scholarly journals SARS-CoV-2 infection: can ferroptosis be a potential treatment target for multiple organ involvement?

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Ming Yang ◽  
Ching Lung Lai
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Science Studies ◽  
Severe Disease ◽  
Multiple Organ ◽  
Organ Involvement ◽  
Treatment Target ◽  
New Treatment

AbstractSince the outbreak of the new coronavirus in 2019 (SARS-CoV-2), many studies have been performed to better understand the basic mechanisms and clinical features of the disease. However, uncertainties of the underlying mechanisms of multiple organ involvement remain. A substantial proportion of severe coronavirus disease 2019 (COVID-19) patients have lymphopenia, low serum iron levels, and multiple organ involvement. Several therapeutic agents have been used for different stages of the disease, but the treatment for severe disease is still suboptimal. Understanding the mechanism of programmed cell death in COVID-19 may lead to better therapeutic strategies for these patients. On the basis of observations of basic science studies and clinical researches on COVID-19, we hypothesize that ferroptosis, a novel programmed cell death, may be an important cause of multiple organ involvement in COVID-19 and it might serve as a new treatment target. In spite of the existing findings on the involvement of ferroptosis in SARS-CoV-2 infection, there is no reported study to uncover how does ferroptosis acts in SARS-CoV-2 infection yet. Uncovering the role of ferroptosis in SARS-CoV-2 infection is essential to develop new treatment strategies for COVID-19. Intracellular cell iron depletion or new generation of ferroptosis inhibitors might be potential drug candidates for COVID-19. We hope this hypothesis may launch a new wave of studies to uncover the association of ferroptosis and SARS-CoV-2 infection in vitro and in vivo.

scholarly journals Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2

2012 ◽  
Vol 209 (6) ◽  
pp. 1201-1217 ◽  
Author(s):  
Tadashi Yokosuka ◽  
Masako Takamatsu ◽  
Wakana Kobayashi-Imanishi ◽  
Akiko Hashimoto-Tane ◽  
Miyuki Azuma ◽  
...  
Keyword(s):  
Cell Death ◽  
T Cell ◽  
Programmed Cell Death ◽  
T Cell Activation ◽  
Cell Activation ◽  
Tyrosine Phosphatase ◽  
Cell Receptor ◽  
Programmed Cell Death 1

Programmed cell death 1 (PD-1) is a negative costimulatory receptor critical for the suppression of T cell activation in vitro and in vivo. Single cell imaging elucidated a molecular mechanism of PD-1–mediated suppression. PD-1 becomes clustered with T cell receptors (TCRs) upon binding to its ligand PD-L1 and is transiently associated with the phosphatase SHP2 (Src homology 2 domain–containing tyrosine phosphatase 2). These negative costimulatory microclusters induce the dephosphorylation of the proximal TCR signaling molecules. This results in the suppression of T cell activation and blockade of the TCR-induced stop signal. In addition to PD-1 clustering, PD-1–TCR colocalization within microclusters is required for efficient PD-1–mediated suppression. This inhibitory mechanism also functions in PD-1hi T cells generated in vivo and can be overridden by a neutralizing anti–PD-L1 antibody. Therefore, PD-1 microcluster formation is important for regulation of T cell activation.

scholarly journals The Importance of Exosomal PD-L1 in Cancer Progression and Its Potential as a Therapeutic Target

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3247
Author(s):  
Lingxiao Ye ◽  
Zhengxin Zhu ◽  
Xiaochuan Chen ◽  
Haoran Zhang ◽  
Jiaqi Huang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Cancer Progression ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immune Escape ◽  
Tumor Treatment

Binding of programmed cell death ligand 1 (PD-L1) to its receptor programmed cell death protein 1 (PD-1) can lead to the inactivation of cytotoxic T lymphocytes, which is one of the mechanisms for immune escape of tumors. Immunotherapy based on this mechanism has been applied in clinic with some remaining issues such as drug resistance. Exosomal PD-L1 derived from tumor cells is considered to play a key role in mediating drug resistance. Here, the effects of various tumor-derived exosomes and tumor-derived exosomal PD-L1 on tumor progression are summarized and discussed. Researchers have found that high expression of exosomal PD-L1 can inhibit T cell activation in in vitro experiments, but the function of exosomal PD-L1 in vivo remains controversial. In addition, the circulating exosomal PD-L1 has high potential to act as an indicator to evaluate the clinical effect. Moreover, therapeutic strategy targeting exosomal PD-L1 is discussed, such as inhibiting the biogenesis or secretion of exosomes. Besides, some specific methods based on the strategy of inhibiting exosomes are concluded. Further study of exosomal PD-L1 may provide an effective and safe approach for tumor treatment, and targeting exosomal PD-L1 by inhibiting exosomes may be a potential method for tumor treatment.

Targeting the multiple myeloma hypoxic niche with TH-302, a hypoxia-activated prodrug

Blood ◽  
2010 ◽  
Vol 116 (9) ◽  
pp. 1524-1527 ◽  
Author(s):  
Jinsong Hu ◽  
Damian R. Handisides ◽  
Els Van Valckenborgh ◽  
Hendrik De Raeve ◽  
Eline Menu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Metastatic Potential ◽  
Treatment Target ◽  
Hypoxic Conditions ◽  
Cycle Arrest ◽  
G1 Cell Cycle Arrest ◽  
New Treatment

Hypoxia is associated with increased metastatic potential and poor prognosis in solid tumors. In this study, we demonstrated in the murine 5T33MM model that multiple myeloma (MM) cells localize in an extensively hypoxic niche compared with the naive bone marrow. Next, we investigated whether hypoxia could be used as a treatment target for MM by evaluating the effects of a new hypoxia-activated prodrug TH-302 in vitro and in vivo. In severely hypoxic conditions, TH-302 induces G0/G1 cell-cycle arrest by down-regulating cyclinD1/2/3, CDK4/6, p21cip-1, p27kip-1, and pRb expression, and triggers apoptosis in MM cells by up-regulating the cleaved proapoptotic caspase-3, -8, and -9 and poly ADP-ribose polymerase while having no significant effects under normoxic conditions. In vivo treatment of 5T33MM mice induces apoptosis of the MM cells within the bone marrow microenvironment and decreases paraprotein secretion. Our data support that hypoxia-activated treatment with TH-302 provides a potential new treatment option for MM.

scholarly journals Treatment of melanoma cells with the synthetic retinoid CD437 induces apoptosis via activation of AP-1 in vitro, and causes growth inhibition in xenografts in vivo.

1996 ◽  
Vol 135 (6) ◽  
pp. 1889-1898 ◽  
Author(s):  
D Schadendorf ◽  
M A Kern ◽  
M Artuc ◽  
H L Pahl ◽  
T Rosenbach ◽  
...  
Keyword(s):  
Cell Death ◽  
Malignant Melanoma ◽  
Programmed Cell Death ◽  
Melanoma Cells ◽  
Human Melanoma ◽  
Mrna Levels ◽  
Synthetic Retinoid ◽  
Human Melanoma Cells

Human malignant melanoma is notoriously resistant to pharmacological modulation. We describe here for the first time that the synthetic retinoid CD437 has a strong dose-dependent antiproliferative effect on human melanoma cells (IC50: 5 x 10(-6) M) via the induction of programmed cell death, as judged by analysis of cell morphology, electron microscopical features, and DNA fragmentation. Programmed cell death was preceded by a strong activation of the AP-1 complex in CD437-treated cells as demonstrated by gel retardation and chloramphenicol transferase (CAT) assays. Northern blot analysis showed a time-dependent increase in the expression of c-fos and c-jun encoding components of AP-1, whereas bcl-2 and p53 mRNA levels remained constant. CD437 also exhibited a strong growth inhibitory effect on MeWo melanoma cells in a xenograft model. In tissue sections of CD437-treated MeWo tumors from these animals, apoptotic melanoma cells and c-fos overexpressing cells were colocalized by TdT-mediated deoxyuridine triphosphate-digoxigenin nick end labeling (TUNEL) staining and in situ hybridization. Taken together, this report identifies CD437 as a retinoid that activates and upregulates the transcription factor AP-1, leading eventually to programmed cell death of exposed human melanoma cells in vitro and in vivo. Further studies are needed to evaluate whether synthetic retinoids such as CD437 represent a new class of retinoids, which may open up new ways to a more effective therapy of malignant melanoma.

scholarly journals Modulation of the extrinsic cell death signaling pathway by viral Flip induces acute-death mediated liver failure

2019 ◽  
Vol 10 (12) ◽  
Author(s):  
Miriam Bittel ◽  
Andreas E. Kremer ◽  
Michael Stürzl ◽  
Stefan Wirtz ◽  
Iris Stolzer ◽  
...  
Keyword(s):  
Cell Death ◽  
Viral Infections ◽  
Tissue Injury ◽  
Multiple Organ ◽  
Severe Liver ◽  
Transgenic Expression ◽  
Effector Caspase ◽  
The Impact

AbstractDuring viral infections viruses express molecules that interfere with the host-cell death machinery and thus inhibit cell death responses. For example the viral FLIP (vFLIP) encoded by Kaposi’s sarcoma-associated herpesvirus interacts and inhibits the central cell death effector, Caspase-8. In order to analyze the impact of anti-apoptotic viral proteins, like vFlip, on liver physiology in vivo, mice expressing vFlip constitutively in hepatocytes (vFlipAlbCre+) were generated. Transgenic expression of vFlip caused severe liver tissue injury accompanied by massive hepatocellular necrosis and inflammation that finally culminated in early postnatal death of mice. On a molecular level, hepatocellular death was mediated by RIPK1-MLKL necroptosis driven by an autocrine TNF production. The loss of hepatocytes was accompanied by impaired bile acid production and disruption of the bile duct structure with impact on the liver-gut axis. Notably, embryonic development and tissue homeostasis were unaffected by vFlip expression. In summary our data uncovered that transgenic expression of vFlip can cause severe liver injury in mice, culminating in multiple organ insufficiency and death. These results demonstrate that viral cell death regulatory molecules exhibit different facets of activities beyond the inhibition of cell death that may merit more sophisticated in vitro and in vivo analysis.

scholarly journals Novel cucurmosin‐based immunotoxin targeting programmed cell death 1‐ligand 1 with high potency against human tumor in vitro and in vivo

2020 ◽  
Vol 111 (9) ◽  
pp. 3184-3194
Author(s):  
Caiyun Zhang ◽  
Jiani Xiong ◽  
Yinxiang Lan ◽  
Jingyu Wu ◽  
Chengyan Wang ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Human Tumor ◽  
High Potency ◽  
Programmed Cell Death 1

scholarly journals In VitroandIn VivoEfficacies of Mefloquine-Based Treatment against Alveolar Echinococcosis

2010 ◽  
Vol 55 (2) ◽  
pp. 713-721 ◽  
Author(s):  
Tatiana Küster ◽  
Britta Stadelmann ◽  
Corina Hermann ◽  
Sabrina Scholl ◽  
Jennifer Keiser ◽  
...  
Keyword(s):  
Alveolar Echinococcosis ◽  
Severe Disease ◽  
Treatment Options ◽  
Drug Candidate ◽  
Combined Application ◽  
New Treatment ◽  
Complete Detachment ◽  
Laminated Layer

ABSTRACTAlveolar echinococcosis (AE) is caused by the metacestode stage of the fox tapewormEchinococcus multilocularisand causes severe disease in the human liver, and occasionally in other organs, that is fatal when treatment is unsuccessful. The present chemotherapy against AE is based on mebendazole and albendazole. Albendazole treatment has been found to be ineffective in some instances, is parasitostatic rather than parasiticidal, and usually involves the lifelong uptake of large doses of drugs. Thus, new treatment options are urgently needed. In this study we investigated thein vitroandin vivoefficacy of mefloquine againstE. multilocularismetacestodes. Treatment using mefloquine (20 μM) againstin vitrocultures of metacestodes resulted in rapid and complete detachment of large parts of the germinal layer from the inner surface of the laminated layer within a few hours. Thein vitroactivity of mefloquine was dependent on the dosage.In vitroculture of metacestodes in the presence of 24 μM mefloquine for a period of 10 days was parasiticidal, as determined by murine bioassays, while treatment with 12 μM was not. Oral application of mefloquine (25 mg/kg of body weight administered twice a week for a period of 8 weeks) inE. multilocularis-infected mice was ineffective in achieving any reduction of parasite weight, whereas treatment with albendazole (200 mg/kg/day) was highly effective. However, when the same mefloquine dosage was applied intraperitoneally, the reduction in parasite weight was similar to the reduction seen with oral albendazole application. Combined application of both drugs did not increase the treatment efficacy. In conclusion, mefloquine represents an interesting drug candidate for the treatment of AE, and these results should be followed up in appropriatein vivostudies.

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