Telbivudine Reduces Parvovirus B19-Induced Apoptosis in Circulating Angiogenic Cells

Aims: Human parvovirus B19 (B19V) infection directly induces apoptosis and modulates CXCR4 expression of infected marrow-derived circulating angiogenic cells (CACs). This leads to dysfunctional endogenous vascular repair. Treatment for B19V-associated disease is restricted to symptomatic treatment. Telbivudine, a thymidine analogue, established in antiviral treatment for chronic hepatitis B, modulates pathways that might influence induction of apoptosis. Therefore, we tested the hypothesis of whether telbivudine influences B19V-induced apoptosis of CAC. Methods and Results: Pretreatment of two CAC-lines, early outgrowth endothelial progenitor cells (eo-EPC) and endothelial colony-forming cells (ECFC) with telbivudine before in vitro infection with B19V significantly reduced active caspase-3 protein expression (−39% and −40%, both p < 0.005). Expression of Baculoviral Inhibitor of apoptosis Repeat-Containing protein 3 (BIRC3) was significantly downregulated by in vitro B19V infection in ECFC measured by qRT-PCR. BIRC3 downregulation was abrogated with telbivudine pretreatment (p < 0.001). This was confirmed by single gene PCR (p = 0.017) and Western blot analysis. In contrast, the missing effect of B19V on angiogenic gene expression postulates a post-transcriptional modulation of CXCR4. Conclusions: We for the first time show a treatment approach to reduce B19V-induced apoptosis. Telbivudine reverses B19V-induced dysregulation of BIRC3, thus, intervening in the apoptosis pathway and protecting susceptible cells from cell death. This approach could lead to an effective B19V treatment to reduce B19V-related disease.

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Encephalitozoon cuniculi and Vittaforma corneae (Phylum Microsporidia) inhibit staurosporine-induced apoptosis in human THP-1 macrophages in vitro

Parasitology ◽

10.1017/s0031182018001968 ◽

2018 ◽

Vol 146 (5) ◽

pp. 569-579 ◽

Cited By ~ 1

Author(s):

Yuliya Y. Sokolova ◽

Lisa C. Bowers ◽

Xavier Alvarez ◽

Elizabeth S. Didier

Keyword(s):

Expression Profiles ◽

Life Cycles ◽

Host Cells ◽

Human Macrophage ◽

Inflammasome Activation ◽

Encephalitozoon Cuniculi ◽

Apoptosis Pathway ◽

Intrinsic Apoptosis Pathway ◽

Induced Apoptosis

AbstractObligately intracellular microsporidia regulate their host cell life cycles, including apoptosis, but this has not been evaluated in phagocytic host cells such as macrophages that can facilitate infection but also can be activated to kill microsporidia. We examined two biologically dissimilar human-infecting microsporidia species, Encephalitozoon cuniculi and Vittaforma corneae, for their effects on staurosporine-induced apoptosis in the human macrophage-differentiated cell line, THP1. Apoptosis was measured after exposure of THP-1 cells to live and dead mature organisms via direct fluorometric measurement of Caspase 3, colorimetric and fluorometric TUNEL assays, and mRNA gene expression profiles using Apoptosis RT2 Profiler PCR Array. Both species of microsporidia modulated the intrinsic apoptosis pathway. In particular, live E. cuniculi spores inhibited staurosporine-induced apoptosis as well as suppressed pro-apoptosis genes and upregulated anti-apoptosis genes more broadly than V. corneae. Exposure to dead spores induced an opposite effect. Vittaforma corneae, however, also induced inflammasome activation via Caspases 1 and 4. Of the 84 apoptosis-related genes assayed, 42 (i.e. 23 pro-apoptosis, nine anti-apoptosis, and 10 regulatory) genes were more affected including those encoding members of the Bcl2 family, caspases and their regulators, and members of the tumour necrosis factor (TNF)/TNF receptor R superfamily.

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SLC25A21 Suppresses Cell Growth in Bladder Cancer Via The Reactive Oxygen Species-Mediated Mitochondrion-Dependent Apoptosis Pathway

10.21203/rs.3.rs-154355/v1 ◽

2021 ◽

Author(s):

Yong Wang ◽

Jiawen Gao ◽

Shasha Hu ◽

Weiting Zeng ◽

Hongjun Yang ◽

...

Keyword(s):

Bladder Cancer ◽

Treatment Strategies ◽

Migration And Invasion ◽

Loss Of Function ◽

Apoptosis Pathway ◽

Normal Tissues ◽

Induced Apoptosis ◽

New Diagnosis

Abstract Background: Bladder cancer (BCa) is a commonly diagnosed malignancy worldwide that has poor survival depending on its intrinsic biologic aggressiveness and a peculiar radio- and chemoresistance features. Gaining a better understanding of tumorigenesis and developing new diagnosis and treatment strategies for BCa is important for improving BCa clinical outcome. SLC25 family member 21 (SLC25A21), a carrier transporting C5-C7 oxodicarboxylates, has been reported to contribute to oxoadipate acidemia. However, the potential role of SLC25A21 in cancer remains absolutely unknown. Methods: The expression levels of SLC25A21 in BCa and normal tissues were examined by real-time PCR and immunohistochemistry. Gain-of- and loss-of-function experiments were performed to detect the biological functions of SLC25A21 in vitro and in vivo by CCK-8 assay, plate colony formation assay, cell migration, invasion assay and experimental animal models. The subcellular distribution of substrate mediated by SLC25A21, mitochondrial membrane potential and ROS production were assessed to explore the potential mechanism of SLC25A21 in BCa.Results: We found that the expression of SLC25A21 was downregulated in BCa tissues compared to normal tissues. A significant positive correlation between decreased SLC25A21 expression and poor prognosis was observed in BCa patients. Overexpression of SLC25A21 significantly inhibited cell proliferation, migration and invasion and induced apoptosis in vitro. Moreover, the enhanced SLC25A21 expression significantly suppressed tumor growth in a xenograft mouse model. Furthermore, we revealed that SLC25A21 suppressed BCa growth by inducing the efflux of mitochondrial α-KG to the cytosol, decreasing to against oxidative stress, and activating the ROS-mediated mitochondrion-dependent apoptosis pathway. Conclusions: Our findings provide the first link between SLC25A21 expression and BCa and demonstrate that SLC25A21 acts as a crucial suppressor in BCa progression, which may help to provide new targets for BCa intervention.

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Combatting SARS-CoV-2: Potential Therapeutic Candidates Against COVID-19

EMJ Allergy & Immunology ◽

10.33590/emjallergyimmunol/21-00088 ◽

2021 ◽

pp. 61-70

Author(s):

Pramod Kumar Gupta ◽

Savita Kulkarn

Keyword(s):

Antiviral Treatment ◽

Symptomatic Treatment ◽

Antiviral Effect ◽

Therapeutic Agents ◽

Severe Illness ◽

Global Pandemic ◽

Treatment Summary ◽

Therapeutic Compounds

Background: COVID-19, a global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in December 2019 in China and has spread to 210 countries and territories. Since then, it has infected >187.3 million people worldwide, causing >4.0 million deaths, and numbers are continuing to rise. Fever, dry cough, shortness of breath, and pneumonia are the main symptoms of this disease, which does not have any specific antiviral treatment or vaccines to date, and clinical management is mainly symptomatic treatment. Summary: The global spread of SARS-CoV-2 has necessitated the development of novel therapeutic agents against the virus to stop the pandemic. Drugs targeting viral as well as host factors may have a potential antiviral effect. The development of novel drugs may take years; hence, the best alternative available is to repurpose existing antiviral drugs with a known safety profile in humans. Further, compounds with known in vitro and in vivo efficacy against SARS-CoV and Middle East respiratory syndrome coronavirus have been included in recent clinical trials and exhibited encouraging results against SARS-CoV-2. Here, the authors provide a summary of therapeutic compounds that have shown antiviral effects against SARS-CoV-2 infections in cell lines, animal models, and patients. Key Messages: With every passing day, knowledge about SARS-CoV-2 is increasing due to continued efforts of scientists working in this area globally. Approximately 15% of patients with COVID-19 are affected by severe illness and treatments are desperately needed. In this time of global pandemic, collective and co-ordinated efforts are needed to develop therapeutic agents against this disease.

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Effects of different Ca2+ level on fluoride-induced apoptosis pathway of endoplasmic reticulum in the rabbit osteoblast in vitro

Food and Chemical Toxicology ◽

10.1016/j.fct.2018.04.013 ◽

2018 ◽

Vol 116 ◽

pp. 189-195 ◽

Cited By ~ 5

Author(s):

Jinming Wang ◽

Yangfei Zhao ◽

Xiaofang Cheng ◽

Yanyan Li ◽

Huimiao Xu ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Apoptosis Pathway ◽

Induced Apoptosis

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Functional Exosome-Mediated Delivery of Triptolide Endowed with Targeting Properties as Chemotherapy Carriers for Ovarian Carcinoma

Journal of Biomedical Nanotechnology ◽

10.1166/jbn.2021.3041 ◽

2021 ◽

Vol 17 (3) ◽

pp. 426-438

Author(s):

Di He ◽

Xiaoyi Xu ◽

Longxia Li ◽

Chuanrong Chen ◽

Ke Gong ◽

...

Keyword(s):

Ovarian Cancer ◽

Ovarian Cancer Cells ◽

Apoptosis Pathway ◽

Mitochondrial Apoptosis Pathway ◽

Gynaecological Malignancy ◽

Promising Treatment ◽

Induced Apoptosis ◽

Anti Tumor Activity

Ovarian cancer has been the most lethal gynaecological malignancy worldwide. Additionally, triptolide is an active substance that has been extracted from the Chinese herbal medicine T. wilfordii Hook F. , which possesses anti-tumor, immunomodulatory and anti-inflammatory properties. In recent years, TP has attracted increasing attention because of its broad-spectrum efficient anti-tumor activity. Nevertheless, its clinical utility is limited due to its severe side effects. In this study, we constructed an exosome-encapsulated TP targeted drug delivery systems, studying its anti-tumor effects and mechanisms in vivo and in vitro . We observed that compared with free TP, TP-Exos significantly enhanced anti-ovarian cancer effects and reduce toxicity to important organs. We further demonstrated that TP-Exos induced apoptosis of ovarian cancer cells, regulated tumor immunity by activating the mitochondrial apoptosis pathway and selectively inhibited M2 tumor-associated macrophages and their tumor-promoting mediators in the tumor microenvironment. In summary, TP-Exos are a promising treatment for ovarian cancer.

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Targeting highly pathogenic coronavirus-induced apoptosis reduces viral pathogenesis and disease severity

Science Advances ◽

10.1126/sciadv.abf8577 ◽

2021 ◽

Vol 7 (25) ◽

pp. eabf8577

Author(s):

Hin Chu ◽

Huiping Shuai ◽

Yuxin Hou ◽

Xi Zhang ◽

Lei Wen ◽

...

Keyword(s):

Disease Severity ◽

Lung Damage ◽

Intrinsic Apoptosis ◽

Highly Pathogenic ◽

In Vivo Models ◽

Apoptosis Pathway ◽

Intrinsic Apoptosis Pathway ◽

Induced Apoptosis

Infection by highly pathogenic coronaviruses results in substantial apoptosis. However, the physiological relevance of apoptosis in the pathogenesis of coronavirus infections is unknown. Here, with a combination of in vitro, ex vivo, and in vivo models, we demonstrated that protein kinase R–like endoplasmic reticulum kinase (PERK) signaling mediated the proapoptotic signals in Middle East respiratory syndrome coronavirus (MERS-CoV) infection, which converged in the intrinsic apoptosis pathway. Inhibiting PERK signaling or intrinsic apoptosis both alleviated MERS pathogenesis in vivo. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and SARS-CoV induced apoptosis through distinct mechanisms but inhibition of intrinsic apoptosis similarly limited SARS-CoV-2– and SARS-CoV–induced apoptosis in vitro and markedly ameliorated the lung damage of SARS-CoV-2–inoculated human angiotensin-converting enzyme 2 (hACE2) mice. Collectively, our study provides the first evidence that virus-induced apoptosis is an important disease determinant of highly pathogenic coronaviruses and demonstrates that this process can be targeted to attenuate disease severity.

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SLC25A21 Suppresses Cell Growth in Bladder Cancer via an Oxidative Stress-Mediated Mechanism

Frontiers in Oncology ◽

10.3389/fonc.2021.682710 ◽

2021 ◽

Vol 11 ◽

Author(s):

Yong Wang ◽

Jiawen Gao ◽

Shasha Hu ◽

Weiting Zeng ◽

Hongjun Yang ◽

...

Keyword(s):

Oxidative Stress ◽

Bladder Cancer ◽

Treatment Strategies ◽

Migration And Invasion ◽

Loss Of Function ◽

Apoptosis Pathway ◽

Normal Tissues ◽

Induced Apoptosis

BackgroundBladder cancer (BCa) is a commonly diagnosed malignancy worldwide that has poor survival depending on its intrinsic biologic aggressiveness and a peculiar radio- and chemoresistance features. Gaining a better understanding of tumorigenesis and developing new diagnosis and treatment strategies for BCa is important for improving BCa clinical outcome. SLC25 family member 21 (SLC25A21), a carrier transporting C5-C7 oxodicarboxylates, has been reported to contribute to oxoadipate acidemia. However, the potential role of SLC25A21 in cancer remains absolutely unknown.MethodsThe expression levels of SLC25A21 in BCa and normal tissues were examined by real-time PCR and immunohistochemistry. Gain-of- and loss-of-function experiments were performed to detect the biological functions of SLC25A21 in vitro and in vivo by CCK-8 assay, plate colony formation assay, cell migration, invasion assay and experimental animal models. The subcellular distribution of substrate mediated by SLC25A21, mitochondrial membrane potential and ROS production were assessed to explore the potential mechanism of SLC25A21 in BCa.ResultsWe found that the expression of SLC25A21 was downregulated in BCa tissues compared to normal tissues. A significant positive correlation between decreased SLC25A21 expression and poor prognosis was observed in BCa patients. Overexpression of SLC25A21 significantly inhibited cell proliferation, migration and invasion and induced apoptosis in vitro. Moreover, the enhanced SLC25A21 expression significantly suppressed tumor growth in a xenograft mouse model. Furthermore, we revealed that SLC25A21 suppressed BCa growth by inducing the efflux of mitochondrial α-KG to the cytosol, decreasing to against oxidative stress, and activating the ROS-mediated mitochondrion-dependent apoptosis pathway.ConclusionsOur findings provide the first link between SLC25A21 expression and BCa and demonstrate that SLC25A21 acts as a crucial suppressor in BCa progression, which may help to provide new targets for BCa intervention.

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Synthetic and semi-synthetic drugs as promising therapeutic option for the treatment of COVID-19

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557520666201204162103 ◽

2020 ◽

Vol 20 ◽

Author(s):

Ekta Shirbhate ◽

Preeti Patel ◽

Vijay K Patel ◽

Ravichandran Veerasamy ◽

Prabodh C Sharma ◽

...

Keyword(s):

Therapeutic Option ◽

Antiviral Treatment ◽

The Novel ◽

Clinical Experiences ◽

Synthetic Compounds ◽

Synthetic Drugs ◽

Global Pandemic ◽

The World ◽

Novel Coronavirus

: The novel coronavirus disease-19 (COVID-19), a global pandemic that emerged from Wuhan, China has today travelled all around the world, so far 216 countries or territories with 21,732,472 people infected and 770,866 deaths globally (as per WHO COVID-19 update dated August 18, 2020). Continuous efforts are being made to repurpose the existing drugs and develop vaccines for combating this infection. Despite, to date, no certified antiviral treatment or vaccine prevails. Although, few candidates have displayed their efficacy in in vitro studies and are being repurposed for COVID-19 treatment. This article summarizes synthetic and semi-synthetic compounds displaying potent activity in their clinical experiences or studies against COVID-19 and also focuses on mode of action of drugs being repositioned against COVID-19.

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OSI-027 alleviates oxaliplatin chemoresistance in gastric cancer cells by suppressing P-gp induction

Current Molecular Medicine ◽

10.2174/1566524020666201120113538 ◽

2020 ◽

Vol 20 ◽

Author(s):

En Xu ◽

Hao Zhu ◽

Feng Wang ◽

Ji Miao ◽

Shangce Du ◽

...

Keyword(s):

Gastric Cancer ◽

Cell Cycle ◽

Cancer Cells ◽

Mammalian Target Of Rapamycin ◽

Cell Counting ◽

Gastric Cancer Cells ◽

Ags Cells ◽

Dual Inhibitor ◽

Induced Apoptosis

: Gastric cancer is one of the most common malignancies worldwide and the third leading cause of cancer-related death. In the present study, we investigated the potential activity of OSI-027, a potent and selective mammalian target of rapamycin complex 1/2 (mTOR1/2) dual inhibitor, alone or in combination with oxaliplatin against gastric cancer cells in vitro. Cell counting kit-8 assays and EdU staining were performed to examine the proliferation of cancer cells. Cell cycle and apoptosis were detected by flow cytometry. Western blot was used to detect the elements of the mTOR pathway and Pgp in gastric cancer cell lines. OSI-027 inhibited the proliferation of MKN-45 and AGS cells by arresting the cell cycle in the G0/G1 phase. At the molecular level, OSI-027 simultaneously blocked mTORC1 and mTORC2 activation, and resulted in the downregulation of phosphor-Akt, phpspho-p70S6k, phosphor-4EBP1, cyclin D1, and cyclin-dependent kinase4 (CDK4). Additionally, OSI-027 also downregulated P-gp, which enhanced oxaliplatin-induced apoptosis and suppressed multidrug resistance. Moreover, OSI-027 exhibited synergistic cytotoxic effects with oxaliplatin in vitro, while a P-gp siRNA knockdown significantly inhibited the synergistic effect. In summary, our results suggest that dual mTORC1/mTORC2 inhibitors (e.g., OSI-027) should be further investigated as a potential valuable treatment for gastric cancer.

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