scholarly journals Lespedeza bicolor Extract Ameliorated Renal Inflammation by Regulation of NLRP3 Inflammasome-Associated Hyperinflammation in Type 2 Diabetic Mice

Antioxidants ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 148 ◽  
Author(s):  
Ji Eun Park ◽  
Heaji Lee ◽  
Sun Yeou Kim ◽  
Yunsook Lim
Keyword(s):  
Nlrp3 Inflammasome ◽  
Renal Damage ◽  
Low Dose ◽  
Adenosine Monophosphate ◽  
High Dose ◽  
Related Factor ◽  
Functional Changes ◽  
Pyrin Domain ◽  
Lespedeza Bicolor

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by hyperglycemia. The chronic hyperglycemic condition causes hyperinflammation via activation of nucleotide-binding oligomerization domain-like pyrin domain containing receptor 3 (NLRP3) inflammasome and abnormally leads to morphological and functional changes in kidney. A previous study showed a protective effect of Lespedeza bicolor extract (LBE) on endothelial dysfunction induced by methylglyoxal glucotoxicity. We aimed to investigate whether LBE ameliorated renal damage through regulation of NLRP3 inflammasome-dependent hyper-inflammation in T2DM mice. After T2DM induction by a high fat diet and low dose of streptozotocin (30 mg/kg), the mice were administered with different dosages of LBE (100 or 250 mg/kg/day) by gavage for 12 weeks. LBE supplementation ameliorated kidney dysfunction demonstrated by urine albumin-creatinine at a low dose and plasma creatinine, blood urea nitrogen (BUN), and glomerular hypertrophy at a high dose. Furthermore, a high dose of LBE supplementation significantly attenuated renal hyper-inflammation associated with NLRP3 inflammasome and oxidative stress related to nuclear factor erythroid 2-related factor 2 (Nrf-2) in T2DM mice. Meanwhile, a low dose of LBE supplementation up-regulated energy metabolism demonstrated by phosphorylation of adenosine monophosphate kinase (AMPK) and Sirtuin (SIRT)-1 in T2DM mice. In conclusion, the current study suggested that LBE, in particular, at a high dose could be used as a beneficial therapeutic for hyperglycemia-induced renal damage in T2DM.

scholarly journals Combination Therapy with an SGLT2 Inhibitor as Initial Treatment for Type 2 Diabetes: A Systematic Review and Meta-Analysis

2019 ◽  
Vol 8 (1) ◽  
pp. 45 ◽  
Author(s):  
Tamara Y. Milder ◽  
Sophie L. Stocker ◽  
Christina Abdel Shaheed ◽  
Lucy McGrath-Cadell ◽  
Dorit Samocha-Bonet ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Combination Therapy ◽  
Low Dose ◽  
Meta Analysis ◽  
Sglt2 Inhibitor ◽  
Cochrane Library ◽  
High Dose ◽  
Dose Combination ◽  
Inhibitor Combination

Background: Guidelines differ with regard to indications for initial combination pharmacotherapy for type 2 diabetes. Aims: To compare the efficacy and safety of (i) sodium-glucose cotransporter 2 (SGLT2) inhibitor combination therapy in treatment-naïve type 2 diabetes adults; (ii) initial high and low dose SGLT2 inhibitor combination therapy. Methods: PubMed, Embase and Cochrane Library were searched for randomised controlled trials (RCTs) of initial SGLT2 combination therapy. Mean difference (MD) for changes from baseline (HbA1c, weight, blood pressure) after 24–26 weeks of treatment and relative risks (RR, safety) were calculated using a random-effects model. Risk of bias and quality of evidence was assessed. Results: In 4 RCTs (n = 3749) there was moderate quality evidence that SGLT2 inhibitor/metformin combination therapy resulted in a greater reduction in HbA1c (MD (95% CI); −0.55% (−0.67, −0.43)) and weight (−2.00 kg (−2.34, −1.66)) compared with metformin monotherapy, and a greater reduction in HbA1c (−0.59% (−0.72, −0.46)) and weight (−0.57 kg (−0.89, −0.25)) compared with SGLT2 inhibitor monotherapy. The high dose SGLT2 inhibitor/metformin combination resulted in a similar HbA1c but greater weight reduction; −0.47 kg (−0.88, −0.06) than the low dose combination therapy. The RR of genital infection with combination therapy was 2.22 (95% CI 1.33, 3.72) and 0.69 (95% CI 0.50, 0.96) compared with metformin and SGLT2 inhibitor monotherapy, respectively. The RR of diarrhoea was 2.23 (95% CI 1.46, 3.40) with combination therapy compared with SGLT2 inhibitor monotherapy. Conclusions: Initial SGLT2 inhibitor/metformin combination therapy has glycaemic and weight benefits compared with either agent alone and appears relatively safe. High dose SGLT2 inhibitor/metformin combination therapy appears to have modest weight, but no glycaemic benefits compared with the low dose combination therapy.

scholarly journals Metformin Corrects Glucose Metabolism Reprogramming and NLRP3 Inflammasome-Induced Pyroptosis via Inhibiting the TLR4/NF-κB/PFKFB3 Signaling in Trophoblasts: Implication for a Potential Therapy of Preeclampsia

2021 ◽  
Vol 2021 ◽  
pp. 1-22
Author(s):  
Yang Zhang ◽  
Weifang Liu ◽  
Yanqi Zhong ◽  
Qi Li ◽  
Mengying Wu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nlrp3 Inflammasome ◽  
Low Dose ◽  
Therapeutic Potential ◽  
Metabolic Phenotypes ◽  
Pyrin Domain ◽  
Underlying Mechanisms ◽  
And Oxidative Stress ◽  
Receptor Family

NOD-like receptor family, pyrin domain-containing protein 3 (NLRP3) inflammasome-mediated pyroptosis is a crucial event in the preeclamptic pathogenesis, tightly linked with the uteroplacental TLR4/NF-κB signaling. Trophoblastic glycometabolism reprogramming has now been noticed in the preeclampsia pathogenesis, plausibly modulated by the TLR4/NF-κB signaling as well. Intriguingly, cellular pyroptosis and metabolic phenotypes may be inextricably linked and interacted. Metformin (MET), a widely accepted NF-κB signaling inhibitor, may have therapeutic potential in preeclampsia while the underlying mechanisms remain unclear. Herein, we investigated the role of MET on trophoblastic pyroptosis and its relevant metabolism reprogramming. The safety of pharmacologic MET concentration to trophoblasts was verified at first, which had no adverse effects on trophoblastic viability. Pharmacological MET concentration suppressed NLRP3 inflammasome-induced pyroptosis partly through inhibiting the TLR4/NF-κB signaling in preeclamptic trophoblast models induced via low-dose lipopolysaccharide. Besides, MET corrected the glycometabolic reprogramming and oxidative stress partly via suppressing the TLR4/NF-κB signaling and blocking transcription factor NF-κB1 binding on the promoter PFKFB3, a potent glycolytic accelerator. Furthermore, PFKFB3 can also enhance the NF-κB signaling, reduce NLRP3 ubiquitination, and aggravate pyroptosis. However, MET suppressed pyroptosis partly via inhibiting PFKFB3 as well. These results provided that the TLR4/NF-κB/PFKFB3 pathway may be a novel link between metabolism reprogramming and NLRP3 inflammasome-induced pyroptosis in trophoblasts. Further, MET alleviates the NLRP3 inflammasome-induced pyroptosis, which partly relies on the regulation of TLR4/NF-κB/PFKFB3-dependent glycometabolism reprogramming and redox disorders. Hence, our results provide novel insights into the pathogenesis of preeclampsia and propose MET as a potential therapy.

scholarly journals Nutrients and Immunometabolism: Role of Macrophage NLRP3

2020 ◽  
Vol 150 (7) ◽  
pp. 1693-1704
Author(s):  
Kate J Claycombe-Larson ◽  
Travis Alvine ◽  
Dayong Wu ◽  
Nishan S Kalupahana ◽  
Naima Moustaid-Moussa ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Tissue Cell ◽  
Cell Functions ◽  
Pyrin Domain ◽  
Increased Risk ◽  
Vital Cell ◽  
Cell Type Specific ◽  
Specific Regulation

ABSTRACT Inflammation is largely mediated by immune cells responding to invading pathogens, whereas metabolism is oriented toward producing usable energy for vital cell functions. Immunometabolic alterations are considered key determinants of chronic inflammation, which leads to the development of chronic diseases. Studies have demonstrated that macrophages and the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome are activated in key metabolic tissues to contribute to increased risk for type 2 diabetes mellitus, Alzheimer disease, and liver diseases. Thus, understanding the tissue-/cell-type–specific regulation of the NLRP3 inflammasome is crucial for developing intervention strategies. Currently, most of the nutrients and bioactive compounds tested to determine their inflammation-reducing effects are limited to animal models. Future studies need to address how dietary compounds regulate immune and metabolic cell reprograming in humans.

scholarly journals Dimethyl Fumarate Ameliorates Lipopolysaccharide-induced Acute Lung Injury by Inhibiting NLRP3 Inflammasome-mediated Pyroptosis

2021 ◽  
Author(s):  
Huayu Li ◽  
Mengyan Li ◽  
Chao Dong ◽  
Bing Liu
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Nlrp3 Inflammasome ◽  
Therapeutic Potential ◽  
Critical Role ◽  
Specific Effect ◽  
Dimethyl Fumarate ◽  
Related Factor ◽  
Pyrin Domain ◽  
Anti Inflammatory

Abstract Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are clinically severe respiratory disorders, and there are currently no Food and Drug Administration-approved drug therapies. It is established that Dimethyl fumarate (DMF) exhibits anti inflammatory effects, however, the specific effect of DMF on ALI remains largely unknown. The aim of the present study was to investigate whether, and by which mechanism, DMF alleviated lipopolysaccharide (LPS)-induced ALI. We found that intraperitoneal injection of DMF markedly reduced the pulmonary injury, decreased pulmonary edema and pulmonary permeability. Emerging studies suggested that the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome-mediated pyroptosis played a critical role during ALI. NLRP3 inflammasome-mediated pyroptosis is significantly activated with the cleavage of caspase-1 and GSDMD occurring in the lung of LPS-induced ALI. DMF inhibited the activation of the NLRP3 inflammasome and pyroptosis in both lung of ALI mice and LPS-induced BEAS-2B cells. Mechanistically, DMF enhanced expressions of Nuclear factor erythroid-2-related factor 2 (Nrf2), leading to inactivation of NLRP3 inflammasome and reduction of pyroptosis in both ALI mice and LPS-induced BEAS-2B cells. Conversely, Nrf2 inhibitor reduced the inhibitory effects of DMF on NLRP3 inflammasome and pyroptosis, and consequently blocked the improvement roles of DMF on ALI in mice. This study for the first time demonstrated that DMF could improve LPS-induced ALI via inhibiting NLRP3 inflammasome and pyroptosis, and that these effects were mediated by triggering Nrf2 expression, suggesting a therapeutic potential of DMF as an anti-inflammatory agent for ALI/ARDS treatment.

scholarly journals Low-Dose Berberine Attenuates the Anti-Breast Cancer Activity of Chemotherapeutic Agents via Induction of Autophagy and Antioxidation

Dose-Response ◽  
2020 ◽  
Vol 18 (4) ◽  
pp. 155932582093975
Author(s):  
Bing Han ◽  
Kai Wang ◽  
Yanbei Tu ◽  
Lihua Tan ◽  
Chengwei He
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Low Dose ◽  
Negative Impact ◽  
Adenosine Monophosphate ◽  
Chemotherapeutic Agents ◽  
Related Factor ◽  
Anticancer Efficacy ◽  
Hormetic Effect ◽  
Underlying Mechanisms

Berberine (BBR), a major active component of Rhizoma coptidis, is one of the most promising agents for breast cancer adjuvant therapy. It is well accepted that BBR could exhibit remarkable anticancer efficacy with few side effects, and when treated with chemotherapeutic agents in combination, BBR could enhance the chemosensitivity of cancer cells. Our previous study reported that low-dose BBR (LDB) induced hormetic effect and attenuated the anticancer activity of chemotherapeutic agents. However, the underlying mechanisms are still unclear. In this study, we confirmed that LDB could promote cancer cell proliferation and antagonize the anti-breast cancer activities of chemotherapeutic agents. And the mechanisms were proved to be induction of autophagy and antioxidation by LDB. Our results showed that LDB could mildly induce reactive oxygen species, raise the level of autophagy by promoting the phosphorylation of adenosine monophosphate-activated protein kinase, and promote antioxidant enzymes expression through activating nuclear factor erythroid 2-related factor 2 in breast cancer cells. These findings revealed a potential negative impact of BBR on its adjuvant anti-breast cancer therapy, providing guidance for a safe and effective use of naturally originated medicines in the clinic.

152 IS LOW-DOSE CONTINUOUS NATEGLINIDE AS EFFECTIVE AS HIGH-DOSE THREE TIMES DAILY NATEGLINIDE IN TYPE 2 DIABETES?

2006 ◽  
Vol 54 (1) ◽  
pp. S106.2-S106
Author(s):  
Gonzalez D. de Serna ◽  
F. M. Alba ◽  
K. E. Schwarz ◽  
D. W. Tsewang ◽  
M. F. Carroll ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Low Dose ◽  
High Dose

LITHOTRIPTIC ACTIVITY OF NERIUM OLEANDER L.: AN EXPERIMENTAL SCREENING

INDIAN DRUGS ◽  
2016 ◽  
Vol 53 (12) ◽  
pp. 11-17
Author(s):  
S. R Pethakar ◽  
◽  
P. J. Hurkadale ◽  
R. D Hiremath ◽  
S. S. Jalalpure
Keyword(s):  
Wistar Rats ◽  
Renal Damage ◽  
Low Dose ◽  
Normal Values ◽  
Urine Volume ◽  
Nerium Oleander ◽  
High Dose ◽  
Alcoholic Extract ◽  
Hydroalcoholic Extract ◽  
Remarkable Recovery

The present study is aimed at investigating the lithotriptic activity of Nerium oleander L. by inducing experimental urolithiasis in Wistar rats. The screening of lithotriptic effect of hydro-alcoholic extract of Nerium oleander L. 100,200 and 400 mg/kg) was evaluated using ethylene glycol induced urolithiasis in rats. Animals treated with plant extracts (curative and preventive doses) showed promising lithotriptic effects. Particularly low dose (Gr. VI) was more potent compared with medium and high dose of hydroalcoholic extract. Increased urine volume and progressive weight gain was suggestive of diuretic property and protective effect against lithogenesis, respectively, in the animals treated with hydro-alcoholic extract. Increased concentrations of stone-forming components such as calcium, phosphate and oxalate in diseased group were reduced in the animals treated with extracts. Serum creatinine, BUN, and uric acid levels were elevated in calculi induced animals which were close to normal values in animals treated with extract. Severe renal damage was observed in kidney histopathology due to crystal aggregation and deposition. Remarkable recovery with animals treated with extract was confirming about inhibition of process of lithogenesis. It can be concluded that the results are supportive to claims made. The exact mechanism of lithotriptic effect further needs to be studied.

Effects of Scutellaria barbata extracts on serum glycolipid hormones and pancreatic-tissue structure in type 2 diabetic rats

2019 ◽  
Author(s):  
Ruile Song ◽  
Chunyang Tian ◽  
Miao Xian ◽  
Tang LI ◽  
Zhengli Chen ◽  
...  
Keyword(s):  
Low Dose ◽  
Serum Levels ◽  
Pancreatic Tissue ◽  
Diabetic Rats ◽  
Tissue Structure ◽  
High Dose ◽  
Model Group ◽  
Citrate Buffer ◽  
Scutellaria Barbata

The study describes the effect of Chinese herbal medicine extracts from Scutellaria barbata on serum glycolipid hormones and pancreatic-tissue structure in type 2 diabetes mellitus (T2DM) rats. Healthy Wistar rats (n = 150) were divided randomly into two groups: healthy (30) and model (120). The healthy group was fed normally for 30d and injected citrate buffer on day 31. The model group was fed high-fat and high-sugar feed for 30d and injected STZ on day 31. On day 38 the model group was divided randomly into four groups: model group, low-, medium-, and high-dose S. barbata (n = 30 in each). 5, 10, 20, and 30dafter treatment, serum levels of FGB, INS, CORT, TG, TC, HDL-C, and LDL-C in all groups were measured and pancreatic-tissue sections were stained with hematoxylin–eosin and aldehyde fuchsine to observe the tissue structure. The results showed significantly decreased levels of FGB, INS, CORT, and LDL-C (P less than 0.01) and increased level of HDL-C (P greator than 0.05).In addition, the damaged structure of diabetic pancreatic tissue has been partially restored in the low-dose S. barbata group. These results show that low-dose S. barbata extract treatment is effective in treating T2DM.

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