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The intriguing features of two-dimensional (2D) materials such as better charge carrier separation and abundant surface reaction sites endow them with potential applications as cocatalysts in photocatalysis. In this paper, a ternary 2D nickel hydroxide/sulfides nanosheet composed of Ni(OH) 2 , Ni 3 S 2 and Ni x S 6 was loaded on CdS nanospheres by a simple chemical deposition route. The composition of nickel hydroxide/sulfides was determined clearly through an overall analysis using X-ray diffraction, transmission electron microscopy and X-ray photoelectron spectroscopy. Mott-Schottky, electrochemical impedance, steady-state and time-resolved photoluminescence spectroscopy were used to investigate the charge transfer process in CdS and Ni(OH) 2 /Ni 3 S 2 /Ni x S 6 -CdS. The results confirm that a synergistic effect of Ni(OH) 2 /Ni 3 S 2 /Ni x S 6 on CdS has occurred under light irradiation, where the Ni(OH) 2 and nickel sulfides act as hole storage and surface reaction sites, respectively, to promote the charge transfer on CdS. The improved charge transfer and separation efficiency as well as the increased surface reaction sites in Ni(OH) 2 /Ni 3 S 2 /Ni x S 6 -CdS finally result in a dramatically improved photocatalytic performance. The photocatalytic H 2 evolution rate of Ni(OH) 2 /Ni 3 S 2 /Ni x S 6 -CdS is ca . 46 times higher than that of CdS, and the photocatalytic stability of CdS is also improved substantially under visible light irradiation. [ABSTRACT FROM AUTHOR]

The initial entanglement shared between inertial and accelerated observers degrades due to the influence of the Unruh effect. Here, we show that the Unruh effect can be completely eliminated by the technique of partial measurement. The lost entanglement could be entirely retrieved or even amplified, which is dependent on whether the optimal strength of reversed measurement is state-independent or state-dependent . Our work provides a novel and unexpected method to recover the lost entanglement under Unruh decoherence and exhibits the ability of partial measurement as an important technique in relativistic quantum information. [ABSTRACT FROM AUTHOR]

The solid-state Z-scheme trinary/binary heterostructures show the advantage of utilizing the high-energy photogenerated charge carriers in photocatalysis. However, the key factors controlling such Z-scheme in the binary heterostructures are still unclear. In this paper, we showed that oxygen vacancies could act as an interface electron transfer mediator to promote the direct Z-scheme charge transfer process in binary semiconductor heterostructures of CdS/ZnS. Increasing the concentration of surface oxygen vacancies of ZnO crystal can greatly enhance photocatalytic hydrogen generation of CdS/ZnO heterostructure. This was attributed to the strengthened direct Z-scheme charge transfer process in CdS/ZnO, as evidenced by steady-state/time-resolved photoluminescence spectroscopy and selective photodeposition of metal particles on the heterostructure. [ABSTRACT FROM AUTHOR]

Multiple drug resistance (MDR) is the major obstacle for both chemotherapy and molecular-targeted therapy for cancer, which is mainly caused by overexpression of ABC transporters or genetic mutation of drug targets. Based on previous studies, we hypothesized that ROS/Nrf2 is the common target for overcoming acquired drug resistance to both targeted therapy and chemotherapy treatments. In this study, we firstly proved that the levels of ROS and Nrf2 were remarkably up-regulated in both H1975 (Gefitinib-resistant lung cancer cells with T790M) and A549/T (paclitaxel-resistant) cells, which is consistent with the clinical database analysis results of lung cancer patients that Nrf2 expression level is negatively related to survival rate. Nrf2 Knockdown with siRNA or tangeretin (TG, a flavonoid isolated from citrus peels) inhibited the MDR cell growth by suppressing the Nrf2 pathway, and efficiently enhanced the anti-tumor effects of paclitaxel and AZD9291 (the third generation of TKI) in A549/T or H1975, respectively. Moreover, TG sensitized A549/T cells-derived xenografts to paclitaxel via inhibiting Nrf2 and its downstream target P-gp, leading to an increased paclitaxel concentration in tumors. Collectively, targeting Nrf2 to enhance ROS may be a common target for overcoming the acquired drug resistance and enhancing the therapeutic effects of chemotherapy and molecular-targeted therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Nonalcoholic steatohepatitis (NASH) is a common chronic liver disease in clinical practice. It has been considered that NASH is one of the main causes of chronic liver disease, cirrhosis and carcinoma. The mechanism of the NASH progression is complex, including lipid metabolism dysfunction, insulin resistance, oxidative stress, inflammation, apoptosis, fibrosis and gut microbiota dysbiosis. Except for lifestyle modification and bariatric surgery, there has been no pharmacological therapy that is being officially approved in NASH treatment. Traditional Chinese medicine (TCM), as a conventional and effective therapeutic strategy, has been proved to be beneficial in treating NASH in numbers of studies. In the light of this, TCM may provide a potential therapy for treating NASH. In this review, we summarized the associated mechanisms of action TCM treating NASH in preclinical studies and systematically analysis the effectiveness of TCM treating NASH in current clinical trials. [Display omitted] [ABSTRACT FROM AUTHOR]

Soil respiration (SR) is an important process and the largest source of carbon cycle of terrestrial ecosystems, which has a significant impact on global climate and environmental changes. The fluctuation of temperature and precipitation caused by climate change is a driving force for the dynamic change of SR. Therefore, we established the field experiment with 5 levels of precipitation by rainout shelters and 2 levels of temperature by Open-top Chamber (OTC) to determine the SR dynamic in the desert grassland in northwest China. The results show that: soil temperature (ST) and soil moisture (SM) are affected by changed precipitation and increased temperature, but not greatly. Overall, it can be seen that the SR continue to increase with the precipitation increasing and the temperature rising. SR has no significant correlation with above-ground living biomass (ALB), but is significantly correlated with root biomass (RB), so SR mainly comes from the root system, and ALB and RB both increase with rainfall rising. Soil physical and chemical properties are related to SR, but not significantly. These findings provide a reliable theoretical basis for formulating a reasonable response strategy in desert steppe ecosystems. • Ecological responses of desert-steppe SR to temperature increases and precipitation changes along with their ecological sensitivity indexes. • Correlations between SR, soil temperatures, soil moisture, and other soil properties and plant biomass in the desert grasslands. • This research provides a reliable theoretical basis for formulating a reasonable response strategy for desert steppes. [ABSTRACT FROM AUTHOR]

The invisible foodborne pathogens on strawberry surface endanger its food safety. Therefore, detecting and controlling the foodborne pathogens are crucial for food safety of strawberry. This study comprehensively detected and compared their surface bacterial communities under different packaging films (polyethylene film, gelatin film, and gelatin composite film) through high-throughput sequencing. Compared with fresh strawberries, the dominant bacterial genus of strawberries packaged with different films changed from Rosenbergiella to Acinetobacter after storage. However, few foodborne pathogens and spoilage-related bacteria were found in gelatin composite film-packaged strawberries (S-CG), while harmful bacterial genus of Pantoea and Erwinia were detected with high relative abundances in other films-packaged strawberries. Furthermore, the predication analysis of phenotype and metabolism indicated that Pantoea and Erwinia were the main biofilm-forming and stress-resistance bacteria, which increased potential pathogenic. Fortunately, gelatin composite film maintained the relative abundance of pathogenic bacteria on S-CG surface at a low level. Therefore, this work contributed to evaluating the pathogenic of bacteria community on strawberries during storage and providing a theoretical foundation for active packaging film to control surface pathogenic bacteria of strawberries. • Active packaging decreased the relative abundance of Pantoea and Erwinia. • Pantoea and Erwinia were the main biofilm-forming and pathogenic bacteria. • Most bacteria on strawberry surface exhibited positive correlation with each other. • Active packaging effectively decreased the pathogenic of bacterial community. [ABSTRACT FROM AUTHOR]

The synergy between iron doping and (1 1 1) facet engineering in Fe-NiSe octahedron reinforces catalytic activity for IRR to yield impressive photovoltaic performance of DSSCs. [Display omitted] • The possibility of Fe-NiSe (1 1 1) as CE catalysts was investigated by DFT calculation. • The well-defined Fe-doped NiSe octahedron with (1 1 1) plane was synthesized. • Synergy between doping and facet engineering reinforces electrochemical behavior. • PCE can be further enhanced by introducing Fe heteroatom into NiSe (1 1 1). Reasonable design of cost-effective counter electrode (CE) catalysts for triiodide (I 3 −) reduction reaction (IRR) by simultaneously combining heteroatom doping and facet engineering is highly desired in iodine-based dye-sensitized solar cells (DSSCs), but really challenging. Herein, the density function theory (DFT) calculations were first conducted to demonstrate that the Fe-doped NiSe (1 1 1) showed an appropriate adsorption energy for I 3 −, increased number of metal active sites, reinforced charge-transfer ability, and strong interaction between 3 d states of metal sites and 5 p state of I 1 atoms in I 3 −, compared to NiSe (1 1 1). Based on this finding, the well-defined Fe-NiSe octahedron with exposed (1 1 1) plane (marked as Fe-NiSe (1 1 1)) and NiSe octahedron with the same exposed plane (named as NiSe (1 1 1)) are controllably synthesized. When the as-prepared Fe-NiSe (1 1 1) and NiSe (1 1 1) worked as CE catalysts, Fe-NiSe (1 1 1) exhibits improved electrochemical performance with higher power conversion efficiency (PCE) than NiSe (1 1 1), providing new opportunity to replace precious Pt for DSSCs. [ABSTRACT FROM AUTHOR]

Mesoporous TiO 2 nanospheres with engineered surface defects are fabricated through surfactant-mediated self-assembly solvothermal approach combined with surface hydrogenation, which exhibit excellent solar-driven photocatalytic hydrogen evolution, due to surface defects induced charge imbalance improving charge separation, and unique spherical mesoporous structure supplying adequate surface-active sites and facilitating mass transfer. [Display omitted] • Surface defects induced charge imbalance promote charge separation. • Mesoporous TiO 2 nanospheres with engineered surface defects are fabricated. • Nanoscale mesoporous spheres have closed packing and low surface energy. • It exhibits excellent solar-driven photocatalytic H 2 evolution and high stability. • Surface defects and mesostructure favor charge separation and mass transfer. Low charge separation efficiency of semiconductor materials is the main obstacle for high-performance photocatalyst. Herein, we report surface defects engineered uniform mesoporous TiO 2 nanospheres (DMTNSs) through surfactant-mediated self-assembly solvothermal approach combined with hydrogenation strategy to promote charge separation. The surface defects induced charge imbalance result in the formation of built-in field, which can promote photogenerated charge separation efficiently and be confirmed by experimental and density functional theory (DFT) calculations. Under AM 1.5G irradiation, the photocatalytic hydrogen evolution of DMTNSs is ~3.34 mmol h−1 g−1, almost 3.5 times higher than that of pristine non-defective TiO 2 nanospheres (0.97 mmol h−1 g−1), due to the engineered surface defects narrowing the bandgap (~3.01 eV) and inducing charge imbalance to boost spatial charge separation and extend visible-light response. The defect induced charge imbalance strategy opens a new valuable perspective for fabricating other high-efficient oxide photocatalysts. [ABSTRACT FROM AUTHOR]

Oxygen-defective Bi 2 MoO 6 /g-C 3 N 4 hollow tubulars S-scheme heterojunctions are fabricated by hydrothermal and calcination methods and show excellent photocatalytic performance. The S-Scheme heterojunction accelerates the effective charge separation and transfer by internal electric field (IEF) and energy band bending at the interface, thus improving the photocatalytic performance. [Display omitted] Novel S-scheme heterojunction photocatalysts of bismuth molybdate/hollow tube graphite carbon nitride (Bi 2 MoO 6 SOVs/g-C 3 N 4) containing surface defects (SOVs) were prepared by calcination and hydrothermal methods. The hollow tubular structure of g-C 3 N 4 facilitates the enhancement of multiple reflection and scattering of light, and also have a larger range of specific surface areas and more reactive sites, which promotes carrier separation and thus improves photocatalytic performance. The introduction of SOVs to bismuth molybdate not only reduces the band gap of bismuth molybdate, but also promotes the separation of charges. The optimized Bi 2 MoO 6 SOVs/TCN photocatalyst has a hydrogen production efficiency of 2.29 mmol h−1 g−1. It also shows high photocatalytic degradation property of tetracycline and bisphenol A in water, up to 97.3 % and 98.9 %, respectively. Meanwhile, the transfer mechanism of photogenerated charges in S-scheme heterojunctions can be verified by electron paramagnetic resonance and in situ irradiated x-ray photoelectron spectroscopy electron paramagnetic resonance, which accelerated the separation and transfer of photogenerated charge by energy band bending at the interface and internal electric field. This rational structural design strategy provides a new development idea for building high-performance S-scheme heterojunction photocatalysts. [ABSTRACT FROM AUTHOR]

This study aimed to elucidate the effect of Helicobacter pylori ( H. pylori ) and high salt diet on Trefoil factor 2 (TFF2) expression level of Mongolian gerbils (MGs) gastric mucosa. The results of H. pylori identification and histopathology showed that H. pylori infected MGs model was built successfully. According to the immunohistochemical staining results, 25% (4/16) of H. pylori infected MGs with high salt diet showed high TFF2 expression, which was significantly lower than H. pylori infection group 61% (11/18)( P  = 0.045). The results suggested that High salt diet could down-regulated TFF2 expression level of MGs gastric mucosa induced by H. pylori infection. [ABSTRACT FROM AUTHOR]

The overexpression of PDZ-binding kinase/T-LAK cell-originated protein kinase (PBK/TOPK) has been associated with hematologic tumors, breast cancer and various other cancers. However, the three-dimensional structure of PBK has not been solved. In this study, we determined the crystal structure of human PBK, which has two phospho-mimicking mutations T9E and T198E. The structural data indicated that PBK may assemble into an inactive dimer in alkaline conditions. Analytical size-exclusion chromatography and analytical ultracentrifugation confirmed that PBK exists in a conformational transition between dimers and monomers at different pH conditions. Co-IP and kinase assays suggested that the active state of PBK is a monomer and does not form a dimer even under alkaline conditions. These results showed that the conformational transition of PBK is important for its kinase activity regulation. Collectively, our observations may provide a novel starting point for structure-based functional studies. [ABSTRACT FROM AUTHOR]

Polydopamine/defective ultrathin mesoporous graphitic carbon nitride Z-scheme organic assembly is fabricated via N -vacancy defects and π-π interactions, which exhibits robust photocatalytic H 2 production and contaminant degradation, due to the direct Z-scheme charge transfer mechanism to realize efficient spatial charge separation, and the enhanced photothermal effect to promote the photocatalytic reaction. [Display omitted] • Polydopamine/defective ultrathin mesoporous graphitic carbon nitride organic assemblies are fabricated. • N -vacancy and π-π interactions provide strong connection and fast charge transfer. • Z-scheme structure enables efficient of photogenerated charges separation. • Polydopamine extends photoabsorption and produces photothermal effect to improve catalyze activity. Polydopamine/defective ultrathin mesoporous graphitic carbon nitride (PDA/DCN) Z-scheme organic assembly is fabricated through high-temperature surface hydrogenation and ultrasonic freeze-dried strategies. PDA could be anchored on the surface of DCN with adequate N -vacancy defects firmly via π-π interactions, forming Z-scheme heterogenous structure for promoting charge separation. The visible and near-infrared light driven photocatalytic hydrogen evolution rate is up to 3420 μmol h−1 g−1, and the removal ratio of organic contaminant methylene blue is up to 98% within 70 min, which is several times higher than that of pristine graphitic carbon nitride and DCN. The important reason is the defects of DCN not only enhance the interaction with PDA, but also make the obvious polarized inbuilt electric field, and lead to Z-scheme structure for effective charge separation and rapid transfer, which is also confirmed by density functional theory (DFT) calculations. In addition, PDA extends the photoresponse to the near-infrared region and induces obvious photothermal effect to increase the reaction rate of the photocatalytic system. The efficient photothermal conversion of PDA/DCN should be another reason for the enhanced photocatalytic performance. [ABSTRACT FROM AUTHOR]

Environmental exposure to formaldehyde is known to be associated with cancers and many other diseases. Although formaldehyde has been classified as a group I carcinogen, the molecular mechanisms of its carcinogenicity are still not fully understood. Formaldehyde is also involved in the folate-driven one‑carbon metabolism, and excess amount of formaldehyde was found to interfere with other metabolic pathways including glycolysis, which can enhance Warburg effect and induce immunosuppression in tumor microenvironment. Therefore, different tumor cells and THP-1 derived macrophages were utilized to explore the metabolism-related effects induced by formaldehyde at environmentally relevant concentrations. Significant increases of glucose uptake, glycolysis levels, HIF-1α signaling and methylglyoxal production were observed in tumor cells treated with 20 and 50 μM formaldehyde for 24 h, and the overproduced methylglyoxal in the conditioned medium collected from the tumor cells treated with formaldehyde triggered macrophage polarization towards M2 cells. Myricetin, a flavonol scavenging methylglyoxal, reversed the polarization of macrophages induced by methylglyoxal at 50 μM. These results not only provided essential evidences to reveal the molecular mechanisms of Warburg effect and metabolism-related immunosuppression related to formaldehyde exposure, but also indicated that methylglyoxal could be utilized as a target for therapeutic treatment or prevention of formaldehyde-induced immunotoxicity. • FA enhanced glycolysis and HIF-1α signaling in different types of tumor cells. • FA stimulated MGO production in tumor cells through the enhanced glycolysis. • MGO potentiated the polarization of TAMs towards immunosuppressive M2 cells. • MYR reversed the M2 polarization of TAMs by scavenging MGO. [ABSTRACT FROM AUTHOR]

PD-1 blockade therapy has made great breakthroughs in treatment of multiple solid tumors. However, patients with microsatellite-stable (MSS) colorectal cancer (CRC) respond poorly to anti-PD-1 immunotherapy. Although CRC patients with microstatellite instability (MSI) or microsatellite instability-high (MSI-H) can benefit from PD-1 blockade therapy, there are still some problems such as tumor recurrence. Tumor-associated macrophages (TAMs), most abundant immune components in tumor microenvironment (TME), largely limit the therapeutic efficacy of anti-PD-1 against CRC. The CSF1/CSF1R pathway plays a key role in regulating macrophage polarization, and blocking CSF1R signaling transduction may be a potential strategy to effectively reprogram macrophages and remodel TME. Here, we found that increasing expression of CSF1R in macrophages predicted poor prognosis in CRC cohort. Furthermore, we discovered a novel potent CSF1R inhibitor, PXB17, which significantly reprogramed M2 macrophages to M1 phenotype. Mechanically, PXB17 significantly blocked activation of PI3K/AKT/mTORC1 signaling, resulting in inhibition of cholesterol biosynthesis. Results from 3D co-culture system suggested that PXB17-repolarized macrophages could induce infiltration of CD8+ T lymphocytes in tumors and improve the immunosuppressive microenvironment. In vivo , PXB17 significantly halted CRC growth, with a stronger effect than PLX3397. In particular, PXB17 potently enhanced therapeutic activity of PD-1 mAb in CT-26 (MSS) model and prevented tumor recurrence in MC-38 (MSI-H) model by promoting formation of long-term memory immunity. Our study opens a new avenue for CSF1R in tumor innate and adaptive anti-tumor immunomodulatory activity and suggests that PXB17 is a promising immunotherapy molecule for enhancing the efficacy of PD-1 mAb or reducing tumor recurrence of CRC. [Display omitted] [ABSTRACT FROM AUTHOR]

The development of natural products for potential new drugs faces obstacles such as unknown mechanisms, poor solubility, and limited bioavailability, which limit the broadened applicability of natural products. Therefore, there is a need for advanced pharmaceutical formulations of active compounds or natural products. In recent years, novel nano-drug delivery systems (NDDS) for natural products, including nanosuspensions, nanoliposomes, micelle, microemulsions/self-microemulsions, nanocapsules, and solid lipid nanoparticles, have been developed to improve solubility, bioavailability, and tissue distribution as well as for prolonged retention and enhanced permeation. Here, we updated the NDDS delivery systems used for natural products with the potential enhancement in therapeutic efficiency observed with nano-delivery systems. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: The complete nucleotide sequence of cryptic plasmid pXY3 isolated from Lactobacillus plantarum strain XY3 has been determined. It consisted of a 2968-bp circular molecule with a G+C content of 39%. Sequence analysis of pXY3 revealed three putative open reading frames (ORFs). Based on sequence similarity, the Rep protein shared 89% and 88% identity with Rep proteins of pLF24 and pWCFS102, respectively, which belonged to the rolling-circle replication (RCR) pMV158 family. A ssoT-like single-strand origin (sso) and a typical pMV158 family double-strand origin (dso) located upstream of the rep gene. Southern blot analysis indicated pXY3 replicate via a rolling-circle (RC) mechanism. Furthermore, the relative copy number of pXY3 was estimated to be about 97 copies per chromosome equivalent by real-time PCR. [Copyright &y& Elsevier]

The uniform growth of monodisperse nickel phosphide nanoparticles on the surface of graphene can greatly enhance the interfacial polarization effect, and makes it an ideal electromagnetic wave (EM) absorbing material. However, the dispersion and size control of nickel phosphide nanoparticles on graphene remains very challenging. In this work, the monodisperse Ni 2 P nanoparticles had been controllably fabricated and in situ grown uniformly on the surface of reduced graphene oxide (rGO) with the colloidal solution method. The monodisperse mosaic-like nickel phosphide nanoparticles were also obtained by controlling the reaction time and addition amount of rGO. The prepared materials were characterized by the powder XRD, TEM, XPS, Raman and so on. The size of the mosaic large particles and small particles was about 45 and 6 nm, respectively. When this composite was used for EM absorption, excellent EM absorption characteristics in the 2–18 GHz band had been displayed. Its effective EM absorption bandwidth can be up to 3.79 GHz at 1.5 mm thickness, and the minimum reflection loss can be up to −38.3 dB at 2 mm thickness. It could be attributed to the increased EM wave scattering by mosaic large particles in situ grown on rGO, and more interfacial polarization active sites provided by the interface of mosaic small particles and rGO. This unusual hybrid is expected to be a potential candidate for the outstanding EM wave absorption performance. [Display omitted] 1. We successfully synthesized Ni 2 P/rGO using cheap and low-toxic raw materials. 2. The Ni 2 P grown in situ on rGO are highly uniform and dispersed. 3. We explored the growth mechanism of Ni 2 P on rGO. 4. The Ni 2 P/rGO has excellent electromagnetic shielding characteristics. 5. This synthesis method can be extended to the synthesis of other materials. [ABSTRACT FROM AUTHOR]

Cisplatin is one of the most effective anti-cancer drugs, but its efficacy is limited by the development of resistance. Previous studies have shown that mitochondria play critical roles in cisplatin cytotoxicity, however, the exact mechanism of mitochondria involved in cisplatin sensitivity has not been clarified. In this study, cisplatin triggered mitochondrial oxidative stress and the decrease of mitochondria membrane potential in human cervical cancer cells. Then we screened a series of mitochondrial relevant inhibitors, including mitochondrial mPTP inhibitors DIDS and CsA, and mitochondrial respiratory complex inhibitors Rot and TTFA. Among these, only DIDS, as the inhibitor of mitochondrial outer membrane protein VDAC1, showed strong antagonism against cisplatin toxicity. DIDS mitigated cisplatin-induced MFN1-dependent mitochondrial fusion, mitochondrial dysfunction and oxidative damage. These findings demonstrated that VDAC1 may serve as a potential therapeutic target in the increase sensitivity of cisplatin, which provides an attractive pharmacological therapy to improve the effectiveness of chemotherapy. • VDAC1 oligomerization inhibitors DIDS antagonizes cisplatin toxicity. • DIDS inhibits cisplatin-induced mitochondria fusion. [ABSTRACT FROM AUTHOR]

The trade of Chinese medicines (CMs) has developed rapidly worldwide. There is an urgent need for international standards of CMs in international trade. A newly established technical committee TC249 in the International Organization for Standardization (ISO) provides a platform for developing the international standards of traditional Chinese medicine. This article introduces the overview and development strategy of the international standardization of CMs. A quality assurance system for the entire industrial chain was well designed in the fields of seedlings, medicinal materials, and manufactured products. The general standards, testing method standards, and standards for single herbal medicines meet the urgent needs of the market and should be developed with high priority to promote the international trade of CMs and guarantee the quality and safety of clinical use. This article also introduces the significance, classification, and procedures for developing international standards of CMs and helps us better understand the international standardization work of CMs. [ABSTRACT FROM AUTHOR]

Helicobacter pylori (H. pylori) infection can promote the development of gastric cancer (GC); however, the underlying mechanism is not clear. FAM60A has been found showing high levels in some cancer cells, including lung cancer (A549), and pancreatic cancer (Capan-2) cell lines. Data in oncomine showed that FAM60A overexpression was an critical prognostic factor in GC. In this study, we showed that knockdown of FAM60A could revert the increase of proliferation and the decrease of apoptosis caused by H.pylori infection in HGC-27 and AGS cells. Conversely, FAM60A upregulation promoted proliferation and inhibited apoptosis in HGC-27 and AGS cells. We also found that the PI3K/AKT pathway inhibitor LY294002 could revert the changes caused by FAM60A upregulation in HGC-27 and AGS cells. Thus, our study provides evidence that FAM60A act as a carcinogen and suggests that H. pylori-induced upregulation of FAM60A may contribute to the development of gastric cancer. • We firstly demonstrated the overexpression of FAM60A led to the poor prognosis of gastric cancer. • We found FAM60A was increased by H.pylori, which probably helps H.pylori promoting the development of gastric cancer. • We demonstrated that FAM60A could promote the proliferation of gastric cancer cells through the PI3K/AKT pathway. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Inflammatory bowel disease (IBD), majorly include Crohn's disease (CD) and ulcerative colitis (UC), is chronic and relapsing inflammatory disorders of the gastrointestinal tract, which treatment options remain limited. Here we examined the therapeutic effects of an isoquinoline alkaloid, Palmatine (Pal), on mice experimental colitis induced by dextran sulfate sodium (DSS) and explored underlying mechanisms. Colitis was induced in BALB/c mice by administering 3% DSS in drinking water for 7 days. Pal (50 and 100 mg kg−1) and the positive drug Sulfasalazine (SASP, 200 mg kg−1) were orally administered for 7 days. Disease activity index (DAI) was evaluated on day 8, and colonic tissues were collected for biochemistry analysis. The fecal microbiota was characterized by high-throughput Illumina MiSeq sequencing. And plasma metabolic changes were detected by UPLC-MS. Our results showed that Pal treatment significantly reduced DAI scores and ameliorated colonic injury in mice with DSS-induced colitis. Mucosal integrity was improved and cell apoptosis was inhibited. Moreover, gut microbiota analysis showed that mice received Pal-treatment have higher relative abundance of Bacteroidetes and Firmicutes, but reduced amount of Proteobacteria. Moreover, Pal not only suppressed tryptophan catabolism in plasma, but also decreased the protein expression of indoleamine 2,3-dioxygenase 1 (IDO-1, the rate-limiting enzyme of tryptophan catabolism) in colon tissue. This is consolidated by molecular docking, which suggested that Pal is a potent IDO-1 inhibitor. Taken together, our findings demonstrate that Pal ameliorated DSS-induced colitis by mitigating colonic injury, preventing gut microbiota dysbiosis, and regulating tryptophan catabolism, which indicated that Pal has great therapeutic potential for colitis. [ABSTRACT FROM AUTHOR]

Biological responses of a variety of naturally occurring compounds in vivo were restrained by their poor oral bioavailability. Silybin, as one of the active ingredients of silymarin, has presented promising bioactivity for the treatment of chronic liver diseases and cancer. However, its exposure in body was limited. In this study, silybin was demonstrated to be substrates of both BCRP and MRP2 by utilizing monolayer Caco-2 cell model and confirmed in MDCK cells overexpressing specific efflux transporter. Of all compounds screened, tangeretin, a potent inhibitor of efflux transporters of BCRP, MRP2 and P-gp, was able to enhance exposure of silybin by inhibiting functions of the barriers mediating transcellular transport. Moreover, study carried out in sandwich-cultured rat hepatocyte (SCH) model showed that the biliary excretion index (BEI) and in vitro biliary clearance of silybin decreased as levels of tangeretin increased, indicating efflux transporters mediating biliary excretion of silybin might be involved. Pharmacokinetic behaviors of silybin in rats were altered by co-administration of tangeretin, in terms of increased AUC and Cmax of silybin by comparing with that of silybin given alone. In addition, results coming from CCl 4 -induced acute liver injury rat model revealed that protection effect of silybin against liver damage in the presence of tangeretin was significantly enhanced. All these data were evident that efflux transporters play a critical role in transcellular transport of silybin and account for its low bioavailability. Enhanced bioavailability of silybin with co-administration of tangeretin by significantly inhibiting the efflux transporters further boost its bioactivity which is of particular importance in clinical use. [ABSTRACT FROM AUTHOR]

Despite the increased morbidity of ulcerative colitis (UC) in recent years, available treatments remain unsatisfactory. Pogostemon cablin has been widely applied to treat a variety of gastrointestinal disorders in clinic for centuries, in which patchouli alcohol (PA, C 15 H 26 O) has been identified as the major active component. This study attempted to determine the bioactivity of PA on dextran sulfate sodium (DSS)-induced mice colitis and clarify the mechanism of action. Acute colitis was induced in mice by 3% DSS for 7 days. The mice were then given PA (10, 20 and 40 mg/kg) or sulfasalazine (SASP, 200 mg/kg) as positive control via oral administration for 7 days. At the end of study, animals were sacrificed and samples were collected for pathological and other analysis. In addition, a metabolite profiling and a targeted metabolite analysis, based on the Ultra-Performance Liquid Chromatography coupled with mass spectrometry (UPLC–MS) approach, were performed to characterize the metabolic changes in plasma. The results revealed that PA significantly reduced the disease activity index (DAI) and ameliorated the colonic injury of DSS mice. The levels of colonic MPO and cytokines involving TNF-α, IFN-γ, IL-1β, IL-6, IL-4 and IL-10 also declined. Furthermore, PA improved the intestinal epithelial barrier by enhancing the level of colonic expression of the tight junction (TJ) proteins, for instance ZO-1, ZO-2, claudin-1 and occludin, and by elevating the levels of mucin-1 and mucin-2 mRNA. The study also demonstrated that PA inhibited the DSS-induced cell death signaling by modulating the apoptosis related Bax and Bcl-2 proteins and down-regulating the necroptosis related RIP3 and MLKL proteins. By comparison, up-regulation of IDO-1 and TPH-1 protein expression in DSS group was suppressed by PA, which was in line with the declined levels of kynurenine (Kyn) and 5-hydroxytryptophan (5-HTP) in plasma. The therapeutic effect of PA was evidently reduced when Kyn was given to mice. In summary, the study successfully demonstrated that PA ameliorated DSS-induced mice acute colitis by suppressing inflammation, maintaining the integrity of intestinal epithelial barrier, inhibiting cell death signaling, and suppressing tryptophan catabolism. The results provided valuable information and guidance for using PA in treatment of UC. [ABSTRACT FROM AUTHOR]

Foam cell formation, which is caused by imbalanced cholesterol influx and efflux by macrophages, plays a vital role in the occurrence and development of atherosclerosis. Humanin (HN), a mitochondria-derived peptide, can prevent the production of reactive oxygen species and death of human aortic endothelial cells exposed to oxidized low-density lipoprotein (ox-LDL) and has a protective effect on patients with in early atherosclerosis. However, the effects of HN on the regulation of cholesterol metabolism in RAW 264.7 macrophages are still unknown. This study was designed to investigate the role of [Gly14]-humanin (HNG) in lipid uptake and cholesterol efflux in RAW 264.7 macrophages. Flow cytometry and live cell imaging results showed that HNG reduced Dil-ox-LDL accumulation in the RAW 264.7 macrophages. A similar result was obtained for lipid accumulation by measuring cellular cholesterol content. Western blot analysis showed that ox-LDL treatment upregulated not only the protein expression of CD36 and LOX-1, which mediate ox-LDL endocytosis, but also ATP-binding cassette (ABC) transporter A1 and ABCG1, which mediate ox-LDL exflux. HNG pretreatment inhibited the upregulation of CD36 and LOX-1 levels, prompting the upregulation of ABCA1 and ABCG1 levels induced by ox-LDL. Therefore we concluded that HNG could inhibit ox-LDL-induced macrophage-derived foam cell formation, which occurs because of a decrease in lipid uptake and an increase in cholesterol efflux from macrophage cells. [ABSTRACT FROM AUTHOR]

[Display omitted] • The role of the complexin CTD in regulating SV exocytosis is controversial due to conflicting functional studies. • The isolated mCpx1 CTD is largely disordered, but forms two discontinuous helical structures in the presence of micelles. • This helical structure also forms in the presence of SUVs, as confirmed by CD, ESR and fluorescence spectroscopies. • The mCpx1 CTD interacts with LUVs in a lipid dependent fashion. • Differences between the mCpx1 and wCpx1 CTDs suggest a mechanistic basis for functional differences between the proteins. Complexins play a critical role in regulating SNARE-mediated exocytosis of synaptic vesicles. Evolutionary divergences in complexin function have complicated our understanding of the role these proteins play in inhibiting the spontaneous fusion of vesicles. Previous structural and functional characterizations of worm and mouse complexins have indicated the membrane curvature-sensing C-terminal domain of these proteins is responsible for differences in inhibitory function. We have characterized the structure and dynamics of the mCpx1 CTD in the absence and presence of membranes and membrane mimetics using NMR, ESR, and optical spectroscopies. In the absence of lipids, the mCpx1 CTD features a short helix near its N-terminus and is otherwise disordered. In the presence of micelles and small unilamellar vesicles, the mCpx1 CTD forms a discontinuous helical structure in its C-terminal 20 amino acids, with no preference for specific lipid compositions. In contrast, the mCpx1 CTD shows distinct compositional preferences in its interactions with large unilamellar vesicles. These studies identify structural divergences in the mCpx1 CTD relative to the wCpx1 CTD in regions that are known to be critical to the wCpx1 CTD's role in inhibiting spontaneous fusion of synaptic vesicles, suggesting a potential structural basis for evolutionary divergences in complexin function. 1 1 Abbreviations used: SVs, synaptic vesicles; NTD, N-terminal domain; AHD, accessory helical domain; CHD, central helix domain; CTD, C-terminal domain; intrinsically disordered (ID); wCpx1, worm (Caenorhabditis elegans) complexin 1; AH, amphipathic helix; CT, C-terminal motif; mCpx1, mouse (Mus musculus) complexin 1; SUV, small unilamellar vesicle; LUV, large unilamellar vesicle; NMR, nuclear magnetic resonance; CD, circular dichroism; ESR, electron spin resonance; cwESR, continuous wave ESR; DEER, double electron–electron resonance; DPC, dodecylphosphocholine; POPC, 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine; POPS, 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-L-serine; DOPC, 1,2-dioleoyl-sn-glycero-3-phosphocholine; DOPE, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine; DOPS, 1,2-dioleoyl-sn-glycero-3-phospho-L-serine; DO, 1,2-dioleoyl; PO, 1-palmitoyl-2-oleoyl. [ABSTRACT FROM AUTHOR]

Breast cancer, the most frequent cancer in women, is the second leading cause of cancer-related death. Estrogens and estrogen receptors are well recognized to play predominant roles in breast cancer development and growth. Neo-tanshinlactone is a natural product isolated from Salvia miltiorrhiza and showed selective growth inhibition of ER+ breast cancer cell lines as demonstrated by cell proliferation assay and colony formation assay. The selective anti-proliferative effect of neo-tanshinlactone was associated with the induction of apoptosis in ER+ breast cancer cells. We also found that neo-tanshinlactone decreased steady state ESR1 mRNA levels in ER+ breast cancer cells, which was further confirmed by analysis of ER protein levels as well as the mRNA levels of target genes of this transcription factor, such as ESR2 , BRCA1 , CCND1 , GREB1 , TFF1 , SERPINB9 and ABCA3 . Furthermore, analysis of heterogeneous nuclear RNA (hnRNA) demonstrated that neo-tanshinlactone inhibited ESR1 mRNA de novo synthesis. The decrease of steady state ESR1 mRNA upon neo-tanshinlactone treatment was not abolished by protein synthesis inhibitor cycloheximide. And inhibition of mRNA synthesis with actinomycin D revealed no significant effect of neo-tanshinlactone on ESR1 mRNA stability. These results indicated that transcriptional down-regulation of ESR1 mRNA could contribute to the selective activity of neo-tanshinlactone on ER+ breast cancer cells. And as expected, the combination of neo-tanshinlactone and antiestrogen reagent tamoxifen showed a synergistic effect on growth of ER+ MCF7 cells. Our results suggest that neo-tanshinlactone is a promising regimen for ER+ breast tumors. [ABSTRACT FROM AUTHOR]

Multidrug resistance (MDR) and tumor metastasis are the main causes of chemotherapeutic treatment failure and mortality in cancer patients. In this study, at achievable nontoxic plasma concentrations, citrus flavonoid tangeretin has been shown to reverse ABCB1-mediated cancer resistance to a variety of chemotherapeutic agents effectively. Co-treatment of cells with tangeretin and paclitaxel activated apoptosis as well as arrested cell cycle at G2/M-phase. Tangeretin profoundly inhibited the ABCB1 transporter activity since it significantly increased the intracellular accumulation of doxorubicin, and flutax-2 in A2780/T cells and decreased the efflux of ABCB1 substrates in Caco2 cells without altering the expression of ABCB1. Moreover, it stimulated the ATPase activity and inhibited verapamil-stimulated ATPase activity in a concentration-dependent manner, indicating a direct interaction with the transporter. The molecular docking results indicated a favorable binding of tangeretin with the transmemberane region site 1 of homology modeled ABCB1 transporter. The overall results demonstrated that tangeretin could sensitize ABCB1-overexpressing cancer cells to chemotherapeutical agents by directly inhibiting ABCB1 transporter function, which encouraged further animal and clinical studies in the treatment of resistant cancers. [ABSTRACT FROM AUTHOR]

Non-steroidal anti-inflammatory drugs (NSAIDs) relieve inflammation by suppressing prostaglandin E 2 /cyclooxygenase 2 (PGE 2 /COX-2) with cardiovascular and gastrointestinal bleeding risk. Theoretically, suppressing PGE 2 through inhibiting the terminal synthase microsomal prostaglandin E 2 synthase-1 (mPGES-1) instead of upstream COX-2 is ideal for inflammation. Here, (9 S ,13 R)−12-oxo-phytodienoic acid (AA-24) extracted from Artemisia anomala was first screened as an anti-inflammatory candidate and decreased inducible nitric oxide synthase (iNOS), nitric oxide (NO), mPGES-1, and PGE 2 without affecting COX-1/2, thromboxane A 2 (TXA 2) and prostaglandin I 2 (PGI 2). Besides, AA-24 suppressed the differentiation of M0 macrophages to M1 phenotype but enhanced it to M2 phenotype, blocked the activation of NF-κB pathway, and increased the activation of Nrf2 and heme oxygenase-1 (HO-1). Moreover, AA-24 selectively inhibited mPGES-1 and reduced inflamed paw edema in carrageenan-induced mice. In conclusion, AA-24 attenuates inflammation by inhibiting mPGES-1 and modulating macrophage polarization via the NF-κB and Nrf2/HO-1 pathways and could be a promising candidate for developing anti-inflammatory drugs. [Display omitted] • (9S,13R)−12-oxo-phytodienoic acid (AA-24) was first extracted from Artemisia anomala. • AA-24 selectively reduced inducible PGE 2 via inhibiting mPGES-1 but not COX-1/2 in vivo and in vitro. • AA-24 suppressed the differentiation of M0 macrophages to M1 phenotype but enhanced it to M2. • AA-24 regulated the activation of NF-κB and Nrf2/HO-1 pathways but not the MAPK pathway. • AA-24 could be developed as a promising drug to relieve inflammation. [ABSTRACT FROM AUTHOR]

Renal interstitial fibrosis (RIF) is the common irreversible pathway by which chronic kidney disease (CKD) progresses to the end stage. The transforming growth factor-β (TGF-β)/signal transducer and activator of transcription 3 (STAT3) signaling pathway is a common factor leading to inflammation-mediated RIF, but its downstream regulatory mechanism is still unclear. Bioinformatics analysis predicted that serum amyloid A protein 1 (SAA1) was one of the target genes for transcriptional activation of STAT3 signaling. As an acute phase reaction protein, SAA1 plays an important role in many inflammatory reactions, and research has suggested that SAA1 is significantly elevated in the serum of patients with CKD. In this research, multiple experiments were performed to investigate the role of SAA1 in the process of RIF. SAA1 was abnormally highly expressed in kidney tissue from individuals who underwent unilateral ureteral obstruction (UUO) and TGF-β-induced HK2 cells, and the abnormal expression was directly related to the transcriptional activation of STAT3. Additionally, SAA1 can directly target and bind valosin-containing protein (VCP)-interacting membrane selenoprotein (VIMP) to inhibit the function of the Derlin-1/VCP/VIMP complex, preventing the transportation and degradation of the misfolded protein, resulting in endoplasmic reticulum (ER) stress characterized by an increase in glucose-regulated protein 78 (GRP78) levels and ultimately promoting the occurrence and development of RIF. [ABSTRACT FROM AUTHOR]

Currently, conventional methods of treating non-small cell lung cancer (NSCLC) have many disadvantages. An alternative effective therapy with minimal adverse reactions is urgently needed. Weijing decoction (WJD), which is a classic ancient Chinese herbal prescription, has been used successfully to treat pulmonary system diseases containing lung cancer in the clinic. However, the key active component and target of Weijing decoction are still unexplored. Therefore, for the first time, our study aims to investigate the pharmacological treatment mechanism of Weijing decoction in treating NSCLC via an integrated model of network pharmacology, metabolomics and biological methods. Network pharmacology results conjectured that Tricin is a main bioactive component in this formula which targets PRKCA to suppress cancer cell growth. Metabolomics analysis demonstrated that sphingosine-1-phosphate, which is regulated by sphingosine kinase 1 and sphingosine kinase 2, is a differential metabolite in plasma between the WJD-treated group and the control group, participating in the sphingolipid signaling. In vitro experiments demonstrated that Tricin had vital effects on the proliferation, pro-apoptosis, migration and colony formation of Lewis lung carcinoma cells. Through a series of validation assays, Tricin inhibited the tumor growth mainly by suppressing PRKCA/SPHK/S1P signaling and antiapoptotic signaling. On the other hand, Weijing formula could inhibit the tumor growth and prolong the survival time. A high dosage of Tricin was much more potent in animal experiments. In conclusion, we confirmed that Weijing formula and its primary active compound Tricin are promising alternative treatments for NSCLC patients. [Display omitted] • Classic Weijing formula has been explored via network pharmacology and metabolomics for the first time. • Weijing decoction is highly effective in suppressing lung cancer growth and prolonging survival. • Tricin is the main active compound in Weijing decoction which has an inhibitory effect on protein kinase C alpha (PRKCA). • Tricin reduces the expression of sphingosine kinase 1 and 2, resulting in regulation of the sphingolipid signaling. • High-dose of Tricin suppresses lung cancer growth without reducing body weight in a xenograft mouse model. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a chronic multi-system autoimmune disease with extremely complex pathogenesis. Significantly altered lipid paradox related to the inflammatory burden is reported in RA patients, inducing 50% higher cardiovascular risks. Recent studies have also demonstrated that lipid metabolism can regulate many functions of immune cells in which metabolic pathways have altered. The nuclear liver X receptors (LXRs), including LXRα and LXRβ, play a central role in regulating lipid homeostasis and inflammatory responses. Undoubtedly, LXRs have been considered as an attractive therapeutic target for the treatment of RA. However, there are some contradictory effects of LXRs agonists observed in previous animal studies where both pro-inflammatory role and anti-inflammatory role were revealed for LXRs activation in RA. Therefore, in addition to updating the knowledge of LXRs as the prominent regulators of lipid homeostasis, the purpose of this review is to summarize the effects of LXRs agonists in RA-associated immune cells, to explore the underlying reasons for the contradictory therapeutic effects of LXRs agonists observed in RA animal models, and to discuss future strategy for the treatment of RA with LXRs modulators. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: To analyze the anti-arthritic effects of QFGJS (a pharmaceutical preparation from herbs) on rheumatoid arthritis, adjuvant-induced arthritis (AIA) was established in male SD rats, and two administration protocols, i.e., oral treatment with different doses of QFGJS on the day of arthritis induction or on the day when visible clinical signs of arthritis occurred, were initiated and continued until day 30. Treatments with QFGJS using both administration protocols significantly suppressed the incidence and severity of arthritis in a dose-dependent manner, showing dramatic reduction of paw swelling and ESR throughout the disease progression of AIA. Radiological and histopathological examinations showed markedly decreased tissue and bone destruction of ankle joints in the QFGJS-treated rats. The serum levels of TNF-α, IL-1β, and IL-6 were significantly decreased in the QFGJS-treated rats. QFGJS demonstrates pronounced anti-arthritic effects on AIA, indicating that this herbal preparation would be a potent candidate as a novel botanical drug for further investigation. [Copyright &y& Elsevier]

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by inflammatory synovitis and progressive joint. Although the etiology is extremely complex, overwhelming evidence suggests that dysregulation or imbalance of the immune system plays a central role in disease pathogenesis. The bone loss and joint destruction are immunological insults mediated by infiltration and abnormal activation of various immune cells. Since pharmacological inhibition of cyclic nucleotide phosphodiesterases (PDEs), which degrade cyclic AMP and cyclic GMP, can regulate the activity of multiple immune cells, which are considered as a potential strategy for treating RA. Therefore, this review attempted to summarize the modulating effects of PDEs on immune cells and described the molecular underpinnings and potential clinical application of PDEs inhibitors for RA. [ABSTRACT FROM AUTHOR]

The Coronavirus Disease 2019 (COVID-19) has been declared as a global pandemic, but specific medicines and vaccines are still being developed. In China, interventional therapies with traditional Chinese medicine for COVID-19 have achieved significant clinical efficacies, but the underlying pharmacological mechanisms are still unclear. This article reviewed the etiology of COVID-19 and clinical efficacy. Both network pharmacological study and literature search were used to demonstrate the possible action mechanisms of Chinese medicines in treating COVID-19. We found that Chinese medicines played the role of antivirus, anti-inflammation and immunoregulation, and target organs protection in the management of COVID-19 by multiple components acting on multiple targets at multiple pathways. AEC2 and 3CL protein could be the direct targets for inhibiting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Quercetin, kaempferol, luteolin, isorhamnetin, baicalein, naringenin, and wogonin could be the main active ingredients of Chinese medicines for the management of COVID-19 by targeting on AEC2 and 3CL protein and inhibiting inflammatory mediators, regulating immunity, and eliminating free radicals through COX-2, CASP3, IL-6, MAPK1, MAPK14, MAPK8, and REAL in the signaling pathways of IL-17, arachidonic acid, HIF-1, NF-κB, Ras, and TNF. This study may provide meaningful and useful information on further research to investigate the action mechanisms of Chinese medicines against SARS-CoV-2 and also provide a basis for sharing the "China scheme" for COVID-19 treatment. [ABSTRACT FROM AUTHOR]

Ischemia/reperfusion (I/R) injury is a pathological process caused by reperfusion. The prevention of I/R injury is of great importance as it would enhance the efficacy of myocardial infarction treatment in patients. Isovaleroylbinankadsurin A (ISBA) has been demonstrated to possess multiple bioactivities for treating diseases. However, its protective effect on myocardial I/R injury remains unknown. In this study, the cardiomyocytes hypoxia/reoxygenation (H/R) in vitro model and coronary artery ligation in vivo model were used to examine the protective effect of ISBA. Apoptosis was determined by flow cytometry and Caspase 3 activity. Protein level was determined by Western blot. The mitochondrial viability was examined with mitochondrial viability stain assay. Mitochondrial membrane potential was detected by JC-1 staining and reactive oxygen species (ROS) was stained with 2′,7′-dichlorodihydrofluorescein diacetate (DCF-DA). The binding interactions between ISBA and receptors was simulated by molecular docking. Results showed that ISBA effectively protected cardiomyocytes from I/R injury in in vitro and in vivo models. It remarkably blocked the apoptosis induced by H/R injury through the mitochondrial dependent pathway. Activation of the reperfusion injury salvage kinase (RISK) pathway was demonstrated to be essential for ISBA to exert its protective effect on cardiomyocytes. Moreover, molecular docking indicated that ISBA could directly bind to glucocorticoid receptor (GR) and thus induce its activation. Furthermore, the treatment of GR inhibitor RU486 partially counteracted the protective effect of ISBA on cardiomyocytes, consistent with the results of docking.Most attractively, by activating GR dependent RISK pathway, ISBA significantly elevated the cellular anti-oxidative capacity and hence alleviated oxidative damage induced by I/R injury. In conclusion, our study proved that ISBA protected the heart from myocardial I/R injury through activating GR dependent RISK pathway and consequently inhibiting the ROS generation. It provides a valuable reference for ISBA to be developed as a candidate drug for cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Silybin (SB) is widely used to treat chronic liver diseases, especially this compound is much efficient for the treatments of alcoholic and non-alcoholic steatohepatitis (NASH). However, low bioavailability seriously limits wide-application of SB in biomedical niche. Prior to this study, we found that tangeretin (TG) could remarkably increase the bioavailability of SB by the inhibition of efflux transporters, which encourges us to therapeutical discovery of SB and TG combitional use against NASH. Here, we revealed that TG is capable of improving hepatic-protective activity of SB in mice with NASH by interfering liver oxidative stress, inflammation, and lipid accumulation. In addition, TG was observed to enhance the exposural level of SB in the plasma and liver of mice. Our metabolome assay confirmed that amino acid metabolism and lipid biosynthesis mostly accounted for combitional use of SB and TG to teat NASH in mice, basically biosynthesis of unsaturated fatty acids was mostly affected. Notably, significant inhibitions in fatty acid generating and transporting proteins such as G6PD, FABP4, LPL and CD36/FAT, and cholesterol metabolism enzyme CYP27A1 as well as nuclear transcription factors FXR, PPAR-γ, and LXR were illustrated to decipher therapeutic mechanisms of SB and TG against experimental NASH. Taken together, the strategy based combitional use of SB and TG has a potential-capacity to treat NASH. [ABSTRACT FROM AUTHOR]

Previous studies showed that dopamine (DA) significantly reduces the frequency of cancer stem-like cells (CSC) and enhances the efficacy of sunitinib (SUN) in the treatment of breast cancer and non-small cell lung cancer (NSCLC). To overcome the shortcomings of DA in clinical practice, the purpose of this study was to investigate the efficacy as well as the underlying mechanism of an orally available, N-arylpiperazine-containing compound C2, in the treatment of pancreatic cancer when used alone or in combination with SUN. Our results showed that C2 and SUN exerted synergistic effects on inhibiting the growth of SW1990 and PANC-1 pancreatic cancer cells. C2 significantly inhibited colony formation and migration of both cells. SW1990 xenograft and patient-derived xenograft (PDX) models were utilized for pharmacodynamic investigation in vivo. C2 alone showed little inhibition effect on tumor growth but increased the anti-tumor efficacy of SUN in both xenografts. Moreover, C2 down-regulated CSC markers (CD133 and ALDH) of both cancer cells and up-regulated the expression of dopamine receptor D1 (D1DR) in tumor. Besides, the SW1990 tumor growth was dose-dependently inhibited when the cells were pretreated with C2 before implantation. C2 increased intratumoral cAMP level, and the combination with D1DR specific antagonist SCH23390 reversed the above-mentioned effects of C2 both in vitro and in vivo , indicating the activation of D1DR may be involved in the underlying mechanism of C2 action. In summary, C2 could reduce the CSC frequency and enhance the anti-cancer effect of SUN in the treatment of pancreatic cancer, demonstrating its potential in cancer therapy. [ABSTRACT FROM AUTHOR]

Nasopharyngeal carcinoma (NPC) is a malignancy with ethnic and geographic distribution in southern China. The pathogenesis of NPC is a complicated process involving environment factors, genetic susceptibility, infection with the Epstein-Barr virus (EBV) and epigenetic changes. Unlike all other head neck squamous cell carcinomas, NPC is strongly associated with EBV infection, which can mediate nitrative and oxidative DNA damage and epigenetic changes. Reactive nitrogen and oxygen species are considered to participate in inflammation-related carcinogenesis through DNA damage. It is reported that nitric oxide (NO) can activate DNA methyltransferase (DNMT) and modify CpG island methylation. We have found promoter hypermethylation in several candidate genes for tumor suppressor genes in NPC. By examined the expression levels of EBV encoded small RNA (EBER) s, the formation of 8-nitroguanine and 8-hydroxy-2′-deoxyguanosine (8-OHdG), DMNT1 and 5-methyl-dC in NPC biopsies and non-cancerous controls, we studied the relationship between EBV infection, inflammation and epigenetic modification in NPC. Strong DNA lesions were observed in cancer cells and inflammatory cells in stroma of NPC tumor biopsies. Intensive immunoreactivity of iNOS was detected in the cytoplasm of 8-nitroguanine-positive cancer cells. Significantly higher levels of serum 8-OHdG, IL-6 and higher titers of EB-viral capsid antigen-IgA were observed in NPC patients than those of controls. Interestingly, the results of EBER in situ hybridization showed significant association with DNMT1 and 5-methyl-dC. These results indicate that EBV-mediated inflammation may play a role in cytosine methylation during NPC development. [Copyright &y& Elsevier]