A reliable and cost-effective protocol for creating bilirubin cerebral palsy model in rhesus macaque.

BACKGROUND: Cerebral palsy is a severe motor disability in childhood that poses challenges for children, families, and society. Rhesus macaques are the preferred animals for cerebral palsy model, but surgical excision of motor cortex has low success rate and high cost. In this work, we created cerebral palsy rhesus macaque models by intrathecal injection of bilirubin. METHODS: The puncture point for injection was identified as the intervertebral disc space two, located below the intersection of the iliac crest line and the posterior median line. RESULTS: The models showed abnormal posture and increased muscle tension. Diffuse deposits of bilirubin were found in the basal ganglia from the magnetic resonance imaging. Pathological slides also revealed the presence of brain lesions, such as vacuole formation, contraction of neuronal nuclei, and deep staining of nuclei in the histopathological sections of the hippocampus and basal ganglia. CONCLUSION: The model's symptoms closely resemble those observed in humans with spastic cerebral palsy.

Electrochemical Detection of Flutamide by the Composite of Complex Based on Thiacalix[4]arene Derivatives and Reduced Graphene Oxide.

In this paper, a thiacalix[4]arene complex [Zn2(TIT4A)L2]·4DMF·2CH3OH (H2L = 4,4'-oxybisbenzoic acid) (Zn-TIT4A-L) was synthesized by a solvothermal method. The composites were prepared by combining Zn-TIT4A-L with reduced graphene oxide (RGO), mesoporous carbon (MC), and multi-walled carbon nanotubes (MWCNTs), respectively. Three representative composites are Zn-TIT4A-L@RGO(1:1), Zn-TIT4A-L@MC(1:2), and Zn-TIT4A-L@MWCNT(1:2). X-ray diffraction and scanning electron microscopy characterized their structures and morphologies. The results showed that three composites were successfully prepared, and the crystals of the complex remained in the composites. The electrochemical properties of the composites were characterized by electrochemical impedance spectroscopy and cyclic voltammetry. The results indicated that they had good electrocatalytic activity and conductivity. Among them, Zn-TIT4A-L@RGO(1:1) had the best performance and was used for the quantitative detection of flutamide (FTA). The linear range of detection is 0.1-200 µM, and the limit of detection is 0.015 µM. At the same time, the sensor also had good reproducibility, anti-interference, and stability. The sensor was also used for the detection of FTA in lake water, human urine, and serum with a satisfactory recovery rate. The possible mechanism of electrochemical detection of FTA was also discussed.

Simultaneous electrochemical detection of gallic acid and uric acid with p-tert-butylcalix[4]arene-based coordination polymer/mesoporous carbon composite.

Design and synthesis of an efficient electrocatalyst for simultaneous determination of gallic acid (GA) and uric acid (UA) is vital in the biological field. Herein, we synthesized a new p-tert-butylcalix[4]arene-based metal-organic electrocatalyst (Mn-L@MC) by combining Mn-L (H4L = tetrakis[(2-biphenylcarboxyl)oxy]-p-tertbutylcalix[4]arene) and mesoporous carbon (MC) via a simple mechanical grinding method. Synergistic effect between Mn-L and MC made the Mn-L@MC composite behave high-efficiency electrocatalytic performance toward simultaneous detection of GA and UA. Under optimal experimental conditions, the Mn-L@MC-2 electrode material featured relatively wide linear range (0.5-90 µM) for the two analytes, and low determination limits of 0.043 µM for GA and 0.059 µM for UA. The remarkable electrochemical detection behavior of Mn-L@MC-2 electrode material toward GA and UA are comparable to those known sensors containing precious metals. The Mn-L@MC-2 material exhibited high selectivity, superior reproducibility, and acceptable stability during the determination of the two analytes. The sensor was assembled to simultaneously detect GA and UA in healthy human urine with satisfactory recoveries.

Thiacalix[4]arene-based complex with Co(II) ions as electrode modifier for simultaneous electrochemical determination of Cd(II), Pb(II), and Cu(II).

A complex [Co4(TCTA)2(H2O)8]∙10H2O (Co-TCTA) based on thiacalix[4]arene derivative has been synthesized for the first time using the solvothermal method. The glassy carbon electrode (GCE) modified with Co-TCTA (Co-TCTA/GCE) could simultaneously determine Cd2+, Pb2+, and Cu2+ at around - 0.75 V, - 0.60 V, and - 0.10 V (vs. ref. Ag/AgCl) and had good stability, selectivity, and reproducibility with relative standard deviation (RSD) of 4.4% for Cd2+, 1.4% for Pb2+, and 5.4% for Cu2+. Co-TCTA/GCE showed wide linear range of 0.4-8.0 µM for Cd2+, 0.4-7.0 µM for Pb2+, and 0.6-6.0 µM for Cu2+ when three ions were determined simultaneously. The limits of detection (LODs) of Cd2+, Pb2+, and Cu2+ were 0.071 µM, 0.022 µM, and 0.021 µM, respectively. Moreover, the sensor was used to determine three ions in lake water sample with satisfactory recoveries of 93.6-93.8% for Cd2+, 93.8-103.3% for Pb2+ and 94.6-95.3% for Cu2+. The good adsorption capacity of Co-TCTA and Co(II)/Co(0) circular mechanism on the surface of the electrode were proposed to enhance the electrochemical signals. This work enriched the theoretical research on the complexes for the determination of heavy metal ions.

Established Liposome-Coated IMB16-4 Polymeric Nanoparticles (LNPs) for Increasing Cellular Uptake and Anti-Fibrotic Effects In Vitro.

As a global health problem, liver fibrosis still does not have approved treatment. It was proved that N-(3,4,5-trichlorophenyl)-2(3-nitrobenzenesulfonamide) benzamide (IMB16-4) has anti-hepatic fibrosis activity. However, IMB16-4 displays poor water solubility and poor bioavailability. We are devoted to developing biodegraded liposome-coated polymeric nanoparticles (LNPs) as IMB16-4 delivery systems for improving aqueous solubility, cellular uptake, and anti-fibrotic effects. The physical states of IMB16-4-LNPs were analyzed using a transmission electron microscope (TEM), high-performance liquid chromatography (HPLC), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD) and differential scanning calorimeter (DSC). The results show that IMB16-4-LNPs increased the drug loading compared to liposomes and enhanced cellular uptake behavior compared with IMB16-4-NPs. In addition, IMB16-4-LNPs could repress the expression of hepatic fibrogenesis-associated proteins, indicating that IMB16-4-LNPs exhibited evident anti-fibrotic effects.

The frequency of CpG and non-CpG methylation of Notch3 gene promoter determines its expression levels in breast cancer cells.

Notch3 can act as a tumor suppressor in the breast cancer epithelial cells. Unfortunately, Notch3 expression is decreased or lost, especially in triple-negative breast cancer (TNBC) cells, and the reasons remain unclear. Here, we found Notch3 was upregulated in MDA-MB-231 cells with 5-Aza treatment. Two CpG islands were observed in notch3 promoter. Interestingly, bisulfite sequencing exhibited that large amounts of unconverted cytosines were not only followed by guanine, but also adenine, cytosine and thymine, which implied that there simultaneously existed CpG and non-CpG methylation in notch3 promoter. To better analyze the methylation frequency of non-CpG locus, we designed CpG/non-CpG methylation analysis software. The results showed that the methylation frequency of notch3 gene in different breast cancer cell lines was in order T47D, MCF-7, SKBR3, BT-549 and MDA-MB-231. Furthermore, we identified that DNMT3b, DNMT1, DNMT3L, Mecp2 and EZH2 were important regulators of non-CpG locus of notch3 gene. Immunohistochemistry staining revealed a negative correlation between EZH2 and Notch3 from 22 luminal and 26 TNBC cases. In vitro methylation combined luciferase activity assays showed that non-CpG methylation was still crucial cause leading to notch3 transcriptional repression in TNBC. Our findings provide possible explanation for the downregulation or loss of Notch3 expression in TNBC.

Novel IMB16-4 Compound Loaded into Silica Nanoparticles Exhibits Enhanced Oral Bioavailability and Increased Anti-Liver Fibrosis In Vitro.

BACKGROUND: Liver fibrosis, as a common and refractory disease, is challenging to treat due to the lack of effective agents worldwide. Recently, we have developed a novel compound, N-(3,4,5-trichlorophenyl)-2(3-nitrobenzenesulfonamide) benzamide (IMB16-4), which is expected to have good potential effects against liver fibrosis. However, IMB16-4 is water-insoluble and has very low bioavailability. METHODS: Mesoporous silica nanoparticles (MSNs) were selected as drug carriers for the purpose of increasing the dissolution of IMB16-4, as well as improving its oral bioavailability and inhibiting liver fibrosis. The physical states of IMB16-4 and IMB16-4-MSNs were investigated using nitrogen adsorption, thermogravimetric analysis (TGA), HPLC, UV-Vis, X-ray diffraction (XRD) and differential scanning calorimetry (DSC). RESULTS: The results show that MSNs enhanced the dissolution rate of IMB16-4 significantly. IMB16-4-MSNs reduced cytotoxicity at high concentrations of IMB16-4 on human hepatic stellate cells LX-2 cells and improved oral bioavailability up to 530% compared with raw IMB16-4 on Sprague-Dawley (SD) rats. In addition, IMB16-4-MSNs repressed hepatic fibrogenesis by decreasing the expression of hepatic fibrogenic markers, including α-smooth muscle actin (α-SMA), transforming growth factor-beta (TGF-ß1) and matrix metalloproteinase-2 (MMP2) in LX-2 cells. CONCLUSIONS: These results provided powerful information on the use of IMB16-4-MSNs for the treatment of liver fibrosis in the future.

Preparation of a novel Ni-MOF and porous graphene aerogel composite and application for simultaneous electrochemical determination of nitrochlorobenzene isomers with partial least squares.

Metal-organic framework Ni2(BDC)2(DABCO) (Ni-MOF)/porous graphene aerogel (PGA) composites were fabricated for the first time. The introduction of PGA enhances conductivity of Ni-MOF, prevents Ni-MOF from accumulating, reduces the size of Ni-MOF, and increases the pore size of composites, which improve the electrocatalytic activity of Ni-MOF@PGA-2. The prepared sensors based on Ni-MOF@PGA-2 composite show the highest catalytic current towards electroreduction of 2-nitrochlorobenzene (2-NCB), 3-nitrochlorobenzene (3-NCB), and 4-nitrochlorobenzene (4-NCB) at around - 0.61 V, - 0.56 V, and - 0.57 V (vs. Ag/AgCl) with respect to other sensors. The reaction mechanisms also are discussed. Under optimized experiment conditions, the Ni-MOF@PGA-2/GCE displays the widest linear range (6-1260, 4-980, and 2-1280 µM for 2-NCB, 3-NCB, and 4-NCB, respectively) for determination of individual nitrochlorobenzene isomers (NCBIs) compared to that of recent reports, and relatively low detection limit (0.093, 0.085, and 0.051 µM for 2-NCB, 3-NCB, and 4-NCB, respectively). More importantly, three NCBIs in the mixture were for the first time simultaneously determined by combining differential pulse voltammetry (DPV) based on Ni-MOF@PGA-2/GCE with partial least squares (PLS) chemometrics modeling method. The proposed method was evaluated towards the determination of NCBI mixtures in tap water and Jing lake water, and satisfactory recoveries were obtained. Graphical abstract.

Inhibition of the PI3K/Akt signaling pathway impedes the restoration of neurological function following hypoxic-ischemic brain damage in a neonatal rabbit model.

OBJECTIVE: Hypoxic-ischemic brain damage (HIBD), frequently occurring in infancy and childhood, is a major cause of mortality and severe neurologic impairment. This study was performed to examine the effect of the PI3K/Akt signaling pathway on HIBD in a neonatal rabbit model. MATERIALS AND METHODS: Uterine artery occlusion was used to establish HIBD models in neonatal rabbits, which were then subjected to sham operation, dimethyl sulfoxide (2 mL) or LY294002 (inhibitor of PI3K/Akt signaling pathway, 6.4 µg/kg). Behavioral neurological assessment was performed in neonatal rabbits delivered by cesarean section, after which serum neuron-specific enolase (NSE) level and cerebral water content were determined. The level of cleaved caspase-3 level and apoptosis of neurons were observed by immunohistochemistry and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining. Furthermore, the expression of PI3K/Akt signaling pathway- and apoptosis-related factors was examined. RESULTS: In neonatal rabbits, HIBD increased the fetal death rate; reduced neurological scores of posture, righting reflex, and deglutition reflex; elevated serum NSE levels, cerebral water content, cleaved caspase-3-positive expression in hippocampal CA1 region and apoptotic neurons; inactivated PI3K/Akt signaling pathway as well as reduced Bcl-2 expression and increased BAD and Bax expression. Notably, the treatment of LY294002 further aggravated neurological impairment in neonatal rabbits in response to HIBD. CONCLUSION: Following the HIBD caused by intrauterine asphyxia, the LY294002 administered through auricular vein infusion into pregnant rabbits exacerbates neurological impairment of neonatal rabbits, suggesting that inhibition of PI3K/Akt signaling pathway may serve as a candidate therapeutic target for neurological recovery.

Medium entropy FeCoNi nanoalloy supported on reduced graphene oxide for efficient electrochemical detection of roxarsone in food samples.

Herein, a novel FeCoNi(b)-800 ternary metal nanoalloy was uniformly mixed with reduced graphene oxide (RGO) to synthesize the FeCoNi(b)-800@RGO(2:1) composite. The addition of RGO not only stopped the accumulation of FeCoNi(b)-800 alloy, but also heightened the electrocatalytic activity of composite. Particularly, the FeCoNi(b)-800@RGO(2:1) composite displayed the significantly strong electrocatalytic capacity for the reduction of roxarsone (ROX). Furthermore, the FeCoNi(b)-800@RGO(2:1) composite possessed enough porosity and metal catalytic sites, facilitating the transport and electrochemical reduction of the ROX. Thus, the FeCoNi(b)-800@RGO(2:1) composite modified glassy carbon electrode (FeCoNi(b)-800@RGO(2:1)/GCE) showed the superb electrochemical detection effect for ROX with relatively wide working range (0.1-1500 µM) and low detection limit (0.013 µM). Importantly, the FeCoNi(b)-800@RGO(2:1)/GCE sensor could accurately determine the contents of ROX in actual pork, chicken, duck and egg samples, indicating that it had good suitability in food safety monitoring.

Serum metabolism alteration behind different etiology, diagnosis, and prognosis of disorders of consciousness.

BACKGROUND: Patients with disorders of consciousness (DoC) exhibit varied revival outcomes based on different etiologies and diagnoses, the mechanisms of which remain largely unknown. The fluctuating clinical presentations in DoC pose challenges in accurately assessing consciousness levels and prognoses, often leading to misdiagnoses. There is an urgent need for a deeper understanding of the physiological changes in DoC and the development of objective diagnostic and prognostic biomarkers to improve treatment guidance. METHODS: To explore biomarkers and understand the biological processes, we conducted a comprehensive untargeted metabolomic analysis on serum samples from 48 patients with DoC. Patients were categorized based on etiology (TBI vs. non-TBI), CRS-R scores, and prognosis. Advanced analytical techniques, including PCA and OPLS-DA models, were employed to identify differential metabolites. RESULTS: Our analysis revealed a distinct separation in metabolomic profiles among the different groups. The primary differential metabolites distinguishing patients with varying etiologies were predominantly phospholipids, with a notable decrease in glycerophospholipids observed in the TBI group. Patients with higher CRS-R scores exhibited a pattern of impaired carbohydrate metabolism coupled with enhanced lipid metabolism. Notably, serum concentrations of both LysoPE and PE were reduced in patients with improved outcomes, suggesting their potential as prognostic biomarkers. CONCLUSIONS: Our study underscores the critical role of phospholipid metabolism in the brain's metabolic alterations in patients with DoC. It identifies key biomarkers for diagnosis and prognosis, offering insights that could lead to novel therapeutic targets. These findings highlight the value of metabolomic profiling in understanding and potentially treating DoC.

Thiacalix[4]arene-based metal-organic framework/reduced graphene oxide composite for electrochemical detection of chlorogenic acid.

A novel metal-organic framework [Co2LCl4]·2DMF (Co-L) based on thiacalix[4]arene derivative was synthesized using the solvothermal method. Then Co-L was respectively mixed with reduced graphene oxide (RGO), multi-walled carbon nanotubes (MWCNT) and mesoporous carbon (MC) to prepare corresponding composite materials. PXRD, SEM and N2 adsorption-desorption illustrated that composite materials have been successfully prepared. After optimizing experimental conditions for detecting chlorogenic acid (CGA), the Co-L@RGO(1:1) composite material showed the optimal electrocatalytic activity for CGA, which may be because RGO possessed large specific surface area and hydroxyl and carboxyl groups that could form hydrogen-bonding with the oxide of CGA. Benefiting from the synergetic effect of Co-L and RGO, the glassy carbon electrode modified with Co-L@RGO(1:1) (Co-L@RGO(1:1)/GCE) exhibited a low limit of detection (LOD) of 7.24 nM for CGA within the concentration of 0.1-2 µM and 2-20 µM. Co-L@RGO(1:1)/GCE also showed excellent selectivity, stability, and reproducibility for the CGA detection. Co-L@RGO(1:1)/GCE could detect the CGA in honeysuckle with satisfactory results. This work provided a great example for the thiacalix[4]arene-based MOF in the application of electrochemical sensors.

Urinary complement proteins in IgA nephropathy progression from a relative quantitative proteomic analysis.

Aim: IgA nephropathy (IgAN) is one of the leading causes of end-stage renal disease (ESRD). Urine testing is a non-invasive way to track the biomarkers used for measuring renal injury. This study aimed to analyse urinary complement proteins during IgAN progression using quantitative proteomics. Methods: In the discovery phase, we analysed 22 IgAN patients who were divided into three groups (IgAN 1-3) according to their estimated glomerular filtration rate (eGFR). Eight patients with primary membranous nephropathy (pMN) were used as controls. Isobaric tags for relative and absolute quantitation (iTRAQ) labelling, coupled with liquid chromatography-tandem mass spectrometry, was used to analyse global urinary protein expression. In the validation phase, western blotting and parallel reaction monitoring (PRM) were used to verify the iTRAQ results in an independent cohort (N = 64). Results: In the discovery phase, 747 proteins were identified in the urine of IgAN and pMN patients. There were different urine protein profiles in IgAN and pMN patients, and the bioinformatics analysis revealed that the complement and coagulation pathways were most activated. We identified a total of 27 urinary complement proteins related to IgAN. The relative abundance of C3, the membrane attack complex (MAC), the complement regulatory proteins of the alternative pathway (AP), and MBL (mannose-binding lectin) and MASP1 (MBL associated serine protease 2) in the lectin pathway (LP) increased during IgAN progression. This was especially true for MAC, which was found to be involved prominently in disease progression. Alpha-N-acetylglucosaminidase (NAGLU) and α-galactosidase A (GLA) were validated by western blot and the results were consistent with the iTRAQ results. Ten proteins were validated in a PRM analysis, and these results were also consistent with the iTRAQ results. Complement factor B (CFB) and complement component C8 alpha chain (C8A) both increased with the progression of IgAN. The combination of CFB and mucosal addressin cell adhesion molecule-1 (MAdCAM-1) also showed potential as a urinary biomarker for monitoring IgAN development. Conclusion: There were abundant complement components in the urine of IgAN patients, indicating that the activation of AP and LP is involved in IgAN progression. Urinary complement proteins may be used as biomarkers for evaluating IgAN progression in the future.

Hepatic Stellate Cell- and Liver Microbiome-Specific Delivery System for Dihydrotanshinone I to Ameliorate Liver Fibrosis.

Liver fibrosis is a major contributor to the morbidity and mortality associated with liver diseases, yet effective treatment options remain limited. Hepatic stellate cells (HSCs) are a promising target for hepatic fibrogenesis due to their pivotal role in disease progression. Our previous research has demonstrated the potential of Dihydrotanshinone I (DHI), a lipophilic component derived from the natural herb Salvia miltiorrhiza Bunge, in treating liver fibrosis by inhibiting the YAP/TEAD2 interaction in HSCs. However, the clinical application of DHI faces challenges due to its poor aqueous solubility and lack of specificity for HSCs. Additionally, recent studies have implicated the impact of liver microbiota, distinct from gut microbiota, on the pathogenesis of liver diseases. In this study, we have developed an HSC- and microbiome-specific delivery system for DHI by conjugating prebiotic-like cyclodextrin (CD) with vitamin A, utilizing PEG2000 as a linker (VAP2000@CD). Our results demonstrate that VAP2000@CD markedly enhances the cellular uptake in human HSC line LX-2 and enhances the deposition of DHI in the fibrotic liver in vivo. Subsequently, intervention with DHI-VAP2000@CD has shown a notable reduction in bile duct-like structure proliferation, collagen accumulation, and the expression of fibrogenesis-associated genes in rats subjected to bile duct ligation. These effects may be attributed to the regulation of the YAP/TEAD2 interaction. Importantly, the DHI-VAP2000@CD intervention has also restored microbial homeostasis in the liver, promoting the amelioration of liver inflammation. Overall, our findings indicate that DHI-VAP2000@CD represents a promising therapeutic approach for liver fibrosis by specifically targeting HSCs and restoring the liver microbial balance.

Cerebrospinal fluid metabolite alterations in patients with different etiologies, diagnoses, and prognoses of disorders of consciousness.

INTRODUCTION: Medical management of disorders of consciousness (DoC) is a growing issue imposing a major burden on families and societies. Recovery rates vary widely among patients with DoC, and recovery predictions strongly influence decisions on medical care. However, the specific mechanisms underlying different etiologies, consciousness levels, and prognoses are still unclear. METHODS: We analyzed the comprehensive cerebrospinal fluid (CSF) metabolome through liquid chromatography-mass spectrometry. Metabolomic analyses were used to identify the metabolic differences between patients with different etiologies, diagnoses, and prognoses. RESULTS: We found that the CSF levels of multiple acylcarnitines were lower in patients with traumatic DoC, suggesting mitochondrial function preservation in the CNS, which might contribute to the better consciousness outcomes of these patients. Metabolites related to glutamate and GABA metabolism were altered and showed a good ability to distinguish the patients in the minimally conscious state and the vegetative state. Moreover, we identified 8 phospholipids as potential biomarkers to predict the recovery of consciousness. CONCLUSIONS: Our findings shed light on the differences in physiological activities underlying DoC with different etiologies and identified some potential biomarkers used for DoC diagnosis and prognosis.

Untargeted Metabolomic Analyses of Body Fluids to Differentiate TBI DOC and NTBI DOC.

OBJECTIVE: To investigate the metabolomic differences between Traumatic brain injury (TBI) disorder of consciousness (DOC) patients and non-traumatic brain injury (NTBI) DOC patients by using cerebrospinal fluid (CSF), serum and urine samples beneficial to understand the pathological mechanism differences between the two etiologies, provide potential clues for the subsequent treatment and prognosis, and investigate the metabolome differences and similarities between TBI and NTBI among three different body fluids. METHODS: In total, 24 TBI DOC subjects and 29 NTBI DOC subjects were enrolled. CSF, serum and urine samples from TBI DOC and NTBI DOC patients were collected and analyzed by performing UPLC-MS. The statistical methods and pathway analyses were applied to discover potential biomarkers and altered metabolic functions. RESULTS: When comparing TBI DOC and NTBI DOC, 36, 31 and 52 differential metabolites were obtained in CSF, serum and urine, respectively. The functional analysis of differential metabolites obtained in CSF, serum and urine were all related to amino acid metabolism. Except for amino acid metabolism, metabolic biomarkers in CSF, serum and urine mainly focus on central function, cognitive function, necrosis and apoptosis and neurological function, respectively. In CSF, the highest AUC was 0.864 (Isoproturon) and 0.816 (Proline betaine). Then, the AUC of NFurfurylformamide in serum was 0.941, while the AUC of Dihydronepetalactone and Doxepin N-oxide glucuronide were 1.0 in urine. CONCLUSION: CSF, serum and urine metabolomic analyses could differentiate TBI DOC from NTBI DOC and functional analyses showed a metabolic change difference between TBI DOC and NTBI DOC.

Liposome Nanoparticles as a Novel Drug Delivery System for Therapeutic and Diagnostic Applications.

Liposome nanoparticles (LNPs), as a promising platform in drug delivery, combine the advantages of both liposomes and inorganic/organic nanoparticles into a single system. Both liposomes and nanoparticles have demonstrated optimized drug efficacy in the clinic. LNPs are proven to be multifunctional systems and thus utilized in various research applications (e.g., spatiotemporal control of drug release, hyperthermia, photothermal therapy, and biological imaging). The type of nanoparticles involved in LNPs largely affects the features of LNPs. Besides, diverse nanoparticles enable liposomes to overcome the defects such as poor stability, few functions, and rapid elimination from blood circulation. In this review, multiple nanoparticles materials and further prepared LNPs as well as their structure, physicochemical properties, manipulation and the latest applications in biomedical field are introduced. Future directions in advancing of LNPs are also discussed in the end.

Established new compound IMB16-4 self-emulsifying drug delivery systems for increasing oral bioavailability and enhancing anti-hepatic fibrosis effect.

Liver fibrosis results from the chronic liver injury and no specific medical therapy is approved so far. Recently, new compound, N-(3,4,5-trichlorophenyl) - 2 (3-nitrobenzenesulfonamido) benzamide, referred to as IMB16-4, was developed to resist liver fibrosis. However, IMB16-4 displays poor aqueous solubility and poor oral bioavailability. To increase the dissolution rate, improve the oral bioavailability and enhance the anti-hepatic fibrosis action of IMB16-4, IMB16-4 self-emulsifying drug delivery systems (SEDDS) with negative charge or positive charge were prepared using simple stirring, respectively. Their stability, oral bioavailability and anti-liver fibrosis effect were evaluated. The results showed IMB16-4 SEDDS in simulated gastric juice were nearly spherical with the diameter of 100～200 nm and possessed good stability in 30 days. The oral bioavailability of IMB16-4 SEDDS with negative charge and positive charge were increased to 33 folds and 58 folds compared with that of pure IMB16-4, respectively. In bile duct ligation (BDL) rats, IMB16-4 SEDDS attenuated the degree of liver damage and decreased collagen accumulation. In addition, IMB16-4 SEDDS with negative charge easily accumulated in the liver and alleviated hepatic fibrosis by TGF-ß/Smad signaling. These findings indicate that IMB16- 4 SEDDS may be a potential therapy for the treatment of liver fibrosis.

New IMB16-4 Nanoparticles Improved Oral Bioavailability and Enhanced Anti-Hepatic Fibrosis on Rats.

Liver fibrosis is challenging to treat because of the lack of effective agents worldwide. Recently, we have developed a novel compound, N-(3,4,5-trichlorophenyl)-2(3-nitrobenzenesulfonamido) benzamide referred to as IMB16-4. However, its poor aqueous solubility and poor oral bioavailability obstruct the drug discovery programs. To increase the dissolution, improve the oral bioavailability and enhance the antifibrotic activity of IMB16-4, PVPK30 was selected to establish the IMB16-4 nanoparticles. Drug release behavior, oral bioavailability, and anti-hepatic fibrosis effects of IMB16-4 nanoparticles were evaluated. The results showed that IMB16-4 nanoparticles greatly increased the dissolution rate of IMB16-4. The oral bioavailability of IMB16-4 nanoparticles was improved 26-fold compared with that of pure IMB16-4. In bile duct ligation rats, IMB16-4 nanoparticles significantly repressed hepatic fibrogenesis and improved the liver function. These findings indicate that IMB16-4 nanoparticles will provide information to expand a novel anti-hepatic fibrosis agent.

Role of the mucin-like glycoprotein FCGBP in mucosal immunity and cancer.

IgGFc-binding protein (FCGBP) is a mucin first detected in the intestinal epithelium. It plays an important role in innate mucosal epithelial defense, tumor metastasis, and tumor immunity. FCGBP forms disulfide-linked heterodimers with mucin-2 and members of the trefoil factor family. These formed complexes inhibit bacterial attachment to mucosal surfaces, affect the motility of pathogens, and support their clearance. Altered FCGBP expression levels may be important in the pathologic processes of Crohn's disease and ulcerative colitis. FCGBP is also involved in regulating the infiltration of immune cells into tumor microenvironments. Thus, the molecule is a valuable marker of tumor prognosis. This review summarizes the functional relevance and role of FCGBP in immune responses and disease development, and highlights the potential role in diagnosis and predicting tumor prognosis.