Frontiers in Aging Neuroscience
·
2025
·
IF 4.5
Wen Peng Shan,Shi Lei Yan,Yuan Yuan Guo,Hua Ke Yang,Jing Chun Wang,Jie Xiang
Background: Parkinson’s disease (PD) is a common neurodegenerative disorder. It is marked by motor dysfunction and cognitive decline. In recent years, scientific studies have found that PD’s pathogenesis may be tied to an imbalance in the gut microbiota. This offers new perspectives for PD treatment. Modulating the gut microbiota is recognized as a potential way to enhance PD symptoms. While aerobic exercise can positively influence the gut microbiota, research on how the gut microbiota mediates aerobic exercise’s effects on PD cognitive impairment is still limited. Thus, this study aimed to explore the potential mechanisms by which aerobic exercise improves cognitive impairment in PD patients. It does so by modulating the gut microbiota’s structure and, in turn, improving cognitive function. Through this study, we hope to offer new strategies and a theoretical basis for treating PD cognitive impairment.Methods: This study focused on the potential neuroprotective effects of long-term aerobic exercise in an MPTP-induced PD mouse model. Research methods included using 16S rRNA gene sequencing and plasma untargeted metabolomics to precisely describe the composition of the mouse gut microbiota and its metabolite changes. We also monitored the mice’s motor and cognitive functions via behavioral assessments. Pathological features and molecular-level changes in PD mice were analyzed using morphological and molecular biology techniques. To further study the role of gut microbes in aerobic exercise, we conducted antibiotic treatment experiments on mice. Finally, Pearson correlation analysis was used to explore the correlation between gut microbiota, plasma metabolite outcomes, and molecules related to cognitive function.Results: Our results showed that aerobic exercise effectively intervened in PD mice. It alleviated PD-related pathological impairments and cognitive deficits and promoted the secretion of FNDC5 and BDNF, producing neuroprotective effects. Aerobic exercise regulated the gut flora imbalance in PD mice. 16S rRNA analysis revealed a significant increase in the abundance of Alloprevotella, Akkermansia, Lachnospiraceae_NK4A136_group, Bacteroides, and Prevotellaceae_UCG-001. In contrast, the abundance of Parabacteroides, Helicobacter, Alistipes, and Odaribacter decreased significantly. The gut flora mediated the role of aerobic exercise by regulating FNDC5 secretion through PGC1-α/CREB and influencing BDNF production.Conclusion: Aerobic exercise improves gut flora imbalance in PD mice. It also attenuates PD-related pathological impairments and cognitive deficits. However, its efficacy on non-motor symptoms can be nullified by antibiotics. The gut flora-mediated aerobic exercise exerts neuroprotective effects on PD by regulating FNDC5 secretion via PGC1-α/CREB.
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CRYSTAL GROWTH & DESIGN
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2026
·
IF 3.6
He-Mei Yin,Xin-Yu Sun,Ping Xu,Shu-Long Liu,Fu-Min Xue
Baloxavir marboxil (BXM), a novel oral antiviral drug, is classified as BCS II and suffers from bioavailability limitations due to its low solubility. To overcome these limitations, a cocrystallization strategy was adopted in the present study. It is noteworthy that no cocrystal form of BXM has been reported in the CSD database. This study reports the synthesis and comprehensive characterization of a novel baloxavir marboxil and probenecid (PRO) pharmaceutical cocrystal (BXM-PRO), which was designed to improve the dissolution performance of BXM for enhanced therapeutic efficacy. The single crystal was successfully prepared via slow evaporation from a mixed solvent of methanol and water and thoroughly characterized using single-crystal X-ray diffraction, powder X-ray diffraction, thermogravimetric and differential scanning calorimetry, Fourier transform infrared spectra, scanning electron microscopy, Hirshfeld surface analysis, and density functional theory calculations. Structural analysis confirmed the formation of a cocrystal stabilized by strong O–H···O hydrogen bonds. Subsequent evaluations included the powder dissolution rate, accelerated stability, and antiviral activity. The dissolution profiles revealed that the BXM-PRO cocrystal exhibits a significantly enhanced dissolution rate and higher solubility in both water and pH 6.8 buffer compared to pure BXM. Theoretical analysis suggests that strong hydrogen bonding between hydrogens of the O–H···O complexes plays a critical role in facilitating the improved dissolution performance of the cocrystal. Additionally, cytotoxicity assessment via CCK-8 assay indicated that the cocrystal possesses lower cytotoxicity against MDCK cells than BXM. The antiviral activity of the BXM-PRO cocrystals was compared with that of BXM alone as well as with that of physical mixtures of BXM with PRO in adequate stoichiometric ratios. Antiviral assays demonstrated that the cocrystal exhibits superior efficacy against the Yamagata strain, reduced effectiveness against H1N1 PR8 and H3N2 strains, and comparable activity against the Victoria strain relative to BXM alone. These findings indicate that the BXM-PRO cocrystal represents a promising strategy to enhance the solubility and bioavailability of BXM, with potential clinical benefits for the treatment of influenza virus infections.
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GREEN CHEMISTRY
·
2021
·Vol. 23
·期 4
·1782-1793
·
IF 10.182
Hang Mei,Huajing Liu,Qianqian Shang,Ying Dong,Stig Pedersen-Bjergaard,Chuixiu Huang,Xiantao Shen
In this work, a green, stable and versatile organic-solvent-free electromembrane extraction (EME) system based on semi-interpenetrating polymer networks (semi-IPN) is proposed for the extraction and enrichment of both basic and acidic drugs from human urine. Because of its non-toxicity and high affinity in target separation, semi-solid polypropylene glycol (PPG) was selected as a component for the synthesis of semi-IPN networks via an ultrasonic-assisted blending (UAB) method. Using the homogeneous semi-IPN membrane as the supported liquid membrane (SLM), the organic-solvent-free EME system was obtained. Under the optimized conditions, the organic-solvent-free EME system showed high recovery efficiency for both basic analytes (70–97%) and acidic analytes (86–100%). Moreover, the organic-solvent-free EME set-up could be reused in eight successive extraction batches without an obvious decrease in extraction efficiency. In addition, the EME system could be conveniently stored at ambient temperature for a long time, which will greatly promote the commercialization of EME. We believe this study provides new insights and attempts in the development of green sample preparation approaches.
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JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES
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2020
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IF 3.004
Chen Sun,Mingyu Zhang,Yanhong Zhao,Jianxin Pang,Ying Peng,Jiang Zheng
Urate anion exchanger 1 (URAT1) expressed in the proximal renal tubules is responsible for about 90% of the reabsorption of uric acid. URAT1 is identified as an important target of uricosuric drugs. Here we present an LC-MS/MS-based approach, combined with URAT1-transgenic MDCK cells, for the assessment of uric acid. Cell lysis was executed with 50 mM NaOH to release uric acid. 1,3- 15 N 2 uric acid was employed as the internal standard. The harvested uric acid, along with the stable isotope-labeled uric acid, was analyzed by LC-MS/MS in multiple reactions monitoring and negative modes. Validation, i.e. determination of selectivity, precision, accuracy, extraction recovery, and matrix effect, and feasibility was evaluated by use of the approach developed. The linearity was observed in the range of 1.0–250 μM (r = 0.9960) with limit of detection of 50 nM and limit of quantitation of 200 nM. The precision and accuracy were found to be RSD ≤ 20% and 80–120% of the nominal value, respectively. Uric acid uptake showed concentration and time dependency in URAT1-transgenic cells. The observed inhibitory effects of three URAT1-targeted uricosuric drugs were consistent with those reported in literature. The stable isotope dilution-based approach was proven to be selective, sensitive, and convenient, which is a good in vitro model for URAT1-targeted drug candidate screening.
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Nature Communications
·
2023
·Vol. 14
·期 1
·1-17
·
IF 16.6
Xiao Fei,Jiang Haizhou,Li Zi,Jiang Xiaoxue,Chen Shanghai,Niu Yuguo,Yin Hanrui,Shu Yousheng,Peng Bo,Lu Wei,Li Xiaoying,Li Zhigang,Lan Shujue,Xu Xiaoyan,Guo Feifan
An important role for liver in the regulation of adipose tissue thermogenesis upon cold exposure has been suggested; however, the underlying mechanisms remain incompletely defined. Here, we identify elevated serum bradykinin levels in response to acute cold exposure in male mice. A bolus of anti-bradykinin antibodies reduces body temperature during acute cold exposure, whereas bradykinin has the opposite effect. We demonstrate that bradykinin induces brown adipose tissue thermogenesis and white adipose tissue browning, and bradykinin increases uncoupling protein 1 (UCP1) expression in adipose tissue. The bradykinin B2 receptor (B2R), adrenergic signaling and nitric oxide signaling are involved in regulating bradykinin-increased UCP1 expression. Moreover, acute cold exposure inhibits hepatic prolyl endopeptidase (PREP) activity, causing reduced liver bradykinin degradation and increased serum bradykinin levels. Finally, by blocking the breakdown of bradykinin, angiotensin-converting enzyme inhibitors (ACEIs) increase serum bradykinin levels and induce brown adipose tissue thermogenesis and white adipose tissue browning via B2R. Collectively, our data provide new insights into the mechanisms underlying organ crosstalk in whole-body physiology control during cold exposure and also suggest bradykinin as a possible anti-obesity target.
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JOURNAL OF ETHNOPHARMACOLOGY
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2023
·
IF 5.4
Fan Wu,Ting Zhao,Yu Zhang,Yan Wang,Guoxin Liao,Baojing Zhang,Chao Wang,Xiangge Tian,Lei Feng,Bangjiang Fang,Xiaokui Huo,Xiaochi Ma
Ethnopharmacological relevance Jinhongtang as a traditional Chinese medicine (TCM) formula, has been widely used as a clinical adjuvant in the treatment of acute abdominal diseases and sepsis. Clinical benefits of the concurrent use of Jinhongtang and antibiotics have been observed, however, the mechanism has not been fully understood. Aim of the study The present study aimed to explore the effect of Jinhongtang on the antibacterial activity of Imipenem/Cilastatin and to clarify the underlying mechanism of herb-drug interaction (HDI). Materials and methods A mouse model of sepsis induced by Staphylococcus aureus ( S. aureus) was used to evaluate the pharmacodynamic interaction in vivo . In vitro antibacterial activity of Imipenem/Cilastatin was studied by determining minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC). Pharmacokinetic interaction was investigated by pharmacokinetic studies in rats and uptake assays using OAT1/3-HEK293 cells. The main constituents ingested into blood of rats were qualitatively identified by UHPLC-Q-TOF-MS. Results Mice treated by Imipenem/Cilastatin and Jinhongtang exhibited higher survival rate, lower bacteria load and less inflammation in blood and lung tissues, compared with those treated by Imipenem/Cilastatin alone after injection of S. aureus . However, MIC and MBC of Imipenem/Cilastatin against S. aureus in vitro were not significantly changed in the presence of Jinhongtang. On the contrary, Jinhongtang increased the plasma concentration of Imipenem and decreased its urinary excretion in rats. CL r of Imipenem was reduced by 58.5%, while its half-life (t 1/2 ) was prolonged for approximate 1.2 times after coadministered Jinhongtang. Furthermore, the extracts of Jinhongtang, single herb in the prescription, and main absorbable constituents inhibited cellular uptake of probe substrates and Imipenem by OAT1/3-HEK293 cells to different extents. Among them, rhein exhibited the strongest inhibition capacity with IC 50 values of 0.08 ± 0.01 μM (OAT1) and 2.86 ± 0.28 μM (OAT3). Moreover, coadministration of rhein also significantly enhanced the antibacterial activity of Imipenem/Cilastatin in sepsis mice. Conclusion Concomitant administration of Jinhongtang enhanced antibacterial activity of Imipenem/Cilastatin in sepsis mice induced by S. aureus through reducing renal elimination of Imipenem via inhibition of OATs . Our investigation provided the insight of Jinhongtang as an effective supplement to enhance the antibacterial activity of Imipenem/Cilastatin and can be useful for future clinical studies.
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ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
·
2019
·
IF 4.715
Qingquan Zeng,Mengru Bai,Cui Li,Shuanghui Lu,Zhiyuan Ma,Yunchun Zhao,Hui Zhou,Huidi Jiang,Dongli Sun,Caihong Zheng
Emtricitabine (FTC) is a first-line antiviral drug recommended for the treatment of AIDS during pregnancy. We hypothesized that transporters located in the placenta contribute to FTC transfer across the blood-placenta barrier. BeWo cells, cell models with stable or transient expression of transporter genes, primary human trophoblast cells (PHTCs), and small interfering RNAs (siRNAs) were applied to demonstrate which transporters were involved. FTC accumulation in BeWo cells was reduced markedly by inhibitors of equilibrative nucleoside transporters (ENTs), concentrative nucleoside transporters (CNTs), organic cation transporters (OCTs), and organic cation/carnitine transporter 1 (OCTN1) and increased by inhibitors of breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins (MRPs). ENT1, CNT1, OCTN1, MRP1/2/3, and BCRP, but not ENT2, CNT3, OCTN2, or multidrug resistance protein 1 (MDR1), were found to transport FTC. FTC accumulation in PHTCs was decreased significantly by inhibitors of ENTs and OCTN1. These results suggest that ENT1, CNT1, and OCTN1 probably contribute to FTC uptake from maternal circulation to trophoblasts and that ENT1, CNT1, and MRP1 are likely involved in FTC transport between trophoblasts and fetal blood, whereas BCRP and MRP1/2/3 facilitate FTC transport from trophoblasts to maternal circulation. Coexistence of tenofovir or efavirenz with FTC in the cell medium did not influence FTC accumulation in BeWo cells or PHTCs.
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TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2018
·
IF 3.616
Lili Wu,Yulian Chen,Han Liu,Zhikun Zhan,Zhi Liang,Tao Zhang,Zheng Cai,Ling Ye,Menghua Liu,Jie Zhao,Shuwen Liu,Lan Tang
Aggravating effect of probenecid (a traditional anti-gout agent) on emodin-induced hepatotoxicity was evaluated in this study. 33.3% rats died in combination group, while no death was observed in rats treated with emodin alone or probenecid alone, indicating that emodin-induced (150 mg/kg) hepatotoxicity was exacerbated by probenecid (100 mg/kg). In toxicokinetics-toxicodynamics (TK-TD) study, aspartate aminotransferase (AST) and systemic exposure (area under the serum concentration-time curve, AUC ) of emodin and its glucuronide were significantly increased in rats after co-administrated with emodin and probenecid for 28 consecutive days. Results showed that the increased AUC (increased by 85.9%) of emodin was mainly caused by the decreased enzyme activity of UDP-glucuronosyltransferases (UGTs, decreased by 11.8%–58.1%). In addition, AUC of emodin glucuronide was increased 5-fold, which was attributed to the decrease of multidrug-resistant-protein 2 (MRP2) protein levels (decreased by 54.4%). Similarly, in vitro experiments proved that probenecid reduced the cell viability of emodin-treated HepG2 cells through inhibiting UGT1A9, UGT2B7 and MRP2. Our findings demonstrated that emodin-induced hepatoxicity was exacerbated by probenecid through inhibition of UGTs and MRP2 in vivo and in vitro , indicating that gout patients should avoid taking emodin-containing preparations in combination with probenecid for a long time.
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Medicina-Lithuania
·
2018
·Vol. 54
·期 3
·39
·
IF 1.429
Wei Li,Bi-De Liu,Kai Liao,Yong Liu,Zi-Jin Wan,Yu-Fen Dong,Qian-Qian Cao,Qian Zhu,Xiao Gu
Background and Objective:Although triptolide was effective for prostate cancer (PCa), the mechanism is still unclear. Androgen receptor (AR) plays a large role in the development and progression of PCa, even after castration. The present study aimed at investigating the effects of triptolide on AR protein stability and the possible mechanism.Materials and Methods:By blocking protein synthesis with cycloheximide (CHX), the effect of triptolide on AR protein stability was investigated with western blot assay. The potential role of calpains in triptolide reduced AR protein stability was investigated with calpain inhibitor and Ca2+chelator.Results:Triptolide down-regulated AR protein level when protein synthesis was blocked by CHX, demonstrating the decrease of AR protein stability. The AR protein level was restored when the cells were co-treated with triptolide and calpain inhibitor or Ca2+chelator, indicating the important role of calpains.Conclusions:The results indicate that triptolide can activate calpain via promoting intracellular Ca2+accumulation, and thus decrease the stability of AR protein, subsequently resulting in the breakdown of the AR protein in LNCaP cells. This work provides an experimental basis and evidence to elucidate the anti-PCa mechanisms of triptolide.Keywords:triptolide;androgen receptor;calpain;protein stability
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PHARMAZIE
·
2018
·Vol. 73
·期 9
·503-507
·
IF 1.016
Liu Yixian,Wang Yafeng,Peng Youmei,Liu Bingjie,Ma Fang,Jiang Jinhua,Wang Qingduan,Chang Junbiao
The purpose of the present study was to dig into recent studies designed to characterize the impacts of 2'-deoxy-2'-β-fluoro-4'-azidocytidine (FNC) on P-glycoprotein (P-gp), multidrug resistance-associated protein 2 (MRP2) and breast cancer resistance protein (BCRP). Specifically,
the modulation effects of FNC on P-gp, MRP2 and BCRP protein expressions were assessed by western blot methods. 5 (and 6)-Carboxy-2',7'-dichloroflourescein (CDF) and BODIPY-prazosin were used to provide indications of alterations of MRP2 and BCRP activities. The effects of P-gp, MRP2 and BCRP
on FNC were evaluated in the in situ single-pass intestinal perfusion model. The results showed that FNC at higher concentrations and with longer incubation times can upregulate the protein expression of P-gp, MRP2 and BCRP in Caco-2 cells. The upregulated proteins were also functionally
active, as revealed by a lower degree of CDF and BODIPY-prazosin uptake by the cell monolayers. The intestinal absorptive coefficient (Peff) was observed to significantly increase with the inhibitors of P-gp, MRP2 and BCRP. These results suggested that FNC could modulate the expressions and
functions of P-gp, MRP2 and BCRP, while P-gp, MRP2 and BCRP were involved in the efflux transport of FNC. The inductive effects of FNC on P-gp, MRP2 and BCRP suggested the possibility of FNC to contribute to the inter- and intra-individual variability of itself, as well as to alter the absorption
of other drugs that may be administered concomitantly.
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JOURNAL OF MEMBRANE SCIENCE
·
2018
·
IF 6.578
Bin Lin,Libin Wan,Xiaojie Sun,Chuixiu Huang,Stig Pedersen-Bjergaard,Xiantao Shen
Numerous efficient extraction methods have been developed for material recovery. However, most of these methods lack selectivity. Recently, we reported electromembrane extraction (EME) as a green, efficient and selective technology for simultaneous extraction and purification of trace targets for sample preparation purpose. Accordingly, EME could be a promising technique on resource conservation, for example, selective recovery of templates with high purity in molecular imprinting. In this work, we first investigated the potential of EME with different configurations for selective recovery of targets at high level (≥ 1000 μg mL −1 ). A semi-dynamic EME system was applied for EME of a basic template (propranolol) from molecularly imprinted samples prepared by precipitation polymerization and bulk polymerization, and the recoveries were 61% and 55%, respectively. The selectivity of EME for template recovery from real samples was confirmed by UV–vis, HPLC-UV and MS measurements. Moreover, the universality of EME for template recovery was verified by efficient extraction of an acidic template (probenecid). Definitely, EME could be used to solve the historic issue of template recovery in molecular imprinting, and shows great potential for selective extraction of ionizable compounds from complex samples in a single step.
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Food & Function
·
2019
·Vol. 10
·期 8
·5215-5227
·
IF 3.241
Yufeng Chen,Fan Xue,Guobin Xia,Zhenlei Zhao,Chun Chen,Yunhong Li,Ying Zhang
7,8-Dihydroxyflavone (7,8-DHF), as a high-affinity TrkB receptor agonist, has been extensively explored in many human disorders involving brain-derived neurotrophic factor (BDNF) such as Alzheimer's disease, Parkinson's disease, depression, and obesity. However, to date, the transepithelial transport mechanisms of 7,8-DHF in the intestines remain unclear. The aim of our work was to quantify and to characterize in vitro transport of naturally occurring 7,8-DHF distinguished by its physicochemical and pharmacological properties. We discussed the transport mechanisms of 7,8-DHF using the Caco-2 cell model to determine the bi-directional permeability with different environmental factors (time, concentration, pH, metabolic inhibitors etc.). The influx and efflux characteristics of 7,8-DHF were also clarified. 7,8-DHF was poorly transported across Caco-2 cell monolayers by mainly passive diffusion via a transcellular pathway and not a paracellular pathway. The transport of 7,8-DHF was time and concentration-dependent in both the apical (AP) to basolateral (BL) side and the reverse direction. Interestingly, decreasing the pH from 7.4 to 6.0 markedly enhanced 7,8-DHF transport. It is noteworthy that 7,8-DHF transport was strongly inhibited by metabolic inhibitors and was highly dependent on temperature. The efflux ratio (ER) values at different concentrations were all above 1.5, indicating the existence of the efflux transporter. We found that breast cancer resistance protein (BCRP) was not involved in 7,8-DHF secretion and that the transport mechanism of 7,8-DHF was passive transport with an active efflux mediated by P-glycoprotein (P-gp) and multidrug resistance associated proteins (MRPs), particularly MRP 2. Moreover, the use of various influx transporter inhibitors in Caco-2 cells showed that organic cation transporters (OCTs) and organic anion-transporting polypeptides (OATPs) participated in 7,8-DHF transport. Taken together, the elucidated transport characteristics of 7,8-DHF provide useful information for designing novel and efficient delivery systems and avoiding food–food or food–drug interactions.
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