Protease-Triggered, Spatially Controlled DNA Assembly in Apoptotic Cells for Early Evaluation of Therapeutic Efficacy.

Despite numerous advances in the use of DNA as building blocks to assemble complex structures, the dearth of strategies that allow for protease-controlled in situ DNA assembly in living cells remains a bottleneck in this field. Here, we present a modular engineering approach to achieve protease-triggered self-assembly of DNA in apoptotic cells for early evaluation of tumor response to drug treatment. In the design, peptide nucleic acid is introduced as a building bridge to engineer DNA building blocks with peptides and thus to suppress their self-assembly activity, while caspase-3 (Casp-3) protease-mediated enzymatic cleavage of the peptide substrate enables the activation of the DNA assembly, generating fluorescence signal output for real-time monitoring of Casp-3 activity.

Low-Temperature Photothermal Therapy: Strategies and Applications.

Although photothermal therapy (PTT) with the assistance of nanotechnology has been considered as an indispensable strategy in the biomedical field, it still encounters some severe problems that need to be solved. Excessive heat can induce treated cells to develop thermal resistance, and thus, the efficacy of PTT may be dramatically decreased. In the meantime, the uncontrollable diffusion of heat can pose a threat to the surrounding healthy tissues.

Pharmacodynamics and pharmacokinetics of a new type of recombinant insulin Lisargine injection.

Background: Recombinant insulin Lisargine is a new type of insulin. In this study, we aimed to compare its pharmacodynamic (PD) and pharmacokinetic (PK) with Lantus.

Methods: The PD test was performed by exploring the effect of single administration on blood glucose of normal rats and STZ-induced diabetic rats, and the effect of multiple administrations on blood glucose of STZ-induced diabetic rats.

Pharmacokinetics, tissue distribution and excretion of a novel long-acting human insulin analogue - recombinant insulin LysArg in rats.

As a novel long-acting recombinant human insulin analogue, it is necessary to carry out the preclinical research for insulin LysArg. The purpose of this study was to characterise the pharmacokinetic, tissue distribution and excretion of insulin LysArg and provide a reference for its development. Three methods were used to measure the content of insulin LysArg in biological samples after a single subcutaneous administration in rats, including radioassay, radioassay after precipitation with TCA and separation by HPLC.

Transporters (OATs and OATPs) contribute to illustrate the mechanism of medicinal compatibility of ingredients with different properties in yuanhuzhitong prescription.

Various medicinal ingredients with different tastes are combined according to the theory of compatibility in Chinese materia medica to achieve a better efficacy, while the mechanism was not very clear. Here, the authors studied the interaction between ingredients and human transporters such as the kidney transporters OAT1 and OAT3, the liver transporters OATP1B1 and OATP1B3, and the intestine transporter OATP2B1 to discern the compatibility mechanism of ingredients with different tastes in the Yuanhuzhitong preparation (YHP) comprising (CYH) and (AD), which could relieve pain by restraining the central system. The results show that tetrahydropalmatine (TDE), the major component of CYH, could be transported by OAT3 into kidney, OATP1B1 and OATP1B3 into liver, while imperatorin (IPT) and isoimperatorin (ISP), the two key components of AD, and AD extract showed strong inhibition to OAT1 and OAT3.

Absorption, tissue disposition, and excretion of fasudil hydrochloride, a RHO kinase inhibitor, in rats and dogs.

Fasudil hydrochloride as an intracellular calcium ion antagonist that dilates blood vessels has exhibited a very potent pharmacological effect in the treatment of angina pectoris. The purpose of this study was to determine the absorption, distribution, and excretion profiles of fasudil in rats and beagle dogs, respectively, to clarify its pharmacokinetic pattern. A sensitive and reliable LC-MS/MS method has been developed and established and successfully applied to pharmacokinetic study, including absorption, tissue distribution, and excretion.

Potential synergic mechanism of Wutou-Gancao herb-pair by inhibiting efflux transporter P-glycoprotein.

Wutou-Gancao herb-pair is extensively used to attenuate the toxicity and enhance the efficacy of aconite. In this study, potential synergic mechanism of the herb pair was investigated by utilizing multiple approaches. In silico and in vitro Caco-2 cell models were applied to study the potential binding mode of bioactive ingredients existing in liquorice with P-glycoprotein (P-gp), as well as the inhibition effects on P-gp.

Identification of key transporters mediating uptake of aconitum alkaloids into the liver and kidneys and the potential mechanism of detoxification by active ingredients of liquorice.

Aconite as a commonly used herb has been extensively applied in the treatment of rheumatoid arthritis, as pain relief, as well as for its cardiotonic actions. Aconitum alkaloids have been shown to be the most potent ingredients in aconite, in terms of efficacy against disease, but they are also highly toxic. Apart from neurological and cardiovascular toxicity exposed, the damage to hepatocytes and nephrocytes with long-term use of aconitum alkaloids should also be carefully considered.

Effects of liquorice on pharmacokinetics of aconitine in rats.

Aconite alkaloids are the main bioactive ingredients existing in , for instance aconitine (AC), which exhibit potent analgesic, antirheumatic and other pharmacological effects. In this study, effects of long-term treatment with liquorice on pharmacokinetics of AC in rats were investigated. Pharmacokinetics of AC after oral administration of AC at 1.

Potential detoxification effect of active ingredients in liquorice by upregulating efflux transporter.

Background: As one of most widely used herbal medicine, liquorice exhibits diverse pharmacological activities, for instance, analgesic, antitussive, antiarrhythmic, anti-inflammatory, and immune regulation. Additionally, detoxification effects were observed in combination of liquorice with other herbal drugs. The mechanism of detoxification of liquorice has been extensively investigated through material basis and interference with CYPs though, investigations of its effect on transporters were very limited, according to the literature.

The effect of polymorphism of uric acid transporters on uric acid transport.

The abnormal metabolism of uric acid results in many disease such as chronic kidney disease, hyperuricemia, nephrolithiasis, gout, hypertension, vascular disease and so on. Serum uric acid levels are maintained by the balance between production and elimination. There are many factors that maintain the balance of serum uric acid.

Progress of Oral Insulin and Related Drug Delivery Systems and their Pharmacokinetics.

Background: As society has developed and living standards have improved, diabetes has become a severe public health issue. Insulin plays a crucial role in managing hyperglycemia caused by type I diabetes and particular type II diabetes. Many researchers are seeking alternative, more acceptable methods of insulin delivery, such as oral insulin.

Nanoparticles induced by embedding self-assembling cassette into glucagon-like peptide 1 for improving in vivo stability.

The multiple physiologic characteristics of glucagon-like peptide 1 (GLP-1) make it a promising drug candidate for treating type 2 diabetes mellitus. However, the half-life of GLP-1 is short as a result of degradation by dipeptidyl peptidase IV and renal clearance. Stabilizing GLP-1 is therefore critical for its use in drug development.

Pharmacokinetics, tissue distribution, and excretion of FGF-21 following subcutaneous administration in rats.

As one of the fibroblast growth factor (FGF) superfamily, FGF-21 has been extensively investigated for its functions and roles since its discovery. It has been demonstrated to be one of the key regulators for glucose and lipid metabolism, and exhibits beneficial effects on cardiovascular disease. However, studies focusing on its pharmacokinetic behavior in vivo as a novel therapeutic agent have not been reported.

Myricetin: a potent approach for the treatment of type 2 diabetes as a natural class B GPCR agonist.

The physiologic properties of glucagon-like peptide 1 (GLP-1) make it a potent candidate drug target in the treatment of type 2 diabetes mellitus (T2DM). GLP-1 is capable of regulating the blood glucose level by insulin secretion after administration of oral glucose. The advantages of GLP-1 for the avoidance of hypoglycemia and the control of body weight are attractive despite its poor stability.

Combination of l-Carnitine with Lipophilic Linkage-Donating Gemcitabine Derivatives as Intestinal Novel Organic Cation Transporter 2-Targeting Oral Prodrugs.

Novel organic cation transporter 2 (OCTN2, SLC22A5) is responsible for the uptake of carnitine through the intestine and, therefore, might be a promising molecular target for designing oral prodrugs. Poor permeability and rapid metabolism have greatly restricted the oral absorption of gemcitabine. We here describe the design of intestinal OCTN2-targeting prodrugs of gemcitabine by covalent coupling of l-carnitine to its N4-amino group via different lipophilic linkages.

[The in vitro inhibition and induction of cytochrome P450 activities by bentysrepinine: a novel candidate of anti-hepatitis B virus drug].

Bentysrepinine (Y101), a derivative of phenyalanine dipeptide, has a novel mechanism in the treatment of hepatitis B virus (HBV) infection with a good anti-HBV effect. In the present study, a fluorometric-based high throughput method using cytochrome P450 (CYP) screening kit was adopted to evaluate in vitro inhibition potential of Y101 on CYP isoenzymes by calculating remaining enzyme activities and inhibitory potential (IC(50) values) using the determined values of fluorescence intensity. The result showed that Y101 exhibited little activity in the inhibition of CYP1A2, CYP3A4, CYP2C9, CYP2C19 and CYP2D6 (IC(50) > 100 μmol·L(-1)).

[The in vitro transport mechanism of bentysrepinine: a novel anti-hepatitis B virus drug candidate].

Bentysrepinine (Y101), a derivative of phenylalanine dipeptide, is a novel drug candidate for the treatment of hepatitis B virus (HBV) infection. Our previous preclinical pharmacokinetic study showed that its in vivo absorption and distribution characteristics were probably related to transmembrane transport after Y101 was administered intragastically in rats. In this study, Caco-2 and MDCK-MDR1 cell models were used to investigate interactions between Y101 and P-gp through the apparent permeation coefficient (P(app)) and efflux ratio (RE); the results showed that Y101 was a substrate of P-gp.

Controlled release strategy of paclitaxel by conjugating to matrix metalloproteinases-2 sensitive peptide.

Peptide drug conjugates offer a novel strategy to achieve controlled drug release. This approach avoids the clinical obstacles of non-specific toxicity and overall drug resistance of conventional cytotoxic agents, such as paclitaxel. MMP2 plays important functions in tumour proliferation and metastasis.

The Targeted-liposome Delivery System of Antitumor Drugs.

The liposome delivery system has been intensively explored as novel drug delivery system (DDS) for antitumor drugs, due to its safety, selective cytotoxicity, long circulation and slow elimination in blood, which is favorable for cancer therapy. The liposome-based chemotherapeutics are used to treat a variety of cancers to enhance the therapeutic index of antitumor drugs. Here, the author reviewed the important targets for cancer therapy and the pharmacokinetic behavior of liposomal drugs in vivo, as well as the application of the targeting liposomal system in cancer therapy.

Effects of Drug Transporters on Pharmacological Responses and Safety.

Recently, it is realized that transporters, apart from enzymes, play a key role in drug metabolism and pharmacokinetics. More and more pharmaceutical researchers focused on transporter study and found that drug transporters not only involved in pharmacokinetics including absorption, distribution, metabolism and excretion (ADME). but also in Drug-Drug interactions (DDIs).

Aspartate-modified doxorubicin on its N-terminal increases drug accumulation in LAT1-overexpressing tumors.

L-type amino acid transporter 1 (LAT1), overexpressed on the membrane of various tumor cells, is a potential target for tumor-targeting therapy. This study aimed to develop a LAT1-mediated chemotherapeutic agent. We screened doxorubicin modified by seven different large neutral amino acids.

Inhibitory effect of medicinal plant-derived carboxylic acids on the human transporters hOAT1, hOAT3, hOATP1B1, and hOATP2B1.

A significant number of organic carboxylic acids have been shown to influence the absorption and distribution of drugs mediated by organic anion transporters (OATs). In this study, uptake experiments were performed to assess the inhibitory effects of cinnamic acid, ferulic acid, oleanolic acid, deoxycholic acid, and cynarin on hOAT1, hOAT3, hOATP1B1, and hOATP2B1. After a drug-drug interaction (DDI) investigation, cinnamic acid, ferulic acid, deoxycholic acid, and cynarin were found and validated to inhibit hOAT1 in a competitive manner, and deoxycholic acid was found to be an inhibitor of all four transporters.

Herb-drug interactions involving drug metabolizing enzymes and transporters.

Herbal medicines and their active ingredients are widely used worldwide, and they have become an important part of clinical medicine. The combined use of herbs and drugs has increased the possibility of pharmacokinetic and pharmacodynamic interactions. Clinical studies have demonstrated that the combined use of herbs and drugs can enhance or attenuate the drug efficacy and toxicity.