Springer Science and Business Media LLC

Celastrol has been reported to possess anticancer effects in various cancers; however, the precise mechanism underlying ROS-mediated mitochondria-dependent apoptotic cell death triggered by celastrol treatment in melanoma cells remains unknown. We showed that celastrol effectively induced apoptotic cell death and inhibited tumor growth using tissue culture and in vivo models of B16 melanoma. In addition to apoptotic cell death in B16 cells, several apoptotic events such as PARP cleavage and activation of caspase were confirmed. Pretreatment with caspase inhibitor modestly attenuated the celastrol-induced increase in PARP cleavage and sub-G1 cell population, implying that caspases play a partial role in celastrol-induced apoptosis. Moreover, ROS generation was detected following celastrol treatment. Blocking of ROS accumulation with ROS scavengers resulted in inhibition of celastrol-induced Bcl-2 family-mediated apoptosis, indicating that celastrol-induced apoptosis involves ROS generation as well as an increase in the Bax/Bcl-2 ratio leading to release of cytochrome c and AIF. Importantly, silencing of AIF by transfection of siAIF into cells remarkably attenuated celastrol-induced apoptotic cell death. Moreover, celastrol inhibited the activation of PI3K/AKT/mTOR signaling cascade in B16 cells. Our data reveal that celastrol inhibits growth and induces apoptosis in melanoma cells via the activation of ROS-mediated caspase-dependent and -independent pathways and the suppression of PI3K/AKT signaling.

The original version of this article unfortunately contained an error in acknowledgment text. The authors would like to include a statement: “Moumita Dasgupta is supported by Junior Research Fellowship from University Grant Commission, India.” in acknowledgment section.

Maintenance of cellular homeostasis requires tight and coordinated control of numerous metabolic pathways, which are governed by interconnected networks of signaling pathways and energy-sensing regulators. Autophagy, a lysosomal degradation pathway by which the cell self-digests its own components, has over the past decade been recognized as an essential part of metabolism. Autophagy not only rids the cell of excessive or damaged organelles, misfolded proteins, and invading microorganisms, it also provides nutrients to maintain crucial cellular functions. Besides serving as essential structural moieties of biomembranes, lipids including sphingolipids are increasingly being recognized as central regulators of a number of important cellular processes, including autophagy. In the present review we describe how sphingolipids, with special emphasis on ceramides and sphingosine-1-phosphate, can act as physiological regulators of autophagy in relation to cellular and organismal growth, survival, and aging.

This analysis covers 4494 anoikis-related publications (2003–2022). It explores annual trends, top countries, core journals, leading institutions, keywords, references, authors, and collaborations. Key findings include the United States leading in publications, Chulalongkorn University as the top institution, and Oncogene as the most prolific journal. The Journal of Biological Chemistry holds the highest influence. Burst keywords like “signal transduction,” “apoptosis resistance,” “metabolism,” and “tumor microenvironment” highlight emerging research areas. This study offers a comprehensive overview, aiding researchers in grasping anoikis research trends, contributors, and prospects.

Post-traumatic stress disorder (PTSD) is characterized with abnormal learning and memory. Impairments in learning and memory are closely associated with apoptosis in the medial prefrontal cortex (mPFC). We previously examined the endoplasmic reticulum (ER) stress was involved in the apoptosis in the mPFC of PTSD. The PERK pathway plays the important role in the ER stress-induced apoptosis. The aim of the present study was to explore the role of PERK pathway in neuronal apoptosis in the mPFC of rat models of PTSD. We used the single prolonged stress (SPS) to mimic PTSD in rats and studied the effects of the PERK pathway in mPFC. Learning and memory behavior were examined by Morris water maze and novel object recognition tests. Apoptosis in mPFC was detected by TUNEL staining. Our results showed decreased learning memory and increased apoptosis of mPFC neurons in rats exposed to SPS. SPS exposure upregulate mRNA expressions of PERK, p-PERK, eIF2α, p-eIF2α, nuclear ATF4 and C/EBP-homologous protein (CHOP) in mPFC neurons, but the protein levels of these molecules showed difference in magnitude and time course. GSK2606414 (an antagonist of PERK) treatment successfully reversed the above changes. These results suggested that the PERK pathway mediated SPS-induced neural apoptosis in the mPFC. These findings will be helpful in understanding mPFC-related pathogenesis of PTSD.

Apoptosis is involved in the pathogenesis of Sjögren’s syndrome (SS), an autoimmune disease affecting exocrine glands. Our recent studies revealed diminished histamine H4 receptor (H4R) expression and impaired histamine transport in the salivary gland epithelial cells in SS. The aim was now to test if nanomolar histamine and high-affinity H4R signaling affect apoptosis of human salivary gland epithelial cell. Simian virus 40-immortalized acinar NS-SV-AC cells were cultured in serum-free keratinocyte medium ± histamine H4R agonist HST-10. Expression and internalization of H4R were studied by immunofluorescence staining ± clathrin inhibitor methyl-β-cyclodextrin (MβCD). Apoptosis induced using tumor necrosis factor-α with nuclear factor-κB inhibitor IMD-0354 was studied using phase contrast microscopy, Western blot, flow cytometry and polymerase chain reaction (qRT-PCR). HST-10-stimulated H4R internalization was inhibited by MβCD. Western blotting revealed diminished phosphorylated c-Jun N-terminal kinase JNK, but unchanged levels of phosphorylated extracellular signal regulated kinase pERK1/2 in H4R-stimulated samples compared to controls. qRT-PCR showed up-regulated expression of anti-apoptotic B cell lymphoma-extra large/Bcl-xL mRNAs and proteins, whereas pro-apoptotic Bcl-2-associated X protein/BAX remained unchanged in H4R-stimulated samples. H4R stimulation diminished cleavage of PARP and flow cytometry showed significant dose-dependent inhibitory effect of H4R stimulation on apoptosis. As far as we know this is the first study showing inhibitory effect of H4R activation on apoptosis of human salivary gland cells. Diminished H4R-mediated activation may contribute to loss of immune tolerance in autoimmune diseases and in SS in particular.

Fibroblasts are cultured in three-dimensional collagen matrices to investigate the effect of mechanical tension on the regulation of apoptosis. Under the influence of mechanical loading, the cells show little apoptosis whereas releasing of tension leads to an increase up to tenfold during the first 24 h and remains constant for further 48 h. An autocrine loop of the integrin αVβ3/CD47 receptor complex and thrombospondin-1 is identified as the molecular coupling device between mechanical loading and apoptosis: The integrin αVβ3 is expressed under mechanical loading as well as unloading whereas the CD47 could only be identified after the release of tension. The secreted thrombospondin binds to the active receptor and induces apoptosis. The presented mechanosensitive regulation of apoptosis in fibroblast cultures could be an essential mechanism for the regression of the granulation tissue by apoptosis in the process of wound healing.

Imidazoacridinone C-1311 is a DNA-targeting antitumor intercalator/alkylator currently undergoing Phase II clinical trials. Here, we elucidated the sequence of death responses to C-1311 in human leukemia MOLT4 cells using drug concentration (30 nM) that causes near complete cell growth inhibition at 48 h. Early (6–12 h) responses included transient accumulation of cells at the G2/M border followed by also transient rise in several mitotic markers. Mitotic attempts were largely abnormal, resulting in numerous multinucleated cells (peaking at 24–39 h and declining markedly at later times). These events, indicative of mitotic catastrophe, were not associated with immediate cell death. The fraction of necrotic cells did not exceed 3%. Also, the classical manifestations of apoptosis were marginal at 24 h and their progression clearly followed the decline in the fraction of mitotic and multinucleated cells. Quantification of several apoptotic markers (including phosphatidylserine externalization, apoptotic DNA breaks, mitochondrial dysfunction, caspase activation, and cell membrane integrity) showed a considerable progression and the shift from early to late apoptosis at later times. At 72 h, >80% of cells were apoptotic. Collectively, these findings show that C-1311-induced mitotic catastrophe is not the ultimate death event but rather a step precipitating delayed, albeit massive, apoptotic responses.

Khoảng ba trên một trăm nghìn người được chẩn đoán mắc glioblastoma đa hình, hay còn gọi là glioblastoma, đây là loại khối u não nguyên phát phổ biến nhất ở người lớn. Với tiên lượng ảm đạm chỉ hơn một năm, việc nhận được chẩn đoán glioblastoma thường dẫn đến cái chết. Một bước tiến lớn trong điều trị bệnh này đã được thực hiện gần hai thập kỷ trước khi tác nhân hóa trị liệu kiềm hóa temozolomide (TMZ) được kết hợp với xạ trị (RT). Kể từ đó, ít tiến bộ đã được thực hiện. Các liệu pháp tập trung vào việc điều hòa quá trình tự tiêu hoại, một quá trình quan trọng điều chỉnh cân bằng tế bào, đã được phát triển nhằm ngăn chặn sự tiến triển của glioblastoma. Vai trò kép của tự tiêu hoại (sinh tồn tế bào hoặc chết tế bào) trong glioblastoma đã dẫn đến sự phát triển của các chất ức chế và kích thích tự tiêu hoại, hoạt động như liệu pháp đơn hoặc như một phần của liệu pháp kết hợp để gây ra cái chết tế bào, lão hóa tế bào và chống lại khả năng của các tế bào gốc glioblastoma (GSCs) trong việc khởi phát tái phát khối u. Sự phong phú của các con đường tế bào tác động lên việc điều hòa tự tiêu hoại đã tạo ra sự tranh chấp giữa hai nhóm: những người sử dụng ức chế tự tiêu hoại và những người sử dụng kích thích tự tiêu hoại để kiểm soát sự phát triển của glioblastoma. Chúng tôi thảo luận về lý do sử dụng các liệu pháp chính hiện tại, cơ chế phân tử của chúng trong việc điều hòa tự tiêu hoại ở glioblastoma và GSCs, tiềm năng của chúng trong việc tiến bộ trong việc chống lại sự tiến triển của glioblastoma, và có thể có những thiếu sót của chúng. Những thiếu sót này có thể thúc đẩy sự đổi mới về hệ thống cung cấp và liệu pháp mới liên quan đến TMZ kết hợp với một tác nhân khác nhằm mở đường cho tiêu chuẩn vàng mới trong điều trị glioblastoma.