Chinese herbal medicine decreases incidence of hepatocellular carcinoma in diabetes mellitus patients with regular insulin management.

BACKGROUND: Type 2 diabetes mellitus (DM) is an independent risk factor for hepatocellular carcinoma (HCC), while insulin is a potent mitogen. Identifying a new therapeutic modality for preventing insulin users from developing HCC is a critical goal for researchers. AIM: To investigate whether regular herbal medicine use can decrease HCC risk in DM patients with regular insulin control. METHODS: We used data acquired from the Taiwanese National Health Insurance research database between 2000 and 2017. We identified patients with DM who were prescribed insulin for > 3 months. The herb user group was further defined as patients prescribed herbal medication for DM for > 3 months per annum during follow-up. We matched the herb users to nonusers at a 1:3 ratio according to age, sex, comorbidities and index year by propensity score matching. We analyzed HCC incidence, HCC survival rates, and the herbal prescriptions involved. RESULTS: We initially enrolled 657144 DM patients with regular insulin use from 2000 to 2017. Among these, 46849 patients had used a herbal treatment for DM, and 140547 patients were included as the matched control group. The baseline variables were similar between the herb users and nonusers. DM patients with regular herb use had a 12% decreased risk of HCC compared with the control group [adjusted hazard ratio (aHR) = 0.88, 95%CI = 0.80-0.97]. The cumulative incidence of HCC in the herb users was significantly lower than that of the nonusers. Patients with a herb use of > 5 years cumulatively exhibited a protective effect against development of HCC (aHR = 0.82, P < 0.05). Of patients who developed HCC, herb users exhibited a longer survival time than nonusers (aHR = 0.78, P = 0.0001). Additionally, we report the top 10 herbs and formulas in prescriptions and summarize the potential pharmacological effects of the constituents. Our analysis indicated that Astragalus propinquus (Huang Qi) plus Salvia miltiorrhiza Bunge (Dan Shen), and Astragalus propinquus (Huang Qi) plus Trichosanthes kirilowii Maxim. (Tian Hua Fen) were the most frequent combination of single herbs. Meanwhile, Ji Sheng Shen Qi Wan plus Dan Shen was the most frequent combination of herbs and formulas. CONCLUSION: This large-scale retrospective cohort study reveals that herbal medicine may decrease HCC risk by 12% in DM patients with regular insulin use.

Unveiling nature's potential weapon: Magnolol's role in combating bladder cancer by upregulating the miR-124 and inactivating PKC-δ/ERK axis.

BACKGROUND: Bladder cancer (BC) is a challenging disease to manage. Researchers have been investigating the potential of magnolol, a compound derived from Magnolia officinalis, as an anti-cancer agent. However, the exact regulatory mechanism of magnolol and its impact on the NF-κB signaling pathway in BC remain unclear. MATERIALS: To comprehensively evaluate its therapeutic potential, the researchers conducted a series of experiments using BC cell lines (TSGH8301, T24, and MB49) and in vivo animal models. RESULTS: The results of the study demonstrated that magnolol exhibits cytotoxic effects on BC cells by activating both the extrinsic and intrinsic apoptosis signaling pathways. Additionally, the expression of anti-apoptotic genes was downregulated by magnolol treatment. The researchers also uncovered the regulatory role of PKCδ/ERK and miR-124-3p in the NF-κB pathway, which may be influenced by magnolol. Treatment with magnolol led to the inactivation of PKCδ/ERK and an increase in miR-124-3p expression, effectively inhibiting NF-κB-mediated progression of BC. Importantly, the administration of magnolol did not result in significant toxicity in normal tissues, highlighting its potential as a safe adjunctive therapy with minimal adverse effects. CONCLUSION: These findings position magnolol as a promising therapeutic agent for the treatment of BC. By activating apoptosis signaling pathways and inhibiting NF-κB pathway through the upregulation of miR-124-3p and downregulation of PKCδ/ERK activation, magnolol holds promise for suppressing tumor progression and improving patient outcomes in BC. Further research and clinical trials are warranted to explore the full potential of magnolol in the future.

Total syntheses and antibacterial evaluations of cudraflavones A-C and related Flavones.

The total syntheses of the natural prenylated flavones cudraflavones A-C (1-3), artoheterophyllin D (28) and artelasticin (29) are reported, along with the evaluations of their antibacterial activities. The key steps of the synthesis involved a Baker-Venkataraman rearrangement and an intramolecular cyclization for the construction of the flavone core and the regioselective formation of the pyran and isopentenyl scaffolds. The tested natural flavones 1-3 and 27-29 exhibited potent activity against S. aureus ATCC 29213, S. epidermidis ATCC 14990, E. faecalis ATCC 29212 and B. subtilis ATCC 6633 with MIC values ranging from 0.125 µg/mL to 16 µg/mL. Compound 3 displayed the strongest potency, with MIC values in the range between 0.125 and 1 µg/mL, as a potential candidate to combat G+ bacterial infections. Preliminary mechanism of action studies suggested that this compound killed bacteria by disrupting bacterial membrane integrity.

Effect of transdermal drug delivery therapy on anxiety symptoms in schizophrenic patients.

Objective: To evaluate the efficacy and safety of transdermal drug delivery therapy for schizophrenia with anxiety symptoms. Methods: A total of 80 schizophrenic patients (34 males and 56 females) with comorbid anxiety disorders were randomly assigned to the treatment group (n = 40) and the control group (n = 40) with 6 weeks of follow-up. The patients in the treatment group received the standard antipsychotic drug treatment along with transdermal drug delivery therapy. The evaluation of the patients included the Hamilton Anxiety Scale (HAMA), Hamilton Depression Scale (HAMD-17), and treatment emergent symptom scale (TESS) at baseline, 3 weeks, and 6 weeks after transdermal drug delivery therapy. The Positive and Negative Symptom Scale (PANSS) was assessed at baseline and after 6 weeks of treatment. Results: After 3 and 6 weeks of treatment, the HAMA scale scores in the treatment group were lower than those in the control group (p < 0.001). However, there were no significant differences in the HAMD-17 scale scores, PANSS total scores, and subscale scores between the two groups (p > 0.05). Additionally, no significant differences in adverse effects were observed between the two groups during the intervention period (p > 0.05). After 6 weeks of penetration therapy, there was a low negative correlation between total disease duration and the change in HAMA scale score (pretreatment-posttreatment) in the treatment group. Conclusion: Combined traditional Chinese medicine directed penetration therapy can improve the anxiety symptoms of patients with schizophrenia and has a safe profile.

Roles of conventional and complementary therapies in recurrent hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the fifth most common type of cancer and the fourth leading cause of cancer-related deaths in the world. HCC has a reported recurrence rate of 70%-80% after 5 years of follow-up. Controlling tumor recurrence is the most critical factor associated with HCC mortality. Conventional salvage therapies for recurrent HCC include re-hepatectomy or liver transplantation, transcatheter arterial chemoembolization, Y-90, target therapy, and immunotherapy; however, these conventional treatment modalities have yet to achieve consistently favorable outcomes. Meanwhile, previous studies have demonstrated that conventional therapies in combination with traditional Chinese medicine (TCM), acupuncture, moxibustion or dietary supplements could notably benefit patients with HCC recurrence by strengthening and augmenting the overall management strategy. However, systemic reviews related to the interactions between complementary therapies and conventional therapy in recurrent HCC are limited. In this review, we discuss the molecular mechanisms underlying the functions of complementary therapies for recurrent HCC, which include augmenting the local control to improve the congestion status of primary tumors and reducing multicentric tumor occurrence via inducing autophagy, apoptosis or cell cycle arrest. TCM and its derivatives may play important roles in helping to control HCC recurrence by inhibiting epithelial-mesenchymal transition, migration, invasion, and metastasis, inhibiting cancer stem cells, and ameliorating drug resistance.

Total Syntheses and Antibacterial Evaluations of Neocyclomorusin and Related Flavones.

Neocyclomorusin (1), a natural bioactive pyranoflavone mainly isolated from plants of the Moraceae family, was synthesized for the first time using a Friedel-Crafts reaction, a Baker-Venkataraman (BK-VK) rearrangement, a selective epoxidation, and a novel SN2-type cyclization as the key steps. The present protocol was also successfully applied for the total synthesis of oxyisocyclointegrin (2). Structurally related natural products morusin (23) and cudraflavone B (24) were also prepared. We investigated the antibacterial activities of these natural compounds against both Gram-negative and Gram-positive strains. The prenylated flavones, morusin (23) and cudraflavone B (24), showed comparable activity to ampicillin and kanacycin A against Staphylococcus aureus. Both morusin (23) and cudraflavone B (24) showed better antibacterial activities than ampicillin against the Gram-positive bacteria Staphylococcus epidermidis and Bacillus subtilis. Both neocyclomorusin (1) and oxyisocyclointegrin (2) displayed disappointing antimicrobial activities against Escherichia coli, Staphylococcus aureus, Staphylococcus epidermidis, and Bacillus subtilis strains.

The effectiveness of Tuina in managing chronic non-specific low back pain: A protocol of a multicenter international randomized controlled trial.

BACKGROUND: Chronic non-specific low back pain (CNLBP) is a common complaint about medical care and carries a heavy social burden. The efficacy of Tuina (TN) or physiotherapy (PT) for CNLBP has been evaluated in previous systematic reviews. However, there is no high-quality evidence to support the efficacy of Tuina. Therefore, this study aims to conduct a large-scale, multicenter, high-quality clinical trial to provide evidence for Tuina to treat CNLBP. METHODS: This is a multicenter, assessor-, and analyst-blinded, randomized controlled trial with 3 parallel arms: TN, PT, and TN combined with PT (Tuina combined with physiotherapy) group. Six hundred twelve eligible CNLBP patients will be randomly assigned to the groups in a 1:1:1 ratio in 3 centers. The TN intervention includes 9-step routine techniques, while the PT intervention includes a physiotherapy treatment plan based on a patient's symptoms. The interventions for both groups will last for 30 minutes and will be carried out for 6 sessions in 8 weeks. The primary outcome will be the visual analog scale pain score. And the secondary outcomes will include the Oswestry Disability Index, spinal range of motion, 36-item short-form health survey. Safety evaluation will be recorded during the whole study. All data in this randomized controlled trial will be analyzed by SAS 9.4. DISCUSSION: The results of this trial will provide evidence to evaluate the efficacy of Tuina's value as a treatment for CNLBP. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR2000040288, November 27, 2020).

Androgen Receptor Enhances the Efficacy of Sorafenib Against Hepatocellular Carcinoma Through Enriched EpCAM Stemness.

BACKGROUND/AIM: The role of androgen receptor (AR) in hepatocellular carcinoma (HCC) development is controversial. Therefore, the translational value of targeting AR in HCC is unknown. Sorafenib, a multiple kinase inhibitor, is the standard therapy for patients with unresectable HCC. This study investigated sorafenib effect on AR in experimental models of HCC. MATERIAL AND METHODS: AR cDNA was introduced into HCC cells and in vitro cell growth and in vivo tumor growth were measured. Sphere cells, as well as epithelial cell adhesion molecule-positive (EpCAM+) and CD133+ cells were isolated from HCC cells with/without AR expression to observe in vitro/in vivo effects. Liver specific AR knockout in mouse models of spontaneous HCC (carcinogen-induced and hepatitis B virus-related HCC) was also implemented to examine gene expression. HCC cells/tumors were treated with sorafenib in order to determine effects on tumor growth and related gene expression. RESULT: AR cDNA increased transactivation function, increased colony/sphere-forming activities, and enhanced tumorigenicity in HCC cells compared to their parental cells. Expression of the stemness marker EpCAM was also dramatically increased. In carcinogen-and HBV-induced HCC models, EpCAM+ cells were significantly reduced in AR-knockout mice compared to wild-type HCCs. In addition, AR reduced sorafenib-related signals, e.g. extracellular-regulated kinase, AKT serine/threonine kinase 1, and p38 mitogen-activated protein kinase, compared to that in parental cells. Regarding sorafenib cytotoxicity, AR-expressing cells were vulnerable to treatment. Moreover, the half maximal-inhibitory concentration (IC50) was drastically lowered in AR+/EpCAM+ compared to AR-/EpCAM- sphere cells. Strikingly, the IC50 in AR+/CD133+ vs. AR-/CD133+ cells were similar. Moreover, sorafenib robustly suppressed tumor growth in implanted AR+/EpCAM+ cells but not AR-/EpCAM- ones. Finally, bioinformatics analyses revealed EpCAM to be a prognostic biomarker in Asian and non-alcohol-consuming patients with HCC, suggesting suitability of a sorafenib regimen for such patients. CONCLUSION: AR+/EpCAM+ may be a marker of responsiveness to sorafenib for patients with HCC. Prospective surveys associating AR/EpCAM expression with therapy outcomes are essential.

Dynamic observation and analysis of metabolic response to moxibustion stimulation on ethanol-induced gastric mucosal lesions (GML) rats.

BACKGROUND: Gastric mucosal lesion (GML) is the initiating pathological process in many refractory gastric diseases. And moxibustion is an increasingly popular alternative therapy that prevents and treats diseases. However, there are few published reports about developing pathology of GML and therapeutic mechanism of moxibustion treatment on GML. In this study, we investigated pathology of GML and therapeutic mechanism of moxibustion treatment on GML. METHODS: The male Sprague-Dawley (SD) rats were induced by intragastric administration of 75% ethanol after fasting for 24 h and treated by moxibustion at Zusanli (ST36) and Liangmen (ST21) for 1 day, 4 days or 7 days. Then we applied 1H NMR-based metabolomics to dynamic analysis of metabolic profiles in biological samples (stomach, cerebral cortex and medulla). And the conventional histopathological examinations as well as metabolic pathways assays were also performed. RESULTS: Moxibustion intervention showed a beneficial effect on GML by modulating comprehensive metabolic alterations caused by GML, including energy metabolism, membrane metabolism, cellular active and neurotransmitters function. CONCLUSIONS: Moxibustion can effectively treat gastric mucosal damage and effectively regulate the concentration of some related differential metabolites to maintain the stability of the metabolic pathway.

Network pharmacology-based identification for therapeutic mechanism of Ling-Gui-Zhu-Gan decoction in the metabolic syndrome induced by antipsychotic drugs.

BACKGROUND: The metabolic syndrome (MetS) is a common side effect of second-generation antipsychotic drugs (SGAs), leading to poor prognosis in patients with mental illness. The traditional Chinese herbal formula Ling-Gui-Zhu-Gan decoction (LGZGD) is a clinically validated remedy for SGAs-induced MetS, but its underlying mechanism remains unclear. METHODS: A network pharmacology-based analysis was performed to explore predicted plasma-absorbed components, putative therapeutic targets, and main pathways involved in LGZGD bioactivity. We constructed a target interaction network between the predicted targets of LGZGD and the known targets of MetS, after which we extracted major hubs using topological analysis. Thereafter, the maximum value of "edge betweenness" of all interactions was defined as a bottleneck, which suggested its importance in connecting all targets in the network. Finally, a pathway enrichment analysis of major hubs was used to reveal the biological functions of LGZGD. RESULTS: This approach identified 120 compounds and 361 candidate targets of LGZGD. According to the data generated in this study, the interaction between JUN and APOA1 plays a vital role in the treatment of SGAs-induced MetS using LGZGD. Interestingly, JUN was a putative target of LGZGD and APOA1 is one of the known targets of both MetS and SGAs (olanzapine and clozapine). LGZGD was significantly associated with several pathways including PI3K-Akt signaling, insulin resistance, and MAPK signaling pathway. CONCLUSIONS: LGZGD might inhibit JUN and thereby increases the expression of APOA1 to maintain metabolic homeostasis via some vital pathways.

Dynamic Analysis of Metabolic Response in Gastric Ulcer (GU) Rats with Electroacupuncture Treatment Using 1H NMR-Based Metabolomics.

Gastric ulcer (GU), a common digestive disease, has a high incidence and seriously endangers health of human. According to the previous studies, it has been proved that electroacupuncture at acupoints of stomach meridian had a good effect on GU. However, there are few published studies on metabolic response in gastric ulcer (GU) rats with electroacupuncture treatment. Herein, we observed the metabolic profiles in biological samples (stomach, liver, and kidney) of GU rats with electroacupuncture treatment by 1H NMR metabolomics combined with pathological examination. The male SD rats were induced by intragastric administration of 70% ethanol after fasting for 24 hours and treated by electroacupuncture at Zusanli (ST36) and Liangmen (ST21) for 1 day, 4 days, or 7 days, respectively. And the conventional histopathological examinations as well as metabolic pathways assays were also performed. We found that GU rats were basically cured after electroacupuncture treatment for 4 days and had a complete recovery after electroacupuncture treatment for 7 days by being modulated comprehensive metabolic changes, involved in the function of neurotransmitters, energy metabolism, cells metabolism, antioxidation, tissue repairing, and other metabolic pathways. These findings may be helpful to facilitate the mechanism elucidating of electroacupuncture treatment on GU.

Effect of Moxibustion on Intestinal Microbiome in Acute Gastric Ulcer Rats.

In Traditional Chinese Medicine (TCM), moxibustion had been used for thousands of years. Many clinical case reports and scientific studies had proved that moxibustion had a good effect in treating acute gastric ulcer (AGU). Some studies had shown that the relative content and species of bacteria in the intestinal would be changed when gastric mucosal injury happened. However, there was little research on the effect of intestinal microbiome with AGU rats that were treating by moxibustion. This study is aimed at analyzing the effect of fecal microbiome in rats with AGU by the 16S rDNA sequencing technology. Male SD rats were established by orally feeding once with 70% ethanol at 4 ml/kg except the control group, then treated by moxibustion in the stomach meridian group ("Liangmen," "Zusanli") and the gallbladder meridian group ("Riyue," "Yanglingquan") for 5 days. The 16S rDNA sequencing technology analysis of feces combined with histopathological methods and molecular biological detection methods was used to evaluate the therapeutic mechanism of moxibustion on AGU. AGU brought cause changes in the number and species of intestinal bacteria. Moxibustion on stomach meridian group could reduce the area of gastric mucosal injury and regulate the relative content of GAS and EGF. Moreover, moxibustion on the stomach meridian group could increase the relative content and species of beneficial bacteria in the intestine of rats with AGU. The relative abundance of intestinal probiotics was significantly upregulated in Alphaproteobacteria, Actinomycetales, and Bacillales. In addition, moxibustion might promote the repair of gastric mucosal injury by increasing the number and species of beneficial bacteria in the intestine.

Difference of Liver and Kidney Metabolic Profiling in Chronic Atrophic Gastritis Rats between Acupuncture and Moxibustion Treatment.

Acupuncture and moxibustion proved to be very effective in chronic atrophic gastritis (CAG). According to the Chinese traditional medicine theory, chronic diseases have an influence on the function of liver and kidney. However, there is little research to demonstrate this theory. This study is aimed at assessing the 1H NMR-based metabolic profiling in liver and kidney of CAG rats and comparing the difference between electroacupuncture and moxibustion treatment. Male SD rats were subjected to CAG modeling by intragastric administration of mixture of 2% sodium salicylate and 30% alcohol coupled with compulsive sporting and irregular fasting for 12 weeks and then treated by electroacupuncture or moxibustion at Liangmen (ST 21) and Zusanli (ST 36) acupoints for 2 weeks. A 1H NMR analysis of liver and kidney samples along with histopathological examination and molecular biological assay was employed to assess and compare the therapeutic effects of electroacupuncture and moxibustion. CAG brought characterization of metabolomic signatures in liver and kidney of rats. Both electroacupuncture and moxibustion treatment were found to normalize the CAG-induced changes by restoring energy metabolism, neurotransmitter metabolism, antioxidation metabolism, and other metabolism, while the moxibustion treatment reversed more metabolites related to energy metabolism in liver than electroacupuncture treatment. CAG did have influence on liver and kidney of rats. Both of these treatments had good effects on CAG by reversing the CAG-induced perturbation in liver and kidney. For regulating the energy metabolism in liver, the moxibustion played more important role than electroacupuncture treatment.

Effects of Omega-3 in the treatment of violent schizophrenia patients.

OBJECTIVE: This study was designed to explore the relationship in between the daily consumption of fish oil (360mg DHA+540mg EPA), and reduction of symptoms and violent behavior among patients with schizophrenia. METHOD: Fifty inpatients meeting ICD-10 criteria for schizophrenia and scoring more than four of Modified Overt Aggression Scale (MOAS) with antipsychotics treatment were randomly assigned to receive either fish oil (N=28) or a placebo (N=22) in a twelve week, double-blind supplementation trial. Assessments were performed at baseline and at weeks 4, 8 and 12. RESULTS: The PANSS and CGI scores decreased at the week of 4, 8 and 12, but no differences were found between the two groups. MOAS scores declined significantly at weeks 4, 8 and 12. At week 12, MOAS scores of the fish oil group declined significantly than the placebo group (t=-2.40, P<0.05). CONCLUSIONS: violent schizophrenia patients treated with fish oil (360mg DHA+540mg EPA) demonstrated a decrease in violence, but improvement in positive and negative symptoms was no greater than patients treated with the placebo after twelve weeks.

Inhibition of autophagy enhances the targeted therapeutic effect of sorafenib in thyroid cancer.

The multi-target kinase inhibitor sorafenib has been approved for the treatment of patients with advanced differentiated thyroid cancer. However, different sensitivities to sorafenib have been observed, and few patients have benefited from sorafenib treatment in the long term. In the event of acquired resistance to sorafenib it is not beneficial to continue treatment in most patients. Autophagy can be induced in a variety of cancer treatments and plays an important role in cancer treatment. The role of autophagy in sorafenib treatment of thyroid cancer has not been fully demonstrated. The present study investigated whether autophagy is activated by sorafenib during the treatment of thyroid cancer, examined the underlying mechanisms, and explored potential strategies to enhance the therapeutic sensitivity of sorafenib. Chloroquine (CQ) is an autophagy inhibitor that has been reported to increase sensitivity to various cancer treatments. Thyroid cancer xenograft model mice were treated with sorafenib, CQ, or a combination of sorafenib and CQ. We observed that CQ or sorafenib treatment suppressed tumor growth, while mice treated with the combination of sorafenib and CQ displayed significantly reduced tumor growth compared with those treated with sorafenib or CQ alone. Western blotting results indicated that sorafenib concurrently inhibited the activities of the MAPK and AKT/mTOR pathways in thyroid cancer. Autophagy was activated by sorafenib in thyroid cancer, both in vitro and in vivo, which was at least in part due to suppression of the AKT/mTOR pathway. Combination treatment including CQ could inhibit the autophagic flux induced by sorafenib. Silencing the key autophagy gene ATG5 using small interfering RNA also increased the anticancer effect of sorafenib. In summary, the present study revealed that inhibition of autophagy enhances the anticancer effect of sorafenib, and the combination of CQ with sorafenib treatment represents a potential therapeutic strategy for treating advanced differentiated thyroid cancer.

Inhibition of the AKT/mTOR Pathway Augments the Anticancer Effects of Sorafenib in Thyroid Cancer.

BACKGROUND: Sorafenib is a multikinase inhibitor that has been approved for the treatment of patients with advanced 131iodine (131I) refractory differentiated thyroid cancer (DTC). However, the progression-free survival of patients with advanced 131I refractory DTC is short, and most DTC patients eventually acquire resistance to sorafenib. Therefore, new therapeutic strategies need to be developed. MATERIALS AND METHODS: The thyroid cancer cell lines 8505C and FTC133 were treated with sorafenib in the presence or absence of BEZ235 or small interfering RNA (siRNA) directed against AKT. A CCK8 kit was used to evaluate cell viability. Protein expression levels of relevant genes were determined by Western blotting analysis, whereas messenger RNA expression levels were determined by real-time PCR analysis. Flow cytometry was performed to assess the number of apoptotic cells. RESULTS: The results indicate that sorafenib simultaneously inhibited the activities of the MAPK and PI3K/AKT/mTOR pathways in thyroid cancer cells. Treatment of 8505C and FTC133 cells with NVP-BEZ235, siRNA against AKT, or sorafenib induced tumor cell apoptosis and led to reduced tumor cell proliferation. Sorafenib in combination with PI3K/AKT/mTOR inhibition by NVP-BEZ235 or AKT siRNA enhanced apoptosis and proliferation suppression. CONCLUSIONS: The evidence of this study suggests that a combinatorial approach that inhibits both the MAPK and PI3K/AKT/mTOR pathways exerts a greater antitumor effect than sorafenib alone in thyroid cancer cell lines.

Zanthoxylum avicennae extract enhances GSK-3ß to attenuate ß-catenin via phosphatase 2A to block metastatic effects of HA22T cells and hepatocellular carcinoma xenografted nude mice.

Hepatocellular carcinoma (HCC) metastasis is often associated with the activation of Wnt/ß-catenin signaling pathway. Zanthoxylum avicennae (Ying Bu Bo, YBB), a traditional herb with hepatoprotective effect, has been proven to inhibit human HCC in in vivo models however, the in vitro and in vivo effect of YBB on tumor metastasis is not clear yet. To determine whether YBB could inhibit HA22T human HCC cell by acting on ß-catenin metastatic signaling in vitro and in vivo, HA22T cells were treated with different concentrations of YBB extracts (YBBE) and analyzed by Immunofluorescence staining assay, western blot analysis, siRNA mediated gene knock-down assays and co-immunoprecipitation assay. Additionally, the HA22T-implanted xenograft nude mice were used to confirm the assessed cellular effects. Mice treated with YBBEs showed a strong increasing trend in PP2Acα, GSK-3ß, APC, and ß-TrCP/HOS levels, however the expression of ß-catenin, p-GSK-3ß, TBX 3, and IL8 proteins showed a decreasing trend. YBBE significantly downregulated the nuclear and cytosolic ß-catenin levels by facilitating the proteosomal degradation of ß-catenin. Moreover, as observed by co-immunoprecipitation assay, YBBE directly promoted the protein interactions between GSK-3ß, ß-TrCP, APC, PP2A, and ß-catenin. In conclusion, both in vitro and in vivo models clearly demonstrated that YBBE inhibits ß-catenin involved metastatic signaling in highly metastatic HA22T cells through PP2A activation.

HATT: a phase IV, single-arm, open-label study of sorafenib in Taiwanese patients with advanced hepatocellular carcinoma.

BACKGROUND: Sorafenib significantly improves survival in patients with advanced hepatocellular carcinoma (HCC). This phase IV study assessed sorafenib efficacy/safety in Taiwanese patients with advanced HCC and Child-Pugh A status. METHODS: All patients received 400 mg sorafenib BID. Safety, efficacy, sorafenib pharmacokinetics, and Child-Pugh progression were evaluated. A hand-foot skin reaction (HFSR) prevention substudy assessed HFSR incidence and grade/severity and time to HFSR in 29 and 34 patients randomized to corticosteroid and noncorticosteroid ointments, respectively, and in 88 nonrandomized patients. RESULTS: The 151 patients included 120 (80%) male patients and 81 (54%) with stage IV disease. Mean sorafenib dose was 626 mg/day, and median treatment duration was 4.2 months. Median overall survival (OS), progression-free survival, and time to progression (TTP) were 8.6, 2.7, and 3.8 months, respectively. Disease control and response rates (partial responses only) were 48 and 6.6%, respectively. Median TTP from Child-Pugh A to B/C was 88 days. Drug-related adverse events (AEs) occurred in 89.4% of patients; none were new or unexpected. The most frequent grade ≥3 drug-related, treatment-emergent AEs were HFSR (13.2%), diarrhea (11.9%), and hypertension (6.6%). Corticosteroid ointment tended to reduce the severity and incidence of all HFSR-associated parameters. Pharmacokinetic exposure was unaltered by Child-Pugh progression. The final pharmacokinetic model predicted 13.1 and 33.8% reductions in sorafenib exposure over 6 and 12 months, respectively. CONCLUSIONS: There was a trend of longer OS and TTP in Taiwanese patients with advanced HCC compared with patients with advanced HCC in the Asia-Pacific trial. Sorafenib exposure did not correlate with liver function. Reduced pharmacokinetic exposure over time was unrelated to reduced or interrupted dosing.

Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL study.

PURPOSE: Brivanib is a dual inhibitor of vascular-endothelial growth factor and fibroblast growth factor receptors that are implicated in the pathogenesis of hepatocellular carcinoma (HCC). Our multinational, randomized, double-blind, phase III trial compared brivanib with sorafenib as first-line treatment for HCC. PATIENTS AND METHODS: Advanced HCC patients who had no prior systemic therapy were randomly assigned (ratio, 1:1) to receive sorafenib 400 mg twice daily orally (n = 578) or brivanib 800 mg once daily orally (n = 577). Primary end point was overall survival (OS). Secondary end points included time to progression (TTP), objective response rate (ORR), disease control rate (DCR) based on modified Response Evaluation Criteria in Solid Tumors (mRECIST), and safety. RESULTS: The primary end point of OS noninferiority for brivanib versus sorafenib in the per-protocol population (n = 1,150) was not met (hazard ratio [HR], 1.06; 95.8% CI, 0.93 to 1.22), based on the prespecified margin (upper CI limit for HR ≤ 1.08). Median OS was 9.9 months for sorafenib and 9.5 months for brivanib. TTP, ORR, and DCR were similar between the study arms. Most frequent grade 3/4 adverse events for sorafenib and brivanib were hyponatremia (9% and 23%, respectively), AST elevation (17% and 14%), fatigue (7% and 15%), hand-foot-skin reaction (15% and 2%), and hypertension (5% and 13%). Discontinuation as a result of adverse events was 33% for sorafenib and 43% for brivanib; rates for dose reduction were 50% and 49%, respectively. CONCLUSION: Our study did not meet its primary end point of OS noninferiority for brivanib versus sorafenib. However, both agents had similar antitumor activity, based on secondary efficacy end points. Brivanib had an acceptable safety profile, but was less well-tolerated than sorafenib.

Protective effects of the calcium-channel blocker flunarizine on crush injury of sciatic nerves in a rat model.

BACKGROUND: Neural damage can be mitigated by calcium-channel blockers (CCBs). However, the mechanism of action of CCBs is not yet fully understood. Objective : To investigate the mechanism of action and efficacy of CCB, flunarizine in restoring neural function after crush injury to the nerves. MATERIALS AND METHODS: The sciatic nerves of rats were crushed using pincers to establish the model for crush injury. Two hundred and eighty-eight Sprague-Dawley (SD) rats were randomly divided into sham-operated, saline, and low-dose flunarizine and high-dose flunarizine (FI and FII) groups. The expression of the protein c-fos in the dorsal root ganglia (DRG) after crush injury to the sciatic nerves was investigated by using reverse transcription-polymerase chain reaction (RT-PCR) and Western blot. The effect of flunarizine on c-fos expression and its efficacy in restoring neural function was evaluated. RESULTS: The c-fos messenger ribonucleic acid (mRNA) and protein expression in FI and FII groups was significantly lower than in the saline group and was the least in the FII group. Nerve-conduction velocity was increased in the order of: saline < FI< FII< sham-operated. There was no significant difference in the nerve-conduction velocity in the sham-operated and FII groups (P>.05). CONCLUSIONS: When administered after crush injury to peripheral nerves, flunarizine may protect neurons with lesions from further damage and improve neural function by downregulating c-fos expression.