bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2024–11–03
seventeen papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. Senescence suppresses the integrated stress response and activates a stress-remodeled secretory phenotype.
  2. Editorial: Role of mitochondrial stress response in metabolic health.
  3. Glucose deprivation impairs hypoxia-inducible factor-1α synthesis.
  4. The UPRising connection between endoplasmic reticulum stress and the tumor microenvironment.
  5. GDF15 is still a mystery hormone.
  6. Branched-chain α-ketoacids aerobically activate HIF1α signalling in vascular cells.
  7. HIF1α-regulated glycolysis promotes activation-induced cell death and IFN-γ induction in hypoxic T cells.
  8. Mitochondrial-targeted plastoquinone therapy ameliorates early onset muscle weakness that precedes ovarian cancer cachexia in mice.
  9. Interleukin-11 receptor is an alternative α-receptor for interleukin-6 and the chimeric cytokine IC7.
  10. GDF15 Associates with, but is not Responsible for, Exercise-Induced Increases in Corticosterone and Indices of Lipid Utilization in Mice.
  11. Re-programming by a six-factor-secretome in the patient tumor ecosystem during nutrient stress and drug response.
  12. GDF15 research from bench to bedside.
  13. Muscle inflammation is regulated by NF-κB from multiple cells to control distinct states of wasting in cancer cachexia.
  14. ATF4/NUPR1 axis promotes cancer cell survival and mediates immunosuppression in clear cell renal cell carcinoma.
  15. GCN2-SLC7A11 axis coordinates autophagy, cell cycle and apoptosis and regulates cell growth in retinoblastoma upon arginine deprivation.
  16. Hypoxic Stress Induces Complement-Mediated Lysis of Mesenchymal Stem Cells by Downregulating Factor H and CD59.
  17. Inhibition of angiogenesis and regenerative lung growth in Lepob/ob mice through adiponectin-VEGF/VEGFR2 signaling.
  1. Mol Cell. 2024 Oct 24. pii: S1097-2765(24)00826-8. [Epub ahead of print]
    Senescence suppresses the integrated stress response and activates a stress-remodeled secretory phenotype.
    Matthew J Payea, Showkat A Dar, Carlos Anerillas, Jennifer L Martindale, Cedric Belair, Rachel Munk, Sulochan Malla, Jinshui Fan, Yulan Piao, Xiaoling Yang, Abid Rehman, Nirad Banskota, Kotb Abdelmohsen, Myriam Gorospe, Manolis Maragkakis.
      Senescence is a state of indefinite cell-cycle arrest associated with aging, cancer, and age-related diseases. Here, we find that translational deregulation, together with a corresponding maladaptive integrated stress response (ISR), is a hallmark of senescence that desensitizes senescent cells to stress. We present evidence that senescent cells maintain high levels of eIF2α phosphorylation, typical of ISR activation, but translationally repress production of the stress response activating transcription factor 4 (ATF4) by ineffective bypass of the inhibitory upstream open reading frames (uORFs). Surprisingly, ATF4 translation remains inhibited even after acute proteotoxic and amino acid starvation stressors, resulting in a highly diminished stress response. We also find that stress augments the senescence-associated secretory phenotype with sustained remodeling of inflammatory factors expression that is suppressed by non-uORF carrying ATF4 mRNA expression. Our results thus show that senescent cells possess a unique response to stress, which entails an increase in their inflammatory profile.
    Keywords:  ATF4; ER stress; ISR; SASP; integrated stress response; nanopore direct RNA sequencing; proteomics; ribosome sequencing; senescence; senescence-associated secretory phenotype; translation
    DOI:  https://doi.org/10.1016/j.molcel.2024.10.003
  2. Front Endocrinol (Lausanne). 2024 ;15 1504718
    Editorial: Role of mitochondrial stress response in metabolic health.
    Renata O Pereira, Susanne Keipert.
      
    Keywords:  FGF21; GDF15; MOTS-c; integrated stress response (ISR); metabolic health; mitochondria; mitohormesis; mitokine
    DOI:  https://doi.org/10.3389/fendo.2024.1504718
  3. Discov Oncol. 2024 Oct 28. 15(1): 595
    Glucose deprivation impairs hypoxia-inducible factor-1α synthesis.
    Mia Hubert, Sarah Stuart, Michael Ohh.
      Hypoxia-inducible factors (HIFs) are key transcriptional mediators of the hypoxic response and are implicated in oncogenesis. HIFα is regulated by a well-characterized, oxygen-dependent degradation pathway involving the von Hippel Lindau (VHL) tumor suppressor protein. However, comparatively little is known about HIFα regulation at the translational level, particularly under cellular stress. There is evidence that HIFα expression not only responds to changes in oxygen tension, but also nutrient availability. In this study, we monitored global translation rates, ATP levels and HIF1α synthesis rates in response to glucose starvation or glycolysis inhibition. We found that both global and HIF1α-specific translation rates decline under glucose deprivation that is concomitant with ATP reduction. These results are in contrast with previous reports showing preferential HIF1α synthesis despite global translation suppression under hypoxia and suggest that a glucose requirement in cellular metabolism is associated with HIF1α translation.
    DOI:  https://doi.org/10.1007/s12672-024-01484-1
  4. Trends Cancer. 2024 Oct 29. pii: S2405-8033(24)00213-9. [Epub ahead of print]
    The UPRising connection between endoplasmic reticulum stress and the tumor microenvironment.
    Hery Urra, Raúl Aravena, Lucas González-Johnson, Claudio Hetz.
      The tumor microenvironment (TME) represents a dynamic network of cancer cells, stromal cells, immune mediators, and extracellular matrix components, crucial for cancer progression. Stress conditions such as oncogene activation, nutrient deprivation, and hypoxia disrupt the endoplasmic reticulum (ER), activating the unfolded protein response (UPR), the main adaptive mechanism to restore ER function. The UPR regulates cancer progression by engaging cell-autonomous and cell-non-autonomous mechanisms, reprogramming the stroma and promoting immune evasion, angiogenesis, and invasion. This review explores the role of UPR beyond cancer cells, focusing on how ER stress signaling reshapes the TME, supporting tumor growth. The therapeutic potential of targeting the UPR is also discussed.
    Keywords:  angiogenesis; cancer; endoplasmic reticulum stress; tumor microenvironment; unfolded protein response
    DOI:  https://doi.org/10.1016/j.trecan.2024.09.011
  5. Trends Endocrinol Metab. 2024 Oct 29. pii: S1043-2760(24)00254-6. [Epub ahead of print]
    GDF15 is still a mystery hormone.
    Casper M Sigvardsen, Michael M Richter, Sarah Engelbeen, Maximilian Kleinert, Erik A Richter.
      Growth differentiation factor 15 (GDF15) is a member of the transforming growth factor-β (TGF-β) superfamily. Despite its identification over 20 years ago, the functions of GDF15 remain complex and not fully elucidated. Its concentration in plasma varies widely depending on the physiological and pathophysiological state of the organism. GDF15 has been described to regulate food intake and insulin sensitivity in rodents via the GDNF family receptor α-like (GFRAL) receptor, and to be elevated in pregnancy and many disease states and decreased in physically fit individuals. We discuss the latest developments in the regulation of GDF15 secretion and its diverse physiological effects, and touch upon possible GFRAL-independent effects of GDF15. In addition, we discuss the effects of proteins and peptides derived from the same precursor protein as GDF15.
    Keywords:  appetite; energy expenditure; insulin sensitivity; weight loss
    DOI:  https://doi.org/10.1016/j.tem.2024.09.002
  6. Nat Metab. 2024 Oct 29.
    Branched-chain α-ketoacids aerobically activate HIF1α signalling in vascular cells.
    Wusheng Xiao, Nishith Shrimali, Niv Vigder, William M Oldham, Clary B Clish, Huamei He, Samantha J Wong, Bradley M Wertheim, Elena Arons, Marcia C Haigis, Jane A Leopold, Joseph Loscalzo.
      Hypoxia-inducible factor 1α (HIF1α) is a master regulator of biological processes in hypoxia. Yet, the mechanisms and biological consequences of aerobic HIF1α activation by intrinsic factors, particularly in normal (primary) cells, remain elusive. Here we show that HIF1α signalling is activated in several human primary vascular cells in normoxia and in vascular smooth muscle cells of normal human lungs. Mechanistically, aerobic HIF1α activation is mediated by paracrine secretion of three branched-chain α-ketoacids (BCKAs), which suppress PHD2 activity via direct inhibition and via LDHA-mediated generation of L-2-hydroxyglutarate. BCKA-mediated HIF1α signalling activation stimulated glycolytic activity and governed a phenotypic switch of pulmonary artery smooth muscle cells, which correlated with BCKA metabolic dysregulation and pathophenotypic changes in pulmonary arterial hypertension patients and male rat models. We thus identify BCKAs as previously unrecognized signalling metabolites that aerobically activate HIF1α and that the BCKA-HIF1α pathway modulates vascular smooth muscle cell function, an effect that may be relevant to pulmonary vascular pathobiology.
    DOI:  https://doi.org/10.1038/s42255-024-01150-4
  7. Nat Commun. 2024 Oct 30. 15(1): 9394
    HIF1α-regulated glycolysis promotes activation-induced cell death and IFN-γ induction in hypoxic T cells.
    Hongxing Shen, Oluwagbemiga A Ojo, Haitao Ding, Logan J Mullen, Chuan Xing, M Iqbal Hossain, Abdelrahman Yassin, Vivian Y Shi, Zach Lewis, Ewa Podgorska, Shaida A Andrabi, Maciek R Antoniewicz, James A Bonner, Lewis Zhichang Shi.
      Hypoxia is a common feature in various pathophysiological contexts, including tumor microenvironment, and IFN-γ is instrumental for anti-tumor immunity. HIF1α has long been known as a primary regulator of cellular adaptive responses to hypoxia, but its role in IFN-γ induction in hypoxic T cells is unknown. Here, we show that the HIF1α-glycolysis axis controls IFN-γ induction in both human and mouse T cells, activated under hypoxia. Specific deletion of HIF1α in T cells (Hif1α-/-) and glycolytic inhibition suppresses IFN-γ induction. Conversely, HIF1α stabilization by hypoxia and VHL deletion in T cells (Vhl-/-) increases IFN-γ production. Hypoxic Hif1α-/- T cells are less able to kill tumor cells in vitro, and tumor-bearing Hif1α-/- mice are not responsive to immune checkpoint blockade (ICB) therapy in vivo. Mechanistically, loss of HIF1α greatly diminishes glycolytic activity in hypoxic T cells, resulting in depleted intracellular acetyl-CoA and attenuated activation-induced cell death (AICD). Restoration of intracellular acetyl-CoA by acetate supplementation re-engages AICD, rescuing IFN-γ production in hypoxic Hif1α-/- T cells and re-sensitizing Hif1α-/- tumor-bearing mice to ICB. In summary, we identify HIF1α-regulated glycolysis as a key metabolic control of IFN-γ production in hypoxic T cells and ICB response.
    DOI:  https://doi.org/10.1038/s41467-024-53593-8
  8. bioRxiv. 2024 Oct 25. pii: 2024.10.22.619751. [Epub ahead of print]
    Mitochondrial-targeted plastoquinone therapy ameliorates early onset muscle weakness that precedes ovarian cancer cachexia in mice.
    Luca J Delfinis, Shahrzad Khajehzadehshoushtar, Luke D Flewwelling, Nathaniel J Andrews, Madison C Garibotti, Shivam Gandhi, Aditya N Brahmbhatt, Brooke A Morris, Bianca Garlisi, Sylvia Lauks, Caroline Aitken, Stavroula Tsitkanou, Jeremy A Simpson, Nicholas P Greene, Arthur J Cheng, Jim Petrik, Christopher G R Perry.
      Cancer cachexia, and the related loss of muscle and strength, worsens quality of life and lowers overall survival. Recently, a novel 'pre-atrophy' muscle weakness was identified during early-stage cancer. While mitochondrial stress responses are associated with early-stage pre-atrophy weakness, a causal relationship has not been established. Using a robust mouse model of metastatic epithelial ovarian cancer (EOC)-induced cachexia, we found the well-established mitochondrial-targeted plastoquinone SkQ1 partially prevents pre-atrophy weakness in the diaphragm. Furthermore, SkQ1 improved force production during atrophy without preventing atrophy itself in the tibialis anterior and diaphragm. EOC reduced flexor digitorum brevis (FDB) force production and myoplasmic free calcium ([Ca 2+ ] i ) during contraction in single muscle fibers, both of which were prevented by SkQ1. Remarkably, changes in mitochondrial reactive oxygen species and pyruvate metabolism were heterogeneous across time and between muscle types which highlights a considerable complexity in the relationships between mitochondria and muscle remodeling throughout EOC. These discoveries identify that muscle weakness can occur independent of atrophy throughout EOC in a manner that is linked to improved calcium handling. The findings also demonstrate that mitochondrial-targeted therapies exert a robust effect in preserving muscle force during the early pre-atrophy period and in late-stage EOC once cachexia has become severe.
    DOI:  https://doi.org/10.1101/2024.10.22.619751
  9. FEBS J. 2024 Oct 29.
    Interleukin-11 receptor is an alternative α-receptor for interleukin-6 and the chimeric cytokine IC7.
    Hendrik T Weitz, Julia Ettich, Puyan Rafii, Christoph Wittich, Laura Schultz, Nils C Frank, Denise Heise, Matthias Krusche, Juliane Lokau, Christoph Garbers, Kristina Behnke, Doreen M Floss, Harald Kolmar, Jens M Moll, Jürgen Scheller.
      The cytokine interleukin 6 (IL-6) signals via the IL-6 α-receptor (IL-6Rα or IL-6R) in complex with the gp130 β-receptor. Cell type restricted expression of the IL-6R limits the action of IL-6 mainly to hepatocytes and some immune cells. Here, we show that IL-6 also binds to the IL-11 α receptor (IL-11Rα or IL-11R) and induces signaling via IL-11R:gp130 complexes, albeit with a lower affinity compared to IL-11. Antagonistic antibodies directed against IL-11R, but not IL-6R, inhibit IL-6 signaling via IL-11R:gp130 receptor complexes. Notably, IL-11 did not cross-react with IL-6R. IL-11R has also been identified as an alternative α receptor for the CNTF/IL-6-derived chimeric cytokine IC7, which has recently been shown to induce weight loss in mice. Accordingly, the effects of therapeutic monoclonal antibodies against IL-6 or IL-6R, which both block IL-6 signaling, may be slightly different. These findings provide new insights into IL-6 signaling and therefore offer new potential therapeutic intervention options in the future.
    Keywords:  IL‐11; cross‐talk; cytokine; gp130; interleukin 6
    DOI:  https://doi.org/10.1111/febs.17309
  10. J Appl Physiol (1985). 2024 Oct 31.
    GDF15 Associates with, but is not Responsible for, Exercise-Induced Increases in Corticosterone and Indices of Lipid Utilization in Mice.
    Meagan Arbeau, Bradley J Baranowski, Stewart Jeromson, Annalaura Bellucci, Michael Akcan, Serena Trang, Katelyn Eisner, Kyle D Medak, David C Wright.
      Growth differentiation factor 15 (GDF15) is a stress-induced cytokine that increases with exercise and is thought to increase corticosterone and lipid utilization. How post-exercise nutrient availability impacts GDF15 and the physiological role that GDF15 plays during and/or in the recovery from exercise has not been elucidated. The purpose of this investigation was to examine how post-exercise nutrient availability impacts GDF15 and to use this as a model to explore associations between GDF15, corticosterone and indices of lipid and carbohydrate metabolism. In addition, we explored the causality of these relationships using GDF15 deficient mice. Male and female C57BL/6J mice ran for 2 hours on a treadmill and were sacrificed immediately or 3 hours after exercise with or without access to a chow diet. In both sexes, circulating concentrations of GDF15, corticosterone, non-esterified fatty acids (NEFA), and beta hydroxybutyrate (BHB) were higher immediately post-exercise and remained elevated when food was withheld during the recovery period. While serum GDF15 was positively associated with corticosterone, BHB and NEFA, increases in these factors were similar in wildtype and GDF15-/- mice following exercise. The lack of a genotype effect was not explained by differences in insulin, glucagon or epinephrine after exercise. Our findings provide evidence that while GDF15 is associated with increases in corticosterone and indices of lipid utilization this is not a causal relationship.
    Keywords:  GDF15; corticosterone; exercise; mice; nutrition
    DOI:  https://doi.org/10.1152/japplphysiol.00519.2024
  11. iScience. 2024 Oct 18. 27(10): 110932
    Re-programming by a six-factor-secretome in the patient tumor ecosystem during nutrient stress and drug response.
    M Tarek Elghetany, Jie-Ling Pan, Karthik Sekar, Angela Major, Jack Mf Su, Adekunle Adesina, Kam-Man Hui, Xiao-Nan Li, Wan-Yee Teo.
      Cancer cells need nutrients to grow and proliferate. During nutrient stress in the microenvironment, it is unclear if or how cancer cells can adopt alternative resources to re-wire and survive in patients. We discovered a 6-factor-secretome remarkably sustains a critical cell mass during nutrient stress in a pediatric embryonal brain tumor, atypical teratoid rhabdoid tumor (ATRT). Specific ATRT subtypes emerged as secretome-enriched, matching macrophage-enrichment patterns and were high-relapse-risk subtypes. The secretome alters drug response, protects against cell death, and provides pro-survival niches to rescue drugged cells. Secretome-grown tumor cells rearrange into a web-like architecture-stable during drug exposure, suggesting a mechanism for therapy resistance. Secretome prevents tumor cell death in aggressive tumor models, and in cerebrospinal dissemination, suggesting a role in tumor resistance/relapse. Our results unravel, a previously unexplored role of a specific 6-factor-secretome, providing an alternative fuel to sustain cancer cells during nutrient stress, and implications in relapse subtypes.
    Keywords:  Cancer; Cell biology
    DOI:  https://doi.org/10.1016/j.isci.2024.110932
  12. Cancer Cell. 2024 Oct 16. pii: S1535-6108(24)00365-9. [Epub ahead of print]
    GDF15 research from bench to bedside.
    Samuel N Breit, David A Brown, Vicky W W Tsai.
      Pre-clinical data suggest that increased circulating growth differentiation factor 15 (GDF15) is a cause of both anorexia/cachexia syndromes and hyperemesis gravidarum in pregnancy, serious conditions with no highly effective treatment. A phase 2 study of a therapeutic GDF15 monoclonal antibody in the New England Journal of Medicine suggests that effective treatment of anorexia/cachexia in cancer may be approaching.
    DOI:  https://doi.org/10.1016/j.ccell.2024.10.002
  13. Cell Rep. 2024 Oct 29. pii: S2211-1247(24)01276-2. [Epub ahead of print]43(11): 114925
    Muscle inflammation is regulated by NF-κB from multiple cells to control distinct states of wasting in cancer cachexia.
    Benjamin R Pryce, Alexander Oles, Erin E Talbert, Martin J Romeo, Silvia Vaena, Sudarshana Sharma, Victoria Spadafora, Lauren Tolliver, David A Mahvi, Katherine A Morgan, William P Lancaster, Eryn Beal, Natlie Koren, Bailey Watts, Morgan Overstreet, Stefano Berto, Suganya Subramanian, Kubra Calisir, Anna Crawford, Brian Neelon, Michael C Ostrowski, Teresa A Zimmers, James G Tidball, David J Wang, Denis C Guttridge.
      Although cancer cachexia is classically characterized as a systemic inflammatory disorder, emerging evidence indicates that weight loss also associates with local tissue inflammation. We queried the regulation of this inflammation and its causality to cachexia by exploring skeletal muscle, whose atrophy strongly associates with poor outcomes. Using multiple mouse models and patient samples, we show that cachectic muscle is marked by enhanced innate immunity. Nuclear factor κB (NF-κB) activity in multiple cells, including satellite cells, myofibers, and fibro-adipogenic progenitors, promotes macrophage expansion equally derived from infiltrating monocytes and resident cells. Moreover, NF-κB-activated cells and macrophages undergo crosstalk; NF-κB+ cells recruit macrophages to inhibit regeneration and promote atrophy but, interestingly, also protect myofibers, while macrophages stimulate NF-κB+ cells to sustain an inflammatory feedforward loop. Together, we propose that NF-κB functions in multiple cells in the muscle microenvironment to stimulate macrophages that both promote and protect against muscle wasting in cancer.
    Keywords:  CP: Cancer; CP: Immunology; NF-κB; cancer cachexia; fibro-adipogenic progenitors; macrophages; muscle progenitor cells; pancreatic cancer
    DOI:  https://doi.org/10.1016/j.celrep.2024.114925
  14. Discov Oncol. 2024 Oct 31. 15(1): 607
    ATF4/NUPR1 axis promotes cancer cell survival and mediates immunosuppression in clear cell renal cell carcinoma.
    Yongliang Lu, Weihao Chen, Yundong Xuan, Xiubin Li, Shengpan Wu, Hanfeng Wang, Tao Guo, Chenfeng Wang, Shuo Tian, Huaikang Li, Dong Lai, Wenlei Zhao, Xing Huang, Xupeng Zhao, Baojun Wang, Xu Zhang, Hongzhao Li, Yan Huang, Xin Ma.
      Cancer cells encounter unavoidable stress during tumor growth. The stress-induced transcription factor, activating transcription factor 4 (ATF4), has been reported to upregulate various adaptive genes involved in salvage pathways to alleviate stress and promote tumor progression. However, this effect is unknown in clear cell renal cell carcinoma (ccRCC). In this study, we found that ATF4 expression was remarkably upregulated in tumor tissues and associated with poor ccRCC outcomes. ATF4 depletion significantly impaired ccRCC cell proliferation, migration, and invasion in vitro and in vivo by inhibiting the AKT/mTOR and epithelial-mesenchymal transition (EMT)-related signaling pathway. RNA sequencing and functional studies identified nuclear protein 1 (NUPR1) as a key downstream target of ATF4 for repressing ferroptosis and promoting ccRCC cell survival. In addition, targeting ATF4 or pharmacological inhibition using NUPR1 inhibitor ZZW115 promoted antitumor immunity in syngeneic graft mouse models, represented by increased infiltration of CD4+ and CD8+ T cells. Furthermore, ZZW115 could improve the response to the PD-1 immune checkpoint blockade. The results demonstrate that the ATF4/NUPR1 signaling axis promotes ccRCC survival and facilitates tumor-mediated immunosuppression, providing a set of potential targets and prognostic indicators for ccRCC patients.
    Keywords:  ATF4; Ferroptosis; Immunosuppression; NUPR1; ccRCC
    DOI:  https://doi.org/10.1007/s12672-024-01485-0
  15. Cancer Metab. 2024 Oct 26. 12(1): 31
    GCN2-SLC7A11 axis coordinates autophagy, cell cycle and apoptosis and regulates cell growth in retinoblastoma upon arginine deprivation.
    Dan Wang, Wai Kit Chu, Jason Cheuk Sing Yam, Chi Pui Pang, Yun Chung Leung, Alisa Sau Wun Shum, Sun-On Chan.
       BACKGROUND: Arginine deprivation was previously shown to inhibit retinoblastoma cell proliferation and induce cell death in vitro. However, the mechanisms by which retinoblastoma cells respond to arginine deprivation remain to be elucidated.
    METHODS: The human-derived retinoblastoma cell lines Y79 and WERI-Rb-1 were subjected to arginine depletion, and the effects on inhibiting cell growth and survival were evaluated. This study investigated potential mechanisms, including autophagy, cell cycle arrest and apoptosis. Moreover, the roles of the general control nonderepressible 2 (GCN2) and mechanistic target of rapamycin complex 1 (mTORC1) signaling pathways in these processes were examined.
    RESULTS: We demonstrated that arginine deprivation effectively inhibited the growth of retinoblastoma cells in vitro. This treatment caused an increase in the autophagic response. Additionally, prolonged arginine deprivation induced G2 cell cycle arrest and was accompanied by an increase in early apoptotic cells. Importantly, arginine depletion also induced the activation of GCN2 and the inhibition of mTOR signaling. We also discovered that the activation of SLC7A11 was regulated by GCN2 upon arginine deprivation. Knockdown of SLC7A11 rendered retinoblastoma cells partially resistant to arginine deprivation. Furthermore, we found that knockdown of GCN2 led to a decrease in the autophagic response in WERI-Rb-1 cells and arrested more cells in S phase, which was accompanied by fewer apoptotic cells. Moreover, knockdown of GCN2 induced the constant expression of ATF4 and the phosphorylation of 70S6K and 4E-BP1 regardless of arginine deprivation.
    CONCLUSIONS: Collectively, our findings suggest that the GCN2‒SLC7A11 axis regulates cell growth and survival upon arginine deprivation through coordinating autophagy, cell cycle arrest, and apoptosis in retinoblastoma cells. This work paves the way for the development of a novel treatment for retinoblastoma.
    Keywords:  Arginine deprivation; GCN2; Retinoblastoma; SCL7A11
    DOI:  https://doi.org/10.1186/s40170-024-00361-3
  16. Tissue Eng Regen Med. 2024 Nov 01.
    Hypoxic Stress Induces Complement-Mediated Lysis of Mesenchymal Stem Cells by Downregulating Factor H and CD59.
    Ramada R Khaswaneh, Ejlal Abu-El-Rub, Ayman Alzu'bi, Fatimah A Almahasneh, Rawan A Almazari, Heba F Ai-Jariri, Raed M Al-Zoubi.
       BACKGROUND: Factor H and membrane inhibitor of reactive lysis (CD59) are key regulators of complement activation. Mesenchymal stem cells (MSCs) secrete Factor H and express CD59 to protect themselves from complement-mediated damage. Severe hypoxia found to decrease the survival chances of MSCs after transplantation; however, little is known about the impact of severe hypoxia on modulating the complement system activity and its effect on MSCs survival. Our study seeks to explore the effect of severe hypoxia on modulating the complement cascade in MSCs.
    METHODS: Human adipose tissue-derived MSCs (hAD-MSCs) were cultured under severe hypoxia using 400 μM Cobalt Chloride (CoCl2) for 48 h. The protein expressions of survival marker; Phosphoinositide 3-kinases (PI3K), and pro-apoptotic marker; Caspase-3 were assessed using western blotting. The level of complement system related factors; Factor H, CD59, C3b, iC3b, C5b, C9, and the complement membrane attack complex (MAC) were analyzed using Elisa assays, western blotting, and immunocytochemistry.
    RESULTS: Our results showed for the first time that severe hypoxia can significantly impair Factor H secretion and CD59 expression in MSCs. This has been associated with upregulation of MAC complex and increased level of cell lysis and apoptosis marked by downregulation of PI3K and upregulation of Annexin v and Caspase-3.
    CONCLUSION: The loss of Factor H and CD59 in hypoxic MSCs can initiate their lysis and apoptosis mediated by activating MAC complex. Preserving the level of Factor H and CD59 in MSCs has significant clinical implication to increase their retention rate in hypoxic conditions and prolong their survival.
    Keywords:  Apoptosis; CD59; Factor H; Hypoxia; MAC complex; MSCs; Survival
    DOI:  https://doi.org/10.1007/s13770-024-00678-6
  17. Front Cardiovasc Med. 2024 ;11 1491971
    Inhibition of angiogenesis and regenerative lung growth in Lepob/ob mice through adiponectin-VEGF/VEGFR2 signaling.
    Tendai Hunyenyiwa, Priscilla Kyi, Mikaela Scheer, Mrudula Joshi, Mario Gasparri, Tadanori Mammoto, Akiko Mammoto.
       Introduction: Obesity is associated with impairment of wound healing and tissue regeneration. Angiogenesis, the formation of new blood capillaries, plays a key role in regenerative lung growth after unilateral pneumonectomy (PNX). We have reported that obesity inhibits angiogenesis. The effects of obesity on post-PNX lung vascular and alveolar regeneration remain unclear.
    Methods: Unilateral PNX is performed on Lep ob/ob obese mice to examine vascular and alveolar regeneration.
    Results: Regenerative lung growth and expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR2 induced after PNX are inhibited in Lep ob/ob obese mice. The levels of adiponectin that exhibits pro-angiogenic and vascular protective properties increase after unilateral PNX, while the effects are attenuated in Lep ob/ob obese mice. Post-PNX regenerative lung growth and increases in the levels of VEGF and VEGFR2 are inhibited in adiponectin knockout mice. Adiponectin stimulates angiogenic activities in human lung endothelial cells (ECs), which is inhibited by decreasing the levels of transcription factor Twist1. Adiponectin agonist, AdipoRon restores post-PNX lung growth and vascular and alveolar regeneration in Lep ob/ob obese mice.
    Discussion: These findings suggest that obesity impairs lung vascular and alveolar regeneration and adiponectin is one of the key factors to improve lung regeneration in obese people.
    Keywords:  VEGF; adiponectin; angiogenesis; lung regeneration; obesity
    DOI:  https://doi.org/10.3389/fcvm.2024.1491971
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