scholarly journals Cellular Resilience as a Potential Predictor of Lifespan

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 163-163
Author(s):  
Adam Salmon
Keyword(s):  
Functional Outcomes ◽  
Cell Model ◽  
Donor Age ◽  
Biological Mechanisms ◽  
Progressive Decline ◽  
Primary Fibroblasts ◽  
Skin Biopsies ◽  
Translational Models ◽  
Important Marker ◽  
Cellular Resilience

Abstract The progressive decline of resilience during the aging process across multiple functional systems suggests basic biological mechanisms of regulation. We exploited a primary cell model to identify markers of cellular resilience or the ability of cells in culture to respond and return to homeostasis following acute challenge including metabolic, oxidative, or proteostatic stress. Using primary fibroblasts from minimally-invasive skin biopsies of genetically heterogeneous mice, we are able to determine individual cellular resilience as well as the normal lifespan and healthspan of each donor. Our studies suggest donor age and sex affect cellular resilience and that this measure of resilience can predict functional outcomes in some interventional studies. While longevity studies continue, these studies point to a potential highly important marker of healthspan and longevity as well as a model to delineate the biology of resilience in animal and translational models.

Human primary fibroblasts in vitro express a purinergic P2X7 receptor coupled to ion fluxes, microvesicle formation and IL-6 release

1999 ◽  
Vol 112 (3) ◽  
pp. 297-305
Author(s):  
A. Solini ◽  
P. Chiozzi ◽  
A. Morelli ◽  
R. Fellin ◽  
F. Di Virgilio
Keyword(s):  
Purinergic Receptor ◽  
Morphological Changes ◽  
Human Fibroblasts ◽  
Ion Fluxes ◽  
Disulfonic Acid ◽  
Triggered Release ◽  
Primary Fibroblasts ◽  
Purinergic P2x7 Receptor ◽  
Skin Biopsies

We have investigated reponses to extracellular ATP in human fibroblasts obtained by skin biopsies. Our data show that these cells express a P2X7 purinergic receptor, as judged by (1) RT-PCR with specific primers, (2) reactivity with a specific anti-P2X7 antiserum, (3) activation by the selective P2X agonist benzoylbenzoylATP and (4) stimulation of transmembrane ion fluxes. Stimulation with benzoylbenzoylATP, and to a lesser extent with ATP, also caused striking morphological changes and increased formation of cytoplasmic microvesicles. These changes were fully reversible upon nucleotide removal. Two known blockers of P2X receptors, oxidised ATP and pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid, inhibited the morphological changes fully and the ion fluxes partially. The residual rise in intracellular Ca2+ levels and membrane depolarization observed in the presence of the inhibitors were dependent upon activation of a P2Y-type receptor exhibiting a peculiar pharmacological profile, in that CTP was the preferred agonist. ATP stimulation triggered release of the pro-inflammatory cytokine IL-6 in fibroblasts pre-treated with PMA and bacterial endotoxin. These observations reveal a novel pathway for fibroblast activation and for their recruitment in the inflammatory response.

scholarly journals Chondral Defect Repair with Particulated Juvenile Cartilage Allograft

2017 ◽  
Vol 5 (3_suppl3) ◽  
pp. 2325967117S0012
Author(s):  
Nicole Belkin ◽  
Alissa Burge ◽  
Brenda Chang ◽  
Riley J. Williams
Keyword(s):  
Articular Cartilage ◽  
Functional Outcomes ◽  
Rating Scale ◽  
T2 Mapping ◽  
Cartilage Defects ◽  
Activity Levels ◽  
Donor Age ◽  
Outcome Scores ◽  
Activity Rating

Objectives: To evaluate the functional outcomes and morphologic appearance of repair tissue in patients with symptomatic knee articular cartilage defects treated with minced juvenile articular cartilage (DeNovo NT). Methods: Thirty-four patients underwent treatment of cartilage defects of the knee with minced juvenile articular cartilage allograft. Mean postoperative follow up was 33.6 months. MRIs were obtained at 24-months (16 patients) and 48-months or greater (13 patients). MRIs were evaluated for greyscale cartilage repair assessment score and quantitative T2 mapping. Baseline clinical outcome scores (IKDC, ADL, Marx Activity Rating Scale) were obtained prior to surgery, and at a minimum follow up interval of 24-months. Results: The mean IKDC and ADL scores significantly improved following surgery. The magnitude of improvement in IKDC scores was 30 (Std Dev 31). The Marx activity Rating Scale score demonstrated a resumption of pre-operative activity levels, Figure 1a . Donor age had no significant effect on functional outcomes scores of treated patients. MRI assessment revealed greater than 66% lesion fill (a score of 2) in 80% of patients. A trend toward significance in difference in % lesion fill was observed when patients were grouped according to donor age ≤ 5 vs. > 5 years (p = 0.09), Figure 1b . Lesion fill did not correlate with functional outcome score. Using one-way analysis of variance with post-hoc testing, a significant difference was found between T2 mapping of the deep zones of the graft and normal cartilage (p=0.003), Table 1 . [Figure: see text][Table: see text] Conclusion: Functional outcome scores significantly improved in patients treated with minced juvenile articular cartilage (De Novo NT) for the treatment of symptomatic articular cartilage lesions of the knee. Activity levels, as noted by the Marx Activity Scale were preserved. Morphologic analysis demonstrated greater than 66% lesion fill in 80% of the patients studied. T2 mapping demonstrated the sensitivity to assess differences between repair tissue and native cartilage.

Conduct disorder in ADHD

2018 ◽  
Author(s):  
Anita Thapar ◽  
Stephanie van Goozen
Keyword(s):  
Conduct Disorder ◽  
Functional Outcomes ◽  
Neural Correlates ◽  
Language Impairments ◽  
Emotional Processes ◽  
Risk Characteristics ◽  
Genetic Risks ◽  
Multiple Levels ◽  
Important Marker

Conduct disorder (CD) is an important marker of ADHD clinical and cognitive impairment and neurodevelopmental multimorbidity. It is also predictive of poor psychiatric and functional outcomes. Although traditionally considered as a consequence of ADHD, association of ADHD and CD can be explained at multiple levels—in terms of enriched familial/genetic risks, higher levels of psychosocial adversity, a likely different pattern of cognitive and neural correlates that involve emotional processes components, earlier temperamental risk characteristics, and additional neurodevelopmental burden such as language impairments and lower cognitive ability. The presence of CD does not alter current ADHD guideline recommendations on treatment but should be taken into account when making decisions upon the intensity and nature of follow-up.

Cognitive Impairment Following Critical Illness

2014 ◽  
Author(s):  
Ramona O Hopkins ◽  
James C Jackson
Keyword(s):  
Cognitive Impairment ◽  
Critical Illness ◽  
Cognitive Impairments ◽  
Biological Mechanisms ◽  
Early Mobility ◽  
Progressive Decline ◽  
Mobility Protocols ◽  
Clinically Significant ◽  
Post Intensive Care Syndrome

Millions of individuals each year survive critical illness, many of whom will develop post-intensive care syndrome which includes new or worsening impairments in physical, psychiatric, or cognitive functioning. Cognitive impairments are common in survivors of critical illness, are often severe, and persist years after hospital discharge. Cognitive impairments improve in some patients and, in others, appear stable over time, rather display a pattern of progressive decline. Cognitive impairment contributes to clinically significant functional decrements as well as decreased quality of life. The biological mechanisms of cognitive impairment are not well defined, although numerous risk factors have been identified. As the number of ICU survivors increases, there is a growing population of patients with cognitive impairments following critical illness, underscoring the need to address cognitive impairments through prevention, treatment, and rehabilitation. Interventions to prevent or reduce the severity of cognitive impairments (i.e. sedation, delirium, and early mobility protocols) need to be investigated. Although there are very limited examples in which rehabilitation is used in ICU populations, it may hold the potential to facilitate improvements in cognition, particularly among individuals with deficits in memory, attention, and executive functioning. Despite over a decade of focused investigation, fundamental questions pertaining to cognitive impairments after critical illness exist. Research is needed on methods to proactively identify those at risk for cognitive impairment and to develop methods which will robustly prevent and improve deficits in ICU survivors.

scholarly journals Molecular Resiliency and Aging

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 163-163
Author(s):  
Adam Salmon
Keyword(s):  
Healthy Aging ◽  
Regulatory Mechanisms ◽  
Human Populations ◽  
Biological Mechanisms ◽  
Short Term ◽  
Biology Of Aging ◽  
Physiological Markers ◽  
Molecular Regulatory Mechanisms ◽  
Insight Into ◽  
Translational Models

Abstract Resilience is described as the ability to respond to acute forms of stress and recover to normal homeostasis. There is growing evidence that biology of resilience is entwined with the biology of aging. With increasing age, resilience decreases and is a likely contributor to increased morbidity, frailty and susceptibility to death with age. Conversely, increased resilience across numerous physiological markers of function is associated with longevity and healthy aging. The variation in resilience in populations suggests biological and molecular regulatory mechanisms that might provide insight into interventions to improve resilience, healthy aging and longevity. In this session, speakers will provide insight regarding short-term assays of resilience in animal models that prove useful both in delineating these biological mechanisms as well as inform on potential translational models to better understand biological resilience in human populations. The sessions focus is on defining these assays and discussion of the biological relevance each resilience assay in terms of the regulation of aging. The goals of these studies range from identifying potential predictors of individual lifespan within markers of functional resilience to leveraging geroscience to define whether markers of resilience can be modified through interventions to the aging process. Moreover, better understanding of the biology of resilience could assist in defining novel interventions that improve resilience and thereby enhance longevity.

scholarly journals Induction Of Chronic Stress Reveals An Interplay Of Stress Granules And TDP-43 Pathological Aggregates In Human ALS Fibroblasts And iPSC-Neurons

2020 ◽  
Author(s):  
Antonia Ratti ◽  
Valentina Gumina ◽  
Paola Lenzi ◽  
Patrizia Bossolasco ◽  
Federica Fulceri ◽  
...  
Keyword(s):  
Chronic Stress ◽  
Cell Response ◽  
Rna Binding ◽  
Protein Quality ◽  
Cell Model ◽  
Stress Granules ◽  
Acute And Chronic Stress ◽  
Primary Fibroblasts ◽  
Response To Stress ◽  
Oxidative Insult

AbstractAmyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative diseases characterized by the presence of neuropathological aggregates of phosphorylated TDP-43 (P-TDP-43). The RNA-binding protein TDP-43 is also a component of stress granules (SG), cytoplasmic foci forming to arrest translation under sub-lethal stress conditions. Although commonly considered as distinct structures, a link between SG and pathological TDP-43 inclusions may occur despite evidence that TDP-43 pathology directly arises from SG is still under debate. Primary fibroblasts and iPSC-derived neurons (iPSC-N) from ALS patients carrying mutations in TARDBP (n=3) and C9ORF72 (n=3) genes and from healthy controls (n=3) were exposed to oxidative stress by sodium arsenite. SG formation and cell response to stress was evaluated and quantified by immunofluorescence and electron microscopy analyses. We found that, not only an acute, but also a chronic oxidative insult, better mimicking a persistent condition of stress as in neurodegeneration, is able to induce SG formation in primary fibroblasts and iPSC-N. Importantly, only upon chronic stress, we observed TDP-43 recruitment into SG and the formation of distinct P-TDP-43 aggregates, very similar to the abnormal inclusions observed in ALS/FTD autoptic brains. Moreover, in fibroblasts, cell response to stress was different in control compared with mutant ALS cells, probably due to their different vulnerability. A quantitative analysis revealed also differences in terms of number of SG-forming cells and SG size, suggesting a different composition of foci in acute and chronic stress. In condition of prolonged stress, SG and P-TDP-43 aggregate formation was concomitant with p62 increase and autophagy dysregulation in both ALS fibroblasts and iPSC-N, as confirmed by immunofluorescence and ultrastructural analyses. We found that exposure to a chronic oxidative insult promotes the formation of both SG and P-TDP-43 aggregates in patient-derived cells, reinforcing the idea that SG fail to properly disassemble, interfering with the protein quality control system. Moreover, we obtained a disease cell model recapitulating ALS/FTD P-TDP-43 aggregates, which represents an invaluable bioassay to study TDP-43 pathology and develop therapeutic strategies aimed at disaggregating or preventing the formation of pathological inclusions.

scholarly journals Promising Opportunities for Treating Neurodegenerative Diseases with Mesenchymal Stem Cell-Derived Exosomes

Biomolecules ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 1320
Author(s):  
Reut Guy ◽  
Daniel Offen
Keyword(s):  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Neurodegenerative Diseases ◽  
Functional Outcomes ◽  
Pathological Condition ◽  
Unmet Need ◽  
Therapeutic Effects ◽  
Neuronal Function ◽  
Progressive Decline ◽  
Immune System Modulation

Neurodegenerative disease refers to any pathological condition in which there is a progressive decline in neuronal function resulting from brain atrophy. Despite the immense efforts invested over recent decades in developing treatments for neurodegenerative diseases, effective therapy for these conditions is still an unmet need. One of the promising options for promoting brain recovery and regeneration is mesenchymal stem cell (MSC) transplantation. The therapeutic effect of MSCs is thought to be mediated by their secretome, and specifically, by their exosomes. Research shows that MSC-derived exosomes retain some of the characteristics of their parent MSCs, such as immune system modulation, regulation of neurite outgrowth, promotion of angiogenesis, and the ability to repair damaged tissue. Here, we summarize the functional outcomes observed in animal models of neurodegenerative diseases following MSC-derived exosome treatment. We will examine the proposed mechanisms of action through which MSC-derived exosomes mediate their therapeutic effects and review advanced studies that attempt to enhance the improvement achieved using MSC-derived exosome treatment, with a view towards future clinical use.

scholarly journals Animal Models of Cancer-Related Pain: Current Perspectives in Translation

2020 ◽  
Vol 11 ◽  
Author(s):  
Jorge B. Pineda-Farias ◽  
Jami L. Saloman ◽  
Nicole N. Scheff
Keyword(s):  
Animal Models ◽  
Cancer Pain ◽  
Cancer Detection ◽  
Biological Mechanisms ◽  
Nociceptive Responses ◽  
Poor Understanding ◽  
Patient Prognosis ◽  
Preclinical Animal Models ◽  
Translational Models ◽  
Animal Models Of Cancer

The incidence of pain in cancer patients during diagnosis and treatment is exceedingly high. Although advances in cancer detection and therapy have improved patient prognosis, cancer and its treatment-associated pain have gained clinical prominence. The biological mechanisms involved in cancer-related pain are multifactorial; different processes for pain may be responsible depending on the type and anatomic location of cancer. Animal models of cancer-related pain have provided mechanistic insights into the development and process of pain under a dynamic molecular environment. However, while cancer-evoked nociceptive responses in animals reflect some of the patients’ symptoms, the current models have failed to address the complexity of interactions within the natural disease state. Although there has been a recent convergence of the investigation of carcinogenesis and pain neurobiology, identification of new targets for novel therapies to treat cancer-related pain requires standardization of methodologies within the cancer pain field as well as across disciplines. Limited success of translation from preclinical studies to the clinic may be due to our poor understanding of the crosstalk between cancer cells and their microenvironment (e.g., sensory neurons, infiltrating immune cells, stromal cells etc.). This relatively new line of inquiry also highlights the broader limitations in translatability and interpretation of basic cancer pain research. The goal of this review is to summarize recent findings in cancer pain based on preclinical animal models, discuss the translational benefit of these discoveries, and propose considerations for future translational models of cancer pain.

scholarly journals Biological Mechanisms Induced by Soybean Agglutinin Using an Intestinal Cell Model of Monogastric Animals

2021 ◽  
Vol 8 ◽  
Author(s):  
Li Pan ◽  
Yan Liu ◽  
Hainan Lan ◽  
Nan Bao ◽  
Yuan Zhao ◽  
...  
Keyword(s):  
Excision Repair ◽  
Cell Model ◽  
Phase Cell ◽  
Intestinal Cell ◽  
Soybean Agglutinin ◽  
Biological Mechanisms ◽  
Comprehensive Information ◽  
Peptide Biosynthesis ◽  
Base Excision ◽  
And Function

Soybean agglutinin (SBA) has a toxic effect on most animals. The anti-nutritional mechanisms of SBA are not fully understood, in terms of cell survival activity and metabolism of intestinal cells. This study aims to investigate the effects of SBA on the cell cycle, apoptosis, and to verify the mechanism of SBA anti-nutritional characters based on proteomic-based analysis. The IPEC-J2 cell line was cultured with medium containing 0.0, 0.5, or 2.0 mg/mL SBA. With increasing SBA levels, the percentage of the cells at G0/G1 phase, cell apoptosis rates, expressions of Bax and p21, and the activities of Casp-3 and Casp-9 were increased, while cyclin D1 and Bcl-2 expressions were declined (p < 0.05). The proteomic analysis showed that the numbers of differentially expressed proteins, induced by SBA, were mainly enriched in different pathways including DNA replication, base excision repair, nucleus excision repair, mismatch repair, amide and peptide biosynthesis, ubiquitin-mediated proteolysis, as well as structures and functions of mitochondria and ribosome. In conclusion, the anti-nutritional mechanism of SBA is a complex cellular process. Such process including DNA related activities; protein synthesis and metabolism; signal-conducting relation; as well as subcellular structure and function. This study provides comprehensive information to understand the toxic mechanism of SBA in monogastrics.

The diagnosis of metabolic storage disease in skin biopsies (a light-, electronmicroscopic, and analytical study)

1978 ◽  
Vol 36 (2) ◽  
pp. 648-649
Author(s):  
W. Jurecka ◽  
W. Gebhart ◽  
H. Lassmann
Keyword(s):  
Storage Disease ◽  
Hunter Syndrome ◽  
Histochemical Demonstration ◽  
Sweat Glands ◽  
Type I ◽  
Storage Material ◽  
Scheie Syndrome ◽  
Storage Products ◽  
Skin Biopsies ◽  
Type V

Diagnosis of metabolic storage disease can be established by the determination of enzymes or storage material in blood, urine, or several tissues or by clinical parameters. Identification of the accumulated storage products is possible by biochemical analysis of isolated material, by histochemical demonstration in sections, or by ultrastructural demonstration of typical inclusion bodies. In order to determine the significance of such inclusions in human skin biopsies several types of metabolic storage disease were investigated. The following results were obtained.In MPS type I (Pfaundler-Hurler-Syndrome), type II (Hunter-Syndrome), and type V (Ullrich-Scheie-Syndrome) mainly “empty” vacuoles were found in skin fibroblasts, in Schwann cells, keratinocytes and macrophages (Dorfmann and Matalon 1972). In addition, prominent vacuolisation was found in eccrine sweat glands. The storage material could be preserved in part by fixation with cetylpyridiniumchloride and was also present within fibroblasts grown in tissue culture.

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