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As two important subcellular organelles in eukaryotic cells, the Golgi apparatus (GA) and endoplasmic reticulum (ER) have recently captivated much interest due to their considerable importance in many biofunctions and role as critical biomarkers for various diseases. The development of efficient GA- and ER-specific probes is of great significance, but remains an appealing yet significantly challenging task. Herein, we reported for the first time the construction of an aggregation-induced emission (AIE) platform for GA and ER fluorescent probes, termed as AIE-GA and AIE-ER, by facile synthesis and simple functionalization. Their excellent targeting specificity to GA or ER, remarkable photostability, high brightness, and low working concentration make AIE-GA and AIE-ER significantly impressive and superior to commercially available probes. Moreover, molecular docking calculations are performed to validate the targeting mechanism of the two AIE probes., As two important subcellular organelles in eukaryotic cells, the Golgi apparatus (GA) and endoplasmic reticulum (ER) have recently captivated much interest due to their considerable importance in many biofunctions and role as critical biomarkers for various diseases.

Background and aims: Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) reduce hepatic events and death in patients with acute-on-chronic liver failure (ACLF), but the efficacy of Tenofovir alafenamide (TAF) is less well studied. We aimed to assess the effectiveness of TAF in hepatitis B virus (HBV) related ACLF.Methods: We analyzed 106 patients with HBV-ACLF received TAF (25mg/d), ETV(0.5mg/d) for 12 weeks. The primary endpoints were overall mortality and liver transplantation (LT) at week 12. Other determined factors of biochemical response, virologic response, mortality rate, and drug safety and side-effect were also evaluated.Results: At 4 weeks and 12 weeks, patients received TAF got significantly higher HBV-DNA reduction (PPPP=0.003) at 4 weeks in TAF group, but CTP scores showed no difference in two groups at 12 weeks (P=1.143). Lower ALT levels in TAF group at week 4 and week 12 (P=0.023, PP=0.038), but two group got similar mortality rate at week 8 and week 12. As for reason cause death in HBV-ACLF patients, we found that two group patients developed similar rates of liver-related complications (P>0.05).Conclusions: The antiviral efficacy of TAF was superior than ETV for the treatment of HBV-related ACLF. TAF therapy reduced 4-week mortality rate in patients with HBV-related ACLF.

Background The altered gut microbiota is implicated in the pathogenesis of liver fibrosis. Resveratrol is a candidate for the treatment of liver fibrosis, which could ameliorate the dysregulation of gut microbiota in mice. This study aimed to clarify the role and mechanism of resveratrol in gut microbiota during liver fibrosis. Methods A mouse model of liver fibrosis induced by CCl4 was conducted to assess the effect of resveratrol on liver fibrosis. The changes of gut microbiota in liver fibrotic mice after resveratrol intervention were assessed using 16S ribosomal RNA sequencing. The mechanism of the gut microbiota dysregulation in liver fibrosis was investigated by Sirius red staining, immunohistochemical assay, bacterial translocation (BT), EUB338 fluorescence in situ hybridization, immunofluorescence, trans-epithelial electrical resistance analysis and paracellular permeability analysis. Results Resveratrol relieved CCl4-induced liver fibrosis. Besides, resveratrol restrained the gut microbiota Staphylococcus_lentus and Staphylococcus_xylosus in the liver fibrotic mice, and the Staphylococcus_xylosus and Staphylococcus_lentus facilitated the occurrence of BT and the cultures of them enhanced the permeability of intestine. The in vivo assay corroborated that the excessive Staphylococcus_xylosus and Staphylococcus_lentus canceled the protecting effect of resveratrol on liver fibrosis, and Staphylococcus_xylosus or Staphylococcus_lentus alone had a limited impact on the liver injury of normal mice. Conclusion Resveratrol ameliorated liver fibrosis by restraining the growth of Staphylococcus_xylosus and Staphylococcus_lentus.

To investigate the effect of Chaiqin Chengqi decoction (CQCQD) on acute pancreatitis (AP) by janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway in vitro and in vivo.AP was induced by caerulein both in AR42J cells and in mice. AR42J cells were divided into five groups: the control group, the AP group, the CQCQD group, JAK/STAT signaling pathway inhibitor AG490 group, and the CQCQD and AG490 group. After induction, cellular supernatant of five groups were collected for measuring the concentrations of inflammatory cytokine amylase, interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), nuclear factor κB (NF-κB) by enzyme-linked immunosorbent assay and the expression of JAK-2, STAT-3 signaling transduction proteins by Western blot, respectively. Experiments in mice were performed similar to that of in AR42J cells.Treatment of AR42J cells with CQCQD reduced the pancreatic injury and negatively regulated the activities of amylase, as well as inhibited expression of several inflammatory cytokines such as IL-6, TNF-α, IL-1β, NF-κB. Administration of CQCQD significantly inhibited JAK-2 activation and down-regulated phosphorylation of downstream substrate STAT-3 the same as AG490, resulting in inhibition of inflammatory mediators and amelioration of pancreatitis.The results suggested that CQCQD exerted anti-inflammatory effects on AP via reducing expression and phosphorylation of JAK and STAT.

Long-term and daily injection of insulin for the treatment of diabetes mellitus often bring great suffering to patients. In order to reduce injection frequency and improve patient compliance, an injectable in-situ forming phospholipid-based phase separation gel (PPSG) was formulated in the present study. Insulin was loaded into PPSG for sustained and controlled delivery, which could maintain the bioactivity of insulin during its release process. The in-situ formation and degradation behavior of PPSG in vivo indicated that solvent exchange could be the driving force for phase transition and that phospholipid vesicle formation and burst could be the mechanism of drug release and gel degradation. In the foreign body response study, PPSG implants were demonstrated to be biodegradable, and the degree of inflammation and fibrotic responses could be decreased by increasing the phospholipid content. The applicability of insulin on PPSG was justified by studying the drug release property and the bioactivity of insulin in PPSG. As a result, the insulin-loaded PPSG showed a sustained drug release behavior and a long-lasting hypoglycemic effect in diabetic rats. In conclusion, PPSG is of good biocompatibility and biodegradability, which is promising to serve as a sustained insulin delivery system and improve patient compliance effectively.

It is necessary to discover a novel antitumor liposome with prolonged circulation time, high efficacy, and low cost. Here, we reported a liposomal honokiol (HNK) prepared with a new type of excipient, Kolliphor HS15, which was termed as HS15-LP-HNK. In addition, we employed PEGylated liposomal honokiol (PEG-LP-HNK) as positive control. The HS15-LP-HNK was prepared by thin-film hydration method. It was near-spherical morphology with an average size of 80.62 ± 0.72 nm (PDI = 0.234 ± 0.007) and a mean zeta potential of -3.91 ± 0.06 mv. In vivo studies exhibited no significant difference between HS15-LP-HNK and PEG-LP-HNK. The pharmacokinetic and biodistribution results showed that HS15-LP-HNK could improve the bioavailability and increase tumor accumulation of honokiol. Furthermore, HS15-LP-HNK could enhance antitumor efficacy of honokiol with low toxicity. In summary, HS15-LP-HNK is promising in tumor targeted drug delivery system.

The aim of this study was to design hyaluronic acid (HA) layer-by-layer (LbL) nanoparticles, which carried paclitaxel (PTX) and Indocyanine green (ICG) to both tumor cells and tumor associated cells to achieve synergistic chemo-photothermal therapeutic effect. The LbL-engineered nanoparticles (PDIH) were prepared by dopamine self-polymerization on PTX nanocrystal to form thin, surface-adherent polydopamine (PDA) films, which subsequently absorbed ICG and HA. The tumor cell and tumor associated cell targeting and antitumor efficacy of PDIH were investigated both in vitro an in vivo using 4 T1 murine mammary cancer cell lines and mice bearing orthotopic 4 T1 breast tumor. PDIH presented a long-rod shape in TEM and showed enhanced photothermal effect and cytotoxicity upon NIR laser irradiation both in vitro and in vivo. PDIH also displayed high target ability to CD44 overexpressed tumor cells and tumor associated cells mediated by HA. In vivo antitumor study indicated that PDIH therapeutic strategy could achieve remarkable antitumor efficacy. PDIH showed excellent tumor-targeting property and chemo-photothermal therapeutic efficacy.

In our study, we aimed to develop a codelivery nanoparticulate system of pirarubicin (THP) and paclitaxel (PTX) (Co-AN) using human serum albumin to improve the therapeutic effect and reduce systemic toxicities. The prepared Co-AN demonstrated a narrow size distribution around 156.9 ± 3.2 nm (PDI = 0.16 ± 0.02) and high loading efficiency (87.91 ± 2.85% for THP and 80.20 ± 2.21% for PTX) with sustained release profiles. Significantly higher drug accumulation in tumors and decreased distribution in normal tissues were observed for Co-AN in xenograft 4T1 murine breast cancer bearing BALB/c mice. Cytotoxicity test against 4T1 cells in vitro and antitumor assay on 4T1 breast cancer in vivo demonstrated that the antitumor effect of Co-AN was superior to that of the single drug or free combination. Also, Co-AN induced increased apoptosis and G2/M cell cycle arrest against 4T1 cells compared to that of the single drug formulation. Remarkably, Co-AN exhibited significantly lower side effects regarding bone marrow suppression and organ and gastrointestinal toxicities. This human serum albumin-based codelivery system represents a promising platform for combination chemotherapy in breast cancers.

Our study aimed to develop an amorphous 9-nitrocamptothecin solid dispersion (9-NC-SD) using polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus(®)) for improving its oral bioavailability and antitumor efficacy in vivo. Freeze-dried 9-NC-SD with an optimized drug/polymer ratio at 1:15 (w/w) was characterized by powder X-ray diffraction, scanning electron microscopy and Fourier transform infrared spectroscopy. The amorphous form of 9-NC was obtained by freeze-drying and the aqueous solubility of 9-NC was increased to 1.42 mg/mL. Upon dilution, 9-NC-SD was proven to form micellar structures with an average size distribution around 58 nm ± 5 nm (PDI=0.107 ± 0.016). Moreover, 9-NC-SD showed significantly increased intracellular uptake efficiency in Caco-2 cells compared to free 9-NC. Furthermore, the AUC0-8h of 9-NC-SD following oral administration showed a 2.68-fold increase in the lactone form of 9-NC compared to that of free 9-NC in Sprague-Dawley rats. The 9-NC-SD did not show obvious inflammatory responses and gastrointestinal toxicity following oral administration as demonstrated by the histological analysis of the rat intestinal sections. Thus, 9-NC-SD represents a promising approach for improving the solubility and oral bioavailability of drugs with poor solubility.

Clinical application of ivermectin (IVM) is limited by several unfavorable properties, induced by its insolubility in water. Slight differences in formulation may change the plasma pharmacokinetics and efficacy. In this study, an IVM-loaded Soy phosphatidylcholine-sodium deoxycholate mixed micelles (IVM-SPC-SDC-MMs) were developed to improve its aqueous solubility, aiming to make it more applicable for clinical use. First, IVM-SPC-SDC-MMs were prepared using the co-precipitation method. After formulation optimization, the particle size was 9.46 ± 0.16 nm according to dynamic light scattering. The water solubility of IVM in SPC-SDC-MMs (4.79 ± 0.02 mg/mL) was improved by 1200-fold, comparing with free IVM (0.004 mg/mL). After subcutaneous administration, the pharmacokinetic study showed that IVM-SPC-SDC-MMs and commercially available IVM injection were bioequivalent. Also, the local irritation study confirmed that IVM-SPC-SDC-MMs reduced side reactions of the commercially available IVM injection. These results indicated that IVM-SPC-SDC-MMs represented a promising new drug formulation suitable for subcutaneous delivery of IVM.

Finding effective cures against aggressive malignancy remains a major challenge in cancer chemotherapy. Here, we report a "tadpole"-like peptide by covalently conjugating the alanine-alanine-asparagine "tail" residual to the cyclic tumor homing peptide iRGD (CCRGDKGPDC) to afford nRGD, which significantly enhanced tumoricidal effects of doxorubicin, by either co-administered as a physical mixture or as a targeting ligand covalently conjugated to the liposomal carrier. Given twice at an equivalent dose of 5 mg/kg, doxorubicin loaded liposomes modified with nRGD (nRGD-Lipo-Dox) showed excellent antitumor efficacy in 4T1 breast cancer mice, of which 44.4% remained alive for over 90 days without recurrence during the period of investigation. The dramatic improvement in antitumor efficacy was attributed to nRGD-Lipo-Dox which appeared to specifically interact with tumor vascular endothelial cells to achieve efficient tumor penetration, and modulate tumor microenvironment with depletion of tumor associated macrophages.

Abstract It is well-known that in oil and gas fields development process, foam is widely used as mobility control agent or blocking agent to displace oil and gas, block gas channels and fractures or high permeability layers etc. However, higher oil recovery efficiency is undoubtedly a top-priority factor for managers to decide whether foam flooding can be adopted. According to laboratory percolation and oil displacement experiments, this paper presented a new method of using foam as a displacing agent to recover oil in heterogeneous reservoir. Unlike other foam flooding methods, this work based on the mechanism of both lowering interfacial tensions to a super-low value (10-3mN/m grade) and improving sweep efficiency of displacing fluid. The foam preformed by co-injecting natural gas and a kind of three-component combined solution has a greater blocking effect in high permeability layer of heterogeneous physical model. The percolation result showed that the diversion of fluid from high permeability layer into medium and low permeability layers apparently depends on the flowing resistance in high permeability layer; the diversion ability of foam is far greater than that of polymer. The oil displacement experiments showed that, for this foam composition, the final oil recovery factor can be improved nearly 30% initial reserves over waterflood recovery factor for model whose permeability variation coefficient is 0.72, nearly one and half times than that of alkaline-surfactant-polymer system. This paper modeled the field injecting project of foam flooding in Daqing oil field and got a good match result. Besides, this paper put forward some measures of improving foam flooding effect. Introduction Generally speaking, the waterflood efficiency of heterogeneous reservoir is relatively lower. In order to promote the production of hydrocarbons, one often injects displacement fluids into subterranean hydrocarbon-bearing formations to improve the final oil recovery factor of oilfield. Various gases and more complex fluids, such as alkaline solutions, polymer solutions, surfactant solutions, alkaline-surfactant-polymer (ASP) solutions and foams, are widely used as displacement fluids in both miscible and immiscible oil displacement floods. Since Fried first put forward foam flooding method in 1961, foams are receiving increasing attention in the oil industry. The merits of foams lie in that foams have some advantageous characteristics, notably as excellent blocking effect and distinguished mobility control effect in enhanced recovery operations. Although foams were first utilized to block fractures, to prevent gas channeling and gas override during gas flood (or steam flood), they have now been applied in many new technique fields with the development of investigations on foam system, oil displacement mechanism and flowing behavior etc. For example, strong and super-strong foam was used to plug fractures or high permeability streaks, the foam provided a considerable reduction in chemical costs relative to gels without significantly reducing the effectiveness of the conformance improvement treatment (CIT)[1]. In addition, some viscofying foams were used as mobility control agents to efficiently sweep oil from a subterranean oil-bearing formation and particularly from oil-bearing fractures containing gravity-segregated oil or from oil-bearing fractures in fluid communication with an aquifer. In general, the CIT and related plugging treatment are static applications of the foam, in that the foam remains substantially stationary in the formaion once it is placed therein. The mobility control process is a dynamic application of the foam, in that the foam moves across the formation in correspondence with a flood front. According to the concept of foam, a foam is commonly defined as a composition comprising a gas phase dispersed throughout a surrounding medium, such as a liquid. In this definition, the term "surrounding medium" can be either one single composition or a multi-composition. As such, foams have been used in a number of roles according to their different fluid components.

Many oil and water wells are distributed over the all developing reservoirs, of which one well's pressure test data are controlled by multiple well system. People used to solve this problem by taking testing well as a single well system with constant pressure or closed outer boundary. This paper touches upon the outer boundary with constant rate, that is, the effect of multiple well system on testing well is reflected on the injection rate at the outer boundary of testing well, whose relation with the production rate of testing well is Injection-Production Ratio (IPR) of the drainage area. Obviously, such dealing reflects the mutual relationship of oil wells and water wells more truly and universally. For example, closed boundary can be regarded as a special case of outer boundary with constant rate (when IPR=0). A new type-curve is presented for considering IPR. Using it on well test analysis, not only the usual well and reservoir parameters can be obtained, such as permeability, skin factor and wellbore storage constant etc., but only yield IPR in drainage area of testing well. The practicality of this type-curve is proved by the illustration of test data from Daqing Oil Field. This paper has successfully solved the well test analysis problem of multi well system, and it is of great importance in guiding well test data interpretation, pattern modification and injection-production balance analysis for present waterflooding reservoirs.