bims-mistre 2024-12-29 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2024–12–29
twenty-one papers selected by
Ellen Siobhan Mitchell, MitoQ

Puerarin Protects Myocardium From Ischaemia/Reperfusion Injury by Inhibiting Ferroptosis Through Downregulation of VDAC1.
An update on the role of ferroptosis in ischemic stroke: from molecular pathways to Neuroprotection.
Identification of VDAC1 as a cardioprotective target of Ginkgolide B.
Harnessing ROS Amplification and GSH Depletion Using a Carrier-Free Nanodrug to Enhance Ferroptosis-Based Cancer Therapy.
Quercetin attenuates the symptoms of osteoarthritis in vitro and in vivo by suppressing ferroptosis via activation of AMPK/Nrf2/Gpx4 signaling.
Mitochondrial fatty acid oxidase CPT1A ameliorates postoperative cognitive dysfunction by regulating astrocyte ferroptosis.
Nuclear respiratory factor-1 (NRF1) induction drives mitochondrial biogenesis and attenuates amyloid beta-induced mitochondrial dysfunction and neurotoxicity.
Resveratrol promotes autophagosome elimination via SIRT1 in cardiomyocytes.
Ferroptosis, a therapeutic target for cardiovascular diseases, neurodegenerative diseases and cancer.
The Mitochondria-Targeted Micelle Inhibits Alzheimer's Disease Progression by Alleviating Neuronal Mitochondrial Dysfunction and Neuroinflammation.
Penilumamide, a novel SIRT1 activator, protects UVB-induced photodamages in HaCaT cells.
Resveratrol alleviates reactive oxygen species and inflammation in diabetic retinopathy via SIRT1/HMGB1 pathway-mediated ferroptosis.
Investigating the neuroprotective properties of Sargassum wightii extract against MPP+-induced apoptosis in SH-SY5Y human neuroblastoma cells.
Aconitine promotes ROS-activated P38/MAPK/Nrf2 pathway to inhibit autophagy and promote myocardial injury.
Omics-based analysis of mitochondrial dysfunction and BBB integrity in post-COVID-19 sequelae.
Urolithin A attenuates Doxorubicin-induced cardiotoxicity by enhancing PINK1-regulated mitophagy via Ambra1.
Mechanisms of He Shi Yu Lin formula in treating premature ovarian insufficiency: insights from network pharmacology and animal experiments.
Sulforaphane Induces Transient Reactive Oxygen Species-Mediated DNA Damage in HeLa Cells.
Overexpression of Growth Differentiation Factor 15 Reduces Neuronal Cell Damage Induced by Oxygen-Glucose Deprivation/Reoxygenation via Inhibiting Endoplasmic Reticulum Stress-Mediated Ferroptosis.
The complex interplay between redox dysregulation and mTOR signaling pathway in cancer: A rationale for cancer treatment.
Influence of the Microbial Metabolite Acetyl Phosphate on Mitochondrial Functions Under Conditions of Exogenous Acetylation and Alkalization.

J Cell Mol Med. 2024 Dec;28(24): e70313

Puerarin Protects Myocardium From Ischaemia/Reperfusion Injury by Inhibiting Ferroptosis Through Downregulation of VDAC1.

Fajia Hu, Tie Hu, Andi He, Yong Yuan, Xiuqi Wang, Chenchao Zou, Yamei Qiao, Huaihan Xu, Lanxiang Liu, Qun Wang, Jichun Liu, Songqing Lai, Huang Huang.

  Despite improvements in interventional techniques leading to faster myocardial reperfusion postmyocardial infarction, there has been a significant rise in the occurrence of myocardial ischaemia/reperfusion injury (MI/RI). A deeper understanding of the underlying mechanisms of MI/RI could offer a crucial approach to reducing myocardial damage and enhancing patient outcomes. This study examined the myocardial protective properties of puerarin (PUE) in the context of MI/RI using hypoxia/reoxygenation (H/R) or ischaemia/reperfusion (I/R) injury models were employed in H9c2 cells and C57BL/6 mice. Our findings demonstrate that pretreatment with PUE effectively mitigated cardiomyocyte ferroptosis, restored redox balance, preserved mitochondrial energy production and maintained mitochondrial function following MI/RI. Furthermore, these cardioprotective effects of PUE were found to be mediated by the downregulation of voltage-dependent anion channel 1 (VDAC1) protein. These data reveal a novel mechanism by which PUE inhibits MI/RI and reveal that this protective effect of PUE is dependent on the downregulation of VDAC1.

Keywords:  VDAC1; ferroptosis; mitochondria; myocardial ischaemia–reperfusion injury; puerarin

DOI:  https://doi.org/10.1111/jcmm.70313
Expert Opin Ther Targets. 2024 Dec 25. 1-27

An update on the role of ferroptosis in ischemic stroke: from molecular pathways to Neuroprotection.

A Gowtham, Chandan Chauhan, Vikrant Rahi, Ravinder K Kaundal.

   INTRODUCTION: Ischemic stroke (IS), a major cause of mortality and disability worldwide, remains a significant healthcare challenge due to limited therapeutic options. Ferroptosis, a distinct iron-dependent form of regulated cell death characterized by lipid peroxidation and oxidative stress, has emerged as a crucial mechanism in IS pathophysiology. This review explores the role of ferroptosis in IS and its potential for driving innovative therapeutic strategies.
AREA COVERED: This review delves into the practical implications of ferroptosis in IS, focusing on molecular mechanisms like lipid peroxidation, iron accumulation, and their interplay with inflammation, reactive oxygen species (ROS), and the Nrf2-ARE antioxidant system. It highlights ferroptotic proteins, small-molecule inhibitors, and non-coding RNA modulators as emerging therapeutic targets to mitigate neuroinflammation and neuronal cell death. Studies from PubMed (1982-2024) were identified using MeSH terms such as 'Ferroptosis' and 'Ischemic Stroke,' and only rigorously screened articles were included.
EXPERT OPINION: Despite preclinical evidence supporting the neuroprotective effects of ferroptosis inhibitors, clinical translation faces hurdles such as suboptimal pharmacokinetics and safety concerns. Advances in drug delivery systems, bioinformatics, and AI-driven drug discovery may optimize ferroptosis-targeting strategies, develop biomarkers, and improve therapeutic outcomes for IS patients.

Keywords:  ACSL4; Ferroptosis; GPX4; SLC7A11; ischemic stroke

DOI:  https://doi.org/10.1080/14728222.2024.2446319
Chem Biol Interact. 2024 Dec 21. pii: S0009-2797(24)00504-0. [Epub ahead of print]406 111358

Identification of VDAC1 as a cardioprotective target of Ginkgolide B.

Tingbiao Wu, Deyao Li, Qiuyu Chen, Dezhi Kong, Hongxuan Zhu, Hefeng Zhou, Qingwen Zhang, Guozhen Cui.

  Ginkgolide B (GB), a compound derived from Ginkgo biloba, exhibits significant cardioprotective properties, although its precise molecular target has yet to be identified. In this study, we synthesized a biotin-labeled GB probe (GB-biotin) to identify the molecular targets of GB. Our experiments demonstrated that treatment with GB or GB-biotin reduced mitochondrial injury, restored mitochondrial membrane potential, and decreased cell apoptosis in a concentration-dependent manner. Additionally, GB increased mitochondrial oxygen consumption rate, indicating improved mitochondrial bioenergetics. Proteomic analysis revealed that the voltage-dependent anion channel 1 (VDAC1) is a key protein that interacts with GB-biotin. This finding was further confirmed through cellular thermal shift assay (CETSA) and molecular docking, which revealed hydrogen bond formation between GB and VDAC1. Furthermore, overexpression of VDAC1 diminished the protective effects of GB, highlighting the crucial role of VDAC1 in GB-mediated cardioprotection. These findings identify VDAC1 as a therapeutic target for GB in vitro, providing valuable insights into the cardioprotective mechanisms of GB and the development of novel cardioprotective strategies.

Keywords:  Cardioprotection; Ginkgolide B; Hypoxia/reoxygenation; Mitochondrial function; Probe; VDAC1

DOI:  https://doi.org/10.1016/j.cbi.2024.111358
Small. 2024 Dec 26. e2409250

Harnessing ROS Amplification and GSH Depletion Using a Carrier-Free Nanodrug to Enhance Ferroptosis-Based Cancer Therapy.

Huiru Zhang, Guisong Shan, Mengyu Liu, Qiuting Sun, Tianhao Yang, Rui Peng, Xueqian Li, Yuxiao Mei, Xiaoyan He, Lei Qiao.

  Ferroptosis, a non-apoptotic form of cell death characterized by the production of reactive oxygen species (ROS) and massive accumulation of lipid peroxidation (LPO), shows significant promise in cancer therapy. However, the overexpression of glutathione (GSH) at the tumor site and insufficient ROS often result in unsatisfactory therapeutic efficacy. A multistage, GSH-consuming, and ROS-providing carrier-free nanodrug capable of efficiently loading copper ions (Cu2+), sorafenib (SRF), and chlorogenic acid (CGA) (Cu2+-CGA-SRF, CCS-NDs) is developed to mediate enhanced ferroptosis therapy. Through a reductive intracellular environment, Cu2+ in the CCS-NDs reacted with intracellular GSH, alleviating the antioxidant capacity of tumor tissues and triggering the release of drugs. Meanwhile, the released SRF inhibited system xc-, thereby blocking cystine uptake and reducing GSH synthesis in tumor cells. By depleting stored GSH and inhibiting its synthesis, CCS-NDs achieved efficient GSH depletion and increased accumulation of toxic LPO. More importantly, the high concentration of CGA in the CCS-NDs induced ROS generation, further promoting ferroptosis. Both in vitro and in vivo results demonstrated that CCS-NDs effectively triggered ferroptosis in tumor cells by inactivating glutathione peroxidase 4 and inducing LPO. Overall, the carrier-free nanodrug CCS-NDs offer a promising strategy for regulating GSH and LPO levels in ferroptosis-based cancer therapy.

Keywords:  GSH depletion; carrier‐free nanodrugs; drug composition adjustment; ferroptosis; lipid peroxidation

DOI:  https://doi.org/10.1002/smll.202409250
Mol Med Rep. 2025 Mar;pii: 60. [Epub ahead of print]31(3):

Quercetin attenuates the symptoms of osteoarthritis in vitro and in vivo by suppressing ferroptosis via activation of AMPK/Nrf2/Gpx4 signaling.

Shiyu Dong, Xiaoliang Li, Genrong Xu, Liming Chen, Jiyang Zhao.

  Osteoarthritis (OA) is a common joint disorder involving the cartilage and other joint tissues. Quercetin (QCT) serves a protective role in the development of OA. However, to the best of our knowledge, the regulatory mechanisms of QCT in the progression of OA have not yet been fully elucidated. In order to mimic a model of OA in vitro, IL‑1β was used to stimulate chondrocytes. Furthermore, an in vivo animal model of OA was induced by anterior cruciate ligament transection (ACLT). 5‑Ethynyl‑2'‑deoxyuridine assays, TUNEL assays, ELISAs, western blotting and immunohistochemical assays were conducted to assess the chondroprotective properties of QCT in the development of OA. The results revealed that 100 µM QCT significantly promoted the proliferation, reduced the apoptosis and inflammation, and inhibited the extracellular matrix (ECM) degradation in IL‑1β‑stimulated chondrocytes. Additionally, QCT attenuated the IL‑1β‑induced ferroptosis of chondrocytes, as demonstrated by the reduced lipid reactive oxygen species and Fe2+ levels. Conversely, the inhibitory effects of QCT on the apoptosis and inflammatory responses were reversed by the activation of ferroptosis by erastin in IL‑1β‑stimulated chondrocytes. Furthermore, QCT significantly elevated the level of phosphorylated (p‑)5' AMP‑activated protein kinase (AMPK) and the levels of two negative regulators of ferroptosis [nuclear factor erythroid 2‑related factor 2 (Nrf2) and glutathione peroxidase 4 (Gpx4)] in IL‑1β‑stimulated chondrocytes. The AMPK inhibitor compound C notably reversed the promoting effects of QCT on phosphorylated‑AMPK, Nrf2 and Gpx4 expression in IL‑1β‑stimulated chondrocytes. Additionally, QCT markedly ameliorated the destruction and degradation of articular cartilage, and elevated the p‑AMPK, Nrf2 and Gpx4 levels in the mouse model of ACLT‑induced OA. Overall, the present study demonstrated that QCT inhibited the development of OA by suppressing ferroptosis via the activation of the AMPK/Nrf2/Gpx4 signaling pathway. These findings provide novel insights into the regulatory mechanisms of QCT for the treatment of patients with OA.

Keywords:  5' AMP‑activated protein kinase; ferroptosis; nuclear factor erythroid 2‑related factor 2; osteoarthritis; quercetin

DOI:  https://doi.org/10.3892/mmr.2024.13425
Brain Res. 2024 Dec 24. pii: S0006-8993(24)00679-6. [Epub ahead of print] 149424

Mitochondrial fatty acid oxidase CPT1A ameliorates postoperative cognitive dysfunction by regulating astrocyte ferroptosis.

Yinglan Su, Qian Yuan.

   BACKGROUND: Postoperative cognitive dysfunction (POCD) is a significant surgery-related complication marked by cognitive decline. Studies indicated that neuroinflammation, ferroptosis, and mitochondrial fatty acid metabolism might play parts in POCD, and might be mediated by Carnitine palmitoyl transferase 1a (CPT1A), but requires further investigations. Therefore, this study aims to investigate the mechanism of mitochondrial fatty acid oxidase CPT1A on mitochondrial function, ferroptosis, and inflammation in POCD pathogenesis.
METHODS: SVG P12 astrocytes were used to investigate CPT1A's control over mitochondrial function, ferroptosis, and inflammation affecting neurons. CPT1A was overexpressed using shRNA, with or without oligomycin to modulate mitochondrial function. Co-culture of these astrocytes with neurons, under similar conditions, assessed CPT1A's impact on neuron damage via ferroptosis and inflammation. Gene and protein expressions of CPT1A, SYN, PSD95 were measured via RT-PCR and WB. Detection of JC-1, mitochondrial oxygen consumption rate (OCR), ROS, Fe2+ concentration, MOD, SOD and GSH/GSSG using kits was conducted to explore mitochondrial function and ferroptosis. Inflammation was quantified by ELISA for IL-6, IL-1β, and TGF-β.
RESULTS: We successfully established CPT1A overexpression and knockdown models in astrocytes, confirming CPT1A's ability to enhance mitochondrial membrane potential. Elevated CPT1A levels led to improved mitochondrial function, synaptic integrity, reduced oxidative stress, maintained iron homeostasis, and attenuated neuroinflammation, as reflected by increased SYN, PSD95, OCR, GSH and SOD, decreased ROS,GSSG, MDA, iron levels, and lowered inflammatory factors expression. Treatment with oligomycin reversed these protective effects, demonstrating the dependency of CPT1A's benefits on intact mitochondrial respiration. In co-culture experiments with hippocampal neurons, astrocytes with manipulated CPT1A levels, particularly those co-treated with oligomycin, exacerbated neuronal mitochondrial dysfunction, oxidative stress, iron accumulation, and inflammation.
CONCLUSION: Overexpression of mitochondrial fatty acid oxidase CPT1A might improve synaptic integrity and rescue POCD by ameliorating astrocyte ferroptosis and neuroinflammation.

Keywords:  Carnitine palmitoyl transferase 1a; Ferroptosis; Mitochondrial function; Neuroinflammation; Postoperative cognitive dysfunction

DOI:  https://doi.org/10.1016/j.brainres.2024.149424
Neurotherapeutics. 2024 Dec 26. pii: S1878-7479(24)00200-9. [Epub ahead of print] e00513

Nuclear respiratory factor-1 (NRF1) induction drives mitochondrial biogenesis and attenuates amyloid beta-induced mitochondrial dysfunction and neurotoxicity.

Matteo Massaro, Gherardo Baudo, Hyunho Lee, Haoran Liu, Elvin Blanco.

  Mitochondrial dysfunction is an important driver of neurodegeneration and synaptic abnormalities in Alzheimer's disease (AD). Amyloid beta (Aβ) in mitochondria leads to increased reactive oxygen species (ROS) production, resulting in a vicious cycle of oxidative stress in coordination with a defective electron transport chain (ETC), decreasing ATP production. AD neurons exhibit impaired mitochondrial dynamics, evidenced by fusion and fission imbalances, increased fragmentation, and deficient mitochondrial biogenesis, contributing to fewer mitochondria in brains of AD patients. Nuclear respiratory factor-1 (NRF1) is a regulator of mitochondrial biogenesis through its activation of mitochondrial transcription factor A (TFAM). Our hypothesis posited that NRF1 induction in neuronal cells exposed to amyloid β1-42 (Aβ1-42) would increase de novo mitochondrial synthesis and improve mitochondrial function, restoring neuronal survival. Following NRF1 messenger RNA (mRNA) transfection of Aβ1-42-treated SH-SY5Y cells, a marked increase in mitochondrial mass was observed. Metabolic programming toward enhanced oxidative phosphorylation resulted in increased ATP production. Oxidative stress in the form of mitochondrial ROS accumulation was reduced and mitochondrial membrane potential preserved. Mitochondrial homeostasis was maintained, evidenced by balanced fusion and fission processes. Ultimately, improvement of mitochondrial function was associated with significant decreases in Aβ1-42-induced neuronal death and neurite disruption. Our findings highlight the potential of NRF1 upregulation to counteract Aβ1-42-associated mitochondrial dysfunction and neurodegenerative cell processes, opening avenues for innovative therapeutic approaches aimed at safeguarding mitochondrial health in AD neurons.

Keywords:  Alzheimer's disease; Amyloid beta; Mitochondrial biogenesis; Mitochondrial dysfunction; Nuclear respiratory factor-1 (NRF1)

DOI:  https://doi.org/10.1016/j.neurot.2024.e00513
J Pharmacol Sci. 2025 Jan;pii: S1347-8613(24)00076-8. [Epub ahead of print]157(1): 25-34

Resveratrol promotes autophagosome elimination via SIRT1 in cardiomyocytes.

Atsushi Kuno, Ryusuke Hosoda, Yukika Saga, Naotoshi Iwahara, Yuki Tatekoshi, Ryo Numazawa, Yoshiyuki Horio.

  The processes of autophagy, including autophagosome formation, fusion of autophagosomes with lysosomes, and degradation of autophagosomes by lysosomes, are regulated by various mechanisms. We recently found that treatment with resveratrol, an activator of the NAD+-dependent protein deacetylase Sirtuin-1 (SIRT1), in a mouse model prevented autophagosome accumulation in the heart with high mTORC1 activity. In this study, we investigated whether SIRT1 mediates the effects of resveratrol on autophagosome elimination using a cardiomyocyte model. In H9c2 cardiomyocytes, treatment with the mTORC1 activator MHY1485 induced autophagosome accumulation accompanied by increases in fragmented mitochondria within the autophagosomes and levels of intracellular reactive oxygen species (ROS), indicative of impaired autophagy-mediated elimination of mitochondria and resultant oxidative stress. MHY1485 suppressed the fusion of autophagosomes with lysosomes. Co-treatment with resveratrol attenuated the MHY1485-induced increases in autophagosomes, mitochondria within autophagosomes, and levels of ROS. Knockdown of Sirt1 reversed the reductions in autophagosomes and ROS levels induced by resveratrol under the condition of MHY1485 treatment. Neither resveratrol treatment nor Sirt1 knockdown modulated the phosphorylation levels of UVRAG, a target of mTORC1 for suppression of autophagosome-lysosome fusion. Our findings suggest that SIRT1 mediates the resveratrol-induced promotion of autophagosome elimination in cells with high mTORC1 activity.

Keywords:  Autophagosome elimination; Reactive oxygen species; Resveratrol; SIRT1; mTORC1

DOI:  https://doi.org/10.1016/j.jphs.2024.11.006
J Transl Med. 2024 Dec 22. 22(1): 1137

Ferroptosis, a therapeutic target for cardiovascular diseases, neurodegenerative diseases and cancer.

Yinghui Li, Cuiyun Liu, Bo Fang, Xinzhe Chen, Kai Wang, Hui Xin, Kun Wang, Su-Min Yang.

  The identification of ferroptosis represents a pivotal advancement in the field of cell death research, revealing an entirely novel mechanism of cellular demise and offering new insights into the initiation, progression, and therapeutic management of various diseases. Ferroptosis is predominantly induced by intracellular iron accumulation, lipid peroxidation, or impairments in the antioxidant defense system, culminating in membrane rupture and consequent cell death. Studies have associated ferroptosis with a wide range of diseases, and by enhancing our comprehension of its underlying mechanisms, we can formulate innovative therapeutic strategies, thereby providing renewed hope for patients.

Keywords:  Cancer; Cardiovascular diseases; Ferroptosis; Immunotherapy; Neurodegenerative diseases

DOI:  https://doi.org/10.1186/s12967-024-05881-6
Small. 2024 Dec 23. e2408581

The Mitochondria-Targeted Micelle Inhibits Alzheimer's Disease Progression by Alleviating Neuronal Mitochondrial Dysfunction and Neuroinflammation.

Wenqiang Qian, Daozhou Liu, Jie Liu, Miao Liu, Qifeng Ji, Bangle Zhang, Zhifu Yang, Ying Cheng, Siyuan Zhou.

  Mitochondrial dysfunction plays an important role in neuroinflammation and cognitive impairment in Alzheimer's disease (AD). Herein, this work designs a mitochondria-targeted micelle CsA-TK-SS-31 (CTS) to block the progression of AD by simultaneously alleviating mitochondrial dysfunction in microglia and neurons. The mitochondria-targeted peptide SS-31 drives cyclosporin A (CsA) to penetrate the blood-brain barrier (BBB) and delivers CsA to mitochondria of microglia and neurons in the brains of 5 × FAD mice. Under the high level of reactive oxygen species (ROS) environment in damaged mitochondria of microglia and neurons, the linker (thioketal, TK) between CsA and SS-31 is broken and CsA and SS-31 are released while consuming ROS in the microenvironment. The released CsA and SS-31 synergistically restore the mitochondrial membrane potential and the balance between the fission and fusion of mitochondria, which subsequently protect neurons from apoptosis and reduce the activation of microglia in the brains of 5 × FAD mice. Ultimately, the neuroinflammation and cognitive impairment of 5 × FAD mice are ameliorated. This research provides a synergistic treatment strategy for AD through alleviating mitochondrial dysfunction to reduce neuroinflammation and restore the function of neurons simultaneously.

Keywords:  alzheimer's disease; amyloid β; microglia; mitochondrial dysfunction; neuroinflammation

DOI:  https://doi.org/10.1002/smll.202408581
J Toxicol Environ Health A. 2025 Feb;88(3): 106-121

Penilumamide, a novel SIRT1 activator, protects UVB-induced photodamages in HaCaT cells.

Ji Won Park, Jae Hyeon Park, Haeun Lee, Cong Wang, Shugeng Cao, Hyung Sik Kim.

  Ultraviolet-B (UVB) radiation is a major physical factor that induces structural changes in human skin. The aim of this study was to determine whether the novel silent information regulator 1 (sirtuin 1 SIRT1) protein activator, penilumamide, exerted any protective effects against UVB-induced skin damage using human HaCaT keratinocytes as a model. Enzymatic assays were performed to determine the SIRT1-activating ability of penilumamide, which was compared with that of resveratrol, a potent natural product SIRT1 activator with antioxidant and anti-inflammatory properties. Penilumamide markedly activated SIRT1 enzyme activity compared to resveratrol. To further investigate the protective effect of penilumamide against UVB-induced cytotoxicity, HaCaT cells were pretreated with penilumamide (10 μM) for 24 hr followed by irradiation with UVB (40 mJ/cm2). UVB (40 mJ/cm2) irradiation significantly reduced cell viability in a time-dependent manner, whereas pretreatment with penilumamide blocked this effect. Further, penilumamide decreased the levels of intracellular reactive oxygen species (ROS) generated by UVB irradiation in HaCaT cells. Pretreatment with penilumamide also prevented UVB irradiation-induced changes in mitochondrial membrane potential (ΔΨm). In addition, pretreatment with penilumamide significantly reduced the expression levels of pro-inflammatory cytokines, interleukin (IL)-6, IL-8, and IL-10 and phosphorylation of nuclear factor-kB (NF-kB). These results indicate that penilumamide protects HaCaT cells from UVB-induced inflammation. Taken together data demonstrate that penilumamide exerted protective effects against UVB-induced ROS generation in HaCaT cells. Therefore, penilumamide may be considered to be used as a new SIRT1 activator to protect human keratinocyte against UVB-induced damage.

Keywords:  HaCaT cells; Keratinocyte; SIRT1; UVB radiation; natural antioxidants; penilumamide

DOI:  https://doi.org/10.1080/15287394.2024.2387041
Toxicol Appl Pharmacol. 2024 Dec 22. pii: S0041-008X(24)00413-7. [Epub ahead of print] 117214

Resveratrol alleviates reactive oxygen species and inflammation in diabetic retinopathy via SIRT1/HMGB1 pathway-mediated ferroptosis.

Ye Peng, Long Hu, Huilei Xu, Jian Fang, Hongliang Zhong.

  This study aims to explore the potential of using resveratrol (RES) to treat diabetic retinopathy (DR), as well as the involved molecular mechanisms underlying RES-mediated protection against DR. High concentration of glucose (HG)-induced Human retinal capillary endothelial cells (HRCECs) cell model and streptozotocin (STZ)-induced DR mice model were established. Then, cell viability, apoptosis, reactive oxygen species (ROS) levels, pro-inflammatory factors, and expression of the related proteins SIRT1, HMGB1, VEGF, and CD31 were assayed by a series of cell biology methods. Also, the ferroptosis-related indicators were also explored, including contents of Fe2+, glutathione (GSH), malondialdehyde (MDA), SLC7A11 and GPX4 protein expression. Results showed that RES could alleviate inflammation and oxidative stress in HG-induced HRCECs. In addition, the mRNA and protein expression of SIRT1 and HMGB1 were significantly changed in HG-induced HRCECs and STZ-induced DR mice, while RES treatment could reverse this alteration. In addition, the HMGB1 acetylation level was enhanced after downregulation of SIRT1. Moreover, the ROS generation, expression of inflammatory cytokines (IL-1β, IL-6, and TNF-α), CD31, and VEGF changed by RES administration were reversed by SIRT1-silence. Besides, HG implement could dramatically up-regulated the Fe2+ and MDA contents, and down-regulated the content of GSH and SLC7A11 and GPX4 protein expression in HRCECs, as well as STZ-induced DR mice. RES implement could reverse the above alterations, while SIRT1-silence dramatically reversed these alterations changed by RES treatment. In conclusion, RES suppresses inflammation in DR, as well as inhibit retinal angiogenesis and oxidative stress, and inhibits ferroptosis to alleviate DR via SIRT1/HMGB1 pathway.

Keywords:  Diabetic retinopathy; Ferroptosis; HMGB1; Resveratrol; SIRT1

DOI:  https://doi.org/10.1016/j.taap.2024.117214
3 Biotech. 2025 Jan;15(1): 22

Investigating the neuroprotective properties of Sargassum wightii extract against MPP+-induced apoptosis in SH-SY5Y human neuroblastoma cells.

Rajeswari Ramasamy, Muthukumaran Azhaguchamy, Johnson Retnaraj Samuel Selvan Christyraj, Lalithalakshmi Kanagaraj.

  This study aims to assess the neuroprotective effects of the methanolic extract of Sargassum wightii against oxidative stress and cell death induced by neurotoxins MPP + in SH-SY5Y cells. Briefly, the methanolic extract of S.wightii decreased the cytotoxicity of MPP + in SH-SY5Y cells. Treatment with S.wightii extract at a concentration of 400 µg/ml resulted in a notable decrease in cell death, particularly in MPP + -induced cells. Flow cytometry analysis with annexin V/PI staining reveals apoptosis and necrosis in SH-SY5Y cell lines upon exposure to 1 mM of MPP + . However, 100-400 µg/ml concentrations of S.wightii extract effectively decrease apoptosis in SH-SY5Y cells. Furthermore, S.wightii inhibits caspase-3 activity, effectively shielding neuronal cells against MPP + -induced cell death. Mitochondrial membrane potential (MMP) assay using a JC-1 fluorescent probe indicates that the methanolic extract of S.wightii exhibits protective effects against MPP + -induced cell death and maintains mitochondrial membrane potential. Our results conclude that exposing SH-SY5Y cells to a methanolic extract of S.wightii could potentially increase the likelihood of inhibiting the cascade mechanism, stopping MPP+-induced apoptosis, and preventing the rupture of the mitochondrial membrane. However, the lack of low solubility and poor bioavailability reduce the therapeutic efficacy of S.wightii. Liposome-based drug delivery systems can improve the bioavailability and stability of bioactive compounds, enhancing their therapeutic potential. Hence, S.wightii may hold promise as an innovative treatment for neurological ailments.

Keywords:  Apoptosis; Human neuroblastoma SH-SY5Y cells; Neuroprotective; Sargassum wightii

DOI:  https://doi.org/10.1007/s13205-024-04185-2
J Cardiothorac Surg. 2024 Dec 20. 19(1): 665

Aconitine promotes ROS-activated P38/MAPK/Nrf2 pathway to inhibit autophagy and promote myocardial injury.

Chunai Yang, Jinxiao Fu, Fenshuang Zheng, Yangshan Fu, Xueqiong Duan, Ruiling Zuo, Junbo Zhu.

   BACKGROUND: Aconitine has cardiotoxicity, but the mechanism of cardiotoxicity induced by aconitine is limited. The aim of this study was to investigate the mechanism of myocardial injury induced by aconitine.
METHODS: Using aconitine, ROS inhibitor N-acetylcysteine(NAC), the autophagy activitor Rapamycin (Rap) or the P38/MAPK pathway activitor Dehydrocorydaline treats H9C2 cells. CCK-8 assay was used to assay cell proliferation activity. Flow Cytometry was used to detect cell apoptosis. Dichloro-dihydrofluorescein diacetate was used to detect ROS levels. The expression of LC3 was detected by Immunofluorescence Staining. Western blotting detected the expression of related proteins. The mRNA levels of inflammatory factors were detected by RT-qPCR.
RESULTS: Aconitine inhibits cardiomyocyte proliferation, induces apoptosis and secretion of inflammatory factors. Aconitine activates the P38/MAPK/Nrf2 pathway, induces ROS increase, and promotes autophagy. NAC can inhibit proliferation inhibition, apoptosis, inflammation and P38/MAPK/Nrf2 pathway activation induced by aconitine. Rap and P38 activators can partially recover the effects of NAC on proliferation, apoptosis, inflammation and autophagy of cardiomyocytes.
CONCLUSION: Aconitine promotes ROS-activated P38/MAPK/Nrf2 pathway to inhibit autophagy and promote myocardial injury.

Keywords:  Aconitine; Autophagy; Myocardial injury; P38/MAPK/Nrf2 pathway; ROS

DOI:  https://doi.org/10.1186/s13019-024-03149-0
Sci Rep. 2024 Dec 28. 14(1): 31016

Omics-based analysis of mitochondrial dysfunction and BBB integrity in post-COVID-19 sequelae.

Rupal Dhariwal, Kirtan Dave, Mukul Jain.

  The SARS-CoV-2 virus that resulted in the COVID-19 pandemic has been implicated in a range of neurological issues, such as encephalopathy, stroke, and cognitive decline. Although the precise mechanism causing these issues is unknown, mounting evidence shows that blood-brain barrier (BBB) disruption is probable2 a major factor. The integrity of the blood-brain barrier (BBB), a highly selective barrier that divides the brain from the systemic circulation, is crucial for preserving normal brain function. By analysing the multi-transcriptome data, this work explores the neurological impacts of the SARS-CoV-2 virus and provides insight into the molecular mechanisms behind BBB breakdown and neurological symptoms in COVID-19 patients. The endothelial cells of BBB expresses inflammatory genes in response to the systemic inflammation induced due to SARS-CoV-2 remnants in the body. This raises the possibility that systemic inflammation brought on by SARS-CoV-2 and BBB integrity are correlated. Furthermore, the study highlights the pathways involved in oxidative stress and endothelial cell activation, revealing their role in COVID-19 passage through BBB and induction of systemic inflammation and advancement toward neurological disorders. The article showcases the evidence that mitochondrial dysfunction is a major aftermath associated with SARS-CoV-2 infection as the impaired Mitochondria leads to an accumulation of reactive oxygen species (ROS), triggering endothelial dysfunction, and leading to the passage of harmful molecules across the BBB. This study offers insightful information that may open up the possibilities for new treatment plans by targeting biomarkers specifically associated with inflammation and BBB dysfunctioning conditions.

Keywords:  Blood–brain barrier; COVID-19; Cognitive impairment; Neurovascular unit; PBMCs; SARS-CoV-2; hiPSC

DOI:  https://doi.org/10.1038/s41598-024-82180-6
Chem Biol Interact. 2024 Dec 24. pii: S0009-2797(24)00509-X. [Epub ahead of print] 111363

Urolithin A attenuates Doxorubicin-induced cardiotoxicity by enhancing PINK1-regulated mitophagy via Ambra1.

Xiaoyan Wang, Chao Ma, Keying Mi, Xinran Cao, Yinghua Tan, Haitao Yuan, Jun Ren, Xinyue Liang.

  Doxorubicin (Dox) is a widely used antineoplastics although its clinical usage is greatly limited by its cardiotoxicity. Several studies have depicted an essential role for dampened mitophagy and mitochondrial injury in Dox cardiotoxicity. However, preventative measure to alleviate Dox-evoked cardiotoxicity via targeting mitophagy and mitochondrial integrity remains elusive. Urolithin A (UA) is a newly identified mitophagy inducer with antioxidant and anti-apoptotic properties although its effect on Dox-induced cardiotoxicity is unknown. This study was designed to explore the effect of UA on Dox cardiotoxicity and mechanisms involved. Our results indicated that UA alleviated Dox-induced cardiac dysfunction exhibited by echocardiographic parameters and histological analyses, and partially relieved Dox-induced apoptosis in vitro and in vivo, and mitochondrial dysfunction including ΔΨm dissipation and ROS production in vitro. The ability of UA to facilitate restoration of mitophagy in mice and H9C2s underscored its advantageous effects, manifested as upregulation of mitophagy-related proteins, including p62, LC3, PINK1 and Parkin, as well as the co-location between LC3 and mitochondria. Incubation with 3MA nearly reversed the UA-evoked rise of mitophagy-related proteins, and inhibition of apoptosis. Given that knockdown of Ambra1 almost abolished UA-induced protective effect, the enhanced expression of Ambra1 owing to UA increased PINK1 levels by inhibiting its degradation via LONP1. Collectively, our results suggest that the cardioprotective properties of UA depend on the stimulation of PINK1-dependent mitophagy through promoting Ambra1 expression to inhibit PINK1 degradation by LONP1. This highlights UA's potential as a valuable treatment option and its importance in cardioprotective strategies against Dox-induced cardiotoxicity.

Keywords:  Ambra1; cardiotoxicity; doxorubicin; mitophagy; urolithin A

DOI:  https://doi.org/10.1016/j.cbi.2024.111363
J Ovarian Res. 2024 Dec 27. 17(1): 254

Mechanisms of He Shi Yu Lin formula in treating premature ovarian insufficiency: insights from network pharmacology and animal experiments.

Yun Huang, Qin Zhang, Dan Shen, Xi Bao.

   OBJECTIVE: He Shi Yu Lin Formula (HSYLF) is a clinically proven prescription for treating premature ovarian insufficiency (POI), and has shown a good curative effect. However, its molecular mechanisms are unclear. This study aimed to investigate the molecular mechanisms of HSYLF and clarify how network pharmacology analysis guides the design of animal experiments, including the selection of effective treatment doses and key targets, to ensure the relevance of the experimental results.
METHODS: Network pharmacology, molecular docking, and animal experiments were utilized to investigate the effects of HSYLF. Key targets were identified by intersecting herb and disease targets to construct protein-protein interaction and "active components-intersection targets-disease" networks. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed using the clusterProfiler package in R. A total of 50 specific pathogen-free female mice of reproductive age were included in the animal experiments. They were divided into five groups: the positive control group, the high-dose HSYLF group, the low-dose HSYLF group, the model blank group, and the normal control group, to evaluate the serum anti-müllerian hormone levels, mitochondrial morphology in oocytes, the levels of reactive oxygen species (ROS), and mitochondrial membrane potential.
RESULTS: Network pharmacology identified 204 active components connecting 219 key therapeutic targets for POI. Gene Ontology enrichment analysis indicated that the anti-POI targets of HSYLF mainly regulated response to xenobiotic stimulus, cellular response to chemical stress, and response to oxidative stress; and the Kyoto Encyclopedia of Genes and Genomes pathway analysis suggested the primary pathways, including lipid and atherosclerosis, advanced glycation end product-receptor for advanced glycation end product signaling pathway in diabetic complications, bladder cancer, tumor necrosis factor signaling pathway, and interleukin-17 signaling pathway. The low-dose (33 g/kg/d) HSYLF and high-dose (66 g/kg/d) HSYLF groups exhibited a marked elevation in serum anti-müllerian hormone levels (low-dose group: 2657.63 ± 354.82 PG/ml; high-dose group: 2823.73 ± 316.04 PG/ml) and mitochondrial membrane potential compared to the model blank group (P < 0.05 or P < 0.01), along with a significant decline in fluorescence intensity of 2',7'-dichlorofluorescein for the levels of ROS in oocytes (P < 0.05 or P < 0.01). Additionally, both groups showed varying degrees of improvement in the morphology, quantity, and distribution of mitochondria.
CONCLUSION: This study provides definite evidence for the molecular mechanism by which HSYLF treats POI by decreasing mitochondrial ROS, increasing membrane potential, and improving mitochondrial function. The results from active components of HSYLF and their related key targets also confirmed the characteristics of its multi-component, multi-target, multi-pathway, and overall regulatory effects on POI. Further research regarding the mechanisms is required to generalize these results, and the deeper clinical value of HSYLF also needs to be investigated in the future.

Keywords:  Active oxygen; He Shi Yu Lin Formula; Mitochondria; Network pharmacology; Premature ovarian insufficiency; Traditional Chinese medicine

DOI:  https://doi.org/10.1186/s13048-024-01575-1
Genes Cells. 2025 Jan;30(1): e13190

Sulforaphane Induces Transient Reactive Oxygen Species-Mediated DNA Damage in HeLa Cells.

Sakine Kobayashi, Seiya Nishiba, Chinatsu Sato, Kazuya Toriumi, Yuduki Someya, Noritaka Adachi, Shigeki Takeda, Aya Kurosawa.

  Sulforaphane (SFN), an isothiocyanate found in plants of the Brassicaceae family, possesses antioxidant, apoptosis-inducing, and radiosensitizing effects. As one of the mechanisms of cytotoxicity by SFN, SFN has been suggested to be involved in the induction of DNA damage and inhibition of DNA repair. Recently, we reported on the potency of SFN in inducing single-ended double-strand breaks (DSBs) that are caused by the collision of replication forks with single-strand breaks (SSBs). However, the mechanism of SSB accumulation by SFN remains unclear. In this study, we examined the effect of SFN on SSB-inducing factors in HeLa cells. Although the inhibitory effect of SFN on DNA topoisomerase I was not observed, we found that the reduced form of glutathione (GSH; an antioxidant) level was decreased in an SFN concentration-dependent manner. Furthermore, the addition of ascorbic acid partially increased the viability of SFN-treated HeLa cells. We subsequently observed that poly(ADP-ribose) accumulated in SFN-treated HeLa cells, which occurs during early SSB repair. Collectively, these findings suggest that SFN may transiently induce SSBs via reactive oxygen species in HeLa cells.

Keywords:  DNA damage; reactive oxygen species; single‐strand break; sulforaphane

DOI:  https://doi.org/10.1111/gtc.13190
Dev Neurobiol. 2025 Jan;85(1): e22957

Overexpression of Growth Differentiation Factor 15 Reduces Neuronal Cell Damage Induced by Oxygen-Glucose Deprivation/Reoxygenation via Inhibiting Endoplasmic Reticulum Stress-Mediated Ferroptosis.

Haiming Li, Bin Chen, Zhelin Chen, Jianming Luo, Binyuan Yang.

  Growth differentiation factor 15 (GDF15) can be induced under various stress conditions. This study aimed to explore the role of GDF15 in oxygen-glucose deprivation/reoxygenation (OGD/R)-induced HT22 cells. OGD/R was employed to induce the HT22 cell model, and GDF15 expression was upregulated via transfection. Subsequently, the effects on inflammatory factors, oxidative stress markers, apoptosis-related proteins, and ferroptosis markers were detected. Relevant indicators were evaluated using techniques such as ELISA, probes, flow cytometry, and western blotting. Furthermore, changes in these phenotypes under the influence of the endoplasmic reticulum (ER) stress agonist tunicamycin (TM) were evaluated. The result showed that GDF15 was significantly up-regulated in OGD/R-treated HT22 cells. Overexpression of GDF15 significantly reduced the levels of inflammatory factors tumor necrosis factor-α, IL (interleukin)-1β, and IL-6, inhibited the production of reactive oxygen species and MDA, and improved activity of superoxide dismutase and GSH-Px. Flow cytometry and western blotting results showed that GDF15 overexpression significantly reduced cell apoptosis, reduced caspase3 activity, and regulated the expression of Bcl2 and Bax. In addition, overexpression of GDF15 reduces the levels of ferroptosis markers by inhibiting ER stress. ER stress inducer TM can reverse the protective effects of GDF15 overexpression and promote inflammation, oxidative stress, and apoptosis. This study shows that overexpression of GDF15 reduces OGD/R-induced HT22 cell damage, and ER stress-mediated ferroptosis is included in the regulatory mechanisms. This provides a theoretical basis for GDF15 as a new target for the treatment of cerebral ischemia-reperfusion injury.

Keywords:  ER stress; HT22; ferroptosis; growth differentiation factor; inflammation; ischemia‐reperfusion injury

DOI:  https://doi.org/10.1002/dneu.22957
Biochem Pharmacol. 2024 Dec 19. pii: S0006-2952(24)00730-5. [Epub ahead of print]232 116729

The complex interplay between redox dysregulation and mTOR signaling pathway in cancer: A rationale for cancer treatment.

Christophe Glorieux, Cinthya Enríquez, Pedro Buc Calderon.

  The mechanistic target of rapamycin (mTOR) is a highly conserved serine/threonine kinase that plays a critical role in regulating cellular processes such as growth, proliferation, and metabolism in healthy cells. Dysregulation of mTOR signaling and oxidative stress have been implicated in various diseases including cancer. This review aims to provide an overview of the current understanding of mTOR and its involvement in cell survival and the regulation of cancer cell metabolism as well as its complex interplay with reactive oxygen species (ROS). On the one hand, ROS can inhibit or activate mTOR pathway in cancer cells through various mechanisms. Conversely, mTOR signaling can induce oxidative stress in tumor cells notably due to the inhibition in the expression of antioxidant enzyme genes. Since mTOR is often activated and plays crucial role in cancer cell survival, the use of mTOR inhibitors, which often induce ROS accumulation, could be an interesting approach for cancer treatment. This review will address the advantages, disadvantages, combination strategies, and limitations associated with therapeutic modulation of mTOR signaling pathway in cancer treatment.

Keywords:  Cancer; Cell survival; Metabolism; Oxidative stress; ROS; mTOR; mTOR inhibitors

DOI:  https://doi.org/10.1016/j.bcp.2024.116729
Metabolites. 2024 Dec 13. pii: 703. [Epub ahead of print]14(12):

Influence of the Microbial Metabolite Acetyl Phosphate on Mitochondrial Functions Under Conditions of Exogenous Acetylation and Alkalization.

Natalia V Beloborodova, Nadezhda I Fedotcheva.

   BACKGROUND: Acetyl phosphate (AcP) is a microbial intermediate involved in the central bacterial metabolism. In bacteria, it also functions as a donor of acetyl and phosphoryl groups in the nonenzymatic protein acetylation and signal transduction. In host, AcP was detected as an intermediate of the pyruvate dehydrogenase complex, and its appearance in the blood was considered as an indication of mitochondrial breakdown. In vitro experiments showed that AcP is a powerful agent of nonenzymatic acetylation of proteins. The influence of AcP on isolated mitochondria has not been previously studied.
METHODS: In this work, we tested the influence of AcP on the opening of the mitochondrial permeability transition pore (mPTP), respiration, and succinate dehydrogenase (SDH) activity under neutral and alkaline conditions stimulating the nonenzymatic acetylation using polarographic, cation-selective, and spectrophotometric methods.
RESULTS: It was found that AcP slowed down the opening of the mPTP by calcium ions and decreased the efficiency of oxidative phosphorylation and the activity of SDH. These effects were observed only at neutral pH, whereas alkaline pH by itself caused a decrease in these functions to a much greater extent than AcP. AcP at a concentration of 0.5-1 mM decreased the respiratory control and the swelling rate by 20-30%, while alkalization decreased them twofold, thereby masking the effect of AcP. Presumably, the acetylation of adenine nucleotide translocase involved in both the opening of mPTP and oxidative phosphorylation underlies these changes. The intermediate electron carrier phenazine methosulfate (PMS), removing SDH inhibition at the ubiquinone-binding site, strongly activated SDH under alkaline conditions and, partially, in the presence of AcP. It can be assumed that AcP weakly inhibits the oxidation of succinate, while alkalization slows down the electron transfer from the substrate to the acceptor.
CONCLUSIONS: The results show that both AcP and alkalization, by promoting nonmetabolic and nonenzymatic acetylation from the outside, retard mitochondrial functions.

Keywords:  acetyl phosphate; adenine nucleotide translocase; alkalization; mitochondrial permeability transition pore; nonenzymatic acetylation; respiration; succinate dehydrogenase

DOI:  https://doi.org/10.3390/metabo14120703