BACKGROUND:Low temperatures have detrimental effects on the human cardiovascular system,with a higher prevalence of hypertension and related cardiovascular diseases,especially among people living in cold climates.Transient receptor potential M8(TRPM8)is often recognized as a physiological sensor of environmental cold,and glutamate receptor-3(GLR-3)/glutamate receptor ionotropic,kainate 2(GluK2)is also cold-sensitive.However,the specific molecular mechanisms of cold-associated TRPM8 and GLR-3/GluK2 in regulating hypertension remain puzzling.OBJECTIVE:Through a review of the literature in this field,to find out the general pattern of TRPM8 and GLR-3/GluK2 in regulating the body's cold response,as well as the specific mechanism of action in hypertension,thereby providing a theoretical basis for subsequent research on the treatment of hypertension based on cold-stimulation-related targets,and further expanding the new ideas and methods for the treatment of hypertension.METHODS:We searched,reviewed and screened the relevant literature on"cold stimulation,TRPM8,GLR-3/GluK2 and hypertension"to lay the theoretical foundation for the analysis of the whole article.Comparative analysis method,through reading and analyzing the obtained literature,comparing the similarities and differences between the literature,was performed to provide reasonable theoretical support for the argument.Through further comparative analysis of the literature,the relationship between the relevant indicators was clarified,and the ideas were clarified for the analysis of the full text.RESULTS AND CONCLUSION:(1)TRPM8 can be activated by cold and mainly mediates cool temperature perception in mammals.Its activation can trigger neurogenic inflammatory response and indirectly affect the inflammatory process.Abnormal TRPM8 signal can lead to excessive activation of immune cells,which is significantly associated with the occurrence and development of hypertension.(2)The activation threshold of GLR-3/GluK2 is lower than that of TRPM8,which may preferentially respond to noxious cold stimulation rather than ordinary cool temperature.In cold environment,GLR-3/GluK2 activation enhances sympathetic nerve excitability by regulating interneuron signal transduction and causes peripheral vascular constriction.Long-term effects can lead to increased peripheral vascular resistance.To conclude,TRPM8 and GLR-3/GluK2 are involved in the interaction of the nerve-immune-vascular system by sensing different cold stimuli.Abnormal TRPM8 signaling indirectly promotes the progression of hypertension through inflammation and immune dysregulation,while GLR-3/GluK2 directly exacerbates vascular constriction and resistance by enhancing sympathetic nerve activity.The combination of the two factors may constitute the key molecular mechanism of the occurrence and development of hypertension in cold environment,and provide a potential target for the intervention of cold-related cardiovascular diseases.

BACKGROUND:Low temperatures have detrimental effects on the human cardiovascular system,with a higher prevalence of hypertension and related cardiovascular diseases,especially among people living in cold climates.Transient receptor potential M8(TRPM8)is often recognized as a physiological sensor of environmental cold,and glutamate receptor-3(GLR-3)/glutamate receptor ionotropic,kainate 2(GluK2)is also cold-sensitive.However,the specific molecular mechanisms of cold-associated TRPM8 and GLR-3/GluK2 in regulating hypertension remain puzzling.OBJECTIVE:Through a review of the literature in this field,to find out the general pattern of TRPM8 and GLR-3/GluK2 in regulating the body's cold response,as well as the specific mechanism of action in hypertension,thereby providing a theoretical basis for subsequent research on the treatment of hypertension based on cold-stimulation-related targets,and further expanding the new ideas and methods for the treatment of hypertension.METHODS:We searched,reviewed and screened the relevant literature on"cold stimulation,TRPM8,GLR-3/GluK2 and hypertension"to lay the theoretical foundation for the analysis of the whole article.Comparative analysis method,through reading and analyzing the obtained literature,comparing the similarities and differences between the literature,was performed to provide reasonable theoretical support for the argument.Through further comparative analysis of the literature,the relationship between the relevant indicators was clarified,and the ideas were clarified for the analysis of the full text.RESULTS AND CONCLUSION:(1)TRPM8 can be activated by cold and mainly mediates cool temperature perception in mammals.Its activation can trigger neurogenic inflammatory response and indirectly affect the inflammatory process.Abnormal TRPM8 signal can lead to excessive activation of immune cells,which is significantly associated with the occurrence and development of hypertension.(2)The activation threshold of GLR-3/GluK2 is lower than that of TRPM8,which may preferentially respond to noxious cold stimulation rather than ordinary cool temperature.In cold environment,GLR-3/GluK2 activation enhances sympathetic nerve excitability by regulating interneuron signal transduction and causes peripheral vascular constriction.Long-term effects can lead to increased peripheral vascular resistance.To conclude,TRPM8 and GLR-3/GluK2 are involved in the interaction of the nerve-immune-vascular system by sensing different cold stimuli.Abnormal TRPM8 signaling indirectly promotes the progression of hypertension through inflammation and immune dysregulation,while GLR-3/GluK2 directly exacerbates vascular constriction and resistance by enhancing sympathetic nerve activity.The combination of the two factors may constitute the key molecular mechanism of the occurrence and development of hypertension in cold environment,and provide a potential target for the intervention of cold-related cardiovascular diseases.

Objective To investigate the effect of triglyceride-glucose index(TyG)on the short-term prognosis of patients with initial acute ischemic stroke.Methods A total of 391 patients with initial acute ischemic stroke who were hospitalized in Kunshan Second People's Hospital and The Affiliated Suzhou Hospital of Nanjing Medical University from Jun.2020 to Jun.2023 were retrospectively included.According to the modified Rankin scale(mRS)scores at 90 d follow-up,they were assigned to good prognosis group(286 cases)or poor prognosis group(105 cases).Logistic regression and receiver operating characteristic(ROC)curve were used to evaluate the effect of TyG on the short-term prognosis of patients with initial acute ischemic stroke.Results Compared with the good prognosis group,the patients of poor prognosis group had older age,higher proportion of atrial fibrillation,higher levels of homocysteine,triglyceride,total cholesterol,low-density lipoprotein,and TyG,and higher National Institutes of Health stroke scale(NIHSS)score(all P＜0.05).Multivariate logistic regression analysis showed that age,homocysteine,TyG and NIHSS score were independent risk factors for poor prognosis in patients with initial acute ischemic stroke(all P＜0.05).ROC curve analysis showed that TyG combined with NIHSS score had good predictive value for poor prognosis of patients with initial acute ischemic stroke,and the area under curve value was 0.795.Conclusion The combination of TyG and NIHSS score is an independent influencing factor for poor short-term prognosis in patients with initial acute ischemic stroke.

BACKGROUND:Circadian rhythms are closely related to the life activities of most mammals and insects.Timless gene plays a crucial role in the generation of circadian rhythms as key components encoding the Timeless/Period gene complex.However,its specific mechanism in circadian rhythms is still unclear.OBJECTIVE:To study the relationship between Timless protein gene,Period gene,circadian rhythm,environment and cryptochrome gene,so as to have a more comprehensive understanding of the nucleation and accumulation mechanism of circadian cycle and the influence of environment on circadian rhythm.METHODS:Literature retrieval was conducted in the Web of science Core Collection database,PubMed and CNKI,and the relevant literature was searched,consulted and screened after the keyword was set as"Timless,Period,circadian rhythm,environment"in English and Chinese.Non-relevant literature was progressively excluded through full-text reading,and 126 papers were finally included for the review.RESULTS AND CONCLUSION:In the circadian clock,the circadian spontaneous output of the cyclins kaput and CYCLE activate the Timeless/Period gene,Timeless gene regulates the nucleation mechanism and stability of Period gene,and Period gene can also be nucleated individually by a number of mechanisms.Casein kinase 2,Shaggy protein kinase and double time genes can regulate circadian rhythms and participate in transcription by phosphorylating Timeless gene/Period gene.Cryptochrome gene-mediated degradation of Timeless gene has a very important role in transcriptional integrity.External factors such as environmental factors and dietary patterns can influence circadian rhythms through the Timeless gene/Period gene.Interestingly,time-restricted eating can be used as an effective way to improve circadian rhythm disturbances.

By integrating existing research,this paper systematically analyzes the impact of exercise training in low-temperature environments on immune regulation and infection defense,in order to explore its potential benefits and risks.Strictly following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses:2020(PRISMA 2020)guidelines,multiple databases were systematically reviewed,to include original studies on the impact of exercise training in low-temperature environments on immune regulation and infection defense,and to evaluate the quality of the studies.The 25 included literature indicated that moderate-intensity exercise training in low-temperature environments could cause an increase in white blood cell count,neutrophils and natural killer cells,changes in both pro-inflammatory and anti-inflammatory factors,and predominant upregulation of most mucosal immunity level,as well as accelerated infection recovery in several studies.High-intensity exercise training in low-temperature environments has shown an immunosuppressive trend in individual studies,and physiological indicators such as body temperature,heart rate and metabolism have also been affected to varying degrees.This suggests that moderate-intensity exercise training in a low-temperature environment is conducive to enhancing immunity and preventing infection,which is of great significance for health management and occupational protection in cold climates.Reasonable control of exercise intensity and duration in a low-temperature environment is crucial for preventing immunosuppression.

BACKGROUND: Severe stroke has high rates of mortality and morbidity. This study aimed to investigate the clinical course, causes of worsening, and outcomes of severe ischemic stroke. METHODS: This prospective, multicenter cohort study enrolled adult patients admitted ≤30 days after ischemic stroke from nine hospitals in China between September 2017 and December 2019. Severe stroke was defined as a score of ≥15 on the National Institutes of Health Stroke Scale (NIHSS). Clinical worsening was defined as an increase of 4 in the NIHSS score from baseline. Unfavorable functional outcome was defined as a modified Rankin scale score ≥3 at 3 months and 1 year after stroke onset, respectively. We performed Logistic regression to explore baseline features and reperfusion therapies associated with clinical worsening and functional outcomes. RESULTS: Among 4201 patients enrolled, 854 patients (20.33%) had severe stroke on admission. Of 3347 patients without severe stroke on admission, 142 (4.24%) patients developed severe stroke in hospital. Of 854 patients with severe stroke on admission, 33.95% (290/854) experienced clinical worsening (median time from stroke onset: 43 h, Q1-Q3: 20-88 h), with brain edema (54.83% [159/290]) as the leading cause; 24.59% (210/854) of these patients died by 30 days, and 81.47% (677/831) and 78.44% (633/807) had unfavorable functional outcomes at 3 months and 1 year respectively. Reperfusion reduced the risk of worsening (adjusted odds ratio [OR]: 0.24, 95% confidence interval [CI]: 0.12-0.49, P  <0.01), 30-day death (adjusted OR: 0.22, 95% CI: 0.11-0.41, P  <0.01), and unfavorable functional outcomes at 3 months (adjusted OR: 0.24, 95% CI: 0.08-0.68, P <0.01) and 1 year (adjusted OR: 0.17, 95% CI: 0.06-0.50, P  <0.01). CONCLUSIONS: Approximately one-fifth of patients with ischemic stroke had severe neurological deficits on admission. Clinical worsening mainly occurred in the first 3 to 4 days after stroke onset, with brain edema as the leading cause of worsening. Reperfusion reduced the risk of clinical worsening and improved functional outcomes. REGISTRATION ClinicalTrials.gov , NCT03222024.
Humans ; Male ; Female ; Prospective Studies ; Ischemic Stroke/mortality* ; Aged ; Middle Aged ; Aged, 80 and over ; Stroke ; Brain Ischemia

Cell-free biosensors are detection tools that involve cell-free protein synthesis and consist of recognition elements and reporting elements.These biosensors offer several advantages,such as the ease of construction,a significant specificity and a high sensitivity.By overcoming the limitations associated with cell survival and cell membrane barriers,cell-free biosensors can considerably reduce response times.This article reviewed the recognition and reporting compo-nents of cell-free biosensors,summarizes recent research advancements in their applications to such spheres of public health as environmental monitoring and disease diagnosis,and explores the programmability and logical analysis capabili-ties of these biosensors.Future developments in this field are also predicted.

Objective:To prepare domestic 64Cu-1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid- D-Phe1-Tyr3-Thr8-octreotide (DOTATATE), and to verify its distribution and preliminary diagnostic value in neuroendocrine tumors (NETs). Methods:DOTATATE was labeled with the domestic 64Cu to obtain 64Cu-DOTATATE. The lipophilicity, in vitro stability, and pharmacokinetics were studied. Biodistribution experiments and microPET imaging were performed on NCI-H727 (somatostatin receptor (SSTR)2 positive expression) tumor-bearing nude mice. The preliminary clinical applications were conducted on 10 NETs patients (5 males, 5 females; age (58.5±13.0) years) from Chinese PLA General Hospital between May 2023 and April 2024. Data were analyzed by using independent-sample t test. Results:64Cu-DOTATATE was successfully prepared with the radiochemical purity greater than 98%, log P of -2.609±0.051 and good stability. Pharmacokinetic experiments in BALB/c mice suggested rapid blood clearance of the drug (elimination half-time of 22.78min). Biodistribution results in tumor-bearing mice showed that 64Cu-DOTATATE was mainly metabolized through the liver and kidneys, with significant tumor uptake at 1h ((2.519±0.273) percentage activity of injection dose per gram of tissue (%ID/g)) and sustained high uptake at 24h ((4.331±0.549)%ID/g). MicroPET imaging of tumor-bearing mice showed a slight increase in uptake and good retention at 24h, with a significant statistical difference compared to the blocked group ((2.197±0.250) vs (0.985±0.064) % ID/g; t=6.40, P=0.008). The tumor/liver ratios were 0.075±0.007, 0.083±0.011, 0.118±0.005, 0.263±0.031 at 1, 2, 6 and 24h, respectively. Preliminary clinical application indicated that 64Cu-DOTATATE exhibited good targeting in patients, and the liver radioactivity distribution was moderate (SUV max=10.62±3.46), providing good image quality. Conclusion:Domestic 64Cu-DOTATATE PET/CT imaging is a promising imaging evaluation method in NETs with the value for further clinical research.

Objective:To evaluate the association between triglyceride-glucose(TyG) index level, their variability, and the risk of incident hyperuricemia(HUA).Methods:A total of 1 583 cases with good compliance who underwent follow-up at the health examination center of a tertiary hospital physical in Zhengzhou were enrolled. The TyG index mean(TyG-mean) and variability indexes, including standard deviation(TyG-SD), coefficient of variation(TyG-CV), and adjusted standard deviation(adj-TyG-SD), were calculated based on TyG index values from three consecutive annual health check-ups. Cox proportional risk regression model was used to assess the relationship between the variability of TyG index and the risk of new-onset HUA; the dose-response relationship between different TyG indexes and HUA was examined using restricted cubic spline(RCS). Results:After a 3-year follow-up, 146 participants developed incident HUA. Both TyG-mean and TyG index variability indicators were significantly higher in the HUA group compared to the non-HUA group( P<0.05). After adjusting for multiple confounders, each standard deviation σincrease in TyG-SD, TyG-CV, and adj-TyG-SD was associated with a 1.23-fold(95% CI 1.06-1.43), 1.22-fold(95% CI 1.05-1.42), and 1.26-fold(95% CI 1.08-1.45) higher risk of incident HUA, respectively. RCS analysis revealed a nonlinear association between adj-TyG-SD and HUA risk( P<0.05), with a critical threshold of 0.55 at a hazard ratio( HR) of 1. Conclusions:Increased TyG index variability is associated with a higher risk of incident HUA, with adj-TyG-SD showing the strongest correlation with HUA risk.

Objective:To prepare domestic 64Cu-1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid- D-Phe1-Tyr3-Thr8-octreotide (DOTATATE), and to verify its distribution and preliminary diagnostic value in neuroendocrine tumors (NETs). Methods:DOTATATE was labeled with the domestic 64Cu to obtain 64Cu-DOTATATE. The lipophilicity, in vitro stability, and pharmacokinetics were studied. Biodistribution experiments and microPET imaging were performed on NCI-H727 (somatostatin receptor (SSTR)2 positive expression) tumor-bearing nude mice. The preliminary clinical applications were conducted on 10 NETs patients (5 males, 5 females; age (58.5±13.0) years) from Chinese PLA General Hospital between May 2023 and April 2024. Data were analyzed by using independent-sample t test. Results:64Cu-DOTATATE was successfully prepared with the radiochemical purity greater than 98%, log P of -2.609±0.051 and good stability. Pharmacokinetic experiments in BALB/c mice suggested rapid blood clearance of the drug (elimination half-time of 22.78min). Biodistribution results in tumor-bearing mice showed that 64Cu-DOTATATE was mainly metabolized through the liver and kidneys, with significant tumor uptake at 1h ((2.519±0.273) percentage activity of injection dose per gram of tissue (%ID/g)) and sustained high uptake at 24h ((4.331±0.549)%ID/g). MicroPET imaging of tumor-bearing mice showed a slight increase in uptake and good retention at 24h, with a significant statistical difference compared to the blocked group ((2.197±0.250) vs (0.985±0.064) % ID/g; t=6.40, P=0.008). The tumor/liver ratios were 0.075±0.007, 0.083±0.011, 0.118±0.005, 0.263±0.031 at 1, 2, 6 and 24h, respectively. Preliminary clinical application indicated that 64Cu-DOTATATE exhibited good targeting in patients, and the liver radioactivity distribution was moderate (SUV max=10.62±3.46), providing good image quality. Conclusion:Domestic 64Cu-DOTATATE PET/CT imaging is a promising imaging evaluation method in NETs with the value for further clinical research.