Doxorubicin Induced Apoptosis Enhances Monocyte Infiltration and Adverse Cardiac Remodeling in Diabetic Animals

2021 ◽  
Author(s):  
Chandrakala Aluganti Narasimhulu ◽  
Dinender Kumar Singla
Keyword(s):  
Cardiac Remodeling ◽  
Molecular Mechanisms ◽  
Caspase 3 ◽  
Cardiac Toxicity ◽  
Heart Function ◽  
Chemotherapeutic Drug ◽  
Glucose Levels ◽  
Tnf Α ◽  
Inflammatory Immune Response ◽  
Induced Apoptosis

Diabetic cancer patients treated with Doxorubicin (DOX), a potent chemotherapeutic drug induces cardiac toxicity. However, molecular mechanisms of cardiac toxicity in this specific disease progression in patients and animal models are completely unknown. Therefore, we designed a study to understand the effects of doxorubicin induced cardiac toxicity in diabetic animals and involved pathophysiological mechanisms. C57BL/6J mice were divided into DOX and diabetic (STZ) treated four groups; control, STZ, DOX and DOX+STZ. At Day 14, animals were sacrificed, echocardiography was used to examine heart function, heart and blood samples were collected to investigate apoptotic mechanisms (Caspase 3, BAX, Bcl2), inflammation and cardiac remodeling. Our data shows a significant (p<0.05) increase in glucose levels, apoptotic markers, monocyte infiltration at the site of apoptosis and triggered inflammatory immune response (TNF-α and IL-6), in DOX+STZ animals compared to control and experimental groups. We also observed significant (p<0.05) increase in myofibrillar area, fibrosis and significantly decreased (p<0.05) cardiac function in DOX-treated diabetic animals compared with controls. In conclusion, our data suggest that DOX-induces significantly increased apoptosis, fibrosis and structural alterations in diabetic hearts compared to non-diabetic animals.

A novel TNFR1-triggered apoptosis pathway mediated by class IA PI3Ks in neutrophils

Blood ◽  
2011 ◽  
Vol 117 (22) ◽  
pp. 5953-5962 ◽  
Author(s):  
Barbara Geering ◽  
Ursina Gurzeler ◽  
Elena Federzoni ◽  
Thomas Kaufmann ◽  
Hans-Uwe Simon
Keyword(s):  
Molecular Mechanisms ◽  
Caspase 3 ◽  
Caspase 8 ◽  
Tnf Receptor ◽  
Caspase Activation ◽  
Apoptosis Pathway ◽  
Tnf Α ◽  
Pi3k Activation ◽  
Amplification Loop ◽  
Induced Apoptosis

Abstract The most common form of neutrophil death is apoptosis. In the present study, we report surprising differences in the molecular mechanisms used for caspase activation between FAS/CD95-stimulated and TNF receptor 1 (TNFR1)–stimulated neutrophils. Whereas FAS-induced apoptosis was followed by caspase-8 activation and required Bid to initiate the mitochondrial amplification loop, TNF-α–induced apoptosis involved class IA PI3Ks, which were activated by MAPK p38. TNF-α–induced PI3K activation resulted in the generation of reactive oxygen species, which activated caspase-3, a mechanism that did not operate in neutrophils without active NADPH oxidase. We conclude that in neutrophils, proapoptotic pathways after TNFR1 stimulation are initiated by p38 and PI3K, but not by caspase-8, a finding that should be considered in anti-inflammatory drug-development strategies.

scholarly journals Blocking Caspase-3-Mediated Proteolysis of IKKβ Suppresses TNF-α-Induced Apoptosis

2001 ◽  
Vol 8 (5) ◽  
pp. 1005-1016 ◽  
Author(s):  
Guilin Tang ◽  
Jun Yang ◽  
Yuzuru Minemoto ◽  
Anning Lin
Keyword(s):  
Caspase 3 ◽  
Tnf Α ◽  
Induced Apoptosis

scholarly journals Mast cells regulate myofilament calcium sensitization and heart function after myocardial infarction

2016 ◽  
Vol 213 (7) ◽  
pp. 1353-1374 ◽  
Author(s):  
Anta Ngkelo ◽  
Adèle Richart ◽  
Jonathan A. Kirk ◽  
Philippe Bonnin ◽  
Jose Vilar ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Mast Cells ◽  
Cardiac Function ◽  
Cardiac Remodeling ◽  
Molecular Mechanisms ◽  
Troponin I ◽  
Heart Function ◽  
Ischemic Disease ◽  
Cardiomyocyte Contractility ◽  
The Impact

Acute myocardial infarction (MI) is a severe ischemic disease responsible for heart failure and sudden death. Inflammatory cells orchestrate postischemic cardiac remodeling after MI. Studies using mice with defective mast/stem cell growth factor receptor c-Kit have suggested key roles for mast cells (MCs) in postischemic cardiac remodeling. Because c-Kit mutations affect multiple cell types of both immune and nonimmune origin, we addressed the impact of MCs on cardiac function after MI, using the c-Kit–independent MC-deficient (Cpa3Cre/+) mice. In response to MI, MC progenitors originated primarily from white adipose tissue, infiltrated the heart, and differentiated into mature MCs. MC deficiency led to reduced postischemic cardiac function and depressed cardiomyocyte contractility caused by myofilament Ca2+ desensitization. This effect correlated with increased protein kinase A (PKA) activity and hyperphosphorylation of its targets, troponin I and myosin-binding protein C. MC-specific tryptase was identified to regulate PKA activity in cardiomyocytes via protease-activated receptor 2 proteolysis. This work reveals a novel function for cardiac MCs modulating cardiomyocyte contractility via alteration of PKA-regulated force–Ca2+ interactions in response to MI. Identification of this MC-cardiomyocyte cross-talk provides new insights on the cellular and molecular mechanisms regulating the cardiac contractile machinery and a novel platform for therapeutically addressable regulators.

scholarly journals Molecular mechanisms of estrogen receptor β-induced apoptosis and autophagy in tumors: implication for treating osteosarcoma

2019 ◽  
Vol 47 (10) ◽  
pp. 4644-4655
Author(s):  
Zheng-ming Yang ◽  
Min-fei Yang ◽  
Wei Yu ◽  
Hui-min Tao
Keyword(s):  
Estrogen Receptor ◽  
Estrogen Receptors ◽  
Tumor Cells ◽  
Molecular Mechanisms ◽  
Caspase 3 ◽  
Critical Role ◽  
Osteosarcoma Cells ◽  
Proliferation And Metastasis ◽  
Induced Apoptosis

The estrogen receptors α (ERα) and β (ERβ) are located in the nucleus and bind to estrogen to initiate transcription of estrogen-responsive genes. In a variety of tumor cells, ERβ has been shown to be a tumor suppressor. In particular, ERβ has anti-proliferative effects in osteosarcoma cells. Additionally, ERβ has been proven to regulate the apoptosis-related molecules IAP, BAX, caspase-3, and PARP, and to act on the NF-κB/BCL-2 pathway to induce apoptosis in tumors. Moreover, ERβ can regulate the expression of the autophagy associated markers LC3-I/LC-3II and p62 and induce autophagy in tumors by inhibiting the PI3K/AKT/mTOR pathway and activating the AMPK pathway. Here, we review the molecular mechanisms by which ERβ induces apoptosis and autophagy in a variety of tumors to further delineate more specific molecular mechanisms underlying osteosarcoma tumorigenesis and pathogenesis. Considering the broad involvement of ERβ in apoptosis, autophagy, and their interaction, it is plausible that the critical role of ERβ in inhibiting the proliferation and metastasis of osteosarcoma cells is closely related to its regulation of apoptosis and autophagy.

Polyamines are required for activation of c-Jun NH2-terminal kinase and apoptosis in response to TNF-α in IEC-6 cells

2003 ◽  
Vol 285 (5) ◽  
pp. G980-G991 ◽  
Author(s):  
Sujoy Bhattacharya ◽  
Ramesh M. Ray ◽  
Mary Jane Viar ◽  
Leonard R. Johnson
Keyword(s):  
Cytochrome C ◽  
Dna Fragmentation ◽  
Caspase 3 ◽  
Specific Inhibitor ◽  
Cell Types ◽  
Caspase 9 ◽  
Cytochrome C Release ◽  
Tnf Α ◽  
Induced Apoptosis ◽  
Jnk Activation

Intracellular polyamine homeostasis is important for the regulation of cell proliferation and apoptosis and is necessary for the balanced growth of cells and tissues. Polyamines have been shown to play a role in the regulation of apoptosis in many cell types, including IEC-6 cells, but the mechanism is not clear. In this study, we analyzed the mechanism by which polyamines regulate the process of apoptosis in response to tumor necrosis factor-α (TNF-α). TNF-α or cycloheximide (CHX) alone did not induce apoptosis in IEC-6 cells. Significant apoptosis was observed when CHX was given along with TNF-α, as indicated by a significant increase in the detachment of cells, caspase-3 activity, and DNA fragmentation. Polyamine depletion by treatment with α-difluoromethylornithine significantly reduced the level of apoptosis, as judged by DNA fragmentation and the caspase-3 activity of attached cells. Apoptosis in IEC-6 cells was accompanied by the activation of upstream caspases-6, -8, and -9 and NH2-terminal c-Jun kinase (JNK). Inhibition of JNK activation prevented caspase-9 activation. Polyamine depletion prevented the activation of JNK and of caspases-6, -8, -9, and -3. SP-600125, a specific inhibitor of JNK activation, prevented cytochrome c release from mitochondria, JNK activation, DNA fragmentation, and caspase-9 activation in response to TNF-α/CHX. In conclusion, we have shown that polyamine depletion delays and decreases TNF-α-induced apoptosis in IEC-6 cells and that apoptosis is accompanied by the release of cytochrome c, the activation of JNK, and of upstream caspases as well as caspase-3. Polyamine depletion prevented JNK activation, which may confer protection against apoptosis by modulation of upstream caspase-9 activation.

scholarly journals miR-154-5p Functions as an Important Regulator of Angiotensin II-Mediated Heart Remodeling

2019 ◽  
Vol 2019 ◽  
pp. 1-16 ◽  
Author(s):  
Que Wang ◽  
Xiaoxue Yu ◽  
Lin Dou ◽  
Xiuqing Huang ◽  
Kaiyi Zhu ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Remodeling ◽  
Structural Changes ◽  
Molecular Mechanisms ◽  
Heart Function ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Left Ventricular Myocardium ◽  
Chronic Hypertension ◽  
Arylsulfatase B

Chronic hypertension, valvular heart disease, and heart infarction cause cardiac remodeling and potentially lead to a series of pathological and structural changes in the left ventricular myocardium and a progressive decrease in heart function. Angiotensin II (AngII) plays a key role in the onset and development of cardiac remodeling. Many microRNAs (miRNAs), including miR-154-5p, may be involved in the development of cardiac remolding, but the underlying molecular mechanisms remain unclear. We aimed to characterize the function of miR-154-5p and reveal its mechanisms in cardiac remodeling induced by AngII. First, angiotensin II led to concurrent increases in miR-154-5p expression and cardiac remodeling in adult C57BL/6J mice. Second, overexpression of miR-154-5p to a level similar to that induced by AngII was sufficient to trigger cardiomyocyte hypertrophy and apoptosis, which is associated with profound activation of oxidative stress and inflammation. Treatment with a miR-154-5p inhibitor noticeably reversed these changes. Third, miR-154-5p directly inhibited arylsulfatase B (Arsb) expression by interacting with its 3′-UTR and promoted cardiomyocyte hypertrophy and apoptosis. Lastly, the angiotensin type 1 receptor blocker telmisartan attenuated AngII-induced cardiac hypertrophy, apoptosis, and fibrosis by blocking the increase in miR-154-5p expression. Moreover, upon miR-154-5p overexpression in isolated cardiomyocytes, the protective effect of telmisartan was partially abolished. Based on these results, increased cardiac miR-154-5p expression is both necessary and sufficient for AngII-induced cardiomyocyte hypertrophy and apoptosis, suggesting that the upregulation of miR-154-5p may be a crucial pathological factor and a potential therapeutic target for cardiac remodeling.

scholarly journals Rhein ElicitsIn VitroCytotoxicity in Primary Human Liver HL-7702 Cells by Inducing Apoptosis through Mitochondria-Mediated Pathway

2015 ◽  
Vol 2015 ◽  
pp. 1-19 ◽  
Author(s):  
Guy-Armel Bounda ◽  
Wang Zhou ◽  
Dan-dan Wang ◽  
Feng Yu
Keyword(s):  
Cytochrome C ◽  
Molecular Mechanisms ◽  
Caspase 3 ◽  
Morphological Changes ◽  
Fatty Degeneration ◽  
Apoptotic Cells ◽  
Dependent Manner ◽  
Caspase 9 ◽  
Cytochrome C Release ◽  
Induced Apoptosis

Objective. To study rhein-induced apoptosis signaling pathway and to investigate its molecular mechanisms in primary human hepatic cells.Results. Cell viability of HL-7702 cells treated with rhein showed significant decrease in dose-dependent manner. Following rhein treatment (25 μM, 50 μM, and 100 μM) for 12 h, the detection of apoptotic cells was significantly analyzed by flow cytometry and nuclear morphological changes by Hoechst 33258, respectively. Fatty degeneration studies showed upregulation level of the relevant hepatic markers (P< 0.01). Caspase activities expressed significant upregulation of caspase-3, caspase-9, and caspase-8. Moreover, apoptotic cells by rhein were significantly inhibited by Z-LEHD-FMK and Z-DEVD-FMK, caspase-9 inhibitor, and caspase-3 inhibitor, respectively. Overproduction of reactive oxygen species, lipid peroxidation, and loss of mitochondrial membrane potential were detected by fluorometry. Additionally, NAC, a ROS scavenger, significantly attenuated rhein-induced oxidative damage in HL-7702 cells. Furthermore, real-time qPCR results showed significant upregulation of p53, PUMA, Apaf-1, and Casp-9 and Casp-3 mRNA, with no significant changes of Fas and Cytochrome-c. Immunoblotting revealed significant Cytochrome-c release from mitochondria into cytosol and no change in Fas expression.Conclusion. Taken together, these observations suggested that rhein could induce apoptosis in HL-7702 cells via mitochondria-mediated signal pathway with involvement of oxidative stress mechanism.

scholarly journals hnRNP K plays a protective role in TNF-α-induced apoptosis in podocytes

2018 ◽  
Vol 38 (3) ◽  
Author(s):  
Shili Zhao ◽  
Junxia Feng ◽  
Qi Wang ◽  
Lu Tian ◽  
Yunfang Zhang ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Glycogen Synthase ◽  
Kidney Diseases ◽  
Cell Cycle Distribution ◽  
Caspase 8 ◽  
G1 Arrest ◽  
Inhibitory Protein ◽  
Hnrnp K ◽  
Tnf Α ◽  
Induced Apoptosis

Apoptosis of podocytes contributes to proteinuria in many chronic kidney diseases. The cytokine, tumor necrosis factor-α (TNF-α) is thought to be involved in podocyte apoptosis, but the underlying mechanism is not understood. In our study, we established a model of TNF-α-induced apoptosis by isolating primary podocytes from mice. After exposing cells to TNF-α, we determined the expression levels of heterogeneous nuclear ribonucleoprotein K (hnRNP K) and cellular FLICE-inhibitory protein (c-FLIP) and the phosphorylation levels of glycogen synthase kinase β (GSK3β) and extracellular signal-regulated kinase (ERK). We then knocked down or overexpressed the levels of hnRNP K and observed its effects on the expressions of c-FLIP, caspase-8, caspase-3, and the phosphorylation of GSK3β and ERK. In addition, we examined the percentage of cells undergoing apoptosis and studied cell cycle distribution. We found that TNF-α induced apoptosis in podocytes and that the expressions of hnRNP K and c-FLIP were significantly decreased, whereas the phosphorylations of GSK3β and ERK were significantly increased. Both gene knockdown and overexpression of hnRPN K resulted in varied expressions/phosphorylations of c-FLIP, GSK3β, and ERK. Moreover, decreased hnRPN K expression contributed to increased levels of caspase-8 and capase-3, as well as an increase in cell apoptosis and G0/G1 arrest. In conclusion, down-regulated expression of hnRNP K by TNF-α resulted in a decrease in the expression of c-FLIP as well as increases in phosphorylated GSK3β, ERK, caspase-8, and caspase-3, and then critically contributed to the podocyte apoptosis.

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