Theranostics
·
2019
·
IF 8.063
Shuai Wang,Yanke Lin,Ziyue Zhou,Lu Gao,Zemin Yang,Feng Li,Baojian Wu
Controlling bilirubin to a low level is necessary in physiology because of its severe neurotoxicity. Therefore, it is of great interest to understand the regulatory mechanisms for bilirubin homeostasis. In this study, we uncover a critical role for circadian clock in regulation of bilirubin detoxification and homeostasis. Methods : The mRNA and protein levels of Bmal1 (a core clock gene), metabolic enzymes and transporters were measured by qPCR and Western blotting, respectively. Luciferase reporter, mobility shift and chromatin immunoprecipitation were used to investigate transcriptional gene regulation. Experimental hyperbilirubinemia was induced by injection of bilirubin or phenylhydrazine. Unconjugated bilirubin (UCB) and conjugated bilirubin were assessed by ELISA. Results : We first demonstrated diurnal variations in plasma UCB levels and in main bilirubin-detoxifying genes Ugt1a1 and Mrp2 . Of note, the circadian UCB levels were antiphase to the circadian expressions of Ugt1a1 and Mrp2. Bmal1 ablation abrogated the circadian rhythms of UCB and bilirubin-induced hepatotoxicity in mice. Bmal1 ablation also decreased mRNA and protein expressions of both Ugt1a1 and Mrp2 in mouse livers, and blunted their circadian rhythms. A combination of luciferase reporter, mobility shift, and chromatin immunoprecipitation assays revealed that Bmal1 trans-activated Ugt1a1 and Mrp2 through specific binding to the E-boxes in the promoter region. Further, Bmal1 ablation caused a loss of circadian time-dependency in bilirubin clearance and sensitized mice to chemical induced-hyperbilirubinemia. Moreover, bilirubin stimulated Bmal1 expression through antagonism of Rev-erbα, constituting a feedback mechanism in bilirubin detoxification. Conclusion : These data supported a dual role for circadian clock in regulation of bilirubin detoxification, generating circadian variations in bilirubin level via direct transactivation of detoxifying genes Ugt1a1 and Mrp2, and defending the body against hyperbilirubinemia via Rev-erbα antagonism. Thereby, our study provided a potential mechanism for management of bilirubin related diseases.
研究领域:
分子生物学
·
昼夜节律
·
肝病学
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产品关联
DOI
PubMed
高影响因子
Communications Biology
·
2019
·Vol. 2
·期 1
·1-11
·
IF 0
Lin Yanke,Wang Shuai,Zhou Ziyue,Guo Lianxia,Yu Fangjun,Wu Baojian
Metabolism is a major defense mechanism of the body against xenobiotic threats. Here we unravel a critical role of Bmal1 for circadian clock-controlled Cyp3a11 expression and xenobiotic metabolism. Bmal1 deficiency decreases the mRNA, protein and microsomal activity of Cyp3a11, and blunts their circadian rhythms in mice. A screen for Cyp3a11 regulators identifies two circadian genes Dbp and Hnf4α as potential regulatory mediators. Cell-based experiments confirm that Dbp and Hnf4α activate Cyp3a11 transcription by their binding to a D-box and a DR1 element in the Cyp3a11 promoter, respectively. Bmal1 binds to the P1 distal promoter to regulate Hnf4α transcriptionally. Cellular regulation of Cyp3a11 by Bmal1 is Dbp- and Hnf4α-dependent. Bmal1 deficiency sensitizes mice to toxicities of drugs such as aconitine and triptolide (and blunts circadian toxicity rhythmicities) due to elevated drug exposure. In summary, Bmal1 connects circadian clock and Cyp3a11 metabolism, thereby impacting drug detoxification as a function of daily time.
研究领域:
药理学
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分子生物学
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时间生物学
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DOI
PubMed
Ocular Surface
·
2024
·
IF 5.9
Xiaozhao Zhang,Guangjin Chen,Yan He,Qingming Tang,Ying Yin,Ying Jie
Secretory glands, responsible for tears and saliva production, play essential roles in maintaining ocular and oral well-being. Disruptions in gland secretion can arise from various factors, including rhythm disturbances associated with sleep disorders. However, the underlying mechanisms governing these disruptions remain largely unexplored. We demonstrate that BMAL1, a core component of the circadian system, plays a critical role in regulating secretory gland secretion. Loss of BMAL1 induces vacuolation and atrophy phenotypes in acinar cells, subsequently leading to cell apoptosis and gland hypofunction, but does not cause Sjogren's syndrome, which is characterized by localized inflammatory cell infiltration. Mechanically, BMAL1 directly modulates the transcription of ITPR2 and ITPR3, thereby altering the secretion of Lactoferrin and Lysozyme. Restoration of ITPR2 and ITPR3 expression in Bmal1 -deficient rats effectively alleviated the symptoms of lacrimal and parotid glands secretory dysfunction and significantly reduced dry mouth and dry eye conditions in rhythm-disordered rats. These findings highlight the essential role of BMAL1 in regulating salivary and lacrimal gland secretion and suggest a novel therapeutic approach for treating dry mouth and dry eyes associated with rhythm disorders.
研究领域:
昼夜生物学
·
分泌生理学
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分子生物学
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治疗学
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DOI
高影响因子
Food Bioscience
·
2025
·
IF 5.9
Shufeng Wu,Xiang Kuang,Haizhao Song,Zhigang Liu,Ling Xiong,Bo Ren,Fang Wang,Xinchun Shen,Luanfeng Wang
Limosillactobacillus reuteri ( L. reuteri ) is known to play a beneficial role in various aspects of human health, including diabetes, inflammatory bowel disease, and neurological disorders. However, its role in regulating obesity-induced metabolic disorders remains poorly understood. We demonstrate that administering L. reuteri C501 to male mice for 10 weeks significantly alleviates high-fat diet (HFD)-induced obesity and related metabolic disorders. Treatment with L. reuteri C501 led to reduced body weight gain, improved insulin sensitivity, and attenuated inflammatory responses. Moreover, the treatment activated the aryl hydrocarbon receptor (AhR) and the circadian rhythm regulator brain and muscle ARNT-like protein 1 (Bmal1)-two key players in immune function and energy metabolism-thereby influencing lipid metabolism in HFD-fed mice. In addition, L. reuteri C501 modulated gut microbiota composition and enhanced the production of indole derivatives. Supplementation with indole-3-lactic acid (ILA), one such derivative, also improved obesity outcomes in HFD-fed mice. Notably, administering L. reuteri C501 at zeitgeber time 0 (ZT0, the beginning of the light cycle) resulted in stronger therapeutic effects, suggesting that timing of intake may critically influence its efficacy. These findings highlight L. reuteri C501 as a promising probiotic intervention for obesity, with chronobiological factors playing a key role in optimizing its metabolic benefits.
研究领域:
微生物学
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代谢病学
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免疫代谢
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分子营养学
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昼夜节律生物学
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肠道微生物组学
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转化医学
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产品关联
DOI
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2025
·
IF 5.6
Jiaxian Weng,Zicong Wu,Yuwei Huang,Haiman Xu,Lianxia Guo,Zanjin Li,Kengran Zeng,Tingying Hao,Luomin Lin,Baojian Wu,Dong Dong
Ulcerative colitis (UC), a chronic inflammatory bowel disease associated with circadian rhythm disruption, presents a critical need for novel therapeutic strategies. While the natural flavonoid tangeretin (TAN) exhibits anti-inflammatory properties, its effect of alleviating UC and the mechanism through intestinal circadian clock modulation remains unclear. Using a dextran sulfate sodium (DSS)-induced murine colitis model, we demonstrated that Prophylactic TAN administration significantly alleviated colitis severity, restored locomotor rhythms, and reversed UC-induced disruptions in colonic clock gene oscillations ( Bmal1 , Per1/2 , Cry1/2 , Dbp , Rev-erbα , and Rorα ), inflammatory cytokines ( Il-6 and Il-1β ), and tight junction proteins (ZO-1 and Occludin). Importantly, TAN robustly enhanced the expression and rhythmicity of BMAL1, which mechanistically drove its therapeutic effects. The critical role of BMAL1 was confirmed by the abolished protective effect of TAN in intestine specific Bmal1 knockout ( Bmal1 iKO ) mice. In vitro studies in MODE-K cells further demonstrated that siRNA -mediated Bmal1 knockdown abolished TAN-mediated suppression of inflammation and barrier repair in lipopolysaccharide (LPS) treated MODE-K cells. Dual-luciferase reporter assays validated that BMAL1 directly enhanced the Zo-1 and Occludin promoter activities. Notably, TAN exhibited chronotherapeutic efficacy, with ZT2 administration significantly improving UC symptoms, whereas ZT14 dosing showed minimal benefits. In conclusion, TAN ameliorates UC by upregulating BMAL1-dependent inflammation suppression and barrier integrity enhancement. This study underscores circadian clock modulation as a promising strategy for UC management and provides a mechanistic foundation for optimizing timed dosing regimens in clinical translation.
研究领域:
胃肠病学
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时间生物学
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分子生物学
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药理学
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营养生物化学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2026
·
IF 6.5
Yifei Xiao,Jiatian He,Yi Zheng,Xinyu Zhang,Jintao Li,Meng Jin,Min Chen,Yushan Wu,Xiaowen Liu,Haiman Xu,Luomin Lin,Baojian Wu,Lianxia Guo,Dong Dong
Disruption of bile acid (BA) homeostasis and circadian rhythm are interconnected in chronic liver diseases, yet how circadian dysfunction exacerbates cholestasis remains unclear. This study demonstrates that hepatocyte-specific knockout of the core clock gene Bmal1 in female mice markedly aggravates liver injury, inflammation, and fibrosis in an α-naphthylisothiocyanate (ANIT)-induced intrahepatic cholestasis model. The pathological exacerbation is attributed to a profound loss of circadian oscillation and reduced expression of the detoxification enzyme sulfotransferase family 2A member 1 (SULT2A1), resulting in deficient sulfation and hepatic accumulation of cytotoxic bile acids. This hypersusceptibility was further validated in primary hepatocytes under BA overload. Notably, specific in vivo restoration of hepatic Sult2a1 significantly reversed these pathological progressions. Mechanistically, BMAL1 transcriptionally activates Sult2a1 by directly binding to the E-box element within its promoter region. Taken together, our work elucidates the BMAL1-SULT2A1 axis as an essential circadian defense mechanism that maintains hepatic bile acid detoxification homeostasis in female mice, providing a novel theoretical basis for chronotherapeutic strategies in cholestatic liver diseases.
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2022
·
IF 5.988
Sun Guanghui,Dang Yongkang,Lin Yanke,Zeng Wanying,Wu Zongjian,Zhang Xingwang,Dong Dong,Wu Baojian
Scutellaria baicalensis Georgi (SBG) is a traditional Chinese medicine widely used to treat disorders such as hypertension, dysentery and hemorrhaging. Here, we aimed to assess the pharmacological effects of SBG on skin aging and to investigate the underlying mechanisms. Mice with skin aging were established by treatment with D-galactose and ultraviolet-B. SBG (topical application) showed a protective effect on skin aging in mice, as evidenced by less formation of skin wrinkles, higher levels of SOD (superoxide dismutase) and HYP (hydroxyproline) as well as a lower level of MDA (malondialdehyde). In the meantime, skin MMP-1 and p53 expression were lower, epidermis was thinner and collagen amount was higher in SBG-treated mice. Anti-skin aging effects of SBG were also confirmed in NIH3T3 and HaCaT cells, as well as in mouse primary dermal fibroblasts and human primary epidermal keratinocytes. Furthermore, we found that loss of Rev-erbα (a known repressor of Bmal1) up-regulated skin BMAL1 (a clock component and a known anti-aging factor) and ameliorated skin aging in mice. Moreover, SBG dose-dependently increased the expression of BMAL1 in the skin of aged mice and in senescent NIT3H3 cells. In addition, based on a combination of Gal4 chimeric, luciferase reporter and expression assays, SBG was identified as an antagonist of REV-ERBα and thus an inducer of BMAL1 expression. In conclusion, SBG antagonizes REV-ERBα to up-regulate BMAL1 and to protect against skin aging in mice.
研究领域:
药理学
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分子生物学
·
皮肤病学
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DOI
PubMed
高影响因子
Journal of Neuroinflammation
·
2026
·Vol. 23
·期 1
·90
·
IF 11.5
Tang Fenglin,Li Yufeng,Bai Xue,Zhu Zhongmou,Dong Hongwei,Chen Jianhui,Ye Bo,Yuan Meng,Wu Qilong,Fu Weishan,Zhang Yuan,Wang Chao
Alzheimer’s disease (AD) is the most common neurodegenerative disorder, with circadian rhythm disturbances strongly linked to its pathogenesis. The choroid plexus (ChP) is a circadian-regulated structure in the brain ventricles, but the role of the core clock gene brain and muscle ARNT-like protein 1 ( BMAL1 ) in ChP in relation to AD pathology remains unclear. Here, we report that knockdown of Bmal1 in ChP epithelial cells of 5xFAD mice alleviates amyloid-β (Aβ) pathology, primarily by improving the function of astrocytes and border-associated macrophages (BAMs), with the latter potentially mediated by the upregulation of the secreted protein glutathione peroxidase 3 (GPX3), which reduces lipid peroxidation in BAMs. Collectively, our findings establish the ChP-driven BMAL1-GPX3 axis as a new Aβ clearance mechanism, with GPX3 representing a promising therapeutic target. These findings provide new mechanistic insights into AD and suggest innovative treatment approaches.
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DOI
高影响因子
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
·
2024
·
IF 11.4
Haiman Xu,Lianxia Guo,Tingying Hao,Xiaocao Guo,Meiping Huang,Haobin Cen,Min Chen,Jiaxian Weng,Meixia Huang,Zicong Wu,Zifei Qin,Jing Yang,Baojian Wu
Background While the daily rhythm of allergic rhinitis (AR) has long been recognized, the molecular mechanism underlying this phenomenon remains enigmatic. Objective We aim to investigate the role of circadian clock in AR development and to clarify the mechanism by which the daily rhythm of AR is generated. Methods AR was induced in mice using the ovalbumin method. Toluidine blue staining, LC-MS/MS analysis, qPCR, and immunoblotting were performed with AR and control mice. Results Ovalbumin-induced AR is diurnally rhythmic and associated with clock gene disruption in nasal mucosa. In particular, Rev-erbα is generally down-regulated, and its rhythm retained but with a near 12-h phase shift. Furthermore, global knockout of the core clock gene Bmal1 or Rev-erbα increases the susceptibility of mice to AR and blunts AR rhythmicity. Importantly, nasal SCCs (solitary chemosensory cells) are rhythmically activated, and inhibition of the SCC pathway leads to attenuated AR and a loss of its rhythm. Moreover, rhythmic activation of SCCs is accounted for by diurnal expression of ChAT (an enzyme responsible for the synthesis of acetylcholine) and temporal generation of the neurotransmitter acetylcholine. Mechanistically, REV-ERBα trans-represses Chat through direct binding to a specific response element, generating a diurnal oscillation in this target gene. Conclusion These findings identify SCCs, under the control of REV-ERBα, as a driver of AR rhythmicity, and suggest targeting SCCs as a new avenue for AR management.
研究领域:
免疫学
·
时间生物学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
ANALYTICA CHIMICA ACTA
·
2025
·
IF 6
Hong Zhang,Xuekun Bai,Chenxi Wang,Wei Pang,Jiaxin Zhang,Junhuai Song,Huanying Zhou,Zhixian Gao,Bin Zheng
Background Biorhythmic played an important role in physical health. Biorhythmic disorders led to various health issue, including cardiovascular diseases and metabolic disorders. Early diagnosis of biorhythmic disorders was crucial in slowing the progression of disease. Therefore, it was important to develop technologies for detecting biorhythmic and their disorder markers. This study selected HMGB1(High mobility group box 1), BMAL1 (Brain and Muscle Aryl hydrocarbon receptor nuclear translocator-like 1), and MICU (mitochondrial calcium uptake 1) mRNA for detection. Results CRISPR/Cas12a/SERS (surface-enhanced Raman spectroscopy) ultrasensitive biosensing platform was developed for the detection of biorhythmic markers. The biosensor was partly an ultrabright Raman signal reporter (on) of a novel satellite structure formed by gold/silver bimetallic nanoparticles. This novel satellite structure utilizes the potential difference between gold and silver nanoparticles to promote the transfer of electrons from the core structure to the AuNPs and MBA (4-mercaptobenzoic acid) molecules, while enhancing the electromagnetic field distribution. Compared with the Raman signal of the satellite structure composed of Au/Au bimetallic, the Raman signal of the satellite structure in this study is increased by about 10 times. CRISPR/Cas12a recognized the target molecule and activated trans -cleavage activity, cleaving the DNA/RNA hairpin structure and releasing RNA 2∗ . RNA 2∗ caused the satellite structure to disperse, significantly attenuating the ultra-strong Raman signal (off), thereby enabling quantitative detection of the target nucleic acid. The LOD for three targets were of less than 1 fM. Significance In summary, the CRISPR/Cas12a/SERS biosensing platform enables mRNA detection without preamplification. This biosensing platform can detect target molecules at the fM level, achieving ultra-sensitive detection. In addition, the satellite structure exhibits long-term stability, providing a theoretical basis for the practical application of this biosensing platform.
研究领域:
生物传感器
·
分子诊断学
·
纳米技术
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CRISPR技术
·
RNA检测
·
生物医学工程
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产品关联
DOI
PubMed
高影响因子
Bioactive Materials
·
2023
·
IF 18.9
Han Sun,Juan Xu,Yangyufan Wang,Siyu Shen,Xingquan Xu,Lei Zhang,Qing Jiang
Large bone defects resulting from fractures and disease are a major clinical challenge, being often unable to heal spontaneously by the body's repair mechanisms. Lines of evidence have shown that hypoxia-induced overproduction of ROS in bone defect region has a major impact on delaying bone regeneration. However, replenishing excess oxygen in a short time cause high oxygen tension that affect the activity of osteoblast precursor cells. Therefore, reasonably restoring the hypoxic condition of bone microenvironment is essential for facilitating bone repair. Herein, we designed ROS scavenging and responsive prolonged oxygen-generating hydrogels (CPP-L/GelMA) as a “bone microenvironment regulative hydrogel” to reverse the hypoxic microenvironment in bone defects region. CPP-L/GelMA hydrogels comprises an antioxidant enzyme catalase (CAT) and ROS-responsive oxygen-releasing nanoparticles ( [email protected] /PPS) co-loaded liposome (CCP-L) and GelMA hydrogels. Under hypoxic condition, CPP-L/GelMA can release CAT for degrading hydrogen peroxide to generate oxygen and be triggered by superfluous ROS to continuously release the oxygen for more than 2 weeks. The prolonged oxygen enriched microenvironment generated by CPP-L/GelMA hydrogel significantly enhanced angiogenesis and osteogenesis while inhibited osteoclastogenesis. Finally, CPP-L/GelMA showed excellent bone regeneration effect in a mice skull defect model through the Nrf2-BMAL1-autophagy pathway. Hence, CPP-L/GelMA, as a bone microenvironment regulative hydrogel for bone tissue respiration, can effectively scavenge ROS and provide prolonged oxygen supply according to the demand in bone defect region, possessing of great clinical therapeutic potential.
研究领域:
组织工程
·
生物材料
·
再生医学
·
骨科
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2024
·
IF 6.7
Dihao Xie,Simin Zhong,Meixue Luo,Jiahao Xu,Ruoyan Zheng,Jiading Luo,Yiting Wang,Yongxing Guo,Lianxia Guo,Baojian Wu,Danyi Lu
Background Aristolochic acid I (AAI), an emerging biogenic contaminant widely present in Aristolochic plants, has been implicated in the progression of tubulointerstitial disease, known as aristolochic acid nephropathy (AAN). The circadian clock, a vital regulator of organ homeostasis, is susceptible to external chemical cues, including toxins. However, the reciprocal interactions between AAI and the circadian clock remain unexplored. Methods We initially assessed sex- and time-dependent nephropathy and behavioral responses in C57BL/6J mice exposed to AAI. Subsequently, we evaluated changes in the expression of circadian clock genes following treatment with AAI or its bioactive metabolite, aristolactam I, using real-time quantitative PCR and immunoblotting in renal tissues and cells. Additionally, real-time reporter assays were conducted on kidney explants from PER2::Luc knock-in reporter mice and Per2-dLuc / Bmal1-dLuc reporter cell lines. To further elucidate the regulatory role of circadian clocks in AAI-induced nephropathy, mice with global or kidney-specific knockout of Bmal1 , as well as mice subjected to experimental jetlag, were utilized. Results Our findings revealed a sex-dependent nephrotoxicity of AAI, with males exhibiting greater vulnerability. AAI-induced nephropathy was accompanied by impaired spatial cognitive function, disruptions in free-running locomotor activity, altered renal expression of multiple core clock genes, and disturbances in the circadian rhythm of renal PER2::Luc activity. Notably, kidney-specific ablation of the core clock gene Bmal1 significantly exacerbated renal injury and inflammation, whereas disruptions to the central clock, either genetically (through conventional knockout of Bmal1 ) or environmentally (mimicking jetlag), had minimal effects on AAI nephrotoxicity. Furthermore, both AAI and its bioactive metabolite aristolactam I demonstrated the ability to disrupt circadian clocks in human osteosarcoma cells (U2OS) and mouse renal tubular epithelial cells (mRTEC). Conclusion Collectively, these findings highlight the detrimental impact of aristolochic acids on local renal circadian clocks, ultimately exacerbating kidney damage. This study provides novel insights into the molecular mechanisms underlying AAI nephrotoxicity, potentially opening avenues for therapeutic interventions aimed at modulating the renal circadian clock to treat AAN.
研究领域:
肾病学
·
药理学
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分子生物学
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时间生物学
·
毒理学
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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）