Journal of Crohns & Colitis
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2023
·Vol. 17
·期 8
·1278-1290
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IF 8
Hu Xiaoming,Jiao Fuxin,Deng Jiali,Zhou Ziheng,Chen Shanghai,Liu Changqin,Liu Zhanju,Guo Feifan
Background and AimsThe incidence of inflammatory bowel disease [IBD] in the elderly has increased in recent years. However, the mechanisms underlying the ageing-related IBD susceptibility remain elusive. Cytokine-inducible SH2-containing protein [CISH] is involved in regulating metabolism, the expansion of intestinal tuft cells and type-2 innate lymphoid cells, and ageing-related airway inflammation. Here, we investigated the role of CISH in ageing-related colitis susceptibility.MethodsCISH and phosphorylated signal transducer and activator of transcription-3 [p-STAT3] levels were evaluated in the colons of ageing mice and older ulcerative colitis [UC] patients. Mice with intestinal epithelial cell-specific knockout of Cish [CishΔIEC] and Cish-floxed mice were administered dextran sodium sulphate [DSS] or trinitrobenzene sulphonic acid [TNBS] to induce colitis. Colonic tissues were analysed in quantitative real-time polymerase chain reaction, immunoblotting, immunohistochemical, and histological staining experiments. Differentially expressed genes from colonic epithelia were analysed by RNA sequencing.ResultsAgeing increased the severity of DSS-induced colitis and the expression of colonic epithelial CISH in mice. CishΔIEC prevented DSS- or TNBS-induced colitis in middle-aged mice but not in young mice. RNA-sequencing analysis revealed that CishΔIEC significantly suppressed DSS-induced oxidative stress and proinflammatory responses. During ageing in the CCD841 cell model, knockdown of CISH decreased ageing-induced oxidative stress and proinflammatory responses, whereas these effects were compromised by knocking down or inhibiting STAT3. The increase in CISH expression was higher in the colonic mucosa of older patients with UC than in that of healthy controls.ConclusionsCISH might be a proinflammatory regulator in ageing; therefore, targeted therapy against CISH may provide a novel strategy for treating ageing-related IBD.
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FOOD CHEMISTRY
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2023
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IF 8.8
Ying-zhuo Shen,Zheng Wang,Kangping Ning,Chuanli Ren,Dandan Yang,Xiao-Ya Hu,Qin Xu
A highly sensitive and selective split-type perovskite-based photoelectrochemical (PEC) platform was developed for measuring alkaline phosphatase (ALP) activity in milk and serum samples. ALP in the test sample hydrolyzed 2-phosphate sesquimagnesium salt hydrate (AAPS) in a 96-microwell plate to produce ascorbic acid (AA), a PEC electron donor. The resulting AA, which could preferentially annihilate the photogenerated holes, indirectly reflects ALP activity. The PEC used a cetyltrimethylammonium bromide (CTAB)-functionalized CH 3 NH 3 PbI 3 ( [email protected] 3 NH 3 PbI 3 ) film as the cathode to monitor the controlled AA production. Due to the excellent photoelectric characteristics of the CH 3 NH 3 PbI 3 perovskite and the split-type assay, excellent sensitivity and selectivity for ALP detection were obtained. Under the optimum experimental conditions, ALP activity with a limit of detection (LOD) of 2.6 × 10 −4 U/L in a linear dynamic range of 10 −3 ∼ 10 2 U/L was obtained. With its sensitive, rapid, and high-throughput detection capabilities, this split-type and label-free PEC platform has great potential for use in food and biomedical analysis.
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Biomaterials Research
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2023
·Vol. 27
·期 1
·1-16
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IF 11.3
Li Chengnan,Gan Yingying,Li Zongshao,Fu Mengjing,Li Yuzhen,Peng Xinran,Yang Yongqiang,Tian Guo-bao,Yang Yi Yan,Yuan Peiyan,Ding Xin
Background
P. aeruginosa , a highly virulent Gram-negative bacterium, can cause severe nosocomial infections, and it has developed resistance against most antibiotics. New therapeutic strategies are urgently needed to treat such bacterial infection and reduce its toxicity caused by endotoxin (lipopolysaccharide, LPS). Neutrophils have been proven to be able to target inflammation site and neutrophil membrane receptors such as Toll-like receptor-4 (TLR4) and CD14, and exhibit specific affinity to LPS. However, antibacterial delivery system based on the unique properties of neutrophils has not been reported. Methods A neutrophil-inspired antibacterial delivery system for targeted photothermal treatment, stimuli-responsive antibiotic release and endotoxin neutralization is reported in this study. Specifically, the photothermal reagent indocyanine green (ICG) and antibiotic rifampicin (RIF) are co-loaded into poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NP-ICG/RIF), followed by coating with neutrophil membrane to obtain antibacterial delivery system (NM-NP-ICG/RIF). The inflammation targeting properties, synergistic antibacterial activity of photothermal therapy and antibiotic treatment, and endotoxin neutralization have been studied in vitro. A P. aeruginosa -induced murine skin abscess infection model has been used to evaluate the therapeutic efficacy of the NM-NP-ICG/RIF. Results Once irradiated by near-infrared lasers, the heat generated by NP-ICG/RIF triggers the release of RIF and ICG, resulting in a synergistic chemo-photothermal antibacterial effect against P. aeruginosa (~ 99.99% killing efficiency in 5 min). After coating with neutrophil-like cell membrane vesicles (NMVs), the nanoparticles (NM-NP-ICG/RIF) specifically bind to inflammatory vascular endothelial cells in infectious site, endowing the nanoparticles with an infection microenvironment targeting function to enhance retention time. Importantly, it is discovered for the first time that NMVs-coated nanoparticles are able to neutralize endotoxins. The P. aeruginosa murine skin abscess infection model further demonstrates the in vivo therapeutic efficacy of NM-NP-ICG/RIF. Conclusion The neutrophil-inspired antibacterial delivery system (NM-NP-ICG/RIF) is capable of targeting infection microenvironment, neutralizing endotoxin, and eradicating bacteria through a synergistic effect of photothermal therapy and antibiotic treatment. This drug delivery system made from FDA-approved compounds provides a promising approach to fighting against hard-to-treat bacterial infections.
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ADVANCED FUNCTIONAL MATERIALS
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2023
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IF 19
Siyu Gui,Weiwei Tang,Zhihao Huang,Xinchen Wang,Siyin Gui,Xiang Gao,Duncheng Xiao,Liming Tao,Zhengxuan Jiang,Xianwen Wang
Diabetic retinopathy (DR) is the most prevalent type of retinal vasculopathy and the most widespread cause of preventable blindness in adults. Excessive increases in reactive oxygen species (ROS) and vascular endothelial growth factor are major initiators and drivers of DR progression, respectively. However, current DR treatment options remain limited, particularly for early DR. Nanotechnology-mediated antioxidant strategies are gaining increasing popularity to treat ocular diseases. Quercetin has excellent ROS scavenging efficiency but poor stability and low bioavailability in physiological environments. In this study, ultrasmall Fe-Quer nanozymes (NZs) formed by coupling quercetin with low-toxic iron ions are reported that can mimic the activities of three important antioxidant enzymes, superoxide dismutase, catalase, and peroxidase, thereby exhibiting excellent water dispersion and efficient ROS scavenging ability. In vitro and in vivo assays validate the effects of Fe-Quer NZs against inflammation, oxidative stress damage, microvascular leakage, and angiogenesis, particularly their vascular protective effect in early DR. Transcriptomic analysis further reveals a potential multitarget-specific therapeutic mechanism of Fe-Quer NZs against DR. These observations open avenues for Fe-Quer NZs, composed of molecules of a natural product and metal ions with artificial NZ activity, as microvascular protective agents for DR and other ROS-related diseases.
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TISSUE & CELL
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2023
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IF 2.6
Jing Cong,Mubai Li,Yu Wang,Hongli Ma,Xinming Yang,Jingshu Gao,Long Wang,Xiaoke Wu
Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder affecting women at reproductive age. The therapeutic effect of electroacupuncture (EA) on PCOS has been revealed, while the anti-PCOS mechanisms of EA have not been fully explored. In this study, PCOS were induced in rats by daily injection with dehydroepiandrosterone (DHEA) for 20 days and EA treatment was performed for 5 weeks. The mRNA expression profiles in ovarian tissues from control, PCOS, and EA-treated rats were examined by high-throughput mRNA sequencing. 5'-aminolevulinate synthase 2 (Alas2), a vital rate-limiting enzyme of the heme synthesis pathway, was selected to be further studied. PCOS led to the upregulation of Alas2 mRNA, whereas EA treatment restored this change. In vitro, primary ovarian granulosa cells (GCs) were challenged with H 2 O 2 to mimic the oxidative stress (OS) state in PCOS. H 2 O 2 induced apoptosis, OS, mitochondrial dysfunction, as well as Alas2 overexpression in GCs, while lentivirus-mediated Alas2 knockdown evidently restrained the above impairments. In summary, this study highlights the crucial role of Alas2 in cell apoptosis, OS, and mitochondrial dysfunction of PCOS GCs and provides potential therapeutic candidates for further investigation on PCOS treatment.
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DIGESTIVE DISEASES AND SCIENCES
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2023
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IF 3.1
Zhao Lianrong,Wu Di,Qu Qiao,Li Zhilong,Yin Hongzhuan
Background/Aims Aberrant nuclear factor-κB p65 (NF-κB p65) nuclear import commonly occurs in multiple cancers, including colon cancer. According to BioGRID, we noted that Karyopherin subunit alpha 1 (KPNA1), an important molecular transporter between the nucleus and the cytoplasm, may interact with NF-κB p65. KPNA1 itself is highly expressed in colon adenocarcinoma samples ( N = 286) based on The Cancer Genome Atlas (TCGA) database. We aimed to explore the role of KPNA1 in colonic carcinogenesis and to determine whether NF-κB p65 nuclear translocation was involved. Methods KPNA1 expressions at mRNA and protein levels were analyzed in colon cancer tissues. The regulatory effect of KPNA1 on malignant biological properties was detected in SW480 and HCT116 colon cancer cells. Coimmunoprecipitation and immunofluorescence were performed to verify the relationship between KPNA1 and NF-κB p65. KPNA1 ubiquitination was also preliminarily investigated. Results KPNA1 was firstly confirmed as a significantly upregulated gene in our collected clinical colon cancer samples ( N = 35). KPNA1 depletion inhibited cell proliferation, induced cell cycle arrest, and diminished migratory and invasive capacity of SW480 and HCT116 cells. Colon cancer cells overexpressing KPNA1 acquired more aggressive behaviors. KPNA1 acted as a transporter to induce the nuclear accumulation of NF-κB p65, thereby activating NF-κB signaling pathway in colon cancer cells. Furthermore, HECT, C2, and WW Domain-Containing E3 Ubiquitin (HECW2) interacted with KPNA1 to induce its ubiquitination. KPNA1 labeled with polyubiquitins was degraded through ubiquitin–proteasome system. Conclusion The present study uncovers a role of KPNA1-NF-κB p65 axis in promoting colonic carcinogenesis. Graphical Abstract
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JOURNAL OF NANOBIOTECHNOLOGY
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2023
·Vol. 21
·期 1
·1-19
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IF 10.2
Wang Xueqian,Dai Geyang,Jiang Guiying,Zhang Danya,Wang Ling,Zhang Wen,Chen Huang,Cheng Teng,Zhou Ying,Wei Xiao,Li Fei,Ma Ding,Tan Songwei,Wei Rui,Xi Ling
Background TMVP1 is a novel tumor targeting polypeptide screened by our laboratory with a core sequence of five amino acids LARGR. It specially binds to vascular endothelial growth factor receptor-3 (VEGFR-3), which is mainly expressed on neo-lymphatic vessels in sentinel lymph node (SLN) with tumor metastasis in adults. Here, we prepared a targeted nanoprobe using TMVP1-modified nanomaterials for tumor metastasis SLN imaging.Results In this study, TMVP1-modified polymer nanomaterials were loaded with the near-infrared (NIR) fluorescent dye, indocyanine green (ICG), to prepare a molecular imaging TMVP1-ICG nanoparticles (NPs) to identify tumor metastasis in SLN at molecular level. TMVP1-ICG-NPs were successfully prepared using the nano-precipitation method. The particle diameter, morphology, drug encapsulation efficiency, UV absorption spectrum, cytotoxicity, safety, and pharmacokinetic properties were determined. The TMVP1-ICG-NPs had a diameter of approximately 130 nm and an ICG loading rate of 70%. In vitro cell experiments and in vivo mouse experiments confirmed that TMVP1-ICG-NPs have good targeting ability to tumors in situ and to SLN with tumor metastasis by binding to VEGFR-3. Effective photothermal therapy (PTT) with TMVP1-ICG-NPs was confirmed in vitro and in vivo. As expected, TMVP1-ICG-NPs improved ICG blood stability, targeted tumor metastasis to SLN, and enhanced PTT/photodynamic (PDT) therapy, without obvious cytotoxicity, making it a promising theranostic nanomedicine.Conclusion TMVP1-ICG-NPs identified SLN with tumor metastasis and were used to perform imaging-guided PTT, which makes it a promising strategy for providing real-time NIR fluorescence imaging and intraoperative PTT for patients with SLN metastasis.
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Asian Journal of Pharmaceutical Sciences
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2023
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IF 10.2
Run Han,Zhuyifan Ye,Yunsen Zhang,Yaxin Cheng,Ying Zheng,Defang Ouyang
Liposome is one of the most widely used carriers for drug delivery because of the great biocompatibility and biodegradability. Due to the complex formulation components and preparation process, formulation screening mostly relies on trial-and-error process with low efficiency. Here liposome formulation prediction models have been built by machine learning (ML) approaches. The important parameters of liposomes, including size, polydispersity index (PDI), zeta potential and encapsulation, are predicted individually by optimal ML algorithm, while the formulation features are also ranked to provide important guidance for formulation design. The analysis of key parameter reveals that drug molecules with logS [-3, -6], molecular complexity [500, 1000] and XLogP3 (≥2) are priority for preparing liposome with higher encapsulation. In addition, naproxen (NAP) and palmatine HCl (PAL) represented the insoluble and water-soluble molecules are prepared as liposome formulations to validate prediction ability. The consistency between predicted and experimental value verifies the satisfied accuracy of ML models. As the drug properties are critical for liposome particles, the molecular interactions and dynamics of NAP and PAL liposome are further investigated by coarse-grained molecular dynamics simulations. The modeling structure reveals that NAP molecules could distribute into lipid layer, while most PAL molecules aggregate in the inner aqueous phase of liposome. The completely different physical state of NAP and PAL confirms the importance of drug properties for liposome formulations. In summary, the general prediction models are built to predict liposome formulations, and the impacts of key factors are analyzed by combing ML with molecular modeling. The availability and rationality of these intelligent prediction systems have been proved in this study, which could be applied for liposome formulation development in the future.
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EUROPEAN POLYMER JOURNAL
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2023
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IF 6
Yangyang Lu,Haojie Yu,Li Wang,Di Shen,Jian Liu
Phenylboronic acid (PBA)-based glucose-responsive microneedles that can painlessly deliver insulin and self-regulate the release of insulin according to the blood glucose levels (BGLs) have been considered promising in the treatment of diabetes. However, the reported PBA-based glucose-responsive microneedles are still faced with the challenges of complicated insulin loading process or insulin denaturation. Herein, we report a novel kind of PBA‐based glucose-responsive microneedles derived from PBA‐based glucose-responsive hydrogels. 3-fluoro-4-carboxy-phenylboronic acid-grafted polylysine (PLL-PBA) were synthesized and combined with natural guar gum (GG) to produce PLL-PBA/GG hydrogels via the phenylboronate ester bonds formed between the FCPBA groups on PLL-PBA and the diols on GG. The resulting hydrogels could regulate the release amount of insulin according to the glucose concentrations based on the glucose-induced disintegration mechanism. The PLL-PBA/GG microneedles were prepared via micro-mold casting method using the hydrogels as the precursors. Due to the simple and mild preparation conditions of the microneedles, the bioactivity of insulin was greatly preserved. The microneedles had uniform morphology, moderate skin penetration ability as well as good glucose-responsive insulin release capability. In animal experiments, the PLL-PBA/GG microneedles demonstrated BGLs lowering and maintain performance via glucose-responsive transdermal insulin delivery.
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MACROMOLECULAR RAPID COMMUNICATIONS
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2023
·Vol. 44
·期 13
·2300084
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IF 4.6
Jinyi Liu,Haojie Yu,Li Wang,Tao Chen,Sergey Z. Vatsadze,Dingning Chen,Di Shen,Yu Wang
As a common oxidizer, ammonium perchlorate (AP) is an important component in composite solid propellants (CSPs). Ferrocene (Fc)-based compounds are often selected as burning rate catalysts (BRCs) to catalyze AP decomposition owing to their excellent catalytic behavior. However, one of the drawbacks of Fc-based BRCs is migration in CSPs. In this study, five Fc-terminated dendrimers are designed and synthesized to improve the anti-migration properties, and their chemical structures are confirmed systemically by the related spectra characterization techniques. Moreover, the redox performance, catalytic effect on AP decomposition, combustion performance, and mechanical properties in CSPs are also studied. The shapes of the prepared propellant samples are observed via scanning electron microscopy. The obtained Fc-based BRCs have good redox performance, a positive effect on promoting AP decomposition, excellent combustion catalytic performance, and good mechanical properties. Meanwhile, they have a higher anti-migration ability than catocene ( Cat ) and Fc. This study demonstrates that Fc-terminated dendrimers have great potential to be applied as anti-migration BRCs in CSPs.
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Frontiers in Molecular Biosciences
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2023
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IF 5
Shi Hanqiang,Xiong Lie,Yan Guang,Du Shuqin,Liu Jie,Shi Yanbo
The clinical therapeutics of cervical cancer is limited due to the drug resistance and metastasis of tumor. As a novel target for antitumor therapy, ferroptosis is deemed to be more susceptible for those cancer cells with resistance to apoptosis and chemotherapy. Dihydroartemisinin (DHA), the primary active metabolites of artemisinin and its derivatives, has exhibited a variety of anticancer properties with low toxicity. However, the role of DHA and ferroptosis in cervical cancer remained unclear. Here, we showed that DHA could time-dependently and dose-dependently inhibit the proliferation of cervical cancer cells, which could be alleviated by the inhibitors of ferroptosis rather than apoptosis. Further investigation confirmed that DHA treatment initiated ferroptosis, as evidenced by the accumulation of reactive oxygen species (ROS), malondialdehyde (MDA) and liquid peroxidation (LPO) levels and simultaneously depletion of glutathione peroxidase 4 (GPX4) and glutathione (GSH). Moreover, nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy was also induced by DHA leading to subsequent increases of intracellular labile iron pool (LIP), exacerbated the Fenton reaction resulting in excessive ROS production, and enhanced cervical cancer ferroptosis. Among them, we unexpectedly found that heme oxygenase-1 (HO-1) played an antioxidant role in DHA-induced cell death. In addition, the results of synergy analysis showed that the combination of DHA and doxorubicin (DOX) emerged a highly synergistic lethal effect for cervical cancer cells, which was related also to ferroptosis. Overall, our data revealed the molecular mechanisms that DHA triggered ferritinophagy-dependent ferroptosis and sensitized to DOX in cervical cancer, which may provide novel avenues for future therapy development.
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JOURNAL OF CONTROLLED RELEASE
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2023
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IF 10.8
Qianlong Wang,Tiantian Wang,Chonkit Lio,Xina Yu,Xiaoyi Chen,Lancong Liu,Youjiao Wu,Hui Huang,Linsen Qing,Pei Luo
Macrophages, innate immune cells, are key players in the maintenance of myocardial homeostasis under normal conditions and tissue repair after injury. The infiltration of macrophages into the injured heart makes them a potentially appealing vehicle for noninvasive imaging and targeted drug delivery of myocardial infarction (MI). In this study, we demonstrated the use of surface hydrolysis-designed AuNPs-zwitterionic-glucose to label macrophages and track their infiltration into isoproterenol hydrochloride (ISO)-induced MI sites noninvasively using CT . The AuNPs-zwitterionic-glucose did not affect the viability or cytokine release of macrophages and were highly taken up by these cells. The in vivo CT images were obtained on Day 4, Day 6, Day 7, and Day 9, and the attenuation was seen to increase in the heart over time compared to the Day 4 scan. In vitro analysis also confirmed the presence of macrophages around injured cardiomyocytes. Additionally, we also addressed the concern of cell tracking or merely AuNP tracking, which is the inherent problem for any form of nanoparticle-labeled cell tracking by using zwitterionic and glucose-functionalized AuNPs. The glucose coated on the surface of AuNPs-zwit-glucose will be hydrolyzed in macrophages, forming only zwitterionic protected AuNPs that cannot be taken up again by endogenous cells in vivo. This will greatly improve the accuracy and precision of imaging and target delivery. We believe this is the first study to noninvasively visualize the infiltration of macrophages into MI hearts using CT, which could be used for imaging and evaluating the possibility of macrophage-mediated delivery in infarcted hearts.
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