Integrating Chinese and Western medicines reduced the incidence of hepatocellular carcinoma in patients with diabetes mellitus: A Taiwanese population-based cohort study.

OBJECTIVES: Much epidemiological evidence links diabetes mellitus (DM) to the development of multiple cancers and, in particular, the development of hepatocellular carcinoma (HCC). The aim of this study was to investigate whether Chinese herbal medicine (CHM) reduces the incidence of HCC in patients receiving Western antidiabetic drugs. INTERVENTIONS AND MAIN OUTCOME MEASURES: This retrospective cohort study used data from the National Health Insurance Research Database involving 81,105 diabetic patients, including 5122 CHM users and 25,966 non-CHM users. Analyses of treatment effects were adjusted for covariates including gender, age, comorbidities, antidiabetic drugs and liver medications. NodeXL software performed a network analysis to identify the 50 most commonly used CHM herbs and formulas. RESULTS: In Cox proportional hazards models adjusted for demographic and clinical characteristics, DM patients exposed to adjuvant CHM therapy were significantly less likely to develop HCC compared with non-CHM users (adjusted hazard ratio [aHR] 0.59; 95 % confidence interval [CI], 0.41-0.87; p = 0.01). Kaplan-Meier analysis revealed a lower 10-year cumulative risk of HCC among CHM users compared with non-CHM users. Amongst the 10 individual CHM herbs and herbal formulas most commonly prescribed for DM, the most frequent were Salvia miltiorrhiza (Dan Shen) and Liu Wei Di Huang Wan, respectively. CONCLUSION: This nationwide retrospective cohort study from Taiwan provides some valuable insights into the prescribing characteristics of CHM treatment in patients with DM. Compared with use of Western antidiabetic medications alone, use of adjuvant CHM effectively reduces the incidence of HCC in patients with DM.

Temporal expression of wound healing-related genes inform wound age estimation in rats after a skeletal muscle contusion: a multivariate statistical model analysis.

Although many time-dependent parameters involved in wound healing have been exhaustively investigated, establishing an objective and reliable means for estimating wound age remains a challenge. In this study, 78 Sprague-Dawley rats were divided randomly into a control group and contusion groups at 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48 h post-injury (n = 6 per group). The expression of 35 wound healing-related genes was explored in contused skeletal muscle by real-time polymerase chain reaction. Differences between the groups were assessed by partial least squares discriminant analysis (PLS-DA). The results show that the samples were classified into three groups by wound age (4-12, 16-24, and 28-48 h). A Fisher discriminant analysis model of 14 selected genes was constructed, and 94.9% cross-validated grouped cases were correctly classified. A PLS regression analysis using 14 genes showed reasonable internal predictive validity, with a root mean squared error of cross-validation of approximately 8 h. To examine whether the prediction models were capable of analyzing new (ungrouped) cases, an external validation was carried out using the expression data from an additional 30 rats. Approximately 76.7% of ungrouped cases were correctly classified, which was a lower proportion than that for cross-validation. Similarly, the prediction results of the PLS model showed lower relatively external predictive validity (root mean squared error of prediction = 11 h) than internal predictive validity. Although the prediction results were less accurate than expected, the gene expression modeling and multivariate analyses showed great potential for estimating injury time. These multivariate methods may be valuable when devising future wound time estimation strategies.

Clinical Significance of Dynamics of Programmed Death Ligand-1 Expression on Circulating CD14+ Monocytes and CD19+ B Cells with the Progression of Hepatitis B Virus Infection.

Programmed death-1 (PD-1) expression has been revealed to be upregulated on T cells and contributes to T cell exhaustion in patients with hepatitis B virus (HBV) infection. In this study, we investigated the dynamic expression of programmed death ligand-1 (PD-L1), the ligand of PD-1, on circulating CD14+ monocytes and CD19+ B cells of HBV-infected patients at the stages of chronic HBV (CHB) infection, liver cirrhosis (LC), and hepatocellular carcinoma (HCC), respectively. The results showed that compared with healthy controls, the levels of PD-L1 expression on CD14+ and CD19+ populations were both upregulated in CHB, LC, and HCC groups. Although there was no significant difference of PD-L1 expression on CD14+ population among three disease groups, further analysis demonstrated that the frequency of CD14+PD-L1+ population was negatively correlated with HBV DNA load, the levels of alanine aminotransaminase (ALT), and the levels of aspartate aminotransferase (AST), respectively, at CHB stage, while it did not present significant correlation with such parameters at LC stage and was only positively correlated with HBV DNA load at HCC stage. Similarly, the levels of PD-L1 expression on CD19+ population also did not present much difference among three disease groups. Intriguingly, the frequencies of CD19+PD-L1+ population at CHB and LCC stages were both positively correlated with the levels of ALT and AST, but they were not significantly correlated with HBV DNA load. Thereby, the current study elucidated the dynamics of PD-L1 expression on monocytes and B cells, along with the dynamic regulation of PD-1 on T cells, which had a close relationship during the progression of HBV infection. Collectively, our findings demonstrated that in the course of HBV infection development, PD-L1 expression on CD14+ monocytes and CD19+ B cells varied and significantly correlated with clinical parameters, which could be utilized as a potential clinical indicator.

Characterization of imidazoline receptors in blood vessels for the development of antihypertensive agents.

It has been indicated that activation of peripheral imidazoline I2-receptor (I-2R) may reduce the blood pressure in spontaneously hypertensive rats (SHRs). Also, guanidinium derivatives show the ability to activate imidazoline receptors. Thus, it is of special interest to characterize the I-2R using guanidinium derivatives in blood vessels for development of antihypertensive agent(s). Six guanidinium derivatives including agmatine, amiloride, aminoguanidine, allantoin, canavanine, and metformin were applied in this study. Western blot analysis was used for detecting the expression of imidazoline receptor in tissues of Wistar rats. The isometric tension of aortic rings isolated from male rats was also estimated. The expression of imidazoline receptor on rat aorta was identified. However, guanidinium derivatives for detection of aortic relaxation were not observed except agmatine and amiloride which induced a marked relaxation in isolated aortic rings precontracted with phenylephrine or KCl. Both relaxations induced by agmatine and amiloride were attenuated by glibenclamide at concentration enough to block ATP-sensitive potassium (KATP) channels. Meanwhile, only agmatine-induced relaxation was abolished by BU224, a selective antagonist of imidazoline I2-receptors. Taken together, we suggest that agmatine can induce vascular relaxation through activation of peripheral imidazoline I2-receptor to open KATP channels. Thus, agmatine-like compound has the potential to develop as a new therapeutic agent for hypertension in the future.

Antihypertensive action of allantoin in animals.

The agonists of imidazoline I-1 receptors (I-1R) are widely used to lower blood pressure. It has been indicated that guanidinium derivatives show an ability to activate imidazoline receptors. Also, allantoin has a chemical stricture similar to guanidinium derivatives. Thus, it is of special interest to characterize the effect of allantoin on I-1R. In conscious male spontaneous hypertensive rats (SHRs), mean blood pressure (MBP) was recorded using the tail-cuff method. Furthermore, the hemodynamic analyses in catheterized rats were applied to measure the actions of allantoin in vivo. Allantoin decreased blood pressures in SHRs at 30 minutes, as the most effective time. Also, this antihypertensive action was shown in a dose-dependent manner from SHRs treated with allantoin. Moreover, in anesthetized rats, allantoin inhibited cardiac contractility and heart rate as showing in hemodynamic dP/dt max significantly. Also, the peripheral blood flow was markedly increased by allantoin. Both actions were diminished by efaroxan at the dose sufficient to block I-1R. Thus, we suggest that allantoin, as I-1R agonist, has the potential to develop as a new therapeutic agent for hypertension in the future.

Protection of the extracts of Lentinus edodes mycelia against carbon-tetrachloride-induced hepatic injury in rats.

Lentinus edodes is the medicinal macrofungus showing potential for therapeutic applications in infectious disorders including hepatitis. In an attempt to develop the agent for handling hepatic injury, we used the extracts of Lentinus edodes mycelia (LEM) to screen the effect on hepatic injury in rats induced by carbon tetrachloride (CCl4). Intraperitoneal administration of CCl4 not only increased plasma glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) but also decreased hepatic superoxide dismutase (SOD) and glutathione peroxidase (GPx) levels in rats. Similar to the positive control silymarin, oral administration (three times daily) of this product (LEM) for 8 weeks significantly reduced plasma GOT and GPT. Also, the activities of antioxidant enzymes of SOD and GPx were elevated by LEM. in liver from CCl4-treated rats, indicating that mycelium can increase antioxidant-like activity. Moreover, the hepatic mRNA and protein levels of SOD and GPx were both markedly raised by LEM. The obtained results suggest that oral administration of the extracts of Lentinus edodes mycelia (LEM) has the protective effect against CCl4-induced hepatic injury in rats, mainly due to an increase in antioxidant-like action.