scholarly journals Tang Luo Ning, a Traditional Chinese Compound Prescription, Ameliorates Schwannopathy of Diabetic Peripheral Neuropathy Rats by Regulating Mitochondrial Dynamics In Vivo and In Vitro

2021 ◽  
Vol 12 ◽  
Author(s):  
Jiayue Zhu ◽  
Xinwei Yang ◽  
Xiao Li ◽  
Shuo Han ◽  
Yanbo Zhu ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Mitochondrial Function ◽  
Diabetic Peripheral Neuropathy ◽  
Mitochondrial Dynamics ◽  
Branch Length ◽  
Network Size ◽  
Mitofusin 2 ◽  
Atp Levels

Tang Luo Ning (TLN), a traditional Chinese compound prescription, has been used clinically to treat diabetic peripheral neuropathy (DPN) in China. However, the exact mechanisms remain unclear. The objective of this study is to unravel the effects of TLN on mitochondrial dynamics of DPN in streptozotocin-induced rat models and Schwann cells cultured in 150 mM glucose. Mitochondrial function was determined by Ca2+ and ATP levels of streptozotocin (STZ)-induced DPN rats and mitochondria structure, mitochondrial membrane potential (MMP), and mtDNA of high glucose incubated SCs. Mitochondrial dynamics protein including mitofusin 1 (Mfn1), mitofusin 2 (Mfn2), optic atrophy 1 (Opa1), and dynamin-related protein 1 (Drp1) were investigated using Western blot or immunofluorescence. Myelin basic protein (MBP), myelin protein zero (MPZ), and sex-determining region Y (SRY)-box 10 (Sox10) were measured to represent schwannopathy. Our results showed that TLN increased ATP levels (0.38 of model, 0.69 of HTLN, 0.61 of LTLN, P＜0.01; 0.52 of 150 mM glucose, 1.00 of 10% TLN, P＜0.01, 0.94 of 1% TLN, P＜0.05), MMP (0.56 of 150 mM glucose, P＜0.01, 0.75 of 10% TLN, P＜0.05, 0.83 of 1% TLN, P＜0.01), and mtDNA (0.32 of 150 mM glucose, 0.43 of 10% TLN, P＜0.01) while decreased Ca2+ (1.54 of model, 1.06 of HTLN, 0.96 of LTLN, P＜0.01) to improve mitochondrial function in vivo and in vitro. TLN helps maintain balance of mitochondrial dynamics: it reduces the mitochondria number (1.60 of 150 mM glucose, 1.10 of 10% TLN, P＜0.01) and increases the mitochondria coverage (0.51 of 150 mM glucose, 0.80 of 10% TLN, 0.87 of 1% TLN, P＜0.01), mitochondrial network size (0.51 of 150 mM glucose, 0.95 of 10% TLN, 0.94 of 1% TLN, P＜0.01), and branch length (0.63 of 150 mM glucose, P＜0.01, 0.73 of 10% TLN, P＜0.05, 0.78 of 1% TLN, P＜0.01). Further, mitochondrial dynamics–related Mfn1 (0.47 of model, 0.82 of HTLN, 0.77 of LTLN, P＜0.01; 0.42 of 150 mM glucose, 0.56 of 10% TLN, 0.57 of 1% TLN, P＜0.01), Mfn2 (0.40 of model, 0.84 of HTLN, 0.63 of LTLN, P＜0.01; 0.46 of 150 mM glucose, 1.40 of 10% TLN, 1.40 of 1% TLN, P＜0.01), and Opa1 (0.58 of model, 0.71 of HTLN, 0.90 of LTLN, P＜0.01; 0.69 of 150 mM glucose, 0.96 of 10% TLN, 0.98 of 1% TLN, P＜0.05) were increased, while Drp1 (1.39 of model, 0.96 of HTLN, 1.18 of LTLN, P＜0.01; 1.70 of 150 mM glucose, 1.20 of 10% TLN, 1.10 of 1% TLN, P＜0.05), phosphorylated Drp1 (2.61 of model, 1.44 of HTLN, P＜0.05; 2.80 of 150 mM glucose, 1.50 of 10% TLN, 1.30 of 1% TLN, P＜0.01), and Drp1 located in mitochondria (1.80 of 150 mM glucose, 1.00 of 10% TLN, P＜0.05) were decreased after treatment with TLN. Additionally, TLN improved schwannopathy by increasing MBP (0.50 of model, 1.05 of HTLN, 0.94 of HTLN, P＜0.01; 0.60 of 150 mM glucose, 0.78 of 10% TLN, P＜0.01, 0.72 of 1% TLN, P＜0.05), Sox101 (0.41 of model, 0.99 of LTLN, P＜0.01; 0.48 of 150 mM glucose, 0.65 of 10% TLN, P＜0.05, 0.69 of 1% TLN, P＜0.01), and MPZ (0.48 of model, 0.66 of HTLN, 0.55 of HTLN, P＜0.01; 0.60 of 150 mM glucose, 0.78 of 10% TLN, P＜0.01, 0.75 of 1% TLN, P＜0.05) expressions. In conclusion, our study indicated that TLN’s function on DPN may link to the improvement of the mitochondrial dynamics, which provides scientific evidence for the clinical application.

scholarly journals HDAC6: A Key Link Between Mitochondria and Development of Peripheral Neuropathy

2021 ◽  
Vol 14 ◽  
Author(s):  
Krystal English ◽  
Michelle Craig Barton
Keyword(s):  
Neuropathic Pain ◽  
Peripheral Neuropathy ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Dynamics ◽  
Health Concern ◽  
Major Player ◽  
Class Iib ◽  
Voltage Gated Ion Channels

Peripheral neuropathy, which is the result of nerve damage from lesions or disease, continues to be a major health concern due to the common manifestation of neuropathic pain. Most investigations into the development of peripheral neuropathy focus on key players such as voltage-gated ion channels or glutamate receptors. However, emerging evidence points to mitochondrial dysfunction as a major player in the development of peripheral neuropathy and resulting neuropathic pain. Mitochondrial dysfunction in neuropathy includes altered mitochondrial transport, mitochondrial metabolism, as well as mitochondrial dynamics. The mechanisms that lead to mitochondrial dysfunction in peripheral neuropathy are poorly understood, however, the Class IIb histone deacetylase (HDAC6), may play an important role in the process. HDAC6 is a key regulator in multiple mechanisms of mitochondrial dynamics and may contribute to mitochondrial dysregulation in peripheral neuropathy. Accumulating evidence shows that HDAC6 inhibition is strongly associated with alleviating peripheral neuropathy and neuropathic pain, as well as mitochondrial dysfunction, in in vivo and in vitro models of peripheral neuropathy. Thus, HDAC6 inhibitors are being investigated as potential therapies for multiple peripheral neuropathic disorders. Here, we review emerging studies and integrate recent advances in understanding the unique connection between peripheral neuropathy and mitochondrial dysfunction through HDAC6-mediated interactions.

scholarly journals The E3 ligase MARCH5 is a PPARγ target gene that regulates mitochondria and metabolism in adipocytes

2019 ◽  
Vol 316 (2) ◽  
pp. E293-E304 ◽  
Author(s):  
Simon T. Bond ◽  
Sarah C. Moody ◽  
Yingying Liu ◽  
Mete Civelek ◽  
Claudio J. Villanueva ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Mitochondrial Dynamics ◽  
Mouse Strains ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Metabolic Genes ◽  
And Function

Mitochondrial dynamics refers to the constant remodeling of mitochondrial populations by multiple cellular pathways that help maintain mitochondrial health and function. Disruptions in mitochondrial dynamics often lead to mitochondrial dysfunction, which is frequently associated with disease in rodents and humans. Consistent with this, obesity is associated with reduced mitochondrial function in white adipose tissue, partly via alterations in mitochondrial dynamics. Several proteins, including the E3 ubiquitin ligase membrane-associated RING-CH-type finger 5 (MARCH5), are known to regulate mitochondrial dynamics; however, the role of these proteins in adipocytes has been poorly studied. Here, we show that MARCH5 is regulated by peroxisome proliferator-activated receptor-γ (PPARγ) during adipogenesis and is correlated with fat mass across a panel of genetically diverse mouse strains, in ob/ob mice, and in humans. Furthermore, manipulation of MARCH5 expression in vitro and in vivo alters mitochondrial function, affects cellular metabolism, and leads to differential regulation of several metabolic genes. Thus our data demonstrate an association between mitochondrial dynamics and metabolism that defines MARCH5 as a critical link between these interconnected pathways.

scholarly journals Ammonium Glycyrrhizinate Prevents Apoptosis and Mitochondrial Dysfunction Induced by High Glucose in SH-SY5Y Cell Line and Counteracts Neuropathic Pain in Streptozotocin-Induced Diabetic Mice

Biomedicines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 608
Author(s):  
Laura Ciarlo ◽  
Francesca Marzoli ◽  
Paola Minosi ◽  
Paola Matarrese ◽  
Stefano Pieretti
Keyword(s):  
Neuropathic Pain ◽  
Peripheral Neuropathy ◽  
High Glucose ◽  
Diabetic Peripheral Neuropathy ◽  
Glycyrrhizic Acid ◽  
Repeated Treatment ◽  
Diabetic Mice ◽  
Painful Condition

Glycyrrhiza glabra, commonly known as liquorice, contains several bioactive compounds such as flavonoids, sterols, triterpene, and saponins; among which, glycyrrhizic acid, an oleanane-type saponin, is the most abundant component in liquorice root. Diabetic peripheral neuropathy is one of the major complications of diabetes mellitus, leading to painful condition as neuropathic pain. The pathogenetic mechanism of diabetic peripheral neuropathy is very complex, and its understanding could lead to a more suitable therapeutic strategy. In this work, we analyzed the effects of ammonium glycyrrhizinate, a derivate salt of glycyrrhizic acid, on an in vitro system, neuroblastoma cells line SH-SY5Y, and we observed that ammonium glycyrrhizinate was able to prevent cytotoxic effect and mitochondrial fragmentation after high-glucose administration. In an in vivo experiment, we found that a short-repeated treatment with ammonium glycyrrhizinate was able to attenuate neuropathic hyperalgesia in streptozotocin-induced diabetic mice. In conclusion, our results showed that ammonium glycyrrhizinate could ameliorate diabetic peripheral neuropathy, counteracting both in vitro and in vivo effects induced by high glucose, and might represent a complementary medicine for the clinical management of diabetic peripheral neuropathy.

scholarly journals Quercetin Affects Erythropoiesis and Heart Mitochondrial Function in Mice

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Lina M. Ruiz ◽  
Celia Salazar ◽  
Erik Jensen ◽  
Paula A. Ruiz ◽  
William Tiznado ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Serum Insulin ◽  
Food Supplement ◽  
Prooxidant Effect ◽  
Mitofusin 2 ◽  
Cellular Models ◽  
Voltage Dependent ◽  
Dietary Flavonoid

Quercetin, a dietary flavonoid used as a food supplement, showed powerful antioxidant effects in different cellular models. However, recentin vitroandin vivostudies in mammals have suggested a prooxidant effect of quercetin and described an interaction with mitochondria causing an increase inO2∙-production, a decrease in ATP levels, and impairment of respiratory chain in liver tissue. Therefore, because of its dual actions, we studied the effect of quercetinin vivoto analyze heart mitochondrial function and erythropoiesis. Mice were injected with 50 mg/kg of quercetin for 15 days. Treatment with quercetin decreased body weight, serum insulin, and ceruloplasmin levels as compared with untreated mice. Along with an impaired antioxidant capacity in plasma, quercetin-treated mice showed a significant delay on erythropoiesis progression. Heart mitochondrial function was also impaired displaying more protein oxidation and less activity for IV, respectively, than no-treated mice. In addition, a significant reduction in the protein expression levels of Mitofusin 2 and Voltage-Dependent Anion Carrier was observed. All these results suggest that quercetin affects erythropoiesis and mitochondrial function and then its potential use as a dietary supplement should be reexamined.

scholarly journals Tracking Macrophages in Diabetic Neuropathy With Two-Color Nanoemulsions for Near-Infrared Fluorescent Imaging and Microscopy

2021 ◽  
Author(s):  
James M. Nichols ◽  
Caitlin V. Crelli ◽  
Lu Liu ◽  
Hoang Vu Pham ◽  
Jelena M. Janjic ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Diabetic Peripheral Neuropathy ◽  
Colloidal Stability ◽  
Near Infrared ◽  
Fluorescent Imaging ◽  
Wild Type ◽  
Infra Red ◽  
Peripheral Sensory

Abstract Background The incidence of diabetes and diabetic peripheral neuropathy continues to rise, and studies have shown that macrophages play an important role in their pathogenesis. Here we present a novel two-color fluorescently labeled perfluorocarbon nanoemulsion to monitor phagocytic macrophages in vitro and in vivo using non-invasive near infrared fluorescence imaging and fluorescence microscopy in diabetic neuropathy. We next applied this nanoemulsion to the Leprdb/db model of Type 2 Diabetes Mellitus to track macrophages along the length of the peripheral sensory pathway of the hindlimb, where diabetic peripheral neuropathy tends to originate. Methods In vitro assessment of the nanoemulsion was performed by measuring fluorescent signal stability, colloidal stability, and macrophage uptake and subsequent viability. In vivo tracking of the nanoemulsion within Leprdb/db and wild-type mice was performed using both near infra-red fluorescent imaging and confocal microscopy to assess its biodistribution within phagocytic macrophages along the peripheral sensory apparatus of the hindlimb. Results In vitro experiments show two-color nanoemulsion had high levels of fluorescent and colloidal stability, and that it was readily incorporated into RAW 264.7 macrophages. In vivo tracking revealed distribution of the two-color nanoemulsion to macrophages within most tissues of Leprdb/db and wild-type mice which persisted for several weeks, however it did not cross the blood brain barrier. Reduced fluorescence was seen in sciatic nerves of both Leprdb/db and wildtype mice, implying that the nanoemulsion may also have difficulty crossing an intact blood nerve barrier. Additionally, distribution of the nanoemulsion in Lepr db/db mice was reduced in several tissues as compared to wild-type mice. This reduction in biodistribution appears to be caused by the increased number of adipose tissue macrophages in Leprdb/db mice. Conclusions The nanoemulsion in this study has the ability to identify phagocytic macrophages in the Leprdb/db model using both near infra-red fluorescent imaging and fluorescence microscopy. Based on the drug loading capacity of this new nanoemulsion and the role of inflammatory macrophages in diabetes, we foresee this agent being a useful tool in the assessment and treatment of diabetic peripheral neuropathy.

scholarly journals PIAS1 alleviates diabetic peripheral neuropathy through SUMOlation of PPAR-γ and miR-124-induced downregulation of EZH2/STAT3

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Zixin Hou ◽  
Ji Chen ◽  
Huan Yang ◽  
Xiaoling Hu ◽  
Fengrui Yang
Keyword(s):  
Peripheral Neuropathy ◽  
Schwann Cells ◽  
Diabetic Peripheral Neuropathy ◽  
Nerve Tissue ◽  
In Vitro Assays ◽  
In Vivo Experiments ◽  
Ppar Γ ◽  
Gene Reporter Assay

AbstractDiabetic peripheral neuropathy (DPN) is a frequently occurring chronic complication of diabetes. In this study, we aim to explore the regulatory mechanism of protein inhibitor of activated STAT1 (PIAS1) in DPN in terms of autophagy and apoptosis of Schwann cells. The SUMOlation of PPAR-γ by PIAS1 was examined, and ChIP was performed to verify the binding of PPAR-γ to miR-124 promoter region. Dual-luciferase gene reporter assay was used to validate the binding affinity between miR-124 and EZH2/STAT3. Following loss‐ and gain‐of-function experiments, in vitro assays in high glucose-treated Schwann cells (SC4) and in vivo assays in db/db and ob/ob mice were performed to detect the effects of PIAS1 on autophagy and apoptosis of Schwann cells as well as symptoms of DPN by regulating the PPAR-γ-miR-124-EZH2/STAT3. The expression of PIAS1, PPAR-γ, and miR-124 was downregulated in the sciatic nerve tissue of diabetic mice. PIAS1 enhanced the expression of PPAR-γ through direct binding and SUMOlation of PPAR-γ. PPAR-γ enhanced the expression of miR-124 by enhancing the promoter activity of miR-124. Furthermore, miR-124 targeted and inversely modulated EZH2 and STAT3, promoting the autophagy of Schwann cells and inhibiting their apoptosis. In vivo experiments further substantiated that PIAS1 could promote the autophagy and inhibit the apoptosis of Schwann cells through the PPAR-γ-miR-124-EZH2/STAT3 axis. In conclusion, PIAS1 promoted SUMOlation of PPAR-γ to stabilize PPAR-γ expression, which upregulated miR-124 to inactivate EZH2/STAT3, thereby inhibiting apoptosis and promoting autophagy of Schwann cells to suppress the development of DPN.

scholarly journals Inhibition of Mitofusin-2 Promotes Cardiac Fibroblast Activation via the PERK/ATF4 Pathway and Reactive Oxygen Species

2019 ◽  
Vol 2019 ◽  
pp. 1-16 ◽  
Author(s):  
Yanguo Xin ◽  
Wenchao Wu ◽  
Jing Qu ◽  
Xiaojiao Wang ◽  
Song Lei ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Mitochondrial Dynamics ◽  
Cardiac Fibroblasts ◽  
Reactive Oxygen ◽  
Cardiac Fibroblast ◽  
Oxygen Species ◽  
Mitofusin 2 ◽  
Fibroblast Activation

Mitofusin-2 (Mfn2) is a key outer mitochondrial membrane protein, which maintains normal mitochondrial dynamics and function. However, its role in cardiac fibroblast activation remains poorly understood. In the present study, a rat model of transverse aortic constriction (TAC) was established to observe the cardiac fibroblast activation in vivo. TGF-β1 treatment for 24 hours was used to induce cardiac fibroblast activation in vitro. As a result, the expression of Mfn2 decreased in the hypertrophic heart tissues and cardiac fibroblasts treated with TGF-β1. siMfn2 and adenovirus were applied to mediate Mfn2 gene silencing and overexpression in cardiac fibroblasts to elucidate the relationship between Mfn2 and cardiac fibroblast activation, as well as the possible underlying mechanisms. Knockdown of Mfn2 further promoted TGF-β1-induced cardiac fibroblast activation, while forced expression of Mfn2 attenuated this pathological reaction. The PERK/ATF4 pathway, one of the branches of endoplasmic reticulum (ER) stress, was identified to be involved in this process. Knockdown and overexpression of Mfn2 lead to aggravation or alleviation of the PERK/ATF4 pathway. Blocking this pathway by silencing ATF4 with siATF4 attenuated the pathological process. During the activation of cardiac fibroblasts, knockdown of Mfn2 also increased the production of reactive oxygen species (ROS), while ROS scavenger N-acetyl-l-cysteine (NAC) could attenuate the effect caused by knockdown of Mfn2. Our data suggested that inhibition of Mfn2 could promote cardiac fibroblast activation by activating the PERK/ATF4 signaling pathway and increasing the generation of ROS.

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