Objective To analyze the characteristics of methadone-related poisoning cases and provide a reference for forensic identification.Methods A total of 71 cases of methadone-related poisoning re-ported from 1998 to 2023 in China and 26 cases of methadone-related deaths reported from 2013 to 2018 in Italy were retrieved from databases including PubMed,Wanfang and CNKI.The general infor-mation,forensic pathological and toxicological characteristics were analyzed.Results Among the 71 methadone-related poisoning cases in China,there were 54 cases(76.06%)of poisoning without death and 17 cases(23.94%)of death from poisoning.There were 54 male cases(76.06%),and 51 cases(71.83%)aged 19 to 39 years old.There were 35 cases(49.30%)of poisoning caused by methadone alone,and 32 cases(45.07%)were poisoning caused by methadone combined with other substances or drugs including heroin and benzodiazepines.Most of the poisoned showed coma,respiratory depres-sion and miosis.Signs of asphyxia were often found by autopsy.The mass concentration of methadone detected in the blood of 6 deceased ranged from 0.112 to 3.000 mg/L.Among the 26 methadone-related deaths in Italy,22 cases were male(84.62%).There were 6 cases(23.08%)caused by methadone alone,and 20 cases(76.92%)died from methadone combined with other substances or drugs.The mass concentration of methadone in blood ranged from 0.181 to 4.059 mg/L.Conclusion The propor-tions of poisoning cases caused by methadone alone and methadone combined with other substances or drugs are comparable in China.The majority of deceased caused by methadone poisoning shows typi-cal triad of coma,respiratory depression and miosis,which helps forensic experts determine the cause of death related to methadone.Additionally,it is necessary to increase the routine testing of the con-centration of methadone and its combined substances or drugs in deceased,and collect data for the in-terpretation of the results of related cases.

Aromatic traditional Chinese medicine(TCM) has played an important role against epidemics and viruses, and volatile components are the main components that exert the pharmacological effects of aromatic TCM. By screening the related monomer components in aromatic TCM against epidemic and viruses and analyzing and endowing TCM with medicinal properties based on its clinical application and pharmacological research according to the theoretical thinking of TCM, the key technical issues of compatibility of TCM monomer components were solved from a theoretical perspective, providing new ideas and methods for screening raw materials and formulas for the development of new TCM drugs. Based on the conditions of antiviral activity, clinical application foundation, definite therapeutic effect, and high safety, a gradient screening of aromatic TCM was carried out. Firstly, 30 aromatic TCM were screened from anti-epidemic literature and clinical trial formulas, and seven volatile monomers were further screened from them. Then, four monomer components with significant effects, namely patchouli alcohol, carvacrol, p-cymene, and eucalyptol were screened. By adopting the "four-step method for a systematic study of TCM properties", the four monomer components were endowed with medicinal properties, and compatibility and combination studies were conducted to explore the theoretical basis of monomer formulas and form monomer formulas guided by TCM theory. The screening results of volatile monomers in aromatic TCM against viral pneumonia included patchouli alcohol, carvacrol, p-cymene, and eucalyptol. The medicinal properties and compatibility theory of volatile monomer components in TCM were explored. Patchouli alcohol was the main herb, with a cool and pungent nature. It entered the lung meridian to dispel evil Qi and has the effects of aromatization, detoxification, and epidemic prevention. Carvacrol was a minister drug with a cool and pungent taste. It had the effects of aromatizing, moistening, and dissolving the exterior, as well as strengthening the spleen and stomach. p-Cymene was an adjunctive medicine with a mild and pungent nature. It entered the lungs and kidneys and had the effects of aromatic purification, cough relief, and asthma relief. Eucalyptol was also an adjunctive medicine with a pungent and warm taste. It had the functions of aromatic purification, cough relief, phlegm reduction, and pain relief. The combination of the four medicines had the effects of aromatizing, moistening, detoxifying, and epidemic prevention, as well as relieving cough and asthma and strengthening the spleen and stomach. They were used to treat viral pneumonia caused by upper respiratory tract viral infections, with symptoms such as chest tightness, cough, wheezing, fatigue, nasal congestion, runny nose, nausea, and vomiting. This study has laid a literature and theoretical foundation for further drug efficacy verification experiments, compatibility efficacy experiments, and subsequent product development and clinical applications, and it serves as an innovative practice that combines literature research, theoretical research, experimental research, and clinical practice to develop new products.
Drugs, Chinese Herbal/therapeutic use* ; Antiviral Agents/pharmacology* ; Humans ; Pneumonia, Viral/virology* ; Medicine, Chinese Traditional ; Volatile Organic Compounds/pharmacology* ; Animals

This paper aims to investigate the influence of eucalyptol on the biological effects of spleen cold and spleen heat syndromes in rats and its regulation of transient receptor potential vanilloid 1(TRPV1), transient receptor potential melastatin 8(TRPM8), and uncoupling protein 1(UCP1), so as to explore the cold-heat properties of eucalyptol. Rats were randomly divided into groups as follows: blank group, spleen cold syndrome model group, spleen cold syndrome+Atractylodis Rhizoma group, spleen cold syndrome + low-dose eucalyptol group, and spleen cold syndrome+high-dose eucalyptol group, as well as blank group, spleen heat syndrome model group, spleen heat syndrome+Coptidis Rhizoma group, spleen heat syndrome + low-dose eucalyptol group, and spleen heat syndrome + high-dose eucalyptol group. Spleen cold and spleen heat syndromes were induced by disorders of hunger and satiety combined with bitter cold drugs, as well as a high-fat diet combined with liquor. Except for the blank and model groups, the other groups were administered once a day during the modeling process for 14 consecutive days. The general condition and body weight of rats in each group were observed, and the histopathological morphology of the gastric antrum and small intestine was observed by hematoxylin-eosin(HE) staining. The contents of cyclic adenosine monophosphate(cAMP), cyclic guanosine monophosphate(cGMP), triiodothyronine(T3), thyroxine(T4), Na~+-K~+-ATPase, total cholesterol(TC), triglyceride(TG), gastrin(GAS), motilin(MTL), D-xylose, and other related indices were detected in rats. The expression levels of TRPV1, TRPM8, and UCP1 in small intestine tissue of rats with spleen cold syndrome were detected. The results showed that eucalyptol had a certain degree of improvement in the overall state and body weight of rats with spleen cold syndrome. Compared with the spleen cold syndrome model group, high-dose eucalyptol significantly increased the levels of serum cAMP, cAMP/cGMP, TG, and TC in rats with spleen cold syndrome(P<0.05, P<0.01), decreased the content of cGMP, and significantly elevated the levels of gastrointestinal function-related indicators GAS, MTL, and D-xylose(P<0.05, P<0.01). Low-dose eucalyptol significantly increased the level of cAMP/cGMP in the serum and Na~+-K~+-ATPase levels in hepatic tissue(P<0.05, P<0.01), and significantly increased the levels of GAS and D-xylose(P<0.01). Eucalyptol showed similar effects to Atractylodis Rhizoma with a warm nature on rats with spleen cold syndrome. Compared with the spleen heat syndrome model group, the high-dose and low-dose eucalyptol groups showed a trend of increase in gastrointestinal indicators, with no significant changes in other indicators. In addition, high-dose eucalyptol increased the expression of TRPV1 and UCP1 and decreased the expression of TRPM8 in the small intestine tissue of rats with spleen cold syndrome. Eucalyptol could affect the cyclic nucleotide and material energy metabolism levels of rats with spleen cold syndrome and had a certain improvement effect on their gastrointestinal digestion and absorption function, thereby improving spleen cold syndrome. Eucalyptol had no significant improvement effect on rats with spleen heat syndrome, suggesting that eucalyptol may have a warm nature and regulate spleen meridians. It is speculated that eucalyptol may exhibit its medicinal properties by activating the TRPV1 pathway, promoting the expression of UCP1, and inhibiting the TRPM8 channel.
Animals ; Rats ; Spleen/metabolism* ; Male ; TRPV Cation Channels/genetics* ; Rats, Sprague-Dawley ; Eucalyptol/administration & dosage* ; TRPM Cation Channels/genetics* ; Uncoupling Protein 1/genetics* ; Humans ; Drugs, Chinese Herbal/administration & dosage* ; Cold Temperature ; Cyclic GMP/metabolism*

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*

Utilizing network pharmacology, molecular docking, and cellular experimental validation, this study delved into the therapeutic efficacy and underlying mechanisms of matrine in combating senescence. Databases were utilized to predict targets related to the anti-senescence effects of matrine, resulting in the identification of 81 intersecting targets for matrine in the treatment of senescence. A protein-protein interaction(PPI) network was constructed, and key targets were screened based on degree values. Gene Ontology(GO) function and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analyses were performed on the key targets to elucidate the critical pathways involved in the anti-senescence effects of matrine. Molecular docking was conducted between matrine and key targets. A senescence model was established using human umbilical vein endothelial cells(HUVECs) induced with hydrogen peroxide(H_2O_2). Following treatment with varying concentrations of matrine(0.5, 1, and 2 mmol·L~(-1)), cell viability was assessed by using the CCK-8. SA-β-galactosidase staining was employed to observe the positive rate of senescent cells. Flow cytometry was utilized to measure the apoptosis rate. Real-time quantitative PCR(RT-PCR) was utilized to measure the mRNA expression of apoptosis-related cysteine peptidase 3(CASP3), albumin(ALB), glycogen synthase kinase 3β(GSK3B), CD44 molecule(CD44), and tumor necrosis factor-α(TNF-α). Western blot was performed to detect the protein expression of tumor protein p53(p53), cyclin-dependent kinase inhibitor 1A(p21), cyclin-dependent kinase inhibitor 2A(p16), and retinoblastoma tumor suppressor protein(pRb) in the senescence signaling pathway, p38 protein kinase(p38), c-Jun N-terminal kinase(JNK), and extracellular regulated protein kinases(ERK) in the mitogen-activated protein kinase(MAPK) pathway, and phosphatidylinositol 3-kinase(PI3K) and protein kinase B(Akt) in the PI3K/Akt signaling pathway. The experimental results revealed that matrine significantly increased the viability of HUVECs(P<0.05), decreased the positive rate of senescent cells and the apoptosis rate(P<0.05), and reduced the mRNA expression levels of CASP3, ALB, GSK3B, CD44, and TNF-α(P<0.05). It also inhibited the protein expression of p53, p21, p16 and pRb in the senescence signaling pathway(P<0.05), upregulated the protein expression of p-PI3K/PI3K and p-Akt/Akt(P<0.05), and downregulated the protein expression of p-p38/p38, p-JNK/JNK, and p-ERK/ERK(P<0.05). Collectively, these findings suggest that matrine exerts an inhibitory effect on HUVECs senescence, and its mechanism involves the modulation of the senescence signaling pathway, MAPK pathway, and PI3K/Akt signaling pathway to suppress cell apoptosis and inflammation.
Humans ; Matrines ; Quinolizines/chemistry* ; Alkaloids/chemistry* ; Human Umbilical Vein Endothelial Cells/cytology* ; Cellular Senescence/drug effects* ; Network Pharmacology ; Molecular Docking Simulation ; Signal Transduction/drug effects* ; Protein Interaction Maps/drug effects* ; Cell Survival/drug effects* ; Apoptosis/drug effects* ; Drugs, Chinese Herbal/pharmacology*

OBJECTIVE: To investigate the short-term efficacy and safety of low-dose venetoclax combined with CHG (cytarabine+homoharringtonine+G-CSF) priming regimen in patients with acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) ineligible for intensive chemotherapy. METHODS: The data of 14 patients with AML or high-risk MDS admitted to the department of hematology/oncology of the First Hospital of Tsinghua University and 2 cooperative institutions from July 2022 to August 2023 were retrospectively analyzed. All the patients were treated with low-dose venetoclax combined with CHG priming regimen and the early induction (one course) efficacy and adverse reactions were observed. RESULTS: Among the 14 patients, 10 were males and 4 were females, with a median age of 69.5 (46-83) years. After 1 cycle of induction chemotherapy, the complete remission (CR) rate was 64.3% (9/14) and overall response rate (ORR) was 78.6% (11/14). Among the 10 patients with adverse prognosis according to cytogenetics and molecular genetics, the CR rate was 50.0% (5/10), and ORR was 70.0% (7/10). In 7 patients with TP53 mutation, the CR rate was 42.9% (3/7) and ORR was 71.4% (5/7). In the 6 patients with complex karyotype, CR rate was 33.3% (2/6) and ORR was 66.7% (4/6). While the CR rate and ORR of 8 non-complex karyotype patients were both 87.5% (7/8), and the difference in CR rate between patients with complex karyotype and non-complex karyotype was statistically significant ( P < 0.05). The adverse reactions of chemotherapy were tolerable, without early treatment-related deaths. CONCLUSION Low-dose venetoclax combined with CHG priming regimen can be used as an effective treatment for AML and high-risk MDS patients who are ineligible for intensive chemotherapy, and it is safe and worthy of clinical application.
Humans ; Leukemia, Myeloid, Acute/drug therapy* ; Aged ; Male ; Female ; Sulfonamides/therapeutic use* ; Middle Aged ; Myelodysplastic Syndromes/drug therapy* ; Bridged Bicyclo Compounds, Heterocyclic/therapeutic use* ; Aged, 80 and over ; Retrospective Studies ; Cytarabine/administration & dosage* ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Homoharringtonine/therapeutic use*

BACKGROUND: The association between uric acid-albumin ratio (UAR) with different diseases has been evaluated before. However, the association between UAR with spontaneous reperfusion (SR) in patients with ST-segment elevation myocardial infarction (STEMI) has not been explored. METHODS: STEMI patients admitted to our department and underwent primary coronary angiography between 1^st November 2018 and 31^st December 2020 were retrospectively enrolled. The patients were divided into the SR group and the non-SR group according to the index coronary angiography results. The association between UAR and SR was evaluated by uni-variable and multi-variable logistic analysis. Receiver operating characteristic curve analysis was used to determine the optimum cut-off level of UAR in predicting SR. RESULTS: Three hundred and fifty-seven patients were finally enrolled in our study, 55 patients were divided into the SR group and 302 patients were divided into the non-SR group. In uni-variable analysis, patients with SR were older (P = 0.032), with higher red blood cell distribution width (P < 0.001) and red blood cell distribution width-to-platelet ratio (P < 0.001), higher level of C-reactive protein (P = 0.046), higher level of uric acid (P < 0.001) compared with patients without SR. Patients with SR had a lower level of platelets (P = 0.008), lower level of on-admission B-type natriuretic peptide (P < 0.001). As for the level of UAR, STEMI patients with SR had significantly higher levels of UAR compared with STEMI patients without SR [11.1 (8.9-13.4) vs. 8.3 (6.6-10.0), P < 0.001]. Further multi-variable logistic analysis reveals that UAR was the independent risk factor of SR in different models after adjusting different variables. Receiver operating characteristic analysis showed that UAR had good predictive value in SR (AUC = 0.75, 95% CI: 0.702-0.794, P < 0.01). CONCLUSIONS Our study shows that UAR is an independent risk factor for predicting SR in STEMI patients.

Objective:Exploring the effect of Pinocembrin(Pino)regulating the Ras homolog gene family member A/Rho associated with curly helix binding protein kinase(RhoA/ROCK)signaling pathway of Ras homologous gene family members on the malignant biological behavior of gastric cancer cells.Methods:Cultivate human gastric cancer cells MGC803 with different concentrations of Pino(0～240μmol/L),detect cell survival rate using CCK-8 method,and screen for the optimal drug concentration.MGC803 cells were rseparated into MGC803 group(Control group),Pino-L group,Pino-M group,Pino-H group,and Pino-H+RhoA agonist CN03 group.The clone formation experiment was applied to detect the number of clones formed of cells in each group.Assessment of cell apoptosis using flow cytometry.Tran-swell invasion and migration experiments were used to detect the number of cells undergoing migration and invasion in each group;Detection of RhoA/ROCK signaling pathway and expression of epithelial mesenchymal transition related proteins in MGC803 cells using Western blot method.Results:Compared with the MGC803 group,the cell survival rate,clone formation number,migration cell number,and invasion cell number were all reduced in the Pino-L group,Pino-M group,and Pino-H group,and RhoA was also present in the cells,ROCK2,The expression levels of vimentin and N-cadherin gradually decreased(P<0.05),while the apoptosis rate and E-cadherin expression level gradually in-creased(P<0.05).The Pino-H+CN03 group reversed the trend of changes in the above indicators).Conclusion:Pino can prevent malignant biological behavior of gastric cancer cells,which may be related to the inhibition of the RhoA/ROCK signaling pathway.

Objective:To investigate the significance of serum β2-microglobulin(β2-MG)for survival and relapse of patients with diffuse large B-cell lymphoma(DLBCL)in the rituximab era.Methods:Clinical data of 92 patients with DLBCL admitted from December 2003 to July 2015 were retrospectively analyzed.The optimal cutoff value of β2-MG levels for predicting prognosis of the DLBCL patients was determined using receiver operating characteristic(ROC)curve.Kaplan-Meier analysis was used to estimate progression-free survival(PFS)and overall survival(OS).Cox logistic regression analysis was used to explore potential prognostic factors associated with survival.Binary logistic regression analysis was used to analyze the relationship between various factors and relapse.Results:The most discriminative cutoff value for β2-MG level was determined to be 2.25 mg/L by the ROC curve.Subgroup analysis showed that patients in the elevated β2-MG(＞2.25 mg/L)group had significantly worse PFS(P=0.006)and a trend toward worse OS compared with those in the low β2-MG(≤2.25 mg/L)group(P=0.053).Univariate analysis showed that elevated β2-MG,age＞60 years,Ann Arbor stage Ⅲ-Ⅳ,as well as IPI score ≥ 3 were associated with worse PFS.Binary logistic regression analysis showed that age＞60 years and β2-M G＞2.25 mg/L were potential influencing factors for relapse of DLBCL patients.Conclusion:Serum β2-MG might be an important predictor for the survival and relapse of DLBCL patients in the rituximab era.

AIM To investigate the effects of Gan Jiang-Huang Qin-Huang Lian-Ren Shen Decoction(GJHQHLRSD)on the pyroptosis,pathway of colonic epithelial cells in mouse models of ulcerative colitis(UC).METHODS Among the 63 C57BL/6J mice,13 were randomly selected and assigned to the model group,and the others were divided into the control group,the positive Sulfasalazine Enteric-Coated Tablets group(0.6 g/kg),and low,medium,and high dose GJHQHLRSD groups(3.9,7.8,15.6 g/kg),with 10 mice in each group.The UC mouse model was established using DSS,and the corresponding drugs were administered by gavage.The mice had their general condition observed;their disease activity index(DAI)score assessed;their colon length measured;their histopathological damage of the colon analyzed using HE staining;their colonic IL-1β,IL-8,and TNF-α levels measured by ELISA method;their colonic NLRP3,GSDMD,pro-IL-1β,pro-caspase-1,and IL-1βprotein expression detected by Western blot method;and their cell pyroptosis detected by TUNEL and GSDMD fluorescence double staining.RESULTS Compared with the control group,the model group exhibited significant decrease in body weight and a shortened colon length(P＜0.01);increases in DAI score,levels of IL-1β,IL-8,TNF-α,as well as the protein expressions of NLRP3,GSDMD,and active-caspase-1(P＜0.05,P＜0.01);significant increase of colonic GSDMD and TUNEL positivity;indicating increased tissue damage and inflammatory response.Compared with the model group,the groups intervened with GJHQHLRSD showed a significant increase in body weight and colonic elongation(P＜0.05,P＜0.01);decreases in DAI score,levels of IL-1β,IL-8,TNF-α,as well as the protein expressions of NLRP3,GSDMD,and active-caspase-1(P＜0.05,P＜0.01);a gradient decrease in positivity of GSDMD and TUNEL;indicating a significantly reduced colonic pathological damage.CONCLUSION GJHQHLRSD can improve the DSS-induced inflammatory reaction of colonic mucosa in UC mice,and its mechanism mainly involves the NLRP3/caspase-1,thereby the regulation of the cell pyroptosis process.