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BACKGROUND Vascular injury initiates rapid platelet activation which is critical for hemostasis, while it also cause fatal thrombotic diseases, such as myocardial infarction or ischemic stroke. OBJECTIVES To study the inhibitory effects and underlying mechanisms of XJ-8, a natural compound isolated from Sanguis draxonis, on platelet activation and thrombosis. METHODS The regulatory effects of XJ-8 on the dense granule release, thromboxane A2 synthesis, α-granule release, activation of integrin αIIbβ3, and aggregation of platelets induced by multiple agonists were investigated in in vitro experiments. The effects of XJ-8 on bleeding time and FeCl3 -induced carotid artery thrombosis were also evaluated in in vivo experiments. Furthermore, we investigated the underlying mechanisms by which XJ-8 exerted its pharmacological effects. RESULTS XJ-8 not only significantly inhibited the dense granule release, thromboxane A2 synthesis, and aggregation of platelets induced by multiple agonists, but also exerted extending effects on bleeding time and therapeutic effects on thrombotic disease. In addition, XJ-8 selectively and moderately inhibited the activity of mitogen-activated protein kinase kinase kinase 3 (MAP3K3) and the activation of signaling pathways downstream MAP3K3, which play important roles in platelet activation. CONCLUSION XJ-8 can inhibit platelet function and thrombosis by targeting MAP3K3, and has potential to be developed into a novel therapeutic agent for the treatment of thrombotic diseases.

Four new chalchonoid trimers, named cochinchinenins N–Q (1–4), along with a pair of known enantiomers (5–6), were isolated from the total phenolic extract of Chinese dragon's blood (the red resin of Dracaena cochinchinensis). The planar structures of 1–4 were elucidated by extensive spectroscopic analysis including HRESIMS and 1D/2D NMR. The absolute configurations of new compounds were established by ECD data. Compound 1 exhibited significant inhibition of nitric oxide production in lipopolysaccharide-stimulated BV-2 microglial cells with IC50 value of 11.5 ± 1.7 μM.

Two new diterpenoids, penicichrysogene A (

To explore the method for inducing the differentiation of bone marrow cells into megakaryocytes in vitro so as to use for evaluating the activity of traditional Chinese medicines.The bone marrow cells were separated from femurs and tibias of mice. The experiments were divided into 4 groups: control (no adding cytokines), TPO (adding 50 ng/ml TPO), TPO+SCF (50 ng/ml+50 ng/ml) and TPO+SCF+IL-6+IL-9 (50 ng/ml+50 ng/ml+20 ng/ml+20 ng/ml). The bone marrow cells in 4 groups were cultured in vitro for 6 d. Then the cell growth status was observed by the inverted microscopy, and the cell count was detected by using the automatic cell counter. The ratio and absolute count of megakaryocytes were detected by flow cytometry.Compared with control, three induction methods could stimulate the differentiation of bone marrow cells into megakaryocytes in vitro. TPO could slightly enhance the differentiation of bone marrow cells into megakaryocytes. Both the combination of TPO and SCF, and the combination of TPO, SCF, IL-6 and IL-9 could intensively stimulate proliferation of bone morrow cells and promote the differentiation of bone marrow cells into megakaryocytes. The addition of IL-6 and IL-9 could decrease the proliferation of non-megakaryocytes, but promote the differentiation of bone marrow cells into megakaryocytes.The optimized differentiation of bone marrow cells into megakaryocytes has been completed by co-induction regimen of TPO, SCF, IL-6 and IL-9, which can be used to screen and evaluate traditional Chinese medicines promoting formation of platelets.体外诱导骨髓细胞分化成巨核细胞的方法学研究.探讨体外将小鼠骨髓细胞诱导分化为巨核细胞的方案,用于中药活性评价.从小鼠股骨和胫骨取骨髓细胞，在血小板生成素（TPO）及TPO和干细胞因子（SCF）或TPO、SCF、白介素-6（IL-6）和白介素-9（IL-9）联合诱导下，体外培养6 d。然后用倒置显微镜观察培养体系中的细胞生长情况，自动细胞计数仪检测细胞数量，流式细胞术分析培养体系中巨核细胞比例，并计算巨核细胞绝对数量.单因子或多因子联合诱导方法均能体外促进骨髓细胞分化成巨核细胞，TPO轻微促进骨髓细胞分化成巨核细胞，TPO和SCF联合及TPO、SCF、IL-6和IL-9联合均显著促进骨髓细胞增殖和分化成巨核细胞，添加IL-6和IL-9可促进骨髓细胞分化成巨核细胞，减少非巨核细胞增殖.TPO、SCF、IL-6和IL-9联合具有最强的促进骨髓细胞分化为巨核细胞的作用，可以用于促血小板形成中药活性筛选和评价.

Four new diterpenoids including one cis clerodane-type (1) and three highly oxygenated labdane-type diterpenes (2–4) were isolated from the aerial parts of Leonurus macranthus. Their structures were elucidated on the basis of spectroscopic data (NMR, UV, IR, and MS). Compound 1 represents the first example of cis clerodane-type diterpene in the plants of Leonurus genus. Compounds 1 and 4 exhibited weak inhibition of nitric oxide production in lipopolysaccharide-stimulated BV-2 microglial cells with IC50 values of 35.8 ± 3.6 μmol/L and 48.6 ± 4.8 μmol/L, respectively

High voltage circuit-breakers with superior performance are demanded as the transmission distance extends and voltage rises, which are often subject to high current and voltage surges. Commercial circuit-breaker contacts are conventionally manufactured with CuW alloy by infiltration method, limiting their performance improvement in withstanding current (or voltage) and lifespan. In this paper, we optimize the microstructure and component of Al2O3 reinforced Cu@W80 composites (Al2O3/Cu@W80), which fabricates the Cu@W powder first by chemical coating and the composites by spark plasma sintering (SPS) method. The composites exhibit enhanced hardness (maximum value up to 273 HV) due to the addition of Al2O3 powder and a more homogeneous and refined tungsten phase compared to the CuW counterpart. Moreover, the dispersed Al2O3 particles with low work function become the preferred ablation phase and guide the electrical arcs, further improving the anti-arc erosion performance of Al2O3/Cu@W80. Our findings suggest that the Al2O3/Cu@W80 composite with optimized components could be potentially used as a candidate for high-voltage circuit-breaker contacts.

In this paper, the characteristics of NOx reduction by reagent injection into the fuel-rich zone (RIFR) in coal combustion were investigated, under high temperatures and reducing atmosphere conditions. The stoichiometry and temperature have a major influence on the chemistry of NO and NH3 reagent (ammonia or urea). Therefore, experiments were conducted on a bench-scale test system with urea solution as the reagent to investigate the key factors influencing NOx reduction, including primary stoichiometric ratio (SR1), temperature in the reaction zone, and normalized stoichiometric ratio (NSR) of the injected reagent. The results indicated that the primary stoichiometric ratio SR1 was the key parameter affecting the reduction of NOx emissions. Better NOx reduction was achieved with a decrease in the SR1 for bare air staging. However, there was no benefit for NOx reduction by reagent injection in the very fuel-rich zone (SR1 ≤ 0.75), which depended on the distribution of N-intermediates and initial NO concent...

Ethnopharmacological relevance Ilex asprella (Hook. et Arn.) Champ. ex Benth. (IA) is a representative medicinal plant from the South of the Five Ridges of China. Its roots (RIA) and stems (SIA) have been traditionally used for the inflammation-related diseases, such as acute and chronic pharyngitis, cough, and sore throats. Aim of the study To evaluate the in vivo anti-inflammatory effects of IA extracts to provide evidence for its traditional use and to enhance the knowledge of the medicinal properties of IA. Materials and methods Models of xylene-induced ear edema in mice and carrageenan-induced paw edema in rats were used for the pharmacological evaluations. The mice were randomly divided into eight groups (n = 10 per group): a model group, a positive control group [dexamethasone (Dex), 10 mg/kg, intragastrically (i.g.)], RIA aqueous extract groups with three dosages (30, 15, and 7.5 mg/kg, i.g.), and SIA aqueous extract groups with three dosages (60, 30, and 15 mg/kg, i.g.). The rats were randomly divided into eight groups (n = 6 per group): a model group, a positive control group [acetylsalicylic acid (ASA), 300 mg/kg, i.g.], RIA groups with three dosages (80, 40, and 20 mg/kg, i.g.) and SIA aqueous extract groups with three dosages (160, 80, and 40 mg/kg, i.g.). Histological examinations of the ear and paw tissues were observed by hematoxylin-eosin (HE) staining, and neutrophil elastase levels were assessed in ear tissues by immunohistochemical analysis. Serum levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) were measured by ELISAs, and expression levels of TNF-α, IL-6, and IL-1β in rat paw tissues were measured by RT-PCR. The signal transduction proteins p65, IκBα, Janus kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3), p38 mitogen-activated protein kinases (p38), extracellular regulated protein kinases (ERK1/2), and c-Jun N-terminal kinase (JNK) in the rat paw tissues were investigated by western blot analyses. RIA and SIA were characterized by HPLC and LC-MS analyses, and the components were confirmed by comparison with isolated compounds. Results Intragastric administration with RIA (30 mg/kg) and SIA (60, 30 mg/kg) significantly mitigated ear edema in mice. RIA administration at 80 and 40 mg/kg reduced paw edema in rats 2‒3 h after injection. SIA administration with 160 mg/kg inhibited paw edema in rats after the injection of carrageenan for 1‒4 h, and SIA administration at 80 mg/kg inhibited paw edema after the injection of carrageenan for 2‒4 h. Meanwhile, RIA (80, 40 mg/kg) and SIA (160, 80 mg/kg) reduced inflammatory cell infiltration in the ear and paw tissues and infiltration of neutrophil leukocytes in rat paw tissues. RIA (80, 40, and 20 mg/kg) and SIA (160, 80, and 40 mg/kg) notably inhibited the increases of TNF-α, IL-6 and IL-1β in the serum and mRNA expression in the rat paw tissues. RIA (80, 40 mg/kg) and SIA (160, 80 mg/kg) reduced the p-p65/p-IκBα, p-JAK2/p-STAT3, and p-p38/p-ERK1/2/p-JNK levels in the pathological tissues of the animals. Phenolic acids and triterpenoids likely contributed to the anti-inflammatory activity. Conclusions Both RIA and SIA aqueous extracts showed anti-inflammatory effects in vivo in a dose-independent manner (20‒80 and 40‒160 mg/kg, respectively). The underlying mechanisms are mediated by inhibiting the pro-inflammatory cytokines TNF-α, IL-6, and IL-1β via regulation of the NF-κB, JAK2/STAT3, and MAPK signaling pathways. The present results provided pharmacological evidence that stems are alternative medicinal parts of IA but function at different doses. Additionally, this study supports the use of IA as an anti-inflammatory herbal medicine.

Twelve new polyketides, penicichrysogenins A-L (1-10, 11a, and 11b) along with five known compounds (12a, 12b, and 13-15) were isolated from the solid substrate fermentation cultures of a Huperzia serrata endophytic fungus Penicillium chrysogenum MT-12. The structures of the new compounds were established using extensive spectroscopic (1D and 2D NMR, IR, and HRESIMS) and calculated electronic circular dichroism (ECD) methods. Compounds 11a/11b and 12a/12b were two pairs of enantiomers successfully separated by chiral HPLC resolution. Compounds 4, 5, 8, 9, 11a/11b, and 12a/12b exhibited inhibition of nitric oxide production in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells with IC50 values in the range of 17.5-98.4μM.

Eight new chrysogenolides (A–H (1–8)) and seven known (9–15) 3,5-dimethylorsellinic acid derived meroterpenoids were isolated from the solid substrate fermentation cultures of a Huperzia serrata endophytic fungus, Penicillium chrysogenum MT-12. The structures of the new compounds were elucidated by interpretation of spectroscopic and spectrometric data (1D and 2D NMR, IR, and HRESIMS). The absolute configurations of 1–4 were determined by single-crystal X-ray crystallographic analysis, and those of 5–8 were assigned on the basis of experimental and calculated electronic circular dichroism spectra. Compounds 3, 4, 6, 11, and 12 showed inhibition of nitric oxide production in lipopolysaccharide-activated RAW 264.7 macrophage cells with IC50 values in the range of 4.3–78.2 μM (positive control, indomethacin, IC50 = 33.6 ± 1.4 μM).

Ethnopharmacological relevance Corydalis hendersonii Hemsl. (CH) with heat clearing and detoxifying effects are well described in Tibetan folk medicine. It has been used for centuries in China largely for the treatment of high altitude polycythemia, a pathophysiological condition referred to “plethora” in Tibetan medicine, hypertension, hepatitis, edema, gastritis, and other infectious diseases. Aim of the study To investigate the cardioprotective effects of Corydalis hendersonii extract in an ICR mouse model of myocardial ischemic injury. Materials and methods Ethanol [85% (v/v)] extract of CH whole plant was prepared, and their chemical profile was analyzed with use of HPLC-DAD and IT-TOF-ESI-MS. A mouse model of AMI was established by ligation of the left ventricular dysfunction (LAD) coronary artery. Mice were randomly divided into six groups (n = 12 per group): sham group, model group, CH groups treated with three doses of CH (100, 200, and 400 mg/kg, intragastric), and a positive control group (captopril, 16.67 mg/kg, intragastric). Heart function was evaluated by measurement of ejection fraction (EF) and fractional shortening (FS) by echocardiography. Serum levels of creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH), plasma levels of angiotensin II (AngII), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1s (IL-1s) and expressions of matrix metalloproteinase-2 (MMP-2) and MMP-9 in the cardiac tissue homogenate, protein expressions of signal-transduction proteins, p65, IκBα, JAK2, and STAT3 in heart tissues were measured by ELISA and Western blot analyses. Inflammatory cell infiltration and changes in collagen deposition in the myocardial ischemic heart tissues were observed by histopathological examination. Platelet aggregation in vitro was also assessed. Results CH treatment showed a dose-dependent cardioprotective effect. It significantly reduced left ventricular end-diastolic diameter (LVEDd) and left ventricular end-diastolic diameter (LVEDs), improved EF and FS as compared to those in the model group; attenuated the increase levels of CK-MB and LDH in serum; reduced expressions of AngII, TNF-α, IL-6 and IL-1s in plasma, MMP-2 and MMP-9 expressions in the cardiac tissue homogenate; and down-regulated myocardial expressions of p-p65, p-IκBα, p-JAK2, p-STAT3, MMP-2, and MMP-9 in AMI mice. Also, an obvious reduction in inflammatory cell infiltration in the myocardial infarct was found in all CH treated groups. Besides, CH also inhibited platelet aggregation induced by THR, ADP, and AA. Conclusion CH extract exerted a protective effect against myocardial ischemic injury via inhibition of inflammation, myocardial fibrosis, and platelet aggregation. This study demonstrates such protection for the first time and provides a basis for development of CH-based drugs for treatment of ischemic heart disease in clinical settings.

The anti-inflammatory effects of boldine and reticuline isolated from Litsea cubeba were evaluated by using xylene-induced ear edema and carrageenan-induced paw edema in mice and rats. Our results demonstrated that intragastric administration with boldine and reticuline significantly mitigated ear weight in mice and decreased paw volume in rats. A combination administration of boldine (0.5 mg/kg) + reticuline (0.25 mg/kg) resulted in a potentiated inhibition in these two models. In parallel, boldine or reticuline reduce the infiltration of neutrophil leukocytes in rat paw tissue, respectively, and the combination of the two groups performed a better anti-inflammatory activity as shown in histopathologies. Boldine, reticuline, and their combination notably inhibited mRNA expressions of TNF-α, and IL-6 and reduced the phosphorylation levels of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3). Beyond that, their combination also can reduce the phosphorylation levels of p65 and IκBα in the pathological tissues of animals, as observed by real-time PCR and western blot analyses, respectively. These findings indicate for the first time that boldine and reticuline have not only anti-inflammatory activity but also potential synergistic effects in vivo. The underlying mechanism may relate to the inhibition on the expression of pro-inflammatory cytokines, such as TNF-α and IL-6, which may be a consequence of JAK2/STAT3 and NF-κB pathway involvements. This study provides useful data for further exploration and application of boldine and reticuline as potential anti-inflammatory medicines.

Two new diterpenoids, penicichrysogene A (1) and penicichrysogene B (2), were isolated from the solid substrate fermentation cultures of Penicillium chrysogenum MT-12, an endophytic fungus isolated from the medicinal plant of Huperzia serrata. Their structures were elucidated on the basis of extensive spectroscopic and spectrometric data (1D and 2D NMR, UV, IR, and HRESIMS). The absolute configurations of 1 and 2 were assigned on the basis of experimental and calculated electronic circular dichroism spectra. Compound 1 exhibited inhibitory activity on ATP release of thrombin-activated platelets with IC50 = 42.7 ± 3.5 μM.

Stachyodin A (1), a rearrangement product of pterocarpan featuring a 6/5/5/6 tetracyclic ring system with an unusual spirotetrahydrofuran ring, and stachyodin B (2), a new dihydrochalcone, along with five known analogues (3–7) were isolated from the roots of Indigofera stachyodes. The structures of 1 and 2 were elucidated on the basis of their HRESIMS and NMR spectroscopic data, and their absolute configurations were determined by X-ray crystallographic analysis and electronic circular dichroism (ECD) data, respectively. Compounds 2–4 showed inhibition of nitric oxide production in lipopolysaccharide-activated BV-2 microglial cells.

Based on the analysis of existing wireless sensor networks(WSNs) security vulnerability, combining the characteristics of high encryption efficiency of the symmetric encryption algorithm and high encryption intensity of asymmetric encryption algorithm, a hybrid encryption algorithm based on wireless sensor networks is proposed. Firstly, by grouping plaintext messages, this algorithm uses advanced encryption standard (AES) of symmetric encryption algorithm and elliptic curve encryption (ECC) of asymmetric encryption algorithm to encrypt plaintext blocks, then uses data compression technology to get cipher blocks, and finally connects MAC address and AES key encrypted by ECC to form a complete ciphertext message. Through the description and implementation of the algorithm, the results show that the algorithm can reduce the encryption time, decryption time and total running time complexity without losing security.

Hematopoietic stem cell transplantation (HSCT) plays an important role in the therapy of hematological malignancies and some nonmalignant diseases. Granulocyte colony-stimulating factor (G-CSF) is generally used to mobilize and collect hematopoietic stem cells from donors and accelerate neutrophil recovery in transplantation recipients. However, less attention has been paid to the fact that G-CSF administration might result in thrombocytopenia and enhance bleeding risk in HSCT. In this study, we investigated the effects of G-CSF on platelet counts in healthy mice and mice that received bone marrow transplantation. It was observed that G-CSF administration induced thrombocytopenia in healthy mice and aggravated thrombocytopenia in mice that received bone marrow transplantation. Furthermore, we analyzed the regulatory effects of G-CSF on the differentiation of hematopoietic progenitors and megakaryocytes, and activation of platelets and endothelial cells. The results reveal that G-CSF administration causes thrombocytopenia mainly by inhibiting the differentiation of common myeloid progenitors and megakaryotic erythroid progenitors into megakaryocytes and platelet formation but not through enhancing activation of platelets or endothelial cells and following platelet consumption. Collectively, G-CSF administration can result in thrombocytopenia in hematopoietic stem cell donors and exacerbate existing thrombocytopenia in transplantation recipients. More attention should be paid to bleeding risk of G-CSF administration in HSCT, especially autologous HSCT.

Four new polyketides, alternatains A-D (1–4), along with 17 known compounds (5–21) were obtained from the solid substrate fermentation cultures of Alternaria alternata MT-47, an endophytic fungus isolated from the medicinal plant of Huperzia serrata. Their structures were elucidated by extensive spectroscopic and spectrometric techniques (1D and 2D NMR, IR, and HRESIMS) and calculated electronic circular dichroism (ECD) method. Compounds 4, 6, 15, and 21 exhibited inhibitory activities on ATP release of thrombin-activated platelets with IC50 values in the range of 18.2–68.8 μM.

Jinling Wang,1 Wenzhuan Ma,1,2 Qiang Guo,1,2 Ying Li,1,2 Zhongdong Hu,1 Zhixiang Zhu,1 Xiaohui Wang,1 Yunfang Zhao,1 Xingyun Chai,1 Pengfei Tu1 1Modern Research Center for Traditional Chinese Medicine, 2School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, People’s Republic of China Abstract: Tumor-targeted delivery system has been developed as an attractive strategy for effective tumor therapy. In this study, in order to enhance the antitumor effects of doxorubicin (DOX), amphiphilic hyaluronic acid (HA)-conjugated vitamin E succinate (VES) copolymers (HA-VES) with different degrees of substitution (DS) were prepared with synergistic antitumor effects and active targeting activities, and utilized as nanocarriers for the efficient delivery of DOX. DOX-loaded HA-VES polymeric micelles (HA-VES/DOX) self-assembled from dual-functional HA-VES copolymer and exhibited excellent loading efficiency and superior colloidal stability. In vitro, HA-VES/DOX displayed enhanced cytotoxicity with synergistic anticancer effects of HA-VES copolymer, high apoptosis-inducing activities of tumor cells, and reversal effects of DOX on multidrug resistance, in comparison with DOX. Also, in vitro cellular uptake and subcellular localization studies revealed that HA-VES/DOX could more efficiently internalize into cancer cells and selectively release DOX within lysosomes, thereby enhancing the distribution of DOX in nuclei and facilitating its interactions with DNA. Specifically, HA-VES/DOX decreased the activity of CD44 mRNA and improved the targeting efficiency on MCF-7 cells, based on the active recognition between HA and CD44 receptor. More importantly, HA-VES/DOX displayed better tumor accumulation and targeting, and enhanced antitumor efficacy with reduced systemic toxicity in 4T1 tumor-bearing mice. In summary, the developed HA-VES–based drug delivery system, which increased drug targeting on the tumor site and exhibited preferable anticancer activity, could hold great potential as an effective and promising strategy for efficient tumor therapy. Keywords: hyaluronic acid, self-assembled micelles, tumor targeting, doxorubicin, vitamin E succinate

Induction of excessive, prolonged, or dysregulated immune responses causes immunological disorders, such as inflammatory diseases, autoimmune diseases, allergic diseases, and organ-graft rejections. In the present study, we investigated the inhibitory effects of HHX-5, a derivative of sesquiterpene from Chinese agarwood, on innate and adaptive immunity for revealing its potential to treat above immunological disorders. The results showed that HHX-5 significantly inhibited the activation of macrophages and neutrophils which play important roles in innate immunity. Furthermore, HHX-5 strongly suppressed adaptive immunity via inhibiting differentiation of naive CD4+ T cells into Th1, Th2, and Th17 cells and suppressing activation, proliferation and differentiation of CD8+ T cells and B cells. The mechanism study showed that HHX-5 significantly inhibited STAT1 signaling pathway in macrophages and suppressed STAT1, STAT4, STAT5, and STAT6 signaling pathways in naive CD4+ T cells. In conclusion, we demonstrated that HHX-5 can strongly inhibit innate and adaptive immunity via suppressing STAT signaling pathways and has potential to be developed into therapeutic drug for treat immunological disorders.

A new dihydroisocoumarin (1) and a new coumarin (2), along with eight known metabolites (3–10), were isolated from the solid substrate fermentation cultures of the fungus Penicillium purpurogenum MHZ 111. Their structures were elucidated by extensive spectroscopic analysis and comparison of their spectroscopic and physicochemical data with the literature values. Compounds 2 and 8 showed inhibition of nitric oxide production in lipopolysaccharide-activated BV-2 microglial cells with IC50 values of 26.5 and 52.7 μM, respectively.

GYF-17, a 2-(2-phenethyl)-chromone derivative, was isolated from agarwood and showed superior activity of inhibiting NO production of RAW264.7 cells induced by LPS in our preliminary pharmacodynamic screening. In order to develop novel therapeutic drug for acute and chronic inflammatory disorders, the anti-inflammatory activity and underlying mechanism of GYF-17 were investigated in LPS-induced RAW264.7 cells. The results showed that GYF-17 could reduce LPS-induced expression of iNOS and then result in the decrement of NO production. More meaningful, the expression and secretion of key pro-inflammatory factors, including TNF-α, IL-6 and IL-1β, were intensively inhibited by GYF-17. Furthermore, GYF-17 also down regulated the expression of COX2 and the production of PGE2 which plays important role in causing algesthesia during inflammatory response. In mechanism study, GYF-17 selectively suppressed phosphorylation of STAT1/3 and ERK1/2 during the activation of NF-κB, MAPK and STAT signaling pathways induced by LPS. Collectively, GYF-17 can intensively suppress the production of LPS-induced inflammatory mediators in RAW264.7 cells by inhibiting STAT1/3 and ERK1/2 signaling pathways and thereby shows great potential to be developed into therapeutic drug for inflammatory diseases.

Five new meroterpenoids, purpurogenolides A-E (1-5), and four known metabolites (6-9) were isolated from the solid substrate fermentation cultures of the fungus Penicillium purpurogenum MHz 111. The structures of the new meroterpenoids were elucidated by analysis of spectroscopic and spectrometric data (1D and 2D NMR, IR, and HRESIMS). The absolute configurations of 1 and 5 were determined by single-crystal X-ray crystallographic analysis, and those of 2-4 were elucidated on the basis of experimental and calculated electronic circular dichroism spectra. Compounds 2-4 and 6 showed inhibition of nitric oxide production in lipopolysaccharide-activated BV-2 microglial cells with IC50 values of 0.8-30.0 μM.

It has particular heat-resistant property and conductivity of high-conductivity heat-resistant Aluminium alloys, which would be wildly applied in transmission and transformation flied. Al-Er-Zr alloys containing different content of Zr were prepared. The effect of Zr on microstructure of heat-resistance Aluminum alloy were studied by using of STEM, and thermodynamic behavior of Zr in Aluminium alloy was analyzed based on the theory of alloy phase formation. The results showed that the effect of Zr content on the grain size of heat-resistant aluminum alloy was remarkable, and the conductivity of heat-resistance Aluminum alloy was influenced.

CD40 ligand (CD40L) and B-cell activating factor (BAFF) play important roles in the function of B cells. However, the difference of their regulatory effects remains obscure. In this study, we used anti-CD40 to imitate CD40L and investigated the different regulatory effects of CD40L and BAFF on the function of B cells. In the functional analyses, both anti-CD40 and BAFF significantly enhanced the survival and differentiation of B cells, and slightly increased the activation and proliferation. However, in the transcriptome analysis, anti-CD40 and BAFF exerted very different regulation on the gene expression profile of B cells. Anti-CD40 upregulated the expression of genes related to the adaptive immune function of B cells, but BAFF enhanced the genes associated with the innate immune function. Furthermore, the effect analysis of the combination of anti-CD40 or BAFF with anti-IgM also demonstrated that anti-CD40 could cooperate with anti-IgM to promote the proliferation of B cells, but BAFF could not do it. The mechanism study revealed that the different effects of anti-CD40 and BAFF on B cells were resulting from the different modulation on NF-кB, ERK1/2, and PI3K-AKT signaling pathways. Collectively, the results suggest that CD40L mainly promotes adaptive immune function of B cells, but BAFF primarily enhances innate immune function.

Trametes robiniophila Murr. (Huaier) is a mushroom with a long history of use as a medicinal ingredient in China and exhibits good clinical efficacy in cancer management. However, the antitumor components of Huaier and the underlying molecular mechanisms remain poorly understood. Here, we isolated a proteoglycan with a molecular mass of ∼5.59 × 10(4) Da from Huaier aqueous extract. We named this proteoglycan TPG-1, and using FTIR and additional biochemical analyses, we determined that its total carbohydrate and protein compositions are 43.9 and 41.2%, respectively. Using biochemical assays and immunoblotting, we found that exposing murine RAW264.7 macrophages to TPG-1 promotes the production of nitric oxide (NO), tumor necrosis factor α (TNFα), and interleukin-6 (IL-6) through Toll-like receptor 4 (TLR4)-dependent activation of NF-κB and mitogen-activated protein kinase (MAPK) signaling. Of note, the TPG-1 treatment significantly inhibited the tumorigenesis of human hepatoma HepG2 cells likely at least in part by increasing serum levels of TNFα and promoting leukocyte infiltration into tumors in nude mice. TPG-1 also exhibited good antitumor activity in hepatoma H22-bearing mice and had no obvious adverse effects in these mice. We conclude that TPG-1 exerts antitumor activity partially through an immune-potentiating effect due to activation of the TLR4–NF-κB/MAPK signaling cassette. Therefore, TPG-1 may be a promising candidate drug for cancer immunotherapy. This study has identified the TPG-1 proteoglycan as an antitumor agent and provided insights into TPG-1's molecular mechanism, suggesting a potential utility for applying this agent in cancer therapy.

Activated B cells targeted to autoantigens proliferate and differentiate into antibody-secreting cells. Overproduced autoantibodies will give rise to autoimmune diseases. In this study, we investigated the inhibitory effects of GYF-21, an epoxide 2‑(2‑phenethyl)‑chromone derivative extracted from Chinese agarwood, on the survival, activation, proliferation, and differentiation of B cells for revealing its potential to treat autoimmune diseases related to B cell dysfunction. The results showed that GYF-21 slightly inhibited the survival, activation and proliferation of B cells stimulated by combination of anti-IgM, anti-CD40 and IL-4 while weakly up-regulated differentiation of B cells induced by combination of anti-CD40 and IL-4. In addition, GYF-21 intensively suppressed survival, activation, proliferation, and differentiation of B cells stimulated by B-cell activating factor (BAFF) which plays extremely important roles in autoantibody production and pathogenesis of autoimmune diseases. The mechanism study revealed that GYF-21 slightly down-regulated phosphorylation of NF-κB p65, Akt, STAT3, but up-regulated phosphorylation of Erk1/2 in B cells activated by anti-IgM, anti-CD40, IL-4 or their combinations. However, GYF-21 not only moderately down-regulated phosphorylation of NF-κB p65 and MAPK p38, but also intensively inhibited phosphorylation of Erk1/2 and Akt induced by BAFF. These data suggest the inhibitory effects of GYF-21 on the survival, activation, proliferation, and differentiation of B cells mainly via blocking BAFF activated signaling pathways, and its potential to be developed into therapeutic drug for autoimmune diseases, especially systemic lupus erythematosus (SLE).

Fifteen previously undescribed 2-(2-phenylethyl)chromone dimers, along with two known analogues were isolated from Chinese agarwood ( Aquilaria sinensis ) by a LC-MS-guided fractionation procedure. Their structures were elucidated on the basis of spectroscopic and spectrometric data (1D and 2D NMR, IR, and HRESIMS). The isolated compounds exhibited significant inhibition of nitric oxide production in lipopolysaccharide-stimulated RAW264.7 cells with IC 50 values in the range 0.6–37.1 μ M.

Many medical centers in the United States have implemented pharmacogenomics (PGx) programs to integrate PGx into clinical practice. The roles of pharmacists in optimizing medication use based on genetic testing results are emergently evolving. A literature search was conducted to assess pharmacists’ roles in pharmacogenetics/pharmacogenomics or precision/personalized medicine programs. Fifteen PGx pharmacy practice models implemented in eleven hospitals and one community pharmacy in the U.S. were selected for evaluation. Pharmacists perform results interpretation, genotype-guided medication selection and adjustment, medication acquisition, adverse reactions monitoring, and patient education. Institutions that are interested in implementing a PGx program should plan the strategies to overcome the challenges, such as educational knowledge gaps, informatics, and reimbursement issues. Strong institutional support, well-defined goals, standardized procedures, and strategies to educate clinicians and patients are the prerequisites to comprehensively deliver genomic data for individualized drug therapy.

Two new polyketides, penicilloxalones A (1) and B (2), together with 13 known compounds (3–15), were isolated from the ethyl acetate extract of the solid substrate fermentation cultures of the fungus Penicillium oxalicum MHZ153. The structures of the isolates were determined by spectroscopic analysis and comparison of their spectroscopic and physicochemical data with the literature values. Compounds 7 and 11 showed inhibition of nitric oxide production in lipopolysaccharide-stimulated BV-2 microglial cells with IC50 values of 0.9 ± 0.2 μM and 87.9 ± 0.7 μM, respectively.

Poly(ADP-ribose)polymerase-1 (PARP-1) has emerged as a promising anticancer drug target due to its key role in the DNA repair process. In this work, a novel series of 1-benzyl-quinazoline-2,4(1H,3H)-dione derivatives were designed and synthesized as human PARP-1 inhibitors, structure-activity relationships were conducted and led to a number of potent PARP-1 inhibitors having IC50 values of single or double digit nanomolar level. Compound 7j was a potent PARP-1 and PARP-2 inhibitor and it could selectively kill the breast cancer cells MX-1 and MDA-MB-468 with mutated BRCA1/2 and PTEN, respectively, in comparison with homologous recombination proficient cell types such as breast cancer cells MDA-MB-231. In addition, compound 7j displayed the strongest potentiation effect on temozolomide in MX-1 cells (PF50=3.77) in this series of PARP-1 inhibitors.

Sixteen new 2-(2-phenylethyl)chromone dimers, including four pairs of enantiomers (1a/1b, 3a/3b, 6a/6b, and 8a/8b), along with eight optically pure analogues (2, 4, 5, 7, and 9–12) were isolated from the resinous wood of Aquilaria sinensis. Their structures were determined by extensive spectroscopic analysis (1D and 2D NMR, UV, IR, and HRMS) and experimental and computed ECD data. Compounds 1–10 feature an unusual 3,4-dihydro-2H-pyran ring linkage connecting two 2-(2-phenylethyl)chromone monomeric units, while compounds 11 and 12 possess an unprecedented 6,7-dihydro-5H-1,4-dioxepine moiety in their structures. A putative biosynthetic pathway of the representative structures via a diepoxy derivative of a chromone with a nonoxygenated A-ring is also proposed. Compounds 1a/1b, 2, 3a/3b, 5, 7, 8a/8b, and 10–12 exhibited significant inhibition of nitric oxide production in lipopolysaccharide-stimulated RAW264.7 cells with IC50 values in the range 7.0–12.0 μM.

Five new megastigmane glycosides, urenalobasides A–E (1–5), together with 11 known ones (6–16) were isolated from Urena lobata. Their structures were determined by extensive spectroscopic and spectrometric data (1D and 2D NMR, IR, and HRESIMS) and calculated electronic circular dichroism method. Compounds 1 and 2 are two unusual megastigmanes structurally containing a 6/5 fused ring system. Compound 3 exhibits inhibition of nitric oxide production in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells with IC50 value of 53.7 ± 1.0 μM (positive control, dexamethasone, IC50 = 16.6 ± 0.8 μM).

Dense Pb(Zr

Multiple sclerosis is a chronic inflammatory autoimmune disease of the central nervous system characterized by demyelinating plaques and axonal loss. Inhibition on over activation of innate and adaptive immunity provides a rationale strategy for treatment of multiple sclerosis. In the present study, we investigated the inhibitory effects of GYF-21, an epoxide 2-(2-phenethyl)-chromone derivative isolated from Chinese agarwood, on innate and adaptive immunity for revealing its potential to treat multiple sclerosis. The results showed that GYF-21 markedly inhibited the activation of microglia, and dendritic cells as well as neutrophils, all of which play important roles in innate immunity. Furthermore, GYF-21 significantly suppressed adaptive immunity via inhibiting the differentiation of naive CD4+ T cells into T helper 1 (Th1) and T helper 17 (Th17) cells, and suppressing the activation, proliferation, and IFN-γ secretion of CD8+ T cells. The mechanism study showed that GYF-21 evidently inhibited the activation of STAT1/3 and NF-κB signaling pathways in microglia. In conclusion, we demonstrated that GYF-21 can significantly inhibit innate and adaptive immunity via suppressing STAT1/3 and NF-κB signaling pathways, and has potential to be developed into therapeutic drug for multiple sclerosis.

Berkeleyacetal C (BAC), a meroterpenoid compound, was isolated from the fungus Penicillium purpurogenum MHZ 111 and showed favorable activity of inhibiting nitrogen oxide (NO) production of macrophages stimulated by lipopolysaccharide (LPS) in our preliminary screening. In order to develop novel therapeutic drug for acute and chronic inflammatory diseases, the anti-inflammatory activity and underlying mechanisms of BAC were investigated in macrophages and neutrophils. The results showed that BAC significantly inhibited the expression of inducible nitric oxide synthase (iNOS) and the following NO production by macrophages. The expression and secretion of key pro-inflammatory factors and chemokines, including tumor necrosis factor-α (TNF-α)，interleukin-6 (IL-6), interleukin-1β (IL-1β), macrophage inflammatory protein-1α (MIP-1α), and monocyte chemotactic protein-1 (MCP-1) were also intensively suppressed by BAC. Furthermore, BAC also markedly inhibited activation of neutrophils and reactive oxygen species production. In mechanism study, BAC selectively suppressed phosphorylation of nuclear factor-κB (NF-κB), extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), and interferon regulatory transcription factor 3 (IRF3) during the activation of NF-κB, mitogen-activated protein kinase (MAPK), signal transducer and activator of transcription 1 and 3 (STAT1/3), and IRF3 signaling pathways induced by LPS. In summary, BAC exerts strong anti-inflammatory effects by inhibiting NF-κB, ERK1/2 and IRF3 signaling pathways and thereby shows great potential to be developed into therapeutic agent for inflammatory disorders.

Superoxide plays a key role in normal immune function and inflammatory diseases. In order to evaluate normal immune function or screen inhibitors of superoxide production for treating inflammatory diseases, it is very important to detect superoxide with good accuracy, sensitivity, and flexibility. In present study, we investigated three analysis methods of superoxide, colorimetric assay by WST-8, fluorescence assay by dihydroethidium and chemiluminescence assay by lucigenin, compared their precisions, specificities, sensitivities and time curve characteristics in superoxide analysis, and then validate their values in the screening of anti-inflammatory compounds. The results reveal that three analysis methods of superoxide all have good precisions and high specificities but have different sensitivities and time curve characteristics, which suggest their different applications. In addition, they can all be used in the screening of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitors and anti-inflammatory compounds.

A bioassay-guided fractionation of the roots and stems of Litsea cubeba led to the isolation of 14 constituents, including three new compounds, cubebanone (1), N-cis-3,4-methylenedioxycinnamoyl-3-methoxytyramine (2), and 9,9'-O-di-(E)-feruloyl-(+)-secoisolariciresinol (3), together with 11 known ones (4-14). Compounds 1, 4, and 8-11 showed obvious in vitro anti-inflammatory activities against NO production in LPS-induced murine microglial (BV-2) cell line and RAW 264.7 macrophages. A cytotoxic evaluation showed that 2, 3, and 5-8 exhibited considerable inhibition against the growth of hepatocyte carcinoma (HepG2) cell line. These findings are evidence, to some extent, for the traditional medicinal application of L. cubeba, especially as folk medicine in the treatment of inflammation-related diseases.

The Bocconieae tribe, consisting of only the genera Macleaya and Bocconia, possesses significant economic and medicinal value and plays an important role in health management for people in developing countries. During the past decades, research on metabolites and relative pharmacology, including the isolation and identification of a variety of molecules, has shed light on the tribe. Among those molecules, isoquinoline alkaloids, and their antimicrobial, antifungal, and anti-inflammatory activities are especially noteworthy. This paper presents a comprehensive compilation of current research progress, with emphasis on the alkaloids and their distribution, phytochemical and pharmacological investigation, toxicity and side effects, related chemotaxonomy and future use prospects, and hopefully provides a valuable reference as an effort to promote further exploration and application of this tribe.

Activated platelets release adenosine trisphosphate (ATP) and bioluminescence analysis of ATP release is usually used to monitor activation of platelets induced by various stimulants. However, bioluminescence analysis of ATP possesses poor linearity, the signal is quickly attenuated, and the accuracy of ATP release from platelets is hard to determine accurately enough to be used in a high throughput screening of platelet inhibitors. The present study was designed to optimize bioluminescence analysis of ATP released by platelets and expand its application in high throughput screening of platelet inhibitors. The results showed that accuracy of ATP analysis was significantly improved by adding coenzyme A (CoA) and signal attenuation of ATP analysis was greatly postponed by adding bovine serum albumin (BSA) both in Hank's balanced salt solution (HBSS) and Tyrode's buffer. Furthermore, ATP release of activated platelets and inhibitory effects of Ly294002 and Staurosporine on platelet activation were accurately determined by our optimized bioluminescence analysis of ATP. Thus, we have successfully constructed an optimized bioluminescence analysis of ATP which can be used in high throughput screening of platelet inhibitors.

Five new 2-(2-phenylethyl)chromone derivatives (1-5), along with eleven known compounds (6-16) were isolated from Chinese agarwood. Their structures were elucidated by spectroscopic data (NMR, UV, IR, and MS) analyses and comparison of their spectroscopic and physical data with the literature values. The absolute configurations of 2-4 were determined by electronic circular dichroism (ECD) calculations. Compounds 2-4, 11, 12, and 15 exhibited significant inhibition of nitric oxide production in lipopolysaccharide-stimulated RAW 264.7 cells with IC50 values in the range 1.6-7.3μM.

Novel 1H-benzo[d]immidazole-4-carboxamide derivatives bearing five-membered or six-membered N-heterocyclic moieties at the 2-position were designed and synthesized as PARP-1 inhibitors. Structure-activity relationships were conducted and led to a number of potent PARP-1 inhibitors having IC50 values in the single or double digit nanomolar level. Some potent PARP-1 inhibitors also had similar inhibitory activities against PARP-2. Among all the synthesized compounds, compound 10a and 11e displayed strong potentiation effects on temozolomide (TMZ) in MX-1 cells (PF50 = 7.10, PF50 = 4.17). In vivo tumor growth inhibition was investigated using compound 10a in combination with TMZ, and it was demonstrated that compound 10a could strongly potentiate the cytotoxicity of TMZ in MX-1 xenograft tumor model. Two co-crystal structures of compounds 11b and 15e complexed with PARP-1 were achieved and demonstrated a unique binding mode of these benzo-imidazole derivatives.

Three new dimeric furanocoumarins, dahuribiethrins H–J (1–3), and a new ester coumarin, dahurinol A (4), were isolated from the roots of Angelica dahurica. Their structures were elucidated on the basis of extensive spectroscopic data including UV, IR, HRESIMS, 1D and 2D NMR. Compounds 2 and 3 exhibited inhibition of nitric oxide production in the lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells with IC50 values of 8.7 ± 0.6 and 27.3 ± 0.9 μM, respectively.

Eight new flavonoid dimers, named cochinchinenins I–M (1–5), including three pairs of enantiomers (1a/1b–3a/3b) and two optically pure flavonoid dimers (4–5), along with a known analogue (6), were isolated from total phenolic extract of the red resin of Dracaena cochinchinensis (Chinese dragon's blood). The planar structures of 1–5 were elucidated by extensive spectroscopic analysis including HRESIMS and 1D/2D NMR. Their absolute configurations were determined on the basis of experimental and calculated electronic circular dichroism (ECD) data. Compounds 4 and 5 exhibited significant inhibition of nitric oxide production in lipopolysaccharide-stimulated BV-2 microglial cells with IC50 value of 4.9 ± 0.4 and 5.4 ± 0.6 μM, respectively.

The Quantitative Genetic Analysis Station (QGAStation) is a software package that has been developed to perform statistical analysis for complex traits. It consists of five domains for handling data from diallel crosses, regional trials, core germplasm collections, QTL mapping, and microarray experiments. The first domain contains genetic models for diallel cross analysis, in which genetic variance components and genetic-by-environment interactions can be estimated, and genetic effects can be predicted. The second domain evaluates the performance of varieties in regional trials by implementing a general statistical method that outperforms ANOVA in tackling unbalanced data that arises frequently in trials across multiple locations and over a number of years. The third domain, using predicted genotypic values as proxy, constructs core germplasm collections covering sufficient genetic diversity with lower redundancy. The fourth domain manages genotypic and phenotypic data for QTL mapping. Linkage maps can be constructed and genetic distances can be estimated; the statistical methods that have been implemented apply to both chiasmatic and achiasmatic organisms. Another part of this domain can filter systematic noises in phenotypic data. The fifth domain focuses on the cDNA expression data that is generated by microarray experiments. A two-step strategy has been implemented to detect differentially expressed genes and to estimate their effects. Except in the fourth domain, the major statistical methods that have been used are mixed linear model approaches that have been implemented in the C language. Computational efficiency is further boosted for computers that are equipped with graphics processing units (GPUs). A user friendly graphic interface is provided for Microsoft Windows and Apple Mac operating systems. QGAStation is available at http://ibi.zju.edu.cn/software/qga/.