Inhibition of RhoGEF/RhoA alleviates regorafenib resistance and cancer stemness via Hippo signaling pathway in hepatocellular carcinoma.

Patients with hepatocellular carcinoma (HCC) are vulnerable to drug resistance. Although drug resistance has been taken much attention to HCC therapy, little is known of regorafenib and regorafenib resistance (RR). This study aimed to determine the drug resistance pattern and the role of RhoA in RR. Two regorafenib-resistant cell lines were constructed based on Huh7 and Hep3B cell lines. In vitro and in vivo assays were conducted to study RhoA expression, the activity of Hippo signaling pathway and cancer stem cell (CSC) traits. The data showed that RhoA was highly expressed, Hippo signaling was hypoactivated and CSC traits were more prominent in RR cells. Inhibiting RhoA could reverse RR, and the alliance of RhoA inhibition and regorafenib synergistically attenuated CSC phenotype. Furthermore, inhibiting LARG/RhoA increased Kibra/NF2 complex formation, prevented YAP from shuttling into the nucleus and repressed CD44 mRNA expression. Clinically, the high expression of RhoA correlated with poor prognosis. LARG, RhoA, YAP1 and CD44 show positive correlation with each other. Thus, inhibition of RhoGEF/RhoA has the potential to reverse RR and repress CSC phenotype in HCC.

Effect of Porcine Placental Extract Mixture on Alcohol-Induced Hepatotoxicity in Rats.

This study was conducted to examine the effect of porcine placenta extract mixture (pPEM, enzymatic/acidic extract = 1/3) on alcoholic hepatotoxicity after pPEM dosing with alcohol in rats. The experimental groups were normal, control, silymarin, three pPEM (590, 1771, and 2511 mg/kg/day, po), and silymarin (100 mg/kg/day, po) groups (n = 10). Alcoholic hepatotoxicity was caused by a liquid ethanol diet for 4 weeks. The effect of pPEM and silymarin on alcoholic hepatotoxicity was evaluated by serology, hepatic ADH and ALDH activities, and histopathological findings. After oral dosing with alcohol for 4 weeks, ALT and AST were significantly increased to 33.7 → 115.6 and 81.37 → 235.0 in the alcohol group, respectively. These levels were decreased significantly to 83.9 and 126.7 in the silymarin group and dose-dependently to 73.6-56.9 and 139.2-122.8 in all pPEM groups. Hepatic ADH and ALDH might have been increased in the control and not in the silymarin and pPEM groups for hepatic ADH. All pPEM groups exhibited no effects on hepatic ALDH except for the high pPEM group. Mild inflammation and fatty lesions were observed in the alcohol group and were attenuated in the silymarin and pPEM groups. As a results, the pPEM showed protective activities against alcoholic hepatotoxicity on the serological markers, hepatic ADH and ALDH, and pathological findings.

Toxicity study of compound granules of Hedyotis diffusa: Acute toxicity and long-term toxicity.

ETHNOPHARMACOLOGICAL RELEVANCE: The clinical efficacy of the hospital preparation compound granules of Hedyotis diffusa (CGHD), which is composed of Hedyotis diffusa Willd, Smilax china L., Solanum lyratum Thunb., has accumulated a good reputation over the past decades. However, because it is a hospital preparation, few researchers have paid attention to it, resulting in a lack of systematic basic research studies. Thus, it is not clear whether there are safety concerns that restrict its clinical application, and toxicological evaluation of CGHD is needed. AIM OF THE STUDY: The aim of this study was to evaluate the safety of CGHD by conducting acute toxicity and long-term toxicity experiments, with the objective of providing evidence for its clinical safety and a theoretical foundation for its clinical application. MATERIALS AND METHODS: KM mice were selected for the acute toxicity experiment and were administered water or CGHD-E 3 times within 24 h. The reactions of the animals to CGHD treatment were observed and recorded within 1 h after administration and then once a day for 14 consecutive days. SD rats were selected to conduct the long-term toxicity experiment. The drug-treated groups were administered different doses of CGHD-E, which were equivalent to 10 times, 20 times and 50 times the clinical dose in humans. The rats were administered the drug for 28 consecutive days. After 28 days, the animals were sacrificed, and routine blood tests, blood coagulation function analysis, liver and kidney function tests, and glycolipid metabolism related tests were conducted. The major organs of the rats were collected to calculate organ coefficients and perform hematoxylin-eosin (HE) staining. RESULTS: In the CGHD-E acute toxicity experiment, the drug-treated groups did not show adverse reactions or poisoning symptoms, and the maximum tolerated dose of CGHD-E in mice was greater than 45.072 g/kg. In the long-term toxicity experiment, drug-treated rats generally exhibited a good condition, but continuous administration decreased on body weight and food intake, especially in male rats. Coagulation function alterations and the impact on the liver during long-term drug administration were also assessed, which should be emphasized in clinical applications. No significant toxic effects were observed according to routine blood tests or test of liver and kidney function, glucose and lipid metabolism, or ion metabolism. CONCLUSIONS: The results of this study showed that CGHD was nontoxic or had low toxicity, providing not only a scientific basis for its clinical application, determining the appropriate clinical dose and monitoring clinical toxicity but also theoretical support for subsequent clinical drug trials.

Transcervical incision of septa: 447 cases.

BACKGROUND: Although uterine septum does not cause infertility, it may lead to recurrent abortion, preterm delivery, and premature rupture of membrane in over 25% of patients. The aim of this study was to evaluate feasibility and clinical value of hysteroscopic bipolar electric vaporization technique (Versapoint Bipolar Electrosurgical System) used in transcervical incision of septa (TCIS) in an outpatient setting. METHODS: Retrospectively, 447 cases of hysteroscopic TCIS were analyzed. Operative time, blood loss, consumption of uterus distension medium, and period of postoperative hospital stay were compared between outpatients and inpatients. Feasibility of outpatient TCIS using bipolar electric vaporization system under analgesia and without anesthesia was investigated. All hysteroscopic procedures were performed after review and approval by institutional ethical committee. Stata 8.0 software was used for statistical analysis, and t test and chi (2) test were used to evaluate association among numerical and categorical variables. p < 0.05 indicated statistically significant difference. RESULTS: The study included 121 inpatients (27.1%) and 326 outpatients (72.9%). Three hundred sixty-two cases (80.98%) were under only pethidine analgesia and 420 cases (93.96%) under local infiltration anaesthesia or analgesia. Of 447 cases of TCIS, 433 (96.87%) were accomplished under intravenous, local infiltration anaesthesia or pethidine analgesia. In all TCIS, 421 cases (94.18%) were carried out with mechanical microscissors and bipolar electric vaporization incision. No significant difference was identified between inpatients and outpatients in terms of operative time, blood loss, or consumption of uterus distension medium (p > 0.05). However, period of postoperative hospital stay was significantly shorter in outpatient TCIS than in inpatient TCIS by an average of 24 h or more (p < 0.01). CONCLUSIONS: Hysteroscopic bipolar electric vaporization TCIS could be carried out safely and efficaciously in an outpatient setting, by using smaller hysteroscope and bipolar electrodes.