Membrane Potential Research Articles (Page 1)

GLP-1/GIP dual agonist tirzepatide alleviates mice model of Parkinson's disease by promoting mitochondrial homeostasis.

Crocin facilitates peripheral nerve regeneration through modulation of the STAT3/Bcl-2/Beclin-1 signaling axis-mediated autophagic pathway.

Liver cancer is the third most common cause of cancer-related death after lung and colorectal cancers. Hepatocellular carcinoma (LIHC) is the predominant subtype. Doxorubicin (DOX), an anthracycline chemotherapy drug, is extensively employed in the clinical treatment of early-stage and mid-stage liver cancer. Unfortunately, resistance that develops with long-term treatment severely undermines its therapeutic efficacy. Dihydroartemisinin (DHA), an antimalarial drug, has shown great potential in modulating the tumor microenvironment and inhibiting tumor growth, yet our understanding of its mechanisms remains limited. Network pharmacology identified CCT3 as a potential DHA target. Autodock predicted the binding of CCT3 and DHA. CCT3 expression in tumor and normal samples was analyzed using the TCGA-LIHC dataset. GSEA mapped out the pathways enriched by CCT3. qPCR and WB were used to measure CCT3 expression. Drug affinity responsive target stability assay verified the binding of CCT3 and DHA. The effects of DOX and DHA on cancer cell viability were probed using CCK-8, TUNEL, and flow cytometry. Cellular oxidative stress (OS) levels were assessed with intracellular reactive oxygen species (ROS) detection and JC-1 staining. DHA and DOX both proved effective in suppressing cancer cell viability and boosting apoptosis. Their combined use further amplified these effects. CCT3 was identified as a crucial target protein for DHA in LIHC treatment, with a strong binding capacity. This protein was particularly enriched in pathways associated with OS. In DOX-resistant cells, overexpressing CCT3 remarkably heightened resistance and reduced apoptosis, which possibly stemmed from the role of CCT3 in maintaining cellular ROS and mitochondrial membrane potential homeostasis, thereby reducing OS. Notably, these effects of CCT3 could be effectively inhibited by targeting DHA. DHA can target and inhibit CCT3 to induce OS, thereby enhancing the therapeutic efficacy of DOX.

Melatonin ameliorates oxybenzone-induced meiotic defects in mouse oocytes via regulation of mitochondrial dynamics and calcium signaling.

FHF (fibroblast growth factor homologous factor) variants associate with arrhythmias. Although FHFs are best characterized as regulators of voltage-gated sodium channel (VGSC) gating, recent studies suggest broader, non-VGSC-related functions, including regulation of Cx43 (connexin 43) gap junctions and hemichannels, mechanisms that have generally been understudied or disregarded. We assessed cardiac conduction and cardiomyocyte action potentials in mice with constitutive cFgf13KO while targeting Cx43 gap junctions and hemichannels pharmacologically. We characterized FGF (fibroblast growth factor) 13 regulation of Cx43 abundance and subcellular distribution. With proximity labeling proteomics, we investigated novel candidate mechanisms underlying FGF13 regulation of Cx43. FGF13 ablation prolonged the QRS and QT intervals. Carbenoxolone, a Cx43 gap junction uncoupler, markedly prolonged the QRS duration, leading to conduction system block in cFgf13KO but not in wild-type mice. Optical mapping revealed markedly decreased conduction velocity during ventricular pacing. Microscopy revealed perturbed trafficking of Cx43, reduced localization in the intercalated disc, and suggested decreased membrane Cx43 but increased Cx43 hemichannels in cardiomyocytes from cFgf13KO mice. Resting membrane potential was depolarized, and action potential duration at 50% repolarization was prolonged in cFgf13KO cardiomyocytes. Both were restored toward wild-type values with Gap19 (a Cx43 hemichannel inhibitor), expression of FGF13, or expression of a mutant FGF13 incapable of binding to VGSCs, emphasizing VGSC-independent regulation by FGF13. To assess the functional impact of resting membrane potential depolarization, hearts were subjected to hypokalemia, which had no effect in wild-type hearts but fully rescued conduction velocity in cFgf13KO hearts. Proteomic analyses revealed candidate roles for FGF13 in the regulation of vesicular-mediated transport. FGF13 ablation destabilized microtubules and reduced the expression of tubulins and MAP4, the major cardiac microtubule regulator. FGF13 regulates microtubule-dependent trafficking and targeting of Cx43 and impacts cardiac impulse propagation via VGSC-independent mechanisms.

Peiminine, an active alkaloid, has been reported to exhibit antitumor properties in several malignancies. This study aims to examine the role and potential mechanism of peiminine in prostate cancer (PCa). CCK-8, wound healing, colony formation, and Transwell assays were employed to evaluate PCa cell phenotypes. Cell cycle progression and apoptosis were examined by flow cytometry. Mitochondrial ROS, mitochondrial membrane potential, and ATP levels were measured to evaluate mitochondrial function in PCa cells. Western blotting was used to assess protein levels associated with apoptosis, EMT, and Wnt/β-catenin signaling. Immunofluorescence staining was performed to detect β-catenin expression. The in vivo effects of peiminine were evaluated using a xenograft mouse model. Peiminine dose-dependently impaired PCa cell viability without significantly affecting non-tumor cells. Peiminine inhibited PCa cell growth and motion and triggered apoptosis, cell cycle arrest, and mitochondrial dysfunction in vitro. Peiminine reduced PCa cell-derived tumor growth in the xenograft mouse model. Peiminine inhibited Wnt/β-catenin signal transduction. Peiminine exhibits an antitumor role in PCa by targeting Wnt/β-catenin signaling.

This study investigates the antifungal properties of a liquid Cinchona-Based Formulation (CBF) against Rhizoctonia solani. CBF, a stable acidic extract of Cinchona bark (0.1N HCl), effectively suppressed mycelial growth (58.75 ± 0.48%) and sclerotia biomass (22.1 ± 0.65mg), with an EC50 of 217.14µg/mL. GC-MS and HPLC revealed quinine as the primary active alkaloid. Molecular docking revealed a strong binding affinity of quinine to the fungal tryptophan (Trp) transporters (-6.5 to -7.8 Kcal/mol). Supplementation of 400µg/mL Trp in the media reversed the fungal growth with increased fungal dry weight (33.33 ± 1.53mg), and sclerotia weight (67.67 ± 3.06mg), highlighting Trp starvation as a key factor for reduced growth of the fungus. Expression of amino acid permease (rhAAP-I/II) increased 4-9 fold during Trp scarcity in fungus. CBF also elevated levels of ROS, which results in loss of Mitochondrial Membrane Potential (MMP). CBF reduced Cyt. P450 expression (2.73-fold) while increasing mitochondrial QCR and COX expression, indicating a combined impact of Trp scarcity and oxidative stress, demonstrating a dual antifungal mechanism of the CBF on the fungus. These results suggest CBF as a promising eco-friendly biopesticide for long-term disease management.

To investigate the effects of Porphyromonas endodontalis on the viability of stem cells from the apical papilla (SCAP) and to explore the role of mitochondrial function in supporting SCAP survival. SCAP were isolated from immature third molars, and P. endodontalis was added to the cell culture medium. Cell proliferation and apoptosis were assessed using the CCK8 assay and flow cytometry, with vascular endothelial cells (VECs) serving as a comparative group. Transmission electron microscopy was utilised to observe the mitochondrial morphology and bacterial ultrastructure. Changes in mitochondrial membrane potential (MMP) were assessed using laser scanning confocal microscopy. Additionally, the effects of mitophagy or mitochondrial fission inhibitors on SCAP cell viability and MMP were evaluated. Transcriptomic high-throughput sequencing was conducted to analyse differentially expressed mRNAs in SCAP and VECs after P. endodontalis infection using gene set enrichment analysis. Western blotting was performed to detect the expression of proteins associated with mitophagy and mitochondrial fission. The co-localisation of microtubule-associated protein light chain 3 with translocase of the outer mitochondrial membrane 20 (TOM20), as well as dynamin-related protein 1 with TOM20, was examined using laser scanning confocal microscopy. Data were analysed using SPSS 22.0, and a p-value < 0.05 was considered statistically significant. Following 6 h of P. endodontalis infection, SCAP exhibited higher cell viability and lower cell apoptosis rates than VECs. In addition, SCAP maintained more stable mitochondrial morphology and higher MMP compared to VECs. Transcriptomic analysis revealed that differentially expressed mRNAs between infected SCAP and VECs were enriched in terms related to mitochondrial membrane, depolarisation and mitochondrial fission. P. endodontalis infection also upregulated the expression of proteins associated with mitophagy and mitochondrial fission in SCAP. Inhibition of either mitophagy or mitochondrial fission in SCAP decreased the viability of SCAP. SCAP could maintain cell viability after short-term P. endodontalis infection. The underlying mechanism may involve mitochondrial fission and mitophagy, which appear to function as key protective processes enabling SCAP to counteract infection-induced cellular damage. This study helps elucidate the molecular basis of SCAP survival under bacterial infection.

Alzheimer's disease (AD) exhibits progressive cognitive decline and recent scientific studies hint to the peripheral immune system as a contributor. In this study, we isolated peripheral immune cells including CD4 + and CD8 + T cells, CD14 + monocytes and CD19 + B cells from AD patients and age-matched controls via fluorescence-activated cell sorting. Label-free LC-MS/MS-based proteomic expression analysis within each cell type, comparing AD and control groups independently, 387 significantly altered proteins were identified in CD4 + and 121 in CD8 + T cells. Bioinformatic analysis uncovered distinct, cell-type-specific signatures: CD4 + cells showed dysregulation in ribosomal and RNA-binding proteins linked to neurodegeneration and oxidative stress while CD8 + cells showed elevated glycolytic enzyme expression and hyperpolarized mitochondrial membrane potential. Furthermore, mitochondrial functional assays, JC-1 and MitoSOX Red, further supported cell-type-dependent differences in mitochondrial activity. These findings may suggest that peripheral T cells have unique proteomic and functional alterations in AD, implicating mitochondrial dysfunction as a potential contributor to disease pathology.

Neuroinflammation plays a central role in a wide spectrum of neurological diseases, driven generally by reactive microglia and astrocytes. Inflammatory stimulation of microglia and astrocytes leads to a metabolic shift from oxidative phosphorylation (OXPHOS) to glycolysis, which is required to support pro-inflammatory effector functions. This metabolic reprogramming is associated with impaired mitochondrial dynamics, including reduced biogenesis, increased fragmentation, and loss of membrane potential. Targeting microglia and astrocyte metabolism may offer a novel therapeutic approach for modulating neuroinflammation and restoring homeostatic immune functions. Here, we examined the potential of 2-Deoxy-D-Glucose (2DG), a glycolysis inhibitor, to attenuate neuroinflammation by restoring mitochondrial dynamics. In BV2 and primary glial cultures, low-dose 2DG reversed LPS-induced metabolic reprogramming, restoring OXPHOS, reducing mitochondrial fragmentation, and enhancing biogenesis. In vivo, it preserved spare respiratory capacity and increased complex-V activity in brain mitochondria from LPS-treated mice without affecting oxidative stress. At a mechanistic level, 2DG restored activation of AMP-activated protein kinase, a master regulator of mitochondrial dynamics. In conjunction with these metabolic effects, 2DG suppressed LPS-induced pro-inflammatory gene expression while enhancing markers associated with the resolution of inflammation and tissue repair. Critically, systemic low-dose 2DG reduced neuroinflammation and restored immune homeostasis in two LPS-induced mouse models, highlighting its therapeutic potential in neurological disorders.

Dexmedetomidine (Dex), an α2 adrenergic receptor agonist, has been shown to exert protective effects against postoperative neurocognitive disorder (PND) following anesthesia and surgery. This study aimed to investigate the underlying mechanisms, with a focus on the inositol 1,4,5-triphosphate receptor (IP3R)-voltage-dependent anion channel 1 (VDAC1)-chaperone glucose-regulated protein 75 (GRP75) calcium transport protein complex-mediated mitochondrial dysfunction. An in vitro sevoflurane-induced SH-SY5Y cell injury model and an in vivo PND rat model induced by sevoflurane anesthesia plus laparotomy were established, and both models were pretreated with Dex. Subsequent assessment included cell viability, apoptosis, inflammatory cytokines, reactive oxygen species (ROS), mitochondrial calcium ion (Ca2+), mitochondrial membrane potential (MMP), mitochondrial ultrastructure, and ATP production. Cognitive functions including spatial memory, anxiety-like behavior, and recognition memory were evaluated in rats. The expression levels and interactions among IP3R, GRP75, and VDAC1 were examined to elucidate the mechanisms involved. Sevoflurane exposure reduced cell viability, increased apoptosis and inflammation, and induced mitochondrial impairments including ROS overproduction, Ca2+ overload, loss of MMP, ultrastructural damage, and reduced ATP production. Dex pretreatment effectively alleviated all these cellular injuries. Furthermore, Dex alleviated cognitive deficits in PND rats and mitigated neuronal loss, histological damage, apoptosis, neuroinflammation, and mitochondrial ultrastructural damage in hippocampal tissues. Mechanistically, Dex reversed sevoflurane-induced upregulation of IP3R, GRP75, and VDAC1 and disrupted their enhanced interaction. VDAC1 exhibited the most pronounced changes in response to both sevoflurane injury and Dex treatment. Rescue experiments suggested that VDAC1 overexpression abrogated Dex-mediated mitochondrial protection. Dex alleviates cognitive deficits in PND rats by preserving mitochondrial calcium homeostasis and mitigating mitochondrial dysfunction through regulating the IP3R-GRP75-VDAC1 complex. This study may provide critical insights into the neuroprotective mechanisms of Dex in PND and identify potential therapeutic targets.

Pathological retinal neovascularization, a major cause of blindness, occurs in conditions such as age-related macular degeneration (AMD) and diabetic retinopathy (DR). Microglial activation and chronic neuroinflammation play critical roles in disease progression by promoting vascular permeability and angiogenesis. While anti-VEGF therapies are the current standard of care, their efficacy is limited, requiring frequent intraocular injections and raising concerns about long-term retinal health. Noninvasive transpalpebral electrical stimulation (TpES) has emerged as a potential alternative therapy, but its mechanism and therapeutic impact remain poorly understood. To investigate the therapeutic effects of TpES, we applied daily microcurrent stimulation (300 µA, 20Hz, 4min) in laser-induced choroidal neovascularization (CNV) and streptozotocin (STZ)-induced DR mouse models. Vascular pathology was assessed using fluorescein angiography, optical coherence tomography (OCT), and immunohistochemistry. Mechanistic studies were conducted using primary microglia and human retinal endothelial cells (HREC) to evaluate TpES-induced changes in intracellular calcium ([Ca²⁺]i) signaling, mitochondrial membrane potential, and ATP production. Additionally, human RPE/choroidal explants from healthy, AMD, and DR donors were cultured to assess TpES effects on angiogenesis in healthy and pathological human tissues. TpES significantly reduced vascular leakage (by ~ 30%, p < 0.001) and lesion size in the CNV model (p < 0.05), while also suppressing microglial infiltration and VEGF-A expression. In the DR model, TpES attenuated microaneurysm formation, preserved endothelial tight junctions (in vitro). Mechanistic studies revealed that TpES suppressed ATP-induced microglial activation by reducing mitochondrial membrane potential and intracellular ATP levels, leading to depletion of ER calcium stores and inhibition of proinflammatory and proangiogenic signaling. TpES also directly suppressed endothelial cell migration and tube formation, as well as angiogenic sprouting in human RPE/choroidal explants. These findings establish TpES as a dual-action therapy that mitigates both inflammation and pathological angiogenesis by modulating microglial and endothelial metabolism. Given its noninvasive nature and ability to target key pathways in retinal pathology, TpES represents a promising therapeutic strategy for AMD, DR, and other retinal vascular diseases.

Photodynamic therapy (PDT) is a photochemistry-based treatment modality that synergizes with traditional agents and can overcome chemoresistance. Eighty percent of ovarian cancer patients develop chemoresistant disease, highlighting the need to identify sources of treatment failure and develop rational combinations. Studies have shown that perfluoroalkyl substances (PFAS) induce chemoresistance in a duration-dependent manner in OVCAR-3 cells. PFAS are widespread drinking water contaminants present in the blood of nearly all Americans. The present study evaluated the ability of photodynamic priming (PDP), a sub-cytotoxic variant of PDT, in combination with chemotherapy to overcome chemoresistance in two OVCAR-3 cell cohorts: PFAS chronically-exposed and outgrown (allowed to "recover" from chronic PFAS exposure). Effectiveness of benzoporphyrin derivative- (BPD-) or aminolevulinic acid-induced protoporphyrin IX-PDP (ALA-PpIX-PDP) was assessed in combination with carboplatin and doxorubicin. In PFAS chronically-exposed cells, BPD-PDP + carboplatin reduced survival fraction compared to carboplatin alone. Mitochondrial membrane potential also decreased significantly in both cohorts following ALA-PpIX-PDP-based combinations. PDP + doxorubicin also successfully overcame chemoresistance arising from chronic PFAS exposure but was less effective than PDP + carboplatin. Together, these findings demonstrate the efficacy of PDP-based combinations in overcoming chronic PFAS exposure-induced chemoresistance and should be explored in pre-clinical models of ovarian cancer.

Supramolecular complexes (SMCs) based on cholesterol, menadione, and redox-active ceria nanoparticles (NPs) with a pronounced antitumor effect triggered by the addition of ascorbic acid were obtained. Ascorbic acid plays the role of electron donor, increasing sufficiently the ability of ceria NPs in SMCs to oxidize thiol-containing biological molecules including glutathione and cysteine. The mechanism of the enhanced oxidizing ability of SMCs is based on the redox cycling of both ceria NPs and menadione with superoxide anions formed as an intermediate product. As a result of strong prooxidant activity, SMCs provide significant cytotoxicity toward mouse fibrosarcoma cells in 2D and 3D models accompanied by reduced cell viability, a decrease of the mitochondrial membrane potential, and cell shrinkage. The absence of such an effect on murine fibroblasts indicates that the cytotoxic action of an ascorbate-nanoceria pair is highly selective, targeting tumor cells but not nontumor ones.

Commercial turkey breeding relies almost entirely on artificial insemination, yet avian sperm are unusually vulnerable to cooling and freezing injury. As a result, extender chemistry and processing steps, especially low-temperature equilibration, are pivotal for post-thaw performance. We evaluated how extender choice, paired with equilibration time, shapes the post-thaw quality of turkey semen. Ejaculates were diluted in Beltsville, Sperm Motility Medium (SMM), Botucrio, or Kobidil+, then equilibrated for 20 or 40 min before freezing; samples were cryostored for one month and assessed immediately after thawing. The outcomes included motility/kinematics, membrane integrity, mitochondrial activity and membrane potential, apoptosis/necrosis, reactive oxygen species (ROS), DNA fragmentation, and bacteriological load. Overall, 20 min equilibration improved post-thaw motility and membrane integrity, and reduced DNA fragmentation and ROS. Among extenders, Beltsville delivered the best overall sperm quality. Considering the extender × time interaction, Beltsville, Botucrio, and Kobidil+ performed best at 20 min, whereas SMM performed best at 40 min. Thus, Beltsville and SMM provide strong, time-specific options for turkey semen cryopreservation—Beltsville at 20 min and SMM at 40 min.

Osteoarthritis (OA) is a prevalent degenerative joint disease. This study combines bioinformatics analysis with invivo and invitro experiments to elucidate the molecular mechanisms through which melatonin (MT) regulates mitophagy to alleviate OA. Rat and chondrocyte OA models were established via anterior cruciate ligament transection or interleukin (IL)-1β induction, followed by treatment with MT, Cyclosporine A (a mitophagy inhibitor), and 740Y-P (a phosphatidylinositol-3 kinase [PI3K] activator). Pathological changes in cartilage, histological scores, and cell apoptosis were evaluated alongside chondrocyte viability, apoptosis, mitochondrial morphology, mitochondrial membrane potential, and mitophagy using H&E and Safranin O-fast green staining, Osteoarthritis Research Society International scoring (OARSI), TUNEL staining, CCK-8, flow cytometry, transmission electron microscopy, JC-1 staining, and immunofluorescence. Levels of inflammatory factors and mitophagy-related protein levels were determined by ELISA and western blot. Bioinformatics analysis was applied to investigate the regulatory mechanisms of MT on mitophagy in OA. Invivo, MT mitigated OA by enhancing mitophagy and reducing apoptosis of cartilage cells. Invitro, MT attenuated IL-1β-induced chondrocyte apoptosis through mitophagy activation, and this effect was partially reversed by mitophagy inhibition. Mechanistically, the PI3K/protein kinase B (AKT)/forkhead box O3 (FoxO3) axis appeared to play a central role. MT suppressed PI3K/AKT signaling, thereby upregulating FoxO3 expression and promoting mitophagy, ultimately reducing chondrocyte apoptosis. Collectively, these findings suggest that MT enhances mitophagy via inhibition of the PI3K/AKT pathway, and subsequent upregulation of FoxO3, leading to reduced apoptosis of cartilage cells and attenuation of OA progression in rats.

Introduction Cryptococcus neoformans is a fungus that poses a significant threat to human health, with its polysaccharide capsule being a key virulence factor that can upregulate the expression of host gene ARG1 , encoding arginase-1, which suppresses T-cell-mediated antifungal immune responses. Nanoplastics may cause oxidative and mitochondrial stress in mammalian cells, potentially impacting fungal physiology and pathogenic mechanisms as well. Methods We utilized mouse models and fungal burden assays to investigate the effects of polystyrene nanoparticles (PS-NPs) on C. neoformans infection. Mice were subjected to oropharyngeal aspiration of 50 μl of 80 nm PS-NPs at a concentration of 5 μg/μl, administered three times a week over a specified duration. To assess the impact of PS-NPs on C. neoformans mitochondria, we measured intracellular reactive oxygen species (ROS) levels, mitochondrial superoxide, mitochondrial membrane potential, and intracellular ATP levels in whole fungal cells. Additionally, we performed RNA-Seq analysis and metabolomics studies to evaluate the effects of PS-NPs at a concentration of 0.3 μg/μL on the RNA and metabolic profiles of C. neoformans mitochondria. Results Our study demonstrated that PS-NPs significantly prolonged the survival of mice infected with C. neoformans ( P = 0.0058). PS-NPs exposure resulted in a 30% reduction in ARG1 mRNA expression and enhanced T-cell-mediated antifungal immunity. Additionally, PS-NPs inhibited fungal capsule formation by approximately 40% in infected mice and 70% in capsule induction medium. Given the close link between the mitochondria of C. neoformans and capsule formation, we further investigated the effects of PS-NPs on mitochondrial function. Exposure to PS-NPs led to mitochondrial dysfunction in C. neoformans , as evidenced by a threefold increase in ROS, a 1.7-fold increase in mitochondrial membrane potential, and disruptions in mitochondrial transcription and metabolism. Conclusion These results suggest that PS-NPs inhibit the formation of the C. neoformans capsule, potentially by inducing mitochondrial dysfunction. Furthermore, the findings highlight the broader implications of PS-NPs on fungal virulence and the dynamics of host-pathogen interactions, underscoring their significance in advancing our understanding of these complex relationships.

Mitochondrial dysfunction is a key contributor to cardiac injury and heart failure, and extracellular vesicles (EVs) have emerged as promising therapeutic agents due to their ability to deliver mitochondrial-targeted cargo. This review systematically maps the evidence on how EVs modulate mitochondrial dynamics—including fusion, fission, mitophagy, and biogenesis—in regenerative cardiology. We comprehensively searched PubMed, Scopus, and Web of Science up to September 2025 for original studies. A total of 48 studies were included, with most utilizing EVs from mesenchymal stem cells, induced pluripotent stem cells, or cardiac progenitors. The review found that EV cargo influences key pathways such as DRP1 and MFN2, restores mitochondrial membrane potential, reduces ROS accumulation, and improves cardiomyocyte survival. While engineered EVs showed enhanced specificity, a lack of standardized preparation and quantitative assessment methods remains a significant challenge. We conclude that EV-mediated mitochondrial modulation is a promising strategy for cardiac repair, but the field needs harmonized protocols, deeper mechanistic understanding, and improved translational readiness to advance beyond preclinical research. The future of this research lies in integrating systems biology and precision targeting.

It was shown that blocking of glycolysis by 2-deoxy-D-glucose (DG) inhibits LPS-induced NO production in glial cell cultures and reduces the mitochondrial membrane potential. Lactate partially prevented the decrease in the mitochondrial membrane potential of gliocytes, but did not affect the inhibitory effect of DG. Immunocytochemical typing showed the presence of a large number of astrocytes and microglia in the culture. In the control, microglial cells had a large number of processes, which is typical of nonactivated cells, whereas in LPS-treated cultures, microglia had a flattened amoeboid morphology typical of activated microglia. In cultures treated with LPS against the background of DG, both cells with processes and amoeboid cells were present. Our results indicate that inhibition of glycolysis is a strong modulating factor in inflammation.

Malaria continues to be a significant global health challenge, necessitating the development of novel antimalarial compounds. This study explores the effects of ferulenol on multiple lifecycle stages of Plasmodium falciparum. Ferulenol has been identified as a promising antimalarial candidate, demonstrating high efficacy in inhibiting asexual blood-stage parasites at low micromolar concentrations. However, its effects on other parasite stages remain unexplored, despite its mitochondrial target being critical for sexual stage development. This study aims to investigate ferulenol's potential as a dual-target antimalarial by assessing its effects on development of asexual blood-stage and transmission precursor-stage parasites. Falciparum malaria parasites were cultured in vitro and incubated with or without ferulenol. Effects of the treatment on the development of the asexual blood-stage, early-stage gametocyte, late-stage gametocyte, and gamete formation were assessed using light microscopy. The impact of ferulenol on mitochondrial membrane potential was investigated using JC-1 staining and analyzed by fluorescence microscopy. The highest dose of ferulenol inhibited asexual blood-stage proliferation by 88%, early-stage gametocyte development by 82%, and stage V gametocyte maturation at about 90%. Moreover, the effect of ferulenol was more pronounced on male gamete formation than on female gamete formation, with the development inhibited at 81% and 27%, respectively. These findings position ferulenol as a promising dual antimalarial activity on asexual blood-stage and gametocyte stages, which could lead the compound to disrupt both severity and transmission of disease.