CURRENT ISSUES IN MOLECULAR BIOLOGY
·
2022
·Vol. 44
·期 2
·470-482
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IF 2.976
Jiawang Tao,Yan Chen,Yuanqi Zhuang,Ruzhi Wei,Anteneh Getachew,Tingcai Pan,Fan Yang,Yinxiong Li
Liver regeneration is a complicated biological process orchestrated by various liver resident cells. Hepatic cell proliferation and reconstruction of the hepatic architecture involve multiple signaling pathways. It has been reported that the Hh signal is involved in liver regeneration. However, the signal transduction pathways and cell types involved are ill studied. This study aimed to investigate hedgehog signal response cell types and the specific molecular mechanism involved in the process of liver regeneration. Partial hepatectomy (PH) of 70% was performed on ICR (Institute of Cancer Research) mice to study the process of liver regeneration. We found that the hedgehog signal was activated significantly after PH, including hedgehog ligands, receptors and intracellular signaling molecules. Ligand signals were mainly expressed in bile duct cells and non-parenchymal hepatic cells, while receptors were expressed in hepatocytes and some non-parenchymal cells. Inhibition of the hedgehog signal treated with vismodegib reduced the liver regeneration rate after partial hepatectomy, including inhibition of hepatic cell proliferation by decreasing Cyclin D expression and disturbing the cell cycle through the accumulation of Cyclin B. The current study reveals the important role of the hedgehog signal and its participation in the regulation of hepatic cell proliferation and the cell cycle during liver regeneration. It provides new insight into the recovery of the liver after liver resection.Keywords:vismodegib;smoothened;liver regeneration;hedgehog signaling;mitosis
研究领域:
分子生物学
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细胞生物学
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肝病学
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DOI
PubMed
高影响因子
DIFFERENTIATION
·
2022
·
IF 3.533
Yan Guo,Di Wu,QingJiang Xu,Weihui Chen
The mandible is an important part of the craniofacial skeleton. Mandibular development is complex and involves multiple signaling pathways. These signaling pathways participate in a complex regulatory mechanism to regulate mandibular growth. The function of hedgehog signaling has previously been shown to be crucial for mandibular arch development. We treated pregnant ICR mice with the hedgehog pathway inhibitor vismodegib by oral gavage to establish a micrognathia model, which was mandible development defective. Compared to control, this model exhibited reduced mesenchymal cell proliferation and increased apoptosis. The development of the Meckel's cartilage and the condensations of mesenchymal cells were delayed by approximately one day in treated embryos. These results reveal that Smoothened may have shaped the mandible during mandibular growth by ensuring cell survival, proliferation, and development of Merkel's cartilage.
研究领域:
发育生物学
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分子生物学
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颅面研究
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DOI
PubMed
高影响因子
Insects
·
2026
·Vol. 17
·期 8
·769
·
IF 3
Lina Guo,Yu Zhang,Chang Song,Yuan Guo
Simple SummaryThe Hedgehog signaling pathway is highly conserved across species, yet its role in insect olfaction remains poorly understood. Here, we characterized the Smoothened (Smo) gene—a core component of this pathway—in the eastern honey beeApis cerana cerana (A. c. cerana). We found thatAcerSmoexhibits a unique spatial segregation pattern: its mRNA is transcribed in sensory neurons beneath antennal trichoid and placoid sensilla, while the protein localizes to adjacent non-neuronal supporting cells, revealing a spatial separation betweenAcerSmomRNA and protein localization, suggesting cell-type-specific regulation ofAcerSmoexpression during olfactory function. RNA interference-mediated silencing ofAcerSmoupregulated the expression of key olfactory receptor genesAcerOr1andAcerOr2, and altered bees’ electrophysiological and behavioral responses to ecologically relevant odorants including 2-heptanone, 1-nonanol, and eugenol. Our findings demonstrate thatAcerSmomodulates honey bee olfactory recognition by regulating olfactory receptor expression, expanding the known physiological functions of the Hedgehog pathway beyond development into adult sensory regulation.Smoothened (Smo) is a core component of the Hedgehog signaling pathway and plays an important role in insect tissue growth, but its function in honey bees remains unclear. In this study, we investigated the expression localization ofAcerSmoin the antennae ofApis cerana cerana (A. c. cerana)and its impact on olfactory behavior using in situ hybridization, immunohistochemistry, RNA interference, transcriptome sequencing, and behavioral and electrophysiological techniques. The results showed thatAcerSmomRNA is expressed in the sensory neurons beneath trichoid and placoid sensilla, while the protein is localized to the non-neuronal supporting cells of these sensilla, revealing a spatial separation betweenAcerSmomRNA and protein localization. Although this pattern suggests cell-type-specific post-transcriptional regulation, the present data do not directly demonstrate intercellular mRNA transport or translation. RNAi-mediated silencing ofAcerSmosignificantly upregulated the expression ofAcerOr1andAcerOr2. Transcriptome sequencing identified 19 olfaction-related differentially expressed genes involved in signal transduction, substance transport, and various metabolic pathways. Electroantennogram and Y-tube olfactometer assays revealed that afterAcerSmointerference, the responses ofA. c. ceranato odorants changed significantly: EAG responses to 2-heptanone and hexyl acetate decreased, while avoidance behavior toward 2-heptanone increased; EAG responses to 1-nonanol and eugenol increased, and Y-tube tests showed enhanced attraction to 1-nonanol and increased avoidance of eugenol. Conclusions: These findings indicate thatAcerSmoplays an important role in regulating olfactory receptor expression and modulating odorant responses in honey bees, thereby influencing their olfactory behavior.
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高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2025
·Vol. 26
·期 4
·1631
·
IF 4.9
Wang Chen,Feifan Lai,Jianghe Xu
The Hedgehog (Hh) signaling pathway plays a crucial role in the initiation and progression of tumors, and Hh inhibitors have been used as potential chemotherapeutic agents for the treatment of basal cell carcinomas (BCCs). Vitamin D3(VD3) and its derivatives have been identified as potent Hh inhibitors. However, the selectivity of VD3derivatives to vitamin D receptor (VDR) and the Hh signaling pathway still needs optimization. In this study, a series of aromatic A-ring mimics VD3analogues that contain a C-23 oxygen atom or incorporate C-25 hydroxyl on side chains were designed and synthesized. These compounds were tested in various cell lines for anti-Hh activity, with analogues3jand4iidentified as potent inhibitors. Mechanism studies showed their anti-Hh effects are mainly due to targeting Smoothened (Smo) without binding to the cyclopamine site. Structure-activity relationship (SAR) studies revealed that VD3-based inhibitors enhance anti-Hh activity by adding a hydroxyl group at C25 while reducing VDR activity by incorporating an oxygen atom into the side chain.
研究领域:
药理学
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肿瘤学
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分子生物学
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DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2021
·Vol. 10
·期 12
·2100028
·
IF 9.933
Hang Yang,Yan Luo,Hang Hu,Sibo Yang,Yanan Li,Huijuan Jin,Shengcai Chen,Quanwei He,Candong Hong,Jiehong Wu,Yan Wan,Man Li,Zifu Li,Xiangliang Yang,Ying Su,Yifan Zhou,Bo Hu
Angiogenesis, an essential restorative process following ischemia, is a promising therapeutic approach to improve neurological deficits. However, overcoming the blood–brain barrier (BBB) and effective drug enrichment are challenges for conventional drug delivery methods, which has limited the development of treatment strategies. Herein, a dual-targeted therapeutic strategy is reported to enable pH-sensitive drug release and allow cerebral ischemia targeting to improve stroke therapeutic efficacy. Targeted delivery is achieved by surface conjugation of Pro-His-Ser-Arg-Asn (PHSRN) peptides, which binds to integrin α 5 β 1 enriched in the cerebral vasculature of ischemic tissue. Subsequently, smoothened agonist (SAG), an activator of sonic hedgehog (Shh) signaling, is coupled to PHSRN-HES by pH-dependent electrostatic adsorption. SAG@PHSRN-HES nanoparticles can sensitively release more SAG in the acidic environment of ischemic brain tissue. More importantly, SAG@PHSRN-HES exerts the synergistic mechanisms of PHSRN and SAG to promote angiogenesis and BBB integrity, thus improving neuroplasticity and neurological function recovery. This study proposes a new approach to improve the delivery of medications in the ischemic brain. Dual-targeted therapeutic strategies have excellent potential to treat patients suffering from cerebral infarction.
研究领域:
神经科学
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药学
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分子生物学
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治疗学
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PubMed
高影响因子
BIOORGANIC CHEMISTRY
·
2023
·
IF 5.1
Huanxian Wu,Lishun Zhang,Boyu Chen,Baofang Ou,Jiahuan Xu,Nannan Tian,Danni Yang,Yangcheng Ai,Qianqing Chen,Dongling Quan,Tingting Zhang,Lin Lv,Yuanxin Tian,Jiajie Zhang,Shaoyu Wu
Abnormal activation of Hedgehog (Hh) signaling pathway mediates the genesis and progression of various tumors [1] . Currently, three drugs targeting the Hh signaling component Smoothened (Smo) have been marketed for the clinical treatment of basal cell tumors or acute myeloid leukemia. However, drug resistance is a common problem in those drugs, so the study of Smo inhibitors that can overcome drug resistance has important guiding significance for clinical adjuvant drugs. MTT assay, clone formation assay and EdU assay were used to detect the proliferation inhibitory activity of the drugs on tumor cells. The effect of B13 on cell cycle and apoptosis were detected by flow cytometry. An acute toxicity test was used to detect the toxicity of B13 in vivo , and xenograft tumor model was used to detect the efficacy of B13 in vivo . The binding of B13 to Smo was studied by BODIPY-cyclopamine competitive binding assay and molecular docking. The effect of B13 on the expression and localization of downstream target gene Gli1/2 of Smo was investigated by Western Blot and immunofluorescence assay. Smo D473H mutant cell line was constructed to study the effect of B13 against drug resistance. (1) B13 had the strongest inhibitory activity against colorectal cancer cells. (2) B13 can effectively inhibit the clone formation and EdU positive rate of colon cancer cells. (3) B13 can block the cell cycle in the G2/M phase and cell apoptosis. (4) B13 has low toxicity in vivo , and its efficacy in vivo is better than that of the Vismodegib. (5) Molecular docking and BODIPY-cyclopamine experiments showed that B13 could bind to Smo protein. (6) B13 can inhibit the protein expression of Gli1, the downstream of Smo, and inhibit its entry into the nucleus. (7) B13 could inhibit the expression of Gli1 in the HEK293 cells with Smo D473H , and the molecular docking results showed that B13 could bind Smo D473H protein. B13 with the best anti-tumor activity was screened out by MTT assay. In vitro , pharmacodynamics experiments showed that B13 could effectively inhibit the proliferation and metastasis of colorectal cancer cells, induce cell cycle arrest, and induce cell apoptosis. In vivo pharmacodynamics experiments showed that B13 was superior to Vismodegib in antitumor activity and had low toxicity in vivo . Mechanism studies have shown that B13 can bind Smo protein, inhibit the expression of downstream Gli1 and its entry into the nucleus. Notably, B13 overcomes resistance caused by Smo D473H mutations.
研究领域:
肿瘤学
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药理学
·
分子生物学
·
细胞生物学
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产品关联
DOI
PubMed
高影响因子
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