scholarly journals Induced Human Intestinal Organoids (iHIOs) as Model Systems for Chemotherapy-associated Clostridium difficile (CD) Infections

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S382-S382
Author(s):  
Senu Apewokin ◽  
Suman Pradhan ◽  
Michael Frerick ◽  
Alison Weiss
Keyword(s):  
Cell Death ◽  
Clostridium Difficile ◽  
Experimental Models ◽  
Cytotoxic Chemotherapy ◽  
Model Systems ◽  
Epithelial Barrier ◽  
Histological Changes ◽  
Human Dose ◽  
Therapeutic Doses ◽  
Pathophysiologic Mechanisms

Abstract Background Patients undergoing cytotoxic chemotherapy are ten times more likely to develop Clostridium difficile infections (CDI) than the general patient population. Efforts to outline pathophysiologic mechanisms underlying this disproportionate incidence have been limited by the lack of disease-representative experimental models. We hypothesized that iHIOs could serve as toxicity models to evaluate chemotherapy-associated CDI Methods Intact iHIOs were exposed to cytotoxic chemotherapy (melphalan) in gut media at therapeutic doses (9 μg/mL; which is the equivalent of 140 mg/m2 human dose). Cellular death was assessed by accumulation of the membrane permeant dye, Sytox-orange added at 5-days post treatment. iHIOs were also exposed to CD toxin A and B (TcdA and TcdB respectively) and epithelial barrier damage assessed by actin mislocalization and loss of E-cadherin. For controls iHIOs were exposed / microinjected with saline/PBS. Morphological and histological changes were then captured using light and confocal microscopy Results Morphologic and histologic assessments demonstrated cell death and epithelial barrier damage Conclusion iHIOs demonstrate cell death on exposure to CD toxins and melphalan chemotherapy. These properties could be harnessed in establishing toxicity models for evaluation of chemotherapy-associated CDI Disclosures S. Apewokin, T2 biosystems: Investigator, Research support Astellas: Scientific Advisor, Consulting fee

Therapeutic doses of phosphoramide mustard cause germ cell death in the prepubertal mouse testis

2016 ◽  
Author(s):  
Siobhan Rice ◽  
Ellie Smart ◽  
Federica Lopes ◽  
Rod Mitchell ◽  
Norah Spears
Keyword(s):  
Cell Death ◽  
Germ Cell ◽  
Mouse Testis ◽  
Phosphoramide Mustard ◽  
Therapeutic Doses

scholarly journals Experimental Models to Study COVID-19 Effect in Stem Cells

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 91
Author(s):  
Rishi Man Chugh ◽  
Payel Bhanja ◽  
Andrew Norris ◽  
Subhrajit Saha
Keyword(s):  
Stem Cells ◽  
Ex Vivo ◽  
Drug Efficacy ◽  
Cell Loss ◽  
Experimental Models ◽  
Model Systems ◽  
Virus Infectivity ◽  
Ex Vivo Model ◽  
Global Pandemic ◽  
The Impact

The new strain of coronavirus (severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2)) emerged in 2019 and hence is often referred to as coronavirus disease 2019 (COVID-19). This disease causes hypoxic respiratory failure and acute respiratory distress syndrome (ARDS), and is considered as the cause of a global pandemic. Very limited reports in addition to ex vivo model systems are available to understand the mechanism of action of this virus, which can be used for testing of any drug efficacy against virus infectivity. COVID-19 induces tissue stem cell loss, resulting inhibition of epithelial repair followed by inflammatory fibrotic consequences. Development of clinically relevant models is important to examine the impact of the COVID-19 virus in tissue stem cells among different organs. In this review, we discuss ex vivo experimental models available to study the effect of COVID-19 on tissue stem cells.

scholarly journals The Effects of Lycopene and Insulin on Histological Changes and the Expression Level of Bcl-2 Family Genes in the Hippocampus of Streptozotocin-Induced Diabetic Rats

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Masoume Soleymaninejad ◽  
Seyed Gholamali Joursaraei ◽  
Farideh Feizi ◽  
Iraj Jafari Anarkooli
Keyword(s):  
Cell Death ◽  
Wistar Rats ◽  
Diabetic Rats ◽  
Expression Level ◽  
Histological Changes ◽  
Group D

The aim of this study was to evaluate the effects of antioxidants lycopene and insulin on histological changes and expression of Bcl-2 family genes in the hippocampus of streptozotocin-induced type 1 diabetic rats. Forty-eight Wistar rats were divided into six groups of control (C), control treated with lycopene (CL), diabetic (D), diabetic treated with insulin (DI), diabetic treated with lycopene (DL), and diabetic treated with insulin and lycopene (DIL). Diabetes was induced by an injection of streptozotocin (60 mg/kg, IP), lycopene (4 mg/kg/day) was given to the lycopene treated groups as gavages, and insulin (Sc, 1-2 U/kg/day) was injected to the groups treated with insulin. The number of hippocampus neurons undergoing cell death in group D had significant differences with groups C and DIL (p<0.001). Furthermore, insulin and lycopene alone or together reduced the expression of Bax, but increased Bcl-2 and Bcl-xL levels in DI, DL, and DIL rats, especially when compared to group D (p<0.001). The ratios of Bax/Bcl-2 and Bax/Bcl-xL in DI, DL, and DIL rats were also reduced (p<0.001). Our results indicate that treatment with insulin and/or lycopene contribute to the prevention of cell death by reducing the expression of proapoptotic genes and increasing the expression of antiapoptotic genes in the hippocampus.

scholarly journals Epithelial-Mesenchymal Transition Induces GSDME Transcriptional Activation for Inflammatory Pyroptosis

2021 ◽  
Vol 9 ◽  
Author(s):  
Chenqiang Jia ◽  
Zhuqing Zhang ◽  
Jun Tang ◽  
Mei-Chun Cai ◽  
Jingyu Zang ◽  
...  
Keyword(s):  
Cell Death ◽  
Transcriptional Activation ◽  
Promoter Region ◽  
Drug Exposure ◽  
Epithelial Mesenchymal Transition ◽  
Experimental Models ◽  
Cytokine Release ◽  
Functional Importance ◽  
Bioinformatics Analyses ◽  
Mesenchymal Transition

GSDME is a newly recognized executor of cellular pyroptosis, and has been recently implicated in tumor growth and immunity. However, knowledge about the molecular regulators underlying GSDME abundance remains limited. Here, we performed integrative bioinformatics analyses and identified that epithelial-mesenchymal transition (EMT) gene signatures exhibited positive correlation with GSDME levels across human cancers. A causal role was supported by the observation that EMT dictated GSDME reversible upregulation in multiple experimental models. Mechanistically, transcriptional activation of GSDME was directly driven by core EMT-activating transcription factors ZEB1/2, which bound to the GSDME promoter region. Of functional importance, elevated GSDME in mesenchymally transdifferentiated derivatives underwent proteolytic cleavage upon antineoplastic drug exposure, leading to pyroptotic cell death and consequent cytokine release. Taken together, our findings pinpointed a key transcriptional machinery controlling GSDME expression and indicated potential therapeutic avenues to exploit GSDME-mediated inflammatory pyroptosis for the treatment of mesenchymal malignancies.

scholarly journals Bacteroides fragilis defense against Cronobacter sakazakii-induced pathogenicity by regulating the intestinal epithelial barrier function and attenuating both apoptotic and pyroptotic cell death

2018 ◽  
Author(s):  
Hongying Fan ◽  
Ruqin Lin ◽  
Zhenhui Chen ◽  
Xingyu Leng ◽  
Xianbo Wu ◽  
...  
Keyword(s):  
Cell Death ◽  
Necrotizing Enterocolitis ◽  
Neonatal Rat ◽  
Epithelial Barrier ◽  
Intestinal Epithelial ◽  
Cronobacter Sakazakii ◽  
Barrier Dysfunction ◽  
Epithelial Barrier Dysfunction

AbstractCronobacter sakazakii (CS), an important pathogen, is associated with the development of necrotizing enterocolitis (NEC), infant sepsis, and meningitis. Several randomized prospective clinical trials demonstrated that oral probiotics could decrease the incidence of NEC. Previously, we isolated and characterized a novel probiotic, B. fragilis strain ZY-312. However, it remains unclear how ZY-312 protects the host from the effects of CS infection. To understand the underlying mechanisms triggering the probiotic effects, we tested the hypothesis that there was a cross-talk between probiotics/probiotics-modulated microbiota and the local immune system, governed by the permeability of the intestinal mucosa using in vitro and in vivo models for the intestinal permeability. The probiotic effects of ZY-312 on intestinal epithelial cells were first examined, which revealed that ZY-312 inhibited CS invasion, CS-induced dual cell death (pyroptosis and apoptosis), and epithelial barrier dysfunction in vitro and in vivo. ZY-312 also decreased the expression of an inflammasome (NOD-like receptor family member pyrin domain-containing protein 3 (NLRP3), caspase-3, and serine protease caspase-1 in a neonatal rat model. Furthermore, ZY-312 significantly modulated the compositions of the intestinal bacterial communities, and decreased the relative abundances of Proteobacteria, Gamma proteobacteria, but increased the relative abundance of Bacteroides and Bacillus in neonatal rats. In conclusion, our findings have shown for the first time that the probiotic, B. fragilis ZY-312, suppresses CS-induced NEC by modulating the pro-inflammatory response and dual cell death (apoptosis and pyroptosis).Author summaryCronobacter sakazakii, a major necrotizing enterocolitis pathogen, is used as a model microorganism for the study of opportunistic bacteria in the pathogenesis of necrotizing enterocolitis. Here, we have now unequivocally demonstrated that both apoptotic and pyroptotic stimuli contribute to the pathogenesis of Cronobacter sakazakii -induced necrotizing enterocolitis. Previously, we isolated and characterized a novel probiotic, B. fragilis strain ZY-312. We found that the ZY-312 defense against Cronobacter sakazakii-induced necrotizing enterocolitis by inhibiting Cronobacter sakazakii invasion, epithelial barrier dysfunction, the expression of inflammatory cytokines and dual cell death (pyroptosis and apoptosis). This study demonstrates the utility of ZY-312 as a promising probiotic agent for the prevention and treatment of various intestinal diseases, including NEC.

scholarly journals Experimental Models of Brugada syndrome

2019 ◽  
Vol 20 (9) ◽  
pp. 2123 ◽  
Author(s):  
Sendfeld ◽  
Selga ◽  
Scornik ◽  
Pérez ◽  
Mills ◽  
...  
Keyword(s):  
Brugada Syndrome ◽  
Experimental Models ◽  
Model Systems ◽  
Patient Specific ◽  
Canine Heart ◽  
Stem Cell Technology ◽  
St Segment Elevation ◽  
St Segment ◽  
Cardiac Sodium Channel ◽  
The Right

Brugada syndrome is an inherited, rare cardiac arrhythmogenic disease, associated with sudden cardiac death. It accounts for up to 20% of sudden deaths in patients without structural cardiac abnormalities. The majority of mutations involve the cardiac sodium channel gene SCN5A and give rise to classical abnormal electrocardiogram with ST segment elevation in the right precordial leads V1 to V3 and a predisposition to ventricular fibrillation. The pathophysiological mechanisms of Brugada syndrome have been investigated using model systems including transgenic mice, canine heart preparations, and expression systems to study different SCN5A mutations. These models have a number of limitations. The recent development of pluripotent stem cell technology creates an opportunity to study cardiomyocytes derived from patients and healthy individuals. To date, only a few studies have been done using Brugada syndrome patient-specific iPS-CM, which have provided novel insights into the mechanisms and pathophysiology of Brugada syndrome. This review provides an evaluation of the strengths and limitations of each of these model systems and summarizes the key mechanisms that have been identified to date.

Huperzine a provides neuroprotection against several cell death inducers usingin vitro model systems of motor neuron cell death

2008 ◽  
Vol 13 (1) ◽  
pp. 49-61 ◽  
Author(s):  
Richelle A. Hemendinger ◽  
Edward J. Armstrong ◽  
Rafal Persinski ◽  
Julianne Todd ◽  
Jean-Luc Mougeot ◽  
...  
Keyword(s):  
Cell Death ◽  
Motor Neuron ◽  
Huperzine A ◽  
Model Systems ◽  
Vitro Model

scholarly journals Mathematical analysis and simulation study of a phase-field model of prostate cancer growth with chemotherapy and antiangiogenic therapy effects

2020 ◽  
Vol 30 (07) ◽  
pp. 1253-1295 ◽  
Author(s):  
Pierluigi Colli ◽  
Hector Gomez ◽  
Guillermo Lorenzo ◽  
Gabriela Marinoschi ◽  
Alessandro Reali ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Death ◽  
Tumor Growth ◽  
Phase Field ◽  
Clinical Studies ◽  
Advanced Prostate Cancer ◽  
Antiangiogenic Therapy ◽  
Specific Antigen ◽  
Cytotoxic Chemotherapy ◽  
Cancer Growth

Chemotherapy is a common treatment for advanced prostate cancer. The standard approach relies on cytotoxic drugs, which aim at inhibiting proliferation and promoting cell death. Advanced prostatic tumors are known to rely on angiogenesis, i.e. the growth of local microvasculature via chemical signaling produced by the tumor. Thus, several clinical studies have been investigating antiangiogenic therapy for advanced prostate cancer, either as monotherapy or in combination with standard cytotoxic protocols. However, the complex genetic alterations that originate and sustain prostate cancer growth complicate the selection of the best chemotherapeutic approach for each patient’s tumor. Here, we present a mathematical model of prostate cancer growth and chemotherapy that may enable physicians to test and design personalized chemotherapeutic protocols in silico. We use the phase-field method to describe tumor growth, which we assume to be driven by a generic nutrient following reaction–diffusion dynamics. Tumor proliferation and apoptosis (i.e. programmed cell death) can be parameterized with experimentally-determined values. Cytotoxic chemotherapy is included as a term downregulating tumor net proliferation, while antiangiogenic therapy is modeled as a reduction in intratumoral nutrient supply. An additional equation couples the tumor phase field with the production of prostate-specific antigen, which is a prostate cancer biomarker that is extensively used in the clinical management of the disease. We prove the well posedness of our model and we run a series of representative simulations leveraging an isogeometric method to explore untreated tumor growth as well as the effects of cytotoxic chemotherapy and antiangiogenic therapy, both alone and combined. Our simulations show that our model captures the growth morphologies of prostate cancer as well as common outcomes of cytotoxic and antiangiogenic mono therapy and combined therapy. Additionally, our model also reproduces the usual temporal trends in tumor volume and prostate-specific antigen evolution observed in experimental and clinical studies.

scholarly journals Endothelin-1 contributes to the development of virus-induced demyelinating disease

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Young-Hee Jin ◽  
Bongsu Kang ◽  
Hyun S. Kang ◽  
Chang-Sung Koh ◽  
Byung S. Kim
Keyword(s):  
T Cell ◽  
Demyelinating Disease ◽  
Autoimmune Encephalitis ◽  
T Cell Responses ◽  
Experimental Models ◽  
Demyelinating Diseases ◽  
Model Systems ◽  
Endothelin 1 ◽  
Cell Responses ◽  
Experimental Model Systems

Abstract Background Experimental autoimmune encephalitis (EAE) and virally induced demyelinating disease are two major experimental model systems used to study human multiple sclerosis. Although endothelin-1 level elevation was previously observed in the CNS of mice with EAE and viral demyelinating disease, the potential role of endothelin-1 in the development of these demyelinating diseases is unknown. Methods and results In this study, the involvement of endothelin-1 in the development and progression of demyelinating diseases was investigated using these two experimental models. Administration of endothelin-1 significantly promoted the progression of both experimental diseases accompanied with elevated inflammatory T cell responses. In contrast, administration of specific endothelin-1 inhibitors (BQ610 and BQ788) significantly inhibited progression of these diseases accompanied with reduced T cell responses to the respective antigens. Conclusions These results strongly suggest that the level of endothelin-1 plays an important role in the pathogenesis of immune-mediated CNS demyelinating diseases by promoting immune responses.

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