bims-drumid 2024-11-03 papers

bims-drumid

Biomed News

on Drugs for mitochondrial diseases

Issue of 2024–11–03
nine papers selected by
Volkmar Weissig, Midwestern University

Advancements in mitochondrial-targeted nanotherapeutics: overcoming biological obstacles and optimizing drug delivery.
Targeting mitochondria: a novel approach for treating platinum-resistant ovarian cancer.
Unraveling Mitochondrial Reactive Oxygen Species Involvement in Psoriasis: The Promise of Antioxidant Therapies.
Mitochondrial Dysfunction as a Potential Mechanism Mediating Cardiac Comorbidities in Parkinson's Disease.
Demystifying the management of cancer through smart nano-biomedicine via regulation of reactive oxygen species.
Signaling Pathways Concerning Mitochondrial Dysfunction: Implications in Neurodegeneration and Possible Molecular Targets.
Unraveling the redox code to improve physiological research in human health and disease.
A reactive oxygen species-triggerable theranostic prodrug system.
Molybdenum nanodots act as antioxidants for photothermal therapy osteoarthritis.

Front Immunol. 2024 ;15 1451989

Advancements in mitochondrial-targeted nanotherapeutics: overcoming biological obstacles and optimizing drug delivery.

Yang Li, Xiao-Meng Li, Li-Si Wei, Jun-Feng Ye.

  In recent decades, nanotechnology has significantly advanced drug delivery systems, particularly in targeting subcellular organelles, thus opening new avenues for disease treatment. Mitochondria, critical for cellular energy and health, when dysfunctional, contribute to cancer, neurodegenerative diseases, and metabolic disorders. This has propelled the development of nanomedicines aimed at precise mitochondrial targeting to modulate their function, marking a research hotspot. This review delves into the recent advancements in mitochondrial-targeted nanotherapeutics, with a comprehensive focus on targeting strategies, nanocarrier designs, and their therapeutic applications. It emphasizes nanotechnology's role in enhancing drug delivery by overcoming biological barriers and optimizing drug design for specific mitochondrial targeting. Strategies exploiting mitochondrial membrane potential differences and specific targeting ligands improve the delivery and mitochondrial accumulation of nanomedicines. The use of diverse nanocarriers, including liposomes, polymer nanoparticles, and inorganic nanoparticles, tailored for effective mitochondrial targeting, shows promise in anti-tumor and neurodegenerative treatments. The review addresses the challenges and future directions in mitochondrial targeting nanotherapy, highlighting the need for precision, reduced toxicity, and clinical validation. Mitochondrial targeting nanotherapy stands at the forefront of therapeutic strategies, offering innovative treatment perspectives. Ongoing innovation and research are crucial for developing more precise and effective treatment modalities.

Keywords:  biocompatibility; drug delivery systems; mitochondrial targeting; nanotechnology; subcellular organelles; therapeutic nanocarriers

DOI:  https://doi.org/10.3389/fimmu.2024.1451989
J Transl Med. 2024 Oct 25. 22(1): 968

Targeting mitochondria: a novel approach for treating platinum-resistant ovarian cancer.

Xin Cui, Juan Xu, Xuemei Jia.

  Ovarian cancer is a prevalent gynecologic malignancy with the second-highest mortality rate among gynecologic malignancies. Platinum-based chemotherapy is the first-line treatment for ovarian cancer; however, a majority of patients with ovarian cancer experience relapse and develop platinum resistance following initial treatment. Despite extensive research on the mechanisms of platinum resistance at the nuclear level, the issue of platinum resistance in ovarian cancer remains largely unresolved. It is noteworthy that mitochondrial DNA (mtDNA) exhibits higher affinity for platinum compared to nuclear DNA (nDNA). Mutations in mtDNA can modulate tumor chemosensitivity through various mechanisms, including DNA damage responses, shifts in energy metabolism, maintenance of Reactive Oxygen Species (ROS) homeostasis, and alterations in mitochondrial dynamics. Concurrently, retrograde signals produced by mtDNA mutations and their subsequent cascades establish communication with the nucleus, leading to the reorganization of the nuclear transcriptome and governing the transcription of genes and signaling pathways associated with chemoresistance. Furthermore, mitochondrial translocation among cells emerges as a crucial factor influencing the effectiveness of chemotherapy in ovarian cancer. This review aims to explore the role and mechanism of mitochondria in platinum resistance, with a specific focus on mtDNA mutations and the resulting metabolic reprogramming, ROS regulation, changes in mitochondrial dynamics, mitochondria-nucleus communication, and mitochondrial transfer.

Keywords:  Metabolic reprogramming; Mitochondria; Mitochondria DNA (mtDNA); Mitochondria transfer; Mitochondria-nucleus communication; Mitochondrial dynamics; Platinum resistance

DOI:  https://doi.org/10.1186/s12967-024-05770-y
Antioxidants (Basel). 2024 Oct 11. pii: 1222. [Epub ahead of print]13(10):

Unraveling Mitochondrial Reactive Oxygen Species Involvement in Psoriasis: The Promise of Antioxidant Therapies.

Hajar Ahmad Jamil, Norwahidah Abdul Karim.

  Psoriasis is a chronic inflammatory skin disorder characterized by immune dysregulation and aberrant keratinocyte proliferation. Despite tremendous advances in understanding its etiology, effective therapies that target its fundamental mechanisms remain necessary. Recent research highlights the role of reactive oxygen species dysregulation and mitochondrial dysfunction in psoriasis pathogenesis. Mitochondrial reactive oxygen species mediate cellular signaling pathways involved in psoriasis, such as proliferation, apoptosis, and inflammation, leading to oxidative stress, exacerbating inflammation and tissue damage if dysregulated. This review explores oxidative stress biomarkers and parameters in psoriasis, including myeloperoxidase, paraoxonase, sirtuins, superoxide dismutase, catalase, malondialdehyde, oxidative stress index, total oxidant status, and total antioxidant status. These markers provide insights into disease mechanisms and potential diagnostic and therapeutic targets. Modulating mitochondrial reactive oxygen species levels and enhancing antioxidant defenses can alleviate inflammation and oxidative damage, improving patient outcomes. Natural antioxidants like quercetin, curcumin, gingerol, resveratrol, and other antioxidants show promise as complementary treatments targeting oxidative stress and mitochondrial dysfunction. This review aims to guide the development of personalized therapeutic methods and diagnostic techniques, emphasizing the importance of comprehensive clinical studies to validate the efficacy and safety of these interventions, paving the way for more effective and holistic psoriasis care.

Keywords:  antioxidant; mitochondrial dysfunction; mitochondrial reactive oxygen species; natural products; oxidative stress; psoriasis

DOI:  https://doi.org/10.3390/antiox13101222
Int J Mol Sci. 2024 Oct 12. pii: 10973. [Epub ahead of print]25(20):

Mitochondrial Dysfunction as a Potential Mechanism Mediating Cardiac Comorbidities in Parkinson's Disease.

Agustina Salis Torres, Ji-Eun Lee, Andrea Caporali, Robert K Semple, Mathew H Horrocks, Vicky E MacRae.

  Individuals diagnosed with Parkinson's disease (PD) often exhibit heightened susceptibility to cardiac dysfunction, reflecting a complex interaction between these conditions. The involvement of mitochondrial dysfunction in the development and progression of cardiac dysfunction and PD suggests a plausible commonality in some aspects of their molecular pathogenesis, potentially contributing to the prevalence of cardiac issues in PD. Mitochondria, crucial organelles responsible for energy production and cellular regulation, play important roles in tissues with high energetic demands, such as neurons and cardiac cells. Mitochondrial dysfunction can occur in different and non-mutually exclusive ways; however, some mechanisms include alterations in mitochondrial dynamics, compromised bioenergetics, biogenesis deficits, oxidative stress, impaired mitophagy, and disrupted calcium balance. It is plausible that these factors contribute to the increased prevalence of cardiac dysfunction in PD, suggesting mitochondrial health as a potential target for therapeutic intervention. This review provides an overview of the physiological mechanisms underlying mitochondrial quality control systems. It summarises the diverse roles of mitochondria in brain and heart function, highlighting shared pathways potentially exhibiting dysfunction and driving cardiac comorbidities in PD. By highlighting strategies to mitigate dysfunction associated with mitochondrial impairment in cardiac and neural tissues, our review aims to provide new perspectives on therapeutic approaches.

Keywords:  Parkinson’s disease (PD); cardiac dysfunction; mitochondria; mitochondrial dysfunction

DOI:  https://doi.org/10.3390/ijms252010973
Naunyn Schmiedebergs Arch Pharmacol. 2024 Oct 31.

Demystifying the management of cancer through smart nano-biomedicine via regulation of reactive oxygen species.

Abhay Prakash Mishra, Rajesh Kumar, Seetha Harilal, Manisha Nigam, Deepanjan Datta, Sudarshan Singh, Neti Waranuch, Chuda Chittasupho.

  Advancements in therapeutic strategies and combinatorial approaches for cancer management have led to the majority of cancers in the initial stages to be regarded as treatable and curable. However, certain high-grade cancers in the initial stages are still regarded as chronic and difficult to manage, requiring novel therapeutic strategies. In this era of targeted and precision therapy, novel strategies for targeted delivery of drug and synergistic therapies, integrating nanotherapeutics, polymeric materials, and modulation of the tumor microenvironment are being developed. One such strategy is the study and utilization of smart-nano biomedicine, which refers to stimuli-responsive polymeric materials integrated with the anti-cancer drug that can modulate the reactive oxygen species (ROS) in the tumor microenvironment or can be ROS responsive for the mitigation as well as management of various cancers. The article explores in detail the ROS, its types, and sources; the antioxidant system, including scavengers and their role in cancer; the ROS-responsive targeted polymeric materials, including synergistic therapies for the treatment of cancer via modulating the ROS in the tumor microenvironment, involving therapeutic strategies promoting cancer cell death; and the current landscape and future prospects.

Keywords:  Cancer; Cancer theranostics; Free radicals; Metallic nanomaterials; Nano-biomedicine; Reactive oxygen species

DOI:  https://doi.org/10.1007/s00210-024-03469-x
J Mol Neurosci. 2024 Oct 28. 74(4): 101

Signaling Pathways Concerning Mitochondrial Dysfunction: Implications in Neurodegeneration and Possible Molecular Targets.

Yati Sharma, Jeetendra Kumar Gupta, M Arockia Babu, Sumitra Singh, Rakesh K Sindhu.

  Mitochondrion is an important organelle present in our cells responsible for meeting energy requirements. All higher organisms rely on efficient mitochondrial bioenergetic machinery to sustain life. No other respiratory process can produce as much power as generated by mitochondria in the form of ATPs. This review is written in order to get an insight into the magnificent working of mitochondrion and its implications in cellular homeostasis, bioenergetics, redox, calcium signaling, and cell death. However, if this machinery gets faulty, it may lead to several disease states. Mitochondrial dysfunctioning is of growing concern today as it is seen in the pathogenesis of several diseases which includes neurodegenerative disorders, cardiovascular disorders, diabetes mellitus, skeletal muscle defects, liver diseases, and so on. To cover all these aspects is beyond the scope of this article; hence, our study is restricted to neurodegenerative disorders only. Moreover, faulty functioning of this organelle can be one of the causes of early ageing in individuals. This review emphasizes mutations in the mitochondrial DNA, defects in oxidative phosphorylation, generation of ROS, and apoptosis. Researchers have looked into new approaches that might be able to control mitochondrial failure and show a lot of promise as treatments.

Keywords:  Mitochondrial dysfunction; Neurodegeneration; Neurotoxicity; Oxidative stress

DOI:  https://doi.org/10.1007/s12031-024-02269-5
Physiol Rep. 2024 Nov;12(21): e70105

Unraveling the redox code to improve physiological research in human health and disease.

Josh Thorley.

  Redox reactions, involving electron transfer, are critical to human physiology. However, progress in understanding redox metabolism is hindered by flawed analytical methods. This review highlights emerging techniques that promise to revolutionize redox research, enhancing our comprehension of human health and disease. Oxygen, vital for aerobic metabolism, also produces reactive oxygen species (ROS), such as superoxide and hydrogen peroxide. While historically seen as harmful, ROS at low concentrations are now recognized as key regulators of cell signaling. A balance between ROS and antioxidants, known as redox balance, is crucial, and deviations can lead to oxidative stress. Recent studies have distinguished beneficial "oxidative eustress" from harmful "oxidative distress." New techniques, such as advanced mass spectrometry and high-throughput immunoassays, offer improved accuracy in measuring redox states and oxidative damage. These advancements are pivotal for understanding redox signaling, cysteine oxidation, and their implications for disease. Looking ahead, the development of precision redox medicine could lead to better treatments for oxidative stress-related diseases and foster interventions promoting health.

Keywords:  ROS; cysteine; hydrogen peroxide; redox signaling

DOI:  https://doi.org/10.14814/phy2.70105
J Control Release. 2024 Oct 28. pii: S0168-3659(24)00727-2. [Epub ahead of print]

A reactive oxygen species-triggerable theranostic prodrug system.

Feiyang Liu, Lingyan Liu, Peng Wei, Tao Yi.

  Abnormally elevated levels of reactive oxygen species (ROS) are considered one of the characteristics of tumors and have been extensively employed in the construction of tumor-activated prodrugs. However, ideal ROS-activated molecular triggers that possess high sensitivity and easy functionalization for tailoring specific prodrugs, remain scarce. In this work, we developed a highly reactive oxygen species (hROS, such as •OH, ONOO- and HOCl)-responsive molecular trigger (namely FDROS-4) through the conjunction of methylene blue (MB) and 2, 6-bis (hydroxymethyl) aniline via urea bond, integrating imaging and therapeutic functions. FDROS-4 could be readily modified as multifunctional prodrugs and efficiently activated by hROS, leading to the release of near-infrared emissive MB and parent drugs. By using chlorambucil as a model drug and incorporating varying numbers of galactose as liver-targeting ligands, we designed and synthesized a series of prodrugs named FDROS-6, FDROS-7, and FDROS-8. The optimal prodrug, FDROS-7, could self-assemble into monocomponent nanoparticles, exhibiting enhanced biocompatibility and therapeutic efficacy compared to the parent drug. This hROS-activated molecular trigger holds promise for the development of stimulus-responsive prodrugs in chemotherapy.

Keywords:  Molecular trigger; Prodrug; Reactive oxygen species; Theranostics

DOI:  https://doi.org/10.1016/j.jconrel.2024.10.054
Biomaterials. 2024 Oct 22. pii: S0142-9612(24)00443-5. [Epub ahead of print]315 122909

Molybdenum nanodots act as antioxidants for photothermal therapy osteoarthritis.

Guang Shi, Shenghui Lan, Qi Zhang, Junwu Wang, Feihong Shu, Zhuowen Hao, Tianhong Chen, Mengyue Zhu, Renxin Chen, Jiayao Chen, Zijian Wu, Bo Wu, Zhenwei Zou, Jingfeng Li.

  Osteoarthritis (OA) manifests as the degradation of cartilage and remodeling of subchondral bone. Restoring homeostasis within the joint is imperative for alleviating OA symptoms. Current interventions primarily target singular aspects, such as anti-aging, inflammation inhibition, free radical scavenging, and regeneration of cartilage and subchondral bone. Herein, we developed molybdenum nanodots (MNDs) as bionic photothermal nanomaterials to mimic the antioxidant synthase to concurrently protected cartilage and facilitate subchondral bone regeneration. With near-infrared (NIR) irradiation, MNDs effectively eliminate reactive oxygen and nitrogen species (ROS/RNS) from OA chondrocytes, thereby reversed mitochondrial dysfunction, mitigating chondrocyte senescence, and simultaneously suppresses inflammation, hence preserving the inherent homeostasis between cartilage matrix synthesis and degradation while circumventing safety concerns. RNA sequencing of OA chondrocytes treated with MNDs-NIR revealed the reinstatement of chondrocyte functionality, activation of antioxidant enzymes, anti-aging properties, and regulation of inflammation. NIR irradiation induces thermogenesis and synergistically promotes subchondral bone regeneration via MNDs, as validated through histological assessments and microcomputed tomography (Micro-CT) scans. MNDs-NIR effectively attenuate cellular senescence and inhibit inflammation in vivo, while also remodeling mitochondrial dynamics by upregulating fusion proteins and inhibiting fission proteins, thereby regulating the oxidative stress microenvironment. Additionally, MNDs-NIR exhibited remarkable therapeutic effects in alleviating articular cartilage degeneration in an OA mouse model, evidenced by a 1.67-fold reduction in subchondral bone plate thickness, an 88.57 % decrease in OARSI score, a 5.52-fold reduction in MMP13 expression, and a 6.80-fold increase in Col II expression. This novel disease-modifying approach for OA utilizing MNDs-NIR offers insight and a paradigm for improving mitochondrial dysfunction by regulating the accumulation of mitochondrial ROS and ultimately alleviating cellular senescence. Moreover, the dual-pronged therapeutic approach of MNDs-NIR, which addresses both cartilage erosion and subchondral bone lesions in OA, represents a highly promising strategy for managing OA.

Keywords:  Articular cartilage; Mitochondrial homeostasis; Molybdenum nanodots; Osteoarthritis; Photothermal therapy; Reactive oxygen species; Subchondral bone

DOI:  https://doi.org/10.1016/j.biomaterials.2024.122909