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PHYTOTHERAPY RESEARCH · 2024 · IF 6.1

Oxyberberine Inhibits Hepatic Gluconeogenesis via AMPK-Mediated Suppression of FoxO1 and CRTC2 Signaling Axes

Fan Wu,Fuer Lu,Hui Dong,Meilin Hu,Lijun Xu,Dingkun Wang

Oxyberberine (OBB), a natural metabolite of berberine, has been shown to exhibit inhibitory effects on gluconeogenesis in our previous work. This work was designed to investigate the potential effects and underlying mechanisms of OBB on hepatic gluconeogenesis. Our work found that OBB significantly inhibited the expressions of glucose 6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK), and decreased the glucose production in palmitic acid-induced HepG2 cells. Then, AMPK/Akt/FoxO1 and AMPK/CRTC2 signaling pathways were confirmed by transcriptomics and network pharmacology analyses. It was shown that AMPK activation may phosphorylate and promote nuclear exclusion of FoxO1 and CRTC2, two key regulators of hepatic gluconeogenesis transcriptional pathways, resulting in the inhibition of gluconeogenesis under OBB administration. Afterwards, AMPK/Akt/FoxO1, AMPK/CRTC2 signaling pathways were evidenced by western blot, immunoprecipitation and confocal immunofluorescence, and the targeted inhibitor (Compound C) and siRNA of AMPK were applied for further mechanism verification. Moreover, it was found that OBB treatment activated AMPK/Akt/FoxO1 and AMPK/CRTC2 signaling pathways to decrease hepatic gluconeogenesis in db/db mice. Similarly, the in vivo inhibitory effects of OBB on gluconeogenesis were also diminished by AMPK inhibition. Our work demonstrated that OBB can inhibit hepatic gluconeogenesis in vitro and in vivo, and its underlying mechanisms were associated with AMPK-mediated suppression of FoxO1 and CRTC2 signaling axes.

CAS / MDL: 867-56-1
研究领域: 药理学 · 分子生物学 · 代谢 · 内分泌学
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NEW JOURNAL OF CHEMISTRY · 2024 · IF 2.7

Tuning charge density and crosslinking of precise amphiphilic oligo(ethanamino)amides for efficient and biocompatible gene delivery

Jiamin Wang,Hao Lin,Mengli Liu,Bo Xiong,Dingyuan He,Jiasheng Tu,Dongsheng He

Cationic polymers are a class of promising carriers for nucleic acid delivery. However, the balance between biosafety and transfection efficiency is still a major obstacle for nucleic acid delivery. Accurate structural design can effectively evaluate the relationship between structural factors and nucleic acid delivery. Previous series of vectors optimized based on artificial amino acid Stp have been shown to effectively improve gene transfection. Here, a series of sequenced-defined oligomers containing hydrophobic oleic acid with different topologies, different charge densities and with or without crosslinking cystine domains were designed and synthesized for a better understanding of the structure activity relationship. The oligomers were further mixed with either pDNA or siRNA to form polyplexes. The particle size, zeta potential, polyplexes formation properties, in vitro stability and reductive responsiveness of the polyplexes were investigated. In addition, studies regarding the transfection efficiency, cellular uptake, cellular trafficking, cytotoxicity and hemolysis were performed. The resulting oligomers display general good complexation ability with pDNA and siRNA with enhanced stability and redox sensitivity. some of the oligomers showed adequate or surpassed transfection efficiency compared with PEI. The polyplexes formed with oligomer #1 have good cellular uptake and endo-lysosome escape property. In addition, all the oligomers and the polyplexes showed low cytotoxicity and hemolysis, demonstrated high biocompatibility. In summary, the results evidenced that proper charge density with hydrophobic oleic acid and thiol crosslinking cystine improves the overall performance of delivering pDNA and siRNA.

研究领域: 生物医学工程 · 药学 · 分子生物学 · 纳米技术
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Nano Today · 2024 · IF 13.2

Enhanced cytosolic RNA delivery through early endosome fusion-mediated release via probiotic-derived lipopolysaccharide (LPS)-incorporated vesicles

Di Nie,Yishan Lv,Duo Gao,Anqi Xu,Qinyu Li,Jiaxin Li,Xiang Lu,Bingqi Wang,Jie Wang,Chang Liu,Zhuan Zhang,Xiang Li,Ning Wang,Shiyan Guo,Chunliu Zhu,Miaorong Yu,Yong Gan

Achieving efficient and secure cytosolic delivery is crucial for RNA therapeutics. Presently, delivery systems predominantly attain cytosolic release through membrane rupture or destabilization of late endosomes and lysosomes. However, these approaches lead to restricted RNA release and undesirable cytotoxicity, ultimately diminishing therapeutic efficacy. Herein, we proposed an efficient strategy based on early endosome fusion-mediated release, employing probiotic-derived lipopolysaccharide (LPS)-incorporated vesicles to enhance RNA delivery. The LPS is derived from Escherichia coli Nissle 1917 (EcN) and has a high safety confirmed by the authoritative pyrogen test. The LPS-rich outer membrane vesicles (OMVs) and synthetic chimeric liposomes (LPS-Lips) are found capable of efficient cytosolic RNA delivery by using LPS to fuse with early endosomes, as evidenced by super-resolution and real-time imaging. The OMVs and LPS-Lips (containing 10 % and 30 % EcN-derived LPS) exhibit enhanced ability to deliver functional BCL-xL siRNA, leading to more significant gene silencing and cell apoptosis in comparison to the commercial Lipofectamine 2000 and RNAiMAX groups. The in vivo results demonstrate their superior efficacy on inhibiting tumor growth and prolonged survival time with enhanced safety. These findings highlight the early endosome fusion strategy with facilitated release efficiency and safety, offering guidelines for the rational design of enhanced RNA delivery systems.

CAS / MDL: 2016-88-8
研究领域: 药学 · 分子生物学 · 癌症研究 · 生物技术 · 药物递送系统
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Journal of Functional Foods · 2024 · IF 3.8

Lycopene alleviates Bisphenol a-induced lipid accumulation via activating the SIRT1/PGC-1α signaling in PK15 cells

Dan Song,Yuan Liu,Kehui Wu,Manting Lyu,Yongshu Wu,Yanan Zhang,Panling Wang,Xiangchen Li

The present study sought to investigate the protective effect of Lycopene (LYC) on Bisphenol A (BPA)-induced lipid accumulation and elucidate the potential molecular mechanism. In vitro, the PK15 cells with or without LYC were exposed to BPA for 6 h to detect the lipid accumulation using Nile red’s and Oil Red O’ staining. Meanwhile, redox status, mitochondrial function, gene expression and protein levels relating to lipid accumulation were evaluated by cellular biochemical assays, immunofluorescence staining, quantitative real-time PCR (qRT-PCR) and Western blot, respectively. In addition, ROS scavenger N-acetylcysteine (NAC), SIRT1 inhibitor EX527, SIRT1 siRNA and PGC-1α siRNA were used to verify the target signaling pathways responsible for the protective effect of LYC against BPA-indcued lipid accumulation. In vivo, the twenty four male Wistar rats were randomly divided into three groups, received either BPA (50 mg/kg/day BW) or LYC (10 mg/kg/day BW) orally for 60 days. The kidney tissues were evaluated by HE’s and Oil Red O’s staining, lipid-associated genes and proteins expression were detected through qRT-PCR and Western blot. The results showed that BPA-exposed PK15 cells and rats had increased lipid droplets with elevated transcription of lipogenic factors SREBP1 and PPARγ, and down-regulated PPARα expression, and which is accompanied by redox imbalance and abnormal mitochondrial function. Conversely, LYC prevented BPA-induced lipid metabolism disorder and lipid accumulation through impeding ROS overproduction. Moreover, PK15 cells and rats exposed to BPA showed decrease in SIRT1 and PGC-1α levels, whereas LYC blocked the decrease of SIRT1 and PGC-1α protein levels. Furthermore, inhibition or silence of SIRT1 and PGC-1α abrogated the improvements of LYC on ROS generation, mitochondrial mass impairement and lipid accumulation in BPA-treated PK15 cells. Collectively, these findings indicate that SIRT1/PGC-1α signaling pathway is involved in the protective effect of LYC on BPA-induced lipid accumulation. These results also provide a potential promising therapeutic of LYC against BPA-induced lipid accumulation in kidney cells and organs.

CAS / MDL: 80-05-7
研究领域: 药理学 · 细胞生物学 · 分子生物学 · 毒理学
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Advanced Healthcare Materials · 2024 · IF 10

Synergistic Target-Attacking Tumor Cells and M2 Macrophages via a Triple-Responsive Nanoassembly for Complete Metastasis Blocking

Bei Wang,Hao Cheng,Zhongsheng Ji,Zijun Jiang,Rong Wang,Yang Ding,Jiang Ni

Collaboration of cancerous cells and microenvironment is the root for tumor spreading, leading to difficulty in complete metastasis blockage via mono-intervention. Herein, a triple-responsive nanoassembly is designed for orienting tumor cells and migration-driving M2 tumor associated macrophages (TAMs) in microenvironment for efficient anti-metastatic therapy. Structurally, a reactive oxygen species (ROS)-responsive crosslinked short-chain polyquaternium is synthesized to bridge graphene oxide (GO) scaffold with apolipoprotein A-I crown via borate-crosslinking, electrostatic adherence, and coordinative coupling. The protein-crowning polymeric GO nanoparticles could give multimodal shielding and triple-responsive release of doxorubicin and Snail-targeted siRNA. Tailor-made apolipoprotein A-I crown fulfills nanoparticles synergistically attacking tumor cells and M2 TAMs via binding with overexpressed scavenger receptors. The findings witness the targeted accumulation and potent cytotoxicity of the hybrid nanoparticles for M2 TAMs and tumor cells; especially, elimination of M2 TAMs in tumor microenvironment holds back Snail-enhancing transforming growth factor (TGF)-β signal pathway, which collaborates with Snail silencing in tumor cells to reverse epithelial mesenchymal transition (EMT) and metastasis-promoting niche. Collectively, the synergistic targeting therapeutic platform could provide a promising solution for metastatic tumor treatment.

研究领域: 肿瘤学 · 纳米技术 · 药学 · 癌症生物学
✓ 已验证 产品关联 DOI PubMed 高影响因子
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JOURNAL OF CONTROLLED RELEASE · 2016 · IF 7.441

Smart nanoparticles with a detachable outer shell for maximized synergistic antitumor efficacy of therapeutics with varying physicochemical properties

Tingjie Yin,Jiyong Liu,Zekai Zhao,Lihui Dong,Han Cai,Lifang Yin,Jianping Zhou,Meirong Huo

Co-delivery systems capable of transporting hydrophobic chemotherapeutics and hydrophilic siRNA to the same cell population with simultaneous burst release of both drugs to maximize synergistic anticancer efficacy remains elusive. In this light, a multifunctional nanoparticle (HA-PSR) consisting of a redox-sensitive core and detachable crosslinked hyaluronic acid (HA) shell was developed. Octyl modified PEI containing disulfide linkages (PSR) were synthesized as the core materials for co-encapsulation of chemotherapeutics and siRNA, while a HAase-sensitive thiolated HA (HA-SH) was collaboratively assembled to the anionic shell for CD44-mediated active targeting along with enhanced and detachable protection for drug loaded inner cores. Resultantly, HA de-protected redox-sensitive inner cores achieved co-burst release of both cargoes when triggered by glutathione (GSH) rich environments in cytoplasm. Results of in-vivo and in-vitro testing indicated successful co-encapsulation of hydrophobic drugs and hydrophilic siRNA with adjustable ratios. Selective delivery to CD44 overexpressing tumors was achieved through passive and active targeting, followed by HAase-triggered HA de-shielding and GSH-triggered burst release of both cargos. Rapid intracellular trafficking maximized synergistic cytotoxicities of chemotherapeutics and siRNA for remarkable tumor inhibition in a xenograft animal tumor model. Consequently, the HA-PSR nanoparticle holds great potential for combined chemotherapeutics/siRNA treatment in cancer with maximized synergistic antitumor efficacy.

CAS / MDL: 9002-98-6 70-18-8
研究领域: 纳米技术 · 癌症研究 · 药学科学 · 分子生物学
✓ 已验证 产品关联 DOI PubMed 高影响因子
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International Journal of Medical Sciences · 2024 ·Vol. 21 ·期 15 ·3018 · IF 3.2

Comparative Efficacy of Tumor Microenvironment-responsive Nanotherapeutics Targeting PSD95/Discs-large/ZO-1 Binding Kinase in Different Histological Subgroups of Medulloblastoma

Qi Zhang,Chao Hu,Baoqing Qu,Cuiping Zhang,Longtao He

This work aimed to demonstrate the therapeutic effects of tumor microenvironment-responsive nanotherapeutic drugs targeting PSD95/Discs-large/ZO-1 domain (PDZ)-binding-kinase (PBK) in medulloblastoma Daoy and ONS-76 cells. The objective was to provide critical theoretical and practical foundations for the clinical adoption of tumor microenvironment-responsive nanotherapeutic drugs targeting PBK. The rabies virus glycoprotein (RVG) was utilized as a specific targeting molecule to form a tumor microenvironment-responsive nanocomplex, HPAA/RVG/PBK-siRNA, which incorporated glutathione (GSH) as a microenvironment stimulus factor within a hyperbranched polymer polyamide amine (HPAA). This nanocomplex also carried PBK-small interfering RNA (siRNA) for targeted PBK therapy. Characterization of HPAA, maleimide-polyethylene glycol-N-succinyl ester (MAL-PEG-NHS), HPAA-PEG, RVG, HPAA-RVG, and HPAA/RVG/PBK-siRNA was conducted using nuclear magnetic resonance spectroscopy, high-performance liquid chromatography (HPLC), dynamic light scattering, and transmission electron microscopy (TEM). Flow cytometry was employed to assess endocytosis and cell transfection of HPAA-RVG and HPAA/RVG/PBK-siRNA in Daoy and ONS-76 cells. The two cell lines were treated with HPAA/RVG/PBK-siRNA (HPAA/siRNA group), methoxy-PEG polyethylenimine (PEI-25k)/PBK-siRNA (PEI group), HPAA/RVG nanocarriers without PBK-siRNA (HPAA/RVG group), Dharmacon™ non-targeting siRNA (shNTC group), PBK-siRNA (Control group 1), AChR inhibitor (Control group 2), and GSH inhibitor (Control group 3), and compared with the control group (medium without any substances). Western blot analysis validated PBK expression levels (ELs) in various cell groups. Additionally, cell viability and proliferation were evaluated using methyl tetrazolium (MTT) assays and 5-Bromo-2'-deoxyuridine (BrdU) incorporation assays. The results revealed proton absorption peaks for HPAA at 2.78 ppm, 3.21 ppm, and 3.49 ppm, while RVG and HPAA-RVG exhibited characteristic absorption peaks at 23.653 min and 23.584 min, respectively, with peak areas of 4,856.6 and 6,927.3 for RVG. The nanoparticle sizes were 50-100 nm for HPAA-RVG and 100 nm for HPAA/RVG/PBK-siRNA, displaying spherical morphology and uniform size distribution. The average potential of HPAA-PEG was lower than that of HPAA ( P <0.05), and HPAA-RVG showed dramatically lower potential than HPAA ( P <0.001). At 8 hours, Daoy cells displayed higher endocytosis rates versus ONS-76 cells ( P <0.05). The transfection rates of HPAA-RVG in both ONS-76 and Daoy cells were higher than those of HPAA, with Daoy cells showing higher transfection rates than HPAA ( P <0.05). Under HPAA-RVG treatment, AChR levels in ONS-76 cells were significantly lower than those in Daoy cells ( P < 0.05). Compared to the control group, the PBK protein expression levels, cell survival rates, and the number of cells in the proliferative phase were significantly reduced in Control group 1, the PEI group, and the HPAA/siRNA group in both ONS-76 and Daoy cells, with the ONS-76 cells in the HPAA/siRNA group showing the lowest values among these groups ( P < 0.05). In summary, the findings indicated that the tumor microenvironment-responsive nanocomposite HPAA/RVG/PBK-siRNA selectively inhibited PBK expression in Daoy medulloblastoma cells, showcasing potential applicability in medulloblastoma therapy.

研究领域: 肿瘤学 · 药学 · 分子生物学 · 纳米技术
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PHYTOMEDICINE · 2023 · IF 7.9

Catalpol attenuates osteoporosis in ovariectomized rats through promoting osteoclast apoptosis via the Sirt6-ERα-FasL axis

Shuai Chen,Jie Jin,Ziqing Xu,Huawei Han,Lan Wu,Zhiwei Li

Background Catalpol , a major active component of the Chinese herb Rehmannia glutinosa , possesses various pharmacological benefits, including anti-inflammatory, antidiabetic , and antitumor properties. Recent studies have reported that catalpol can attenuate bone loss and enhance bone formation. Nevertheless, the molecular mechanisms underlying its effects on osteoporosis pathogenesis remain unclear. Purpose We investigated whether catalpol had a protective effect against postmenopausal osteoporosis (PMOP) and explored its exact mechanism of action. Methods Seventy-two rats were randomly divided into six groups: sham, model, low-dose catalpol (5 mg/kg/day), medium-dose catalpol (10 mg/kg/day), high-dose catalpol (20 mg/kg/day), and positive control (alendronate, 2.5 mg/kg). In this experiment, a ovariectomy was performed to establish a female rat model of PMOP. After 12 weeks of gavage, micro-computed tomography (micro-CT) and histochemical staining were performed to evaluate bone mass, bone microstructure and histological parameters. Furthermore, RAW 264.7 cells were induced by RANKL to form mature osteoclasts to investigate the effect of catalpol on osteoclast differentiation and apoptosis in vitro . Additionally, the osteoclast apoptosis-related proteins of Sirt6 , ERα, FasL , NFATc1, cleaved-caspase 8, cleaved-caspase 3, and Bax were assessed using western blotting . The expressions of NFATc1, Ctsk, Oscar , and Trap were quantified using RT-qPCR. The apoptotic rate of the osteoclasts was determined using flow cytometry. Sirt6 knockdown was performed using siRNA gene silencing in experiments to investigate its role in catalpol-mediated osteoclast apoptosis. The deacetylation of ERα in osteoclasts was tested via co-immunoprecipitation. Results Catalpol (10 and 20 mg/kg) and alendronate (2.5 mg/kg) could significantly improve bone mineral density (BMD) and microstructure and decrease osteoclast density in ovariectomized (OVX) rats. In addition, catalpol (10 and 20 mg/kg) upregulated the expression of Sirt6, ERα, FasL, cleaved-caspase 8, cleaved-caspase 3, Bax, and downregulated the expression of NFATc1, Ctsk, Oscar, Trap both in vivo and in vitro . Catalpol also promoted ERα deacetylation and stabilized ERα protein to enhance the expression of FasL. In addition, Sirt6 knockdown by siRNA prevented ERα deacetylation and eliminated catalpol-mediated osteoclast apoptosis. Conclusions The present study demonstrated that catalpol prevents estrogen deficiency-induced osteoporosis by promoting osteoclast apoptosis via the Sirt6-ERα-FasL axis. These findings revealed a novel molecular mechanism underpinning the impact of catalpol in the progression of osteoporosis and provided novel insights into the treatment of osteoporosis.

研究领域: 药理学 · 骨骼生物学 · 分子生物学 · 内分泌学
✓ 已验证 DOI PubMed 高影响因子
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES · 2024 · IF 7.7

Ionic liquid combined with cationic liposome co-delivers microphthalmia-associated transcription factor small interfering RNA to regulate melanogenesis

De Bai,Haowei Chen,Nanxi Xiang,Chunqiao Zhang,Zhenyuan Wang,Jichuan Zhang,Chengyu Wu,Fang Wang,Jiaheng Zhang

Suppressing allele-specific genes using small interfering RNAs (siRNAs) can effectively whiten skin by influencing cellular gene and protein expression. Topical delivery of siRNA is a promising alternative to injections for RNA interference. However, the barrier function of the skin hinders the effective penetration of siRNA. Here, we report, a novel approach to achieve the transdermal delivery of effective siRNA doses using a complementary synergistic strategy of an ionic liquid (IL) and cationic liposome (CL). Microphthalmia-associated transcription factor (MITF) siRNA molecules were formed through electrostatic adsorption of the IL and CL to form positively charged nanocomposites, which were named IL-CL/p-siM. IL-CL/p-siM has a particle size of 171.47 nm, ζ-potential of 29.94 mV, high encapsulation rate of 92.11 %, and pH-sensitive release properties. In vitro studies on porcine skin confirmed the additive/synergistic effect of this strategy in enhancing epidermal and dermal penetration. This combination enabled superior transfection efficiency and cell viability while inhibiting melanin synthesis in skin melanocytes by downregulating the expression of genes downstream of MITF, namely tyrosinase-related protein-1, tyrosinase, and tyrosinase-related protein-2, which are associated with the melanocortin 1 receptor. We also conducted clinical studies that demonstrated its potential in treating melasma and its anti-melanotic efficacy. To summarize, IL-CL/p-siM represents a simple, personalized, and scalable platform for effective local delivery of siRNA to treat skin complications.

研究领域: 药学 · 纳米技术 · 皮肤病学 · 基因治疗
✓ 已验证 产品关联 DOI PubMed 高影响因子
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Bioactive Materials · 2024 · IF 18

NIR-II photo-accelerated polymer nanoparticles boost tumor immunotherapy via PD-L1 silencing and immunogenic cell death

Tian Zhang,Dongsheng Tang,Pengfei Wu,Shaoping Jiang,Yuquan Zhang,Abid Naeem,Yong Li,Chunhui Li,Bo Hu,Shuai Guo,Caixia Sun,Haihua Xiao,Ran Yan,Yuhua Weng,Yuanyu Huang

Immune checkpoint blockade (ICB) therapy is a widely favored anti-tumor treatment, but it shows limited response to non-immunogenic “cold” tumors and suffers from drug resistance. Photodynamic therapy (PDT), as a powerful localized treatment approach, can convert a “cold tumor” into a “hot tumor” by inducing immunogenic cell death (ICD) in tumor cells, thereby enhancing tumor immunogenicity and promoting tumor immunotherapy. However, the effectiveness of PDT is largely hindered by the limited penetration depth into tumor tissues. To address these issues, we proposed an all-in-one drug system with NIR-II photo-accelerated PDT effects, efficient immune checkpoint gene silencing, and a facile manufacturing process. The so-called all-in-one drug system comprises a multi-modal designed polymer PPNP and siRNA. PPNP is an amphipathic polymer that includes the near infrared-II (NIR-II) photosensitizer Aza-boron-dipyrromethene (Aza-BODIPY), a glutathione (GSH)-cleavable linker, and a cationic monomer derived from cholesterol. PPNP can self-assemble and efficiently load siRNA. Under laser irradiation, PPNP triggers a potent ICD cascade, causing the on-demand release of siPD-L1, reshaping the tumor's immunosuppressive microenvironment, effectively inhibiting the growth of various tumors, and stimulating the immune memory. This study represents a generalized platform for PDT and gene silencing, designed to modulate immune-related signaling pathways for improved anticancer therapy.

研究领域: 肿瘤学 · 免疫治疗 · 药理学 · 生物医学工程 · 纳米技术
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Cureus Journal of Medical Science · 2024 · IF 1

Melittin Alleviates Oxidative Stress Injury in Schwann Cells by Targeting Interleukin-1 Receptor Type 1 to Downregulate Nuclear Factor Kappa B-Mediated Inflammatory Response In Vitro

Ye-Ran Mao,Ling-Yi Zhu,Ruo-Fei Du,Xiao-Yu Liu,Zhidan Liu,Li Li

Background and objectives: In ancient China, bee venom was widely used to treat various diseases. Although using bee venom is not currently a mainstream medical method, some have applied it to treat certain conditions, including idiopathic facial paralysis (IFP). Recently, melittin (Mel), the main active component of bee venom, has been shown strong anti-inflammatory and analgesic effects. However, how bee venom improves neurological dysfunction in facial paralysis remains unknown. This study aimed to investigate the anti-neurotraumatic effect of Mel on Schwann cells (SCs), the main cells of the neuron sheath, injured by oxidative stress. Methods: A model of hypoxic SCs was established, and CCK-8 assay, siRNA transfection, enzyme-linked immunosorbent assay, quantitative reverse transcription-polymerase chain reaction, western blot, immunofluorescence, and cell ultrastructure analyses were conducted to investigate the mitigation of hypoxia-induced damage to SCs in vitro, revealing the effects of Mel on oxidative stress injury in SCs. Results: The overexpression of HIF-1α in CoCl 2 -induced SCs (p < 0.05) indicated the establishment of an SCs hypoxia model. The proliferation and regeneration process of the hypoxic SCs enhanced in the Mel-treated group compared to the CoCl 2 group has been proven through the CCK-8 experiment (p < 0.0001) and S-100 mRNA expression detection (p < 0.0001). The increased level of reactive oxygen species (ROS) (p < 0.001) and decreased superoxide dismutase (SOD) levels (p < 0.05) in the CoCl 2 -induced SCs indicated that Mel can alleviate the oxidative stress damage to SCs induced by CoCl 2 . Mel alleviated oxidative stress and inflammation in hypoxic SCs by reducing pro-inflammatory cytokines IL-1β (p < 0.0001) and TNF-α (p < 0.0001). In addition, Mel augmented cellular vitality and regulated indicators related to oxygen metabolism, cell repair, neurometabolism, and vascular endothelial formation after hypoxia, such as C-JUN (p < 0.05), glial cell line-derived neurotrophic factor (GDNF; p < 0.001), vascular endothelial growth factor (VEGF; p < 0.05), hypoxia-inducible factor 1-alpha (HIF-1α; p < 0.05), interleukin-1 receptor type 1 (IL-1R1; p < 0.05), enolase1 (ENO1; p < 0.05), aldose reductase (AR; p < 0.01), SOD (p < 0.05), nerve growth factor (NGF; p < 0.05), and inducible nitric oxide synthase (iNOS; p < 0.05). In terms of its mechanism, Mel inhibited the expression of proteins associated with the NF-κB pathway such as IKK (p < 0.01), p65 (p < 0.05), p60 (p < 0.001), IRAK1 (p < 0.05), and increased IKB-α (p < 0.0001). Moreover, knocking out of IL-1R1 in the si-IL-1R1 group enhanced the therapeutic effect of Mel compared to the Mel-treated group (all of which p < 0.05). Conclusion: This research provided evidence of the substantial involvement of IL-1R1 in oxidative stress damage caused by hypoxia in SCs and proved that Mel alleviated oxidative stress injury in SCs by targeting IL-1R1 to downregulate the NF-κB-mediated inflammatory response. Mel could potentially serve as an innovative therapeutic approach for the treatment of IFP.

CAS / MDL: 512-26-5
研究领域: 神经科学 · 药理学 · 细胞生物学 · 分子生物学 · 炎症 · 氧化应激 · 面瘫
✓ 已验证 产品关联 DOI PubMed 高影响因子
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