Pharmacokinetics and tissue distribution study of two novel quinazoline PI3K/mTOR dual-inhibitors, potential anticancer agents.

S and S, two structurally similar quinazoline derivatives, are novel anticancer drugs targeting the PI3K/AKT/mTOR signaling pathway channel. However, their pharmacokinetic and tissue distribution characteristics are unknown, which has hindered further development and in-depth studies. In this study, a simple, rapid and sensitive method using high performance liquid chromatography was established and validated to quantitatively study the pharmacokinetics and tissue distribution profiles of S and S in rats following intravenous injection.

Study on the interaction of two quinazoline derivatives as novel PI3K/mTOR dual inhibitors and anticancer agents to human serum albumin utilizing spectroscopy and docking.

Interactions of human serum albumin (HSA) with two structurally similar quinazoline derivatives, S and S , which are potential anticancer drugs acting on PI3K/mTOR targets, were investigated in vitro utilizing multiple spectroscopy as well as molecular docking. The fluorescence quenching study demonstrated that HSA fluorescence could be statically quenched by S and S through the formation of an HSA-drug complex. Furthermore, the details of the binding site number, binding constant, as well as the thermodynamic parameters, were estimated at 298, 303, and 310 K.

Long non-coding RNA metastasis-related lung adenocarcinoma transcript 1 (MALAT1) forms a negative feedback loop with long non-coding RNA colorectal neoplasia differentially expressed (CRNDE) in sepsis to regulate lung cell apoptosis.

It has been reported that long non-coding RNAs (lncRNAs) metastasis-related lung adenocarcinoma transcript 1 (MALAT1) and colorectal neoplasia differentially expressed (CRNDE) play opposite roles in sepsis. Therefore, we explored their potential interaction with sepsis. To this end, we determined MALAT1 and CRNDE levels using RT-qPCR in plasma samples collected from healthy controls (n = 60) and sepsis patients (n = 60) before and after treatment and the effects of MALAT1 and CRNDE overexpression in human bronchial epithelial cells (HBEpCs) on the expression of each other and HBEpC apoptosis.

Protective ballooning technique for prevention of side branch occlusion in coronary nonleft main true bifurcation lesions: A single-center study.

Objectives: We aimed to evaluate the efficacy of a protective ballooning technique in preventing side branch (SB) occlusion and to assess the long-term clinical outcomes for coronary nonleft main true bifurcation lesions.

Background: SB occlusion is a major complication associated with percutaneous coronary intervention (PCI) for coronary bifurcation lesions.

Methods: Patients were consecutively enrolled and randomly assigned to protective ballooning technique or jailed wire technique group.

Effectiveness and safety of pyrotinib-based therapy in patients with HER2-positive metastatic breast cancer: A real-world retrospective study.

The previous studies had demonstrated the promising effectiveness and acceptable safety of pyrotinib in patients with HER2-positive metastatic breast cancer. We aimed to investigate the real-world data of pyrotinib in complex clinical practice and complement the findings of clinical trials. Two hundred and eighteen patients were included for effectiveness analysis.

1,3-Benzodioxole-based fibrate derivatives as potential hypolipidemic and hepatoprotective agents.

A series of target compounds 1,3-benzodioxole-based fibrate derivatives were designed and synthesized. All the target compounds were preliminarily evaluated by hyperlipidemia mice induced by Triton WR-1339, in which compound 12 displayed a greater anti-hyperlipidemia activity than other compounds as well as positive drug fenofibrate (FF). 12 showed a significant reduction of plasma lipids, such as triglycerides (TG), total cholesterol (TC) and low-density lipoprotein cholesterin (LDL-C), in high fat diet (HFD) induced hyperlipidemic mice.

miR-92a-3p promotes ox-LDL induced-apoptosis in HUVECs via targeting SIRT6 and activating MAPK signaling pathway.

Atherosclerosis could be induced by multiple factors, including hypertension, hyperlipidemia, and smoking, and its pathogenesis has not been fully elucidated. MicroRNAs have been shown to possess great anti-atherosclerotic potential, but the precise function of miR-92a-3p in atherosclerosis and its potential molecular mechanism have not been well clarified. Flow cytometry assay and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazol-3-ium bromide (MTT) assay were performed to evaluate effects of oxidized low-density lipoprotein (ox-LDL) on proliferation and apoptosis of human umbilical vein endothelial cells (HUVECs), respectively.

miR-96-5p Regulates Proliferation, Migration, and Apoptosis of Vascular Smooth Muscle Cell Induced by Angiotensin II via Targeting NFAT5.

Background: Aberrant proliferation, migration, and apoptosis of vascular smooth muscle cells (VSMCs) are major pathological phenomenon in hypertension. MicroRNAs (miRNAs/miRs) serve crucial roles in the progression of hypertension. We aimed to determine the role of miR-96-5p in the proliferation, migration, and apoptosis of VSMCs and its underlying mechanisms.

Design, synthesis and evaluation of 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione-Based fibrates as potential hypolipidemic and hepatoprotective agents.

Six novel target compounds 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione (ADT) based fibrates were synthesized and evaluated. All the synthesized compounds were preliminarily screened by using the Triton WR-1339-induecd hyperlipidemia model, in which T1 exhibited more potent hypolipidemic property than positive drug fenofibrate (FF). T1 also significantly decreased serum triglycerides (TG), total cholesterol (TC) and low density lipoprotein cholesterin (LDL) in methionine solution (Mets) induced hyperlipidemic mice.

Design, synthesis and evaluation of phenylfuroxan nitric oxide-donor phenols as potential anti-diabetic agents.

Both nitric oxide (NO) dysfunction and oxidative stress have been regarded as the important factors in the development and progression of diabetes and its complications. Multifunctional compounds with hypoglycemic, NO supplementation and anti-oxidation will be the promising agents for treatment of diabetes. In this study, six phenylfuroxan nitric oxide (NO) donor phenols were synthesized, which were designed via a combination approach with phenylfuroxan NO-donor and natural phenols.

A New Series of Salicylic Acid Derivatives as Non-saccharide α-Glucosidase Inhibitors and Antioxidants.

In this study, a series of salicylic acid derivatives were designed and synthesized as novel non-saccharide α-glucosidase inhibitors. Biological evaluation indicated that when compared to acarbose, compounds T9, T10, and T32 exhibited a higher potency of α-glucosidase inhibitory activity with IC values of 0.15 ± 0.

Synthesis, nitric oxide release, and dipeptidyl peptidase-4 inhibition of sitagliptin derivatives as new multifunctional antidiabetic agents.

Nitric oxide (NO) dysfunction has been found to be an important factor in both the development and progression of diabetic complications due to its many roles in the vascular system. Multifunctional compounds with hypoglycemic and endothelial protective action will be promising agents for the treatment of diabetes and its complications. In this study, a series of novel NO-donating sitagliptin derivatives and relevant metabolites were synthesized and evaluated as potential multifunctional hypoglycemic agents.

5-(4-Hydroxyphenyl)-3H-1,2-dithiole-3-thione-based fibrates as potential hypolipidemic and hepatoprotective agents.

Hypolipidemic effects of the newly synthesized 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione-based fibrates were evaluated in Triton WR-1339 and high-fat diet (HFD)-induced hyperlipidemic mice. Preliminary screening of all the synthesized compounds was done by using an acute model (Triton WR-1339 model), in which compound 6 shown more significant antidyslipidemic activity than fenofibrate (FF). The compound 6 was also found to reduce serum triglyceride (TG), total cholesterol (TC) and low density lipoprotein cholesterin (LDL) in HFD-induced hyperlipidemic mice.

A new multifunctional hydroxytyrosol-clofibrate with hypolipidemic, antioxidant, and hepatoprotective effects.

Oxidative stress has been regarded as the leading mechanism of the hepatotoxicity of clofibrate (CF). To achieve multifunctional novel hypolipidemic agents with hypolipidemia, antioxidant, and ameliorating liver injury, clofibric acid derivative hydroxytyrosol-clofibrate (CF-HT) was synthesized by molecular hybridization. CF-HT exhibited significant hypolipidemia, reducing serum triglyceride (TG), total cholesterol (TC), and malonaldehyde (MDA) by 30%, 33%, and 29% in hyperlipidemic mice induced by Triton WR 1339.

Hydroxytyrosol nicotinate, a new multifunctional hypolipidemic and hypoglycemic agent.

Hydroxytyrosol (HT) is a natural polyphenol antioxidant that exists in olive oil. In the study of multifunctional hypolipidemic of nicotinic derivatives, we found that hydroxytyrosol nicotinate (HT-N) incorporation of niacin with HT displayed ?-glucosidase inhibitory activities in vitro, such as yeast ?-glucosidase (IC?=?117.72??M) and rat intestinal ?-glucosidases maltase (IC?=?31.

A new multifunctional hydroxytyrosol-fenofibrate with antidiabetic, antihyperlipidemic, antioxidant and antiinflammatory action.

Dyslipidemia, oxidative stress and inflammation are major risky factors involved in the pathophysiology of type 2 diabetes mellitus and atherosclerosis. Multifunctional intervene is more meaningful. The aim of this study was to evaluate the multifunctional effects of two new compounds, combination of fenofibric acid (FA) with tyrosol (T) or hydroxytyrosol (HT).

In vitro evaluation of α-lipoic acid-loaded lipid nanocapsules for topical delivery.

This study aimed at in vitro evaluation of α-lipoic acid-loaded lipid nanocapsules for topical delivery, which was prepared by hot high-pressure homogenisation. Stable particles could be formed and particle size was 148.54 ± 2.

Phenylsulfonylfuroxan NO-donor phenols: Synthesis and multifunctional activities evaluation.

Phenylsulfonyfuroxan nitric oxide (NO)-donor phenols were designed, synthesized and evaluated. The compounds were designed through a symbiotic approach using selected phenols and phenylsulfonylfuroxan NO-donor. The antioxidant activities of the hybrid compounds T-T showed to be good in vivo.

Definition of the binding mode of phosphoinositide 3-kinase α-selective inhibitor A-66S through molecular dynamics simulation.

Activation of the phosphatidylinositol 3-kinase α (PI3Kα) is commonly observed in human cancer and is critical for tumor progression, which has made PI3Kα an attractive target for anticancer drug discovery. To systematically investigate the binding mode of A-66S, a new selective PI3Kα inhibitor for PI3Kα, molecular docking, molecular dynamics simulation and ensuing energetic analysis were performed. The binding free energy between PI3Kα and A-66S is -11.

Synthesis and α-glucosidase inhibitory activity evaluation of N-substituted aminomethyl-β-d-glucopyranosides.

A series of N-substituted 1-aminomethyl-β-d-glucopyranoside derivatives was prepared. These novel synthetic compounds were assessed in vitro for inhibitory activity against yeast α-glucosidase and both rat intestinal α-glucosidases maltase and sucrase. Most of the compounds displayed α-glucosidase inhibitory activity, with IC50 values covering the wide range from 2.

Fluorescence spectroscopy of osthole binding to human serum albumin.

The interaction of human serum albumin (HSA) with osthole was investigated by fluorescence spectroscopy. Osthole can quench the fluorescence of HSA and the quenching mechanism is a static process. The binding site number and apparent binding constant were measured at different temperatures.

A new series of N2-substituted-5-(p-toluenesulfonylamino)phthalimide analogues as α-glucosidase inhibitors.

Several members of a new family of non-sugar-type α-glycosidase inhibitors, bearing a 5-(p-toluenesulfonylamino)phthalimide moiety and various substituent at the N2 position, were synthesized and their activities were investigated. The newly synthesized compounds displayed different inhibition profile towards yeast α-glycosidase and rat intestinal α-glycosidase. Almost all the compounds had strong inhibitory activities against yeast α-glycosidase.

SIRT1 regulates CD40 expression induced by TNF-α via NF-ĸB pathway in endothelial cells.

Background: Compelling evidence suggests that SIRT1, NAD(+)-dependent class III protein deacetylase, plays an important role in the prevention and treatment of atherosclerosis by counteracting inflammation. Cluster of differentiation 40 (CD40), as a pro-inflammatory cytokine, has been shown to participate in the pathophysiology of atherosclerosis. The relationship between SIRT1 and CD40, however, remained elusive.

[Synthesis of 2-hydroxyl-5-butyramidobenzoic acid and its effect on acetic acid-induced colitis in rats].

Objective: To study the method for synthesis of 2-hydroxyl-5- butyramidobenzoic acid and test its effect on acetic acid-induced colitis in rats.

Methods: 2-hydroxyl-5-butyramidobenzoic acid was synthesized from 5-aminosalicylic acid and butyric acid by amidation, esterification and hydrolization. The effect of 2-hydroxyl-5-butyramidobenzoic acid on acetic acid enema-induced colitis in rats was investigated.

Synthesis and antihyperglycemic evaluation of various protoberberine derivatives.

Various berberine derivatives (2-17) were synthesized and their antihyperglycemic activities were evaluated in a model of beta-cell-membrane chromatography and a model of alloxan-induced diabetes mice. The results indicated that compounds 5 and 14 exhibited antihyperglycemic activity. Their structure-activity relationships were discussed.