The neurodynamic treatment induces biological changes in sensory and motor neurons in vitro

AbstractNerves are subjected to tensile forces in various paradigms such as injury and regeneration, joint movement, and rehabilitation treatments, as in the case of neurodynamic treatment (NDT). The NDT induces selective uniaxial repeated tension on the nerve and was described to be an effective treatment to reduce pain in patients. Nevertheless, the biological mechanisms activated by the NDT promoting the healing processes of the nerve are yet still unknown. Moreover, a dose–response analysis to define a standard protocol of treatment is unavailable. In this study, we aimed to define in vitro whether NDT protocols could induce selective biological effects on sensory and motor neurons, also investigating the possible involved molecular mechanisms taking a role behind this change. The obtained results demonstrate that NDT induced significant dose-dependent changes promoting cell differentiation, neurite outgrowth, and neuron survival, especially in nociceptive neurons. Notably, NDT significantly upregulated PIEZO1 gene expression. A gene that is coding for an ion channel that is expressed both in murine and human sensory neurons and is related to mechanical stimuli transduction and pain suppression. Other genes involved in mechanical allodynia related to neuroinflammation were not modified by NDT. The results of the present study contribute to increase the knowledge behind the biological mechanisms activated in response to NDT and to understand its efficacy in improving nerve regenerational physiological processes and pain reduction.

Download Full-text

Crocetin Mitigates Irradiation Injury in an In Vitro Model of the Pubertal Testis: Focus on Biological Effects and Molecular Mechanisms

Molecules ◽

10.3390/molecules26061676 ◽

2021 ◽

Vol 26 (6) ◽

pp. 1676

Author(s):

Giulia Rossi ◽

Martina Placidi ◽

Chiara Castellini ◽

Francesco Rea ◽

Settimio D'Andrea ◽

...

Keyword(s):

In Vitro Model ◽

Molecular Mechanisms ◽

Biological Effects ◽

Cellular Damage ◽

X Rays ◽

Adolescent Cancer ◽

Radiation Induced ◽

Vitro Model ◽

Underlying Mechanisms

Infertility is a potential side effect of radiotherapy and significantly affects the quality of life for adolescent cancer survivors. Very few studies have addressed in pubertal models the mechanistic events that could be targeted to provide protection from gonadotoxicity and data on potential radioprotective treatments in this peculiar period of life are elusive. In this study, we utilized an in vitro model of the mouse pubertal testis to investigate the efficacy of crocetin to counteract ionizing radiation (IR)-induced injury and potential underlying mechanisms. Present experiments provide evidence that exposure of testis fragments from pubertal mice to 2 Gy X-rays induced extensive structural and cellular damage associated with overexpression of PARP1, PCNA, SOD2 and HuR and decreased levels of SIRT1 and catalase. A twenty-four hr exposure to 50 μM crocetin pre- and post-IR significantly reduced testis injury and modulated the response to DNA damage and oxidative stress. Nevertheless, crocetin treatment did not counteract the radiation-induced changes in the expression of SIRT1, p62 and LC3II. These results increase the knowledge of mechanisms underlying radiation damage in pubertal testis and establish the use of crocetin as a fertoprotective agent against IR deleterious effects in pubertal period.

Download Full-text

The LPA-CDK5-Tau Pathway Mediates Neuronal Injury in an In Vitro Model of Ischemia-Reperfusion Insult

10.21203/rs.3.rs-685165/v1 ◽

2021 ◽

Author(s):

Yaya Wang ◽

Jie Zhang ◽

Liqin Huang ◽

Yanhong Mo ◽

Changyu Wang ◽

...

Keyword(s):

Brain Injury ◽

Molecular Mechanisms ◽

Biological Effects ◽

Ischemia Reperfusion ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Ischemic Brain ◽

Pathophysiological Process ◽

Vitro Model

Abstract Lysophosphatidic acid (LPA) is a common glycerol phospholipid and an important extracellular signaling molecule. LPA binds to its receptors and mediates a variety of biological effects, including the pathophysiological process underlying ischemic brain damage and traumatic brain injury. However, the molecular mechanisms mediating the pathological role of LPA are not clear. Here, we found that LPA activates cyclin-dependent kinase 5 (CDK5). CDK5 phosphorylates tau, which leads to neuronal cell death. Inhibition of LPA production or blocking its receptors reduced the abnormal activation of CDK5 and phosphorylation of tau, thus reversing the death of neurons. Our data indicate that the LPA-CDK5-Tau pathway plays an important role in the pathophysiological process after ischemic stroke. Inhibiting the LPA pathway may be a potential therapeutic target for treating ischemic brain injury.

Download Full-text

Antioxidant, Anti-Inflammatory and Anti-Angiogenic Properties of Citrus lumia Juice

Frontiers in Pharmacology ◽

10.3389/fphar.2020.593506 ◽

2020 ◽

Vol 11 ◽

Author(s):

Antonella Smeriglio ◽

Marcella Denaro ◽

Valeria D’Angelo ◽

Maria Paola Germanò ◽

Domenico Trombetta

Keyword(s):

Ascorbic Acid ◽

Acid Content ◽

Molecular Mechanisms ◽

Biological Effects ◽

Ascorbic Acid Content ◽

Zebrafish Embryos ◽

Anti Inflammatory ◽

Dose Dependent

Citrus juices are a rich source of bioactive compounds with various and well-known health benefits. The aim of this study was to investigate the polyphenols and ascorbic acid content as well as to investigate the antioxidant, anti-inflammatory and anti-angiogenic properties of the juice of an ancient Mediterranean species, Citrus lumia Risso (CLJ). The antioxidant and anti-inflammatory activities were evaluated by several in vitro cell-free and cell-based assays, whereas two different in vivo models, the chick chorioallantoic membrane (CAM) and the zebrafish embryos, were used to characterize the anti-angiogenic properties. Twenty-eight polyphenols were identified by RP-LC-DAD-ESI-MS analysis (flavonoids 68.82% and phenolic acids 31.18%) with 1-caffeoyl-5-feruloylquinic acid and kaempferol 3′-rhamnoside, which represent the most abundant compounds (25.70 and 23.12%, respectively). HPLC-DAD analysis showed a high ascorbic acid content (352 mg/kg of CLJ), which contributes with polyphenols to the marked and dose-dependent antioxidant and anti-inflammatory properties observed. CLJ showed strong and dose-dependent anti-angiogenic activity as highlighted by the inhibition of blood vessel formation on CAMs and the decrease of endogenous alkaline phosphatase on zebrafish embryos. Moreover, within the concentration range tested, no dead or malformed embryos were recorded. Certainly, further studies are needed to investigate the molecular mechanisms underlying these promising biological effects, but considering the evidence of the present study, the use of CLJ as a ready-to drink safe prevention strategy for inflammatory-based diseases correlated to angiogenesis could be justified.

Download Full-text

Pleiotropic Biological Effects of Dietary Phenolic Compounds and their Metabolites on Energy Metabolism, Inflammation and Aging

Molecules ◽

10.3390/molecules25030596 ◽

2020 ◽

Vol 25 (3) ◽

pp. 596 ◽

Cited By ~ 3

Author(s):

María del Carmen Villegas-Aguilar ◽

Álvaro Fernández-Ochoa ◽

María de la Luz Cádiz-Gurrea ◽

Sandra Pimentel-Moral ◽

Jesús Lozano-Sánchez ◽

...

Keyword(s):

Energy Metabolism ◽

Phenolic Compounds ◽

Molecular Mechanisms ◽

Biological Effects ◽

Biological Properties ◽

In Vivo Studies ◽

Wide Range ◽

High Prevalence

Dietary phenolic compounds are considered as bioactive compounds that have effects in different chronic disorders related to oxidative stress, inflammation process, or aging. These compounds, coming from a wide range of natural sources, have shown a pleiotropic behavior on key proteins that act as regulators. In this sense, this review aims to compile information on the effect exerted by the phenolic compounds and their metabolites on the main metabolic pathways involved in energy metabolism, inflammatory response, aging and their relationship with the biological properties reported in high prevalence chronic diseases. Numerous in vitro and in vivo studies have demonstrated their pleiotropic molecular mechanisms of action and these findings raise the possibility that phenolic compounds have a wide variety of roles in different targets.

Download Full-text

ESR1 Mutations Associated With Estrogen Insensitivity Syndrome Change Conformation of Ligand-Receptor Complex and Altered Transcriptome Profile

Endocrinology ◽

10.1210/endocr/bqaa050 ◽

2020 ◽

Vol 161 (6) ◽

Cited By ~ 1

Author(s):

Yin Li ◽

Katherine J Hamilton ◽

Lalith Perera ◽

Tianyuan Wang ◽

Artiom Gruzdev ◽

...

Keyword(s):

Molecular Mechanisms ◽

Reproductive Tract ◽

Biological Effects ◽

Estrogen Receptor Α ◽

Female Reproductive Tract ◽

Receptor Complexes ◽

Esr1 Gene ◽

Esr1 Mutations

Abstract Estrogen insensitivity syndrome (EIS) arises from rare mutations in estrogen receptor-α (ERα, encoded by ESR1 gene) resulting in the inability of estrogen to exert its biological effects. Due to its rarity, mutations in ESR1 gene and the underlying molecular mechanisms of EIS have not been thoroughly studied. Here, we investigate known ESR1 mutants, Q375H and R394H, associated with EIS patients using in vitro and in vivo systems. Comparison of the transcriptome and deoxyribonucleic acid methylome from stable cell lines of both Q375H and R394H clinical mutants shows a differential profile compared with wild-type ERα, resulting in loss of estrogen responsiveness. Molecular dynamic simulation shows that both ESR1 mutations change the ERα conformation of the ligand-receptor complexes. Furthermore, we generated a mouse model Esr1-Q harboring the human mutation using CRISPR/Cas9 genome editing. Female and male Esr1-Q mice are infertile and have similar phenotypes to αERKO mice. Overall phenotypes of the Esr1-Q mice correspond to those observed in the patient with Q375H. Finally, we explore the effects of a synthetic progestogen and a gonadotropin-releasing hormone inhibitor in the Esr1-Q mice for potentially reversing the impaired female reproductive tract function. These findings provide an important basis for understanding the molecular mechanistic consequences associated with EIS.

Download Full-text

Rare loss-of-function mutations of PTGIR are enriched in fibromuscular dysplasia

Cardiovascular Research ◽

10.1093/cvr/cvaa161 ◽

2020 ◽

Cited By ~ 1

Author(s):

Adrien Georges ◽

Juliette Albuisson ◽

Takiy Berrandou ◽

Délia Dupré ◽

Aurélien Lorthioir ◽

...

Keyword(s):

Molecular Mechanisms ◽

Fibromuscular Dysplasia ◽

Biological Effects ◽

Receptor Gene ◽

Artery Dissection ◽

Loss Of Function ◽

Coronary Artery Dissection ◽

Atherosclerotic Stenosis ◽

Significant Enrichment

Abstract Aims Fibromuscular dysplasia (FMD) and spontaneous coronary artery dissection (SCAD) are related, non-atherosclerotic arterial diseases mainly affecting middle-aged women. Little is known about their physiopathological mechanisms. We aimed to identify rare genetic causes to elucidate molecular mechanisms implicated in FMD and SCAD. Methods and results We analysed 29 exomes that included familial and sporadic FMD. We identified one rare loss-of-function variant (LoF) (frequencygnomAD = 0.000075) shared by two FMD sisters in the prostaglandin I2 receptor gene (PTGIR), a key player in vascular remodelling. Follow-up was conducted by targeted or Sanger sequencing (1071 FMD and 363 SCAD patients) or lookups in exome (264 FMD) or genome sequences (480 SCAD), all independent and unrelated. It revealed four additional LoF allele carriers, in addition to several rare missense variants, among FMD patients, and two LoF allele carriers among SCAD patients, including one carrying a rare splicing mutation (c.768 + 1C>G). We used burden test to test for enrichment in patients compared to gnomAD controls, which detected a putative enrichment in FMD (PTRAPD = 8 × 10−4), but not a significant enrichment (PTRAPD = 0.12) in SCAD. The biological effects of variants on human prostaclycin receptor (hIP) signalling and protein expression were characterized using transient overexpression in human cells. We confirmed the LoFs (Q163X and P17RfsX6) and one missense (L67P), identified in one FMD and one SCAD patient, to severely impair hIP function in vitro. Conclusions Our study shows that rare genetic mutations in PTGIR are enriched among FMD patients and found in SCAD patients, suggesting a role for prostacyclin signalling in non-atherosclerotic stenosis and dissection.

Download Full-text

Synergistic integration of Netrin and ephrin axon guidance signals by spinal motor neurons

eLife ◽

10.7554/elife.10841 ◽

2015 ◽

Vol 4 ◽

Cited By ~ 36

Author(s):

Sebastian Poliak ◽

Daniel Morales ◽

Louis-Philippe Croteau ◽

Dayana Krawchuk ◽

Elena Palmesino ◽

...

Keyword(s):

Motor Neurons ◽

Molecular Mechanisms ◽

Neural Circuit ◽

Growth Cones ◽

In Vitro Assays ◽

Dependent Manner ◽

Motor Axons ◽

Spinal Motor Neurons ◽

Spinal Motor

During neural circuit assembly, axonal growth cones are exposed to multiple guidance signals at trajectory choice points. While axonal responses to individual guidance cues have been extensively studied, less is known about responses to combination of signals and underlying molecular mechanisms. Here, we studied the convergence of signals directing trajectory selection of spinal motor axons entering the limb. We first demonstrate that Netrin-1 attracts and repels distinct motor axon populations, according to their expression of Netrin receptors. Quantitative in vitro assays demonstrate that motor axons synergistically integrate both attractive or repulsive Netrin-1 signals together with repulsive ephrin signals. Our investigations of the mechanism of ephrin-B2 and Netrin-1 integration demonstrate that the Netrin receptor Unc5c and the ephrin receptor EphB2 can form a complex in a ligand-dependent manner and that Netrin–ephrin synergistic growth cones responses involve the potentiation of Src family kinase signaling, a common effector of both pathways.

Download Full-text

Cell-type specific in vitro gene expression profiling of stem-cell derived neural models

10.1101/2020.04.30.064709 ◽

2020 ◽

Author(s):

James A. Gregory ◽

Emily Hoelzli ◽

Rawan Abdelaal ◽

Catherine Braine ◽

Miguel Cuevas ◽

...

Keyword(s):

Stem Cell ◽

Motor Neurons ◽

Molecular Mechanisms ◽

Induced Pluripotent Stem Cell ◽

Underlying Disease ◽

Mouse Tissue ◽

Cell Type ◽

Primary Mouse ◽

Cell Type Specific

AbstractGenetic and genomic studies of brain disease increasingly demonstrate disease-associated interactions between the cell types of the brain. Increasingly complex and more physiologically relevant human induced pluripotent stem cell (hiPSC)-based models better explore the molecular mechanisms underlying disease, but also challenge our ability to resolve cell-type specific perturbations. Here we report an extension of the RiboTag system, first developed to achieve cell-type restricted expression of epitope-tagged ribosomal protein (RPL22) in mouse tissue, to a variety of in vitro applications, including immortalized cell lines, primary mouse astrocytes, and hiPSC-derived neurons. RiboTag expression enables efficient depletion of off-target RNA in mixed species primary co-cultures and in hiPSC-derived neural progenitor cells, motor neurons, and GABAergic neurons. Nonetheless, depletion efficiency varies across independent experimental replicates. The challenges and potential of implementing RiboTags in complex in vitro cultures are discussed.

Download Full-text

Rutin as Neuroprotective Agent: From Bench to Bedside

Current Medicinal Chemistry ◽

10.2174/0929867324666171003114154 ◽

2019 ◽

Vol 26 (27) ◽

pp. 5152-5164 ◽

Cited By ~ 10

Author(s):

Barbara Budzynska ◽

Caterina Faggio ◽

Marta Kruk-Slomka ◽

Dunja Samec ◽

Seyed Fazel Nabavi ◽

...

Keyword(s):

Disease Burden ◽

Molecular Mechanisms ◽

Biological Effects ◽

Neuroprotective Effects ◽

Brain Functions ◽

High Prevalence ◽

Biological Effectiveness ◽

In Vivo Effects

Flavonoids are major dietary constituents of plant-based food found ubiquitously in plant kingdom where they are usually present in substantial amounts. Rutin is a flavonol-type polyphenol which consists of the flavonol quercetin and the disaccharide rutinose. Rutin has been reported to exert diverse biological effects such as antitumor and antimicrobial mainly associated to its antioxidant and anti-inflammatory activities. Mental, neurological, and behavioural disorders are an important and growing cause of morbidity. Most of these disorders combine a high prevalence, early onset, progressive clinical course, and impairment of critical brain functions making them a major contributor to the global disease burden. In the present work, the biological in vitro and in vivo effects and the potential therapeutic applications of rutin in neurodegenerative processes are reviewed, as well as their bioavailability and pharmacokinetics, which are essential for a better understanding of its biological effectiveness. Moreover, the present review also provides an overview of the molecular mechanisms through which rutin is proposed to exert its neuroprotective effects.

Download Full-text

An Appraisal of Current Pharmacological Perspectives of Sesamol: A Review

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557520666200313120419 ◽

2020 ◽

Vol 20 (11) ◽

pp. 988-1000 ◽

Cited By ~ 1

Author(s):

Bellamkonda Bosebabu ◽

Sri Pragnya Cheruku ◽

Mallikarjuna Rao Chamallamudi ◽

Madhavan Nampoothiri ◽

Rekha R. Shenoy ◽

...

Keyword(s):

Molecular Mechanisms ◽

Biological Effects ◽

Hepatoprotective Activity ◽

In Vivo Studies ◽

Therapeutic Effects ◽

Pharmacological Effects ◽

Bioactive Constituents ◽

Anti Inflammatory

Sesame (Sesamum indicum L.) seeds have been authenticated for its medicinal value in both Chinese and Indian systems of medicine. Its numerous potential nutritional benefits are attributed to its main bioactive constituents, sesamol. As a result of those studies, several molecular mechanisms are emerging describing the pleiotropic biological effects of sesamol. This review summarized the most interesting in vitro and in vivo studies on the biological effects of sesamol. The present work summarises data available from Pubmed and Scopus database. Several molecular mechanisms have been elucidated describing the pleiotropic biological effects of sesamol. Its major therapeutic effects have been elicited in managing oxidative and inflammatory conditions, metabolic syndrome and mood disorders. Further, compelling evidence reflected the ability of sesamol in inhibiting proliferation of the inflammatory cell, prevention of invasion and angiogenesis via affecting multiple molecular targets and downstream mechanisms. Sesamol is a safe, non‐toxic chemical that mediates anti‐inflammatory effects by down‐regulating the transcription of inflammatory markers such as cytokines, redox status, protein kinases, and enzymes that promote inflammation. In addition, sesamol also induces apoptosis in cancer cells via mitochondrial and receptor‐mediated pathways, as well as activation of caspase cascades. In the present review, several pharmacological effects of sesamol are summarised namely, antioxidant, anti-cancer, neuroprotective, cardioprotective, anti-inflammatory, hypolipidemic, radioprotective, anti-aging, anti-ulcer, anti-dementia, anti-depressant, antiplatelet, anticonvulsant, anti-anxiolytic, wound healing, cosmetic (skin whitening), anti-microbial, matrix metalloproteinase (MMPs) inhibition, hepatoprotective activity and other biological effects. Here we have summarized the proposed mechanism behind these pharmacological effects.

Download Full-text