Foam cell formation and macrophage polarization are involved in the pathologic development of atherosclerosis, one of the most important human diseases affecting large and medium artery walls. This study was designed to assess the effects of rapamycin and FTY720 (fingolimod) on macrophages and foam cells. Mouse peritoneal macrophages were collected and treated with rapamycin and FTY720 to study autophagy, polarization, and lipid accumulation. Next, foam cells were formed by oxidizing low-density lipoprotein to observe changes in lipid accumulation, autophagy, and polarization in rapamycin-treated or FTY720-treated foam cells. Lastly, foam cells that had been treated with rapamycin and FTY720 were evaluated for sphingosine 1-phosphate receptor (S1prs) expression. Autophagy microtubule-associated protein 1 light chain 3- (LC3-) II was increased, and classically activated macrophage phenotype markers interleukin- (IL-) 6, cyclooxygenase-2 (COX2), and inducible nitric oxide synthase (iNOS) were increased, whereas alternatively activated macrophage phenotype markers transforming growth factor- (TGF-) β, arginase 1 (Arg1), and mannose receptor C-type 1 (Mrc1) were decreased by rapamycin in peritoneal macrophages. LC3-II was also obviously enhanced, though polarization markers were unchanged in rapamycin-treated foam cells. Moreover, lipid accumulation was inhibited in rapamycin-treated macrophage cells but was unchanged in rapamycin-treated foam cells. For FTY720, LC3-II did not change, whereas TGF-β, Arg1 and Mrc1 were augmented, and IL-6 was suppressed in macrophages. However, LC3-II was increased, and TGF-β, ARG1 and MRC1 were strikingly augmented, whereas IL-6, COX2 and iNOS could be suppressed in foam cells. Furthermore, lipid accumulation was alleviated in FTY720-treated foam cells. Additionally, S1pr1 was markedly decreased in foam cells (P < .05); S1pr2, S1pr3, S1pr4 and S1pr5 were unchanged in rapamycin-treated foam cells. In FTY720-treated foam cells, S1pr3 and S1pr4 were decreased, and S1pr1, S1pr2 and S1pr5 were unchanged. Therefore, we deduced that rapamycin stimulated classically activated macrophages and supressed early atherosclerosis. Rapamycin may also stabilize artery plaques by preventing apoptosis and S1PR1 in advanced atherosclerosis. FTY720 allowed transformation of foam cells into alternatively activated macrophages through the autophagy pathway to alleviate advanced atherosclerosis.
Objective To determine contact allergens and their clinical significance in patients with dermatitis or eczema in Wuxi city.Methods Patch test was conducted in 1065 patients with a clinical diagnosis of dermatitis or eczema.A statistical analysis was carried out.Results Positive patch test reactions were observed in 83.19％ of the patients,with no statistical differences in the frequency of positive patch test reactions between female and male patients or between patients of different age groups.The most frequent 6 allergens were potassium dichromate,cobalt chloride,nickle sulfate,formaldehyde,carba mix and fragrance mix in these patients.Female patients showed a higher frequency of positive patch test reaction to nickle sulfate and formaldehyde,but a lower frequency to potassium dichromate and carba mix compared with male patients (all P＜ 0.01 ); young,middle-aged,and old patients exhibited an increased frequency of positive reaction to cobaly chloride compared with child patients,while young and middle-aged patients showed a decreased frequency to nickel sulfate compared with child patients (all P ＜ 0.05).Conclusion Potassium dichromate,cobalt chloride,nickle sulfate,formaldehyde,carba mix and fragrance mix are the main allergens causing dermatitis and eczema in Wuxi city.
The fumonisins are a group of common mycotoxins found around the world that mainly contaminate maize. As environmental toxins, they pose a threat to human and animal health. Fumonisin B1 (FB1) is the most widely distributed and the most toxic. FB1 can cause pulmonary edema in pigs. However, the current toxicity mechanism of fumonisins is still in the exploratory stage, which may be related to sphingolipid metabolism. Our study is designed to investigate the effect of FB1 on the cell proliferation and barrier function of swine umbilical vein endothelial cells (SUVECs). We show that FB1 can inhibit the cell viability of SUVECs. FB1 prevents cells from entering the S phase from the G1 phase by regulating the expression of the cell cycle-related genes cyclin B1, cyclin D1, cyclin E1, Cdc25c, and the cyclin-dependent kinase-4 (CDK-4). This results in an inhibition of cell proliferation. In addition, FB1 can also change the cell morphology, increase paracellular permeability, destroy tight junctions and the cytoskeleton, and reduce the expression of tight junction-related genes claudin 1, occludin, and ZO-1. This indicates that FB1 can cause cell barrier dysfunction of SUVECs and promote the weakening or even destruction of the connections between endothelial cells. In turn, this leads to increased blood vessel permeability and promotes exudation. Our findings suggest that FB1 induces toxicity in SUVECs by affecting cell proliferation and disrupting the barrier function.
Abstract The objectives of this report are to summarize the content and status of transporter‐related postmarketing requirement (PMR)/postmarketing commitment (PMC) studies in new drug applications (NDAs) approved by the U.S. Food and Drug Administration (FDA) and to discuss the reasons for requesting such studies and the impact of PMR/PMC study results on labeling to guide the optimal use of the drugs. Multiple data sources were searched to collect information on transporter‐related PMR/PMC studies between January 1999 and May 2015. A total of 40 transporter‐related PMR/PMC study requests were issued for 35 NDAs. Among these PMR/PMC studies, 27 requested studies related to P‐glycoprotein. As of May 31, 2015, 34 transporter‐related PMR/PMC studies (85%) are considered “fulfilled” (per the FDA's PMR/PMC website), and 22 (65%) resulted in labeling updates. The majority of the PMR/PMC studies are for drugs in the therapeutic areas of anti‐infectives, oncology, and neurology. The results from PMR/PMC studies are important for dosing optimization and are often included in the updated labeling. Because a significant lag time is anticipated between drug approval and PMR/PMC fulfillment, NDA applicants are encouraged to include transporter‐related assessments in clinical drug development programs for drug products.
Background: Myeloid cell leukemia-1 (Mcl-1) protein, as a critical pro-survival member of the B-cell lymphoma 2 (Bcl-2) protein family, plays an important role in apoptosis, carcinogenesis and resistance to chemotherapies. Hence, potently and selectively inhibiting Mcl-1 to induce apoptosis has become a widely accepted anticancer strategy. Objective: This review intends to provide a comprehensive overview of patents and primary literature, published from 2017 to present, on small molecule Mcl-1 inhibitors with various scaffolds. By analyzing the modes of compound-protein interactions, the similarities and differences of those structures are discussed, which could provide guidance for future drug design. Methods: The primary accesses for patent searching are SciFinder and Espacenet®. Besides the data disclosed in patents, some results published in the follow-up research papers will be included in this review. Results: The review covers dozens of patents on Mcl-1 inhibitors in the past three years, and the scaffolds of compounds are mainly divided into indole scaffolds and non-indole scaffolds. The compounds described here are compared with the relevant inhibitors disclosed in previous patents, and representative compounds, especially those launched in clinical trials, are emphasized in this review. Conclusion: For most of the compounds in these patents, analyses of the binding affinity to Mcl-1 and studies in multiple cell lines were conducted, wherein some compounds were tested in preclinical cancer models or were included in other biological studies. Some compounds showed promising results and potential for further study.
'/%3e%3cuse xlink:href='%23a' transform='rotate(23.036 .093 25.536)'/%3e%3cuse xlink:href='%23a' transform='rotate(45.87 1.273 16.18)'/%3e%3cuse xlink:href='%23a' transform='rotate(69.945 .996 12.078)'/%3e%3cuse xlink:href='%23a' transform='rotate(20.66 -19.689 31.932)'/%3e%3c/svg%3e)
