TOXICOLOGY
·
2016
·
IF 3.817
Jie Li,Yanli Zhang,Xianhui Cai,Qingqing Xia,Jingmeng Chen,Yi Liao,Zuguo Liu,Yalin Wu
Effective clearance of all- trans -retinal (atRAL) from retinal pigment epithelial (RPE) cells is important for avoiding its cytotoxicity. However, the metabolism of atRAL in RPE cells is poorly clarified. The present study was designed to analyze metabolic products of atRAL and to compare the cytotoxicity of atRAL versus its derivative all- trans -retinal dimer (atRAL-dimer) in human RPE cells. We found that all- trans -retinol (atROL) and a mixture of atRAL condensation metabolites including atRAL-dimer and A2E were generated after incubating RPE cells with atRAL for 6 h, and the amount of atRAL-dimer was significantly higher than that of A2E. In the eyes of Rdh8 −/− Abca4 −/− mice, a mouse model with defects in retinoid cycle that displays some symbolic characteristics of age-related macular degeneration (AMD), the level of atRAL-dimer was increased compared to wild-type mice, and was even much greater than that of A2E & isomers. The cytotoxicity of atRAL-dimer was reduced compared with its precursor atRAL. The latter could provoke intracellular reactive oxygen species (ROS) overproduction, increase the mRNA expression of several oxidative stress related genes ( Nrf2 , HO-1, and γ-GCSh ), and induce ΔΨ m loss in RPE cells. By contrast, the abilities of atRAL-dimer to induce intracellular ROS and oxidative stress were much weaker versus that of concentration-matched atRAL, and atRAL-dimer exhibited no toxic effect on mitochondrial function at higher concentrations. In conclusion, the formation of atRAL-dimer during atRAL metabolic process ameliorates the cytotoxicity of atRAL by reducing oxidative stress.
研究领域:
眼科学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
·
2019
·Vol. 44
·期 5
·1952-1962
·
IF 2.928
Chao Yang,Xian Sun,Hengbing Wang,Ting Lu,Keqing Wu,Yusheng Guan,Jing Tang,Jian Liang,Rongli Sun,Zhongying Guo,Sinian Zheng,Xiaoli Wu,Hesong Jiang,Xi Jiang,Bing Zhong,Xiaobing Niu,Suan Sun,Xinru Wang,Minjian Chen,Guangbo Fu
Bladder cancer (BCa) is a common urinary tract malignancy with frequent recurrences after initial resection. Submucosal injection of gemcitabine prior to transurethral resection of bladder tumor (TURBT) may prevent recurrence of urothelial cancer. However, the underlying mechanism remains unknown. In the present study, ultra‑performance liquid chromatography Q‑Exactive mass spectrometry was used to profile tissue metabolites from 12 BCa patients. The 48 samples included pre‑ and post‑gemcitabine treatment BCa tissues, as well as adjacent normal tissues. Principal component analysis (PCA) revealed that the metabolic profiles of pre‑gemcitabine BCa tissues differed significantly from those of pre‑gemcitabine normal tissues. A total of 34 significantly altered metabolites were further analyzed. Pathway analysis using MetaboAnalyst identified three metabolic pathways closely associated with BCa, including glutathione, purine and thiamine metabolism, while glutathione metabolism was also identified by the enrichment analysis using MetaboAnalyst. In search of the possible targets of gemcitabine, metabolite profiles were compared between the pre‑gemcitabine normal and post‑gemcitabine BCa tissues. Among the 34 metabolites associated with BCa, the levels of bilirubin and retinal recovered in BCa tissues treated with gemcitabine. When comparing normal bladder tissues with and without gemcitabine treatment, among the 34 metabolites associated with BCa, it was observed that histamine change may be associated with the prevention of relapse, whereas thiamine change may be involved in possible side effects. Therefore, by employing a hypothesis‑free tissue‑based metabolomics study, the present study investigated the metabolic signatures of BCa and found that bilirubin and retinal may be involved in the mechanism underlying the biomolecular action of submucosal injection of gemcitabine in urothelial BCa.
研究领域:
肿瘤学
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代谢组学
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泌尿外科
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DOI
PubMed
高影响因子
Journal of Zhejiang University-SCIENCE B
·
2019
·
IF 1.879
Qing-qing Xia,Ling-min Zhang,Ying-ying Zhou,Ya-lin Wu,Jie Li
The present study was designed to analyze the metabolites of all- trans -retinal (atRal) and compare the cytotoxicity of atRal versus its derivative all- trans -retinoic acid (atRA) in human retinal pigment epithelial (RPE) cells. We confirmed that atRA was produced in normal pig neural retina and RPE. The amount of all- trans -retinol (atROL) converted from atRal was about 2.7 times that of atRal-derived atRA after incubating RPE cells with 10 μmol/L atRal for 24 h, whereas atRA in medium supernatant is more plentiful (91 vs. 29 pmol/mL), suggesting that atRA conversion facilitates elimination of excess atRal in the retina. Moreover, we found that mRNA expression of retinoic acid - specific hydroxylase CYP26b1 was dose-dependently up-regulated by atRal exposure in RPE cells, indicating that atRA inactivation may be also initiated in atRal-accumulated RPE cells. Our data show that atRA-caused viability inhibition was evidently reduced compared with the equal concentration of its precursor atRal. Excess accumulation of atRal provoked intracellular reactive oxygen species (ROS) overproduction, heme oxygenase-1 ( HO-1 ) expression, and increased cleaved poly(ADP-ribose) polymerase 1 (PARP1) expression in RPE cells. In contrast, comparable dosage of atRA-induced oxidative stress was much weaker, and it could not activate apoptosis in RPE cells. These results suggest that atRA generation is an antidotal metabolism pathway for atRal in the retina. Moreover, we found that in the eyes of ABCA4 −/− RDH8 −/− mice, a mouse model with atRal accumulation in the retina, the atRA content was almost the same as that in the wild type. It is possible that atRal accumulation simultaneously and equally promotes atRA synthesis and clearance in eyes of ABCA4 −/− RDH8 −/− mice, thus inhibiting the further increase of atRA in the retina. Our present study provides further insights into atRal clearance in the retina.
研究领域:
眼科学
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分子生物学
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毒理学
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DOI
PubMed
高影响因子
Cell Communication and Signaling
·
2024
·Vol. 22
·期 1
·1-13
·
IF 8.2
Zhao Changrui,Bo Jiaqiang,Li Tianyu,Tian Jiameng,Long Tian,He Yingying,Chen Siyu,Liu Chang
Background Papillary thyroid carcinoma (PTC) is the most common type of thyroid malignancy, with a rising incidence. Traditional treatments, such as thyroidectomy and radiotherapy, often lead to significant side effects, including impaired thyroid function. Therefore, there is an urgent need for non-invasive therapeutic approaches. This study aims to explore the potential of photobiomodulation therapy (PBMT), a non-invasive treatment using specific wavelengths of light, in the management of PTC. Methods We investigated the effects of blue light PBMT on PTC cells, focusing on the Retinal-OPSIN 3 (OPN3) complex’s role in mediating cellular responses. Blue light exposure was applied to PTC cells, and subsequent changes in cellular proliferation, cell cycle progression, and protein expression were analyzed. Statistical tests, including one-way ANOVA and t-tests, were used to evaluate the significance of the findings. Results Blue light exposure led to the dissociation of 11-cis-retinal from OPN3, resulting in the accumulation of all-trans retinal. This accumulation disrupted cellular proliferation pathways and induced G0/G1 cell cycle arrest in PTC cells. The Retinal-OPN3 complex was found to be a key mediator in these processes, demonstrating that thyroid cells can respond to specific light wavelengths and utilize their photoreceptive potential for therapeutic purposes. Conclusions Our findings suggest that PBMT, through the modulation of the Retinal-OPN3 complex, offers a promising non-invasive approach for treating PTC. This study highlights the therapeutic potential of light signal transduction in non-ocular tissues and opens new avenues for non-invasive cancer therapies.
研究领域:
肿瘤学
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分子生物学
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治疗科学
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DOI
高影响因子
ISME Journal
·
2021
·Vol. 15
·期 6
·1844-1857
·
IF 10.302
Liu Qing,Li Wei,Liu Di,Li Lingyan,Li Jie,Lv Na,Liu Fei,Zhu Baoli,Zhou Yuguang,Xin Yuhua,Dong Xiuzhu
Bacteria that inhabit glaciers usually produce carotenoids. Here, we report that a group of zeaxanthin-producing glacial Flavobacterium exhibited light-promoted growth. Of the tested 47 strains, 45 showed increased growths but two died under illumination at 50 μmol photon m −2 s −1 . Light stimulation occurred mainly in either anoxic or nutrient-poor cultures, while the same levels of light promotion were found for that grown at 14 and 7 °C. Pigment assays identified overrepresentative zeaxanthin but trace retinal in the light promoted 45 strains, while flexirubin was exclusively in the light-lethal two. Genomic analysis revealed the gene cluster for zeaxanthin synthesis in the 45 strains, in which 37 strains also harbored the proteorhodopsin gene prd . Transcriptomic analysis found that light-induced expressions of both the zeaxanthin synthesis and proteorhodopsin genes. Whereas, deletion of the prd gene in one strain did not diminish light promotion, inhibition of zeaxanthin synthesis did. In comparison, no light promotion was determined in a glacier Cryobacterium luteum that produced a non-zeaxanthin-type carotenoid. Therefore, light stimulation on the glacial Flavobacterium is mostly likely related to zeaxanthin, which could provide better photoprotection and sustain membrane integrity for the organisms living in cold environments.
研究领域:
微生物学
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环境科学
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分子生物学
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DOI
PubMed
高影响因子
METABOLIC ENGINEERING
·
2025
·
IF 6.8
Cong Fan,Jian Fan,Haofeng Chen,Shujin Lin,Danli Zhang,Jingya Song,Junyi Wang,Yan Wang,Xiao Han,Jifeng Yuan
Saccharomyces cerevisiae predominantly ferments sugar to ethanol, irrespective of the presence of oxygen, which is known as the Crabtree-effect. Traditional methods rely on static controls of glycolytic flux to make S. cerevisiae Crabtree-negative, which are not favorable for future biomanufacturing applications. Considering native metabolic pathways typically harness dynamic regulatory networks, we therefore aim to develop an alternative strategy using dynamic regulation of the yeast central metabolism to generate Crabtree-negative S. cerevisiae . We report that manipulating a single step at sugar phosphorylation can alter the mode of yeast metabolism with an attenuated Crabtree-effect. By implementing catabolite-regulated sugar phosphorylation, the diauxic shift in budding yeast was effectively reduced. The Crabtree-attenuated metabolism in the engineered yeast was confirmed by multidimensional characterizations such as cell morphology, the measurements of sugar utilization rate and ethanol production, and transcriptomics. In addition, we demonstrated that the Crabtree-attenuated metabolism could substantially improve the mitochondrial synthesis of short branched-chain fatty acids from amino acid catabolism, and allow the synthesis and accumulation of retinaldehyde. Taken together, we present for the first time that manipulation of sugar phosphorylation can alter the mode of yeast metabolism, and the synthetic Crabtree-attenuated yeast factory established here might serve as a non-fermentative biomanufacturing chassis.
研究领域:
微生物学
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代谢工程
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生物技术
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF BIOLOGICAL CHEMISTRY
·
2021
·Vol. 298
·期 2
·
IF 5.157
Binxiang Cai,Chunyan Liao,Danxue He,Jingmeng Chen,Jiahuai Han,Jiaying Lu,Kaiqi Qin,Wenxu Liang,Xiaoling Wu,Zuguo Liu,Yalin Wu
The breakdown of all-trans-retinal (atRAL) clearance is closely associated with photoreceptor cell death in dry age-related macular degeneration (AMD) and autosomal recessive Stargardt's disease (STGD1), but its mechanisms remain elusive. Here, we demonstrate that activation of gasdermin E (GSDME) but not gasdermin D promotes atRAL-induced photoreceptor damage by activating pyroptosis and aggravating apoptosis through a mitochondria-mediated caspase-3-dependent signaling pathway. Activation of c-Jun N-terminal kinase was identified as one of the major causes of mitochondrial membrane rupture in atRAL-loaded photoreceptor cells, resulting in the release of cytochrome c from mitochondria to the cytosol, where it stimulated caspase-3 activation required for cleavage of GSDME. Aggregation of the N-terminal fragment of GSDME in the mitochondria revealed that GSDME was likely to penetrate mitochondrial membranes in photoreceptor cells after atRAL exposure. ABC (subfamily A, member 4) and all-trans-retinol dehydrogenase 8 are two key proteins responsible for clearing atRAL in the retina. Abca4−/−Rdh8−/− mice exhibit serious defects in atRAL clearance upon light exposure and serve as an acute model for dry AMD and STGD1. We found that N-terminal fragment of GSDME was distinctly localized in the photoreceptor outer nuclear layer of light-exposed Abca4−/−Rdh8−/− mice. Of note, degeneration and caspase-3 activation in photoreceptors were significantly alleviated in Abca4−/−Rdh8−/−Gsdme−/− mice after exposure to light. The results of this study indicate that GSDME is a common causative factor of photoreceptor pyroptosis and apoptosis arising from atRAL overload, suggesting that repressing GSDME may represent a potential treatment of photoreceptor atrophy in dry AMD and STGD1.
研究领域:
眼科学
·
分子生物学
·
细胞生物学
·
神经退行性疾病
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF BIOLOGICAL CHEMISTRY
·
2023
·Vol. 299
·期 5
·
IF 4.8
Danxue He,Lei Tao,Binxiang Cai,Xiangjun Chen,Yan Wang,Shiying Li,Chunyan Liao,Yuling Chen,Jingmeng Chen,Zuguo Liu,Yalin Wu
Dry age-related macular degeneration (AMD) and recessive Stargardt’s disease (STGD1) lead to irreversible blindness in humans. The accumulation of all-trans-retinal (atRAL) induced by chaos in visual cycle is closely associated with retinal atrophy in dry AMD and STGD1 but its critical downstream signaling molecules remain ambiguous. Here, we reported that activation of eukaryotic translation initiation factor 2α (eIF2α) by atRAL promoted retinal degeneration and photoreceptor loss through activating c-Jun N-terminal kinase (JNK) signaling-dependent apoptosis and gasdermin E (GSDME)-mediated pyroptosis. We determined that eIF2α activation by atRAL in photoreceptor cells resulted from endoplasmic reticulum homeostasis disruption caused at least in part by reactive oxygen species production, and it activated JNK signaling independent of and dependent on activating transcription factor 4 and the activating transcription factor 4/transcription factor C/EBP homologous protein (CHOP) axis. CHOP overexpression induced apoptosis of atRAL-loaded photoreceptor cells through activating JNK signaling rather than inhibiting the expression of antiapoptotic gene Bcl2. JNK activation by eIF2α facilitated photoreceptor cell apoptosis caused by atRAL via caspase-3 activation and DNA damage. Additionally, we demonstrated that eIF2α was activated in neural retina of light-exposed Abca4−/−Rdh8−/− mice, a model that shows severe defects in atRAL clearance and displays primary features of human dry AMD and STGD1. Of note, inhibition of eIF2α activation by salubrinal effectively ameliorated retinal degeneration and photoreceptor apoptosis in Abca4−/−Rdh8−/− mice upon light exposure. The results of this study suggest that eIF2α is an important target to develop drug therapies for the treatment of dry AMD and STGD1.
研究领域:
眼科学
·
分子生物学
·
细胞生物学
·
神经科学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF BIOLOGICAL CHEMISTRY
·
2020
·Vol. 295
·期 20
·6958-6971
·
IF 4.238
Chunyan Liao,Binxiang Cai,Yufeng Feng,Jingmeng Chen,Yiping Wu,Jingbin Zhuang,Zuguo Liu,Yalin Wu
Disrupted clearance of all-trans-retinal (atRAL), a component of the visual (retinoid) cycle in the retina, may cause photoreceptor atrophy in autosomal recessive Stargardt disease (STGD1) and dry age-related macular degeneration (AMD). However, the mechanisms underlying atRAL-induced photoreceptor loss remain elusive. Here, we report that atRAL activates c-Jun N-terminal kinase (JNK) signaling at least partially through reactive oxygen species production, which promoted mitochondria-mediated caspase- and DNA damage-dependent apoptosis in photoreceptor cells. Damage to mitochondria in atRAL-exposed photoreceptor cells resulted from JNK activation, leading to decreased expression of Bcl2 apoptosis regulator (Bcl2), increased Bcl2 antagonist/killer (Bak) levels, and cytochrome c (Cyt c) release into the cytosol. Cytosolic Cyt c specifically provoked caspase-9 and caspase-3 activation and thereby initiated apoptosis. Phosphorylation of JNK in atRAL-loaded photoreceptor cells induced the appearance of γH2AX, a sensitive marker for DNA damage, and was also associated with apoptosis onset. Suppression of JNK signaling protected photoreceptor cells against atRAL-induced apoptosis. Moreover, photoreceptor cells lacking Jnk1 and Jnk2 genes were more resistant to atRAL-associated cytotoxicity. The Abca4−/− Rdh8−/− mouse model displays defects in atRAL clearance that are characteristic of STGD1 and dry AMD. We found that JNK signaling was activated in the neural retina of light-exposed Abca4−/−Rdh8−/− mice. Of note, intraperitoneal administration of JNK–IN-8, which inhibits JNK signaling, effectively ameliorated photoreceptor degeneration and apoptosis in light-exposed Abca4−/−Rdh8−/− mice. We propose that pharmacological inhibition of JNK signaling may represent a therapeutic strategy for preventing photoreceptor loss in retinopathies arising from atRAL overload.
研究领域:
眼科学
·
细胞生物学
·
分子生物学
·
神经科学
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产品关联
DOI
PubMed
高影响因子
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
·
2019
·Vol. 60
·期 8
·3034-3045
·
IF 3.812
Yi Liao,Houjian Zhang,Danxue He,Yan Wang,Binxiang Cai,Jingmeng Chen,Jianxing Ma,Zuguo Liu,Yalin Wu
Purpose:Visual (retinoid) cycle anomalies induce aberrant build-up of all-transretinal (atRAL) in the retinal pigment epithelium (RPE), which is a cause of RPE atrophy in Stargardt disease type 1 and age-related macular degeneration. NLR family pyrin domain containing 3 (NLRP3) inflammasome activation is implicated in the etiology of age-related macular degeneration. Here, we elucidated the relationship between NLRP3 inflammasome activation and atRAL-induced death of RPE cells.Methods:Cellular toxicities were assessed by MTS or MTT assays. Expression levels of mRNAs and proteins were determined by quantitative reverse transcription–polymerase chain reaction, Western blotting, or enzyme-linked immunosorbent assay. Fluorescence microscopy was used to examine intracellular signals. Ultrastructural features of organelles were examined by transmission electron microscope.Results:Abnormal accumulation of atRAL was associated with a significant increase in the proportion of human ARPE-19 cells exhibiting features of apoptosis and Caspase-3/gasdermin E (GSDME)-mediated pyroptosis. These cells also exhibited elevated expression of NLRP3, ASC, cleaved Caspase-1/poly ADP-ribose polymerase (PARP)/Caspase-3/GSDME, interleukin-1β (IL-1β), and IL-18, as well as NLRP3 inflammasome-related genes (IL1BandIL18). After exposure of human ARPE-19 cells to excess atRAL, reactive oxygen species (ROS) (including mitochondrial ROS) and cathepsins released from lysosomes transmitted signals leading to NLRP3 inflammasome activation. Suppressing the production of ROS, NLRP3 inflammasome, Caspase-1, cathepsin B, or cathepsin D protected ARPE-19 cells against atRAL-associated cytotoxicity. Damage to mitochondria, lysosomes, and endoplasmic reticulum in atRAL-exposed ARPE-19 cells was partially alleviated by treatment with MCC950, a selective NLRP3 inflammasome inhibitor.Conclusions:Aberrant build-up of atRAL promotes the death of RPE cells via NLRP3 inflammasome activation.
研究领域:
眼科学
·
细胞生物学
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分子生物学
·
炎症
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产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL SCIENCE & TECHNOLOGY
·
2024
·
IF 10.8
Haisu Liu,Lei Xie,Yang Xiao,Ruiwei Ran,Yuhang Fang,Baoling Yang,Liying Tan,Juanchan Xu,Songhui Lu,Yuelei Dong,Lei Cui
Marine microalgae serve as an aquaculture bait. To enhance algal cell growth and breeding profits, high-intensity light conditions are standard for cultivating bait microalgae, potentially altering microalgal metabolite production. This research revealed that Thalassiosira pseudonana, when subjected to high-intensity light conditions, accumulated significant quantities of retinal (RAL) that transferred through the food chain and transformed into all-trans retinoic acid (atRA) in marine medaka. The study further explored the toxic effects on individual fish and specific tissues, as well as the mechanisms behind this toxicity. The accumulation of atRA in the liver, intestine, and spinal column resulted in structural damage and tissue inflammation, as well as oxidative stress. It also down-regulated the gene transcription levels of key pathways involved in immune function and growth. Furthermore, it disrupted the homeostasis of the intestinal microbial communities. The implications for wildlife and human health, which are influenced by the regulation of microalgal metabolite accumulation and their transfer via the food chain, require further investigation and could hold broader significance.
研究领域:
海洋生物学
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毒理学
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环境科学
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水产养殖
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分子生物学
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产品关联
DOI
PubMed
高影响因子
FOOD CHEMISTRY
·
2022
·
IF 9.231
Rong Zhang,Wei Jia
The efficiently extraction and accurately quantify of β-carotene and its metabolites are crucial for authenticity and traceability in goat milk. Nevertheless, its reliability can be largely improved. In this study, meticulously designed native ESI-MS, fluorescence spectroscopy and molecular docking in combination with cold-induced acetonitrile aqueous two-phase separation system weaken the interaction between β-lactoglobulin and β-carotene metabolites and realized the efficiently extraction. Furthermore, established non-targeted quantitative metabolomics with optimal ion source and variable data-independent acquisition minimized the matrix effects and potential ion suppression. Validated atmospheric pressure chemical ionization-ultra high performance liquid chromatography-Orbitrap method showed that β-carotene as distinctive biomarker in cow milk, and retinol, retinaldehyde, retinoic acid and abscisic acid in goat milk. Collectively, the proposed method is a powerful tool to detect cow adulteration risks in goat milk samples and provides valuable information for availability on authenticity of goat milk.
研究领域:
食品科学
·
分析化学
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分子生物学
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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）