bims-redobi 2024-09-08 papers

bims-redobi

Biomed News

on Redox biology

Issue of 2024–09–08
seven papers selected by
Vanesa Cepas López, Candiolo Cancer Institute

Inflammation-induced epigenetic imprinting regulates intestinal stem cells.
Concise review: breast cancer stems cells and their role in metastases.
Sequential Responsive Multifunctional Nanomicelle Effectuates Collective Elimination of Breast Cancer and Cancer Stem Cells.
A quartet of cancer stem cell niches in hepatocellular carcinoma.
Novel Anti-Cancer Stem Cell Compounds: A Comprehensive Review.
Exosomal misfolded proteins released by cancer stem cells: dual functions in balancing protein homeostasis and orchestrating tumor progression.
Unacylated Ghrelin Protects Against Age-Related Loss of Muscle Mass and Contractile Dysfunction in Skeletal Muscle.

Cell Stem Cell. 2024 Aug 24. pii: S1934-5909(24)00292-3. [Epub ahead of print]

Inflammation-induced epigenetic imprinting regulates intestinal stem cells.

Dongchang Zhao, Visweswaran Ravikumar, Tyler J Leach, Daniel Kraushaar, Emma Lauder, Lu Li, Yaping Sun, Katherine Oravecz-Wilson, Evan T Keller, Fengju Chen, Laure Maneix, Robert R Jenq, Robert Britton, Katherine Y King, Ana E Santibanez, Chad J Creighton, Arvind Rao, Pavan Reddy.

  It remains unknown whether and how intestinal stem cells (ISCs) adapt to inflammatory exposure and whether the adaptation leaves scars that will affect their subsequent regeneration. We investigated the consequences of inflammation on Lgr5+ ISCs in well-defined clinically relevant models of acute gastrointestinal graft-versus-host disease (GI GVHD). Utilizing single-cell transcriptomics, as well as organoid, metabolic, epigenomic, and in vivo models, we found that Lgr5+ ISCs undergo metabolic changes that lead to the accumulation of succinate, which reprograms their epigenome. These changes reduced the ability of ISCs to differentiate and regenerate ex vivo in serial organoid cultures and also in vivo following serial transplantation. Furthermore, ISCs demonstrated a reduced capacity for in vivo regeneration despite resolution of the initial inflammatory exposure, demonstrating the persistence of the maladaptive impact induced by the inflammatory encounter. Thus, inflammation imprints the epigenome of ISCs in a manner that persists and affects their sensitivity to adapt to future stress or challenges.

Keywords:  allogeneic hematopoietic stem cell transplantation; epigenetics; epithelial cell memory; graft-versus-host disease; intestinal stem cells; intestine organoids; metabolism; oxidative phosphorylation

DOI:  https://doi.org/10.1016/j.stem.2024.08.006
Ann Med Surg (Lond). 2024 Sep;86(9): 5266-5275

Concise review: breast cancer stems cells and their role in metastases.

Mohammad Kamalabadi Farahani, Mohammad Farjadmehr, Amir Atashi, Alireza Momeni, Mahin Behzadifard.

   Background: Breast cancer stem cells (BCSCs) have been suggested to be responsible for the development of Breast cancer (BC). The aim of this study was to evaluate BCSCs and the target organs microenvironment immunophenotyping markers in common BC metastases, and therapeutic targets regarding to the mentioned criteria.
Material and methods: This narrative review involved searching international databases; PubMed, Google Scholar using predetermined keywords including breast cancer, breast cancer stem cells, breast cancer metastases, immunophenotyping, immunohistochemistry and metastases. The search results were assessed based on the title, abstract, and full text of the articles, and relevant findings were included in the review.
Results: BCSCs express high amounts of aldehyde dehydrogenase 1 (ALDH1), Ganglioside 2 (GD2), CD44 and CD133 but are negative for CD24 marker. CXCR4 and OPN have high expression in the cells and may contribute in BC metastasis to the bone. Nestin, CK5, prominin-1 (CD133) markers in BCSCs have been reported to correlate with brain metastasis. High expression of CD44 in BCSCs and CXCL12 expression in the liver microenvironment may contribute to BC metastasis to the liver. Aberrantly expressed vascular cell adhesion molecule-1 (VCAM-1) that binds to collagen and elastin fibers on pulmonary parenchyma, and CXCR4 of BCSCs and CXCL12 in lung microenvironment may promote the cells homing and metastasis to lung.
Conclusion: As in various types of BC metastases different markers that expressed by the cells and target organ microenvironment are responsible, BCSCs immunophenotyping can be used as target markers to predict the disease prognosis and treatment.

Keywords:  breast cancer; breast cancer stem cells; cancer stem cells; chemoresistance; immunophenotyping; metastasis

DOI:  https://doi.org/10.1097/MS9.0000000000002270
Small. 2024 Aug 30. e2404219

Sequential Responsive Multifunctional Nanomicelle Effectuates Collective Elimination of Breast Cancer and Cancer Stem Cells.

Xing Wang, Yuqi Tang, Li Yang, Xiaohan Wang, Zhengjian Qi.

  Designing effective multifunctional nanodrugs to achieve multimodal treatment of tumors is an ideal choice to improve the poor clinical outcomes of current anti-tumor therapies. Here, a multifunctional nanomicelle DC@H loaded with sarcoma kinase and cyclooxygenase-2 protein dual target inhibitor DI02 is designed and prepared, which is sequentially catalyzed by carboxylesterase and glutathione for reduction, and strengthens the inhibition of cancer stem cell (CSC) related protein STAT3. The camptothecin carried by the DC@H ensures the effectiveness of chemotherapy. Ultimately, DC@H precisely releases and achieves effective inhibition of xenograft tumors based on the combination of chemotherapy, targeted therapy, and chemodynamic therapy, with a tumor inhibition rate of up to 90.89% in BALB/c nude mice. Research on lung metastasis proves that the CSC inhibitory characteristic of DC@H is a direct cause of the elimination of tumor metastatic nodules. There is no doubt that the multifunctional nano drug DC@H, which effectuates the collective elimination of breast cancer and cancer stem cells, provides a promising direction for achieving complete tumor cure in clinical practice.

Keywords:  STAT3; cancer stem cell; dual target inhibitor; nanomicelle; sequential response

DOI:  https://doi.org/10.1002/smll.202404219
Cytokine Growth Factor Rev. 2024 Aug 28. pii: S1359-6101(24)00064-9. [Epub ahead of print]

A quartet of cancer stem cell niches in hepatocellular carcinoma.

Neha Balaji, Samiksha Kukal, Anjali Bhat, Nikita Pradhan, Shilpi Minocha, Saran Kumar.

  Hepatocellular Carcinoma (HCC), the most prevalent type of primary liver cancer, is known for its aggressive behavior and poor prognosis. The Cancer Stem Cell theory, which postulates the presence of a small population of self-renewing cells called Cancer Stem Cells (CSCs), provides insights into various clinical and molecular features of HCC such as tumor heterogeneity, metabolic adaptability, therapy resistance, and recurrence. These CSCs are nurtured in the tumor microenvironment (TME), where a mix of internal and external factors creates a tumor-supportive niche that is continuously evolving both spatially and temporally, thus enhancing the tumor's complexity. This review details the origins of hepatic CSCs (HCSCs) and the factors influencing their stem-like qualities. It highlights the reciprocal crosstalk between HCSCs and the TME (hypoxic, vascular, invasive, and immune niches), exploring the signaling pathways involved and how these interactions control the malignant traits of CSCs. Additionally, it discusses potential therapeutic approaches targeting the HCSC niche and their possible uses in clinical practice.

Keywords:  Cancer stem cell niche; Hepatic cancer stem cell; Hepatocellular carcinoma; Therapy resistance; Tumor microenvironment; Tumor recurrence

DOI:  https://doi.org/10.1016/j.cytogfr.2024.08.007
Pharmaceutics. 2024 Aug 01. pii: 1024. [Epub ahead of print]16(8):

Novel Anti-Cancer Stem Cell Compounds: A Comprehensive Review.

Shanchun Guo, Shilong Zheng, Mingli Liu, Guangdi Wang.

  Cancer stem cells (CSCs) possess a significant ability to renew themselves, which gives them a strong capacity to form tumors and expand to encompass additional body areas. In addition, they possess inherent resistance to chemotherapy and radiation therapies used to treat many forms of cancer. Scientists have focused on investigating the signaling pathways that are highly linked to the ability of CSCs to renew themselves and maintain their stem cell properties. The pathways encompassed are Notch, Wnt/β-catenin, hedgehog, STAT3, NF-κB, PI-3K/Akt/mTOR, sirtuin, ALDH, MDM2, and ROS. Recent studies indicate that directing efforts towards CSC cells is essential in eradicating the overall cancer cell population and reducing the likelihood of tumor metastasis. As our comprehension of the mechanisms that stimulate CSC activity, growth, and resistance to chemotherapy advances, the discovery of therapeutic drugs specifically targeting CSCs, such as small-molecule compounds, holds the potential to revolutionize cancer therapy. This review article examines and analyzes the novel anti-CSC compounds that have demonstrated effective and selective targeting of pathways associated with the renewal and stemness of CSCs. We also discussed their special drug metabolism and absorption mechanisms. CSCs have been the subject of much study in cancer biology. As a possible treatment for malignancies, small-molecule drugs that target CSCs are gaining more and more attention. This article provides a comprehensive review of the current state of key small-molecule compounds, summarizes their recent developments, and anticipates the future discovery of even more potent and targeted compounds, opening up new avenues for cancer treatment.

Keywords:  ALDH; Notch; Wnt/β-catenin; compound; targeted therapy

DOI:  https://doi.org/10.3390/pharmaceutics16081024
Discov Oncol. 2024 Aug 31. 15(1): 392

Exosomal misfolded proteins released by cancer stem cells: dual functions in balancing protein homeostasis and orchestrating tumor progression.

Anuran Bhattacharya, Urmi Chatterji.

  Cancer stem cells (CSCs), the master regulators of tumor heterogeneity and progression, exert profound influence on cancer metastasis, via various secretory vesicles. Emerging from CSCs, the exosomes serve as pivotal mediators of intercellular communication within the tumor microenvironment, modulating invasion, angiogenesis, and immune responses. Moreover, CSC-derived exosomes play a central role in sculpting a dynamic landscape, contributing to the malignant phenotype. Amidst several exosomal cargoes, misfolded proteins have recently gained attention for their dual functions in maintaining protein homeostasis and promoting tumor progression. Disrupting these communication pathways could potentially prevent the maintenance and expansion of CSCs, overcome treatment resistance, and inhibit the supportive environment created by the tumor microenvironment, thereby improving the effectiveness of cancer therapies and reducing the risk of tumor recurrence and metastasis. Additionally, exosomes have also shown potential therapeutic applications, such as in drug delivery or as biomarkers for cancer diagnosis and prognosis. Therefore, comprehending the biology of exosomes derived from CSCs is a multifaceted area of research with implications in both basic sciences and clinical applications. This review explores the intricate interplay between exosomal misfolded proteins released by CSCs, the potent contributor in tumor heterogeneity, and their impact on cellular processes, shedding light on their role in cancer progression.

Keywords:  Cancer stem cells; Drug resistance; Exosomes; Metastasis; Misfolded proteins; Proteostasis

DOI:  https://doi.org/10.1007/s12672-024-01262-z
Aging Cell. 2024 Sep 02. e14323

Unacylated Ghrelin Protects Against Age-Related Loss of Muscle Mass and Contractile Dysfunction in Skeletal Muscle.

Hyunyoung Kim, Rojina Ranjit, Dennis R Claflin, Constantin Georgescu, Jonathan D Wren, Susan V Brooks, Benjamin F Miller, Bumsoo Ahn.

  Sarcopenia, the progressive loss of muscle mass and function, universally affects older adults and is closely associated with frailty and reduced quality of life. Despite the inevitable consequences of sarcopenia and its relevance to healthspan, no pharmacological therapies are currently available. Ghrelin is a gut-released hormone that increases appetite and body weight through acylation. Acylated ghrelin activates its receptor, growth hormone secretagogue receptor 1a (GHSR1a), in the brain by binding to it. Studies have demonstrated that acyl and unacylated ghrelin (UnAG) both have protective effects against acute pathological conditions independent of receptor activation. Here, we investigated the long-term effects of UnAG in age-associated muscle atrophy and contractile dysfunction in mice. Four-month-old and 18-month-old mice were subjected to either UnAG or control treatment for 10 months. UnAG did not affect food consumption or body weight. Gastrocnemius and quadriceps muscle weights were reduced by 20%-30% with age, which was partially protected against by UnAG. Specific force, force per cross-sectional area, measured in isolated extensor digitorum longus muscle was diminished by 30% in old mice; however, UnAG prevented the loss of specific force. UnAG also protected from decreases in mitochondrial respiration and increases in hydrogen peroxide generation of skeletal muscle of old mice. Results of bulk mRNA-seq analysis and our contractile function data show that UnAG reversed neuromuscular junction impairment that occurs with age. Collectively, our data revealed the direct role of UnAG in mitigating sarcopenia in mice, independent of food consumption or body weight, implicating UnAG treatment as a potential therapy against sarcopenia.

Keywords:  loss of muscle mass; mitochondria; neurogenic atrophy; neuromuscular junction; protein synthesis and degradation; sarcopenia; unacylated ghrelin

DOI:  https://doi.org/10.1111/acel.14323