Proteolysis-targeting chimera (PROTAC), as an emerging treatment method, has become one of the hottest technologies in the field of new drug research with a near-20-year development. PROTAC utilizes the natural ubiquitin-protease system in cells to induce targeted protein degradation, especially for protein of interest that are difficult to target by traditional small molecules. Moreover, PROTAC is expected to solve the problem of drug resistance that often occurs with small molecule drugs. However, the excessive relative molecular weight, poor solubility and membrane permeability, and low oral absorption of PROTAC make it challenging to druggability study. Currently, take pharmacokinetic characteristics as the entry point to continuously optimize and improve, so as to accelerate the transformation of PROTAC from laboratory to clinical application. Based on the basic structure and mechanism of PROTACs, this review introduces its pharmacokinetic properties, analyzes how to design efficient and stable PROTAC molecules, summarizes its current research progress in various diseases treatments, evaluates the development prospects and limitations of PROTAC, in order to provide more references for further research and application of PROTAC.

Objective To investigate the possibility of using poly-hydroxybutyate-hydroxyhexate p(3HB-co-3HH)), a modified extracellular matrix, the third generation of PHA family, as a scaffold for seeding of chondrocytes from the residual ear of microtia patients to generate tissue engineered cartilage in athymus mice. Methods The residual ear cartilage from eight 7-years-old microtia patients was enzymatically dissolved by collagenase, and chondrocytes were harvested and seeded into foams of PHB-PHH. After incubation for 1 week in vitro, chondrocyte-polymer constructs were implanted subcutaneously into 8 athymus mice. A control groups was established by subcutaneous implantation of PHB-PHH foams alone. One athymus mice were killed at 4 weeks postoperatively, and 6 were sacrificed at 8 weeks. The specimens were dissected and examined macroscopically and histologically. Results Specimens harvested from chondrocyte-polymer constructs subjected to gross morphologic and histology analysis demonstrated new cartilage formation, and those from control groups showed no cartilage formation. The one of 4 weeks still had some remains of the scaffold with nodules of neocartilage. After 8 weeks, all the 6 mice had neocartilage formed almost the same as natural. The PHB-PHH scaffold were totally absorbed. Conclusion These findings demonstrate that the foam of PHB-PHH is not only a good "matrix" for cartilage tissue engineering, but also optimal scaffold for the seeding of chondrocytes from the residual ear to generate new cartilage that would be useful in plastic and reconstructive surgery. Chondrocytes from the residual ear of microtia patients are good candidates for generation of tissue engineered cartilage.

Bile acids (BAs) are a major component of bile salt, which plays a vital role in the metabolism of lipids in humans. Ninety-five percent of bile acids are recycled by the enterohepatic circulation (EHC), and therefore EHC is essential for bile acid homeostasis. There are four transporters that mediate the transmembrane transport of bile acids, each of which plays an important role in the enterohepatic circulation. Gene defects in bile acid transporters can lead to disorders of the enterohepatic circulation, ultimately leading to clinical phenotypes such as metabolic diseases and even death. Bile transporter expression is altered in patients with various metabolic disease states, suggesting that disruption of bile acid transporters may be a pivotal pathological mechanism for the development of metabolism diseases. Thus, many drugs targeting bile acid transporters are being developed. We provide a concise overview of the progress of bile acid transporters research, discuss the relationship between different bile acid transporters and disease development, and summarize the current progress in drug development targeting bile acid transporters.

The morbidity and mortality of gastrointestinal malignancies are the highest in the world. For patients with poor response to conventional chemotherapy, new treatment methods are urgently needed. In recent years, under the background of precision medicine, antibody-drug conjugates (ADCs) with high tumor specificity and potent toxicity have become a hot research spot in the field of biomedicine. However, due to the complex structure and mechanism of ADCs, its pharmacokinetic research is facing great challenges which are the biggest resistance to the development of ADCs at present. In this case, it is of great significance to understand the pharmacokinetic properties of ADCs and make use of it to improve the efficacy of ADCs in the treatment of gastrointestinal malignancies. Based on the basic composition and mechanism of ADCs, this review summarizes the pharmacokinetic properties of ADCs, discusses its recent advances in the treatment of gastrointestinal malignancies, in order to provide more references for follow-up research on ADCs.

Objective To explore the changes of atrial natriuretic peptide(ANP)and parathyroid hormone(PTH)in umbilical cord blood of newborn infants with intrauterine growth retardation(IUGR)and their relationships with electrolytic.Methods A total of 71 IUGR infants borned between Jan.2006 and Aug.2007 were enrolled in this study.Another 40 normal appropriate for gestational age neonates were selected as control group.The study group were divided into 2 groups:mature IUGR group(n=29)and premature IUGR group(n=42).The samples of umbilical cord blood of every group were collected at the time of delivery,and ANP,PTH levels in umbilical cord blood were mea-sured by radioimmunoassay.The sodium,calcium levels in their peripheral vein were measured simultaneously.Results 1.Compared with control group[(0.78?0.42)?g/L],the ANP levels of premature IUGR group[(1.26?0.47)?g/L] and the mature IUGR group[(1.09?0.51)?g/L] were significantly increased(t=5.98,2.76 Pa0.05).The calcium levels of the premature IUGR group[(1.85?0.37)mmol/L]significantly decreased(t=1.93 P0.05)compared with control group [(2.02?0.44)mmol/L].3.The serum sodium level was negatively correlated with the umbilical ANP level(r=-0.93 P

Animals ; Anti-Inflammatory Agents ; pharmacology ; Asthma ; pathology ; physiopathology ; Budesonide ; pharmacology ; Eosinophils ; drug effects ; pathology ; Inflammation ; pathology ; physiopathology ; NF-kappa B ; metabolism ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Respiratory System ; pathology

AIM: To investigate the new processing method of Radix Polygonum Multiflorum,determine the content of 2,3,5,4′-stilbene glucoside by HPLC. METHODS: Referring to content of 2,3,5,4′-stilbene glucoside as marker,we have screened out processing time for Radix Polygonum Multiflorum by orthogonal design, by HPLC. RESULTS: 48 h of steaming time can guarantee processing quality of Radix Polygonum Multiflorum. CONCLUSION: The method can be used for processing standard of Radix Polygonum Multiflorum

Objective To study the effects of high salt intake on blood pressure and renin-angiotensin in male rats with different plasm androgen levels.Methods Thirty male Wistar rats were randomized to sham(n=10)or operated(n=10),or castration(n=10),or testosterone replacement after castarion(26.7 mg/kg,n=10)and fed with 8% NaCl for 8 weeks.Tall arterial pressure were recorded before,4 and 8 weeks after experiment.Serum PRA,plasma angiotensin Ⅱ(Ang Ⅱ)and testosterone(T)were determined by radioimmunoassey respectively. Results After 8 weeks high salt dietary,blood pressure was significantly increased in sham and testosterone replace ment rats(Sham operation group:137.3?4.0 vs the basal line:117.5?5.9 mmHg,testosterone replacement group: 134.4?5.2 vs the basal line:116.6?7.7 mmHg,P0.05).Concomitantly,sham operation or testosterone re placement rats had higher PRA and plasm Ang Ⅱ content compared with castrated rats(PRA:Sham operation 5.90 ?0.77 vs testosterone replacement group:5.69?0.47 vs castrated rats:4.90?0.55 mol/(L?h),P

Objective To study intermediate and long term efficacy of uterine arterial embolization (UAE)with sodium alginate microspheres(KMG)at diameters 500-700μm in treatment of diffuse adenomyosis.Methods Totally 40 patients with standard difluse adenomyosis were enrolled and treated with UAE.KMG at diameters 500-700 μm for vascular embolization were used to embolize the arteries.The degree of dysmenorrhea,amount of menorrhea and uterine volume,as well as the level of serum CA125,follicle stimulating hormone(FSH),luteinizing hormone(LH),estradiol(E2)were investigated before andafter UAE.Results The follow up rates were 100%(40/40),100%(40/40),80%(32/40),68%(27/40),58%(23/40)after uterine arterial UAE 12,24,36,48 and 60 months respectively.The early,intermediate and long-term effective rates were 90%(36/40),88%(28/32),83%(19/23).The degree of dysmenorrhea,the amount of menorrhea and the uterine volume,as well as serum CA125 all decreased significantly 3 mouths after UAE at varying degrees(P＜0.05).Compared with other follow-up time,thedegree of dysmenorrhea and the amount of menorrhea declined to their lowest point at 6 month after UAE (P＜0.01).Paralleled with the decrease of volume of uterine,serum CA125 also decreased significantly and reached the lowest level 12 months later compared with other follow-up times(P＜0.01).Even at the 12th month after UAE serum CA125was not normal and FSH,LH and E2 did not change all the times after UAE(P>0.05).No recurrence was found during the 60 months after UAE.Condusion KMG used in UAE at diameters 500-700 μm has good intermediate and long term effectiveness in treatment of diffuse adenomyosis with no side effects.

The work aims to study the drug metabolizing enzymes involved in the metabolism of butylphthalide and evaluate the induction and inhibition activities of butylphthalide on CYP450 isoenzymes by using in vitro (liver microsome incubation system of rats and human) and in vivo (CYP induced model of rats) method. Butylphthalide was incubated with selective inhibitors of CYP450, and its metabolic rate was determined to identify the metabolizing isoenzymes of NBP in rat (normal and induced rats) and human liver microsomes. The in vitro inhibition effect of butylphthalide on 6 main liver microsomal CYP450 isoenzymes was evaluated by using probe drugs; the induction and inhibition activities in vivo of butylphthalide on CYP450 isoenzymes were evaluated by NBP ig dosing (160 mg x kg(-1)) and iv dosing (20 mg x kg(-1)) in rats. After adding the specific inhibitors of CYP2C11, 2E1 and 3A 1/2 for rat, CYP2C19, 2E1 and 3A4/5 for human, the metabolism of NBP in rat and human liver microsomes were reduced 38.8%, 86.2%, 78.4% and 51.0%, 92.0%, 58.9% of control, respectively. The metabolic rates of NBP in CYP2E1 and 3A 1/2 induced rat liver microsomes were increased 25.5% and 68.9%. High concentration of NBP (≥ 200 μmol x L(-1), in vitro) could inhibit the activities of CYP1A2, 2C6, 2C11 and 2D2 in rats, and high concentration of NBP ( ≥ 15 μmol x L(-1), in vitro) could inhibit the activity of CYP2C19 in human. All the results indicated that NBP should be mainly metabolized by CYP2E1, 2C11 and 3A 1/2 in rats and CYP2E1, 2C19 and 3A4/5 in human. High concentration of NBP could inhibit human CYP2C19 in vitro. No significant induction/inhibition effects of NBP were observed on rat liver CYP450 isoforms after ig 160 mg x kg(-1) NBP or iv 20 mg x kg(-1) NBP.
Animals ; Benzofurans ; pharmacology ; Cytochrome P-450 Enzyme Inhibitors ; pharmacology ; Cytochrome P-450 Enzyme System ; metabolism ; Humans ; Isoenzymes ; metabolism ; Liver ; metabolism ; Microsomes, Liver ; metabolism ; Rats