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Role of autophagy in cholangiocarcinoma: An autophagy-based treatment strategy.

Cholangiocarcinomas (CCAs) are diverse biliary epithelial tumours involving the intrahepatic, perihilar and distal parts of the biliary tree. The three entirely variable entities have distinct epidemiology, molecular characteristics, prognosis and strategy for clinical management. However, many cholangiocarcinoma tumor-cells appear to be resistant to current chemotherapeutic agents. The role of autophagy and the therapeutic value of autophagy-based therapy are largely unknown in CCA. The multistep nature of autophagy offers a plethora of regulation points, which are prone to be deregulated and

Cellular and molecular mechanisms of muscle atrophy.

Skeletal muscle is a plastic organ that is maintained by multiple pathways regulating cell and protein turnover. During muscle atrophy, proteolytic systems are activated, and contractile proteins and organelles are removed, resulting in the shrinkage of muscle fibers. Excessive loss of muscle mass is associated with poor prognosis in several diseases, including myopathies and muscular dystrophies, as well as in systemic disorders such as cancer, diabetes, sepsis and heart failure. Muscle loss also occurs during aging. In this paper, we review the key mechanisms that regulate the turnover of co

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… Interestingly, fast glycolytic muscles display a higher content of autophagosomes than slow β-oxidative muscles ( Mizushima et al., 2004 ). … Bnip3 and Bnip3L reportedly bind directly to LC3, and can therefore recruit the growing autophagosome to mitochondria ( Hanna et al., 2012 ; Novak et al., 2010 ). …

CXCL13 Повреждает позвоночник крови, поощряя RNF6/Sqstm1-Ubictiination.

Повреждение позвоночника крови (BSCB) приводит к нарушению иммунной микроокружающей среды в центральной нервной системе во время развития множественного склероза (MS) и экспериментального аллергического энцефаломиэлита (EAE). Тем не менее основные механизмы, связанные с повреждением барьера, по-прежнему недостаточно изучены. Здесь, анализируя белковые профили в периферической сыворотке крови, хемокин (C-X-C motif) Ligand 13 (CXCL13) был определен как возрастающий по мере развития MS и EAE. Отсутствие CXCL13 привело к снижению симптомов EAE, о чем свидетельствует сокращение числа клинических оц

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… Yellow puncta indicate autophagosomes and red puncta represent autolysosomes. F) Quantification analyses of puncta in E. G) TEM images show the autophagosomes and autolysosomes in bEnd.3 cells. N indicates nuclei. Single arrows represent autophagosomes, double arrows indicate autophagosomes. … H) Quantification analyses of autophagosomes and autophagosomes G. n   = 15. Data are presented as the mean ± SD. *p < 0.05, **p < 0.01, *** p <  0.001, **** p <  0.0001 versus Vehicle . # p < 0.05, ## p < 0.01 versus CXCL13. …

Nanomedicine Approaches for Autophagy Modulation in Cancer Therapy.

Cancer is a daunting global health problem with a steadily rising incidence. Despite the wide arsenal of current anticancer therapies, challenges such as drug resistance, tumor heterogeneity, poor targeting, and severe side effects often lead to suboptimal efficacy and poor patient outcomes, highlighting the need for innovative therapies. Autophagy modulation has emerged as an attractive approach to complement existing therapies. The dual role of autophagy in cancer promotion and suppression has inspired the development of new drugs and therapeutic strategies focusing on both inhibition and in

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… formation. p62 (SQSTM1) functions as an autophagy adaptor by binding ubiquitinated cargo and interacting with LC3 on autophagosomes, facilitating cargo recruitment into autophagosomes for lysosomal degradation. [ 36 , 37 ] Once the autophagosome is completed, the ATG12‐ATG5 complex dissociates, and … Activation of the AMPK/mTOR pathway was reported to cause autophagosome accumulation by blocking autophagosome‐lysosome fusion. Additionally, autophagy inhibition by NBP/TiO2NPs enhanced the effects of bortezomib and photothermal therapy (PTT). …

Autophagy in tumor immune escape and immunotherapy.

The immunotherapy targeting tumor immune escape mechanisms has become a critical strategy in anticancer treatment; however, the challenge of immune resistance remains significant. Autophagy, a cellular response to various stressors, involves the degradation of damaged proteins and organelles via lysosomal pathways, maintaining cellular homeostasis. This process not only supports tumor cell survival but also profoundly impacts the efficacy of cancer immunotherapies. The modulation of autophagy in tumor cells or immune cells exerts dual effects on tumor immune escape and immunotherapy. However,

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… The lipidated form, LC3-II, associates with autophagosome membranes, promoting autophagosome formation [ 21 , 28 ]. … Afterward, nascent autophagosomes fuse with vesicles that originate from endolysosomal compartments prior to the formation of degradative autolysosomes, and this process is called autophagosome maturation. …

APOE4 ослабляет липофагическую липофагию и поощряет демиэлизацию спиральных ганглионов в мышином кохлее.

АпоЭ-4 Ген представляет собой прочно установившийся генетический фактор риска для нейродегенеративных заболеваний, таких, как болезнь Альцгеймера и множественный склероз, которые характеризуются аксонной демиелинацией в центральной нервной системе. В недавних исследованиях были замешаны АпоЕ-4 в связи с возрастной потерей слуха (ARHL), что предполагает потенциальную роль изоформы APOE4 в дегенерации периферической нервной системы. Однако роль APOE4 в ARHL по-прежнему не ясна. В этом исследовании мы изучили потенциальную роль APOE4 в аксонной демиелиции спиральных ганглионов (SGN). АпоЭ-4/ __4

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… A TEM of RCM autophagosomes (Solid circle) near SGNs in cochleae of 6- and 10-month-old APOE4 and APOE3 mice. Scale bar: 1 μm. The arrows denote the enlarged region showing RCM autophagosomes. Scale bar: 0.25 μm. … B Quantification of RCM autophagosomes per scope. (10 autophagosomes in every view, each dot represents all autophagosomes in a microscope field, n  = 6; * P  < 0.05, ** P  < 0.01 by one-way ANOVA). C Immunofluorescent staining of LDs (BODIPY in green) in APOE3 and APOE4 BMDMs (LC3 in red). …

Modulating glycosphingolipid metabolism and autophagy improves outcomes in pre-clinical models of myeloma bone disease.

Patients with multiple myeloma, an incurable malignancy of plasma cells, frequently develop osteolytic bone lesions that severely impact quality of life and clinical outcomes. Eliglustat, a U.S. Food and Drug Administration-approved glucosylceramide synthase inhibitor, reduced osteoclast-driven bone loss in preclinical in vivo models of myeloma. In combination with zoledronic acid, a bisphosphonate that treats myeloma bone disease, eliglustat provided further protection from bone loss. Autophagic degradation of TRAF3, a key step for osteoclast differentiation, was inhibited by eliglustat as ev

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… Diao J ATG14 promotes membrane tethering and fusion of autophagosomes to endolysosomes Nature 2015 520 563 566 25686604 10.1038/nature14147 PMC4442024 Diao, J. et al. ATG14 promotes membrane tethering and fusion of autophagosomes to endolysosomes. … Matarrese P Evidence for the involvement of GD3 ganglioside in autophagosome formation and maturation Autophagy 2014 10 750 765 24589479 10.4161/auto.27959 PMC5119056 Matarrese, P. et al. Evidence for the involvement of GD3 ganglioside in autophagosome formation and maturation. …

Targeting Autophagy Using Long Non-Coding RNAs (LncRNAs): New Landscapes in the Arena of Cancer Therapeutics.

Cancer has become a global health hazard accounting for 10 million deaths in the year 2020. Although different treatment approaches have increased patient overall survival, treatment for advanced stages still suffers from poor clinical outcomes. The ever-increasing prevalence of cancer has led to a reanalysis of cellular and molecular events in the hope to identify and develop a cure for this multigenic disease. Autophagy, an evolutionary conserved catabolic process, eliminates protein aggregates and damaged organelles to maintain cellular homeostasis. Accumulating evidence has implicated the

Inhibition of autophagy enhances the antitumour activity of tigecycline in multiple myeloma.

Accumulating evidence shows that tigecycline, a first-in-class glycylcycline, has potential antitumour properties. Here, we found that tigecycline dramatically inhibited the proliferation of multiple myeloma (MM) cell lines RPMI-8226, NCI-H929 and U266 in a dose and time-dependent manner. Meanwhile, tigecycline also potently impaired the colony formation of these three cell lines. Mechanism analysis found that tigecycline led to cell cycle arrest at G0/G1 with down-regulation of p21, CDK2 and cyclin D1, rather than induced apoptosis, in MM cells. Importantly, we found that tigecycline induced

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… Finally, the autophagosomes were observed under a transmission electron microscope (H‐7500, Hitachi, Japan). … C, After treatment with 20 μmol/L tigecycline for 48 h, autophagosomes were observed in RPMI‐8226 cells under a transmission electron microscope. On the left panel, the arrow indicates the mitochondrial; on the right panel, the arrows indicate the autophagosomes. …

CD13 downregulation mediated by ubenimex inhibits autophagy to overcome 5-FU resistance by disturbing the EMP3/FAK/NF-κB pathway in gastric cancer cells.

BackgroundGastric cancer (GC) is one of the most common malignant tumours in China, but the efficacy of chemotherapy on GC is significantly reduced due to the occurrence of drug resistance. Some studies have shown that the expression level of CD13 is associated with tumour resistance, but whether ubenimex, as a CD13 inhibitor, reverses GC drug resistance and the underlying mechanism remain unclear.MethodsHerein, resistance to 5-fluorouracil (5-FU) was reversed in GC by ubenimex, and the underlying mechanism was determined using Cell Counting Kit-8 (CCK-8) assays, gene chip analysis, high conte

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… The arrows indicate the appearance of autophagosomes (scale bar, 2 µm). Untreated cells were used as control. (D) Quantification of the autophagosomes of 3 independent experiments is shown. ***P<0.001 vs . control untreated cells. Ube, ubenimex; 5-FU, 5-fluorouracil; SD, standard deviation. … Cells 2021 ; 10 : 867 . 10.3390/cells10040867 33920284 PMC8068966 22 Hara T Takamura A Kishi C FIP200, a ULK-interacting protein, is required for autophagosome formation in mammalian cells. …

Shengma Biejia Decoction Inhibits Cell Growth in Multiple Myeloma by Inducing Autophagy-Mediated Apoptosis Through the ERK/mTOR Pathway.

Shengma Biejia decoction (SMBJD), a traditional Chinese formula recorded in the Golden Chamber, has been widely used for the treatment of malignant tumors. However, its underlying molecular targets and mechanisms are still unclear. This study showed that SMBJD inhibited tumor growth and stimulated hemogram recovery significantly in a multiple myeloma xenograft model. Western blot and immunohistochemistry assays of tumor tissues showed that SMBJD reduced the ratio of autophagy-related proteins LC3-II/LC3-I, while P62 and apoptosis-related proteins cleaved caspase-3/caspase-3 and Bax/Bcl-2 were

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… There was a substantial accumulation of autophagosomes and autophagolysosomes in both H929 and U266 cells. However, numbers of GFP-LC3 puncta were decreased after treatment with SMBJD ( Figure 4C ). … However, as autophagy is a dynamic process, the reduction in LC3-II/LC3-I could indicate that SMBJD inhibited the formation of autophagosomes or that it promoted the degradation of autophagolysosomes. …

Regulating the regulators: long non-coding RNAs as autophagic controllers in chronic disease management.

The increasing prevalence of chronic diseases and their associated morbidities demands a deeper understanding of underlying mechanism and causative factors, with the hope of developing novel therapeutic strategies. Autophagy, a conserved biological process, involves the degradation of damaged organelles or protein aggregates to maintain cellular homeostasis. Disruption of this crucial process leads to increased genomic instability, accumulation of reactive oxygen species (ROS), decreased mitochondrial functions, and suppression of ubiquitination, leading to overall decline in quality of intrac

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… It is a dynamic, regulated cellular process that involves the degradation of cellular components within specialized compartments called autophagosomes [ 13 ]. … For example, the lncRNA MEG3 promoted autophagy by interacting with the autophagy-related gene 5 (ATG5) and facilitating the formation of autophagosomes [ 31 ]. …

ER-mitochondria tethering and its signaling: A novel therapeutic target in breast cancer.

Communication between the endoplasmic reticulum (ER) and mitochondria through mitochondria-associated ER membranes (MAMs) is assisted by tethering proteins and signaling pathways, manifesting the dynamic exchange of lipids, calcium, and signaling molecules. However, dysregulation of tethering and signaling proteins contributes to the progression of breast cancer (BC). Abnormal MAM structures and altered ER-mitochondrial tethering impair mitochondrial functions and thereby drive BC progression. Altered mitochondrial dynamics, often characterized by dysregulated dynamin-related protein 1 (Drp1)

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… This results in binding of mitochondria with the LC3 of autophagosome (8, 9). The stressors on the other hand also cause cardiolipin reorganization on the OMM (10). These changes result in generating an “eat me signal” by mitochondria to bind to the LC3 receptor of autophagosomes (11). … Thus, the autophagosome formed through various mechanisms engulfs the damaged mitochondria (12). Also, AMBRA1 binds to LC3 autophagosome (13). Parallelly, PRKN upregulates TEEB for lysosomes synthesis (14, 15, 16). The lysosome thus formed encounters LC3 autophagosome and mediates mitophagy (17). …

Role of autophagy in cholangiocarcinoma: Pathophysiology and implications for therapy.

Cholangiocarcinoma (CCA) is a malignant tumour of the biliary system that originates from the neoplastic transformation of cholangiocytes. CCA is characterized by late diagnosis and poor outcome, with surgery considered as the last option for management. Autophagy is a physiological lysosomal degradation process, essential for cellular homeostasis and ubiquitous in all eukaryotic cells. Several studies have reported a potential involvement of autophagy in cancer, but it remains unclear whether activation of this process represents a survival mechanism of cancer cells. In the present review, we

CS-6-induced p62 accumulation exacerbates DNA damage in colorectal cancer.

BACKGROUND: Gamabufotalin (CS-6), a bufadienolide derived from Chansu, has been reported to exhibit anti-tumor effects in various cancers, including glioblastoma, nonsmall cell lung cancer, and breast cancer. However,its role in colorectal cancer (CRC) remains unexplored. OBJECTIVE: Our study aimed to evaluate the inhibition of CS-6 to CRC cells by cell viability assay, colony formation assay, comet assay, and cell cycle analysis firstly. And its molecular mechanism was studied by immunofluorescence (IF) assay, western blot (WB) assay, siRNA transfection, protein-protein interaction (PPI) net

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… Positioned as an adaptable protein between the autophagosome and its substrate, p62 is selectively wrapped into the autophagosome, acting as a bridge between microtubule-associated proteins I/II light chain 3II, commonly known as LC3, the protein that plays a significant role in cellular processes, particularly … ATG5 is an autophagy-related protein required for the formation of autophagosomes ( Fernández et al., 2018 ). …

Deciphering the impact of circRNA-mediated autophagy on tumor therapeutic resistance: a novel perspective.

Cancer therapeutic resistance remains a significant challenge in the pursuit of effective treatment strategies. Circular RNAs (circRNAs), a class of non-coding RNAs, have recently emerged as key regulators of various biological processes, including cancer progression and drug resistance. This review highlights the emerging role of circRNAs-mediated autophagy in cancer therapeutic resistance, a cellular process that plays a dual role in cancer by promoting both cell survival and death. Increasing evidence suggests that circRNAs can modulate autophagy pathways, thereby influencing the response o

Pluripotent Stem Cells for Disease Modeling and Drug Discovery in Niemann-Pick Type C1.

The lysosomal storage disorders Niemann-Pick disease Type C1 (NPC1) and Type C2 (NPC2) are rare diseases caused by mutations in the NPC1 or NPC2 gene. Both NPC1 and NPC2 are proteins responsible for the exit of cholesterol from late endosomes and lysosomes (LE/LY). Consequently, mutations in one of the two proteins lead to the accumulation of unesterified cholesterol and glycosphingolipids in LE/LY, displaying a disease hallmark. A total of 95% of cases are due to a deficiency of NPC1 and only 5% are caused by NPC2 deficiency. Clinical manifestations include neurological symptoms and systemic

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… Treatment with recombinant VEGF decreased the protein level of these markers and decreased autophagosome accumulation, suggesting that VEGF elevates autophagosome-lysosome fusion. Thus, VEGF demonstrates a potential therapeutic intervention strategy for NPC1 disease. … All studies about autophagy in NPC1 depicted the accumulation of LC3BII and p62 as a result of an inhibited clearance of autophagosomes due to an inhibited fusion of autophagosomes and lysosomes, displaying a major component of the overall defective autophagy. …

Chemotherapy-Induced Tissue Injury: An Insight into the Role of Extracellular Vesicles-Mediated Oxidative Stress Responses.

The short- and long-term side effects of chemotherapy limit the maximum therapeutic dose and impair quality of life of survivors. Injury to normal tissues, especially chemotherapy-induced cardiomyopathy, is an unintended outcome that presents devastating health impacts. Approximately half of the drugs approved by the Food and Drug Administration for cancer treatment are associated with the generation of reactive oxygen species, and Doxorubicin (Dox) is one of them. Dox undergoes redox cycling by involving its quinone structure in the production of superoxide free radicals, which are thought to

Mechanisms and effects of metformin on skeletal muscle disorders.

Skeletal muscle disorders are mostly genetic and include several rare diseases. With disease progression, muscle fibrosis and adiposis occur, resulting in limited mobility. The long course of these diseases combined with limited treatment options affect patients both psychologically and economically, hence the development of novel treatments for neuromuscular diseases is crucial to obtain a better quality of life. As a widely used hypoglycemic drug in clinical practice, metformin not only has anti-inflammatory, autophagy-regulating, and mitochondrial biogenesis-regulating effects, but it has a

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… The process of autophagy is divided into three stages: the formation of phagophores or isolation membranes, autophagosomes, and autolysosomes ( 47–49 ). The formation of an autophagosome is a hallmark of autophagy initiation. … During autophagosome formation, microtubule-associated protein 1A/1B-light chain 3 (LC3) is processed into the soluble form, LC3-I. Then, LC3-I binds to phosphatidylethanolamine (PE) on the surface of the autophagosome membrane, becoming membrane bound LC3-II. …

α2-3-sialylated Гликосфинголипиды при нейроинфламмации, иммунитете и запрограммированной смерти клеток: механистические доказательства и регулирование в зависимости от контекста: всеобъемлющий обзор.

α2-3-sialylated glycosphingolids (α2)3-GSLs) являются основными составляющими нейронных мембран и липидных плотов, где они формируют сепарацию рецепторов, комплекс сигналов и связь с клетками. Однако их биологическое воздействие варьируется в зависимости от молекулярного подтипа, типа клеток, стадии заболевания, концентрации и местной микроокружающей среды. В настоящем обзоре обобщены данные о перепончатых изменениях в α2-3-GSL профили и их связи с нейроинфламмацией, иммунной реакцией, протеостазом и запрограммированной клеточной смертностью через болезнь Паркинсона, болезнь Альцгеймера, болез