scholarly journals Axon degeneration: Molecular mechanisms of a self-destruction pathway

2012 ◽  
Vol 196 (1) ◽  
pp. 7-18 ◽  
Author(s):  
Jack T. Wang ◽  
Zachary A. Medress ◽  
Ben A. Barres
Keyword(s):  
Molecular Mechanisms ◽  
Nerve Degeneration ◽  
Axon Degeneration ◽  
Common Mechanism ◽  
Traumatic Injuries ◽  
Calcium Dependent ◽  
Survival Factor ◽  
Acute Injuries ◽  
Proposed Model ◽  
Axon Loss

Axon degeneration is a characteristic event in many neurodegenerative conditions including stroke, glaucoma, and motor neuropathies. However, the molecular pathways that regulate this process remain unclear. Axon loss in chronic neurodegenerative diseases share many morphological features with those in acute injuries, and expression of the Wallerian degeneration slow (WldS) transgene delays nerve degeneration in both events, indicating a common mechanism of axonal self-destruction in traumatic injuries and degenerative diseases. A proposed model of axon degeneration is that nerve insults lead to impaired delivery or expression of a local axonal survival factor, which results in increased intra-axonal calcium levels and calcium-dependent cytoskeletal breakdown.

scholarly journals Lessons from Injury: How Nerve Injury Studies Reveal Basic Biological Mechanisms and Therapeutic Opportunities for Peripheral Nerve Diseases

2021 ◽  
Author(s):  
Peter Arthur-Farraj ◽  
Michael P. Coleman
Keyword(s):  
Schwann Cell ◽  
Peripheral Nerve ◽  
Schwann Cells ◽  
Nerve Injury ◽  
Peripheral Nerves ◽  
Molecular Mechanisms ◽  
Axon Degeneration ◽  
Axon Loss ◽  
Factor C ◽  
Inherited Neuropathies

AbstractSince Waller and Cajal in the nineteenth and early twentieth centuries, laboratory traumatic peripheral nerve injury studies have provided great insight into cellular and molecular mechanisms governing axon degeneration and the responses of Schwann cells, the major glial cell type of peripheral nerves. It is now evident that pathways underlying injury-induced axon degeneration and the Schwann cell injury-specific state, the repair Schwann cell, are relevant to many inherited and acquired disorders of peripheral nerves. This review provides a timely update on the molecular understanding of axon degeneration and formation of the repair Schwann cell. We discuss how nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) and sterile alpha TIR motif containing protein 1 (SARM1) are required for axon survival and degeneration, respectively, how transcription factor c-JUN is essential for the Schwann cell response to nerve injury and what each tells us about disease mechanisms and potential therapies. Human genetic association with NMNAT2 and SARM1 strongly suggests aberrant activation of programmed axon death in polyneuropathies and motor neuron disorders, respectively, and animal studies suggest wider involvement including in chemotherapy-induced and diabetic neuropathies. In repair Schwann cells, cJUN is aberrantly expressed in a wide variety of human acquired and inherited neuropathies. Animal models suggest it limits axon loss in both genetic and traumatic neuropathies, whereas in contrast, Schwann cell secreted Neuregulin-1 type 1 drives onion bulb pathology in CMT1A. Finally, we discuss opportunities for drug-based and gene therapies to prevent axon loss or manipulate the repair Schwann cell state to treat acquired and inherited neuropathies and neuronopathies.

scholarly journals Genetic mapping and transcriptomic characterization of a new fuzzless-tufted cottonseed mutant

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Qian-Hao Zhu ◽  
Warwick Stiller ◽  
Philippe Moncuquet ◽  
Stuart Gordon ◽  
Yuman Yuan ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Agronomic Traits ◽  
Gene Families ◽  
Mutant Phenotype ◽  
Wild Type ◽  
Calcium Dependent ◽  
Dependent Protein ◽  
Flanking Region ◽  
Comparative Transcriptomic Analysis

Abstract Fiber mutants are unique and valuable resources for understanding the genetic and molecular mechanisms controlling initiation and development of cotton fibers that are extremely elongated single epidermal cells protruding from the seed coat of cottonseeds. In this study, we reported a new fuzzless-tufted cotton mutant (Gossypium hirsutum) and showed that fuzzless-tufted near-isogenic lines (NILs) had similar agronomic traits and a higher ginning efficiency compared to their recurrent parents with normal fuzzy seeds. Genetic analysis revealed that the mutant phenotype is determined by a single incomplete dominant locus, designated N5. The mutation was fine mapped to an approximately 250-kb interval containing 33 annotated genes using a combination of bulked segregant sequencing, SNP chip genotyping, and fine mapping. Comparative transcriptomic analysis using 0–6 days post-anthesis (dpa) ovules from NILs segregating for the phenotypes of fuzzless-tufted (mutant) and normal fuzzy cottonseeds (wild-type) uncovered candidate genes responsible for the mutant phenotype. It also revealed that the flanking region of the N5 locus is enriched with differentially expressed genes (DEGs) between the mutant and wild-type. Several of those DEGs are members of the gene families with demonstrated roles in cell initiation and elongation, such as calcium-dependent protein kinase and expansin. The transcriptome landscape of the mutant was significantly reprogrammed in the 6 dpa ovules and, to a less extent, in the 0 dpa ovules, but not in the 2 and 4 dpa ovules. At both 0 and 6 dpa, the reprogrammed mutant transcriptome was mainly associated with cell wall modifications and transmembrane transportation, while transcription factor activity was significantly altered in the 6 dpa mutant ovules. These results imply a similar molecular basis for initiation of lint and fuzz fibers despite certain differences.

Molecular mechanisms of calcium-dependent excitotoxicity

2000 ◽  
Vol 78 (1) ◽  
pp. 3-13 ◽  
Author(s):  
Rita Sattler ◽  
Michael Tymianski
Keyword(s):  
Molecular Mechanisms ◽  
Calcium Dependent

Multiple mechanisms are responsible for altered expression of gap junction genes during oncogenesis in rat liver

1994 ◽  
Vol 107 (1) ◽  
pp. 83-95
Author(s):  
M.J. Neveu ◽  
J.R. Hully ◽  
K.L. Babcock ◽  
E.L. Hertzberg ◽  
B.J. Nicholson ◽  
...  
Keyword(s):  
Gap Junction ◽  
Cellular Localization ◽  
Molecular Mechanisms ◽  
Northern Blotting ◽  
Mrna Abundance ◽  
Common Mechanism ◽  
Cx43 Expression ◽  
Bile Duct Proliferation ◽  
Altered Expression ◽  
Connexin Expression

Although several abnormalities in gap junction (GJ) structure and/or function have been described in neoplasms, the molecular mechanisms responsible for many of the alterations remain unknown. The identification of a family of GJ proteins, termed connexins, prompted this study of connexin32 (Cx32), connexin26 (Cx26) and connexin43 (Cx43) expression during rat hepatocarcinogenesis. Using antibody, cDNA and cRNA probes, we investigated connexin mRNA and protein expression in preneoplastic and neoplastic rat livers. In normal liver, Cx32 is expressed in hepatocytes throughout the hepatic acinus, Cx26 is restricted to periportal hepatocytes, and Cx43 is expressed by mesothelial cells forming Glisson's capsule. Most preneoplastic altered hepatic foci generated by diethylnitrosamine (DEN) initiation and either phenobarbital (PB) or 2,3,7,8-dichlorodibenzo-p-dioxin (TCDD) promotion exhibited decreased Cx32 or increased Cx26 staining. Foci from either protocol failed to display Cx43 immunoreactivity. In the majority of PB-promoted foci, Cx32 immunoreactivity decreased independently of changes in mRNA abundance. Continuous thymidine labeling, following cessation of PB promotion, showed that downregulation of Cx32 staining is reversible in foci that are promoter-dependent for growth, but irreversible in lesions that are promoter-independent for growth. Hepatic neoplasms from rats initiated with DEN and promoted with PB or TCDD also displayed modified connexin expression. While all 24 neoplasms studied were deficient in normal punctate Cx32 and Cx26 staining, altered cellular localization of these proteins was apparent in some tumors. Immunoblotting of crude tissue extracts revealed that neoplasms with disordered Cx32 staining showed immunoreactive bands with altered electrophoretic mobility. These observations show that hepatomas may downregulate Cx32 expression through changes in the primary structure of Cx32 or by post-translational modifications. Northern blotting of total tumor mRNAs failed to demonstrate consistent changes in the abundance of Cx32, Cx26 or Cx43 transcripts. Some tumors expressed steady-state transcripts without observable immunoreactivity, indicating that some hepatomas downregulate connexin immunoreactivity independently of mRNA abundance. Increased levels of Cx43 mRNA and protein were found in several neoplasms, but immunostaining was always localized to nonparenchymal cells. Areas of bile duct proliferation and cholangiomas displayed Cx43 staining, whereas, cholangiocarcinomas were deficient in immunoreactivity. These findings show that alterations in the expression of connexins, by either downregulation or differential induction, represent common modifications during hepatocarcinogenesis. Although our results imply that connexins represent useful markers for the boundary between tumor promotion and progression, preneoplastic and neoplastic rat hepatocytes fail to use a common mechanism to modify connexin expression.

Cross-species Transcriptomes Reveal Species-specific and Shared Molecular Adaptations for Plants Development on Iron-rich Rocky Outcrops Soils

2021 ◽  
Author(s):  
Mariana Costa Dias ◽  
Cecílio Caldeira ◽  
Markus Gastauer ◽  
Silvio Ramos ◽  
Guilherme Oliveira
Keyword(s):  
Circadian Rhythm ◽  
Differential Expression ◽  
Native Species ◽  
Molecular Mechanisms ◽  
Light Stimulus ◽  
Differential Expression Analysis ◽  
Common Mechanism ◽  
Dependent Manner ◽  
Rocky Outcrops ◽  
Species Specific

Abstract BackgroundCanga is the Brazilian term for the savanna-like vegetation harboring several endemic species on iron-rich rocky outcrops, usually considered for mining activities. Parkia platycephala Benth. and Stryphnodendron pulcherrimum (Willd.) Hochr. naturally occur in the cangas of Serra dos Carajás (eastern Amazonia, Brazil) and the surrounding forest, indicating high phenotypic plasticity. The morphological and physiological mechanisms of the plants’ establishment in the canga environment are well studied, but the molecular adaptative responses are still unknown. We aimed to identify molecular mechanisms that allow the establishment of these plants in the canga environment.ResultsPlants were grown in canga and forest substrates collected in the Carajás Mineral Province. RNA was extracted from pooled leaf tissue, and RNA-seq paired-end reads were assembled into representative transcriptomes for P. platycephala and S. pulcherrimum containing 31,728 and 31,311 primary transcripts, respectively. We identified both species-specific and core molecular responses in plants grown in the canga substrate using differential expression analyses. In the species-specific analysis, we identified 1,112 and 838 differentially expressed genes for P. platycephala and S. pulcherrimum, respectively. Enrichment analyses showed unique biological processes and metabolic pathways affected for each species. Comparative differential expression analysis was based on shared single-copy orthologs. The overall pattern of ortholog expression was species-specific. Even so, almost 300 altered genes were identified between plants in canga and forest substrates, responding the same way in both species. The genes were functionally associated with the response to light stimulus and the circadian rhythm pathway.ConclusionsPlants possess species-specific adaptative responses to cope with the substrates. Our results also suggest that plants adapted to both canga and forest environments can adjust the circadian rhythm in a substrate-dependent manner. The circadian clock gene modulation might be a central mechanism regulating the plants’ development in the canga substrate in the studied legume species. The mechanism may be shared as a common mechanism to abiotic stress compensation in other native species.

scholarly journals DETERMINATION OF THE STRUCTURE OF ACUTE INJURY OF TEMPORARY AND PERMANENT FRONTAL TEETH IN CHILDREN, ANALYSIS OF DIAGNOSTIC AND TREATMENT MEASURES AND THEIR EFFECTS

2020 ◽  
Vol 73 (4) ◽  
pp. 737-742
Author(s):  
Valentina P. Trufanova ◽  
Olha V. Sheshukova ◽  
Natalia A. Lyakhova ◽  
Tetiana V. Polishchuk ◽  
Sofia S. Bauman ◽  
...  
Keyword(s):  
Self Regulation ◽  
Pediatric Dentistry ◽  
Permanent Tooth ◽  
Acute Injury ◽  
Permanent Teeth ◽  
Traumatic Injuries ◽  
Acute Injuries ◽  
Jaw Apparatus ◽  
Treatment Measures

The aim: To determine the structure of acute injuries of temporary and permanent frontal teeth in children, to analyze the applied diagnostic and treatment measures for acute tooth trauma and to investigate their effectiveness. Materials and methods: The subject of the study were 31 children aged 2-12 years with acute temporary and permanent tooth trauma. Methods: clinical (radiological, thermodiagnosis), medical and statistical. Results: The number of injured permanent teeth was greater than the number of injured temporary teeth. The pattern of temporary and permanent tooth injuries differed, so in temporary teeth dislocations were observed, and in permanent teeth fractures prevailed over dislocations. In our opinion, this is due to the peculiarities of the anatomy of the temporary teeth. Usually, the therapeutic tactics of acute temporary teeth injuries is to remove them, despite their important role in the growth and development of jaws, physiological formation and eruption of permanent teeth. The therapeutic tactics of dynamic observation in the case of intrusive dislocation of the temporary tooth were selected in the clinic of the Department of Pediatric Dentistry. In some cases, with a slight change in the position of the temporary tooth, self-regulation of its position was observed, in other cases the tooth remained dystopic, but its viability remained in 50% of cases. Therapeutic tactics of acute injuries of permanent teeth were selected according to the type of trauma. In the case of permanent tooth dislocation, with a slight change in its position, tooth immobilization was carried out by splinting with fiberglass tape and photopolymer composite material. Conclusions: Our observations have shown that the complex of modern specialized medical care for the affected children with acute traumatic injuries of the teeth should be guided by their preservation, which ensures the subsequent normal formation of the dental-jaw apparatus. To ensure these conditions, a long, reliable immobilization of the damaged tooth is required as soon as possible after injury.

scholarly journals Nicotinic acid mononucleotide is an allosteric SARM1 inhibitor promoting axonal protection

2021 ◽  
Author(s):  
Yo Sasaki ◽  
Jian Zhu ◽  
Yun Shi ◽  
Weixi Gu ◽  
Bostjan Kobe ◽  
...  
Keyword(s):  
Nicotinic Acid ◽  
Neurodegenerative Disorders ◽  
Axon Degeneration ◽  
Biosynthetic Enzyme ◽  
Allosteric Site ◽  
Nicotinamide Mononucleotide ◽  
Bacterial Enzyme ◽  
Axon Loss ◽  
Metabolic Sensor

SARM1 is an inducible NAD+ hydrolase that is the central executioner of pathological axon loss. Recently, we elucidated the molecular mechanism of SARM1 activation, demonstrating that SARM1 is a metabolic sensor regulated by the levels of NAD+ and its precursor, nicotinamide mononucleotide (NMN), via their competitive binding to an allosteric site. In healthy neurons with abundant NAD+, binding of NAD+ blocks access of NMN to this allosteric site. However, with injury or disease the levels of the NAD+ biosynthetic enzyme NMNAT2 drop, increasing the NMN/NAD+ ratio and thereby promoting NMN binding to the SARM1 allosteric site, which in turn induces a conformational change activating the SARM1 NAD+ hydrolase. Hence, NAD+ metabolites both regulate the activation of SARM1 and, in turn, are regulated by the SARM1 NAD+ hydrolase. This dual upstream and downstream role for NAD+ metabolites in SARM1 function has hindered mechanistic understanding of axoprotective mechanisms that manipulate the NAD+ metabolome. Here we reevaluate two methods that potently block axon degeneration via modulation of NAD+ related metabolites, 1) the administration of the NMN biosynthesis inhibitor FK866 in conjunction with the NAD+ precursor nicotinic acid riboside (NaR) and 2) the neuronal expression of the bacterial enzyme NMN deamidase. We find that these approaches not only lead to a decrease in the levels of the SARM1 activator NMN, but also an increase in the levels of the NAD+ precursor nicotinic acid mononucleotide (NaMN). We show that NaMN competes with NMN for binding to the SARM1 allosteric site, that NaMN inhibits SARM1 activation, and that this NaMN-mediated inhibition is important for the long-term axon protection induced by these treatments. Together, these results demonstrate that the SARM1 allosteric pocket can bind a diverse set of metabolites including NMN, NAD+, and NaMN to monitor cellular NAD+ homeostasis and regulate SARM1 NAD+ hydrolase activity. The relative promiscuity of the allosteric site may enable the development of potent pharmacological inhibitors of SARM1 activation for the treatment of neurodegenerative disorders.

Analysis of the molecular mechanisms by flavonoids with potential use for osteoporosis prevention or therapy

2021 ◽  
Vol 28 ◽  
Author(s):  
Valeria Rodríguez ◽  
María Rivoira ◽  
Gabriela Picotto ◽  
Gabriela Díaz de Barboza ◽  
Alejandro Collin ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Osteoporosis Treatment ◽  
Epidemiological Studies ◽  
Common Mechanism ◽  
Osteoporotic Bone ◽  
Osteoporosis Prevention ◽  
Mineral Density ◽  
Pubmed Database ◽  
Molecular Aspects ◽  
Potential Use

Background: Osteoporosis is the most common skeletal disorder worldwide. Flavonoids have the potential to alleviate bone alterations in osteoporotic patients with the advantage of being safer and less expensive than the conventional therapies. Objective: The main objective is to analyze the molecular mechanisms triggered in bone by different subclasses of flavonoids. In addition, this review provides an up-to-date overview on the cellular and molecular aspects of osteoporotic bones versus healthy bones, and a brief description of some epidemiological studies indicating that flavonoids could be useful for osteoporosis treatment. Methods: The PubMed database was searched in the range of years 2001- 2021 using the keywords osteoporosis, flavonoids, and their subclasses such as flavones, flavonols, flavanols, isoflavones, flavanones and anthocyanins, focusing the data on the molecular mechanisms triggered in bone. Results: Although flavonoids comprise many compounds that differ in structure, their effects on bone loss in postmenopausal women or in ovariectomized-induced osteoporotic animals are quite similar. Most of them increase bone mineral density and bone strength, which occur through enhancement of osteoblastogenesis and osteoclast apoptosis, decrease in osteoclastogenesis as well as increase in neovascularization on the site of the osteoporotic fracture. Conclusion: Several molecules of signaling pathways are involved in the effect of flavonoids on osteoporotic bone. Whether all flavonoids have a common mechanism or they act as ligands of estrogen receptors remain to be established. More clinical trials are necessary to know better their safety, efficacy, delivery and bioavailability in humans, as well as comparative studies with conventional therapies.

scholarly journals Understanding the Effects of General Anesthetics on Cortical Network Activity Using Ex Vivo Preparations

2019 ◽  
Vol 130 (6) ◽  
pp. 1049-1063 ◽  
Author(s):  
Logan J. Voss ◽  
Paul S. García ◽  
Harald Hentschke ◽  
Matthew I. Banks
Keyword(s):  
Molecular Mechanisms ◽  
Ex Vivo ◽  
Brain Slices ◽  
Brain Regions ◽  
Cortical Network ◽  
Network Activity ◽  
Common Mechanism ◽  
General Anesthetics ◽  
Neural Basis

Abstract General anesthetics have been used to ablate consciousness during surgery for more than 150 yr. Despite significant advances in our understanding of their molecular-level pharmacologic effects, comparatively little is known about how anesthetics alter brain dynamics to cause unconsciousness. Consequently, while anesthesia practice is now routine and safe, there are many vagaries that remain unexplained. In this paper, the authors review the evidence that cortical network activity is particularly sensitive to general anesthetics, and suggest that disruption to communication in, and/or among, cortical brain regions is a common mechanism of anesthesia that ultimately produces loss of consciousness. The authors review data from acute brain slices and organotypic cultures showing that anesthetics with differing molecular mechanisms of action share in common the ability to impair neurophysiologic communication. While many questions remain, together, ex vivo and in vivo investigations suggest that a unified understanding of both clinical anesthesia and the neural basis of consciousness is attainable.

scholarly journals Cyclophilin a as a Mediator of Tissue Injure and Nephrotoxicity

2012 ◽  
Vol 4 (2) ◽  
pp. 42-44
Author(s):  
Grace Moscoso-Solorzano ◽  
Gianna Mastroianni-Kirsztajn
Keyword(s):  
Molecular Mechanisms ◽  
Tissue Injury ◽  
Cyclophilin A ◽  
Common Mechanism ◽  
Ppiase Activity ◽  
Expression Of Genes ◽  
Inflammatory Stimuli ◽  
Genes Encoding ◽  
Inflammatory Processes

Cyclophilin A (CypA) belongs to the peptidyl-prolil isomerase (PPlase) family of proteins and it is also known as the cellular receptor for cyclosporine A (CsA). CsA binds to CypA and inhibits the PPIase activity, but the CypA-CsA complex also binds to calcineurin that promotes the expression of genes encoding cytokines and other proteins required for immune response. In addition, the polymorphism variation of CypA promoter seems to have an influence on the expression of CypA in in vitro studies. CypA was also implicated in inflammatory processes (such as, among others, those observed in rheumatoid arthritis, atherosclerotic disease, nephrotoxicity) and it can be secreted by cells in response to inflammatory stimuli. CypA can also have a role in the molecular mechanisms by which CsA induces nephroxicity but these remain poorly understood. Recent studies suggest that CsA inhibition of CypA PPlase activity is a possible mechanism of this drug toxicity. In addition, CypA overexpression could be protective against CsA nephrotoxicity. Finally, the putative common mechanism by which CypA could be involved in CsA nephrotoxicity and tissue injury is related to its proinflammatory effects in cells.

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