Abstract 1485: Ischemic Postconditioning’s Protection Is Lost In Aged And Stat3-deficient Mice

The cardioprotection by ischemic preconditioning is lost in aged wildtype (WT) mice and in STAT3-deficient mice (signal transducer and activator of transcription 3). The aim of the present study was to analyze whether or not ischemic postconditioning (iPo) is effective in aged WT mice hearts, and whether or not it is dependent on the presence of STAT3. Young (3 months) and aged (>13 months) C57Bl6/J female mice underwent 30 min of ischemia and 2 h reperfusion (I/R) without or with iPo (3 cycles of 10 s ischemia and 10 s reperfusion (iPo3) or 5 cycles of 5 s ischemia and 5 s reperfusion (iPo5) at the beginning of reperfusion). In young mice hearts, iPo3 and iPo5 reduced the infarct size (IS, % of the area at risk) to a similar extent from 65.8±2.8 (n=11) to 50.7±2.8 (3×10, n=10, p<0.05) and to 49.8±3.8 (5×5, n=10, p<0.05). In contrast, in aged WT hearts IS was similar following I/R and iPo3 (60.1±3.2, n=10 vs. 66.4±3.0, n=7), but was reduced by iPo5 (46.5±4.2, n=7, p<0.05). Western blot analysis on right ventricular protein extracts from aged WT mice hearts indicated a reduction of phosphorylated STAT3 (Ser727) to 72.0±7.6% (n=19, p<0.05) and of total STAT3 to 72.1±5.5% (n=27, p<0.05) of that in young WT mice, which was set as 100% (n=18). In young mice (3 months) with a cardiomyocyte-restricted deletion of STAT3 (STAT3-KO) only iPo3 failed to reduce IS compared to I/R (62.2±3.5, n=5 vs. 64.4±3.1, n=8), whereas the stronger stimulus iPo5 once again significantly reduced IS (55.0±2.8, n=9, p<0.05). In conclusion, lower efficiency of iPO protection against I/R in aged mice hearts was associated with a reduced cardiac expression of STAT3. In line with a crucial role of STAT3 for iPO protection in I/R, STAT3-KO mice displayed also an attenuated susceptibility for iPO mediated protection in I/R. Thus age mediated reduction of cardiac STAT3 expression may contribute to the age-related reduced efficienty of iPo to protect from I/R injury.

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Myeloid ERK5 deficiency suppresses tumor growth by blocking protumor macrophage polarization via STAT3 inhibition

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1707929115 ◽

2018 ◽

Vol 115 (12) ◽

pp. E2801-E2810 ◽

Cited By ~ 27

Author(s):

Emanuele Giurisato ◽

Qiuping Xu ◽

Silvia Lonardi ◽

Brian Telfer ◽

Ilaria Russo ◽

...

Keyword(s):

Macrophage Polarization ◽

Signal Transducer ◽

Targeted Interventions ◽

Proinflammatory Mediators ◽

Signaling Mechanisms ◽

Transcriptional Switch ◽

Macrophage Polarity ◽

Transcription 3 ◽

Deficient Mice

Owing to the prevalence of tumor-associated macrophages (TAMs) in cancer and their unique influence upon disease progression and malignancy, macrophage-targeted interventions have attracted notable attention in cancer immunotherapy. However, tractable targets to reduce TAM activities remain very few and far between because the signaling mechanisms underpinning protumor macrophage phenotypes are largely unknown. Here, we have investigated the role of the extracellular-regulated protein kinase 5 (ERK5) as a determinant of macrophage polarity. We report that the growth of carcinoma grafts was halted in myeloid ERK5-deficient mice. Coincidentally, targeting ERK5 in macrophages induced a transcriptional switch in favor of proinflammatory mediators. Further molecular analyses demonstrated that activation of the signal transducer and activator of transcription 3 (STAT3) via Tyr705 phosphorylation was impaired in erk5-deleted TAMs. Our study thus suggests that blocking ERK5 constitutes a treatment strategy to reprogram macrophages toward an antitumor state by inhibiting STAT3-induced gene expression.

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Involvement of interleukin-21 in the regulation of colitis-associated colon cancer

Journal of Experimental Medicine ◽

10.1084/jem.20111106 ◽

2011 ◽

Vol 208 (11) ◽

pp. 2279-2290 ◽

Cited By ~ 90

Author(s):

Carmine Stolfi ◽

Angelamaria Rizzo ◽

Eleonora Franzè ◽

Angela Rotondi ◽

Massimo Claudio Fantini ◽

...

Keyword(s):

Colon Cancer ◽

Dextran Sulfate ◽

Mucosal Damage ◽

Chronic Inflammatory Disease ◽

Wild Type ◽

Gut Mucosa ◽

Inflammatory Milieu ◽

Transcription 3 ◽

Deficient Mice

Chronic inflammation is a major driving force in the development of cancer in many tissues, but the array of factors involved in this neoplastic transformation are not well understood. We have investigated the role of interleukin (IL)-21 in colitis-associated colon cancer (CAC), as this cytokine is overexpressed in the gut mucosa of patients with ulcerative colitis (UC), a chronic inflammatory disease associated with colon cancer. IL-21 was increased in the gut of patients with UC-associated colon cancer, and in mice with CAC induced by azoxymethane (AOM) and dextran sulfate sodium (DSS). After AOM+DSS treatment, IL-21 KO mice showed reduced mucosal damage, reduced infiltration of T cells, and diminished production of IL-6 and IL-17A. IL-21–deficient mice also developed fewer and smaller tumors compared with wild-type (WT) mice. Absence of IL-21 reduced signal transducer and activator of transcription 3 activation in tumor and stromal cells. Administration of a neutralizing IL-21 antibody to WT mice after the last DSS cycle decreased the colonic T cell infiltrate and the production of IL-6 and IL-17A and reduced the number of tumors. These observations indicate that IL-21 amplifies an inflammatory milieu that promotes CAC, and suggest that IL-21 blockade may be useful in reducing the risk of UC-associated colon cancer.

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Cytoplasmic mislocalization and mitochondrial colocalization of TDP-43 are common features between normal aged and young mice

Experimental Biology and Medicine ◽

10.1177/1535370220914253 ◽

2020 ◽

Vol 245 (17) ◽

pp. 1584-1593 ◽

Cited By ~ 1

Author(s):

Pichet Termsarasab ◽

Thananan Thammongkolchai ◽

Ju Gao ◽

Luwen Wang ◽

Jingjing Liang ◽

...

Keyword(s):

Neurodegenerative Disorders ◽

Neuronal Loss ◽

Critical Factor ◽

Brain Regions ◽

Normal Aging ◽

Age Related ◽

Wide Range ◽

Cytoplasmic Accumulation ◽

Young Mice

Transactive response DNA binding protein 43 (TDP-43) pathologies have been well recognized in various neurodegenerative disorders including frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and Alzheimer’s disease (AD). However, there have been limited studies on whether there are any TDP-43 alterations in normal aging. We investigated TDP-43 distribution in different brain regions in normal aged ( n = 3 for 26- or 36-month-old) compared to young ( n = 3 for 6- or 12-month-old) mice. In both normal aged and young mice, TDP-43 and phosphorylated TDP-43 (pTDP-43) demonstrated a unique pattern of distribution in neurons in some specific brain regions including the pontine nuclei, thalamus, CA3 region of the hippocampus, and orbital cortex. This pattern was demonstrated on higher magnification of high-resolution double fluorescence images and confocal microscopy as mislocalization of TDP-43 and pTDP-43, characterized by neuronal nuclear depletion and cytoplasmic accumulation in these brain regions, as well as colocalization between TDP-43 or pTDP-43 and mitochondria, similar to what has been described previously in neurodegenerative disorders. All these findings were identical in both normal aged and young mice. In summary, TDP-43 and pTDP-43 mislocalization from nucleus to cytoplasm and their colocalization with mitochondria in the specific brain regions are present not only in aging, but also in young healthy states. Our findings provide a new insight for the role of TDP-43 proteinopathy in health and diseases, and that aging may not be a critical factor for the development of TDP-43 proteinopathy in subpopulations of neurons. Impact statement Despite increasing evidence implicating the important role of TDP-43 in the pathogenesis of a wide range of age-related neurodegenerative diseases, there is limited study of TDP-43 proteinopathy and its association with mitochondria during normal aging. Our findings of cytoplasmic accumulation of TDP-43 that is highly colocalized with mitochondria in neurons in selective brain regions in young animals in the absence of neuronal loss provide a novel insight into the development of TDP-43 proteinopathy and its contribution to neuronal loss.

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Role of Interleukin33 in Rejuvenation of Aged Neurons and Age-Related Dementias

Neuroscience Insights ◽

10.1177/26331055211030251 ◽

2021 ◽

Vol 16 ◽

pp. 263310552110302

Author(s):

Yahuan Lou

Keyword(s):

Oxidative Stress ◽

Potential Risk ◽

Middle Age ◽

Late Onset ◽

Double Strand Breaks ◽

Dna Double Strand Breaks ◽

Strand Breaks ◽

Age Related ◽

Deficient Mice

Late-onset Alzheimer’s disease (LOAD) is the most common age-related dementia, and its etiology remains unclear. Recent studies have linked abnormal neuronal aging to LOAD. Neurons are non-proliferative, and thus, majority of aged neurons must be rejuvenated through repairing or eliminating damaged molecules to regain their healthy status and functionalities. We discovered a surge of oxidative stress in neurons at middle age in mice. A rapid upregulation of neuronal rejuvenation is vital, while astrocyte-expressed interleukin33 (IL33), an IL1-like cytokine, is critical for this process. Thus, IL33-deficiency cripples the neuronal rejuvenation mechanisms, such as repairing DNA double strand breaks, eliminating damaged molecules by autophagy or by glymphatic drainage. IL33-deficient mice develop tau deposition and age-related dementia following a path similar to LOAD. We hypothesize that any interferences on IL33-initiated rejuvenation process for aged neurons after middle life is a potential risk for LOAD development.

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Deletion of mouseSetd4promotes the recovery of hematopoietic failure

10.1101/860239 ◽

2019 ◽

Author(s):

Xing Feng ◽

Huimei Lu ◽

Jingyin Yue ◽

Megha Shettigar ◽

Jingmei Liu ◽

...

Keyword(s):

Bone Marrow ◽

Progenitor Cells ◽

Whole Body ◽

List Type ◽

Bone Marrow Niche ◽

Hematopoietic Stem ◽

Adult Mice ◽

Bm Niche ◽

Deficient Mice

AbstractAcquired hematopoietic failure is commonly caused by therapeutic and accidental exposure to toxic agents to the bone marrow (BM). Efficient recovery from the BM failure is not only dictated by the intrinsic sensitivity and proliferation capacity of the hematopoietic stem and progenitor cells, but also nourished by the BM environment niche. Identification of genetic factors that improve the recovery from hematopoietic failure is essential. Vertebrate SETD4 is a poorly characterized, putative non-histone methyl-transferase whose physiological substrates have not yet been fully identified. By inducingSetd4deletion in adult mice, we found that loss ofSetd4improved the survival of whole body irradiation induced BM failure. This was associated with improved recoveries of long-term and short-term hematopoietic stem cells (HSC), and early progenitor cells. BM transplantation analyses surprisingly showed that the improved recovery was not due to a radiation resistance of theSetd4deficient HSC, but thatSetd4deficient HSC were actually more sensitive to radiation. However, theSetd4deficient mice were better recipients for allogeneic HSC transplantation. Furthermore, there was an enhanced splenic erythropoiesis inSetd4deficient mice. These findings not only revealed a previously unrecognized role of theSetd4as a unique modulator of hematopoiesis, but also underscored the critical role of the BM niche in the recovery of hematopoietic failure. These studies also implicatedSetd4as a potential target for therapeutic inhibition to improve the conditioning of the BM niche prior to allogeneic transplantation.Key pointsDeletion ofSetd4in adult mice improved the survival from hematopoietic failure.Setd4deficiency sensitized HSCs to radiation, but improved bone marrow environment niche.The study suggests that SETD4 as a potential inhibitory target to improve bone marrow niche function for recovery of bone marrow failure.

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Lifespan of Catalase-Deficient Mice Decreases Due to Lysosomal Dysfunction

10.21203/rs.3.rs-965044/v1 ◽

2021 ◽

Author(s):

Raghbendra Kumar Dutta ◽

Joon No Lee ◽

Yunash Maharjan ◽

Channy Park ◽

Seong-Kyu Choe ◽

...

Keyword(s):

Antioxidant Defense ◽

Autophagosome Formation ◽

Peroxisomal Enzyme ◽

Lysosomal Function ◽

Age Related ◽

Autophagy Pathway ◽

Macromolecular Damage ◽

Progressive Accumulation ◽

Deficient Mice

Abstract Background: Lysosomes are a central hub for cellular metabolism and are involved in the regulation of cell homeostasis through the degradation or recycling of unwanted or dysfunctional organelles through the autophagy pathway. Catalase, a peroxisomal enzyme, plays an important role in cellular antioxidant defense by decomposing hydrogen peroxide into water and oxygen. In accordance with pleiotropic significance, both impaired lysosomes and catalase have been linked to many age-related pathologies with a decline in lifespan. Aging is characterized by progressive accumulation of macromolecular damage and the production of high levels of reactive oxygen species (ROS). Although lysosomes degrade the most long-lived proteins and organelles via the autophagic pathway, the role of lysosomes and their effect on peroxisomes during aging is not known. The present study investigated the role of catalase and lysosomal function in catalase-knockout (KO) mice.Results: We found that catalase-deficient mice exhibited an aging phenotype faster than wild-type (WT) mice. We also found that aged catalase-KO mice induced leaky lysosomes by progressive accumulation of lysosomal contents, such as cathespin D, into the cytosol. Leaky lysosomes inhibited autophagosome formation and triggered impaired autophagy. The dysregulation of autophagy triggered mTORC1 (mechanistic target of rapamycin complex 1) activation, which plays a pivotal role in modulating aging. However, the antioxidant N-acetyl-L-cysteine (NAC) and mTORC1 inhibitor rapamycin rescued leaky lysosomes and aging phenotypes in catalase-deficient aged mice.Conclusion: This study unveils the new role of catalase and its role in lysosomal function during aging.

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Loss of ischemic preconditioning's cardioprotection in aged mouse hearts is associated with reduced gap junctional and mitochondrial levels of connexin 43

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01071.2006 ◽

2007 ◽

Vol 292 (4) ◽

pp. H1764-H1769 ◽

Cited By ~ 124

Author(s):

Kerstin Boengler ◽

Ina Konietzka ◽

Astrid Buechert ◽

Yvonne Heinen ◽

David Garcia-Dorado ◽

...

Keyword(s):

Connexin 43 ◽

Left Ventricular ◽

Aged Mouse ◽

Area At Risk ◽

Aged Mice ◽

Age Related ◽

Tissue Homogenates ◽

Endothelial Nitric Oxide ◽

Young Mice

Connexin 43 (Cx43) is localized at left ventricular (LV) gap junctions and in cardiomyocyte mitochondria. A genetically induced reduction of Cx43 as well as blockade of mitochondrial Cx43 import abolishes the infarct size (IS) reduction by ischemic preconditioning (IP). With progressing age, Cx43 content in ventricular and atrial tissue homogenates is reduced. We now investigated whether or not 1) the mitochondrial Cx43 content is reduced in aged mice hearts and 2) IS reduction by IP is lost in aged mice hearts in vivo. Confirming previous results, sarcolemmal Cx43 content was reduced in aged (>13 mo) compared with young (<3 mo) C57Bl/6 mice hearts, whereas the expression levels of protein kinase C ε and endothelial nitric oxide synthase remained unchanged. Also in mitochondria isolated from aged mice LV myocardium, Western blot analysis indicated a 40% decrease in Cx43 content compared with mitochondria isolated from young mice hearts. In young mice hearts, IP by one cycle of 10 min ischemia and 10 min reperfusion reduced IS (% of area at risk) following 30 min regional ischemia and 120 min reperfusion from 67.7 ± 3.3 ( n = 17) to 34.2 ± 6.6 ( n = 5, P < 0.05). In contrast, IP's cardioprotection was lost in aged mice hearts, since IS in nonpreconditioned (57.5 ± 4.0, n = 10) and preconditioned hearts (65.4 ± 6.3, n = 8, P = not significant) was not different. In conclusion, mitochondrial Cx43 content is decreased in aged mouse hearts. The reduced levels of Cx43 may contribute to the age-related loss of cardioprotection by IP.

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