Synthesis and Preclinical Evaluation of PSMA-Targeted ¹¹¹In-Radioconjugates Containing a Mitochondria-Tropic Triphenylphosphonium Carrier

Molecular Pharmaceutics, Год журнала: 2023, Номер 21(1), С. 216 - 233

Опубликована: Ноя. 22, 2023

Nuclear DNA is the canonical target for biological damage induced by Auger electrons (AE) in context of targeted radionuclide therapy (TRT) cancer, but other subcellular components might also be relevant this purpose, such as energized mitochondria tumor cells. Having mind, we have synthesized novel DOTA-based chelators carrying a prostate-specific membrane antigen (PSMA) inhibitor and triphenyl phosphonium (TPP) group that were used to obtain dual-targeted 111In-radioconjugates ([111In]In-TPP-DOTAGA-PSMA [111In]In-TPP-DOTAGA-G3-PSMA), aiming promote selective uptake an AE-emitter radiometal (111In) PSMA+ prostate cancer (PCa) cells enhanced accumulation mitochondria. These 111In-radiocomplexes are highly stable under physiological conditions cell culture media. The complexes showed relatively similar binding affinities toward PSMA compared reference tracer [111In]In-PSMA-617, line with their high cellular internalization PCa compromised survival dose-dependent manner case [111In]In-TPP-DOTAGA-G3-PSMA higher extent than observed single-targeted congener [111In]In-PSMA-617. μSPECT imaging studies xenografts TPP pharmacophore did not interfere excellent vivo "golden standard" although it led kidney retention. Such retention does necessarily compromise usefulness radiotherapeutics due short tissue range Auger/conversion emitted 111In. Overall, our results provide valuable insights into potential use mitochondrial targeting PSMA-based radiocomplexes efficient AE-emitting radionuclides TRT, giving impetus extend trivalent radiometals (e.g., 161Tb or 165Er) further optimize designed dual-targeting constructs.

Язык: Английский

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Nutraceuticals a Food for Thought in the Treatment of Parkinson’s Disease

Current Nutrition & Food Science, Год журнала: 2023, Номер 19(9), С. 961 - 977

Опубликована: Май 16, 2023

Background: Brain disorders are presently one of the most serious and challenging health issues in world. A significant portion morbidities fatalities worldwide caused by these brain disorders. Parkinson's disease (PD) is a neurological condition that develops when dopaminergic neurons lost substantia nigra, causing cognitive motor impairment. Objectives: Conventional treatment modalities, including dopamine replacement therapy optimization transmission approaches, don’t address pathogenic processes primary to symptoms PD usually become least essential with time. Researchers aiming provide effective treating minimizing adverse consequences. In past few years, number studies on nutraceuticals have been conducted produce foods fewer effects increased therapeutic effectiveness. The use typically risk-free can be coupled patient's current common pharmacological enhance standard living lessen symptoms. Conclusion: review focuses important nutritional compounds dietary changes shown against pathways involved onset progression (PD), further lights justification for their prospect prevention PD.

Язык: Английский

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Mitochondrial defects in sporadic inclusion body myositis—causes and consequences

Frontiers in Cell and Developmental Biology, Год журнала: 2024, Номер 12

Опубликована: Май 14, 2024

Sporadic inclusion body myositis (sIBM) is a distinct subcategory of Idiopathic Inflammatory Myopathies (IIM), characterized by unique pathological features such as muscle inflammation, rimmed vacuoles, and protein aggregation within the myofibers. Although hyperactivation immune system widely believed primary cause IIM, it debated whether non-immune tissue dysfunction might contribute to disease's onset patients with sIBM are refractory conventional immunosuppressant treatment. Moreover, findings that mitochondrial can elicit non-apoptotic programmed cell death subsequent response further support this hypothesis. Notably, abnormal structure activities more prominent in than other types suggesting presence defective mitochondria represent an overlooked contributor disease onset. The large-scale DNA deletion, aberrant aggregation, slowed organelle turnover have provided mechanistic insights into genesis impaired sIBM. This article reviews hallmarks sIBM, plausible contributors damage muscle, immunological responses associated perturbations. Additionally, potential application mitochondrial-targeted chemicals new treatment strategy explored discussed.

Язык: Английский

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Study on the mechanism of glucocorticoid receptor mitochondrial translocation and glucocorticoid-induced apoptosis in macrophages

Immunopharmacology and Immunotoxicology, Год журнала: 2024, Номер 46(4), С. 482 - 495

Опубликована: Июнь 12, 2024

Objective: Our research aimed to investigate the therapeutic effects of Tubastatin-A, a glucocorticoid receptor (GR) mitochondrial translocation inhibitor, and mitoquinone (MitoQ), an antioxidant, on attenuating dexamethasone (DEX)-induced macrophage apoptosis.

Язык: Английский

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Mitochondria-targeted antioxidant, mitoQ protects hepatic tissue from N-nitrosodiethylamine-induced damage by modulating mitochondrial function and redox status

Advances in Redox Research, Год журнала: 2024, Номер 12, С. 100108 - 100108

Опубликована: Июль 20, 2024

Targeting mitochondrial oxidative stress can be a promising strategy for the prevention of hepatocellular carcinoma (HCC). In current study, we investigated modulatory effect mitochondria-targeted antioxidant, mitoQ against N-nitrosodiethylamine (NDEA)-induced hepatic damage in mouse. BALB/c mice were administered NDEA (10 mg/kg b. w., single dose, intraperitoneally) and hepatoprotective was studied by administering (0.125 orally once week) to animals. The administration started two weeks prior administration. animals sacrificed 24 h following after which blood samples tissues collected. Serum used estimation liver injury markers analyzed histopathological changes, antioxidant defense status, functional level reactive oxygen species (mtROS) lipid peroxidation (mtLPO). MitoQ treatment NDEA-challenged group normalized markers, mtROS mtLPO. also improved status system, complex enzymes. Our findings indicate that mito-Q significantly protected NDEA-induced modulating function redox may one causes its purported chemopreventive effect.

Язык: Английский

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Glucosamine mitigates ischemia-reperfusion-induced acute kidney injury through anti-inflammatory mechanisms

Frontiers in Materials, Год журнала: 2024, Номер 11

Опубликована: Ноя. 26, 2024

Objective Acute kidney injury (AKI), a syndrome with high morbidity and mortality worldwide, frequently arises from renal ischemia-reperfusion (I/R) injury, particularly in surgical contexts. Despite extensive research, effective therapies for both AKI its progression to interstitial fibrosis remain elusive. This study investigates the potential therapeutic efficacy of glucosamine (GS), an endogenous amino sugar, alleviating I/R-induced AKI. Methods A murine I/R model was utilized evaluate protective effects GS. Mice were treated GS prior tissues harvested biochemical, histological, molecular analyses. Key markers oxidative stress, mitochondrial integrity, endoplasmic reticulum (ER) stress measured. Additionally, inflammatory responses proximal convoluted tubular epithelial cells exposed TPHP, environmental toxin, assessed vitro . Results administration markedly reduced levels, preserved structure, mitigated ER following injury. Moreover, significantly attenuated TPHP-induced cells, suggesting targeted anti-inflammatory action. Conclusion These findings highlight glucosamine’s as agent AKI, offering protection through modulation oxidative, mitochondrial, pathways. provides foundational evidence promising candidate intervention opens avenues further exploration disease therapeutics.

Язык: Английский

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OXPHOS TARGETING OF MYCN-AMPLIFIED NEUROBLASTOMA

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Авг. 6, 2024

Abstract/Summary High risk - neuroblastoma (HR-NB) is a pediatric solid tumor with high lethality. Half of HR-NB are driven by MYCN gene amplification (MNA). These HR-NBs require dosage chemotherapy and often relapse. Moreover, current therapies can cause severe long-term side effects new urgently needed. This study investigates novel therapeutic approach targeting the metabolic vulnerabilities MNA NB cells. We discovered that Diphenyleneiodonium chloride (DPI), an inhibitor flavoprotein enzymes mitochondrial complex I, synergizes mitoquinone mesylate (MitoQ), mitochondria-targeted antioxidant in 2D 3D vitro models NB. Similarly to DPI, MitoQ affects cells MYCN-dependent way, being more toxic when levels high. Furthermore, low nanomolar concentrations significantly decrease protein expression induce differentiation The DPI combination further vincristine, chemotherapeutic agent used treatment. Phosphoproteomics proteomics analysis suggests drug induces cell death arresting cycle inhibiting oxidative phosphorylation (OXPHOS) mitochondria. Thus, interference metabolism may represent effective strategy enhance activity drugs MNA-NB.

Язык: Английский

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An Ultimate Approach to Retarding the Aging Process by Integrating Traditional Chinese Medicine and Western Medicine

Chinese Medicine, Год журнала: 2024, Номер 15(03), С. 35 - 48

Опубликована: Янв. 1, 2024

Aging and death are unavoidable in life. While immortality may be impossible, many people dream of living a long healthy Throughout history, humans have searched for ways to stay young, but not found an effective way. This because the methods used do target causes aging directly. To address this, we investigated how delay using traditional Chinese medicine (TCM) Western approaches. In this article, will explain context TCM suggest it. By integrating medicine, I hope help everyone age healthily enjoy

Язык: Английский

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Preventive effect of MitoQ supplementation and endurance training on glioblastoma and its consequences: TLR4/CREB/ NF-κβ /IL-1β pathway and behaviors

International Immunopharmacology, Год журнала: 2024, Номер 145, С. 113756 - 113756

Опубликована: Дек. 10, 2024

Язык: Английский

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Protective Effect of Silymarin and Mitoquinone (MitoQ) Aganist Hepatotoxicity of Cadmium Telluride Quantum Dot (CdTe QDs) Nanoparticles in Mice

Revista Científica de la Facultad de Ciencias Veterinarias, Год журнала: 2024, Номер XXXIV(3), С. 1 - 12

Опубликована: Дек. 5, 2024

As a result of the increasing use quantum dots (QDs) and increased exposure human beings to dots, study toxicity particles has become an important issue. In this study, protective activity silymarin mitoquinone (MitoQ), which are known have antioxidant properties, on histopathological biochemical changes observed in liver mice treated with CdTe QDs was investigated. 26 male Swiss were randomly divided into four groups: Control (G1), (G2), + (G3), (G4) application groups. Animals sacrificed 24 hours (h) after injections hyperspectral microscopy images obtained. According ICP–MS results, injected through tail vein accumulated at end h caused tissue damage according hematoxylin & eosin examination, better preservation pre–treatment. The immunofluorescence results showed inflammation apoptosis group. It that decreased anti–MMP–9, anti–IL–10, anti–IL–1b, anti–TNF–α, anti–caspase–9, TUNEL–positive cell ratio, MDA levels. There no significant difference serum TAS (P=0.509), TOS (P=0.588) levels, but antioxidants also SOD CAT Antioxidants had effect anti–MT–MMP2 anti–caspase–8 levels (P<0.001). conclusion, it shown pretreatment QD–administered can reduce oxidative stress may reduction inflammation.

Язык: Английский

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