Neuronal reprogramming is an innovative technique for converting non-neuronal somatic cells into neurons that can be used to replace lost or damaged neurons, providing a potential effective therapeutic strategy for central nervous system (CNS) injuries or diseases. Transcription factors have been used to induce neuronal reprogramming, while their reprogramming efficiency is relatively low, and the introduction of exogenous genes may result in host gene instability or induce gene mutation. Therefore, their future clinical application may be hindered by these safety concerns. Compared with transcription factors, small-molecule compounds have unique advantages in the field of neuronal reprogramming, which can overcome many limitations of traditional transcription factor-induced neuronal reprogramming. Here, we review the recent progress in the research of small-molecule compound-mediated neuronal reprogramming and its application in CNS regeneration and repair.
Humans ; Cellular Reprogramming/drug effects* ; Neurons/cytology* ; Animals ; Transcription Factors ; Small Molecule Libraries/pharmacology* ; Nerve Regeneration

Nuclear receptor co-activator 4 (NCOA4) acts as a selective cargo receptor that binds to ferritin, a cytoplasmic iron storage complex. By mediating ferritinophagy, NCOA4 regulates iron metabolism and releases free iron in the body, thus playing a crucial role in a variety of biological processes, including growth, development, and metabolism. Recent studies have shown that NCOA4-mediated ferritinophagy is closely associated with the occurrence and development of iron metabolism-related diseases, such as liver fibrosis, renal cell carcinoma, and neurodegenerative diseases. In addition, a number of clinical drugs have been identified to modulate NCOA4-mediated ferritinophagy, significantly affecting disease progression and treatment efficacy. This paper aims to review the current research progress on the role of NCOA4-mediated ferritinophagy in related diseases, in order to provide new ideas for targeted clinical therapy.
Humans ; Nuclear Receptor Coactivators/physiology* ; Ferritins/metabolism* ; Animals ; Neurodegenerative Diseases/metabolism* ; Iron/metabolism* ; Autophagy/physiology* ; Liver Cirrhosis/metabolism* ; Carcinoma, Renal Cell/metabolism* ; Kidney Neoplasms/physiopathology*

This study explores the mechanism of Guben Jiannao Liquid on Alzheimer's disease(AD) by regulating autophagy based on the liver kinase B1(LKB1)/adenosine monophosphate-activated protein kinase(AMPK)/mammalian target of rapamycin(mTOR) pathway. Male SD rats were randomly divided into the blank group, model group, low-dose and high-dose groups of Guben Jiannao Liquid, and rapamycin group, with 10 rats in each group. Except for the blank group, all other groups of rats were injected bilaterally in the hippocampus with β-amyloid(Aβ)_(1-42) to establish the AD model. The low-dose(6.21 g·kg~(-1)) and high-dose(12.42 g·kg~(-1)) groups of Guben Jiannao Liquid and rapamycin group(1 mg·kg~(-1)) were given the corresponding drugs by gavage, and the blank and model groups were given an equal volume of saline by gavage for four weeks. Morris water maze was used to test the learning and memory ability of rats in each group; hematoxylin-eosin(HE) and Nissl staining were used to observe the morphological and quantitative changes of neurons and Nissl bodies in the CA1 region of rat hippocampus; immunohistochemistry was utilized to detect Aβ-positive cell expression in the CA1 region of rat hippocampus; transmission electron microscopy was employed to observe ultrastructural changes in rat hippocampal tissue, and Western blot was used to examine the protein expression levels of LKB1, p-AMPK/AMPK, p-mTOR/mTOR, Beclin1, p62, and LC3-Ⅱ in the hippocampal tissue of the rats. The results showed that compared with those in the blank group, rats in the model group had elevated evasion latency and decreased number of platform transversal and residence time in the platform quadrant. The number of neurons in the hippocampal area was reduced, and the morphology was impaired. The average integral optical density value of Aβ-positive cells was elevated; the expression levels of LKB1, p-AMPK/AMPK, Beclin1, and LC3-Ⅱ were decreased, and the expression levels of p-mTOR/mTOR and p62 were increased. Compared with those in the model group, rats in the low-dose and high-dose groups of Guben Jiannao Liquid had shorter evasion latency, higher number of platform transversal, longer residence time in the platform quadrant, increased number of neurons, decreased expression of Aβ-positive cells and average integral optical density values, and increased number of autophagic lysosomes in hippocampal tissue. The expression levels of LKB1, Beclin1, and LC3-Ⅱ were elevated in the hippocampus of rats in the low-dose group of Guben Jiannao Liquid. The expression levels of LKB1, p-AMPK/AMPK, Beclin1, and LC3-Ⅱ were elevated in the hippocampal tissue of rats in the high-dose group of Guben Jiannao Liquid, and the expression levels of p-mTOR/mTOR and p62 were decreased. The findings suggest that Guben Jiannao Liquid can improve cognitive impairment in AD rats, and its mechanism of action may be related to the activation of the LKB1/AMPK/mTOR signaling pathway and the up-regulation of autophagy level.
Animals ; Alzheimer Disease/physiopathology* ; Male ; TOR Serine-Threonine Kinases/genetics* ; Autophagy/drug effects* ; Rats, Sprague-Dawley ; Protein Serine-Threonine Kinases/genetics* ; AMP-Activated Protein Kinases/genetics* ; Rats ; Drugs, Chinese Herbal/administration & dosage* ; Signal Transduction/drug effects* ; AMP-Activated Protein Kinase Kinases ; Humans ; Hippocampus/metabolism*

BACKGROUND: Atrial fibrillation (AF) is a common cardiac arrhythmia in the elderly. This study aimed to evaluate urban-rural disparities in its prevalence and management in elderly Chinese. METHODS: Consecutive participants aged ≥ 65 years attending outpatient clinics were enrolled for AF screening using handheld single-lead electrocardiogram (ECG) from April 2017 to December 2022. Each ECG rhythm strip was reviewed from the research team. AF or uninterpretable single-lead ECGs were referred for 12-lead ECG. Primary study outcome comparison was between rural and urban areas for the prevalence of AF. The Student's t-test was used to compare mean values of clinical characteristics between rural and urban participants, while the Pearson's chi-square test was used to compare between-group proportions. Multivariate stepwise logistic regression analysis was performed to estimate the association between AF and various patient characteristics. RESULTS: The 29,166 study participants included 13,253 men (45.4%) and had a mean age of 72.2 years. The 7073 rural participants differed significantly (P ≤ 0.02) from the 22,093 urban participants in several major characteristics, such as older age, greater body mass index, and so on. The overall prevalence of AF was 4.6% (n = 1347). AF was more prevalent in 7073 rural participants than 22,093 urban participants (5.6% vs. 4.3%, P < 0.01), before and after adjustment for age, body mass index, blood pressure, pulse rate, cigarette smoking, alcohol consumption and prior medical history. Multivariate logistic regression analysis identified overweight/obesity (OR = 1.35, 95% CI: 1.17-1.54) in urban areas and cigarette smoking (OR = 1.62, 95% CI: 1.20-2.17) and alcohol consumption (OR = 1.42, 95% CI: 1.04-1.93) in rural areas as specific risk factors for prevalent AF. In patients with known AF in urban areas (n = 781) and rural areas (n = 338), 60.6% and 45.9%, respectively, received AF treatment (P < 0.01), and only 22.4% and 17.2%, respectively, received anticoagulation therapy (P = 0.05). CONCLUSIONS In China, there are urban-rural disparities in AF in the elderly, with a higher prevalence and worse management in rural areas than urban areas. Our study findings provide insight for health policymakers to consider urban-rural disparity in the prevention and treatment of AF.

OBJECTIVE: To investigate possible associations between physical function assessment scales, such as Short Physical Performance Battery (SPPB) and Berg Balance Scale (BBS), with all-cause mortality in acute decompensated heart failure (ADHF) patients. METHODS: A total of 108 ADHF patients were analyzed from October 2020 to October 2022, and followed up to May 2023. The association between baseline clinical characteristics and all-cause mortality was analyzed by univariate Cox regression analysis, while for SPPB and BBS, univariate Cox regression analysis was followed by receiver operating characteristic curves, in which the area under the curve represented their predictive accuracy for all-cause mortality. Incremental predictive values for both physical function assessments were measured by calculating net reclassification index and integrated discrimination improvement scores. Optimal cut-off value for BBS was then identified using restricted cubic spline plots, and survival differences below and above that cut-off were compared using Kaplan-Meier survival curves and the log-rank test. The clinical utility of BBS was measured using decision curve analysis. RESULTS: For baseline characteristics, age, female, blood urea nitrogen, as well as statins, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, or angiotensin receptor-neprilysin inhibitors, were predictive for all-cause mortality for ADHF patients. With respect to SPPB and BBS, higher scores were associated with lower all-cause mortality rates for both assessments; similar area under the curves were measured for both (0.774 for SPPB and 0.776 for BBS). Furthermore, BBS ≤ 36.5 was associated with significantly higher mortality, which was still applicable even adjusting for confounding factors; BBS was also found to have great clinical utility under decision curve analysis. CONCLUSIONS BBS or SPPB could be used as tools to assess physical function in ageing ADHF patients, as well as prognosticate on all-cause mortality. Moreover, prioritizing the improvement of balance capabilities of ADHF patients in cardiac rehabilitation regimens could aid in lowering mortality risk.

Objective To evaluate the diagnostic value of transrectal contrast-enhanced ultrasound (CEUS) for rectal cancer with intestinal stenosis caused by tumors. Methods Forty-nine patients with rectal cancer underwent transrectal CEUS and magnetic resonance imaging (MRI) before surgery.Intraoperative tumor localization and postoperative pathological results were taken as the gold standard for diagnosis.The differences in T stage,localization,and tumor length of rectal cancer were compared between the two methods. Results The total accuracy rates of transrectal CEUS and MRI in diagnosing T stage were 75.5% (36/49) and 67.3% (33/49),which had no significant difference (χ²=0.8,P=0.371).The total accuracy rates of transrectal CEUS and MRI in judging tumor localization were 79.5% (39/49) and 77.5% (38/49),which had no significant difference (χ²=0.061,P=0.806).The measurement results of tumor length in pathological examination had no significant difference from the transrectal CEUS results (t=1.42,P=0.162) but a significant difference from the MRI results (t=3.38,P=0.001).Furthermore,transrectal CEUS detected 8 (16.3%) cases of colonic polyps among the 49 patients,while MRI did not detect colon lesions. Conclusions Transrectal CEUS has good consistency with MRI in T staging and localization judgement of rectal cancer with intestinal stenosis,and this method can more accurately evaluate the tumor length and simultaneously evaluate whether there is a lesion in the entire colon at the proximal end of stenosis.It can be used as a supplementary examination before rectal cancer treatment in clinical practice.
Humans ; Rectal Neoplasms/complications* ; Male ; Middle Aged ; Female ; Aged ; Contrast Media ; Ultrasonography ; Adult ; Magnetic Resonance Imaging ; Constriction, Pathologic/diagnostic imaging* ; Aged, 80 and over ; Intestinal Obstruction/etiology*

Objective This study aimed to comprehensively analyze and compare the clinicopathological features and prognosis of Chinese patients with human epidermal growth factor receptor 2(HER2)-low early breast cancer(BC)and HER2-IHC0 BC. Methods Patients diagnosed with HER2-negative BC(N=999)at our institution between January 2011 and December 2015 formed our study population.Clinicopathological characteristics,association between estrogen receptor(ER)expression and HER2-low,and evolution of HER2 immunohistochemical(IHC)score were assessed.Kaplan-Meier method and log-rank test were used to compare the long-term survival outcomes(5-year follow-up)between the HER2-IHC0 and HER2-low groups. Results HER2-low BC group tended to demonstrate high expression of ER and more progesterone receptor(PgR)positivity than HER2-IHC0 BC group(P<0.001).The rate of HER2-low status increased with increasing ER expression levels(Mantel-Haenszel χ2 test,P<0.001,Pearson's R=0.159,P<0.001).Survival analysis revealed a significantly longer overall survival(OS)in HER2-low BC group than in HER2-IHC0 group(P=0.007)in the whole cohort and the hormone receptor(HR)-negative group.There were no significant differences between the two groups in terms of disease-free survival(DFS).The discordance rate of HER2 IHC scores between primary and metastatic sites was 36.84%. Conclusion HER2-low BC may not be regarded as a unique BC group in this population-based study due to similar clinicopathological features and prognostic roles.

Objective To investigate the factors influencing the occurrence of small for gestational age(SGA)at different degrees and provide a basis for early identification of severe SGA cases.Methods Neonatal and maternal prenatal information were retrospectively collected from January 2018 to December 2022 at Peking University People's Hospital.The neonates were divided into three groups:severe SGA group(birth weight below the 3rd percentile for gestational age and sex),mild SGA group(birth weight ≥3rd percentile and＜10th percentile),and non-SGA group(birth weight ≥10th percentile).An ordered multinomial logistic regression model was used to analyze the factors influencing the occurrence of SGA at different degrees.Results A total of 14 821 neonates were included,including 258 cases(1.74％)in the severe SGA group,902 cases(6.09％)in the mild SGA group,and 13 661 cases(92.17％)in the non-SGA group.The proportions of preterm births and stillbirths were higher in the severe SGA group compared to the mild SGA and non-SGA groups(P＜0.0125).The proportion of neonatal asphyxia was higher in both the severe SGA and mild SGA groups compared to the non-SGA group(P＜0.0125).Ordered multinomial logistic regression analysis showed that maternal pre-pregnancy underweight(OR=1.838),maternal pre-pregnancy obesity(OR=3.024),in vitro fertilization-embryo transfer(OR=2.649),preeclampsia(OR=1.743),connective tissue disease during pregnancy(OR=1.795),nuchal cord(OR=1.213),oligohydramnios(OR=1.848),and intrauterine growth restriction(OR=27.691)were all associated with a higher risk of severe SGA(P＜0.05).Maternal parity as a multipara(OR=0.457)was associated with a lower likelihood of severe SGA(P＜0.05).Conclusions Maternal pre-pregnancy underweight,maternal pre-pregnancy obesity,in vitro fertilization-embryo transfer,preeclampsia,connective tissue disease during pregnancy,oligohydramnios,nuchal cord,and intrauterine growth restriction are closely related to the occurrence of more severe SGA.Maternal parity as a multipara acts as a protective factor against the occurrence of severe SGA.[Chinese Journal of Contemporary Pediatrics,2024,26(3):262-268]

Objective To observe the therapeutic effect and mechanism of acupuncture at Zusanli-Zhongwan combined matching points on rats with exercise-induced stress gastric ulcer.Methods Forty male SD rats were randomly divided into blank group,model group,acupuncture group and Omeprazole group,with 10 rats in each group.Except for the blank group,the rats in the other groups were used to construct the model of exercise stress gastric ulcer by daily exhaustive swimming.After successful modeling,the acupuncture group was intervened by acupuncture at Zusanli(ST36)and Zhongwan(RN12),once a day,10 minutes each time.Rats in the Omeprazole group were given Omeprazole Enteric-Coated Tablets distilled water suspension by gavage two hours before daily swimming.After continuous 7-day intervention,the overall state and behavior of rats were observed,the gastric mucosal injury index was calculated by Guth method,the pathological morphology of gastric mucosa was observed by hematoxylin-eosin(HE)staining,the contents of superoxide dismutase(SOD),glutathione peroxidase(GSH-PX)and malondialdehyde(MDA)in serum were correspondingly determined by WST-1 method,colorimetry and TBA method,respectively,enzyme-linked immunosorbent assay(ELISA)was used to detect the contents of gastrin(GAS),somatostatin(SS),tumor necrosis factor-α(TNF-α),interleukin-1 β(IL-1β),interleukin-6(IL-6)and interleukin-10(IL-10)in serum,the expression levels of epidermal growth factor receptor(EGFR),matrix metalloproteinase 3(MMP3),nuclear factor erythroid-related factor 2(NRF2),heme oxygenase 1(HO-1)and mitochondrial SOD2,TNF-α,IL-1β,IL-6 and IL-10 mRNA in gastric mucosa were detected by real-time fluorescence quantitative polymerase chain reaction(qPCR).Results Compared with the blank group,the body mass of rats in the model group was increased slowly,the activity distance and activity in the open field test were decreased,the gastric mucosal ulcer index was increased significantly,the gastric mucosal function indexes involving GAS level was increased and SS level was decreased in serum,the mRNA expression level of EGFR in gastric mucosa was decreased and the mRNA expression level of MMP3 in gastric mucosa was increased.The serum levels of antioxidant substances SOD and GSH-PX were decreased significantly,and the serum level of oxidation product MDA was increased significantly.The mRNA expression levels of antioxidant genes NRF2,HO-1 and SOD2 in gastric mucosa were significantly decreased.The serum contents and the gastric mucosa mRNA levels of inflammatory factors TNF-α,IL-1α,IL-6 were significantly increased,while the serum content and the gastric mucosa mRNA level of IL-10 were significantly decreased.The differences were statistically significant(P＜0.05 or P＜0.01 or P＜0.001).HE staining showed obvious gastric mucosal injury.Compared with the model group,the above indexes in the acupuncture group and the Omeprazole group were significantly improved(P＜0.05 or P＜0.01 or P＜0.001).HE staining showed that the gastric mucosal injury was significantly reduced.Conclusion Acupuncture at Zusanli-Zhongwan combined matching points can reduce the local oxidative stress and inflammatory response in rats with exercise-induced stress gastric ulcer,reduce gastric mucosal injury,improve the emotional state of rats,and maintain the overall vitality of rats.

Objective To investigate the effects of exercise and complex environment on lipopolysaccharide(LPS)-induced dopaminergic neuron death in the substantia nigra of midbrain.Methods C57BL/6 mice were divided into control group,LPS group,LPS+swimming group and LPS+complex environment group,with 7 mice in each group.The mice in the LPS group were injected with LPS into the brain to establish an inflammatory model of Parkinson's disease and lived in cages for 2 weeks.Mice in LPS+swimming group were forced to swim for 15 minutes every day for 2 weeks after modeling.The mice in the LPS+complex environment group were placed in a complex environment for 2 weeks after modeling.The control group mice were not treated.After 14 days of modeling,behavioral experiments such as footprint,open field and rotating rod were performed on each group of mice to detect the autonomous exercise ability,exercise balance ability and depression level of mice.The expressions of tyrosine hydroxylase(TH)in substantia nigra was detected by immunohistochemical staining and Western blotting.The expressions of brain-derived neurotrophic factor(BDNF),Caspase-3,interleukin-1β(IL-1β),interleukin-6(IL-6)and tumor necrosis factor-α(TNF-α)in the substantia nigra of the midbrain were detected by Western blotting.The transcription levels of IL-1β,IL-6 and TNF-α in substantia nigra were detected by RT-PCR.Results Compared with the control group,the exercise ability and balance ability of mice in LPS group,LPS+swimming group and LPS+complex environment group decreased,the depression level increased(P＜0.001),the number of TH positive neurons and BDNF protein decreased significantly(P＜0.001),and the contents of Caspase-3,IL-1β,IL-6 and TNF-α increased significantly(P＜0.001).Compared with the LPS group,the exercise ability and balance ability of the mice in the LPS+swimming group and the LPS+complex environment group were restored,the depression level decreased significantly(P＜0.01),the survival number of TH positive neurons and the content of BDNF increased significantly(P＜0.01),Caspase-3,IL-1β,IL-6 and TNF-α reduced significantly(P＜0.01),and the phenomenon in the LPS+complex environment group was more significant.Conclusion Exercise and complex environment can inhibit LPS-induced central nervous system inflammation in mice,thereby reducing damage to midbrain substantia nigra neurons,and the inhibitory effect of LPS+complex environment group is more significant.