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Melanoma bone metastasis-induced osteocyte ferroptosis via the HIF1α-HMOX1 axis.

Osteocytes are the main cells in mineralized bone tissue. Elevated osteocyte apoptosis has been observed in lytic bone lesions of patients with multiple myeloma. However, their precise contribution to bone metastasis remains unclear. Here, we investigated the pathogenic mechanisms driving melanoma-induced osteocyte death. Both in vivo models and in vitro assays were combined with untargeted RNA sequencing approaches to explore the pathways governing melanoma-induced osteocyte death. We could show that ferroptosis is the primary mechanism behind osteocyte death in the context of melanoma bone m

Recent Trends in anti-tumor mechanisms and molecular targets of celastrol.

Celastrol, a compound derived from traditional Chinese medicine, has therapeutic effects and has been used to treat inflammation-related diseases, cancer, cardiovascular diseases, and neurodegenerative diseases. However, current reviews lack a comprehensive and systematic summary of the anti-tumor mechanisms and molecular targets of celastrol. For this reason, this paper reviews the anticancer properties of celastrol and the molecular mechanisms underlying its anticancer effects. This paper primarily focuses on the mechanism of action of celastrol in terms of inhibition of cell proliferation a

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… Treatment with celastrol has been shown to increase the expression of Atg5 and Atg7, facilitate the formation of autophagosomes, and promote the degradation of p62, thereby enhancing autophagy activity and reducing cell viability 46 . … Studies have reported that celastrol inhibits TNF-α-induced proliferation of fibroblast-like synoviocytes (FLSs) decreases the secretion of pro-inflammatory cytokines while increasing the levels of autophagosomes and expression of LC3-II and Beclin-1 proteins in TNF-α-treated FLSs, and decreases the …

Аккумулирование опустошающих липидов в Arf1-Ablanted Neurorons способствует нейродегенерации с помощью mtDNA и активации воспаляющих путей в Микроглии.

В нейронах и глиальных клетках были обнаружены липидные метаболические расстройства у пациентов с нейродегенеративной (ND) и животных. Однако патологическая связь между липидными капельками и НУ остается слабой. Недавняя работа высветила полезность модели мыши Arf1-knockout с учетом особенностей нейронов и соответствующих клеток для разъяснения связи между расстройствами липидного метаболизма и амиотропическим боковым склерозом (ALS) и множественным склерозом (MS). В этом исследовании было установлено, что недостача арф1 вызвала первичный синтез избытка жирной кислоты через ось АКТ-mTORC1-SREB

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… However, due to the substantial accumulation of sphingolipids in lysosomes, which impairs their degradative function, damaged mitochondria within autophagosomes cannot be degraded upon fusion with lysosome. … In such cases, cells may fuse these undigested autophagosomes with the plasma membrane, thereby releasing the damaged mitochondria in the form of extracellular vesicles. …

Роль альфа-рецептора, активированного пероксидисом, в нейродегенеративных заболеваниях и других неврологических расстройствах: перспективы клинического применения.

Альфа-рецептор, активированный с помощью пероксисом, является членом сверхсемейства суперрецептора ядерного гормона и функционирует в качестве коэффициента транскрипции, связанного с регулированием клеточного метаболизма. Предыдущие исследования показали, что PPARα играет ключевую роль в возникновении и развитии нейродегенеративных заболеваний. Таким образом, альфа-агонисты, работающие на рецепторах, привлекают все большее внимание в качестве потенциальных средств лечения неврологических расстройств. Цель этого обзора состоит в том, чтобы прояснить прогресс в области исследований, касающихся п

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… This reduction facilitates the gathering of microglia and astrocytes around Aβ plaques, boosts the formation of autophagosomes, and encourages lysosomal development (Luo et al., 2020; Raha et al., 2021). … TFEB is a key orchestrator of autophagy, enhancing autophagosome formation and facilitating their fusion with lysosomes (Settembre et al., 2011). Notably, the mouse Tfeb promoter contains a PPARα response element (PPRE) and an RXRα binding site. …

From undruggable to degradable: A deep learning-enabled framework for precision orthopaedic protein degradation.

BACKGROUND/OBJECTIVE: A fundamental translational impasse in musculoskeletal disorders-from osteoarthritis to bone metastases-is the "undruggability" of critical pathological drivers sequestered within anatomically restricted and avascular skeletal niches. While Targeted Protein Degradation (TPD) offers a revolutionary event-driven modality to eradicate these refractory targets, its clinical translation to orthopaedics is severely hindered by the physicochemical incompatibility of large degraders with dense extracellular matrices and the scarcity of bone-specific E3 ligases. METHODS: In this

Targeting Death Receptor 5 (DR5) for the imaging and treatment of primary bone and soft tissue tumors: an update of the literature.

BackgroundDeath Receptor 5 (DR5) is expressed on the surface of primary bone and soft tissue sarcoma cells, and its activation induces cell death primarily through apoptosis. The combination of DR5 agonists and commonly used chemotherapeutic agents, such as doxorubicin, can promote cell death. Currently, clinical trials are investigating the effectiveness of DR5 activation using new biological agents, such as bi-specific or tetravalent antibodies, in improving the survival of patients with relapsed or refractory cancers. Furthermore, investigations continue into the use of novel combination th

Gambogic Acid as a Candidate for Cancer Therapy: A Review.

Gambogic acid (GA), a kind of dry resin secreted by the Garcinia hanburyi tree, is a natural active ingredient with various biological activities, such as anti-cancer, anti-inflammatory, antioxidant, anti-bacterial effects, etc. An increasing amount of evidence indicates that GA has obvious anti-cancer effects via various molecular mechanisms, including the induction of apoptosis, autophagy, cell cycle arrest and the inhibition of invasion, metastasis, angiogenesis. In order to improve the efficacy in cancer treatment, nanometer drug delivery systems have been employed to load GA and form mice

Каннабиноиды в раке: Молекулярные механизмы смерти клеток и возможности перевода.

Каннабиноиды представляют собой терпенофенолические соединения, полученные из Cannabis sativa L., которые осуществляют широкий спектр биологической и фармакологической деятельности. Растущие данные свидетельствуют об их потенциале как модуляторов развития рака, особенно посредством подавления роста клеток опухоли, ангиогенеза и метастаза в различных моделях опухоли. В настоящем обзоре содержится всеобъемлющий обзор молекулярных механизмов, с помощью которых природные и синтетические каннабиноиды вызывают регулируемую смерть раковых клеток. Текущие данные свидетельствуют о том, что каннабиноиды

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… Morphologically, autophagy-dependent cell death displays features including the formation of double membraned autophagosomes that engulf organelles and cytoplasmic material. These autophagosomes then fuse with lysosomes to form autolysosomes for degradation [ 25 ]. … LC3 is cleaved by Atg4, activated by Atg7, and transferred to Atg3, before conjugation to phosphatidylethanolamine (PE), generating LC3-II, a hallmark of autophagosome maturation [ 31 ]. …

Протеиновый ингибитор смягчает белку в мышах Lmx1b с дисфункциональной доменой LIM.

Мутации в коэффициенте транскрипции LMX1B были определены в качестве причины синдрома автосомали-доминантного заболевания гвозди-пареллы. Он проявляется в небольших или отсутствующих пателле и диспластике или в отсутствии пальцев и ногтей, но прогноз пациентов определяется появлением почечных симптомов из-за дисфункциональных подоцитов. Патогенетические механизмы, ведущие к повреждению подоцита, и их связь с конкретными мутациями в гене LMX1B не понимаются, что препятствует разработке конкретных терапевтических стратегий. Здесь мы идентифицируем патогенетический механизм, затрагивающий многих

Targeting Abnormal Hematopoietic Stem Cells in Chronic Myeloid Leukemia and Philadelphia Chromosome-Negative Classical Myeloproliferative Neoplasms.

Myeloproliferative neoplasms (MPNs) are unique hematopoietic stem cell disorders sharing mutations that constitutively activate the signal-transduction pathways involved in haematopoiesis. They are characterized by stem cell-derived clonal myeloproliferation. The key MPNs comprise chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). CML is defined by the presence of the Philadelphia (Ph) chromosome and BCR-ABL1 fusion gene. Despite effective cytoreductive agents and targeted therapy, complete CML/MPN stem cell eradication is r

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… Targeting Autophagy in CML Stem Cells Autophagy is the stress-induced formation of autophagosome for recycling and degradation of damaged and/or aged cytoplasmic components to sustain bioenergetic and nutritional demands [ 24 , 29 , 230 , 231 , 232 ]. … Chloroquine (CQ) CQ becomes protonated and trapped in lysosomes to alkalize acidic hydrolases, prevents fusion with autophagosomes, increases cellular stress and drives apoptosis [ 236 ]. …

Role of mitochondria in physiological activities, diseases, and therapy.

Mitochondria are generally considered essential for life in eukaryotic organisms because they produce most of the energy or adenosine triphosphate (ATP) needed by the cell. Beyond energy production, it is now widely accepted that mitochondria also play a pivotal role in maintaining cellular homeostasis and signaling. The two core processes of mitochondrial dynamics, fission and fusion, serve as crucial foundations for maintaining mitochondrial morphology, distribution, and quantity, thereby ensuring cellular homeostasis. Mitochondrial autophagy (mitophagy) ensures the selective degradation of

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… Mitochondrial autophagosomes are formed and fuse with lysosome. The fusion of these organelles leads to the formation of autolysosome. The final step involves the degradation and recycling of mitochondria within the autolysosome. c . … Parkin then ubiquitinates multiple OMM proteins such as Mfn1, Mfn2, and VDAC1, and these labeled proteins become signals for autophagosome recognition and encapsulation, facilitating the initiation of mitophagy [ 52 , 53 ]. …

Lifestyle and Pharmacological Interventions to Prevent Anthracycline-Related Cardiotoxicity in Cancer Patients.

Anthracyclines remain a cornerstone of cancer therapy but are associated with a significant risk of cardiotoxicity, which can lead to overt heart failure. The risk is modulated by cumulative dose, pre-existing cardiovascular disease, and patient-specific factors. As cancer survival improves, the long-term cardiovascular consequences of anthracycline exposure have become a growing concern, underscoring the need for effective preventive strategies. This narrative review examines lifestyle and pharmacological interventions aimed at mitigating anthracycline-induced cardiotoxicity. Evidence suggest

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… While autophagy activation through AMP-activated protein kinase (AMPK) and p53 pathways may serve as a compensatory mechanism to mitigate oxidative damage, excessive autophagosome accumulation due to lysosomal dysfunction can lead to cell death [ 37 ]. … Anthracyclines inhibit lysosomal acidification and impair the fusion of lysosomes with autophagosomes, leading to the accumulation of undegraded cellular debris and further promoting oxidative stress [ 38 ]. …

Regulation of HDAC6 Catalytic Activity in Cancer: The Role of Post-Translational Modifications and Protein-Protein Interactions.

Histone deacetylase 6 (HDAC6) is a large multidomain protein that deacetylates lysine residues on cytoplasmic proteins, influencing numerous cellular processes. Both the catalytic and noncatalytic functions of HDAC6 have been implicated in cancer development and progression. Over a decade of research on catalytic domain inhibitors has shown that these drugs are well tolerated, exhibit anticancer activity, and can alleviate chemotherapy-induced peripheral neuropathies. However, their effectiveness in treating solid tumours remains uncertain. HDAC6 activity is regulated by protein-protein intera

Marine-Derived Compounds: A New Horizon in Cancer, Renal, and Metabolic Disease Therapeutics.

Marine-derived compounds represent a rich source of structurally diverse molecules with therapeutic potential for cancer, renal disorders, metabolic-associated fatty liver disease (MAFLD), and atherosclerosis. This review systematically evaluates recent advances, highlighting compounds such as Microcolin H, Benzosceptrin C, S14, HN-001, Equisetin, glycosides (e.g., cucumarioside A2-2), ilimaquinone, and Aplidin (plitidepsin). Key mechanisms include autophagy modulation, immune checkpoint inhibition, anti-inflammatory effects, and mitochondrial homeostasis. Novel findings reveal glycosides' dua

Direct Endoplasmic Reticulum Targeting by the Selective Alkylphospholipid Analog and Antitumor Ether Lipid Edelfosine as a Therapeutic Approach in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC), the most common malignancy of the pancreas, shows a dismal and grim overall prognosis and survival rate, which have remained virtually unchanged for over half a century. PDAC is the most lethal of all cancers, with the highest mortality-to-incidence ratio. PDAC responds poorly to current therapies and remains an incurable malignancy. Therefore, novel therapeutic targets and drugs are urgently needed for pancreatic cancer treatment. Selective induction of apoptosis in cancer cells is an appealing approach in cancer therapy. Apoptotic cell death is highly

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… At the ultrastructural level, several changes are observed with age, including mitochondrial swelling, vacuolization, and increased lipid droplets, lysosomes, and autophagosomes [ 91 ]. … , as the amount of LC3-II is correlated with the abundance of autophagosomes [ 244 ]. …

[Effect and mechanism of chloroquine on supressing the growth of pancreatic neuroendocrine tumors].

Objective: To investigate the effect and mechanism of chloroquine on the growth of pancreatic neuroendocrine tumors (pNET). Methods: This study was divided into animal experiments and cell experiments. (1) Animal experiments: ten male BALB/c nude mice, 6-8 weeks old, were selected. The suspension of QGP-1 cells (human pNET cell line) in the logarithmic growth phase was inoculated subcutaneously into the right axilla of nude mice to establish a subcutaneous xenograft tumor model. According to the random number table method, the mice were divided into a control group (intraperitoneal injection o

Семья гистона деацетилазы в здравии и болезни.

Классические деацетилазы, включая классы I, II и IV, в зависимости от цинка, повсеместно присутствуют у млекопитающих и играют жизненно важную роль в многочисленных биологических процессах. На сегодняшний день eleven Были выявлены члены < < хисттон деацетилаза > > , а именно < < хиттон деацетилаза > > . 1 через гистонную деацетилазу 11. Растущий объем данных подчеркивает важнейшую роль этих гистоновых деацетилазов как в физиологических, так и патологических условиях. В частности, эти гистонные деацетилазы участвуют в различных клеточных процессах, включая воспаление, ме

Liposomal Nanoparticle Delivery of Ginkgo Flavone Glycosides Enhances SIRT1 Activation and Improves Diabetic Cardiomyopathy.

PurposeThis study aims to explore the therapeutic mechanisms of Ginkgo Flavone Glycosides (GFGs) delivered via liposomal nanoparticles in treating Diabetic Cardiomyopathy (DCM) by upregulating Sirtuin 1 (SIRT1) to restore energy metabolism and autophagy homeostasis.MethodsA DCM mouse model was employed, with groups treated with different doses of GFGs. Various evaluations, including body weight, blood glucose levels, and cardiac function, were performed. Network pharmacology, transcriptomic analysis, and molecular docking studies were conducted to elucidate the key role of SIRT1 in inhibiting

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… Immunofluorescence detection showed an increase in the number of mitochondria and autophagosomes in H9c2 cells treated with GFGs Lipo compared to those treated with Lipo. However, these numbers decreased in the shSIRT1+GFGs Lipo group compared to the shNC+GFGs Lipo group ( Figure 10D ). … Notes : ( A ) WB analysis of SIRT1, TSPAN4, and FOSL1 protein levels; ( B ) CCK-8 assay measuring H9c2 cell viability; ( C ) Flow cytometry analysis of H9c2 cell changes; ( D ) Immunofluorescence staining showing autophagosome and mitochondria morphology; ( E ) WB analysis of key autophagy proteins LC3 …

Salvage therapies in relapsed and/or refractory myeloma: what is current and what is the future?

The treatment landscape for multiple myeloma (MM) is evolving with our understanding of its pathophysiology. However, given the inevitable cohort heterogeneity in salvage therapy, response to treatment and overall prognoses tend to vary widely, making meaningful conclusions about treatment efficacy difficult to derive. Despite the hurdles in current research, progress is underway toward more targeted therapeutic approaches. Several new drugs with novel mechanism of action and less toxic profile have been developed in the past decade, with the potential for use as single agents or in synergy wi

Crosstalk of thioredoxin system and programmed cell death: from pathophysiology to novel therapy.

The thioredoxin (Trx) system, an integral component of cellular redox regulation, preserves protein dithiol-disulfide equilibrium through its conserved Cys-Gly-Pro-Cys active site and is involved in key cellular functions, including cell proliferation, apoptosis, and signal transduction. In cancer biology, the thioredoxin system plays dual roles: overexpression can suppress oxidative stress and promote tumor growth, whereas dysfunction can trigger programmed cell death (PCD). However, a critical area for future research is to delineate how Trx modulates the intricate networks of PCD, and to id