JOURNAL OF PHARMACY AND PHARMACOLOGY
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2021
·Vol. 73
·期 4
·535-544
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IF 3.765
Yang Zemin,Lin Yanke,Su Chong,Wang Shuai,Gao Lu,Lin Jingpan,Wang Zhigang,Wu Baojian
ObjectivesIdentifying drugs with time-varying efficacy or toxicity, and understanding the underlying mechanisms would help to improve treatment efficacy and reduce adverse effects. In this study, we uncovered that the therapeutic effect of Fuzi (the lateral root of Aconitum carmichaelii Debeaux) depended on the dosing time in mice with adenine-induced chronic kidney disease (CKD).MethodsThe Fuzi efficacy was determined by biomarker measurements [i.e. plasma creatinine (CRE), blood urea nitrogen (BUN) and urinary N-acetyl-β-D-glucosaminidase (NAG)], as well as inflammation, fibrosis and histological analyses. Circadian regulation of Fuzi pharmacokinetics and efficacy was evaluated using brain and muscle Arnt-like protein-1 (Bmal1)-deficient (Bmal1−/−) mice.Key findingsThe Fuzi efficacy was higher when the drug was dosed at ZT10 and was lower when the drug was dosed at other times (ZT2, ZT6, ZT14, ZT18 and ZT22) according to measurements of plasma CRE, BUN and urinary NAG. Consistently, ZT10 (5 PM) dosing showed a stronger protective effect on the kidney (i.e. less extensive tubular injury) as compared to ZT22 (5 AM) dosing. This was supported by lower levels of inflammatory and fibrotic factors (IL-1β, IL-6, Tnf-α, Ccl2, Tgfb1 and Col1a1) at ZT10 than at ZT22. Pharmacokinetic analyses showed that the area under the curve (AUC) values (reflective of systemic exposure) and renal distribution of aconitine, hypaconitine and mesaconitine (three putative active constituents) for Fuzi dosing at ZT10 were significantly higher than those for herb dosing at ZT22, suggesting a role of circadian pharmacokinetics in Fuzi chronoefficacy. Drug efficacy studies confirmed that aconitine, hypaconitine and mesaconitine possessed a kidney-protecting effect. In addition, genetic knockout of Bmal1 in mice abolished the time-dependency of Fuzi pharmacokinetics and efficacy. This reinforced the existence of chronoefficacy for Fuzi and supported the role of circadian pharmacokinetics in Fuzi chronoefficacy.ConclusionsThe efficacy of Fuzi against CKD depends on the dosing time in mice, which is associated with circadian pharmacokinetics of the three main active constituents (i.e. aconitine, hypaconitine and mesaconitine). These findings highlight the relevance of dosing time in the therapeutic outcomes of herbal medicines.
研究领域:
药理学
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生物钟学
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中医
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肾病
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Metabolism
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2025
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IF 30.9
Lianxia Guo,Yifei Xiao,Zanjin Li,Yuwei Huang,Haobin Cen,Zicong Wu,Hongbo Wang,Xinyu Liu,Zhehan Yang,Caifeng Zhao,Tingying Hao,Hui Chen,Meng Jin,Danyi Lu,Min Chen,Baojian Wu
The intestinal clock plays a role in transmitting feeding signals and generating circadian events, but how this clock system may time homeostatic processes related to sleep-wake regulation is unknown. Our functional dissections of the circadian clock in intestinal epithelial cells (IECs) demonstrate that its integrity is required for maintenance of the diurnal sleep-wake cycle. In IECs, BMAL1 generates diurnal rhythmic SLC6A19 expression that promotes intestinal absorption of glutamine during the active phase, which enhances glutamatergic neuron activities in hypothalamic nuclei and contributes to increased wakefulness and decreased sleep. The involvement of glutamine homeostasis in sleep-wake regulation is also pronounced during the rest phase, as an elevation of glutamine in the rest phase caused by IEC deficiency of REV-ERBα is causally linked to sleep abnormalities characterized by reduced sleep. Overall, the intestinal clock shapes the diurnal sleep-wake cycle through temporally gating glutamine homeostasis and serves as a potential target for boosting the sleep rhythm and for managing sleep disorders.
研究领域:
时间生物学
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神经科学
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代谢学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
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2023
·
IF 17.1
Lang Chen,Chenyan Yu,Wanting Xu,Yuan Xiong,Peng Cheng,Ze Lin,Zhenhe Zhang,Leonard Knoedler,Adriana C. Panayi,Samuel Knoedler,Junqing Wang,Bobin Mi,Guohui Liu
Ongoing research has highlighted the significance of the cross-play of macrophages and mesenchymal stem cells (MSCs). Lysine-specific demethylase 6B (KDM6B) has been shown to control osteogenic differentiation of MSCs by depleting trimethylated histone 3 lysine 27 (H3K27me3). However, to date, the role of KDM6B in bone marrow-derived macrophages (BMDMs) remains controversial. Here, a chromatin immunoprecipitation assay (ChIP) proved that KDM6B derived from osteogenic-induced BMSCs could bind to the promoter region of BMDMs’ brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein-1 (BMAL1) gene in a coculture system and activate BMAL1. Transcriptome sequencing and experiments in vitro showed that the overexpression of BMAL1 in BMDM could inhibit the TLR2/NF-κB signaling pathway, reduce pyroptosis, and decrease the M1/M2 ratio, thereby promoting osteogenic differentiation of BMSCs. Furthermore, bone and macrophage dual-targeted GSK-J4 (KDM6B inhibitor)-loaded nanodiscs were synthesized via binding SDSSD-apoA-1 peptide analogs (APA) peptide, which indirectly proved the critical role of KDM6B in osteogenesis in vivo. Overall, we demonstrated that KDM6B serves as a positive circulation trigger during osteogenic differentiation by decreasing the ratio of M1/M2 both in vitro and in vivo. Collectively, these results provide insight into basic research in the field of osteoporosis and bone repair.
研究领域:
干细胞生物学
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免疫学
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骨生物学
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分子生物学
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纳米技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR NUTRITION & FOOD RESEARCH
·
2025
·
IF 4.2
Qianru Xiang,Xiao Chen,Enhui Tang,Zhi Chen,Zijun Xia,Wenzhen Liao
Current research indicates that insulin secretion deficiency in β-cells contributes to Type 2 diabetes mellitus (T2DM), which is associated with neuropeptide Y 1 receptor (Npy1r) overexpression from neuropeptide Y (NPY) system dysregulation. To date, limited literature has explored nobiletin (NOB) as a circadian modulator for restoring β-cell function through Npy1r regulation. This study investigates NOB's stimulatory effects on insulin secretion via Npy1r and clock-modulatory signaling to elucidate its underlying mechanism. The findings demonstrated that NOB ameliorated hyperglycemia and promoted insulin secretion in two distinct mouse models: T2DM induced by a high-fat diet with low-dose streptozotocin, and acute hyperglycemia triggered by NPY. Moreover, NOB reduced NPY family peptides in the serum and suppressed Npy1r overexpression in β-cells. Comprehensive investigations revealed that NOB mitigated Npy1r-mediated β-cell dysfunction through activating clock-modulatory signaling, evidenced by restored Bmal1::Luc bioluminescence rhythmicity in mouse insulinoma6 (MIN6) cells. Molecular docking confirmed a direct NOB-Npy1r interaction, while mechanistic analyses demonstrated modulation of the retinoic acid-related orphan receptors (RORs)/Bmal1-Yes-associated protein (Yap) pathway via Yap suppression and Bmal1 activation, based on the interventions with palmitic acid, BMS 193885 (Npy1r antagonist), and NPY. Therefore, this study provides evidence that NOB can protect β-cells from insulin secretion dysfunction by downregulating Npy1r expression and activating the RORs/Bmal1-Yap pathway.
研究领域:
内分泌学
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分子生物学
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时间生物学
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糖尿病研究
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药理学
✓ 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）