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Antibody-drug conjugates (ADCs) are gradually revolutionizing clinical cancer therapy. The antibody-drug conjugate linker molecule determines both the efficacy and the adverse effects, and so has a major influence on the fate of ADCs. An ideal linker should be stable in the circulatory system and release the cytotoxic payload specifically in the tumor. However, existing linkers often release payloads nonspecifically and inevitably lead to off-target toxicity. This defect is becoming an increasingly important factor that restricts the development of ADCs. The pursuit of ADCs with optimal therapeutic windows has resulted in remarkable progress in the discovery and development of novel linkers. The present review summarizes the advance of the chemical trigger, linker‒antibody attachment and linker‒payload attachment over the last 5 years, and describes the ADMET properties of ADCs. This work also helps clarify future developmental directions for the linkers.
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Objective: To study the dose-effect relationship of Yuning ointment and its decomposed recipes in the treatment of oleic acid induced acne in mice. Methods: Oleic acid was administrated to the back (2 cm ×2 cm) of the mice (once a day) for 21 days to induce acne. At d22, the gradient dosage of Anemone flaccida crude drug (1. 06-1 060. 23 mg?kg-1?d-1,k=3. 16), Yuning oint-ment without Anemone flaccida crude drug (4. 73-1 767. 75 mg?kg-1?d-1, k=3. 16) and Yuning ointment (2. 84-2 827. 28 mg?kg-1?d-1, k=3. 16) was respectively administrated to the back of mice for 14 days. The pathological changes of skin were observed by hematoxylin-eosin (HE) staining. The diameter of sebaceous glands and the ratio of follicular keratinization area were morphomet-rically analyzed. The serum levels of IL-1, IL-6 and TNF-α were detected by ELISA assay. The median effective dosages (ED50) of A-nemone flaccida in the three prescriptions were regressed by Prism 5. 01 software to determine the prescription dose-effect. Results: All the therapy groups were with significantly relieved pathological changes of sebaceous glands hypertrophy and follicular keratinization, and decreased serum levels of IL-1, IL-6 and TNF-α in a dose-dependent manner. The dose-response curves showed an "S" shape. A-mong the three therapy groups, the effect of Yuning ointment was the best. The ED50of Yuning ointment regressed by Anemone flaccida dose was 0. 28-fold for improving sebaceous glands hypertrophy, 0. 14-fold for inhibiting follicular keratinization, and 0. 15-, 0. 49-and 0. 24-fold for decreasing serum levels of IL-1, IL-6 and TNF-α. . Regressed by Yuning ointment without Anemone flaccida, the ED50of Yuning ointment was lower than Yuning ointment without Anemone flaccid in terms of improving pathological changes and inhibiting the secretion of cytokines. Conclusion: Yuning ointment can prevent and treat acne through regulating immune function. And the prescrip-tion compatibility can enhance the effects of Anemone flaccida.
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Objective:To investigate the dose-effect relationship of Xianfu ointment and its decomposed recipes the 1-chloro-2,4-dini-trochlorobenzene(DNCB) induced chronic eczema in mice, and confirm the median effective dose (ED50) of each formula and the synergetic effect by compatibility. Methods:DNCB was used to induce chronic eczema in C57 mice. The mice were treated with gradient dosages of the Xianfu ointment (11.71-11 662.50 mg?kg-1?d-1,k = 0.316), Anemone flaccid (0.53-530.12 mg?kg-1?d-1,k = 0.316), Xianfu ointment without Anemone flaccid (11.18-11 132.40 mg?kg-1?d-1,k =0.316),respectively. The pathological features were observed after hematoxylin-eosin staining. The volume ratio of epidermides and the number of lymphocyte infiltrated in dermis were analyzed with morphometry. The serum levels of IL-2,IFN-γ,IL-4,and IL-13 were detected by ELISA assay. The ED50was calculated by non-linear regression with various slope using Prism-5.0 software.Results:The effects of Xianfu ointment and its decomposed recipes on chronic eczema showed a dose-dependent tendency. The dose-response curves showed"S"shape. The efficacy of Xianfu ointment on chronic eczema was the most significant among the three formulas, which was demonstrated by decreased epidemical thicknes (ED50= 377.90 mg?kg-1?d-1), reduced infiltrated lymphocyte number(ED50= 153.20 mg?kg-1?d-1), increased serum IL-2(ED50=608.90 mg?kg-1?d-1) and IFN-γ (ED50= 205.50 mg?kg-1?d-1) levels, and decreased serum IL-4(ED50= 198.70 mg?kg-1?d-1) and IL-13 levels (ED50= 117.60 mg?kg-1?d-1). And the dose-effect curves of Anemone flaccid and Xianfu ointment without Anemone flaccid groups were both right shift when compared with that of Xianfu ointment. Conclusion:Xianfu ointment and its decomposed recipes can effectively treat chronic eczema. Anemone flaccid has obvious compatibility synergy in the whole formula. The effects of Xianfu ointment is most significant.
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This study was aimed to summarize the adverse drug reaction (ADR) caused by the toxicity of Tripterygium Wilfordiiand its preparations, in order to explore possible relationship betweenTripterygium Wilfordiifactors and reported ADR. Relevant articles on toxicity ofTripterygium Wilfordiiand its preparations were systematically searched in 5 databases, including the Pubmed, CNKI,Wanfang Data, VIP Data and Sinomed from the database was established until Feb 25th, 2014. And then, the randomized controlled trials (RCTs) were systematically collected, analyzed and summarized. The results showed that there were 260 RCTs with 13301 patients included. The outcome of data analysis showed that ADR rates of digestive system and reproductive system of RCT1 and RCT2 were different. ADR rates (per hundred people) in RCT1 and RCT2 were as follows: digestive system were 14.73 and 12.26, reproductive system were 8.25 and 8.00, liver was 6.50 and 5.66, kidneys were 6.79 and 3.03, blood system were 6.73 and 6.50, cardiovascular system were 2.35 and 0.67, skin and mucous system were 11.42 and 4.78, respectively. Articles on rheumatoid arthritis (RA) of both RCT1 and RCT2 were the highest, which occupied 22.17% in RCT1 and 63.16% in RCT2. The corresponding ADR rates were 34.18 and 27.26. The standard deviation (SD) of 7 disease types, which were RA, IgA nephropathy, nephritis, nephrotic syndrome (NS), diabetic nephropathy, psoriasis, lichen and rashes, as well as uterine fibroids, was 8.69 in RCT1. The SD of RA, IgA nephropathy, psoriasis, lichen and rashes was 7.11 in RCT2. It was concluded that the possible ADR distribution ofTripterygium Wilfordiiand its preparations were the highest in the digestive system, reproductive system and liver. Besides, different diseases (i.e., RA, nephritis, NS, and etc.) had huge differences with their correspondent ADR rates. Therefore, it was suggested that specific measures should be taken to select the appropriateTripterygium Wilfordiipreparation, protect the stomach and liver during the application ofTripterygium Wilfordiiand its preparations. During medication, attentions should be paid to the reaction of patients. Stop the medication when necessary to minimize ADR rates to the lowest.
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Objective To investigate the influence of stigma on QOL of patients with mental disorders.Methods By using Link stigma series scale and schizophrenic quality of life scale,we assessed and analyzed 406 psychiatric patients′stigma and QOL, as well as the correlation and influence between them.Results The score of perceived devaluation-discrimination dimension of the stigma scale had positive correlation with total score of QOL,score of psycho-social dimension and score of motivation and energy dimension (P <0.05).The scores of challenge dimension and separation dimension in the stigma scale had positive correlation with motivation and energy dimension of the QOL scale (P <0.05).Regression analysis showed that stigma did not have influence on QOL of patients with mental disorders.Conclusion Stigma in psychiatric patients has no significant influence on QOL,but correla-tion relationship exists between them.The higher score of perceived devaluation-discrimination dimension,challenge dimension and separation dimension of stigma scale,the poor QOL the patient would have.
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BACKGROUND:Experimental studies have showed that puerarin has an obvious protective effect on osteoporosis in ovariectomized and orchiectomized mice. But the influence of puerarin in the molecular level in the process of osteoblast differentiation is seldom reported. OBJECTIVE:To observe the effect of puerarin on the mRNA expression of alkaline phosphatase, bone sialoprotein, osteopontin and osteocalcin in osteoblasts. METHODS:The MC3T3-E1 cells from mice cultured in vitro were randomly divided into control group, puerarin group (10-6 mol/L puerarin) and estradiol group (10-7 mol/L estradiol) to observe the effects of puerarin on the differentiation of osteoblasts. mRNA expression of alkaline phosphatase, bone sialoprotein, osteopontin and osteocalcin in MC3T3-E1 cells was determined using RT-PCR method. RESULTS AND CONCLUSION:Puerarin and estradiol both could prolong the expression of alkaline phosphatase that reached the peak at 12 days. Puerarin and estradiol strengthened the mRNA expression of bone sialoprotein at 10 and 12 days, reduced expression of osteopontin at 5 and 12 days, and increased expression of osteocalcin at 10 and 12 days. These results reveal that puerarin can induce the differentiation of cultured osteoblasts by influencing osteoblast differentiation-related protein mRNA expressions, which may be one of the important molecular mechanisms of puerarin for prevention of osteoporosis.
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BACKGROUND: Ovariectomized animals usually are employed for the study of women osteoporosis while little is known about theenergy balance of ovariectomized animals. Many previous studies showed that soy isoflavone could decrease the hyperlipemia resulted by high-fat feed, and how about the effect of soy isoflavone on the energy metabolism in ovariectomized animals?OBJECTIVE: To explore the pathologic effect of soy extract and its active components on the energy metabolism in ovariectomized rats so as to provide adequate evidences for the primary rehabilitation and prevention of type Ⅱ diabetes mellitus, disturbance of lipid metabolism as well as hypertension and coronary atherosclerotic heart disease.DESIGN: A randomized and controlled trial with the experimental animals as subjects.SETTING: Laboratory of Cell and Biochemistry in a university.MATERIALS: Ninety Wistar rats (SFP grade, license code: scxk11-00-006) were randomized into 9 groups: normal group, sham group,model group, estrogen group, high-dose soy flavone group, low-dose soy flavone group, high-dose soy extract group, low-dose soy extract group and soy polysaccharide group, with 10 rats in each group.INTERVENTION: Except the rats in normal group and sham group,the bilateral ovaries of other rats were all removed. From one week after operation, body weight and daily food intake were detected once a week.Six weeks later, the rats were killed to calculate the forage transformation efficiency, measure body length, work out the body mass index (BMI),and separate the abdominal fat and weight.MAIN OUTCOME MEASURES: ①Effect of soy extract on the abdominal fat accumulation of ovariectomized rats. ②Effect of soy extract on food intake of ovariectomized rats. ③Effect of soy extract on forage transformation efficiency of ovariectomized rats.RESULTS: After ovariectomy, the food intake, body weight and BMI all raised, and the forage transformation efficiency increased, with abdominal fat accumulation. The changes of energy metabolism induced by ovariectomy were all weakened at different degrees in estrogen group, soy extract group and soy flavone group, while no influenced was found in soy polysaccharide group.CONCLUSION: The ovariectomized rats can be used as animal model of the climacteric fat women. The soy extract, with the effective component of flavonoid, can reduce the pathologic changes such as the increase of food intake, body weight and forage transformation efficiency induced by ovariectomy.