bims-lycede 2024-06-02 papers

Biochim Biophys Acta Mol Basis Dis. 2024 May 25. pii: S0925-4439(24)00252-7. [Epub ahead of print]1870(6): 167263

Autophagy and machine learning: Unanswered questions.

Ying Yang, Zhaoying Pan, Jianhui Sun, Joshua Welch, Daniel J Klionsky.

Autophagy is a critical conserved cellular process in maintaining cellular homeostasis by clearing and recycling damaged organelles and intracellular components in lysosomes and vacuoles. Autophagy plays a vital role in cell survival, bioenergetic homeostasis, organism development, and cell death regulation. Malfunctions in autophagy are associated with various human diseases and health disorders, such as cancers and neurodegenerative diseases. Significant effort has been devoted to autophagy-related research in the context of genes, proteins, diagnosis, etc. In recent years, there has been a surge of studies utilizing state of the art machine learning (ML) tools to analyze and understand the roles of autophagy in various biological processes. We taxonomize ML techniques that are applicable in an autophagy context, comprehensively review existing efforts being taken in this direction, and outline principles to consider in a biomedical context. In recognition of recent groundbreaking advances in the deep-learning community, we discuss new opportunities in interdisciplinary collaborations and seek to engage autophagy and computer science researchers to promote autophagy research with joint efforts.

Keywords: Artificial intelligence; Lysosome; Macroautophagy; Stress

DOI: https://doi.org/10.1016/j.bbadis.2024.167263

Chin J Nat Med. 2024 May;pii: S1875-5364(24)60638-2. [Epub ahead of print]22(5): 387-401

Hernandezine promotes cancer cell apoptosis and disrupts the lysosomal acidic environment and cathepsin D maturation.

Qianwen Feng, Lu Sun, Muhammad Jibran Sualeh, Qingli Zhao, Songji Zhao, Zhengguo Cui, Hidekuni Inadera.

Hernandezine (Her), a bisbenzylisoquinoline alkaloid extracted from Thalictrum flavum, is recognized for its range of biological activities inherent to this herbal medicine. Despite its notable properties, the anti-cancer effects of Her have remained largely unexplored. In this study, we elucidated that Her significantly induced cytotoxicity in cancer cells through the activation of apoptosis and necroptosis mechanisms. Furthermore, Her triggered autophagosome formation by activating the AMPK and ATG5 conjugation systems, leading to LC3 lipidation. Our findings revealed that Her caused damage to the mitochondrial membrane, with the damaged mitochondria undergoing mitophagy, as evidenced by the elevated expression of mitophagy markers. Conversely, Her disrupted autophagic flux, demonstrated by the upregulation of p62 and accumulation of autolysosomes, as observed in the RFP-GFP-LC3 reporter assay. Initially, we determined that Her did not prevent the fusion of autophagosomes and lysosomes. However, it inhibited the maturation of cathepsin D and increased lysosomal pH, indicating an impairment of lysosomal function. The use of the early-stage autophagy inhibitor, 3-methyladenine (3-MA), did not suppress LC3II, suggesting that Her also induces noncanonical autophagy in autophagosome formation. The application of Bafilomycin A1, an inhibitor of noncanonical autophagy, diminished the recruitment of ATG16L1 and the accumulation of LC3II by Her, thereby augmenting Her-induced cell death. These observations imply that while autophagy initially plays a protective role, the disruption of the autophagic process by Her promotes programmed cell death. This study provides the first evidence of Her's dual role in inducing apoptosis and necroptosis while also initiating and subsequently impairing autophagy to promote apoptotic cell death. These insights contribute to a deeper understanding of the mechanisms underlying programmed cell death, offering potential avenues for enhancing cancer prevention and therapeutic strategies.

Keywords: Apoptosis; Autophagic flux; Hernandezine; Lysosome; Mitophagy; Noncanonical autophagy

DOI: https://doi.org/10.1016/S1875-5364(24)60638-2

Clin Cosmet Investig Dermatol. 2024 ;17 1165-1181

Autophagy Dysfunction: The Kernel of Hair Loss?

Xiaofan Jin, Xiuzu Song.

Autophagy is recognized as a crucial regulatory process, instrumental in the removal of senescent, dysfunctional, and damaged cells. Within the autophagic process, lysosomal digestion plays a critical role in the elimination of impaired organelles, thus preserving fundamental cellular metabolic functions and various biological processes. Mitophagy, a targeted autophagic process that specifically focuses on mitochondria, is essential for sustaining cellular health and energy balance. Therefore, a deep comprehension of the operational mechanisms and implications of autophagy and mitophagy is vital for disease prevention and treatment. In this context, we examine the role of autophagy and mitophagy during hair follicle cycles, closely scrutinizing their potential association with hair loss. We also conduct a thorough review of the regulatory mechanisms behind autophagy and mitophagy, highlighting their interaction with hair follicle stem cells and dermal papilla cells. In conclusion, we investigate the potential of manipulating autophagy and mitophagy pathways to develop innovative therapeutic strategies for hair loss.

Keywords: alopecia; dermal papilla cell; hair follicle; hair follicle stem cell; mitophagy

DOI: https://doi.org/10.2147/CCID.S462294

Cell Death Discov. 2024 May 27. 10(1): 256

Inhibition of lysosomal TRPML1 channel eliminates breast cancer stem cells by triggering ferroptosis.

Chunhong Fan, Haotian Wu, Xin Du, Canjun Li, Wenping Zeng, Lili Qu, Chunlei Cang.

Cancer stem cells (CSCs) are a sub-population of cells possessing high tumorigenic potential, which contribute to therapeutic resistance, metastasis and recurrence. Eradication of CSCs is widely recognized as a crucial factor in improving patient prognosis, yet the effective targeting of these cells remains a major challenge. Here, we show that the lysosomal cation channel TRPML1 represents a promising target for CSCs. TRPML1 is highly expressed in breast cancer cells and exhibits sensitivity to salinomycin, a drug known to selectively eliminate CSCs. Pharmacological inhibition and genetic depletion of TRPML1 promote ferroptosis in breast CSCs, reduce their stemness, and enhance the sensitivity of breast cancer cells to chemotherapy drug doxorubicin. The inhibition and knockout of TRPML1 also demonstrate significant suppression of tumor formation and growth in the mouse xenograft model. These findings suggest that targeting TRPML1 to eliminate CSCs may be an effective strategy for the treatment of breast cancer.

DOI: https://doi.org/10.1038/s41420-024-02026-y

Comput Biol Chem. 2024 May 10. pii: S1476-9271(24)00072-0. [Epub ahead of print]111 108084

Bioinformatics and in vitro study reveals ERα as the potential target gene of Honokiol to enhance trastuzumab sensitivity in HER2+ trastuzumab-resistant breast cancer cells.

I Made Rhamanadana Putra, Intan Ayu Lestari, Nurul Fatimah, Naufa Hanif, Navista Sri Octa Ujiantari, Dyaningtyas Dewi Pamungkas Putri, Adam Hermawan.

Trastuzumab resistance presents a significant challenge in the treatment of HER2+ breast cancer, necessitating the investigation of combination therapies to overcome this resistance. Honokiol, a compound with broad anticancer activity, has shown promise in this regard. This study aims to discover the effect of honokiol in increasing trastuzumab sensitivity in HER2+ trastuzumab-resistant breast cancer cells HCC1954 and the underline mechanisms behind. A bioinformatics study performed to explore the most potential target hub gene for honokiol in HER2+ breast cancer. Honokiol, trastuzumab and combined treatment cytotoxicity activity was then evaluated in both parental HCC1954 and trastuzumab resistance (TR-HCC1954) cells using MTT assay. The expression levels of these hub genes were then analyzed using qRT-PCR and those that could not be analyzed were subjected to molecular docking to determine their potential. Honokiol showed a potent cytotoxicity activity with an IC50 of 41.05 μM and 69.61 μM in parental HCC1954 and TR-HCC1954 cell line respectively. Furthermore, the combination of honokiol and trastuzumab resulted in significant differences in cytotoxicity in TR-HCC1954 cells at specific concentrations. Molecular docking and the qRT-PCR showed that the potential ERα identified from the bioinformatics analysis was affected by the treatment. Our results show that honokiol has the potential to increase the sensitivity of trastuzumab in HER2+ trastuzumab resistant breast cancer cell line HCC1954 by affecting regulating estrogen receptor signaling. Further research is necessary to validate these findings.

Keywords: Breast cancer; Estrogen receptor; HER2; Honokiol; Trastuzumab; Trastuzumab resistance

DOI: https://doi.org/10.1016/j.compbiolchem.2024.108084