bims-mistre 2025-01-19 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2025–01–19
nineteen papers selected by
Ellen Siobhan Mitchell, MitoQ

The total extract of Abelmoschus manihot (L.) medic flowers (TEA) mediated Nrf2-TFAM signalling to regulate mitochondrial antioxidant mechanism.
Roles of the Receptor for Advanced Glycation End Products and Its Ligands in the Pathogenesis of Alzheimer's Disease.
Plant Secondary Metabolites as Modulators of Mitochondrial Health: An Overview of Their Anti-Oxidant, Anti-Apoptotic, and Mitophagic Mechanisms.
DAG-MAG-ΒHB: A Novel Ketone Diester Modulates NLRP3 Inflammasome Activation in Microglial Cells in Response to Beta-Amyloid and Low Glucose AD-like Conditions.
Microglial activation states and their implications for Alzheimer's Disease.
New possibilities of the prevention and treatment of cardiovascular pathologies. the potential of molecular hydrogen in the reduction of oxidative stress and its consequences.
Therapeutic potential of trazodone in trigeminal neuralgia based on inflammation and oxidative stress: an in vitro experimental study.
Effects of Exercise Training on Cardiac Mitochondrial Functions in Diabetic Heart: A Systematic Review.
Oxidative/Nitrosative Stress, Apoptosis, and Redox Signaling: Key Players in Neurodegenerative Diseases.
Quercetin mediates the therapeutic effect of Centella asiatica on psoriasis by regulating STAT3 phosphorylation to inhibit the IL-23/IL-17A axis.
Reacting to reductive stress at the mitochondrial import gate.
Understanding glucose metabolism and insulin action at the blood-brain barrier: Implications for brain health and neurodegenerative diseases.
Interaction and regulation of the mitochondrial proteome - in health and disease.
Platelet Mitochondrial Function and Endogenous Coenzyme Q10 Levels Could Be Used as Markers of Mitochondrial Health in Infertile Men: A Pilot Study.
Unlocking the Potential: How Flavonoids Affect Angiogenesis, Oxidative Stress, Inflammation, Proliferation, Invasion, and Alter Receptor Interactions in Endometriosis.
Nrf2 mediates mitochondrial and NADPH oxidase-derived ROS during mild heat stress at 40 °C.
Mitochondria-Targeted Antioxidant (MitoQ) and Nontargeted Antioxidant (Idebenone) Mitigate Mitochondrial Dysfunction in Corneal Endothelial Cells.
Ameliorative Effects of Raisin Polyphenol Extract on Oxidative Stress and Aging In Vitro and In Vivo via Regulation of Sirt1-Nrf2 Signaling Pathway.
A Review on Current Aspects of Curcumin-Based Effects in Relation to Neurodegenerative, Neuroinflammatory and Cerebrovascular Diseases.

Sci Rep. 2025 Jan 10. 15(1): 1614

The total extract of Abelmoschus manihot (L.) medic flowers (TEA) mediated Nrf2-TFAM signalling to regulate mitochondrial antioxidant mechanism.

Ying Song, Xinyi Zhu, Beibei Wang, Qisong Li, Biwei Song.

  Skin, as the first line of defence of the human body, is exposed to dangers such as overheating substances, ultraviolet rays, and environmental pollutants, and the incidence of skin diseases is increasing annually. Oxidative stress plays a dominant role in most skin diseases. Abelmoschus manihot (L.) medic flower (TEA) is a traditional Chinese medicine widely used to treat injuries to the skin such as water and fire scalds. It has been reported that TEA has excellent antioxidant effects. In this study, we aimed to explore the antioxidant and mitochondrial protection effects of TEA in H2O2-mediated HaCaT cell damage. HaCaT cells were incubated with H2O2 to simulate oxidative stress in the skin. The effect of TEA on HaCaT cells was also evaluated. Cell morphology was observed via inverted microscopy, and cell viability was measured via the MTT reagent. The cells were stained with Hoechst 33,324 solution. Reactive oxygen species (ROS), superoxide dismutase (SOD), malondialdehyde (MDA) and ATP detection kits were used to detect the corresponding indicators. The mitochondrial membrane potential was detected by JC-1. RT-PCR was used to detect mRNA and mtDNA expression. The expression of the target protein was detected by Western blotting and immunofluorescence. H2O2 triggered oxidative damage in HaCaT cells, which manifested as apoptosis, increased ROS and MDA contents, and decreased SOD activity. H2O2 activates the KEAP1/Nrf2/NQO1 signalling pathway, which decreases the expression of the intracellular KEAP1 protein and slightly increases the expression of the Nrf2 and NQO1 proteins, further causing mitochondrial oxidative stress, resulting in changes in the mitochondrial membrane potential, a reduction in the mtDNA copy number, and decreased expression of the PGC-1α and TFAM proteins. In addition the expression of mitochondrial respiratory chain genes and proteins decreased. TEA promoted the expression of Nrf2 in HaCaT cells, activated the downstream antioxidant response, and alleviated the oxidative stress and mitochondrial damage caused by H2O2. ML385 is an Nrf2 inhibitor, under which the antioxidant and mitochondrial protective effects of TEA are inhibited. When TFAM was knocked down, the protective effect of TEA on mitochondria was also inhibited. TEA protects HaCaT cells from H2O2-induced oxidative damage and mitochondrial oxidative damage through the KEAP1/Nrf2/NQO1/PGC-1α/TFAM pathway.

Keywords:  Mitochondria; Nrf2; Oxidative stress; TFAM; The total extract of Abelmoschus manihot (L.) Medic flowers (TEA)

DOI:  https://doi.org/10.1038/s41598-024-84022-x
Int J Mol Sci. 2025 Jan 05. pii: 403. [Epub ahead of print]26(1):

Roles of the Receptor for Advanced Glycation End Products and Its Ligands in the Pathogenesis of Alzheimer's Disease.

Wen Li, Qiuping Chen, Chengjie Peng, Dan Yang, Si Liu, Yanwen Lv, Langqi Jiang, Shijun Xu, Lihua Huang.

  The Receptor for Advanced Glycation End Products (RAGE), part of the immunoglobulin superfamily, plays a significant role in various essential functions under both normal and pathological conditions, especially in the progression of Alzheimer's disease (AD). RAGE engages with several damage-associated molecular patterns (DAMPs), including advanced glycation end products (AGEs), beta-amyloid peptide (Aβ), high mobility group box 1 (HMGB1), and S100 calcium-binding proteins. This interaction impairs the brain's ability to clear Aβ, resulting in increased Aβ accumulation, neuronal injury, and mitochondrial dysfunction. This further promotes inflammatory responses and oxidative stress, ultimately leading to a range of age-related diseases. Given RAGE's significant role in AD, inhibitors that target RAGE and its ligands hold promise as new strategies for treating AD, offering new possibilities for alleviating and treating this serious neurodegenerative disease. This article reviews the various pathogenic mechanisms of AD and summarizes the literature on the interaction between RAGE and its ligands in various AD-related pathological processes, with a particular focus on the evidence and mechanisms by which RAGE interactions with AGEs, HMGB1, Aβ, and S100 proteins induce cognitive impairment in AD. Furthermore, the article discusses the principles of action of RAGE inhibitors and inhibitors targeting RAGE-ligand interactions, along with relevant clinical trials.

Keywords:  AD; AGES; Aβ; HMGB1; RAGE; S100

DOI:  https://doi.org/10.3390/ijms26010403
Int J Mol Sci. 2025 Jan 04. pii: 380. [Epub ahead of print]26(1):

Plant Secondary Metabolites as Modulators of Mitochondrial Health: An Overview of Their Anti-Oxidant, Anti-Apoptotic, and Mitophagic Mechanisms.

Julia Anchimowicz, Piotr Zielonka, Slawomir Jakiela.

  Plant secondary metabolites (PSMs) are a diverse group of bioactive compounds, including flavonoids, polyphenols, saponins, and terpenoids, which have been recognised for their critical role in modulating cellular functions. This review provides a comprehensive analysis of the effects of PSMs on mitochondrial health, with particular emphasis on their therapeutic potential. Emerging evidence shows that these metabolites improve mitochondrial function by reducing oxidative stress, promoting mitochondrial biogenesis, and regulating key processes such as apoptosis and mitophagy. Mitochondrial dysfunction, a hallmark of many pathologies, including neurodegenerative disorders, cardiovascular diseases, and metabolic syndrome, has been shown to benefit from the protective effects of PSMs. Recent studies show that PSMs can improve mitochondrial dynamics, stabilise mitochondrial membranes, and enhance bioenergetics, offering significant promise for the prevention and treatment of mitochondrial-related diseases. The molecular mechanisms underlying these effects, including modulation of key signalling pathways and direct interactions with mitochondrial proteins, are discussed. The integration of PSMs into therapeutic strategies is highlighted as a promising avenue for improving treatment efficacy while minimising the side effects commonly associated with synthetic drugs. This review also highlights the need for future research to elucidate the specific roles of individual PSMs and their synergistic interactions within complex plant matrices, which may further optimise their therapeutic utility. Overall, this work provides valuable insights into the complex role of PSMs in mitochondrial health and their potential as natural therapeutic agents targeting mitochondrial dysfunction.

Keywords:  alkaloids; cardiovascular diseases; metabolic diseases; mitochondrial dysfunction; neurodegenerative diseases; plant secondary metabolites; polyphenols; saponins; side effects; terpenoids

DOI:  https://doi.org/10.3390/ijms26010380
Nutrients. 2024 Dec 31. pii: 149. [Epub ahead of print]17(1):

DAG-MAG-ΒHB: A Novel Ketone Diester Modulates NLRP3 Inflammasome Activation in Microglial Cells in Response to Beta-Amyloid and Low Glucose AD-like Conditions.

Valentina Gentili, Giovanna Schiuma, Latha Nagamani Dilliraj, Silvia Beltrami, Sabrina Rizzo, Djidjell Lara, Pier Paolo Giovannini, Matteo Marti, Daria Bortolotti, Claudio Trapella, Marco Narducci, Roberta Rizzo.

   BACKGROUND: A neuroinflammatory disease such as Alzheimer's disease, presents a significant challenge in neurotherapeutics, particularly due to the complex etiology and allostatic factors, referred to as CNS stressors, that accelerate the development and progression of the disease. These CNS stressors include cerebral hypo-glucose metabolism, hyperinsulinemia, mitochondrial dysfunction, oxidative stress, impairment of neuronal autophagy, hypoxic insults and neuroinflammation. This study aims to explore the efficacy and safety of DAG-MAG-ΒHB, a novel ketone diester, in mitigating these risk factors by sustaining therapeutic ketosis, independent of conventional metabolic pathways.
METHODS: We evaluated the intestinal absorption of DAG-MAG-ΒHB and the metabolic impact in human microglial cells. Utilizing the HMC3 human microglia cell line, we examined the compound's effect on cellular viability, Acetyl-CoA and ATP levels, and key metabolic enzymes under hypoglycemia. Additionally, we assessed the impact of DAG-AG-ΒHB on inflammasome activation, mitochondrial activity, ROS levels, inflammation and phagocytic rates.
RESULTS: DAG-MAG-ΒHB showed a high rate of intestinal absorption and no cytotoxic effect. In vitro, DAG-MAG-ΒHB enhanced cell viability, preserved morphological integrity, and maintained elevated Acetyl-CoA and ATP levels under hypoglycemic conditions. DAG-MAG-ΒHB increased the activity of BDH1 and SCOT, indicating ATP production via a ketolytic pathway. DAG-MAG-ΒHB showed remarkable resilience against low glucose condition by inhibiting NLRP3 inflammasome activation.
CONCLUSIONS: In summary, DAG-MAG-ΒHB emerges as a promising treatment for neuroinflammatory conditions. It enhances cellular health under varying metabolic states and exhibits neuroprotective properties against low glucose conditions. These attributes indicate its potential as an effective component in managing neuroinflammatory diseases, addressing their complex progression.

Keywords:  Alzheimer’s disease; DAG-MAG-ΒHB; blood–brain barrier; exogenous ketones; ketone diester; neuroprotection; therapeutic ketosis

DOI:  https://doi.org/10.3390/nu17010149
J Prev Alzheimers Dis. 2025 Jan;pii: S2274-5807(24)00605-8. [Epub ahead of print]12(1): 100013

Microglial activation states and their implications for Alzheimer's Disease.

Zachary Valiukas, Kathy Tangalakis, Vasso Apostolopoulos, Jack Feehan.

  Alzheimer's Disease (AD) is a chronic neurodegenerative disorder characterized by the accumulation of toxic amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFTs) of tau protein in the brain. Microglia, key immune cells of the central nervous system, play an important role in AD development and progression, primarily through their responses to Aβ and NFTs. Initially, microglia can clear Aβ, but in AD, chronic activation overwhelms protective mechanisms, leading to sustained neuroinflammation that enhances plaque toxicity, setting off a damaging cycle that affects neurons, astrocytes, cerebral vasculature, and other microglia. Current AD treatments have been largely ineffective, though emerging immunotherapies focusing on plaque removal show promise, but often overlook the role of neuroinflammation. Activated microglia display a complex range of phenotypes that can be broadly broken into pro- or anti-inflammatory states, although this dichotomy does not describe the significant overlap between states. Aβ can strongly induce inflammatory activity, triggering the production of reactive oxygen species, inflammatory cytokines (e.g., TNF-α, IL-1β, IL-6), synapse engulfment, blood-brain barrier compromise, and impaired Aβ clearance. These processes contribute to neural tissue loss, manifesting as cognitive decline such as impaired executive function and memory. Conversely, anti-inflammatory activation exerts neuroprotective effects by suppressing inflammatory pathways and releasing neurotrophic factors that aid neuron repair and protection. Induction of anti-inflammatory states may offer a dual therapeutic approach to address both neuroinflammation and plaque accumulation in AD. This approach suggests potential strategies to modulate microglial phenotypes, aiming to restore neuroprotective functions and mitigate disease progression by simultaneously targeting inflammation and plaque pathology.

Keywords:  Alzheimer's Disease; Amyloid Beta; Microglia; Neuroinflammation; Tau

DOI:  https://doi.org/10.1016/j.tjpad.2024.100013
Physiol Res. 2024 12 31. 73(S3): S671-S684

New possibilities of the prevention and treatment of cardiovascular pathologies. the potential of molecular hydrogen in the reduction of oxidative stress and its consequences.

J Slezák, T Ravingerová, B Kura.

Disproportion between reactive oxygen species (ROS) production and the body's antioxidant system can cause oxidative stress, which is considered a common denominator in various pathological conditions, including cardiovascular diseases, aging, and cognitive disorders. The generation of free radicals, which occurs through partial reduction of oxygen, can quickly overwhelm the endogenous antioxidant system capacity of the cell. This causes lipid, protein, DNA and RNA damage, inflammation, and overall cell degeneration, which can be mitigated by various antioxidants. However, their use in human medicine did not bring the expected effect. Molecular hydrogen (H2), due to its unique physical and chemical properties, provides a number of benefits for alleviating oxidative stress. H2 is superior to conventional antioxidants as it can selectively reduce (.)OH radicals while preserving important ROS that are otherwise used for normal cell signaling. Key words Oxidative stress, Cardiovascular diseases, Molecular hydrogen, ROS, Inflammation.
J Oral Facial Pain Headache. 2024 Jun;38(2): 119-125

Therapeutic potential of trazodone in trigeminal neuralgia based on inflammation and oxidative stress: an in vitro experimental study.

Jun Yang, Junling Huang, Zhimin Pan, Xiao Wang.

  Trigeminal neuralgia (TN) is a debilitating condition affecting the patients' life quality. New therapeutic approaches and novel drugs are required to treat TN. Trazodone being a serotonin antagonist and reuptake inhibitor (SARI) provides neuroprotection, however its role and underlying mechanism in TN in vitro or in vivo are not clear. This study was aimed to investigate the trazodone impact on glial BV-2 cells regarding TN. It was found that trazodone inhibited the BV-2 cells growth and suppressed the inflammation and oxidative stress in Lipopolysaccharide (LPS)-treated BV-2 cells. Trazodone treatment specifically decreased the levels of Tumor Necrosis Factor-alpha (TNF-α), Interleukin-6 (IL-6), Interleukin-1 beta (IL-1β) (p < 0.05), and Reactive Oxygen Species (ROS) (p < 0.01). Moreover, trazodone suppressed the Mitogen-Activated Protein Kinase (MAPK) pathway in LPS-treated BV-2 cells. These outcomes demonstrate that trazodone suppressed glial cell hyperproliferation, inflammation, and oxidative stress through MAPK pathway activation.

Keywords:  Inflammation; MAPK pathway; Oxidative stress; Trazodone; Trigeminal neuralgia (TN)

DOI:  https://doi.org/10.22514/jofph.2024.020
Int J Mol Sci. 2024 Dec 24. pii: 8. [Epub ahead of print]26(1):

Effects of Exercise Training on Cardiac Mitochondrial Functions in Diabetic Heart: A Systematic Review.

Iqbal Ali Shah, Shahid Ishaq, Shin-Da Lee, Bor-Tsang Wu.

  A diabetic heart is characterized by fibrosis, autophagy, oxidative stress, and altered mitochondrial functions. For this review, three databases (PubMed, EMBASE, and Web of Science) were searched for articles written in English from September 2023 to April 2024. Studies that used exercise training for at least 3 weeks and which reported positive, negative, or no effects were included. The CAMARADES checklist was used to assess the quality of the included studies, and ten studies (CAMARADES scores 4-7/10) were included. Nine studies showed that exercise training improved cardiac mitochondrial oxidative phosphorylation by decreasing ROS, increasing electron transport chain activity, and enhancing the production of ATP. Eight studies indicated that exercise training ameliorated mitochondrial biogenesis by increasing the levels of AMPK, PGC-1α, Akt, Irisin, and Sirtuin-III. Moreover, four studies focused on mitochondrial dynamics and concluded that exercise training helped decrease the levels of mitochondrial fission factor and dynamin-related protein- 1. Finally, six studies revealed improvements in mitochondrial physiological characteristics such as size, potential, and permeability. Our findings demonstrate the beneficial effects of exercise training on cardiac mitochondrial function in diabetic hearts. Exercise training improves cardiac mitochondrial physiological characteristics, oxidative phosphorylation, biogenesis, and dynamics.

Keywords:  diabetic heart; exercise training; mitochondrial biogenesis; mitochondrial dynamics; mitochondrial function; mitochondrial oxidative phosphorylation

DOI:  https://doi.org/10.3390/ijms26010008
J Biochem Mol Toxicol. 2025 Jan;39(1): e70133

Oxidative/Nitrosative Stress, Apoptosis, and Redox Signaling: Key Players in Neurodegenerative Diseases.

Nuray Üremiş, Muhammed Mehdi Üremiş.

  Neurodegenerative diseases are significant health concerns that have a profound impact on the quality and duration of life for millions of individuals. These diseases are characterized by pathological changes in various brain regions, specific genetic mutations associated with the disease, deposits of abnormal proteins, and the degeneration of neurological cells. As neurodegenerative disorders vary in their epidemiological characteristics and vulnerability of neurons, treatment of these diseases is usually aimed at slowing disease progression. The heterogeneity of genetic and environmental factors involved in the process of neurodegeneration makes current treatment methods inadequate. However, the existence of common molecular mechanisms in the pathogenesis of these diseases may allow the development of new targeted therapeutic strategies. Oxidative and nitrosative stress damages membrane components by accumulating ROS and RNS and disrupting redox balance. This process results in the induction of apoptosis, which is important in the pathogenesis of neurodegenerative diseases through oxidative stress. Studies conducted using postmortem human samples, animal models, and cell cultures have demonstrated that oxidative stress, nitrosative stress, and apoptosis are crucial factors in the development of diseases such as Alzheimer's, Parkinson's, Multiple Sclerosis, amyotrophic lateral sclerosis, and Huntington's disease. The excessive production of reactive oxygen and nitrogen species, elevated levels of free radicals, heightened mitochondrial stress, disturbances in energy metabolism, and the oxidation and nitrosylation of cellular macromolecules are recognized as triggers for neuronal cell death. Challenges in managing and treating neurodegenerative diseases require a better understanding of this field at the molecular level. Therefore, this review elaborates on the molecular mechanisms by which oxidative and nitrosative stress are involved in neuronal apoptosis.

Keywords:  Oxidative stress; apoptosis; molecular mechanisms; neurodegenerative diseases; nitrosative stress; redox signaling

DOI:  https://doi.org/10.1002/jbt.70133
Nan Fang Yi Ke Da Xue Xue Bao. 2025 Jan 20. pii: 1673-4254(2025)01-0090-10. [Epub ahead of print]45(1): 90-99

Quercetin mediates the therapeutic effect of Centella asiatica on psoriasis by regulating STAT3 phosphorylation to inhibit the IL-23/IL-17A axis.

Qing Liu, Jing Liu, Yihang Zheng, Jin Lei, Jianhua Huang, Siyu Liu, Fang Liu, Qunlong Peng, Yuanfang Zhang, Junjie Wang, Yujuan Li.

   OBJECTIVES: To explore the active components that mediate the therapeutic effect of Centella asiatica on psoriasis and their therapeutic mechanisms.
METHODS: TCMSP, TCMIP, PharmMapper, Swiss Target Prediction, GeneCards, OMIM and TTD databases were searched for the compounds in Centella asiatica and their targets and the disease targets of psoriasis. A drug-active component-target network and the protein-protein interaction network were constructed, and DAVID database was used for pathway enrichment analysis. In a RAW264.7 macrophage model of LPS-induced inflammation, the anti-inflammatory effect of 7.5, 15, 30, and 60 μmol/L quercetin, asiaticoside, and asiatic acid, which were identified as the main active components in Centella asiatica, were tested by measuring cellular production of NO, TNF‑α and IL-6 using Griess method and ELISA and by detecting mRNA expressions of IL-23, IL-17A, TNF-α and IL-6 and protein expressions of p-STAT3 (Tyr705) and p-STAT3 (Ser727) with RT-qPCR and Western blotting.
RESULTS: A total of 139 targets of Centella asiatica and 4604 targets of psoriasis were obtained, and among them CASP3, EGFR, PTGS2, and ESR1 were identified as the core targets. KEGG analysis suggested that quercetin, asiaticoside, and asiatic acid in Centella asiatica were involved in cancer and IL-17 and MAPK signaling pathways. In the RAW264.7 macrophage model of inflammation, treatment with quercetin significantly reduced cellular production of NO, TNF‑α and IL-6, and lowered mRNA expressions of IL-23, IL-17A, TNF‑α and IL-6 and protein expressions of p-STAT3 (Tyr705) and p-STAT3 (Ser727).
CONCLUSIONS: Quercetin, asiaticoside and asiatic acid are the main active components in Centella asiatica to mediate the therapeutic effect against psoriasis, and quercetin in particular is capable of suppressing cellular production of NO, TNF‑α and IL-6 and regulating the IL-23/IL-17A inflammatory axis by mediating STAT3 phosphorylation to inhibit inflammatory response.

Keywords:  Centella asiatica; IL-23/IL-17A; network pharmacology; psoriasis; quercetin

DOI:  https://doi.org/10.12122/j.issn.1673-4254.2025.01.12
Trends Cell Biol. 2025 Jan 13. pii: S0962-8924(24)00281-2. [Epub ahead of print]

Reacting to reductive stress at the mitochondrial import gate.

Sylvie Callegari.

  A byproduct of mitochondrial energy production is the generation of reactive oxygen species (ROS). Too much ROS is toxic, but ROS deficiency is equally deleterious (reductive stress). In a recent study, McMinimy et al. uncovered a ubiquitin proteasome-mediated mechanism at the translocase of the outer membrane (TOM) complex, which senses ROS depletion and adjusts mitochondrial protein import accordingly.

Keywords:  TOM complex; mitochondrial import; proteasome; reactive oxygen species; reductive stress; ubiquitin

DOI:  https://doi.org/10.1016/j.tcb.2024.12.013
Acta Physiol (Oxf). 2025 Feb;241(2): e14283

Understanding glucose metabolism and insulin action at the blood-brain barrier: Implications for brain health and neurodegenerative diseases.

Yiyi Zhu, Alexei Verkhratsky, Hui Chen, Chenju Yi.

  The blood-brain barrier (BBB) is a highly selective, semipermeable barrier critical for maintaining brain homeostasis. The BBB regulates the transport of essential nutrients, hormones, and signaling molecules between the bloodstream and the central nervous system (CNS), while simultaneously protecting the brain from potentially harmful substances and pathogens. This selective permeability ensures that the brain is nourished and shielded from toxins. An exception to this are brain regions, such as the hypothalamus and circumventricular organs, which are irrigated by fenestrated capillaries, allowing rapid and direct response to various blood components. We overview the metabolic functions of the BBB, with an emphasis on the impact of altered glucose metabolism and insulin signaling on BBB in the pathogenesis of neurodegenerative diseases. Notably, endothelial cells constituting the BBB exhibit distinct metabolic characteristics, primarily generating ATP through aerobic glycolysis. This occurs despite their direct exposure to the abundant oxygen in the bloodstream, which typically supports oxidative phosphorylation. The effects of insulin on astrocytes, which form the glial limitans component of the BBB, show a marked sexual dimorphism. BBB nutrient sensing in the hypothalamus, along with insulin signaling, regulates systemic metabolism. Insulin modifies BBB permeability by regulating the expression of tight junction proteins, angiogenesis, and vascular remodeling, as well as modulating blood flow in the brain. The disruptions in glucose and insulin signaling are particularly evident in neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, where BBB breakdown accelerates cognitive decline. This review highlights the critical role of normal glucose metabolism and insulin signaling in maintaining BBB functionality and investigates how disruptions in these pathways contribute to the onset and progression of neurodegenerative diseases.

Keywords:  Alzheimer's disease; Huntington's disease; Parkinson's disease; amyotrophic lateral sclerosis; fenestrated capillaries; glucose transporter; insulin resistance; neurodegeneration

DOI:  https://doi.org/10.1111/apha.14283
Expert Rev Proteomics. 2025 Jan 15. 1-15

Interaction and regulation of the mitochondrial proteome - in health and disease.

Johan Palmfeldt.

   INTRODUCTION: Mitochondria contain multiple pathways including energy metabolism and several signaling and synthetic pathways. Mitochondrial proteomics is highly valuable for studying diseases including inherited metabolic disorders, complex and common disorders like neurodegeneration, diabetes, and cancer, since they all to some degree have mitochondrial underpinnings.
AREAS COVERED: The main mitochondrial functions and pathways are outlined, and systematic protein lists are presented. The main energy metabolic pathways are as follows: iron-sulfur cluster synthesis, one carbon metabolism, catabolism of hydrogen sulfide, kynurenines and reactive oxygen species (ROS), and others, described with the aim of laying a foundation for systematic mitochondrial pathway analysis based on proteomics data. The links of the proteins and pathways to functional effects and diseases are discussed. The disease examples are focussed on inherited metabolic disorders, cancer, neurological, and cardiovascular disorders.
EXPERT OPINION: To elucidate the role of mitochondria in health and disease, there is a need for comprehensive proteomics analyses with stringent, systematic data treatment for proper interpretation of mitochondrial pathway data. In that way, comprehensive hypothesis-based research can be performed based on proteomics data.

Keywords:  Mitochondrion; NAD; biomarker panels; kynurenine; metabolic disorders; oxidative phosphorylation; proteomics; stress response

DOI:  https://doi.org/10.1080/14789450.2025.2451704
Int J Mol Sci. 2024 Dec 31. pii: 268. [Epub ahead of print]26(1):

Platelet Mitochondrial Function and Endogenous Coenzyme Q10 Levels Could Be Used as Markers of Mitochondrial Health in Infertile Men: A Pilot Study.

Zuzana Sumbalová, Zuzana Rausová, Jarmila Kucharská, Patrik Šranko, Peter Harbulák, Pavel Svitok, Guillermo López-Lluch, Anna Gvozdjáková.

  Fertility disorders are a worldwide problem affecting 8-12% of the population, with the male factor substantially contributing to about 40-50% of all infertility cases. Mitochondria, crucial organelles for cellular viability, play a pivotal role in the processes of spermatogenesis and significantly affect sperm quality and their fertilizing ability. Mitochondrial oxidative phosphorylation (OXPHOS) dysfunction, reduced energy supply for sperm, reduced endogenous coenzyme Q10 (CoQ10) levels, and oxidative stress are among the main factors that contribute to male infertility. There is great interest in the role of mitochondrial dysfunction in male infertility, and the diagnosis and assessment of mitochondrial health in infertile men present challenges. Platelets are a source of viable mitochondria that can be obtained non-invasively. Changes in platelet mitochondrial respiration were documented in various diseases, confirming platelet mitochondrial bioenergetics as a marker of systemic mitochondrial health. The aim of our study was to determine whether (a) platelet mitochondrial bioenergetics and CoQ10 levels could be used as metabolic markers of mitochondrial health in infertile men and whether (b) the parameters of mitochondrial respiration in platelets correlate with sperm parameters. The high-resolution respirometry method was used for platelet bioenergetics, and the high-performance liquid chromatography (HPLC) method was used for CoQ10 level measurement. The static oxidation-reduction potential (sORP) of the ejaculate was evaluated by MiOXSYS®System. We found a deficit in mitochondrial complex I-linked OXPHOS and electron transfer capacity and CoQ10 and α-tocopherol levels in infertile men. The proportion of sperm, heads, and midpiece abnormalities correlated negatively with the complex I-linked parameters of platelet mitochondrial bioenergetics. We suppose that dysfunctional mitochondria contribute to increased oxidative stress, and these imbalances can be considered a cause of Male Oxidative Stress Infertility (MOSI). Our results suggest that platelet mitochondrial function and the endogenous levels of CoQ10 in platelets could be used as metabolic markers for monitoring mitochondrial health and targeted therapy in infertile men. sORP could be a useful clinical biomarker of MOSI.

Keywords:  bioenergetics; coenzyme Q10; infertility; mitochondria; oxidation–reduction potential; oxidative stress; platelets; semen quality; spermatozoa; tocopherols

DOI:  https://doi.org/10.3390/ijms26010268
Food Sci Nutr. 2025 Jan;13(1): e4607

Unlocking the Potential: How Flavonoids Affect Angiogenesis, Oxidative Stress, Inflammation, Proliferation, Invasion, and Alter Receptor Interactions in Endometriosis.

Pouya Goleij, Mohanna Khandan, Mohammad Amin Khazeei Tabari, Pantea Majma Sanaye, Dorsa Alijanzadeh, Afsaneh Soltani, Zahra Hosseini, Danaé S Larsen, Haroon Khan, Alan Prem Kumar, Maria Daglia.

  Endometriosis, though not classified as a carcinogenic condition, shares features such as oxidative stress, migration, invasion, angiogenesis, and inflammation with tumor cells. This study aims to review the effects of flavonoids on these processes and their molecular mechanisms in preventing and treating endometriosis. A comprehensive review was conducted, involving a literature search in online databases using keywords like "endometriosis," "endometrioma," and "flavonoid." Two authors screened the literature based on predefined criteria, and the selected studies were summarized in a structured data extraction table. Studies reviewed showed that various flavonoids impact key processes in endometriosis, including angiogenesis, inflammation, oxidative stress, and invasiveness. Flavonoids such as 2',7'-dichlorodihydrofluorescein diacetate (H2DCF-DA), naringenin, apigenin, myricetin, 5,7-dimethoxyflavone (DMF), chrysin, and 6,8-diprenylorobol were found to induce oxidative stress. Xanthohumol, isoliquiritigenin, and luteolin demonstrated effects on angiogenesis. Apigenin, isoliquiritigenin, and luteolin exhibited anti-inflammatory properties. Additionally, 3,6-dihydroxyflavone, isoliquiritigenin, and naringenin displayed anti-invasive activities. Flavonoid-receptor interactions further enhance their therapeutic potential in endometriosis management. Flavonoids such as nobiletin, chrysin, and daidzein modulate PPARγ and PPARα, reducing inflammation, promoting apoptosis, and improving lipid metabolism. These interactions regulate critical pathways in angiogenesis and immune responses. Additionally, flavonoids impact the aryl hydrocarbon receptor (AhR), with compounds like resveratrol inhibiting cell proliferation and cholesterol biosynthesis, further suppressing lesion growth. The ability of flavonoids like quercetin and kaempferol to antagonize NR4A1 leads to reduced cell proliferation and oxidative stress in endometriotic tissues. These findings offer insights into the mechanisms through which specific flavonoids modulate angiogenesis, inflammation, oxidative stress, and invasiveness in endometriosis. By targeting receptors such as PPARs, AhR, and NR4A1, flavonoids demonstrate the capacity to modulate both metabolic and inflammatory pathways, offering a multifaceted approach to managing endometriosis. Flavonoids can selectively target pathophysiologic molecules and pathways implicated in the condition. Consequently, leveraging the therapeutic attributes of flavonoids could lead to novel strategies for managing endometriosis.

Keywords:  angiogenesis; endometriosis; flavonoids; inflammation; invasion; oxidative stress; proliferation; receptor interactions

DOI:  https://doi.org/10.1002/fsn3.4607
Biochim Biophys Acta Mol Cell Res. 2025 Jan 10. pii: S0167-4889(25)00002-3. [Epub ahead of print] 119897

Nrf2 mediates mitochondrial and NADPH oxidase-derived ROS during mild heat stress at 40 °C.

Georges Hraoui, Mélanie Grondin, Sophie Breton, Diana A Averill-Bates.

  Hyperthermia is an adjuvant to chemotherapy and radiotherapy and sensitizes tumors to these treatments. However, repeated heat treatments result in acquisition of heat resistance (thermotolerance) in tumors. Thermotolerance is an adaptive survival response that appears to be mediated by upregulated cellular defenses. However, the mechanisms of activation remain unclear. When HeLa cells were exposed to mild heat shock at 40 °C for 3 h, levels of superoxide and peroxides increased. Cells were treated with mitochondrial antioxidant MitoQ and NADPH oxidase (NOX) inhibitor apocynin to characterize the contribution of these two sources to the total reactive oxygen species (ROS) pool. We found that both mitochondria and NOX are sources of ROS during mild heat shock at 40 °C. Heat-derived ROS are thought to activate the adaptive survival response at 40 °C. Nrf2, the master regulator of the cellular antioxidant response, is thought to play a pivotal role in establishing the adaptive survival response. Nrf2 was overexpressed or knocked down to assess its role. Moreover, Nrf2 levels correlate with the cellular redox state, and do so via scavenging of mitochondria- and NOX-derived ROS. Knockdown of Nrf2 markedly increased levels of ROS that were scavenged by either apocynin or MitoQ. Finally, critical defense proteins such as DJ-1 and PGAM5 seemed to require a two-key activation system mediated by Nrf2 and mitochondrial ROS. Our study characterized mitochondrial and NOX-derived ROS as being essential in activating cellular defenses alongside Nrf2 and underlines potential therapeutic targets that may contribute to the acquisition of thermotolerance.

Keywords:  Adaptive survival response; Heat shock; Mitochondria; Nrf2; Oxidative stress; Thermotolerance

DOI:  https://doi.org/10.1016/j.bbamcr.2025.119897
Cornea. 2025 Jan 17.

Mitochondria-Targeted Antioxidant (MitoQ) and Nontargeted Antioxidant (Idebenone) Mitigate Mitochondrial Dysfunction in Corneal Endothelial Cells.

Myriam Böhm, Mohit Parekh, Neha Deshpande, Queenie Cheung, Nathan Shatz, Varun Kumar, Ula V Jurkunas.

PURPOSE: To investigate the effectiveness of mitochondrial-targeted antioxidant mitoquinone (MitoQ) and nontargeted antioxidant idebenone (Idb) in alleviating mitochondrial dysfunction in corneal endothelial cells (CEnCs).
METHODS: In vitro experiments were conducted using immortalized normal human corneal endothelial cells (HCEnC-21T; SVN1-67F) and Fuchs endothelial corneal dystrophy (FECD) cells (SVF5-54F; SVF3-76M). Cells were pretreated with MitoQ or Idb and then exposed to menadione (MN) with simultaneous antioxidant treatment. Mitochondrial parameters were evaluated through adenosine triphosphate viability assays, JC-1 staining for mitochondrial membrane potential, and Tom-20 antibody staining for fragmentation, with analysis performed using ImageJ software. HCEnC-21T cells were additionally exposed to ultraviolet-A (25 J/cm2) to assess drug effects under physiological stress. Mitochondrial fragmentation in FECD specimens was analyzed pre- and post-treatment with the drugs. Statistical analysis was conducted using 1-/2-way analysis of variance with post-hoc Tukey test.
RESULTS: MitoQ and Idb enhanced cell viability and mitochondrial membrane potential in both normal and FECD cells under MN-induced stress. Idb reduced MN-induced mitochondrial fragmentation by 32% more than MitoQ in HCEnC-21T cells and by 13% more in SVF5-54F cells. Under ultraviolet-A stress, Idb and MitoQ improved mitochondrial function by 31% and 25%, respectively, with MitoQ increasing mitochondrial function by 42% in FECD specimens.
CONCLUSIONS: Differential responses in mitochondrial dysfunction across cell lines highlight disease heterogeneity. MitoQ and Idb protected CEnCs from oxidative stress and improved mitochondrial bioenergetics, suggesting that mitochondrial-targeted antioxidants could be considered for mitochondrial dysfunction in CEnCs.

DOI: https://doi.org/10.1097/ICO.0000000000003801
Foods. 2024 Dec 30. pii: 71. [Epub ahead of print]14(1):

Ameliorative Effects of Raisin Polyphenol Extract on Oxidative Stress and Aging In Vitro and In Vivo via Regulation of Sirt1-Nrf2 Signaling Pathway.

Wenjing Gao, Caiyun Zhao, Xin Shang, Bin Li, Jintian Guo, Jingteng Wang, Bin Wu, Yinghua Fu.

  Raisins are an important source of polyphenolic compounds in plant foods, and polyphenols are associated with antioxidant and anti-aging activity. In this work, 628 polyphenols in raisin extracts were characterized using UPLC-MS/MS, mainly including tricetin 3'-glucuronide, diisobutyl phthalate, butyl isobutyl phthalate, isoquercitrin and 6-hydroxykaempferol-7-O-glucoside. The oxidative stress in H2O2-induced HepG2 cells and D-gal-induced aging mice was alleviated by raisin polyphenols (RPs) via increases in the cellular levels of superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH), along with decreases in malonaldehyde (MDA), reactive oxygen species (ROS) and advanced glycosylation end-products (AGEs) levels. In addition, it was observed that RPs enhanced Sirt1 and Sirt3 expression, initiating the Keap1-Nrf2 signaling pathway, by upregulating the levels of nuclear Nrf2, facilitating the expressions of the antioxidant proteins NQO1 and HO-1, and downregulating Keap1 and cytoplasmic Nrf2 protein levels in H2O2-induced HepG2 cells and D-gal-induced aging mice. In summary, RP exerted antioxidant and anti-aging effects via regulating the Sirt1-Nrf2 signaling pathway in vitro and in vivo.

Keywords:  Sirt1–Nrf2 signaling pathway; aging mice; oxidative stress; oxidatively damaged HepG2 cells; raisin polyphenols

DOI:  https://doi.org/10.3390/foods14010071
Molecules. 2024 Dec 26. pii: 43. [Epub ahead of print]30(1):

A Review on Current Aspects of Curcumin-Based Effects in Relation to Neurodegenerative, Neuroinflammatory and Cerebrovascular Diseases.

Claudia-Andreea Moldoveanu, Maria Tomoaia-Cotisel, Alexandra Sevastre-Berghian, Gheorghe Tomoaia, Aurora Mocanu, Csaba Pal-Racz, Vlad-Alexandru Toma, Ioana Roman, Madalina-Anca Ujica, Lucian-Cristian Pop.

  Curcumin is among the most well-studied natural substances, known for its biological actions within the central nervous system, its antioxidant and anti-inflammatory properties, and human health benefits. However, challenges persist in effectively utilising curcumin, addressing its metabolism and passage through the blood-brain barrier (BBB) in therapies targeting cerebrovascular diseases. Current challenges in curcumin's applications revolve around its effects within neoplastic tissues alongside the development of intelligent formulations to enhance its bioavailability. Formulations have been discovered including curcumin's complexes with brain-derived phospholipids and proteins, or its liposomal encapsulation. These novel strategies aim to improve curcumin's bioavailability and stability, and its capability to cross the BBB, thereby potentially enhancing its efficacy in treating cerebrovascular diseases. In summary, this review provides a comprehensive overview of molecular pathways involved in interactions of curcumin and its metabolites, and brain vascular homeostasis. This review explores cellular and molecular current aspects, of curcumin-based effects with an emphasis on curcumin's metabolism and its impact on pathological conditions, such as neurodegenerative diseases, schizophrenia, and cerebral angiopathy. It also highlights the limitations posed by curcumin's poor bioavailability and discusses ongoing efforts to surpass these impediments to harness the full therapeutic potential of curcumin in neurological disorders.

Keywords:  benefits and limiting effects; bioavailability; cerebrovascular diseases; curcumin; formulations blood–brain barrier

DOI:  https://doi.org/10.3390/molecules30010043