scholarly journals The 19 kDaMycobacterium tuberculosisLipoprotein (LpqH) Induces Macrophage Apoptosis through Extrinsic and Intrinsic Pathways: A Role for the Mitochondrial Apoptosis-Inducing Factor

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Alejandro Sánchez ◽  
Patricia Espinosa ◽  
Teresa García ◽  
Raúl Mancilla
Keyword(s):  
Caspase 3 ◽  
Transmembrane Potential ◽  
Death Receptor ◽  
Signaling Cascade ◽  
Mitochondrial Apoptosis ◽  
Caspase 9 ◽  
Macrophage Apoptosis ◽  
Tlr2 Activation ◽  
Death Receptor Signaling ◽  
Apoptosis Inducing Factor

We describe the association of caspase-dependent and caspase-independent mechanisms in macrophage apoptosis induced by LpqH, a 19 kDaMycobacterium tuberculosislipoprotein. LpqH triggered TLR2 activation, with upregulation of death receptors and ligands, which was followed by a death receptor signaling cascade with activation of initiator caspase 8 and executioner caspase 3. In this caspase-mediated phase, mitochondrial factors were involved in loss of mitochondrial transmembrane potential (ΔΨm), release of cytochrome c, and caspase 9 activation. Interestingly, a caspase-independent pathway was also identified; by immunoblot, the mitochondrial apoptosis inducing factor (AIF) was demonstrated in nuclei and cytosol of LpqH-treated macrophages. Confocal microscopy revealed translocation of AIF to the nuclei of the majority of apoptotic cells. These findings emphasize the complex and redundant nature of the macrophage death response to mycobacteria.

Parathyroid hormone-related protein ameliorates death receptor-mediated apoptosis in lung cancer cells

2003 ◽  
Vol 285 (6) ◽  
pp. C1429-C1436 ◽  
Author(s):  
Randolph H. Hastings ◽  
Flavio Araiza ◽  
Douglas W. Burton ◽  
Lu Zhang ◽  
Maxwell Bedley ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Parathyroid Hormone ◽  
Cancer Cells ◽  
Uv Irradiation ◽  
Cancer Progression ◽  
Caspase 3 ◽  
Death Receptor ◽  
Related Protein ◽  
Caspase 9 ◽  
Parathyroid Hormone Related Protein

Parathyroid hormone-related protein (PTHrP) is expressed in more advanced, aggressive tumors and may play an active role in cancer progression. This study investigated the effects of PTHrP on apoptosis after UV irradiation, Fas ligation, or staurosporine treatment in BEN human squamous lung carcinoma cells. Cells at 70% confluency were treated for 24 h with 100 nM PTHrP-(1-34), PTHrP-(38-64), PTHrP-(67-86), PTHrP-(107-139), or PTHrP-(140-173) in media with serum, exposed for 30 min to UV-B radiation (0.9 mJ/cm2), and maintained for another 24 h. Caspase-3, caspase-8, and caspase-9 activities increased fivefold. Pretreatment with PTHrP-(1-34) and PTHrP-(140-173) ameliorated apoptosis after UV irradiation, as indicated by reduced caspase activities, increased cell protein, decreased nuclear condensation, and increased clonal survival. Other peptides had no effect on measures of apoptosis. PTHrP-(140-173) also reduced caspase activities after Fas ligation by activating antibody, but neither peptide had effects on caspase-3 or caspase-9 activity after 1 μM staurosporine. These data indicate that PTHrP-(1-34) and PTHrP-(140-173) protect against death receptor-induced apoptosis in BEN lung cancer cells but are ineffective against mitochondrial pathways. PTHrP contributes to lung cancer cell survival in culture and could promote cancer progression in vivo. The mechanism for the protective effect against apoptosis remains to be determined.

Omi/HtrA2 and XIAP are components of platelet apoptosis signalling

2013 ◽  
Vol 109 (03) ◽  
pp. 532-539 ◽  
Author(s):  
Jeannine Winkler ◽  
Margaret Rand ◽  
Markus Schmugge ◽  
Oliver Speer
Keyword(s):  
Cytochrome C ◽  
Caspase 3 ◽  
Transmembrane Potential ◽  
Signalling Pathway ◽  
Ionophore A23187 ◽  
Caspase 9 ◽  
Cytochrome C Release ◽  
Thrombin Inhibition ◽  
Induction Of Apoptosis ◽  
Apoptotic Proteins

SummaryAlthough platelets possess the hallmarks of apoptosis such as activation of caspases, cytochrome c release and depolarisation of the mitochondrial transmembrane potential (ΔΨm), their entire apoptotic-signalling pathway is not totally understood. Therefore we studied the expression of various apoptotic proteins and found that platelets contain the pro-apoptotic proteins Omi/HtrA2 and Smac/Diablo, as well as their target the X-linked inhibitor of apoptosis XIAP. Omi/HtrA2 and Smac/Diablo were released from mitochondria into the platelet cytosol together with cytochrome c after induction of apoptosis by the Ca2+ ionophore A23187 or the BH3 mimetic ABT-737, and to a lesser extent, after platelet stimulation with collagen and thrombin. Inhibition of Omi/HtrA2 led to decreased levels of activated caspase-3/7 and caspase-9, but did not abolish loss of ΔΨm or prevent release of Omi/HtrA2 from mitochondria. These results indicate that platelets have a functional intrinsic apoptotic-signalling pathway including the pro-apoptotic protease Omi/HtrA2 and its target protein XIAP.

A Newly-Synthesized Chalcone Derivative of Ligustrazine Induces Caspase-Dependent and Apoptosis-Inducing Factor-Dependent Apoptosis in Cochlear Hair Cells

2021 ◽  
Vol 11 (2) ◽  
pp. 210-220
Author(s):  
Rongjun Man ◽  
Haiyan Yin ◽  
Jia Zhao ◽  
Qianqian Yang ◽  
Huiming Yang ◽  
...  
Keyword(s):  
Western Blot ◽  
Hair Cells ◽  
Caspase 3 ◽  
Morphological Changes ◽  
Biological Activities ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Dependent Manner ◽  
Caspase 9 ◽  
Cochlear Hair Cells ◽  
Apoptosis Inducing Factor

Objective: A newly synthesized derivative of ligustrazine chalcone, named as Z11, has shown a variety of promising biological activities. Here we aim to explore the effects of Z11 on the cochlear hair cells (HCs). Methods: Immunostaining and transmission electron microscopy (TEM) were used to examine the survival of HCs and their morphological changes. Furthermore, apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and the mRNA expression of apoptosis related genes including Caspase-9, Caspase-3, Bcl-2, Bax and Apaf1 were measured by RT-PCR. In addition, the protein expression of cleaved-Caspas-3 and cleaved-Caspase-9 were analyzed by Western blot respectively, and the protein expressionof AIF and cleaved-Caspase-3 were assessed by immunofluorescence as well. Results: Immunostaining showed that Z11 was ototoxic to mouse cochlear hair cells and significantly triggered cell death in a concentration-, time- and location-dependent manner. TUNEL assays evidenced that Z11 exerts its cytotoxicity through induction of apoptosis of cochlear hair cells in vitro. Immunofluorescence and western blot assay showed that Z11 activated the translation of apoptosis-inducing factor (AIF) and Caspase-9/Caspase-3 dependent apoptotic pathway in cochlear hair cells (HCs). Conclusion:These findings suggest that Z11 exhibits its ototoxicity through inducing apoptosis of HCs via both Caspase-dependent and AIF translocation pathways in mouse cochlear cultures.

The extrinsic caspase pathway modulates endotoxin-induced diaphragm contractile dysfunction

2007 ◽  
Vol 102 (4) ◽  
pp. 1649-1657 ◽  
Author(s):  
Gerald S. Supinski ◽  
Xinying Ji ◽  
Wenyi Wang ◽  
Leigh A. Callahan
Keyword(s):  
Caspase 3 ◽  
Death Receptor ◽  
Interferon Γ ◽  
Caspase 8 ◽  
Contractile Dysfunction ◽  
Tnf Receptor ◽  
Caspase Activation ◽  
Caspase 9 ◽  
Diaphragm Dysfunction ◽  
Tnf Α

The mechanisms by which infections induce diaphragm dysfunction remain poorly understood. The purpose of this study was to determine which caspase pathways (i.e., the extrinsic, death receptor-linked caspase-8 pathway, and/or the intrinsic, mitochondrial-related caspase-9 pathway) are responsible for endotoxin-induced diaphragm contractile dysfunction. We determined 1) whether endotoxin administration (12 mg/kg IP) to mice induces caspase-8 or -9 activation in the diaphragm; 2) whether administration of a caspase-8 inhibitor ( N-acetyl-Ile-Glu-Thr-Asp-CHO, 3 mg/kg iv) or a caspase-9 inhibitor ( N-acetyl-Leu-Glu-His-Asp-CHO, 3 mg/kg iv) blocks endotoxin-induced diaphragmatic weakness and caspase-3 activation; 3) whether TNF receptor 1-deficient mice have reduced caspase activation and diaphragm dysfunction following endotoxin; and 4) whether cytokines (TNF-α or cytomix, a mixture of TNF-α, interleukin-1β, interferon-γ, and endotoxin) evoke caspase activation in C2C12 myotubes. Endotoxin markedly reduced diaphragm force generation ( P < 0.001) and induced increases in caspase-3 and caspase-8 activity ( P < 0.03), but failed to increase caspase-9. Inhibitors of caspase-8, but not of caspase-9, prevented endotoxin-induced reductions in diaphragm force and caspase-3 activation ( P < 0.01). Mice deficient in TNF receptor 1 also had reduced caspase-8 activation ( P < 0.001) and less contractile dysfunction ( P < 0.01) after endotoxin. Furthermore, incubation of C2C12 cells with either TNF-α or cytomix elicited significant caspase-8 activation. The caspase-8 pathway is strongly activated in the diaphragm following endotoxin and is responsible for caspase-3 activation and diaphragm weakness.

scholarly journals Gasdermine E-Dependent Mitochondrial Pyroptotic Pathway in Dermatomyositis: A Possible Mechanism of Perifascicular Atrophy

2020 ◽  
Vol 79 (5) ◽  
pp. 551-561
Author(s):  
Meirong Liu ◽  
Ling Li ◽  
Tingjun Dai ◽  
Ying Hou ◽  
Wei Li ◽  
...  
Keyword(s):  
Cell Death ◽  
Caspase 3 ◽  
Immunohistochemical Analysis ◽  
Positive Staining ◽  
Mrna Levels ◽  
Mitochondrial Apoptosis ◽  
Histologic Feature ◽  
Caspase 9 ◽  
Perifascicular Atrophy ◽  
And Control

Abstract Different mechanisms have been proposed to explain the pathological basis of perifascicular atrophy (PFA), a pathognomonic histologic feature of dermatomyositis (DM); however, the detailed mechanisms remain to be elucidated. There is mitochondrial dysfunction in PFA and expression of mitochondrial apoptosis molecules has been reported in DM. Overexpression of gasdermin E (GSDME) can turn mitochondrial apoptosis to mitochondrial pyroptosis, a newly characterized form of programmed cell death. We determined the expression of proteins involved in the caspase-3- and GSDME-dependent mitochondrial pyroptotic pathway, including BAX, BAK, cytochrome C, caspase-9, caspase-3, GSDME, and IL-1α, in biopsied muscles from DM and control patients. Immunohistochemical analysis showed that those markers were expressed in most fibers in PFA in DM. GSDME-positive and IL-1α-positive staining was mainly localized around punched-out vacuoles or sarcolemma. These markers were significantly upregulated at the protein and mRNA levels in DM versus controls. Our results suggest that caspase-3- and GSDME-dependent mitochondrial pyroptosis are involved in the pathogenetic mechanisms of PFA in DM and that targeting GSDME-dependent mitochondrial pyroptosis may be an effective therapeutic approach for this condition.

scholarly journals Compartmentalized megakaryocyte death generates functional platelets committed to caspase-independent death

2003 ◽  
Vol 160 (4) ◽  
pp. 577-587 ◽  
Author(s):  
Murray C.H. Clarke ◽  
John Savill ◽  
David B. Jones ◽  
Brendon S. Noble ◽  
Simon B. Brown
Keyword(s):  
Cell Death ◽  
Cytochrome C ◽  
Progenitor Cell ◽  
Caspase 3 ◽  
Transmembrane Potential ◽  
Blood Platelets ◽  
Apoptotic Bodies ◽  
Caspase 9 ◽  
Daughter Cells ◽  
Membrane Bound

Caspase-directed apoptosis usually fragments cells, releasing nonfunctional, prothrombogenic, membrane-bound apoptotic bodies marked for rapid engulfment by macrophages. Blood platelets are functional anucleate cells generated by specialized fragmentation of their progenitors, megakaryocytes (MKs), but committed to a constitutive caspase-independent death. Constitutive formation of the proplatelet-bearing MK was recently reported to be caspase-dependent, apparently involving mitochondrial release of cytochrome c, a known pro-apoptogenic factor. We extend those studies and report that activation of caspases in MKs, either constitutively or after Fas ligation, yields platelets that are functionally responsive and evade immediate phagocytic clearance, and retain mitochondrial transmembrane potential until constitutive platelet death ensues. Furthermore, the exclusion from the platelet progeny of caspase-9 present in the progenitor accounts for failure of mitochondrial release of cytochrome c to activate caspase-3 during platelet death. Thus, progenitor cell death by apoptosis can result in birth of multiple functional anucleate daughter cells.

P3-299 TNF death receptor signaling cascade is required for amyloid-β protein induced neuron death

2004 ◽  
Vol 25 ◽  
pp. S440
Author(s):  
Yong Shen ◽  
Rena Li ◽  
Libang Yang ◽  
Kristina Lindholm ◽  
Yoshihiro Konishi ◽  
...  
Keyword(s):  
Death Receptor ◽  
Amyloid Β ◽  
Signaling Cascade ◽  
Amyloid Β Protein ◽  
Receptor Signaling ◽  
Neuron Death ◽  
Β Protein ◽  
Death Receptor Signaling ◽  
Induced Neuron

Atiprimod inhibits the growth of mantle cell lymphoma in vitro and in vivo and induces apoptosis via activating the mitochondrial pathways

Blood ◽  
2007 ◽  
Vol 109 (12) ◽  
pp. 5455-5462 ◽  
Author(s):  
Michael Wang ◽  
Liang Zhang ◽  
Xiaohong Han ◽  
Jing Yang ◽  
Jianfei Qian ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Cell Apoptosis ◽  
Caspase 3 ◽  
Cell Lymphoma ◽  
Caspase 9 ◽  
Mantle Cell ◽  
Induced Apoptosis ◽  
Apoptosis Inducing Factor

Abstract Atiprimod is a novel cationic amphiphilic compound and has been shown to exert antimyeloma effects both in vitro and in mouse experiments. This study was undertaken to evaluate the therapeutic efficacy of atiprimod on mantle cell lymphoma (MCL) and elucidate the mechanism by which it induces cell apoptosis. Atiprimod inhibited the growth and induced apoptosis of MCL cell lines and freshly isolated primary tumor cells in vitro. More importantly, atiprimod significantly inhibited tumor growth in vivo and prolonged the survival of tumor-bearing mice. However, atiprimod also exhibited lower cytotoxicity toward normal lymphocytes. Atiprimod activated c-Jun N-terminal protein kinases (JNK) and up-regulated the level of Bax, Bad, and phosphorylated Bcl-2, resulting in release of apoptosis-inducing factor (AIF) and cytochrome c from mitochondria and activation and cleavage of caspase-9, caspase-3, and PARP. However, AIF, but not activation of caspases or PARP, was responsible for apoptosis in MCL cells because an AIF inhibitor, but not pan-caspase or paspase-9 inhibitors, completely abrogated atiprimod-induced apoptosis. Taken together, our results demonstrate that atiprimod displays a strong anti-MCL activity. Cell apoptosis was induced mainly via activation of the AIF pathway. These results support the use of atiprimod as a potential agent in MCL chemotherapy.

Photodynamic Effects of Vitamin K3 on Cervical Carcinoma Cells Activating Mitochondrial Apoptosis Pathways

2020 ◽  
Vol 21 (1) ◽  
pp. 91-99
Author(s):  
Yong Xin ◽  
Wenwen Guo ◽  
Chunsheng Yang ◽  
Qian Huang ◽  
Pei Zhang ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Caspase 3 ◽  
Mitochondrial Apoptosis ◽  
Caspase 9 ◽  
Vitamin K3 ◽  
Cervical Cancer Cells ◽  
Apoptosis Pathways

Background: Photodynamic Therapy (PDT) is a photoactivation or photosensitization process, wherein vitamin K3 (Vit K3) serves as a photosensitizer to produce Reactive Oxygen Species (ROS) against bacteria at appropriate wavelengths. In this study, we used Vit K3 treatment combined with Ultraviolet radiation A (UVA) to produce photodynamic effects on cervical cancer. Methods: The dose-concentration relationship between Vit K3 treatment and UVA on tumor cells was analyzed through the Cell Counting Kit-8 method. Then, the morphological characteristics of apoptosis cells were observed through fluorescent staining and fluorescence microscopy. Apoptosis after treatment with Vit K3 treatment, UVA, and Vit K3 treatment plus UVA was further observed through Western blot analysis, flow cytometry, and TUNEL assay. The xenograft models from HeLa cells were established for the exploration of the photodynamic effect of Vit K3 treatment on cervical cancer in vivo. Results: Vit K3 treatment plus UVA reduced tumor cell viability in a dose-dependent manner. Further studies indicated that Vit K3 treatment plus UVA can inhibit tumor growth and enhance the apoptosis of cervical cancer cells. In the combination group, the expression levels of cleaved caspase-3, cleaved caspase-9, B-cell lymphoma- extra large (Bcl-xl), and cytochrome c (cyt-c) increased obviously, whereas the expression level of Bcell lymphoma 2 (Bcl-2) decreased relative to the expression levels of UVA- or Vit K3-treated cells. In the in vivo experiments, tumor growth was inhibited significantly in the VitK3 treatment plus UVA group. Additionally, we demonstrated that the combination therapy mediated an increase in cleaved caspase-3 and cleaved caspase-9 expression and decrease in Bcl-2 expression in vivo. Conclusion: Our results showed that Vit K3 treatment combined with UVA exerted photodynamic effects on cervical cancer cells by activating mitochondrial apoptosis pathways.

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