Expert Opinion on Drug Delivery
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2024
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IF 5
Huixian Tian,Minsi Chang,Yanlin Lyu,Nan Dong,Nini Yu,Tian Yin,Yu Zhang,Haibing He,Jingxin Gou,Xing Tang
Background Exendin-4 (Ex4) is a promising drug for diabetes mellitus with a half-life of 2.4 h in human bodies. Besides, the Ex4 formulations currently employed in the clinic or under development have problems pertaining to stability. In this study, palmitic acid-modified Ex4 (Pal-Ex4) was prepared and purified to extend the half-life of Ex4. In addition, Pal-Ex4-MVLs were further designed and optimized as a long-acting delivery system for intramuscular injection.Methods Pal-Ex4 was encapsulated within multivesicular liposomes (MVLs) via a two-step double emulsification process. The formulated products were then assessed for their vesicle size, encapsulation efficiency, and in vitro and in vivo.Results Pal-Ex4-MVLs with a notable encapsulation efficiency of 99.18% were successfully prepared. Pal-Ex4-MVLs, administered via a single intramuscular injection in Sprague-Dawley rats, sustained stable plasma concentrations for 168 h, presenting extended half-life (77.28 ± 12.919 h) and enhanced relative bioavailability (664.18%). MVLs protected Ex4 through providing stable retention and slow release. This approach considerably improved the in-situ stability of the drug for intramuscular administration.Conclusions The combination of palmitic acid modification process with MVLs provides dual protection for Ex4 and can be a promising strategy for other hydrophilic protein/polypeptide-loaded sustained-release delivery systems with high drug bioactivity.
研究领域:
药剂学
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药理学
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药物递送系统
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DOI
PubMed
高影响因子
Frontiers in Microbiology
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2024
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IF 4
Wang Liping,Liang Aihua,Huang Jukai
Introduction: Diabetic nephropathy (DN) presents a significant therapeutic challenge, compounded by complex pathophysiological mechanisms. Recent studies suggest Exendin-4 (Ex-4) as a potential ameliorative agent for DN, albeit with unclear mechanisms. This research investigates the effects and underlying mechanisms of Ex-4-enriched exosomes derived from human umbilical cord mesenchymal stem cells (hUCMSCs) on DN, focusing on their renoprotective properties and interactions with gut microbiota.Method: Exosomes from hUCMSCs (hUCMSCs-Exo) were loaded with Ex-4 via electroporation. A streptozotocin (STZ) -induced DN mouse model was employed to assess the therapeutic impact of these engineered exosomes. The study further explored immune cell dynamics, mainly CD4+ regulatory T (Treg) cells, using bioinformatics, flow cytometry, and the influence of gut microbiota through antibiotic treatment and specific bacterial reintroduction.Results: Treatment with hUCMSCs-Exo@Ex-4 significantly improved key DN markers, including blood glucose and proteinuria, alleviating kidney damage. A notable decrease in natural Treg cell infiltration in DN was observed, while Ex-4-loaded exosomes promoted CD4+ Treg cell induction. The therapeutic benefits of hUCMSCs-Exo@Ex-4 were diminished upon CD4+ Treg cell depletion, underscoring their role in this context. Notably, CD4+ Treg cell induction correlated with the presence of Prevotella species, and disruption of gut microbiota adversely affected these cells and the therapeutic efficacy of the treatment. However, the reintroduction of Prevotella strains counteracted these adverse effects.Discussion: This study elucidates a novel therapeutic mechanism of Ex-4-loaded hUCMSCs exosomes in DN, highlighting the induction of CD4+ Treg cells mediated by specific gut microbiota components. These findings underscore the potential of leveraging gut microbiota and immune cell interplay in developing effective DN treatments.
研究领域:
糖尿病
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肾病学
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干细胞治疗
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免疫学
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微生物组研究
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
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2016
·Vol. 37
·期 4
·889-900
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IF 2.348
Jieqiong He,Chao Wang,Yunpeng Sun,Bo Lu,Jinjin Cui,Nana Dong,Maomao Zhang,Youbing Liu,Bo Yu
Exendin-4 (ex-4) is a long-acting glucagon-like peptide-1 receptor (GLP-1R) agonist which exerts beneficial effects on glycemic control and promotes cell viability. In the present study, we investigated the anti-apoptotic effects of ex-4, as well as the potential mechanisms responsible for these effects in rat bone marrow-derived mesenchymal stem cells (BM-MSCs) under conditions of oxygen, glucose and serum deprivation (OGD). The apoptosis of the MSCs was induced by subjecting the cells to OGD conditions for 4 h and was detected by Annexin V/PI and Hoechst 33258 staining. The MSCs were pre-conditioned with ex-4 for 12 h prior to being subjected to OGD conditions, and the expression levels of an apoptotic marker (cleaved caspase-3), endoplasmic reticulum (ER) stress markers [phosphorylated (p-)protein kinase RNA-like endoplasmic reticulum kinase (PERK), PERK, binding immunoglobulin protein (BIP), activating transcription factor 4 (ATF-4) and C/EBP homologous protein (CHOP)], as well as those of a survival marker (Bcl-2) were measured by western blot analysis. Furthermore, the mRNA levels of ATF-4 and CHOP were determined by RT-qPCR. ELISA was used to examine the activity of intracellular cAMP. Moreover, the GLP-1R antagonist, exendin9-39 (ex9-39), the protein kinase A (PKA) inhibitor, H89, and small interfering RNA (siRNA) targeting rat ATF-4 and CHOP were co-incubated with the MSCs. The apoptotic rate was markedly diminished following pre-conditioning with ex-4 in a dose‑dependent manner (P<0.05). The ER stress markers, p-PERK, BIP, ATF-4 and CHOP, were upregulated in the cells subjected to OGD conditions. Ex-4 pre-conditioning significantly decreased the mRNA and protein levels of ATF-4 and CHOP (P<0.05), and increased the activity of intracellular cAMP (P<0.05). Furthermore, the anti-apoptotic effects of ex-4 were almost reversed by treatment with either H89 or ex9-39 (P<0.05); transfection with siRNA-CHOP significantly reduced the apoptotic rate of the MSCs and did not impair the cytoprotective effects of ex-4. Taken together, these findings suggest that ex-4 protects rat BM-MSCs from OGD-induced apoptosis through the activation of the PKA/cAMP pathway and the attenuation of the ER stress signaling pathway. Ex-4 may thus prove to be a therapeutic agent with the potential to improve the viability of MSCs in the ischemic milieu, and consequently, to optimize the therapeutic effects of MSC therapy in acute myocardial infarction.
研究领域:
干细胞生物学
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药理学
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细胞信号传导
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心血管疾病
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2024
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IF 4.2
Wenyuan Yu,Jianghuiwen Lu,Xinqi Huang,Huiru Zhuang,Yumei An,Mingyang Zhang
Background Effective drugs for preventing or treating skin flap necrosis remain elusive. In this study, we investigated the potential protective effect of exendin-4 against skin flap ischemia-reperfusion injury (IRI) through the inhibition of ferroptosis. Method A rat abdomen was constructed with an island skin flap, and the superficial vascular pedicle of the abdominal wall was closed using a vascular clamp, which was removed after 8 h. Before surgery, RSL3 and ferrostatin-1 solutions were intraperitoneally injected. After the surgery, subcutaneous injections of exendin-4 were administered daily. The number of inflammatory cells, mean vascular density, collagen fiber content, and apoptosis and ferroptosis indicators were quantified 24 h after reperfusion. Survival, contraction rate, and blood perfusion of the skin flap were evaluated on days 1, 3, 5, and 7 after reperfusion. Results The flap survival rate was significantly higher in the exendin-4 group than that in the injury group, whereas the contraction rate was lower. Compared with the injury group, the exendin-4 group showed less inflammatory cell infiltration, higher vascular density, and less collagen fiber loss. At the molecular level, the exendin-4 group demonstrated opposite or elevated expression of apoptosis and ferroptosis indicators than those in the injury group, with significantly increased glutathione peroxidase 4 (Gpx4). Ferroptosis inhibitors and agonists enhanced and reversed the protective effects of exendin-4, respectively. Conclusion Exendin-4 alleviates skin flap IRI by upregulating Gpx4 expression to inhibit ferroptosis. Therefore, exendin-4 may serve as a novel clinical treatment for skin flap IRI.
研究领域:
药理学
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外科手术
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分子生物学
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病理学
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DOI
PubMed
高影响因子
Materials Today Bio
·
2025
·
IF 10.2
Qifan Yang,Jing Liu,Yanwei Liu,Shun Liu,Xiaokang Wei,Yilin Yang,Weijie Zhang,Shuqi Zhang,Maosheng Zhang,Bin Liu,Xinyu Wang,Dong Zhu
Background Obesity-induced osteoporosis is a prevalent complication among obese individuals. Conventional anti-osteoporosis medications often lack therapeutic specificity and may exacerbate lipid metabolism disorders. Consequently, identifying suitable pharmacological interventions for obesity-induced osteoporosis, elucidating its underlying biological mechanisms, and developing nanodrug delivery systems with enhanced biocompatibility and targeted delivery remain significant challenges. Methods This study reveals that the pathogenesis of obesity-induced osteoporosis is primarily driven by excessive mitophagy. Notably, Exendin-4 (Ex-4) has been shown to ameliorate mitophagy and mitigate obesity-induced osteoporosis. The nanocomposite DSPE-PEG-ALN (DPA)@Neutrophil membrane (NM)@Cu-TCPP(Zn)/Ex-4 (CTZE), characterized by high biocompatibility and reactive oxygen species (ROS) responsiveness, effectively targets bone tissue, reduces ROS levels, and regulates the release of Cu 2+ , Zn 2+ , Ex-4, and Alendronate (ALN). This composite interferes with B-cell lymphoma-2 (BCL2)- Beclin-1 (BECN1) binding via the tet methylcytosine dioxygenase 2 (TET2)/ PTEN-induced putative kinase protein 1 (PINK1)/Parkin (E3 ubiquitin-protein ligase parkin) pathway, thereby promoting osteoblast differentiation and mineralization. The safety and efficacy of this nano-delivery platform were validated in a mouse model of obesity-induced osteoporosis. Conclusions In summary, our study illustrates that excessive mitophagy plays a crucial role in obesity-induced osteoporosis. Furthermore, DPA@NM@CTZE exhibits significant potential for the precise treatment of obesity-induced osteoporosis, mitigating the side effects of Ex-4, and enhancing the bone microenvironment.
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高影响因子
Neural Regeneration Research
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2021
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IF 5.135
Ling-Yu Zhang,Qian-Qian Jin,Christian Hölscher,Lin Li
Patients with Parkinson’s disease (PD) have impaired insulin signaling in the brain. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), can re-sensitize insulin signaling. In a recent phase II clinical trial, the first GLP-1 mimic, exendin-4, has shown reliable curative effect in patients with PD. DA-CH5 is a novel GLP-1/GIP receptor unimolecular co-agonist with a novel peptide sequence added to cross the blood-brain barrier. Here we showed that both exendin-4 and DA-CH5 protected against 6-hydroxydopamine (6-OHDA) cytotoxicity, inhibited apoptosis, improved mitogenesis and induced autophagy flux in SH-SY5Y cells via activation of the insulin receptor substrate-1 (IRS-1)/alpha serine/threonine-protein kinase (Akt)/cAMP response element-binding protein (CREB) pathway. We also found that DA-CH5 (10 nmol/kg) daily intraperitoneal administration for 30 days post-lesion alleviated motor dysfunction in rats and prevented stereotactic unilateral administration of 6-OHDA induced dopaminergic neurons loss in the substantia nigra pars compacta. However, DA-CH5 showed curative effects in reducing the levels of α-synuclein and the levels of pro-inflammatory cytokines (tumor necrosis factor-α, interleukin-1β). It was also more effective than exendin-4 in inhibiting apoptotic process and protecting mitochondrial functions. In addition, insulin resistance was largely alleviated and the expression of autophagy-related proteins was up-regulated in PD model rats after DA-CH5 treatment. These results in this study indicate DA-CH5 plays a therapeutic role in the 6-OHDA-unilaterally lesioned PD rat model and is superior to GLP-1 analogue exendin-4. The study was approved by the Animal Ethics Committee of Shanxi Medical University of China.
研究领域:
神经科学
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药理学
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分子生物学
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神经退行性疾病
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DOI
PubMed
高影响因子
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