Apoptosis: A Comprehensive Overview of Signaling Pathways, Morphological Changes, and Physiological Significance and Therapeutic Implications

Cells, Год журнала: 2024, Номер 13(22), С. 1838 - 1838

Опубликована: Ноя. 6, 2024

Cell survival and death are intricately governed by apoptosis, a meticulously controlled programmed cell death. Apoptosis is vital in facilitating embryonic development maintaining tissue homeostasis immunological functioning. It complex interplay of intrinsic extrinsic signaling pathways that ultimately converges on executing the apoptotic program. The pathway initiated binding ligands such as TNF-α Fas to their respective receptors surface. In contrast, leads increased permeability outer mitochondrial membrane release apoptogenic factors like cytochrome c, which regulated Bcl-2 family proteins. Once activated, these lead cascade biochemical events, including caspase activation, DNA fragmentation, dismantling cellular components. Dysregulation apoptosis implicated various disorders, cancer, autoimmune diseases, neurodegenerative cardiovascular diseases. This article focuses elucidating molecular mechanisms underlying regulation, develop targeted therapeutic strategies. Modulating holds immense potential cancer treatment, where promoting malignant cells could tumor regression. demonstrates targeting providing options for treating neurological illnesses. safety effectiveness apoptosis-targeting drugs being assessed ongoing preclinical clinical trials (phase I-III), opening door more effective approaches better patient outcomes.

Язык: Английский

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MTMR7 attenuates the proliferation and migration of pulmonary arterial smooth muscle cells in pulmonary hypertension by suppressing ERK/STAT3 signaling

Molecular and Cellular Biochemistry, Год журнала: 2025, Номер unknown

Опубликована: Фев. 7, 2025

Язык: Английский

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Drug resistance and tumor immune microenvironment: An overview of current understandings (Review)

International Journal of Oncology, Год журнала: 2024, Номер 65(4)

Опубликована: Авг. 30, 2024

The use of antitumor drugs represents a reliable strategy for cancer therapy. Unfortunately, drug resistance has become increasingly common and contributes to tumor metastasis local recurrence. immune microenvironment (TME) consists cells, cytokines immunomodulators, collectively they influence the response treatment. Epigenetic changes including DNA methylation histone modification, as well increased exportation have been reported contribute development in cancers. In past few years, majority studies on tumors only focused progression from mechanistic standpoint; examined whether TME can also affect growth resistance. Recently, emerging evidence raised more concerns regarding role present review, it was discussed how suppressive adapts characterized by cooperation cytokines, stromal cells extracellular matrix. Furthermore, reviewed these immunological or metabolic alter immuno‑surveillance thus facilitate addition, potential targets developing novel therapeutic strategies improve individualized therapy treatment were revealed.

Язык: Английский

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Discovery of SD-436: A Potent, Highly Selective and Efficacious STAT3 PROTAC Degrader Capable of Achieving Complete and Long-Lasting Tumor Regression

Journal of Medicinal Chemistry, Год журнала: 2024, Номер 67(22), С. 20495 - 20513

Опубликована: Ноя. 7, 2024

STAT3 is an attractive therapeutic target for cancer and other human diseases. We have previously reported the discovery of potent, selective, efficacious PROTAC degraders SD-36 SD-91. In this study, we designed synthesized a novel series using new, high-affinity ligand with excellent chemical stability cereblon ligands. Our efforts led to SD-436, highly potent selective degrader. A single intravenous administration SD-436 at 5 mg/kg effectively induces rapid, complete, durable depletion in mouse native xenograft tumor tissues. achieves complete long-lasting regression even weekly dosing schedule leukemia lymphoma models mice. represents promising degrader advanced preclinical development as new therapy treatment cancers

Язык: Английский

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Potential of Bioactive Compounds In Coleus amboinicus, Lour., Leaves Against Breast Cancer By Assessment Using A Network Pharmacology Approach and Cytotoxic Test

Journal of Multidisciplinary Applied Natural Science, Год журнала: 2025, Номер 5(1), С. 267 - 287

Опубликована: Янв. 26, 2025

Breast cancer is a disease that significantly contributes to global women death. The study aims conduct in vitro activity testing and assessment with bioinformatics approach using pharmacological network of bioactive compounds from bangun-bangun (Coleus amboinicus) leaves extract as breast drug. methods used are extraction by maceration partition, identification analysis the Liquid Chromatography High-Resolution Mass Spectrometry (LC-HRMS) instrument, cytotoxic cells (MCF-7) normal (CV-1) MTT method, through pharmacology. results test ethyl acetate provided better IC50 value 102.30 457.09 µg/mL against MCF-7 CV-1 cells. selectivity index 4.23 indicates potential for further development treatment cancer. chemical compound content show various types anticancer; networks pharmacology pathways provides predictions signal transducer activator transcription 3 (STAT3) protein main therapeutic mechanism target treatment. This initial information research on utilizing C. amboinicus an alternative

Язык: Английский

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STAT signaling in the pathogenesis and therapy of acute myeloid leukemia and myelodysplastic syndromes

Neoplasia, Год журнала: 2025, Номер 61, С. 101137 - 101137

Опубликована: Фев. 10, 2025

Язык: Английский

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METTL14‐mediated m6A modification of ZFP14 inhibits clear cell renal cell carcinoma progression via promoting STAT3 ubiquitination

Clinical and Translational Medicine, Год журнала: 2025, Номер 15(2)

Опубликована: Фев. 1, 2025

Abstract Therapeutic options for advanced clear cell renal carcinoma (ccRCC) are currently inadequate. Earlier research has shown that the enzyme methyltransferase‐like 14 (METTL14) can suppress ccRCC development through modification of N6‐methyladenosine (m6A). This study further explored its complex biological functions and underlying molecular mechanisms. Here, we identified zinc finger protein (ZFP14) as a novel target METTL14‐mediated m6A, under‐expression was associated with tumourigenesis progression. Detailed investigations revealed METTL14 interacted directly 3′ untranslated region ZFP14 mRNA, promoting m6A at two specific sites. These modifications were recognised by insulin‐like growth factor 2 mRNA‐binding (IGF2BP2), which stabilised enhanced expression mRNA. Functionally, METTL14/ZFP14 axis suppressed in vitro growth, migration invasiveness vivo proliferation metastasis cells. potentially regulated numbers transcripts, among matrix metalloproteinase 1/3 (MMP1/3) validated to be under‐expressed ZFP14. Crucially, signal transducer activator transcription 3 (STAT3), augmenting K48‐linked ubiquitination destabilising it via proteasome pathway. Moreover, repressed well decreasing MMP1/3 levels under‐expressing STAT3. observations confirmed served both significant tumour suppressor ccRCC, shedding light on cellular operations opening up possibilities therapeutic strategies. Key points is enhances mRNA stability IGF2BP2 reader ccRCC. promotes degradation STAT3 enhancing ubiquitination, inhibiting

Язык: Английский

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Efficacy and safety of immunotherapy plus chemotherapy in advanced or metastatic pulmonary large-cell neuroendocrine carcinoma

Discover Oncology, Год журнала: 2025, Номер 16(1)

Опубликована: Март 14, 2025

Patients with advanced pulmonary large-cell neuroendocrine carcinoma (LCNEC) have a progressive clinical course and poor prognosis, effective treatment options remain limited. This study assessed the efficacy safety of immunotherapy plus chemotherapy for LCNEC. We retrospectively collected medical records patients LCNEC who attended Shandong Cancer Hospital from January 2018 to December 2022. were divided into two groups based on their previous regimen: alone. Kaplan–Meier survival curves Cox regression models used evaluate different regimens. The median follow-up was 29.33 months (95% confidence interval [CI]: 24.04–not reached). overall (OS) 15.01 CI: 11.99–26.31) 7.19 5.15–10.57) in groups, respectively (P = 0.001). Following propensity score matching, OS 17.41 11.99–29.20) 5.88 4.50–11.53) respectively. progression-free 6.70 5.48–13.27) 3.12 2.52–4.20) also found that increasing age may contribute poorer prognosis < 0.05). Immunotherapy significantly improved compared LCNEC, tolerable profile without life-threatening adverse events. be an option

Язык: Английский

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STAT3 Signaling Pathway in Health and Disease

MedComm, Год журнала: 2025, Номер 6(4)

Опубликована: Март 30, 2025

ABSTRACT Signal transducer and activator of transcription 3 (STAT3) is a critical factor involved in multiple physiological pathological processes. While STAT3 plays an essential role homeostasis, its persistent activation has been implicated the pathogenesis various diseases, particularly cancer, bone‐related autoimmune disorders, inflammatory cardiovascular neurodegenerative conditions. The interleukin‐6/Janus kinase (JAK)/STAT3 signaling axis central to activation, influencing tumor microenvironment remodeling, angiogenesis, immune evasion, therapy resistance. Despite extensive research, precise mechanisms underlying dysregulated disease progression remain incompletely understood, no United States Food Drug Administration (USFDA)‐approved direct inhibitors currently exist. This review provides comprehensive evaluation STAT3's health disease, emphasizing involvement cancer stem cell maintenance, metastasis, inflammation, drug We systematically discuss therapeutic strategies, including JAK (tofacitinib, ruxolitinib), Src Homology 2 domain (S3I‐201, STATTIC), antisense oligonucleotides (AZD9150), nanomedicine‐based delivery systems, which enhance specificity bioavailability while reducing toxicity. By integrating molecular mechanisms, pathology, emerging interventions, this fills knowledge gap STAT3‐targeted therapy. Our insights into crosstalk, epigenetic regulation, resistance offer foundation for developing next‐generation with greater clinical efficacy translational potential.

Язык: Английский

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Mebendazole induces apoptosis and inhibits migration via the reactive oxygen species-mediated STAT3 signaling downregulation in non-small cell lung cancer

Journal of Thoracic Disease, Год журнала: 2024, Номер 16(2), С. 1412 - 1423

Опубликована: Фев. 1, 2024

Background: The incidence and mortality of non-small cell lung cancer (NSCLC) are extremely high. Previous research has confirmed that the signal transducer activator transcription 3 (STAT3) protein critically participate in tumorigenesis NSCLC. Mebendazole (MBZ) exerts a larger number pharmacological activities anticancer effects cancer, but its mechanism action remains unclear. This study thus aimed to clarify impacts MBZ on NSCLC cell. Methods: Cell proliferation, migration, apoptosis were investigated via counting kit 8 (CCK-8) assay, Transwell colony formation wound-healing flow cytometry. Reactive oxygen species (ROS) detected with multifunctional microplate reader. Markers migration Western blotting. transcriptional activity STAT3 was luciferase assay. ROS scavenger N-acetylcysteine (NAC) used determine effect ROS-regulated inactivation apoptosis. A xenograft model constructed vivo investigate role tumor growth. Results: findings demonstrated inhibited proliferation while promoting through triggering generation. In addition, Janus kinase 2 (JAK2)-STAT3 signaling pathway abrogated treatment MBZ. NAC could distinctly weaken MBZ-induced inactivation. Moreover, growth vivo. Conclusions: summary, viability by inducing ROS-JAK2-STAT3 pathway. These data provide theoretical basis for use treating

Язык: Английский

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