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TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS.

Cytoplasmic accumulation of TDP-43 is a disease hallmark for many cases of amyotrophic lateral sclerosis (ALS), associated with a neuroinflammatory cytokine profile related to upregulation of nuclear factor κB (NF-κB) and type I interferon (IFN) pathways. Here we show that this inflammation is driven by the cytoplasmic DNA sensor cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) when TDP-43 invades mitochondria and releases DNA via the permeability transition pore. Pharmacologic inhibition or genetic deletion of cGAS and its downstream signaling partner STING prevents upregulation of NF

Nitric oxide regulates cell survival in purified cultures of avian retinal neurons: involvement of multiple transduction pathways.

Nitric oxide (NO) is an important signaling molecule in the CNS, regulating neuronal survival, proliferation and differentiation. Here, we e … rentiation, and blocked cell death induced by hydrogen peroxide. Cyclosporin A, an inhibitor of the mitochondrial permeability transition pore considered an important mediator of apoptosis and necrosis, as well as boc-aspartyl (OMe) fluoromethylketone (BAF), a caspase inhibitor, also blocked cell death induced by re-feeding the cultures. These findings demonstrate that NO inhibits apoptosi …

Hepatoprotective potential of alpha-lipoic acid against gliclazide-induced liver injury in high-glucose-exposed human liver cells and experimental type 2 diabetic rats.

Growing clinical evidence shows that sulfonylurea therapy for patients with type 2 diabetic mellitus (T2DM) contributes to progressive worse … nducible nitric oxide synthase; KATP, ATP-dependent potassium channels; MDA, Malondialdehyde; MPTP, Mitochondrial permeability transition pore; NO, Nitric oxide; P/S, Penicillin/streptomycin; PAS, Periodic acid-Schiff; RIA, Radioimmunoassay; ROS, Reactive oxygen species; SOD, Superoxide dismutase; T2DM, Type 2 diabetes mellitus; TBARS, Thiobarbituric acid reactive substances; TNF-α, Tumor …

Oxidative and inflammatory biomarkers of ischemia and reperfusion injuries.

Ischemia-reperfusion injuries occur when the blood supply to an organ or tissue is temporarily cut-off and then restored. Even though the re … er anti-oxidant enzymes. It also possesses anti-inflammatory properties and is known to inhibit the mitochondrial permeability transition pore during reperfusion. This inhibiting property has been shown to be of great importance in reducing ischemia-reperfusion injuries. Furthermore, melatonin is a relatively non-toxic molecule, which has proven to be safe for use in clinical trials. Thus, …

An understanding of mitochondria and its role in targeting nanocarriers for diagnosis and treatment of cancer.

Nanotechnology has changed the entire paradigm of drug targeting and has shown tremendous potential in the area of cancer therapy due to its specificity. In cancer, several targets have been explored which could be utilized for the better treatment of disease. Mitochondria, the so-called powerhouse of cell, portrays significant role in the survival and death of cells, and has emerged as potential target for cancer therapy. Direct targeting and nanotechnology based approaches can be tailor-made to target mitochondria and thus improve the survival rate of patients suffering from cancer. With thi

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… Mitochondrial permeability transition pore (mPTP). mPTP is a pore that is commonly believed to be responsible for increasing the MIM permeabilization usually referred to as mitochondrial permeability transition (MPT) [32] . … Mitochondrial permeability transition pore as a selective target for anti-cancer therapy Front Oncol 3 2013 41 23483560 10.3389/fonc.2013.00041 PMC3592197 34 Folda A. Citta A. Scalcon V. Calì T. Zonta F. Scutari G. …

P2X7 Рецептор рентгеновских заболеваний: общие молекулярные механизмы и терапевтические последствия.

Редкие заболевания (РЛ) в индивидуальном порядке редко встречаются, но в совокупности они затрагивают большое число людей во всем мире, и подавляющее большинство из них по-прежнему не имеют эффективных методов лечения, позволяющих вести борьбу с заболеваниями. Благодаря достижениям в области геномики и платформ для обмена данными исследования все чаще переходят от одного заболевания к поиску конвергентных молекулярных путей, которые можно было бы использовать в различных клинически отличных друг от друга структурах. В этом контексте purinergic P2X7 рецептор (P2X7R) превратился в предполагаемую

Methyl jasmonate: putative mechanisms of action on cancer cells cycle, metabolism, and apoptosis.

Methyl jasmonate (MJ), an oxylipid that induces defense-related mechanisms in plants, has been shown to be active against cancer cells both in vitro and in vivo, without affecting normal cells. Here we review most of the described MJ activities in an attempt to get an integrated view and better understanding of its multifaceted modes of action. MJ (1) arrests cell cycle, inhibiting cell growth and proliferation, (2) causes cell death through the intrinsic/extrinsic proapoptotic, p53-independent apoptotic, and nonapoptotic (necrosis) pathways, (3) detaches hexokinase from the voltage-dependent

Ion Channels in Multiple Myeloma: Pathogenic Role and Therapeutic Perspectives.

Ion channels are pore-forming proteins that allow ions to flow across plasma membranes and intracellular organelles in both excitable and non-excitable cells. They are involved in the regulation of several biological processes (i.e., proliferation, cell volume and shape, differentiation, migration, and apoptosis). Recently, the aberrant expression of ion channels has emerged as an important step of malignant transformation, tumor progression, and drug resistance, leading to the idea of "onco-channelopathy". Here, we review the contribution of ion channels and transporters in multiple myeloma (

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… These data emphasize the importance of VDAC in the formation of the mitochondrial permeability transition pores and in the activation of the intrinsic apoptotic pathway. … Essential role of the voltage-dependent anion channel (VDAC) in mitochondrial permeability transition pore opening and cytochrome c release induced by arsenic trioxide. Oncogene. 2004;23:1239–1247. doi: 10.1038/sj.onc.1207205. 77. …

Окисляющий стресс и воспаление в патогенезе неврологических расстройств: механизмы и последствия.

Нейрозащита — это активный подход к защите нервной системы, включая мозг, спинной мозг и периферийные нервы, путем предотвращения или ограничения повреждения нервных клеток и других компонентов. Она защищает центральную нервную систему от повреждений от острых и прогрессивных нейродегенеративных расстройств. Окисляющий стресс, дисбаланс между естественными механизмами защиты тела и образованием реактивных видов кислорода, имеет решающее значение для развития неврологических расстройств. Из-за высокой скорости метаболизма и потребления кислорода мозг особенно уязвим к окисляющему стрессу. Чрезм

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… Additionally, the decrease in mitochondrial membrane potential (Δ Ψ m ) prompts the opening of mitochondrial permeability transition pores (MPTPs). … Pro-apoptotic proteins like Bax and Bad, for example, facilitate the opening of the mitochondrial permeability transition pore (mPTP). In contrast, anti-apoptotic proteins such as Bcl-2 and Bcl-xL prevent cell death by binding to and blocking the actions of pro-apoptotic proteins. …

Dual Roles of NIX/BNIP3L in Tumors: Friend or Foe.

Cancer is one of the leading causes of disease-related death worldwide, and targeting key regulatory genes to induce programmed cell death in tumor cells has emerged as a crucial therapeutic strategy, following surgery, radiotherapy, and chemotherapy. As a mitochondrial outer membrane protein, NIX/BNIP3L can both mediate apoptosis to inhibit tumor cell growth and promote tumor cell survival by clearing intracellular reactive oxygen species (ROS) through mitophagy. Therefore, we summarize a brief overview of the structure and function of NIX/BNIP3L, as well as the mechanisms of NIX/BNIP3L gener

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… The pro-apoptotic function of BNIP3L/NIX does not strictly rely on its BH3 domain, and the process is dependent on the opening of the mitochondrial permeability transition pore (MPTP). … However, in CRC with functional p53, NIX can cooperate with other pro-apoptotic proteins and modulate the mitochondrial permeability transition pore to promote apoptosis ( Figure 5 ). 6.7. …

Potential Therapeutic Benefits of Maintaining Mitochondrial Health in Peripheral Neuropathies.

BackgroundPeripheral neuropathies are a group of diseases characterized by malfunctioning of peripheral nervous system. Neuropathic pain, one of the core manifestations of peripheral neuropathy remains as the most severe disabling condition affecting the social and daily routine life of patients suffering from peripheral neuropathy.MethodThe current review is aimed at unfolding the possible role of mitochondrial dysfunction in peripheral nerve damage and to discuss on the probable therapeutic strategies against neuronal mitotoxicity. The article also highlights the therapeutic significance of

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… Mitochondrial permeability transition pore (mPTP) is found to be responsible for the release of certain pro apoptotic mediators from the mitochondria to cytosol and found to mediate apoptosis [ 115 ]. … Mitochondrial permeability transition pore opening as a promising therapeutic target in cardiac diseases. J. Pharmacol. Exp. Ther. 2009;330(3):670–678. doi: 10.1124/jpet.109.153213. [http://dx.doi.org/10.1124/jpet.109.153213]. [PMID: 19509316]. 119. Auten R.L., Davis J.M. …

2,4 Dinitrophenol as Medicine.

In the sanctity of pure drug discovery, objective reasoning can become clouded when pursuing ideas that appear unorthodox, but are spot on physiologically. To put this into historical perspective, it was an unorthodox idea in the 1950's to suggest that warfarin, a rat poison, could be repositioned into a breakthrough drug in humans to protect against strokes as a blood thinner. Yet it was approved in 1954 as Coumadin® and has been prescribed to billions of patients as a standard of care. Similarly, no one can forget the horrific effects of thalidomide, prescribed or available without a prescri

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… After TBI in animal models, it is the ligand for and binds mitochondrial cyclophilin D, preventing its participation in and therefore inhibiting the formation of the mitochondrial permeability transition pore (mPTP). … Post-injury administration of the mitochondrial permeability transition pore inhibitor, NIM811, is neuroprotective and improves cognition after traumatic brain injury in rats. J. Neurotrauma. 2011;28:1845–1853. doi: 10.1089/neu.2011.1755. 11. …

Novel intriguing strategies attenuating to sarcopenia.

Sarcopenia, the age-related loss of skeletal muscle mass, is characterized by a deterioration of muscle quantity and quality leading to a gradual slowing of movement, a decline in strength and power, increased risk of fall-related injury, and, often, frailty. Since sarcopenia is largely attributed to various molecular mediators affecting fiber size, mitochondrial homeostasis, and apoptosis, the mechanisms responsible for these deleterious changes present numerous therapeutic targets for drug discovery. Resistance training combined with amino acid-containing supplements is often utilized to pre

Кинуреньенс и митохондриальные расстройства в многоразовом склерозе.

Множественный склероз (MS) — хроническое аутоиммунное заболевание, характеризующееся воспалением, обезвоживанием и нейродегенерацией в центральной нервной системе. Патогенез MS связан с иммунной атаки на миелин и нейроны, сопровождаемой дисфункцией мозга в крови и хроническим воспалением CNS. Центральное значение для патологии MS имеет дисрегулирование кинуреньинового пути, который метаболизирует триптофан в нейроактивные соединения. Активация Kynurenin Translation (KP) под воздействием подстрекательских цитокинов приводит к образованию как нейрозащитных (например, кинуриновой кислоты, КИНА),

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… Intracellular QUIN inhibits mitochondrial respiratory complexes and induces opening of the mitochondrial permeability transition pore (PTP) by calcium overload [ 32 , 33 ]. … Electron microscopy also reveals swollen, vacuolated mitochondria with disrupted cristae and activation of the mitochondrial permeability transition pore (PTP), indicating severe mitochondrial damage [ 61 ]. …

Physiological functions and pharmacological targeting of transient receptor potential channels.

Transient receptor potential (TRP) channels represent an extensive and diverse protein family fulfilling salient roles as versatile cellular sensors and effectors. The pivotal role of TRP and related ion channels in sensory processes has been well documented. Over the last few years, a new concept has emerged that TRP proteins control an exceptionally broad spectrum of homeostatic physiological functions such as maintenance of body temperature, blood pressure, transmitter release from neurons, mineral and energy homeostasis, and reproduction. This notion is further supported by more than 20 he

Organelle-oriented nanomedicines in tumor therapy: Targeting, escaping, or collaborating?

Precise tumor therapy is essential for improving treatment specificity, enhancing efficacy, and minimizing side effects. Targeting organelles is a key strategy for achieving this goal and is a frontier research area attracting a considerable amount of attention. The concept of organelle targeting has a significant effect on the structural design of the nanodrugs employed. Most notably, the intricate interactions among different organelles in a tumor cell essentially create a unified system. Unfortunately, this aspect might have been somewhat overlooked when existing organelle-targeting nanodru

Mitochondrial Kv1.3 Channels as Target for Treatment of Multiple Myeloma.

Despite several new developments in the treatment of multiple myeloma, all available therapies are only palliative without curative potential and all patients ultimately relapse. Thus, novel therapeutic options are urgently required to prolong survival of or to even cure myeloma. Here, we show that multiple myeloma cells express the potassium channel Kv1.3 in their mitochondria. The mitochondrial Kv1.3 inhibitors PAPTP and PCARBTP are efficient against two tested human multiple myeloma cell lines (L-363 and RPMI-8226) and against ex vivo cultured, patient-derived myeloma cells, while healthy b

The Potential of Nuclear Pore Complexes in Cancer Therapy.

Nuclear pore complexes (NPCs) play a critical role in regulating transport-dependent gene expression, influencing various stages of cancer development and progression. Dysregulation of nucleocytoplasmic transport has profound implications, particularly in the context of cancer-associated protein mislocalization. This review provides specific information about the relationship between nuclear pore complexes, key regulatory proteins, and their impact on cancer biology. Highlighting the influence of tumor-suppressor proteins as well as the potential of gold nanoparticles and intelligent nanosyste

Liposomal Drug Delivery Systems and Anticancer Drugs.

Cancer is a life-threatening disease contributing to ~3.4 million deaths worldwide. There are various causes of cancer, such as smoking, being overweight or obese, intake of processed meat, radiation, family history, stress, environmental factors, and chance. The first-line treatment of cancer is the surgical removal of solid tumours, radiation therapy, and chemotherapy. The systemic administration of the free drug is considered to be the main clinical failure of chemotherapy in cancer treatment, as limited drug concentration reaches the tumour site. Most of the active pharmaceutical ingredien

MicroRNA-7: a versatile player and core target in brain disorders.

OBJECTIVE: This article provides a systematic review of the biological characteristics, regulatory mechanisms, and roles of MicroRNA-7 (miR-7) in the nervous system, as well as explores its clinical translation potential and challenges. METHODS: A review analysis integrating the progress of basic and clinical research related to miR-7. RESULTS: Characteristics and Regulation: miR-7 is highly expressed in mammalian brain tissues, with its function finely regulated by ceRNA networks (such as ciRS-7 and lncRNA SNHG1) and epigenetic modifications, forming a multi-layer dynamic regulatory system.

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… For instance, miR-7 can target the pro-apoptotic proteins Bax and Sirt2, suppressing MPP + -induced neuronal apoptosis [ 18 ], a mechanism that may also apply to cerebral ischemia models. miR-7 also regulates the key component of the mitochondrial permeability transition pore (mPTP), VDAC1, to maintain …