Background/Aims: Chronic hepatitis C (CHC) patients who failed antiviral therapy are at increased risk for hepatocellular carcinoma (HCC). This study assessed the potential role of metformin and statins, medications for diabetes mellitus (DM) and hyperlipidemia (HLP), in reducing HCC risk among these patients. Methods: We included CHC patients from the T-COACH study who failed antiviral therapy. We tracked the onset of HCC 1.5 years post-therapy by linking to Taiwan’s cancer registry data from 2003 to 2019. We accounted for death and liver transplantation as competing risks and employed Gray’s cumulative incidence and Cox subdistribution hazards models to analyze HCC development. Results: Out of 2,779 patients, 480 (17.3%) developed HCC post-therapy. DM patients not using metformin had a 51% increased risk of HCC compared to non-DM patients, while HLP patients on statins had a 50% reduced risk compared to those without HLP. The 5-year HCC incidence was significantly higher for metformin non-users (16.5%) versus non-DM patients (11.3%; adjusted sub-distribution hazard ratio [aSHR]=1.51; P=0.007) and metformin users (3.1%; aSHR=1.59; P=0.022). Statin use in HLP patients correlated with a lower HCC risk (3.8%) compared to non-HLP patients (12.5%; aSHR=0.50; P<0.001). Notably, the increased HCC risk associated with non-use of metformin was primarily seen in non-cirrhotic patients, whereas statins decreased HCC risk in both cirrhotic and non-cirrhotic patients. Conclusions Metformin and statins may have a chemopreventive effect against HCC in CHC patients who failed antiviral therapy. These results support the need for personalized preventive strategies in managing HCC risk.

OBJECTIVES: To explore the medication rules of traditional Chinese medicine (TCM) and mechanism of action of hub herb pairs for treating insomnia. METHODS: Totally 104 prescriptions were statistically analyzed. The association rule algorithm was applied to mine the hub herb pairs. Network pharmacology was utilized to analyze the mechanism of the hub herb pairs, while molecular docking was applied to simulate the interaction between receptors and herb molecules, thereby predicting their binding affinities. RESULTS: The most frequently used herbs in TCM prescriptions for treating insomnia included Semen Ziziphi Spinosae, Radix Glycyrrhizae, Radix et Rhizoma Ginseng, and Poria cum Radix Pini. Among them, the most commonly used were the supplementing herbs, followed by heat-clearing, mind-calming, and exterior-releasing ones, with their properties of warm and cold, flavors of sweet, Pungent, and bitter, and meridian tropisms of liver, lungs, spleen, kidneys, heart, and stomach. The hub herb pairs based on the association rules included Radix Astragali-Radix et Rhizoma Ginseng, Rhizoma Chuanxiong-Radix Glycyrrhizae, Seman Platycladi-Semen Ziziphi Spinosae, Pericarpium Citri Reticulatae-Radix Glycyrrhizae, Radix Polygalae-Semen Ziziphi Spinosae, and Radix Astragali-Semen Ziziphi Spinosae. Network pharmacology revealed that the cAMP signaling pathway might play a key role in treating insomnia synergistically with HIF-1 signaling pathway, prolactin signaling pathway, chemical carcinogenesis receptor activation, and PI3K-Akt signaling pathway. Molecular docking indicated that there was good binding between the active ingredients of the hub herb pairs and the hub targets. CONCLUSIONS This study identified six hub herb pairs for treating insomnia in TCM. These hub herb pairs may synergistically treat insomnia with HIF-1 signaling pathway, prolactin signaling pathway, chemical carcinogenesis receptor activation, and PI3K-Akt signaling pathway through the cAMP signaling pathway.
Molecular Docking Simulation ; Sleep Initiation and Maintenance Disorders/drug therapy* ; Drugs, Chinese Herbal/therapeutic use* ; Network Pharmacology ; Humans ; Data Mining ; Medicine, Chinese Traditional

Uric acid (UA) is the final product of purine metabolism in human body,and its metabolic disorder will induce hyperuricemia (HUA).The occurrence and development of HUA are associated with a variety of pathological mechanisms such as oxidative stress injury,activation of inflammatory cytokines,and activation of renin-angiotensin-aldosterone system.These mechanisms directly or indirectly affect the bioavailability of endogenous nitric oxide (NO).The decrease in NO bioavailability is common in the diseases with high concentration of UA as an independent risk factor.In this review,we summarize the mechanisms by which high concentrations of UA affect the endogenous NO bioavailability,with a focus on the mechanisms of high-concentration UA in decreasing the synthesis and/or increasing the consumption of NO.This review aims to provide references for alleviating the multisystem symptoms and improving the prognosis of HUA,and lay a theoretical foundation for in-depth study of the correlations between HUA and other metabolic diseases.
Humans ; Nitric Oxide ; Uric Acid ; Hyperuricemia ; Biological Availability ; Cytokines

Objective To analyze the medication rules of traditional Chinese medicine (TCM) for malaria treatment.Methods Statistical analysis was conducted on the basic attributes of TCM drugs with regard to property, therapeutic methods, flavor, and meridian tropism. A complex network of TCM drug associations was constructed. Cluster analysis was applied to obtain the core drugs for malaria treatment. The Apriori algorithm was applied to analyze the association rules of these core drugs.Results A total of 357 herbs were used 3,194 times in 461 prescriptions for malaria treatment. Radix Glycyrrhizae (), Rhizoma Pinelliae (), Radix Bupleuri (), and Radix Dichroae () were the frequently used herbs through supplementing, exterior-releasing, heat-clearing, qi-rectifying, and damp-resolving therapeutic methods. Such herbs had warm, natural, and cold herbal properties; pungent, bitter, and sweet flavors; and spleen, lung, and stomach meridian tropisms. Cluster analysis showed 61 core drugs, including Radix Glycyrrhizae, Rhizoma Pinelliae, Radix Bupleuri, and Radix Scutellariae (). Apriori association rule analysis yielded 12 binomial rules (herb pairs) and 6 trinomial rules (herb combinations). Radix Bupleuri plus Radix Scutellariae was the core herbal pair for treating malaria. This pair could be combined with Rhizoma Atractylodis Macrocephalae () for treating warm or cold malaria, combined with Pericarpium Citri Reticulatae () or Radix Dichroae () for treating miasmic malaria, or combined with turtle shells () for treating malaria with splenomegaly.Conclusions TCM can be used to classify and treat malaria in accordance with the different stages of development. As the core herbal pair, Radix Bupleuri and Radix Scutellariae can be combined with other drugs to treat malaria with different syndrome types.
Medicine, Chinese Traditional ; Drugs, Chinese Herbal/therapeutic use* ; Data Mining

This paper aimed to study the effect of Dalbergia cochinchinensis heartwood on plasma endogenous metabolites in rats with ligation of the left anterior descending coronary artery, and to analyze the mechanism of D. cochinchinensis heartwood in improving acute myocardial ischemic injury. The stability and consistency of the components in the D. cochinchinensis heartwood were verified by the establishment of fingerprint, and 30 male SD rats were randomly divided into a sham group, a model group, and a D. cochinchinensis heartwood(6 g·kg~(-1)) group, with 10 rats in each group. The sham group only opened the chest without ligation, while the other groups established the model of ligation. Ten days after administration, the hearts were taken for hematoxylin-eosin(HE) staining, and the content of heart injury indexes in the plasma creatine kinase isoenzyme(CK-MB) and lactate dehydrogenase(LDH), energy metabolism-related index glucose(Glu) content, and vascular endothelial function index nitric oxide(NO) was determined. The endogenous metabolites were detected by ultra-high-performance liquid chromatography-time-of-flight-mass spectrometry(UPLC-Q-TOF-MS). The results showed that the D. cochinchinensis heartwood reduced the content of CK-MB and LDH in the plasma of rats to relieve myocardial injury, reduced the content of Glu in the plasma, improved myocardial energy metabolism, increased the content of NO, cured the vascular endothelial injury, and promoted vasodilation. D. cochinchinensis heartwood improved the increase of intercellular space, myocardial inflammatory cell infiltration, and myofilament rupture caused by ligation of the left anterior descending coronary artery. The metabolomic study showed that the content of 26 metabolites in the plasma of rats in the model group increased significantly, while the content of 27 metabolites decreased significantly. Twenty metabolites were significantly adjusted after the administration of D. cochinchinensis heartwood. D. cochinchinensis heartwood can significantly adjust the metabolic abnormality in rats with ligation of the left anterior descending coronary artery, and its mechanism may be related to the regulation of cardiac energy metabolism, NO production, and inflammation. The results provide a corresponding basis for further explaining the effect of D. cochinchinensis on the acute myocardial injury.
Male ; Animals ; Rats ; Rats, Sprague-Dawley ; Dalbergia ; Myocardial Ischemia ; Metabolomics ; Heart ; Heart Injuries ; Creatine Kinase, MB Form

OBJECTIVE To evaluate the cost-effectiveness of tislelizumab monotherapy in the second-line treatment of advanced or metastatic esophageal squamous cell carcinoma （ESCC），so as to provide reference for rational use of drug in clinic. METHODS A three-state partitioned survival model was constructed from the perspective of China’s health system， based on the data of RATIONALE-302 study，with simulation time limit of 10 years， cycle period of 1 month. The incremental cost-effectiveness ratio （ICER） was calculated with quality-adjusted life year （QALY） as utility index. The cost-effectiveness of tislelizumab monotherapy was compared with that of chemotherapy for second-line treatment of advanced or metastatic ESCC by cost-utility analysis. The stability of basic analysis results was validated through sensitivity analysis and scenario analysis. RESULTS The results of basic analysis showed that compared with chemotherapy group， incremental cost per capita of tislelizumab group was 35 025.32 yuan，and incremental utility per capita was 2.71 QALYs； ICER was 12 892.31 yuan/QALY， which was far lower than the willingness-to-pay （WTP） threshold of 3 times of China’s per capita gross domestic product （GDP） 242 928 yuan in 2021. The results of univariate sensitivity analysis showed that parameters such as the cost of apatinib， the utility value of disease progression status and the cost of adverse reactions in the chemotherapy group had a great impact on the ICER value， but these parameters could not cause the reversal of the basic analysis results. Probabilistic sensitivity analysis showed that WTP threshold was higher than 80 000 yuan/QALY，the probability of tislelizumab monotherapy possessed cost-effectiveness was 100%. Results of scenario analysis showed that in which model simulation time lasted for 5 or 20 years，ICER of tislelizumab was 8 331.00 yuan/QALY and 12 981.00 yuan/QALY， which were less than 3 times of China’s per capita GDP in 2021 as WTP threshold. CONCLUSIONS When three times of China’s GDP per capita in 2021 is taken as the WTP threshold， the second-line treatment of tirelizumab monotherapy for advanced or metastatic ESCC is more cost-effective than chemotherapy.

Objective: To explore the effect of P311 microspheres-loaded thermosensitive chitosan hydrogel on the wound healing of full-thickness skin defects in rats. Methods: The method of experimental study was adopted. The polyvinyl alcohol/sodium alginate microspheres (simple microspheres), P311 microspheres, and bovine serum albumin labeled with fluorescein isothiocyanate (FITC-BSA) microspheres were prepared by water-in-oil emulsification, and then their morphology was observed under a light microscope/inverted fluorescence microscope. Chitosan solution was prepared, chitosan solution and β-glycerol phosphate disodium hydrate were mixed to prepare simple thermosensitive hydrogels, and thermosensitive hydrogels loaded with simple microspheres or P311 microspheres were prepared by adding corresponding substances in simple thermosensitive hydrogels. The morphological changes of the prepared four liquids in the state of tilt was observed at 37 ℃. After being freeze-dried, the micromorphology of the prepared four liquids was observed under a scanning electron microscope. Eighteen 3-4-week-old male Sprague-Dawley rats were divided into normal group without any treatment, dressing group, chitosan group, hydrogel alone group, simple microspheres-loaded hydrogel group, and P311 microspheres-loaded hydrogel group, which were inflicted with one full-thickness skin defect wound on both sides of the back spine and were dealt correspondingly, with 3 rats in each group. Rats with full-thickness skin defects in the five groups were collected, the wound healing was observed on post injury day (PID) 0 (immediately), 5, 10, and 15, and the wound healing rates on PID 5, 10, and 15 were calculated. The wound and wound margin tissue of rats with full-thickness skin defects in the five groups on PID 15 and normal skin tissue in the same site of rats in normal group were collected, hematoxylin and eosin staining was conducted to observe the histological changes, immunohistochemical staining was performed to observe the expressions of CD31 and vascular endothelial growth factor (VEGF), and Western blotting was conducted to detect the protein expressions of CD31 and VEGF. The number of samples was all three. Data were statistically analyzed with one-way analysis of variance, analysis of variance for repeated measurement, and Bonferroni correction. Results: Simple microspheres were spherical, with loose and porous surface. The surfaces of P311 microspheres and FITC-BSA microspheres were smooth without pores, and the FITC-BSA microspheres emitted uniform green fluorescence. The diameters of the three microspheres were basically consistent, being 33.1 to 37.7 μm. Compared with chitosan solution and simple thermosensitive hydrogel, the structures of the two microspheres-loaded hydrogels were more stable in the state of tilt at 37 ℃. The two microspheres-loaded hydrogels had denser network structures than those of chitosan solution and simple thermosensitive hydrogel, and in the cross section of which microspheres with a diameter of about 30 μm could be seen. Within PID 15, the wounds of rats in the five groups were healed to different degrees, and the wound healing of rats in P311 microspheres-loaded hydrogel group was the best. On PID 5, 10, and 15, the wound healing rates of rats in dressing group and chitosan group were (26.6±2.4)%, (38.5±3.1)%, (50.9±1.5)%, (47.6±2.0)%, (58.5±3.6)%, and (66.7±4.1)%, respectively, which were significantly lower than (59.3±4.8)%, (87.6±3.2)%, (97.2±1.0)% in P311 microspheres-loaded hydrogel group (P<0.05 or P<0.01). The wound healing rates of rats in hydrogel alone group on PID 10 and 15, and in simple microspheres-loaded hydrogel group on PID 15 were (76.0±3.3)%, (84.5±3.6)%, and (88.0±2.6)%, respectively, which were significantly lower than those in P311 microspheres-loaded hydrogel group (P<0.05). The epidermis, hair follicles, and sebaceous glands could be seen in the normal skin of rats in normal group, without positive expressions of CD31 or VEGF. The wounds of rats in P311 microspheres-loaded hydrogel group on PID 15 were almost completely epithelialized, with more blood vessels, hair follicles, sebaceous glands, and positive expressions of CD31 and VEGF in the wounds than those of rats with full-thickness skin defects in the other four groups, and more protein expressions of CD31 and VEGF than those of rats in the other five groups. Conclusions: The P311 microspheres-loaded thermosensitive chitosan hydrogel can release the encapsulated drug slowly, prolong the drug action time, and promote wound healing in rats with full-thickness skin defects by promoting wound angiogenesis and re-epithelialization.
Rats ; Male ; Animals ; Hydrogels ; Vascular Endothelial Growth Factor A ; Chitosan/pharmacology* ; Serum Albumin, Bovine/pharmacology* ; Microspheres ; Polyvinyl Alcohol/pharmacology* ; Hematoxylin/pharmacology* ; Eosine Yellowish-(YS)/pharmacology* ; Rats, Sprague-Dawley ; Wound Healing ; Skin/injuries* ; Skin Abnormalities ; Soft Tissue Injuries ; Water/pharmacology* ; Alginates/pharmacology*

Aim To explore the arrhythmic risk of Chan Su intravenous injection(CS)and its underlying mechanismin in the absent or presence of IL-6.Methods The recording techniques of guinea pig in vivo ECG, the action potential, L-type Ca2+ and Na+ currents from left ventricular myocytes were used to analyze heart rate(HR), P-R, QRS and QTc intervals and the underlying mechanism.Results① CS at one time CRD(clinically relevant dose)insignificantly changed the guinea pig in vivo ECG.However, the IL-6(18.4 μg·kg-1)only and the combinational use of IL-6(18.4 μg·kg-1)plus CS(one time CRD)remarkably prolonged the P-R and QTc intervals.② The CS at one time CRC(clinically relevant concentration)had no significant change in the action potential duration at 90% repolarization level(APD90).The IL-6(20 μg·L-1)only and the combination of CS at one time CRC plus IL-6(20 μg·L-1)significantly prolonged APD90.③ Moreover, the IL-6(20 μg·L-1)combined with CS at one time CRC significantly inhibited the L-type Ca2+ current. CS at one, five, ten time CRC, IL-6(20 μg·L-1)alone and IL-6(20 μg·L-1)combined with CS had no significant effects on Na+current.Conclusions CS intravenous injection has low risk of arrhythmia in the clinical settings.However, in presence of high titer of IL-6 characterized by inflammation, CS may induce the atrioventricular conduction block due to the blockade effect on Ca2+ current by both of CS and IL-6.

Hie high altitude hypoxic environment affects the pharmacokinetic process of rlnjgs by changing the body's gastrointestinal emptying rate, organ blood flow, drug plasma protein binding rate, dnjg metabolizing enzymes and transporter expression.Epilepsy is a brain disease that requires long-term medication.Most anti-epileptic drugs have a low therapeutic index and a narrow range of effective blood drug concentrations.'Ilierapeu- tic dnjg monitoring (TDM) is commonly used clinically to find the best individualized medication method for antiepileptic dnjgs.rI1iis article summarizes the commonly used anti-epileptic dnjgs and their treatment windows in clinical practice, and analyzes the influence of the pharmacokinetics of anti-epileptic dnjgs in the high altitude hypoxic environment, so as to provide reference for the clinical use of anti-epileptic drugs at high altitude.

Hyaluronic acid is widely used in biomaterials, cosmetics, clinical medicine and other fields due to its good biocompatibility, degradability, hydrophilicity, tumor targeting, viscosity and other characteristics. Pharmacodynamic activities of natural small molecular products which derived from traditional Chinese medicine (TCM) are significant, but their low solubility and poor targeting limit the clinical application. Based on supramolecular properties of hyaluronic acid, in this review, numerous studies were reviewed on the improvement of solubility, bioavailability, targeting and suitable dosage forms of small molecular compounds in TCM by domestic and foreign scholars using hyaluronic acid as carrier. It provides new ideas and inspirations for exploring the potential application value of small molecule compounds in TCM and even for the research and development of new drugs.