scholarly journals Upregulated PD-1 Signaling is an Important Antagonist to Glomerular Health in Aged Kidneys

2021 ◽  
Author(s):  
Jeffrey W Pippin ◽  
Natalya Kaverina ◽  
Yuliang Wang ◽  
Diana Eng ◽  
Yuting Zeng ◽  
...  
Keyword(s):  
Regulatory Networks ◽  
Critical Role ◽  
Socioeconomic Factor ◽  
Aged Mice ◽  
Lower Egfr ◽  
Surface Receptor ◽  
Arterial Intima ◽  
Underlying Mechanisms ◽  
Programed Cell Death

Kidney aging and its contribution to disease and its underlying mechanisms are not well understood. With an aging population, kidney health becomes an important medical and socioeconomic factor. We previously showed that podocytes isolated from aged mice exhibit increased expression of Programed Cell Death Protein 1 (PD-1) surface receptor and its two ligands (PD-L1, PD-L2). PDCD1 transcript increases with age in micro-dissected human glomeruli, which correlates with lower eGFR, and higher segmental glomerulosclerosis and vascular arterial intima to lumen ratio. In vitro studies in podocytes demonstrate a critical role for PD-1 signaling in cell survival and induction of a Senescence-Associated Secretory Phenotype (SASP). To prove PD-1 signaling is critical to podocyte aging, aged mice were injected with anti-PD-1 antibody (aPD-1ab). Treatment significantly improved the aging phenotype in both kidney and liver. In the glomerulus, it increased the life-span of podocytes, but not parietal epithelial, mesangial or endothelial cells. Transcriptomic and immunohistochemistry studies demonstrate that anti-PD-1 treatment improved the health-span of podocytes. It restored the expression of canonical podocyte genes, transcription factors and gene regulatory networks, increased cellular metabolism signatures and lessened SASPs. These results suggest a critical contribution for increased PD-1 signaling towards both kidney and liver aging.

scholarly journals Punicalagin protects H9c2 cardiomyocytes from doxorubicin-induced toxicity through activation of Nrf2/HO-1 signaling

2019 ◽  
Vol 39 (5) ◽  
Author(s):  
Mingfang Ye ◽  
Linlin Zhang ◽  
Yuanming Yan ◽  
Huizhong Lin
Keyword(s):  
Wide Spectrum ◽  
Critical Role ◽  
Antitumor Agent ◽  
Cytochrome C Release ◽  
Beneficial Effects ◽  
H9c2 Cardiomyocytes ◽  
Underlying Mechanisms ◽  
Interfering Rna

Abstract Doxorubicin (DOX) is a wide-spectrum antitumor agent, but its clinical application is largely limited by its cardiotoxicity. Therefore, identification of effective agents against DOX-induced cardiotoxicity is of critical importance. The present study aimed to determine the beneficial role of punicalagin (PUN), a polyphenol isolated from pomegranate, in DOX-induced cardiotoxicity in vitro and explored the underlying mechanisms. H9c2 cardiomyocytes were pretreated with different concentrations (50, 100 and 200 μM) of PUN prior to DOX exposure. The results showed that PUN pretreatment significantly increased cell viability, inhibited lactate dehydrogenase (LDH) release and suppressed cell apoptosis induced by DOX. Additionally, PUN pretreatment attenuated the loss of mitochondrial membrane potential and cytochrome c release. Besides, PUN further enhanced the expression of nuclear Nrf2 and HO-1 in DOX-treated H9c2 cells, and the aforementioned beneficial effects of PUN were partially abolished by small interfering RNA (siRNA)-mediated Nrf2 knockdown. Hence, our findings clearly revealed that PUN might be a promising agent for alleviating the cardiotoxicity of DOX, and Nrf2/HO-1 signaling might serve a critical role during this process.

scholarly journals Aging predisposes to acute inflammatory induced pathology after tumor immunotherapy

2013 ◽  
Vol 210 (11) ◽  
pp. 2223-2237 ◽  
Author(s):  
Myriam N. Bouchlaka ◽  
Gail D. Sckisel ◽  
Mingyi Chen ◽  
Annie Mirsoian ◽  
Anthony E. Zamora ◽  
...  
Keyword(s):  
Critical Role ◽  
The Elderly ◽  
Mouse Tumor ◽  
Aged Mice ◽  
Liver Histopathology ◽  
Multiple Organs ◽  
The Impact ◽  
Young Mice

Cancer commonly occurs in the elderly and immunotherapy (IT) is being increasingly applied to this population. However, the majority of preclinical mouse tumor models assessing potential efficacy and toxicities of therapeutics use young mice. We assessed the impact of age on responses to systemic immune stimulation. In contrast to young mice, systemic cancer IT regimens or LPS given to aged mice resulted in rapid and lethal toxicities affecting multiple organs correlating with heightened proinflammatory cytokines systemically and within the parenchymal tissues. This inflammatory response and increased morbidity with age was independent of T cells or NK cells. However, prior in vivo depletion of macrophages in aged mice resulted in lesser cytokine levels, increased survival, and decreased liver histopathology. Furthermore, macrophages from aged mice and normal human elderly volunteers displayed heightened TNF and IL-6 production upon in vitro stimulation. Treatment of both TNF knockout mice and in vivo TNF blockade in aged mice resulted in significant increases in survival and lessened pathology. Importantly, TNF blockade in tumor-bearing, aged mice receiving IT displayed significant anti-tumor effects. These data demonstrate the critical role of macrophages in the age-associated hyper-inflammatory cytokine responses to systemic immunostimulation and underscore the importance of performing preclinical assessments in aged mice.

scholarly journals Impaired Differentiation of Osteoclasts in TREM-2–deficient Individuals

2003 ◽  
Vol 198 (4) ◽  
pp. 645-651 ◽  
Author(s):  
Marina Cella ◽  
Cecilia Buonsanti ◽  
Carey Strader ◽  
Takayuki Kondo ◽  
Andrea Salmaggi ◽  
...  
Keyword(s):  
Brain Function ◽  
Critical Role ◽  
Cell Surface Receptor ◽  
Genetic Defects ◽  
Bone Modeling ◽  
Bone Cysts ◽  
Presenile Dementia ◽  
Surface Receptor ◽  
Resorptive Activity

TREM-2 is an immunoglobulin-like cell surface receptor associated with DAP12/KARAP that activates monocyte-derived dendritic cells (DCs) in vitro. Recently, it has been shown that genetic defects of human DAP12/KARAP and TREM-2 result in a rare syndrome characterized by bone cysts and presenile dementia called Nasu-Hakola disease. This observation suggests that TREM-2 may function in myeloid cells other than DCs, most probably osteoclasts (OCs) and microglial cells, which are involved in bone modeling and brain function. Consistent with this prediction, here we show that OC differentiation is dramatically arrested in TREM-2–deficient patients, resulting in large aggregates of immature OCs that exhibit impaired bone resorptive activity. These results demonstrate a critical role for TREM-2 in the differentiation of mononuclear myeloid precursors into functional multinucleated OCs.

scholarly journals The antioxidant (−)-epigallocatechin-3-gallate inhibits activated hepatic stellate cell growth and suppresses acetaldehyde-induced gene expression

2002 ◽  
Vol 368 (3) ◽  
pp. 695-704 ◽  
Author(s):  
Anping CHEN ◽  
Li ZHANG ◽  
Jianye XU ◽  
Jun TANG
Keyword(s):  
Transforming Growth Factor ◽  
Stellate Cell ◽  
Present Report ◽  
Smooth Muscle Actin ◽  
Critical Role ◽  
Dependent Manner ◽  
Liver Fibrogenesis ◽  
Underlying Mechanisms

Activated hepatic stellate cells (HSC) are the primary source of excessive production of extracellular matrix during liver fibrogenesis. Although the underlying mechanisms remain incompletely understood, it is widely accepted that oxidative stress plays a critical role in liver fibrogenesis. Suppression of HSC growth and activation, as well as induction of apoptosis, have been proposed as therapeutic strategies for treatment and prevention of this disease. In the present report, we elucidated, for the first time, effects of the antioxidant (—)-epigallocatechin-3-gallate (EGCG), a major (and the most active) component of green tea extracts, on cultured HSC growth and activation. Our results revealed that EGCG significantly inhibited cultured HSC growth by inducing cell cycle arrest and apoptosis in a dose- and time-dependent manner. In addition, EGCG markedly suppressed the activation of cultured HSC as demonstrated by blocking transforming growth factor-β signal transduction and by inhibiting the expression of α1(I) collagen, fibronectin and α-smooth muscle actin genes induced by acetaldehyde, the most active metabolite of ethanol. Furthermore, EGCG reacted differently in the inhibition of nuclear factor-κB activity between cultured HSC with or without acetaldehyde stimulation. Taken together, our results indicated that EGCG was a novel and effective inhibitor for activated HSC growth and activation in vitro. Further studies are necessary to evaluate the effect of this polyphenol in prevention of quiescent HSC activation in vivo, and to further elucidate the underlying mechanisms.

scholarly journals PD-1highCXCR5–CD4+ Peripheral Helper T (Tph) cells Promote Tissue-Homing Plasmablasts in COVID-19

2021 ◽  
Author(s):  
Hiromitsu Asashima ◽  
Subhasis Mohanty ◽  
Michela Comi ◽  
William E. Ruff ◽  
Kenneth B. Hoehn ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Acute Phase ◽  
Chemokine Receptors ◽  
Critical Role ◽  
Viral Immunity ◽  
B Cell Differentiation ◽  
Follicular Helper ◽  
Underlying Mechanisms

SummaryA dysregulated immune response against coronavirus-2 (SARS-CoV-2) plays a critical role in the outcome of patients with coronavirus disease 2019 (COVID-19). A significant increase in circulating plasmablasts is characteristic of COVID-19 though the underlying mechanisms and its prognostic implications are not known. Here, we demonstrate that in the acute phase of COVID-19, activated PD-1highCXCR5−CD4+ T cells, peripheral helper T cells, (Tph) are significantly increased and promote inflammatory tissue-homing plasmablasts in patients with stable but not severe COVID-19. Analysis of scRNA-seq data revealed that plasmablasts in stable patients express higher levels of tissue-homing receptors including CXCR3. The increased Tph cells exhibited “B cell help” signatures similar to that of circulating T follicular helper (cTfh) cells and promoted B cell differentiation in vitro. Compared with cTfh cells, Tph cells produced more IFNγ, inducing tissue-homing chemokine receptors on plasmablasts. Finally, expansion of activated Tph cells was correlated with the frequency of CXCR3+ plasmablasts in the acute phase of patients with stable disease. Our results demonstrate a novel role for Tph cells in acute viral immunity by inducing ectopic, antibody secreting plasmablasts.

scholarly journals Up-regulation of CXCL8 expression is associated with a poor prognosis and enhances tumor cell malignant behaviors in liver cancer

2020 ◽  
Vol 40 (8) ◽  
Author(s):  
Song Yang ◽  
Han Wang ◽  
Chundi Qin ◽  
Hongmei Sun ◽  
Yupeng Han
Keyword(s):  
Liver Cancer ◽  
Hepg2 Cells ◽  
Human Liver ◽  
Clinical Stage ◽  
Critical Role ◽  
Human Liver Tissue ◽  
Underlying Mechanisms ◽  
And Migration ◽  
High Level

Abstract CXCL8, a member of CXC chemokines, was constitutively expressed in many types of human cancers, and its overexpression has been shown to play a critical role in promoting tumorigenesis. The purpose of the present study was to determine CXCL8 expression in a commercial human liver tissue microarray, and elucidate the effects and underlying mechanisms by which CXCL8 is involved in the malignant progression of human liver cancer. Our data showed that high level expression of CXCL8 in tissues with liver cancer was identified as compared with non-cancer tissues, and its up-regulation was closely associated with clinical stage and tumor infiltration. In vitro, exogenous CXCL8 at concentrations of 10, 20 or 40 ng/ml obviously stimulated the proliferation abilities of HepG2 cells. Coupled with this, 10, 20 or 40 ng/ml of exogenous CXCL8 also triggered a significant elevation in HepG2 cells migration. Additionally, overexpression of CXCL8 in HepG2 cells also resulted in increased cell proliferation and migration capacities. Finally, Western blotting analysis showed that overexpression of CXCL8 increased the expression of ERK, p-ERK and survivin, decreased the expression of caspase-3 and BAX at protein level.

scholarly journals HSP90α Mediates Sorafenib Resistance in Human Hepatocellular Carcinoma by Necroptosis Inhibition under Hypoxia

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 243
Author(s):  
Yan Liao ◽  
Yue Yang ◽  
Di Pan ◽  
Youxiang Ding ◽  
Heng Zhang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Imaging System ◽  
Morphological Changes ◽  
Critical Role ◽  
Tumor Xenograft ◽  
Target Drug ◽  
Transmission Electron ◽  
Underlying Mechanisms

As one of the most common malignancies worldwide, Hepatocellular carcinoma (HCC) has been treated by Sorafenib, which is the first approved target drug by FDA for advanced HCC. However, drug resistance is one of the obstacles to its application. As a typical characteristic of most solid tumors, hypoxia has become a key cause of resistance to chemotherapy and radiotherapy. It is important to elucidate the underlying mechanisms of Sorafenib resistance under hypoxia. In this study, the morphological changes of hepatocellular carcinoma cells were observed by Live Cell Imaging System and Transmission Electron Microscope; Sorafenib was found to induce necroptosis in liver cancer. Under hypoxia, the distribution of necroptosis related proteins was changed, which contributed to Sorafenib resistance. HSP90α binds with the necrosome complex and promotes chaperone-mediated autophagy (CMA) degradation, which leads necroptosis blocking and results in Sorafenib resistance. The patient-derived tumor xenograft (PDX) model has been established to investigate the potential therapeutic strategies to overcome Sorafenib resistance. 17-AAG inhibited HSP90α and presented obvious reversal effects of Sorafenib resistance in vivo and in vitro. All the results emphasized that HSP90α plays a critical role in Sorafenib resistance under hypoxia and 17-AAG combined with Sorafenib is a promising therapy for hepatocellular carcinoma.

scholarly journals The Ubiquitin-Dependent Targeting Pathway in Saccharomyces cerevisiae Plays a Critical Role in Multiple Chromatin Assembly Regulatory Steps

Genetics ◽  
2002 ◽  
Vol 162 (2) ◽  
pp. 615-632 ◽  
Author(s):  
Troy A A Harkness ◽  
Gerald F Davies ◽  
Vijay Ramaswamy ◽  
Terra G Arnason
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Translational Control ◽  
Regulatory Networks ◽  
Critical Role ◽  
Chromatin Assembly ◽  
Temperature Sensitive ◽  
Anaphase Promoting Complex ◽  
Free Media

Abstract In a screen designed to isolate Saccharomyces cerevisiae strains defective for in vitro chromatin assembly, two temperature-sensitive (ts) mutants were obtained: rmc1 and rmc3 (remodeling of chromatin). Cloning of RMC1 and RMC3 revealed a broad role for the ubiquitin-dependent targeting cascade as the ubiquitin-protein ligases (E3s), the anaphase promoting complex (APC; RMC1 encodes APC5) and Rsp5p, respectively, were identified. Genetic studies linked the rmc1/apc5 chromatin assembly defect to APC function: rmc1/apc5 genetically interacted with apc9Δ, apc10Δ, and cdc26Δ mutants. Furthermore, phenotypes associated with the rmc1/apc5 allele were consistent with defects in chromatin metabolism and in APC function: (i) UV sensitivity, (ii) plasmid loss, (iii) accumulation of G2/M cells, and (iv) suppression of the ts defect by growth on glucose-free media and by expression of ubiquitin. On the other hand, the multifunctional E3, Rsp5p, was shown to be required for both in vitro and in vivo chromatin assembly, as well as for the proper transcriptional and translational control of at least histone H3. The finding that the distinctly different E3 enzymes, APC and Rsp5p, both play roles in regulating chromatin assembly highlight the depth of the regulatory networks at play. The significance of these findings will be discussed.

scholarly journals SRGN Promotes Colorectal Cancer Metastasis as a Critical Downstream Target of HIF-1α

2018 ◽  
Vol 48 (6) ◽  
pp. 2429-2440 ◽  
Author(s):  
Yang Xu ◽  
Jie  Xu ◽  
Yanfang Yang ◽  
Lei Zhu ◽  
Xubin Li ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Metastasis ◽  
Critical Role ◽  
Underlying Mechanism ◽  
Migration And Invasion ◽  
Potential Candidate ◽  
Metastatic Progression ◽  
Downstream Target ◽  
Underlying Mechanisms

Background/Aims: The chondroitin sulfate proteoglycan serglycin (SRGN), a hematopoietic cell granule proteoglycan, has been implicated in promoting tumor metastasis; however, the underlying mechanisms remain to be elucidated. The present study aimed to investigate the SRGN gene expression and its regulation as downstream signaling of hypoxia-inducible transcription factor 1 alpha (HIF-1α) in colorectal cancer (CRC) cells and tissues. Methods: The expression of SRGN was analyzed in CRC specimens for its correlation with progression and metastasis. Using chromatin-immunoprecipitation (ChIP), quantitative real-time PCR, Western blot, and transwell assay, the functional role and underlying mechanism of SRGN in CRC metastasis were elucidated. Thus, this study provides evidence of a critical role of SRGN in metastatic progression of CRC. Results: Our results indicated that SRGN overexpression was significantly associated with poor prognosis in CRC specimens. SRGN overexpression promoted CRC cell migration and invasion in vitro; however, SRGN depletion exhibited contrasting effects. Mechanistic investigations revealed that HIF-1α regulated SRGN transcription via physically binding to a hypoxia response element in its promoter region. Conclusions: In conclusion, we demonstrated that dysregulated HIF-1α/SRGN signaling promotes CRC progression and metastasis. SRGN may serve as a potential candidate therapeutic target for metastatic CRC.

scholarly journals LncRNA SNHG5 promotes the proliferation and cancer stem cell-like properties of hepatocellular carcinoma by regulating UPF1 and Wnt signaling pathway

2020 ◽  
Author(s):  
Yarui Li ◽  
Junbi Hu ◽  
Guifang Lu ◽  
Mudan Ren ◽  
Zhiyong Zhang ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cancer Stem Cell ◽  
Critical Role ◽  
Wnt Signaling Pathway ◽  
Bioinformatic Analysis ◽  
Luciferase Reporter ◽  
Underlying Mechanisms ◽  
Hcc Cells

Abstract Background: It have been revealed that lncRNAs had a critical role in human cancers, including HCC. Our previous study found a lncRNA SNHG5 related to the development of HCC. However, the role and exact mechanism of SNHG5 in HCC proliferation and the liver CSC-like properties is still unclear. Materials and Methods: We investigated the HCC cells proliferation and CSC-like properties in vitro and in vivo by knockdown or upregulate SNHG5, and detected underlying mechanisms by qRT-PCR, Western blotting, bioinformatic analysis, luciferase reporter assay, RNA immunoprecipitation. Results: Knockdown of SNHG5 repressed HCC cells proliferation and CSC-like properties, while overexpression of SNHG5 promoted cells growth. At the same time, CSCs markers ( CD44, CD133 and ALDH1) and related transcription factors (OCT4, SOX2 and NANOG) were downregulated when SNHG5 knockdown. Further investigations showed that SNHG5 regulated the proliferation and CSC-like properties of HCC by binding UPF1 and regulating Wnt/β-catenin pathway. Conclusions: SNHG5 plays critical role to promote HCC cells proliferation and cancer stem cell-like properties via UPF1 and Wnt/β-catenin pathway.

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