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
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 ζ(s) 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
Short-chain fatty acids,metabolites produced by the fermentation of dietary fiber by gut microbiota,have garnered significant attention due to their correlation with neurodegenerative diseases,particularly Parkinson’...Short-chain fatty acids,metabolites produced by the fermentation of dietary fiber by gut microbiota,have garnered significant attention due to their correlation with neurodegenerative diseases,particularly Parkinson’s disease.In this review,we summarize the changes in short-chain fatty acid levels and the abundance of short-chain fatty acid-producing bacteria in various samples from patients with Parkinson’s disease,highlighting the critical role of gut homeostasis imbalance in the pathogenesis and progression of the disease.Focusing on the nervous system,we discuss the molecular mechanisms by which short-chain fatty acids influence the homeostasis of both the enteric nervous system and the central nervous system.We identify key processes,including the activation of G protein-coupled receptors and the inhibition of histone deacetylases by short-chain fatty acids.Importantly,structural or functional disruptions in the enteric nervous system mediated by these fatty acids may lead to abnormalα-synuclein expression and gastrointestinal dysmotility,which could serve as an initiating event in Parkinson’s disease.Furthermore,we propose that short-chain fatty acids help establish communication between the enteric nervous system and the central nervous system via the vagal nerve,immune circulation,and endocrine signaling.This communication may shed light on their potential role in the transmission ofα-synuclein from the gut to the brain.Finally,we elucidate novel treatment strategies for Parkinson’s disease that target short-chain fatty acids and examine the challenges associated with translating short-chain fatty acid-based therapies into clinical practice.In conclusion,this review emphasizes the pivotal role of short-chain fatty acids in regulating gut-brain axis integrity and their significance in the pathogenesis of Parkinson’s disease from the perspective of the nervous system.Moreover,it highlights the potential value of short-chain fatty acids in early intervention for Parkinson’s disease.Future research into the molecular mechanisms of short-chain fatty acids and their synergistic interactions with other gut metabolites is likely to advance the clinical translation of innovative short-chain fatty acid-based therapies for Parkinson’s disease.展开更多
Neurodegenerative diseases(neurodegenerative disorders)are marked by the progressive degeneration of the structure and function of the central nervous system.They may res ult in the deterioration of cognitive,motor,an...Neurodegenerative diseases(neurodegenerative disorders)are marked by the progressive degeneration of the structure and function of the central nervous system.They may res ult in the deterioration of cognitive,motor,and functional abilities.Diseases such as Alzheimer s disease,Parkinson's disease,Huntington's disease,and amyotrophic lateral sclerosis represent some of the most prominent examples of neurodegenerative disorders.Des pite scientific advancement in understanding disease pathology and prognosis,the therapeutic strategies available for management remain limited.In recent years,microRNAs,small non-coding RNA molecules,have emerged as key players in the pathogenesis of neurodegenerative disorde rs.Therefo re,understanding how these microRNAs affect disease pathology and pathway signaling is essential,and may open microRNAs as new avenues for potential therapeutic intervention.This review explores the role of microRNAs in va rious neurodegenerative diseases,discuss how microRNAs affect signaling pathways,and examine the potential of microRNAs as therapeutic targets.展开更多
In recent years,an increasing number of researchers have become interested in the bidirectional communication between the gut microbiota and the central nervous system.This communication occurs through the microbiota-...In recent years,an increasing number of researchers have become interested in the bidirectional communication between the gut microbiota and the central nervous system.This communication occurs through the microbiota-gut-brain axis.As people age,the composition of the gut microbiota undergoes considerable changes,which are now known to play an important role in the development of many neurodegenerative diseases.This review aims to investigate the complex bidirectional signaling pathways between the gut and the brain.It summarizes the latest research findings on how the gut microbiota and its metabolites play critical roles in regulating inflammation,maintaining gut health,and influencing the development of neurodegenerative diseases such as Alzheimer’s disease,Parkinson’s disease,and amyotrophic lateral sclerosis.The review also analyzes the current clinical applications of gut microbiota-based treatments for neurological disorders,including fecal microbiota transplantation,probiotics,and prebiotics.Many studies show that the gut microbiota affects the brain in several ways.For example,it can produce substances such as short-chain fatty acids and activate inflammatory pathways.Studies involving animals and laboratory models have demonstrated that adjusting the gut microbiota can help improve behavior and reduce neurological problems.Recent metagenomic and metabolomics studies have shown that the microbiota plays a crucial role in maintaining the organism’s health.Microorganisms primarily colonize the gut and are involved in host nutrient metabolism,maintaining the structural integrity of the intestine,preserving the intestinal mucosal barrier,and modulating the immune system.The gut microbiota communicates with the brain through a bidirectional microbiota-gut-brain axis.The composition of the gut flora changes considerably with age,and ecological dysregulation has been recognized as one of the twelve most recent hallmarks of aging.Recent studies have linked these changes to a variety of age-related neurological disorders,including Alzheimer’s disease,amyotrophic lateral sclerosis,Parkinson’s disease,multiple sclerosis,and Huntington’s disease.Specifically,the gut microbiota influences the brain through the production of key metabolites such as short-chain fatty acids and the activation of inflammatory and other relevant signaling pathways.In preclinical studies,targeted modulation of the gut microbiota,through methods such as fecal microbiota transplantation,probiotics,and prebiotics,has demonstrated potential in improving host behavioral outcomes.Therefore,gut microbiota-based treatments offer new hope for the treatment of nervous system diseases.However,due to the complexity of the gut microbiota and the potential adverse reactions associated with these therapies,researchers need to carefully assess their safety and efficacy before widespread clinical application.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
With the gradual advancement of research methods and technologies,various biological processes have been identified as playing roles in the pathogenesis of neurodegenerative diseases.However,current descriptions of th...With the gradual advancement of research methods and technologies,various biological processes have been identified as playing roles in the pathogenesis of neurodegenerative diseases.However,current descriptions of these biological processes do not fully explain the onset,progression,and development of these conditions.Therefore,exploration of the pathogenesis of neurodegenerative diseases remains a valuable area of research.This review summarizes the potential common pathogeneses of Alzheimer’s disease,Parkinson’s disease,amyotrophic lateral sclerosis,Huntington’s disease,frontotemporal lobar dementia,and Lewy body disease.Research findings have indicated that several common biological processes,including aging,genetic factors,progressive neuronal dysfunction,neuronal death and apoptosis,protein misfolding and aggregation,neuroinflammation,mitochondrial dysfunction,axonal transport defects,and gut microbiota dysbiosis,are involved in the pathogenesis of these six neurodegenerative diseases.Based on current information derived from diverse areas of research,these biological processes may form complex pathogenic networks that lead to distinctive types of neuronal death in neurodegenerative diseases.Furthermore,promoting the regeneration of damaged neurons may be achievable through the repair of affected neural cells if the underlying pathogenesis can be prevented or reversed.Hence,these potential common biological processes may represent only very small,limited elements within numerous intricate pathogenic networks associated with neurodegenerative diseases.In clinical treatment,interfering with any single biological process has proven insufficient to completely halt the progression of neurodegenerative diseases.Therefore,future research on the pathogenesis of neurodegenerative diseases should focus on uncovering the complex pathogenic networks,rather than isolating individual biological processes.Based on this,therapies that aim to block or reverse various targets involved in the potential pathogenic mechanisms of neurodegenerative diseases may be promising directions,as current treatment methods that focus on halting a single pathogenic factor have not achieved satisfactory efficacy.展开更多
The voltage-gated sodium channel Nav1.6,encoded by the sodium voltage-gated channel alpha subunit 8 gene,is a crucial regulator of neuronal excitability,with widespread expression throughout the central and peripheral...The voltage-gated sodium channel Nav1.6,encoded by the sodium voltage-gated channel alpha subunit 8 gene,is a crucial regulator of neuronal excitability,with widespread expression throughout the central and peripheral nervous systems.Recent breakthroughs in structural biology,particularly the elucidation of the cryo-EM architecture of Nav1.6 at a resolution of 0.31 nm,have provided unprecedented insights into its molecular organization and functional modulation.As a key mediator of action potential initiation and propagation,Nav1.6 possesses unique biophysical properties,including persistent and resurgent sodium currents that critically influence neuronal firing patterns.This comprehensive review synthesizes current knowledge on the physiological functions and pathological roles of Nav1.6 in multiple neurological conditions.Key findings include the following:(1)Epilepsy studies reveal more than 250 sodium voltage-gated channel alpha subunit 8 mutations with distinct genotype-phenotype correlations,where gain-of-function variants lead to severe epileptic encephalopathies,while loss-of-function variants are associated with generalized epilepsy,highlighting the potential of Nav1.6-selective blockers such as XEN901 and GS967.(2)In Alzheimer’s disease,Nav1.6 mediates amyloid-βoligomer-induced neuronal hyperexcitability through amyloid precursor protein-dependent membrane trafficking and regulates beta-secretase 1 expression via nuclear factor of activated T cells 1 signaling,suggesting novel disease-modifying strategies.(3)Parkinson’s disease research has demonstrated that Nav1.6 upregulation in reactive astrocytes in the globus pallidus contributes to motor deficits through calcium-mediated abnormalities in neuronal synchronization.(4)Amyotrophic lateral sclerosis involves Nav1.6-dependent cortical hyperexcitability preceding motor neuron degeneration,with riluzole showing partial efficacy through sodium current modulation.(5)Multiple sclerosis pathophysiology features Nav1.6 redistribution in demyelinated axons,which drives calcium-dependent axonal injury via reverse Na+/Ca2+exchange.(6)Chronic pain mechanisms involve Nav1.6 overexpression in dorsal root ganglia neurons,regulated by the p38 mitogen-activated protein kinase and tumor necrosis factor-αsignaling pathways.(7)Traumatic brain injury models show that exercise-induced cognitive improvement is correlated with the normalization of Nav1.6-mediated excitability.Therapeutic development has progressed from nonselective sodium channel blockers to precision approaches,including state-dependent pore blockers designed using structural insights;allosteric modulators targeting specific conformations;gene therapy strategies using clustered regularly interspaced short palindromic repeats and antisense oligonucleotides;and miRNA-based regulation of channel expression.Current challenges include achieving sufficient subtype selectivity,optimizing blood-brain barrier penetration,and developing clinically relevant biomarkers for patient stratification.Future directions emphasize the integration of advanced technologies-such as single-cell multiomics to map neuronal subtype-specific expression patterns,patient-derived organoids for personalized drug testing,and machine learning-assisted drug design-to accelerate translation.Large-scale collaborative efforts will be essential to validate therapeutic candidates and establish genotype-guided treatment protocols for Nav1.6-related disorders.展开更多
Phosphatidylethanolamine is a major phospholipid class abundant in the brain,particularly in the inner leaflet of the plasma and mitochondrial membranes.Although it is primarily synthesized from phosphatidylserine via...Phosphatidylethanolamine is a major phospholipid class abundant in the brain,particularly in the inner leaflet of the plasma and mitochondrial membranes.Although it is primarily synthesized from phosphatidylserine via decarboxylation in mitochondria or from ethanolamine via the cytidine diphosphate-ethanolamine pathway in the endoplasmic reticulum,phosphatidylethanolamine that resides in mitochondria is preferentially produced locally and is distinct and separate from the pool of phosphatidylethanolamine made in the endoplasmic reticulum.Mitochondria-derived phosphatidylethanolamine is not only essential for mitochondrial integrity but also is exported to other organelles to fulfill diverse cellular functions.Neurons are highly enriched with phosphatidylethanolamine,and the importance of phosphatidylethanolamine metabolism in neuronal health has recently been recognized following its reported links to Alzheimer’s disease,Parkinson’s disease,and hereditary spastic paraplegia,among other neurological disorders.Indeed,disturbances in mitochondrial function and phosphatidylethanolamine metabolism and the resulting neuronal dysfunction are the common features of individuals suffering from these diseases,highlighting the great importance of maintaining proper phosphatidylethanolamine homeostasis in neurons.In this review,we summarize the current knowledge of phosphatidylethanolamine metabolism and its role in neuronal function with a special emphasis on the phosphatidylethanolamine biosynthetic pathway in mitochondria.We then review findings on how phosphatidylethanolamine biosynthesis is affected in major neurodegenerative diseases.Finally,we highlight promising future research areas that will help advance the understanding of neuronal phosphatidylethanolamine mechanisms and identify phosphatidylethanolamine-targeted therapeutic strategies for combating such brain diseases.展开更多
In recent years,exosomes have garnered extensive attention as therapeutic agents and early diagnostic markers in neurodegenerative disease research.Exosomes are small and can effectively cross the blood-brain barrier,...In recent years,exosomes have garnered extensive attention as therapeutic agents and early diagnostic markers in neurodegenerative disease research.Exosomes are small and can effectively cross the blood-brain barrier,allowing them to target deep brain lesions.Recent studies have demonstrated that exosomes derived from different cell types may exert therapeutic effects by regulating the expression of various inflammatory cytokines,mRNAs,and disease-related proteins,thereby halting the progression of neurodegenerative diseases and exhibiting beneficial effects.However,exosomes are composed of lipid bilayer membranes and lack the ability to recognize specific target cells.This limitation can lead to side effects and toxicity when they interact with non-specific cells.Growing evidence suggests that surface-modified exosomes have enhanced targeting capabilities and can be used as targeted drug-delivery vehicles that show promising results in the treatment of neurodegenerative diseases.In this review,we provide an up-to-date overview of existing research aimed at devising approaches to modify exosomes and elucidating their therapeutic potential in neurodegenerative diseases.Our findings indicate that exosomes can efficiently cross the blood-brain barrier to facilitate drug delivery and can also serve as early diagnostic markers for neurodegenerative diseases.We introduce the strategies being used to enhance exosome targeting,including genetic engineering,chemical modifications(both covalent,such as click chemistry and metabolic engineering,and non-covalent,such as polyvalent electrostatic and hydrophobic interactions,ligand-receptor binding,aptamer-based modifications,and the incorporation of CP05-anchored peptides),and nanomaterial modifications.Research into these strategies has confirmed that exosomes have significant therapeutic potential for neurodegenerative diseases.However,several challenges remain in the clinical application of exosomes.Improvements are needed in preparation,characterization,and optimization methods,as well as in reducing the adverse reactions associated with their use.Additionally,the range of applications and the safety of exosomes require further research and evaluation.展开更多
Alzheimer’s disease is initially thought to be caused by age-associated accumulation of plaques,in recent years,research has increasingly associated Alzheimer’s disease with lysosomal storage and metabolic disorders...Alzheimer’s disease is initially thought to be caused by age-associated accumulation of plaques,in recent years,research has increasingly associated Alzheimer’s disease with lysosomal storage and metabolic disorders,and the explanation of its pathogenesis has shifted from amyloid and tau accumulation to oxidative stress and impaired lipid and glucose metabolism aggravated by hypoxic conditions.However,the underlying mechanisms linking those cellular processes and conditions to disease progression have yet to be defined.Here,we applied a disease similarity approach to identify unknown molecular targets of Alzheimer’s disease by using transcriptomic data from congenital diseases known to increase Alzheimer’s disease risk,namely Down syndrome,Niemann-Pick type C disease,and mucopolysaccharidoses I.We uncovered common pathways,hub genes,and miRNAs across in vitro and in vivo models of these diseases as potential molecular targets for neuroprotection and amelioration of Alzheimer’s disease pathology,many of which have never been associated with Alzheimer’s disease.We then investigated common molecular alterations in brain samples from a Niemann-Pick type C disease mouse model by juxtaposing them with brain samples of both human and mouse models of Alzheimer’s disease.Detailed phenotypic,molecular,chronological,and biological aging analyses revealed that the Npc1tm(I1061T)Dso mouse model can serve as a potential short-lived in vivo model for brain aging and Alzheimer’s disease research.This research represents the first comprehensive approach to congenital disease association with neurodegeneration and a new perspective on Alzheimer’s disease research while highlighting shortcomings and lack of correlation in diverse in vitro models.Considering the lack of an Alzheimer’s disease mouse model that recapitulates the physiological hallmarks of brain aging,the short-lived Npc1^(tm(I1061T)Dso) mouse model can further accelerate the research in these fields and offer a unique model for understanding the molecular mechanisms of Alzheimer’s disease from a perspective of accelerated brain aging.展开更多
The selective vulnerability of nigrostriatal dopaminergic neurons is a hallmark of Parkinson’s disease and underlies its progressive motor decline.These neurons are uniquely susceptible to degeneration due to their e...The selective vulnerability of nigrostriatal dopaminergic neurons is a hallmark of Parkinson’s disease and underlies its progressive motor decline.These neurons are uniquely susceptible to degeneration due to their extensive axonal arborization,high energy demands,sustained pacemaking activity,and cytosolic dopamine metabolism,which collectively promote oxidative stress and mitochondrial dysfunction.Advances in single-nucleus RNA sequencing and spatial transcriptomics have revealed transcriptionally distinct dopaminergic subtypes within the human substantia nigra pars compacta,such as AGTR1+/SOX6+and RIT2+populations,which exhibit subtype-specific transcriptional stress signatures and are preferentially lost in Parkinson’s disease.These findings underscore the role of intrinsic vulnerability,influenced by genetic risk loci,mitochondrial stress,and protein misfolding pathways,includingα-synuclein aggregation.Furthermore,neuroinflammation,iron accumulation,and vascular dysfunction act synergistically to amplify neuronal loss.This review integrates molecular,cellular,and systems-level mechanisms contributing to dopaminergic degeneration and evaluates emerging neuroprotective strategies.These include anti-oxidative,anti-inflammatory,mitochondrial therapies,novel biomarkers,gene editing,and cell replacement techniques.Understanding the selective vulnerability of nigrostriatal subtypes offers a promising path toward precision-targeted,disease-modifying treatments for Parkinson’s disease.展开更多
AIM: To determine whether normal genetically immunocompetent rodent hosts could be manipulated to accept human hepatocyte transplants with long term survival without immunosuppression. METHODS: Tolerance towards human...AIM: To determine whether normal genetically immunocompetent rodent hosts could be manipulated to accept human hepatocyte transplants with long term survival without immunosuppression. METHODS: Tolerance towards human hepatocytes was established by injection of primary human hepatocytes or Huh7 human hepatoma cells into the peritoneal cavities of fetal rats. Corresponding cells were subsequently transplanted into newborn rats via intrasplenic injection within 24h after birth. RESULTS: Mixed lymphocyte assays showed that spleen cells from non-tolerized rats were stimulated to proliferate when exposed to human hepatocytes, while cells from tolerized rats were not. Injections made between 15 d and 17 d of gestation produced optimal tolerization. Transplanted human hepatocytes in rat livers were visualized by immunohistochemical staining of human albumin. By dot blotting of genomic DNA in livers of tolerized rats 16 weeks after hepatocyte transplantation, it was found that approximately 2.5 X 10(5) human hepatocytes survived per rat liver. Human albumin mRNA was detected in rat livers by RT-PCR for 15 wk, and human albumin protein was also detectable in rat serum. CONCLUSION: Tolerization of an immuno-competent rat can permit transplantation, and survival of functional human hepatocytes.展开更多
The nucleotide sequence deduced from the amino acid sequence of the scorpion insectotoxin AaIT was chemically synthesized and was expressed in Escherichia coli. The authenticity of this in vitro expressed peptide was ...The nucleotide sequence deduced from the amino acid sequence of the scorpion insectotoxin AaIT was chemically synthesized and was expressed in Escherichia coli. The authenticity of this in vitro expressed peptide was confirmed by N-terminal peptide sequencing. Two groups of bioassays, artificial diet incorporation assay and contact insecticidal effect assay, were carried out separately to verify the toxicity of this recombinant toxin. At the end of a 24 h experimental period, more than 60% of the testing diamondback moth (Plutella xylostella) larvae were killed in both groups with LC50 value of 18.4 microM and 0.70 microM respectively. Cytotoxicity assay using cultured Sf9 insect cells and MCF-7 human cells demonstrated that the toxin AaIT had specific toxicity against insect cells but not human cells. Only 0.13 microM recombinant toxin was needed to kill 50% of cultured insect cells while as much as 1.3 microM toxin had absolutely no effect on human cells. Insect cells produced obvious intrusions from their plasma membrane before broken up. We infer that toxin AaIT bind to a putative sodium channel in these insect cells and open the channel persistently, which would result in Na+ influx and finally cause destruction of insect cells.展开更多
Alzheimer’s disease(AD)is the most common form of dementia.In addition to the lack of effective treatments,there are limitations in diagnostic capabilities.The complexity of AD itself,together with a variety of other...Alzheimer’s disease(AD)is the most common form of dementia.In addition to the lack of effective treatments,there are limitations in diagnostic capabilities.The complexity of AD itself,together with a variety of other diseases often observed in a patient’s history in addition to their AD diagnosis,make deciphering the molecular mechanisms that underlie AD,even more important.Large datasets of single-cell RNA sequencing,single-nucleus RNA-sequencing(snRNA-seq),and spatial transcriptomics(ST)have become essential in guiding and supporting new investigations into the cellular and regional susceptibility of AD.However,with unique technology,software,and larger databases emerging;a lack of integration of these data can contribute to ineffective use of valuable knowledge.Importantly,there was no specialized database that concentrates on ST in AD that offers comprehensive differential analyses under various conditions,such as sex-specific,region-specific,and comparisons between AD and control groups until the new Single-cell and Spatial RNA-seq databasE for Alzheimer’s Disease(ssREAD)database(Wang et al.,2024)was introduced to meet the scientific community’s growing demand for comprehensive,integrated,and accessible data analysis.展开更多
Current evidence for oligodendrocyte precursor cell involvement in Parkinson’s disease:Oligodendroglial cells comprise a large cell population in the substantia nigra(SN).We recently reported a stable portion of olig...Current evidence for oligodendrocyte precursor cell involvement in Parkinson’s disease:Oligodendroglial cells comprise a large cell population in the substantia nigra(SN).We recently reported a stable portion of oligodendrocyte precursor cells(OPCs)in the SN pars compacta(SNpc)in a 1:1 ratio with dopaminergic neurons:15%of cells in neonate and young mice,rising to 20%in aged mice.Moreover,this portion represents only 45%of all oligodendroglial cells in the SNpc and 54%of all oligodendroglial cells in the SN pars reticulata(SNpr)(Fitzgerald et al.,2025).The SN is a deeply located area of the midbrain and the site of dopaminergic degeneration in Parkinson’s disease(PD).Recent advancement of single-cell transcriptomics revealed the involvement of non-neuronal cells in PD,with PD risk variants being strongly associated with oligodendroglia(reviewed by Salazar Campos et al.,2025).展开更多
Although momentum strategies result in abnormal profitability,thereby challenging the efficient market hypothesis(EMH),concerns persist regarding their reliability due to their significant volatility and susceptibilit...Although momentum strategies result in abnormal profitability,thereby challenging the efficient market hypothesis(EMH),concerns persist regarding their reliability due to their significant volatility and susceptibility to substantial losses.In this study,we investigate the limitations of these strategies and propose a solution.Our literature review reveals that the volatile profits are due to statistical analyses that assume the persistence of past patterns,leading to unreliable results in out-of-sample scenarios when underlying mechanisms evolve.Statistical analysis,the predominant method in financial economics,often proves inadequate in explaining market fluctuations and predicting crashes.To overcome these limitations,a paradigm shift towards dynamic approaches is essential.Drawing inspiration from three groundbreaking economists,we introduce the extended Samuelson model(ESM),a dynamic model that connects price changes to market participant actions.This paradigm transition uncovers several significant findings.First,timely signals indicate momentum initiations,cessations,and reversals,validated using S&P 500 data from 1999 to 2023.Second,ESM predicts the 1987 Black Monday crash weeks in advance,offering a new perspective on its underlying cause.Third,we classify sequential stock price data into eight distinct market states,including their thresholds for transitions,laying the groundwork for market trend predictions and risk assessments.Fourth,the ESM is shown to be a compelling alternative to EMH,offering potent explanatory and predictive power based on a single,realistic assumption.Our findings suggest that ESM has the potential to provide policymakers with proactive tools,enabling financial institutions to enhance their risk assessment and management strategies.展开更多
Neurodegenerative diseases,which are characterized by progressive neuronal loss and the lack of disease-modifying therapies,are becoming a major global health challenge.The existing neuromodulation techniques,such as ...Neurodegenerative diseases,which are characterized by progressive neuronal loss and the lack of disease-modifying therapies,are becoming a major global health challenge.The existing neuromodulation techniques,such as deep brain stimulation and transcranial magnetic stimulation,show limitations such as invasiveness,restricted cortical targeting,and irreversible tissue effects.In this context,low-intensity transcranial ultrasound has emerged as a promising noninvasive alternative that can penetrate deep into the brain and modulate neuroplasticity.This review comprehensively assesses the therapeutic mechanisms,efficacy,and translational potential of low-intensity transcranial ultrasound in treating neurodegenerative diseases,with emphasis on its role in promoting neuronal regeneration,modulating neuroinflammation,and enhancing functional recovery.We summarize the findings of previous studies and systematically illustrate the potential of low-intensity transcranial ultrasound in regulating cell death mechanisms,enhancing neural repair and regeneration,and alleviating symptoms associated with neurodegenerative diseases.Preclinical findings indicate that low-intensity transcranial ultrasound can enhance the release of neurotrophic factors(e.g.,brain-derived neurotrophic factor),promote autophagy to clear protein aggregates,modulate microglial activation,and temporarily open the blood-brain barrier to facilitate targeted drug delivery.Existing clinical trial data show that low-intensity transcranial ultrasound can reduce amyloid-βplaques,improve motor and cognitive deficits,and promote remyelination in various disease models.Early clinical trials suggest that low-intensity transcranial ultrasound may enhance cognitive scores in Alzheimer’s disease and alleviate motor symptoms in Parkinson’s disease,all while demonstrating a favorable safety profile.Past studies support the notion that by integrating safety,precision,and reversibility,low-intensity transcranial ultrasound can transform the treatment landscape for neurodegenerative disease.However,more advancements are necessary for future clinical application of low-intensity transcranial ultrasound,including optimizing parameters such as frequency,intensity,and duty cycle;considering individual anatomical differences;and confirming long-term efficacy.We believe establishing standardized protocols,conducting larger trials,and investigating the underlying mechanisms to clarify dose-response relationships and refine personalized application strategies are essential in this regard.Future research should focus on translating preclinical findings into clinical practice,addressing technical challenges,and exploring combination therapies with pharmacological or gene interventions.展开更多
A century ago the classical physics couldn’t explain many atomic physical phenomena. Now the situation has changed. It’s because within the framework of classical physics with the help of Maxwell’s equations we can...A century ago the classical physics couldn’t explain many atomic physical phenomena. Now the situation has changed. It’s because within the framework of classical physics with the help of Maxwell’s equations we can derive Schrödinger’s equation, which is the foundation of quantum physics. The equations for energy, momentum, frequency and wavelength of the electromagnetic wave in the atom are derived using the model of atom by analogy with the transmission line. The action constant A0 = (μ0/ε0)1/2s02e2 is a key term in the above mentioned equations. Besides the other well-known constants, the only unknown constant in the last expression is a structural constant of the atom s0. We have found that the value of this constant is 8.277 56 and that it shows up as a link between macroscopic and atomic world. After calculating this constant we get the theory of atoms based on Maxwell’s and Lorentz equations only. This theory does not require knowledge of Planck’s constant h, which is replaced with theoretically derived action constant A0, while the replacement for the fine structure constant α-1 is theoretically derived expression 2s02 = 137.036. So, the structural constant s0 replaces both constants h and α. This paper also defines the stationary states of atoms and shows that the maximal atomic number is equal to Zmax = 137. The presented model of the atoms covers three of the four fundamental interactions, namely the electromagnetic, weak and strong interactions.展开更多
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 ζ(s) 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 National Key R&D Program of China,No.2021YFC2501200(to PC).
文摘Short-chain fatty acids,metabolites produced by the fermentation of dietary fiber by gut microbiota,have garnered significant attention due to their correlation with neurodegenerative diseases,particularly Parkinson’s disease.In this review,we summarize the changes in short-chain fatty acid levels and the abundance of short-chain fatty acid-producing bacteria in various samples from patients with Parkinson’s disease,highlighting the critical role of gut homeostasis imbalance in the pathogenesis and progression of the disease.Focusing on the nervous system,we discuss the molecular mechanisms by which short-chain fatty acids influence the homeostasis of both the enteric nervous system and the central nervous system.We identify key processes,including the activation of G protein-coupled receptors and the inhibition of histone deacetylases by short-chain fatty acids.Importantly,structural or functional disruptions in the enteric nervous system mediated by these fatty acids may lead to abnormalα-synuclein expression and gastrointestinal dysmotility,which could serve as an initiating event in Parkinson’s disease.Furthermore,we propose that short-chain fatty acids help establish communication between the enteric nervous system and the central nervous system via the vagal nerve,immune circulation,and endocrine signaling.This communication may shed light on their potential role in the transmission ofα-synuclein from the gut to the brain.Finally,we elucidate novel treatment strategies for Parkinson’s disease that target short-chain fatty acids and examine the challenges associated with translating short-chain fatty acid-based therapies into clinical practice.In conclusion,this review emphasizes the pivotal role of short-chain fatty acids in regulating gut-brain axis integrity and their significance in the pathogenesis of Parkinson’s disease from the perspective of the nervous system.Moreover,it highlights the potential value of short-chain fatty acids in early intervention for Parkinson’s disease.Future research into the molecular mechanisms of short-chain fatty acids and their synergistic interactions with other gut metabolites is likely to advance the clinical translation of innovative short-chain fatty acid-based therapies for Parkinson’s disease.
基金1RO1EY032959-01 from NIH,Leonard A Mann Chair Endowment Fund,from the University of Dayton(to AS)Knights Templar Eye Foundation grant(to MS)。
文摘Neurodegenerative diseases(neurodegenerative disorders)are marked by the progressive degeneration of the structure and function of the central nervous system.They may res ult in the deterioration of cognitive,motor,and functional abilities.Diseases such as Alzheimer s disease,Parkinson's disease,Huntington's disease,and amyotrophic lateral sclerosis represent some of the most prominent examples of neurodegenerative disorders.Des pite scientific advancement in understanding disease pathology and prognosis,the therapeutic strategies available for management remain limited.In recent years,microRNAs,small non-coding RNA molecules,have emerged as key players in the pathogenesis of neurodegenerative disorde rs.Therefo re,understanding how these microRNAs affect disease pathology and pathway signaling is essential,and may open microRNAs as new avenues for potential therapeutic intervention.This review explores the role of microRNAs in va rious neurodegenerative diseases,discuss how microRNAs affect signaling pathways,and examine the potential of microRNAs as therapeutic targets.
基金supported by the National Natural Science Foundation of China,No.32200782(to ZL)the Science and Technology Development Plan Project of Jilin Province,No.20240404014ZP(to ZL).
文摘In recent years,an increasing number of researchers have become interested in the bidirectional communication between the gut microbiota and the central nervous system.This communication occurs through the microbiota-gut-brain axis.As people age,the composition of the gut microbiota undergoes considerable changes,which are now known to play an important role in the development of many neurodegenerative diseases.This review aims to investigate the complex bidirectional signaling pathways between the gut and the brain.It summarizes the latest research findings on how the gut microbiota and its metabolites play critical roles in regulating inflammation,maintaining gut health,and influencing the development of neurodegenerative diseases such as Alzheimer’s disease,Parkinson’s disease,and amyotrophic lateral sclerosis.The review also analyzes the current clinical applications of gut microbiota-based treatments for neurological disorders,including fecal microbiota transplantation,probiotics,and prebiotics.Many studies show that the gut microbiota affects the brain in several ways.For example,it can produce substances such as short-chain fatty acids and activate inflammatory pathways.Studies involving animals and laboratory models have demonstrated that adjusting the gut microbiota can help improve behavior and reduce neurological problems.Recent metagenomic and metabolomics studies have shown that the microbiota plays a crucial role in maintaining the organism’s health.Microorganisms primarily colonize the gut and are involved in host nutrient metabolism,maintaining the structural integrity of the intestine,preserving the intestinal mucosal barrier,and modulating the immune system.The gut microbiota communicates with the brain through a bidirectional microbiota-gut-brain axis.The composition of the gut flora changes considerably with age,and ecological dysregulation has been recognized as one of the twelve most recent hallmarks of aging.Recent studies have linked these changes to a variety of age-related neurological disorders,including Alzheimer’s disease,amyotrophic lateral sclerosis,Parkinson’s disease,multiple sclerosis,and Huntington’s disease.Specifically,the gut microbiota influences the brain through the production of key metabolites such as short-chain fatty acids and the activation of inflammatory and other relevant signaling pathways.In preclinical studies,targeted modulation of the gut microbiota,through methods such as fecal microbiota transplantation,probiotics,and prebiotics,has demonstrated potential in improving host behavioral outcomes.Therefore,gut microbiota-based treatments offer new hope for the treatment of nervous system diseases.However,due to the complexity of the gut microbiota and the potential adverse reactions associated with these therapies,researchers need to carefully assess their safety and efficacy before widespread clinical application.
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.
基金supported by the National Natural Science Foundation of China,No.82160255(to RX)the Natural Science Foundation of Jiangxi Province,No.20212BAB216026(to HL)+2 种基金Science and Technology Plan Project of Health Commission of Jiangxi Province,No.202110016(to HL)Science and Technology Plan Project of Jiangxi Provincial Administration of Traditional Chinese Medicine,No.2022B975(to HL)a grant from Jiangxi Province Key Laboratory of Neurology,No.2024SSY06081(to RX).
文摘With the gradual advancement of research methods and technologies,various biological processes have been identified as playing roles in the pathogenesis of neurodegenerative diseases.However,current descriptions of these biological processes do not fully explain the onset,progression,and development of these conditions.Therefore,exploration of the pathogenesis of neurodegenerative diseases remains a valuable area of research.This review summarizes the potential common pathogeneses of Alzheimer’s disease,Parkinson’s disease,amyotrophic lateral sclerosis,Huntington’s disease,frontotemporal lobar dementia,and Lewy body disease.Research findings have indicated that several common biological processes,including aging,genetic factors,progressive neuronal dysfunction,neuronal death and apoptosis,protein misfolding and aggregation,neuroinflammation,mitochondrial dysfunction,axonal transport defects,and gut microbiota dysbiosis,are involved in the pathogenesis of these six neurodegenerative diseases.Based on current information derived from diverse areas of research,these biological processes may form complex pathogenic networks that lead to distinctive types of neuronal death in neurodegenerative diseases.Furthermore,promoting the regeneration of damaged neurons may be achievable through the repair of affected neural cells if the underlying pathogenesis can be prevented or reversed.Hence,these potential common biological processes may represent only very small,limited elements within numerous intricate pathogenic networks associated with neurodegenerative diseases.In clinical treatment,interfering with any single biological process has proven insufficient to completely halt the progression of neurodegenerative diseases.Therefore,future research on the pathogenesis of neurodegenerative diseases should focus on uncovering the complex pathogenic networks,rather than isolating individual biological processes.Based on this,therapies that aim to block or reverse various targets involved in the potential pathogenic mechanisms of neurodegenerative diseases may be promising directions,as current treatment methods that focus on halting a single pathogenic factor have not achieved satisfactory efficacy.
基金supported by the Science and Technology Program Joint Program(Applied Basic Research Project)of Liaoning Province,China,No.2023JH2/101700079(to JunW).
文摘The voltage-gated sodium channel Nav1.6,encoded by the sodium voltage-gated channel alpha subunit 8 gene,is a crucial regulator of neuronal excitability,with widespread expression throughout the central and peripheral nervous systems.Recent breakthroughs in structural biology,particularly the elucidation of the cryo-EM architecture of Nav1.6 at a resolution of 0.31 nm,have provided unprecedented insights into its molecular organization and functional modulation.As a key mediator of action potential initiation and propagation,Nav1.6 possesses unique biophysical properties,including persistent and resurgent sodium currents that critically influence neuronal firing patterns.This comprehensive review synthesizes current knowledge on the physiological functions and pathological roles of Nav1.6 in multiple neurological conditions.Key findings include the following:(1)Epilepsy studies reveal more than 250 sodium voltage-gated channel alpha subunit 8 mutations with distinct genotype-phenotype correlations,where gain-of-function variants lead to severe epileptic encephalopathies,while loss-of-function variants are associated with generalized epilepsy,highlighting the potential of Nav1.6-selective blockers such as XEN901 and GS967.(2)In Alzheimer’s disease,Nav1.6 mediates amyloid-βoligomer-induced neuronal hyperexcitability through amyloid precursor protein-dependent membrane trafficking and regulates beta-secretase 1 expression via nuclear factor of activated T cells 1 signaling,suggesting novel disease-modifying strategies.(3)Parkinson’s disease research has demonstrated that Nav1.6 upregulation in reactive astrocytes in the globus pallidus contributes to motor deficits through calcium-mediated abnormalities in neuronal synchronization.(4)Amyotrophic lateral sclerosis involves Nav1.6-dependent cortical hyperexcitability preceding motor neuron degeneration,with riluzole showing partial efficacy through sodium current modulation.(5)Multiple sclerosis pathophysiology features Nav1.6 redistribution in demyelinated axons,which drives calcium-dependent axonal injury via reverse Na+/Ca2+exchange.(6)Chronic pain mechanisms involve Nav1.6 overexpression in dorsal root ganglia neurons,regulated by the p38 mitogen-activated protein kinase and tumor necrosis factor-αsignaling pathways.(7)Traumatic brain injury models show that exercise-induced cognitive improvement is correlated with the normalization of Nav1.6-mediated excitability.Therapeutic development has progressed from nonselective sodium channel blockers to precision approaches,including state-dependent pore blockers designed using structural insights;allosteric modulators targeting specific conformations;gene therapy strategies using clustered regularly interspaced short palindromic repeats and antisense oligonucleotides;and miRNA-based regulation of channel expression.Current challenges include achieving sufficient subtype selectivity,optimizing blood-brain barrier penetration,and developing clinically relevant biomarkers for patient stratification.Future directions emphasize the integration of advanced technologies-such as single-cell multiomics to map neuronal subtype-specific expression patterns,patient-derived organoids for personalized drug testing,and machine learning-assisted drug design-to accelerate translation.Large-scale collaborative efforts will be essential to validate therapeutic candidates and establish genotype-guided treatment protocols for Nav1.6-related disorders.
基金supported by the National Institutes of Health(grant numbers R01NS089737,RF1NS130881,and R21AG089974,to QC).
文摘Phosphatidylethanolamine is a major phospholipid class abundant in the brain,particularly in the inner leaflet of the plasma and mitochondrial membranes.Although it is primarily synthesized from phosphatidylserine via decarboxylation in mitochondria or from ethanolamine via the cytidine diphosphate-ethanolamine pathway in the endoplasmic reticulum,phosphatidylethanolamine that resides in mitochondria is preferentially produced locally and is distinct and separate from the pool of phosphatidylethanolamine made in the endoplasmic reticulum.Mitochondria-derived phosphatidylethanolamine is not only essential for mitochondrial integrity but also is exported to other organelles to fulfill diverse cellular functions.Neurons are highly enriched with phosphatidylethanolamine,and the importance of phosphatidylethanolamine metabolism in neuronal health has recently been recognized following its reported links to Alzheimer’s disease,Parkinson’s disease,and hereditary spastic paraplegia,among other neurological disorders.Indeed,disturbances in mitochondrial function and phosphatidylethanolamine metabolism and the resulting neuronal dysfunction are the common features of individuals suffering from these diseases,highlighting the great importance of maintaining proper phosphatidylethanolamine homeostasis in neurons.In this review,we summarize the current knowledge of phosphatidylethanolamine metabolism and its role in neuronal function with a special emphasis on the phosphatidylethanolamine biosynthetic pathway in mitochondria.We then review findings on how phosphatidylethanolamine biosynthesis is affected in major neurodegenerative diseases.Finally,we highlight promising future research areas that will help advance the understanding of neuronal phosphatidylethanolamine mechanisms and identify phosphatidylethanolamine-targeted therapeutic strategies for combating such brain diseases.
基金supported by the National Natural Science Foundation of China,No.22103055(to JG)the Natural Science Foundation of Hebei Province,No.F2024110001(to HC)Open Project of Tianjin Key Laboratory of Optoelectronic Detection Technology and System,Nos.2024LODTS215(to NL),2024LODTS216(to XS).
文摘In recent years,exosomes have garnered extensive attention as therapeutic agents and early diagnostic markers in neurodegenerative disease research.Exosomes are small and can effectively cross the blood-brain barrier,allowing them to target deep brain lesions.Recent studies have demonstrated that exosomes derived from different cell types may exert therapeutic effects by regulating the expression of various inflammatory cytokines,mRNAs,and disease-related proteins,thereby halting the progression of neurodegenerative diseases and exhibiting beneficial effects.However,exosomes are composed of lipid bilayer membranes and lack the ability to recognize specific target cells.This limitation can lead to side effects and toxicity when they interact with non-specific cells.Growing evidence suggests that surface-modified exosomes have enhanced targeting capabilities and can be used as targeted drug-delivery vehicles that show promising results in the treatment of neurodegenerative diseases.In this review,we provide an up-to-date overview of existing research aimed at devising approaches to modify exosomes and elucidating their therapeutic potential in neurodegenerative diseases.Our findings indicate that exosomes can efficiently cross the blood-brain barrier to facilitate drug delivery and can also serve as early diagnostic markers for neurodegenerative diseases.We introduce the strategies being used to enhance exosome targeting,including genetic engineering,chemical modifications(both covalent,such as click chemistry and metabolic engineering,and non-covalent,such as polyvalent electrostatic and hydrophobic interactions,ligand-receptor binding,aptamer-based modifications,and the incorporation of CP05-anchored peptides),and nanomaterial modifications.Research into these strategies has confirmed that exosomes have significant therapeutic potential for neurodegenerative diseases.However,several challenges remain in the clinical application of exosomes.Improvements are needed in preparation,characterization,and optimization methods,as well as in reducing the adverse reactions associated with their use.Additionally,the range of applications and the safety of exosomes require further research and evaluation.
基金supported by the NIA/NIH(1K01AG060040).Studies performed by JN were funded by the NICHD/NIH(5R00HD096117)Microscopy Core Facility supported,in part,with funding from NIH-NCI Cancer Center Support Grant P30 CA016059.
文摘Alzheimer’s disease is initially thought to be caused by age-associated accumulation of plaques,in recent years,research has increasingly associated Alzheimer’s disease with lysosomal storage and metabolic disorders,and the explanation of its pathogenesis has shifted from amyloid and tau accumulation to oxidative stress and impaired lipid and glucose metabolism aggravated by hypoxic conditions.However,the underlying mechanisms linking those cellular processes and conditions to disease progression have yet to be defined.Here,we applied a disease similarity approach to identify unknown molecular targets of Alzheimer’s disease by using transcriptomic data from congenital diseases known to increase Alzheimer’s disease risk,namely Down syndrome,Niemann-Pick type C disease,and mucopolysaccharidoses I.We uncovered common pathways,hub genes,and miRNAs across in vitro and in vivo models of these diseases as potential molecular targets for neuroprotection and amelioration of Alzheimer’s disease pathology,many of which have never been associated with Alzheimer’s disease.We then investigated common molecular alterations in brain samples from a Niemann-Pick type C disease mouse model by juxtaposing them with brain samples of both human and mouse models of Alzheimer’s disease.Detailed phenotypic,molecular,chronological,and biological aging analyses revealed that the Npc1tm(I1061T)Dso mouse model can serve as a potential short-lived in vivo model for brain aging and Alzheimer’s disease research.This research represents the first comprehensive approach to congenital disease association with neurodegeneration and a new perspective on Alzheimer’s disease research while highlighting shortcomings and lack of correlation in diverse in vitro models.Considering the lack of an Alzheimer’s disease mouse model that recapitulates the physiological hallmarks of brain aging,the short-lived Npc1^(tm(I1061T)Dso) mouse model can further accelerate the research in these fields and offer a unique model for understanding the molecular mechanisms of Alzheimer’s disease from a perspective of accelerated brain aging.
文摘The selective vulnerability of nigrostriatal dopaminergic neurons is a hallmark of Parkinson’s disease and underlies its progressive motor decline.These neurons are uniquely susceptible to degeneration due to their extensive axonal arborization,high energy demands,sustained pacemaking activity,and cytosolic dopamine metabolism,which collectively promote oxidative stress and mitochondrial dysfunction.Advances in single-nucleus RNA sequencing and spatial transcriptomics have revealed transcriptionally distinct dopaminergic subtypes within the human substantia nigra pars compacta,such as AGTR1+/SOX6+and RIT2+populations,which exhibit subtype-specific transcriptional stress signatures and are preferentially lost in Parkinson’s disease.These findings underscore the role of intrinsic vulnerability,influenced by genetic risk loci,mitochondrial stress,and protein misfolding pathways,includingα-synuclein aggregation.Furthermore,neuroinflammation,iron accumulation,and vascular dysfunction act synergistically to amplify neuronal loss.This review integrates molecular,cellular,and systems-level mechanisms contributing to dopaminergic degeneration and evaluates emerging neuroprotective strategies.These include anti-oxidative,anti-inflammatory,mitochondrial therapies,novel biomarkers,gene editing,and cell replacement techniques.Understanding the selective vulnerability of nigrostriatal subtypes offers a promising path toward precision-targeted,disease-modifying treatments for Parkinson’s disease.
文摘AIM: To determine whether normal genetically immunocompetent rodent hosts could be manipulated to accept human hepatocyte transplants with long term survival without immunosuppression. METHODS: Tolerance towards human hepatocytes was established by injection of primary human hepatocytes or Huh7 human hepatoma cells into the peritoneal cavities of fetal rats. Corresponding cells were subsequently transplanted into newborn rats via intrasplenic injection within 24h after birth. RESULTS: Mixed lymphocyte assays showed that spleen cells from non-tolerized rats were stimulated to proliferate when exposed to human hepatocytes, while cells from tolerized rats were not. Injections made between 15 d and 17 d of gestation produced optimal tolerization. Transplanted human hepatocytes in rat livers were visualized by immunohistochemical staining of human albumin. By dot blotting of genomic DNA in livers of tolerized rats 16 weeks after hepatocyte transplantation, it was found that approximately 2.5 X 10(5) human hepatocytes survived per rat liver. Human albumin mRNA was detected in rat livers by RT-PCR for 15 wk, and human albumin protein was also detectable in rat serum. CONCLUSION: Tolerization of an immuno-competent rat can permit transplantation, and survival of functional human hepatocytes.
基金This work was supported by a grant from 863High Technology Program,Chinese Ministry of Sci-ence and Technology
文摘The nucleotide sequence deduced from the amino acid sequence of the scorpion insectotoxin AaIT was chemically synthesized and was expressed in Escherichia coli. The authenticity of this in vitro expressed peptide was confirmed by N-terminal peptide sequencing. Two groups of bioassays, artificial diet incorporation assay and contact insecticidal effect assay, were carried out separately to verify the toxicity of this recombinant toxin. At the end of a 24 h experimental period, more than 60% of the testing diamondback moth (Plutella xylostella) larvae were killed in both groups with LC50 value of 18.4 microM and 0.70 microM respectively. Cytotoxicity assay using cultured Sf9 insect cells and MCF-7 human cells demonstrated that the toxin AaIT had specific toxicity against insect cells but not human cells. Only 0.13 microM recombinant toxin was needed to kill 50% of cultured insect cells while as much as 1.3 microM toxin had absolutely no effect on human cells. Insect cells produced obvious intrusions from their plasma membrane before broken up. We infer that toxin AaIT bind to a putative sodium channel in these insect cells and open the channel persistently, which would result in Na+ influx and finally cause destruction of insect cells.
文摘Alzheimer’s disease(AD)is the most common form of dementia.In addition to the lack of effective treatments,there are limitations in diagnostic capabilities.The complexity of AD itself,together with a variety of other diseases often observed in a patient’s history in addition to their AD diagnosis,make deciphering the molecular mechanisms that underlie AD,even more important.Large datasets of single-cell RNA sequencing,single-nucleus RNA-sequencing(snRNA-seq),and spatial transcriptomics(ST)have become essential in guiding and supporting new investigations into the cellular and regional susceptibility of AD.However,with unique technology,software,and larger databases emerging;a lack of integration of these data can contribute to ineffective use of valuable knowledge.Importantly,there was no specialized database that concentrates on ST in AD that offers comprehensive differential analyses under various conditions,such as sex-specific,region-specific,and comparisons between AD and control groups until the new Single-cell and Spatial RNA-seq databasE for Alzheimer’s Disease(ssREAD)database(Wang et al.,2024)was introduced to meet the scientific community’s growing demand for comprehensive,integrated,and accessible data analysis.
文摘Current evidence for oligodendrocyte precursor cell involvement in Parkinson’s disease:Oligodendroglial cells comprise a large cell population in the substantia nigra(SN).We recently reported a stable portion of oligodendrocyte precursor cells(OPCs)in the SN pars compacta(SNpc)in a 1:1 ratio with dopaminergic neurons:15%of cells in neonate and young mice,rising to 20%in aged mice.Moreover,this portion represents only 45%of all oligodendroglial cells in the SNpc and 54%of all oligodendroglial cells in the SN pars reticulata(SNpr)(Fitzgerald et al.,2025).The SN is a deeply located area of the midbrain and the site of dopaminergic degeneration in Parkinson’s disease(PD).Recent advancement of single-cell transcriptomics revealed the involvement of non-neuronal cells in PD,with PD risk variants being strongly associated with oligodendroglia(reviewed by Salazar Campos et al.,2025).
文摘Although momentum strategies result in abnormal profitability,thereby challenging the efficient market hypothesis(EMH),concerns persist regarding their reliability due to their significant volatility and susceptibility to substantial losses.In this study,we investigate the limitations of these strategies and propose a solution.Our literature review reveals that the volatile profits are due to statistical analyses that assume the persistence of past patterns,leading to unreliable results in out-of-sample scenarios when underlying mechanisms evolve.Statistical analysis,the predominant method in financial economics,often proves inadequate in explaining market fluctuations and predicting crashes.To overcome these limitations,a paradigm shift towards dynamic approaches is essential.Drawing inspiration from three groundbreaking economists,we introduce the extended Samuelson model(ESM),a dynamic model that connects price changes to market participant actions.This paradigm transition uncovers several significant findings.First,timely signals indicate momentum initiations,cessations,and reversals,validated using S&P 500 data from 1999 to 2023.Second,ESM predicts the 1987 Black Monday crash weeks in advance,offering a new perspective on its underlying cause.Third,we classify sequential stock price data into eight distinct market states,including their thresholds for transitions,laying the groundwork for market trend predictions and risk assessments.Fourth,the ESM is shown to be a compelling alternative to EMH,offering potent explanatory and predictive power based on a single,realistic assumption.Our findings suggest that ESM has the potential to provide policymakers with proactive tools,enabling financial institutions to enhance their risk assessment and management strategies.
基金supported by STI2030-Major Project,No,2021ZD0204200(to LX).
文摘Neurodegenerative diseases,which are characterized by progressive neuronal loss and the lack of disease-modifying therapies,are becoming a major global health challenge.The existing neuromodulation techniques,such as deep brain stimulation and transcranial magnetic stimulation,show limitations such as invasiveness,restricted cortical targeting,and irreversible tissue effects.In this context,low-intensity transcranial ultrasound has emerged as a promising noninvasive alternative that can penetrate deep into the brain and modulate neuroplasticity.This review comprehensively assesses the therapeutic mechanisms,efficacy,and translational potential of low-intensity transcranial ultrasound in treating neurodegenerative diseases,with emphasis on its role in promoting neuronal regeneration,modulating neuroinflammation,and enhancing functional recovery.We summarize the findings of previous studies and systematically illustrate the potential of low-intensity transcranial ultrasound in regulating cell death mechanisms,enhancing neural repair and regeneration,and alleviating symptoms associated with neurodegenerative diseases.Preclinical findings indicate that low-intensity transcranial ultrasound can enhance the release of neurotrophic factors(e.g.,brain-derived neurotrophic factor),promote autophagy to clear protein aggregates,modulate microglial activation,and temporarily open the blood-brain barrier to facilitate targeted drug delivery.Existing clinical trial data show that low-intensity transcranial ultrasound can reduce amyloid-βplaques,improve motor and cognitive deficits,and promote remyelination in various disease models.Early clinical trials suggest that low-intensity transcranial ultrasound may enhance cognitive scores in Alzheimer’s disease and alleviate motor symptoms in Parkinson’s disease,all while demonstrating a favorable safety profile.Past studies support the notion that by integrating safety,precision,and reversibility,low-intensity transcranial ultrasound can transform the treatment landscape for neurodegenerative disease.However,more advancements are necessary for future clinical application of low-intensity transcranial ultrasound,including optimizing parameters such as frequency,intensity,and duty cycle;considering individual anatomical differences;and confirming long-term efficacy.We believe establishing standardized protocols,conducting larger trials,and investigating the underlying mechanisms to clarify dose-response relationships and refine personalized application strategies are essential in this regard.Future research should focus on translating preclinical findings into clinical practice,addressing technical challenges,and exploring combination therapies with pharmacological or gene interventions.
文摘A century ago the classical physics couldn’t explain many atomic physical phenomena. Now the situation has changed. It’s because within the framework of classical physics with the help of Maxwell’s equations we can derive Schrödinger’s equation, which is the foundation of quantum physics. The equations for energy, momentum, frequency and wavelength of the electromagnetic wave in the atom are derived using the model of atom by analogy with the transmission line. The action constant A0 = (μ0/ε0)1/2s02e2 is a key term in the above mentioned equations. Besides the other well-known constants, the only unknown constant in the last expression is a structural constant of the atom s0. We have found that the value of this constant is 8.277 56 and that it shows up as a link between macroscopic and atomic world. After calculating this constant we get the theory of atoms based on Maxwell’s and Lorentz equations only. This theory does not require knowledge of Planck’s constant h, which is replaced with theoretically derived action constant A0, while the replacement for the fine structure constant α-1 is theoretically derived expression 2s02 = 137.036. So, the structural constant s0 replaces both constants h and α. This paper also defines the stationary states of atoms and shows that the maximal atomic number is equal to Zmax = 137. The presented model of the atoms covers three of the four fundamental interactions, namely the electromagnetic, weak and strong interactions.
