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The literature analysis conducted in this review discusses the latest achievements in the identification of cardiovascular damage induced by oxidative stress with secondary platelet mitochondrial dysfunction. Damage to the platelets of mitochondria as a result of their interactions with reactive oxygen species (ROS) and reactive nitrogen species (RNS) can lead to their numerous ischemic events associated with hypoxia or hyperoxia processes in the cell. Disturbances in redox reactions in the platelet mitochondrial membrane lead to the direct oxidation of cellular macromolecules, including nucleic acids (DNA base oxidation), membrane lipids (lipid peroxidation process) and cellular proteins (formation of reducing groups in repair proteins and amino acid peroxides). Oxidative changes in biomolecules inducing tissue damage leads to inflammation, initiating pathogenic processes associated with faster cell aging or their apoptosis. The consequence of damage to platelet mitochondria and their excessive activation is the induction of cardiovascular and neurodegenerative diseases (Parkinson's and Alzheimer's), as well as carbohydrate metabolism disorders (diabetes). The oxidation of mitochondrial DNA can lead to modifications in its bases, inducing the formation of exocyclic adducts of the ethano and propano type. As a consequence, it disrupts DNA repair processes and conduces to premature neoplastic transformation in critical genes such as the p53 suppressor gene, which leads to the development of various types of tumors. The topic of new innovative methods and techniques for the analysis of oxidative stress in platelet mitochondria based on methods such as a nicking assay, oxygen consumption assay, Total Thrombus formation Analysis System (T-Tas), and continuous-flow left ventricular assist devices (CF-LVADs) was also discussed. They were put together into one scientific and research platform. This will enable the facilitation of faster diagnostics and the identification of platelet mitochondrial damage by clinicians and scientists in order to implement adequate therapeutic procedures and minimize the risk of the induction of cardiovascular diseases, including ischemic events correlated with them. A quantitative analysis of the processes of thrombus formation in cardiovascular diseases will provide an opportunity to select specific anticoagulant and thrombolytic drugs under conditions of preserved hemostasis. [ABSTRACT FROM AUTHOR]

Escalating the production and application of tungsten disulfide (WS2) nanosheets inevitably increases environmental human exposure and warrants the necessity of studies to elucidate their biological impacts. Herein, we assessed the toxicity of WS2 nanosheets and focused on the impacts of low doses (≤10 μg/mL) on normal (BEAS-2B) and tumorigenic (A549) lung epithelial cells. The low doses, which approximate real-world exposures, were found to induce cell apoptosis, while doses ≥ 50 μg/mL cause necrosis. Focused studies on low-dose exposure to WS2 nanosheets revealed more details of the impacts on both cell lines, including reduction of cell metabolic activity, induction of lipid peroxidation in cell membranes, and uncoupling of mitochondrial oxidative phosphorylation that led to the loss of ATP production. These phenomena, along with the expression situations of a few key proteins involved in apoptosis, point toward the occurrence of mitochondria-dependent apoptotic signaling in exposed cells. Substantial differences in responses to WS2 exposure between normal and tumorigenic lung epithelial cells were noticed as well. Specifically, BEAS-2B cells experienced more adverse effects and took up more nanosheets than A549 cells. Our results highlight the importance of dose and cell model selection in the assessment of nanotoxicity. By using doses consistent with real-world exposures and comparing normal and diseased cells, we can gain knowledge to guide the development of safety precautions for mitigating the adverse impacts of nanomaterial exposure on human health.

Boye Zhang,1,2 Jianliang Man,3,4 Lingyun Guo,1 Xiaoxia Ru,1 Chengwu Zhang,1,2 Wen Liu,1,2,5 Lihong Li,1,2,5 Sufang Ma,1,2 Lixia Guo,2,4 Haojiang Wang,1,2 Bin Wang,1,2 Haipeng Diao,1,5 Renchao Che,6,7 Lili Yan1,2,5 1School of Basic Medical Sciences, Shanxi Medical University, Taiyuan, 030001, People’s Republic of China; 2Shanxi Province Brain Degenerative Diseases Precision Diagnosis and Treatment Engineering Research Center, Shanxi Medical University, Jinzhong, 030606, People’s Republic of China; 3Academy of Medical Sciences, Shanxi Medical University, Taiyuan, 030001, People’s Republic of China; 4College of Pharmacy, Shanxi Medical University, Taiyuan, 030001, People’s Republic of China; 5Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, 030001, People’s Republic of China; 6Laboratory of Advanced Materials, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Academy for Engineering &Technology, Fudan University, Shanghai, 200438, People’s Republic of China; 7Zhejiang Laboratory, Hangzhou, 311100, People’s Republic of ChinaCorrespondence: Lili Yan; Renchao Che, Email yanlili@sxmu.edu.cn; rcche@fudan.edu.cnBackground: Challenges such as poor drug selectivity, non-target reactivity, and the development of drug resistance continue to pose significant obstacles in the clinical application of cancer therapeutic drugs. To overcome the limitations of drug resistance in chemotherapy, a viable treatment strategy involves designing multifunctional nano-platforms that exploit the unique physicochemical properties of tumor microenvironment (TME).Methods: Herein, layer-by-layer nanoparticles with polyporous CuS as delivery vehicles, loaded with a sonosensitizer (tetra-(4-aminophenyl) porphyrin, TAPP) and sequentially functionalized with pH‐responsive CaCO3, targeting group hyaluronic acid (HA) were designed and synthesized for synergistic treatment involving chemodynamic therapy (CDT), sonodynamic therapy (SDT), photothermal therapy (PTT), and calcium overload. Upon cleavage in an acidic environment, CaCO3 nanoparticles released TAPP and Ca2+, with TAPP generating 1O2 under ultrasound trigger. Exposed CuS produced highly cytotoxic ·OH in response to H2O2 and also exhibited a strong PTT effect.Results: CuS@TAPP-CaCO3/HA (CTCH) delivered an enhanced ability to release more Ca2+ under acidic conditions with a pH value of 6.5, which in situ causes damage to HeLa mitochondria. In vitro and in vivo experiments both demonstrated that mitochondrial dysfunction greatly amplified the damage caused by reactive oxygen species (ROS) to tumor, which strongly confirms the synergistic effect between calcium overload and reactive oxygen therapy.Conclusion: Collectively, the development of CTCH presents a novel therapeutic strategy for tumor treatment by effectively responding to the acidic TME, thus holding significant clinical implications.Keywords: mitochondria damage, calcium overload, reactive oxygen oncotherapy, pH-responsive, synergistic treatment

Endometrial cancer (EC) stands as one of the most prevalent gynecological malignancies affecting women, with its incidence and disease-related mortality steadily on the rise. Disulfiram (DSF), an FDA-approved medication primarily used for treating alcohol addiction, has exhibited promising anti-tumor properties. Studies have revealed DSF's capacity for enhanced anti-tumor activity, particularly when combined with copper. The novel Copper-Cysteamine (CuCy) compound, Cu3Cl(SR)2 (RCH2CH2NH2), showcases photodynamic effects and demonstrates significant anti-tumor potential under various conditions, including exposure to ultraviolet light, X-ray, microwave, and ultrasound. This study delves into exploring the synergistic anti-tumor effects and underlying mechanisms by utilizing copper-cysteamine in conjunction with DSF against endometrial cancer. The investigation involved comprehensive analyses encompassing in vitro experiments utilizing Ishikawa cells, in vivo studies, and transcriptomic analyses. Remarkably, the combined administration of both compounds at a low dose of 0.5 μM exhibited pronounced efficacy in impeding tumor growth, inhibiting blood vessel formation, and stimulating cell apoptosis. Notably, experiments involving transplanted tumors in nude mice vividly demonstrated the significant in vivo anti-tumor effects of this combination treatment. Detailed examination through transmission electron microscopy unveiled compelling evidence of mitochondrial damage, cellular swelling, and rupture, indicative of apoptotic changes in morphology due to the combined treatment. Moreover, transcriptomic analysis unveiled substantial downregulation of mitochondrial-related genes at the molecular level, coupled with a significant hindrance in the DNA repair pathway. These findings strongly suggest that the combined application of CuCy and DSF induces mitochondrial impairment in Ishikawa cells, thereby fostering apoptosis and ultimately yielding potent anti-tumor effects.

Neuronal ceroid lipofuscinoses (NCLs) are a growing group of neurodegenerative storage diseases, in which specific features are sought to facilitate the creation of a universal diagnostic algorithm in the future. In our ultrastructural studies, the group of NCLs was represented by the CLN2 disease caused by a defect in the TPP1 gene encoding the enzyme tripeptidyl-peptidase 1. A 3.5-year-old girl was affected by this disease. Due to diagnostic difficulties, the spectrum of clinical, enzymatic, and genetic tests was extended to include analysis of the ultrastructure of cells from a rectal biopsy. The aim of our research was to search for pathognomonic features of CLN2 and to analyse the mitochondrial damage accompanying the disease. In the examined cells of the rectal mucosa, as expected, filamentous deposits of the curvilinear profile (CVP) type were found, which dominated quantitatively. Mixed deposits of the CVP/fingerprint profile (FPP) type were observed less frequently in the examined cells. A form of inclusions of unknown origin, not described so far in CLN2 disease, were wads of osmophilic material (WOMs). They occurred alone or co-formed mixed deposits. In addition, atypically damaged mitochondria were observed in muscularis mucosae. Their deformed cristae had contact with inclusions that looked like CVPs. Considering the confirmed role of the c subunit of the mitochondrial ATP synthase in the formation of filamentous lipopigment deposits in the group of NCLs, we suggest the possible significance of other mitochondrial proteins, such as mitochondrial contact site and cristae organizing system (MICOS), in the formation of these deposits. The presence of WOMs in the context of searching for ultrastructural pathognomonic features in CLN2 disease also requires further research.

Bovine viral diarrhea virus (BVDV) belongs to the family Flaviviridae and includes two biotypes in cell culture: cytopathic (CP) or non-cytopathic (NCP) effects. Ferroptosis is a non-apoptotic form of programmed cell death that contributes to inflammatory diseases. However, whether BVDV induces ferroptosis and the role of ferroptosis in viral infection remain unclear. Here, we provide evidence that both CP and NCP BVDV can induce ferroptosis in Madin-Darby bovine kidney cells at similar rate. Mechanistically, biotypes of BVDV infection downregulate cytoplasmic and mitochondrial GPX4 via Nrf2-GPX4 pathway, thereby resulting in lethal lipid peroxidation and promoting ferroptosis. In parallel, BVDV can degrade ferritin heavy chain and mitochondrial ferritin via NCOA4-mediated ferritinophagy to promote the accumulation of Fe2+ and initiate ferroptosis. Importantly, CP BVDV-induced ferroptosis is tightly associated with serious damage of mitochondria and hyperactivation of inflammatory responses. In contrast, mild or unapparent damage of mitochondria and slight inflammatory responses were detected in NCP BVDV-infected cells. More importantly, different mitophagy pathways in response to mitochondria damage by both biotypes of BVDV are involved in inflammatory responses. Overall, this study is the first to show that mitochondria may play key roles in mediating ferroptosis and inflammatory responses induced by biotypes of BVDV in vitro. IMPORTANCE Bovine viral diarrhea virus (BVDV) threatens a wide range of domestic and wild cattle population worldwide. BVDV causes great economic loss in cattle industry through its immunosuppression and persistent infection. Despite extensive research, the mechanism underlying the pathogenesis of BVDV remains elusive. Our data provide the first direct evidence that mitochondria-mediated ferroptosis and mitophagy are involved in inflammatory responses in both biotypes of BVDV-infected cells. Importantly, we demonstrate that the different degrees of injury of mitochondria and inflammatory responses may attribute to different mitophagy pathways induced by biotypes of BVDV. Overall, our findings uncover the interaction between BVDV infection and mitochondria-mediated ferroptosis, which shed novel light on the physiological impacts of ferroptosis on the pathogenesis of BVDV infection, and provide a promising therapeutic strategy to treat this important infectious disease with a worldwide distribution. [ABSTRACT FROM AUTHOR]

Background: Various cellular models were used for assessment of mitochondrial damage in cardiomyocyte, but most of them are based on silent cells without contractility. The mitochondria in cells at working should be more sensitive to toxic or reperfusion damage due to their high level mitochondrial respiration. Therefore, contracting cells can represent inotropic agent-mediated high-energy demand states. Objective: To establish a cellular model to detect mitochondrial damage in cardiomyocytes at contraction. Method: Freshly isolated Sprague–Dawley rat cardiomyocytes were incubated with or without bupivacaine, in the presence or absence of isoprenaline, and electrically stimulated to induce rhythmic contractions. Results: Contraction under electrical field stimulation did not induce mitochondrial swelling or ROS production in DMEM; the silent cells in the presence of bupivacaine showed mild mitochondrial swelling, but contracting cells exhibited significantly higher mitochondrial swelling and increased ROS production (P < 0.05, vs. silent cells). Isoprenaline induced a further enhancement in mitochondrial swelling and ROS production in contracting cells. Conclusions: Contracting cells are more sensitive to bupivacaine toxicity and could be more accurately represent mitochondrial damage in vivo condition. [ABSTRACT FROM AUTHOR]

Neuronal ceroid lipofuscinoses (NCLs) are a growing group of neurodegenerative storage diseases, in which specific features are sought to facilitate the creation of a universal diagnostic algorithm in the future. In our ultrastructural studies, the group of NCLs was represented by the CLN2 disease caused by a defect in the TPP1 gene encoding the enzyme tripeptidyl-peptidase 1. A 3.5-year-old girl was affected by this disease. Due to diagnostic difficulties, the spectrum of clinical, enzymatic, and genetic tests was extended to include analysis of the ultrastructure of cells from a rectal biopsy. The aim of our research was to search for pathognomonic features of CLN2 and to analyse the mitochondrial damage accompanying the disease. In the examined cells of the rectal mucosa, as expected, filamentous deposits of the curvilinear profile (CVP) type were found, which dominated quantitatively. Mixed deposits of the CVP/fingerprint profile (FPP) type were observed less frequently in the examined cells. A form of inclusions of unknown origin, not described so far in CLN2 disease, were wads of osmophilic material (WOMs). They occurred alone or co-formed mixed deposits. In addition, atypically damaged mitochondria were observed in muscularis mucosae. Their deformed cristae had contact with inclusions that looked like CVPs. Considering the confirmed role of the c subunit of the mitochondrial ATP synthase in the formation of filamentous lipopigment deposits in the group of NCLs, we suggest the possible significance of other mitochondrial proteins, such as mitochondrial contact site and cristae organizing system (MICOS), in the formation of these deposits. The presence of WOMs in the context of searching for ultrastructural pathognomonic features in CLN2 disease also requires further research. [ABSTRACT FROM AUTHOR]

Ischemia-reperfusion (I/R) injury constitutes a significant risk factor for a range of diseases, including ischemic stroke, myocardial infarction, and trauma. Following the restoration of blood flow post-tissue ischemia, oxidative stress can lead to various forms of cell death, including necrosis, apoptosis, autophagy, and necroptosis. Recent evidence has highlighted the crucial role of mitochondrial dysfunction in I/R injury. Nevertheless, there remains much to be explored regarding the molecular signaling network governing cell death under conditions of oxidative stress. Voltage-dependent anion channel 1 (VDAC1), a major component in the outer mitochondrial membrane, is closely involved in the regulation of cell death. In a cellular model of oxygen-glucose deprivation and reoxygenation (OGD/R), which effectively simulates I/R injury in vitro, our study reveals that OGD/R induces VDAC1 oligomerization, consequently exacerbating cell death. Furthermore, we have revealed the translocation of mixed lineage kinase domain-like protein (MLKL) to the mitochondria, where it interacts with VDAC1 following OGD/R injury, leading to an increased mitochondrial membrane permeability. Notably, the inhibition of MLKL by necrosulfonamide hinders the binding of MLKL to VDAC1, primarily by affecting the membrane translocation of MLKL, and reduces OGD/R-induced VDAC1 oligomerization. Collectively, our findings provide preliminary evidence of the functional association between MLKL and VDAC1 in the regulation of necroptosis.

Melittin, a naturally occurring polypeptide found in bee venom, has been recognized for its potential anti-tumor effects, particularly in the context of lung cancer. Our previous study focused on its impact on human lung adenocarcinoma cells A549, revealing that melittin induces intracellular reactive oxygen species (ROS) burst and oxidative damage, resulting in cell death. Considering the significant role of mitochondria in maintaining intracellular redox levels and ROS, we further examined the involvement of mitochondrial damage in melittin-induced apoptosis in lung cancer cells. Our findings demonstrated that melittin caused changes in mitochondrial membrane potential (MMP), triggered mitochondrial ROS burst (Figure 1), and activated the mitochondria-related apoptosis pathway Bax/Bcl-2 by directly targeting mitochondria in A549 cells (Figure 2). Further, we infected A549 cells using a lentivirus that can express melittin-Myc and confirmed that melittin can directly target binding to mitochondria, causing the biological effects described above (Figure 2). Notably, melittin induced mitochondrial damage while inhibiting autophagy, resulting in abnormal degradation of damaged mitochondria (Figure 5). To summarize, our study unveils that melittin targets mitochondria, causing mitochondrial damage, and inhibits the autophagy-lysosomal degradation pathway. This process triggers mitoROS burst and ultimately activates the mitochondria-associated Bax/Bcl-2 apoptotic signaling pathways in A549 cells. [ABSTRACT FROM AUTHOR]

Mitochondria and endoplasmic reticulum (ER) are essential organelles playing pivotal roles in the regulation of cellular metabolism, energy production, and protein synthesis. In addition, these organelles are important targets susceptible to external stimuli, such as environmental pollutants. Exposure to environmental pollutants can cause the mitochondrial damage, endoplasmic reticulum stress (ERS), and oxidative stress, leading to cellular dysfunction and death. Therefore, understanding the toxic effects and molecular mechanisms of environmental pollution underlying these processes is crucial for developing effective strategies to mitigate the adverse effects of environmental pollutants on human health. In the present study, we summarized and reviewed the toxic effects and molecular mechanisms of mitochondrial damage, ERS, and oxidative stress caused by exposure to environmental pollutants as well as interactions inducing the cell apoptosis and the roles in exposure to environmental pollutants. [ABSTRACT FROM AUTHOR]

After parturition, bovine endometrial epithelial cells (BEECs) undergo serious inflammation and imbalance between oxidation and antioxidation, which is widely acknowledged as a primary contributor to the development of endometritis in dairy cows. Nevertheless, the mechanism of oxidative stress-mediated inflammation and damage in bovine endometrial epithelial cells remains inadequately defined, particularly the molecular pathways associated with mitochondria-dependent apoptosis. Hence, the present study was designed to explore the mechanism responsible for mitochondrial dysfunction-induced BEEC damage. In vivo, the expressions of proapoptotic protein caspase 3 and cytochrome C were increased significantly in dairy uteri with endometritis. Similarly, the levels of proapoptotic protein caspase 3, BAX, and cytochrome C were markedly increased in H2O2-treated BEECs. Our findings revealed pronounced BEEC damage in dairy cows with endometritis, accompanied by heightened expression of cyto-C and caspase-3 both in vivo and in vitro. The reduction in apoptosis-related protein of BEECs due to oxidant injury was notably mitigated following N-acetyl-L-cysteine (NAC) treatment. Furthermore, mitochondrial vacuolation was significantly alleviated, and mitochondrial membrane potential returned to normal levels after the removal of ROS. Excessive ROS may be the main cause of mitochondrial dysfunction. Mitochondrial permeability transition pore (mPTP) blockade by cyclophilin D (CypD) knockdown with CSA significantly blocked the flow of cytochrome C (cyto-C) and Ca2+ to the cytoplasm from the mitochondria. Our results indicate that elevated ROS and persistent opening of the mPTP are the main causes of oxidative damage in BEECs. Collectively our results reveal a new mechanism involving ROS-mPTP signaling in oxidative damage to BEECs, which may be a potential avenue for the clinical treatment of bovine endometritis. [ABSTRACT FROM AUTHOR]

ABSTRACTMelittin, a naturally occurring polypeptide found in bee venom, has been recognized for its potential anti-tumor effects, particularly in the context of lung cancer. Our previous study focused on its impact on human lung adenocarcinoma cells A549, revealing that melittin induces intracellular reactive oxygen species (ROS) burst and oxidative damage, resulting in cell death. Considering the significant role of mitochondria in maintaining intracellular redox levels and ROS, we further examined the involvement of mitochondrial damage in melittin-induced apoptosis in lung cancer cells. Our findings demonstrated that melittin caused changes in mitochondrial membrane potential (MMP), triggered mitochondrial ROS burst (Figure 1), and activated the mitochondria-related apoptosis pathway Bax/Bcl-2 by directly targeting mitochondria in A549 cells (Figure 2). Further, we infected A549 cells using a lentivirus that can express melittin-Myc and confirmed that melittin can directly target binding to mitochondria, causing the biological effects described above (Figure 2). Notably, melittin induced mitochondrial damage while inhibiting autophagy, resulting in abnormal degradation of damaged mitochondria (Figure 5). To summarize, our study unveils that melittin targets mitochondria, causing mitochondrial damage, and inhibits the autophagy-lysosomal degradation pathway. This process triggers mitoROS burst and ultimately activates the mitochondria-associated Bax/Bcl-2 apoptotic signaling pathways in A549 cells.

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Gastrointestinal (GI) tumor is a serious disease with high mortality rates and morbidity rates worldwide. Chemotherapy is a key treatment for GI, however, systematic side effects and inevitable drug resistance complicate the situation. In the process of therapy, P-glycoprotein (P-gp) could remove chemotherapy drugs from cells, thus causing multi-drug resistance. Chemodynamic therapy (CDT) utilizing Fenton chemistry has been used for cancer therapy, along with various combination therapies. The reactive oxygen species produced by CDT could inhibit P-gp’s efflux pump function, which reduce chemoagents excretion and reverse drug resistance. In the present study, we developed novel nanocrystals (Cu2O@Pt NCs) to overcome drug resistance by reducing mitochondria-derived ATP through chemo/CDT in GI cancer. Furthermore, in vivo results in tumor-bearing mice demonstrated that treatment with Cu2O@Pt NCs with CDT and chemotherapy could achieve the most effective antitumor therapeutic effect with the least amounts of adverse effects. As a result, Cu2O@Pt NCs could provide a promising strategy for chemo/CDT-synergistic therapy.

Metallic nanomaterials (MNMs) are widely used in the medical field because of their photocatalytic, optical, electrical, electronic, antibacterial, and bactericidal properties. Despite the advantages of MNMs, there is a lack of complete understanding of their toxicological behavior and their interactions with cellular mechanisms that determine cell fate. Most of the existing studies are acute toxicity studies with high doses, which is not conducive to understanding the toxic effects and mechanisms of homeostasis-dependent organelles, such as mitochondria, which are involved in many cellular functions. In this study, four types of MNMs were used to investigate the effects of metallic nanomaterials on mitochondrial function and structure. We first characterized the four MNMs and selected the appropriate sublethal concentration for application in cells. Mitochondrial characterization, energy metabolism, mitochondrial damage, mitochondrial complex activity, and expression levels were evaluated using various biological methods. The results showed that the four types of MNMs greatly inhibited mitochondrial function and cell energy metabolism and that the material entering the mitochondria damaged the mitochondrial structure. Additionally, the complex activity of mitochondrial electron transport chains is critical for assessing the mitochondrial toxicity of MNMs, which may serve as an early warning of MNM-induced mitochondrial dysfunction and cytotoxicity. [ABSTRACT FROM AUTHOR]

Excessive manganese (Mn) exposure produces neurotoxicity with mitochondrial damage. Mitophagy is a protective mechanism to eliminate damaged mitochondria to protect cells. The aim of this study was to determine the dose-response of Mn-induced mitochondria damage, the expression of mitophagy-mediated protein PINK1/Parkin and mitophagy in dopamine-producing SK-N-SH cells. Cells were exposed to 0, 300, 900, and 1500 μM Mn2+ for 24 h, and ROS production, mitochondrial damage and mitophagy were examined. The levels of dopamine were detected by ELISA and neurotoxicity and mitophagy-related proteins (α-synuclein, PINK1, Parkin, Optineurin, and LC3II/I) were detected by western blot. Mn increased intracellular ROS and apoptosis and decreased mitochondrial membrane potential in a concentration-dependent manner. However, at the low dose of 300 μM Mn, autophagosome was increased 11-fold, but at the high dose of 1500 μM, autophagosome was attenuated to 4-fold, together with decreased mitophagy-mediated protein PINK1/Parkin and LC3II/I ratio and increased Optineurin expression, resulting in increased α-synuclein accumulation and decreased dopamine production. Thus, Mn-induced mitophagy exhibited a novel biphasic regulation: at the low dose, mitophagy is activated to eliminate damaged mitochondria, however, at the high dose, cells gradually loss the adaptive machinery, the PINK1/Parkin-mediated mitophagy weakened, resulting in neurotoxicity. Graphical Abstract [ABSTRACT FROM AUTHOR]

Chemodynamic therapy (CDT) can effectively induce immunogenic cell death (ICD) in tumours and is thus a promising strategy for boosting the efficacy of immunotherapy. However, the mechanism by which CDT enhances ICD and lowers ICD efficiency is unknown and this restricts its clinical application. In this study, a second near-infrared (NIR-II) window irradiation-triggered hydrogen peroxide (H 2 O 2) self-supplying nanocomposite ((Cu 2 Se-CaO 2)@LA) was constructed. The modified lauric acid was melted by the heat energy of the NIR-II irradiation, to expose the CaO 2 nanoparticles, and they then reacted with water to produce H 2 O 2 and Ca2+. H 2 O 2 was then converted to hydroxyl radicals by the photothermal-enhanced CDT process of the Cu 2 Se nanocubes. Notably, the CDT and Ca2+ overload was found to induce sequential damage to the mitochondria and endoplasmic reticulum (ER), which upregulated the PERK-mediated eIF2α phosphorylation pathway and caused subsequent ICD. NIR-II irradiation of the (Cu 2 Se-CaO 2)@LA also increased reactive oxygen species (ROS) formation and this was sufficient to increase dendritic cell maturation, attracting cytotoxic T lymphocytes, and suppressing tumour growth in vivo. Overall, we demonstrated that an enhanced CDT strategy under NIR-II exposure and H 2 O 2 self-supply can induce extensive ICD by inducing mitochondria-associated ER stress, which represents a highly effective and promising strategy for ICD amplification and tumour immunotherapy. In this study, a second near-infrared window (NIR-II) irradiation-triggered and H 2 O 2 self-supplying nanocomposite (named (Cu 2 Se-CaO 2)@LA) was constructed and tested both in vitro and in vivo. These nanoparticles demonstrated promising antitumor activity as designed. Mechanistically, the nanoparticles could damage mitochondria and upregulate the PERK-mediated eIF2αphosphorylation pathway, further causing endoplasmic reticulum stress, and inducing immunogenic cell death through dendritic cell maturation and cytotoxic T lymphocyte recruitment augmented activity. This system represents a highly effective and promising strategy for enhancing tumor immunotherapy and provides new insights for future studies and design refinements. [Display omitted] [ABSTRACT FROM AUTHOR]

Quercetin has been shown to mitigate the cytotoxic effects of heavy metals. While copper is an essential trace element for bodily functions, excessive intake has been linked to impaired female reproductive function. Transcriptome analysis was employed to identify genes that are differentially expressed in response to high copper and were validated through qRT-PCR and western blotting. ATP content and Tunel were used to identify the damage of mitochondrial and cell apoptosis. PPI analysis revealed that MKI67 , TOPII , ASPM , CASP3 , PLK1 , and TTK are central proteins within the network. Additionally, exposure to elevated levels of copper resulted in the dysregulation of 86 genes associated with mitochondria. Conversely, treatment with quercetin (QUE) in combination with high copper led to the normalization of 42 mitochondria-related genes previously affected by high copper levels. Furthermore, CuSO 4 decreases ATP content and induces cell apoptosis, which can be reversed by QUE. Results suggest that elevated copper levels could lead to oxidative stress and apoptosis by inducing mitochondrial damage, while QUE has the potential to mitigate these effects, ultimately safeguarding granulosa cells and halting the progression of cell death. This study provides novel insights into the molecular pathways involved in female reproductive toxicity caused by excessive copper exposure. [ABSTRACT FROM AUTHOR]

After parturition, bovine endometrial epithelial cells (BEECs) undergo serious inflammation and imbalance between oxidation and antioxidation, which is widely acknowledged as a primary contributor to the development of endometritis in dairy cows. Nevertheless, the mechanism of oxidative stress-mediated inflammation and damage in bovine endometrial epithelial cells remains inadequately defined, particularly the molecular pathways associated with mitochondria-dependent apoptosis. Hence, the present study was designed to explore the mechanism responsible for mitochondrial dysfunction-induced BEEC damage. In vivo, the expressions of proapoptotic protein caspase 3 and cytochrome C were increased significantly in dairy uteri with endometritis. Similarly, the levels of proapoptotic protein caspase 3, BAX, and cytochrome C were markedly increased in H2O2-treated BEECs. Our findings revealed pronounced BEEC damage in dairy cows with endometritis, accompanied by heightened expression of cyto-C and caspase-3 both in vivo and in vitro. The reduction in apoptosis-related protein of BEECs due to oxidant injury was notably mitigated following N-acetyl-L-cysteine (NAC) treatment. Furthermore, mitochondrial vacuolation was significantly alleviated, and mitochondrial membrane potential returned to normal levels after the removal of ROS. Excessive ROS may be the main cause of mitochondrial dysfunction. Mitochondrial permeability transition pore (mPTP) blockade by cyclophilin D (CypD) knockdown with CSA significantly blocked the flow of cytochrome C (cyto-C) and Ca2+ to the cytoplasm from the mitochondria. Our results indicate that elevated ROS and persistent opening of the mPTP are the main causes of oxidative damage in BEECs. Collectively our results reveal a new mechanism involving ROS-mPTP signaling in oxidative damage to BEECs, which may be a potential avenue for the clinical treatment of bovine endometritis.

We have previously shown that a fatty acid-binding protein7 (FABP7) inhibitor ameliorates cerebral ischemia-reperfusion injury in mice, suggesting an association between FABPs and ischemic neuronal injury. However, the precise role of FABPs in ischemic neuronal injury remains unclear. In this study, we investigated the role of FABPs in ischemia-reperfusion neuronal injury. FABP3, FABP5, and FABP7 were upregulated in the ischemic penumbra regions in mice. However, only FABP3 and FABP5 were expressed in injured neurons. Furthermore, FABP3 and FABP5 accumulated in the mitochondria of ischemic neurons. Overexpressing either FABP3 or FABP5 aggravated the reduced mitochondrial membrane potential and induced cell death in human neuroblastoma SH-SY5Y cells during oxidative stress. This damage was mediated by the formation of BAX-containing pores in the mitochondrial membrane. Moreover, FABP5 mediates lipid peroxidation and generates toxic by-products (i.e., 4-HNE) in SH-SY5Y cells. HY11-08 (HY08), a novel FABP3 and 5 inhibitor that does not act on FABP7, significantly reduced cerebral infarct volume and blocked FABP3/5-induced mitochondrial damage, including lipid peroxidation and BAX-related apoptotic signaling. Thus, FABP3 and FABP5 are key players in triggering mitochondrial damage in ischemic neurons. In addition, the novel FABP inhibitor, HY08, may be a potential neuroprotective treatment for ischemic stroke.

Gastrointestinal (GI) tumor is a serious disease with high mortality rates and morbidity rates worldwide. Chemotherapy is a key treatment for GI, however, systematic side effects and inevitable drug resistance complicate the situation. In the process of therapy, P-glycoprotein (P-gp) could remove chemotherapy drugs from cells, thus causing multi-drug resistance. Chemodynamic therapy (CDT) utilizing Fenton chemistry has been used for cancer therapy, along with various combination therapies. The reactive oxygen species produced by CDT could inhibit P-gp's efflux pump function, which reduce chemoagents excretion and reverse drug resistance. In the present study, we developed novel nanocrystals (Cu2O@Pt NCs) to overcome drug resistance by reducing mitochondria-derived ATP through chemo/CDT in GI cancer. Furthermore, in vivo results in tumor-bearing mice demonstrated that treatment with Cu2O@Pt NCs with CDT and chemotherapy could achieve the most effective antitumor therapeutic effect with the least amounts of adverse effects. As a result, Cu2O@Pt NCs could provide a promising strategy for chemo/CDT-synergistic therapy. [ABSTRACT FROM AUTHOR]

Despite the promise of cold atmospheric plasma (CAP) for cancer treatment, the challenges associated with the treatment of solid tumors and penetration depth limitations remain, restricting its clinical application. Here, biological evidence is provided that the killing effect of CAP treatment is confined to less than 500 µm subcutaneously and the actual biological dose decreased gradually with depth for the first time, indicating that the limited penetration depth has become an urgent problem that demands immediate solutions. Significantly, it is showed that different from high-dose treatments, CAP decreased the doses to the low-dose range but still exhibited anti-tumor effects via mitotic catastrophe. Unlike radiotherapy or chemotherapy, low-dose CAP treatment induces mitochondrial structural damage and dysfunction, disrupts energy metabolism and redox balance, and results in mitotic catastrophe. Collectively, these findings suggest that better understanding and taking full advantage of the dose-response gradient effect of CAP is a potential strategy to prompt its clinical application beyond improving CAP penetration., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Immunotherapy stands as a groundbreaking strategy for cancer treatment, due to its ability to precisely and safely detect and eradicate tumors. However, the efficacy of immunotherapy is often limited by tumor autophagy, a natural defense mechanism that tumors exploit to resist immune attacks. Herein, we introduce a spatiotemporally controlled method to modulate tumor autophagy via sonocatalysis, aiming to improve immunotherapeutic outcomes. Specifically, we synthesized a tumor-targeting nanocatalyst based on a semiconductor heterojunction composed of Barium Titanate (BTO), Black Phosphorus (BP) integrated with Hyaluronic Acid (HA), referred to as BTO/BP-HA. Compared to traditional catalysts, the heterojunction structure enhances energy band bending and rapid electron-hole separation under ultrasonic stimulation, splitting water to generate H 2 . This promotes tumor cell apoptosis by inhibiting mitochondrial respiration and induces immunogenic cell death, triggering immune responses to eliminate tumor cells. However, the concurrent activation of autophagy mitigates the cytotoxic effectiveness of nanocatalysts. Within the nanocatalyst, BP undergoes lysosomal degradation to generate PO 4 3- , which subsequently interacts with H + to generate a conjugated acidic anion, increasing the lysosomal pH. This research ingeniously combines sonocatalysis with tumor autophagy, disrupting the activity of acidic hydrolases to inhibit autophagy, thereby enhancing the immune response and improving the effectiveness of immunotherapy.

Abstract Background Intestinal ischemia/reperfusion (I/R) injury commonly occurs during perioperative periods, resulting in high morbidity and mortality on a global scale. Dexmedetomidine (Dex) is a selective α2-agonist that is frequently applied during perioperative periods for its analgesia effect; however, its ability to provide protection against intestinal I/R injury and underlying molecular mechanisms remain unclear. Methods To fill this gap, the protection of Dex against I/R injury was examined in a rat model of intestinal I/R injury and in an inflammation cell model, which was induced by tumor necrosis factor-alpha (TNF-α) plus interferon-gamma (IFN-γ) stimulation. Results Our data demonstrated that Dex had protective effects against intestinal I/R injury in rats. Dex was also found to promote mitophagy and inhibit apoptosis of enteric glial cells (EGCs) in the inflammation cell model. PINK1 downregulated p53 expression by promoting the phosphorylation of HDAC3. Further studies revealed that Dex provided protection against experimentally induced intestinal I/R injury in rats, while enhancing mitophagy, and suppressing apoptosis of EGCs through SIRT3-mediated PINK1/HDAC3/p53 pathway in the inflammation cell model. Conclusion Hence, these findings provide evidence supporting the protective effect of Dex against intestinal I/R injury and its underlying mechanism involving the SIRT3/PINK1/HDAC3/p53 axis.

Zearalenone (ZEA) is a fungal mycotoxin known to exert strong reproductive toxicity in animals. As a newly identified type of programmed cell death, necroptosis is regulated by receptor-interacting protein kinase 1 (RIPK1), receptor-interacting protein kinase 3 (RIPK3), and mixed-lineage kinase domain-like pseudokinase (MLKL). However, the role and mechanism of necroptosis in ZEA toxicity remain unclear. In this study, we confirmed the involvement of necroptosis in ZEA-induced cell death in goat endometrial stromal cells (gESCs). The release of lactate dehydrogenase (LDH) and the production of PI-positive cells markedly increased. At the same time, the expression of RIPK1 and RIPK3 mRNAs and P-RIPK3 and P-MLKL proteins were significantly upregulated in ZEA-treated gESCs. Importantly, the MLKL inhibitor necrosulfonamide (NSA) dramatically attenuated gESCs necroptosis and powerfully blocked ZEA-induced reactive oxygen species (ROS) generation and mitochondrial dysfunction. The reactive oxygen species (ROS) scavengers and N-acetylcysteine (NAC) inhibited ZEA-induced cell death. In addition, the inhibition of MLKL alleviated the intracellular Ca2+ overload caused by ZEA. The calcium chelator BAPTA-AM markedly suppressed ROS production and mitochondrial damage, thus inhibiting ZEA-induced necroptosis. Therefore, our results revealed the mechanism by which ZEA triggers gESCs necroptosis, which may provide a new therapeutic strategy for ZEA poisoning. [ABSTRACT FROM AUTHOR]

2,2‐bis(6‐bromo‐1H‐indol‐3‐yl) ethanamine, a marine bisindole alkaloid, showed anticancer property in several tumor cell lines thanks to the presence of a 3,3′‐diindolylmethane scaffold. Here, the modifications in its chemical structure into alkaloid‐like derivatives, have been evaluated, to investigate changes in its biological activities. Three derivatives have been considered and their potential apoptotic action has been evaluated through morpho‐functional analyses in a human cancer cell line. Apoptosis appears strongly decreased in the derivatives without the bromine atoms (1) and in those where the bromine atoms have been substituted with fluorine atoms (2). On the contrary, the methylation of indole NH (3) does not alter the alkaloid apoptotic activity that occurs through mitochondria involvement supported by cardiolipin peroxidation and dysfunctional mitochondria presence. This manuscript highlights the alkaloid derivative cytotoxic effect, which is strictly correlated to the presence of N‐methylated bisindole alkaloid and bromine atoms, conditions which assure to maintain the pro‐apoptotic activity. Since molecular therapies, by targeting mitochondria pathways, have shown positive outcomes against several cancer cells, the alkaloid with bisindole methylated scaffold and the two bromine atoms can be considered a promising candidate to develop new derivatives with strong anticancer property. Research Highlights: 2,2‐bis(6‐bromo‐1H‐indol‐3‐yl) ethanamine is an alkaloid known for its anticancer properties.Morpho‐functional analyses evaluated cytotoxicity of its synthetic derivatives in tumor cells.Anticancer properties depend on the presence of bisindole scaffold and the two bromine units. [ABSTRACT FROM AUTHOR]

Metallic nanomaterials (MNMs) are widely used in the medical field because of their photocatalytic, optical, electrical, electronic, antibacterial, and bactericidal properties. Despite the advantages of MNMs, there is a lack of complete understanding of their toxicological behavior and their interactions with cellular mechanisms that determine cell fate. Most of the existing studies are acute toxicity studies with high doses, which is not conducive to understanding the toxic effects and mechanisms of homeostasis-dependent organelles, such as mitochondria, which are involved in many cellular functions. In this study, four types of MNMs were used to investigate the effects of metallic nanomaterials on mitochondrial function and structure. We first characterized the four MNMs and selected the appropriate sublethal concentration for application in cells. Mitochondrial characterization, energy metabolism, mitochondrial damage, mitochondrial complex activity, and expression levels were evaluated using various biological methods. The results showed that the four types of MNMs greatly inhibited mitochondrial function and cell energy metabolism and that the material entering the mitochondria damaged the mitochondrial structure. Additionally, the complex activity of mitochondrial electron transport chains is critical for assessing the mitochondrial toxicity of MNMs, which may serve as an early warning of MNM-induced mitochondrial dysfunction and cytotoxicity.

Yersinia ruckeri , as a facultative intracellular pathogen, can cause two different infection phenotypes of fish. An important phenotype is diffuse acute inflammation (DAI), which is mainly characterized by systemic hemorrhage and multiple tissues damage. Another phenotype is enteric redmouth symptom (EM) with predominantly digestive system damage, while slight damage to other tissues and organs. At present, the causes and mechanisms of heterogeneity of Y. ruckeri infection are not clear. According to our previous research and related bioinformatics analysis, it is suggested that the heterogeneity of infection of Y. ruckeri may be related to the activation of intracellular pattern recognition receptor (NLRP3). Furthermore, combined with the transmission electron microscope observation and ultrastructural pathological analysis of DAI and EM phenotypes, it is hypothesized that Y. ruckeri infection may mediate the occurrence of DAI by inducing mitochondrial damage and activation of NLRP3. In this study, we established DAI and EM phenotypes of channel catfish (Ictalurus punctatus) through the artificial infection experiment. Subsequently, we observed the pathological changes and characteristics of different tissues in DAI and EM phenotypes, such as liver, spleen, kidney, intestine and gill. In addition, the mitochondrial damage of head kidney mediated by Y. ruckeri infection was confirmed by transmission electron microscope observation. Furthermore, by detecting the expression of proinflammatory factors and related pattern recognition receptors in various tissues, we preliminarily clarified the molecular characteristics of immune response in DAI and EM phenotype fish. Moreover, the head kidney macrophages isolated from DAI and EM were observed through transmission electron microscope, and the expression levels of NLRP3, Caspase-1 and IL-1β were detected. Finally, the correlation between mitochondrial damage induced by Y. ruckeri infection and NLRP3 signal transduction was preliminary revealed. Taken together, our results showed that the inflammatory DAI phenotype of fish mediated by Y. ruckeri infection is closely related to mitochondrial damage and NLRP3 activation, which will provide theoretical basis for further study on the pathogenic mechanism of Y. ruckeri infection and clinical diagnosis of the disease, and also provide some insights into the role of NLRP3 in the natural immunity of aquatic animals. [Display omitted] • Yersinia ruckeri infection is capable of inducing varying degrees of inflammation. • Yersinia ruckeri infection mediated serious damage to mitochondria in DAI phenotype. • Yersinia ruckeri infection mediated severe activation of NLRP3 in DAI phenotype. [ABSTRACT FROM AUTHOR]

Aims: Diabetic nephropathy (DN) is characterized by microalbuminuria, mainly associated with pathological and morphological alterations of podocyte. New drug targeting podocyte injury is a promising approach for treating DN. The present study is aimed at developing new drug targeting podocyte injury for treating DN. Results: In this study, germacrone ameliorated kidney damage and inhibited podocyte apoptosis in a DN mouse model. Based on RNA-seq, mmu_mmu_circRNA_0000309, located in host gene vascular endothelial zinc finger 1 (Vezf1), showed a sharp decline in DN mice and a remarkable recovery in germacrone-challenged DN mice. mmu_circRNA_0000309 silence or miR-188-3p mimics abrogated the antiapoptosis and anti-injury effects of germacrone through aggravating mitochondria damage, and elevating reactive oxygen species and ferroptosis-related protein levels. Mechanistically, mmu_circRNA_0000309 competitively sponged miR-188-3p, and subsequently promoted glutathione peroxidase 4 (GPX4) expression, thereby inactivating ferroptosis-dependent mitochondrial damage and podocyte apoptosis. In addition, GPX4 overexpression neutralized mmu_circRNA_0000309 silence-mediated mitochondria damage and ferroptosis in germacrone-exposed MPC5 cells. Innovation: We describe the novel effect and mechanism of germacrone on treating DN, which is linked to ferroptosis for the first time. Conclusion: mmu_circRNA_0000309 silence mediates drug resistance to germacrone in DN mice. mmu_circRNA_0000309 sponges miR-188-3p, and subsequently upregulates GPX4 expression, inactivating ferroptosis-dependent mitochondrial function and podocyte apoptosis. Possibly germacrone-based treatment for DN can be further motivated by regulating mmu_circRNA_0000309/miR-188-3p/GPX4 signaling axis. Antioxid. Redox Signal. 36, 740–759. [ABSTRACT FROM AUTHOR]

EsxA, secreted by the ESAT-6 secretion system 1 (ESX-1) secretion system, is considered the major Mycobacterium tuberculosis (Mtb) virulence determinant. However, the roles of the individual ESX-1 substrates, such as EspC, remain unclear due to their interdependency for secretion with EsxA. Here, we validated that EspC triggered ER stress-mediated apoptosis in macrophages. The EspC-mediated ER stress was involved in pro-inflammatory cytokines generation, intracellular Ca2+ release, and reactive oxygen species accumulation. Mitochondrial transmembrane potential dissipation and mitochondrial outer membrane permeabilization occurred in EspC-treated macrophages, causing apoptosis. Furthermore, ER stress-mediated apoptosis was effectively induced in EspC-overexpressing Mycobacterium smegmatis-infected macrophages and mice. EspC overexpression caused a significant increase in bacterial survival in the macrophages, spleens, and lungs, and accelerated mouse death was observed. Moreover, the increased viability of bacteria in the macrophages was significantly reduced by pretreatment with the apoptosis inhibitor. Overall, our results revealed that EspC is an essential ESX-1 protein for Mtb–host interactions and EspC-induced ER stress-mediated apoptosis may be employed by Mtb to establish and spread infection. Given the critical roles of the ESX systems in Mtb pathogenesis and immunity, our findings offer new perspectives on the complex host-pathogen interactions and mechanisms underlying ESX-1-mediated pathogenesis.

Background: Cervical cancer is the fourth most common cancer in women worldwide, and arsenic has a certain effect in solid tumor chemotherapy. As the rate-limiting enzyme subunit of GSH synthesis, GCLC may be an important target for arsenic to induce apoptosis through mitochondrial apoptosis pathway to exert anti-tumor effect. NF-κB plays an important role in the occurrence and development of cervical cancer and can regulate the expression of GCLC. miR-21 is a potential biomarker of cervical cancer, which can induce apoptosis through ROS regulated the mitochondrial pathway of cells. However, the role of miR-21 in the mitochondrial pathway of cervical cancer cells induced by NaAsO2 through NF-κB/GCLC and GSH synthesis regulated oxidative stress is rarely reported. Therefore, the purpose of this study was to investigate whether NaAsO2 might induce mitochondrial damage and apoptosis of cervical cancer cells through NF-κB/ miR-21 /GCLC induced oxidative stress, and play the anti-tumor role of arsenic as a potential drug for the treatment of cervical cancer. Methods: Hela cells were treated with different concentrations of NaAsO2, D, L-Buthionine-(SR)-sulfoximine (BSO), IκBα inhibitor (BAY 11-7082) and miR-21 Inhibitor. CCK-8 assay, Western Blot, qRT PCR, immunofluorescence, transmission electron microscopy, mitochondrial Membrane Potential Assay Kit with JC-1,2′,7′-Dichlorofluorescin diacetate fluorescent probe and Annexin V-FITC were used to measure cell activity, GSH and ROS, mitochondrial morphology and membrane potential (ΔΨm), protein and mRNA expression of GCLC, GCLM, p65, IκBα, p-P65, p-I κBα, Bcl-2, BAX, Caspase3, cleaved-caspase3 and miR-21. Results: Compared with the control group, with the gradual increasing dose of NaAsO2, cell viability was considerable reduced, and increased rate of apoptosis, intracellular GSH level was decreased significantly, ROS was increased, mitochondrial structure was damaged, mitochondrial membrane potential ΔΨm and Bcl2/BAX lowered, the expression of Caspase3 and cleaved-caspase3 were significantly increased, resulting in mitochondrial apoptosis. When Hela cells were treated with 15, 20, and 25 μmol/L NaAsO2, the mRNA and protein levels of GCLC and GCLM were reduced, the expression of p65 in the nucleus was increased, the expression of p-p65/p65, p-IκBα/IκBα and miR-21 were significantly increased. When BSO increased the inhibitory effect of NaAsO2 on GCLC, Compared with NaAsO2 group, the ΔΨm and protein of Bcl-2/BAX, caspase3 and cleaved-capsase3 were increased. When BAY 11–7082 combined with NaAsO2 co-treated, compared with the NaAsO2 group, the protein and mRNA expression of GCLC was increased, NaAsO2-increased expression level of miR-21 was suppressed, and the ΔΨm and cell viability were higher. In addition, compared with the combination of NaAsO2 and miR-21NC, the protein expression of GCLC was increased, the ΔΨm and cell viability reduction were alleviated by miR-21 Inhibitor combined with NaAsO2. Conclusion: NaAsO2 may lead to ROS accumulation in Hela cells and trigger mitochondrial apoptosis. The mechanism may be related to the activation of NF-κB signaling pathway and the promotion of miR-21 expression which leads to the inhibition of GCLC expression and the significant decrease of intracellular reductive GSH synthesis.

Radiation-induced lung injury (RILI) is a prevalent complication of thoracic tumor radiotherapy and accidental radiation exposure. Pyrroloquinoline quinone (PQQ), a novel vitamin B, plays a crucial role in delaying aging, antioxidation, anti-inflammation, and antiapoptosis. This study aims to investigate the protective effect and mechanisms of PQQ against RILI. C57BL/6 mice were exposed to a 20 Gy dose of X-ray radiation on the entire thorax with or without daily oral administration of PQQ for 2 weeks. PQQ effectively mitigated radiation-induced lung tissue damage, inflammation, oxidative stress, and epithelial cell apoptosis. Additionally, PQQ significantly inhibited oxidative stress and mitochondrial damage in MLE-12 cells. Mechanistically, PQQ upregulated the mRNA and protein levels of MOTS-c in irradiated lung tissue and MLE-12 cells. Knockdown of MOTS-c by siRNA substantially attenuated the protective effects of PQQ on oxidative stress, inflammation, and apoptosis. In conclusion, PQQ alleviates RILI by preserving mitochondrial function through a MOTS-c-dependent mechanism, suggesting that PQQ may serve as a promising nutraceutical intervention against RILI.

Background: Intestinal ischemia/reperfusion (I/R) injury commonly occurs during perioperative periods, resulting in high morbidity and mortality on a global scale. Dexmedetomidine (Dex) is a selective α2-agonist that is frequently applied during perioperative periods for its analgesia effect; however, its ability to provide protection against intestinal I/R injury and underlying molecular mechanisms remain unclear.Methods: To fill this gap, the protection of Dex against I/R injury was examined in a rat model of intestinal I/R injury and in an inflammation cell model, which was induced by tumor necrosis factor-alpha (TNF-α) plus interferon-gamma (IFN-γ) stimulation.Results: Our data demonstrated that Dex had protective effects against intestinal I/R injury in rats. Dex was also found to promote mitophagy and inhibit apoptosis of enteric glial cells (EGCs) in the inflammation cell model. PINK1 downregulated p53 expression by promoting the phosphorylation of HDAC3. Further studies revealed that Dex provided protection against experimentally induced intestinal I/R injury in rats, while enhancing mitophagy, and suppressing apoptosis of EGCs through SIRT3-mediated PINK1/HDAC3/p53 pathway in the inflammation cell model.Conclusion: Hence, these findings provide evidence supporting the protective effect of Dex against intestinal I/R injury and its underlying mechanism involving the SIRT3/PINK1/HDAC3/p53 axis. [ABSTRACT FROM AUTHOR]

Two mononuclear Pt(II) compounds, [Pt(BQL1)Cl]Cl (BQL1-Pt) and [Pt(BQL2)Cl]Cl (BQL2-Pt), with [5-(benzo[4,5]furo[3,2-b]quinolin-11-yloxy)-pentyl]-bis-pyridin-2-ylmethyl-amine (BQL1) and [9-(benzo[4,5]furo[3,2-b]quinolin-11-yloxy)-nonyl]-bis-pyridin-2-ylmethyl-amine (BQL2), were prepared as new chemotypes for potential antitumor agents. In this study, the effects of cryptolepine derivatives in BQL1-Pt, 2,2′-dipicolylamine Pt(II) complex, and BQL2-Pt on cellular Pt(II) accumulation, cytotoxicity, and in vitro and in vivo antitumor activities against T-24 cancer cells and normal HL-7702 cells were evaluated. BQL1-Pt and BQL2-Pt displayed cytotoxic activities in the micromolar range (1.3 ± 0.1 and 0.2 ± 0.2 μM, respectively) on T-24 cancer cells; however, they did not exhibit any toxicity against HL-7702 cells. They triggered T-24 cell apoptosis through a mitochondrial dysfunction pathway. BQL1-Pt and BQL2-Pt prepared from the neutral BQL1 and BQL2 ligands with cryptolepine derivatives showed better antitumor activities than 2,2′-dipicolylamine. Furthermore, BQL2-Pt effectively inhibited the growth of bladder T-24 tumor in vivo. BQL2-Pt could be a potential therapeutic candidate for cancers. [ABSTRACT FROM AUTHOR]

Burn injury leads to mitochondrial dysfunction and autophagy, also known as mitophagy. The alleviation of mitochondrial damage may be a potential method for the treatment of burn injury and complications. In this animal study, we analyzed the expression of mitochondrial damage- and mitophagy-related factors, specifically PINK1 and PRKN. The results showed mitochondria damage in the skin; compared with the normal control group, genes involved in the mitochondrial damage, such as Nrf-1, UQCRC2, CYC1, and NDUFA9, as well as in the mitophagy, including PINK1, PRKN, MFN1, and USP30, were differentially expressed. Furthermore, PINK1 interacted with PRKN and participated in mitophagy in the skin. In conclusion, our data reveal more about the mechanism underlying mitophagy in burns, providing a potential clinical treatment. [ABSTRACT FROM AUTHOR]

Despite a growing body of studies demonstrating the specific anti-tumor effect of nano-hydroxyapatite (n-HA), the underlying mechanism remained unclear. Endoplasmic reticulum (ER) and mitochondria are two key players in intracellular Ca 2+ homeostasis and both require Ca 2+ to participate. Moreover, the ER-mitochondria interplay coordinates the maintenance of cellular Ca 2+ homeostasis to prevent any negative consequences from excess of Ca 2+ , hence there needs in-depth study of n-HA effect on them. In this study, we fabricated needle-like n-HA to investigate the anti-tumor effectiveness as well as the underlying mechanisms from cellular and molecular perspectives. Data from in vitro experiments indicated that the growth and invasion of glioma cells were obviously reduced with the aid of n-HA. It is interesting to note that the expression of ER stress biomarkers (GRP78, p-IRE1, p-PERK, PERK, and ATF6) were all upregulated after n-HA treatment, along with the activation of the pro-apoptotic transcription factor CHOP, showing that ER stress produced by n-HA triggered cell apoptosis. Moreover, the increased expression level of intracellular reactive oxygen species and the mitochondrial membrane depolarization, as well as the downstream cell apoptotic signaling activation, further demonstrated the pro-apoptotic roles of n-HA induced Ca 2+ overload through inducing mitochondria damage. The in vivo data provided additional evidence that n-HA caused ER stress and mitochondria damage in cells and effectively restrain the growth of glioma tumors. Collectively, the work showed that n-HA co-activated intracellular ER stress and mitochondria damage are critical triggers for cancer cells apoptosis, offering fresh perspectives on ER-mitochondria targeted anti-tumor therapy., (© The Author(s) 2024. Published by Oxford University Press.)

Abstract Background Autophagy is a cell degradation pathway that eliminates damaged or unwanted proteins and organelles. Autophagy protects cells from chemotherapeutic agents by scavenging damaged mitochondria. Methods Plasmid transfection and shRNA were used to regulate SHP-2 expression. Annexin V/PI staining were employed to analysis apoptosis. Flow cytometry was used to analyse intracellular calcium level and ROS. Immunofluorescence was used to detect mitochondria membrane potential, autophagy and Parkin translocation. Results In cervical cancer, we found that SHP-2 suppressed apoptosis induced by Oxaliplatin and 5-FU. Further studies have found that SHP-2 protects against mitochondrial damage. This role of SHP-2 is associated with the activation of autophagy. In addition, SHP-2 degraded impaired mitochondria dependent on the ubiquitin ligase function of Parkin. Conclusions These results suggest that SHP-2 inhibits the apoptosis induced by chemotherapeutic drugs through activating autophagy to degrade damaged mitochondria and ubiquitin ligase Parkin involved in SHP-2 induced autophagy.

The intestinal barrier dysfunction is closely implicated in low-grade chronic inflammation for insulin resistance in diet-induced obesity (DIO). It is generally believed that degradation of colon enterocytes contributes to intestinal barrier dysfunction in the pathological process of obesity. Sennoside A (SA) is reported to improve metabolic disorders, but the effect and mechanism of SA on colonic barrier function of DIO remains unknown. In this study, SA was found to restore colonic barrier function by protecting the continuity and integrity of colon enterocytes in DIO mice. An increase in mRNA expression of tight junction proteins Occludin, Claudin-2 and ZO-1 provides another mechanism of restoring colonic barrier function in SA-treated group. In the research of mechanism, mitophagy was inhibited by SA via a protection of mitochondrial structure and function in colon. A reduction was found in production of reactive oxygen species (ROS) in the colon, and the benefical effect was attributed to an inhibition of activity in complex I and III with a reduction of protein expression and an increase of Mn-SOD activity. The results indicate that SA can restores colonic barrier function through protecting colon enterocytes from ROS-induced mitochondrial damage in DIO mice. • Oral administration of Sennoside A (SA) restored colonic barrier function and improved the insulin sensitivity in DIO mice. • SA inhibited the PINK1/Parkin pathway of mitophagy in the colonic tissue of the mice. • SA effectively reduced mitochondrial ROS production through protecting colon enterocytes from mitochondrial damage. • A reduction of ROS production by SA was attributed to an inhibition of complex I and III, and an increase activity of Mn-SOD. [ABSTRACT FROM AUTHOR]

Increased anthropogenic activity and subsequent environmental exposure to heavy metals induce the production of reactive oxygen species (ROS), which increases oxidative stress and the risk of associated diseases. The aim of this study, in a subacute model of toxicity, was to investigate the effects of copper (Cu), manganese (Mn), and mercury (Hg) alone and in combination on the liver tissue of male Sprague-Dawley rats, exposed orally to 100 times the World Health Organization's acceptable water limits of each metal. General histological alterations as well as ultrastructural changes were investigated using light microscopy and transmission electron microscopy (TEM) respectively. Exposure to Cu, Mn, and Hg, alone and in combinations, caused hydropic swelling of the hepatocytes, dilation of the sinusoids, formation of binucleated hepatocytes with an increased inflammatory cell accumulation at the portal triad. Increased collagen deposition with associated fibrosis was also observed. Evaluation of hepatocyte ultrastructure revealed mitochondrial membrane damage and inner membrane swelling especially for hepatocytes exposed to Mn. Extracellular vesicle (EV) formation was observed in the liver tissue of all exposed rats. Furthermore, increased damage observed for metal combinations was possibly due to synergism. In conclusion, Cu, Mn, and Hg alone and as part of a mixture cause cellular damage, inflammation, and fibrosis increasing the risk of associated diseases. [ABSTRACT FROM AUTHOR]

Dityrosine (Dityr) has been detected in commercial food as a product of protein oxidation and has been shown to pose a threat to human health. This study aims to investigate whether Dityr causes a decrease in lactic acid metabolism in the gastrocnemius muscle during endurance exercise. C57BL/6 mice were administered Dityr or saline by gavage for 13 weeks and underwent an endurance exercise test on a treadmill. Dityr caused a severe reduction in motion displacement and endurance time, along with a significant increase in lactic acid accumulation in the blood and gastrocnemius muscle in mice after exercise. Dityr induced significant mitochondrial defects in the gastrocnemius muscle of mice. Additionally, Dityr induced serious oxidative stress in the gastrocnemius muscle, accompanied by inflammation, which might be one of the causes of mitochondrial dysfunction. Moreover, significant apoptosis in the gastrocnemius muscle increased after exposure to Dityr. This study confirmed that Dityr induced oxidative stress in the gastrocnemius muscle, which further caused significant mitochondrial damage in the gastrocnemius muscle cell, resulting in decreased capacity of lactic acid metabolism and finally affected performance in endurance exercise. This may be one of the possible mechanisms by which highly oxidized foods cause a decreased muscle energy metabolism.

Endometrial cancer (EC) stands as one of the most prevalent gynecological malignancies affecting women, with its incidence and disease-related mortality steadily on the rise. Disulfiram (DSF), an FDA-approved medication primarily used for treating alcohol addiction, has exhibited promising anti-tumor properties. Studies have revealed DSF's capacity for enhanced anti-tumor activity, particularly when combined with copper. The novel Copper-Cysteamine (CuCy) compound, Cu 3 Cl(SR) 2 (R[bond, double bond]CH 2 CH 2 NH 2 ), showcases photodynamic effects and demonstrates significant anti-tumor potential under various conditions, including exposure to ultraviolet light, X-ray, microwave, and ultrasound. This study delves into exploring the synergistic anti-tumor effects and underlying mechanisms by utilizing copper-cysteamine in conjunction with DSF against endometrial cancer. The investigation involved comprehensive analyses encompassing in vitro experiments utilizing Ishikawa cells, in vivo studies, and transcriptomic analyses. Remarkably, the combined administration of both compounds at a low dose of 0.5 μM exhibited pronounced efficacy in impeding tumor growth, inhibiting blood vessel formation, and stimulating cell apoptosis. Notably, experiments involving transplanted tumors in nude mice vividly demonstrated the significant in vivo anti-tumor effects of this combination treatment. Detailed examination through transmission electron microscopy unveiled compelling evidence of mitochondrial damage, cellular swelling, and rupture, indicative of apoptotic changes in morphology due to the combined treatment. Moreover, transcriptomic analysis unveiled substantial downregulation of mitochondrial-related genes at the molecular level, coupled with a significant hindrance in the DNA repair pathway. These findings strongly suggest that the combined application of CuCy and DSF induces mitochondrial impairment in Ishikawa cells, thereby fostering apoptosis and ultimately yielding potent anti-tumor effects., (© 2024 The Authors.)

Bovine viral diarrhea virus (BVDV) belongs to the family Flaviviridae and includes two biotypes in cell culture: cytopathic (CP) or non-cytopathic (NCP) effects. Ferroptosis is a non-apoptotic form of programmed cell death that contributes to inflammatory diseases. However, whether BVDV induces ferroptosis and the role of ferroptosis in viral infection remain unclear. Here, we provide evidence that both CP and NCP BVDV can induce ferroptosis in Madin-Darby bovine kidney cells at similar rate. Mechanistically, biotypes of BVDV infection downregulate cytoplasmic and mitochondrial GPX4 via Nrf2-GPX4 pathway, thereby resulting in lethal lipid peroxidation and promoting ferroptosis. In parallel, BVDV can degrade ferritin heavy chain and mitochondrial ferritin via NCOA4-mediated ferritinophagy to promote the accumulation of Fe 2+ and initiate ferroptosis. Importantly, CP BVDV-induced ferroptosis is tightly associated with serious damage of mitochondria and hyperactivation of inflammatory responses. In contrast, mild or unapparent damage of mitochondria and slight inflammatory responses were detected in NCP BVDV-infected cells. More importantly, different mitophagy pathways in response to mitochondria damage by both biotypes of BVDV are involved in inflammatory responses. Overall, this study is the first to show that mitochondria may play key roles in mediating ferroptosis and inflammatory responses induced by biotypes of BVDV in vitro .IMPORTANCEBovine viral diarrhea virus (BVDV) threatens a wide range of domestic and wild cattle population worldwide. BVDV causes great economic loss in cattle industry through its immunosuppression and persistent infection. Despite extensive research, the mechanism underlying the pathogenesis of BVDV remains elusive. Our data provide the first direct evidence that mitochondria-mediated ferroptosis and mitophagy are involved in inflammatory responses in both biotypes of BVDV-infected cells. Importantly, we demonstrate that the different degrees of injury of mitochondria and inflammatory responses may attribute to different mitophagy pathways induced by biotypes of BVDV. Overall, our findings uncover the interaction between BVDV infection and mitochondria-mediated ferroptosis, which shed novel light on the physiological impacts of ferroptosis on the pathogenesis of BVDV infection, and provide a promising therapeutic strategy to treat this important infectious disease with a worldwide distribution., Competing Interests: The authors declare no conflict of interest.

Ferroptosis-related cancer therapy is limited by insufficient Fe 2+ /Fe 3+ redox pair and hydrogen peroxide (H 2 O 2 ) for producing lethal hydroxyl radicals (·OH). Although exogenous iron or ROS-producing drugs can enhance ferroptosis, exploiting endogenous iron (labile iron pool, LIP) stored in ferritin and promoting ROS generation may be safer. Herein, a metal/drug-free nanomedicine is developed for responsive LIP release and H 2 O 2 generation on the mitochondria membranes, amplifying hydroxyl radical production to enhance ferroptosis-mediated antitumor effects. A glutathione(GSH)/pH dual activatable fluorinated and cross-linked polyethyleneimine (PEI) with dialdehyde polyethylene glycol layer nanocomplex loaded with MTS-KR-SOD (Mitochondria-targeting-sequence-KillerRed-Superoxide Dismutase) and CRISPR/Cas9-CA IX (Carbonic anhydrase IX (CA IX)) plasmids (FP@MC) are developed for enhanced ferroptosis through endogenous iron de-hijacking and in situ ROS amplification. Two plasmids are constructed to knockdown CA IX and translate KillerRed-SOD recombinant protein specifically on mitochondria membranes, respectively. The CA IX knockdown acidifies the intracellular environment, leading the release of LIP from ferritin as a "flare" to initiate endogenous chemodynamic therapy. Meanwhile, MTS-KR-SOD generates H 2 O 2 when irradiated by a 590 nm laser to assist chemodynamic therapy, leading to ROS amplification for mitochondria damage and lipid peroxide accumulation. The combined therapeutic effects aggravate cancer ferroptosis and suppress tumor growth, providing a new paradigm for amplifying ROS and iron ions to promote ferroptosis-related cancer therapy., (© 2023 Wiley-VCH GmbH.)

Transient receptor potential protein (TRP) ion channels TRPA1 and TRPV1 may be important in mediating airway tissue injury and inflammation. This study was designed to clarify the role of TRPA1 and TRPV1 channels in cigarette smoke extract (CSE)-induced damage to bronchial and alveolar epithelial cells. Alveolar epithelial (A549) cells and bronchial epithelial (Beas-2B) cells were treated with CSE in the presence and absence of a TRPA1 inhibitor (100 μM, A967079), a TRPV1 inhibitor (100 μM, AMG9810) or both. DCFH-DA and MitoSOX Red probes were used to assay intracellular and mitochondrial oxidative stress, respectively. The mRNA levels of inflammatory mediators (IL-1β, IL-8, IL-18, IL-33) and antioxidants (HO-1, NQO1, MnSOD, catalase) and the protein expression levels of mitochondrial and inflammasome factors (MFN2, OPA1, DRP1, MFF, NLRP3,caspase-1) were respectively detected by RT-PCR and Western Blot. The results were validated in TRPA1 shRNA and TRPV1 shRNA cells. In both cell types, 10% CSE increased intracellular and mitochondrial oxidative stress, induced Ca2+ influx, increased inflammatory gene expression, reduced antioxidant gene expression and inhibited the activities of mitochondrial respiratory chain (MRC) complexes. 10% CSE increased the expression of mitochondrial fission proteins (MFF and DRP1), Caspase-1 and NLRP3 protein expression and decreased that of mitochondrial fusion proteins (MFN2 and OPA1). Both inhibitors and gene-knockout of TRPA1 and TRPV1 reduced oxidative stress, blocked Ca2+ influx, and inhibited inflammatory and increased antioxidant gene expression. They also prevented the changes in mitochondrial fission and fusion proteins and in MRC complexes activities induced by CSE. Both TRPA1 and TRPV1 mediate CSE-induced damage of bronchial and alveolar epithelial cells via modulation of oxidative stress, inflammation and mitochondrial damage and their inhibition should be considered as potential therapy for COPD. fx1 • TRPA1 and TRPV1 mediate CSE-induced airway epithelial cells injury. • TRPA1 and TRPV1 can modulate oxidative stress, inflammation and mitochondrial damage. • Inhibition of TRPA1and TRPV1 should be considered as potential therapy for COPD. [ABSTRACT FROM AUTHOR]

Although it is well reported that mitochondrial damage and endoplasmic reticulum (ER) stress (ERS) are involved in heavy metal-induced cytotoxicity, the role of mitochondrial damage in hexavalent chromium [Cr(VI)]-induced ERS and the correlation between the two have not been described and remain to be elucidated. The present study evaluated the ability of Cr(VI) to induce ERS in L-02 hepatocytes, and subsequently examined the role of reactive oxygen species (ROS)-mediated mitochondrial damage in Cr(VI)-induced ERS. The findings demonstrated that Cr(VI) induced ERS, which was characterized by the upregulation of ERS-associated genes and the substantial release of Ca2+ from the ER. The Cr(VI)-induced mitochondrial production of ROS, by disturbing mitochondrial respiratory chain complexes I and II, may damage mitochondria directly by inducing mitochondrial permeability transition pore opening and mitochondrial membrane potential collapse. The results additionally demonstrated that Cr(VI) induced Ca2+ release from the ER through ROS/caveolin-1/protein kinase B/inositol 1,4,5-trisphosphate receptor signaling. The application of the ROS scavenger N-acetyl-cysteine confirmed the role of ROS in Cr(VI)-mediated mitochondrial damage, ERS and apoptotic cell death. The data obtained demonstrated the role of mitochondrial damage in Cr(VI)-induced ERS and provide novel insight into the elucidation of Cr(VI)-induced cytotoxicity. [ABSTRACT FROM AUTHOR]

The intestinal protozoan parasite, Giardia duodenalis, infects a large number of people in the world annually. Giardia infection has been considered a negative effect on intestinal epithelial cell growth, while the underlying mechanisms remain to be explored. Here we evaluated reactive oxygen species (ROS) production and apoptotic events in Giardia trophozoites-stimulated Caco-2 cells via fluorescence microscopy, transmission electron microscopy, flow cytometry, western blot, and cell counting kit-8 analyses. The results showed that Giardia trophozoite treatment could induce lactate dehydrogenase release and Caco-2 cell apoptosis. The ROS levels were increased post treatment. The observed typical characteristics of mitochondria damage include significant swelling and degeneration of matrix and cristae. After trophozoite treatment, the level of Bax protein expression was increased, while Bcl-2 protein decreased. Trophozoite stimulation also led to reduction of mitochondrial membrane potential and release of cytochrome c from the mitochondria to the cytoplasm, and this process was accompanied by activation of caspase-9 and caspase-3 and poly (ADP-ribose) polymerase 1 cleavage. Pretreatment with N-acetyl-L-cysteine, a ROS inhibitor, reversed G. duodenalis-induced Caco-2 cell apoptosis. Taken together, we indicated that G. duodenalis could induce Caco-2 cell apoptosis through a ROS- and mitochondria-mediated caspase-dependent pathway. This study furthers our understanding of the cellular mechanism of the interaction between Giardia trophozoites and host cells.