scholarly journals Evidence for hormonal control of heart regenerative capacity during endothermy acquisition

Science ◽  
2019 ◽  
pp. eaar2038 ◽  
Author(s):  
Kentaro Hirose ◽  
Alexander Y. Payumo ◽  
Stephen Cutie ◽  
Alison Hoang ◽  
Hao Zhang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Thyroid Hormones ◽  
Standard Metabolic Rate ◽  
Hormonal Control ◽  
Hormone Signaling ◽  
Regenerative Capacity ◽  
Cycle Arrest ◽  
Kleiber’S Law ◽  
Underlying Mechanisms ◽  
Zebrafish Heart

Tissue regenerative potential displays striking divergence across phylogeny and ontogeny, but the underlying mechanisms remain enigmatic. Loss of mammalian cardiac regenerative potential correlates with cardiomyocyte cell-cycle arrest and polyploidization, as well as the development of postnatal endothermy. We reveal that diploid cardiomyocyte abundance across 41 species conforms to Kleiber’s law−the ¾-power law scaling of metabolism with bodyweight−and inversely correlates with standard metabolic rate, body temperature, and serum thyroxine level. Inactivation of thyroid hormone signaling reduces mouse cardiomyocyte polyploidization, delays cell-cycle exit, and retains cardiac regenerative potential in adults. Conversely, exogenous thyroid hormones inhibit zebrafish heart regeneration. Thus, our findings suggest that loss of heart regenerative capacity in adult mammals is triggered by increasing thyroid hormones and may be a tradeoff for the acquisition of endothermy.

Abstract 20492: Mlf1 Regulates Myocyte Proliferation in Postnatal Hearts

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Shalini Muralidhar ◽  
Feng Xiao ◽  
Suwannee Thet ◽  
Hesham Sadek
Keyword(s):  
Cell Cycle ◽  
Transcription Factors ◽  
Cell Cycle Arrest ◽  
Molecular Mechanisms ◽  
Gene Array ◽  
Bhlh Transcription Factor ◽  
Cardiomyocyte Proliferation ◽  
Regenerative Capacity ◽  
Cycle Arrest ◽  
Endogenous Expression

Lower vertebrates, such as newt and zebrafish, retain a robust cardiac regenerative capacity following injury. Although adult mammals lack this cardiac regenerative potential, there is ample interest in understanding how heart regeneration occurs, and to reawaken this process in adult humans. Recently, we showed that mice are capable of regenerating their hearts shortly after birth following injury. This regenerative response is associated with robust proliferation of cardiomyocytes without significant hypertrophy or fibrosis. However, this regenerative capacity is lost by 7 days postnatally, coinciding with cell cycle arrest. In an effort to determine the mechanism of cardiomyocytes cell cycle arrest after the first week of life, we performed a gene array after cardiac injury at multiple post-natal time points. This enabled us to identify a number of transcription factors that are differentially expressed during this postnatal window. We recently reported that one of these transcription factors Meis1 regulates postnatal cell cycle arrest of cardiomyocytes. Furthermore, Myeloid leukemia factor 1 (Mlf1), a bhlh transcription factor that has not been previously studied in the heart has similar dysregulated pattern following injury. Our preliminary data with in-vitro knockdown of Mlf1 in cardiomyocyte resulted in 2-fold increase in cardiomyocyte proliferation. Furthermore, immunohistochemistry results indicated that the endogenous expression and nuclear localization of Mlf1 in the post-natal cardiomyocytes coincides with cell cycle arrest. To explore this pattern, we generated a cardiomyocyte-specific Mlf1 knockout mouse, and showed that loss of Mlf1 results in robust cardiomyocyte proliferation in postnatal hearts (P14). Additionally, we confirmed previous reports that Mlf1 regulates p53 and induces cell cycle arrest by induction of CDK inhibitors like p21 and p57 in these Mlf1 KO mice. This suggests a role of Mlf1 in promoting reactivation of injured myocardium through induction of cardiomyocyte proliferation. These findings will further provide evidences of molecular mechanisms involved in the dormant regenerative capacity in adult mammals that can be a potential target of therapeutic approaches.

scholarly journals IGHG1 Regulates Prostate Cancer Growth via the MEK/ERK/c-Myc Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Jing Chu ◽  
Yutong Li ◽  
Zhihai Deng ◽  
Zhenlin Zhang ◽  
Qun Xie ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Cell Growth ◽  
Heavy Chain ◽  
Cancer Growth ◽  
Prostate Cancer Cells ◽  
Cycle Arrest ◽  
Underlying Mechanisms

Increasing evidence indicates that immunoglobulins are important for the regulation of various cancers including prostate cancer (PCa). However, the underlying mechanisms of IgG regulated PCa development remain to be further explored. Here, we demonstrated that IgG1 heavy chain (IGHG1) was increased in tissues from PCa patients. Inhibition of IGHG1 by antibody blocking or genetic knockdown suppressed cell growth and induced cell cycle arrest and ultimate apoptosis. Expression levels of c-Myc were positively correlated with the levels of IGHG1. Furthermore, MEK/ERK/c-Myc pathway lied downstream of IGHG1 in cultured prostate cancer cells. Inhibition of IGHG1 restrained the tumor growth in nude mice and inactivated MEK/ERK/c-Myc pathway both in vitro and in vivo. These findings suggest that IGHG1 play a crucial role during the development of prostate cancer and inhibition of IGHG1 may be a potential therapy in the treatment of PCa.

scholarly journals Cardiomyocyte cell cycling, maturation, and growth by multinucleation in postnatal swine

2019 ◽  
Author(s):  
Nivedhitha Velayutham ◽  
Christina M. Alfieri ◽  
Emma J. Agnew ◽  
Kyle W. Riggs ◽  
R. Scott Baker ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Growth Dynamics ◽  
Postnatal Period ◽  
Left Ventricular ◽  
Cell Cycle Gene ◽  
Matrix Remodeling ◽  
Regenerative Capacity ◽  
Cycle Arrest ◽  
Cardiac Maturation

AbstractAimsCardiomyocyte (CM) cell cycle arrest, decline of mononucleated-diploid CMs, sarcomeric maturation, and extracellular matrix remodeling are implicated in loss of cardiac regenerative potential in mice after birth. Recent studies show a 3-day neonatal regenerative capacity in pig hearts similar to mice, but postnatal pig CM growth dynamics are unknown. We examined cardiac maturation in postnatal pigs and mice, to determine the relative timing of developmental events underlying heart growth and regenerative potential in large and small mammals.Methods and ResultsLeft ventricular tissue from White Yorkshire-Landrace pigs at postnatal day (P)0 to 6 months (6mo) was analyzed to span birth, weaning, and adolescence in pigs, compared to similar physiological timepoints in mice. Collagen remodeling increases by P7 in postnatal pigs, but sarcomeric and gap junctional maturation only occur at 2mo. Also, there is no postnatal transition to beta-oxidation metabolism in pig hearts. Mononucleated CMs, predominant at birth, persist to 2mo in swine, with over 50% incidence of mononucleated-diploid CMs at P7-P15. Extensive multinucleation with 4-16 nuclei per CM occurs beyond P30. Pigs also exhibit increased CM length relative to multinucleation, preceding increase in CM width at 2mo-6mo. Further, robust CM mitotic nuclear pHH3 activity and cardiac cell cycle gene expression is apparent in pig left ventricles up to 2mo. By contrast, in mice, these maturational events occur concurrently in the first two postnatal weeks alongside loss of cardiac regenerative capacity.ConclusionsCardiac maturation occurs over a 6mo postnatal period in pigs, despite a similar early-neonatal heart regenerative window as mice. Postnatal pig CM growth includes increase in CM length alongside multinucleation, with CM cell cycle arrest and loss of mononucleated-diploid CMs occurring at 2mo-6mo. These CM characteristics are important to consider for pig preclinical studies and may offer opportunities to study aspects of heart regeneration unavailable in other models.

scholarly journals Ferritinophagy-Mediated ROS Production Contributed to Proliferation Inhibition, Apoptosis, and Ferroptosis Induction in Action of Mechanism of 2-Pyridylhydrazone Dithiocarbamate Acetate

2021 ◽  
Vol 2021 ◽  
pp. 1-17
Author(s):  
Longlong Li ◽  
Hao Li ◽  
Yongli Li ◽  
Jiankang Feng ◽  
Deng Guan ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Biological Effects ◽  
Underlying Mechanism ◽  
Mechanistic Study ◽  
Ros Production ◽  
Nuclear Receptor Coactivator ◽  
Cellular Events ◽  
Cycle Arrest ◽  
Underlying Mechanisms

Reactive oxygen species (ROS) production is involved in the mechanism of action of a number of drugs, but the biological effects of ROS remain to be clarified. Furthermore, ferroptosis involves iron-dependent ROS production that may be derived from ferritinophagy; however, the association between ferroptosis and ferritinophagy has not been fully established. The present study demonstrated that dithiocarbamate derivatives (iron chelators) exhibited antineoplastic properties involving ferritinophagy induction, but whether the underlying mechanisms involved ferroptosis was unknown. To gain insight into the underlying mechanism, a dithiocarbamate derivative, 2-pyridylhydrazone dithiocarbamate s-acetic acid (PdtaA), was prepared. An MTT assay demonstrated that PdtaA inhibited proliferation involving ROS production ( I C 50 = 23.0 ± 1.5  μM for HepG2 cells). A preliminary mechanistic study revealed that PdtaA induced both apoptosis and cell cycle arrest. Notably, PdtaA also induced ferroptosis via downregulation of GPx4 and xCT, which was first reported for a dithiocarbamate derivative. Moreover, these cellular events were associated with ROS production. To explore the origin of ROS, expression of the ferritinophagy-related genes, ferritin, and nuclear receptor coactivator (NCOA4) were measured. Immunofluorescence and western blotting analysis indicated that PdtaA-induced ferritinophagy may contribute to ROS production. To investigate the role of ferritinophagy, autophagy inhibitor 3-methyladenin or genetic knockdown of NCOA4 was employed to inhibit ferritinophagy, which significantly neutralized the action of PdtaA in both apoptosis and ferroptosis. Taken together, PdtaA-induced cell cycle arrest, apoptosis, and ferroptosis were associated with ferritinophagy.

scholarly journals Sorghum Phenolic Compounds Are Associated with Cell Growth Inhibition through Cell Cycle Arrest and Apoptosis in Human Hepatocarcinoma and Colorectal Adenocarcinoma Cells

Foods ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 993
Author(s):  
Xi Chen ◽  
Jiamin Shen ◽  
Jingwen Xu ◽  
Thomas Herald ◽  
Dmitriy Smolensky ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Phenolic Compounds ◽  
Cell Growth ◽  
Growth Inhibition ◽  
Cancer Prevention ◽  
Cell Cycle Arrest ◽  
Colorectal Adenocarcinoma ◽  
Cell Growth Inhibition ◽  
Cycle Arrest ◽  
Underlying Mechanisms

Phenolic compounds in some specialty sorghums have been associated with cancer prevention. However, direct evidence and the underlying mechanisms for this are mostly unknown. In this study, phenolics were extracted from 13 selected sorghum accessions with black pericarp while F10000 hybrid with white pericarp was used as a control, and cell growth inhibition was studied in hepatocarcinoma HepG2 and colorectal adenocarcinoma Caco-2 cells. Total phenolic contents of the 13 high phenolic grains, as determined by Folin–Ciocalteu, were 30–64 mg GAE/g DW in the phenolic extracts of various accessions compared with the control F10000 at 2 mg GAE/g DW. Treatment of HepG2 with the extracted phenolics at 0–200 μM GAE up to 72 h resulted in a dose- and time-dependent reduction in cell numbers. The values of IC50 varied from 85 to 221 mg DW/mL while the control of F10000 was 1275 mg DW/mL. The underlying mechanisms were further examined using the highest phenolic content of PI329694 and the lowest IC50 of PI570481, resulting in a non-cytotoxic decrease in cell number that was significantly correlated with increased cell cycle arrest at G2/M and apoptotic cells in both HepG2 and Caco-2 cells. Taken together, these results indicated, for the first time, that inhibition of either HepG2 or Caco-2 cell growth by phenolic extracts from 13 selected sorghum accessions was due to cytostatic and apoptotic but not cytotoxic mechanisms, suggesting some specialty sorghums are a valuable, functional food, providing sustainable phenolics for potential cancer prevention.

scholarly journals BAI1 Acts as a Tumor Suppressor in Triple-Negative Breast Cancer via Modulating p73 Transactivation

2020 ◽  
Author(s):  
Xia yang ◽  
Ping Wei ◽  
Ruohong Shui
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Cycle Arrest ◽  
Triple Negative Breast Cancer ◽  
Cell Apoptosis ◽  
Transcriptional Activity ◽  
Triple Negative ◽  
Cycle Arrest ◽  
Underlying Mechanisms

Abstract Background: Brain-specific angiogenesis inhibitor 1 (BAI1) which belongs to putative G-protein-coupled receptors (GPCRs), has been found down-expressed in various cancers and involved in cancer pathogenesis. However, the role and underlying mechanisms of BAI1 in triple negative breast cancer (TNBC) are still unclear. Methods: The expression levels of BAI1 in TNBC samples and cell lines were examined by immunohistochemistry (IHC), quantitative real-time polymerase chain reaction (qRT-PCR), and western blotting (WB). The functional effects of BAI1 on biological behaviors of TNBC cells were detected using plasmid and siRNA for BAI1 overexpression and knockdown, and the underlying mechanisms were investigated by Immunoprecipitation (IP), immunofluorescence (IF) and luciferase reporter assay. Results: BAI1 was downregulated in TNBC tissues and was significantly associated with poor disease-free survival. Functional experiments indicated that BAI1 inhibited cell proliferation and induced cell apoptosis and cell cycle arrest. Additionally, BAI1 overexpressed cells were more sensitive to cisplatin. Mechanistically, BAI1 interacted with MDM2, thereby enhanced p73 transcriptional activity, then promoted p21and BAX mRNA and protein expression. Overexpression of p73 abolished the BAI1 knockdown induced cell proliferation and the G2 phase cell population of TNBC, the sensitivity to cisplatin also rescued by overregulating p73 in BAI1 knockdown TNBC cells. Conclusions: Our results indicate that BAI1 is a promising prognostic factor in TNBC, and the expression of BAI1 inhibits cell proliferation and induces cell apoptosis and cell cycle arrest; Meanwhile, BAI1 increases the sensitivity of TNBC to cisplatin. For the underlying mechanism, BAI1 specifically binds to MDM2, and exerts its anti-tumor function by affecting the transcriptional activity of p73 protein, then inhibits the malignant progression of TNBC. The BAI1/MDM2/p73 axis may represent a potential target in the future research for TNBC.

Helicobacter pylori induces cell cycle arrest of T-lymphocytes

2005 ◽  
Vol 43 (05) ◽  
Author(s):  
M Gerhard ◽  
C Schmees ◽  
R Rad ◽  
P Voland ◽  
T Treptau ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Helicobacter Pylori ◽  
T Lymphocytes ◽  
Cell Cycle Arrest ◽  
Cycle Arrest
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