Morin exerts neuroprotection via attenuation of ROS induced oxidative damage and neuroinflammation in experimental diabetic neuropathy

Bachewal, Pragna; Gundu, Chayanika; Yerra, Veera Ganesh; Kalvala, Anil Kumar; Areti, Aparna; Kumar, Ashutosh

doi:10.1002/biof.1397

Cited by 67 publications

(30 citation statements)

References 75 publications

(90 reference statements)

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“…However, if oxidative stress persistently exists, the inflammation will cause the progressive tissue damage. Recent findings showed that Morin and natural rotenoid deguelin exerted neuroprotection in experimental diabetic neuropathy through antioxidative stress and antineuroinflammation [7,25]. Thus, targeting the cellular oxidative stress and inflammation pathway will be likely important therapeutic approaches in the future to reduce the incidence of diabetic neuropathy.…”

Section: Discussionmentioning

confidence: 99%

“…Nuclear factor-E2-related factor 2 (Nrf2) belongs to the family of transcription factors regulating a set of antioxidants and detoxification enzymes. It was reported that Nrf2 acted as a bridge linking oxidative stress and inflammation and impacted progression of diabetic neuropathy, which has been demonstrated by treatment with Morin and alpha lipoic acid [7,8]. Antioxidant strategies have been most widely explored; nevertheless, whether antioxidants alone prevent DPN still remains inconclusive since the molecular mechanisms are more complex.…”

Section: Introductionmentioning

confidence: 99%

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Neuroprotective Effect of Salvianolic Acid A against Diabetic Peripheral Neuropathy through Modulation of Nrf2

Hou

et al. 2020

Oxidative Medicine and Cellular Longevity

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Oxidative stress has been recognized as the contributor to diabetic peripheral neuropathy (DPN). Antioxidant strategies have been most widely explored; nevertheless, whether antioxidants alone prevent DPN still remains inconclusive. In the present study, we established an in vitro DPN cell model for drug screening using Schwann RSC96 cells under high glucose (HG) stimulation, and we found that salvianolic acid A (SalA) mitigated HG-induced injury evidenced by cell viability and myelination. Mechanistically, SalA exhibited strong antioxidative effects by inhibiting 1,1-diphenyl-2-picrylhydrazyl (DPPH) and reducing reactive oxygen species (ROS), malondialdehyde (MDA), and oxidized glutathione (GSSG) content, as well as upregulating antioxidative enzyme mRNA expression. In addition, SalA significantly extenuated neuroinflammation with downregulated inflammatory factor mRNA expression. Furthermore, SalA improved the mitochondrial function of HG-injured Schwann cells by scavenging mitochondrial ROS, decreasing mitochondrial membrane potential (MMP), and enhancing ATP production, as well as upregulating oxidative phosphorylation gene expression. More importantly, we identified nuclear factor-E2-related factor 2 (Nrf2) as the upstream regulator which mediated protective effects of SalA on DPN. SalA directly bound to the Kelch domain of Kelch-like ECH-associated protein 1 (Keap1) and thus disrupted the interaction of Nrf2 and Keap1 predicted by LibDock of Discovery Studio. Additionally, SalA significantly inhibited Nrf2 promoter activity and downregulated Nrf2 mRNA expression but without affecting Nrf2 protein expression. Interestingly, SalA upregulated the nuclear Nrf2 expression and promoted Nrf2 nuclear translocation by high content screening assay, which was confirmed to be involved in its antiglucotoxicity effect by the knockdown of Nrf2 in RSC96 cells. In KK-Ay mice, we demonstrated that SalA could effectively improve the abnormal glucose and lipid metabolism and significantly protect against DPN by increasing the mechanical withdrawal threshold and sciatic nerve conduction velocity and restoring the ultrastructural impairment of the injured sciatic nerve induced by diabetes. Hence, SalA protected against DPN by antioxidative stress, attenuating neuroinflammation, and improving mitochondrial function via Nrf2. SalA may be prospective therapeutics for treating DPN.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Neuroprotective Effect of Salvianolic Acid A against Diabetic Peripheral Neuropathy through Modulation of Nrf2

Hou

et al. 2020

Oxidative Medicine and Cellular Longevity

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“…Currently, there are very few available therapies for diabetic neuropathy because therapeutic opportunities are limited by many factors, such as serious adverse reactions and ineffectiveness. Therefore, we still need to find a suitable treatment for these complications of neuropathy [7].…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective effect of diosgenin in a mouse model of diabetic peripheral neuropathy involves the Nrf2/HO-1 pathway

Jin-hong

Tian

et al. 2020

BMC Complement Med Ther

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Background: Diabetic peripheral neuropathy (DPN) is one of the most common chronic complications of diabetes. Diosgenin is a natural steroidal saponin with a variety of beneficial effects, including antidiabetic effects, and is a raw material for the synthesis of carrier hormones. In our study, we aimed to assess the antioxidant effects of diosgenin in diabetic mice. Methods: Male C57 mice were fed a high-fat diet for 8 weeks and intraperitoneally injected with streptozotocin (STZ) at a dose of 100 mg/kg for 2 consecutive days. Eligible mice were divided into the normal control group (CON), diabetic group (DM), low-dose diosgenin (50 mg/kg) group (DIO50) and high-dose diosgenin (100 mg/kg) group (DIO100). Treatment was started 6 weeks after the induction of diabetes by STZ and continued for 8 weeks. Blood sugar and body weight were monitored dynamically. The behavioural effects of diosgenin were detected by a hot tail immersion test and paw tactile responses. HE staining was used to evaluate edema and degeneration of the sciatic nerve. The levels of SOD, MDA and GPx were tested according to the instructions of the respective kits. The levels of Nrf2, HO-1 and NQO1 were detected by immunofluorescence and Western blotting. Statistical analysis was performed using SPSS, and P < 0.05 was considered statistically significant. Results: Diosgenin decreased the blood glucose levels and increased the body weight of diabetic mice. There was a significant increase in the tail withdrawal latency of diabetic animals, and mechanical hyperalgesia was significantly alleviated after diosgenin treatment. Histopathological micrographs of HE-stained sciatic nerves showed improvement after diosgenin treatment. Diosgenin attenuated the level of MDA but increased the activities of SOD and GPx. Diosgenin increased the expression of Nrf2, HO-1 and NQO1. Conclusions: Our results demonstrate that diosgenin can ameliorate behavioural and morphological changes in DPN by reducing oxidative stress. The Nrf2/HO-1 signalling pathway was involved in its neuroprotective effects.

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“…Previous studies have reported that Nrf2 is involved in the regulation of antioxidant responses and inflammation (21)(22)(23)(24). Western blotting demonstrated that the protein expression of Nrf2 and HO-1, which lies downstream of Nrf2, was further upregulated in osthole-treated BV2 microglia, compared with cells exposed to LPS alone (Fig.…”

Section: Effects Of Osthole On the Protein Expression Of Nrf2 And Ho-1mentioning

confidence: 71%

Protective effects of osthole against inflammation induced by lipopolysaccharide in BV2 cells

et al. 2018

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Inflammation and oxidative stress are implicated in the development of neurodegenerative diseases. Osthole is a compound that is extracted from She Chuang Zi, which is a type of traditional Chinese medicine. Osthole has previously been demonstrated to exhibit anticancer activities and has a low toxicity. However, to the best of our knowledge, the anti‑inflammatory effects of osthole in microglial cells have not been investigated extensively. The aim of the present study was to investigate the potential protective effects of osthole against inflammation induced by lipopolysaccharide (LPS) in microglial cells. The present study employed LPS‑stimulated BV2 mouse microglia to establish an inflammatory cell model and to investigate the anti‑inflammatory effects of osthole. Cells were pretreated with osthole for 1 h prior to LPS (10 µg/ml) stimulation. At 6 h after the addition of LPS, alterations in the levels of inflammatory factors, including tumor necrosis factor (TNF)‑α, interleukin (IL)‑6 and IL‑1β, were determined by ELISA. Furthermore, at 24 h after the addition of LPS, western blot analysis was performed to analyze the alterations in the protein expression of nuclear factor‑κB (NF‑κB) p65, phosphorylated‑NF‑κB p65, nuclear factor erythroid 2‑related factor 2 (Nrf2) and heme oxygenase (HO)‑1. The results demonstrated that the secretion of the inflammatory cytokines TNF‑α, IL‑6 and IL‑1β by LPS‑stimulated BV2 cells was significantly reduced by osthole treatment. Simultaneously, osthole treatment inhibited the LPS‑induced activation of the NF‑κB signaling pathway. In addition, osthole upregulated the expression of Nrf2 and HO‑1 in a dose‑dependent manner. Based on these results, osthole may exhibit anti‑inflammatory effects via the NF‑κB and Nrf2 pathways, indicating that osthole has the potential to be developed into an effective anti-inflammatory drug.

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Morin exerts neuroprotection via attenuation of ROS induced oxidative damage and neuroinflammation in experimental diabetic neuropathy

Cited by 67 publications

References 75 publications

Neuroprotective Effect of Salvianolic Acid A against Diabetic Peripheral Neuropathy through Modulation of Nrf2

Neuroprotective Effect of Salvianolic Acid A against Diabetic Peripheral Neuropathy through Modulation of Nrf2

Neuroprotective effect of diosgenin in a mouse model of diabetic peripheral neuropathy involves the Nrf2/HO-1 pathway

Protective effects of osthole against inflammation induced by lipopolysaccharide in BV2 cells

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