The new mechanism of cognitive decline induced by hypertension: High homocysteine-mediated aberrant DNA methylation.

The prevalence and severity of hypertension-induced cognitive impairment increase with the prolonging of hypertension. The mechanisms of cognitive impairment induced by hypertension primarily include cerebral blood flow perfusion imbalance, white and gray matter injury with blood-brain barrier disruption, neuroinflammation and amyloid-beta deposition, genetic polymorphisms and variants, and instability of blood pressure. High homocysteine (HHcy) is an independent risk factor for hypertension that also increases the risk of developing early cognitive impairment. Homocysteine (Hcy) levels increase in patients with cognitive impairment induced by hypertension. This review summarizes a new mechanism whereby HHcy-mediated aberrant DNA methylation and exacerbate hypertension. It involves changes in Hcy-dependent DNA methylation products, such as methionine adenosyltransferase, DNA methyltransferases, S-adenosylmethionine, S-adenosylhomocysteine, and methylenetetrahydrofolate reductase (MTHFR). The mechanism also involves DNA methylation changes in the genes of hypertension patients, such as brain-derived neurotrophic factor, apolipoprotein E4, and estrogen receptor alpha, which contribute to learning, memory, and attention deficits. Studies have shown that methionine (Met) induces hypertension in mice. Moreover, DNA hypermethylation leads to cognitive behavioral changes alongside oligodendroglial and/or myelin deficits in Met-induced mice. Taken together, these studies demonstrate that DNA methylation regulates cognitive dysfunction in patients with hypertension. A better understanding of the function and mechanism underlying the effect of Hcy-dependent DNA methylation on hypertension-induced cognitive impairment will be valuable for early diagnosis, interventions, and prevention of further cognitive defects induced by hypertension.

[MtDNA haplogroup U4b is a genetic susceptibility factor for high altitude essential hypertension in the Chinese Tajik population].

Objective: To investigate the relationship between mitochondrial DNA (mtDNA) variation and high altitude essential hypertension(HAEH) in the Chinese Tajik population. Methods: Fifty-three patients with HAEH and 46 healthy subjects were enrolled from the Chinese Tajik population. The mtDNA fragments were amplificated by polymerase chain reaction, and products were sequenced to acquire full sequence of mtDNA. The mtDNA sequences of all subjects were compared to the Cambridge sequence to explore mtDNA variations and analyze difference between HAEH and healthy controls. Online softwares were applied to predict function changes caused by positive associated mtDNA variations. Results: Compared to the control group, the frequency of haplogroup U4b was significant higher in HAEH group(P=0.023,OR=7.062,CI(95%)=1.306-38.182), and the frequencies of 8 mutations from haplogroup U4b showed a significant difference between the HAEH group and control group (all with P values below 0.05). The mt DNA15693T＞C mutation was the only missense mutation, which affected amino acid 316 in mitochondrial cytochrome b (MTCYB) by changing it from methionine to threonine. Bioinformatics analysis indicated that the mutation in MTCYB may play a biological role through affecting the second structure of protein. Conclusion: MtDNA subhaplogroup U4b is a genetic factor for HAEH in the Chinese Tajik population, and mtDNA15693T＞C mutation may be an important molecular mechanism of HAEH.

DNA Hypermethylation Induced by L-Methionine Leads to Oligodendroglial and Myelin Deficits and Schizophrenia-Like Behaviors in Adolescent Mice.

Increasing evidence has demonstrated that in addition to dysfunction of neuronal circuitry, oligodendroglial dysfunction and/or disruption of white matter integrity are found in the brains of patients with schizophrenia. DNA methylation, a well-established risk factor for schizophrenia, has been demonstrated to cause neuronal dysfunction; however, whether dysregulation of DNA methylation contributes to oligodendroglial/myelin deficits in the pathogenesis of schizophrenia remains unclear. In the present study, by using L-methionine-treated mice, we confirmed that mice with DNA hypermethylation exhibited an anxious phenotype, impaired sociability, and sensorimotor gating deficits. Notably, DNA hypermethylation in oligodendroglial cells led to dysregulation of multiple oligodendroglia-specific transcription factors, which indicated disruption of the transcriptional architecture. Furthermore, DNA hypermethylation caused a reduction of oligodendroglial lineage cells and myelin integrity in the frontal white matter of mice. Taken together, these results indicate that DNA hypermethylation leads to oligodendroglial and/or myelin deficits, which may, at least in part, contribute to schizophrenia-like behaviors in mice. This study provides new insights into the possibility that precise modulation of DNA methylation status in oligodendroglia could be beneficial for the white matter pathology in schizophrenia.

Association between medical resources and the proportion of oldest-old in the Chinese population.

The potential association between medical resources and the proportion of oldest-old (90 years of age and above) in the Chinese population was examined, and we found that the higher proportion of oldest-old was associated with the higher number of beds in hospitals and health centers.

[Epidemiology, Treatment, and Epidemic Prevention and Control of the Coronavirus Disease 2019: a Review].

This review summarizes the ongoing researches regarding etiology, epidemiology, transmission dynamics, treatment, and prevention and control strategies of the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with comparison to severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV) and pandemic H1N1 virus. SARS-CoV-2 may be originated from bats, and the patients and asymptomatic carriers are the source of epidemic infection. The virus can be transmitted human-to-human through droplets and close contact, and people at all ages are susceptible to this virus. The main clinical symptoms of the patients are fever and cough, accompanied with leukocytopenia and lymphocytopenia. Effective drugs have been not yet available thus far. In terms of the prevention and control strategies, vaccine development as the primary prevention should be accelerated. Regarding the secondary prevention, ongoing efforts of the infected patients and close contacts quarantine, mask wearing promotion, regular disinfection in public places should be continued. Meanwhile, rapid detection kit for serological monitoring of the virus in general population is expected so as to achieve early detection, early diagnosis, early isolation and early treatment. In addition, public health education on this disease and prevention should be enhanced so as to mitigate panic and mobilize the public to jointly combat the epidemic.

MeCP2 Deficiency in Neuroglia: New Progress in the Pathogenesis of Rett Syndrome.

Rett syndrome (RTT) is an X-linked neurodevelopmental disease predominantly caused by mutations of the methyl-CpG-binding protein 2 (MeCP2) gene. Generally, RTT has been attributed to neuron-centric dysfunction. However, increasing evidence has shown that glial abnormalities are also involved in the pathogenesis of RTT. Mice that are MeCP2-null specifically in glial cells showed similar behavioral and/or neuronal abnormalities as those found in MeCP2-null mice, a mouse model of RTT. MeCP2 deficiency in astrocytes impacts the expression of glial intermediate filament proteins such as fibrillary acidic protein (GFAP) and S100 and induces neuron toxicity by disturbing glutamate metabolism or enhancing microtubule instability. MeCP2 deficiency in oligodendrocytes (OLs) results in down-regulation of myelin gene expression and impacts myelination. While MeCP2-deficient microglia cells fail in response to environmental stimuli, release excessive glutamate, and aggravate impairment of the neuronal circuit. In this review, we mainly focus on the progress in determining the role of MeCP2 in glial cells involved in RTT, which may provide further insight into a therapeutic intervention for RTT.

DNA Methylation: a New Player in Multiple Sclerosis.

Multiple sclerosis (MS) is a neurological and chronic inflammatory disease that is mediated by demyelination and axonal degeneration in the central nervous system (CNS). Studies have shown that immune system components such as CD4+, CD8+, CD44+ T cells, B lymphatic cells, and inflammatory cytokines play a critical role in inflammatory processes and myelin damage associated with MS. Nevertheless, the pathogenesis of MS remains poorly defined. DNA methylation, a significant epigenetic modification, is reported to be extensively involved in MS pathogenesis through the regulation of gene expression. This review focuses on DNA methylation involved in MS pathogenesis. Evidence showed the hypermethylation of human leukocyte antigen-DRB1 (HLA-DRB1) in CD4+ T cells, the genome-wide DNA methylation in CD8+ T cells, the hypermethylation of interleukin-4 (IL-4)/forkhead winged helix transcription factor 3 (Foxp3), and the demethylation of interferon-γ (IFN-γ)/IL-17a in CD44+ encephalitogenic T cells. Studies also showed the hypermethylation of SH2-containing protein tyrosine phosphatase-1 (SHP-1) in peripheral blood mononuclear cells (PBMCs) and methylated changes of genes regulating oligodendrocyte and neuronal function in normal-appearing white matter. Clarifying the mechanism of aberrant methylation on MS may explain part of the pathology and will lead to the development of a new therapeutic target for the treatment of MS in the future.

Advancements in the Underlying Pathogenesis of Schizophrenia: Implications of DNA Methylation in Glial Cells.

Schizophrenia (SZ) is a chronic and severe mental illness for which currently there is no cure. At present, the exact molecular mechanism involved in the underlying pathogenesis of SZ is unknown. The disease is thought to be caused by a combination of genetic, biological, psychological, and environmental factors. Recent studies have shown that epigenetic regulation is involved in SZ pathology. Specifically, DNA methylation, one of the earliest found epigenetic modifications, has been extensively linked to modulation of neuronal function, leading to psychiatric disorders such as SZ. However, increasing evidence indicates that glial cells, especially dysfunctional oligodendrocytes undergo DNA methylation changes that contribute to the pathogenesis of SZ. This review primarily focuses on DNA methylation involved in glial dysfunctions in SZ. Clarifying this mechanism may lead to the development of new therapeutic interventional strategies for the treatment of SZ and other illnesses by correcting abnormal methylation in glial cells.

Hierarchically clustering to 1,033 genes differentially expressed in mouse superior colliculus in the courses of optic nerve development and injury.

Tempo spatially specific expression of many development-related genes is the molecular basis for the formation of the central nervous system (CNS), especially those genes regulating the proliferation, differentiation, migration, axon growth, and orientation of nerve cells. The development-related genes are usually prominent during the embryonic and newborn stages, but rarely express during the adulthood. These genes are believed to be suitable target genes for promoting CNS regeneration, despite majority of which remains unknown. Hence, the aim of this study was to screen development-related genes which might contribute to CNS regeneration. In this study, 1,033 differentially-expressed genes of superior colliculus in the courses of mouse optic nerve development and injury, as previously identified by cDNA microarrays, were hierarchically clustered to display expression pattern of each gene and reveal the relationships among these genes, and infer the functions of some unknown genes based on function-identified genes with the similar expression patterns. Consequently, the expression patterns of 1,033 candidate genes were revealed at eight time points during optic nerve development or injury. According to the similarity among gene expression patterns, 1,033 genes were divided into seven groups. The potential function of genes in each group was inferred on the basis of the dynamic trend for mean gene expression values. Moreover, the expression patterns of six function-unidentified genes were extremely similar to that of the ptn gene which could promote and guide axonal extension. Therefore, these six genes are temporally regarded as candidate genes related to axon growth and guidance. The results may help to better understand the roles of function-identified genes in the stages of CNS development and injury, and offer useful clues to evaluate the functions of hundreds of unidentified genes.

Progesterone alleviates neural behavioral deficits and demyelination with reduced degeneration of oligodendroglial cells in cuprizone-induced mice.

Demyelination occurs widely in neurodegenerative diseases. Progesterone has neuroprotective effects, is known to reduce the clinical scores and the inflammatory response. Progesterone also promotes remyelination in experimental autoimmune encephalomyelitis and cuprizone-induced demyelinating brain. However, it still remains unclear whether progesterone can alleviate neural behavioral deficits and demyelination with degeneration of oligodendroglial cells in cuprizone-induced mice. In this study, mice were fed with 0.2% cuprizone to induce demyelination, and treated with progesterone to test its potential protective effect on neural behavioral deficits, demyelination and degeneration of oligodendroglial cells. Our results showed noticeable alleviation of neural behavioral deficits following progesterone treatment as assessed by changes in average body weight, and activity during the open field and Rota-rod tests when compared with the vehicle treated cuprizone group. Progesterone treatment alleviated demyelination as shown by Luxol fast blue staining, MBP immunohistochemical staining, and electron microscopy. There was an obvious decrease in TUNEL and Caspase-3-positive apoptotic cells, and an increase in the number of oligodendroglial cells staining positive for PDGFRα, Olig2, Sox10 and CC-1 antibody in the brains of cuprizone-induced mice after progesterone administration. These results indicate that progesterone can alleviate neural behavioral deficits and demyelination against oligodendroglial cell degeneration in cuprizone-induced mice.

ID2: A negative transcription factor regulating oligodendroglia differentiation.

Remyelination of the central nervous system in multiple sclerosis patients is often incomplete. Remyelination depends on normal oligodendrogenesis and the differentiation of oligodendrocyte precursor cells (OPC) into mature oligodendrocytes (OL). Inhibitor of DNA binding (ID), a transcription factor, is thought to inhibit oligodendrogenesis and the differentiation of OPC. This Mini-Review aims to reveal the roles of and mechanisms used by IDs (mainly ID2) in this process. An interaction between ID2 and retinoblastoma tumor suppressor is responsible for the cell cycle transition from G1 to S. The translocation of ID2 between the nucleus and cytoplasm is regulated by E47 and OLIG. An interaction between ID2 and OLIG mediates the inhibitory effects of bone morphogenic proteins and G protein-coupled receptor 17 on oligodendroglia differentiation. ID2 expression is regulated by Wnt and histone deacetylases during the differentiation of OPC. ID4, another member of the ID family, functions similarly to ID2 in regulating the differentiation of OPC. The main difference is that ID4 is essential for oligodendrogenesis, whereas ID2 is nonessential. This could have important implications for demyelinating diseases, and interfering with these pathways might represent a viable therapeutic approach for these diseases.

Developmental changes and subcellular location in inhibitor of DNA binding 2 (Id2) immunoreactivity in the rat Corpus callosum.

The mechanisms underlying oligodendrocyte differentiation and myelination are still unclear, but understanding them will be critical for the development of therapies for multiple sclerosis. Inhibitor of DNA binding 2 (Id2) is a transcription factor thought to inhibit oligodendrocyte differentiation, however, it is not known whether the developmental changes and subcellular localization of Id2 are related to myelination. Therefore, we investigated the developmental changes in and the subcellular localization of Id2 immunoreactivity in the rat Corpus callosum, at post-natal developmental stages P0, P7, P14, P21, P42 and P90, by immunohistochemistry. Id2 expression increased from P0 to a peak at P42, the late stage of myelination in the Corpus callosum. Id2 immunostaining decreased slightly, but still remained high at P90. Subcellular localization of Id2 changed from presence in cytoplasm at P14 to the nuclei at P42. Moreover, Id2 was mainly co-localized with CC-1-immunopositive mature oligodendrocytes at P42. These results may be consistent with Id2 inhibitory function in oligodendrocyte differentiation, at the end of myelination or in compaction of myelin in the Corpus callosum of postnatal rat brain.

Protective effects of catalpol on oligodendrocyte death and myelin breakdown in a rat model of chronic cerebral hypoperfusion.

Chronic cerebral hypoperfusion is thought to induce white matter lesions (WMLs) with oligodendrocyte (OLG) death and myelin breakdown. Although apoptosis is believed to be involved in the pathologic process of WMLs, effective therapies for such remain lacking. In the present study, we investigated whether catalpol, an iridoid glycoside, could act on oligodendrocytes (OLGs) and myelin sheaths in a rat chronic hypoperfusion model, and whether transcription factor cAMP-responsive element binding protein (CREB) phosphorylation is involved in the resulting neuroprotection. A rat model of chronic cerebral hypoperfusion was prepared by bilateral common carotid artery ligation. On the 30th day after hypoperfusion, OLG loss and myelin disruption in the ischemic white matter were more severe and evident than in the sham control. Spatial memory was also more seriously impaired in rats after hypoperfusion. Treatment with catalpol significantly suppressed diminished OLGs and myelin breakdown, and promoted the recovery of cognitive decline. The expression of Bcl-2 and phosphorylated CREB (p-CREB) was also significantly increased by catalpol treatment. In conclusion, catalpol could protect against hypoperfusion-induced WMLs and cognitive impairment through the p-CREB signaling pathway leading to downstream upregulation of Bcl-2. Our results suggest that catalpol may be a useful approach for treating cerebrovascular WMLs.

Progesterone attenuates neurological behavioral deficits of experimental autoimmune encephalomyelitis through remyelination with nucleus-sublocalized Olig1 protein.

Multiple sclerosis (MS) is the most common demyelination disease of central nervous system (CNS). The deterioration of the disease is characterized by the axonal loss with defective remyelination. Progesterone can promote the remyelination, but whether it exerts beneficial effect on treatment of MS still remains unclear. Olig1 protein is a key regulator in the remyelination, when the intracellular sublocalization plays an import role too. We observed the effect of progesterone on experimental autoimmune encephalomyelitis (EAE) in rats by injecting the progesterone after the neurological behavioral deficits were shown up. The results showed no continuous increase of the nervous function score from day 10 after injection (p<0.05). Electron microscopy and LFB staining found prominent increase of OD value of normal myelin in the brain from day 6 after injection (p<0.05). Olig1 protein was localized almost completely in the cytoplasm of Olig1-positive cells from normal rats' brain. In EAE rats, the Olig1 protein has been translocated to the nucleus of 32.17% of Olig1-positive cells, which was increased to 68.52% after injection with progesterone at day 6 after injection (p<0.01). The results indicate that the progesterone is beneficial to attenuating neurological behavioral deficits, for it can promote more successful remyelination of EAE with aid of the nucleus-sublocalized Olig1 protein.

Expression and subcellular location of alpha-synuclein during mouse-embryonic development.

Alpha-synuclein (alpha-SYN) is one of the major components of intracellular fibrillary aggregates in the brains of a subset of neurodegenerative disorders. Although alpha-SYN expression has been found in developing mouse brain, a detailed distribution during mouse-embryonic development has not been made. Here we describe the expression pattern of alpha-SYN during the development of mice from E9.5 to P0 by immunohistochemistry (IHC). As a result, alpha-SYN was detected as early as E9.5. During the embryonic stages, alpha-SYN was dynamically expressed in several regions of the brain. In the neocortex, expression was detected in the marginal zone (MZ) in the early stages and was later condensed in the MZ and in the subplate (SP); in the cerebellum, expression was initially detected in the deep cerebellar nuclei (DCN) and was later condensed in the Purkinje cells. These spatio-temporal expression patterns matched the neuronal migratory pathways and the formation of the synapse connections. Additionally, alpha-SYN was detected in the sensory systems, including the nasal mucosa, the optic cup, the sensory ganglia, and their dominating nerve fibers. Furthermore, the nuclear location of alpha-SYN protein was found in developing neurons in the early stages, and later it was mostly found in the non-nuclear compartments. This finding was further confirmed by Western blot analysis. These results suggest that alpha-SYN may be involved not only in the migration of neurons and in the synaptogenesis of the central nervous system (CNS) but also in the establishment of the sensory systems. The nuclear location of alpha-SYN may hint at an important function in these events.

Dynamic expression and heterogeneous intracellular location of En-1 during late mouse embryonic development.

Engrailed-1 (En-1) is a transcription factor involved in the development of the midbrain/hindbrain during mouse early embryogenesis. Although En-1 is expressed from embryogenesis to adulthood, there has been no detailed description of its expression during late mouse embryonic development. Here we report the expression pattern of En-1 in the mouse embryo from E10.5 to the neonatal state. With immunohistochemistry we found that En-1 was expressed in the central nervous system (CNS) from E10.5 to the neonatal state, mostly restricted to the midbrain/hindbrain junction. Outside the CNS, En-1 is dynamically expressed in several neural crest-associated structures including the cranial mesenchyme, the mandibular arches, the vagus nerve, the dorsal root ganglia, the sympathetic ganglia, the somites, the heart and the cloaca. Additionally, we found that in the CNS, most of the En-1 was located in the nuclei, while outside the CNS, En-1 was mainly expressed in the cytoplasm. These findings provided additional evidence that En-1 may be involved in the development of neural crest cells.

Differential expression of PTEN in normal adult rat brain and upregulation of PTEN and p-Akt in the ischemic cerebral cortex.

The tumor suppressor phosphatase and tensin homologue (PTEN) is a protein and lipid phosphatase. PTEN mutations have been associated with a large number of human cancers. To understand the physiological role of PTEN in the brain and its relationship to Akt in ischemic injury, we first investigated the localization of PTEN immunoreactivity in the brains of normal adult rats using immunohistochemistry. We then detected the modulation of PTEN and p-Akt following transient global ischemia by Western blot and immunohistochemistry analyses. Our observation of normal brains showed that PTEN was heterogeneously distributed in the cytoplasm, nuclei, and processes in different regions. It was shown immunohistochemically that PTEN was distributed differentially in rat brain, with the highest levels in the anterior olfactory nucleus, cerebral cortex, amygdaloid nucleus, hippocampus, Purkinje's cells, and several nuclei in the basal ganglia, thalamus, midbrain, and pons. After global cerebral ischemia, PTEN and p-Akt immunoreactivities were increased in the cerebral cortex. This was accompanied by the nuclear translocation of p-Akt. Double-labeling experiments revealed that PTEN and p-Akt were most likely localized to neurons. These results suggest a role for PTEN in normal adult brain and that the PTEN/Akt pathway may be involved in neuronal survival or plasticity after ischemic injury.

The inhibitor of DNA binding 2 is mainly expressed in oligodendrocyte lineage cells in adult rat brain.

The inhibitor of DNA binding 2 (Id2) plays an important role in the brain both during embryogenesis and adulthood. But in adult rat brain, it is still unknown whether Id2 immunoreactivity mainly exhibits in neuronal, astrocytic and/or oligodendrocyte lineage cells. It is also unclear where and when Id2 immunoreactivity mainly exhibits in oligodendrocyte lineage cells. The present study showed 90% of Id2-immunoreactivity in oligodendrocyte lineage cells in such brain regions as the corpus callosum, optic chiasm, the longitudinal fasciculus of pons, the medial septal nucleus, the fimbria of hippocampus, the anterior commissure, and the pyramidal tract. Five percent of Id2-immunoreactivity was found in astrocytes. Id2 immunoreactivity was localized in neurons of only a few brain regions. Seventy percent of Id2 immunoreactivity was found in CC-1-positive mature oligodendrocytes. These observations suggest that Id2 may be mainly involved in terminal maturation of oligodendrocytes and myelination.