Free Radical Biology and Medicine最新文献

Mitochondria, commonly referred to as "energy factories"of cells, play a crucial role in the function and survival of cardiomyocytes. However, as research on cardiac fibrosis has advanced, mitochondrial dysfunction(including changes in energy metabolism, calcium ion imbalance, increased oxidative stress, and apoptosis)is now recognized as a significant pathophysiological pathway involved in cardiac remodeling and progression, which also negatively affects the function and structure of the heart. In recent years, research focusing on targeting mitochondria has gained significant attention, offering new approaches for treating cardiac fibrosis. Targeted mitochondrial therapy for cardiac fibrosis represents an emerging therapeutic strategy that aims to inhibit cardiac fibroblast proliferation or protect cardiomyocytes from damage by enhancing mitochondrial function. However, current research on epigenetic treatments for cardiac fibrosis through mitochondrial targeting remains limited. This review explores the relationship between mitochondrial dysfunction and cardiac fibrosis, as well as the epigenetic regulatory mechanisms involved in targeted mitochondrial therapy for cardiac fibrosis.

The connection between the respiratory capacity of skeletal muscle mitochondria and athletic performance is widely acknowledged in contemporary research. Building on a solid foundation of prior studies, current research has fostered an environment where scientists can effectively demonstrate how a tailored regimen of exercise intensity, duration, and frequency significantly boosts mitochondrial function within skeletal muscles. The range of exercise modalities is broad, spanning from endurance and high-intensity interval training to resistance-based exercises, allowing for an in-depth exploration of effective strategies to enhance mitochondrial respiratory capacity-a key factor in improving exercise performance, in other words offering a better skeletal muscle capacity to cope with exercise demands. By identifying optimal training strategies, individuals can significantly improve their performance, leading to better outcomes in their fitness and athletic endeavours. This review provides the prevailing insights on skeletal muscle mitochondrial respiratory capacity and its role in exercise performance, covering essential instrumental and methodological aspects, findings from animal studies, potential sex differences, a review of existing human studies, and considerations for future research directions.

Ferroptosis, a recently identified form of regulated cell death, is characterized by lipid peroxidation and iron accumulation, plays a critical role in early brain injury after subarachnoid hemorrhage. Ginsenoside Rd, an active compound isolated from ginseng, is known for its neuroprotective properties. However, its influence on SAH-induced ferroptosis remains unclear. In this study, we constructed an SAH model using intravascular perforation in vivo and treated HT22 cells with oxyhemoglobin to simulate the condition in vitro. We observed significant changes in ferroptosis markers, including GPX4 and ACSL4, following SAH. Administration of ginsenoside Rd to both rats and HT22 cells effectively inhibited neuronal ferroptosis induced by SAH, alleviating neurological deficits and cognitive dysfunction in rats. Notably, the neuroprotective properties of ginsenoside Rd were countered by the STING pathway agonist 2'3'-cGAMP. Experiments conducted in vitro and in vivo illustrated that the impacts of ginsenoside Rd were counteracted by the BQR inhibitor. Our findings suggest that ginsenoside Rd mitigates EBI after SAH by suppressing neuronal ferroptosis through the cGAS/STING pathway while upregulating DHODH levels. These outcomes emphasize the potential of ginsenoside Rd as a therapeutic candidate for subarachnoid hemorrhage.

Akhuni, an ethnic food of northeast India, induces ROS-mediated apoptosis in cancer cells. This is the first report on the anticancer potential of Akhuni. Akhuni is a traditional fermented soybean product known for its umami taste and delicacy, commonly used in Northeast India's cuisine. The current work demonstrates the antiproliferative potential of Akhuni ethanolic extract (AKET) against B16-F10 and MDA-MB-231 cancer cells and its mechanism of action supported by metabolic profiling and molecular docking. The investigation evaluated cytotoxicity, cell cycle distribution, caspase activity, apoptosis-related gene and protein expression, and oxidative stress imposed by excess reactive oxygen species (ROS) in both cell types. Phytochemical characterization of AKET was performed using HPLC. The growth of both cells is concentration-dependently inhibited after AKET treatment in MTT and flow cytometry experiments, leading to an arrest in the cell cycle at the G2 phase. Intracellular ROS levels increased in response to AKET treatment, suggesting that ROS in both cells triggered the mitochondrial pathway. Compared to the untreated cells, qRT-PCR analysis showed that AKET significantly reduced Cdk2 and Bcl-2 and increased the mRNA expression levels of Caspase-9, Bax, FasL, and Bid. Additionally, Caspase-8, Caspase-3, and the protein p53 were significantly upregulated in AKET-treated cells, as confirmed by both real-time and ELISA assays. In both the B16-F10 and MDA-MB-231 cell lines, the Western blot analysis showed that AKET caused an elevation of the expression of the Bax protein and downregulation of the Erk1/2, Akt, and Bcl2 proteins. Six isoflavones were identified from AKET through HPLC analysis. Molecular docking results indicate compounds in the AKET extract like daidzein, genistein and glycitein act as potent inhibitors of the key oncoprotein, AKT. These findings suggest that AKET has an anticancer effect through ROS-mediated ERK1/2 and AKT signalling pathways.

Cytoglobin (Cygb) regulates vascular tone by modulating nitric oxide (NO) metabolism in vascular smooth muscle cells (VSMCs). In the presence of its cytochrome B5a (B5)/B5 reductase-isoform-3 (B5R) reducing system, Cygb controls NO metabolism via oxygen-dependent NO dioxygenation. Electronic cigarette (EC) use has been shown to induce vascular dysfunction and decrease NO bioavailability; however, the role of Cygb-mediated NO metabolism in the pathophysiology of this process has not been previously investigated. Therefore, we utilized aortic VSMCs with EC vape extract (ECE) exposure to elucidate the effects of EC vape constituents on NO degradation and alterations in the process of Cygb-mediated NO metabolism. VSMCs were exposed to ECE, either nicotine-free (ECEV) or nicotine-containing (ECEN), for various durations. NO decay rates were measured along with cellular expression of Cygb and its B5/B5R reducing system. Exposure to ECEV led to a much higher rate of NO consumption by VSMCs, with an even larger effect following ECEN exposure. With 4 h of exposure, a modest increase in NO decay rate occurred that was followed by much higher increases with exposure times of 24-48 h. This effect was paralleled by upregulation of Cygb and B5/B5R expression. siRNA-mediated knock-down of Cygb expression largely reversed this ECE-induced increase in NO metabolism rate. Thus, ECE exposure led to increased Cygb-mediated NO metabolism in VSMCs with diminished NO bioavailability, which in turn can play a key role in EC-induced vascular dysfunction.

Background: Posttranslational modifications (PTM) of albumin occur in liver diseases; however, little is known about the source and function of sulfonated albumin, a significant modification of albumin occurring in nonalcoholic fatty liver disease (NAFLD). We aimed to investigate the mechanism underlying sulfonated albumin production and its role in the progression of NAFLD-related liver fibrosis.

Methods: Serum samples from healthy controls and patients with NAFLD were used to measure the proportion of sulfonated albumin. Mice models with NAFLD fed with high-fat diet (HFD) and methionine choline-deficient diet (MCD) were constructed. RNA sequencing, KEGG analysis, and GSEA were used to explore the mechanism of sulfonated albumin production and its mechanism of activating hepatic stellate cells (HSCs) and promoting the progression of liver fibrosis in NAFLD.

Results: Sulfonated albumin levels increased significantly in both human and mouse NAFLD serum samples. In vivo studies in mice have shown that the intraperitoneal injection of sulfonated albumin promotes inflammation, hepatic steatosis, and liver fibrosis in NAFLD. In addition, autophagy has been verified as a key mechanism in the regulation of sulfonated albumin production. We also demonstrated that reactive oxygen species (ROS) production depends on the accumulation of damaged mitochondria and affects the production of sulfonated albumin under the regulation of autophagy. Hepatocyte-derived sulfonated albumin activates HSCs through the GAL3 receptor, thereby activating the endoplasmic reticulum (ER) stress pathway and promoting profibrotic activation of HSCs.

Conclusions: Our study demonstrated that sulfonated albumin activated HSCs through GAL3, thereby accelerating NAFLD-related liver fibrosis. Serum sulfonated albumin may be a potential diagnostic marker for liver fibrosis and an important target for the treatment of NAFLD-related liver fibrosis.

Background: Sorafenib is a tyrosine kinase inhibitor (TKI) that belongs to the landscape of treatments for advanced stages of hepatocellular carcinoma (HCC). The induction of cell death and cell cycle arrest by Sorafenib has been associated with mitochondrial dysfunction in liver cancer cells. Our research aim was to decipher underlying oxidative and nitrosative stress induced by Sorafenib leading to mitochondrial dysfunction in liver cancer cells.

Methods: MnTBAP, catalase and the scavenger of peroxynitrite FeTPPs were administered to Sorafenib (0-10 μM)-treated HepG2 cells. Oxygen consumption and glycolytic flux were determined in cultured cells. Mitochondrial complex activities were measured in mitochondrial fraction and cell lysates. The protein and mRNA expression of subunits of electron transport chain (ETC) were assessed by immunoblot and RNA-seq.

Results: Sorafenib (10 μM) increased nitric oxide (NO) and superoxide anion (O₂^.-) leading to peroxynitrite generation, and drastically reduced oxygen consumption. Moreover, Sorafenib led to mitochondrial network disorganization and loss of membrane potential. The administration of FeTPPs influenced the recovery of mitochondrial network and oxygen consumption, as well as associated ATP production. Sorafenib downregulated the mRNA expression of all mitochondrial-encoded subunits of ETC and, at to a lesser extent, nuclear-encoded mitochondrial genes. The protein expression of complex I, complex III and complex IV was greatly affected by Sorafenib. Furthermore, Sorafenib diminished the activity of complex I in in-gel assays, whose expression and activity were restored by FeTPPs. However, Sorafenib did not affect the assembly of mitochondrial supercomplexes. Sorafenib altered glycolysis and reduced Krebs cycle intermediates and increased NAD/NADH ratio.

Conclusions: The induction of cell death by Sorafenib was associated with peroxynitrite generation, which impacted the expression of ETC subunits and mitochondrial functionality in liver cancer cells.

The occurrence and progression of traumatic brain injury involve a complex process. The pathophysiological mechanisms triggered by neuronal damage include various forms of programmed cell death, including ferroptosis. We observed upregulation of TNFAIP3 in mice after traumatic brain injury. Overexpression of TNFAIP3 inhibits HT-22 proliferation and cell viability through ferroptosis. Mechanistically, TNFAIP3 interacts with the HMOX1 protein and promotes its stability through the deubiquitination pathway. Additionally, TNFAIP3 can enhance lipoperoxidation, mitochondrial damage, and neuronal cell death by promoting ACSL3 degradation via NEDD4-mediated ubiquitination. Mice injected with AAV-shTNFAIP3 exhibited reduced neuronal degeneration and improved motor and cognitive function following cortical impact injury. In conclusion, our findings demonstrate that TNFAIP3 deficiency inhibits neuronal cell ferroptosis and ameliorates cognitive impairment caused by traumatic brain injury and demonstrate its potential applicability in the treatment of traumatic brain injury.

Sperm cells are highly susceptible to oxidative stress, which decreases their motility and fertility. However, glutathione (GSH) plays a critical role in protecting sperm cells from oxidative damage, a common byproduct of mitochondrial oxidative phosphorylation. On the other hand, GSH biosynthesis in sperm is limited by the availability of cysteine (Cys), which is inherently unstable and found at low concentrations in boar seminal plasma. In somatic cells, Cys can be produced through the transsulfuration pathway, catalyzed by cystathionine β-synthase (CBS) and cystathionine γ-lyase (CTH). In this study, we report that a group of enzymes involved in GSH synthesis is present in boar sperm. Notably, CBS and CTH protein levels increase during incubation, suggesting active regulation of their synthesis. This increase is inhibited by cycloheximide (CHX), indicating that ongoing protein synthesis is necessary for maintaining these levels. Our study also identified the presence of translation factors, such as eukaryotic initiation factor 4E (eIF4E), and their activation through phosphorylation of the ERK1/2-RSK-eIF4E pathway during incubation. Additionally, we found that CBS mRNA transcripts with short poly(A) tails are present in boar sperm, and polyadenylation of these short-tailed mRNAs occurs during incubation to enhance their translation. The use of cordycepin, a polyadenylation inhibitor, significantly reduced the translation of CBS, leading to decreased GSH synthesis and impaired sperm motility. However, the addition of cysteine counteracted the inhibitory effects of cordycepin, underscoring the essential role of cysteine in maintaining GSH levels. These findings provide new insights into the post-transcriptional regulation of GSH synthesis in sperm and suggest potential strategies for enhancing sperm preservation and fertility by targeting polyadenylation and translation mechanisms.

Despite the improvements in outcomes for patients with multiple myeloma (MM) over the past decade, the disease remains incurable, and even those patients who initially respond favorably to induction therapy eventually suffer from relapse. Consequently, there is an urgent need for the development of novel therapeutic agents and strategies to enhance the treatment outcomes for patients with MM. The proteasome inhibitor bortezomib (BTZ) elicits endoplasmic reticulum (ER) stress and oxidative stress in MM cells, subsequent DNA damage, ultimately inducing cell apoptosis. Poly (ADP-ribose) polymerase 1 (PARP1) acts as a pivotal enzyme for DNA repair and thus deficient PARP1 renders cells more susceptible to DNA-damaging agents. Conceivably, targeting PARP1 may enhance BTZ-induced DNA damage and cell death in MM cells. In this study, Colony formation, CCK-8, and EdU-labeling assays were conducted to evaluate the effects on MM cell proliferation. The ZIP score was used to assess synergy. Apoptosis and intercellular ROS levels were analyzed using flow cytometry and fluorescence microscopy, respectively. Immunofluorescence and Western blot analyses were used to assess protein expression. The correlation between PARP1 expression levels and the clinical prognosis was examined by tumor-related databases and bioinformatics. The results show that PARP1 is overexpressed in patient MM cells and is associated with a poor prognosis. PARP1 inhibitor niraparib decreases MM cell growth and arrests cell cycle progression at the G2/M phase. When combined with BTZ, it synergistically increases DNA damage, inhibits proliferation, and induces apoptosis. Mechanistically, Niraparib facilitates BTZ-induced ROS elevation, causing DNA double-strand breaks (DSBs), and simultaneously inhibits lesion repair by impeding the expression of repair proteins XRCC1 (X-ray repair cross-complementing protein 1) and POLβ (DNA polymerase beta). Overall, Niraparib plus bortezomib represent a promising approach for treatment of MM.