Characteristics of early short-term traditional Chinese medicine in breast cancer patients: A population-based cohort study.

BACKGROUND: Traditional Chinese medicine (TCM) is frequently utilized as a complementary therapy for breast cancer patients. TCM primarily involves the use of Chinese herbal products (CHPs), which consist of single or multiherb formulas with diverse therapeutic effects documented in medical classics. The study aims to investigate the association between medication possession ratios to CHPs within 2-year post breast cancer diagnosis and 5-year survival, to explore the potential beneficial class effect of TCM. METHODS: This retrospective population-based cohort study included newly diagnosed breast cancer patients between 2003 and 2006, identified from the National Health Insurance Research Database of Taiwan. Logistic regression and Cox proportional hazards analysis were utilized to assess the likelihood of medication possession ratios (MPRs) for CHPs and to examine the association of variables with 5-year survival. RESULTS: A total of 3472 patients with breast cancer were included. Patients who had MPR of 1% to 9% and 10% to 19% for CHPs within 2 years after breast cancer diagnosis exhibited better 5-year survival rates compared with those who did not use CHPs (adjusted hazard ratio [aHR] 0.69, 95% confidence interval [CI] 0.55-0.86, p = 0.001; aHR 0.50, 95% CI 0.28-0.88, p = 0.016). Furthermore, the use of TCM formulations specifically targeting insomnia, such as Tian-wang-bu-xin-dan and Suan-zao-ren-tang, demonstrated a significantly positive association with survival (aHR 0.71, 95% CI 0.52-0.98, p = 0.035) among patients who were short-term users of CHPs (MPR of 1% to 19%). CONCLUSION: Short-term use of TCM (ie, MPR to CHPs 1~19%) within 2-year post breast cancer diagnosis present positive association with survival outcome. Tian-wang-bu-xin-dan and Suan-zao-ren-tang may have benefits to 5-year survival, but their causality still need further investigation.

The mechanism study of inhibition effect of prepared Radix Rehmanniainon combined with Radix Astragali osteoporosis through PI3K-AKT signaling pathway.

PURPOSE: To observe the mechanism of prepared Radix Rehmanniainon combined with Radix Astragali in treating osteoporosis. METHODS: Osteoporosis rat model was established by bilateral ovariectomy combined with low-calcium diet feeding. Bone mineral density was measured by bone densitometer. Bone metabolism markers in serum were detected by enzyme linked immunosorbent assay (ELISA), bone tissue structure was observed by hematoxylin-eosin staining, and the effect of prepared Radix Rehmanniainon combined with Radix Astragali on PI3K-AKT signaling pathway was investigated by immunohistochemistry and reverse transcription polymerase chain reaction. RESULTS: Compared with the model group, the bone tissue structure and imbalance of bone metabolism were improved, and the bone mineral density was significantly increased in the prepared Radix Rehmanniainon combined with Radix Astragali groups. After intervention with prepared Radix Rehmanniainon combined with Radix Astragali, the positive expression of PIK3CA and Akt1 in rat bone tissue was enhanced, and the expression levels of Akt1 mRNA were significantly increased. CONCLUSIONS: Prepared Radix Rehmanniainon combined with Radix Astragali may treat osteoporosis by activating PI3K/AKT pathway.

NOVEL-1st: an observational study to assess the safety and efficacy of nilotinib in newly diagnosed patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase in Taiwan.

Nilotinib has been approved for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP). However, the real-world evidence of nilotinib in newly diagnosed untreated Ph+ CML-CP is limited in Taiwan. The NOVEL-1st study was a non-interventional, multi-center study collecting long-term safety and effectiveness data in patients with newly diagnosed and untreated Ph+ CML-CP receiving nilotinib. We enrolled 129 patients from 11 hospitals. Overall, 1,466 adverse events (AEs) were reported; among these, 151 were serious and 524 were nilotinib-related. Common hematological AEs were thrombocytopenia (31.0%), anemia (20.9%), and leukopenia (14.0%); common nilotinib-related AEs were thrombocytopenia (29.5%), anemia (14.7%), and leukopenia (12.4%). Early molecular response, defined as BCR-ABL ≤ 10% at Month 3, was seen in 87.6% of patients. By 36 months, the cumulative rates of complete hematologic response, complete cytogenetic response, major molecular response, molecular response 4.0-log reduction, and molecular response 4.5-log reduction were 98.5, 92.5, 85.8, 65.0, and 45.0%, respectively. Nilotinib is effective and well-tolerated in patients with newly diagnosed Ph+ CML-CP in the real-world setting. Long-term holistic care and a highly tolerable AE profile may contribute to good treatment outcomes in Ph+ CML-CP under first-line treatment with nilotinib.

Influence of Traditional Chinese Medicine on Medical Adherence and Outcome in Estrogen Receptor (+) Breast Cancer Patients in Taiwan: A Real-World Population-Based Cohort Study.

BACKGROUND: Medical adherence is often higher in clinical trials than in real world practice. The aim of this study was to investigate the effects of traditional Chinese medicine (TCM) on medical adherence to hormonal therapy (HT) and survival outcome in ER (+) breast cancer patients in Taiwan. SUBJECTS AND METHODS: Using a nationwide longitudinal population-based database, we enrolled patients with newly diagnosed ER-positive breast cancer who had received HT, and followed for up to 5 years (N = 872). Medication adherence in terms of medication possession ratios (MPR) and patient outcome were evaluated with or without TCM exposure. We applied logistic regression and Cox proportional hazards (PH) analysis to identify factors, including TCM exposure, associated with adherence to HT and mortality. RESULTS: MPR to HT in general decreased over the 5-year period post breast cancer diagnosis. Both TCM and MPR to HT ≥ 80% were significantly associated with reduced risk of breast cancer-associated mortality. Subgroup analysis revealed that TCM annual visits ≥ 3 times with CHP prescription 1~90 days per year affected mortality reduction most significantly (HR: 0.26; 95% CI = 0.08-0.83; p < 0.05) compared to other TCM use. In contrast, using TCM (either short-term or long-term) was not associated with MPR in HT. CONCLUSIONS: Our results supported the potential advantage of TCM on breast cancer-associated mortality, whereas TCM use does not compromise medical adherence to HT. This study offers important insights in integrative therapy for HT in patients with estrogen receptor (+) breast cancer.

[Protective effect of Fuzheng Yanggan Mixture on drug-induced liver injury].

The model of drug-induced liver injury (DILI) induced by acetaminophen (APAP) in mice was established to investigate the anti-oxidation and anti-ferroptosis mechanisms of Fuzheng Yanggan Mixture on DILI. C57BL/6 mice were randomly divided into five groups: control group, model group, positive group, and low and high-dose Fuzheng Yanggan Mixture groups (0.12, 0.24 g·kg⁻¹). Mice were intragastrically administration with Fuzheng Yanggan Mixture (0.12, 0.24 g·kg⁻¹) once per day for 21 consecutive days, and at the same time, mice were weighted every day. The mice were injected intraperitoneally with 600 mg·kg⁻¹ of APAP to establish a mouse model of acute DILI after 16 h from the last administration of Fuzheng Yanggan Mixture. After 6 h from APAP challenge, the experimental animals were weighted and sacrificed to collect blood and liver tissue samples. And then, the effect of Fuzheng Yanggan Mixture on liver weight and the liver weight ratio of mice were examined; the content of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the serum and the level of malondialdehyde (MDA), glutathione (GSH) and nicotinamide adenine dinucleotide phosphate (NADPH) in the liver tissue were measured. Prostaglandinendoperoxide synthase 2(ptgs2) mRNA level in liver tissues was detected by Q-PCR, and protein expression levels of SLC7A11 and GPX4 in liver tissues were detected by Western blot. Moreover, HE staining, immunohistochemical assay and TUNEL staining were used to observe pathological changes of the liver tissue sections. It is found that Fuzheng Yanggan Mixture could relieve APAP-induced liver enlargement and inhibit hepatic weight ratio increase. Compared with model group, the mice in Fuzheng Yanggan Mixture groups showed decreases in the content of ALT, AST and MDA, and increases in the content of GSH and NADPH. What is more, Fuzheng Yanggan Mixture could down-regulate ptgs2 mRNA level and up-regulate SLC7A11 and GPX4 protein levels. All of the results lead to a conclusion that Fuzheng Yanggan Mixture plays a protective effect on DILI in mice, which may be associated with the inhibition of ferroptosis.

Sorafenib analogue SC-60 induces apoptosis through the SHP-1/STAT3 pathway and enhances docetaxel cytotoxicity in triple-negative breast cancer cells.

Recurrent triple-negative breast cancer (TNBC) needs new therapeutic targets. Src homology region 2 domain-containing phosphatase-1 (SHP-1) can act as a tumor suppressor by dephosphorylating oncogenic kinases. One major target of SHP-1 is STAT3, which is highly activated in TNBC. In this study, we tested a sorafenib analogue SC-60, which lacks angiokinase inhibition activity, but acts as a SHP-1 agonist, in TNBC cells. SC-60 inhibited proliferation and induced apoptosis by dephosphorylating STAT3 in both a dose- and time-dependent manner in TNBC cells (MDA-MB-231, MDA-MB-468, and HCC1937). By contrast, ectopic expression of STAT3 rescued the anticancer effect induced by SC-60. SC-60 also increased the SHP-1 activity, but this effect was inhibited when the N-SH2 domain (DN1) was deleted or with SHP-1 point mutation (D61A), implying that SHP-1 is the major target of SC-60 in TNBC. The use of SC-60 in combination with docetaxel synergized the anticancer effect induced by SC-60 through the SHP-1/STAT3 pathway in TNBC cells. Importantly, SC-60 also displayed a significant antitumor effect in an MDA-MB-468 xenograft model by modulating the SHP-1/STAT3 axis, indicating the anticancer potential of SC-60 in TNBC treatment. Targeting SHP-1/p-STAT3 and the potential combination of SHP-1 agonist with chemotherapeutic docetaxel is a feasible therapeutic strategy for TNBC.

Effects of phenolic constituents of daylily flowers on corticosterone- and glutamate-treated PC12 cells.

BACKGROUND: Daylily flowers, the flower and bud parts of Hemerocallis citrina or H. fulva, are well known as Wang-You-Cao in Chinese, meaning forget-one's sadness plant. However, the major types of active constituents responsible for the neurological effects remain unclear. This study was to examine the protective effects of hydroalcoholic extract and fractions and to identify the active fractions. METHODS: The extract of daylily flowers was separated with AB-8 resin into different fractions containing non-phenolic compounds, phenolic acid derivatives and flavonoids as determined using UPLC-DAD chromatograms. The neuroprotective activity was measured by evaluating the cell viability and lactate dehydrogenase release using PC12 cell damage models induced by corticosterone and glutamate. The neurological mechanisms were explored by determining their effect on the levels of dopamine (DA), 5-hydroxy tryptamine (5-HT), γ-aminobutyric acid (GABA), noradrenaline (NE) and acetylcholine (ACh) in the cell culture medium measured using an LC-MS/MS method. RESULTS: Pretreatment of PC12 cells with the extract and phenolic fractions of daylily flowers at concentrations ranging from 0.63 to 5 mg raw material/mL significantly reversed corticosterone- and glutamate-induced neurotoxicity in a dose-dependent manner. The fractions containing phenolic acid derivatives (0.59% w/w in the flowers) and/or flavonoids (0.60% w/w) exerted similar dose-dependent neuroprotective effect whereas the fractions with non-phenolic compounds exhibited no activity. The presence of phenolic acid derivatives in the corticosterone- and glutamate-treated PC12 cells elevated the DA level in the cell culture medium whereas flavonoids resulted in increased ACH and 5-HT levels. CONCLUSION: Phenolic acid derivatives and flavonoids were likely the active constituents of daylily flowers and they conferred a similar extent of neuroprotection, but affected the release of neurotransmitters in a different manner.

Solid lipid nanoparticles for sustained pulmonary delivery of Yuxingcao essential oil: Preparation, characterization and in vivo evaluation.

The objective of this study was to prepare solid lipid nanoparticles (SLNs) for sustained pulmonary delivery of Yuxingcao essential oil (YEO). Three YEO loaded SLNs (SLN-200, SLN-400 and SLN-800) with different particle size were prepared and separated following a high-shear homogenization technique using Compritol 888 ATO as lipid and polyvinyl alcohol as an emulsifier. The particle size, zeta potential, drug encapsulation efficiency and drug loading of the SLNs were determined to be between 171 and 812nm, -17.1 and -19.3mV, between 76.6 and 90.2% and between 2.34 and 3.12%, respectively whereas the in vitro release data showed that the SLNs led to sustained drug release up to 48h. In addition, the SLN suspensions after nebulization conferred the fine particle fractions (<5.4µm) of 67.4-75.8%. Following intratracheal administration to rats, YEO loaded SLNs not only prolonged pulmonary retention up to 24h, but also increased AUC values (15.4, 18.2 and 26.3µg/gh for SLN-200, SLN-400 and SLN-800, respectively) by 4.5-7.7 folds compared to the intratracheally dosed YEO solution and by 257-438 folds to the intravenously dosed YEO solution, respectively. The present results were the first to show that YEO loaded SLNs may sustain YEO inhalation delivery and improve local bioavailability, representing a promising inhalable carrier to attain once daily application.

Effect of total flavonoids from the seeds of Astragali complanati on natural killer cell function.

ETHNOPHARMACOLOGICAL RELEVANCE: The seeds of Astragalus complanatus R.Br. (AC), a traditional Chinese medicine, have been extensively used for clinical treatment of liver and kidney complaints and tumors for more than a thousand years. It was believed that AC is warm and sweet in the most authoritative medical book of Ancient China "Compendium of Materia Medica". Our previous studies showed that the flavonoid component from the seeds of Astragalus complanatus (FAC) is mainly an active constituent and has the hepatoprotective effect, anti-liver fibrosis, and anti-tumor and immune enhancement. AIM: The aim of this study was to investigate in vitro the regulation effect of FAC on NK cells function and possible mechanism of action. METHODS: The effect of FAC on the proliferation ability of NK-92 cells and the cytolysis of NK-92 cells to K562 and SMMC-7721 were measured by MTT assay and lactase dehydrogenase (LDH)-releasing assay, respectively. The phenotypical characterization (CD3, CD16 and CD56) and activation markers (CD25, CD69 and CD95) of NK-92 cell were detected by flow cytometry analysis. IFN-γ production of NK-92 cells stimulating by K562 cells was quantitated using ELISA. To explore the mechanism of action, mRNA and protein expressions of activating receptors (NKp30, NKp44, NKp46 and NKG2D) in NK-92 cells were detected by quantitative real-time PCR and flow cytometry analysis. RESULTS: Our results demonstrated that FAC significantly promoted the proliferation and the cytotoxicity of NK-92 cells in a dose-dependent manner by enhancing IFN-γ and increasing the expression of the activation markers CD25 and CD69. In addition, FAC had not changed the NK-92 cells phenotypical characterization, but markedly enhanced the expression intensity of CD56. Furthermore, FAC significantly enhanced mRNA and protein expressions lever of NKp44 and NKG2D in NK-92 cells. CONCLUSION: These results suggest that FAC upregulate the expressions of NKG2D, NKp44, which in turn influence NK-92 cells activation. FAC may serve as an immunostimulatory of NK cells for tumor treatment.

Pulmonary delivered polymeric micelles--pharmacokinetic evaluation and biodistribution studies.

Polymeric micelles represent interesting delivery systems for pulmonary sustained release. However, little is known about their in vivo release and translocation profile after delivery to the lungs. In the present study, curcumin acetate (CA), which is an ester prodrug of curcumin, or the mixture of CA and Nile red was encapsulated into PEG­PLGA micelles by a solvent evaporation method. The micellar formulation increased the stability of CA in water and physiologically relevant fluids and led to a sustained drug release in vitro. Following intratracheal (IT) administration to rats, CA loaded micelles achieved not only prolonged pulmonary retention with AUC values almost 400-fold higher than by IV route, but also local sustained release up to 24 h. In addition, IT delivery of micelles appeared to facilitate the uptake into the pulmonary vascular endothelium and efficiently translocate across the air­blood barrier and penetrate into the brain. Co-localization of CA and Nile red confirmed that micelles in lung and brain tissue were still intact. This study is the first to demonstrate that aerosolized PEG­PLGA micelles are a promising carrier for both pulmonary and non-invasive systemic sustained release of labile drugs.

Discovery of novel Src homology region 2 domain-containing phosphatase 1 agonists from sorafenib for the treatment of hepatocellular carcinoma.

UNLABELLED: Sorafenib is the first approved targeted therapeutic reagent for hepatocellular carcinoma (HCC). Here, we report that Src homology region 2 (SH2) domain-containing phosphatase 1 (SHP-1) is a major target of sorafenib and generates a series of sorafenib derivatives to search for potent SHP-1 agonists that may act as better anti-HCC agents than sorafenib. Sorafenib increases SHP-1 activity by direct interaction and impairs the association between the N-SH2 domain and the catalytic protein tyrosine phosphatase domain of SHP-1. Deletion of the N-SH2 domain (dN1) or point mutation (D61A) of SHP-1 abolished the effect of sorafenib on SHP-1, phosphorylated signal transducer and activator of transcription 3 (p-STAT3), and apoptosis, suggesting that sorafenib may affect SHP-1 by triggering a conformational switch relieving its autoinhibition. Molecular docking of SHP-1/sorafenib complex confirmed our findings in HCC cells. Furthermore, novel sorafenib derivatives SC-43 and SC-40 displayed more potent anti-HCC activity than sorafenib, as measured by enhanced SHP-1 activity, inhibition of p-STAT3, and induction of apoptosis. SC-43 induced substantial apoptosis in sorafenib-resistant cells and showed better survival benefits than sorafenib in orthotopic HCC tumors. CONCLUSION: In this study, we identified SHP-1 as a major target of sorafenib. SC-43 and SC-40, potent SHP-1 agonists, showed better anti-HCC effects than sorafenib in vitro and in vivo. Further clinical investigation is warranted.

New triterpenoids and other constituents from the fruits of Benincasa hispida (Thunb.) Cogn.

Benincasa hispida (Thunb.) Cogn. fruits are widely consumed in China and tropical countries. This study identifies three new triterpenoids, 3α,29-O-di-trans-cinnamoyl-D:C-friedooleana-7,9(11)-diene (1), oleanolic acid 28-O-ß-d-xylopyranosyl-[ß-d-xylopyranosyl-(1→4)]-(1→3)-α-l-rhamnopyranosyl-(1→2)-α-l-arabinopyranoside (2), and oleanolic acid 28-O-ß-d-glucopyranosyl-(1→3)-ß-d-xylopyranosyl-[ß-d-xylopyranosyl-(1→4)]-(1→3)-α-l-rhamnopyranosyl-(1→2)-α-l-arabinopyranoside (3), together with 12 known compounds, multiflorenol (4), isomultiflorenyl acetate (5), stigmasterol (6), stigmasterol 3-O-ß-d-glucopyranoside (7), α-spinasterol (8), α-spinasterol 3-O-ß-d-glucopyranoside (9), ß-sitosterol (10), daucosterol (11), arbutin (12), nicotinic acid (13), (+)-pinonesinol (14), and ethyl ß-d-glucopyranoside (15). The structures of compounds 1-15 were determined by spectroscopic and chemical methods. All the compounds with the exception of 4, 5, and 9-11 were isolated from B. hispida for the first time. The anticomplement activities of compounds 1-15 were assessed by Mayer's modified method. Compounds 1-15 showed no significant cytotoxic activity against HeLa human cervical, HL-60 human hepatoma, and SMMC-7721 human hepatoma cell lines.

[Clinical evaluation of stiletto needle for pain of knee osteoarthritis].

OBJECTIVE: To objectively evaluate the clinical efficacy of stiletto needle for pain of knee osteoarthri tis (KOA), and analyze its function mechanism. METHODS: Seventy-six cases of KOA (76 knees) were selected. Under the guide of Jingjin theory in TCM, stiletto needle was applied at pain point of Jingjin in extra-articular area to have a loose solution effect, 1 to 3 points were selected each time, 1 to 2 times of treatment were required. The results of tenderness measurement instrument was adopted as main evaluation index of joint pain, and all data of evaluation indices before and after the treatment were statistical analyzed. RESULTS: There were significant differences in visual analogue scale (VAS) score, tenderness score, HSS function score and movement range of joint before and after the treatment (all P < 0.05). The effective rate of stiletto needle therapy was 89.5%. There was apparent regression trend between VAS score and tenderness score with Y (VAS) = 7.841-1.569 X (tenderness score) as its regressive equation. CONCLUSION: The stiletto needle therapy is an effective method to relieve the pain of knee osteoarthritis, and its clinical efficacy evaluation could be more objective and digital with tenderness measurement instrument.

Oily nanosuspension for long-acting intramuscular delivery of curcumin didecanoate prodrug: preparation, characterization and in vivo evaluation.

The objective of this study was to prepare the nanocrystals of curcumin didecanoate (CurDD) by wet ball milling and to investigate the comparative pharmacokinetics of oily nano- and micro-suspensions after intramuscular (i.m.) administration to rats. Upon optimizing the wet ball milling parameters, CurDD nanocrystals were produced with median particle size of ~500 nm and the freeze-dried nanocrystals were readily dispersed in peanut oil to form stable nanosuspensions. Although the nanosuspension appeared to exhibit slower clearance from the injection site after i.m. injection, compared to microsuspension (~5 µm), a significantly higher maximum plasma curcumin concentration (69.0 ng/ml) was observed for the former than that for the latter (18.5 ng/ml). In addition, the nanosuspension provided significant higher plasma curcumin concentrations and brain CurDD contents for at least 15 days than the microsuspension, except for the initial times. A single i.m. injection of nanosuspension appeared to achieve reversal effect on reserpine-induced hypothermia for at least 13 days. This study demonstrates that CurDD nanosuspension may act as a long-acting i.m. injectable for sustained delivery of curcumin, potentially applicable to elicit a long-lasting antidepressant effect.

Identifying the relationships between water quality and land cover changes in the Tseng-Wen reservoir watershed of Taiwan.

The effects on water quality of land use and land cover changes, which are associated with human activities and natural factors, are poorly identified. Fine resolution satellite imagery provides opportunities for land cover monitoring and assessment. The multiple satellite images after typhoon events collected from 2001 to 2010 covering land areas and land cover conditions are evaluated by the Normalized Difference Vegetation Index (NDVI). The relationship between land cover and observed water quality, such as suspended solids (SS) and nitrate-nitrogens (NO(3)-N), are explored in the study area. Results show that the long-term variations in water quality are explained by NDVI data in the reservoir buffer zones. Suspended solid and nitrate concentrations are related to average NDVI values on multiple spatial scales. Annual NO(3)-N concentrations are positively correlated with an average NDVI with a 1 km reservoir buffer area, and the SS after typhoon events associated with landslides are negatively correlated with the average NDVI in the entire watershed. This study provides an approach for assessing the influences of land cover on variations in water quality.

Sorafenib and its derivative SC-49 sensitize hepatocellular carcinoma cells to CS-1008, a humanized anti-TNFRSF10B (DR5) antibody.

BACKGROUND AND PURPOSE: Previously, we have shown that sorafenib sensitizes hepatocellular carcinoma (HCC) to apoptosis induced by TNF-related apoptosis-inducing ligand (TNFSF10; TRAIL). Here, we report that sorafenib and SC-49 sensitize HCC cells to CS-1008, a novel anti-human death receptor 5 (TNFRSF10B) antibody. EXPERIMENTAL APPROACH: HCC cell lines (PLC5, Huh-7, and Hep3B) were treated with CS-1008 and/or sorafenib and analysed in terms of apoptosis and signal transductions. KEY RESULTS: SC-49 is a sorafenib derivative, which is devoid of kinase inhibitory activity. Both sorafenib and SC-49 down-regulated the phosphorylation of STAT3 at Tyr(705) and subsequently reduced the levels of STAT3-regulated proteins, Mcl-1, survivin and cylcin D1, in CS-1008-treated HCC cells. Knockdown of STAT3 by RNA interference overcame apoptotic resistance to CS-1008 in HCC cells, and ectopic expression of STAT3 in HCC cells abolished the sensitizing effects of sorafenib and SC-49 on CS-1008-induced apoptosis, indicating that inhibition of STAT3 mediates the enhancing effects of these compounds when combined with CS-1008. Importantly, inhibition of SHP-1 by adding a specific SHP-1 inhibitor reduced the effects of SC-49 and CS-1008 on p-STAT3 and apoptosis, whereas co-treatment of CS-1008 with SC-49 increased the activity of SHP-1. These data indicate that the combined effects of CS-1008 and SC-49 on HCC are mediated by SHP-1. Moreover, the combination of CS-1008 and SC-49 inhibited HCC xenograft tumour growth in vivo. CONCLUSIONS AND IMPLICATIONS: Sorafenib and its derivative SC-49 sensitize HCC cells to the antitumour effects of CS-1008 through SHP-1-dependent inactivation of STAT3.

Gene expression-based chemical genomics identifies heat-shock protein 90 inhibitors as potential therapeutic drugs in cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma (CCA) is an aggressive tumor with a poor prognosis. There is no standard therapy for CCA, and novel drugs for treating refractory CCA need to be identified. METHODS: The authors hypothesized that, if a drug could reverse the gene expression signature of CCA, then it may inhibit the carcinogenesis of CCA and, hence, would be a potential therapeutic agent. Thus, the gene expression signatures from patients with CCA were queried using the bioinformatic method Connectivity Map, resulting in the enrichment of heat-shock protein 90 (HSP90) inhibitors with therapeutic potentials. RESULTS: Two HSP90 inhibitors, 17-AAG (tanespimycin) and the synthetic diarylisoxazole amide resorcinol NVP-AUY922, demonstrated potent antiproliferative activity in in vitro studies. In a thioacetamide-induced animal model, NVP-AUY922 also had antitumor activity and resulted in objective tumor regression. In addition, NVP-AUY922 reduced the expression of client oncoproteins involved in CCA oncogenesis and inhibited downstream proteins of both the phosphatidylinositol 3-kinase catalytic subunit α/v-akt murine thymoma viral oncogene homolog 1 protein kinase (PIK3/AKT) pathway and the v-Ki-ras2 Kirsten rat sarcoma viral oncogene/mitogen-activated protein kinase (KRAS/MAPK) pathway. CONCLUSIONS: Preclinical data from the current study suggest that NVP-AUY922 may be an effective treatment option for patients with CCA.

Preparation and in vitro aerosol performance of spray-dried Shuang-Huang-Lian corrugated particles in carrier-based dry powder inhalers.

The development of dry powder inhalation (DPI) products of traditional Chinese medicine (TCM) remains to be a challenge due to chemical complexity and batch-to-batch variations in constituent composition. This study was to investigate the feasibility of using spray-dried corrugated particles to improve the aerodynamic performance of a TCM, Shuang-Huang-Lian (SHL), in carrier-based DPI. Particles with different surface roughness were spray-dried by the addition of leucine and concomitant manipulation of spray-drying parameters. The surface roughness was determined by atomic force microscopy, whilst the aerodynamic performance of drug particle-mannitol/lactose blends was evaluated using a next-generation pharmaceutical impactor through a Cyclohaler. Although the emission efficiency for corrugated particle-based DPI was ~10% lower than that for smooth SHL, the fine particle fractions (FPF(<4.4 µm)) of 32.4-36.8% for the former were significantly higher than those of 14.7-16.2% for the latter. In particular, the FPF and fraction of drug detached from the carrier appeared not to be significantly affected by the variation in constituent composition of SHL. This study demonstrates that the use of corrugated particles in carrier-based DPI improved aerosol performance by facilitating drug detachment from the carrier, independent of variation in constituent composition, and such particles were potentially applicable to the development of SHL DPI products.

Evaluating pulmonary toxicity of Shuang-Huang-Lian in vitro and in vivo.

UNLABELLED: ETHNOPHARMAOCOLOGICAL RELEVANCE: Shuang-Huang-Lian (SHL) is a traditional Chinese formula and has been used for the treatment of respiratory tract infections by inhalation. However, the pulmonary toxicity via inhalation is largely uninvestigated. AIM OF STUDY: To evaluate the pulmonary toxicity of SHL following in vivo intratracheal spray to rats and in vitro exposures to A549 and Calu-3 cells. METHODS: Calu-3 and A549 cells were exposed to SHL, chlorogenic acid, baicalin and forsythin solutions and in vitro cytotoxicity was evaluated using an MTT assay, whilst rats were subjected to intratracheal administration of SHL solutions and in vivo toxicity was indicated by assaying the LDH activity and total protein content in bronchoalveolar lavage fluid (BALF) and observing the histopathologic changes of the lungs. Secretion of inflammatory mediators, including IL-6, IL-8 and TNF-α, in cell culture media and BALF was quantified by ELISA. RESULTS: The MTT cell viability data revealed the presence of minor toxicity to Calu-3 or A549 cells following exposure to SHL and its major ingredients for 24h or 48 h. However, the cell cultural media showed no sign of inflammatory responses. The in vivo results showed that exposures to SHL at doses of up to 50mg/kg did not significantly increase the total protein content, the LDH activity and the concentrations of IL-6, IL-8 and TNF-α in BALF. However, although intratracheal sprayed SHL at doses of up to 6 mg/kg for histopathologic study and up to 25mg/kg for cell counts showed no sign of adverse effects, inhaled SHL at elevated doses appeared to induce alveolar fusion in the lung and significant increases in the cell number of monocytes and granulocytes in the BALF. CONCLUSION: The results demonstrated that the pulmonary safety of inhaled SHL was dependent on the administered dose. Inhalation therapy of SHL may be safely used when the inhaled dose was properly controlled.

Protective effect of flavonoids from Astragalus complanatus on radiation induced damages in mice.

This study aimed to evaluate the radioprotective effect of flavonoids extracted from the seeds of Astragalus complanatus R.Br. (FAC) and their protective mechanism against radiation damage. FAC increased the survival rate of mice and made the damaged organ injured by (60)Co γ-irradiation recovered to normal appearance with the mechanism of enhancing immune function and blood-producing function in vivo. The molecule mechanism of FAC against radiation is involved in the reduction of DNA injury and mutation in vitro. Eleven monomers of the FAC were analyzed by HPLC. These results seem to support the use of FAC in relieving radiation damage.