Mitochondria-Targeted Antioxidants: A Step towards Disease Treatment

Age-related changes in mammalian hearts often result in cardiac hypertrophy and fibrosis that are preceded by inflammatory infiltration. In this paper, we show that lifelong treatment of BALB/c and C57BL/6 mice with the mitochondria-targeted antioxidant SkQ1 retards senescence-associated myocardial disease (cardiomyopathy), cardiac hypertrophy, and diffuse myocardial fibrosis. To investigate the molecular basis of the action of SkQ1, we have applied DNA microarray analysis. The global gene expression profile in heart tissues was not significantly affected by administration of SkQ1. However, we found some small but statistically significant modifications of the pathways related to cell-to-cell contact, adhesion, and leukocyte infiltration. Probably, SkQ1-induced decrease in leukocyte and mesenchymal cell adhesion and/or infiltration lead to a reduction in age-related inflammation and subsequent fibrosis. The data indicate a causative role of mitochondrial reactive oxygen species in cardiovascular aging and imply that SkQ1 has potential as a drug against age-related cardiac dysfunction.

Mursaleen L., Noble B., Chan S.H., Somavarapu S., Zariwala M.G.

Oxidative stress is a key mediator in the development and progression of Parkinson’s disease (PD). The antioxidant N-acetylcysteine (NAC) has generated interest as a disease-modifying therapy for PD but is limited due to poor bioavailability, a short half-life, and limited access to the brain. The aim of this study was to formulate and utilise mitochondria-targeted nanocarriers for delivery of NAC alone and in combination with the iron chelator deferoxamine (DFO), and assess their ability to protect against oxidative stress in a cellular rotenone PD model. Pluronic F68 (P68) and dequalinium (DQA) nanocarriers were prepared by a modified thin-film hydration method. An MTT assay assessed cell viability and iron status was measured using a ferrozine assay and ferritin immunoassay. For oxidative stress, a modified cellular antioxidant activity assay and the thiobarbituric acid-reactive substances assay and mitochondrial hydroxyl assay were utilised. Overall, this study demonstrates, for the first time, successful formulation of NAC and NAC + DFO into P68 + DQA nanocarriers for neuronal delivery. The results indicate that NAC and NAC + DFO nanocarriers have the potential characteristics to access the brain and that 1000 μM P68 + DQA NAC exhibited the strongest ability to protect against reduced cell viability (p = 0.0001), increased iron (p = 0.0033) and oxidative stress (p ≤ 0.0003). These NAC nanocarriers therefore demonstrate significant potential to be transitioned for further preclinical testing for PD.

Ho U., Luff J., James A., Lee C.S., Quek H., Lai H., Apte S., Lim Y.C., Lavin M.F., Roberts T.L.

Suppressor of morphogenesis in genitalia 1 (SMG1) and ataxia telangiectasia mutated (ATM) are members of the PI3-kinase like-kinase (PIKK) family of proteins. ATM is a well-established tumour suppressor. Loss of one or both alleles of ATM results in an increased risk of cancer development, particularly haematopoietic cancer and breast cancer in both humans and mouse models. In mice, total loss of SMG1 is embryonic lethal and loss of a single allele results in an increased rate of cancer development, particularly haematopoietic cancers and lung cancer. In this study, we generated mice deficient in Atm and lacking one allele of Smg1, Atm-/- Smg1gt/+ mice. These mice developed cancers more rapidly than either of the parental genotypes, and all cancers were haematopoietic in origin. The combined loss of Smg1 and Atm resulted in a higher level of basal DNA damage and oxidative stress in tissues than loss of either gene alone. Furthermore, Atm-/- Smg1gt/+ mice displayed increased cytokine levels in haematopoietic tissues compared with wild-type animals indicating the development of low-level inflammation and a pro-tumour microenvironment. Overall, our data demonstrated that combined loss of Atm expression and decreased Smg1 expression increases haematopoietic cancer development.

Jiang Q., Zhang H., Yang R., Hui Q., Chen Y., Mats L., Tsao R., Yang C.

Red-osier dogwood extracts (RDE) contain high levels of phenolic compounds which have been recognized as natural antioxidants. In this study, the potential of RDE to prevent cardiovascular diseases (CVDs) was evaluated using Caco-2 cells and a co-culture model of Caco-2 BBe1/EA.hy926 cells in Transwell® plates. The results showed that RDE supplementation significantly prevented interleukin-8 (IL-8) production and suppressed the gene expression of IL-8, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and cyclooxygenase 2 (COX-2) in the TNF-α inflamed Caco-2 cells. Meanwhile, the polyphenols (quercetin-3-glucoside, quercetin-glucuronide, rutin, quercetin-3-O-malonylglucoside, and kaempferol-glucoside) in the RDE were validated to be absorbed by Caco-2 BBe1 cells and transported to the basal chamber where EA.hy926 cells were located during 12 h incubation. The transported polyphenols were able to prevent IL-8 production and suppress the gene expression of proinflammatory mediators (TNF-α, ICAM-1, VCAM-1, and COX-2) in the TNF-α or oxidized low-density lipoprotein (ox-LDL) treated EA.hy926 cells. These novel findings demonstrated that phenolic compounds in RDE can be transported to the cardiovascular system by intestinal absorption and mitigate the inflammatory responses of vascular endothelial cells, indicating that RDE could be a natural resource of polyphenols to prevent inflammation cytokine or oxidized lipid-induced CVDs.

Zhan W., Liao X., Li L., Chen Z., Tian T., Yu L., Chen Z.

Trist B.G., Hare D.J., Double K.L.

Parkinson's disease prevalence is rapidly increasing in an aging global population. With this increase comes exponentially rising social and economic costs, emphasizing the immediate need for effective disease-modifying treatments. Motor dysfunction results from the loss of dopaminergic neurons in the substantia nigra pars compacta and depletion of dopamine in the nigrostriatal pathway. While a specific biochemical mechanism remains elusive, oxidative stress plays an undeniable role in a complex and progressive neurodegenerative cascade. This review will explore the molecular factors that contribute to the high steady-state of oxidative stress in the healthy substantia nigra during aging, and how this chemical environment renders neurons susceptible to oxidative damage in Parkinson's disease. Contributing factors to oxidative stress during aging and as a pathogenic mechanism for Parkinson's disease will be discussed within the context of how and why therapeutic approaches targeting cellular redox activity in this disorder have, to date, yielded little therapeutic benefit. We present a contemporary perspective on the central biochemical contribution of redox imbalance to Parkinson's disease etiology and argue that improving our ability to accurately measure oxidative stress, dopaminergic neurotransmission and cell death pathways in vivo is crucial for both the development of new therapies and the identification of novel disease biomarkers.

Liu D., Jin F., Shu G., Xu X., Qi J., Kang X., Yu H., Lu K., Jiang S., Han F., You J., Du Y., Ji J.

Oxidative stress is an important pathological mechanism for acute kidney injury (AKI). SS-31, as a mitochondria-targeted peptide with strong antioxidant activity, is a good candidate for the treatment of AKI. However, an efficient treatment of AKI requires frequent administration of SS-31, which is due to its poor specific biodistribution and low delivery efficiency. To overcome these deficiencies, we designed pH-responsive and AKI-kidney targeted nanopolyplexes (NPs) for effectively delivering SS-31, which is new frontier for formulation of HA and CS. NPs are electrostatically complexed using anionic hyaluronic acid and cationic chitosan as materials, which could increase the accumulation in injured areas and uptake into CD44-overexpressed cells. Electrostatic balance of NPs is broken in low pH environment of lysosomes to allow SS-31 releasing and subsequently targeting to mitochondria to represent therapeutic effect. In vitro studies indicate that NPs exhibited higher antioxidative and antiapoptotic effects as compared with free SS-31. AKI mouse model suggests that NPs have significantly higher therapeutic efficiency than bare SS-31. It was found that NPs had excellent ability to decrease oxidative stress, protect mitochondrial structure, reduce inflammatory response, reduce apoptosis and necrosis of tubular cells after intravenious administration. Overall, the results suggest that the NPs have significant potential to enhance the specific biodistribution and delivery of SS-31, therefore have good effects on reducing oxidative stress and inflammation, preventing tubular apoptosis and necrosis. We believe NPs are effective delivery system for AKI treatment in clinical application.

Czigler A., Toth L., Szarka N., Berta G., Amrein K., Czeiter E., Lendvai-Emmert D., Bodo K., Tarantini S., Koller A., Ungvari Z., Buki A., Toth P.

Traumatic brain injury (TBI) induces cerebrovascular oxidative stress, which is associated with neurovascular uncoupling, autoregulatory dysfunction, and persisting cognitive decline in both pre-clinical models and patients. However, single mild TBI (mTBI), the most frequent form of brain trauma, increases cerebral generation of reactive oxygen species (ROS) only transiently. We hypothesized that comorbid conditions might exacerbate long-term ROS generation in cerebral arteries after mTBI. Because hypertension is the most important cerebrovascular risk factor in populations prone to mild brain trauma, we induced mTBI in normotensive and spontaneously hypertensive rats (SHR) and assessed changes in cytoplasmic and mitochondrial superoxide (O2-) production by confocal microscopy in isolated middle cerebral arteries (MCA) 2 weeks after mTBI using dihydroethidine (DHE) and the mitochondria-targeted redox-sensitive fluorescent indicator dye MitoSox. We found that mTBI induced a significant increase in long-term cytoplasmic and mitochondrial O2- production in MCAs of SHRs and increased expression of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit Nox4, which were reversed to the normal level by treating the animals with the cell-permeable, mitochondria-targeted antioxidant peptide SS-31 (5.7 mg kg-1 day-1, i.p.). Persistent mTBI-induced oxidative stress in MCAs of SHRs was significantly decreased by inhibiting vascular NADPH oxidase (apocyinin). We propose that hypertension- and mTBI-induced cerebrovascular oxidative stress likely lead to persistent dysregulation of cerebral blood flow (CBF) and cognitive dysfunction, which might be reversed by SS-31 treatment.

Fetisova E.K., Muntyan M.S., Lyamzaev K.G., Chernyak B.V.

Multiple sclerosis (MS) is a heterogeneous autoimmune disease of unknown etiology characterized by inflammation, demyelination, and axonal degeneration that affects both the white and gray matter of CNS. Recent large-scale epidemiological and genomic studies identified several genetic and environmental risk factors for the disease. Among them are environmental factors of infectious origin, possibly causing MS, which include Epstein-Barr virus infection, reactivation of some endogenous retrovirus groups, and infection by pathogenic bacteria (mycobacteria, Chlamydia pneumoniae, and Helicobacter pylori). However, the nature of the events leading to the activation of immune cells in MS is mostly unknown and there is no effective therapy against the disease. Amazingly, whatever the cause of the disease, signs of damage to the nerve tissue with MS lesions were the same as with infectious leprosy, while in the latter case nitrozooxidative stress was suggested as the main cause of the nerve damage. With this in mind and following the hypothesis that excessive production of mitochondrial reactive oxygen species critically contributes to MS pathogenesis, we studied the effect of mitochondria-targeted antioxidant SkQ1 in an in vitro MS model of the primary oligodendrocyte culture of the cerebellum, challenged with lipopolysaccharide (LPS). SkQ1 was found to accumulate in the mitochondria of oligodendrocytes and microglial cells, and it was also found to prevent LPS-induced inhibition of myelin production in oligodendrocytes. The results implicate that mitochondria-targeted antioxidants could be promising candidates as components of a combined therapy for MS and related neurological disorders.

Yamada Y., Daikuhara S., Tamura A., Nishida K., Yui N., Harashima H.

Failure of autophagy induction results in the accumulation of abnormal mitochondria to cause neurodegenerative diseases.

Shetty S., Kumar R., Bharati S.

Oxidative stress and mitochondrial dysfunction play a significant role in hepatocarcinogenesis. Mitochondria are source organelle as well as target for free radicals. The oxidative damage to mitochondria can be prevented by mitochondria-targeted antioxidant, mito-TEMPO. However, its efficacy in prevention of hepatocellular carcinoma has not been investigated so far.Murine model of hepatocarcinogenesis was developed by intraperitoneal administration of N-nitrosodiethylamine to male BALB/c mice. Mito-TEMPO was administered intraperitoneally at weekly intervals, till the completion of the study. The tumours were histopathologically analysed and anti-cancer efficacy of mito-TEMPO was evaluated in terms of survival index, tumour incidence, tumour multiplicity and tumour dielectric parameters. The antioxidant defence status and molecular composition of tumours were assessed. Gap junctions and gap-junctional intercellular communication (GJIC) were studied using ELISA, IHC and Lucifer yellow assay.Mito-TEMPO treatment increased survival of animals by 30%, decreased tumour incidence (25%) and tumour multiplicity (39%). The dielectric parameters of tumours in Mito-TEMPO group were indicative of retarded carcinogenesis. Mito-TEMPO administration normalized mean saturation levels in phospholipids and improved glycogen content of the hepatic tissue. Gap junctions and GJIC which were severely impaired in hepatocarcinogenesis, improved after mito-TEMPO treatment.Mito-TEMPO was effective in combating hepatocarcinogenesis.

Genrikhs E.E., Stelmashook E.V., Alexandrova O.P., Novikova S.V., Voronkov D.N., Glibka Y.A., Skulachev V.P., Isaev N.K.

The protective effect of SkQR1, a mitochondria-targeted antioxidant, was investigated on the model of focal one-sided traumatic brain injury (TBI) of the sensorimotor cortex region from 1 to 7 days after the injury. TBI caused a reliable disruption of the functions of the limbs contralateral to injury focus. The intravenous single injection of SkQR1 (250 nmol/kg) but not C12R1 (a SkQR1 homologue devoid of the antioxidant group) 30 min after TBI reduced the impairment of the motor functions of the limbs. A statistically significant improvement in limb function in animals was shown using 3 different tests: limb-placing test, beam-walking test and grip strength test. A pronounced therapeutic effect appeared on the 1th day and lasted until the end of the experiment - the 7th day after TBI. Histopathological examination showed that in the group of animals that did not receive SkQR1 in the marginal layer of the lesion there was a marked increase in astroglial expression, infiltration with segmented neutrophils, and poor survivability of neurons compared with animals treated with SkQR1. The obtained results demonstrate that the single use of plastoquinone-containing mitochondria-targeted antioxidant SkQR1 at the early stages of development of traumatic brain damage can reduce TBI-related disruptions of limb functions, and that mechanisms of the brain damage after trauma are dependent on the production of mitochondrial reactive oxygen species.

Chatfield K.C., Sparagna G.C., Chau S., Phillips E.K., Ambardekar A.V., Aftab M., Mitchell M.B., Sucharov C.C., Miyamoto S.D., Stauffer B.L.

Negative alterations of mitochondria are known to occur in heart failure (HF). This study investigated the novel mitochondrial-targeted therapeutic agent elamipretide on mitochondrial and supercomplex function in failing human hearts ex vivo. Freshly explanted failing and nonfailing ventricular tissue from children and adults was treated with elamipretide. Mitochondrial oxygen flux, complex (C) I and CIV activities, and in-gel activity of supercomplex assembly were measured. Mitochondrial function was impaired in the failing human heart, and mitochondrial oxygen flux, CI and CIV activities, and supercomplex-associated CIV activity significantly improved in response to elamipretide treatment. Elamipretide significantly improved failing human mitochondrial function.

Singh A., Kukreti R., Saso L., Kukreti S.

Oxidative stress is proposed as a regulatory element in ageing and various neurological disorders. The excess of oxidants causes a reduction of antioxidants, which in turn produce an oxidation–reduction imbalance in organisms. Paucity of the antioxidant system generates oxidative-stress, characterized by elevated levels of reactive species (oxygen, hydroxyl free radical, and so on). Mitochondria play a key role in ATP supply to cells via oxidative phosphorylation, as well as synthesis of essential biological molecules. Various redox reactions catalyzed by enzymes take place in the oxidative phosphorylation process. An inefficient oxidative phosphorylation may generate reactive oxygen species (ROS), leading to mitochondrial dysfunction. Mitochondrial redox metabolism, phospholipid metabolism, and proteolytic pathways are found to be the major and potential source of free radicals. A lower concentration of ROS is essential for normal cellular signaling, whereas the higher concentration and long-time exposure of ROS cause damage to cellular macromolecules such as DNA, lipids and proteins, ultimately resulting in necrosis and apoptotic cell death. Normal and proper functioning of the central nervous system (CNS) is entirely dependent on the chemical integrity of brain. It is well established that the brain consumes a large amount of oxygen and is highly rich in lipid content, becoming prone to oxidative stress. A high consumption of oxygen leads to excessive production of ROS. Apart from this, the neuronal membranes are found to be rich in polyunsaturated fatty acids, which are highly susceptible to ROS. Various neurodegenerative diseases such as Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), among others, can be the result of biochemical alteration (due to oxidative stress) in bimolecular components. There is a need to understand the processes and role of oxidative stress in neurodegenerative diseases. This review is an effort towards improving our understanding of the pivotal role played by OS in neurodegenerative disorders.

Zhang W., Hu X., Shen Q., Xing D.

Cancer cells exhibit slightly elevated levels of reactive oxygen species (ROS) compared with normal cells, and approximately 90% of intracellular ROS is produced in mitochondria. In situ mitochondrial ROS amplification is a promising strategy to enhance cancer therapy. Here we report cancer cell and mitochondria dual-targeting polyprodrug nanoreactors (DT-PNs) covalently tethered with a high content of repeating camptothecin (CPT) units, which release initial free CPT in the presence of endogenous mitochondrial ROS (mtROS). The in situ released CPT acts as a cellular respiration inhibitor, inducing mtROS upregulation, thus achieving subsequent self-circulation of CPT release and mtROS burst. This mtROS amplification endows long-term high oxidative stress to induce cancer cell apoptosis. This current strategy of endogenously activated mtROS amplification for enhanced chemodynamic therapy overcomes the short lifespan and action range of ROS, avoids the penetration limitation of exogenous light in photodynamic therapy, and is promising for theranostics. Mitochondria are a source of reactive oxygen species, which can be exploited to induce the death of cancer cells. Here, the authors use nanoparticles that release camptothecin in a reactive oxygen species dependent manner, leading to cancer cell death.

Pradeepkiran J.A., Islam M.A., Sehar U., Reddy A.P., Vijayan M., Reddy P.H.

Zhao X., Wu G., Tao X., Dong D., Liu J.

Buck A.C., Maarman G.J., Dube A., Bardien S.

Mitochondria play a significant role in several cellular activities and their function in health and disease has become an important area of research. Since the brain is a high-energy-demanding organ, it is particularly vulnerable to mitochondrial dysfunction. This has been implicated in several brain disorders including neurodegenerative, psychiatric and neurological disorders, e.g., Parkinson’s disease and schizophrenia. Significant efforts are underway to develop mitochondria-targeting pharmaceutical interventions. However, the complex mitochondrial membrane network restricts the entry of therapeutic compounds into the mitochondrial matrix. Nanoparticles (NPs) present a novel solution to this limitation, while also increasing the stability of the therapeutic moieties and improving their bioavailability. This article provides a detailed overview of studies that have investigated the treatment of mitochondrial dysfunction in brain disorders using either targeted or non-targeted NPs as drug delivery systems. All the NPs showed improved mitochondrial functioning including a reduction in reactive oxygen species (ROS) production, an improvement in overall mitochondrial respiration and a reversal of toxin-induced mitochondrial damage. However, the mitochondrial-targeted NPs showed an advantage over the non-targeted NPs as they were able to improve or rescue mitochondrial dynamics and biogenesis, and they required a lower concentration of the in vivo therapeutic dosage of the drug load to show an effect. Consequently, mitochondria-targeted NPs are a promising therapeutic approach. Future studies should exploit advances in nanotechnology, neuroscience and chemistry to design NPs that can cross the blood-brain barrier and selectively target dysfunctional mitochondria, to improve treatment outcomes.

Liu C., Wang L., Tsai F.

Chemotherapeutic agents play a crucial role in cancer treatment. However, their use is often associated with significant adverse effects, particularly cardiotoxicity. Drugs such as anthracyclines (e.g., doxorubicin) and platinum-based agents (e.g., cisplatin) cause mitochondrial damage, which is one of the main mechanisms underlying cardiotoxicity. These drugs induce oxidative stress, leading to an increase in reactive oxygen species (ROS), which in turn damage the mitochondria in cardiomyocytes, resulting in impaired cardiac function and heart failure. Mitochondria-targeted antioxidants (MTAs) have emerged as a promising cardioprotective strategy, offering a potential solution. These agents efficiently scavenge ROS within the mitochondria, protecting cardiomyocytes from oxidative damage. Recent studies have shown that MTAs, such as elamipretide, SkQ1, CoQ10, and melatonin, significantly mitigate chemotherapy-induced cardiotoxicity. These antioxidants not only reduce oxidative damage but also help maintain mitochondrial structure and function, stabilize mitochondrial membrane potential, and prevent excessive opening of the mitochondrial permeability transition pore, thus preventing apoptosis and cardiac dysfunction. In this review, we integrate recent findings to elucidate the mechanisms of chemotherapy-induced cardiotoxicity and highlight the substantial therapeutic potential of MTAs in reducing chemotherapy-induced heart damage. These agents are expected to offer safer and more effective treatment options for cancer patients in clinical practice.

Chen J., Du C., Tang B., Liu J., Xiao P., Wang X., Li Z.A., Huang W., Lei Y.

Munteanu C., Galaction A.I., Onose G., Turnea M., Rotariu M.

Age-related oxidative stress is a critical factor in vascular dysfunction, contributing to hypertension and atherosclerosis. Smooth muscle cells and endothelial cells are particularly susceptible to oxidative damage, which exacerbates vascular aging through cellular senescence, chronic inflammation, and arterial stiffness. Gasotransmitters—hydrogen sulfide (H2S), nitric oxide (NO), and carbon monoxide (CO)—are emerging as promising therapeutic agents for counteracting these processes. This review synthesizes findings from recent studies focusing on the mechanisms by which H2S, NO, and CO influence vascular smooth muscle and endothelial cell function. Therapeutic strategies involving exogenous gasotransmitter delivery systems and combination therapies were analyzed. H2S enhances mitochondrial bioenergetics, scavenges ROS, and activates antioxidant pathways. NO improves endothelial function, promotes vasodilation, and inhibits platelet aggregation. CO exhibits cytoprotective and anti-inflammatory effects by modulating heme oxygenase activity and ROS production. In preclinical studies, gasotransmitter-releasing molecules (e.g., NaHS, SNAP, CORMs) and targeted delivery systems show significant promise. Synergistic effects with lifestyle modifications and antioxidant therapies further enhance their therapeutic potential. In conclusion, gasotransmitters hold significant promise as therapeutic agents to combat age-related oxidative stress in vascular cells. Their multifaceted mechanisms and innovative delivery approaches make them potential candidates for treating vascular dysfunction and promoting healthy vascular aging. Further research is needed to translate these findings into clinical applications.

Fonseka O., Gare S.R., Chen X., Zhang J., Alatawi N.H., Ross C., Liu W.

Heart failure (HF) is a prominent fatal cardiovascular disorder afflicting 3.4% of the adult population despite the advancement of treatment options. Therefore, a better understanding of the pathogenesis of HF is essential for exploring novel therapeutic strategies. Hypertrophy and fibrosis are significant characteristics of pathological cardiac remodeling, contributing to HF. The mechanisms involved in the development of cardiac remodeling and consequent HF are multifactorial, and in this review, the key underlying mechanisms are discussed. These have been divided into the following categories thusly: (i) mitochondrial dysfunction, including defective dynamics, energy production, and oxidative stress; (ii) cardiac lipotoxicity; (iii) maladaptive endoplasmic reticulum (ER) stress; (iv) impaired autophagy; (v) cardiac inflammatory responses; (vi) programmed cell death, including apoptosis, pyroptosis, and ferroptosis; (vii) endothelial dysfunction; and (viii) defective cardiac contractility. Preclinical data suggest that there is merit in targeting the identified pathways; however, their clinical implications and outcomes regarding treating HF need further investigation in the future. Herein, we introduce the molecular mechanisms pivotal in the onset and progression of HF, as well as compounds targeting the related mechanisms and their therapeutic potential in preventing or rescuing HF. This, therefore, offers an avenue for the design and discovery of novel therapies for the treatment of HF.

Shirvani P., Shirvani A., Holick M.F.

Hypermobile Ehlers–Danlos Syndrome (hEDS) is a hereditary connective tissue disorder characterized by joint hypermobility, skin hyperextensibility, and systemic manifestations such as chronic fatigue, gastrointestinal dysfunction, and neurological symptoms. Unlike other EDS subtypes with known genetic mutations, hEDS lacks definitive markers, suggesting a multifactorial etiology involving both mitochondrial dysfunction and non-mitochondrial pathways. This scoping review, conducted in accordance with the PRISMA-ScR guidelines, highlights mitochondrial dysfunction as a potential unifying mechanism in hEDS pathophysiology. Impaired oxidative phosphorylation (OXPHOS), elevated reactive oxygen species (ROS) levels, and calcium dysregulation disrupt cellular energetics and extracellular matrix (ECM) homeostasis, contributing to the hallmark features of hEDS. We reviewed candidate genes associated with ECM remodeling, signaling pathways, and immune regulation. Protein–protein interaction (PPI) network analyses revealed interconnected pathways linking mitochondrial dysfunction with these candidate genes. Comparative insights from Fabry disease and fragile X premutation carriers underscore shared mechanisms such as RNA toxicity, matrix metalloproteinases (MMP) activation, and ECM degradation. These findings may suggest that mitochondrial dysfunction amplifies systemic manifestations through its interplay with non-mitochondrial molecular pathways. By integrating these perspectives, this review provides a potential framework for understanding hEDS pathogenesis while highlighting latent avenues for future research into its molecular basis. Understanding the potential role of mitochondrial dysfunction in hEDS not only sheds light on its complex molecular etiology but also opens new paths for targeted interventions.

Iheagwam F.N., Joseph A.J., Adedoyin E.D., Iheagwam O.T., Ejoh S.A.

Diabetes mellitus represents a complicated metabolic condition marked by ongoing hyperglycemia arising from impaired insulin secretion, inadequate insulin action, or a combination of both. Mitochondrial dysfunction has emerged as a significant contributor to the aetiology of diabetes, affecting various metabolic processes critical for glucose homeostasis. This review aims to elucidate the complex link between mitochondrial dysfunction and diabetes, covering the spectrum of diabetes types, the role of mitochondria in insulin resistance, highlighting pathophysiological mechanisms, mitochondrial DNA damage, and altered mitochondrial biogenesis and dynamics. Additionally, it discusses the clinical implications and complications of mitochondrial dysfunction in diabetes and its complications, diagnostic approaches for assessing mitochondrial function in diabetics, therapeutic strategies, future directions, and research opportunities.

Romero A.H., Delgado F.

Leishmaniasis is one of the most important neglected tropical diseases, with more than two million new cases annually. It is endemic in several regions worldwide, representing a public health problem for more than 88 countries, in particular in the tropical and subtropical regions of developing countries. At the moment, there are neither approved vaccines nor effective drugs for the treatment of human leishmaniasis for any of its three typical clinical manifestations, and, importantly, the drugs of clinical use have several side effects, require complex administration regimens, present high cost, and are ineffective in many populations due to pathogen resistance. Moreover, beyond the pharmacological exigencies, there are other challenges concerning its parasitic nature, such as its great genetic plasticity and adaptability, enabling it to activate a battery of genes to develop resistance quickly. All these aspects demand the identification and development of new, safe, and effective chemical systems, which must not only be focused on medicinal chemistry and pharmacological aspects but also consider key aspects relative to parasite survival.In this sense, the quinolines and, in particular, 4-aminoquinoline, represent a privileged scaffold for the design of potential leishmanicidal candidates due not only to their versatility to generate highly active and selective compounds but also to their correlation with well-defined biological targets. These facts make it possible to generate safe leishmanicidal agents targeted at key aspects of parasite survival.The current review summarizes the most current examples of leishmanicidal agents based on 4-aminoquinolines focusing the analysis on two essential aspects: (i) structure–property relationship to identify the key pharmacophores and (ii) mode of action focused on key targets in parasite survival (e.g., depolarization of potential mitochondrial, accumulation into macrophage lysosome, and immunostimulation of host cells). With that information, we seek to give useful guidelines for interested researchers to face the drug discovery and development process for selective and potent leishmanicidal agents based on 4-aminoquinolines.

Ali I., Adil M., Imran M., Qureshi S.A., Qureshi S., Hasan N., Ahmad F.J.

The global prevalence of Parkinson’s Disease (PD) is on the rise, driven by an ageing population and ongoing environmental conditions. To gain a better understanding of PD pathogenesis, it is essential to consider its relationship with the ageing process, as ageing stands out as the most significant risk factor for this neurodegenerative condition. PD risk factors encompass genetic predisposition, exposure to environmental toxins, and lifestyle influences, collectively increasing the chance of PD development. Moreover, early and precise PD diagnosis remains elusive, relying on clinical assessments, neuroimaging techniques, and emerging biomarkers. Conventional management of PD involves dopaminergic medications and surgical interventions, but these treatments often become less effective over time and do not address disease treatment. Challenges persist due to the blood–brain barrier's (BBB) impermeability, hindering drug delivery. Recent advancements in nanotechnology offer promising novel approaches for PD management. Various drug delivery systems (DDS), including nanosized polymers, lipid-based carriers, and nanoparticles (such as metal/metal oxide, protein, and carbonaceous particles), aim to enhance drug and gene delivery. These modifications seek to improve BBB permeability, ultimately benefiting PD patients. This review underscores the critical role of ageing in PD development and explores how age-related neuronal decline contributes to substantia nigra loss and PD manifestation in susceptible individuals. The review also highlights the advancements and ongoing challenges in nanotechnology-based therapies for PD.

Fetisova E.K., Vorobjeva N.V., Muntyan M.S.

Multiple sclerosis (MS) is among the most common neurological diseases. The number of MS affected people is constantly growing worldwide. Untreated MS leads to disability of the most capable part of the population of young age, and in recent years it has been diagnosed more often in elderly patients. The second part of our review is focused on the prospects of MS therapies under development. Mitochondria and the use of mitochodria-targeted antioxidants, neutrophils, as well as immune cells affected by pathology and other specialized cells, which can be reprogrammed and replaced by healthy cells using stem cells, pre-oligodendrocytes able to accelerate maturation and remyelinating ability on the antihistamine action, are considered as targets in MS treatment. Helminth therapy, accompanied by a shift in the composition of the microbiota of MS patients and the release of antioxidants in the tissues of humans and model animals, may lead to immunomodulation and reduction of oxidative stress, providing significant mitigation of the disease. Approaches to the treatment of elderly MS patients are discussed.

Praveen I.M., Calivarathan L.

AbstractParkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta, leading to hallmark motor symptoms such as bradykinesia, tremors, and rigidity. Emerging evidence suggests that the dysregulation or aberrant expression of long noncoding RNAs (lncRNAs) plays a critical role in the pathogenesis of PD by activating the inflammasome, either directly or via oxidative stress. Aberrant lncRNA expression has been linked to alterations in genes related to oxidative stress, causing an imbalance between reactive oxygen species (ROS) and antioxidant defenses. This imbalance contributes to mitochondrial dysfunction and neuronal damage. The NLRP3 inflammasome is a multiprotein complex comprising a sensor protein (eg, NLRP3), an adaptor protein (ASC), and an effector protein (caspase‐1). Its activation involves priming via NF‐κB signaling and is triggered by ROS, mitochondrial dysfunction, death‐associated molecular patterns, or extracellular ATP. Once activated, the inflammasome promotes the cleavage and maturation of the proinflammatory cytokines IL‐1β and IL‐18, amplifying neuroinflammation and leading to neurodegeneration in PD. Crosstalk between dysregulated lncRNAs, ROS production, and inflammasome activation creates a vicious cycle of neuroinflammation and neurodegeneration, exacerbating PD progression. This review explores the molecular mechanisms linking lncRNA dysregulation to inflammasome activation in PD, either directly or through oxidative stress. It also highlights key lncRNAs involved in these processes. Furthermore, potential therapeutic strategies targeting these pathways, such as antioxidants, lncRNA modulators, and inflammasome inhibitors, offer promising avenues to mitigate neuroinflammation and slow neurodegeneration in PD.

Nithyalakshmi M., Siddharthan N., Lokesh E., Wadaan M.A., Dixit S., Balagurunathan R.

Exploring efficient sustainable approaches for the noble metal nanoparticles (NPs) synthesis has become a recent research attention. Bioreduction with actinobacteria provides a sustainable route for metal NPs synthesis, especially for noble metals. In this study, Palladium nanoparticles (Pd NPs) and a Palladium-reduced graphene oxide nanocomposite (rGO-Pd) were synthesized using Streptomyces maritimus, which acted as a reducing, capping, and stabilizing agent. The nanocomposite was evaluated for antimicrobial, antioxidant, and anticancer properties against MCF-7 human breast cancer cells. The synthesised Pd NPs and rGO-Pd nanocomposite were characterized through Fourier-transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), Dynamic light scattering (DLS), Atomic force microscopy (AFM), Scanning electron microscopy (SEM) and High-resolution Transmission electron microscopy (HR-TEM) analyses. FT-IR analysis revealed the role of various functional groups present in actinobacterial metabolites in formation of Pd NPs and rGO-Pd nanocomposite. The XRD analysis confirmed the Pd NPs and rGO-Pd nanocomposite are crystalline in nature with average crystalline size of 2.48 nm and 11.37 nm, respectively. However, SEM-EDX, AFM and HR-TEM analysis reveals the uniform morphology of nanocomposites with the average particle size of 12 nm. The antibacterial efficacy of Pd NPs and rGO-Pd nanocomposite against Enterococcus sp, Staphylococcus aures, Klebsiella pneumoniae and Escherichia coli exhibited inhibition at 50 µg/mL. In addition, rGO-Pd nanocomposite exhibited the inhibition on DPPH radicals with 80% scavenging activity, and rGO-Pd demonstrated anticancer activity with an IC50 of 58.45 µg/mL, respectively. This study suggests that Streptomyces maritimus mediated Pd NPs can effectively used as a potential therapeutic agent.

Garg S., Jana A., Gupta S., Arshi M.U., Gharai P.K., Khan J., Roy R., Ghosh S.