Recent progress in the applications of presynaptic dopaminergic positron emission tomography imaging in parkinsonism

Nowadays,presynaptic dopaminergic positron emission tomography,which assesses deficiencies in dopamine synthesis,storage,and transport,is widely utilized for early diagnosis and differential diagnosis of parkinsonism.This review provides a comprehensive summary of the latest developments in the application of presynaptic dopaminergic positron emission tomography imaging in disorders that manifest parkinsonism.We conducted a thorough literature search using reputable databases such as PubMed and Web of Science.Selection criteria involved identifying peer-reviewed articles published within the last 5 years,with emphasis on their relevance to clinical applications.The findings from these studies highlight that presynaptic dopaminergic positron emission tomography has demonstrated potential not only in diagnosing and differentiating various Parkinsonian conditions but also in assessing disease severity and predicting prognosis.Moreover,when employed in conjunction with other imaging modalities and advanced analytical methods,presynaptic dopaminergic positron emission tomography has been validated as a reliable in vivo biomarker.This validation extends to screening and exploring potential neuropathological mechanisms associated with dopaminergic depletion.In summary,the insights gained from interpreting these studies are crucial for enhancing the effectiveness of preclinical investigations and clinical trials,ultimately advancing toward the goals of neuroregeneration in parkinsonian disorders.

Molecular mechanism of panaxydol on promoting axonal growth in PC12 cells

Nerve growth factor（NGF） promotes axonal growth in PC12 cells primarily by regulating the RTK-RAS-MEK-ERK pathway. Panaxydol, a polyacetylene isolated from Panax notoginseng, can mimic the effects of NGF. Panaxydol promotes neurite outgrowth in PC12 cells, but its molecular mechanism remains unclear. Indeed, although alkynol compounds such as panaxydol can increase intracellular cyclic adenosine 3′,5′-monophosphate（cAMP） levels and the ERK inhibitor U0126 inhibits alkynol-induced axonal growth, how pathways downstream of cAMP activate ERK have not been investigated. This study observed the molecular mechanism of panaxydol-, NGF-and forskolin-induced PC12 cell axon growth using specific signaling pathway inhibitors. The results demonstrated that although the RTK inhibitor SU5416 obviously inhibited the growth-promoting effect of NGF, it could not inhibit the promoting effect of panaxydol on axonal growth of PC12 cells. The adenylate cyclase inhibitor SQ22536 and cAMP-dependent protein kinase inhibitor RpcAMPS could suppress the promoting effect of forskolin and panaxydol on axonal growth. The ERK inhibitor U0126 inhibited axonal growth induced by all three factors. However, the PKA inhibitor H89 inhibited the promoting effect of forskolin on axonal growth but could not suppress the promoting effect of panaxydol. A western blot assay was used to determine the effects of stimulating factors and inhibitors on ERK phosphorylation levels. The results revealed that NGF activates the ERK pathway through tyrosine receptors to induce axonal growth of PC12 cells. In contrast, panaxydol and forskolin increased cellular cAMP levels and were inhibited by adenylyl cyclase inhibitors. The protein kinase A inhibitor H89 completely inhibited forskolin-induced axonal outgrowth and ERK phosphorylation, but could not inhibit panaxydol-induced axonal growth and ERK phosphorylation. These results indicated that panaxydol promoted axonal growth of PC12 cells through different pathways downstream of cAMP. Considering that exchange protein directly activated by cAMP 1（Epac1） plays an important role in mediating cAMP signaling pathways, RNA interference experiments targeting the Epac1 gene were employed. The results verified that Epac1 could mediate the axonal growth signaling pathway induced by panaxydol. These findings suggest that compared with NGF and forskolin, panaxydol elicits axonal growth through the cAMP-Epac1-Rap1-MEK-ERK-CREB pathway, which is independent of PKA.

Sequential extraction of RNA,DNA and protein from cultured cells of the same group

BACKGROUND Efficient extraction of nucleic acids and proteins(ENAP)from cells is a prerequisite for precise annotation of gene function,and has become laboratory routine for revealing the mysteries of life.However,cell samples are often from different culture dishes,resulting in inevitable experimental errors and sometimes poor repeatability.AIM To explore a method to improve the efficiency of ENAP,minimizing errors in ENAP processes,enhancing the reliability and repeatability of subsequent experimental results.METHODS A protocol for the sequential isolation of RNA,DNA,and proteins from the same cultured HepG2 cells using RNAzol reagent is presented here.The first step involves culturing HepG2 cells to the exponential phase,followed by the sequential isolation of RNA,DNA,and proteins from the same cultured cells in the second step.The yield of nucleic acids and proteins is detected in the third step,and their purity and integrity are verified in the last step.RESULTS The procedure takes as few as 3-4 d from the start to quality verification and is highly efficient.In contrast to the existing kits and reagents,which are primarily based on independent isolation,this RNAzol reagent-based method is characterized by the sequential isolation of RNA,DNA,and proteins from the same cells,and therefore saves time,and has low cost and high efficiency.CONCLUSION The RNA,DNA,and proteins isolated using this method can be used for reverse transcription-polymerase chain reaction,polymerase chain reaction,and western blotting,respectively.

MiR-301a promotes embryonic stem cell differentiation to cardiomyocytes

BACKGROUND Cardiovascular disease is the leading cause of death worldwide.Tissue repair after pathological injury in the heart remains a major challenge due to the limited regenerative ability of cardiomyocytes in adults.Stem cell-derived cardiomyocytes provide a promising source for the cell transplantation-based treatment of injured hearts.AIM To explore the function and mechanisms of miR-301a in regulating cardiomyocyte differentiation of mouse embryonic stem(mES)cells,and provide experimental evidence for applying miR-301a to the cardiomyocyte differentiation induction from stem cells.METHODS mES cells with or without overexpression of miR-301a were applied for all functional assays.The hanging drop technique was applied to form embryoid bodies from mES cells.Cardiac markers including GATA-4,TBX5,MEF2C,andα-actinin were used to determine cardiomyocyte differentiation from mES cells.RESULTS High expression of miR-301a was detected in the heart from late embryonic to neonatal mice.Overexpression of miR-301a in mES cells significantly induced the expression of cardiac transcription factors,thereby promoting cardiomyocyte differentiation and beating cardiomyocyte clone formation.PTEN is a target gene of miR-301a in cardiomyocytes.PTEN-regulated PI3K-AKT-mTOR-Stat3 signaling showed involvement in regulating miR-301a-promoted cardiomyocyte differentiation from mES cells.CONCLUSION MiR-301a is capable of promoting embryonic stem cell differentiation to cardiomyocytes.

Histone modification landscape and the key significance of H3K27me3 in myocardial ischaemia/reperfusion injury

Histone modifications play crucial roles in the pathogenesis of myocardial ischaemia/reperfusion(I/R)injury.However,a genome-wide map of histone modifications and the underlying epigenetic signatures in myocardial I/R injury have not been established.Here,we integrated transcriptome and epigenome of histone modifications to characterize epigenetic signatures after I/R injury.Disease-specific histone mark alterations were mainly found in H3K27me3-,H3K27ac-,and H3K4me1-marked regions 24 and 48 h after I/R.Genes differentially modified by H3K27ac,H3K4me1 and H3K27me3 were involved in immune response,heart conduction or contraction,cytoskeleton,and angiogenesis.H3K27me3 and its methyltransferase polycomb repressor complex 2(PRC2)were upregulated in myocardial tissues after I/R.Upon selective inhibition of EZH2(the catalytic core of PRC2),the mice manifest improved cardiac function,enhanced angiogenesis,and reduced fibrosis.Further investigations confirmed that EZH2 inhibition regulated H3K27me3 modification of multiple pro-angiogenic genes and ultimately enhanced angiogenic properties in vivo and in vitro.This study delineates a landscape of histone modifications in myocardial I/R injury,and identifies H3K27me3 as a key epigenetic modifier in I/R process.The inhibition of H3K27me3 and its methyltransferase might be a potential strategy for myocardial I/R injury intervention.

Cancer,Mankind’s Challenge

Cancer, or malignant tumour, is a group of diseases defined by the uncontrollable growth of the transformed cells, and their capabilities of invasion into surrounding healthy tissues and metastasis to remote sites in the body of organisms[1, 2].

Role of deubiquitinating enzymes in DNA double-strand break repair

DNA is the hereditary material in humans and almost all other organisms. It is essential for maintaining accurate transmission of genetic information. In the life cycle, DNA replication, cell division, or genome damage, including that caused by endogenous and exogenous agents, may cause DNA aberrations. Of all forms of DNA damage, DNA double-strand breaks(DSBs) are the most serious. If the repair function is defective, DNA damage may cause gene mutation, genome instability, and cell chromosome loss, which in turn can even lead to tumorigenesis. DNA damage can be repaired through multiple mechanisms. Homologous recombination(HR) and non-homologous end joining(NHEJ) are the two main repair mechanisms for DNA DSBs. Increasing amounts of evidence reveal that protein modifications play an essential role in DNA damage repair.Protein deubiquitination is a vital post-translational modification which removes ubiquitin molecules or polyubiquitinated chains from substrates in order to reverse the ubiquitination reaction. This review discusses the role of deubiquitinating enzymes(DUBs) in repairing DNA DSBs. Exploring the molecular mechanisms of DUB regulation in DSB repair will provide new insights to combat human diseases and develop novel therapeutic approaches.

Prevalence of cardiovascular diseases in China

Cardiovascular diseases(CVD)cause one third of all deaths in China,and the number is anticipated to double by 2020.They also greatly result in disability and adjusted life year loss.The prevalence of CVD has become a new burden for China,due to an aging population,smoking,and changes in dietary habits and lifestyles.As the largest developing country,China needs to tailor her own national policies for managing CVD with full consideration of epidemiology,local needs,and afford-ability.Smoking cessation,increased physical activity,control of hypertension and hypercholesterolemia,and maintenance of a“traditional Chinese”diet should be important strategies for reducing the burden of CVD in China.Health officials in China should take their responsibilities to implement educational and preventive measures seriously.

Mechanistic and therapeutic perspectives for cardiac arrhythmias：beyond ion channels

Cardiac arrhythmias are among the most common causes of death in the world. Foundational studies established the critical role of ion channel disorders in arrhythmias, yet defects in ion channels themselves, such as mutations, may not account for all arrhythmias. Despite the progress made in recent decades, the antiarrhythmic drugs currently available have limited effectiveness,and the majority of these drugs can have proarrhythmic effects. This review describes novel knowledge on cellular mechanisms that cause cardiac arrhythmias, focuses on the dysfunction of subcellular organelles and intracellular logistics, and discusses potential strategies and challenges for developing novel, safe and effective treatments for arrhythmias.

Identification of a SARS-CoV-2 virus-encoded small non-coding RNA in association with the neurological disorders in COVID-19 patients

Dear Editor,Coronavirus disease 2019(covid-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has led to 460 million cases confirmed and 6.1 million deaths across almost 200 countries until March 2022.In addition to the vaccine-based protection against viral infection,it is urgently needed to accurately diagnose covid-19 patients as early as possible after infection.

Causal Association of Cardiac Function by Magnetic Resonance Imaging with Frailty Index:A Mendelian Randomization Study

Owing to the susceptibility of conventional observational studies to confounding factors and reverse causation,the causal association between cardiac function and frailty is unclear.We aimed to investigate whether cardiac function has causal effects on frailty.In this study,a two-sample Mendelian randomization(MR)study was conducted using genetic variants associated with cardiac function assessed by magnetic resonance imaging phenotypes as instrumental variables.Genetic variants asso-ciated with cardiac function by magnetic resonance imaging(including seven cardiac function phenotypes)and the frailty index(FI)were obtained from two large genome-wide association studies.MR estimates from each genetic instrument were combined using inverse variance weighted(IVW),weighted median,and MR‒Egger regression methods.We found that the increase in genetically determined stroke volume(beta-0.13,95%CI-0.16 to-0.10,p=1.39E-6),rather than other cardiac phenotypes,was associated with lower FI in MR analysis of IVW after Bonferroni correction.Sensitivity analyses examining potential bias caused by pleiotropy or reverse causality revealed similar findings(e.g.,intercept[SE],-0.008[0.011],p=0.47 by MR‒Egger intercept test).The leave-one-out analysis indicated that the association was not driven by single nucleotide polymorphisms.No evidence of heterogeneity was found among the genetic variants(e.g.,MR‒Egger:Q statistic=14.4,p=0.156).In conclusion,we provided evidence that improved cardiac function could contribute to reducing FI.These findings support the hypothesis that enhancing cardiac function could be an effective prevention strategy for frailty.

Analysis of Glial Distribution in Drosophila Adult Brains

Neurons and glia are the two major cell types in the nervous system and work closely with each other to program neuronal interplay. Traditionally, neurons are thought to be the major cells that actively regulate processes like synapse formation, plasticity, and behavioral output. Glia, on the other hand, serve a more supporting role. To date, accumulating evidence has suggested that glia are active participants in virtually every aspect of neuronal function. Despite this, fundamental features of how glia interact with neurons, and their spatial relationships, remain elusive. Here, we describe the glial cell population in Drosophila adult brains. Glial cells extend and tightly associate their processes with major structures such as the mushroom body（MB）, ellipsoid body（EB）,and antennal lobe（AL） in the brain. Glial cells are distributed in a more concentrated manner in the MB. Furthermore, subsets of glia exhibit distinctive association patterns around different neuronal structures. Whereas processes extended by astrocyte-like glia and ensheathing glia wrap around the MB and infiltrate into the EB and AL, cortex glia stay where cell bodies of neurons are and remain outside of the synaptic regions structured by EB or AL.

Trends in cancer mortality in China from 2004 to 2018:A nationwide longitudinal study

Background:The long-term trend in cancer death in a rapidly developing country provides information for cancer prophylaxis.Here,we aimed to identify the trends in cancer mortality in China during the 2004-2018 period.Methods:Using raw data from the national mortality surveillance system of China,we assessed the mortalities of all cancer and site-specific cancers during the 2004-2018 period.The participants were divided into three age groups:≥65 years,40-64 years,and≤39 years.Changing trends in cancer death by gender,residency,and tumor location were estimated using fitting joinpoint models to log-transformed crude mortality rates(CMRs)and age-standardizedmortality rates(ASMRs).Results:Cancer death accounted for 24% of all-cause of death in China during 2014-2018.The CMR of all cancer was 150.0 per 100,000 persons.Cancer was the leading cause of death in the population<65 years.The six major cancer types(lung/bronchus cancer,liver cancer,stomach cancer,esophagus cancer,colorectal cancer,and pancreas cancer)accounted for 75.85% of all cancer deaths.The CMR of all cancer increased while the ASMR decreased during 2014-2018(P<0.001).Lung/bronchus cancer and liver cancer were the leading causes of cancer death in the population<65 years,accounting for 45.31%(CMR)and 44.35%(ASMR)of all cancer death,respectively.The ASMR of liver cancer was higher in the 40-64 years population than in the≥65 years population,in contrast to the other five major cancers.The ASMRs of liver cancer,stomach cancer,and esophagus cancer decreased although they were higher in rural residents than in urban residents;the ASMRs of lung/bronchus cancer,colorectal cancer,and pancreas cancer increased in rural residents although they were higher in urban residents than in rural residents during 2014-2018.Conclusion:Although the ASMR of all cancer decreased in China during 2004-2018,lung/bronchus cancer and liver cancer remained the leading causes of cancer-related premature death.Lung/bronchus cancer,colorectal cancer,and pancreas cancer increased in rural residents.

Binding to m6A RNA promotes YTHDF2-mediated phase separation

Dear Editor,As one of the most abundant modifications on mRNA in mammal,A^6-methyladenosine(m6A)has been demonstrated to play important roles in various biological processes including nuclear RNA export,mRNA splicing,miRNA processing,mRNA degradation and translation(Shi et al.,2019).Importantly,different m6A reader proteins have been shown to play central roles in these processes.

Neuroglial Crosstalk by Mitochondria

Glia-neuron interaction is an integral part of signaling networks in the brain. Abundant evidence has suggested a pivotal role for glia in neuronal survival and activity [1-3], yet the mechanisms that lead to neuroglial crosstalk have not been well elucidated, nor has the diverse function of the exchange and transfer for materials between the two types of cells. Intriguingly, glia have been demonstrated as the recipients of axonal mitochondria from retinal ganglion cells [4]. This transcellular degradation of mitochondria provides an excellent example of how glia and neurons communicate, and prompts us to reconsider the importance and implications of how dysfunctional neuroglial crosstalk might underlie possible causes of brain diseases.

KDM2B promotes IL-6 production and inflammatory responses through Brg1-mediated chromatin remodeling

IL-6 plays important and pleiotropic roles in infection and inflammatory diseases,and its production needs to be tightly regulated.However,the epigenetic mechanism underlying Il6 gene transcription remains to be fully elucidated.Here,we report that lysine-specific demethylase 2b(KDM2B),which demethylates H3K4me3 and H3K36me2,is required in macrophages and dendritic cells for the induction of IL-6 but not TNF-α,IL-1,and IFN-β.Compared to wild-type mice,KDM2B-deficient mice were more resistant to endotoxin shock and colitis,with a less severe inflammatory pathogenesis phenotype and decreased IL-6 production in sera.KDM2B selectively bound the Il6 promoter but did not alter histone demethylation;instead,KDM2B interacted with Brahma-related gene 1(Brg1),the core ATPase subunit of SWI/SNF chromatin remodeling complexes,to facilitate chromatin accessibility of the Il6 promoter.Furthermore,KDM2B directly recruited RNA Polymerase II to further initiate and promote Il6 transcription.Thus,our finding identifies a novel nonclassical function of KDM2B in gene-specific transcription initiation and enhancement of Il6 independent of its demethylase activity and adds new insight into the specific epigenetic modification mechanism of inflammatory immune responses.

Sinoatrial node pacemaker cells share dominant biological properties with glutamatergic neurons

Activation of the heart normally begins in the sinoatrial node(SAN).Electrical impulses spontaneously released by SAN pacemaker cells(SANPCs)trigger the contraction of the heart.However,the cellular nature of SANPCs remains controversial.Here,we report that SANPCs exhibit glutamatergic neuron-like properties.By comparing the single-cell transcriptome of SANPCs with that of cells from primary visual cortex in mouse,we found that SANPCs co-clustered with cortical neurons.Tissue and cellular imaging confirmed that SANPCs contained key elements of glutamatergic neurotransmitter system,expressing genes encoding glutamate synthesis pathway(G/s),ionotropic and metabotropic glutamate receptors(Grina,Gria3,Grm1 and Grm5)t and glutamate transporters(Slc17a7).SANPCs highly expressed cell markers of glutamatergic neurons(Snap25 and S/-c17a7)t whereas Gad1,a marker of GABAergic neurons,was negative.Functional studies revealed that inhibition of glutamate receptors or transporters reduced spontaneous pacing frequency of isolated SAN tissues and spontaneous Ca2+transients frequency in single SANPC.Collectively,our work suggests that SANPCs share dominant biological properties with glutamatergic neurons,and the glutamatergic neurotransmitter system may act as an intrinsic regulation module of heart rhythm,which provides a potential intervention target for pacemaker cell-associated arrhythmias.

ZC4H2 stabilizes RNF220 to pattern ventral spinal cord through modulating Shh/Gli signaling

ZC4H2 encodes a C4H2 type zinc-finger nuclear factor,the mutation of which has been associated with disorders with various clinical phenotypes in human,including developmental delay,intellectual disability and dystonia.ZC4H2 has been suggested to regulate spinal cord patterning in zebrafish as a co-factor for RNF220,an ubiquitin E3 ligase involved in Gli signaling.Here we showed that ZC4H2 and RNF220 knockout animals phenocopy each other in spinal patterning in both mouse and zebrafish,with mispatterned progenitor and neuronal domains in the ventral spinal cord.We showed evidence that ZC4H2 is required for the stability of RNF220 and also proper Gli ubiquitination and signaling in vivo.Our data provides new insights into the possible etiology of the neurodevelopmental impairments observed in ZC4H2-associated syndromes.

Drosophila ubiquitin E3 ligase dSmurf is required for synapse remodeling and axon pruning by glia

Animal behaviors and higher-order functions rely on complex neural circuits built by synaptic connections （synapses） to deliver messages among different brain cells. As the major mediator in the nervous system, neurons communicate via synapses, which undergo constant structural remodeling with strict regulation.

Antiparkinsonian treatment for depression in Parkinson's disease: Are selective serotonin reuptake inhibitors recommended?

Depression is a frequent comorbid syndrome in Parkinson's disease. It is a difficult symptom to manage, as patients continuously receive antiparkinsonian medication and may also have to be treated for the amelioration of the side-effects of antiparkinsonian therapy. The first-line treatment for depression in Parkinson's disease is the use of selective serotonin reuptake inhibitors(SSRIs). The clinical efficacy of these medications in patients with Parkinson's disease is questionable. In fact, based on their mechanism of action, which requires at least a functional serotonergic system, it is predicted that SSRIs will have lower efficacy in patients with Parkinson's disease. Here, we consider the mechanism of action of SSRIs in the context of Parkinson's disease by investigating the fall in the levels of serotonergic markers and the inhibitory outcomes of antiparkinsonian treatment on serotonergic nerve activity. Because certain classes of antidepressant drugs are widely available, it is necessary to perform translational research to address different strategies used to manage depression in Parkinson's disease.