Protective effects of a mitochondria-targeted small peptide SS31 against hyperglycemia-induced mitochondrial abnormalities in the liver tissues of diabetic mice, Tallyho/JngJ mice

High glucose (HG)-induced Drp1 overexpression contributes to mitochondrial dysfunction and promotes apoptosis in retinal endothelial cells. However, it is unknown whether inhibiting Drp1 overexpression protects against the development of retinal vascular cell loss in diabetes. To investigate whether reduced Drp1 level is protective against diabetes-induced retinal vascular lesions, four groups of mice: wild type (WT) control mice, streptozotocin (STZ)-induced diabetic mice, Drp1+/− mice, and STZ-induced diabetic Drp1+/− mice were examined after 16 weeks of diabetes. Western Blot analysis indicated a significant increase in Drp1 expression in the diabetic retinas compared to those of WT mice; retinas of diabetic Drp1+/− mice showed reduced Drp1 level compared to those of diabetic mice. A significant increase in the number of acellular capillaries (AC) and pericyte loss (PL) was observed in the retinas of diabetic mice compared to those of the WT control mice. Importantly, a significant decrease in the number of AC and PL was observed in retinas of diabetic Drp1+/− mice compared to those of diabetic mice concomitant with increased expression of pro-apoptotic genes, Bax, cleaved PARP, and increased cleaved caspase-3 activity. Preventing diabetes-induced Drp1 overexpression may have protective effects against the development of vascular lesions, characteristic of diabetic retinopathy.

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Icariin ameliorates streptozocin-induced diabetic nephropathy through suppressing the TLR4/NF-κB signal pathway

Food & Function ◽

10.1039/d0fo02335c ◽

2021 ◽

Vol 12 (3) ◽

pp. 1241-1251

Author(s):

Min-you Qi ◽

Ying-hao He ◽

Yin Cheng ◽

Qing Fang ◽

Ru-yu Ma ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Signal Pathway ◽

Protective Effects ◽

Diabetic Mice

Protective effects of icariin on streptozotocin-induced diabetic mice by inhibiting the TLR4/NF-κB signal pathway.

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Abstract 300: Alda-1 Attenuates Acute Ischemia-reperfusion Mediated Cardiac Damage in Aldehyde Dehydrogenase 2 Mutant Diabetic Mice

Circulation Research ◽

10.1161/res.119.suppl_1.300 ◽

2016 ◽

Vol 119 (suppl_1) ◽

Author(s):

Guodong Pan

Keyword(s):

Aldehyde Dehydrogenase ◽

Ischemia Reperfusion ◽

Left Ventricular Pressure ◽

Left Ventricular ◽

Acute Ischemia ◽

Protective Effects ◽

Diabetic Mice ◽

Aldehyde Dehydrogenase 2 ◽

Cardiac Damage ◽

Western Blots

Aldehyde dehydrogenase 2 (ALDH2), a mitochondrial enzyme in heart, can remove 4-hydroxy-2-nonenal (4-HNE), a toxic by-products of oxidative stress induced by diabetes and ischemia-reperfusion (I/R) injury. A common inactivating mutation of ALDH2 (termed ALDH2*2) was found in 8% of the world’s population, which causes lower ALDH2 activity in mutation carriers. We hypothesized that Alda-1, the only known activator of both ALDH2 and ALDH2*2 mutation, is able to protect heart from I/R injury in diabetic mice with/without ALDH2*2 mutation. Adult male ALDH2*2 mutant and C57B6 wild-type (WT) mice at 3-4 months of age were made hyperglycemic with streptozotocin injection (150 mg/kg. i.p.). Three weeks after injection, Alzet osmotic pumps were implanted subcutaneously to deliver Alda-1 (10 mg/kg) or vehicle. Mice were sacrificed after one day of pump implantation. Hearts were isolated and subjected to 30-minute ischemic followed by 90-minute reperfusion in a Langendorff apparatus. The basal myocardial ALDH2 activity in diabetic ALDH2*2 mutant was significantly lower than in diabetic WT mice (0.50±0.23 vs 0.83±0.08 mmol/min/μg, -39.8%, p<0.05). Alda-1 significantly increased myocardial ALDH2 activity in both ALDH2*2 (1.17±0.38 mmol/min/μg, +134.0%, p<0.05) and WT (1.46±0.40 mmol/min/μg, +75.9%, p<0.05) diabetic mice. Compared with vehicle, Alda-1 significantly improved left ventricular pressure (LVP), and decreased infarcted areas (IA) both in ALDH2*2 (LVP: 4.30±2.03 vs 15.77±8.99 mmHg, +266.7%, p<0.05; IA: 75.17%±9.49 vs 40.46%±7.20, -46.2%, p<0.05) and WT (LVP: 14.22±7.92 vs 21.96±4.32 mmHg, +54.4%, p<0.05; IA: 42.44%±8.60 vs 28.61%±8.55, -32.6%, p<0.05) subjected to I/R injury. Western-blots showed that Alda-1 decreased levels of 4-HNE protein adducts, and increased levels of mitochondrial complex V in both ALDH2*2 and WT mice. Our data suggest that one-day Alda-1 treatment can confer cardio-protective effects against I/R injury in ALDH2*2 diabetic mice possibly accelerating the detoxification of toxic 4-HNE and thereby protecting mitochondria.

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Crocin Improves Insulin Sensitivity and Ameliorates Adiposity by Regulating AMPK-CDK5-PPARγ Signaling

BioMed Research International ◽

10.1155/2020/9136282 ◽

2020 ◽

Vol 2020 ◽

pp. 1-8

Author(s):

Kai Fang ◽

Ming Gu

Keyword(s):

Protein Level ◽

Biological Activities ◽

Protective Effects ◽

Metabolic Dysfunction ◽

Ampk Activation ◽

Diabetic Mice ◽

Wild Type ◽

Ampk Signaling ◽

Beneficial Effects

Crocin is a carotenoid compound which possesses multiple biological activities. Our and other laboratory’s previous findings show that crocin alleviates obesity and type 2 diabetes-related complications. We have found that crocin activates AMP-activated protein kinase (AMPK) signaling and inhibition of AMPK suppresses crocin-induced protective effects. However, the causal role of AMPK activation in the biological role of crocin is still not verified. In the present study, we showed that crocin markedly inhibits the changes of glucose metabolic parameters and serum lipid profiles in wild type diabetic mice. In AMPKα KO diabetic mice, those protective effects of crocin against glucose and lipid metabolic dysfunction were abolished. These results demonstrated AMPK activation was responsible for the beneficial effects of crocin on metabolic dysfunction. Moreover, we have shown that the antiobese effect of crocin has been abolished by the deficiency of AMPKα. We also showed that crocin induced a significant decrease of CDK5 protein level in wild type diabetic mice, while this effect was abolished in AMPKα KO diabetic mice. The regulation of downstream targets of CDK5/PPARγ by crocin was abolished by the deficiency of AMPK. In conclusion, our study verified that activation of AMPK is involved in crocin-induced protective effects against glucose and lipid metabolic dysfunction. Activation of AMPK downregulates the protein level of CDK5, followed by the decrease of PPARγ phosphorylation, leading to the inhibition of adipose formation and metabolic dysfunction. Our study provides new insights into the mechanism of protective effects of crocin and interaction of AMPK and CDK5/PPARγ signaling.

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Protective Effects of Ligustroflavone, an Active Compound from Ligustrum lucidum, on Diabetes-Induced Osteoporosis in Mice: A Potential Candidate as Calcium-Sensing Receptor Antagonist

The American Journal of Chinese Medicine ◽

10.1142/s0192415x1950023x ◽

2019 ◽

Vol 47 (02) ◽

pp. 457-476 ◽

Cited By ~ 6

Author(s):

Rui Feng ◽

Fan Ding ◽

Xiu-Hua Mi ◽

Shu-Fen Liu ◽

Ai-Ling Jiang ◽

...

Keyword(s):

Calcium Influx ◽

Calcium Excretion ◽

Calcium Balance ◽

Potential Candidate ◽

Protective Effects ◽

Diabetic Mice ◽

Allosteric Site ◽

Mineral Density ◽

Ligustrum Lucidum ◽

Calcium Sensing

Ligustroflavone is one major compound contained in active fraction from Fructus Ligustri Lucidi (the fruit of Ligustrum lucidum), which could regulate parathyroid hormone (PTH) levels and improve calcium balance by acting on calcium-sensing receptors (CaSR). This study aimed to explore the potency of ligustroflavone as a CaSR antagonist and its protective effects against diabetic osteoporosis in mice. LF interacted well with the allosteric site of CaSR shown by molecular docking analysis, increased PTH release of primary parathyroid gland cells and suppressed extracellular calcium influx in HEK-293 cells. The serum level of PTH attained peak value at 2[Formula: see text]h and maintained high during the period of 1[Formula: see text]h and 3[Formula: see text]h than that before treatment in mice after a single dose of LF. Treatment of diabetic mice with LF inhibited the decrease in calcium level of serum and bone and the enhancement in urinary calcium excretion as well as elevated circulating PTH levels. Trabecular bone mineral density and micro-architecture were markedly improved in diabetic mice upon to LF treatment for 8 weeks. LF reduced CaSR mRNA and protein expression in the kidneys of diabetic mice. Taken together, ligustroflavone could transiently increase PTH level and regulate calcium metabolism as well as prevent osteoporosis in diabetic mice, suggesting that ligustroflavone might be an effective antagonist on CaSR.

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C-peptide protects against hyperglycemic memory and vascular endothelial cell apoptosis

Journal of Endocrinology ◽

10.1530/joe-16-0349 ◽

2016 ◽

Vol 231 (1) ◽

pp. 97-108 ◽

Cited By ~ 9

Author(s):

Mahendra Prasad Bhatt ◽

Yeon-Ju Lee ◽

Se-Hui Jung ◽

Yong Ho Kim ◽

Jong Yun Hwang ◽

...

Keyword(s):

Endothelial Cells ◽

Umbilical Vein ◽

Vascular Endothelial Cell ◽

Vascular Damage ◽

Protective Effects ◽

Diabetic Mice ◽

C Peptide ◽

Glucose Levels

C-peptide exerts protective effects against diabetic complications; however, its role in inhibiting hyperglycemic memory (HGM) has not been elucidated. We investigated the beneficial effect of C-peptide on HGM-induced vascular damage in vitro and in vivo using human umbilical vein endothelial cells and diabetic mice. HGM induced apoptosis by persistent generation of intracellular ROS and sustained formation of ONOO− and nitrotyrosine. These HGM-induced intracellular events were normalized by treatment with C-peptide, but not insulin, in endothelial cells. C-peptide also inhibited persistent upregulation of p53 and activation of mitochondrial adaptor p66shc after glucose normalization. Further, C-peptide replacement therapy prevented persistent generation of ROS and ONOO− in the aorta of diabetic mice whose glucose levels were normalized by the administration of insulin. C-peptide, but not insulin, also prevented HGM-induced endothelial apoptosis in the murine diabetic aorta. This study highlights a promising role for C-peptide in preventing HGM-induced intracellular events and diabetic vascular damage.

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Additive protection by LDR and FGF21 treatment against diabetic nephropathy in type 2 diabetes model

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00026.2015 ◽

2015 ◽

Vol 309 (1) ◽

pp. E45-E54 ◽

Cited By ~ 13

Author(s):

Minglong Shao ◽

Lechu Yu ◽

Fangfang Zhang ◽

Xuemian Lu ◽

Xiaokun Li ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Diabetic Nephropathy ◽

Combination Treatment ◽

Combined Treatment ◽

Protective Effects ◽

Diabetic Mice ◽

Renal Protection ◽

Glucose Levels

The onset of diabetic nephropathy (DN) is associated with both systemic and renal changes. Fibroblast growth factor (FGF)-21 prevents diabetic complications mainly by improving systemic metabolism. In addition, low-dose radiation (LDR) protects mice from DN directly by preventing renal oxidative stress and inflammation. In the present study, we tried to define whether the combination of FGF21 and LDR could further prevent DN by blocking its systemic and renal pathogeneses. To this end, type 2 diabetes was induced by feeding a high-fat diet for 12 wk followed by a single dose injection of streptozotocin. Diabetic mice were exposed to 50 mGy LDR every other day for 4 wk with and without 1.5 mg/kg FGF21 daily for 8 wk. The changes in systemic parameters, including blood glucose levels, lipid profiles, and insulin resistance, as well as renal pathology, were examined. Diabetic mice exhibited renal dysfunction and pathological abnormalities, all of which were prevented significantly by LDR and/or FGF21; the best effects were observed in the group that received the combination treatment. Our studies revealed that the additive renal protection conferred by the combined treatment against diabetes-induced renal fibrosis, inflammation, and oxidative damage was associated with the systemic improvement of hyperglycemia, hyperlipidemia, and insulin resistance. These results suggest that the combination treatment with LDR and FGF21 prevented DN more efficiently than did either treatment alone. The mechanism behind these protective effects could be attributed to the suppression of both systemic and renal pathways.

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Protective effects of ethyl pyruvate treatment on paraquat-intoxicated rats

Human & Experimental Toxicology ◽

10.1177/0960327108088976 ◽

2008 ◽

Vol 27 (1) ◽

pp. 49-54 ◽

Cited By ~ 25

Author(s):

JH Lee ◽

WY Kwon ◽

YH Jo ◽

GJ Suh ◽

YK Youn

Keyword(s):

Nitric Oxide ◽

Oxygen Radicals ◽

Ethyl Pyruvate ◽

Ischemia Reperfusion ◽

Oxygen Radical ◽

Protective Effects ◽

Inflammatory Agent ◽

Anti Inflammatory ◽

Inflammatory Action ◽

Liver Tissues

Although, numerous studies have attempted to reduce the oxygen radical injury induced by the antioxidants in paraquat intoxication, these antioxidant therapies have showed few survival benefits. Ethyl pyruvate (EP) may function as an effective scavenger of oxygen radicals, an anti-inflammatory agent and an energy source in many ischemia reperfusion models. The aim of this study was to evaluate the antioxidant and anti-inflammatory effects of EP on the lung and the liver tissues in paraquat-intoxicated rats. Rats were randomly given either a low (2 mg/kg i.p.) or high (40 mg/kg i.p.) EP dose, 30 min before or 1 h after paraquat (50 mg/kg i.p.) administration, and subsequently killed at 6 and 24 h. Glutathione (GSH) and malondialdehyde (MDA) levels of the lungs and the livers, and plasma nitric oxide (NO) concentrations were measured. Pretreatment of EP significantly decreased the MDA level in the lung and the liver tissues. EP also significantly decreased plasma NO concentrations at 6 h. EP pretreatment, however, failed to show significant change in GSH concentration. In post-treatment of EP, MDA levels in the lung tissue and plasma NO levels were significantly decreased. In conclusion, EP decreased the lipid peroxidation and seemed to exert an anti-inflammatory action in the paraquat intoxication rat model.

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