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•GK attenuated apoptosis in HBZY-1 cells induced by H2O2;•GK treatment improved blood glucose levels and renal function in DN rats;•Renal oxidative stress and inflammation markers ...were reduced by GK;•Histopathological analysis showed amelioration of renal damage with GK.
Garcinia kola seeds, the mature seeds of Garcinia kola Heckel, are recognized for their potential to alleviate symptoms associated with hyperglycemia and hepatic dysfunction. However, its efficacy in diabetic nephropathy (DN) remains unclear. In this study, we investigated the potential benefits of the ethanol extract of Garcinia kola seeds(GK) on apoptosis in rat glomerular mesangial cells (HBZY-1) induced by H2O2, as well as its effects on DN in rats induced by a high-fat diet (HFD) combined with streptozotocin (STZ). Our findings indicate that GK significantly attenuated apoptosis, mitochondrial dysfunction, and activation of caspase 3/9 in H2O2-treated HBZY-1 cells. Furthermore, 8-week treatment with GK resulted in improvements in blood glucose levels, renal function, renal oxidative stress and proinflammatory markers. Histopathological analysis revealed amelioration of renal damage, accompanied by reduced activation of caspase 3. These results suggest that Garcinia kola seeds holds promise as a potential adjunctive therapy for DN management.
HHATL, previously implicated in cardiac hypertrophy in the zebrafish model, has emerged as a prioritized HCM risk gene. We identified six rare mutations in HHATL, present in 6.94 % of nonsarcomeric ...HCM patients (5/72). Moreover, a decrease of HHATL in the heart tissue from HCM patients and cardiac hypertrophy mouse model using transverse aortic constriction was observed. Despite this, the precise pathogenic mechanisms underlying HHATL-associated cardiac hypertrophy remain elusive. In this study, we observed that HHATL downregulation in H9C2 cells resulted in elevated expression of hypertrophic markers and reactive oxygen species (ROS), culminating in cardiac hypertrophy and mitochondrial dysfunction. Notably, the bioactive form of SHH, SHHN, exhibited a significant increase, while the mitochondrial fission protein dynamin-like GTPase (DRP1) decreased upon HHATL depletion. Intervention with the SHH inhibitor RU-SKI 43 or DRP1 overexpression effectively prevented Hhatl-depletion-induced cardiac hypertrophy, mitigating disruptions in mitochondrial morphology and membrane potential through the SHH/DRP1 axis. In summary, our findings suggest that HHATL depletion activates SHH signaling, reducing DRP1 levels and thereby promoting the expression of hypertrophic markers, ROS generation, and mitochondrial dysfunction, ultimately leading to cardiac hypertrophy. This study provides additional compelling evidence supporting the association of HHATL with cardiac hypertrophy.
Understanding the mechanisms controlling platelet function is crucial for exploring potential therapeutic targets related to atherothrombotic pathologies and primary hemostasis disorders. Our ...research, which focuses on the role of platelet mitochondria and Ca2+ fluxes in platelet activation, the formation of the procoagulant phenotype, and thrombosis, has significant implications for the development of new therapeutic strategies. Traditionally, Ca2+-dependent cellular signaling has been recognized as a determinant process throughout the platelet activation, controlled primarily by store-operated Ca2+ entry and the PLC-PKC signaling pathway. However, despite the accumulated knowledge of these regulatory mechanisms, the effectiveness of therapy based on various commonly used antiplatelet drugs (such as acetylsalicylic acid and clopidogrel, among others) has faced challenges due to bleeding risks and reduced efficacy associated with the phenomenon of high platelet reactivity. Recent evidence suggests that platelet mitochondria could play a fundamental role in these aspects through Ca2+-dependent mechanisms linked to apoptosis and forming a procoagulant phenotype. In this context, the present review describes the latest advances regarding the role of platelet mitochondria and Ca2+ fluxes in platelet activation, the formation of the procoagulant phenotype, and thrombosis.
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•Frailty syndrome is a geriatric clinical condition affected by alterations in platelet functionality.•iCa2+-dependent signaling is essential for platelet activation and thrombosis.•Ca2+-dependent platelet mitochondrial metabolism is associated with procoagulant formation phenotype and risk of bleeding.•Alterations in mitochondrial function and Ca2+fluxes are associated with a high platelet reactivity and a low response to ASA.
Mitochondrial dysfunction has been reported to occur in the mammary gland of dairy cows suffering from ketosis. Prohibitin 2 (PHB2) plays a crucial role in regulating mitophagy, which clears impaired ...mitochondria to maintain normal mitochondrial function. Therefore, the current study aimed to investigate how PHB2 mediates mitophagy, thereby influencing mitochondrial function in the bovine mammary epithelial cell MAC-T. First, mammary gland tissue and blood samples were collected from healthy cows (control; n = 15, BHB <0.6 mM) and cows with clinical ketosis (CK; n = 15, BHB >3.0 mM). Compared with the control group, the CK group exhibited lower dry matter intake (DMI), milk production, milk protein, milk lactose, and serum glucose. In contrast, milk fat, serum nonesterified fatty acids (NEFA) and BHB were greater in CK group. The protein abundance of PHB2, peroxisome proliferator activated receptor-γ coactivator-1α (PGC-1α), mitofusin 2 (MFN2) in whole cell lysates (WCL), as well as PHB2, sequestosome-1 (SQSTM1, also called p62), microtubule-associated protein 1 light chain 3-II (LC3-II), and ubiquitinated proteins in mitochondrial fraction were significantly lower in the CK group. ATP content of mammary gland tissue in CK group was lower than that of healthy cows. Second, MAC-T were cultured and treated with NEFA (0, 0.3, 0.6, 1.2 mM). MAC-T treated with 1.2 mM NEFA displayed decreased protein abundance of PHB2, PGC-1α, MFN2 in WCL, as well as protein abundance of PHB2, p62, LC3-II, and ubiquitinated proteins in mitochondrial fraction. The content of ATP and JC-1 aggregates in 1.2 mM NEFA group were lower than in the 0 mM NEFA group. Additionally, 1.2 mM NEFA disrupted the fusion between mitochondria and lysosomes. MAC-T were then pretreated with 100 nM rapamycin, followed by treatment with or without NEFA. Rapamycin alleviated impaired mitophagy and mitochondria dysfunction induced by 1.2 mM NEFA. Third, MAC-T were transfected with small interfering RNA to silence PHB2 or a plasmid for overexpression of PHB2, followed by treatment with or without NEFA. The silencing of PHB2 aggravated 1.2 mM NEFA induced impaired mitophagy and mitochondrial dysfunction, whereas the overexpression of PHB2 alleviated these effects. Overall, this study provides evidence that PHB2, in regulation of mitophagy, is a mechanism for bovine mammary epithelial cells to counteract NEFA-induced mitochondrial dysfunction.
Ferroptosis is a form of iron-regulated cell death implicated in ischemic heart disease. Our previous study revealed that Sirtuin 3 (SIRT3) is associated with ferroptosis and cardiac fibrosis. In ...this study, we tested whether the knockout of SIRT3 in cardiomyocytes (SIRT3cKO) promotes mitochondrial ferroptosis and whether the blockade of ferroptosis would ameliorate mitochondrial dysfunction.
Mitochondrial and cytosolic fractions were isolated from the ventricles of mice. Cytosolic and mitochondrial ferroptosis were analyzed by comparison to SIRT3loxp mice. An echocardiography study showed that SIRT3cKO mice developed heart failure as evidenced by a reduction of EF% and FS% compared to SIRT3loxp mice. Comparison of mitochondrial and cytosolic fractions of SIRT3cKO and SIRT3loxp mice revealed that, upon loss of SIRT3, mitochondrial, but not cytosolic, total lysine acetylation was significantly increased. Similarly, acetylated p53 was significantly upregulated only in the mitochondria. These data demonstrate that SIRT3 is the primary mitochondrial deacetylase. Most importantly, loss of SIRT3 resulted in significant reductions of frataxin, aconitase, and glutathione peroxidase 4 (GPX4) in the mitochondria. This was accompanied by a significant increase in levels of mitochondrial 4-hydroxynonenal. Treatment of SIRT3cKO mice with the ferroptosis inhibitor ferrostatin-1 (Fer-1) for 14 days significantly improved preexisting heart failure. Mechanistically, Fer-1 treatment significantly increased GPX4 and aconitase expression/activity, increased mitochondrial iron‑sulfur clusters, and improved mitochondrial membrane potential and Complex IV activity.
Inhibition of ferroptosis ameliorated cardiac dysfunction by specifically targeting mitochondrial aconitase and iron‑sulfur clusters. Blockade of mitochondrial ferroptosis may be a novel therapeutic target for mitochondrial cardiomyopathies.
•SIRT3cKO in mice causes severe cardiac dysfunction similar to the mitochondrial cardiomyopathy seen in Friedreich's ataxia•SIRT3cKO mice exhibit mitochondrial iron dysregulation and mitochondrial ferroptosis•Ferrostatin-1 improves cardiac function in SIRT3cKO mice by targeting mitochondrial iron-sulfur clusters and aconitase
The role of mitochondria in steroidogenesis is well established. However, the specific effects of mitochondrial dysfunction on androgen synthesis are not fully understood. In this study, we ...investigate the effects of various mitochondrial and metabolic inhibitors in H295R adrenal cells and perform a comprehensive analysis of steroid and metabolite profiling. We report that mitochondrial complex I inhibition by rotenone shifts cells toward anaerobic metabolism with a concomitant hyperandrogenic phenotype characterized by rapid stimulation of dehydroepiandrosterone (DHEA, 2 h) and slower accumulation of androstenedione and testosterone (24 h). Screening of metabolic inhibitors confirmed DHEA stimulation, which included mitochondrial complex III and mitochondrial pyruvate carrier inhibition. Metabolomic studies revealed truncated tricarboxylic acid cycle with an inverse correlation between citric acid and DHEA production as a common metabolic marker of hyperandrogenic inhibitors. The current study sheds light on a direct interplay between energy metabolism and androgen biosynthesis that could be further explored to identify novel molecular targets for efficient treatment of androgen excess disorders.
•Evidence for a direct interplay between energy metabolism and androgen biosynthesis.•Inhibition of mitochondrial complex I increases DHEA production with delayed elevation of other androgens.•Metabolic inhibitor screening confirmed DHEA accumulation with inhibition of complex III and mitochondrial pyruvate carrier.•Metabolomics analysis revealed truncated tricarboxylic acid cycle with an inverse correlation between citric acid and DHEA.
•ONC206 induces mitochondria fragmentation and mtROS formation, MMP and ATP depletion, and oxidative stress in HCC cells.•ONC206 elicited apoptosis and protective autophagy and combined with ...autophagy inhibitor enhanced pro-apoptosis activity.•ClpP is highly expressed in HCC tissues and mediated ONC206-induced mitochondrial dysfunction and protective autophagy.•ClpP protein expression could be used as a tool to select patients and predict response for ONC206 therapy.
Hepatocellular carcinoma (HCC) is the most common form of liver cancer, accounting for approximately 90 % of all cases. ONC201, a member of the imipridone drug family, has shown promising therapeutic potential and a good safety profile in both malignant pediatric central nervous system tumors (diffuse midline glioma DMG) and hematologic malignancies. ONC206 is a more potent analog of ONC201. However, the ONC206 potential and mechanism of action in HCC remain to be elucidated. We found that ONC206 hindered HCC growth by suppressing cell proliferation and inducing apoptosis. Moreover, ONC206 induced cytoprotective autophagy, and blocking autophagy enhanced the proapoptotic effect of ONC206. Additionally, ONC206 induced mitochondrial swelling, reduced the mitochondrial membrane potential (MMP), and led to the accumulation of mitochondrial ROS in HCC cells, ultimately resulting in mitochondrial dysfunction. The HCC patient samples exhibited notably elevated levels of caseinolytic protease proteolytic subunit (ClpP), which serves as a mediator of ONC206-induced mitochondrial dysfunction and the activation of protective autophagy. knockdown of ClpP reversed the cytotoxic effects of ONC206 on HCC cells. In summary, our results provide the first insight into the mechanism by which ONC206 exerts its anti-HCC effects and induces protective autophagy in HCC cells through ClpP.
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Development of multifunctional stimuli-responsive nanomedicine is appealing for effective cancer treatment. Herein, we utilize the biocompatible CaCO3 nanoparticles as the template to guide the ...formation of pH-dissociable hollow coordination nanostructures, in which meso-tetra-(4-carboxyphenyl)porphine (TCPP), a sonosensitizer, acts as the organic bridging molecule and ferric ion serves as the metallic center. L-buthionine sulfoximine (BSO), an inhibitor for glutathione (GSH) biosynthesis, can be simultaneously loaded during the preparation of TCPP-Fe@CaCO3, obtaining BSO-TCPP-Fe@CaCO3 with pH-responsive dissociation to endow fast release of Ca2+ and BSO under an acidic tumor microenvironment. Such BSO-TCPP-Fe@CaCO3 confers synergistic oxidative stress amplification via intracellular Ca2+-overloading-induced mitochondria damage, BSO-mediated GSH depletion, and TCPP-mediated sonodynamic therapy (SDT), leading to remarkable cell death. Consequently, tumors on the mice treated with BSO-TCPP-Fe@CaCO3 administration and subsequent ultrasound exposure are effectively suppressed. Our work thus highlights a facile strategy to prepare pH-dissociable nanomedicine for effective SDT treatment of tumors via triple amplification of tumor oxidative stress.
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•Self-templated synthesis is a general method to prepare CaCO3-based nanomedicine•Ca2+ overloading enables ROS generation by inducing mitochondrial dysfunction•Triple amplification of tumor oxidative stress endows enhanced cancer treatment
In this work, we utilize CaCO3 nanoparticles as the template to guide the formation of pH-dissociable hollow metal-organic coordination nanostructures, in which meso-tetra-(4-carboxyphenyl)porphine (TCPP), a sonosensitizer, acts as the organic bridging molecule and ferric ion serves as the metallic center. With loading of L-buthionine sulfoximine (BSO), an inhibitor for glutathione biosynthesis, the obtained nanoparticles show pH-responsive dissociation to endow fast release of Ca2+ and BSO under an acidic tumor microenvironment. Such nanoparticles, upon intravenous administration together with ultrasound exposure, would effectively inhibit the tumor growth ascribing to triple amplification of tumor oxidative stresses by Ca2+-overloading-mediated mitochondrial dysfunction, BSO-mediated glutathione (GSH) depletion, and TCPP-mediated sonodynamic effect. Our work presents a promising way of constructing small nanomedicine platforms based on biocompatible CaCO3.
The authors report a self-templated strategy to prepare pH-dissociable nanomedicine for effective cancer treatment via triple amplification of tumor oxidative stresses by the Ca2+-overloading-induced ROS generation, BSO-induced GSH depletion, and TCPP-mediated sonodynamic therapy.
Gossypol, a naturally occurring compound found in cottonseed meal, shows promising therapeutic potential for human diseases. However, within the aquaculture industry, it is considered an ...antinutritional factor. The incorporation of cottonseed meal into fish feed introduces gossypol, which induces intracellular stresses and hinders overall health of farmed fish. The aim of this study is to determine the role of General control nonderepressible 2 (gcn2), a sensor for intracellular stresses in gossypol-induced stress responses in fish. In the present study, we established two gcn2 knockout zebrafish lines. A feeding trial was conducted to assess the growth-inhibitory effect of gossypol in both wild type and gcn2 knockout zebrafish. The results showed that in the absence of gcn2, zebrafish exhibited increased oxidative stress and apoptosis when exposed to gossypol, resulting in higher mortality rates. In feeding trial, dietary gossypol intensified liver inflammation in gcn2−/− zebrafish, diminishing their growth and feed conversion. Remarkably, administering the antioxidant N-acetylcysteine (NAC) was effective in reversing the gossypol induced oxidative stress and apoptosis, thereby increasing the gossypol tolerance of gcn2−/− zebrafish. Exposure to gossypol induces more severe mitochondrial stress in gcn2−/− zebrafish, thereby inducing metabolic disorders. These results reveal that gcn2 plays a protective role in reducing gossypol-induced oxidative stress and apoptosis, attenuating inflammation responses, and enhancing the survivability of zebrafish in gossypol-challenged conditions. Therefore, maintaining appropriate activation of Gcn2 may be beneficial for fish fed diets containing gossypol.
•Zebrafish lacking Gcn2 showed a significant increase in mortality when exposed to gossypol.•Gcn2 deficiency exacerbated oxidative stress and apoptosis in response to gossypol exposure.•Zebrafish deficient in Gcn2 exhibited more severe liver inflammation upon dietary gossypol exposure.
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