OBJECTIVE: High-altitude hypoxia exposure often damages hippocampus-dependent learning and memory. Nogo-A is an important axonal growth inhibitory factor. However, its function in high-altitude hypoxia and its mechanism of action remain unclear. METHODS: In an in vivo study, a low-pressure oxygen chamber was used to simulate high-altitude hypoxia, and genetic or pharmacological intervention was used to block the Nogo-A/NgR1 signaling pathway. Contextual fear conditioning and Morris water maze behavioral tests were used to assess learning and memory in rats, and synaptic damage in the hippocampus and changes in oxidative stress levels were observed. In vitro, SH-SY5Y cells were used to assess oxidative stress and mitochondrial function with or without Nogo-A knockdown in Oxygen Glucose-Deprivation/Reperfusion (OGD/R) models. RESULTS: Exposure to acute high-altitude hypoxia for 3 or 7 days impaired learning and memory in rats, triggered oxidative stress in the hippocampal tissue, and reduced the dendritic spine density of hippocampal neurons. Blocking the Nogo-A/NgR1 pathway ameliorated oxidative stress, synaptic damage, and the learning and memory impairment induced by high-altitude exposure. CONCLUSION: Our results demonstrate the detrimental role of Nogo-A protein in mediating learning and memory impairment under high-altitude hypoxia and suggest the potential of the Nogo-A/NgR1 signaling pathway as a crucial therapeutic target for alleviating learning and memory dysfunction induced by high-altitude exposure. GRAPHICAL ABSTRACT available in www.besjournal.com.
Animals ; Oxidative Stress ; Hippocampus/metabolism* ; Rats ; Nogo Proteins/genetics* ; Male ; Rats, Sprague-Dawley ; Hypoxia/metabolism* ; Altitude ; Synapses ; Humans ; Altitude Sickness/metabolism*

Objective To analyze the antigen recognition sites of commercial and homemade antibodies against aquaporin(AQP)9,and to identify the application effect.Methods Western blotting was used to compare the efficacy of three commercial antibodies and self-made antibody in identifying AQP9 genotypes.The antigen recognition sites of four antibodies and their specificities in practical applications were analyzed.Results Western blotting showed that protein bands of three commercial antibodies were detected in both WT and Aqp9-/-mice.The keyhole limpet hemocyanin(KLH)conjugated synthetic peptides corresponding to the three commercial antibodies were derived from rat,human and human,respectively.And The sequences of these three synthetic peptides were different from those of mice.AQP3/7 and AQP9 have similar molecular weight and were expressed in the liver with high homology.An obvious band of self-made antibody was observed at the 27 kD position in WT mice,but no band was observed at the corresponding position in Aqp9-/-mice.Conclusion Commercial antibodies 1 and 3 can be used to assist in the identification of genotypes in Aqp9-/-mice.Homemade antibodies can accurately identify genotypes at the protein level.

Objective To investigate the incidence rate,clinical characteristics,and prognosis of neonatal stroke in Shenzhen,China.Methods Led by Shenzhen Children's Hospital,the Shenzhen Neonatal Data Collaboration Network organized 21 institutions to collect 36 cases of neonatal stroke from January 2020 to December 2022.The incidence,clinical characteristics,treatment,and prognosis of neonatal stroke in Shenzhen were analyzed.Results The incidence rate of neonatal stroke in 21 hospitals from 2020 to 2022 was 1/15 137,1/6 060,and 1/7 704,respectively.Ischemic stroke accounted for 75％(27/36);boys accounted for 64％(23/36).Among the 36 neonates,31(86％)had disease onset within 3 days after birth,and 19(53％)had convulsion as the initial presentation.Cerebral MRI showed that 22 neonates(61％)had left cerebral infarction and 13(36％)had basal ganglia infarction.Magnetic resonance angiography was performed for 12 neonates,among whom 9(75％)had involvement of the middle cerebral artery.Electroencephalography was performed for 29 neonates,with sharp waves in 21 neonates(72％)and seizures in 10 neonates(34％).Symptomatic/supportive treatment varied across different hospitals.Neonatal Behavioral Neurological Assessment was performed for 12 neonates(33％,12/36),with a mean score of(32±4)points.The prognosis of 27 neonates was followed up to around 12 months of age,with 44％(12/27)of the neonates having a good prognosis.Conclusions Ischemic stroke is the main type of neonatal stroke,often with convulsions as the initial presentation,involvement of the middle cerebral artery,sharp waves on electroencephalography,and a relatively low neurodevelopment score.Symptomatic/supportive treatment is the main treatment method,and some neonates tend to have a poor prognosis.

Objective: To understand the current status of diagnosis and treatment of chronic lymphocytic leukemia (CLL) /small lymphocytic lymphoma (SLL) among hematologists, oncologists, and lymphoma physicians from hospitals of different levels in China. Methods: This multicenter questionnaire survey was conducted from March 2021 to July 2021 and included 1,000 eligible physicians. A combination of face-to-face interviews and online questionnaire surveys was used. A standardized questionnaire regarding the composition of patients treated for CLL/SLL, disease diagnosis and prognosis evaluation, concomitant diseases, organ function evaluation, treatment selection, and Bruton tyrosine kinase (BTK) inhibitor was used. Results: ①The interviewed physicians stated that the proportion of male patients treated for CLL/SLL is higher than that of females, and the age is mainly concentrated in 61-70 years old. ②Most of the interviewed physicians conducted tests, such as bone marrow biopsies and immunohistochemistry, for patient diagnosis, in addition to the blood test. ③Only 13.7% of the interviewed physicians fully grasped the initial treatment indications recommended by the existing guidelines. ④In terms of cognition of high-risk prognostic factors, physicians' knowledge of unmutated immunoglobulin heavy-chain variable and 11q- is far inferior to that of TP53 mutation and complex karyotype, which are two high-risk prognostic factors, and only 17.1% of the interviewed physicians fully mastered CLL International Prognostic Index scoring system. ⑤Among the first-line treatment strategy, BTK inhibitors are used for different types of patients, and physicians have formed a certain understanding that BTK inhibitors should be preferentially used in patients with high-risk factors and elderly patients, but the actual use of BTK inhibitors in different types of patients is not high (31.6%-46.0%). ⑥BTK inhibitors at a reduced dose in actual clinical treatment were used by 69.0% of the physicians, and 66.8% of the physicians had interrupted the BTK inhibitor for >12 days in actual clinical treatment. The use of BTK inhibitors is reduced or interrupted mainly because of adverse reactions, such as atrial fibrillation, severe bone marrow suppression, hemorrhage, and pulmonary infection, as well as patients' payment capacity and effective disease progression control. ⑦Some differences were found in the perceptions and behaviors of hematologists and oncologists regarding the prognostic assessment of CLL/SLL, the choice of treatment options, the clinical use of BTK inhibitors, etc. Conclusion: At present, a gap remains between the diagnosis and treatment of CLL/SLL among Chinese physicians compared with the recommendations in the guidelines regarding the diagnostic criteria, treatment indications, prognosis assessment, accompanying disease assessment, treatment strategy selection, and rational BTK inhibitor use, especially the proportion of dose reduction or BTK inhibitor discontinuation due to high adverse events.
Female ; Humans ; Male ; Aged ; Middle Aged ; Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy* ; Prognosis ; Lymphoma, B-Cell ; Immunohistochemistry ; Immunoglobulin Heavy Chains/therapeutic use*

Diversity-oriented synthesis is aimed to increase the chemical diversity of target natural products for extensive biological activity evaluation. Indole ring is an important functional group in a large number of drugs and other biologically active agents, and indole-containing natural products have been frequently isolated from marine sources in recent years. In this paper, a series of indole-containing marine natural hyrtioreticulin derivatives, including 19 new ones, were designed, synthesized through a key Pictet-Spengler reaction, and evaluated for their inflammation related activity. Compound 13b displayed the most promising activity by inhibiting TNF-α cytokine release with an inhibitory rate of 92% at a concentration of 20 μmol·L^-1. A preliminary structure-activity relationship analysis was also discussed. This research may throw light on the discovery of marine indole alkaloid derived anti-inflammatory drug leads.
Animals ; Anti-Inflammatory Agents/pharmacology* ; Biological Products/pharmacology* ; Indole Alkaloids/pharmacology* ; Porifera ; Structure-Activity Relationship

Cardiovascular diseases， with high incidence and high mortality， belong to the category of "chest impediment and heart pain" in traditional Chinese medicine （TCM）. Chinese medicines have unique effect on the prevention and treatment of cardiovascular diseases with little side effects. Huoxin pills， one of the National Essential Drugs， is formulated based on the basic pathogenesis of weak pulse at Yang and wiry pulse at Yin and the pathological basis of myocardial ischemia and hypoxia and used for treating angina pectoris of coronary heart disease （Qi deficiency and blood stasis syndrome）. This medicine is derived from the classic famous prescription and is composed of ten precious Chinese medicinal herbs. It can replenish Qi， activate blood， and warm collaterals to diffuse impediment by enhancing myocardial contractility and cardiac output to improve micro-circulation and increase coronary blood flow， regulating immune functions， alleviating inflammation， detoxifying， and tranquilizing mind. Clinically， it is suitable for patients with angina pectoris caused by the lack of heart Yang， chest tightness， shortness of breath， palpitation， fear of cold for limbs and so on， especially for the elderly with Yang deficiency or the patients with a history of myocardial infarction. On the basis of the available research reports， this paper explains the formula meaning of Huoxin pills from the perspective of the basic pathogenesis of coronary heart disease and predicts its action targets， location and links. Furthermore， we expound the mechanism of action of Huoxin pills based on basic research and clinical evidence-based research， aiming to provide data support and evidence for the clinical application of this medicine.

Objective: To evaluate the effect of erianin on the viability, migration, and invasion of KB cells and elucidate its underlying mechanisms. Methods: Cell Counting Kit-8, colony formation, wound healing, and Transwell assays were used to determine the proliferation, migration, and invasion of oral cancer KB cells. Furthermore, malondialdehyde (MDA) and glutathione (GSH) levels were determined. Fluorescent probes were used to detect changes in intracellular reactive oxygen species and iron ions. Additionally, the expressions of ferroptosis-related proteins, NF-E2-related factor 2 (Nrf2), ferritin heavy chain 1 (FTH1), heme oxygenase 1 (HO-1), and glutathione peroxidase 4 (GPX4) were analyzed by Western blotting assays. Results: Erianin induced ferroptosis and inhibited the proliferation, migration, and invasion of KB cells. Moreover, erianin decreased GSH level, increased MDA level, elevated intracellular ROS and Fe

Resveratrol (RES) can inhibit the growth and proliferation of liver cancer cells. However, its role in the precancerous stage is still unclear. This paper aims to study the effect and mechanism of RES on the precancerous stage of liver cancer in rats induced by diethylinitrosamine (DEN). SD rats were divided into normal control group, RES treatment group, DEN treatment group and RES-DEN treatment group. The results showed that after the rats were treated with DEN for 8 weeks, the total expression level of proliferating cell nuclear antigen (PCNA) of hepatocytes increased to 2-fold (P<0.05), and the expression level of PCNA protein in the nucleus increased to 3-fold (P<0.001). However, the expression levels of total PCNA (P<0.05) and nuclear PCNA protein (P<0.001) in hepatocytes of rats treated with RES-DEN decreased, suggesting that RES could significantly inhibit the liver malignant proliferation of cells. Through non-targeted metabolomics and KEGG metabolic pathway enrichment analysis, the results showed that the level of glycolysis did not increase significantly in the hepatocytes of RES-DEN-treated rats, although the transition from the pentose phosphate pathway to the glycolysis pathway was enhanced when compared with the DEN group rats. This finding suggested that the metabolic pathway of phosphoenolpyruvate-pyruvate-lactate was inhibited. Further verification found that the protein expression levels of key enzymes M2-type pyruvate kinase (PKM2) and lactate dehydrogenase (LDHA) in this metabolic pathway were inhibited (P<0.05). RES can reprogram glucose metabolism and inhibit DEN-induced excessive proliferation of rat hepatocytes in the precancerous stage of liver cancer, providing an experimental basis for RES to prevent liver cancer.

The current study aims to rapidly and comprehensively profile the chemical composition of Cistanche salsa using direct infusion coupled with MS/MS~(ALL)(DI-MS/MS~(ALL)). The C. salsa extract was directly imported into electrospray ionization(ESI) source of quadrupole time-of-flight(Q-TOF) mass spectrometer with an infusion pump at a flow rate of 10 μL·min~(-1). Acquisition program was applied under negative ionization polarity to collect one MS~1 spectrum(m/z 50-1 200), followed by 1 150 MS~2 spectra with precursor isolation window(m/z 1) amongst mass range m/z 50-1 200. After each MS~2 spectrum was matched to its precursor ion, putative identification was conducted through matching mass spectral data with literature and database. A total of 31 components were identified from C. salsa, including 9 phenylethanoid glycosides, 2 iridoids, 4 saccharides, 9 organic acids, and 7 other compounds, similar to those from C. tubulosa and C. deserticola. In conclusion, DI-MS/MS~(ALL), a facile and reliable analytical tool, can be employed for qualitative analysis of chemical constituents in C. salsa. The research offers a promising strategy to achieve rapid chemome profiling of herbal medicine and provides an alternative source of Cistanches Herba.
Chromatography, High Pressure Liquid ; Cistanche ; Drugs, Chinese Herbal ; Glycosides ; Plants, Medicinal ; Tandem Mass Spectrometry

BACKGROUND: Many Parkinson disease (PD) patients complain about chronic fatigue and sleep disturbances during the night. The objective of this study is to determine the relationship between fatigue and sleep disturbances by using polysomnography (PSG) in PD patients. METHODS: Two hundred and thirty-two PD patients (152 with mild fatigue and 80 with severe fatigue) were recruited in this study. Demographic information and clinical symptoms were collected. Fatigue severity scale (FSS) was applied to evaluate the severity of fatigue, and PSG was conducted in all PD patients. FSS ≥4 was defined as severe fatigue, and FSS <4 was defined as mild fatigue. Multivariate logistic regression and linear regression models were used to investigate the associations between fatigue and sleep disturbances. RESULTS: Patients with severe fatigue tended to have a longer duration of disease, higher Unified Parkinson Disease Rating Scale score, more advanced Hoehn and Yahr stage, higher daily levodopa equivalent dose, worse depression, anxiety, and higher daytime sleepiness score. In addition, they had lower percentage of rapid eye movement (REM) sleep (P = 0.009) and were more likely to have REM sleep behavior disorder (RBD) (P = 0.018). Multivariate logistic regression analyses found that the presence of RBD and proportion of REM sleep were the independent predictors for fatigue. After the adjustment of age, sex, duration, body mass index, severity of disease, scores of Hamilton Rating Scale for Depression, Hamilton Anxiety Rating Scale, and other sleep disorders, proportion of REM sleep and degree of REM sleep without atonia in patients with PD were still associated with FSS score. CONCLUSION Considering the association between fatigue, RBD, and the altered sleep architecture, fatigue is a special subtype in PD and more studies should be focused on this debilitating symptom.
Humans ; Parkinson Disease/complications* ; Polysomnography ; REM Sleep Behavior Disorder ; Sleep ; Sleep Wake Disorders/etiology*