scholarly journals Regulation of UNC-40/DCC and UNC-6/Netrin by DAF-16 promotes functional rewiring of the injured axon

Development ◽  
2021 ◽  
Vol 148 (11) ◽  
Author(s):  
Atrayee Basu ◽  
Sibaram Behera ◽  
Smriti Bhardwaj ◽  
Shirshendu Dey ◽  
Anindya Ghosh-Roy
Keyword(s):  
Axon Guidance ◽  
Initial Response ◽  
Ventral Side ◽  
Functional Restoration ◽  
Dependent Manner ◽  
Limited Capacity ◽  
Post Injury ◽  
Functional Connection ◽  
Age Related ◽  
Proximal Stump

ABSTRACT The adult nervous system has a limited capacity to regenerate after accidental damage. Post-injury functional restoration requires proper targeting of the injured axon to its postsynaptic cell. Although the initial response to axonal injury has been studied in great detail, it is rather unclear what controls the re-establishment of a functional connection. Using the posterior lateral microtubule neuron in Caenorhabditis elegans, we found that after axotomy, the regrowth from the proximal stump towards the ventral side and accumulation of presynaptic machinery along the ventral nerve cord correlated to the functional recovery. We found that the loss of insulin receptor DAF-2 promoted ‘ventral targeting’ in a DAF-16-dependent manner. We further showed that coordinated activities of DAF-16 in neuron and muscle promoted ‘ventral targeting’. In response to axotomy, expression of the Netrin receptor UNC-40 was upregulated in the injured neuron in a DAF-16-dependent manner. In contrast, the DAF-2-DAF-16 axis contributed to the age-related decline in Netrin expression in muscle. Therefore, our study revealed an important role for insulin signaling in regulating the axon guidance molecules during the functional rewiring process.

scholarly journals Dendranthema zawadskii var. lucidum (Nakai) J.H. Park Extract Inhibits Cellular Senescence in Human Dermal Fibroblasts and Aging-Related Inflammation in Rats

Processes ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 801
Author(s):  
Jehun Choi ◽  
Gwi-Yeong Jang ◽  
Jeonghoon Lee ◽  
Hae-Young Chung ◽  
Hyung-Jun Noh ◽  
...  
Keyword(s):  
Cellular Senescence ◽  
Cell Cycle Progression ◽  
Inflammatory Responses ◽  
Dermal Fibroblast ◽  
Dermal Fibroblasts ◽  
Dependent Manner ◽  
Aged Rats ◽  
Age Related ◽  
Dendranthema Zawadskii ◽  
Beta Galactosidase

Senescence is the phenomenon by which physiological functions of organisms degenerate with time. Cellular senescence is marked by an inhibition of cell cycle progression. Beta-galactosidase accumulates in the lysosomes of aged cells. In this study, human dermal fibroblast cells (HDFs) were treated with 0.5 μM doxorubicin for 4 h to induce cellular senescence. Senescence-associated beta-galactosidase (SA-β-gal) activity was then measured 72 h after treatment with aerial parts of Dendranthema zawadskii var. lucidum (Nakai) J.H. Park (DZ) extract. Treatment with DZ extract significantly decreased SA-β-gal activity in a dose-dependent manner in HDFs. Additionally, DZ extract treatment reduced age-related oxidative stress and inflammation in the aortas of aged rats. The reactive oxygen species (ROS) levels in aortas of aged control rats were higher than those in young rats. However, DZ extract-fed aged rats showed significantly lower ROS levels than the aged control rats. When the aged rats were treated with DZ extract at either 0.2 or 1.0 mg∙kg−1∙day−1, NF-κB levels in aorta tissue decreased significantly compared to those in aorta tissue of the aged control rats without DZ treatment. In addition, DZ extract-fed aged rat aortas showed significant reductions in expression of iNOS and COX-2 induced by NF-κB translocation. Therefore, these results suggest that DZ effectively inhibited senescence-related NF-κB activation and inflammation. DZ extract may have a role in the prevention of the vascular inflammatory responses that occur during vascular aging.

scholarly journals Zebrafish Blunt-Force TBI Induces Heterogenous Injury Pathologies That Mimic Human TBI and Responds with Sonic Hedgehog-Dependent Cell Proliferation across the Neuroaxis

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 861
Author(s):  
James Hentig ◽  
Kaylee Cloghessy ◽  
Manuela Lahne ◽  
Yoo Jin Jung ◽  
Rebecca A. Petersen ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Proliferative Response ◽  
Injury Severity ◽  
Granule Cell Layer ◽  
Dependent Manner ◽  
Adult Zebrafish ◽  
Post Injury ◽  
Blunt Force ◽  
Shh Pathway ◽  
Wide Range

Blunt-force traumatic brain injury (TBI) affects an increasing number of people worldwide as the range of injury severity and heterogeneity of injury pathologies have been recognized. Most current damage models utilize non-regenerative organisms, less common TBI mechanisms (penetrating, chemical, blast), and are limited in scalability of injury severity. We describe a scalable blunt-force TBI model that exhibits a wide range of human clinical pathologies and allows for the study of both injury pathology/progression and mechanisms of regenerative recovery. We modified the Marmarou weight drop model for adult zebrafish, which delivers a scalable injury spanning mild, moderate, and severe phenotypes. Following injury, zebrafish display a wide range of severity-dependent, injury-induced pathologies, including seizures, blood–brain barrier disruption, neuroinflammation, edema, vascular injury, decreased recovery rate, neuronal cell death, sensorimotor difficulties, and cognitive deficits. Injury-induced pathologies rapidly dissipate 4–7 days post-injury as robust cell proliferation is observed across the neuroaxis. In the cerebellum, proliferating nestin:GFP-positive cells originated from the cerebellar crest by 60 h post-injury, which then infiltrated into the granule cell layer and differentiated into neurons. Shh pathway genes increased in expression shortly following injury. Injection of the Shh agonist purmorphamine in undamaged fish induced a significant proliferative response, while the proliferative response was inhibited in injured fish treated with cyclopamine, a Shh antagonist. Collectively, these data demonstrate that a scalable blunt-force TBI to adult zebrafish results in many pathologies similar to human TBI, followed by recovery, and neuronal regeneration in a Shh-dependent manner.

scholarly journals Loss-of-function of p53 isoform Δ113p53 accelerates brain aging in zebrafish

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Ting Zhao ◽  
Shengfan Ye ◽  
Zimu Tang ◽  
Liwei Guo ◽  
Zhipeng Ma ◽  
...  
Keyword(s):  
Replicative Senescence ◽  
Brain Aging ◽  
Ventricular Zone ◽  
Human Fibroblasts ◽  
Cell Lineage ◽  
Lineage Tracing ◽  
Dependent Manner ◽  
Loss Of Function ◽  
Antioxidant Genes ◽  
Age Related

AbstractReactive oxygen species (ROS) stress has been demonstrated as potentially critical for induction and maintenance of cellular senescence, and been considered as a contributing factor in aging and in various neurological disorders including Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS). In response to low-level ROS stress, the expression of Δ133p53, a human p53 isoform, is upregulated to promote cell survival and protect cells from senescence by enhancing the expression of antioxidant genes. In normal conditions, the basal expression of Δ133p53 prevents human fibroblasts, T lymphocytes, and astrocytes from replicative senescence. It has been also found that brain tissues from AD and ALS patients showed decreased Δ133p53 expression. However, it is uncharacterized if Δ133p53 plays a role in brain aging. Here, we report that zebrafish Δ113p53, an ortholog of human Δ133p53, mainly expressed in some of the radial glial cells along the telencephalon ventricular zone in a full-length p53-dependent manner. EDU-labeling and cell lineage tracing showed that Δ113p53-positive cells underwent cell proliferation to contribute to the neuron renewal process. Importantly, Δ113p53M/M mutant telencephalon possessed less proliferation cells and more senescent cells compared to wild-type (WT) zebrafish telencephalon since 9-months old, which was associated with decreased antioxidant genes expression and increased level of ROS in the mutant telencephalon. More interestingly, unlike the mutant fish at 5-months old with cognition ability, Δ113p53M/M zebrafish, but not WT zebrafish, lost their learning and memory ability at 19-months old. The results demonstrate that Δ113p53 protects the brain from aging by its antioxidant function. Our finding provides evidence at the organism level to show that depletion of Δ113p53/Δ133p53 may result in long-term ROS stress, and finally lead to age-related diseases, such as AD and ALS in humans.

scholarly journals Random errors in protein synthesis activate an age-dependent program of muscle atrophy in mice

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
James Moore ◽  
Rashid Akbergenov ◽  
Martina Nigri ◽  
Patricia Isnard-Petit ◽  
Amandine Grimm ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Muscle Atrophy ◽  
Strength Analysis ◽  
Dependent Manner ◽  
Random Errors ◽  
Age Related ◽  
Related Phenotype ◽  
Age Dependent ◽  
Translation Accuracy ◽  
Transcriptomic Changes

AbstractRandom errors in protein synthesis are prevalent and ubiquitous, yet their effect on organismal health has remained enigmatic for over five decades. Here, we studied whether mice carrying the ribosomal ambiguity (ram) mutation Rps2-A226Y, recently shown to increase the inborn error rate of mammalian translation, if at all viable, present any specific, possibly aging-related, phenotype. We introduced Rps2-A226Y using a Cre/loxP strategy. Resulting transgenic mice were mosaic and showed a muscle-related phenotype with reduced grip strength. Analysis of gene expression in skeletal muscle using RNA-Seq revealed transcriptomic changes occurring in an age-dependent manner, involving an interplay of PGC1α, FOXO3, mTOR, and glucocorticoids as key signaling pathways, and finally resulting in activation of a muscle atrophy program. Our results highlight the relevance of translation accuracy, and show how disturbances thereof may contribute to age-related pathologies.

Aging increases p16INK4a expression in vascular smooth-muscle cells

2009 ◽  
Vol 30 (1) ◽  
pp. 11-18 ◽  
Author(s):  
Luis Rodriguez-Menocal ◽  
Si M. Pham ◽  
Dania Mateu ◽  
Melissa St-Pierre ◽  
Yuntao Wei ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Cell Physiology ◽  
Post Injury ◽  
Aged Mice ◽  
Reverse Transcription Pcr ◽  
Serum Stimulation ◽  
Age Related

Alteration of VSMC (vascular smooth-muscle cell) physiology is associated with the development of atherosclerosis and restenosis. We hypothesize that aging up-regulates the expression of p16INK4a in VSMCs, which may increase the susceptibility of blood vessels to vascular occlusive diseases. Aortic VSMCs were obtained from young and aged mice. Cells from aged mice grew more slowly than those from their younger counterparts. Progression of cell cycle in response to serum stimulation was significantly inhibited in those cells with aging, as determined by FACS after propidium iodide staining. A significant up-regulation of p16INK4a (2.5-fold, P=0.0012) was found in VSMC from aged animals using gene arrays. The up-regulation of this gene was further confirmed by quantitative RT–PCR (reverse transcription–PCR) and Western-blot experiments. Immunostaining for p16INK4a confirmed that aortas from aged mice contained more p16INK4a+ SMA (smooth-muscle cell actin)+ cells than aortas from young animals (26.79±2.45 versus 7.06±1.44, P=0.00027, n=4). In conclusion, we have shown that aging up-regulates the expression of p16INK4a in VSMC in both cultures and arteries. The increase in p16INK4a in the vasculature with aging may modify VSMC's response to post-injury stress and therefore accelerate the development of age-related cardiovascular diseases.

In vivo acute testicular testosterone response to injection of luteinizing hormone in the rat fetus

1993 ◽  
Vol 128 (3) ◽  
pp. 268-273 ◽  
Author(s):  
René Habert
Keyword(s):  
Plasma Concentration ◽  
Luteinizing Hormone ◽  
Leydig Cells ◽  
Time Dependent ◽  
Fetal Life ◽  
Dependent Manner ◽  
Adult Rats ◽  
Rat Fetus ◽  
Age Related

The acute in vivo testosterone response to LH stimulation and its change during late fetal life were determined in the rat. In 18.5-day-old fetuses, testicular testosterone content was increased in a dose-and time-dependent manner after fetal subcutaneous LH injection. The maximum response was small: the testicular content and plasma concentration were increased by 200% and 2 50% over basal values respectively, while they were increased 1100% and 1200% in adult rats. Similarly, comparable low responses were obtained after subcutaneously injecting the fetuses with human chorionic gonadotropin (hCG) and after injecting LH into the vitelline vein. Between days 18.5 and 21.5 of fetal life, the testosterone levels in the testis and plasma of uninjected or PBS-injected fetuses decreased and were comparable in both groups. In maximally LH-stimulated fetuses, the testicular content did not change with age, and plasma concentration was lower on day 21.5 than on day 18.5. Since the number of Leydig cells increases 1.5 to 2-fold between days 18.5 and 21.5, these results show an age-related decrease in basal and maximally LH-stimulated in vivo testosterone secretions per Leydig cell during late fetal life.

scholarly journals Low-Dose Ionizing Radiation Therapy: A Novel Treatment for Post-Concussion Syndrome?

Dose-Response ◽  
2021 ◽  
Vol 19 (4) ◽  
pp. 155932582110443
Author(s):  
Paul A. Oakley
Keyword(s):  
Oxidative Stress ◽  
Radiation Therapy ◽  
Ionizing Radiation ◽  
Neurodegenerative Disease ◽  
Low Dose ◽  
Post Injury ◽  
Post Concussion Syndrome ◽  
Persistent Symptoms ◽  
Age Related ◽  
Alzhiemer's Disease

A subset of victims who experience concussion suffer from persistent symptoms spanning months to years post-injury, termed post-concussion syndrome (PCS). Problematically, there is lack of consensus for the treatment of PCS. Concussion injury involves a neurometabolic cascade leading to oxidative stress and neuroinflammation which parallels the oxidative stress loading occuring from age-related neurodegenerative conditions. Historical and recent evidence has emerged showing the efficacy of low-dose radiation therapy for many human diseases including neurodegenerative diseases such as Alzhiemer’s disease (AD). Due to the pathognomonic similarities of oxidative stress and neuroinflammation involved in PCS and neurodegenerative disease, treatments that prove successful for neurodegenerative disease may prove successful for PCS. Recently, low-dose ionizing radiation therapy (LDIR) has been documented to show a reversal of many symptoms in AD, including improved cognition. LDIR is thought to induce a switching from proinflammatory M1 phenotype to an anti-inflammatory M2 phenotype. In other words, a continual upregulation of the adaptive protection systems via LDIR induces health enhancement. It is hypothesized LDIR treatment for PCS would mimic that seen from early evidence of LDIR treatment of AD patients who suffer from similar oxidative stress loading. We propose the application of LDIR is a promising, untapped treatment for PCS.

scholarly journals Acadesine suppresses TNF-α induced complement component 3 (C3), in retinal pigment epithelial (RPE) cells

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0244307
Author(s):  
Nikolaos E. Efstathiou ◽  
Giannis A. Moustafa ◽  
Daniel E. Maidana ◽  
Eleni K. Konstantinou ◽  
Shoji Notomi ◽  
...  
Keyword(s):  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Complement Component ◽  
Adenosine Kinase ◽  
Age Related Macular Degeneration ◽  
Dependent Manner ◽  
Rpe Cells ◽  
Age Related ◽  
Tnf Α ◽  
Complement Component 3

Rationale Age-related macular degeneration (AMD) is the most prevalent form of irreversible blindness in the developed world. Aging, inflammation and complement dysregulation affecting the retinal pigment epithelium (RPE), are considered significant contributors in its pathogenesis and several evidences have linked tumor necrosis factor alpha (TNF-α) and complement component 3 (C3) with AMD. Acadesine, an analog of AMP and an AMP-activated protein kinase (AMPK) activator, has been shown to have cytoprotective effects in human clinical trials as well as having anti-inflammatory and anti-vascular exudative effects in animals. The purpose of this study was to evaluate if acadesine is able to suppress TNF-α induced C3 in RPE cells. Methods ARPE-19 and human primary RPE cells were cultured and allowed to grow to confluence. TNF-α was used for C3 induction in the presence or absence of acadesine. Small molecule inhibitors and siRNA were used to determine if acadesine exerts its effect via the extracellular or intracellular pathway and to evaluate the importance of AMPK for these effects. The expression level of C3 was determined by immunoblot analysis. Results Acadesine suppresses TNF-α induced C3 in a dose dependent manner. When we utilized the adenosine receptor inhibitor dipyridamole (DPY) along with acadesine, acadesine’s effects were abolished, indicating the necessity of acadesine to enter the cell in order to exert it’s action. However, pretreatment with 5-iodotubericidin (5-Iodo), an adenosine kinase (AK) inhibitor, didn’t prevent acadesine from decreasing TNF-α induced C3 expression suggesting that acadesine does not exert its effect through AMP conversion and subsequent activation of AMPK. Consistent with this, knockdown of AMPK α catalytic subunit did not affect the inhibitory effect of acadesine on TNF-α upregulation of C3. Conclusions Our results suggest that acadesine suppresses TNF-α induced C3, likely through an AMPK-independent pathway, and could have potential use in complement over activation diseases.

scholarly journals Lipid droplets modulate proteostasis, SQST-1/SQSTM1 dynamics, and lifespan in C. elegans

2021 ◽  
Author(s):  
Anita Kumar ◽  
Joslyn Mills ◽  
Wesley Parker ◽  
Joshua Leitão ◽  
Celeste Ng ◽  
...  
Keyword(s):  
Translational Regulation ◽  
Lipid Droplets ◽  
Dependent Manner ◽  
Lipase Gene ◽  
Triacylglycerol Lipase ◽  
Selective Autophagy ◽  
C Elegans ◽  
Protein Ubiquitination ◽  
Model Of Alzheimer’S Disease ◽  
Age Related

Abstract The ability of organisms to live long depends largely on the maintenance of proteome stability via proteostatic mechanisms including translational regulation, protein chaperoning and degradation machineries. In several long-lived Caenorhabditis elegans strains, such as insulin/IGF-1 receptor daf-2 mutants, enhanced proteostatic mechanisms are accompanied by elevated intestinal lipid stores, but the role of lipid droplets in longevity has remained obscure. Here, while determining the regulatory network of the selective autophagy receptor SQST-1/SQSTM1, we unexpectedly uncovered a novel role for lipid droplets in proteostasis and longevity. Using an unbiased genomewide RNAi screening approach, we identified several SQST-1 modulators, including proteins found on lipid droplets and those prone to aggregate with age. SQST-1 accumulated on lipid droplets when autophagy was inhibited, suggesting that lipid droplets may serve a role in facilitating selective autophagy. Expansion of intestinal lipid droplets by silencing the conserved cytosolic triacylglycerol lipase gene atgl-1/ATGL enhanced autophagy, and extended lifespan in an HSF-1/HSF1-dependent and CDC-48/VCP-dependent manner. Silencing atgl-1 mitigated the age-related accumulation of SQST-1 and reduced overall ubiquitination of proteins. Reducing atgl-1 also improved proteostasis in a nematode model of Alzheimer’s disease. Subcellular analyses revealed that lipid droplets unexpectedly harbor more ubiquitinated proteins than the cytosol. Accordingly, low lipid droplet levels exacerbated the proteostatic collapse when autophagy or proteasome function was compromised. Altogether, our study uncovers a key role for lipid droplets in C. elegans as a proteostatic mediator that reduces protein ubiquitination, facilitates autophagy, and promotes longevity.

scholarly journals MLN64 Is Involved in Actin-mediated Dynamics of Late Endocytic Organelles

2005 ◽  
Vol 16 (8) ◽  
pp. 3873-3886 ◽  
Author(s):  
Maarit Hölttä-Vuori ◽  
Fabien Alpy ◽  
Kimmo Tanhuanpää ◽  
Eija Jokitalo ◽  
Aino-Liisa Mutka ◽  
...  
Keyword(s):  
Membrane Protein ◽  
Unknown Function ◽  
Cell Periphery ◽  
Dependent Manner ◽  
Protein Overexpression ◽  
Wild Type ◽  
Functional Connection ◽  
Late Endosomes ◽  
Endosomal Membranes ◽  
Cholesterol Binding

MLN64 is a late endosomal cholesterol-binding membrane protein of an unknown function. Here, we show that MLN64 depletion results in the dispersion of late endocytic organelles to the cell periphery similarly as upon pharmacological actin disruption. The dispersed organelles in MLN64 knockdown cells exhibited decreased association with actin and the Arp2/3 complex subunit p34-Arc. MLN64 depletion was accompanied by impaired fusion of late endocytic organelles and delayed cargo degradation. MLN64 overexpression increased the number of actin and p34-Arc-positive patches on late endosomes, enhanced the fusion of late endocytic organelles in an actin-dependent manner, and stimulated the deposition of sterol in late endosomes harboring the protein. Overexpression of wild-type MLN64 was capable of rescuing the endosome dispersion in MLN64-depleted cells, whereas mutants of MLN64 defective in cholesterol binding were not, suggesting a functional connection between MLN64-mediated sterol transfer and actin-dependent late endosome dynamics. We propose that local sterol enrichment by MLN64 in the late endosomal membranes facilitates their association with actin, thereby governing actin-dependent fusion and degradative activity of late endocytic organelles.

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