A retrospective study on the evaluation of the appropriateness of oral anticoagulant therapy for patients with atrial fibrillation.

BACKGROUND: The incidence of atrial fibrillation (AF) is increasing, and effective anticoagulation therapy can prevent adverse events. Selecting the appropriate OAC based on patient characteristics has become a challenge. Interventions are going to be a potential area of focus. OBJECTIVES: To explore the discrepancies between clinician prescriptions and recommended guidelines of oral anticoagulants (OACs) for patients with atrial fibrillation (AF), and to provide direction for improving anticoagulation strategies for treating patients with AF. MATERIALS AND METHODS: Data were collected from the electronic medical record system of Fuwai Yunnan Cardiovascular Hospital between July 2019 and January 2020. The suitability of prescribed OACs for patients with AF was assessed according to the Rules for Avoiding Prescription Inappropriateness, the prescribed medicine label, and any relevant antithrombotic guidelines for treating patients with AF. RESULTS: A total of 460 patients met the inclusion criteria. Of these, 53.7% received an appropriate prescription and 46.3% received an inappropriate prescription. Of the patients who received inappropriate prescriptions, 15.4% were prescribed without the presenting appropriate indicators, 1.3% were prescribed inappropriate drug selection, and 29.6% were prescribed inappropriate drug doses. For patients prescribed without providing appropriate indicators, 2.2% had no indication for medication and 13.3% had an indication for medication, but not a specific OAC. For patients with inappropriate drug selection, 1, 5 patients were on rivaroxaban, dabigatran respectively. The distribution of NOAC doses was as follows: dabigatran standard dose (45.2%), the low dose (54.8%). Rivaroxaban standard dose (58.9%), low dose (36.8%), high dose (4.3%). A total of 44 patients (9.6%) experienced bleeding events, 12 patients (2.6%) experienced embolic events, and 7 patients experienced other adverse events after dosing. CONCLUSIONS: In clinical practice, it is common for patients with AF to receive inappropriate prescriptions of OACs. Therefore there is a need to enhance anticoagulation management in patients with AF to improve the appropriate use of OACs.

Isoforskolin, an adenylyl cyclase activator, attenuates cigarette smoke-induced COPD in rats.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by limited airflow due to pulmonary and alveolar abnormalities from exposure to cigarette smoke (CS). Current therapeutic drugs are limited and the development of novel treatments to prevent disease progression is challenging. Isoforskolin (ISOF) from the plant Coleus forskohlii is an effective activator of adenylyl cyclase (AC) isoforms. Previously we found ISOF could attenuate acute lung injury in animal models, while the effect of ISOF on COPD has not been elucidated. PURPOSE: In this study, we aimed to evaluate the efficacy of ISOF on COPD and reveal its potential mechanisms. METHODS: A rat model of COPD was established by long-term exposure to CS, then the rats were orally administered with ISOF (0.5, 1 and 2 mg/kg). The pulmonary function, lung morphology, inflammatory cells and cytokines in serum or bronchoalveolar lavage fluid (BALF) were evaluated. Transcriptomics, proteomics and network pharmacology analysis were utilized to identify potential mechanisms of ISOF. Droplet digital PCR was used to detect the mRNA expression of AC1-10 in donor lung tissues. AC activation was determined in recombinant human embryonic kidney 293 (HEK293) cells stably expressing human AC isoforms. In addition, ISOF caused trachea relaxation ex vivo were assessed in isolated trachea rings from guinea pigs. RESULTS: ISOF significantly ameliorated pathological damage of lung tissue and improved pulmonary function in COPD rats. ISOF treatment decreased the number of inflammatory cells in peripheral blood, and also the levels of pro-inflammatory cytokines in serum and BALF. Consistent with omics-based analyses, ISOF markedly downregulated the mTOR level in lung tissue. Flow cytometry analysis revealed that ISOF treatment reduced the ratio of Th17/Treg cells in peripheral blood. Furthermore, the expression levels of AC1 and AC2 are relatively higher than other AC isoforms in normal lung tissues, and ISOF could potently activate AC1 and AC2 in vitro and significantly relax isolated guinea pig trachea. CONCLUSION: Collectively, our studies suggest that ISOF exerts its anti-COPD effect by improving lung function, anti-inflammation and trachea relaxation, which may be related to AC activation, mTOR signaling and Th17/Treg balance.

Tianma Formula Alleviates Dementia via ACER2-Mediated Sphingolipid Signaling Pathway Involving Aß.

OBJECTIVE: To reveal the molecular mechanism of the antagonistic effect of traditional Chinese medicine Tianma formula (TF) on dementia including vascular dementia (VaD) and Alzheimer's disease (AD) and to provide a scientific basis for the study of traditional Chinese medicine for prevention and treatment of dementia. METHOD: The TF was derived from the concerted application of traditional Chinese medicine. We detected the pharmacological effect of TF in VaD rats. The molecular mechanism of TF was examined by APP/PS1 mice in vivo, Caenorhabditis elegans (C. elegans) in vitro, ELISA, pathological assay via HE staining, and transcriptome. Based on RNA-seq analysis in VaD rats, the differentially expressed genes (DEGs) were identified and then verified by quantitative PCR (qPCR) and ELISA. The molecular mechanisms of TF on dementia were further confirmed by network pharmacology and molecular docking finally. RESULTS: The Morris water maze showed that TF could improve the cognitive memory function of the VaD rats. The ELISA and histological analysis suggested that TF could protect the hippocampus via reducing tau and IL-6 levels and increasing SYN expression. Meanwhile, it could protect the neurological function by alleviating Aß deposition in APP/PS1 mice and C. elegans. In the RNA-seq analysis, 3 sphingolipid metabolism pathway-related genes, ADORA3, FCER1G, and ACER2, and another 5 nerve-related genes in 45 key DEGs were identified, so it indicated that the protection mechanism of TF was mainly associated with the sphingolipid metabolism pathway. In the qPCR assay, compared with the model group, the mRNA expressions of the 8 genes mentioned above were upregulated, and these results were consistent with RNA-seq. The protein and mRNA levels of ACER2 were also upregulated. Also, the results of network pharmacology analysis and molecular docking were consistent with those of RNA-seq analysis. CONCLUSION: TF alleviates dementia by reducing Aß deposition via the ACER2-mediated sphingolipid signaling pathway.

The discovery, design and synthesis of potent agonists of adenylyl cyclase type 2 by virtual screening combining biological evaluation.

Adenylate cyclases (ACs), play a critical role in the conversion of adenosine triphosphate (ATP) into the second messenger cyclic adenosine monophosphate (cAMP). Studies have indicated that adenylyl cyclase type 2 (AC2) is potential drug target for many diseases, however, up to now, there is no AC2-selective agonist reported. In this research, docking-based virtual screening with the combination of cell-based biological assays have been performed for discovering novel potent and selective AC2 agonists. Virtual screening disclosed a novel hit compound 8 as an AC2 agonist with EC50 value of 8.10 µM on recombinant human hAC2 + HEK293 cells. The SAR (structure activity relationship) based on the derivatives of compound 8 was further explored on recombinant AC2 cells and compound 73 was found to be the most active agonist with the EC50 of 90 nM, which is 160-fold more potent than the reported agonist Forskolin and could selectively activate AC2 to inhibit the expression of Interleukin-6. The discovery of a new class of AC2-selective agonists would provide a novel chemical probe to study the physiological function of AC2.

Gastrodin Alleviates Vascular Dementia in a 2-VO-Vascular Dementia Rat Model by Altering Amyloid and Tau Levels.

Vascular dementia (VaD) is the second most common type of dementia and has become a major public health challenge as the global population ages. VaD is caused by cerebrovascular disease, and most patients with VaD have been reported to also have Alzheimer's pathologies, which is the formation of neurofibrillary tangles and amyloid plaques that are mainly composed of hyperphosphorylated Tau and amyloid ß (Aß) respectively. However, the mechanisms of VaD are not completely understood, and very few drugs are available to treat this condition. Gastrodin (Gas) is the main bioactive component of the traditional Chinese herbal plant named Tian Ma (Gastrodia elata), and it has been used to treat neurasthenia in the clinical practice of Chinese Medicine for many years. Here, we hypothesize that Gas alleviates VaD in a rat model of permanent bilateral common carotid artery occlusion (2-VO)-induced VaD. Based on the results of the Morris water maze test and attention set shift test, either 22.5 or 90 mg/kg/day Gas improved the executive dysfunction and memory impairment of 2-VO rats following an intragastric administration for 4 weeks. Both 22.5 and 90 mg/kg/day Gas reduced Aß1-40 and Aß1-42 plaques in plasma and hippocampus of 2-VO rats. Mechanistically, in 2-VO rats, treatment with Gas (90 mg/kg/day) suppressed Aß plaque deposition by decreasing the hippocampus levels of phosphorylated Tau. Thus, Gas ameliorated the cognitive deficits of 2-VO rats by inhibiting the abnormal phosphorylation of Aß and Tau.

Isoforskolin and forskolin attenuate lipopolysaccharide-induced inflammation through TLR4/MyD88/NF-κB cascades in human mononuclear leukocytes.

The principal active component of isoforskolin (ISOF) is from the plant Coleus forskohlii, native to China, which has attracted much attention for its biological effects. We hypothesize that ISOF and forskolin (FSK) pretreatment attenuates inflammation induced by lipopolysaccharide (LPS) related to toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and nuclear factor kappa B (NF-κB) signaling. Mononuclear leukocytes (MLs) from healthy donors' blood samples were separated by using density gradient centrifugation. Protein levels of TLR4, MyD88, and NF-κB were detected using western blot and inflammatory cytokines interleukin (IL) 1ß, IL-2, IL-6, IL-21, IL-23, tumor necrosis factor (TNF) α, and TNF-ß were tested by enzyme-linked immunosorbent assay and Quantibody array in MLs. Our results showed that LPS augmented the protein levels of TLR4, MyD88, and NF-κB in MLs and the production of IL-1ß, IL-2, IL-6, IL-21, IL-23, TNF-α, and TNF-ß in supernatants of MLs. Despite treatment with ISOF and FSK prior to LPS, the protein levels of TLR4, MyD88, NF-κB, IL-1ß, IL-2, IL-6, IL-21, IL-23, TNF-α, and TNF-ß in MLs were apparently decreased. roflumilast (RF) and dexamethasone (DM) had a similar effect on MLs with ISOF and FSK. Our results, for the first time, have shown that ISOF and FSK attenuate inflammation in MLs induced by LPS through down-regulating protein levels of IL-1ß and TNF-α, in which TLR4/MyD88/NF-κB signal pathway could be involved.

6,7-seco-ent-kaurane diterpenoids from Isodon sculponeatus with cytotoxic activity.

Six new 6,7-seco-ent-kaurane diterpenoids, sculponeatins N-S (1-6, resp.), together with eleven known analogues, 7-17, were isolated from the aerial parts of Isodon sculponeatus. The structures of compounds 1-6 were elucidated by spectroscopic methods including extensive 1D- and 2D-NMR experiments, as well as HR-ESI-MS analysis. All diterpenoids obtained were assayed for their cytotoxic activity against K562 and HepG2 human tumor cell lines. Among them, compound 1 showed the most significant cytotoxicity with the IC50 values of 0.21 and 0.29 µM, respectively. The structure-activity relationships are discussed.

Inhibition of NF-kappaB activation and iNOS induction by ent-kaurane diterpenoids in LPS-stimulated RAW264.7 murine macrophages.

Xerophilusin A (1), xerophilusin B (2), longikaurin B (3), and xerophilusin F (4) from Isodon xerophylus inhibit LPS-induced NO production in RAW 264.7 macrophages, with IC(50) values of 0.60, 0.23, 0.44, and 0.67 muM, respectively, and they all inhibited mRNA production in these same cells. They decreased the luciferase activity in RAW 264.7 cells transiently transfected with the NF-kappaB-dependent luciferase reporter, with IC(50) values of 1.8, 0.7, 1.2, and 1.6 muM, respectively. Compounds 1-3 reduced NF-kappaB activation, with compound 4 showing no effect, but p65 translocation from the cytoplasm to the nucleus and the LPS-induced degradation of IkappaB were inhibited by all four test compounds. These findings indicate that ent-kauranes are potential anti-inflammatory agents, with a specific mechanism in which both the inhibition of NF-kappaB translocation and the consequent decrease of pro-inflammatory mediators are implicated.

Bioactive Nortriterpenoids from Schisandra grandiflora.

Three new nortriterpenoids, schigrandilactones A-C (1-3), along with eight known compounds, were isolated from an organic solvent extract of Schisandra grandiflora. Compounds 1 and 2 feature a spirocyclic moiety in their structures, and compound 3 was characterized with a new oxygenated pattern. The relative configurations of 1 and 3 were determined through single-crystal X-ray experiments. In addition, compounds 1 and 2 displayed cytotoxic activity against two human cancer cell lines, and compound 3 showed anti-HIV-1 inhibition in infected C8166 cells.

Cytotoxic ent-kaurane diterpenoids from Isodon henryi.

Chromatographic fractionation of the extract of Isodon henryi resulted in the isolation of seven new ENT-kaurane diterpenoids, named minheryins A-G (1-7), together with the six known ENT-kaurane diterpenoids leukamenin F (8), excisoidesin (9), leukamenin E (10), wangzaozin A (11), pseurata A (12), and racemosin A (13), which were elucidated by spectroscopic analysis. Compounds 7-13 were tested for their cytotoxicity against K562 and HepG2 cell lines, and they all exhibited significant activities with IC50 values<0.50 microg/mL. Isolates 1-5 were evaluated against the K562 cell line, and only 3 showed weak activity.

Cytotoxic ent-kauranoids from the medicinal plant Isodon xerophilus.

Bioassay-directed fractionation of the leaves of the medicinal plant Isodon xerophilus led to the isolation of a series of potential antitumor molecules. Thirteen new (1-13) and 23 (14-36) known diterpenoids were isolated and identified, representing ent-kauranoids of several structural types. The structures of 1-13 were determined by means of spectroscopic studies. The absolute configurations of the new compounds were clarified by CD spectroscopic studies or were postulated on biogenetic grounds. All compounds obtained were evaluated for their cytotoxic activity against the K562, MKN45, and HepG2 cell lines. Compounds 1, 2, 11, 16-19, 23, 26-28, 30, and 32 demonstrated significant cytotoxic activity for one or more cell lines.

ent-Abietane diterpenoids from Isodon rubescens var. rubescens.

ent-Abietane diterpenoids, hebeiabinins A-F (1-5), together with seven known diterpenoids were isolated from leaves of Isodon rubescens var. rubescens. The structures of 1-5 were established on the basis of spectroscopic analyses, including application of 2D NMR spectroscopic techniques. The diterpenoids isolated were evaluated for the cytotoxicity against A549, HT-29, and K562 tumor cells. Compound 5 was the most active with IC(50) value of 0.91 microM against A549 cells.

Cytotoxic ent-kauranoids from Isodon parvifolius.

Three new ent-kaurane diterpenoids, parvifoline Z (1), parvifoline AA (2), and parvifoline AB (3), together with 14 known compounds, were isolated from the leaves of Isodon parvifolius. The structures of the new compounds were elucidated by 1D- and 2D-NMR spectroscopy and mass spectrometry, and by comparison with known compounds. These three new diterpenoids included three types of ent-kauranoids, namely, C(20)-non-oxygenated-ent-kauranoid, 7,20-cyclo-ent-kauranoid and 6,7-seco-ent-kauranoid-7,20-olide. Compounds 1 and 2 exhibited significant cytotoxicities against A549, HT-29, and K562 cell lines.

Five new triterpene glycosides from Lysimachia foenum-graecum and evaluation of their effect on the arachidonic acid metabolizing enzyme.

Five new oleanane-type triterpene saponins, named foenumosides A ( 1), B ( 2), C ( 3), D ( 4) and E ( 5), were isolated from the aerial parts of Lysimachia foenum-graecum Hance. Their structures were identified on the basis of 1D and 2D NMR techniques, including H-H COSY, HMQC, HMBC, HMQC-TOCSY, ROESY experiments as well as chemical methods. We have evaluated the cytotoxity of 1 - 5 against rat and human polymorphonuclear leukocytes and the effect of 5 on the arachidonic acid metabolizing enzyme. All compounds showed a high degree of toxicity except for compound 5, while 5 notably reduced the production of leukotriene B (4) (LTB (4)) from rat peritoneal leukocytes with an IC (50) value of 74 microM without inhibiting human elastase. Compound 5 also reduced the production of 12-HHTrE and 12-HETE by 14 % and 50 % as a measurement for cyclooxygenase-1 and 12-lipoxygenase inhibition at 100 microM.