AAPS PHARMSCITECH
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2019
·Vol. 20
·期 1
·1-14
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IF 2.608
Wang Xingqi,Zhang Yong,Huang Jie,Tian Chunling,Xia Mengqiu,Liu Liu,Li Zhengguang,Cao Jiaojiao,Gui Shuangying,Chu Xiaoqin
The purpose of this paper was to investigate the potential of liquid crystalline (LC) gels for ophthalmic delivery, so as to enhance the bioavailability of pilocarpine nitrate (PN). The gels were prepared by a vortex method using phytantriol and water (in the ratio of 73:27 w / w ). Their inner structures were confirmed by crossed polarized light microscopy, small-angle X-ray scattering, attenuated total reflectance-Fourier transform infrared spectrum, and rheology. The in vitro release studies revealed that PN could keep sustained release from the gels over a period of 12 h. The ex vivo apparent permeability coefficient of the gels demonstrated a 3.83-folds ( P < 0.05) increase compared with that of eye drops. The corneal hydration levels of the gel maintained in the normal range of 79.46 ± 2.82%, hinting that the gel could be considered non-damaging and safe to the eyes. Furthermore, in vivo residence time evaluation suggested that a better retention performance of LC gel was observed in rabbit’s eyes compared to eye drops. In vivo ocular irritation study indicated that LC gel was nonirritant and might be suitable for various eye applications. In conclusion, LC gels might represent a potential ophthalmic delivery strategy to overcome the limitations of eye drops.
研究领域:
药剂学
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药物递送系统
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眼科学
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ACS Nano
·
2023
·
IF 17.1
Yusheng Zhang,Xiaoyang Wu,Jie Ding,Borui Su,Zhihong Chen,Zhanwen Xiao,Chengheng Wu,Dan Wei,Jing Sun,Fang Luo,Huabing Yin,Hongsong Fan
Electrical deep brain stimulation (DBS) is a top priority for pharmacoresistant epilepsy treatment, while less-invasive wireless DBS is an urgent priority but challenging. Herein, we developed a conceptual wireless DBS platform to realize local electric stimulation via 1D-structured magnetoelectric Fe3O4@BaTiO3 nanochains (FBC). The FBC was facilely synthesized via magnetic-assisted interface coassembly, possessing a higher electrical output by inducing larger local strain from the anisotropic structure and strain coherence. Subsequently, wireless magnetoelectric neuromodulation in vitro was synergistically achieved by voltage-gated ion channels and to a lesser extent, the mechanosensitive ion channels. Furthermore, FBC less-invasively injected into the anterior nucleus of the thalamus (ANT) obviously inhibited acute and continuous seizures under magnetic loading, exhibiting excellent therapeutic effects in suppressing both high voltage electroencephalogram signals propagation and behavioral seizure stage and neuroprotection of the hippocampus mediated via the Papez circuit similar to conventional wired-in DBS. This work establishes an advanced antiepilepsy strategy and provides a perspective for other neurological disorder treatment.
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PEDIATRIC RESEARCH
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2023
·
IF 3.6
Wang Qi,Shi Xulai,Li Ping-Ping,Gao Li,Zhou Yueyuan,Li Luyao,Ye Hao,Fu Xiaoqin,Li Peijun
Background Although previous studies show that microRNAs (miRNAs) can potentially be used as diagnostic markers for epilepsy, there are very few analyses of pediatric epilepsy patients. Methods miRNA profiles using miRNA-seq was performed on plasma samples from 14 pediatric epileptic patients and 14 healthy children. miRNA miR-27a-3p that were significantly changed between two groups were further evaluated. The potential target genes of miR-27a-3p were screened through unbiased mRNA-seq and further validated using Western blot and immunohistochemistry in HEK-293T cells and in the brains of mice with epilepsy induced by lithium chloride–pilocarpine. Results We found 82 upregulated and 76 downregulated miRNAs in the plasma from pediatric patients compared with controls ( p < 0.01), of which miR-27a-3p exhibited a very low p value ( p < 0.0001) and validated in additional plasma samples. Two genes, GOLM1 and LIMK1, whose mRNA levels were decreased ( p < 0.001) with the increase of miR-27a-3p were further validated in both HEK-293T cells and in epileptic mice. Conclusions MiR-27a-3p exhibits potential as a diagnostic and therapeutic marker for epilepsy. We postulate that additional studies on the downstream targets of miR-27a-3p will unravel its roles in epileptogenesis or disease progression. Impact
A total of 158 differentially expressed miRNAs were detected in plasma between epileptic and control children.
Plasma miR-27a-3p was one of the miRNAs with a low p value.
GOLM1 and LIMK1 were validated as downstream target genes of miR-27a-3p.
miR-27a-3p has potential as a diagnostic and therapeutic marker for epilepsy.
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CARBOHYDRATE POLYMERS
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2020
·
IF 7.182
Ziming Zheng,Yu Zhang,Yuxuan Liu,Jinglin Wang,Zheng Cui,Xianglin Pan,Yan Liu,Wenqi Tang,Kaiping Wang
Lentinan (LNT), a typical triple helix β-glucan, has been widely used as drug and biomaterial. However, its pharmacokinetics in vivo is rarely reported, which severely limits its further development and application. The aim of this study is to establish a sensitive method for detecting LNT in biosamples and to evaluate the plasma level, tissue distribution and metabolic degradation of LNT in rats. 5-([4,6-Dichlorotriazin-2-yl] amino) fluorescein (DTAF) was labelled to LNT. After purification and identification, FLNT was intravenously administered to rats at dose of 32 mg/kg. LNT was predominantly incorporated into the liver and liver microsomes were used to study the degradation mechanism of LNT in the liver. The results showed that two cytochrome P450 (CYP450) enzymes subtypes (CYP2D6 and CYP2C9), as well as epoxide hydrolase, were involved in the metabolic degradation of LNT. These findings provide a pharmacokinetic reference for further study and application of LNT and other β-glucans.
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CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY
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2020
·Vol. 98
·期 6
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IF 1.946
Di Wang,Meilan Zhou,Yan Wang,Shiren Sun
Xerostomia is a self-conscious symptom. High-mobility group box 1 (HMGB1) promotes pro-inflammatory effects in many diseases. This study aimed to clarify the role of HMGB1 in Sjögren syndrome (SS)-triggered xerostomia. Nonobese diabetic (NOD)/Ltj mice were used to establish an SS-triggered xerostomia model. The results showed that saliva production was decreased and anti-Sjögren syndrome B (anti-SSB) level was increased in SS. PCR, Western blot, and immunohistochemistry experiments indicated that the HMGB1 and aquaporin 5 (AQP5) levels were enhanced and diminished in SS compared with those in the control, respectively. While the mice were treated with anti-HMGB1, xerostomia was reversed due to the elevated saliva production and reduced anti-SSB level. In addition, it was found that the inhibition of HMGB1 restrained the toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) axis activation. The TLR4 and p-IκB levels were alleviated, while the IκBα and NF-κB p65 levels were augmented. The NF-κB p65 binding activity was attenuated via the electrophoretic mobility shift assay (EMSA) after anti-HMGB1 treatment. Moreover, the repression of HMGB1 facilitated the expression of AQP5. These findings demonstrate that suppression of HMGB1 ameliorates SS-triggered xerostomia via suppressing the HMGB1/TLR4/NF-κB signaling pathway and upregulating AQP5 expression.
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JOURNAL OF CHROMATOGRAPHY A
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2021
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IF 4.759
Xue Zhao,Xiaoying Fu,Xinyi Yuan,Aerduosi Shayiranbieke,Ru Xu,Fang Cao,Jianping Ren,Qi Liang,Xinfeng Zhao
The pursuit of new ligands binding to muscarinic-3 acetylcholine receptor (M 3 R) is viewed as challenging due to the lack of screening methods with high efficiency. To address such challenges, this work developed and characterized an approach to the rapid discovery of M 3 R ligands using the immobilized receptor as the chromatographic stationary phase. We fused haloalkane dehalogenase (Halo) as a tag at the C-terminus of M 3 R. The fusion M 3 R was immobilized on 6-chlorocaproic acid-activated ammino-microspheres by the specific covalent reaction between the Halo-tag and the linker. Comprehensive characterizations of the immobilized M 3 R were performed by scanning electron microscope, X-ray photoelectron spectroscopy, and the investigation on the binding of three specific ligands to the receptor. The feasibility of the immobilized M 3 R in complex matrices was tested by screening the bioactive compounds in Zhisou oral liquid, assessing the interaction between the screened compounds and the receptor using zonal elution, and evaluating the in vivo activity of the targeted compounds. The results evidenced that the immobilized M 3 R has high specificity, good stability, and the capacity to separate M 3 R ligands from complex matrices. These allowed us to identify naringin, hesperidin, liquiritigenin, platycodin D, and glycyrrhizic acid as the potential ligands of M 3 R. The association constants of the five compounds to M 3 R were 4.44 × 10 4 , 1.11 × 10 4 , 7.20 × 10 4 , 4.15 × 10 4 , and 3.36 × 10 4 M −1 . The synergistic application of the five compounds exhibited an equivalent expectorant activity to the original formula. We reasoned that the current method is possible to provide a highly efficient strategy for the discovery of receptor ligands.
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INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
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2019
·Vol. 43
·期 5
·2103-2117
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IF 2.928
Nan Miao,Yuanbo Zhan,Yingying Xu,Haoze Yuan,Chunlin Qin,Feng Lin,Xiaohua Xie,Sen Mu,Mengtong Yuan,Haibin Mu,Shouli Guo,Ying Li,Bin Zhang
Family with sequence similarity 20‑member C (FAM20C), a recently characterized Golgi kinase, performs numerous biological functions by phosphorylating more than 100 secreted proteins. However, the role of FAM20C in the salivary glands remains undefined. The present study demonstrated that FAM20C is mainly located in the cytoplasm of duct epithelial cells in the salivary glands. Fam20cf/f; Mmtv‑Cre mice were created in which Fam20c was inactivated in the salivary gland cells and observed that the number of ducts and the ductal cross‑sectional area increased significantly, while the number of acinar cells was reduced. The granular convoluted tubules (GCTs) exhibited an accumulation of aberrant secretory granules, along with a reduced expression and altered distribution patterns of β nerve growth factor, α‑amylase and bone morphogenetic protein (BMP) 4. This abnormality suggested that the GCT cells were immature and exhibited defects in developmental and secretory functions. In accordance with the morphological alterations and the reduced number of acinar cells, FAM20C deficiency in the salivary glands significantly decreased the salivary flow rate. The Na+, Cl– and K+ concentrations in the saliva were all significantly increased due to dysfunction of the ducts. Furthermore, Fam20c deficiency significantly increased BMP2 and BMP7 expression, decreased BMP4 expression, and attenuated the canonical and noncanonical BMP signaling pathways in the salivary glands. Collectively, the results of the present study demonstrate that FAM20C is a key regulator of acinar and duct structure and duct maturation and provide a novel avenue for investigating novel therapeutic targets for oral diseases including xerostomia.
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NEUROBIOLOGY OF DISEASE
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2024
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IF 5.1
Lu Deng,Hong Jiang,Jingjing Lin,Di Xu,Ailin Qi,Qing Guo,Ping-Ping Li,Xinshi Wang,Judy S. Liu,Xiaoqin Fu,Peijun Li
Summary Epilepsy is a brain disorder affecting up to 1 in 26 individuals. Despite its clinical importance, the molecular mechanisms of epileptogenesis are still far from clarified. Our previous study showed that disruption of Clock in excitatory neurons alters cortical circuits and leads to generation of focal epilepsy. In this study, a GAD-Cre;Clock flox/flox mouse line with conditional Clock gene knockout in inhibitory neurons was established. We observed that seizure latency was prolonged, the severity and mortality of pilocarpine-induced seizure were significantly reduced, and memory was improved in GAD-Cre;Clock flox/flox mice. We hypothesize that mice with CLOCK knockout in inhibitory neurons have increased threshold for seizure, opposite from mice with CLOCK knockout in excitatory neurons. Further investigation showed Clock knockout in inhibitory neurons upregulated the basal protein level of ARC, a synaptic plasticity-associated immediate-early gene product, likely through the BDNF-ERK pathway. Altered basal levels of ARC may play an important role in epileptogenesis after Clock deletion in inhibitory neurons. Although sEPSCs and intrinsic properties of layer 5 pyramidal neurons in the somatosensory cortex exhibit no changes, the spine density increased in apical dendrite of pyramidal neurons in CLOCK knockout group. Our results suggest an underlying mechanism by which the circadian protein CLOCK in inhibitory neurons participates in neuronal activity and regulates the predisposition to epilepsy.
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MOLECULAR NEUROBIOLOGY
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2024
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IF 4.6
Xiong Zhonghua,Deng Jiahui,Xie Pandeng,Tang Chongyang,Wang Jing,Deng Qinqin,Yang Yujiao,Zhang Jing,Guo Mengyi,Wang Xiongfei,Guan Yuguang,Luan Guoming,Zhou Jian,Li Tianfu
Deep brain stimulation (DBS) of the anterior nucleus of the thalamus is an efficacious treatment option for patients with refractory epilepsy. Our previous study demonstrates that adenosine is a potential target of DBS for the treatment of epilepsy. Equilibrative nucleoside transporters-1 (ENT1) and ectonucleotidases (CD39, CD73) function as regulators of extracellular adenosine in the brain. It is unclear whether ENT1, CD39, and CD73 are involved in the mechanism of DBS for epilepsy. A total of 48 SD male rats were divided into four groups: control (naïve rats), Pilo (pilocarpine induced rats with epilepsy), DBS (rats with epilepsy treated with DBS for 8 weeks), and sham. In the present study, video electroencephalogram monitoring, Morris water maze assays, in vivo measurements of adenosine using fiber photometry, histochemistry, and western blot were performed on the hippocampus. DBS markedly attenuated spontaneous recurrent seizures (SRSs) and enhanced spatial learning in rats with epilepsy, assessed through video-EEG and water maze assays. Fibred photometry measurements of an adenosine sensor revealed dynamic increase in extracellular adenosine during DBS. The expressions of ENT1, CD39, and CD73 in Pilo group and sham group increased compared with the control group, while the expressions of ENT1, CD39, and CD73 in DBS group decreased compared to that of Pilo group and sham group. The findings indicate that DBS reduces the number of SRSs and improves spatial memory in rats with epilepsy with concomitant decrease of ENT1, CD39, and CD73 expressions. Adenosine-modulating enzymes might be the potential targets of DBS for the treatment of epilepsy.
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ADVANCED FUNCTIONAL MATERIALS
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2024
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IF 18.5
Han Wang,Caoling Li,Jingwei Zhang,Zhao Yang,Junjun Li,Yu Cao,Kangbing Wu,Zhihong Liu,Junxing Hao,Xiaoxue Ye
Transition metal sulfides have garnered significant interest in the realm of photoelectrochemical (PEC) sensors due to their remarkable optical and electrical properties. However, their intrinsic UV–vis adsorption and electron-donor consumption severely hinder their nonirritating and in situ epidermal PEC applications. Herein, a NIR-808 nm light-excited heterojunction, phosphomolybdic acid-encapsulated ytterbium-doped bismuth sulfide (Yb-Bi 2 S 3 /PMA), is synthesized by hydrothermal method for self-sufficient electron donor-based PEC sensing. Further, the Yb-Bi 2 S 3 /PMA heterojunction is decorated on flexible and integrated laser-induced graphene electrode arrays, providing ultrafast charge carrier transfer capacity and robust mechanical durability (300 bending cycles) for subsequent wearable PEC sensing. As a showcase, the aptamer molecular recognition-based wearable PEC sensor for sweat trace Neuropeptide Y (NPY, a stress or depression biomarker) presents an ultra-low detection limit (0.39 fM) and good anti-interference ability. Moreover, the integration of wearable PEC aptasensor with signal processing and wireless communication facilitates nonirritating and in situ analysis of sweat trace NPY dynamics in various real scenarios (feeding behaviors, physiological stress, and circadian rhythm). More broadly, this research establishes the foundation for NIR-excitable semiconductors equipped with self-sufficient electron donor capabilities, unlocking the potential for ultrasensitive wearable PEC sensing applications.
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Frontiers in Neuroscience
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2024
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IF 3.2
Shuo Li,Alhamdu Adamu,Yucai Ye,Fankai Gao,Rulin Mi,Guofang Xue,Zhaojun Wang
Objective: To investigate the effect of (+)-borneol on neuroinflammation and microglia phenotype polarization in epileptogenesis and its possible mechanism.Methods: Based on mouse models of status epilepticus (SE) induced by pilocarpine, and treated with 15 mg/kg (+)-borneol, western-blot was used to detect the expressions of NeuN, Iba-1, TLR4, p65 and p-p65 in the hippocampus. Immunofluorescence was used to detect the expression of apoptosis-related proteins Bax and Bcl-2. To explore the effect of (+)-borneol on microglia in vitro, we used the kainic acid-induced microglia model and the concentration of (+)-borneol was 25 μM according to CCK-8 results. The levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-10 (IL-10) in the supernatant of each group was detected by ELISA. The nitric oxide (NO) content in the supernatant was detected by Griess method. The expressions of Iba-1 and TLR4-NFκB signaling pathway-related proteins (TLR4, p65, p-p65) were detected by Western-Blot. Immunofluorescence was used to detect microglia’s M1 and M2 phenotype polarization and the expression of Iba-1 and TLR4.Results: (+)-borneol reduced hippocampal neuronal injury, apoptosis, and microglia activation by inhibiting the TLR-NFκB signaling pathway in SE mice. TLR4 agonist LPS partially reversed the neuroprotective effect of (+)-borneol. In the KA-induced microglia model, (+)-borneol inhibited microglia activation, M1 phenotype polarization, and secretion of pro-inflammatory cytokines through the TLR4-NFκB signaling pathway. LPS treatment inhibited the therapeutic effects of (+)-borneol.Conclusion: (+)-borneol inhibits microglial neuroinflammation and M1 phenotype polarization through TLR4-NFκB signaling pathway and reduces neuronal damage and apoptosis in SE mice. Therefore, (+)-borneol may be a potential drug for epilepsy modification therapy.
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BIOMEDICAL CHROMATOGRAPHY
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2025
·Vol. 40
·期 1
·e70278
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IF 1.7
Junni Fan,Yu Li,Ge Wang,Qian Li,Minfeng Fang
This study employed an affinity chromatography approach to investigate the potential molecular mechanism of the Albiziae Cortex and Polygoni Multiflori Caulis herbal pair, which is commonly used for treating insomnia. Briefly, the haloalkane dehalogenase and its substrate were fused separately onto the serotonin 1A receptor and amino microspheres. Receptors were bound onto chromatographic stationary phases specifically through biological orthogonal interactions. Subsequently, catechin, methyl-O-digalloyl-hexose, 2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucoside (THSG), and julibroside J 35 were identified as active components in the herbal pair extract targeting the receptor. A mice model of insomnia was used to validate the anti-insomnia effects. The herbal-pair extract, catechin, and THSG significantly reduced sleep latency and increased sleep duration. Furthermore, on-column analysis and molecular docking revealed the binding characteristic. Adsorption isotherm analysis indicated a homogeneous binding process, which was further supported by injection amount-dependent analysis. The latter also provided binding constants of (5.70 ± 0.61) × 10 5 M −1 for catechin and (4.05 ± 0.20) × 10 5 M −1 for THSG. Molecular docking revealed critical binding residues (Asp116, Val117, Thr121, Lys191, Thr196, and Ser199), primarily via van der Waals forces and hydrogen bonds. Collectively, immobilizing the serotonin 1A receptor enables the screening of biologically active compounds from complex systems effectively and shows a degree of general applicability.
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