PURPOSE: To investigate the protective effect of sub-hypothermic mechanical perfusion combined with membrane lung oxygenation on ischemic hypoxic injury of yorkshire brain tissue caused by traumatic blood loss. METHODS: This article performed a random controlled trial. Brain tissue of 7 yorkshire was selected and divided into the sub-low temperature anterograde machine perfusion group (n = 4) and the blank control group (n = 3) using the random number table method. A yorkshire model of brain tissue injury induced by traumatic blood loss was established. Firstly, the perfusion temperature and blood oxygen saturation were monitored in real-time during the perfusion process. The number of red blood cells, hemoglobin content, NA⁺, K⁺, and Ca²⁺ ions concentrations and pH of the perfusate were detected. Following perfusion, we specifically examined the parietal lobe to assess its water content. The prefrontal cortex and hippocampus were then dissected for histological evaluation, allowing us to investigate potential regional differences in tissue injury. The blank control group was sampled directly before perfusion. All statistical analyses and graphs were performed using GraphPad Prism 8.0 Student t-test. All tests were two-sided, and p value of less than 0.05 was considered to indicate statistical significance. RESULTS: The contents of red blood cells and hemoglobin during perfusion were maintained at normal levels but more red blood cells were destroyed 3 h after the perfusion. The blood oxygen saturation of the perfusion group was maintained at 95% - 98%. NA⁺ and K⁺ concentrations were normal most of the time during perfusion but increased significantly at about 4 h. The Ca²⁺ concentration remained within the normal range at each period. Glucose levels were slightly higher than the baseline level. The pH of the perfusion solution was slightly lower at the beginning of perfusion, and then gradually increased to the normal level. The water content of brain tissue in the sub-low and docile perfusion group was 78.95% ± 0.39%, which was significantly higher than that in the control group (75.27% ± 0.55%, t = 10.49, p < 0.001), and the difference was statistically significant. Compared with the blank control group, the structure and morphology of pyramidal neurons in the prefrontal cortex and CA1 region of the hippocampal gyrus were similar, and their integrity was better. The structural integrity of granulosa neurons was destroyed and cell edema increased in the perfusion group compared with the blank control group. Immunofluorescence staining for glail fibrillary acidic protein and Iba1, markers of glial cells, revealed well-preserved cell structures in the perfusion group. While there were indications of abnormal cellular activity, the analysis showed no significant difference in axon thickness or integrity compared to the 1-h blank control group. CONCLUSIONS Mild hypothermic machine perfusion can improve ischemia and hypoxia injury of yorkshire brain tissue caused by traumatic blood loss and delay the necrosis and apoptosis of yorkshire brain tissue by continuous oxygen supply, maintaining ion homeostasis and reducing tissue metabolism level.
Animals ; Perfusion/methods* ; Disease Models, Animal ; Brain Injuries/etiology* ; Swine ; Male ; Hypothermia, Induced/methods*

Debates persist regarding the efficacy and safety of azvudine, particularly its real-world outcomes. This study involved patients aged ≥60 years who were admitted to 25 hospitals in mainland China with confirmed SARS-CoV-2 infection between December 1, 2022, and February 28, 2023. Efficacy outcomes were all-cause mortality during hospitalization, the proportion of patients discharged with recovery, time to nucleic acid-negative conversion (T _NANC), time to symptom improvement (T _SI), and time of hospital stay (T _HS). Safety was also assessed. Among the 5884 participants identified, 1999 received azvudine, and 1999 matched controls were included after exclusion and propensity score matching. Azvudine recipients exhibited lower all-cause mortality compared with controls in the overall population (13.3% vs. 17.1%, RR, 0.78; 95% CI, 0.67-0.90; P = 0.001) and in the severe subgroup (25.7% vs. 33.7%; RR, 0.76; 95% CI, 0.66-0.88; P < 0.001). A higher proportion of patients discharged with recovery, and a shorter T _NANC were associated with azvudine recipients, especially in the severe subgroup. The incidence of adverse events in azvudine recipients was comparable to that in the control group (2.3% vs. 1.7%, P = 0.170). In conclusion, azvudine showed efficacy and safety in older patients hospitalized with COVID-19 during the SARS-CoV-2 omicron wave in China.

OBJECTIVE: Coptis chinensis (Huanglian in Chinese, HL) is commonly utilized in clinical settings to counteract dyslipidemia in patients with hot syndrome. Its lipid-reducing efficacy has been consistently demonstrated in high-fat diet (HFD)-induced hyperlipidemic animal models. However, whether HL's efficacy differs in HFD-fed animals with hot or cold syndromes remains unclear. This study aims to discern the variations in the anti-hyperlipidemic effects of HL in HFD-fed mice with hot or cold syndromes. METHODS: HFD-induced C57BL/6 mice were subjected to cold or hot syndrome via two weeks of ice water (0 °C) and levothyroxine sodium (240 µg/kg) treatment, respectively. Then, an aqueous extract of HL was administered to the mice via oral gavage over the following four-week period. Lipid levels in the serum and liver were gauged to determine the lipid-reducing effects of HL. Furthermore, gut microbiota composition was elucidated using full-length 16S rRNA gene sequencing. RESULTS: HL notably reduced lipid levels in HFD-induced hyperlipidemic mice. Its efficacy was amplified in hyperlipidemic mice with a hot syndrome but was markedly reduced in those with a cold syndrome. HL treatment led to a decline in alpha-diversity (characterized by ACE, Chao1, Shannon and Simpson index) of the gut microbiota in both sets of mice but affected specific microbial populations based on the syndrome. Specifically, while HL led to a notable increase in Eubacterium, Robinsoniella, and Lachnoclostridium genera, along with the enhancement of Clostridium innocuum and Bacteroides thetaiotaomicron species across all conditions, it syndrome-dependently stimulated Romboutsia ilealis and Parabaceroides_sp_HGS0025 species in mice with hot syndrome. CONCLUSION HL shows stronger lipid-lowering effect on hyperlipidemic mice with hot syndrome, which is in accordance with its traditional usage in clinic. The therapeutic outcomes of HL are intrinsically tied, at least in part, to its modulatory effects on the gut microbiota, offering fresh insights into the foundational principles of traditional Chinese medicine.

The main protease (M^pro) of SARS-CoV-2 is an attractive target in anti-COVID-19 therapy for its high conservation and major role in the virus life cycle. The covalent M^pro inhibitor nirmatrelvir (in combination with ritonavir, a pharmacokinetic enhancer) and the non-covalent inhibitor ensitrelvir have shown efficacy in clinical trials and have been approved for therapeutic use. Effective antiviral drugs are needed to fight the pandemic, while non-covalent M^pro inhibitors could be promising alternatives due to their high selectivity and favorable druggability. Numerous non-covalent M^pro inhibitors with desirable properties have been developed based on available crystal structures of M^pro. In this article, we describe medicinal chemistry strategies applied for the discovery and optimization of non-covalent M^pro inhibitors, followed by a general overview and critical analysis of the available information. Prospective viewpoints and insights into current strategies for the development of non-covalent M^pro inhibitors are also discussed.

Objective To investigate the relationship between serum micro RNA(miRNAs)-873 and micro RNA-138-5p expression and tumor immune microenvironment(TIME)and prognosis in patients with non-small cell lung cancer(NSCLC).Methods A total of 108 NSCLC patients(NSCLC group)and 65 healthy volunteers(control group)who were admitted to Ba'nan Hospital Affiliated to Chongqing Medical University from February 2019 to February 2021 were selected.Real-time quantitative fluorescence polymeric chain reaction(qRT-PCR)was used to detect the expression of miR-873 and miR-138-5p in serum,and multiple immunofluorescence staining was used to detect tumor immune microenvironment indicators.Regular follow-up was conducted after discharge.Pearson analyzed the correlation between the expression of miR-873 and miR-138-5p in serum and the TIME index,and Kaplan-Meier and COX proportional risk regression analyzed the relationship between miR-873 and miR-138-5p and the prognosis of NSCLC patients.Results Comparison with control group,the expressions of miR-873(1.02±0.23 vs 3.15±0.82)and miR-138-5p(1.21±0.26 vs 3.54±0.92)in serum of NSCLC group were decreased,and the differences were statistically significant(t=-25.426,-24.769,all P＜0.05).The expressions of serum miR-873 and miR-138-5p of patients with low-to-moderate differentiation in TNM stages Ⅲ to Ⅳ were lower than those with highly differentiated patients in TNM stages Ⅰ to Ⅱ(t=9.615,10.253;6.889,3.361,all P＜0.05).The expressions of miR-873 and miR-138-5p in serum were negatively correlated with the values of PD-1,PD-L1,CD4 and CD8 H(r=-0.418～-0.673,all P＜0.05).The OS survival rate of NSCLC patients with low expression of miR-873 and miR-138-5p was lower than that of those with high expression of miR-873 and miR-138-5p(Log-Rankχ2=4.724,5.607,P＜0.05).TNM stage Ⅲ～Ⅳ was a risk factor for poor prognosis in patients with NSCLC(P＜0.05),and miR-873 and miR-138-5p were protective factors(P＜0.05).Conclusion The expressions of miR-873 and miR-138-5p in serum of NSCLC patients are down-regulated,which is related to TIME and low survival rate.

Background::Carotid intima-media thickness (IMT) and diameter, stiffness, and wave reflections, are independent and important clinical biomarkers and risk predictors for cardiovascular diseases. The purpose of the present study was to establish nationwide reference values of carotid properties for healthy Chinese adults and to explore potential clinical determinants.Methods::A total of 3053 healthy Han Chinese adults (1922 women) aged 18-79 years were enrolled at 28 collaborating tertiary centers throughout China between April 2021 and July 2022. The real-time tracking of common carotid artery walls was achieved by the radio frequency (RF) ultrasound system. The IMT, diameter, compliance coefficient, β stiffness, local pulse wave velocity (PWV), local systolic blood pressure, augmented pressure (AP), and augmentation index (AIx) were then automatically measured and reported. Data were stratified by age groups and sex. The relationships between age and carotid property parameters were analyzed by Jonckheere-Terpstra test and simple linear regressions. The major clinical determinants of carotid properties were identified by Pearson’s correlation, multiple linear regression, and analyses of covariance.Results::All the parameters of carotid properties demonstrated significantly age-related trajectories. Women showed thinner IMT, smaller carotid diameter, larger AP, and AIx than men. The β stiffness and PWV were significantly higher in men than women before forties, but the differences reversed after that. The increase rate of carotid IMT (5.5 μm/year in women and 5.8 μm/year in men) and diameter (0.03 mm/year in both men and women) were similar between men and women. For the stiffness and wave reflections, women showed significantly larger age-related variations than men as demonstrated by steeper regression slopes (all P for age by sex interaction <0.05). The blood pressures, body mass index (BMI), and triglyceride levels were identified as major clinical determinants of carotid properties with adjustment of age and sex. Conclusions::The age- and sex-specific reference values of carotid properties measured by RF ultrasound for healthy Chinese adults were established. The blood pressures, BMI, and triglyceride levels should be considered for clinical application of corresponding reference values.

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 evaluate the effect of water exchange method versus conventional methods including air insufflation and carbon dioxide insufflation method for the quality of colonoscopy.Methods We searched related randomized controlled trials published up to October 2022 from PubMed,Web of Science,the Cochrane Library,SinoMed databases,CNKI,Wanfang data.Two reviewers independently searched the literatures based on standards to extract the data and evaluate the quality.Meta-analysis was conducted by RevMan 5.4.1.Results 23 studies involving 10654 patients were included.Although cecal intubation time was prolonged in water exchange(MD=1.81,95％CI:1.28～2.35,P=0.000),but water exchange had higher adenoma detection rate(ADR)(O(R)=1.40,95％CI:1.26～1.55,P=0.000),cecal intubation rate(O(R)=1.62,95％CI:1.24～2.10,P=0.000)and scores of bowel preparation quality(MD=0.61,95％CI:0.42～0.79,P=0.000)compared with conventional colonoscopy.In addition,WE had significantly lower pain sores(MD=-1.07,95％CI:-1.39～-0.76,P=0.000),number of abdominal compression(O(R)=0.42,95％CI:0.29～0.60,P=0.000)and number of position change(O(R)=0.59,95％CI:0.42～0.82,P=0.002)than conventional colonoscopy.Conclusion Although water exchange colonoscopy prolongs cecal intubation time,but it can significantly increase ADR,cecal intubation rate and scores of bowel preparation quality.Beyond that,water exchange reduces patient pain,the proportion of abdominal compression and position change.Water exchange is a better choice for high-quality colonoscopy.

As a common protease with high similarity among coronavirus species, the main protease (M^pro) of SARS-CoV-2 is responsible for the catalytic hydrolysis of viral precursor proteins into functional proteins, which is essential for coronavirus replication and is one of the ideal targets for the development of broad-spectrum antiviral drugs. This paper reviews the main protease inhibitors of SARS-CoV-2, including their molecular structures, potencies and drug-like profiles, binding modes and structure-activity relationships, etc.