Griffinmarker5430

In the current study, geniposide treatment greatly decreased the levels of RNA polymerase in HEK-293T cells infected with IAV. Knocking down CAMKII in IAV-infected HEK-293T cells enhanced virus RNA (vRNA) production. Geniposide treatment increased CAMKII expression after IAV infection. Meanwhile, the CREB and c-Fos expressions were inhibited by geniposide after IAV infection. The experimental validation data showed that the geniposide was able to alleviate extracellular Ca2+ influx, dramatically decreased neuraminidase activity, and suppressed IAV replication in vitro via regulating the calcium signaling pathway. These anti-IAV effects might be related to the disrupted interplay between IAV RNA polymerase and CAMKII and the regulation of the downstream calcium signaling pathway essential for IAV replication. Taken together, the findings reveal a new facet of the mechanism by which geniposide fights IAV in a way that depends on CAMKII replication.Atherosclerosis is the major cause of heart attack and stroke that are the leading causes of death in the world. Nanomedicine is a powerful tool that can be engineered to target atherosclerotic plaques for therapeutic and diagnosis purposes. In this review, advances in designing nanoparticles with therapeutic effects on atherosclerotic plaques known as atheroprotective nanomedicine have been summarized to stimulate further development and future translation.Objective The occurrence, development, and prognosis of serious adverse events (SAEs) associated with anticancer drugs in clinical trials have important guiding significance for real-world clinical applications. However, to date, there have been no studies investigating SAEs reporting in randomized clinical trials of colorectal cancer treatments. This article systematically reviewed the SAEs reporting of phase III randomized clinical trials of colorectal cancer treatments and analyzed the influencing factors. Methods We reviewed all articles about phase III randomized clinical trials of colorectal cancer treatments published in the PubMed, Embase, Medline, and New England Journal of Medicine databases from January 1, 1993, to December 31, 2018, and searched the registration information of clinical trials via the internet sites such as "clinicaltrials.gov". We analyzed the correlation between the reported proportion (RP) of SAEs in the literature and nine elements, including the clinical trial sponsor and the .7%, p = 0.030). In the clinical trials referenced by clinical guidelines, the RP of SAEs was higher than that in non-referenced clinical trials (32.0 versus 15.9%, p = 0.023). Binary logistic regression analysis showed that pharmaceutical company sponsorship, new drug research, and sample size greater than 1000 were positive influencing factors for SAEs reporting. RSL3 solubility dmso Conclusion Although the RP of SAEs increased over time, SAEs reporting in clinical trials needs to be further improved. The performance, outcomes and prognosis of SAEs should be reported in detail to guide clinical practice in the real world.Potassium-competitive acid blocker is a new class of drugs inhibiting gastric acid. It is controversial that vonoprazan showed the inhibitory activities of cytochrome P450 3A4. This study aimed to evaluate the pharmacokinetics (PK) of atorvastatin and safety when atorvastatin was administered alone and co-administered with vonoprazan or tegoprazan. An open-label, multiple-dose, 3-intervention, 4-sequence, 4-period, partial replicate crossover study was conducted, and three interventions were; one is orally administered atorvastatin 40 mg alone once daily for 7 days, another is atorvastatin co-administered with vonoprazan 20 mg, and the other is atorvastatin co-administered with tegoprazan 50 mg. PK blood samples were collected up to 24 h after the last dose, and PK parameters for atorvastatin, 2-hydroxyatorvastatin and atorvastatin lactone were estimated by a non-compartmental method. Safety was evaluated, including adverse events and clinical laboratory tests. A total of 28 subjects completed the study. When atorvastatin was co-administered with vonoprazan, the systemic exposures of atorvastatin and atorvastatin lactone significantly increased, and the metabolic ratio of 2-hydroxyatorvastatin significantly decreased. Hypergastrinemia only occurred when atorvastatin was co-administered with vonoprazan. However, the plasma concentration profiles of atorvastatin, 2-hydroxyatorvastatin and atorvastatin lactone were similar when atorvastatin was administered alone or co-administered with tegoprazan. In conclusion, after multiple doses of atorvastatin co-administered with vonoprazan in healthy subjects, the systemic exposure of atorvastatin and the incidence of hypergastrinemia increased. With tegoprazan, however, those interactions were not observed.Since the 1980s, the development of a pharmacology based on nerve growth factor (NGF) has been postulated for the therapy of Alzheimer's disease (AD). This hypothesis was based on the rescuing effect of the neurotrophin on the cholinergic phenotype of the basal forebrain neurons, primarily compromised during the development of AD. Subsequently, the use of NGF was put forward to treat a broader spectrum of neurological conditions affecting the central nervous system, such as Parkinson's disease, degenerative retinopathies, severe brain traumas and neurodevelopmental dysfunctions. While supported by solid rational assumptions, the progress of a pharmacology founded on these hypotheses has been hampered by the difficulty of conveying NGF towards the brain parenchyma without resorting to invasive and risky delivery methods. At the end of the last century, it was shown that NGF administered intranasally to the olfactory epithelium was able to spread into the brain parenchyma. Notably, after such delivery, pharmacologically relevant concentration of exogenous NGF was found in brain areas located at considerable distances from the injection site along the rostral-caudal axis. These observations paved the way for preclinical characterization and clinical trials on the efficacy of intranasal NGF for the treatment of neurodegenerative diseases and of the consequences of brain trauma. In this review, a summary of the preclinical and clinical studies published to date will be attempted, as well as a discussion about the mechanisms underlying the efficacy and the possible development of the pharmacology based on intranasal conveyance of NGF to the brain.Atherosclerotic cardiovascular disease is a common and severe complication of diabetes. There is a large need to identify the effective and safety strategies on diabetic cardiovascular disease (DCVD). 9-PAHSA is a novel endogenous fatty acid, and has been reported to reduce blood glucose levels and attenuate inflammation. We aim to evaluate the effects of 9-PAHSA on DCVD and investigate the possible mechanisms underlying it. Firstly, serum 9-PAHSA levels in human were detected by HPLC-MS/MS analysis. Then 9-PAHSA was synthesized and purified. The synthesized 9-PAHSA was gavaged to db/db mice with 50 mg/kg for 4 weeks. The carotid arterial plaque and cardiac structure was assessed by ultrasound. Cardiac autophagy was tested by western blot analysis, electron microscope and iTRAQ. The results showed that 9-PAHSA, in patients with type 2 diabetes mellitus (T2DM), was significantly lower than that in non-diabetic subjects. Administration of 9-PAHSA for 2 weeks reduced blood glucose levels. Ultrasound observed that continue administration of 9-PAHSA for 4 weeks ameliorated carotid vascular calcification, and attenuated myocardial hypertrophy and dysfunction in db/db mice. Electron microscopy showed continue 9-PAHSA treatment significantly increased autolysosomes, while dramatically decreased greases in the myocardial cells of the db/db mice. Moreover, iTRAQ analysis exhibited that continue 9-PAHSA treatment upregulated BAG3 and HSPB8. Furthermore, western blot analysis confirmed that 9-PAHSA down-regulated Akt/mTOR and activated PI3KIII/BECN1 complex in diabetic myocardium. Thus, 9-PAHSA benefits DCVD in diabetic mice by ameliorating carotid vascular calcification, promoting autophagic flux and reducing myocardial hypertrophy.Unintended pregnancy is a situation that every woman may encounter, and medical abortion is the first choice for women, but abortion often brings many sequelae. Angelica sinensis Radix (Danggui) and Leonuri Herba (Yimucao) are widely used in the treatment of gynecological diseases, which can regulate menstrual disorders, amenorrhea, dysmenorrhea, and promote blood circulation and remove blood stasis, but the mechanism for the treatment of abortion is not clear. We determined the ability of Danggui and Yimucao herb pair (DY) to regulate the Th1/Th2 paradigm by detecting the level of progesterone in the serum and the expression of T-bet and GATA-3 in the spleen and uterus. Then, we detected the level of metabolites in the serum and enriched multiple metabolic pathways. The arachidonic acid pathway can directly regulate the differentiation of Th1/Th2 cells. This may be one of the potential mechanisms of DY in the treatment of abortion.Combinations of two and more drugs with different target sites are being used as a new treatment regimen for resistant clones of bacteria. Though, achieving the right combination of the drugs for optimal dosage regimen is challenging. In our study, we studied the antimicrobial effect of aditoprim, a novel dihydrofolate reductase inhibitor, and its synergistic effect with sulfamethoxazole. Synergy testing was performed by checkerboard micro dilution method and validation of different checkerboard ratios by static and dynamic time-kill analysis and in vitro pharmacokinetic/pharmacodynamics (PK/PD) model, and semi mechanistic PK/PD modeling was used to calculate and validate the synergistic effect of drug combination. Both checkerboard and static time-kill assays demonstrated the greater synergistic effect [fractional inhibitory concentration index (FICI) = 0.37] of the aditoprim [minimum inhibitory concentration (MIC) = 0.25 µg/ml]-sulfamethoxazole (MIC=>64 µg/ml) combination against all T. Pyogenes isolates. In the in vitro PK/PD model, the dosage proportion of sulfamethoxazole 4 mg/ml twice a day in combination with steady-state aditoprim 1 mg/ml efficiently repressed the growth of bacteria in 24 h with the ratio of 2-log10 decrease, related to the early inoculum against three T. Pyogenes isolates. The semi mechanistic PK/PD model projected that a combination of a high dose of aditoprim (2 mg/ml) with sulfamethoxazole (2 mg/day) was necessary to attain the killing of bacteria below the detection limit (limit of detection (LOD); i.e., 1 log10 CFU/ml) at 24 h with an MIC sulfamethoxazole (SMZ) of 64 µg/ml. However, it is anticipated that a combination of high dose of aditoprim with sulfamethoxazole is critical to attain the suppressed bacterial growth to less then LOD. This study represents essential PK/PD modeling for optimization of combination of aditoprim and sulfamethoxazole to suppress growth of T. Pyogenens.Rosuvastatin is a well-known lipid-lowering agent generally used for hypercholesterolemia treatment and coronary artery disease prevention. There is a substantial inter-individual variability in the absorption of statins usually caused by genetic polymorphisms leading to a variation in the corresponding pharmacokinetic parameters, which may affect drug therapy safety and efficacy. Therefore, the investigation of metabolic markers associated with rosuvastatin inter-individual variability is exceedingly relevant for drug therapy optimization and minimizing side effects. This work describes the application of pharmacometabolomic strategies using liquid chromatography coupled to mass spectrometry to investigate endogenous plasma metabolites capable of predicting pharmacokinetic parameters in predose samples. First, a targeted method for the determination of plasma concentration levels of rosuvastatin was validated and applied to obtain the pharmacokinetic parameters from 40 enrolled individuals; then, predose samples were analyzed using a metabolomic approach to search for associations between endogenous metabolites and the corresponding pharmacokinetic parameters.