FGF2 positively regulates osteoclastogenesis via activating the ERK-CREB pathway.

Fibroblast growth factor 2 (FGF2) plays crucial roles in the growth and development of several tissues. However, its function in bone homeostasis remains controversial. Here, we found that exogenous FGF2 supplementation inhibited the mineralization of bone marrow stromal cells (BMSCs), at least partially, via up-regulating the gene expression of osteoclastogenesis. The FGF receptor (FGFR) allosteric antagonist SSR128129E modestly, whereas the FGFR tyrosine kinase inhibitor AZD4547 significantly antagonized the effects of FGF2. Mechanistically, FGF2 stimulated ERK phosphorylation, and the ERK signaling inhibitor PD325901 strongly blocked FGF2 enhancement of osteoclastogenesis. Moreover, the phosphorylation of CREB was also activated in response to FGF2, thereby potentiating the interaction of p-CREB with the promoter region of Rankl gene. Notably, FGF2-deficient BMSCs exhibited higher mineralization capability and lower osteoclastogenic gene expression. Correspondingly, FGF2-knockout mice showed increased bone mass and attenuated expression of osteoclast-related markers, which were associated with moderate inhibition of the ERK signaling. In conclusion, FGF2 positively regulates osteoclastogenesis via stimulating the ERK-CREB pathway. These findings establish the importance of FGF2 in bone homeostasis, hinting the potential use of FGF2/ERK/CREB specific inhibitors to fight against bone-related disorders, such as osteoporosis.

Selenium-enriched Bacillus subtilis yb-114246 improved growth and immunity of broiler chickens through modified ileal bacterial composition.

Here, a Selenium-enriched Bacillus subtilis (SEBS) strain was generated and supplemented to broiler chickens' diet, and the impact in ileum bacterial microbiome, immunity and body weight were assessed. In a nutshell, five hundred 1-old old chicken were randomly divided into five groups: control, inorganic Se, Bacillus subtilis (B. subtilis), SEBS, and antibiotic, and colonization with B. subtilis and SEBS in the gastrointestinal tract (GIT) were measured by fluorescence in situ hybridization (FISH) assay and quantitative real-time polymerase chain reaction (qPCR). In summary, Chicks fed SEBS or B. subtilis had higher body weight than the control chicks or those given inorganic Se. SEBS colonized in distal segments of the ileum improved bacterial diversity, reduced the endogenous pathogen burden and increased the number of Lactobacillus sp. in the ileal mucous membrane. Species of unclassified Lachnospiraceae, uncultured Anaerosporobacter, Peptococcus, Lactobacillus salivarius, and Ruminococcaceae_UCG-014, and unclassified Butyricicoccus in the ileal mucous membrane played a key role in promoting immunity. Inorganic Se supplementation also improved bacterial composition of ileal mucous membranes, but to a less extent. In conclusion, SEBS improved performance and immunity of broiler chickens through colonization and modulation of the ileal mucous membrane microbiome.

Percutaneous thermal ablation combined with simultaneous transarterial chemoembolization for hepatocellular carcinoma ≤5 cm.

BACKGROUND/AIM: Percutaneous thermal ablation combined with transarterial chemoembolization (TACE) becomes a treatment option for unresectable hepatocellular carcinoma (HCC). This study aims to investigate the safety and feasibility of percutaneous thermal ablation combined with simultaneous TACE for patients with HCC ≤ 5 cm. MATERIALS AND METHODS: From June 2010 to February 2017, a total of 280 patients with HCC ≤ 5 cm who underwent percutaneous thermal ablation combined with simultaneous TACE were included in our study. Their clinical data were collected and analyzed. RESULTS: Major complications occurred in five cases (1.8%). The complete necrosis rate was 91.9%. The median overall survival (OS) was 66.5 months (95% confidence interval [CI] = 57.7-75.2). The OS rates in 1-, 3-, 5-, and 7-year were 96.7%, 76.0%, 59.7%, and 31.1%, respectively. Tumor size (hazard ratio = 1.826; 95% CI = 1.131-2.947; P = 0.014) was considered as independent prognostic factors of long-term survival. CONCLUSION: Percutaneous thermal ablation combined with simultaneous TACE is a safe and effective treatment for HCC ≤ 5 cm.

Combined endovascular brachytherapy, sorafenib, and transarterial chemobolization therapy for hepatocellular carcinoma patients with portal vein tumor thrombus.

AIM: To evaluate the safety and efficacy of combined endovascular brachytherapy (EVBT), transarterial chemoembolization (TACE), and sorafenib to treat hepatocellular carcinoma (HCC) patients with main portal vein tumor thrombus (MPVTT). METHODS: This single-center retrospective study involved 68 patients with unresectable HCC or those who were unfit for liver transplantation and percutaneous frequency ablation according to the BCLC classification. All patients had Child-Pugh classification grade A or B, Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and MPVTT. The patients received either EVBT with stent placement, TACE, and sorafenib (group A, n = 37), or TACE with sorafenib (group B, n = 31). The time to progression (TTP) and overall survival (OS) were evaluated by propensity score analysis. RESULTS: In the entire cohort, the 6-, 12-, and 24-mo survival rates were 88.9%, 54.3%, and 14.1% in group A, and 45.8%, 0%, and 0% in group B, respectively (P < 0.001). The median TTP and OS were significantly longer in group A than group B (TTP: 9.0 mo vs 3.4 mo, P < 0.001; OS: 12.3 mo vs 5.2 mo, P < 0.001). In the propensity score-matched cohort, the median OS was longer in group A than in group B (10.3 mo vs 6.0 mo, P < 0.001). Similarly, the median TTP was longer in group A than in group B (9.0 mo vs 3.4 mo, P < 0.001). Multivariate Cox analysis revealed that the EVBT combined with stent placement, TACE, and sorafenib strategy was an independent predictor of favorable OS (HR = 0.18, P < 0.001). CONCLUSION: EVBT combined with stent placement, TACE, and sorafenib might be a safe and effective palliative treatment option for MPVTT.

Isolation, Structure Elucidation, and Absolute Configuration of Highly Oxygenated Germacranolides from Carpesium cernuum.

The new highly oxygenated germacranolides cernuumolides A-J (1-10) and the known compounds 11-20 were isolated from Carpesium cernuum. Among these compounds, 1-4 are 11-methoxymethylgermacranolides and 5-7 as well as 11-17 are 2,9-hemiacetal-linked germacranolides. Their structures were elucidated using NMR and HRESIMS analyses, and X-ray diffraction studies were used to confirm the absolute configurations of 1, 2, 5, 6, 8, and 9. Cernuumolides A-J were evaluated for their in vitro cytotoxicity against the A549, HCT116, MDA-MB-231, and BEL7404 cell lines, and 8 exhibited moderate cytotoxicity with IC50 values in the 0.87-2.02 µM range.

Gleditsia species: An ethnomedical, phytochemical and pharmacological review.

ETHNOPHARMACOLOGICAL RELEVANCE: The plants in the genus Gleditsia, mainly distributed in central and Southeast Asia and North and South America, have been used as local and traditional medicines in many regions, especially in China, for the treatment of measles, indigestion, whooping, smallpox, arthrolithiasis, constipation, diarrhea, hematochezia, dysentery, carbuncle, etc. This present paper systemically reviews the miscellaneous information surrounding its traditional use, phytochemistry and pharmacology to provide opportunities and recommendations for the future research. MATERIALS AND METHODS: The scientific literatures were systematically searched from scientific databases (PubMed, Scopus, Elsevier, SpringerLink, SciFinder, Google Scholar and others). In addition, the ethnopharmacological information on this genus was mainly acquired from Chinese and Korean herbal classics, and library catalogs. RESULTS: More than 60 compounds including triterpenes, sterols, flavonoids, alkaloids, phenolics and their derivatives were isolated from Gleditsia japonica Miq., Gleditsia sinensis Lam., Gleditsia caspica Desf. and Gleditsia triacanthos L. Among these compounds, triterpenoid saponins were the main constituents of Gleditsia species. Moreover, the crude extracts and purified molecules were tested, revealing diverse biological activities such as anti-tumor, anti-inflammatory, anti-allergic, anti-hyperlipidemic, analgesic, antimutagenic, antioxidant, anti-HIV, antibacterial, antifungal activities, etc. Among these biological studies, the possible mechanisms of antitumor action are stressed in this review, and these include causing cytotoxicity to cancer cells, inhibition of proliferation of cancer cells by affecting their growth, regeneration and apoptosis, inhibition of basic fibroblast growth factor (bFGF) and nitric oxide (NO), modulation of the oncogenic expression and telomerase activity results, inhibition of the expression of pro-angiogenic proteins, as well as down-regulation of intra/extracellular proangiogenic modulators, etc. CONCLUSIONS: On the basis of preliminary research on Gleditsia genus it could be stated that saponins investigations may be more promising in future. Although 32 compounds of 67 identified compounds were saponins, modern pharmacological research on saponins were not a priority in Gleditsia species. Therefore, more bioactive experiments and in-depth mechanisms of action are required for elucidating their roles in physiological systems. Moreover, the present review also highlights that analgesic, anti-tumor and anti-HIV activities should have priority in saponins research. Additionally, it is imperative to explore more structure-activity relationships and possible synergistic actions of triterpenoid saponins for revaluating their pharmacological activities.

The genus Carpesium: a review of its ethnopharmacology, phytochemistry and pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE: The plants in the genus Carpesium, which grow naturally in Asia and Europe, have long been used in traditional Chinese, Korean and Japanese medicines. The antipyretic, antimalarial, haemostatic, anti-inflammatory and detoxifying properties of their extracts enabled their use in the treatment of several diseases, such as fevers, colds, contusions, diarrhoea, mastitis, mumps, hepatitis, malaria, etc. This review summarises the state-of-the-art and comprehensive information surrounding its use as traditional medicine, phytochemistry, pharmacology, and toxicology to reveal the potential therapeutic effects of Carpesium plants and to establish a solid foundation for directing future research. MATERIALS AND METHODS: The extensive reading and investigation were actualised by systematically searching the scientific literatures including Chinese, Korean and Japanese herbal classics, library catalogs and scientific databases (PubMed, Scopus, SciFinder and the Web of Science), were systematically searched for topics related to factors like the chemical constituents, pharmacognostic research and pharmacological effects of the Carpesium species. RESULTS: Carpesium plants have been studied extensively as traditional folk medicines in China, Korea and Japan all the time. In past, phytochemical research was the focal point of this genus, and the recent studies of the members of this genus have been focused on the pharmacological activity and potential therapeutic applications of these plants. The research performed revealed that 143 compounds including sesquiterpenoid lactone monomers, sesquiterpenoid lactone dimers, monoterpenes, diterpenoids, phenolic compounds, and several other type of compounds, were isolated and identified within this genus in recent years, and certain of these constituents had demonstrated to possess anti-inflammatory, anti-tumor, anti-plasmodial, anti-oxidant, anti-fungal and anti-bacterial effects. CONCLUSIONS: This review shows that approximately 50 active compounds possess therapeutic potential during the treatment of cancer, inflammatory, parasitosis, etc. However, apart from those bioactive molecules, a considerable part of compounds, including a lot of sesquiterpenes, and several other type of compounds that have been previously isolated but have not been tested biologically need to be further tested. Therefore, more pharmacological experiments should be focused on these untested chemical constituents. Additionally, another issue concerns that most pharmacological studies were only performed in vitro-based experiments, so additional in vivo tests in animal models are required to estimate their side effects for the safety approval of therapeutic applications. Finally, further studies through well controlled, double-blind clinical trials are required to re-evaluate their efficacious and possible side effects, and more pharmacological mechanisms on main active compounds will also be needed for illuminating correlations between ehnopharmacology and pharmacology in future.

Immune-enhancing activity of polysaccharides from Cyrtomium macrophyllum.

The goal of the present study was to investigate the immune-enhancing activity of polysaccharides from Cyrtomium macrophyllum (CMP). Two experiments were carried out. In immunosuppression experiment, the immune-enhancing effect of CMP in immunosuppressive mice was performed. The results showed that CMP at high and medium doses was able to overcome the CY-induced immunosuppression, significantly increases the thymus and spleen indices, enhances lymphocyte proliferation activity and macrophage function, improves immunoglobulin and cytokines levels compared with negative control group. In macrophage immunomodulatory experiment, the immune-enhancing effect of CMP in RAW264.7 cells was measured. The results showed that CMP induced the elevation of NO production, TNF-α secretion and iNOS protein of RAW264.7 cells. CMP can also strongly increase NF-κB levels in nuclear, which is an important transcription factor that can modulate expressions of iNOS, NO and TNF-α. Therefore, the CMP could be an effective immunomodulatory agent.

Acylated iridoids from the roots of Valeriana officinalis var. latifolia.

Phytochemical investigation of the roots of Valeriana officinalis var. latifolia resulted in the isolation and characterization of six new acylated iridoids, (5S,7S,8S,9S)-7-hydroxy-8-isovaleroyloxy-Δ4,¹¹-dihyronepetalactone (1), (5S,7S,8S,9S)-7-hydroxy-10-isovaleroyloxy-Δ4,¹¹-dihyronepetalactone (2), (5S,8S,9S)-10-isovaleroyloxy-Δ4,¹¹-dihyronepetalactone (3), (5S,6S,8S,9R)-6-isovaleroyloxy-Δ4,¹¹-1,3-diol (4), (5S,6S,8S,9R)-1,3-isovaleroxy-Δ4,11-1,3-diol (5), and (5S,6S,8S,9R)-3-isovaleroxy-6-isovaleroyloxy-Δ4,¹¹-1,3-diol (6). Their structures were determined mainly by 1D and 2D NMR spectroscopic techniques. We also report herein for the first time the single crystal X-ray structure of compound 1. In addition, the cytotoxic activities of compounds 1-6 were evaluated against A549 (human lung adenocarcinoma), HCT116 (human colon carcinoma), SK-BR-3 (human breast carcinoma), and HepG2 (human hepatoma) cell lines. Compound 6 showed weak cell growth inhibition of A549, HCT116, SK-BR-3, and HepG2 cells.

Hepatic arterial infusion with oxaliplatin, irinotecan and doxifluridine for unresectable liver metastases of colorectal cancer.

AIM: To evaluate the therapeutic efficacy and safety of combination chemotherapy with oxaliplatin, irinotecan and doxifluridine through hepatic arterial infusion (HAI) in patients with unresectable liver metastases of colorectal cancer. PATIENTS AND METHODS: Individual patients were treated through the tumour-blood supplying arteries with oxaliplatin, irinotecan and doxifluridine and chemoembolised with irinotecan and lipiodol for the detected hypervascular lesions. RESULTS: A total of 173 cumulative cycles of chemotherapy were performed for the 32 patients, with a median of 5.0 cycles, including 96 chemoembolisations. Fifteen patients reached partial remission, 14 patients had stable disease and only 3 patients had progressive disease. The overall response rate was 46.9%. Of the 32 patients, 18 patients received first-line treatment with an overall response rate of 61.1%. The remaining 14 patients received second-line treatment, with an overall response rate of 28.6%. CONCLUSION: Combination chemotherapy through HAI is well tolerated and highly effective in patients with unresectable liver metastases of colorectal cancer.

[Features of blood supply and results of transarterial infusion and embolization in spinal metastases].

OBJECTIVE: To study the features of blood supply and results of transarterial infusion and embolization in spinal metastases. METHODS: Forty-one patients with spinal metastasis received transarterial infusion and embolization between March 2001 and June 2008. The inclusion criteria were: The metastatic lesion caused back pain; The metastatic lesion involved vertebra at or below T3 level. There were 29 males and 12 females with a mean age of 56.0 (33 - 71) years. Epirubicin was used as the chemotherapeutic agent. Lipoid Ultra-Fluid, Contour SE or gelfoam particles were used as embolitic material. RESULTS: The technical success of therapy was achieved in 52 vertebrae (100%) including 14 thoracic, 35 lumbar and 3 sacral vertebrae. 105 arteries were used for infusion and embolization (16 intercostal arteries, 78 lumbar arteries, 4 iliolumbar arteries, 4 branches of iliac arteries, and 3 median sacral arteries). Lipoid Ultra-Fluid (2 - 8 ml) was used in 15, Contour SE (300 approximately 500 microm, 20 - 100 mg) in 20, and gelfoam particles in 33 arteries. Three days after treatment, complete pain relief (CR) was achieved in 17 patients, partial pain relief (PR) in 20, and moderate pain relief (MR) in 4, with an effective rate of 90.2%. Two weeks after treatment, CR was achieved in 17 patients, PR in 21, and MR in 3, with an effective rate of 92.7%. No adverse nervous system effect occurred. 16 patients developed swelling and pain of normal tissues which were alleviated after symptomatic treatment. CONCLUSION: Transarterial infusion and embolization is an effective therapy in relieving pain resulting from spinal metastases.

[Epirubicin in the treatment of malignant obstructive jaundice].

OBJECTIVE: To evaluate the safety and efficiency of epirubicin in the treatment of malignant obstructive jaundice (MOJ). METHODS: Thirty-nine patients with diagnosis of MOJ, whose serum total bilirubin (TB) had not dropped to normal level after stent placement or percutaneous transhepatic biliary drainage, received trans-arterial chemoembolization (TACE). During TACE, epirubicin emulsion containing pharmorubicin at dose of 30 mg/m(2) was used. The toxicity and hepatic injury was observed according to WHO anticancer drug toxicity criterion and Child-Pugh classification criterion, respectively. The time of jaundice recurrence and survival were also observed during follow-up. RESULTS: Median total serum bilirubin in 39 patients was 72.7 micromol/L (range: 52.1 - 91.4 micromol/L) before TACE. The dose of pharmorubicin was 40 - 60 mg with a median of 55.0 mg and the amount of lipiodol was 2 - 25 ml. Decrease in white blood cell count was observed: grade I in 41.0% of patients, grade II in 35.9% and grade III - IV in 15.4%. Grade III - IV nausea and vomiting developed in 100% of the patients. Hepatic injury became aggravated in 8 from A to B class patients, in one from A to C class, and in 3 from B to C class according to Child-Pugh classification criterion. No cardiac toxicity was observed in this series. The median survival time was 6.0 months with a range of 2 to 72 months. Jaundice recurred in 19 patients (48.7%) with a medium jaundice recurrence time of 9.0 months (range: 2 - 20 months). CONCLUSION: Epirubicin-lipiodol emulsion at a dose of 30 mg/m(2) is safe and efficient in the management of patients with malignant obstructive jaundice with total serum bilirubin between 51 and 100 micromol/L after biliary drainage.