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Solamargine induces autophagy-mediated apoptosis and enhances bortezomib activity in multiple myeloma.

Multiple myeloma (MM) is an incurable plasma cell malignancy with a poor survival rate. Conventional chemotherapeutic agent-induced adverse events, including toxicity, neuropathy or drug resistance, significantly decrease the patients' quality of life and can even lead to interruption of treatment. Therefore, novel therapeutic drugs and strategies are urgently needed to improve MM therapy and patient outcomes. Here, we show that solamargine (SM), a steroidal alkaloid glycoside isolated from a Chinese herb Solanum nigrum L., exhibits promising anti-MM activity. In particular, SM suppressed the

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… Cadmium results in accumulation of autophagosomes‐dependent apoptosis through activating Akt‐impaired autophagic flux in neuronal cells. Cell Signal. 2019;55:26‐39. 38. Trapnell C, Roberts A, Goff L, et al. …

Repurposing of nervous system drugs for cancer treatment: recent advances, challenges, and future perspectives.

The nervous system plays a critical role in developmental biology and oncology, influencing processes from ontogeny to the complex dynamics of cancer progression. Interactions between the nervous system and cancer significantly affect oncogenesis, tumor growth, invasion, metastasis, treatment resistance, inflammation that promotes tumors, and the immune response. A comprehensive understanding of the signal transduction pathways involved in cancer biology is essential for devising effective anti-cancer strategies and overcoming resistance to existing therapies. Recent advances in cancer neurosc

A Challenge to Aging Society by microRNA in Extracellular Vesicles: microRNA in Extracellular Vesicles as Promising Biomarkers and Novel Therapeutic Targets in Multiple Myeloma.

Multiple myeloma (MM) is a malignancy of terminally differentiated plasma cells and is the second most common hematological cancer. MM frequently occurs in the elderly population with the median age as the middle sixties. Over the last 10 years, the prognosis of MM has been dramatically improved by new therapeutic drugs; however, MM is still incurable. The pathogenesis of MM is still unclear, thus greater understanding of the molecular mechanisms of MM malignancy is desirable. Recently, microRNAs (miRNAs) were shown to modulate the expression of genes critical for MM pathogenesis. In addition,

Anti-cancer effects of nitrogen-containing bisphosphonates on human cancer cells.

Zoledronic acid, a potent nitrogen-containing bisphosphonate (NBP), has been extensively used to limit bone turnover in a various diseases including tumors. Recent clinical studies have demonstrated direct anti-cancer effects of zoledronic acid, in addition to its clinical benefits for skeletal-related events. Here we investigated the effects of 4 clinically available NBPs on human tumor cell proliferation. Our data demonstrate a potent anti-proliferative effect of zoledronic acid against glioblastoma (GBM) cell lines, breast cancer cells and GBM patient-derived lines. Zoledronic acid also eff

Effect of the specific proteasome inhibitor bortezomib on cancer-related muscle wasting.

BACKGROUND: Muscle wasting, a prominent feature of cancer cachexia, is mainly caused by sustained protein hypercatabolism. The enhanced muscle protein degradation rates rely on the activity of different proteolytic systems, although the Adenosine triphosphate (ATP)-ubiquitin-proteasome-dependent pathway and autophagy have been shown to play a pivotal role. Bortezomib is a potent reversible and selective proteasome and NF-κB inhibitor approved for the clinical use, which has been shown to be effective in preventing muscle wasting in different catabolic conditions. The aim of the present study h

Navigating the landscape of protein folding and proteostasis: from molecular chaperones to therapeutic innovations.

Protein folding is a fundamental process ensuring that polypeptide chains acquire the correct three-dimensional structures required for biological function. This complex journey from nascent polypeptides to mature proteins is tightly regulated by the cellular proteostasis network-an integrated system of molecular chaperones, folding enzymes, and degradation machineries. Disruptions in this network lead to dysproteostasis, a pathological state implicated in a growing list of human diseases, including neurodegenerative disorders, metabolic syndromes, and cancer. In this review, we provide a comp

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… transmembrane domain can directly bind nonglycosylated, misfolded membrane proteins, stabilizing them until they engage canonical quality‑control pathways. 171 – 173 Moreover, calnexin partners with the ER‑phagy receptor FAM134B to escort refractory clients—such as aggregation‑prone α‑synuclein—into autophagosomes …

Emerging and underexplored ginsenosides in cancer therapy (2020-2025): Beyond cytotoxic mechanisms.

Ginsenosides from Panax plants have long been studied as potential anticancer agents. In earlier years, most research focused on a few well-known ginsenosides that showed strong direct cytotoxicity, such as Rg3 and Rh2. As a result, many other ginsenosides were considered less active and received limited attention. However, studies published between 2020 and 2025 indicate that several previously underexplored ginsenosides also exhibit meaningful anticancer activity. These compounds often do not function as strongly cytotoxic agents. Instead, they act through broader and more indirect mechanism

Histone deacetylase 6: A new player in oxidative stress‑associated disorders and cancers (Review).

Histone deacetylase 6 (HDAC6), a distinctive member of the histone deacetylase family, plays a crucial role in regulating the cellular response to oxidative stress. Unlike other HDACs, HDAC6 primarily deacetylates non‑histone proteins, influencing various cellular functions critical to the pathogenesis of numerous oxidative stress‑related diseases. This review summarizes the latest research on how HDAC6 affects oxidative stress pathways and its impact on diseases such as neurodegeneration, cancer and cardiovascular disorders. Additionally, the therapeutic potential of targeting HDAC6, as evide

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… Furthermore, Se-SAHA pretreatment inhibited autophagosome buildup and reversed the upregulation of HDAC1 and HDAC6 caused by ISO exposure ( 58 ). … IPA shows potential efficacy by attenuating oxidative stress, inflammation and apoptosis in cardiomyocytes by inhibition of HDAC6/NOX2 signaling. iii) A role for HDAC6 in the accumulation of autophagosomes is via its ability to increase LC3-II and Beclin-1 expression in hearts with heart failure. …

Genetic and Mechanistic Insights Inform Amyotrophic Lateral Sclerosis Treatment and Symptomatic Management: Current and Emerging Therapeutics and Clinical Trial Design Considerations.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting both upper and lower motor neurons. ALS is classically characterized by painless progressive weakness, causing impaired function of limbs, speech, swallowing, and respiratory function. The disease is fatal within 2-4 years, often the result of respiratory failure. The pathologic hallmark for a majority of ALS cases is aberrant cytoplasmic accumulations of the nuclear protein TAR-DNA binding protein (TDP-43). A total of 10-15% of ALS can be attributed to a single gene mutation, known as genetic or "familia

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… Normally, autophagosomes deliver cellular constituents (such as TDP-43 aggregates and stress granules) to lysosomes, where they are degraded and recycled [ 8 , 220 ]. This lysosomal stress response is regulated by mammalian target of rapamycin (mTOR) and transcription factor EB [ 221 ]. … For example, C9orf72 is part of a protein complex that controls autophagosome formation and lysosomal fusion, and when impaired, leads to accumulation of TDP-43 aggregates [ 222 ]. …

HMGB1 enhances chemotherapy resistance in multiple myeloma cells by activating the nuclear factor-κB pathway.

Chemotherapy resistance is a main obstacle in the clinical chemotherapeutic treatment of multiple myeloma (MM). High-mobility group box 1 (HMGB1) has been revealed to be associated with the sensitivity of MM cells to chemotherapy, but how HMGB1 regulates chemotherapy resistance in MM has yet to be fully elucidated. In the present study, the exact molecular mechanism underlying HMGB1-mediated drug resistance in MM was explored using three chemotherapy-resistant MM cells (RPMI8226/ADR, RPMI8226/BOR and RPMI8226/DEX) that were successfully established. Reverse transcription-quantitative polymeras

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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… In GBM cells, miR-7 induces the formation of autophagosomes by inhibiting the activity of the PI3K/AKT/mTORC1 signaling pathway, thereby relieving its suppression of autophagy initiation [ 27 ]. … However, miR-7 simultaneously inhibits the fusion of autophagosomes with lysosomes by targeting key SNARE proteins STX17 (Syntaxin 17) and SNAP29 involved in the autophagosome-lysosome fusion process, thereby blocking the completion of autophagy [ 27 ]. …

A Journey through the Inter-Cellular Interactions in the Bone Marrow in Multiple Myeloma: Implications for the Next Generation of Treatments.

Tumors are composed of a plethora of extracellular matrix, tumor and non-tumor cells that form a tumor microenvironment (TME) that nurtures the tumor cells and creates a favorable environment where tumor cells grow and proliferate. In multiple myeloma (MM), the TME is the bone marrow (BM). Non-tumor cells can belong either to the non-hematological compartment that secretes soluble mediators to create a favorable environment for MM cells to grow, or to the immune cell compartment that perform an anti-MM activity in healthy conditions. Indeed, marrow-infiltrating lymphocytes (MILs) are associate

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… In the TME, tumor-released autophagosomes induce this B-reg population [ 205 ]. Despite their poorly described role in MM, B-reg cells have become essential players increasing during the initial stages of MM and head for extinction in relapsed or refractory MM [ 206 ]. …

Деменция, расстройства настроения и старение.

С повышением возраста и продолжительности жизни в мире как в развитых, так и в развивающихся странах риск развития когнитивных потерь и расстройств настроения значительно возрастает в той мере, в какой после достижения возраста 65, этот риск почти удваивает каждый 5 Спустя годы. В результате, соответствующий рост неинфекционных заболеваний поразит людей со слабоумием и расстройствами настроения, связанными с болезнью Альцгеймера, множественным склерозом, депрессией и тревогой. На клинической основе многочисленные факторы риска и представления, которые связаны с утратой интеллектуальных способн

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… progression of dementia with AD and MS, as well as depression and anxiety. 7 , 9 Metabolic disease, such as DM, and oxidative stress can both lead to the induction of programmed cell death with autophagy ( Figure 2 ). 67 , 68 Autophagy, which usually involves macroautophagy that recycles organelles through autophagosomes …

Генетический риск нейродегенеративных заболеваний связан с микрогилевыми путями, учитывающими конкретные заболевания.

Исследования, проведенные в рамках общегеномной ассоциации, выявили тысячи общих вариантов, связанных с повышенным риском нейродегенеративных расстройств. Однако некодирование этих вариантов затруднило назначение целевых генов для типов мозговых клеток. Геномические подходы, которые определяют хромосомную 3D-архитектуру, могут увязать некодирующие варианты риска и дистальные элементы регулирования генов, такие, как усилители, с пропагандистами генов. Используя карты улучшения взаимодействия для микроглии, нейронов и олигодендроцитов, мы определили конкретное обогащение генетической наследствен

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… ALS exhibited associations with vacuoles and kinases, while also sharing pathways with PD related to lysosomes and autophagosomes ( Fig 3c and S2 Table ). …

The Role of Intravesicular Proteins and the Protein Corona of Extracellular Vesicles in the Development of Drug-Induced Polyneuropathy.

Extracellular vesicles (EVs) as membrane structures of cellular origin participating in intercellular communication are involved in the molecular mechanisms of the development of various variants of polyneuropathy. Taking into account the increasing role of the protein corona of EVs and protein-protein interactions on the surface of EVs in the pathogenesis of various diseases, we focused our attention in this review on the role of intravesicular proteins and the protein corona of EVs in the development of chemotherapy-induced polyneuropathy (CIPN). It has been shown that EVs are effectively in

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… Autophagy is a stress-induced cell survival program in which cells under metabolic, proteotoxic, or other stresses remove dysfunctional organelles and/or misfolded/polyubiquitinated proteins by shuttling them to the lysosome for degradation via specialised structures called autophagosomes. …

Roles and Clinical Significances of ATF6, EMC6, and APAF1 in Prognosis of Pancreatic Cancer.

Background: Pancreatic cancer (PC) is prevalent among malignant tumors with poor prognosis and lacks efficient therapeutic strategies. Endoplasmic reticulum (ER) stress and apoptosis are associated with chronic inflammation and cancer progression. However, the prognostic value of ER stress-related, and apoptosis-related genes in PC remains to be further elucidated. Our study aimed at confirming the prognostic values of the ER stress-related genes, ATF6, EMC6, XBP1, and CHOP, and the apoptosis-related gene, APAF1, in PC patients. Methods: Gene Expression Profiling Interactive Analysis 2 (GEPIA2

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… EMC6 is an autophagy-related protein that is overexpressed in U2OS osteosarcoma and HCT116 colon carcinoma cells, and that participates in the formation of autophagosomes and in accelerating the degradation of autophagic substrates in lysosomes ( Li et al., 2019 ). …

Targeted Protein Degradation in Cancer: PROTACs, New Targets, and Clinical Mechanisms.

The onset of proteolysis targeting chimeras (PROTACs) has reshaped the entire context of targeted cancer therapy by offering a novel approach for the selective degradation of disease-causing proteins, overcoming the limitations of traditional occupancy-driven inhibition. This heterobifunctional technology recruits endogenous E3 ubiquitin ligases to mark proteins of interest (POI) for proteosomal degradation via the ubiquitin-proteasome system (UPS). Unlike conventional inhibitors, PROTACs function catalytically and can target previously "undruggable proteins", such as transcription factors, sc

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… In addition to AUTACs, Autophagy Tethering Compounds (ATTECs) employ a “molecular glue” strategy to link the protein or organelle of interest to LC3, a key element of autophagosome membranes. … This is followed by the conjugation of LC3-I , resulting in the formation of LC3-II , a crucial step in the maturation of autophagosomes [ 156 ]. Ultimately, the fusion with lysosomes leads to the degradation of cargo within acidic compartments. …

Targeting SREBP-2-Regulated Mevalonate Metabolism for Cancer Therapy.

Recently, targeting metabolic reprogramming has emerged as a potential therapeutic approach for fighting cancer. Sterol regulatory element binding protein-2 (SREBP-2), a basic helix-loop-helix leucine zipper transcription factor, mainly regulates genes involved in cholesterol biosynthesis and homeostasis. SREBP-2 binds to the sterol regulatory elements (SREs) in the promoters of its target genes and activates the transcription of mevalonate pathway genes, such as HMG-CoA reductase (HMGCR), mevalonate kinase and other key enzymes. In this review, we first summarized the structure of SREBP-2 and

Intensive Care Unit-Acquired Weakness: Not just Another Muscle Atrophying Condition.

Intensive care unit-acquired weakness (ICUAW) occurs in critically ill patients stemming from the critical illness itself, and results in sustained disability long after the ICU stay. Weakness can be attributed to muscle wasting, impaired contractility, neuropathy, and major pathways associated with muscle protein degradation such as the ubiquitin proteasome system and dysregulated autophagy. Furthermore, it is characterized by the preferential loss of myosin, a distinct feature of the condition. While many risk factors for ICUAW have been identified, effective interventions to offset these ch

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… Phagophores engulf intracellular cargo, and form double-membraned autophagosomes which ultimately fuse with lysosomes to form autolysosomes [ 86 , 87 , 88 ]. In the autolysosomes, the autophagic cargo is degraded by lysosomal hydrolases. … In critically ill patients, rectus abdominis biopsies revealed increased levels of positive regulators of autophagy (beclin-1 and the Atg5-Atg12 complex), as well as decrease in mature autophagic vesicles indicated by an increase of LC3-I, but not LC3 -II, which is a readout for mature autophagosome …

The nutrigenomic-epigenetic axis in cancer: from dietary bioactives to precision oncology.

Cancer development and progression are increasingly understood to arise from dynamic interactions between genetic alterations and environmentally driven epigenetic regulation, with dietary exposures representing one of the most biologically influential and modifiable factors. Given the expanding evidence linking nutrition to epigenomic remodeling, a comprehensive synthesis of how specific dietary components influence cancer-relevant epigenetic mechanisms is needed to clarify their preventive and therapeutic relevance. This review brings together mechanistic, epidemiologic, and translational fi

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… Cancer cell growth is further promoted by impaired autophagosome maturation driven by p300-mediated acetylation of Atg6 at lysines 430 and 437, establishing a connection between acetylation events and enhanced tumor proliferation [ 225 , 226 ]. … The formation of autophagosomes, critical components of the autophagy pathway, is effectively impeded by histone methyltransferase G9a, a molecule highly expressed in a diverse array of cancers, through transcriptional repression of the genes LC3 and WIPI1 [ 229 ]. …