INTERNATIONAL IMMUNOPHARMACOLOGY
·
2015
·
IF 2.472
Yin-Li Xu,Jian-Qun Kou,Shu-Zhi Wang,Cao-Xin Chen,Zheng-Hong Qin
Background Recent studies reported that Naja naja atra venom (NNAV) regulated immune function and had a therapeutic effect on adjunctive arthritis and nephropathy. We hypothesized that NNAV and its active component, neurotoxin (NTX), might inhibit skin allograft rejection. Methods Skin allografts were used to induce immune rejection in rats. In addition, mixed lymphocyte culture (MLC) was used to mimic immune rejection reaction in vitro. Both NNAV and NTX were orally given starting from 5 days prior to skin allograft surgery. Results The results showed that oral administration of NNAV or NTX prolonged the survival of skin allografts and inhibited inflammatory response. The production of Th1 cytokines (IFN-γ, IL-2) was also suppressed. NTX inhibited T-cell proliferation and CD4 + T cell division induced by skin allografts. NTX also showed immunosuppressive activity in mixed lymphocyte culture. Atropine alone inhibited Con A-induced proliferation of T cells and potentiated NTX' s inhibitory effects on T cells, while pilocarpine only slightly enhanced Con A-induced T cell proliferation and partially reversed the inhibitory effect of NTX. On the other hand, neither nicotine nor mecamylamine had an influence on NTX's inhibitory effects on Con A-induced T cell proliferation in vitro. NTX inhibited T cell proliferation by arresting the cell cycle at the G 0 /G 1 phase. Conclusions The present study revealed that NNAV and NTX suppressed skin allograft rejection by inhibiting T cell-mediated immune responses. These findings suggest both NNAV and NTX as potential immunosuppressants for preventing the immune response to skin allografts.
研究领域:
免疫学
·
移植学
·
药理学
·
毒理学
✓ 已验证
DOI
PubMed
高影响因子
Journal of Ophthalmology
·
2016
·
IF 1.463
Hongyan Zhou,Wensong Zhang,Xunyi Gao,Hongguang Zhang,Ning Kong
Purpose. The study aimed to evaluate the effect of all-trans retinoic acid-loaded nanostructured lipid carriers (ATRA-NLCs) on the zymosan-induced expression of the cytokines IL-4, IL-10, and IFN-γ and the matrix metalloproteinases/tissue inhibitor of metalloproteinases (MMPs/TIMPs) and TLR2 in rabbit corneal fibroblasts (RCFs). Methods. ATRA-NLCs were prepared by emulsification. RCFs were isolated and harvested after four to seven passages in monolayer culture. Cytokine release (IL-4, IL-10, and IFN-γ) induced by zymosan was analyzed by cytokine release assay, reverse transcription, and real-time polymerase chain reaction (RT-PCR) analysis detection. MMP-1, MMP-3, and MMP-13, TIMP-1 and TIMP-2, and TLR2 expression were analyzed by immunoblotting. Results. ATRA-NLCs were resistant to light and physically stable, and the average size of the ATRA-NLCs was 200 nm. ATRA-NLCs increased the zymosan-induced release of IL-4 and IL-10 and decreased the release of IFN-γ by RCFs. ATRA-NLCs decreased the levels of TLR2 and MMPs/TIMPs above. Conclusions. ATRA may be a potent anti-inflammatory agent for the therapy of fungal keratitis (FK).
研究领域:
药理学
·
眼科学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
NUCLEIC ACIDS RESEARCH
·
2018
·Vol. 46
·期 7
·3284-3297
·
IF 11.561
Tong Qingyi,You Huijuan,Chen Xintao,Wang Kongchao,Sun Weiguang,Pei Yufeng,Zhao Xiaodan,Yuan Ming,Zhu Hucheng,Luo Zengwei,Zhang Yonghui
Despite All-trans retinoic acid (ATRA) has transformed acute promyelocytic leukemia (APL) from the most fatal to the most curable hematological cancer, there remains a clinical challenge that many high-risk APL patients who fail to achieve a complete molecular remission or relapse and become resistant to ATRA. Herein, we report that 5-(4-methoxyphenethyl)-[1, 3] dioxolo [4, 5-j] phenanthridin-6(5H)–one (ZYH005) exhibits specific anticancer effects on APL and ATRA-resistant APL in vitro and vivo, while shows negligible cytotoxic effect on non-cancerous cell lines and peripheral blood mononuclear cells from healthy donors. Using single-molecule magnetic tweezers and molecule docking, we demonstrate that ZYH005 is a DNA intercalator. Further mechanistic studies show that ZYH005 triggers DNA damage, and caspase-dependent degradation of the PML-RARa fusion protein. As a result, APL and ATRA-resistant APL cells underwent apoptosis upon ZYH005 treatment and this apoptosis-inducing effect is even stronger than that of arsenic trioxide and anticancer agents including 5-fluorouracil, cisplatin and doxorubicin. Moreover, ZYH005 represses leukemia development in vivo and prolongs the survival of both APL and ATRA-resistant APL mice. To our knowledge, ZYH005 is the first synthetic phenanthridinone derivative, which functions as a DNA intercalator and can serve as a potential candidate drug for APL, particularly for ATRA-resistant APL.
研究领域:
肿瘤学
·
分子生物学
·
药理学
·
血液学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR CELL
·
2024
·
IF 14.5
Huihui An,Yifan Hong,Yeek Teck Goh,Casslynn W.Q. Koh,Shahzina Kanwal,Yi Zhang,Zhaoqi Lu,Phoebe M.L. Yap,Suat Peng Neo,Chun-Ming Wong,Alice S.T. Wong,Yang Yu,Jessica Sook Yuin Ho,Jayantha Gunaratne,Wee Siong Sho Goh
N 6 ,2′-O-dimethyladenosine (m 6 Am) is an abundant mRNA modification that impacts multiple diseases, but its function remains controversial because the m 6 Am reader is unknown. Using quantitative proteomics, we identified transcriptional terminator premature cleavage factor II (PCF11) as a m 6 Am-specific reader in human cells. Direct quantification of mature versus nascent RNAs reveals that m 6 Am does not regulate mRNA stability but promotes nascent transcription. Mechanistically, m 6 Am functions by sequestering PCF11 away from proximal RNA polymerase II (RNA Pol II). This suppresses PCF11 from dissociating RNA Pol II near transcription start sites, thereby promoting full-length transcription of m 6 Am-modified RNAs. m 6 Am’s unique relationship with PCF11 means m 6 Am function is enhanced when PCF11 is reduced, which occurs during all- trans -retinoic-acid (ATRA)-induced neuroblastoma-differentiation therapy. Here, m 6 Am promotes expression of ATF3, which represses neuroblastoma biomarker MYCN. Depleting m 6 Am suppresses MYCN repression in ATRA-treated neuroblastoma and maintains their tumor-stem-like properties. Collectively, we characterize m 6 Am as an anti-terminator RNA modification that suppresses premature termination and modulates neuroblastoma’s therapeutic response.
研究领域:
分子生物学
·
癌症生物学
·
转录组学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF SEPARATION SCIENCE
·
2021
·Vol. 45
·期 4
·812-823
·
IF 3.645
Yuanqing Wei,Ting Liu,Binru Zheng,Yilin Song,Shengsong Wang,Mojuan Zheng,Yanling Xu,Yumei Chi,Ming Zhao,Jin-ao Duan,Shuying Han,Rui Liu
A new strategy combined gold-coated magnetic nanocomposites assisted enrichment with mass spectrometry was developed for the characterization of disulfide bond-contained proteins from Chinese cobra ( Naja atra ) venom. In this work, core-shell nanocomposites were synthesized by the seed-mediated growth method and used for the enrichment of snake venom proteins containing disulfide bonds. A total of 3545 tryptic digested peptides derived from 96 venom proteins in Naja atra venom were identified. The venom proteins comprised 14 toxin families including three-finger toxins, phospholipase A 2 , snake venom metalloproteinase, cobra venom factor, and so forth. Extra 16 venom proteins were detected exclusively in the nanocomposites set, among which 11 venom proteins were from the three-finger toxins family. In the present study, the proposed simple and efficient protocol replaced the tedious and laborious technologies commonly used for pre-separating crude snake venom, suggesting widely implementation in low-abundance or trace disulfide bond-contained proteins or peptides characterization.
研究领域:
生物化学
·
蛋白质组学
·
毒理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
GENE
·
2016
·
IF 2.319
Jing Qian,Chunhua Ren,Jianjun Xia,Ting Chen,Zonghe Yu,Chaoqun Hu
The non-specific protease inhibitor alpha-2-macroglobulin (A 2 M) is a key macromolecular glycoprotein that involved in host immune defense against pathogens in vertebrates and invertebrates. However, no research regarding A 2 M has been developed in echinoderms to date. In this study, the full-length cDNA of A 2 M was cloned from the sea cucumber ( Holothuria atra ), which is a tropical species widely distributed along the coasts of the South China Sea and designated HaA 2 M . HaA 2 M possesses all three conserved functional domains of known A 2 M proteins, including the bait region domain, thioester domain and receptor-binding domain. Compared to fish and shrimp A 2 Ms, the histidine residue from the catalytical regions is well conserved in HaA 2 M. HaA 2 M mRNA was predominantly expressed in coelomocytes and, to a lesser extent, in the body wall, intestine and respiratory tree. A 2 M activity was detected in the coelomic fluids of H. atra . The mRNA expression and activity levels were investigated in the major immune tissues and coelomic fluids of H. atra after challenge with inactivated Vibrio alginolyticus or polyriboinosinic polyribocytidylic acid [Poly (I: C)]. RNA interference (RNAi)-mediated knockdown of HaA 2 M resulted in a significant reduction of HaA 2 M gene transcript level (86%). RNAi-mediated silencing of HaA 2 M gene significantly decreased the A 2 M activity (38%) and increased the number of viable bacteria (2.8-fold) in the coelomic fluids of H. atra infected by V. alginolyticus . Our study, as a whole, supplied the evidences for HaA 2 M as an immune-relevant molecule and it might have multiple functions in the innate immune system of H. atra .
研究领域:
免疫学
·
分子生物学
·
海洋生物学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2025
·
IF 11.5
Huan Yang,Yiyao Pu,Xueyi Hu,Haili Zhang,Shiyi Li,Wei Zhang,Meiwan Chen,Heyang Zhang,Rongrong Jin,Yu Nie
All-trans retinoic acid (ATRA) effectively treats acute promyelocytic leukemia but struggles in solid tumors due to insufficient tumor accumulation from poor targeting delivery and rapid metabolism by cytochrome P450 enzymes (particularly CYP26A1). Herein, we developed a lipoplex with a folic acid (F), utilizing ATRA-derived lipid nanoparticles (RA) for co-delivery of ATRA and siCYP26A1 (FRA/siCYP26A1). As the ATRA could upregulate the folate receptor β (FRβ), the endocytosis of FRA/siCYP26A1 could be consistently promoted. After FRA/siCYP26A1 treatment, the intracellular concentration of ATRA reached up to 10-fold higher than the clinically used 13-cis-retinoic acid (13-cisRA) and free ATRA. The efficient differentiation was reflected by the expression of differentiation markers peaking up to an order of magnitude higher than free ATRA and a remarkable change in cell morphology. Finally, the FRA/siCYP26A1 significantly suppressed neuroblastoma xenografts by 90.2 % and orthotopic hepatocellular carcinoma by 77.4 %. The present study, for the first time, showcased the potential of co-delivering ATRA and siRNA as a therapeutic approach to govern the concentration of ATRA in tumors and thus facilitate differentiation therapy for solid tumor treatment.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Immunology
·
2022
·
IF 8.786
Wang Yufeng,Wang Chunxu,Zuo Nan,Yang Hao,Fang Shaohong,Shi Jialan
The rate of complete remission of acute promyelocytic leukemia (APL) is currently over 90% because of the use of all-trans retinoic acid (ATRA) with arsenic trioxide (ATO). However, hemorrhagic mortality has emerged as the most significant barrier to APL-induced remission. Neutrophils extracellular traps (NETs/ETs) cause vascular leakage by damaging the integrity of endothelial cells. We have previously demonstrated that APL cells treated with ATRA/ATO undergo a cell death process, releasing extracellular chromatin, termed ETosis/NETosis. However, the mechanism underlying the involvement of ETs in endothelial injury in APL remain largely unknown. Here, we analysed the ability of mature and immature neutrophils to release ETs, and their interaction with platelets (PLTs) in APL. Importantly, the effect of ETs on vascular endothelium in APL was discussed. Our results showed that the ability of immature neutrophils to release ETs was impaired in APL, whereas mature neutrophils produced ETs, which were associated with activated PLTs. Moreover, ATRA+ATO induced immature neutrophil differentiation, as well as increased the release of ETs from mature neutrophils. The excessive ETs damaged endothelial cells, causing blood cell leakage. Removing ETs using DNase 1 alleviated endothelial damage and improved blood cells leakage. Our results indicate that vascular endothelial injury is at least partially associated with ETs in APL, and that targeting ETs production may be an effective approach for relieving vascular leakage and reducing the burden of bleeding in APL.
研究领域:
血液学
·
肿瘤学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2026
·
IF 6
Zhidi He,Yulin Xu,Zhipeng Tian,Dong Chen,Ziyan Dong,Shiyu Zhu,Man Li,Rong Guo,Bing Xiang,Qin He
Despite its clinical utility, the therapeutic potential of Venetoclax (ABT-199) in acute myeloid leukemia (AML) remains limited by the heterogeneous nature of the disease, which often leads to reduced efficacy of monotherapy. Herein, we demonstrate that ABT-199-induced apoptosis can be potentiated by all-trans retinoic acid (ATRA) to suppress the DNA damage response. To address the lack of targeted drug delivery against AML and facilitate enhanced therapeutic efficacy, we engineered a biomimetic micelle, HPAA, by co-assembling an amphiphilic mPEG-ATRA conjugate with ABT-199 into micelles, followed by cloaking with P-selectin-rich membranes from activated human umbilical vein endothelial cells to target CD44 overexpressed on AML cells. The resulting HPAA micelles exhibited enhanced cellular uptake in MOLM13 cells, achieving approximately 2-fold higher uptake efficiency than non-targeted PAA micelles. Consequently, HPAA induced robust apoptosis and superior anti-leukemic effects, significantly suppressing MOLM13 cell proliferation in vitro. In an orthotopic AML model, HPAA preferentially accumulated in the bone marrow resident AML cells. Accordingly, treatment substantially reduced the MOLM13 cell burden in the peripheral blood, bone marrow and liver. This work establishes HPAA as a promising biomimetic nanoplatform for AML therapy by integrating active targeting with the novel drug repurposing of ATRA as a Chk1 suppressor to potentiate ABT-199 efficacy. HPAA potentiates ABT-199 efficacy in acute myeloid leukemia by repurposing ATRA to suppress Chk1, thereby inducing significant apoptosis. Download: Download high-res image (110KB) Download: Download full-size image
✓ 已验证
DOI
高影响因子
JOURNAL OF THE WORLD AQUACULTURE SOCIETY
·
2016
·Vol. 48
·期 2
·360-373
·
IF 0.665
Jing Qian,Chunhua Ren,Jianjun Xia,Zonghe Yu,Chaoqun Hu
Alpha-2-macroglobulin (A 2 M) is essential for hosts defending against pathogen infections. In this study, two distinct A 2 Ms were identified from sea cucumbers Stichopus monotuberculatus and Holothuria atra , which belong to different genera in the Phylum Echinodermata, and named StmA 2 M and HaA 2 M, respectively. Structural analysis of StmA 2 M and HaA 2 M revealed that all contain the bait region domain, thioester domain, and receptor-binding domain. Phylogenetic analysis indicated that StmA 2 M and HaA 2 M all belong to the echinoderm A 2 Ms. The cleavage site RXXR and the catalytic histidine residue for complement component C3 were found in StmA 2 M and HaA 2 M. Compared with human A 2 M, the three-dimensional structures of StmA 2 M and HaA 2 M were more similar to that of common carp A 2 M. Both StmA 2 M and HaA 2 M showed the strongest response at transcriptional levels to lipopolysaccharide (LPS) at 12 h and polyriboinosinic polyribocytidylic acid [Poly (I: C)] at 24 h, respectively. Activity of StmA 2 M showed the strongest response to Poly (I: C) at 6 h, while the strongest change of HaA 2 M activity was induced by LPS at 24 h. The differential mRNA expression and enzyme activity levels suggested that A 2 M in sea cucumbers might be involved in different immune responses to LPS or Poly (I: C) challenge.
研究领域:
海洋生物学
·
免疫学
·
分子生物学
·
基因组学
✓ 已验证
DOI
高影响因子
Asian Journal of Pharmaceutical Sciences
·
2023
·
IF 10.2
Shan Gao,Meng Liu,Dongzhu Liu,Xinru Kong,Yuelin Fang,Yingying Li,Hang Wu,Jianbo Ji,Xiaoye Yang,Guangxi Zhai
Growing evidence suggests that the presence of cancer stem cells (CSCs) is a major challenge in current tumor treatments, especially the transition from non-CSCs to differentiation of CSCs for evading conventional therapies and driving metastasis. Here we propose a therapeutic strategy of synergistic differentiation therapy and phototherapy to induce differentiation of CSCs into mature tumor cells by differentiation inducers and synergistic elimination of them and normal cancer cells through phototherapy. In this work, we synthesized a biomimetic nanoplatform loaded with IR-780 and all-trans retinoic acid (ATRA) via biomineralization. This method can integrate aluminum ions into small-sized protein carriers to form nanoclusters, which undergo responsive degradation under acidic conditions and facilitate deep tumor penetration. With the help of CSC differentiation induced by ATRA, IR-780 inhibited the self-renewal of CSCs and cancer progression by generating hyperthermia and reactive oxygen species in a synergistic manner. Furthermore, ATRA can boost immunogenic cell death induced by phototherapy, thereby strongly causing a systemic anti-tumor immune response and efficiently eliminating CSCs and tumor cells. Taken together, this dual strategy represents a new paradigm of targeted eradication of CSCs and tumors by inducing CSC differentiation, improving photothermal therapy/photodynamic therapy and enhancing antitumor immunity.
研究领域:
纳米技术
·
肿瘤学
·
生物医学工程
·
免疫疗法
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Discover Oncology
·
2024
·Vol. 15
·期 1
·1-15
·
IF 2.8
Li Weinan,Fu Yuhan,Sun Jialin,Gong Hexin,Yan Ru,Wang Yanhong
Breast cancer is a major threat to safety and health of women. The breast cancer stem cells (BCSCs) have multi-drug resistance to chemotherapy drugs, which leads to chemotherapy failure. We proposed a strategy of delivery of tumor-killing drugs and a resistance reversal agent, to enhance inhibition of BCSCs. Here, schisandrin B (SchB)/AP NPs are constructed using acid-grafted-poly (β-amino ester) (ATRA-g-PBAE, AP) grafted polymer nanoparticle encapsulated SchB, with pH-sensitive release function. This drug delivery system has good pharmacological properties and can increase the SchB release with the decrease of pH. The NPs showed cytotoxic effects in reversing ATRA resistance to BCSCs. Lysosomal escape was achieved when the nanoparticles were taken up by BCSCs. In addition, we found that NPs may reverse MDR by inhibiting the expression of P-glycoprotein (P-gp) and affecting the energy supply of drug efflux. This study provides a nanodelivery therapy strategy that reverses BCSCs multidrug resistance (MDR) and demonstrates that it did so by interfering with cancer cell energy metabolism. Therefore, the co-delivery strategy of ATRA and SchB provides a new option for the treatment of breast cancer.
研究领域:
肿瘤学
·
药学
·
纳米技术
·
癌症生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）