90 associated gene targets of Curcumin and EGC were collected from databases, and gene ontology studies were done. PPI were obtained from string database for specific genes involved in Pkcδ-Nrf2 and Tlr4 pathway. Protein interaction network was constructed by cytoscape, and networks of Hsp90, Curcumin and EGC were merged to get common genes involved in Pkcδ-Nrf2 and Tlr4 pathway. Cluego analysis was done for obtained common genes to identify functional behavior in human diseases. Main proteins involved were identified as key regulators in Pkcδ-Nrf2 and Tlr4 pathway for controlling expression of Hsp90 from Curcumin and EGC in inflammation. Docking was performed on main proteins, Hsp90, Pkcδ and Tlr4 with Curcumin and EGC, significant binding energy was obtained for docked complexes. Combinatorial effects of Curcumin and EGC were observed in Pkcδ-Nrf2 and Tlr4pathway. Present study is an attempt to unravel common pathways mediated in intervention of Curcumin and EGC for suppression of Hsp90 associated with inflammation.

scholarly journals Application value of combination therapy of periodontal curettage and root planing on moderate-to-severe chronic periodontitis in patients with type 2 diabetes

2021 ◽  
Vol 17 (1) ◽  
Author(s):  
Yonghuan Bian ◽  
Changhao Liu ◽  
Zhaojiang Fu
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Blood Glucose ◽  
Chronic Periodontitis ◽  
Root Planing ◽  
Tnf Α ◽  
Significant Difference ◽  
Hs Crp

Abstract Background Our study attempted to observe the value of periodontal curettage combined with root planing on moderate-to-severe chronic periodontitis in patients with type 2 diabetes. Methods There involved 72 patients with type 2 diabetes mellitus complicated with moderate-to-severe chronic periodontitis who were diagnosed and treated in our hospital from January 2019 to December 2019. The patients enrolled were randomly divided into four groups using a computer-generated table: root planing and periodontal curettage combined group (n = 18), root planning group (n = 18), periodontal curettage group (n = 18) and cleansing group (n = 18). Blood glucose, plaque index (PI), gingival index (GI), probing depth (PD), attachment loss (AL), serum levels of inflammatory factors (Tumor Necrosis Factor Alpha [TNF- α] and hypersensitive C-reactive protein [hs-CRP]) were observed before and after treatment. The collecting dates were analyzed by the chi-square χ 2 test, repeated measurement analysis of variance, or t-test according to different data types and research objectives. Results Before treatment, there was no significant difference in PI, GI, PD and AL among the four groups (P> 0.05), while after 3-month treatment, the levels of PI, GI, PD and AL in the combined group were lower than those in the root planing group, periodontal curettage group and cleansing group, with both root planing group and periodontal curettage group significantly lower than cleansing group (P< 0.05). The fasting blood glucose, 2-h postprandial blood glucose and glycosylated hemoglobin in the combined group, root planing group, periodontal curettage group and cleansing group were significantly lower than those before treatment (P < 0.05). Before treatment, there was no significant difference in TNF- α and hs-CRP among the four groups (P> 0.05), but the levels of TNF- α and hs-CRP in the four groups decreased significantly after 3-month treatment (P< 0.05). The levels of TNF- α and hs-CRP in the combined group were lower than those in the root planing group, periodontal curettage group and cleansing group, and those in the root planing group and periodontal curettage group were significantly lower than those in the cleansing group (P< 0.05). Conclusion The combination therapy of periodontal curettage and root planing exerted beneficial effects on moderate-to-severe chronic periodontitis in patients with type 2 diabetes mellitus, which holds the potential to maintain the level of blood glucose and improve the quality of life of the patients.

scholarly journals Do proinflammatory cytokines play a role in clozapine-associated glycometabolism disorders?

2021 ◽  
Author(s):  
Tongtong Zhao ◽  
Kai Zhang ◽  
Yelei Zhang ◽  
Yating Yang ◽  
Xiaoshuai Ning ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Side Effects ◽  
Proinflammatory Cytokines ◽  
Peripheral Blood ◽  
Animal Experiments ◽  
Pancreatic Tissue ◽  
Mouse Serum ◽  
Healthy Controls ◽  
Immunological Mechanisms ◽  
Tnf Α

Abstract Rationale and objective Clozapine (CLZ) is the most effective drug for treatment-resistant schizophrenia but is associated with many side effects, including glycometabolism disorders. Immunological mechanisms may be involved in the development of clozapine side effects. Research relating the immunomodulatory effects of clozapine and its early markers to clinically relevant adverse events is needed to reduce the harmful side effects of clozapine. This study aimed to investigate the role of proinflammatory cytokines in clozapine-associated glycometabolism disorders. Methods We measured the effect of a range of doses of clozapine on glycometabolism-related parameters and proinflammatory cytokines levels in mice peripheral blood. We also examined the differences between these indicators in the peripheral blood of clozapine-treated schizophrenia patients and healthy controls. Furthermore, we detected proinflammatory cytokines expression in mice pancreatic tissue. Results Following clozapine administration, glucagon significantly decreased in mouse serum, and proinflammatory cytokine IL-β levels markedly increased. Clozapine reliably increased proinflammatory cytokines (IL-1β, IL-6, and TNF-α) expression in murine pancreatic tissue. Compared with healthy controls, clozapine-treated patients’ BMI, blood glucose, and proinflammatory cytokines (IL-1β, IL-6, and TNF-α) increased significantly. In clozapine-treated patients, a higher clozapine daily dosage was associated with higher levels of the proinflammatory cytokines IL-1β and IL-6, and a significant positive correlation was observed between blood glucose levels and the proinflammatory cytokines IL-6 and TNF-α. Conclusion Findings from animal experiments and clinical trials have shown clear evidence that clozapine has a regulatory effect on immune-related proinflammatory cytokines and influences glycometabolism indicators.

scholarly journals Protease nexin-1 deficiency increases mouse hindlimb neovascularisation following ischemia and accelerates femoral artery perfusion

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sonia Selbonne ◽  
Celina Madjene ◽  
Benjamin Salmon ◽  
Yacine Boulaftali ◽  
Marie-Christine Bouton ◽  
...  
Keyword(s):  
Femoral Artery ◽  
Capillary Density ◽  
Leukocyte Recruitment ◽  
Lower Limbs ◽  
Artery Ligation ◽  
Angiogenic Balance ◽  
Important Player ◽  
Protease Nexin ◽  
Artery Perfusion

AbstractWe previously identified the inhibitory serpin protease nexin-1 (PN-1) as an important player of the angiogenic balance with anti-angiogenic activity in physiological conditions. In the present study, we aimed to determine the role of PN-1 on pathological angiogenesis and particularly in response to ischemia, in the mouse model induced by femoral artery ligation. In wild-type (WT) muscle, we observed an upregulation of PN-1 mRNA and protein after ischemia. Angiography analysis showed that femoral artery perfusion was more rapidly restored in PN-1−/− mice than in WT mice. Moreover, immunohistochemistry showed that capillary density increased following ischemia to a greater extent in PN-1−/− than in WT muscles. Moreover, leukocyte recruitment and IL-6 and MCP-1 levels were also increased in PN-1−/− mice compared to WT after ischemia. This increase was accompanied by a higher overexpression of the growth factor midkine, known to promote leukocyte trafficking and to modulate expression of proinflammatory cytokines. Our results thus suggest that the higher expression of midkine observed in PN-1- deficient mice can increase leukocyte recruitment in response to higher levels of MCP-1, finally driving neoangiogenesis. Thus, PN-1 can limit neovascularisation in pathological conditions, including post-ischemic reperfusion of the lower limbs.

scholarly journals (–)-Loliolide Isolated from Sargassum horneri Suppressed Oxidative Stress and Inflammation by Activating Nrf2/HO-1 Signaling in IFN-γ/TNF-α-Stimulated HaCaT Keratinocytes

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 856
Author(s):  
Eui-Jeong Han ◽  
Ilekuttige Priyan Shanura Fernando ◽  
Hyun-Soo Kim ◽  
Dae-Sung Lee ◽  
Areum Kim ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nuclear Factor Κb ◽  
Sargassum Horneri ◽  
Mitogen Activated Protein Kinase ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Nuclear Factor ◽  
Hacat Keratinocytes ◽  
Tnf Α ◽  
Ifn Γ

The present study evaluated the effects of (–)-loliolide isolated from Sargassum horneri (S. horneri) against oxidative stress and inflammation, and its biological mechanism in interferon (IFN)-γ/tumor necrosis factor (TNF)-α-stimulated HaCaT keratinocytes. The results showed that (–)-loliolide improved the cell viability by reducing the production of intracellular reactive oxygen species (ROS) in IFN-γ/TNF-α-stimulated HaCaT keratinocytes. In addition, (–)-loliolide effectively decreased the expression of inflammatory cytokines (interleukin (IL)-4 IL-6, IL-13, IFN-γ and TNF-α) and chemokines (CCL11 (Eotaxin), macrophage-derived chemokine (MDC), regulated on activation, normal T cell expressed and secreted (RANTES), and thymus and activation-regulated chemokine (TARC)), by downregulating the expression of epidermal-derived initial cytokines (IL-25, IL-33 and thymic stromal lymphopoietin (TSLP)). Furthermore, (–)-loliolide suppressed the activation of mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) signaling, whereas it activated nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling. Interestingly, the cytoprotective effects of (–)-loliolide against IFN-γ/TNF-α stimulation were significantly blocked upon inhibition of HO-1. Taken together, these results suggest that (–)-loliolide effectively suppressed the oxidative stress and inflammation by activating the Nrf2/HO-1 signaling in IFN-γ/TNF-α-stimulated HaCaT keratinocytes.

Abstract 15312: Genetic Deletion of Toll-like Receptor 9 Accelerates Blood Flow Recovery after Hindlimb Ischemia

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Sachiko Nishimoto ◽  
Daiju Fukuda ◽  
Yasutomi Higashikuni ◽  
Kimie Tanaka ◽  
Yoichiro Hirata ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Flow ◽  
Femoral Artery ◽  
Cpg Odn ◽  
Toll Like Receptor ◽  
Artery Ligation ◽  
Ischemic Limb ◽  
Tnf Α ◽  
Genetic Deletion ◽  
Inflammatory Molecules

Background: Peripheral artery disease causes significant functional disability and results in impaired quality of life. Toll-like receptor (TLR)-2, 3 and 4 are suggested to participate in blood flow recovery in ischemic limb by modulating inflammation and angiogenesis, however, the role of TLR9 remains unknown. TLR9 recognizes bacterial unmethylated DNA and plays a role in innate defense, although it can also provoke inflammation in response to fragmented DNA released from regenerated mammalian cells. This study tested the hypothesis that genetic deletion of TLR9 accelerates blood flow recovery after femoral artery ligation by inhibiting inflammation and improving endothelial cell function. Methods and Results: Unilateral femoral artery ligation was performed in TLR9-deficient (TLR9KO) mice and wild type (WT) mice. Femoral artery ligation significantly increased RNA expression of TLR9 (20-times) in WT mice and plasma levels of single-stranded DNA and double-stranded DNA, endogenous ligands for TLR9, in both strains of mice compared with each sham-operated group (P<0.05). Laser Doppler perfusion imaging demonstrated that TLR9KO mice significantly improved the ratio of the blood flow in the ischemic to non-ischemic limb compared with WT mice at 2 weeks after ligation (P<0.05). TLR9KO mice showed less accumulation of macrophages and less expression of inflammatory molecules (e.g., TNF-α, MCP-1 and IL-1β in ischemic muscle compared with WT mice (P<0.05, respectively). In vitro experiments using thioglycolate-stimulated peritoneal macrophages demonstrated that CpG ODN, agonistic oligonucleotide for TLR9, promoted the expression of pro-inflammatory molecules (e.g., MCP-1 and TNF-α) in WT macrophages (P<0.05, respectively) but not in TLR9 KO macrophages. Furthermore, activation of TLR9 by CpG ODN inhibited migration and proliferation of endothelial cells as determined by scratch-wound assay and MTS assay, respectively (P<0.05). Conclusion: Our results suggested that TLR9 enhances inflammation and affects migration and proliferation of endothelial cells, leading to impaired blood flow recovery in ischemic limb. TLR9 may serve as a potential therapeutic target for ischemic limb disease.

scholarly journals HO-1/CO Maintains Intestinal Barrier Integrity through NF-κB/MLCK Pathway in Intestinal HO-1-/- Mice

2021 ◽  
Vol 2021 ◽  
pp. 1-19
Author(s):  
Zhenling Zhang ◽  
Lijing Zhang ◽  
Qiuping Zhang ◽  
Bojia Liu ◽  
Fang Li ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Intestinal Barrier ◽  
Heme Oxygenase 1 ◽  
Zinc Protoporphyrin ◽  
Barrier Integrity ◽  
Tnf Α ◽  
Intestinal Barrier Integrity ◽  
Deficient Mice

Background. Intestinal barrier injury is an important contributor to many diseases. We previously found that heme oxygenase-1 (HO-1) and carbon monoxide (CO) protect the intestinal barrier. This study is aimed at elucidating the molecular mechanisms of HO-1/CO in barrier loss. Materials and Methods. We induced gut leakiness by injecting carbon tetrachloride (CCl4) to wildtype or intestinal HO-1-deficient mice. In addition, we administrated tumor necrosis factor-α (TNF-α) to cells with gain- or loss-of-HO-1 function. The effects of HO-1/CO maintaining intestinal barrier integrity were investigated in vivo and in vitro. Results. Cobalt protoporphyrin and CO-releasing molecule-2 alleviated colonic mucosal injury and TNF-α levels; upregulated tight junction (TJ) expression; and inhibited epithelial IκB-α degradation and phosphorylation, NF-κB p65 phosphorylation, long MLCK expression, and MLC-2 phosphorylation after administration of CCl4. Zinc protoporphyrin completely reversed these effects. These findings were further confirmed in vitro, using Caco-2 cells with gain- or loss-of-HO-1-function after TNF-α. Pretreated with JSH-23 (NF-κB inhibitor) or ML-7 (long MLCK inhibitor), HO-1 overexpression prevented TNF-α-induced TJ disruption, while HO-1 shRNA promoted TJ damage even in the presence of JSH-23 or ML-7, thus suggesting that HO-1 dependently protected intestinal barrier via the NF-κB p65/MLCK/p-MLC-2 pathway. Intestinal HO-1-deficient mice further demonstrated the effects of HO-1 in maintaining intestinal barrier integrity and its relative mechanisms. Alleviated hepatic fibrogenesis and serum ALT levels finally confirmed the clinical significance of HO-1/CO repairing barrier loss in liver injury. Conclusion. HO-1/CO maintains intestinal barrier integrity through the NF-κB/MLCK pathway. Therefore, the intestinal HO-1/CO-NF-κB/MLCK system is a potential therapeutic target for diseases with a leaky gut.

scholarly journals Oleuropein alleviates gestational diabetes mellitus by activating AMPK signaling

2020 ◽  
Author(s):  
Zhiwei Zhang ◽  
Hui Zhao ◽  
Aixia Wang
Keyword(s):  
Oxidative Stress ◽  
Diabetes Mellitus ◽  
Body Weight ◽  
Blood Glucose ◽  
Gestational Diabetes ◽  
Gestational Diabetes Mellitus ◽  
Signaling Pathway ◽  
Hepatic Glycogen ◽  
Ampk Signaling ◽  
Tnf Α

Background: Gestational diabetes mellitus (GDM) has a high incidence rate among pregnant women. The objective of the study was to assess the effect of plant-derived oleuropein in attenuating inflammatory and oxidative stress of GDM. Methods: Oleuropein was administered to GDM mice at the doses of 5 or 10 mg/kg/day. Body weight, blood glucose, insulin and hepatic glycogen levels were recorded. To evaluate the effect of oleuropein in reducing oxidative stress, enzyme-linked immunosorbent assay (ELISA) was used to measure the hepatic oxidative stress markers. The inflammation levels of GDM mice were evaluated by measuring serum levels of IL-6 and TNF-α by ELISA, and mRNA levels of IL-1β, TNF-α and IL-6 by real-time PCR (RT-PCR). The AMP-activated protein kinase (AMPK) signaling pathway was assessed by Western blot. Gestational outcome was analyzed through comparing litter size and birth weight. Results: Oleuropein attenuated the elevated body weight of GDM mice, and efficiently reduced blood glucose, insulin and hepatic glycogen levels. Oxidative stress and inflammation were alleviated by oleuropein treatment. The AMPK signaling was activated by oleuropein in GDM mice. Gestational outcome was markedly improved by oleuropein treatment. Conclusions: Our study suggests that oleuropein is effective in alleviating symptoms of GDM and improving gestational outcome in the mouse model. This effect is achieved by attenuating oxidative stress and inflammation, which is mediated by the activation of the AMPK signaling pathway.

scholarly journals Hypoglycemic Effect of Vitexin in C57BL/6J Mice and HepG2 Models

2021 ◽  
Vol 2021 ◽  
pp. 1-7
Author(s):  
Weidong Xu ◽  
Jiayao Li ◽  
Weipeng Qi ◽  
Ye Peng
Keyword(s):  
Insulin Resistance ◽  
Body Weight ◽  
Weight Gain ◽  
Blood Glucose ◽  
Glucose Uptake ◽  
Lipid Content ◽  
Hepg2 Cells ◽  
Body Weight Gain ◽  
Tnf Α ◽  
Hepatic Lipid Content

Apigenin-8-C-glucoside (vitexin), a natural phytochemical contained in hawthorn, has been reported to have versatile beneficial bioactivities, such as antioxidation, anticancer property, and adipogenesis inhibition. The present research aimed to determine the influence of vitexin on insulin resistance elicited by HFD in mice and HepG2 cells. Vitexin markedly alleviated body weight gain and improved glucose and insulin intolerance induced by HFD. Vitexin partially normalized blood glucose, cholesterol, TNF-α, and hepatic lipid content. Moreover, vitexin recovered the reduced glucose uptake induced by glucosamine. The present results indicate that vitexin prevents HFD-induced insulin resistance.

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