E-learning platforms support education systems worldwide, transferring theoretical knowledge as well as soft skills. In the present study high-school pupils’, and adult students’ opinions were evaluated through a mo...E-learning platforms support education systems worldwide, transferring theoretical knowledge as well as soft skills. In the present study high-school pupils’, and adult students’ opinions were evaluated through a modern structured MOODLE interactive course, designed for the needs of the laboratory course “Automotive Systems”. The study concerns Greek secondary vocational education pupils aged 18 and vocational training adult students aged 20 to 50 years. The multistage, equal size simple random cluster sample was used as a sampling method. Pupils and adult students of each cluster completed structured 10-question questionnaires both before and after attending the course. A total of 120 questionnaires were collected. In general, our findings disclosed that the majority of pupils and adult students had significantly improved their knowledge and skills from using MOODLE. They reported strengthening conventional teaching, using the new MOODLE technology. The satisfaction indices improved quite, with the differences in their mean values being statistically significant.展开更多
Purpose: Cotard’s syndrome, Alice in Wonderland Syndrome, and Catatonia are all rare psychiatric disorders that have relatively little research regarding their treatments. The aim of this article is to highlight any ...Purpose: Cotard’s syndrome, Alice in Wonderland Syndrome, and Catatonia are all rare psychiatric disorders that have relatively little research regarding their treatments. The aim of this article is to highlight any gaps in knowledge regarding represented demographics in these treatment studies, and to discuss the current and upcoming treatment options. Background: This literature review explores under-researched psychiatric conditions: Cotard’s syndrome, Alice in Wonderland syndrome, and Catatonic Schizophrenia. Understanding psychiatric disorders requires basic knowledge of brain anatomy. These conditions are often result of or associated with neurological issues, such as migraines or tumors. The brain has eight lobes, two of four kinds: frontal, parietal, occipital, and temporal lobes, which all govern different functions and abilities. Frontal lobes control judgment, decision-making, personality traits, and fine motor movements. Parietal lobes interpret pain and temperature, occipital lobes handle visual stimuli, and temporal lobes enable hearing. The pre-frontal cortex is associated with high intelligence, psychotic traits, and psychosis. The Broca’s Area in the frontal lobes controls expressive language. These areas and divisions of the brain contribute to the complexity of the psychiatric disorders discussed in this review. Introduction: Cotard’s syndrome is a psychiatric disorder characterized by delusions of being dead or not having certain limbs or organs. It is believed that there is a disconnect between their fusiform face area and the amygdala, causing a lack of familiarity between one’s mind and body. Alice in Wonderland Syndrome (AIWS) is another psychiatric disorder which is characterized by visual hallucinations, such as distorted perceptions of color, size, distance, and speed. The most common symptoms include micropsia and macropsia. Catatonia/Catatonic Schizophrenia is an uncommon type of schizophrenia. This type of schizophrenia is characterized by motor rigidity, verbal rigidity, the flat effect, psychomotor retardation, waxy flexibility, and overall negative symptoms. Thus, these people may come off as emotionally detached, and able to stay frozen in odd positions for periods on end. Treatments and Results: Cotard’s syndrome seemed to be most effectively treated by ECT (electroconvulsive therapy). Alice in Wonderland Syndrome (AIWS) had the highest positive responses to treatment by Valproate (an anti-epileptic drug), as well as intervention to treat the associated neurological conditions they had. Catatonia/Catatonic Schizophrenia seemed to be most effectively treated with a combination of benzodiazepines and ECT. Discussion and Demographics: In all 3 disorders, the Latino and African communities were underrepresented. There also seemed to be an underrepresentation of men in Cotard’s syndrome, and of women in Alice in Wonderland Syndrome. Japan and India seemed to have the highest density of treatment studies in all 3 disorders.展开更多
Diseases like Alzheimer’s and Parkinson’s diseases are defined by inflammation and the damage neurons undergo due to oxidative stress. A primary reactive oxygen species contributor in the central nervous system, NAD...Diseases like Alzheimer’s and Parkinson’s diseases are defined by inflammation and the damage neurons undergo due to oxidative stress. A primary reactive oxygen species contributor in the central nervous system, NADPH oxidase 4, is viewed as a potential therapeutic touchstone and indicative marker for these ailments. This in-depth review brings to light distinct features of NADPH oxidase 4, responsible for generating superoxide and hydrogen peroxide, emphasizing its pivotal role in activating glial cells, inciting inflammation, and disturbing neuronal functions. Significantly, malfunctioning astrocytes, forming the majority in the central nervous system, play a part in advancing neurodegenerative diseases, due to their reactive oxygen species and inflammatory factor secretion. Our study reveals that aiming at NADPH oxidase 4 within astrocytes could be a viable treatment pathway to reduce oxidative damage and halt neurodegenerative processes. Adjusting NADPH oxidase 4 activity might influence the neuroinflammatory cytokine levels, including myeloperoxidase and osteopontin, offering better prospects for conditions like Alzheimer’s disease and Parkinson’s disease. This review sheds light on the role of NADPH oxidase 4 in neural degeneration, emphasizing its drug target potential, and paving the path for novel treatment approaches to combat these severe conditions.展开更多
To investigate whether the expression of exogenous heme oxygenase-1 (HO-1) gene within vascular smooth muscle cells (VSMC) could protect the cells from free radical attack and inhibit cell proliferation, we establishe...To investigate whether the expression of exogenous heme oxygenase-1 (HO-1) gene within vascular smooth muscle cells (VSMC) could protect the cells from free radical attack and inhibit cell proliferation, we established an in vitro transfection of human HO-1 gene into rat VSMC mediated by a retroviral vector. The results showed that the profound expression of HO-1 protein as well as HO activity was 1.8- and 2.0-fold increased respectively in the transfected cells compared to the non-transfected ones. The treatment of VSMC with different concentrations of H2O2 led to the remarkable cell damage as indicated by survival rate and LDH leakage. However, the resistance of the HO-1 transfected VSMC against H2O2 was significantly raised. This protective effect was dramatically diminished when the transfected VSMC were pretreated with ZnPP-IX, a specific inhibitor of HO, for 24 h. In addition, we found that the growth potential of the transfected cells was significantly inhibited directly by increased activity of HO-1, and this effect might be related to decreased phosphorylation of MAPK. These results suggest that the overexpression of introduced hHO-1 is potentially able to reduce the risk factors of atherosclerosis, partially due to its cellular protection against oxidative injury and to its inhibitory effect on cellular proliferation.展开更多
Parkinson’s Disease (PD) is a neurodegenerative disorder characterized by motor and non-motor symptoms, including cognitive impairment. Current treatments often involve synthetic drugs with significant side effects a...Parkinson’s Disease (PD) is a neurodegenerative disorder characterized by motor and non-motor symptoms, including cognitive impairment. Current treatments often involve synthetic drugs with significant side effects and potential for dependency. This study investigates the effects of a natural supplement combination of Ginkgo Biloba and Acai Extract on cognitive symptoms in a 77-year-old male with PD. The participant underwent a three-month supplementation regimen, with cognitive function assessed using the Montreal Cognitive Assessment (MoCA) test before and after the intervention. The results indicated an improvement in cognitive scores, suggesting that the combination of Ginkgo Biloba and Acai Extract may offer a promising alternative or adjunct to conventional PD treatments. This study highlights the potential of natural supplements in managing PD symptoms and calls for further research with larger sample sizes to confirm these findings. Human data was performed in accordance with the Declaration of Helsinki by the Roxbury District IRB Board (IRB Number: IRB00011767).展开更多
This article explores the dead universe theory as a novel interpretation for the origin and evolution of the universe, suggesting that our cosmos may have originated from the remnants of a preceding universe. This per...This article explores the dead universe theory as a novel interpretation for the origin and evolution of the universe, suggesting that our cosmos may have originated from the remnants of a preceding universe. This perspective challenges the conventional Big Bang theory, particularly concerning dark matter, the expansion of the universe, and the interpretation of phenomena such as gravitational waves.展开更多
Since the inaugural international collaboration under the framework of the Collaboratory for the Study of Earthquake Predictability(CSEP)in 2007,numerous forecast models have been developed and operated for earthquake...Since the inaugural international collaboration under the framework of the Collaboratory for the Study of Earthquake Predictability(CSEP)in 2007,numerous forecast models have been developed and operated for earthquake forecasting experiments across CSEP testing centers(Schorlemmer et al.,2018).Over more than a decade,efforts to compare forecasts with observed earthquakes using numerous statistical test methods and insights into earthquake predictability,which have become a highlight of the CSEP platform.展开更多
Exosomes are cup-shaped extracellular vesicles with a lipid bilayer that is approximately 30 to 200 nm in thickness.Exosomes are widely distributed in a range of body fluids,including urine,blood,milk,and saliva.Exoso...Exosomes are cup-shaped extracellular vesicles with a lipid bilayer that is approximately 30 to 200 nm in thickness.Exosomes are widely distributed in a range of body fluids,including urine,blood,milk,and saliva.Exosomes exert biological function by transporting factors between different cells and by regulating biological pathways in recipient cells.As an important form of intercellular communication,exosomes are increasingly being investigated due to their ability to transfer bioactive molecules such as lipids,proteins,mRNAs,and microRNAs between cells,and because they can regulate physiological and pathological processes in the central nervous system.Adult neurogenesis is a multistage process by which new neurons are generated and migrate to be integrated into existing neuronal circuits.In the adult brain,neurogenesis is mainly localized in two specialized niches:the subventricular zone adjacent to the lateral ventricles and the subgranular zone of the dentate gyrus.An increasing body of evidence indicates that adult neurogenesis is tightly controlled by environmental conditions with the niches.In recent studies,exosomes released from different sources of cells were shown to play an active role in regulating neurogenesis both in vitro and in vivo,thereby participating in the progression of neurodegenerative disorders in patients and in various disease models.Here,we provide a state-of-the-art synopsis of existing research that aimed to identify the diverse components of exosome cargoes and elucidate the therapeutic potential of exosomal contents in the regulation of neurogenesis in several neurodegenerative diseases.We emphasize that exosomal cargoes could serve as a potential biomarker to monitor functional neurogenesis in adults.In addition,exosomes can also be considered as a novel therapeutic approach to treat various neurodegenerative disorders by improving endogenous neurogenesis to mitigate neuronal loss in the central nervous system.展开更多
Background: Loose bodies (LBs) within the knee joint are commonly encountered during clinical practice and are frequently observed during knee arthroscopy. The primary treatment involves the removal of loose bodies;ho...Background: Loose bodies (LBs) within the knee joint are commonly encountered during clinical practice and are frequently observed during knee arthroscopy. The primary treatment involves the removal of loose bodies;however, their complete eradication is often challenging and may not address underlying diseases, leading to persistent symptoms and the risk of new loose body formation. Aim: This case report aims to present the findings and surgical management of a 52-year-old male with an unusually large osseous loose body in the knee joint and associated pathologies. Case Presentation: The patient, a 52-year-old male, experienced recurrent episodes of severe, sudden, and painful locking of the knee joint, leading to difficulties moving. A plain MRI study was conducted to evaluate the condition of the knee joint, which revealed various degenerative changes and the presence of a loose body. Subsequently, an arthroscopic examination was performed under general anesthesia, uncovering the presence of an abnormally large loose body, as well as other pathologies including chondropathy, meniscal degeneration, and Baker’s cyst. Conclusion: Loose bodies (LBs) in the knee joint pose significant challenges and may lead to debilitating symptoms. Timely diagnosis and appropriate surgical intervention are crucial for symptom relief and the prevention of further joint damage as arthroscopic excision. Comprehensive imaging has a vital role in guiding treatment decisions and optimizing patient outcomes. In this case, the removal of the loose body improved patient outcomes and helped prevent potential joint complications.展开更多
Huntington’s disease is a neurodegenerative disease caused by the expansion mutation of a cytosine-adenine-guanine triplet in the exon 1 of the HTT gene which is responsible for the production of the huntingtin (Htt)...Huntington’s disease is a neurodegenerative disease caused by the expansion mutation of a cytosine-adenine-guanine triplet in the exon 1 of the HTT gene which is responsible for the production of the huntingtin (Htt) protein. In physiological conditions, Htt is involved in many cellular processes such as cell signaling, transcriptional regulation, energy metabolism regulation, DNA maintenance, axonal trafficking, and antiapoptotic activity. When the genetic alteration is present, the production of a mutant version of Htt (mHtt) occurs, which is characterized by a plethora of pathogenic activities that, finally, lead to cell death. Among all the cells in which mHtt exerts its dangerous activity, the GABAergic Medium Spiny Neurons seem to be the most affected by the mHtt-induced excitotoxicity both in the cortex and in the striatum. However, as the neurodegeneration proceeds ahead the neuronal loss grows also in other brain areas such as the cerebellum, hypothalamus, thalamus, subthalamic nucleus, globus pallidus, and substantia nigra, determining the variety of symptoms that characterize Huntington’s disease. From a clinical point of view, Huntington’s disease is characterized by a wide spectrum of symptoms spanning from motor impairment to cognitive disorders and dementia. Huntington’s disease shows a prevalence of around 3.92 cases every 100,000 worldwide and an incidence of 0.48 new cases every 100,000/year. To date, there is no available cure for Huntington’s disease. Several treatments have been developed so far, aiming to reduce the severity of one or more symptoms to slow down the inexorable decline caused by the disease. In this context, the search for reliable strategies to target the different aspects of Huntington’s disease become of the utmost interest. In recent years, a variety of studies demonstrated the detrimental role of neuronal loss in Huntington’s disease condition highlighting how the replacement of lost cells would be a reasonable strategy to overcome the neurodegeneration. In this view, numerous have been the attempts in several preclinical models of Huntington’s disease to evaluate the feasibility of invasive and non-invasive approaches. Thus, the aim of this review is to offer an overview of the most appealing approaches spanning from stem cell-based cell therapy to extracellular vesicles such as exosomes in light of promoting neurogenesis, discussing the results obtained so far, their limits and the future perspectives regarding the neural regeneration in the context of Huntington’s disease.展开更多
α-Synuclein is a protein that mainly exists in the presynaptic terminals.Abnormal folding and accumulation of α-synuclein are found in several neurodegenerative diseases,including Parkinson’s disease.Aggregated and...α-Synuclein is a protein that mainly exists in the presynaptic terminals.Abnormal folding and accumulation of α-synuclein are found in several neurodegenerative diseases,including Parkinson’s disease.Aggregated and highly phospho rylated a-synuclein constitutes the main component of Lewy bodies in the brain,the pathological hallmark of Parkinson s disease.For decades,much attention has been focused on the accumulation of α-synuclein in the brain parenchyma rather than considering Parkinson s disease as a systemic disease.Recent evidence demonstrates that,at least in some patients,the initial α-synuclein pathology originates in the peripheral organs and spreads to the brain.Injection of α-synuclein preformed fibrils into the gastrointestinal tra ct trigge rs the gutto-brain propagation of α-synuclein pathology.However,whether α-synuclein pathology can occur spontaneously in peripheral organs independent of exogenous α-synuclein preformed fibrils or pathological α-synuclein leakage from the central nervous system remains under investigation.In this review,we aimed to summarize the role of peripheral α-synuclein pathology in the pathogenesis of Parkinson’s disease.We also discuss the pathways by which α-synuclein pathology spreads from the body to the brain.展开更多
Polysurfacic tori or kideas are three-dimensional objects formed by rotating a regular polygon around a central axis. These toric shapes are referred to as “polysurfacic” because their characteristics, such as the n...Polysurfacic tori or kideas are three-dimensional objects formed by rotating a regular polygon around a central axis. These toric shapes are referred to as “polysurfacic” because their characteristics, such as the number of sides or surfaces separated by edges, can vary in a non-trivial manner depending on the degree of twisting during the revolution. We use the term “Kideas” to specifically denote these polysurfacic tori, and we represent the number of sides (referred to as “facets”) of the original polygon followed by a point, while the number of facets from which the torus is twisted during its revolution is indicated. We then explore the use of concave regular polygons to generate Kideas. We finally give acceleration for the algorithm for calculating the set of prime numbers.展开更多
Beginning with a 5D homogeneous universe [1], we have provided a plausible explanation of the self-rotation phenomenon of stellar objects previously with illustration of large number of star samples [2], via a 5D-4D p...Beginning with a 5D homogeneous universe [1], we have provided a plausible explanation of the self-rotation phenomenon of stellar objects previously with illustration of large number of star samples [2], via a 5D-4D projection. The origin of such rotation is the balance of the angular momenta of stars and that of positive and negative charged e-trino pairs, within a 3D ⊗1D?void of the stellar object, the existence of which is based on conservation/parity laws in physics if one starts with homogeneous 5D universe. While the in-phase e-trino pairs are proposed to be responsible for the generation of angular momentum, the anti-phase but oppositely charge pairs necessarily produce currents. In the 5D to 4D projection, one space variable in the 5D manifold was compacted to zero in most other 5D theories (including theories of Kaluza-Klein and Einstein [3] [4]). We have demonstrated, using the Fermat’s Last Theorem [5], that for validity of gauge invariance at the 4D-5D boundary, the 4th space variable in the 5D manifold is mapped into two current rings at both magnetic poles as required by Perelman entropy mapping;these loops are the origin of the dipolar magnetic field. One conclusion we draw is that there is no gravitational singularity, and hence no black holes in the universe, a result strongly supported by the recent discovery of many stars with masses well greater than 100 solar mass [6] [7] [8], without trace of phenomena observed (such as strong gamma and X ray emissions), which are supposed to be associated with black holes. We analyze the properties of such loop currents on the 4D-5D boundary, where Maxwell equations are valid. We derive explicit expressions for the dipolar fields over the whole temperature range. We then compare our prediction with measured surface magnetic fields of many stars. Since there is coupling in distribution between the in-phase and anti-phase pairs of e-trinos, the generated mag-netic field is directly related to the angular momentum, leading to the result that the magnetic field can be expressible in terms of only the mechanical variables (mass M, radius R, rotation period P)of a star, as if Maxwell equations are “hidden”. An explanation for the occurrence of this “un-expected result” is provided in Section (7.6). Therefore we provide satisfactory answers to a number of “mysteries” of magnetism in astrophysics such as the “Magnetic Bode’s Relation/Law” [9] and the experimental finding that B-P graph in the log-log plot is linear. Moreover, we have developed a new method for studying the relations among the data (M, R, P) during stellar evolution. Ten groups of stellar objects, effectively over 2000 samples are used in various parts of the analysis. We also explain the emergence of huge magnetic field in very old stars like White Dwarfs in terms of formation of 2D Semion state on stellar surface and release of magnetic flux as magnetic storms upon changing the 2D state back to 3D structure. Moreover, we provide an explanation, on the ground of the 5D theory, for the detection of extremely weak fields in Venus and Mars and the asymmetric distribution of magnetic field on the Martian surface. We predict the equatorial fields B of the newly discovered Trappist-1 star and the 6 nearest planets. The log B?−?log P graph for the 6 planets is linear and they satisfy the Magnetic Bode’s relation. Based on the above analysis, we have discovered several new laws of stellar magnetism, which are summarized in Section (7.6).展开更多
In this research we are going to define two new concepts: a) “The Potential of Events” (EP) and b) “The Catholic Information” (CI). The term CI derives from the ancient Greek language and declares all the Catholic...In this research we are going to define two new concepts: a) “The Potential of Events” (EP) and b) “The Catholic Information” (CI). The term CI derives from the ancient Greek language and declares all the Catholic (general) Logical Propositions (<img src="Edit_5f13a4a5-abc6-4bc5-9e4c-4ff981627b2a.png" width="33" height="21" alt="" />) which will true for every element of a set A. We will study the Riemann Hypothesis in two stages: a) By using the EP we will prove that the distribution of events e (even) and o (odd) of Square Free Numbers (SFN) on the axis Ax(N) of naturals is Heads-Tails (H-T) type. b) By using the CI we will explain the way that the distribution of prime numbers can be correlated with the non-trivial zeros of the function <em>ζ</em>(<em>s</em>) of Riemann. The Introduction and the Chapter 2 are necessary for understanding the solution. In the Chapter 3 we will present a simple method of forecasting in many very useful applications (e.g. financial, technological, medical, social, etc) developing a generalization of this new, proven here, theory which we finally apply to the solution of RH. The following Introduction as well the Results with the Discussion at the end shed light about the possibility of the proof of all the above. The article consists of 9 chapters that are numbered by 1, 2, …, 9.展开更多
Xinqiao Gully is located in the area of the 2008 Wenchuan M_(s)8.0 earthquake in Sichuan province,China.Based on the investigation of the 2023"6-26"Xinqiao Gully debris flow event,this study assessed the eff...Xinqiao Gully is located in the area of the 2008 Wenchuan M_(s)8.0 earthquake in Sichuan province,China.Based on the investigation of the 2023"6-26"Xinqiao Gully debris flow event,this study assessed the effectiveness of the debris flow control project and evaluated the debris flow hazards.Through field investigation and numerical simulation methods,the indicators of flow intensity reduction rate and storage capacity fullness were proposed to quantify the effectiveness of the engineering measures in the debris flow event.The simulation results show that the debris flow control project reduced the flow intensity by41.05%to 64.61%.The storage capacity of the dam decreases gradually from upstream to the mouth of the gully,thus effectively intercepting and controlling the debris flow.By evaluating the debris flow of different recurrence intervals,further measures are recommended for managing debris flow events.展开更多
In patients with Alzheimer’s disease,gamma-glutamyl transferase 5(GGT5)expression has been observed to be downregulated in cerebrovascular endothelial cells.However,the functional role of GGT5 in the development of A...In patients with Alzheimer’s disease,gamma-glutamyl transferase 5(GGT5)expression has been observed to be downregulated in cerebrovascular endothelial cells.However,the functional role of GGT5 in the development of Alzheimer’s disease remains unclear.This study aimed to explore the effect of GGT5 on cognitive function and brain pathology in an APP/PS1 mouse model of Alzheimer’s disease,as well as the underlying mechanism.We observed a significant reduction in GGT5 expression in two in vitro models of Alzheimer’s disease(Aβ_(1-42)-treated hCMEC/D3 and bEnd.3 cells),as well as in the APP/PS1 mouse model.Additionally,injection of APP/PS1 mice with an adeno-associated virus encoding GGT5 enhanced hippocampal synaptic plasticity and mitigated cognitive deficits.Interestingly,increasing GGT5 expression in cerebrovascular endothelial cells reduced levels of both soluble and insoluble amyloid-βin the brains of APP/PS1 mice.This effect may be attributable to inhibition of the expression ofβ-site APP cleaving enzyme 1,which is mediated by nuclear factor-kappa B.Our findings demonstrate that GGT5 expression in cerebrovascular endothelial cells is inversely associated with Alzheimer’s disease pathogenesis,and that GGT5 upregulation mitigates cognitive deficits in APP/PS1 mice.These findings suggest that GGT5 expression in cerebrovascular endothelial cells is a potential therapeutic target and biomarker for Alzheimer’s disease.展开更多
Parkinson’s disease is typically characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta.Many studies have been performed based on the supplementation of lost dopaminergic ...Parkinson’s disease is typically characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta.Many studies have been performed based on the supplementation of lost dopaminergic neurons to treat Parkinson’s disease.The initial strategy for cell replacement therapy used human fetal ventral midbrain and human embryonic stem cells to treat Parkinson’s disease,which could substantially alleviate the symptoms of Parkinson’s disease in clinical practice.However,ethical issues and tumor formation were limitations of its clinical application.Induced pluripotent stem cells can be acquired without sacrificing human embryos,which eliminates the huge ethical barriers of human stem cell therapy.Another widely considered neuronal regeneration strategy is to directly reprogram fibroblasts and astrocytes into neurons,without the need for intermediate proliferation states,thus avoiding issues of immune rejection and tumor formation.Both induced pluripotent stem cells and direct reprogramming of lineage cells have shown promising results in the treatment of Parkinson’s disease.However,there are also ethical concerns and the risk of tumor formation that need to be addressed.This review highlights the current application status of cell reprogramming in the treatment of Parkinson’s disease,focusing on the use of induced pluripotent stem cells in cell replacement therapy,including preclinical animal models and progress in clinical research.The review also discusses the advancements in direct reprogramming of lineage cells in the treatment of Parkinson’s disease,as well as the controversy surrounding in vivo reprogramming.These findings suggest that cell reprogramming may hold great promise as a potential strategy for treating Parkinson’s disease.展开更多
Neurodegenerative diseases are a group of disorders characterized by the progressive degeneration of neurons in the central or peripheral nervous system.Currently,there is no cure for neurodegenerative diseases and th...Neurodegenerative diseases are a group of disorders characterized by the progressive degeneration of neurons in the central or peripheral nervous system.Currently,there is no cure for neurodegenerative diseases and this means a heavy burden for patients and the health system worldwide.Therefore,it is necessary to find new therapeutic approaches,and antisense therapies offer this possibility,having the great advantage of not modifying cellular genome and potentially being safer.Many preclinical and clinical studies aim to test the safety and effectiveness of antisense therapies in the treatment of neurodegenerative diseases.The objective of this review is to summarize the recent advances in the development of these new technologies to treat the most common neurodegenerative diseases,with a focus on those antisense therapies that have already received the approval of the U.S.Food and Drug Administration.展开更多
Alzheimer’s disease is a neurodegenerative disorder characterized by the amyloid accumulation in the brains of patients with Alzheimer’s disease.The pathogenesis of Alzheimer’s disease is mainly mediated by the pho...Alzheimer’s disease is a neurodegenerative disorder characterized by the amyloid accumulation in the brains of patients with Alzheimer’s disease.The pathogenesis of Alzheimer’s disease is mainly mediated by the phosphorylation and aggregation of tau protein.Among the multiple causes of tau hyperphosphorylation,brain insulin resistance has generated much attention,and inositols as insulin sensitizers,are currently considered candidates for drug development.The present narrative review revises the interactions between these three elements:Alzheimer’s disease-tau-inositols,which can eventually identify targets for new disease modifiers capable of bringing hope to the millions of people affected by this devastating disease.展开更多
AIM: To study the effects of aminoguanidine (AG) and two L-arginine analogues N(omega)-nitro-L-arginine methyl ester (L-NAME) and N(omega)-nitro-L-arginine (L-NNA) on nitric oxide (NO) production induced by cytokines ...AIM: To study the effects of aminoguanidine (AG) and two L-arginine analogues N(omega)-nitro-L-arginine methyl ester (L-NAME) and N(omega)-nitro-L-arginine (L-NNA) on nitric oxide (NO) production induced by cytokines (TNF-alpha, IL-1 beta, and IFN-gamma) and bacterial lipopolysaccharide (LPS) mixture (CM) in the cultured rat hepatocytes, and examine their mechanisms action. METHODS: Rat hepatocytes were incubated with AG, L-NAME, L-NNA, Actinomycin D (ActD) and dexamethasone in a medium containing CM (LPS plus TNF-alpha, IL-1 beta, and IFN-gamma) for 24h. NO production in the cultured supernatant was measured with the Griess reaction. Intracellular cGMP level was detected with radioimmunoassy. RESULTS: NO production was markedly blocked by AG and L-NAME in a dose-dependent manner under inflammatory stimuli condition triggered by CM in vitro. The rate of the maximum inhibitory effects of L-NAME (38.9%) was less potent than that obtained with AG(53.7%, P 【 0.05). There was no significant difference between the inhibitory effects of AG and two L-arginine analogues on intracellular cGMP accumulation in rat cultured hepatocytes. Non-specific NOS expression inhibitor dexamethasone (DEX)and iNOS mRNA transcriptional inhibitor ActD also significantly inhibited CM-induced NO production. AG(0.1 mmol x L(-1)) and ActD (0.2 ng x L(-1)) were equipotent in decreasing NO production induced by inflammatory stimuli in vitro, and both effects were more potent than that induced by non-selectivity NOS activity inhibitor L-NAME (0.1 mmol x L(-1)) under similar stimuli conditions (P【0.01). CONCLUSION: AG is a potent selective inhibitor of inducible isoform of NOS,and the mechanism of action may be not only competitive inhibition in the substrate level, but also the gene expression level in rat hepatocytes.展开更多
文摘E-learning platforms support education systems worldwide, transferring theoretical knowledge as well as soft skills. In the present study high-school pupils’, and adult students’ opinions were evaluated through a modern structured MOODLE interactive course, designed for the needs of the laboratory course “Automotive Systems”. The study concerns Greek secondary vocational education pupils aged 18 and vocational training adult students aged 20 to 50 years. The multistage, equal size simple random cluster sample was used as a sampling method. Pupils and adult students of each cluster completed structured 10-question questionnaires both before and after attending the course. A total of 120 questionnaires were collected. In general, our findings disclosed that the majority of pupils and adult students had significantly improved their knowledge and skills from using MOODLE. They reported strengthening conventional teaching, using the new MOODLE technology. The satisfaction indices improved quite, with the differences in their mean values being statistically significant.
文摘Purpose: Cotard’s syndrome, Alice in Wonderland Syndrome, and Catatonia are all rare psychiatric disorders that have relatively little research regarding their treatments. The aim of this article is to highlight any gaps in knowledge regarding represented demographics in these treatment studies, and to discuss the current and upcoming treatment options. Background: This literature review explores under-researched psychiatric conditions: Cotard’s syndrome, Alice in Wonderland syndrome, and Catatonic Schizophrenia. Understanding psychiatric disorders requires basic knowledge of brain anatomy. These conditions are often result of or associated with neurological issues, such as migraines or tumors. The brain has eight lobes, two of four kinds: frontal, parietal, occipital, and temporal lobes, which all govern different functions and abilities. Frontal lobes control judgment, decision-making, personality traits, and fine motor movements. Parietal lobes interpret pain and temperature, occipital lobes handle visual stimuli, and temporal lobes enable hearing. The pre-frontal cortex is associated with high intelligence, psychotic traits, and psychosis. The Broca’s Area in the frontal lobes controls expressive language. These areas and divisions of the brain contribute to the complexity of the psychiatric disorders discussed in this review. Introduction: Cotard’s syndrome is a psychiatric disorder characterized by delusions of being dead or not having certain limbs or organs. It is believed that there is a disconnect between their fusiform face area and the amygdala, causing a lack of familiarity between one’s mind and body. Alice in Wonderland Syndrome (AIWS) is another psychiatric disorder which is characterized by visual hallucinations, such as distorted perceptions of color, size, distance, and speed. The most common symptoms include micropsia and macropsia. Catatonia/Catatonic Schizophrenia is an uncommon type of schizophrenia. This type of schizophrenia is characterized by motor rigidity, verbal rigidity, the flat effect, psychomotor retardation, waxy flexibility, and overall negative symptoms. Thus, these people may come off as emotionally detached, and able to stay frozen in odd positions for periods on end. Treatments and Results: Cotard’s syndrome seemed to be most effectively treated by ECT (electroconvulsive therapy). Alice in Wonderland Syndrome (AIWS) had the highest positive responses to treatment by Valproate (an anti-epileptic drug), as well as intervention to treat the associated neurological conditions they had. Catatonia/Catatonic Schizophrenia seemed to be most effectively treated with a combination of benzodiazepines and ECT. Discussion and Demographics: In all 3 disorders, the Latino and African communities were underrepresented. There also seemed to be an underrepresentation of men in Cotard’s syndrome, and of women in Alice in Wonderland Syndrome. Japan and India seemed to have the highest density of treatment studies in all 3 disorders.
基金supported by the National Research Foundation of the Republic of Korea 2018R1D1A3B07047960the Soonchunhyang University Research Fund(to SSY).
文摘Diseases like Alzheimer’s and Parkinson’s diseases are defined by inflammation and the damage neurons undergo due to oxidative stress. A primary reactive oxygen species contributor in the central nervous system, NADPH oxidase 4, is viewed as a potential therapeutic touchstone and indicative marker for these ailments. This in-depth review brings to light distinct features of NADPH oxidase 4, responsible for generating superoxide and hydrogen peroxide, emphasizing its pivotal role in activating glial cells, inciting inflammation, and disturbing neuronal functions. Significantly, malfunctioning astrocytes, forming the majority in the central nervous system, play a part in advancing neurodegenerative diseases, due to their reactive oxygen species and inflammatory factor secretion. Our study reveals that aiming at NADPH oxidase 4 within astrocytes could be a viable treatment pathway to reduce oxidative damage and halt neurodegenerative processes. Adjusting NADPH oxidase 4 activity might influence the neuroinflammatory cytokine levels, including myeloperoxidase and osteopontin, offering better prospects for conditions like Alzheimer’s disease and Parkinson’s disease. This review sheds light on the role of NADPH oxidase 4 in neural degeneration, emphasizing its drug target potential, and paving the path for novel treatment approaches to combat these severe conditions.
基金This work was kindly supported by Na-tional Natural Science Foundation of China(No.39670308)
文摘To investigate whether the expression of exogenous heme oxygenase-1 (HO-1) gene within vascular smooth muscle cells (VSMC) could protect the cells from free radical attack and inhibit cell proliferation, we established an in vitro transfection of human HO-1 gene into rat VSMC mediated by a retroviral vector. The results showed that the profound expression of HO-1 protein as well as HO activity was 1.8- and 2.0-fold increased respectively in the transfected cells compared to the non-transfected ones. The treatment of VSMC with different concentrations of H2O2 led to the remarkable cell damage as indicated by survival rate and LDH leakage. However, the resistance of the HO-1 transfected VSMC against H2O2 was significantly raised. This protective effect was dramatically diminished when the transfected VSMC were pretreated with ZnPP-IX, a specific inhibitor of HO, for 24 h. In addition, we found that the growth potential of the transfected cells was significantly inhibited directly by increased activity of HO-1, and this effect might be related to decreased phosphorylation of MAPK. These results suggest that the overexpression of introduced hHO-1 is potentially able to reduce the risk factors of atherosclerosis, partially due to its cellular protection against oxidative injury and to its inhibitory effect on cellular proliferation.
文摘Parkinson’s Disease (PD) is a neurodegenerative disorder characterized by motor and non-motor symptoms, including cognitive impairment. Current treatments often involve synthetic drugs with significant side effects and potential for dependency. This study investigates the effects of a natural supplement combination of Ginkgo Biloba and Acai Extract on cognitive symptoms in a 77-year-old male with PD. The participant underwent a three-month supplementation regimen, with cognitive function assessed using the Montreal Cognitive Assessment (MoCA) test before and after the intervention. The results indicated an improvement in cognitive scores, suggesting that the combination of Ginkgo Biloba and Acai Extract may offer a promising alternative or adjunct to conventional PD treatments. This study highlights the potential of natural supplements in managing PD symptoms and calls for further research with larger sample sizes to confirm these findings. Human data was performed in accordance with the Declaration of Helsinki by the Roxbury District IRB Board (IRB Number: IRB00011767).
文摘This article explores the dead universe theory as a novel interpretation for the origin and evolution of the universe, suggesting that our cosmos may have originated from the remnants of a preceding universe. This perspective challenges the conventional Big Bang theory, particularly concerning dark matter, the expansion of the universe, and the interpretation of phenomena such as gravitational waves.
基金granted by the National Natural Science Foundation of China(Grant No.42004038)Earthquake Tracking Orientation Tasks of CEA(Grant No.2024020104)+1 种基金the Special Fund of IEFCEA(Grant No.CEAIEF2022030206)the China Scholarship Council(CSC)exchange program(Grant No.202204190019)。
文摘Since the inaugural international collaboration under the framework of the Collaboratory for the Study of Earthquake Predictability(CSEP)in 2007,numerous forecast models have been developed and operated for earthquake forecasting experiments across CSEP testing centers(Schorlemmer et al.,2018).Over more than a decade,efforts to compare forecasts with observed earthquakes using numerous statistical test methods and insights into earthquake predictability,which have become a highlight of the CSEP platform.
基金supported by grants from the Department of Science and Technology of Sichuan Province,Nos.2021ZYD0093(to LY),2022YFS0597(to LY),2021YJ0480(to YT),and 2022ZYD0076(to JY)。
文摘Exosomes are cup-shaped extracellular vesicles with a lipid bilayer that is approximately 30 to 200 nm in thickness.Exosomes are widely distributed in a range of body fluids,including urine,blood,milk,and saliva.Exosomes exert biological function by transporting factors between different cells and by regulating biological pathways in recipient cells.As an important form of intercellular communication,exosomes are increasingly being investigated due to their ability to transfer bioactive molecules such as lipids,proteins,mRNAs,and microRNAs between cells,and because they can regulate physiological and pathological processes in the central nervous system.Adult neurogenesis is a multistage process by which new neurons are generated and migrate to be integrated into existing neuronal circuits.In the adult brain,neurogenesis is mainly localized in two specialized niches:the subventricular zone adjacent to the lateral ventricles and the subgranular zone of the dentate gyrus.An increasing body of evidence indicates that adult neurogenesis is tightly controlled by environmental conditions with the niches.In recent studies,exosomes released from different sources of cells were shown to play an active role in regulating neurogenesis both in vitro and in vivo,thereby participating in the progression of neurodegenerative disorders in patients and in various disease models.Here,we provide a state-of-the-art synopsis of existing research that aimed to identify the diverse components of exosome cargoes and elucidate the therapeutic potential of exosomal contents in the regulation of neurogenesis in several neurodegenerative diseases.We emphasize that exosomal cargoes could serve as a potential biomarker to monitor functional neurogenesis in adults.In addition,exosomes can also be considered as a novel therapeutic approach to treat various neurodegenerative disorders by improving endogenous neurogenesis to mitigate neuronal loss in the central nervous system.
文摘Background: Loose bodies (LBs) within the knee joint are commonly encountered during clinical practice and are frequently observed during knee arthroscopy. The primary treatment involves the removal of loose bodies;however, their complete eradication is often challenging and may not address underlying diseases, leading to persistent symptoms and the risk of new loose body formation. Aim: This case report aims to present the findings and surgical management of a 52-year-old male with an unusually large osseous loose body in the knee joint and associated pathologies. Case Presentation: The patient, a 52-year-old male, experienced recurrent episodes of severe, sudden, and painful locking of the knee joint, leading to difficulties moving. A plain MRI study was conducted to evaluate the condition of the knee joint, which revealed various degenerative changes and the presence of a loose body. Subsequently, an arthroscopic examination was performed under general anesthesia, uncovering the presence of an abnormally large loose body, as well as other pathologies including chondropathy, meniscal degeneration, and Baker’s cyst. Conclusion: Loose bodies (LBs) in the knee joint pose significant challenges and may lead to debilitating symptoms. Timely diagnosis and appropriate surgical intervention are crucial for symptom relief and the prevention of further joint damage as arthroscopic excision. Comprehensive imaging has a vital role in guiding treatment decisions and optimizing patient outcomes. In this case, the removal of the loose body improved patient outcomes and helped prevent potential joint complications.
文摘Huntington’s disease is a neurodegenerative disease caused by the expansion mutation of a cytosine-adenine-guanine triplet in the exon 1 of the HTT gene which is responsible for the production of the huntingtin (Htt) protein. In physiological conditions, Htt is involved in many cellular processes such as cell signaling, transcriptional regulation, energy metabolism regulation, DNA maintenance, axonal trafficking, and antiapoptotic activity. When the genetic alteration is present, the production of a mutant version of Htt (mHtt) occurs, which is characterized by a plethora of pathogenic activities that, finally, lead to cell death. Among all the cells in which mHtt exerts its dangerous activity, the GABAergic Medium Spiny Neurons seem to be the most affected by the mHtt-induced excitotoxicity both in the cortex and in the striatum. However, as the neurodegeneration proceeds ahead the neuronal loss grows also in other brain areas such as the cerebellum, hypothalamus, thalamus, subthalamic nucleus, globus pallidus, and substantia nigra, determining the variety of symptoms that characterize Huntington’s disease. From a clinical point of view, Huntington’s disease is characterized by a wide spectrum of symptoms spanning from motor impairment to cognitive disorders and dementia. Huntington’s disease shows a prevalence of around 3.92 cases every 100,000 worldwide and an incidence of 0.48 new cases every 100,000/year. To date, there is no available cure for Huntington’s disease. Several treatments have been developed so far, aiming to reduce the severity of one or more symptoms to slow down the inexorable decline caused by the disease. In this context, the search for reliable strategies to target the different aspects of Huntington’s disease become of the utmost interest. In recent years, a variety of studies demonstrated the detrimental role of neuronal loss in Huntington’s disease condition highlighting how the replacement of lost cells would be a reasonable strategy to overcome the neurodegeneration. In this view, numerous have been the attempts in several preclinical models of Huntington’s disease to evaluate the feasibility of invasive and non-invasive approaches. Thus, the aim of this review is to offer an overview of the most appealing approaches spanning from stem cell-based cell therapy to extracellular vesicles such as exosomes in light of promoting neurogenesis, discussing the results obtained so far, their limits and the future perspectives regarding the neural regeneration in the context of Huntington’s disease.
基金supported by the National Natural Science Foundation of China,Nos.82271447,81771382the National Key Research and Development Program of China,No.2019 YFE0115900the"New 20 Terms of Universities in Jinan,No.202228022 (all to ZZ)。
文摘α-Synuclein is a protein that mainly exists in the presynaptic terminals.Abnormal folding and accumulation of α-synuclein are found in several neurodegenerative diseases,including Parkinson’s disease.Aggregated and highly phospho rylated a-synuclein constitutes the main component of Lewy bodies in the brain,the pathological hallmark of Parkinson s disease.For decades,much attention has been focused on the accumulation of α-synuclein in the brain parenchyma rather than considering Parkinson s disease as a systemic disease.Recent evidence demonstrates that,at least in some patients,the initial α-synuclein pathology originates in the peripheral organs and spreads to the brain.Injection of α-synuclein preformed fibrils into the gastrointestinal tra ct trigge rs the gutto-brain propagation of α-synuclein pathology.However,whether α-synuclein pathology can occur spontaneously in peripheral organs independent of exogenous α-synuclein preformed fibrils or pathological α-synuclein leakage from the central nervous system remains under investigation.In this review,we aimed to summarize the role of peripheral α-synuclein pathology in the pathogenesis of Parkinson’s disease.We also discuss the pathways by which α-synuclein pathology spreads from the body to the brain.
文摘Polysurfacic tori or kideas are three-dimensional objects formed by rotating a regular polygon around a central axis. These toric shapes are referred to as “polysurfacic” because their characteristics, such as the number of sides or surfaces separated by edges, can vary in a non-trivial manner depending on the degree of twisting during the revolution. We use the term “Kideas” to specifically denote these polysurfacic tori, and we represent the number of sides (referred to as “facets”) of the original polygon followed by a point, while the number of facets from which the torus is twisted during its revolution is indicated. We then explore the use of concave regular polygons to generate Kideas. We finally give acceleration for the algorithm for calculating the set of prime numbers.
文摘Beginning with a 5D homogeneous universe [1], we have provided a plausible explanation of the self-rotation phenomenon of stellar objects previously with illustration of large number of star samples [2], via a 5D-4D projection. The origin of such rotation is the balance of the angular momenta of stars and that of positive and negative charged e-trino pairs, within a 3D ⊗1D?void of the stellar object, the existence of which is based on conservation/parity laws in physics if one starts with homogeneous 5D universe. While the in-phase e-trino pairs are proposed to be responsible for the generation of angular momentum, the anti-phase but oppositely charge pairs necessarily produce currents. In the 5D to 4D projection, one space variable in the 5D manifold was compacted to zero in most other 5D theories (including theories of Kaluza-Klein and Einstein [3] [4]). We have demonstrated, using the Fermat’s Last Theorem [5], that for validity of gauge invariance at the 4D-5D boundary, the 4th space variable in the 5D manifold is mapped into two current rings at both magnetic poles as required by Perelman entropy mapping;these loops are the origin of the dipolar magnetic field. One conclusion we draw is that there is no gravitational singularity, and hence no black holes in the universe, a result strongly supported by the recent discovery of many stars with masses well greater than 100 solar mass [6] [7] [8], without trace of phenomena observed (such as strong gamma and X ray emissions), which are supposed to be associated with black holes. We analyze the properties of such loop currents on the 4D-5D boundary, where Maxwell equations are valid. We derive explicit expressions for the dipolar fields over the whole temperature range. We then compare our prediction with measured surface magnetic fields of many stars. Since there is coupling in distribution between the in-phase and anti-phase pairs of e-trinos, the generated mag-netic field is directly related to the angular momentum, leading to the result that the magnetic field can be expressible in terms of only the mechanical variables (mass M, radius R, rotation period P)of a star, as if Maxwell equations are “hidden”. An explanation for the occurrence of this “un-expected result” is provided in Section (7.6). Therefore we provide satisfactory answers to a number of “mysteries” of magnetism in astrophysics such as the “Magnetic Bode’s Relation/Law” [9] and the experimental finding that B-P graph in the log-log plot is linear. Moreover, we have developed a new method for studying the relations among the data (M, R, P) during stellar evolution. Ten groups of stellar objects, effectively over 2000 samples are used in various parts of the analysis. We also explain the emergence of huge magnetic field in very old stars like White Dwarfs in terms of formation of 2D Semion state on stellar surface and release of magnetic flux as magnetic storms upon changing the 2D state back to 3D structure. Moreover, we provide an explanation, on the ground of the 5D theory, for the detection of extremely weak fields in Venus and Mars and the asymmetric distribution of magnetic field on the Martian surface. We predict the equatorial fields B of the newly discovered Trappist-1 star and the 6 nearest planets. The log B?−?log P graph for the 6 planets is linear and they satisfy the Magnetic Bode’s relation. Based on the above analysis, we have discovered several new laws of stellar magnetism, which are summarized in Section (7.6).
文摘In this research we are going to define two new concepts: a) “The Potential of Events” (EP) and b) “The Catholic Information” (CI). The term CI derives from the ancient Greek language and declares all the Catholic (general) Logical Propositions (<img src="Edit_5f13a4a5-abc6-4bc5-9e4c-4ff981627b2a.png" width="33" height="21" alt="" />) which will true for every element of a set A. We will study the Riemann Hypothesis in two stages: a) By using the EP we will prove that the distribution of events e (even) and o (odd) of Square Free Numbers (SFN) on the axis Ax(N) of naturals is Heads-Tails (H-T) type. b) By using the CI we will explain the way that the distribution of prime numbers can be correlated with the non-trivial zeros of the function <em>ζ</em>(<em>s</em>) of Riemann. The Introduction and the Chapter 2 are necessary for understanding the solution. In the Chapter 3 we will present a simple method of forecasting in many very useful applications (e.g. financial, technological, medical, social, etc) developing a generalization of this new, proven here, theory which we finally apply to the solution of RH. The following Introduction as well the Results with the Discussion at the end shed light about the possibility of the proof of all the above. The article consists of 9 chapters that are numbered by 1, 2, …, 9.
基金supported by the project of the China Geological Survey(No.DD20221746)the National Natural Science Foundation of China(Grant Nos.41101086)。
文摘Xinqiao Gully is located in the area of the 2008 Wenchuan M_(s)8.0 earthquake in Sichuan province,China.Based on the investigation of the 2023"6-26"Xinqiao Gully debris flow event,this study assessed the effectiveness of the debris flow control project and evaluated the debris flow hazards.Through field investigation and numerical simulation methods,the indicators of flow intensity reduction rate and storage capacity fullness were proposed to quantify the effectiveness of the engineering measures in the debris flow event.The simulation results show that the debris flow control project reduced the flow intensity by41.05%to 64.61%.The storage capacity of the dam decreases gradually from upstream to the mouth of the gully,thus effectively intercepting and controlling the debris flow.By evaluating the debris flow of different recurrence intervals,further measures are recommended for managing debris flow events.
基金supported by STI2030-Major Projects,No.2021ZD 0201801(to JG)Shanxi Province Basic Research Program,No.20210302123429(to QS).
文摘In patients with Alzheimer’s disease,gamma-glutamyl transferase 5(GGT5)expression has been observed to be downregulated in cerebrovascular endothelial cells.However,the functional role of GGT5 in the development of Alzheimer’s disease remains unclear.This study aimed to explore the effect of GGT5 on cognitive function and brain pathology in an APP/PS1 mouse model of Alzheimer’s disease,as well as the underlying mechanism.We observed a significant reduction in GGT5 expression in two in vitro models of Alzheimer’s disease(Aβ_(1-42)-treated hCMEC/D3 and bEnd.3 cells),as well as in the APP/PS1 mouse model.Additionally,injection of APP/PS1 mice with an adeno-associated virus encoding GGT5 enhanced hippocampal synaptic plasticity and mitigated cognitive deficits.Interestingly,increasing GGT5 expression in cerebrovascular endothelial cells reduced levels of both soluble and insoluble amyloid-βin the brains of APP/PS1 mice.This effect may be attributable to inhibition of the expression ofβ-site APP cleaving enzyme 1,which is mediated by nuclear factor-kappa B.Our findings demonstrate that GGT5 expression in cerebrovascular endothelial cells is inversely associated with Alzheimer’s disease pathogenesis,and that GGT5 upregulation mitigates cognitive deficits in APP/PS1 mice.These findings suggest that GGT5 expression in cerebrovascular endothelial cells is a potential therapeutic target and biomarker for Alzheimer’s disease.
基金supported by the National Natural Science Foundation of China,No.31960120Yunnan Science and Technology Talent and Platform Plan,No.202105AC160041(both to ZW).
文摘Parkinson’s disease is typically characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta.Many studies have been performed based on the supplementation of lost dopaminergic neurons to treat Parkinson’s disease.The initial strategy for cell replacement therapy used human fetal ventral midbrain and human embryonic stem cells to treat Parkinson’s disease,which could substantially alleviate the symptoms of Parkinson’s disease in clinical practice.However,ethical issues and tumor formation were limitations of its clinical application.Induced pluripotent stem cells can be acquired without sacrificing human embryos,which eliminates the huge ethical barriers of human stem cell therapy.Another widely considered neuronal regeneration strategy is to directly reprogram fibroblasts and astrocytes into neurons,without the need for intermediate proliferation states,thus avoiding issues of immune rejection and tumor formation.Both induced pluripotent stem cells and direct reprogramming of lineage cells have shown promising results in the treatment of Parkinson’s disease.However,there are also ethical concerns and the risk of tumor formation that need to be addressed.This review highlights the current application status of cell reprogramming in the treatment of Parkinson’s disease,focusing on the use of induced pluripotent stem cells in cell replacement therapy,including preclinical animal models and progress in clinical research.The review also discusses the advancements in direct reprogramming of lineage cells in the treatment of Parkinson’s disease,as well as the controversy surrounding in vivo reprogramming.These findings suggest that cell reprogramming may hold great promise as a potential strategy for treating Parkinson’s disease.
基金supported by Association 2HE(Center for Human Health and Environment)by Regione Puglia-Grant Malattie Rare DUP n.246 of 2019(to CB).
文摘Neurodegenerative diseases are a group of disorders characterized by the progressive degeneration of neurons in the central or peripheral nervous system.Currently,there is no cure for neurodegenerative diseases and this means a heavy burden for patients and the health system worldwide.Therefore,it is necessary to find new therapeutic approaches,and antisense therapies offer this possibility,having the great advantage of not modifying cellular genome and potentially being safer.Many preclinical and clinical studies aim to test the safety and effectiveness of antisense therapies in the treatment of neurodegenerative diseases.The objective of this review is to summarize the recent advances in the development of these new technologies to treat the most common neurodegenerative diseases,with a focus on those antisense therapies that have already received the approval of the U.S.Food and Drug Administration.
基金supported by the European Regional Development Funds-European Union(ERDF-EU),FATZHEIMER project(EU-LAC HEALTH 2020,16/T010131 to FRdF),“Una manera de hacer Europa”Ministerio de Economía,Industria y Competitividad,Gobierno de Espa?a,Programa Estatal de Investigación,Desarrollo e Innovación Orientada a los Retos de la Sociedad(RTC2019-007329-1 to FRdF)+2 种基金Consejería de Economía,Conocimiento y Universidad,Junta de Andalucía,Plan Andaluz de Investigación,Desarrollo e Innovación(P18TP-5194 to FRdF)Instituto de Salud CarlosⅢ(DTS22/00021 to FRdF)DMV(FI20/00227)holds a“PFIS’’predoctoral contract from the National System of Health,EU-ERDF-Instituto de Salud CarlosⅢ。
文摘Alzheimer’s disease is a neurodegenerative disorder characterized by the amyloid accumulation in the brains of patients with Alzheimer’s disease.The pathogenesis of Alzheimer’s disease is mainly mediated by the phosphorylation and aggregation of tau protein.Among the multiple causes of tau hyperphosphorylation,brain insulin resistance has generated much attention,and inositols as insulin sensitizers,are currently considered candidates for drug development.The present narrative review revises the interactions between these three elements:Alzheimer’s disease-tau-inositols,which can eventually identify targets for new disease modifiers capable of bringing hope to the millions of people affected by this devastating disease.
基金Project supported by the National Natural Science Foundation of China,No.39770861.and JANSSEN Science Research Foundation.
文摘AIM: To study the effects of aminoguanidine (AG) and two L-arginine analogues N(omega)-nitro-L-arginine methyl ester (L-NAME) and N(omega)-nitro-L-arginine (L-NNA) on nitric oxide (NO) production induced by cytokines (TNF-alpha, IL-1 beta, and IFN-gamma) and bacterial lipopolysaccharide (LPS) mixture (CM) in the cultured rat hepatocytes, and examine their mechanisms action. METHODS: Rat hepatocytes were incubated with AG, L-NAME, L-NNA, Actinomycin D (ActD) and dexamethasone in a medium containing CM (LPS plus TNF-alpha, IL-1 beta, and IFN-gamma) for 24h. NO production in the cultured supernatant was measured with the Griess reaction. Intracellular cGMP level was detected with radioimmunoassy. RESULTS: NO production was markedly blocked by AG and L-NAME in a dose-dependent manner under inflammatory stimuli condition triggered by CM in vitro. The rate of the maximum inhibitory effects of L-NAME (38.9%) was less potent than that obtained with AG(53.7%, P 【 0.05). There was no significant difference between the inhibitory effects of AG and two L-arginine analogues on intracellular cGMP accumulation in rat cultured hepatocytes. Non-specific NOS expression inhibitor dexamethasone (DEX)and iNOS mRNA transcriptional inhibitor ActD also significantly inhibited CM-induced NO production. AG(0.1 mmol x L(-1)) and ActD (0.2 ng x L(-1)) were equipotent in decreasing NO production induced by inflammatory stimuli in vitro, and both effects were more potent than that induced by non-selectivity NOS activity inhibitor L-NAME (0.1 mmol x L(-1)) under similar stimuli conditions (P【0.01). CONCLUSION: AG is a potent selective inhibitor of inducible isoform of NOS,and the mechanism of action may be not only competitive inhibition in the substrate level, but also the gene expression level in rat hepatocytes.
