Search Results (442)

Background/Objectives: Parkinson’s disease (PD) is a debilitating neurodegenerative disease that targets the nigrostriatal dopaminergic (DAnergic) system residing in the human midbrain and is currently incurable. The aim of this study is to investigate the neuroprotective effects of ascorbic acid, vanillic acid, and ferulic acid in a zebrafish model of PD induced by MPTP by assessing the impact of these compounds on DAnergic neurons, focusing on gene expression, mitochondrial dynamics, and cellular stress responses. Methods/Results: Following exposure and qPCR and immunohistochemical analyses, ascorbic acid enhanced DAnergic function, indicated by an upregulation of the dopamine transporter (dat) gene and increased eGFP+ DAnergic cells, suggesting improved dopamine reuptake and neuroprotection. Ascorbic acid also positively affected mitochondrial dynamics and stress response pathways, countering MPTP-induced dysregulation. Vanillic acid only had modest, if any, neuroprotective effects on DAnergic neurons following MPTP administration. Ferulic acid exhibited the largest neuroprotective effects through the modulation of gene expression related to DAnergic neurons and mitochondrial dynamics. Conclusions: These findings suggest that ascorbic acid and ferulic acid can act as potential protective interventions for DAnergic neuron health, demonstrating various beneficial effects at the molecular and cellular levels. However, further investigation is needed to translate these results into clinical applications. This study enhances the understanding of neuroprotective strategies in neurodegenerative diseases, emphasizing the importance of considering interactions between physiological systems. Full article

Flashes of superoxide anion (O₂⁻) in mitochondria are generated spontaneously or during the opening of the permeability transition pore (mPTP) and a sudden change in the metabolic state of a cell. Under certain conditions, O₂⁻ can leave the mitochondrial matrix and perform signaling functions beyond mitochondria. In this work, we studied the kinetics of the release of O₂⁻ and H₂O₂ from isolated mitochondria upon mPTP opening and the modulation of the metabolic state of mitochondria by the substrates of respiration and oxidative phosphorylation. It was found that mPTP opening leads to suppression of H₂O₂ emission and activation of the O₂⁻ burst. When the induction of mPTP was blocked by its antagonists (cyclosporine A, ruthenium red, EGTA), the level of substrates of respiration and oxidative phosphorylation and the selective inhibitors of complexes I and V determined the type of reactive oxygen species (ROS) emitted by mitochondria. It was concluded that upon complete and partial reduction and complete oxidation of redox centers of the respiratory chain, mitochondria emit H₂O₂, O₂⁻, and nothing, respectively. The results indicate that the mPTP- and substrate-dependent switching of the type of ROS leaving mitochondria may be the basis for O₂⁻- and H₂O₂-selective redox signaling in a cell. Full article

To accommodate the integration of renewable energy, coal-fired power plants must take on the task of peak regulation, making the low-load operation of boilers increasingly routine. Under low-load conditions, the phase transition point (PTP) of the working fluid fluctuates, leading to potential flow instability, which can compromise boiler safety. In this paper, a one-dimensional coupled dynamic model of the combustion and hydrodynamics of a supercritical boiler is developed on the Modelica/Dymola 2022 platform. The spatial distribution of key thermal parameters in the furnace and the PTP position in the water-cooled wall (WCW) are analyzed in a 660 MW supercritical boiler when parameters on the combustion side change under full-load and low-load conditions. The dynamic response characteristics of the temperature, mass flow rate, and the PTP position are investigated. The results show that the over-fire air (OFA) ratio significantly influences the flue gas temperature distribution. A lower OFA ratio increases the flue gas temperature in the burner zone but reduces it at the furnace exit. The lower OFA ratio leads to a higher fluid temperature and shortens the length of the evaporation section. The temperature difference in the WCW outlet fluid between the 20% and 60% OFA ratios is 11.7 °C under BMCR conditions and 7.4 °C under 50% THA conditions. Under the BMCR and 50% THA conditions, a 5% increase in the coal caloric value raises the flue gas outlet temperature by 32.7 °C and 35.4 °C and the fluid outlet temperature by 6.5 °C and 9.9 °C, respectively. An increase in the coal calorific value reduces the length of the evaporation section. The changes in the length of the evaporation section are −2.95 m, 2.95 m, −2.62 m, and 0.54 m when the coal feeding rate, feedwater flow rate, feedwater temperature, and air supply rate are increased by 5%, respectively. Full article

Bone is a dynamic organ with an active metabolism and high sensitivity to mitochondrial dysfunction. The mitochondrial permeability transition pore (mPTP) is a low-selectivity channel situated in the inner mitochondrial membrane (IMM), permitting the exchange of molecules of up to 1.5 kDa in and out of the IMM. Recent studies have highlighted the critical role of the mPTP in bone tissue, but there is currently a lack of reviews concerning this topic. This review discusses the structure and function of the mPTP and its impact on bone-related cells and bone-related pathological states. The mPTP activity is reduced during the osteogenic differentiation of mesenchymal stem cells (MSCs), while its desensitisation may underlie the mechanism of enhanced resistance to apoptosis in neoplastic osteoblastic cells. mPTP over-opening triggers mitochondrial swelling, regulated cell death, and inflammatory response. In particular, mPTP over-opening is involved in dexamethasone-induced osteoblast dysfunction and bisphosphonate-induced osteoclast apoptosis. In vivo, the mPTP plays a significant role in maintaining bone homeostasis, with many bone disorders linked to its excessive opening. Genetic deletion or pharmacological inhibition of the over-opening of mPTP has shown potential in enhancing bone injury recovery and alleviating bone diseases. Here, we review the findings on the relationship of the mPTP and bone at both the cellular and disease levels, highlighting novel avenues for pharmacological approaches targeting mitochondrial function to promote bone healing and manage bone-related disorders. Full article

Background and Objective: The alteration of mitochondrial functions, especially the opening of the mitochondrial permeability transition pore (mPTP), has been proposed as a key mechanism in the development of lesions in cerebral ischemia, wherefore it is considered as an important target for drugs against ischemic injury. In this study, we aimed to investigate the effects of mitochondrial complex I inhibitors as possible regulators of mPTP using an in vitro brain ischemia model of the pentobarbital/ketamine (PBK)-anesthetized rats. Results: We found that PBK anesthesia itself delayed Ca²⁺-induced mPTP opening and partially recovered the respiratory functions of mitochondria, isolated from rat brain cortex and cerebellum. In addition, PBK reduced cell death in rat brain slices of cerebral cortex and cerebellum. PBK inhibited the adenosine diphosphate (ADP)-stimulated respiration of isolated cortical and cerebellar mitochondria respiring with complex I-dependent substrates pyruvate and malate. Moreover, pentobarbital alone directly increased the resistance of isolated cortex mitochondria to Ca²⁺-induced activation of mPTP and inhibited complex I-dependent respiration and mitochondrial complex I activity. In contrast, ketamine had no direct effect on functions of isolated normal cortex and cerebellum mitochondria. Conclusions: Altogether, this suggests that modulation of mitochondrial complex I activity by pentobarbital during PBK anesthesia may increase the resistance of mitochondria to mPTP opening, which is considered the key event in brain cell necrosis during ischemia. Full article

Background: Research has shown the multiple actions of curcumin on different cell systems, including enzymes and mitochondria. The detected effects of curcumin on mitochondria are diverse, ranging from protective to toxic. Objectives: In this present work, the influence of curcumin, as well as cinnamic acid, which is a microbial metabolite and a possible product of the microbial breakdown of curcumin, on isolated mitochondria, was investigated. Methods: Membrane potential, swelling, respiration, and calcium retention capacity were studied using selective electrodes, fluorescence and spectral methods. Results: It was found that curcumin at low concentrations (10–20 μM) activated the opening of the calcium-dependent permeability transition pore (mPTP) and decreased the calcium retention capacity and threshold concentrations necessary for the mPTP opening. Moreover, curcumin caused a concentration-dependent stepwise decrease in the membrane potential, accompanied by the activation of respiration and a decrease in oxidative phosphorylation, which indicates that curcumin is a typical mitochondrial uncoupler. The uncoupling effect strongly depended on the concentration of curcumin, which also increased, stepwise, from weak uncoupling at 25 µM to complete uncoupling at 75–100 µM. Cinnamic acid had similar effects, with the exception of the depolarizing effect, at concentrations that were an order of magnitude higher. Conclusions: Presumably, the uncoupling action of curcumin is a priming event that modulates any energy- and redox-dependent mitochondrial functions, from positive stimulation to toxic disorder. This effect can also underlie the curcumin-induced changes in different cellular processes and be achieved by targeted delivery of curcumin to certain cells, bypassing the microbiota. Full article

Fucosylated chondroitin sulfate (FCS) was prepared from Bohadschia ocellata using protease hydrolysis. The structural characteristics of FCS were confirmed through chemical composition analysis using FTIR spectroscopy, ¹H NMR, and ¹³C NMR. FCS from B. ocellata (FCS-Bo) exhibited an average molecular weight of approximately 122 kDa. The biological activities of FCS-Bo, including anticoagulant, anti-cancer, and Protein Tyrosine Phosphatase 1B (PTP1B) inhibition, were evaluated. FCS-Bo displayed potent anticoagulant properties, markedly extending activated partial thromboplastin time, prothrombin time, and thrombin time when compared to the heparin control. In anti-cancer bioactivity research, FCS-Bo efficiently inhibited colony formation in the colon cancer cell lines HCT-116, HT-29, and DLD-1, achieving inhibition rates of up to 65%. Additionally, FCS-Bo exhibited significant inhibition of PTP1B, with an IC₅₀ as low as 0.0326 µg/mL, suggesting its potential for improving insulin sensitivity and managing conditions such as type 2 diabetes and obesity. Full article

Voltage-dependent anion channels (VDACs) are important proteins of the outer mitochondrial membrane (OMM). Their beta-barrel structure allows for efficient metabolite exchange between the cytosol and mitochondria. VDACs have further been implicated in the control of regulated cell death. Historically, VDACs have been pictured as part of the mitochondrial permeability transition pore (MPTP). New concepts of regulated cell death involving VDACs include its oligomerisation to form a large pore complex in the OMM; however, alternative VDAC localisation to the plasma membrane has been suggested in the literature and will be discussed regarding its potential role during cell death. Very recently, a phospholipid scramblase activity has been attributed to VDAC dimers, which explains the manifold lipidomic changes observed in VDAC-deficient yeast strains. In this review, I highlight the recent advances regarding VDAC’s phospholipid scramblase function and discuss how this new insight sheds new light on VDAC’s implication in regulated cell death, autophagy, and ageing. Full article

A focussed library of pyridyl and 2-hydroxyphenyl chalcones were synthesized and tested for growth inhibitory activity against Mycobacterium tuberculosis H37Rv, and normal and cancer breast cell lines. Pyridyl chalcones bearing lipophilic A-ring, e.g., dichloro-phenyl-(14), pyrene-1-yl (20)- and biphenyl-4-yl (21) moieties were found to be the most potent of the series inhibiting the growth of M. tuberculosis H37Rv with IC₉₀ values ranging from 8.9–28 µM. Aryl chalcones containing a 3-methoxyphenyl A-ring and either p-Br-phenyl (25) or p-Cl-phenyl (26) B-rings showed an IC₉₀ value of 28 µM. Aryl-chalcones were generally less toxic to HepG2 cells compared to pyridyl-chalcones. Dose-dependent antiproliferative activity against MDA468 cells was observed for trimethoxy-phenyl (16) and anthracene-9-yl (19) pyridyl-chalcones with IC₅₀ values of 0.7 and 0.3 µM, respectively. Docking studies revealed that chalone 20 was predicted to bind to the M. tuberculosis protein tyrosine phosphatases B (PtpB) with higher affinity compared to a previously reported PtpB inhibitor. Full article

The novel antiparkinsonian agent PA-96 is the focus of our research. PA-96 supported the survival of cultured naïve dopamine neurons, alleviated motor deficits in MPTP and haloperidol-based mice models of Parkinson’s disease, and increased the density of tyrosine hydroxylase positive neurons and dopamine concentration in the midbrain of an MPTP-damaged brain. In this work, an HPLC–MS/MS method was developed and validated, and the pharmacokinetics of the agent was investigated in mice after a single or multiple oral administration (p.o.) and intravenous injection (i.v.) at various doses. The dose proportionality was also evaluated after a single p.o. administration of three ascending doses (1, 5, and 10 mg/kg) and a single i.v. injection of two doses (1 and 10 mg/kg); also, the bioavailability was estimated. The disproportionality of pharmacokinetic parameters could be explained by the saturation of active centres of enzymes or receptors binding the substance: at low doses, part of the compound is bound, leaving a small amount circulating in blood, and rapidly metabolised and/or bound too. The bioavailability of PA-96 was c.a. 7 and 35% for the doses of 5 and 10 mg/kg, correspondingly. Full article

Recent studies have uncovered intriguing connections between Parkinson’s disease (PD) and cancer, two seemingly distinct disease categories. Disulfidptosis has garnered attention as a novel form of regulated cell death that is implicated in various pathological conditions, including neurodegenerative disorders and cancer. Disulfidptosis involves the dysregulation of intracellular redox homeostasis, leading to the accumulation of disulfide bonds and subsequent cell demise. This has sparked our interest in exploring common molecular mechanisms and genetic factors that may be involved in the relationship between neurodegenerative diseases and tumorigenesis. The Gene4PD database was used to retrieve PD differentially expressed genes (DEGs), the biological functions of differential expression disulfidptosis-related genes (DEDRGs) were analyzed, the ROCs of DEDRGs were analyzed using the GEO database, and the expression of DEDRGs was verified by an MPTP-induced PD mouse model in vivo. Then, the DEDRGs in more than 9000 samples of more than 30 cancers were comprehensively and systematically characterized by using multi-omics analysis data. In PD, we obtained a total of four DEDRGs, including ACTB, ACTN4, INF2, and MYL6. The enriched biological functions include the regulation of the NF-κB signaling pathway, mitochondrial function, apoptosis, and tumor necrosis factor, and these genes are rich in different brain regions. In the MPTP-induced PD mouse model, the expression of ACTB was decreased, while the expression of ACTN4, INF2, and MYL6 was increased. In pan-cancer, the high expression of ACTB, ACTN4, and MYL6 in GBMLGG, LGG, MESO, and LAML had a poor prognosis, and the high expression of INF2 in LIHC, LUAD, UVM, HNSC, GBM, LAML, and KIPAN had a poor prognosis. Our study showed that these genes were more highly infiltrated in Macrophages, NK cells, Neutrophils, Eosinophils, CD8 T cells, T cells, T helper cells, B cells, dendritic cells, and mast cells in pan-cancer patients. Most substitution mutations were G-to-A transitions and C-to-T transitions. We also found that miR-4298, miR-296-3p, miR-150-3p, miR-493-5p, and miR-6742-5p play important roles in cancer and PD. Cyclophosphamide and ethinyl estradiol may be potential drugs affected by DEDRGs for future research. This study found that ACTB, ACTN4, INF2, and MYL6 are closely related to PD and pan-cancer and can be used as candidate genes for the diagnosis, prognosis, and therapeutic biomarkers of neurodegenerative diseases and cancers. Full article

In this study, we developed well-aligned ZnO nanoflowers coated with poly-10,12-pentacosadiyonic acid (p-PCDA@ZnO) and modified with Pt nanoparticle (Pt/p-PCDA@ZnO) hybrid photoanodes for highly efficient photoelectrochemical (PEC) water splitting. The scanning electron microscope (SEM) image shows that thin films of the p-PCDA layer were well coated on the ZnO nanoflowers and that Pt nanoparticles were on it. The photoelectrochemical characterizations were made under simulated solar irradiation AM 1.5. The current density of the p-PCDA@ZnO and the Pt/p- PCDA@ZnO was 0.227 mA/cm² and 0.305 mA/cm², respectively, and these values were three times and four times higher compared to the 0.071 mA/cm² of the bare ZnO nanoflowers. The UV–visible spectrum showed that the absorbance of coated p-PCDA films was extended in visible light region, which agrees with the enhanced PEC data for p-PCDA@ZnO. Also, adding Pt nanoparticles on top of the films as co-catalysts enhanced the PEC performance of Pt/p-PCDA@ZnO further. This indicates that Pt/p- PCDA@ZnO has a great potential to be implemented in solar water splitting. Full article

According to many research groups, high glucose induces the overproduction of superoxide anions, with reactive oxygen species (ROS) generally being considered the link between high glucose levels and the toxicity seen at cellular levels. Respiratory complex anomalies can lead to the production of ROS. Calcium [Ca²⁺] at physiological levels serves as a second messenger in many physiological functions. Accordingly, mitochondrial calcium [Ca²⁺]_m overload leads to ROS production, which can be lethal to the mitochondria through various mechanisms. F1F0-ATPase (ATP synthase or complex V) is the enzyme responsible for catalyzing the final step of oxidative phosphorylation. This is achieved by F1F0-ATPase coupling the translocation of protons in the mitochondrial intermembrane space and shuttling them to the mitochondrial matrix for ATP synthesis to take place. Mitochondrial complex V T8993G mutation specifically blocks the translocation of protons across the intermembrane space, thereby blocking ATP synthesis and, in turn, leading to Neuropathy, Ataxia, and Retinitis Pigmentosa (NARP) syndrome. This study seeks to explore the possibility of [Ca²⁺]_m overload mediating the pathological roles of high glucose in defective respiratory chain-mediated mitochondrial stress. NARP cybrids are the in vitro experimental models of cells with F1FO-ATPase defects, with these cells harboring 98% of mtDNA T8993G mutations. Their counterparts, 143B osteosarcoma cell lines, are the parental cell lines used for comparison. We observed that NARP cells mediated and enhanced the death of cells (apoptosis) when incubated with hydrogen peroxide (H₂O₂) and high glucose, as depicted using the MTT assay of cell viability. Furthermore, using fluorescence probe-coupled laser scanning confocal imaging microscopy, NARP cells were found to significantly enable mitochondrial reactive oxygen species (mROS) formation and enhance the depolarization of the mitochondrial membrane potential (ΔΨm). Elucidating the mechanisms of sugar-enhanced toxicity on the mitochondria may, in the future, help to alleviate the symptoms of patients with NARP syndromes and other neurodegenerative diseases. Full article

NIBV is an acute and highly contagious virus that has a major impact on the poultry industry. Wogonin, as a flavonoid drug, has antiviral effects, but there have been no reports indicating its role in renal injury caused by NIBV infection. The aim of this study is to investigate the antiviral effect of wogonin against NIBV. Renal tubular epithelial cells were isolated and cultured, and divided into four groups: Con, Con+Wog, NIBV and NIBV+Wog. We found that wogonin significantly inhibited the copy number of NIBV and significantly alleviated NIBV-induced cell apoptosis and necrosis. Moreover, wogonin inhibited the reduction in mitochondrial membrane potential and the aberrant opening of mPTP caused by NIBV. In conclusion, wogonin can protect renal tubular epithelial cells from damage by inhibiting the replication of NIBV and preventing mitochondrial apoptosis and necroptosis induced by NIBV. Full article