scholarly journals Mitochondrial functional resilience after TFAM ablation in the adult heart

2021 ◽  
Author(s):  
Nasab Ghazal ◽  
Jessica N. Peoples ◽  
Tahmina A. Mohiuddin ◽  
Jennifer Q. Kwong
Keyword(s):  
Nuclear Genome ◽  
Transcript Abundance ◽  
Mitochondrial Translation ◽  
Adult Heart ◽  
Protein Levels ◽  
Developing Heart ◽  
Mtdna Transcription ◽  
Transcription And Replication

The nuclear genome-encoded mitochondrial DNA (mtDNA) transcription factor A (TFAM) is indispensable for mitochondrial energy production in the developing and postnatal heart; a similar role for TFAM is inferred in adult heart. Here, we provide evidence that challenges this long-standing paradigm. Unexpectedly, conditionalTfam ablation in vivo in adult mouse cardiomyocytes resulted in a prolonged period of functional resilience characterized by preserved mtDNA content, mitochondrial function, and cardiac function, despite mitochondrial structural alterations and decreased transcript abundance. Remarkably, TFAM protein levels did not directly dictate mtDNA content in the adult heart, and mitochondrial translation was preserved with acute TFAM inactivation, suggesting maintenance of respiratory chain assembly/function. Long-term Tfam inactivation, however, downregulated the core mtDNA transcription and replication machinery, leading to mitochondrial dysfunction and cardiomyopathy. Collectively, in contrast to the developing heart, these data reveal a striking resilience of the differentiated adult heart to acute insults to mtDNA regulation.

scholarly journals Mitochondrial functional resilience after TFAM ablation in adult cardiomyocytes

2020 ◽  
Author(s):  
Nasab Ghazal ◽  
Jessica N. Peoples ◽  
Tahmina Mohuiddin ◽  
Jennifer Q. Kwong
Keyword(s):  
Respiratory Chain ◽  
Energy Supply ◽  
Nuclear Genome ◽  
Transcript Abundance ◽  
Mitochondrial Translation ◽  
Adult Heart ◽  
Protein Levels ◽  
Mitochondrial Transcription Factor ◽  
Adult Cardiomyocytes ◽  
Mtdna Transcription

AbstractThe adult heart is a terminally differentiated tissue that depends on mitochondria for its energy supply. Respiratory chain energy supply deficits due to alterations in the mitochondrial genome (mtDNA) or in nuclear genome (nDNA)-encoded mtDNA regulators are associated with cardiac pathologies ranging from primary mitochondrial cardiomyopathies to heart failure. Mitochondrial transcription factor A (TFAM) is an nDNA-encoded regulator of mtDNA transcription, replication, and maintenance. Insufficiency of this protein in embryonic and postnatal cardiomyocytes causes cardiomyopathy and/or lethality, establishing TFAM as indispensable to the developing heart; its role in adult tissue has been inferred from these findings. Here, we provide evidence that challenges this long-standing paradigm using Tfam ablation in the adult heart. Unexpectedly, loss of Tfam in adult cardiomyocytes resulted in a prolonged period of functional resilience characterized by preserved mtDNA content, mitochondrial function, and cardiac function despite mitochondrial structural alterations and decreased transcript abundance. Remarkably, TFAM protein levels did not directly dictate mtDNA content in the adult heart, and mitochondrial translation was preserved with acute TFAM inactivation, suggesting a mechanism whereby respiratory chain assembly and function can be sustained, which we term ‘functional resilience’. Finally, long-term Tfam inactivation induced a coordinated downregulation of the core mtDNA transcription and replication machinery that ultimately resulted in mitochondrial dysfunction and cardiomyopathy. Taken together, adult-onset cardiomyocyte-specific Tfam inactivation reveals a striking resilience of the adult heart to acute insults to mtDNA regulatory mechanisms and provides insight into critical differences between the developing versus differentiated heart.

scholarly journals Knockdown of MicroRNA-1 in the Hippocampus Ameliorates Myocardial Infarction Induced Impairment of Long-Term Potentiation

2018 ◽  
Vol 50 (4) ◽  
pp. 1601-1616 ◽  
Author(s):  
Ji-Chao Ma ◽  
Ming-Jing Duan ◽  
Ke-Xin Li ◽  
Das Biddyut ◽  
Shuai Zhang ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Sham Group ◽  
Long Term Potentiation ◽  
Stimulus Response ◽  
Protein Levels ◽  
Term Potentiation ◽  
Passive And Active Avoidance ◽  
Related Proteins

Backgrounds/Aims: It has been reported that myocardial infarction (MI) is a risk factor for vascular dementia. However, the molecular mechanism remains largely unknown. Methods: MI mice were generated by ligation of the left coronary artery (LCA) for 4 weeks. Passive and active avoidance tests were performed to evaluate the cognitive ability of MI mice. A theta-burst stimulation (TBS) protocol was applied to elicit long-term potentiation (LTP) of the perforant pathway-dentate gyrus synapse (PP-DG). Western blot analysis was employed to assess protein levels. Results: In this study, we demonstrated that after 4 weeks of MI, C57BL/6 mice had significantly impaired memory. Compared with the sham group, in vivo physiological recording in the MI group revealed significantly decreased amplitude of population spikes (PS) with no effect on the latency and duration of the stimulus-response curve. The amplitude of LTP was markedly decreased in the MI group compared with the sham group. Further examination showed that the expression of the TBS-LTP-related proteins BDNF, GluA1 and phosphorylated GluA1 were all decreased in the MI group compared with those in the sham group. Strikingly, all these changes were prevented by hippocampal stereotaxic injection of an anti-miR-1 oligonucleotide fragment carried by a lentivirus vector (lenti-pre-AMO-1). Conclusion: MI induced cognitive decline and TBS-LTP impairment, and decreased BDNF and GluA1 phosphorylation levels from overexpression of miR-1ated were involved in this process.

Regulation of apoptosis in the endocardial cushions of the developing chick heart

2002 ◽  
Vol 282 (6) ◽  
pp. C1348-C1360 ◽  
Author(s):  
William M. Keyes ◽  
Esmond J. Sanders
Keyword(s):  
Heart Development ◽  
Time Course ◽  
Nuclear Staining ◽  
Caspase 9 ◽  
Endocardial Cushions ◽  
Similar Time ◽  
Cleavage Fragment ◽  
Protein Levels ◽  
Developing Heart

During the early stages of heart development, there are two main foci of cell death: outflow tract (OT) and atrioventricular (AV) endocardial cushions. These tissues contribute to the septa and valves of the mature heart and receive cell populations from neural crest (NC) cell migration and epicardial cell invasion. We examined embryonic chick hearts for expression, in the cushions, of bcl-2 family members, caspase-9, and the caspase substrate poly(ADP-ribose) polymerase. Antiapoptotic bcl-2 is expressed heavily in the OT and AV regions throughout embryonic days (ED) 4–7, with a decrease in levels at ED 4 and 5 in OT and AV cushions, respectively. Proapoptotic bax predominantly associated with the prongs of the NC-derived aorticopulmonary (AP) septum but was expressed throughout the AV cushions. Proapoptotic bak also associated with the prongs of the AP septum in the OT, while protein levels were upregulated at ED 4–5 and 4–6 in OT and AV cushions, respectively. Bid expression showed a similar time course. We found the 10-kDa cleavage fragment of active caspase-9 at ED 4–8 and 5–8 in OT and AV cushions, respectively, and the 24-kDa cleavage fragment of poly(ADP-ribose) polymerase throughout ED 3–8 and 7–8 in OT and AV cushions, respectively. Caspase-3 cleavage occurred throughout the time period examined. Using cushion cell cultures, we found that inhibitors of caspases-3 and -9 and a universal caspase inhibitor significantly reduced apoptosis, as did retroviral overexpression of bcl-2 using an RCAS expression vector. Premigratory NC cells were fluorescently labeled in vivo with 1,1-didodecyl-3,3,3′,3′-tetramethylindocarbocyanine. Subsequent nuclear staining of cushion cells with 4,6-diamidino-2-phenylindole revealed the presence of apoptotic nuclei in the NC cells in the OT cushions and in the prongs of the AP septum. These results demonstrate a developmentally regulated role for the bcl-2 and the caspase families of molecules in the endocardial cushions of the developing heart and lend support to the possibility that some of the dying cells in the cushions are derived from the NC.

scholarly journals Ca2+/Calmodulin-NOS/NO-TNFs Pathway Hallmarks the Inflammation Response of Oyster During Aerial Exposure

2021 ◽  
Vol 7 ◽  
Author(s):  
Hao Chen ◽  
Lusheng Xin ◽  
Lin Wang ◽  
Huan Zhang ◽  
Rui Liu ◽  
...  
Keyword(s):  
Aerial Exposure ◽  
Inflammation Response ◽  
Expression Levels ◽  
Protein Levels ◽  
Downstream Effector ◽  
Intracellular Ca ◽  
Oxide Synthase ◽  
Mollusk Species

Aerial exposure (emersion) due to the periodical ebb and flow of tides is a major stressor for intertidal organisms and a key environmental factor in shaping their local communities. Oysters are among the most emersion-tolerant mollusk species and can survive for several days under aerial exposure. Noticeably, overwhelming inflammation responses could occur during the emersion stress. However, mechanisms beneath the activation and modulation of emersion-induced inflammation response have remained largely unknown. Ca2+ is an important intracellular second messenger that plays indispensable roles in inflammation response by cooperation with calmodulin (CaM) genes. Here, we showed that intracellular Ca2+ accumulates rapidly in oyster hemocytes during emersion stress along with the changes in the protein levels of three CaM genes, which function as intracellular sensors of Ca2+. As downstream effector of Ca2+/CaM complex, nitric oxide synthase (NOS) activity in hemocytes was enhanced during the emersion stress, facilitating a greater production of nitrite oxide (NO). Augmentation of NO concentration was associated with the increased mRNA expression levels of two oyster cytokines (CgTNFs) during aerial exposure. The robust accumulation of cytokines and severe injury of tissues in oysters have been regarded as potential cause and marker of their death in prolonged emersion stress. Here, both the expression levels of CgTNFs and the tissue injuries of oysters were attenuated when Ca2+/CaM complex or NOS activity were repressed in vivo during the emersion stress. These findings indicate that Ca2+/CaM-NOS/NO-CgTNFs pathway is critically involved in the emersion-induced inflammation response in oysters and plays a role in the resistance against long-term aerial exposure.

scholarly journals Long-Term Therapy with the Guanine Nucleoside Analog Penciclovir Controls Chronic Duck Hepatitis B Virus Infection In Vivo

1998 ◽  
Vol 42 (8) ◽  
pp. 2132-2137 ◽  
Author(s):  
Enjarn Lin ◽  
Carolyn Luscombe ◽  
Danni Colledge ◽  
Yan Yan Wang ◽  
Stephen Locarnini
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Nucleoside Analog ◽  
Term Therapy ◽  
Duck Hepatitis B Virus ◽  
Protein Levels ◽  
Duck Hepatitis ◽  
B Virus

ABSTRACT Ducks congenitally infected with duck hepatitis B virus (DHBV) were treated with the antiviral guanine nucleoside analog penciclovir for 12 or 24 weeks at a dosage of 10 mg/kg of body weight per day. By the completion of both 12 and 24 weeks of therapy, molecular hybridization studies of the liver tissue revealed that the viral DNA, RNA, and protein levels were significantly reduced compared to those in the placebo-treated controls. Penciclovir treatment for 12 or 24 weeks was not associated with any toxicity, establishing the efficacy and safety of long-term penciclovir therapy in chronic DHBV infection.

Mechanisms towards compensation of long-term haemopoietic injury in mice after 5 Gy irradiation: In vivo and in vitro enhancement of superoxide anion production by granulocytes

1992 ◽  
Vol 12 (4) ◽  
pp. 281-292 ◽  
Author(s):  
Soledad Gaitán ◽  
Elvira Cuenllas ◽  
Pilar Sancho ◽  
Juan A. Bueren ◽  
Concepción Tejero
Keyword(s):  
Superoxide Anion ◽  
Environmental Damage ◽  
X Rays ◽  
Superoxide Anion Production ◽  
Protein Levels ◽  
Anion Production ◽  
Bone Marrow Cultures

This paper analyzes the long-term (6 and 12 months) function of mouse granulocytes after total body irradiation with a single dose (5 Gy) of X-rays. Superoxide anion production has been investigated in granulocytes from peripheral blood, and also in those harvested from long term bone marrow cultures, with the aim of correlating the environmental damage induced by radiation with the functional properties of granulocytes. An in vivo and in vitro enhancement of superoxide anion production and protein levels in granulocytes from irradiated mice is described. The presence of some colony stimulating factor in the supernatant of cultures from irradiated mice could play an important role in the priming of granulocytes.

Long term in vivo reactions to PTFE and polyester in the cardiovascular system - what will be the fate of septal defect occlusion devices?

2014 ◽  
Vol 62 (S 01) ◽  
Author(s):  
M. Sigler ◽  
S. Huell ◽  
R. Foth ◽  
W. Ruschewski ◽  
T. Tirilomis ◽  
...  
Keyword(s):  
Cardiovascular System ◽  
Septal Defect

The depressing (negative) effect of oestradiol benzoate on the in vitro secretion of LH and FSH by the pituitary gland of the LRH-pretreated long-term ovariectomized rat changes into the augmentative (positive) effect after discontinuation of the LRH-pretreatment

1985 ◽  
Vol 110 (3) ◽  
pp. 329-337 ◽  
Author(s):  
G. A. Schuiling ◽  
H. Moes ◽  
T. R. Koiter
Keyword(s):  
Depressing Effect ◽  
Ovx Rats ◽  
Gonadotrophin Secretion ◽  
Oestradiol Benzoate ◽  
Negative Effect ◽  
Positive Effect ◽  
Perifusion System

Abstract. The effect of pretreatment in vivo with oestradiol benzoate on in vitro secretion of LH and FSH was studied in long-term ovariectomized (OVX) rats both at the end of a 5-day continuous in vivo pretreatment with LRH and 4-days after cessation of such LRH pretreatment. Rats were on day 0 sc implanted with osmotic minipumps which released LRH at the rate of 250 ng/h. Control rats were implanted with a piece of silicone elastomer with the dimensions of a minipump. On days 2 and 4 the rats were injected with either 3 μg EB or with oil. On day 5 part of the rats were decapitated and the in vitro autonomous (i.e. non-LRH-stimulated) and 'supra-maximally' LRHstimulated release of LH and FSH was studied using a perifusion system. From other rats the minipumps were removed on day 5 and perifusion was performed on day 9. On the 5th day of the in vivo LRH pretreatment the pituitary LH/FSH stores were partially depleted; the pituitaries of the EB-treated rats more so than those of the oil-injected rats. EB alone had no significant effect on the content of the pituitary LH- and FSH stores. On day 9, i.e. 4 days after removal of the minipumps, the pituitary LH and FSH contents had increased in both the oil- and the EB injected rats, but had not yet recovered to control values. In rats not subjected to the 5-days pretreatment with LRH EB had a positive effect on the supra-maximally LRH-stimulated secretion of LH and FSH as well as on the non-stimulated secretion of LH. EB had no effect on the non-stimulated secretion of FSH. After 5 days of in vivo pretreatment with LRH only, the in vitro non-stimulated and supra-maximally LRH-stimulated secretion of both LH and FSH were strongly impaired, the effect correlating well with the LRH-induced depletion of the pituitary LH/FSH stores. In such LRH-pretreated rats EB had on day 5 a negative effect on the (already depressed) LRH-stimulated secretion of LH (not on that of FSH). EB had no effect on the non-stimulated LH/FSH secretion. It could be demonstrated that the negative effect of the combined LRH/EB pretreatment was mainly due to the depressing effect of this treatment on the pituitary LH and FSH stores: the effect of oestradiol on the pituitary LRH-responsiveness (release as related to pituitary gonadotrophin content) remained positive. In LRH-pretreated rats, however, this positive effect of EB was smaller than in rats not pretreated with LRH. Four days after removal of the minipumps there was again a positive effect of EB on the LRH-stimulated secretion of LH and FSH as well as on the non-stimulated secretion of LH. The positive effect of EB on the pituitary LRH-responsiveness was as strong as in rats which had not been exposed to exogenous LRH. The non-stimulated secretion of FSH was again not affected by EB. The results demonstrate that the effect of EB on the oestrogen-sensitive components of gonadotrophin secretion consists of two components: an effect on the pituitary LRH-responsiveness proper, and an effect on the pituitary LH/FSH stores. The magnitude of the effect of EB on the LRH-responsiveness is LRH dependent: it is very weak (almost zero) in LRH-pretreated rats, but strong in rats not exposed to LRH as well as in rats of which the LRH-pretreatment was stopped 4 days previously. Similarly, the effect of EB on the pituitary LH and FSH stores is LRH-dependent: in the absence of LRH, EB has no influence on the contents of these stores, but EB can potentiate the depleting effect of LRH on the LH/FSH-stores. Also this effect disappear after cessation of the LRH-pretreatment.

Enhanced Stability and Controlled Delivery of MOF Encapsulated Vaccines and Their Immunogenic Response In Vivo

2018 ◽  
Author(s):  
Michael Luzuriaga ◽  
Raymond P. Welch ◽  
Madushani Dharmawardana ◽  
Candace Benjamin ◽  
Shaobo Li ◽  
...  
Keyword(s):  
Viral Vector ◽  
Controlled Delivery ◽  
Conformational Structure ◽  
Spectroscopy Analysis ◽  
Zeolitic Imidazolate Framework ◽  
Structural Conformation ◽  
Depth Study ◽  
Viral Nanoparticle

<div><div><div><p>Vaccines have an innate tendency to lose their structural conformation upon environmental and chemical stressors. A loss in conformation reduces the therapeutic ability to prevent the spread of a pathogen. Herein, we report an in-depth study of zeolitic imidazolate framework-8 (ZIF-8) and its ability to provide protection for a model viral vector against dena- turing conditions. The immunoassay and spectroscopy analysis together demonstrate enhanced thermal and chemical stability to the conformational structure of the encapsulated viral nanoparticle. The long-term biological activity of this virus-ZIF composite was investigated in animal models to further elucidate the integrity of the encapsulated virus, the bio-safety, and immunogenicity of the overall composite. Additionally, histological analysis found no observable tissue damage in the skin or vital organs in mice, following multiple subcutaneous administrations. This study shows that ZIF-based protein composites are strong candidates for improved preservation of proteinaceous drugs, are biocompatible, and capable of controlling the release and adsorption of drugs in vivo.</p></div></div></div>

THE ROLE OF POLYETHYLENIMINE IN ENHANCING PERFORMANCE OF GLUTAMATE BIOSENSORS

2018 ◽  
Vol 8 (3) ◽  
pp. 36-41
Author(s):  
Diep Do Thi Hong ◽  
Duong Le Phuoc ◽  
Hoai Nguyen Thi ◽  
Serra Pier Andrea ◽  
Rocchitta Gaia
Keyword(s):  
First Generation ◽  
Good Reproducibility ◽  
Complex Matrices ◽  
Long Term Stability ◽  
In Vitro Characterization ◽  
Glutamate Oxidase

Background: The first biosensor was constructed more than fifty years ago. It was composed of the biorecognition element and transducer. The first-generation enzyme biosensors play important role in monitoring neurotransmitter and determine small quantities of substances in complex matrices of the samples Glutamate is important biochemicals involved in energetic metabolism and neurotransmission. Therefore, biosensors requires the development a new approach exhibiting high sensibility, good reproducibility and longterm stability. The first-generation enzyme biosensors play important role in monitoring neurotransmitter and determine small quantities of substances in complex matrices of the samples. The aims of this work: To find out which concentration of polyethylenimine (PEI) exhibiting the most high sensibility, good reproducibility and long-term stability. Methods: We designed and developed glutamate biosensor using different concentration of PEI ranging from 0% to 5% at Day 1 and Day 8. Results: After Glutamate biosensors in-vitro characterization, several PEI concentrations, ranging from 0.5% to 1% seem to be the best in terms of VMAX, the KM; while PEI content ranging from 0.5% to 1% resulted stable, PEI 1% displayed an excellent stability. Conclusions: In the result, PEI 1% perfomed high sensibility, good stability and blocking interference. Furthermore, we expect to develop and characterize an implantable biosensor capable of detecting glutamate, glucose in vivo. Key words: Glutamate biosensors, PEi (Polyethylenimine) enhances glutamate oxidase, glutamate oxidase biosensors

Sign in / Sign up

Export Citation Format

Share Document