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Unraveling Apoptosis: Deciphering Molecular Mechanisms

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: 20 November 2025 | Viewed by 1134

Special Issue Editor


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Guest Editor
Department of Biomedical Science, Oncology and Molecular Pathology Unit, University of Cagliari, 09124 Cagliari, Italy
Interests: signal transduction pathways involved in apoptosis and cell proliferation; endoplasmic reticulum stress; mitochondria; natural antioxidants; hepatocarcinoma
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Special Issue Information

Dear Colleagues,

Apoptosis is a regulated cell death process that is essential for proper development and regulation of tissue homeostasis in multicellular organisms. Deregulation of apoptosis has been associated with several diseases, including cancer, immunological disorders, neurodegenerative diseases, and metabolic diseases such as diabetes. In general, the initiation of apoptosis is closely associated with the activation of a class of enzymes known as caspases, and this process can be initiated primarily through two molecular pathways: the receptor-mediated extrinsic pathway and the mitochondria-mediated intrinsic pathway. Although our understanding of the mechanisms controlling this programmed cell death has improved considerably over the last decade, in this issue on apoptosis, we would like to summarize the latest findings on the different modalities of programmed cell death, with particular attention to the molecular pathways involved, their effects on surrounding cells, and their involvement in the pathogenesis of various diseases, in order to provide a relevant theoretical basis for the link between the induction of apoptosis and the treatment of various disease.

Possible topics include, but are not limited to:

  • Apoptosis;
  • Pyroptosis;
  • Necroptosis;
  • Mitochondrial dysfunction;
  • ER stress-mediated apoptosis;
  • Molecular mechanisms;
  • Degenerative diseases;
  • Metabolic diseases;
  • Tumors;
  • Novel pharmacological strategies.

Dr. Gabriella Simbula
Guest Editor

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Keywords

  • apoptosis
  • development
  • microenvironment
  • mitochondria dysfunction
  • molecular mechanisms
  • tumors
  • degenerative diseases
  • diabetes
  • metabolic diseases
  • neurodegenerative disease
  • novel pharmacological strategies

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Published Papers (2 papers)

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Research

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33 pages, 7831 KiB  
Article
Molecular Mechanisms of Biochanin A in AML Cells: Apoptosis Induction and Pathway-Specific Regulation in U937 and THP-1
by Pei-Shan Wu, Jui-Hung Yen, Pei-Yi Chen and Ming-Jiuan Wu
Int. J. Mol. Sci. 2025, 26(11), 5317; https://doi.org/10.3390/ijms26115317 - 31 May 2025
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Abstract
Biochanin A, a naturally occurring isoflavone derived from legumes, possesses anti-inflammatory, estrogenic, and anticancer activities. In this study, we investigated the cytotoxic effects and underlying molecular mechanisms of Biochanin A in acute myeloid leukemia (AML) cell lines, U937 and THP-1, using in vitro [...] Read more.
Biochanin A, a naturally occurring isoflavone derived from legumes, possesses anti-inflammatory, estrogenic, and anticancer activities. In this study, we investigated the cytotoxic effects and underlying molecular mechanisms of Biochanin A in acute myeloid leukemia (AML) cell lines, U937 and THP-1, using in vitro cytotoxicity assays, RNA sequencing, and bioinformatic analyses. Biochanin A induced dose-dependent apoptosis, as evidenced by caspase-7 activation and PARP1 cleavage. Over-representation analysis (ORA) revealed that differentially expressed genes (DEGs) were significantly enriched in pathways related to inflammatory responses, DNA replication, and cell cycle regulation. Gene set enrichment analysis (GSEA) further confirmed the upregulation of apoptosis- and inflammation-related pathways and the downregulation of MYC targets, cholesterol biosynthesis, and G2/M checkpoint gene sets. RT-qPCR analysis demonstrated that Biochanin A downregulated oncogenes such as RUNX1, BCL2, and MYC while upregulating CHOP (GADD153), CDKN1A (p21), and SQSTM1 (p62), contributing to apoptosis and cell cycle arrest across both cell lines. Notably, Biochanin A downregulated PLK1 and UHRF1 in THP-1 cells, indicating a disruption of mitotic progression and epigenetic regulation. In contrast, in U937 cells, Biochanin A upregulated TXNIP and downregulated CCND2, highlighting the involvement of oxidative stress and G1/S cell cycle arrest. These findings support the potential of Biochanin A as a promising therapeutic candidate for AML through both shared and distinct regulatory pathways. Full article
(This article belongs to the Special Issue Unraveling Apoptosis: Deciphering Molecular Mechanisms)
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Review

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45 pages, 1507 KiB  
Review
BDNF/proBDNF Interplay in the Mediation of Neuronal Apoptotic Mechanisms in Neurodegenerative Diseases
by Marina Mitrovic, Dragica Selakovic, Nemanja Jovicic, Biljana Ljujic and Gvozden Rosic
Int. J. Mol. Sci. 2025, 26(10), 4926; https://doi.org/10.3390/ijms26104926 - 21 May 2025
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Abstract
The neurotrophic system includes neurotrophins, such as brain-derived neurotrophic factor (BDNF) and its precursor proBDNF, which play conflicting roles in neuronal survival and apoptosis, with their balance having a significant impact on neurodegenerative outcomes. While BDNF is widely acknowledged as a potent neurotrophin [...] Read more.
The neurotrophic system includes neurotrophins, such as brain-derived neurotrophic factor (BDNF) and its precursor proBDNF, which play conflicting roles in neuronal survival and apoptosis, with their balance having a significant impact on neurodegenerative outcomes. While BDNF is widely acknowledged as a potent neurotrophin that promotes neuronal survival and differentiation, its precursor, proBDNF, has the opposite effect, promoting apoptosis and neuronal death. This review highlights the new and unique aspects of BDNF/proBDNF interaction in the modulation of neuronal apoptotic pathways in neurodegenerative disorders. It systematically discusses the cross-talk in apoptotic signaling at the molecular level, whereby BDNF activates survival pathways such as PI3K/Akt and MAPK/ERK, whereas proBDNF activates p75NTR and sortilin to induce neuronal apoptosis via JNK, RhoA, NFkB, and Rac-GTPase pathways such as caspase activation and mitochondrial injury. Moreover, this review emphasizes the factors that affect the balance between proBDNF and BDNF levels within the context of neurodegeneration, including proteolytic processing, the expression of TrkB and p75NTR receptors, and extrinsic gene transcription regulators. Cellular injury, stress, or signaling pathway alterations can disrupt the balance of BDNF/proBDNF, which may be involved in apoptotic-related neurodegenerative diseases like Alzheimer’s, Parkinson’s, and Huntington’s diseases. This review provides a comprehensive framework for targeting neurotrophin signaling in the development of innovative therapies for neuronal survival and managing apoptotic-related neurodegenerative disorders, addressing the mechanistic complexity and clinical feasibility of BDNF/proBDNF interaction. Full article
(This article belongs to the Special Issue Unraveling Apoptosis: Deciphering Molecular Mechanisms)
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