Identifying the Mechanisms and Molecular Targets of Guchang Zhixie Pills on Ulcerative Colitis: Coupling Network Pharmacology with GEO Database and Experiment Verification.

OBJECTIVE: This research investigates the mechanisms and molecular targets of the Guchang Zhixie pill (GCZXP) against ulcerative colitis (UC) in silico and in vivo. METHODS: The compounds and related targets of GCZXP were collected from the traditional Chinese medicine systems pharmacology database. UC targets were from Gene Expression Omnibus and GeneCards databases. Hub genes were acquired through Cytoscape. Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment were performed in the David database. R packages were used to investigate the relationship between immune cells and hub genes and the diagnostic model. AutoDock was used to verify the molecular docking of the core compounds and hub genes, as well as nuclear factor-kappa B (NF-κB) p65 and IκBα. The hub genes and NF-κB pathway were verified via experiment. RESULTS: In GCZXP, a total of 51 active compounds were discovered. Enrichment analysis was used to study inflammation, chemokine activity, NF-κB signalling pathway, etc. Thirteen key therapeutic targets were involved, of which included three hub genes PTGS2, IL-1ß and CXCL8. Immune infiltration revealed that all of the 3 hub genes were positively correlated with M1 macrophages, neutrophils, and activated memory CD4 cells, and negatively correlated with plasma cells. In the training and validation sets, the area under the curve (AUC) of the diagnostic model developed by hub genes reached 0.929 and 0.905, respectively, indicating a good forecasting potential. The rat experiment proved that GCZXP significantly reduced the expressions of IL-1ß, CXCL8, COX-2, and NF-κB p65 while increasing IκBα and Bcl-2, alleviated colonic inflammatory injury and promoted ulcer healing. CONCLUSION: GCZXP reduced the release of cytokines and regulated Bcl-2 in the treatment of UC by inhibiting the NF-κB signalling pathway.

Identifying key genes involved in yellow leaf variation in 'Menghai Huangye' based on biochemical and transcriptomic analysis.

Albino tea plants generally have higher theanine, which causes their tea leaves to taste fresher, and they are an important mutant for the breeding of tea plant varieties. Earlier, we reported an albino germplasm, 'Menghai Huangye' (MHHY), from Yunnan Province and found that it has a lower chlorophyll content during the yellowing stage, but the mechanism underlying low chlorophyll and the yellowing phenotype is still unclear. In this study, the pigment contents of MHHY_May (yellowing, low chlorophyll), MHHY_July (regreening, normal chlorophyll), and YK10_May (green leaves, normal chlorophyll) were determined, and the results showed that the lower chlorophyll content might be an important reason for the formation of the yellowing phenotype of MHHY. Through transcriptome sequencing, we obtained 654 candidates for differentially expressed genes (DEGs), among which 4 genes were related to chlorophyll synthesis, 10 were photosynthesis-related, 34 were HSP family genes, and 19 were transcription factor genes. In addition, we analysed the transcription levels of the key candidate genes in MHHY_May and MHHY_July and found that they are consistent with the expression trends in MHHY_May and YK10_May, which further indicates that the candidate differential genes we identified are likely to be key candidate factors involved in the low chlorophyll content and yellowing of MHHY. In summary, our findings will assist in revealing the low chlorophyll content of MHHY and the formation mechanism of yellowing tea plants and will be applied to the selection and breeding of albino tea cultivars in the future.

Biodegradable hollow mesoporous organosilica nanotheranostics (HMONs) as a versatile platform for multimodal imaging and phototherapeutic-triggered endolysosomal disruption in ovarian cancer.

A major impediment in the development of nanoplatform-based ovarian cancer therapy is endo/lysosome entrapment. To solve this dilemma, a hollow mesoporous organosilica-based nanoplatform (HMON@CuS/Gd2O3) with a mild-temperature photothermal therapeutic effect and multimodal imaging abilities was successfully synthesized. HMON@CuS/Gd2O3 exhibited an appropriate size distribution, L-glutathione (GSH)-responsive degradable properties, and high singlet oxygen generation characteristics. In this study, the nanoplatform specifically entered SKOV-3 cells and was entrapped in endo/lysosomes. With a mild near infrared (NIR) power density (.5 W/cm2), the HMON@CuS/Gd2O3 nanoplatform caused lysosome vacuolation, disrupted the lysosomal membrane integrity, and exerted antitumour effects in ovarian cancer. Additionally, our in vivo experiments indicated that HMON@CuS/Gd2O3 has enhanced T1 MR imaging, fluorescence (FL) imaging (wrapping fluorescent agent), and infrared thermal (IRT) imaging capacities. Using FL/MRI/IRT imaging, HMON@CuS/Gd2O3 selectively caused mild phototherapy in the cancer region, efficiently inhibiting the growth of ovarian cancer without systemic toxicity in vivo. Taken together, the results showed that these well-synthesized nanoplatforms are likely promising anticancer agents to treat ovarian cancer and show great potential for biomedical applications.

Chloroplast genome characteristics and phylogenetic analysis of the medicinal plant Blumea balsamifera (L.) DC.

Blumea balsamifera (L.) DC., a medicinal plant with high economic value in the Asteraceae family, is widely distributed in China and Southeast Asia. However, studies on the population structure or phylogenetic relationships with other related species are rare owing to the lack of genome information. In this study, through high-throughput sequencing, we found that the chloroplast genome of B. balsamifera was 151,170 bp in length, with a pair of inverted repeat regions (IRa and IRb) comprising 24,982 bp, a large single-copy (LSC) region comprising 82,740 bp, and a small single-copy (SSC) region comprising 18,466 bp. A total of 130 genes were identified in the chloroplast genome of B. balsamifera, including 85 protein-coding, 37 transfer RNA, and 8 ribosomal RNA genes; furthermore, sequence analysis identified 53 simple sequence repeats. Whole chloroplast genome comparison indicated that the inverted regions (IR) were more conserved than large single-copy and SSC regions. Phylogenetic analysis showed that B. balsamifera is closely related to Pluchea indica. Conclusively, the chloroplast genome of B. balsamifera was helpful for species identification and analysis of the genetic diversity and evolution in the genus Blumea and family Asteraceae.

Antidepressant-like Effect of 3-n-Butylphthalide in Rats Exposed to Chronic Unpredictable Mild Stress: Modulation of Brain-Derived Neurotrophic Factor Level and mTOR Activation in Cortex.

3-n-Butylphthalide (NBP), an extract from seeds of Apium graveolens Linn. (Chinese celery), has been demonstrated to have antidepressant effects in suspension chronic-stressed rats by our group. The purpose of this study was to investigate the possible involvement of brain-derived neurotrophic factor (BDNF) and mammalian target of rapamycin (mTOR) in the antidepressant mechanism of NBP. Chronic unpredictable mild stress (CUMS) was applied for 6 weeks to induced a depressive-like behavior, characterized by decreased locomotor activity, sucrose preference and the NE, DA and 5-HT levels in cortex. Oral treatment with NBP (30 or 100 mg/kg, p.o.), similarly to fluoxetine (2 mg/kg, p.o.), can prevention of these alterations. The NBP (30 or 100 mg/kg, p.o.) reversed the decrease in the BDNF, p-ERK, mTOR and synapsin-1 protein levels in rat cortex caused by CUMS. And rapamycin, an mTOR inhibitor, completely inhibited the antidepressant-like activity of NBP in vivo. In conclusion, these findings indicate that NBP treatment attenuated the depression-like behaviors through the modulation of serotonergic system and BDNF-ERK-mTOR signaling in rat.

Garcimultiflorone K from Garcinia multiflora attenuates hepatocellular carcinoma metastasis by suppressing transforming growth factor-ß signaling.

BACKGROUND: Transforming growth factor­ß (TGF-ß) signaling is a crucial inducer of tissue fibrosis and extracellular matrix accumulation and a vital suppressor of epithelial cell proliferation and cancer metastasis. The nature of this multifunctional cytokine has prompted the development of TGF-ß signaling inhibitors as therapeutic agents. Our research group has recently isolated the polyprenylated polycyclic acylphloroglucinol garcimultiflorone K (GMK) from the stems of Garcinia multiflora; GMK exhibits antiangiogenic activity in endothelial cells. PURPOSE: In the current study, we aimed to explore the antitumor effect and detailed mechanisms of Garcimultiflorone K in hepatocellular carcinoma cells. METHODS: Cell proliferation and viability were evaluated using the MTT assay. The migratory ability of HepG2 cells was measured using wound healing assays. The inhibitory effect of GMK against the nuclear translocation of Smad by TGF-ß was assessed through immunofluorescence staining and Western blotting. To investigate TGF-ß-dependent gene expression profiles upon GMK stimulation, RNA transcript levels were determined using reverse transcription polymerase chain reaction. The effects of GMK in Smad2-driven transcriptomic activities were studied using a reporter gene assay. Protein levels were detected using Western blotting. RESULTS: Our data revealed that GMK inhibited TGF-ß-induced cellular responses, including Smad protein phosphorylation, cell migration, and extracellular matrix production, during epithelial-mesenchymal transition (EMT). Mechanistic studies further demonstrated that GMK suppressed TGF-ß signaling by downregulating TGF-ß receptor II (TßRII). CONCLUSION: These findings elucidate that TßRII expression in hepatic cells can be specifically suppressed by GMK to attenuate metastasis and the disease-promoting effects of EMT, representing a therapeutic approach.

Enhancing TNBC Chemo-immunotherapy via combination reprogramming tumor immune microenvironment with Immunogenic Cell Death.

Tumor-associated fibroblasts (TAFs) play an important role in tumor progression and therapeutic response, especially in the immunosuppressive tumor microenvironment (TME). To remodel immunosuppressive TME of 4T1 tumor, we developed a nano liposome to deliver silybin (SLN, an anti-liver fibrosis Chinese Traditional Medicine). Liposomal silybin (SLN/LIP) possessed a spherical shape with particle sizes of 75.2 nm, high stability, and good accumulation in the tumor site. After treated with SLN/LIP, α-SMA positive TAFs and the deposition of stroma were decreased significantly. SLN/LIP also changed the tumor immune microenvironment through the increase of IFN-γ and IL-12, as well as reduced of TGF-ß, SDF-1, IL6 and TNF-α. Importantly, SLN/LIP enhanced the infiltration of cytotoxic T cells (CTLs) and transformed a "cold" tumor into a "hot" tumor. To achieve the higher antitumor efficacy, an immunogenic cell death (ICD) inducer, liposomal doxorubicin (DOX/LIP) was combined with SLN/LIP. The combination treatment led to trigger immunogenic tumor apoptosis, and enhance antitumor immunity, therefore, improved anti-tumor efficiency, and further prolonged survival duration. The combination of liposomal silybin and liposomal doxorubicin might be a new chemo-immunotherapy approach for triple negative breast cancer (TNBC) tumor treatment.

Co-Overexpression of GRK5/ACTC1 Correlates With the Clinical Parameters and Poor Prognosis of Epithelial Ovarian Cancer.

Background: The prognosis of epithelial ovarian cancer (EOC) is poor, and the present prognostic predictors of EOC are neither sensitive nor specific. Objective: The aim of this study was to search the prognostic biomarkers of EOC and to investigate the expression of G protein-coupled receptor kinase 5 (GRK5) and actin alpha cardiac muscle 1 (ACTC1) in EOC tissues (both paraffin-embedded and fresh-frozen tissues) and to explore their association with clinicopathological parameters and prognostic value in patients with EOC. Methods: A total of 172 paraffin-embedded cancer tissues of EOC patients diagnosed and operated at the memorial hospital of Sun Yat-sen University between December 2009 and March 2017 and 41 paratumor tissues were collected and the expression of GRK5 and ACTC1 was examined using immunohistochemistry. Furthermore, 16 fresh-frozen EOC tissues and their matched paratumor tissues were collected from the Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, between August 2013 and November 2019 and subjected to reverse-transcription quantitative PCR analysis to detect the mRNA expression of GRK5 and ACTC1. Results: The expression of GRK5 and ACTC1 was both higher in cancer tissues than in paratumor tissues. GRK5 expression was positively correlated with ACTC1 expression. In addition, GRK5, ACTC1, and GRK5/ACTC1 expression was associated with the recurrence-free survival and overall survival of EOC patients. Furthermore, multivariate logistic regression analysis indicated that GRK5+/ACTC1+ co-expression, intestinal metastasis, postoperative chemotherapy, platinum resistance, and hyperthermic intraperitoneal chemotherapy were independent prognostic factors of EOC. Conclusion: GRK5 and ACTC1 are both upregulated in EOC compared with those in paratumor tissues. The co-expression of GRK5+/ACTC1+ rather than GRK5 or ACTC1 is an independent prognostic biomarker of EOC.

Astilbin influences the progression of osteoarthritis in rats by down-regulation of PGE-2 expression via the NF-κB pathway.

BACKGROUND: Osteoarthritis (OA) is the most common joint disease, affecting most middle-aged and elderly people. Astilin (AST) is the main active ingredient isolated from the traditional Chinese medicine Astilbe chinensis and has anti-inflammatory and anti-arthritis effects. The purpose of this study was to investigate the effect and mechanism of AST on OA in rats mediated by papain. METHODS: In this study, in vivo experiments were conducted to investigate the protective effect and potential mechanism of Astilbin (AST) when it inhibited the development of osteoarthritis (OA). RESULTS: A rat model of OA is constructed. Through HE staining, it is found that AST can protect the articular surface and reduce damage. The results of immunohistochemical staining also prove that AST can inhibit the expression of prostaglandin E2 (PGE2) and has an excellent inhibitory effect on inflammatory factors. It is found that AST can significantly inhibit the protein expression of interleukin 1 beta (IL-1ß), TNF-α, and NF-κB. Polymerase Chain Reaction (PCR) assay shows that the mRNA of IL-1ß, TNF-α, and NF-κB is down-regulated, which also proves that the protective mechanism of AST is related to the NF-κB pathway. CONCLUSIONS: In general, this study proves that AST can be a potential therapy for degenerative joint diseases, including OA.

Glutamate synthase 1 is involved in iron-deficiency response and long-distance transportation in Arabidopsis.

Iron is an essential microelement for plant growth. After uptake from the soil, iron is chelated by ligands and translocated from roots to shoots for subsequent utilization. However, the number of ligands involved in iron chelation is unclear. In this study, we identified and demonstrated that GLU1, which encodes a ferredoxin-dependent glutamate synthase, was involved in iron homeostasis. First, the expression of GLU1 was strongly induced by iron deficiency condition. Second, lesion of GLU1 results in reduced transcription of many iron-deficiency-responsive genes in roots and shoots. The mutant plants revealed a decreased iron concentration in the shoots, and displayed severe leaf chlorosis under the condition of Fe limitation, compared to wild-type. Third, the product of GLU1, glutamate, could chelate iron in vivo and promote iron transportation. Last, we also found that supplementation of glutamate in the medium can alleviate cadmium toxicity in plants. Overall, our results provide evidence that GLU1 is involved in iron homeostasis through affecting glutamate synthesis under iron deficiency conditions in Arabidopsis.

Hypnosis intervention for the management of pain perception during cataract surgery.

OBJECTIVE: To investigate the effectiveness of hypnosis in pain management during cataract surgery. METHODS: Male or female patients with bilateral age-related cataract who wished to have both eyes subjected to phacoemulsification surgery were preliminarily admitted. Immediately after the first-eye surgery, each patient was evaluated for pain using the visual analog scale (VAS), and patients with a VAS score >1 were enrolled. By using block randomization, the enrolled patients were allocated to either the treatment group, which received a hypnosis intervention before the scheduled second-eye surgery, or the control group, which did not undergo hypnosis. The levels of anxiety, pain, and cooperation were evaluated independently by the patients and the surgeon. RESULTS: During the intraoperative pain assessment, 5%, 34%, 38%, and 23% of patients in the control group reported experiencing no pain, mild pain, moderate pain, and severe pain, respectively. In contrast, in the hypnosis group, 18%, 56%, 15%, and 11% of patients reported experiencing no pain, mild pain, moderate pain, and severe pain, respectively, which showed significant differences between the groups (P<0.005). The evaluation of anxiety level showed that the mean score in the control group and hypnosis group was 11.77±0.32 and 6.64±0.21, respectively, revealing a highly significant difference between the two groups (P<0.005). The assessment of patient cooperation showed that only 5% and 18% of patients in the control group and 18% and 36% of patients in the hypnosis group showed excellent and good cooperation, respectively, while 47% of patients in the control group and only 24% of patients in the hypnosis group exhibited poor cooperation, revealing significant differences between the groups (P<0.005). CONCLUSION: Hypnosis may be considered as an auxiliary measure in cataract surgery, especially for patients who experienced obvious pain during the first-eye surgery.

Preparation and application of magnetic molecularly imprinted polymers for the isolation of chelerythrine from Macleaya cordata.

A novel type of magnetic molecularly imprinted polymer was prepared for the selective enrichment and isolation of chelerythrine from Macleaya cordata (Willd) R. Br. The magnetic molecularly imprinted polymers were prepared using functional Fe3 O4 @SiO2 as a magnetic support, chelerythrine as template, methacrylic acid as functional monomer, and ethylene glycol dimethacrylate as cross-linker. Density functional theory at the B3LYP/6-31G (d, p) level with Gaussian 09 software was applied to calculate the interaction energies of chelerythrine, methacrylic acid and the complexes formed from chelerythrine and methacrylic acid in different ratios. The structural features and morphology of the synthesized polymers were characterized by using Fourier transform infrared spectroscopy, X-ray diffraction, transmission electron microscopy, and vibration sample magnetometry. Adsorption experiments revealed that the magnetic molecularly imprinted polymers possessed rapid kinetics, high selectivity, and a higher binding capacity (7.96 mg/g) to chelerythrine than magnetic molecularly non-imprinted polymers (2.36 mg/g). The adsorption process was in good agreement with the Langmuir adsorption isotherm and pseudo-second-order kinetics models. Furthermore, the magnetic molecularly imprinted polymers were successfully employed as adsorbents for the extraction and enrichment of chelerythrine from Macleaya cordata (Willd) R. Br. The results indicated that the magnetic molecularly imprinted polymers were suitable for the selective adsorption of chelerythrine from complex samples such as natural medical plants.

Four New 2-(2-Phenylethyl)-4H-chromen-4-one Derivatives from the Resinous Wood of Aquilaria sinensis and Their Inhibitory Activities on Neutrophil Pro-Inflammatory Responses.

Four new 2-(2-phenylethyl)-4H-chromen-4-one derivatives, 6-hydroxy-5-methoxy-2-[2-(4'-methoxyphenyl)ethyl]chromone (1: ), 6,7-dimethoxy-2-[2-(2'-hydroxyphenyl)ethyl]chromone (2: ), 5-hydroxy-6-methoxy-2-[2-(3'-methoxyphenyl)ethyl]-chromone (3: ), and 7-chloro-8-hydroxy-2-[2-(4'-methoxyphenyl)ethyl]chromone (4: ), have been isolated from the resinous wood of Aquilaria sinensis, together with 16 known compounds (5: -20: ). Among these, 7-methoxy-2-[2-(4'-methoxyphenyl)ethyl]chromone (5: ) was isolated from a natural source for the first time. The structures of the new compounds were established by spectroscopic analyses (1D and 2D NMR, HR-ESI-MS, IR, UV). Nine compounds, including 1: showed more than 80% inhibition of superoxide anion generation by human neutrophils in response to formyl-L-methionyl-L-leucyl-L-phenylalanine at 50 µM.

Sorafenib suppresses TGF-ß responses by inducing caveolae/lipid raft-mediated internalization/degradation of cell-surface type II TGF-ß receptors: Implications in development of effective adjunctive therapy for hepatocellular carcinoma.

Sorafenib is the only FDA approved drug for the treatment of advanced hepatocellular carcinoma (HCC) and other malignancies. Studies indicate that TGF-ß signalling is associated with tumour progression in HCC. Autocrine and paracrine TGF-ß promotes tumour growth and malignancy by inducing epithelial-mesenchymal transition (EMT). Sorafenib is believed to antagonize tumour progression by inhibiting TGF-ß-induced EMT. It improves survival of patients but HCC later develops resistance and relapses. The underlying mechanism of resistance is unknown. Understanding of the molecular mechanism of sorafenib inhibition of TGF-ß-induced signalling or responses in HCC may lead to development of adjunctive effective therapy for HCC. In this study, we demonstrate that sorafenib suppresses TGF-ß responsiveness in hepatoma cells, hepatocytes, and animal liver, mainly by downregulating cell-surface type II TGF-ß receptors (TßRII) localized in caveolae/lipid rafts and non-lipid raft microdomains via caveolae/lipid rafts-mediated internalization and degradation. Furthermore, sorafenib-induced downregulation and degradation of cell-surface TßRII is prevented by simultaneous treatment with a caveolae disruptor or lysosomal inhibitors. On the other hand, sorafenib only downregulates cell-surface TßRII localized in caveolae/lipid rafts but not localized in non-lipid raft microdomains in hepatic stellate cells. These results suggest that sorafenib inhibits TGF-ß signalling mainly by inducing caveolae/lipid raft-mediated internalization and degradation of cell-surface TßR-II in target cells. They may also imply that treatment with agents which promote formation of caveolae/lipid rafts, TGF-ß receptor kinase inhibitors (e.g., LY2157299) or TGF-ß peptide antagonists (by liver-targeting delivery) may be considered as effective adjunct therapy with sorafenib for HCC.

New Sesquiterpenoids and Anti-Platelet Aggregation Constituents from the Rhizomes of Curcuma zedoaria.

Two new sesquiterpenoids-13-hydroxycurzerenone (1) and 1-oxocurzerenone (2)-have been isolated from the rhizomes of Curcuma zedoaria, together with 13 known compounds (3-15). The structures of two new compounds were determined through spectroscopic and MS analyses. Among the isolated compounds, 13-hydroxycurzerenone (1), 1-oxocurzerenone (2), curzerenone (3), germacrone (4), curcolone (5), procurcumenol (6), ermanin (7), curcumin (8), and a mixture of stigmast-4-en-3,6-dione (12) and stigmasta-4,22-dien-3,6-dione (13) exhibited inhibition (with inhibition % in the range of 21.28%-67.58%) against collagen-induced platelet aggregation at 100 µM. Compounds 1, 5, 7, 8, and the mixture of 12 and 13 inhibited arachidonic acid (AA)-induced platelet aggregation at 100 µM with inhibition % in the range of 23.44%-95.36%.

Euphol from Euphorbia tirucalli Negatively Modulates TGF-ß Responsiveness via TGF-ß Receptor Segregation inside Membrane Rafts.

Transforming growth factor-ß (TGF-ß) responsiveness in cultured cells can be modulated by TGF-ß partitioning between lipid raft/caveolae- and clathrin-mediated endocytosis pathways. Lipid rafts are plasma membrane microdomains with an important role in cell survival signaling, and cholesterol is necessary for the lipid rafts' structure and function. Euphol is a euphane-type triterpene alcohol that is structurally similar to cholesterol and has a wide range of pharmacological properties, including anti-inflammatory and anti-cancer effects. In the present study, euphol suppressed TGF-ß signaling by inducing TGF-ß receptor movement into lipid-raft microdomains and degrading TGF-ß receptors.

Pretreatment with Evans blue, a stimulator of BK(Ca) channels, inhibits compound 48/80-induced shock, systemic inflammation, and mast cell degranulation in the rat.

The present study demonstrated that intravenous injection of a high dose of compound 48/80 to the rat induced 50% drop, within a few min, in the mean arterial pressure and pulse pressure as well as systemic inflammatory plasma leakage that might lead to circulatory and respiratory failure. We also investigated whether pretreatment with Evans blue, a stimulator of BK(Ca) channels, could exert inhibitory effect against compound C48/80-induced allergic circulatory shock and systemic inflammation. Different groups of Sprague-Dawley rats received an intravenous injection of a dose of Evans blue (0, 5, 10, or 50 mg/kg) just 20 s prior to injection of compound 48/80 (200 µg/kg, over 2 min). The present study found that pretreatment with Evans blue in a dose of 10 or 50 mg/kg exerted acute inhibitory effect on compound 48/80-induced sudden drop in mean arterial and pulse pressures. We also showed that pretreatment with Evans blue in a dose of 5, 10, or 50 mg/kg significantly inhibited compound 48/80-induced extensive plasma extravasation, mast cell degranulation, and edema formation in various organs including the airways, esophagus, and skin. Pretreatment with Evans blue 50 mg/kg 1 h earlier exhibited longer-term inhibitory effect on compound 48/80-induced arterial hypotension and systemic inflammation. We concluded that Evans blue pretreatment prevented rats from compound 48/80-triggered allergic shock and systemic inflammation, possibly mainly through inhibition of mast cell degranulation. Evans blue might be potentially useful in elucidating the mechanism and acting as a therapeutic agent of allergic shock and systemic inflammation.

Long-term statin use and dementia risk in Taiwan.

BACKGROUND: The effect of statin use on dementia risk remains unclear. This study aims to examine the association between long-term statin use and dementia risk. METHODS: A nest case-control study within a nationwide representative population-based cohort. Individuals aged 50 years and older participating in Taiwan's National Health Insurance program between 1998 and 2009 were enrolled. A total of 9257 patients with at least 3 outpatient or 1 inpatient claims records for dementia were identified. Comparison patients were selected at a 1:2 ratio from age- and sex-matched participants without dementia. The cumulative period and average daily dosages of statins, fibrates, and other lipid-lowering agents were measured. RESULTS: The authors found a duration-response relationship, as dementia risk decreased by 9% per year of treatment of statins (adjusted odds ratio = 0.91; 95% confidence interval, 0.85-0.97). Use of high average dose statins for more than 1 year was associated with a lower risk of dementia than use of low average dose. However, there was no significant difference in dementia risks between lipophilic and hydrophilic statins. Fibrates or other lipid-lowering agents had no significant association with dementia risk. CONCLUSION: Our results suggest that long-term use of statin is associated with a reduced dementia risk.

Cardiovascular protection with danshensu in spontaneously hypertensive rats.

The objective of the present study was to evaluate the cardiovascular protective effects of Danshensu, a water-soluble active component of Danshen, in spontaneously hypertensive rats (SHR). SHR (male, 9 weeks old, n=30) were divided into three groups: 1) saline control (n=10); 2) a Danshensu (10 mg/kg/d, intraperitoneally (i.p.)) treatment group (n=10); and 3) a Valsartan (10 mg/kg/d, intragastrically (i.g.)) treatment group (n=10). Age-matched Wistar-Kyoto rats (n=10) were used as normotensive controls. Saline and drug treatments were administered for 6 weeks. When the rats were 15 weeks old, their hearts were excised and arrhythmias were induced by an ex vivo ischemia/reperfusion protocol. The heart weight to body weight index was significantly increased in SHR, and this increase was attenuated with Danshensu treatment (both p<0.05). Systolic blood pressure and diastolic blood pressure were also decreased with Danshensu treatment, from 145±3 and 103±10 mmHg to 116±7 and 87±2 mmHg in SHR and Danshensu-treated groups, respectively (both p<0.05). The incidences of ventricular tachycardia and ventricular fibrillation decreased from 100 to 50% and 30% in SHR, respectively, with Danshensu treatment (both p<0.05). Serum nitric oxide content and inducible nitric oxide synthase activity were significantly increased with Danshensu (both p<0.05). In addition, Danshensu increased the K(+) current density and Ca(2+) activated K(+) channel current density of mesenteric vascular smooth muscle cells isolated from SHRs. Together, these results demonstrate that Danshensu imparts cardiovascular protection by modifying vascular responses during the progression of hypertension.

Targeting SYK kinase-dependent anti-apoptotic resistance pathway in B-lineage acute lymphoblastic leukaemia (ALL) cells with a potent SYK inhibitory pentapeptide mimic.

The present study found that the pentapeptide mimic C-61, targeting the substrate binding P-site of SYK tyrosine kinase acted as a potent inducer of apoptosis in chemotherapy-resistant SYK-expressing primary leukemic B-cell precursors taken directly from relapsed B-precursor leukaemia (BPL) patients (but not SYK-deficient infant pro-B leukaemia cells), exhibited favourable pharmacokinetics in mice and non-human primates, and eradicated in vivo clonogenic leukaemia cells in severe combined immunodeficient mouse xenograft models of chemotherapy-resistant human BPL at dose levels non-toxic to mice and non-human primates. These in vitro and in vivo findings provide proof of principle for effective treatment of chemotherapy-resistant BPL by targeting SYK-dependent anti-apoptotic blast cell survival machinery with a SYK P-Site inhibitor. Further development of C-61 may provide the foundation for therapeutic innovation against chemotherapy-resistant BPL.