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Lipid nanoemulsions are promising nanodrug delivery carriers that can improve the efficacy and safety of paclitaxel(PTX).However,no intravenous lipid emulsion of PTX has been approved for clinical treatment,and systemic safety profiles have not yet been reported.Here we outline the development of a PTX-loaded tumor-targeting intravenous lipid emulsion(PTX Emul)and describe its characteristics,colloidal stability,and systemic safety profiles in terms of acute toxicity,long-term toxicity,and tox-icokinetics.We also compare PTX Emul with conventional PTX injection.Results showed that PTX Emul exhibited an ideal average particle size(approximately 160 nm)with narrow size distribution and robust colloidal stability under different conditions.Hypersensitivity reaction and hemolysis tests revealed that PTX Emul did not induce hypersensitivity reactions and had no hemolytic potential.In addition,where the alleviated systemic toxicity of PTX Emul may be attributed to the altered toxicokinetic characteristics in beagle dogs,including the decreased AUC and increased plasma clearance and volume of distribution,PTX Emul alleviated acute and long-term toxicity as evidenced by the enhanced the median lethal dose and approximate lethal dose,moderate body weight change,decreased bone marrow suppression and organ toxicity compared with those under PTX injection at the same dose.A fundamental understanding of the systemic safety profiles,high tumor-targeting efficiency,and superior antitumor activity in vivo of PTX Emul can provide powerful evidence of its therapeutic potential as a future treatment for breast cancer.
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To explore the pharmacogenomic markers that affect the platinum-based chemotherapy response in non-small-cell lung carcinoma (NSCLC), we performed a two-cohort of genome-wide association studies (GWAS), including 34 for WES-based and 433 for microarray-based analyses, as well as two independent validation cohorts. After integrating the results of two studies, the genetic variations related to the platinum-based chemotherapy response were further determined by fine-mapping in 838 samples, and their potential functional impact were investigated by eQTL analysis and in vitro cell experiments. We found that a total of 68 variations were significant at P < 1 × 10-3 in cohort 1 discovery stage, of which 3 SNPs were verified in 262 independent samples. A total of 541 SNPs were significant at P < 1 × 10-4 in cohort 2 discovery stage, of which 8 SNPs were verified in 347 independent samples. Comparing the validated SNPs in two GWAS, ADCY1 gene was verified in both independent studies. The results of fine-mapping showed that the G allele carriers of ADCY1 rs2280496 and C allele carriers of rs189178649 were more likely to be resistant to platinum-based chemotherapy. In conclusion, our study found that rs2280496 and rs189178649 in ADCY1 gene were associated the sensitivity of platinum-based chemotherapy in NSCLC patients.
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BackgroundThe coronavirus disease 2019 (COVID-19) has become a global pandemic currently. Many drugs showed potential for COVID-19 therapy. However, genetic factors which can lead to different drug efficiency and toxicity among populations are still undisclosed in COVID-19 therapy. MethodsWe selected 67 potential drugs for COVID-19 therapy (DCTs) from clinical guideline and clinical trials databases. 313 pharmaco-genes related to these therapeutic drugs were included. Variation information in 125,748 exomes were collected for racial differences analyses. The expression level of pharmaco-genes in single cell resolution was evaluated from single-cell RNA sequencing (scRNA-seq) data of 17 healthy adults. ResultsPharmacogenes, including CYP3A4, ABCB1, SLCO1B1, ALB, CYP3A5, were involved in the process of more than multi DCTs. 224 potential drug-drug interactions (DDIs) of DCTs were predicted, while 112 of them have been reported. Racial discrepancy of common nonsynonymous mutations was found in pharmacogenes including: VDR, ITPA, G6PD, CYP3A4 and ABCB1 which related to DCTs including ribavirin, -interferon, chloroquine and lopinavir. Moreover, ACE2, the target of 2019-nCoV, was only found in parts of lung cells, which makes drugs like chloroquine that prevent virus binding to ACE2 more specific than other targeted drugs such as camostat mesylate. ConclusionsAt least 17 drugs for COVID-19 therapy with predictable pharmacogenes should be carefully utilized in risk races which are consisted of more risk allele carriers. At least 29 drugs with potential of DDIs are reported to be affected by other DDIs, they should be replaced by similar drugs without interaction if it is possible. Drugs which specifically targeted to infected cells with ACE2 such as chloroquine are preferred in COVID-19 therapy.
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Translation control in eukaryotes contributes significantly to gene expression regulation during cellular processes,which enables rapid changes of specific proteins to maintain cellular homeostasis.Eukaryotic translation is a multiple-step process that comprised of four phases:initiation,elongation,termination and ribosome recycling.The initiation phase is rate-limiting and orchestrated by a set of eukaryotic translation initiation factors (eIFs).Defects in translation initiation can result in a series of diseases.Among all eIFs,eIF3 is the largest and less-known initiation factor due to its intrinsic complexity.Aberration in eIF3A,the largest subunit of eIF3,is known to contribute to carcinogenesis and protection against evolution into higher-grade malignancy,and the altered expression or mutation of eIF3A affects the responses of cancer patients to platinum-based chemotherapy.Besides its role in cancinogenesis,eIF3A is also implicated in fibrosis,and the agents inhibiting eIF3A delay the progression of this disorder.The dual roles of eIF3A in tumorigenesis are probably due to the regulation of translation of different mRNAs at different stages of tumor progression by eIF3A.In tum the encoded products serve as pro-tumor or anti-tumor proteins at different stages.
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Translation is a fundamental step in regulation of gene expression and abnormalities in this process may lead to cancer. In eukaryotic cells, translation of mRNA is mainly regulated by many eukaryotic initiation factors ( eIFs) . EIF3 plays an impor-tant role in translational regulation, cell growth and oncogenesis. The largest subunit of eIF3, eIF3a may play a role as a regulator of mRNAs. The relationship between eIF3a and oncogenesis has been found. Moreover, the eIF3a mRNA is ubiquitously ex-pressed in different cancer cells and can modulate the cell cycle. However, some studies indicate that eIF3a could provide protec-tion against evolution into higher malignancy and reduce the re-sistance to chemotherapy . The patients of high eIF3a expression could get a better prognosis . In fact, the role of eIF3a is still un-clear in cancer cells. EIF3a may be involved in the process of tumor pathophysiology, but its regulatory role is undulatory.
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One of the most promising antimalarial drugs which are widely used throughout the world is the artemisinin (ARS)and its derivatives,e.g.,artemether,arteether,and artesunate.Their true potential lies in broader anti-disease applications.The mechanism of action of these compounds appears to involve the endoperoxide bridge to produce carbon-centred free radicals.Large clinical studies did not show serious side effects,however,there is a paucity of large-scale clinical trials suitable to detect rare but significant toxicity.Therefore,a final and definitive statement on the safety of artemisinins still cannot be made.In contrast,animal experiments at high doses shown considerable toxicity upon application of artemisinins.In the present review,the authors give a comprehensive overview on toxicity studies in cell culture and in animals (mice,rats,rabbits,dogs,and monkeys)as well as on toxicity reported in human clinical trials.The authors emphasize the current knowledge on neurotoxicity,embryotoxicity, genotoxicity,hemato-and immunotoxicity and cardiotoxicity.Rapid elimination of artemisinins after oral intake represents a relatively safe route of administration compared to delayed drug release after intra-muscular (im ) injection. There are drug-related differences, i.e., intramuscular application of artemether or arteether,but not to artesunate,which is safe and gives good profiles after im administra-tion in severe malaria.It might also be important in determining dose limitations for treatment of other diseases such as cancer.Questions about dosing regimens,safety of long-term use and possible inter-actions with existing therapies and toxicities that might be related to the treatment of tumors should be answered by appropriate clinical and preclinical studies.
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Multidrug resistance-associated protein 1 (MRP1/ABCC1) is the first identified member of ABCC subfamily which belongs to ATP-binding cassette (ABC) transporter superfamily.It is ubiquitously expressed in almost all human tissues and transports a wide spectrum of substrates including drugs,heavy metal anions,toxicants,and conjugates of glutathione,glucuronide and sulfate.With the advance of sequence technology,many MRP1/ABCC1 polymorphisms have been identified.Accumulating evidences show that some polymorphisms are significantly associated with drug resistance and disease susceptibility.In vitro reconstitution studies have also unveiled the mechanism for some polymorphisms.In this review,we present recent advances in understanding the role and mechanism of MRP1/ABCC1 polymorphisms in drug resistance,toxicity,disease susceptibility and severity,prognosis prediction,and methods to select and predict functional polymorphisms.
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Objective To explore the association between rs3758539G-803A and rs10882283 T-179G polymorphism of retinol binding protein 4 (RBP4) and rosiglitazone response in Chinese type 2 diabetes mellitus (T2DM) patients.Methods A total of 472 Chinese T2DM patients and 198 healthy subjects were enrolled to identify G-803A and T-179G genotypes using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP ).assay.Forty-two T2DM patients with different G-803A or T-179G genotypes were selected to undergo a 12-week rosiglitazone treatment (4 mg/d).Serum fasting plasma glucose (FPG),postprandial plasma glucose (PPG),fasting serum insulin (FINS),glycated hemoglobin (HbAlc),postprandial serum insulin ( PINS),triglyceride (TG),low-density lipoprotein-cholesterol ( LDL-c),and high-density lipoprotein-cholesterol (HDL-c) were determined before and after the rosiglitazone treatment.Results T2DM patients with RBP4 G-803A GG genotype showed lower TG and LDL-c concentrations compared with that in the GA +AA genotype subjects.T2DM patients with RBP4 T-179G TT genotype showed lower waist-to-hip ratio (WHR),FPG and FINS values compared with that in the TG + GG genotype individuals.Patients with GG genotype of RBP4 G-803A had an enhanced rosiglitazone efficacy on FPG and FINS compared with that in the GA + AA genotype group.Patients with RBP4 T179G TG + GG genotype showed an enhanced rosiglitazone efficacy on HbAlc level compared with that in the TT genotype group.Conclusion RBP4 G-803A and T-179G polymorphism might be associated with the development of T2DM and affect the therapeutic efficacy of rosignitazone in Chinese T2DM patients.
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Genome-wide association studies ( CWAS) use high-throughout genotyping technologies to investigate the relation of hundreds of thousands of gene markers(genotype) with clinical conditions and measurable traits (phenotype). Type 2 diabetes mellitus results from the interaction of environmental factors with genetic variants. Many progresses have been acquired from GWAS. New gene regions have been discovered to be involved in the development and function of islet (3-cells, which provides new strategies for the etiology investigation, prevention, and treatment of type 2 diabetes mellitus.
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Objective To approach the role of Kupffer cell (KC) in regulation of liver regeneration after partial hepatectomy (PH). Methods Condition medium of kupffer cells (KCCM) was prepared and the role of KCCM in promoting rat primary hepatocytes proliferation was observed by MTT method. The PH animal model was reproduced in mice and the rate of liver regeneration was measured and the expression features of TNF-?, TGF-? and TGF-?_1 were determined by immunohistochemical methods after PH with KC depletion. Results KCCM could promote primary hepatocyte proliferation significantly (A=0.746?0.06) compared with control (A=0.536?0.06, P
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Objective To Investigate the mechanism of augmenter of liver regeneration (ALR) in promoting proliferation of damaged hepatocyte. Methods The inhibitory effects of ALR on the expression of TGF-?_1 in hepatic stellate cell and Kupffer cell were studied by immunohistochemistry and Western blot. The effects of hepatic stellate cell (Ito cell) conditioned medium (ICCM+) and Kupffer cell conditioned medium (KCCM+) prepared by treatment of using augmenter of liver regeneration (ALR) on damaged hepatocytes proliferation were studied by MTT. The antagonistical role of ALR on TGF-?_1, which inhibited damaged hepatocyte proliferation was investigated by MTT determination. Results Immunoreactive positive signal of TGF-?_1 in hepatic stellate cell and Kupffer cell stimulated by ALR were decreased. Immunolabeling of TGF-?_1 in hepatic stellate cell stimulated by ALR was weakened. The proliferation of damaged hepatocytes was increased significantly by administration of ICCM and KCCM. ALR could reverse the inhibitory role of TGF-?_1 on the proliferation of damaged hepatocyte. Conclusion ALR can promote proliferation of injured hepatocyte indirectly by inhibiting expression of TGF-?_1 in hepatic stellate cell and Kupffer cell.
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AIM: To investigate the mechanisms of augmenter of liver regeneration (ALR) in promoting damaged hepatocyte proliferation.METHODS: The effects of Kupffer cell condition medium (KCCM+) stimulated by ALR on damaged hepatocyte proliferation were studied by MTT. The localization of ALR binding to Kupffer cell membrane and in intact rat liver was studied by immunohistochemistry. The IL-6 expression in Kupffer cells stimulated with ALR was observed by immunohistochemistry. RESULTS: The proliferation of damaged hepatocytes stimulated with KCCM+ was increased significantly. ALR immunostaining particles in plasm of hepatocyte were found in intact liver. The rough immunostaining particles of ALR were seen on the surface of Kupffer cell membrane. Immunostaining particles of IL-6 in Kupffer cells induced by ALR increased. CONCLUSION: ALR promotes proliferation of damaged hepatocytes indirectly by stimulating Kupffer cells.
