Transcriptional dysregulation in neurodegenerative diseases:who tipped the balance of Yin Yang 1 in the brain?

Yin Yang 1(YY1) is a multi-functional transcription factor that regulates gene expression in a range of cell types,including neurons.It controls neuronal differentiation,as well as neuronal specification and migration during the development of the mammalian nervous system.Besides,YY1 also mediates the transcription of genes that are required for neuronal survival.An impairment of the transcriptional function of YY1 causes neuronal death.This review summarizes recent research findings that unveil the dysfunction of YY1 in multiple neurodegenerative disorders.The expression of disease proteins perturbs the function of YY1 via distinct molecular mechanisms,including recruitment to protein aggregates,protein degradation and aberrant nuclear/cytoplasmic shuttling.Understanding the pathogenic roles of YY1 will further broaden our knowledge of the disease mechanisms in distinct neurodegenerative disorders.

Regulation of adenosine triphosphate-sensitive potassium channels suppresses the toxic effects of amyloid-beta peptide(25-35)

In this study, we treated PC12 cells with 0-20 μM amyloid-β peptide （25-35） for 24 hours to induce cytotoxicity, and found that 5-20 μM amyloid-β peptide （25-35） decreased PC12 cell viability, but adenosine triphosphate-sensitive potassium channel activator diazoxide suppressed the decrease in PC12 cell viability induced by amyloid-β peptide （25-35）. Diazoxide protected PC12 cells against amyloid-β peptide （25-35）-induced increases in mitochondrial membrane potential and intracellular reactive oxygen species levels. These protective effects were reversed by the selective mitochondrial adenosine triphosphate-sensitive potassium channel blocker 5-hydroxydecanoate. An inducible nitric oxide synthase inhibitor, Nw-nitro-L-arginine, also protected PC12 cells from amyloid-β peptide （25-35）-induced increases in both mitochondrial membrane potential and intracellular reactive oxygen species levels. However, the H202-degrading enzyme catalase could not reverse the amyloid-β peptide （25-35）-induced increase in intracellular reactive oxygen species. A 24-hour exposure to amyloid-13 peptide （25-35） did not result in apoptosis or necrosis, suggesting that the increases in both mitochondrial membrane potential and reactive oxygen species levels preceded cell death. The data suggest that amyloid-β peptide （25-35） cytotoxicity is associated with adenosine triphosphate-sensitive potassium channels and nitric oxide. Regulation of adenosine triphosphate-sensitive potassium channels suppresses PC12 cell cytotoxicity induced by amyloid-β peptide （25-35）.

Discussing the six meridional diseases of Shanghan Lun based on stress theory

As the theoretical source of Traditional Chinese Medicine clinical medicine,Shanghan Lun plays a vital role in guiding the diagnosis and treatment of clinical diseases.Stress is a systemic nonspecific and adaptive response that occurs when the body is stimulated by internal and external environmental factors.This paper discusses the correlation between the three phases of stress containing alarm,resistance,and exhaustion and the three yin and three yang diseases.It was concluded that sanyang diseases were related to the alarm stage and resistance stage,and sanyin diseases were related to the failure stage.The results indicated the essence of diseases of six meridians from the perspective of stress and provided reference for the diagnosis and treatment of six classics diseases.

Role of Voltage-gated Potassium Channels in Pathogenesis of Chronic Pulmonary Heart Disease

The influence of hypoxia on the activity of voltage-gated potassium channel in pulmonary artery smooth muscle cells （PASMCs） of rats and its roles in the pathogenesis of chronic pulmonary heart disease were investigated. Eighty male Sprague-Dawley rats were randomly allocated into control group （n=10）, acute hypoxic group （n=10）, and chronic hypoxic groups （n=60）. The chronic hypoxic groups were randomly divided into 6 subgroups （n=10 each） according to the chronic hypoxic periods. The rats in the control group were kept in room air and those in acute hypoxic group in hypoxia envi- ronmental chamber for 8 h. The rats in chronic hypoxic subgroups were kept in hypoxia environmental chamber for 8 h per day for 5, 10, 15, 20, 25, and 30 days, respectively. The mean pulmonary arterial pressure （mPAP）, right ventricular hypertrophy index （RVHI）, and the current of voltage-gated potas- sium channel （IK） in PASMCs were measured. Results showed that both acute and chronic hypoxia could decrease the IK in PASMCs of rats and the I-V relationship downward shifted to the right. And the peak Ir density at ＋60mV decreased with prolongation of hypoxia exposure. No significant difference was noted in the density oflK （at ＋60 mV） and I-V relationship between control group and chronic hy- poxic subgroup exposed to hypoxia for 5 days （P〉0.05）, but there was a significant difference between control group and chronic hypoxic subgroup exposed to hypoxia for 10 days （P〈0.05）. Significant dif- ferences were noted in the IK density （at ＋60 mV） and I-V relationships between control group and chronic hypoxic subgroups exposed to hypoxia for 20 days and 30 days （P〈0.01）. Compared with con- trol rats, the mPAP and RVHI were significantly increased after chronic exposure to hypoxia for 10 days （P〈0.05）, which were further increased with prolongation of hypoxia exposure, and there were signifi- cant differences between control group and chronic hypoxic subgroups exposed to hypoxia for 20 days and 30 days （P〈0.01）. Both the mPAP and the RVHI were negatively correlated with the density OflK （r---0.89769 and -0.94476, respectively, both P〈0.01）. It is concluded that exposure to hypoxia may cause decreased activity of voltage-gated potassium channel, leading to hypoxia pulmonary vasocon- striction （HPV）. Sustained HPV may result in chronic pulmonary hypertension, even chronic pulmonary heart disease, contributing to the pathogenesis of chronic pulmonary heart disease.

The blind men 'see' the elephant-the many faces of fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is a group of diseases with excess fat in liver in the absence of a poorly defined limit of alcohol consumption. Most common variety, a universal public health problem, is associated with insulin resistance caused by a host of genetic and epigenetic defects modulated by life style and environmental factors. In fact the term NAFLD is loose to incorporate so many etiologies except alcoholism and few other etiologies, presenting as fat in liver. However as a sign fatty liver is very important in predicting the risk of diabetes, cardiovascular disease, stroke, cirrhosis and cancer. Abnormal fat accumulation can result from several defects in nuclear receptors associated with lipid sensing, synthesis and oxidation like LXR, FXR, SREBP, ChREBP and PPAR; defects in the lipid influx-efflux channels, insulin signaling, proteins involved in fatty acid catabolism, defects in adipose tissue development and function, inappropriate nutrition and finally defects in neural regulatory mechanisms. The progress of the disease is determined by the basic defects which results in fat accumulation, an individual’s immunological response to the accumulated fat and its derivatives and the oxidant stress response. Congregation of unrelated genetic defects under same diagnosis ‘NAFLD’ can result in inefficient patient management. Further studies are required to understand the molecular basis of fatty liver to enable a personalized management of diseases presenting as fatty liver in the absence of alcohol abuse.

Research progress on the correlation between ion channel and excitability of striatum neurons in Parkinson's disease

Parkinson's disease(PD)is a neurodegenerative disorder due to gradual loss of dopaminergic neurons in the substantia nigra in the midbrain,however the pathogenesis is unclear.There is a correlation between the excitability of striatal neurons and PD.Ion channels are important to maintain membrane potential and regulate excitability of neurons,while ionic mechanisms for modulation of neurons excitability are not fully understood.This article reviews the relationship between ion channels and excitability of striatal neurons in PD and ion channel changes in the pathogenesis of PD.In order to find new targets to treatment PD by intervening ion channels.

Discussion about the Treatment of Alzheimer's Disease with Yisui Fuyong Decoction Based on Synaptic Plasticity

For Alzheimer's disease(AD),the earliest symptom is memory loss,which runs throughout the disease.The mutual growth and decline of long-term potentiation(LTP)and long-term depression(LTD)in synaptic plasticity is the basic condition of learning and memory.In the early stage of AD,there is no significant change in synaptic plasticity,so the treatment should mainly focus on warming yang and replenishing qi.In the middle stage of AD,LTP is continuously damaged and reduced,and synaptic plasticity is destroyed,such as weakness of the spleen and stomach,causing stagnation of endogenous retention of phlegm in the brain,so the treatment should focus on enriching yin and tonifying yang,resolving phlegm to remove stagnation.In the late stage of AD,due to excessive deposition of amyloid and other metabolites,neurotoxins are produced and brain atrophy is aggravated,such as depression leading to stasis,phlegm and stasis binding together,long term of stasis turning to heat toxin,which invades the brain,excessive heat damages yin,then both yin and yang are damaged,finally,the brain collateral loses nutrition,so the treatment should focus on replenishing essence and reinforcing marrow,detoxifying and resolving stasis.Yisui Fuyong Decoction can replenish essence and reinforce marrow to nourish yin,warm yang and tonify qi to strengthen yang,combine phlegm resolving,stasis elimination and collateral vessels dredging,realizing the treatment effects in all three stages of synaptic plasticity.

Melastatin-related transient receptor potential 2 channel in Aβ_(42)-induced neuroinflammation: implications to Alzheimer's disease mechanism and development of therapeutics

Alzheimer’s disease （AD） is an age-related eurodegenerative disease that represents the most common cause of dementia among the elderly people. With the increasingly aging population, AD has presented an overwhelming healthcare challenge to modern society; the World Alzheimer Report 2015 has estimated that 46.8 million people worldwide lived with dementia in 2015 and this number will rise to 74.7 million in 2030 and that the total cost of dementia was 818 billion in US$ in 2015 and will reach two trillion in 2030. Post-mortem studies have identified two histopathological hallmarks in the brains of AD patients; extracellular senile plaque with elevated deposition of amyloid β （Aβ） peptides, and intracellular neurofibrillary tangle composed of hyper-phosphorylated microtubule-associated protein tau.Etiologically, progressive neuronal loss within the cerebral cortex and hippocampus regions of the brain leads to irreversible decline in, and eventually complete loss of, memory and other cognitive functions that afflict AD patients. The widely-accepted amyloid cascade hypothesis for AD pathogenesis holds that accumulation and aggregation of neurotoxic Aβ peptides, due to imbalance of their generation and clearance as a result of changes in genetic makeup, aging and/or exposure to environmental risk factors, is a major and early trigger of AD. This hypothesis has continuously gained support by preclinical and clinical studies （Selkoe and Hardy, 2016）. However, the intensive and costly drug discovery efforts over the past decades based on such a hypothesis have proved extremely frustrating in developing effective therapeutics to treat or slow down the progress of AD, highlighting the need for more research to improve our understanding towards the cellular and molecular mechanisms by which Aβ peptides bring about neurotoxicity and cognitive dysfunction.

Analysis of Constitutional Factors in Patients with Gallstone Disease

Objective: To summarize the common constitutional types in patients with gallstone disease and analyze influencing factors. Research Hypothesis: Qi stagnation constitution may be a potential predisposing constitution for gallstone disease, whereas the Balanced Constitution and Yin deficiency constitution have a lower tendency towards the development of the disease;gallstone disease is more prevalent among young men engaged in mental labor. Methods: A retrospective study was conducted on 180 patients with gallstone disease who were hospitalized in the Department of Hepatobiliary Surgery, First Affiliated Hospital of Guangxi University of Traditional Chinese Medicine (TCM), from July 2017 to July 2023. Additionally, 180 healthy individuals undergoing physical examinations at the Health Examination Center of the same hospital were selected as the normal control group. Both groups underwent general condition surveys, TCM constitution scales, Eysenck Personality Questionnaires, Brief Coping Styles Questionnaires, and Social Support Rating Scales to determine risk factors and common types. Results: Independent variables such as gender, Qi stagnation constitution, Balanced Constitution, negative coping scores, positive coping scores, and stressful life events were included in the model. The OR values for Balanced Constitution, gender, positive coping style, and overall social support were all less than 1, and the maximum value of the 95% confidence interval was also less than 1. After selecting the intercept into the model and analyzing the standardized regression coefficients, it was found that negative coping scores had a significant impact on the model, while stressful life events showed extremely high relevance to the study. Compared with the normal group, the frequency of Qi stagnation constitution in the study group significantly increased, with a significant difference (P χ2 = 11.109, P = 0.0009, indicating a significant difference (P χ2 = 4.0890, P = 0.0432, indicating a significant difference (P 0.05). However, when comparing mental workers with physical workers within the patient group, the frequency of Qi stagnation constitution in mental workers was significantly higher, with χ2 = 6.8467, P = 0.012, indicating a significant difference (P Conclusion: Qi stagnation constitution is a potential predisposing constitution for gallstone disease, whereas the tendency to develop the disease is relatively low for Balanced Constitution and Yin deficiency constitution. Gallstone disease is more commonly found in young male mental workers.

An Assisted Diagnosis of Alzheimer’s Disease Incorporating Attention Mechanisms Med-3D Transfer Modeling

Alzheimer’s disease(AD)is a complex,progressive neurodegenerative disorder.The subtle and insidious onset of its pathogenesis makes early detection of a formidable challenge in both contemporary neuroscience and clinical practice.In this study,we introduce an advanced diagnostic methodology rooted in theMed-3D transfermodel and enhanced with an attention mechanism.We aim to improve the precision of AD diagnosis and facilitate its early identification.Initially,we employ a spatial normalization technique to address challenges like clarity degradation and unsaturation,which are commonly observed in imaging datasets.Subsequently,an attention mechanism is incorporated to selectively focus on the salient features within the imaging data.Building upon this foundation,we present the novelMed-3D transfermodel,designed to further elucidate and amplify the intricate features associated withADpathogenesis.Our proposedmodel has demonstrated promising results,achieving a classification accuracy of 92%.To emphasize the robustness and practicality of our approach,we introduce an adaptive‘hot-updating’auxiliary diagnostic system.This system not only enables continuous model training and optimization but also provides a dynamic platform to meet the real-time diagnostic and therapeutic demands of AD.

A Novel Apprehension of the Primary Lung Meridian, Sinew Channel, Divergent Channel, Luo-Connecting Channel Acting as a Single Unit System to Serve Respiration Function Based on Modern Neurophysiology and Kinesiology

The TCM philosophy of a meridian and associated channels pertains to the specific function of one or more organs. We define the Lung Primary Meridian (LUM) together with the Lung Sinew (LUSC), Divergent (LUDC), Luo-connecting (LULCC) Channels as a system of routes plus some parts of the body (such as muscles) to fulfil respiration, as a main function under different situations. There is very limited information about the Lung associated channels in classical literature of TCM. With a clear focus on the function of respiration, we have carried out a detailed analysis of the biomedical consequence of stimulating the LUM, analysed the roles played by LUSC, LUDC, and LULCC. The updated LUM and LUDC include acupoints of other meridians, serving the same purpose of performing satisfactory respiration starting from checking the quality of the inflow through the nose. The LUSC includes the respiratory muscles (plus the associated connective tissues) extending to various parts of the body. The muscles of the limb (as part of the LUSC) embrace the nerves that provide routes for somatosensory reflexes and play the role of locomotion, providing voluntary respiration via the pectoralis muscles. The muscles of LUSC are bounded by stiff connective tissue layers, forming compartments, and are part of the pulley system for various body locomotions. Within a compartment, the interstitial fluid, blood, lymph flows must be potent to protect the associated nerves related to LUM;the healthy state of the LUSC also provides freedom of various types of locomotion. The LULCC exists because the vagus nerve has a part of it passing through the spinal cords all the way down to the sacrum domain, with exiting nerve innervating two-third of the large intestine. The crucial steps of our deductions are supported by experimental evidence based on modern neurophysiology and kinesiology. We discover that all the four channels stated above work as a unit system to allow respiration to be possible under various postures/conditions. The complexity of structures and processes is eased off by providing 29 figures and 13 tables for the relevant muscles and nerves. In addition to respiration, the Lung system in TCM context includes interaction of this system with the sweat gland and neuroendocrine system;such aspects will be left to another study.

基于一源三歧理论早期干预产后腹直肌分离症临床观察

目的探讨基于一源三歧理论早期干预产后腹直肌分离症的临床疗效。方法选择50例于2021年1月—2021年12月入住大连市妇女儿童医疗中心(集团)产后康复中心且存在腹直肌分离症(检测大于2 cm)的产妇作为观察组,门诊收治的50例腹直肌分离症患者作为对照组。观察组从产后15 d开始,根据“一源三歧”理论,给予电针治疗;对照组从产后42 d开始,使用神经肌肉刺激治疗仪治疗。两组均持续2个疗程(10次)。采用腹部触诊法、腹围测量、视觉模拟量表(VAS)分别评估腹直肌分离距离、产妇腹围恢复情况、腰背疼痛程度,评估临床疗效并进行统计分析。结果两组治疗后腹直肌分离距离、腹围均有缩减,腰背疼痛情况均有改善,且观察组更显著(P<0.05)。观察组总有效率为90%(45/50),高于对照组的76%(38/50)(P<0.05)。结论基于一源三歧理论取穴的电针治疗对腹直肌分离症的早期介入,可加快产后腹围、腹直肌恢复,并可减轻伴随的不适症状,降低宫内残留的风险,在产后康复方面具有积极作用。

Roles of Na^+/Ca^(2+) exchanger 1 in digestive system physiology and pathophysiology

The Na^+/Ca^(2+) exchanger(NCX) protein family is a part of the cation/Ca^(2+) exchanger superfamily and participates in the regulation of cellular Ca^(2+) homeostasis. NCX1, the most important subtype in the NCX family, is expressed widely in various organs and tissues in mammals and plays an especially important role in the physiological and pathological processes of nerves and the cardiovascular system. In the past few years, the function of NCX1 in the digestive system has received increasing attention; NCX1 not only participates in the healing process of gastric ulcer and gastric mucosal injury but also mediates the development of digestive cancer, acute pancreatitis, and intestinal absorption.This review aims to explore the roles of NCX1 in digestive system physiology and pathophysiology in order to guide clinical treatments.

Abnormal Calcium “Sparks” in Cardiomyocytes of Post-myocardial Infarction Heart

In ischemic hypertrophic myocardium, contractile dysfunction can be attributed to the decreased calcium induced calcium release （CICR） in cytoplasm. This study aimed to investigate the electrophysiological properties and the expression of L calcium channel subunits in post-MI myocardium. The ischemic heart remodeling model was established in SD rats. The expressions of calcium channel subunits were determined by realtime RT-PCR. Whole cell patch clamp was used to record the electrophysiological properties of L calcium channel. The results showed that the L calcium channel agonist Bayk 8644 induced the significantly decreased CICR in the rat cardiomyocyte 6 weeks after myocardial infarction （MI）. In the post-MI cardiomyocytes, the amplitude of ICaL decreased dramatically and the inactivation curve of the current shifted to more negative potential. At mRNA level, the expression of the calcium channel alpha1c, beta2c subunits decreased dramatically in the ventricle of post-MI rats. The expression of alpha2/delta subunit, however, remained constant. It is concluded that the abnormal expression of the L calcium channel subunits in post-MI cardiomyocytes contributes to the ICaL decrease at early stage of the ischemic remodeling in cardiomyocytes, which leads to the decreased CICR in the cell and contractile dysfunction of myocardium.

Role of STIM1 in neurodegeneration

STIM1 is an endoplasmic reticulum(ER) protein with a key role in Ca^(2+)mobilization. Due to its ability to act as an ER-intraluminal Ca^(2+) sensor, it regulates store-operated Ca^(2+) entry(SOCE), which is a Ca^(2+) influx pathway involved in a wide variety of signalling pathways in eukaryotic cells. Despite its important role in Ca^(2+) transport, current knowledge about the role of STIM1 in neurons is much more limited. Growing evidence supports a role for STIM1 and SOCE in the preservation of dendritic spines required for long-term potentiation and the formation of memory. In this regard, recent studies have demonstrated that the loss of STIM1, which impairs Ca^(2+) mobilization in neurons, risks cell viability and could be the cause of neurodegenerative diseases. The role of STIM1 in neurodegeneration and the molecular basis of cell death triggered by low levels of STIM1 are discussed in this review.

ATP-sensitive potassium channels:novel potential roles in Parkinson's disease

The ATP-sensitive potassium（KATP）channels which extensively distribute in diverse tissues（e.g.vascular smooth muscle,cardiac cells,and pancreas）are well-established for characteristics like vasodilatation,myocardial protection against ischemia,and insulin secretion.The aim of this review is to get insight into the novel roles of KATPchannels in Parkinson＇s disease（PD）,with consideration of the specificities KATPchannels in the central nervous system（CNS）, such as the control of neuronal excitability,action potential,mitochondrial function and neurotransmitter release.

Disease Recognition of Apple Leaf Using Lightweight Multi-Scale Network with ECANet

To solve the problem of difficulty in identifying apple diseases in the natural environment and the low application rate of deep learning recognition networks,a lightweight ResNet(LW-ResNet)model for apple disease recognition is proposed.Based on the deep residual network(ResNet18),the multi-scale feature extraction layer is constructed by group convolution to realize the compression model and improve the extraction ability of different sizes of lesion features.By improving the identity mapping structure to reduce information loss.By introducing the efficient channel attention module(ECANet)to suppress noise from a complex background.The experimental results show that the average precision,recall and F1-score of the LW-ResNet on the test set are 97.80%,97.92%and 97.85%,respectively.The parameter memory is 2.32 MB,which is 94%less than that of ResNet18.Compared with the classic lightweight networks SqueezeNet and MobileNetV2,LW-ResNet has obvious advantages in recognition performance,speed,parameter memory requirement and time complexity.The proposed model has the advantages of low computational cost,low storage cost,strong real-time performance,high identification accuracy,and strong practicability,which can meet the needs of real-time identification task of apple leaf disease on resource-constrained devices.

Nerve growth factor in muscle afferent neurons of peripheral artery disease and autonomic function

In peripheral artery disease patients,the blood supply directed to the lower limbs is reduced.This results in severe limb ischemia and thereby enhances pain sensitivity in lower limbs.The painful perception is induced and exaggerate during walking,and is relieved by rest.This symptom is termed by intermittent claudication.The limb ischemia also amplifies autonomic responses during exercise.In the process of pain and autonomic responses originating exercising muscle,a number of receptors in afferent nerves sense ischemic changes and send signals to the central nervous system leading to autonomic responses.This review integrates recent study results in terms of perspectives including how nerve growth factor affects muscle sensory nerve receptors in peripheral artery disease and thereby alters responses of sympathetic nerve activity and blood pressure to active muscle.For the sensory nerve receptors,we emphasize the role played by transient receptor potential vanilloid type 1,purinergic P2X purinoceptor 3 and acid sensing ion channel subtype 3 in amplified sympathetic nerve activity responses in peripheral artery disease.

Modeling protein-protein interactions in axon initial segment to understand their potential impact on action potential initiation

The axon initial segment(AIS)region is crucial for action potential initiation due to the presence of high-density AIS protein voltage-gated sodium channels(Nav).Nav channels comprise several serine residues responsible for the recruitment of Nav channels into the structure of AIS through interactions with ankyrin-G(AnkG).In this study,a series of computational experiments are performed to understand the role of AIS proteins casein kinase 2 and AnkG on Nav channel recruitment into the AIS.The computational simulation results using Virtual cell software indicate that Nav channels with all serine sites available for phosphorylation bind to AnkG with strong affinity.At the low initial concentration of AnkG and casein kinase 2,the concentration of Nav channels reduces significantly,suggesting the importance of casein kinase 2 and AnkG in the recruitment of Nav channels.