This paper aims to study the effect of p-cymene on mice with deficiency-cold syndrome induced by hydrocortisone and deficiency-heat syndrome induced by dexamethasone and explore the medicinal properties and mechanism of p-cymene with mild and warm nature based on the dominant characteristics of the two-way applicable conditions of mild drugs. A total of 80 KM mice were randomly divided into blank group, deficiency-cold syndrome model group, deficiency-cold syndrome + ginseng group, and deficiency-cold syndrome + low-dose and high-dose p-cymene groups, as well as blank group, deficiency-heat syndrome model group, deficiency-heat syndrome + American ginseng group, and deficiency-heat syndrome + low-dose and high-dose p-cymene groups. Hydrocortisone and dexamethasone solution were intragastrically administered for 14 consecutive days to prepare deficiency-cold syndrome and deficiency-heat syndrome models. Except for the blank group and the model group intragastrically administered with normal saline, the other groups were intragastrically administrated with drugs for 14 days. The levels of cyclic adenosine monophosphate(cAMP), cyclic guanosine monophosphate(cGMP), triiodothyronine(T3), thyroxine(T4), total cholesterol(TC), triglyceride(TG), immunoglobin G(IgG), and immunoglobin M(IgM) in serum, as well as the activity of Na~+-K~+-ATPase in liver tissue were detected. The expression of transient receptor potential melastatin 8(TRPM8), transient receptor potential vanilloid 1(TRPV1), and uncoupling protein 1(UCP1) in brown adipose tissue of deficiency-cold syndrome model after intervention with p-cymene was studied. The results showed that p-cymene could effectively improve the levels of cAMP, cAMP/cGMP, TC, IgM, and IgG in serum and the activity of Na~+-K~+-ATPase in liver tissue of mice with deficiency-cold syndrome and reduce the content of cGMP. The effects on T3, T4, and TG were not statistically significant. At the same time, p-cymene could reduce the levels of cAMP, cAMP/cGMP, and T4 in serum and the activity of Na~+-K~+-ATPase in liver tissue of mice with deficiency-cold syndrome and increase the levels of cGMP, IgM, and IgG, and it had no effect on T3, TC, and TG. In addition, p-cymene could up-regulate the expression of TRPV1 and UCP1 in brown fat of mice with deficiency-cold syndrome and down-regulate the expression of TRPM8. In summary, p-cymene could significantly regulate the syndrome indexes of mice with deficiency-cold syndrome, and some indexes of mice with deficiency-heat syndrome could be improved, but the effects on lipid metabolism and energy metabolism indexes were not obvious, indicating that the regulation effect of p-cymene on deficiency-cold syndrome model was more prominent and that the medicinal properties of p-cymene were mild and warm. The regulation of TRPV1/TRPM8/UCP1 channel expression may be the molecular biological mechanism of p-cymene with mild and warm nature affecting the energy metabolism of the body.
Animals ; Cymenes ; Mice ; Drugs, Chinese Herbal/administration & dosage* ; Male ; Disease Models, Animal ; Humans ; Cyclic AMP/metabolism* ; Monoterpenes/administration & dosage* ; Liver/metabolism* ; Cyclic GMP/metabolism* ; TRPV Cation Channels/genetics* ; Uncoupling Protein 1/genetics*

Emodin is a hydroxyanthraquinone compound that is widely distributed and has multiple pharmacological activities, including anti-diarrheal, anti-inflammatory, and liver-protective effects. Research indicates that emodin may be one of the main components responsible for inducing hepatotoxicity. However, studies on the mechanisms of liver injury are relatively limited, particularly those related to bile acids(BAs) metabolism. This study aims to systematically investigate the effects of different dosages of emodin on BAs metabolism, providing a basis for the safe clinical use of traditional Chinese medicine(TCM)containing emodin. First, this study evaluated the safety of repeated administration of different dosages of emodin over a 5-week period, with a particular focus on its impact on the liver. Next, the composition and content of BAs in serum and liver were analyzed. Subsequently, qRT-PCR was used to detect the mRNA expression of nuclear receptors and transporters related to BAs metabolism. The results showed that 1 g·kg~(-1) emodin induced hepatic damage, with bile duct hyperplasia as the primary pathological manifestation. It significantly increased the levels of various BAs in the serum and primary BAs(including taurine-conjugated and free BAs) in the liver. Additionally, it downregulated the mRNA expression of farnesoid X receptor(FXR), retinoid X receptor(RXR), and sodium taurocholate cotransporting polypeptide(NTCP), and upregulated the mRNA expression of cholesterol 7α-hydroxylase(CYP7A1) in the liver. Although 0.01 g·kg~(-1) and 0.03 g·kg~(-1) emodin did not induce obvious liver injury, they significantly increased the level of taurine-conjugated BAs in the liver, suggesting a potential interference with BAs homeostasis. In conclusion, 1 g·kg~(-1) emodin may promote the production of primary BAs in the liver by affecting the FXR-RXR-CYP7A1 pathway, inhibit NTCP expression, and reduce BA reabsorption in the liver, resulting in BA accumulation in the peripheral blood. This disruption of BA homeostasis leads to liver injury. Even doses of emodin close to the clinical dose can also have a certain effect on the homeostasis of BAs. Therefore, when using traditional Chinese medicine or formulas containing emodin in clinical practice, it is necessary to regularly monitor liver function indicators and closely monitor the risk of drug-induced liver injury.
Emodin/administration & dosage* ; Bile Acids and Salts/metabolism* ; Animals ; Male ; Liver/injuries* ; Chemical and Drug Induced Liver Injury/genetics* ; Drugs, Chinese Herbal/adverse effects* ; Humans ; Rats, Sprague-Dawley ; Mice ; Rats

OBJECTIVE: To evaluate the dynamic changes of glucocorticoid (GC) dose and the feasibility of GC discontinuation in rheumatoid arthritis (RA) patients under the background of Chinese medicine (CM). METHODS: This multicenter retrospective cohort study included 1,196 RA patients enrolled in the China Rheumatoid Arthritis Registry of Patients with Chinese Medicine (CERTAIN) from September 1, 2019 to December 4, 2023, who initiated GC therapy. Participants were divided into the Western medicine (WM) and integrative medicine (IM, combination of CM and WM) groups based on medication regimen. Follow-up was performed at least every 3 months to assess dynamic changes in GC dose. Changes in GC dose were analyzed by generalized estimator equation, the probability of GC discontinuation was assessed using Kaplan-Meier curve, and predictors of GC discontinuation were analyzed by Cox regression. Patients with <12 months of follow-up were excluded for the sensitivity analysis. RESULTS: Among 1,196 patients (85.4% female; median age 56.4 years), 880 (73.6%) received IM. Over a median 12-month follow-up, 34.3% (410 cases) discontinued GC, with significantly higher rates in the IM group (40.8% vs. 16.1% in WM; P<0.05). GC dose declined progressively, with IM patients demonstrating faster reductions (median 3.75 mg vs. 5.00 mg in WM at 12 months; P<0.05). Multivariate Cox analysis identified age <60 years [P<0.001, hazard ratios (HR)=2.142, 95% confidence interval (CI): 1.523-3.012], IM therapy (P=0.001, HR=2.175, 95% CI: 1.369-3.456), baseline GC dose ⩽7.5 mg (P=0.003, HR=1.637, 95% CI: 1.177-2.275), and absence of non-steroidal anti-inflammatory drugs use (P=0.001, HR=2.546, 95% CI: 1.432-4.527) as significant predictors of GC discontinuation. Sensitivity analysis (545 cases) confirmed these findings. CONCLUSIONS RA patients receiving CM face difficulties in following guideline-recommended GC discontinuation protocols. IM can promote GC discontinuation and is a promising strategy to reduce GC dependency in RA management. (Trial registration: ClinicalTrials.gov, No. NCT05219214).
Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Arthritis, Rheumatoid/drug therapy* ; Glucocorticoids/therapeutic use* ; Medicine, Chinese Traditional ; Retrospective Studies

Objective To study the application of CE-Chirp in the evaluation of hearing impairment in forensic medicine by testing the auditory brainstem response(ABR)in adults using CE-Chirp to ana-lyze the relationship between the V-wave response threshold of CE-Chirp ABR test and the pure tone hearing threshold.Methods Subjects(aged 20-77 with a total of 100 ears)who underwent CE-Chirp ABR test in Changzhou De'an Hospital from January 2018 to June 2019 were selected to obtain the V-wave response threshold,and pure tone air conduction hearing threshold tests were conducted at 0.5,1.0,2.0 and 4.0 kHz,respectively,to obtain pure tone listening threshold.The differences and statistical differences between the average pure tone hearing threshold and V-wave response threshold were compared in different hearing levels and different age groups.The correlation,differences and statistical differences between the two tests at each frequency were analyzed for all subjects.The lin-ear regression equation for estimating pure tone hearing threshold for all subjects CE-Chirp ABR V-wave response threshold was established,and the feasibility of the equation was tested.Results There was no statistical significance in the CE-Chirp ABR response threshold and pure tone hearing threshold dif-ference between different hearing level groups and different age groups(P>0.05).There was a good correlation between adult CE-Chirp ABR V-wave response threshold and pure tone hearing threshold with statistical significance(P<0.05),and linear regression analysis showed a significant linear correla-tion between the two(P<0.05).Conclusion The use of CE-Chirp ABR V-wave response threshold can be used to evaluate subjects'pure tone hearing threshold under certain conditions,and can be used as an audiological test method for forensic hearing impairment assessment.

A biosynthetic gene cluster for the bioactive fungal sesterterpenoids variecolin ( 1) and variecolactone ( 2) was identified in Aspergillus aculeatus ATCC 16872. Heterologous production of 1 and 2 was achieved in Aspergillus oryzae by expressing the sesterterpene synthase VrcA and the cytochrome P450 VrcB. Intriguingly, the replacement of VrcB with homologous P450s from other fungal terpenoid pathways yielded three new variecolin analogues ( 5- 7). Analysis of the compounds' anticancer activity in vitro and in vivo revealed that although 5 and 1 had comparable activities, 5 was associated with significantly reduced toxic side effects in cancer-bearing mice, indicating its potentially broader therapeutic window. Our study describes the first tests of variecolin and its analogues in animals and demonstrates the utility of synthetic biology for creating molecules with improved biological activities.

Purpose: Numerous studies have produced conflicting findings regarding the efficacy of statins in prostate cancer treatment. Our objective was to examine the correlation between statin usage and clinical outcomes in Taiwanese men with de novo metastatic prostate cancer. Materials and Methods: We identified patients diagnosed with de novo metastatic prostate cancer from the Chang Gung Research Database spanning the years 2007 to 2020. To minimize confounding bias, we employed the inverse probability of treatment weighting (IPTW) method. Clinical outcomes were assessed using IPTW-adjusted Kaplan-Meier curves. Multivariate Cox proportional hazard regression analysis was utilized to evaluate the association between mortality and clinical factors. Results: The study cohort comprised 1,716 statin users and 276 non-users. Patients who used statins exhibited a longer median overall survival (85.4 months compared to 58.2 months; p=0.001) and cancer-specific survival (112.6 months compared to 75.7 months; p<0.001) compared to non-users. The median time to the development of castration-resistant status was similar between statin users and non-users (p=0.069). Multivariable Cox proportional hazards regression analysis, after IPTW adjustment, demonstrated that statin use was associated with improved overall survival. Conclusions Our study indicates that the use of statins following a de novo metastatic prostate cancer diagnosis enhances survival outcomes. However, statins did not appear to delay the onset of castration-resistant status. Further large-scale and long-term studies are warranted to investigate the biological effects of statins in men with prostate cancer.

OBJECTIVE: To explore the association between periconceptional supplementation of folic acid or multiple-micronutrients containing folic acid(MMFA) and risk of preterm delivery in women with natural conception, singleton pregnancy and vaginal delivery. METHODS: A retrospective cohort study was performed based on the prenatal health care system and hospital information system of Tongzhou Maternal and Child Health Hospital of Beijing and the women who had their prenatal care in the hospital from January 2015 to December 2018 were included. The information of 16 332 women who conceived naturally, had a singleton pregnancy, and delivered vaginally was collected. Compliance scores were constructed based on the time of initiation and the frequency of taking nutritional supplements. The association between maternal periconceptional micronutrient supplementation, including pure folic acid (FA) pills or MMFA and the rate of preterm delivery was evaluated using Logistic regression models. RESULTS: The preterm delivery rate (gestational week < 37 weeks) of the study population was 3.8%, and the mean (standard deviation) of gestational age was (38.98±1.37) weeks. A total of 6 174 (37.8%) women took FA during the periconceptional period, 8 646 (52.9%) women took MMFA, and 1 512 (9.3%) women did not take any nutritional supplements. The association between periconceptional supplementation of FA or MMFA and risk of preterm delivery in women was not statistically significant [adjusted odds ratio (aOR)=1.01, 95%CI: 0.74-1.37]. The associations with preterm birth were not statistically significant in further analysis by the type of nutritional supplements, time of initiation, and the frequency of supplementation. In addition, the association between the compliance score of taking supplements and the rate of preterm delivery was not statistically significant, either. CONCLUSION This study did not find an association between the risk of preterm delivery and the use of FA or MMFA during the periconcep-tional period in women with natural conception, singleton pregnancy, and vaginal delivery. In the future, multicenter studies with large-scale prospective cohort or population-based randomized controlled trials are warranted to confirm the association between taking FA or MMFA during the periconceptional period and preterm delivery among women.
Pregnancy ; Female ; Child ; Infant, Newborn ; Humans ; Infant ; Male ; Folic Acid ; Premature Birth/prevention & control* ; Prospective Studies ; Retrospective Studies ; Dietary Supplements ; Micronutrients

Humans ; COVID-19/genetics* ; SARS-CoV-2/genetics* ; Clustered Regularly Interspaced Short Palindromic Repeats/genetics* ; CRISPR-Cas Systems/genetics* ; RNA, Viral/genetics*

Ischemic stroke is a major public health problem worldwide. Although the circadian clock is involved in the process of ischemic stroke, the exact mechanism of the circadian clock in regulating angiogenesis after cerebral infarction remains unclear. In the present study, we determined that environmental circadian disruption (ECD) increased the stroke severity and impaired angiogenesis in the rat middle cerebral artery occlusion model, by measuring the infarct volume, neurological tests, and angiogenesis-related protein. We further report that Bmal1 plays an irreplaceable role in angiogenesis. Overexpression of Bmal1 promoted tube-forming, migration, and wound healing, and upregulated the vascular endothelial growth factor (VEGF) and Notch pathway protein levels. This promoting effect was reversed by the Notch pathway inhibitor DAPT, according to the results of angiogenesis capacity and VEGF pathway protein level. In conclusion, our study reveals the intervention of ECD in angiogenesis in ischemic stroke and further identifies the exact mechanism by which Bmal1 regulates angiogenesis through the VEGF-Notch1 pathway.
Rats ; Animals ; Vascular Endothelial Growth Factor A/pharmacology* ; Brain Ischemia/metabolism* ; Ischemic Stroke ; Signal Transduction ; ARNTL Transcription Factors/pharmacology* ; Neovascularization, Physiologic/physiology*

Objective: To compare the effects of the China Children's Asthma Action Plan (CCAAP)-based remote joint management model with traditional management model on the control of childhood asthma. Methods: A retrospective cohort study was conducted to analyze the general data and asthma control assessment data of 219 children with asthma who attended the respiratory department of Guangzhou Women's and Children's Medical Center from April 2021 to October 2021 and were followed up for 1 year or more. According to the follow-up management model, the CCAAP-based remote joint management model was used in the observation group and the traditional management model was used in the control group, and the propensity score matching method was applied to match the data of children in the two management models for comparison. Paired-samples t-test, Wilcoxon signed-rank test, McNemar χ²-test or χ²-test or nonparametric tests were used to compare the general data and asthma control assessment data between the two matched groups of children. Results: Among 219 children with asthma, 145 were male and 74 were female, aged at consultation (7.2±2.4) years. There were 147 cases in the observation group and 72 cases in the control group, and 27 cases in each of the observation and control groups were successfully matched. The number of asthma exacerbation aura, acute exacerbations, and emergency room visits or hospitalizations for asthma exacerbations were lower in the observation group than in the control group after pairing (1 (0, 2) vs. 3 (1, 5) times, 0 (0,0) vs. 0 (0, 1) times, 0 (0,0) vs. 1 (0, 1) times, Z=-3.42, -2.58, -3.17, all P<0.05). The use of peak flowmeters was higher in children aged 5 years and older in the observation group than in the control group after pairing (100% (22/22) vs. 13% (3/23), χ²=54.00,P<0.001). The ratio of actual to predicted 1st second expiratory volume of force after follow-up in the observation group after pairing was higher than that before follow-up in the observation group and after follow-up in the control group ((95±11)% vs. (85±10)%, (95±11)% vs. (88±11)%, t=-3.40, 2.25, all P<0.05). The rate of complete asthma control after follow-up was higher in both the observation and control groups after pairing than before follow-up for 12 months in both groups (93% (25/27) vs. 41% (11/27), 52% (14/27) vs. 41% (11/27), H=56.19, 45.37, both P<0.001), and the rate of complete control of asthma in children in the observation group was higher than that in the control group at 3 and 12 months of follow-up management (56% (15/27) vs. 25% (5/20), 93% (25/27) vs. 52% (14/27), χ²=47.00, 54.00, both P<0.001). The number of offline follow-up visits, inhaled hormone medication adherence scores, and caregiver's asthma perception questionnaire scores were higher in the observation group than in the control group after pairing (6 (4, 8) vs. 4 (2,5), (4.8±0.3) vs. (4.0±0.6) score, (19.3±2.6) vs. (15.2±2.7) score, Z=6.58, t=6.57, 5.61, all P<0.05), and the children in the observation group had lower school absences, caregiver absences, asthma attack visit costs, and caregiver PTSD scores than the control group (0 (0,0) vs.3 (0, 15) d, 0 (0,0) vs. 3 (0, 10) d, 1 100 (0, 3 700) vs. 5 000 (1 000, 10 000) yuan, 1.3 (1.1, 1.9) vs. 2.0 (1.2, 2.7) score, Z=-2.89, -2.30, 2.74, 2.73, all P<0.05). Conclusion: The CCAAP-based joint management model of asthma control is superior to the traditional management model in the following aspects: it can effectively improve asthma control, self-monitoring, and lung function in children; it can improve treatment adherence and caregivers' asthma awareness; and it can reduce the duration of absenteeism from school, the cost of asthma exacerbation visits, and caregiver's negative psychology.
Humans ; Child ; Female ; Male ; Retrospective Studies ; Asthma/therapy* ; China ; Hospitalization ; Hospitals