Aim To investigate the regulatory mecha-nisms of donepezil on the expression and enzymatic ac-tivity of cytochrome P450 3A4(CYP3A4),elucidate the synergistic impact of hypoxia on CYP3A4 function,and reveal its potential association with drug-induced cardiotoxicity,particularly QT interval prolongation.Methods Western blot,co-immunoprecipitation,and gene knockdown techniques were employed to evaluate the effects of donepezil and hypoxia on CYP3A4 pro-tein expression.CYP3A4 enzymatic activity was as-sessed using an in vitro incubation system with rat liver microsomes combined with high-performance liquid chromatography(HPLC),and the half-maximal inhib-itory concentration(IC50)was determined.Results Donepezil(10 μmol·L-1)and hypoxia reduced CYP3A4 protein expression to 31.75％and 45.90％of the control levels,respectively.Both interventions activated the gp78-mediated ubiquitin-proteasome path-way,significantly increasing CYP3A4 ubiquitination levels by 2.1-fold compared to the control group,thereby promoting proteasomal degradation.Donepezil inhibited CYP3A4 enzyme activity with an IC50 of 83.4μmol·L-1,and hypoxia synergistically enhanced this inhibitory effect,reducing the IC50 to 20.79 μmol·L-1.Conclusion Donepezil downregulates CYP3A4 function through dual mechanisms involving ubiquitin-mediated proteasomal degradation and direct enzymatic inhibition.Hypoxia potentiates this effect,leading to impaired metabolism of CYP3A4 substrate drugs,ele-vated plasma drug concentrations(1.6-2.3-fold in-crease compared to normal metabolic conditions),and an increased risk of QT interval prolongation and other forms of cardiotoxicity.

Aim To investigate the regulatory mecha-nisms of donepezil on the expression and enzymatic ac-tivity of cytochrome P450 3A4(CYP3A4),elucidate the synergistic impact of hypoxia on CYP3A4 function,and reveal its potential association with drug-induced cardiotoxicity,particularly QT interval prolongation.Methods Western blot,co-immunoprecipitation,and gene knockdown techniques were employed to evaluate the effects of donepezil and hypoxia on CYP3A4 pro-tein expression.CYP3A4 enzymatic activity was as-sessed using an in vitro incubation system with rat liver microsomes combined with high-performance liquid chromatography(HPLC),and the half-maximal inhib-itory concentration(IC50)was determined.Results Donepezil(10 μmol·L-1)and hypoxia reduced CYP3A4 protein expression to 31.75％and 45.90％of the control levels,respectively.Both interventions activated the gp78-mediated ubiquitin-proteasome path-way,significantly increasing CYP3A4 ubiquitination levels by 2.1-fold compared to the control group,thereby promoting proteasomal degradation.Donepezil inhibited CYP3A4 enzyme activity with an IC50 of 83.4μmol·L-1,and hypoxia synergistically enhanced this inhibitory effect,reducing the IC50 to 20.79 μmol·L-1.Conclusion Donepezil downregulates CYP3A4 function through dual mechanisms involving ubiquitin-mediated proteasomal degradation and direct enzymatic inhibition.Hypoxia potentiates this effect,leading to impaired metabolism of CYP3A4 substrate drugs,ele-vated plasma drug concentrations(1.6-2.3-fold in-crease compared to normal metabolic conditions),and an increased risk of QT interval prolongation and other forms of cardiotoxicity.

AIM To evaluate the quality of Yanyangke Mixture.METHODS The HPLC fingerprints were established,after which cluster analysis,principal component analysis and partial least squares discriminant analysis were performed.The contents of liquiritin,rosmarinic acid,sheganoside,irisgenin,honokiol,monoammonium glycyrrhizinate,irisflorentin,isoliquiritin and magnolol were determined,the analysis was performed on a 35 ℃ thermostatic Agilent ZORBAX SB-C18 column(5 μm,250 mmx4.6 mm),with the mobile phase comprising of 0.1％phosphoric acid-acetonitrile flowing at 1 mL/min in a gradient elution manner,and multi-wavelength detection was adopted.RESULTS There were ten common peaks in the fingerprints for twelve batches of samples with the similarities of more than 0.9.Various batches of samples were clustered into three types,three principal components displayed the acumulative variance contribution rate of 87.448％,peaks 5、14(honokiol),3(liquiritin),11(monoammonium glycyrrhizinate)and 15(asarinin)were quality markers.Nine constituents showed good linear relationships within their own ranges(r＞0.999 0),whose average recoveries were 98.5％-103.6％with the RSDs of 0.92％-1.7％.CONCLUSION This stable and reliable method can provide a basis for the quality control of Yanyangke Mixture.

COVID-19 has been prevalent for three years. The virulence of SARS-CoV-2 is weaken as it mutates continuously. However, elderly patients, especially those with underlying diseases, are still at high risk of developing severe infections. With the continuous study of the molecular structure and pathogenic mechanism of SARS-CoV-2, antiviral drugs for COVID-19 have been successively marketed, and these anti-SARS-CoV-2 drugs can effectively reduce the severe rate and mortality of elderly patients. This article reviews the mechanism, clinical medication regimens, drug interactions and adverse reactions of five small molecule antiviral drugs currently approved for marketing in China, so as to provide advice for the clinical rational use of anti-SARS-CoV-2 in the elderly.

Humans ; Child ; Primary Myelofibrosis/genetics* ; Prognosis ; Mutation

Work-related musculoskeletal disorders (WMSDs) refer to musculoskeletal disorders caused by work or work as the main cause, which are characterized by high prevalence and heavy burden of disease as a global problem. The classification and catalog of occupational diseases is of great significance for guiding the prevention and control of occupational diseases and safeguarding the rights and interests of workers. The types of WMSDs included in the list of occupational diseases vary greatly from country to country, and the regulations on specific pathogenic factors are also inconsistent. By sorting out and analyzing the lists and characteristics of WMSDs at home and abroad, and using the International Statistical Classification of Diseases and Related Health Problems (ICD-10) in occupational health to standardize of WMSDs in various countries, which would lay the foundation for future multi-country WMSDs occupational health registration and disease burden research, and provide a reference for China to revise the WMSDs list.
Humans ; Musculoskeletal Diseases/prevention & control* ; Occupational Diseases/prevention & control* ; Prevalence ; Risk Factors ; Surveys and Questionnaires

Humans ; Eosinophilia/diagnosis* ; Thrombosis/etiology* ; Heart Diseases/complications*

OBJECTIVE: To evaluate the suitability of two pretreatment methods, the nitric acid digestion method and the elution method, and two measurement modes of inductively coupled plasma-mass spectrometry(ICP-MS), the No gas mode and the helium collision(He) mode, for the determination of lithium and its compounds in the workplace air. METHODS: We collected lithium and its compounds in the air of the workplace using the microporous filter membrane, and two pretreatment methods, the nitric acid digestion and elution methods were used for processing, and measured with the No gas mode and the He mode of ICP-MS. RESULTS: The good linearity range of lithium concentration in No gas mode and He mode of ICP-MS method was 0.00-500.00 μg/L, and the correlation coefficient was 0.999. The detection limit and the lower limit of quantification of lithium were 0.04 and 0.13 μg/L respectively in the No gas mode. In He gas mode: they were 0.12 and 0.39 μg/L respectively. Using the nitric acid digestion method for pre-treatment, the recovery rate of lithium addition was 96.9%-104.9%; the within-run and the between-run relative standard deviations were 3.3%-5.0% and 2.9%-5.3% respectively. Using the elution method for pre-treatment, the recovery rate of lithium addition was 97.6%-102.1%; the within-run and the between-run relative standard deviation were 3.3%-4.6% and 3.4%-4.8%, respectively. The sample could be stored at room temperature for at least 14 days. CONCLUSION: The ICP-MS method can be used as a new technology for detecting lithium and its compounds in the air of workplace. It is recommended that the elution method and the No gas mode be the first choice when measuring lithium and its compounds.

Objective:Study on the mechanism of Tongfengning in promoting uric acid excretion from the perspective of urate transporter and mRNA in renal of hyperuricemia （HUA） model rats. Method:The 80 sprague-dawley rats were randomly divided into two groups， the blank group with 20 rats and the model group with 60 rats. Rats in model group were established as hyperuricemia （HUA） models by intraperitoneal injection of oxonic acid potassium salt （OAPS） and intragastric administration ethambutol hydrochloride （EMB） once a day for 21 days. After successful modeling， rats in the model group were divided into the model group， Tongfengning group and benzbromarone group， with 20 rats per group. Tongfengning solution （15.3 g·kg^-1·d^-1） was administered to the Tongfengning group by gavage feeding. Rats in benzbromarone group were administered 5.2 mg·kg^-1·d^-1 benzbromarone suspension， whereas those in the blank group and the model group were administered the equivalent amount of normal saline for 21 days. On days 14^th and 21^st following intervention， urine， blood， and kidney were collected from rats， serum uric acid （SUA） and urinary uric acid （UUA） levels， blood urea nitrogenand（BUN） and creatinine（CRE） levels and the expression of urate transporter proteins and their mRNAs of all rats were detected by enzyme-colorimetric method， urease method， sarcosine oxidase method， Western blot and Real-time quantitative PCR（Real-time PCR）， respectively. Result:On days 14^th and 21^th following intervention， compared with blank group， SUA， CRE and BUN levels， and urate transporter 1（URAT1），glucose transporter 9（GLUT9） expression increased（P<0.05，P<0.01）， whereas UUA level， and adenosine triphosphate-binding cassette transporter protein G2（ABCG2）， organic anion 1（OAT1）， organic anion 3（OAT3） expression decreased in the model group（P<0.05，P<0.01）. Compared with model group， SUA， CRE and BUN levels， and URAT1， GLUT9 expression decreased in Tongfengning group and the benzbromarone group（P<0.05）， whereas UUA level， and ABCG2， OAT1， OAT3 expression increased（P<0.05）. Creatinine and BUN levels decreased in the Tongfengning group（P<0.05，P<0.01）， with the trend much better than the benzbromarone group（P<0.05）. On day 21^st， except for the BUN level did not change much compared with day 14^th， all the rest indicators got improved obviously. Conclusion:Intraperitoneal injection of OAPS and intragastric administration of EMB can cause HUA models with renal dysfunction. Tongfengning reduced URAT1， GLUT9 mRNA and protein expression， and upregulated ABCG2， OAT1， OAT3 mRNA and protein expression in the rat kidney， which may be one of the mechanisms of promoting uric acid excretion. Tongfengning has a certain protective effect on renal function.