bims-nadaut 2023-08-06 papers

bims-nadaut

Biomed News

on NAD and autophagy

Issue of 2023‒08‒06
eighteen papers selected by
Niall Wilson
Newcastle University

Mitochondrial quality control in hepatic ischemia-reperfusion injury.
Peroxisom proliferator-activated receptor-γ coactivator-1α in neurodegenerative disorders: A promising therapeutic target.
HOTAIRM1 knockdown reduces MPP+-induced oxidative stress injury of SH-SY5Y cells by activating the Nrf2/HO-1 pathway.
Plausible Role of Mitochondrial DNA Copy Number in Neurodegeneration-a Need for Therapeutic Approach in Parkinson's Disease (PD).
UCP1 alleviates renal interstitial fibrosis progression through oxidative stress pathway mediated by SIRT3 protein stability.
Accumulation of TERT in mitochondria exerts two opposing effects on apoptosis.
Resveratrol promotes mitochondrial energy metabolism in exercise-induced fatigued rats.
Promoting axon regeneration by inhibiting RNA N6-methyladenosine demethylase ALKBH5.
The role of dynamin-related protein 1 in cerebral ischemia/hypoxia injury.
Aging, oxidative stress and degenerative diseases: mechanisms, complications and emerging therapeutic strategies.
LncRNA NORAD defects deteriorate the formation of age-related macular degeneration.
Methylene Blue Reduces Retinal Cell Inflammation, Apoptosis, and Oxidative Stress in a Rat Model of Diabetic Retinopathy via Sirtuin 1 Activation.
Mitochondrial biogenesis and apoptosis as underlying mechanisms involved in the cardioprotective effects of Gallic acid against D-galactose-induced aging.
PGC-1α Inhibits Schwann Cell Dedifferentiation and Delays Peripheral Nerve Degeneration by Targeting PON1.
Hexahydrocurcumin mitigates angiotensin II-induced proliferation, migration, and inflammation in vascular smooth muscle cells.
Olaparib Attenuates Demyelination and Neuroinflammation in an Organotypic Slice Culture Model of Metachromatic Leukodystrophy.
Resveratrol ameliorates AGEs-induced thyroid dysfunction: role of oxidative stress, inflammatory cytokines, and mitochondrial damage.
The roles of stress-induced premature senescence and Akt/FoxO1 signaling in periapical lesions.

Heliyon. 2023 Jul;9(7): e17702

Mitochondrial quality control in hepatic ischemia-reperfusion injury.

LiuSong Wang, Zan Jie Feng, Xuan Ma, Kai Li, Xin Yao Li, Yi Tang, Cijun Peng.

  Hepatic ischemia-reperfusion injury is a phenomenon in which exacerbating damage of liver cells due to restoration of blood flow following ischemia during liver surgery, especially those involving liver transplantation. Mitochondria, the energy-producing organelles, are crucial for cell survival and apoptosis and have evolved a range of quality control mechanisms to maintain homeostasis in the mitochondrial network in response to various stress conditions. Hepatic ischemia-reperfusion leads to disruption of mitochondrial quality control mechanisms, as evidenced by reduced mitochondrial autophagy, excessive division, reduced fusion, and inhibition of biogenesis. This leads to dysfunction of the mitochondrial network. The accumulation of damaged mitochondria ultimately results in apoptosis of hepatocytes due to the release of apoptotic proteins like cytochrome C. This worsens hepatic ischemia-reperfusion injury. Currently, hepatic ischemia-reperfusion injury protection is being studied using different approaches such as drug pretreatment, stem cells and exosomes, genetic interventions, and mechanical reperfusion, all aimed at targeting mitochondrial quality control mechanisms. This paper aims to provide direction for future research on combating HIRI by reviewing the latest studies that focus on targeting mitochondrial quality control mechanisms.

Keywords:  Hepatic ischemia-reperfusion injury; Mitochondrial biogenesis; Mitochondrial dynamics; Mitochondrial quality control mechanisms; Mitophagy

DOI:  https://doi.org/10.1016/j.heliyon.2023.e17702
Biochem Pharmacol. 2023 Jul 28. pii: S0006-2952(23)00308-8. [Epub ahead of print]215 115717

Peroxisom proliferator-activated receptor-γ coactivator-1α in neurodegenerative disorders: A promising therapeutic target.

Ya-Na Yang, Mao-Qing Zhang, Feng-Lin Yu, Bing Han, Ming-Yue Bao, Yan-He, Xing Li, Yuan Zhang.

  Neurodegenerative disorders (NDDs) are characterized by progressive loss of selectively vulnerable neuronal populations and myelin sheath, leading to behavioral and cognitive dysfunction that adversely affect the quality of life. Identifying novel therapies that attenuate the progression of NDDs would be of significance. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), a widely expressed transcriptional regulator, modulates the expression of genes engaged in mitochondrial biosynthesis, metabolic regulation, and oxidative stress (OS). Emerging evidences point to the strong connection between PGC-1α and NDDs, suggesting its positive impaction on the progression of NDDs. Therefore, it is urgent to gain a deeper and broader understanding between PGC-1α and NDDs. To this end, this review presents a comprehensive overview of PGC-1α, including its basic characteristics, the post-translational modulations, as well as the interacting transcription factors. Secondly, the pathogenesis of PGC-1α in various NDDs, such as Alzheimer's (AD), Parkinson's (PD), and Huntington's disease (HD) is briefly discussed. Additionally, this study summarizes the underlying mechanisms that PGC-1α is neuroprotective in NDDs via regulating neuroinflammation, OS, and mitochondrial dysfunction. Finally, we briefly outline the shortcomings of current NDDs drug therapy, and summarize the functions and potential applications of currently available PGC-1α modulators (activator or inhibitors). Generally, this review updates our insight of the important role of PGC-1α on the development of NDDs, and provides a promising therapeutic target/ drug for the treatment of NDDs.

Keywords:  Mitochondrial dysfunction; Neurodegenerative disorders; Neuroinflammation; Oxidative stress; Peroxisome proliferator-activated receptor γ coactivator-1α

DOI:  https://doi.org/10.1016/j.bcp.2023.115717
Transl Neurosci. 2023 Jan 01. 14(1): 20220296

HOTAIRM1 knockdown reduces MPP+-induced oxidative stress injury of SH-SY5Y cells by activating the Nrf2/HO-1 pathway.

Hui-Yu Dai, Ming-Xiu Chang, Ling Sun.

  Objective: Parkinson's disease (PD) is the second most common neurodegenerative disease with complex pathogenesis. Although HOXA transcript antisense RNA myeloid-specific 1 (HOTAIRM1) is upregulated in PD, its exact role in HOTAIRM1 is seldom reported. The purpose of this study is to research the effect of HOTAIRM1 on 1-methyl-4-phenylpyridonium (MPP+)-induced cytotoxicity and oxidative stress in SH-SY5Y cells.Methods: SH-SY5Y cells were treated with MPP+ at various concentrations or time points to induce SH-SY5Y cytotoxicity, so as to determine the optimal MPP+ concentration and time point. HOTAIRM1 expression upon MPP+ treatment was analyzed through qRT-PCR. Next, HOTAIRM1 was downregulated to observe the variance of SH-SY5Y cell viability, apoptosis, oxidative stress-related indexes, and protein levels of the Nrf2/HO-1 pathway. In addition, rescue experiments were carried out to assess the role of Nrf2 silencing in HOTAIRM1 knockdown on MPP+-induced oxidative stress in SH-SY5Y cells.
Results: MPP+ treatment-induced cytotoxicity and upregulated HOTAIRM1 expression in SH-SY5Y cells in a dose- and time-dependent manner. Mechanically, HOTAIRM1 knockdown enhanced cell viability, limited apoptosis, and oxidative stress, therefore protecting SH-SY5Y cells from MPP+-induced SH-SY5Y cytotoxicity. On the other hand, HOTAIRM1 knockdown activated the protein levels of Nrf2 and HO-1. Nrf2 silencing could counteract the neuroprotective effect of HOTAIRM1 knockdown on in vitro PD model.
Conclusion: Our data demonstrated that HOTAIRM1 knockdown could inhibit apoptosis and oxidative stress and activated the Nrf2/HO-1 pathway, therefore exerting neuroprotective effect on the PD cell model.

Keywords:  HOXA transcript antisense RNA myeloid-specific 1,1-methyl-4-phenylpyridonium; Nrf2/HO-1; Parkinson’s disease; oxidative stress

DOI:  https://doi.org/10.1515/tnsci-2022-0296
Mol Neurobiol. 2023 Jul 31.

Plausible Role of Mitochondrial DNA Copy Number in Neurodegeneration-a Need for Therapeutic Approach in Parkinson's Disease (PD).

Dhivya Venkatesan, Mahalaxmi Iyer, Arul Narayanasamy, Abilash Valsala Gopalakrishnan, Balachandar Vellingiri.

  Parkinson's disease (PD) is an advancing age-associated progressive brain disorder which has various diverse factors, among them mitochondrial dysfunction involves in dopaminergic (DA) degeneration. Aging causes a rise in mitochondrial abnormalities which leads to structural and functional modifications in neuronal activity and cell death in PD. This ends in deterioration of mitochondrial function, mitochondrial alterations, mitochondrial DNA copy number (mtDNA CN) and oxidative phosphorylation (OXPHOS) capacity. mtDNA levels or mtDNA CN in PD have reported that mtDNA depletion would be a predisposing factor in PD pathogenesis. To maintain the mtDNA levels, therapeutic approaches have been focused on mitochondrial biogenesis in PD. The depletion of mtDNA levels in PD can be influenced by autophagic dysregulation, apoptosis, neuroinflammation, oxidative stress, sirtuins, and calcium homeostasis. The current review describes the regulation of mtDNA levels and discusses the plausible molecular pathways in mtDNA CN depletion in PD pathogenesis. We conclude by suggesting further research on mtDNA depletion which might show a promising effect in predicting and diagnosing PD.

Keywords:  Copy number; Mitochondrial DNA; Molecular pathways; Parkinson’s disease; TFAM; Therapeutic strategies

DOI:  https://doi.org/10.1007/s12035-023-03500-x
J Transl Med. 2023 08 02. 21(1): 521

UCP1 alleviates renal interstitial fibrosis progression through oxidative stress pathway mediated by SIRT3 protein stability.

Wei Xiong, Zhiyong Xiong, Anni Song, Chuntao Lei, Chen Ye, Hua Su, Chun Zhang.

  BACKGROUND: Renal interstitial fibrosis is a common pathway for the progressive development of chronic renal diseases (CKD) with different etiology, and is the main pathological basis leading to end-stage renal disease. Although the current research on renal interstitial fibrosis is gradually deepening, the diagnosis and treatment methods are still very lacking. Uncoupling protein 1 (UCP1) is a nuclear encoded protein in mitochondria inner membrane and plays an important role in regulating energy metabolism and mitochondrial homeostasis. However, the biological significance of UCP1 and potential regulatory mechanisms in the development of CKD remain unclear.METHODS: Unilateral ureteral obstruction (UUO) model was used to construct the animal model of renal fibrosis, and TGF-β1 stimulation of HK2 cells was used to construct the vitro model of renal fibrosis. UCP1 expression was detected by Western blot, immunoblot analysis and immunohistochemistry. UCP1 was upregulated by UCP1 overexpressing lentivirus and UCP1 agonist CL316243. Western blot and immunofluorescence were used to detect epithelial mesenchymal transition (EMT)-related markers, such as collagen I, fibronectin, antioxidant enzyme SOD2 and CAT. Reactive oxygen species (ROS) production was detected by ROS detection kit. SIRT3 knockdown was performed by siRNA.
RESULTS: This study presents that UCP1 is significantly downregulated in patients with renal fibrosis and UUO model. Further studies discover that UCP1 overexpression and CL316243 treatments (UCP1 agonists) reversed EMT and extracellular matrix (ECM) accumulation in renal fibrosis models in vivo and in vitro. Simultaneously, UCP1 reduced the ROS production by increasing the stability of SIRT3. When SIRT3 was knocked down, the production of ROS decreased.
CONCLUSIONS: Elevating the expression of UCP1 can inhibit the occurrence of oxidative stress by stabilizing SIRT3, thereby reducing EMT and ECM accumulation, and ultimately alleviating renal interstitial fibrosis. It will provide new instructions and targets for the treatment of CKD.

Keywords:  Chronic kidney disease (CKD); Reactive oxygen species (ROS); Renal interstitial fibrosis; SIRT3; UCP1

DOI:  https://doi.org/10.1186/s12967-023-04376-0
FEBS Open Bio. 2023 Jul 31.

Accumulation of TERT in mitochondria exerts two opposing effects on apoptosis.

Hiroshi Ebata, Tomohiro Shima, Ryo Iizuka, Sotaro Uemura.

  Telomerase reverse transcriptase (TERT) is a protein that catalyzes the reverse transcription of telomere elongation. TERT is also expected to play a noncanonical role beyond telomere lengthening since it localizes not only in the nucleus but also in mitochondria, where telomeres do not exist. Several studies have reported that mitochondrial TERT regulates apoptosis induced by oxidative stress. However, there is still some controversy as to whether mitochondrial TERT promotes or inhibits apoptosis, mainly due to the lack of information on changes in TERT distribution in individual cells over time. Here, we simultaneously detected apoptosis and TERT localization after oxidative stress in individual HeLa cells by live-cell tracking. Single-cell tracking revealed that the stress-induced accumulation of TERT in mitochondria caused apoptosis, but that accumulation increased over time until cell death. The results suggest a new model in which mitochondrial TERT has two opposing effects at different stages of apoptosis: it predetermines apoptosis at the first stage of cell-fate determination, but also delays apoptosis at the second stage. As such, our data support a model that integrates the two opposing hypotheses on mitochondrial TERT's effect on apoptosis. Furthermore, detailed statistical analysis of TERT mutations, which have been predicted to inhibit TERT transport to mitochondria, revealed that these mutations suppress apoptosis independent of mitochondrial localization of TERT. Together, these results imply that the non-canonical functions of TERT affect a wide range of mitochondria-dependent and mitochondria-independent apoptosis pathways.

Keywords:  Apoptosis; Live-cell Imaging; Mitochondria; Oxidative Stress; TERT

DOI:  https://doi.org/10.1002/2211-5463.13682
Nutr Res Pract. 2023 Aug;17(4): 660-669

Resveratrol promotes mitochondrial energy metabolism in exercise-induced fatigued rats.

Xujia Lou, Yulong Hu, Rong Ruan, Qiguan Jin.

  BACKGROUND/OBJECTIVES: To investigate the effect and regulatory mechanism of resveratrol supplementation on the mitochondrial energy metabolism of rats with exercise-induced fatigue.MATERIALS/METHODS: Forty-eight Sprague-Dawley male rats were divided randomly into a blank control group (C), resveratrol group (R), exercise group (E), and exercise and resveratrol group (ER), with 12 rats in each group. Group ER and group E performed 6-wk swimming training with 5% wt-bearing, 60 min each time, 6 days a wk. Group ER was given resveratrol 50 mg/kg by gavage one hour after exercise; group R was only given resveratrol 50 mg/kg by gavage; group C and group E were fed normally. The same volume of solvent was given by gavage every day.
RESULTS: Resveratrol supplementation could reduce the plasma blood urea nitrogen content, creatine kinase activity, and malondialdehyde content in the skeletal muscle, increase the total superoxide dismutase activity in the skeletal muscle, and improve the fatigue state. Resveratrol supplementation could improve the activities of Ca2+-Mg2+-ATPase, Na+-K+-ATPase, succinate dehydrogenase, and citrate synthase in the skeletal muscle. Furthermore, resveratrol supplementation could up-regulate the sirtuin 1 (SIRT1)-proliferator-activated receptor gamma coactivator-1α (PGC-1α)-nuclear respiratory factor 1 pathway.
CONCLUSIONS: Resveratrol supplementation could promote mitochondrial biosynthesis via the SIRT1/PGC-1α pathway, increase the activity of the mitochondrial energy metabolism-related enzymes, improve the antioxidant capacity of the body, and promote recovery from exercise-induced fatigue.

Keywords:  Fatigue; energy metabolism; mitochondrial turnover; resveratrol

DOI:  https://doi.org/10.4162/nrp.2023.17.4.660
Elife. 2023 08 03. pii: e85309. [Epub ahead of print]12

Promoting axon regeneration by inhibiting RNA N6-methyladenosine demethylase ALKBH5.

Dong Wang, Tiemei Zheng, Songlin Zhou, Mingwen Liu, Yaobo Liu, Xiaosong Gu, Susu Mao, Bin Yu.

  A key limiting factor of successful axon regeneration is the intrinsic regenerative ability in both the peripheral nervous system (PNS) and central nervous system (CNS). Previous studies have identified intrinsic regenerative ability regulators that act on gene expression in injured neurons. However, it is less known whether RNA modifications play a role in this process. Here, we systematically screened the functions of all common m6A modification-related enzymes in axon regeneration and report ALKBH5, an evolutionarily conserved RNA m6A demethylase, as a regulator of axonal regeneration in rodents. In PNS, knockdown of ALKBH5 enhanced sensory axonal regeneration, whereas overexpressing ALKBH5 impaired axonal regeneration in an m6A-dependent manner. Mechanistically, ALKBH5 increased the stability of Lpin2 mRNA and thus limited regenerative growth associated lipid metabolism in dorsal root ganglion neurons. Moreover, in CNS, knockdown of ALKBH5 enhanced the survival and axonal regeneration of retinal ganglion cells after optic nerve injury. Together, our results suggest a novel mechanism regulating axon regeneration and point ALKBH5 as a potential target for promoting axon regeneration in both PNS and CNS.

Keywords:  ALKBH5; DRG neuron; axon regeneration; m6A; mouse; nerve injury; neuroscience; rat; regenerative medicine; stem cells

DOI:  https://doi.org/10.7554/eLife.85309
Biomed Pharmacother. 2023 Jul 27. pii: S0753-3322(23)01038-7. [Epub ahead of print]165 115247

The role of dynamin-related protein 1 in cerebral ischemia/hypoxia injury.

Yu Huan, Guangzhi Hao, Zuolin Shi, Yong Liang, Yushu Dong, Huilin Quan.

  Mitochondrial dysfunction, especially in terms of mitochondrial dynamics, has been reported to be closely associated with neuronal outcomes and neurological impairment in cerebral ischemia/hypoxia injury. Dynamin-related protein 1 (Drp1) is a cytoplasmic GTPase that mediates mitochondrial fission and participates in neuronal cell death, calcium signaling, and oxidative stress. The neuroprotective role of Drp1 inhibition has been confirmed in several central nervous system disease models, demonstrating that targeting Drp1 may shed light on novel approaches for the treatment of cerebral ischemia/hypoxia injury. In this review, we aimed to highlight the roles of Drp1 in programmed cell death, oxidative stress, mitophagy, and mitochondrial function to provide a better understanding of mitochondrial disturbances in cerebral ischemia/hypoxia injury, and we also summarize the advances in novel chemical compounds targeting Drp1 to provide new insights into potential therapies for cerebral ischemia/hypoxia injury.

Keywords:  Cerebral ischemia-hypoxia injury; Drp1; Mitochondrial fission; Post-translational modification

DOI:  https://doi.org/10.1016/j.biopha.2023.115247
Biogerontology. 2023 Jul 30.

Aging, oxidative stress and degenerative diseases: mechanisms, complications and emerging therapeutic strategies.

Mani Raj Chaudhary, Sakshi Chaudhary, Yogita Sharma, Thokchom Arjun Singh, Alok Kumar Mishra, Shweta Sharma, Mohammad Murtaza Mehdi.

  Aging accompanied by several age-related complications, is a multifaceted inevitable biological progression involving various genetic, environmental, and lifestyle factors. The major factor in this process is oxidative stress, caused by an abundance of reactive oxygen species (ROS) generated in the mitochondria and endoplasmic reticulum (ER). ROS and RNS pose a threat by disrupting signaling mechanisms and causing oxidative damage to cellular components. This oxidative stress affects both the ER and mitochondria, causing proteopathies (abnormal protein aggregation), initiation of unfolded protein response, mitochondrial dysfunction, abnormal cellular senescence, ultimately leading to inflammaging (chronic inflammation associated with aging) and, in rare cases, metastasis. RONS during oxidative stress dysregulate multiple metabolic pathways like NF-κB, MAPK, Nrf-2/Keap-1/ARE and PI3K/Akt which may lead to inappropriate cell death through apoptosis and necrosis. Inflammaging contributes to the development of inflammatory and degenerative diseases such as neurodegenerative diseases, diabetes, cardiovascular disease, chronic kidney disease, and retinopathy. The body's antioxidant systems, sirtuins, autophagy, apoptosis, and biogenesis play a role in maintaining homeostasis, but they have limitations and cannot achieve an ideal state of balance. Certain interventions, such as calorie restriction, intermittent fasting, dietary habits, and regular exercise, have shown beneficial effects in counteracting the aging process. In addition, interventions like senotherapy (targeting senescent cells) and sirtuin-activating compounds (STACs) enhance autophagy and apoptosis for efficient removal of damaged oxidative products and organelles. Further, STACs enhance biogenesis for the regeneration of required organelles to maintain homeostasis. This review article explores the various aspects of oxidative damage, the associated complications, and potential strategies to mitigate these effects.

Keywords:  Aging; Antioxidant; Autophagy; Degenerative diseases; Inflammation; Oxidative stress

DOI:  https://doi.org/10.1007/s10522-023-10050-1
Aging (Albany NY). 2023 Jul 29. 15

LncRNA NORAD defects deteriorate the formation of age-related macular degeneration.

Jinfeng Zhang, Jing Jiang, Hongyu Zhou, Shenjun Li, Weihua Bian, Lifu Hu, Daolai Zhang, Cong Xu, Yeying Sun.

  Long noncoding RNAs (lncRNAs) play important roles in the development of age-related macular degeneration (AMD). However, the effect of long non-coding RNA activated by DNA damage (NORAD) on AMD remains unknown. This study aimed to investigate the effect of NORAD on RPE cell senescence and degeneration. Irradiated adult retinal pigment epithelial cell line-19 (ARPE-19) and sodium iodate-treated mice were used as in vitro and in vivo AMD models. Results showed that irradiation-induced AMD characteristics of ARPE-19 and NORAD-knockdown aggravated cell cycle arrest in the G2/M phase, cell apoptosis and cell senescence along with the increased expression of phosphorylated P53 (p-P53) and P21. AMD factors C3, ICAM-1, APP, APOE, and VEGF-A were also increased by NORAD-knockdown. Moreover, NORAD-knockdown increased irradiation-induced reduction of mitochondrial homeostasis factors, (i.e., TFAM and POLG) and mitochondrial respiratory chain complex genes (i.e., ND1 and ND5) along with mitochondrial reactive oxygen species (ROS). We also identified a strong interaction of NORAD and PGC-1α and sirtuin 1 (SIRT1) in ARPE-19; that is, NORAD knockdown increases the acetylation of PGC-1α. In NORAD knockout mice, NORAD-knockout accelerated the sodium iodate-reduced retinal thickness reduction, function impairment and loss of retinal pigment in the fundus. Therefore, NORAD-knockdown accelerates retinal cell senescence, apoptosis, and AMD markers via PGC-1α acetylation, mitochondrial ROS, and the p-P53-P21signaling pathway, in which NORAD-mediated effect on PGC-1α acetylation might occur through the direct interaction with PGC-1α and SIRT1.

Keywords:  LncRNA NORAD; PGC-1α; SIRT1; age-related macular degeneration; senescence

DOI:  https://doi.org/10.18632/aging.204917
Altern Ther Health Med. 2023 Aug 04. pii: AT8514. [Epub ahead of print]

Methylene Blue Reduces Retinal Cell Inflammation, Apoptosis, and Oxidative Stress in a Rat Model of Diabetic Retinopathy via Sirtuin 1 Activation.

Huade Mai, Chenghong Liu, Biwei Fu, Xinbo Ji, Minghui Chen, Yunbo Zhang, Yunyun Lin, Juming Chen, Yanling Song, Shenhong Gu.

Objective: Diabetic retinopathy (DR), characterized by neuronal damage in the retina, is primarily driven by oxidative stress resulting from diabetes (DM). This study investigated the potential effects of methylene blue (MB) on streptozotocin (STZ)-induced DR.Methods: A rat model of DR was established via STZ injection, while a cell model was created using high-glucose (HG) exposure of human retinal microvascular endothelial cells. Evaluation of oxidative stress markers, pro-inflammatory cytokines, and pro-apoptotic proteins was performed based on their expression profiles in human retinal microvascular endothelial cells.
Results: MB treatment significantly upregulated the expression of sirtuin 1 (SIRT1), which was found to be downregulated in the retinal tissues of STZ-treated rats and HG-exposed human retinal microvascular endothelial cells, as determined by polymerase chain reaction (PCR). Furthermore, MB therapy effectively suppressed STZ-induced oxidative stress, inflammation, and cell death. Consistent with the in vivo findings, MB activated the expression of SIRT1, thereby protecting HG-treated human retinal microvascular endothelial cells against oxidative stress, inflammation, and apoptosis.
Conclusion: These results support the conclusion that MB mitigates DR by activating SIRT1, leading to a reduction of inflammation, apoptosis, and oxidative stress.
Mol Biol Rep. 2023 Aug 04.

Mitochondrial biogenesis and apoptosis as underlying mechanisms involved in the cardioprotective effects of Gallic acid against D-galactose-induced aging.

Mohammad Zarei, Abdolrahman Sarihi, Alireza Zamani, Safoura Raoufi, Seyed Asaad Karimi, Fatemeh Ramezani-Aliakbari.

  BACKGROUND: Aging is a main risk factor for the development of cardiovascular diseases (CVDs). Gallic acid (GA) is a phenolic compound derived from a wide range of fruits. GA has a wide spectrum of pharmacological properties, including anti-oxidative, anti-inflammatory, and cardioprotective effects. This research was conducted to determine the cardioprotective effect of GA on cardiac hypertrophy in aged rats.METHODS AND RESULTS: Following histological evaluation and through observing the heart, we found that GA improved the cardiac hypertrophy induced by D-galactose (D-GAL) in cardiac cells. To clarify the causes for this anti-aging effect, we evaluated the malonic dialdehyde levels and antioxidant enzyme activity in rat cardiac tissue. The levels of lactate dehydrogenase (LDH) and creatine kinase (CK-MB) in serum were measured. The levels of genes related to mitochondrial biogenesis, mitophagy, and apoptosis in cardiac tissue were surveyed. The findings represented that GA ameliorated antioxidant enzyme activity while significantly decreasing the malonic dialdehyde levels. Real-time PCR analysis proposed that GA effectively improved mitochondrial biogenesis in the heart via regulating the expression levels of Sirtuin 1 (SIRT1), PPARγ coactivator 1α (PGC1-α), nuclear factor erythroid 2-related factor 2 (Nrf2), and mitochondrial transcription factor A (TFAM). GA also mitigated apoptosis in the heart by modulating the expression levels of B-cell lymphoma protein 2 (Bcl-2) and Bcl-2-associated X (Bax). In addition, GA improved serum LDH and CK-MB levels.
CONCLUSIONS: GA may alleviate aging-induced cardiac hypertrophy via anti-oxidative, mitoprotective, and anti-apoptotic mechanisms.

Keywords:  Aging; Antioxidants; Apoptosis; Gallic acid; Heart; Mitochondria

DOI:  https://doi.org/10.1007/s11033-023-08670-4
Cell Mol Neurobiol. 2023 Aug 01.

PGC-1α Inhibits Schwann Cell Dedifferentiation and Delays Peripheral Nerve Degeneration by Targeting PON1.

Ying Zou, Shu Wu, Fei Wen, Yuanlong Ge, Shengkang Luo.

  PPARγ coactivator-1 alpha (PGC-1α) is an essential transcription factor co-activator that regulates gene transcription and neural regeneration. Schwann cells, which are unique glial cells in peripheral nerves that dedifferentiate after peripheral nerve injury (PNI) and are released from degenerative nerves. Wallerian degeneration is a series of stereotypical events that occurs in response to nerve fibers after PNI. The role of PGC-1α in Schwann cell dedifferentiation and Wallerian degeneration is not yet clear. As Wallerian degeneration plays a crucial role in PNI, we conducted a study to determine whether PGC-1α has an effect on peripheral nerve degeneration after injury. We examined the expression of PGC-1α after sciatic nerve crush or transection using Western blotting and found that PGC-1α expression increased after PNI. Then we utilized ex vivo and in vitro models to investigate the effects of PGC-1α inhibition and activation on Schwann cell dedifferentiation and nerve degeneration. Our findings indicate that PGC-1α negatively regulates Schwann cell dedifferentiation and nerve degeneration. Through the use of RNA-seq, siRNA/plasmid transfection and reversal experiments, we identified that PGC-1α targets inhibit the expression of paraoxonase 1 (PON1) during Schwann cell dedifferentiation in degenerated nerves. In summary, PGC-1α plays a crucial role in preventing Schwann cell dedifferentiation and its activation can reduce peripheral nerve degeneration by targeting PON1. PGC-1α inhibits Schwann cell dedifferentiation and peripheral nerve degeneration. PGC-1α negatively regulates Schwann cell dedifferentiation and peripheral nerve degeneration after injury by targeting PON1.

Keywords:  Dedifferentiation; PGC-1α; Peripheral nerve injury; Schwann cell; Wallerian degeneration

DOI:  https://doi.org/10.1007/s10571-023-01395-9
EXCLI J. 2023 ;22 466-481

Hexahydrocurcumin mitigates angiotensin II-induced proliferation, migration, and inflammation in vascular smooth muscle cells.

Luckika Panthiya, Jiraporn Tocharus, Waraluck Chaichompoo, Apichart Suksamrarn, Chainarong Tocharus.

  The proliferation and migration of vascular smooth muscle cells (VSMCs) play vital roles in the pathogenesis of atherosclerosis and hypertension. It has been proposed and verified that hexahydrocurcumin (HHC), a metabolite form of curcumin, has cardiovascular protective effects. This study examined the effect of HHC on angiotensin II (Ang II)-induced proliferation, migration, and inflammation in rat aortic VSMCs and explored the molecular mechanisms related to the processes. The results showed that HHC significantly suppressed Ang II-induced proliferation, migration, and inflammation in VSMCs. HHC inhibited Ang II-induction of the increase in cyclin D1 and decrease in p21 expression in VSMCs. Moreover, HHC attenuated the generation of reactive oxygen species (ROS), and the expression of nuclear factor kappa B (NF-κB), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and matrix metalloproteinases-9 (MMP9) in Ang II-induced VSMCs. The proliferation, migration, inflammation, and ROS production were also inhibited by GKT137831 (NADPH oxidase, NOX1/4 inhibitor) and the combination of HHC and GKT137831. In addition, HHC restored the Ang-II inhibited expression of peroxisome proliferator-activated receptor-γ (PPAR-γ) and peroxisome proliferator activated receptor-γ coactivator-1α (PGC-1α). These findings indicate that HHC may play a protective role in Ang II-promoted proliferation, migration, and inflammation by suppressing NADPH oxidase mediated ROS generation and elevating PPAR-γ and PGC-1α expression. See also Figure 1(Fig. 1).

Keywords:  angiotensin II; hexahydrocurcumin; inflammation; migration; proliferation; vascular smooth muscle cell

DOI:  https://doi.org/10.17179/excli2023-6124
Neurotherapeutics. 2023 Jul 31.

Olaparib Attenuates Demyelination and Neuroinflammation in an Organotypic Slice Culture Model of Metachromatic Leukodystrophy.

Marianna Mekhaeil, Melissa Jane Conroy, Kumlesh Kumar Dev.

  Metachromatic leukodystrophy (MLD) is a severe demyelinating, autosomal recessive genetic leukodystrophy. The disease is underpinned by mutations in the arylsulfatase A gene (ARSA), resulting in deficient activity of the arylsulfatase A lysosomal enzyme and consequential accumulation of galactosylceramide-3-O-sulfate (sulfatide) in the brain. Using an ex vivo murine-derived organotypic cerebellar slice culture model, we demonstrate that sulfatide induces demyelination in a concentration-dependent manner. Interestingly, our novel data demonstrate that sulfatide-induced demyelination is underpinned by PARP-1 activation, oligodendrocyte loss, pro-inflammatory cytokine expression, astrogliosis, and microgliosis. Moreover, such sulfatide-induced effects can be attenuated by the treatment with the poly (ADP-ribose) polymerase 1 (PARP-1) inhibitor Olaparib (IC50∼100 nM) suggesting that this small molecule may be neuroprotective and limit toxin-induced demyelination. Our data support the idea that sulfatide is a key driver of demyelination and neuroinflammation in MLD and suggest that PARP-1 inhibitors have therapeutic utility in the sphere of rare demyelinating disease.

Keywords:  Cerebellum; Demyelination; Neuro-inflammation; Olaparib; Organotypic slice cultures; PARP-1

DOI:  https://doi.org/10.1007/s13311-023-01409-w
Panminerva Med. 2023 Aug 01.

Resveratrol ameliorates AGEs-induced thyroid dysfunction: role of oxidative stress, inflammatory cytokines, and mitochondrial damage.

Chunjie Lin, Qi Zhou, Weihui Yu, Wenyue Liu, Feifei Jiang, Wenwen Chen, Xiaojun Chen.

DOI: https://doi.org/10.23736/S0031-0808.23.04944-3
Oral Dis. 2023 Aug 02.

The roles of stress-induced premature senescence and Akt/FoxO1 signaling in periapical lesions.

Qian Liu, Shue Li, Ting Tang, Yan Wu.

  OBJECTIVES: There is little knowledge about oxidative stress-induced senescence involvement in apical periodontitis. Here, we explored its molecular mechanism in periapical lesions.METHODS: Ten cases of radicular cysts and five cases of periapical granulomas were randomly selected. Immunohistochemical analysis was performed to detect the expression and correlation between Senescence-associated factor polymerase I and transcript release factor (PTRF) and Akt/FoxO1 signaling. Human periodontal ligament cells (hPDLCs) pretreated with LY294002 were exposed to H2 O2 -induced oxidative stress conditions and then cell proliferation, senescence, apoptosis, and associated signaling were evaluated by EdU labeling, β-galactosidase assay, RT-qPCR, and western blot analysis, respectively.
RESULTS: Polymerase I and transcript release factor and Akt/FoxO1 signaling were more frequently expressed in the radicular cyst than in periapical granulomas. Notably, cells in radicular cysts showed Akt activation, FoxO1 phosphorylation, and cytoplasmic translocation. In vitro, prominent H2 O2 -induced senescence was observed in hPDLCs. LY294002, a PI3K inhibitor, attenuated the expression levels of senescence (Klotho, P16INK4), apoptosis (Bad, Fas), phosphorylated Akt, and phosphorylated FoxO1; however, did not affect cell proliferation.
CONCLUSIONS: Our data indicated that senescence is present in clinical periapical lesions, and Akt/FoxO1 signaling is involved in the H2 O2 -induced cellular senescence, which could serve as a potential therapeutic target.

Keywords:  Akt; FoxO1; FoxO1 phosphorylation; periapical lesions; radicular cysts; senescence

DOI:  https://doi.org/10.1111/odi.14703