PANX1-mediated ATP release confers FAM3A's suppression effects on hepatic gluconeogenesis and lipogenesis.

BACKGROUND: Extracellular adenosine triphosphate (ATP) is an important signal molecule. In previous studies, intensive research had revealed the crucial roles of family with sequence similarity 3 member A (FAM3A) in controlling hepatic glucolipid metabolism, islet ß cell function, adipocyte differentiation, blood pressure, and other biological and pathophysiological processes. Although mitochondrial protein FAM3A plays crucial roles in the regulation of glucolipid metabolism via stimulating ATP release to activate P2 receptor pathways, its mechanism in promoting ATP release in hepatocytes remains unrevealed. METHODS: db/db, high-fat diet (HFD)-fed, and global pannexin 1 (PANX1) knockout mice, as well as liver sections of individuals, were used in this study. Adenoviruses and adeno-associated viruses were utilized for in vivo gene overexpression or inhibition. To evaluate the metabolic status in mice, oral glucose tolerance test (OGTT), pyruvate tolerance test (PTT), insulin tolerance test (ITT), and magnetic resonance imaging (MRI) were conducted. Protein-protein interactions were determined by coimmunoprecipitation with mass spectrometry (MS) assays. RESULTS: In livers of individuals and mice with steatosis, the expression of ATP-permeable channel PANX1 was increased (P < 0.01). Hepatic PANX1 overexpression ameliorated the dysregulated glucolipid metabolism in obese mice. Mice with hepatic PANX1 knockdown or global PANX1 knockout exhibited disturbed glucolipid metabolism. Restoration of hepatic PANX1 rescued the metabolic disorders of PANX1-deficient mice (P < 0.05). Mechanistically, ATP release is mediated by the PANX1-activated protein kinase B-forkhead box protein O1 (Akt-FOXO1) pathway to inhibit gluconeogenesis via P2Y receptors in hepatocytes. PANX1-mediated ATP release also activated calmodulin (CaM) (P < 0.01), which interacted with c-Jun N-terminal kinase (JNK) to inhibit its activity, thereby deactivating the transcription factor activator protein-1 (AP1) and repressing fatty acid synthase (FAS) expression and lipid synthesis (P < 0.05). FAM3A stimulated the expression of PANX1 via heat shock factor 1 (HSF1) in hepatocytes (P < 0.05). Notably, FAM3A overexpression failed to promote ATP release, inhibit the expression of gluconeogenic and lipogenic genes, and suppress gluconeogenesis and lipid deposition in PANX1-deficient hepatocytes and livers. CONCLUSIONS: PANX1-mediated release of ATP plays a crucial role in maintaining hepatic glucolipid homeostasis, and it confers FAM3A's suppressive effects on hepatic gluconeogenesis and lipogenesis.

Jasminoidin and ursodeoxycholic acid exert synergistic effect against cerebral ischemia-reperfusion injury via Dectin-1-induced NF-κB activation pathway.

BACKGROUND: Jasminoidin (JA) and ursodeoxycholic acid (UA) were shown to act synergistically against ischemic stroke (IS) in our previous studies. PURPOSE: To investigate the holistic synergistic mechanism of JA and UA on cerebral ischemia. METHODS: Middle cerebral artery obstruction reperfusion (MCAO/R) mice were used to evaluate the efficacy of JA, UA, and JA combined with UA (JU) using neurological function testing and infarct volume examination. High-throughput RNA-seq combined with computational prediction and function-integrated analysis was conducted to gain insight into the comprehensive mechanism of synergy. The core mechanism was validated using western blotting. RESULTS: JA and UA synergistically reduced cerebral infarct volume and alleviated neurological deficits and pathological changes in MCAO/R mice. A total of 1437, 396, 1080, and 987 differentially expressed genes were identified in the vehicle, JA, UA, and JU groups, respectively. A strong synergistic effect between JA and UA was predicted using chemical similarity analysis, target profile comparison, and semantic similarity analysis. As the 'long-tail' drugs, the top 20 gene ontology (GO) biological processes of JA, UA, and JU groups primarily reflected inflammatory response and regulation of cytokine production, with specific GO terms of JU revealing enhanced regulation on immune response and tumor necrosis factor superfamily cytokine production. Comparably, the Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling of common targets of JA, UA, and JU focused on extracellular matrix organization and signaling by interleukins, immune system, phagosomes, and lysosomes, which interlock and interweave to produce the synergistic effects of JU. The characteristic signaling pathway identified for JU highlighted the crosstalk between autophagy activation and inflammatory pathways, especially the Dectin-1-induced NF-κB activation pathway, which was validated by in vivo experiments. CONCLUSIONS: JA and UA can synergistically protect cerebral ischemia-reperfusion injury by attenuating Dectin-1-induced NF-κB activation. The strategy integrating high throughput data with computational models enables ever-finer mapping of 'long-tail' drugs to dynamic variations in condition-specific omics to clarify synergistic mechanisms.

The Alleviation of LPS-Induced Murine Acute Lung Injury by GSH-Mediated PEGylated Artesunate Prodrugs.

Acute lung injury (ALI) or its aggravated stage acute respiratory distress syndrome (ARDS) is a common severe clinical syndrome in intensive care unit, may lead to a life-threatening form of respiratory failure, resulting in high mortality up to 30-40% in most studies. Nanotechnology-mediated anti-inflammatory therapy is an emerging novel strategy for the treatment of ALI, has been demonstrated with unique advantages in solving the dilemma of ALI drug therapy. Artesunate (ART), a derivative of artemisinin, has been reported to have anti-inflammatory effects. Therefore, in the present study, we designed and synthesized PEGylated ART prodrugs and assessed whether ART prodrugs could attenuate lipopolysaccharide (LPS) induced ALI in vitro and in vivo. All treatment groups were conditioned with ART prodrugs 1 h before challenge with LPS. Significant increased inflammatory cytokines production and decreased GSH levels were observed in the LPS stimulated mouse macrophage cell line RAW264.7. Lung histopathological changes, lung W/D ratio, MPO activity and total neutrophil counts were increased in the LPS-induced murine model of ALI via nasal administration. However, these results can be reversed to some extent by treatment of ART prodrugs. The effectiveness of mPEG2k-SS-ART in inhibition of ALI induced by LPS was confirmed. In conclusion, our results demonstrated that the ART prodrugs could attenuate LPS-induced ALI effectively, and mPEG2k-SS-ART may serve as a novel strategy for treatment of inflammation induced lung injury.

[A mini-review on anti-tumor effect of cannabidiol].

Cannabidiol is the main non-psychoactive component of Cannabis sativa, which has multiple medicinal activities, such as antiepileptic, immunomodulation, analgesic, antioxidant, anticonvulsant, anti-anxiety and other functions. In recent years, it has been found that cannabidiol can inhibit the proliferation of various tumor cells, induce apoptosis and autophagy of tumor cells, arrest cell cycle, interrupt invasion and metastasis of tumor cells, regulate tumor microenvironment, exert synergistic therapy with other chemotherapeutic drugs, and reduce the toxicity of chemotherapeutic drugs. However, its anti-tumor effect remains controversial and its application is limited. The study of microspheres, nano liposomes and other new drug delivery systems can improve the anti-tumor effect of cannabidiol. In this study, the anti-tumor mechanism and application of cannabidiol were summarized and discussed in order to provide inspirations for its further investigation and application.

Isolation of two rare N-glycosides from Ginkgo biloba and their anti-inflammatory activities.

Two rare N-ß-D-glucopyranosyl-1H-indole-3-acetic acid conjugates, N-[2-(1-ß-D-glucopyranosyl)-1H-indol-3-yl)acetyl]-L-glutamic acid (1) and N-[2-(1-ß-D-glucopyranosyl)-1H-indol-3-yl)acetyl]-L-aspartic acid (2) were isolated from Ginkgo biloba. The structures were elucidated by analyses of HRMS and NMR spectroscopic data. In addition, a simplified and efficient synthetic route for compounds 1 and 2 is also disclosed to determine the absolute configurations of them. This concise syntheses of compounds 1 and 2 may facilitate studies of the biology of this type alkaloids. Compounds 1 and 2 were also tested for their cytotoxic and anti-inflammatory activities. The biological evaluation showed that compounds 1 and 2 led to the decrease of interleukin (IL)-6, nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 at mRNA level in lipopolysaccharide (LPS)-stimulated murine macrophage RAW264.7 cells.

pH-Responsive Artesunate Polymer Prodrugs with Enhanced Ablation Effect on Rodent Xenograft Colon Cancer.

PURPOSE: In this study, pH-sensitive poly(2-ethyl-2-oxazoline)-poly(lactic acid)-poly(ß-amino ester) (PEOz-PLA-PBAE) triblock copolymers were synthesized and were conjugated with an antimalaria drug artesunate (ART), for inhibition of a colon cancer xenograft model. METHODS: The as-prepared polymer prodrugs are tended to self-assemble into polymeric micelles in aqueous milieu, with PEOz segment as hydrophilic shell and PLA-PBAE segment as hydrophobic core. RESULTS: The pH sensitivity of the as-prepared copolymers was confirmed by acid-base titration with pKb values around 6.5. The drug-conjugated polymer micelles showed high stability for at least 96 h in PBS and 37°C, respectively. The as-prepared copolymer prodrugs showed high drug loading content, with 9.57%±1.24% of drug loading for PEOz-PLA-PBAE-ART4. The conjugated ART could be released in a sustained and pH-dependent manner, with 92% of released drug at pH 6.0 and 57% of drug released at pH 7.4, respectively. In addition, in vitro experiments showed higher inhibitory effect of the prodrugs on rodent CT-26 cells than that of free ART. Animal studies also demonstrated the enhanced inhibitory efficacy of PEOz-PLA-PBAE-ART2 micelles on the growth of rodent xenograft tumor. CONCLUSION: The pH-responsive artesunate polymer prodrugs are promising candidates for colon cancer adjuvant therapy.

[Preparation of docetaxel-loaded nanomicelles and their anti-Lewis lung cancer effect in vitro].

Docetaxel-loaded nanomicelles were prepared in this study to improve the solubility and tumor targeting effect of docetaxel(DTX),and further evaluate their anticancer effects in vitro. PBAE-DTX nanomicelles were prepared by film-hydration method with amphiphilic block copolymer polyethyleneglycol methoxy-polylactide(PELA) and pH sensitive triblock copolymer polyethyleneglycol methoxy-polylactide-poly-ß-aminoester(PBAE) were used respectively to prepare PELA-DTX nanomicelles and PBAE-DTX nanomicelles. The nanomicelles were characterized by physicochemical properties and the activity of mice Lewis lung cancer cells was studied. The results of particle size measurement showed that the blank micelles and drug-loaded micelles had similar particle sizes, ranging from 10 to 100 nm. The particle size of PBAE micelles was changed under weak acidic conditions, with good pH response. The encapsulation efficiency of the above two types of DTX-loaded nanomicelles determined by HPLC was(93.8±1.70)% and(87.2±4.10)%, and the drug loading amount was(5.3±0.10)% and(4.9±0.05)%,respectively. Furthermore,the DTX micelles also showed significant inhibitory effects on Lewis lung cancer cells by MTT assay, and pH-sensitive PBAE-DTX showed better cytotoxicity. The results of flow cytometry indicated that,the apoptosis rate of lung cancer Lewis cells was(20.72±1.47)%,(29.71±2.38)%,and(40.91±1.90)%(P<0.05) at 48 h after treatment in DTX,PELA-DTX,and PBAE-DTX groups. The results showed that different docetaxel preparations could promote the apoptosis of Lewis cells, and PBAE-DTX had stronger apoptotic-promoting effect. The pH-sensitive DTX-loaded micelles are promising candidates in developing stimuli triggered drug delivery systems in acidic tumor micro-environments with improved inhibitory effects of tumor growth on Lewis lung cancer.

[Optimizing vegetation pattern for the riparian buffer zone along the lower Yellow River based on slope hydrological connectivity]. / åŸºäºŽå¡é¢æ°´æ–‡è¿žé€šæ€§çš„é»„æ²³ä¸‹æ¸¸æ²³å²¸ç¼“å†²å¸¦æ¤è¢«æ ¼å±€ä¼˜åŒ–.

Riparian buffer zone is important ecological transitional region between river and upland. Restoring the degraded vegetation system is important for preventing soil erosion, improving ecological environment and helping to achieve the sustainable development of ecosystems. Based on the scenario simulation of vegetation pattern and flow length index, we analyzed the responses of hydrological connectivity to vegetation pattern under different vegetation coverages and slope gradients, and explored the optimal vegetation pattern of soil and water conservation in riparian buffer zone in the lower reaches of the Yellow River. The results showed that the midslope-coarsness-clustered distribution of vegetation configuration, which exhibited the shortest flow length and the weakest hydrological connectivity, being the optimal vegetation pattern for controlling slope runoff generation and flow concentration. For the optimal vegetation pattern, its flow length increased with increasing slope length, namely, the longer slope length the more significant difference of hydrological connectivity between different slope gradients. Meanwhile, flow length of the optimal vegetation pattern decreased with increasing vegetation coverage. The differences between different slope gradients were obvious under low vegetation coverage, while it was unobvious on slope with vegetation coverage of 45%. Compared with the irregular variation trend of flow length on the actual vegetation slope, there was a consistent trend of first increase and then decrease on the simulated slope with the optimal vegetation pattern. Within the pre-set slope gradient range (5°-20°), the optimal vegetation pattern changed the variation of flow length between different slope gradients in the process of coverage change, which highlighted the influence of riparian buffer zone vegetation pattern on hydrological connectivity.

[Spatial variation in riparian soil properties and its response to environmental factors in typical reach of the middle and lower reaches of the Yellow River].

Soil and vegetation are the foundation of maintaining riparian ecosystem services, and their spatial distribution and variations can determine the effects of ecological functions. In the present study, selecting the typical reach of the middle and lower reaches of the Yellow River as the study area, the spatial distributions of riparian soil physicochemical properties and their response to environmental factors were analyzed by employing methods of field investigation, experimental analysis, and redundancy analysis (RDA). The results showed that soil particle was composed significantly of silt in the study area, with the increase of riparian buffer distance, soil bulk density increased initially and then decreased, whereas soil moisture showed the opposite pattern. Changes in total soil phosphorus (TP), available phosphorus (AP), total carbon (TC), total organic carbon (TOC), total nitrogen (TN); ammonium nitrogen (NH4⁺-N) and nitrate nitrogen (NO3⁻-N) contents under different riparian buffer distance showed no statistically significant differences. The spatial distribution of soil chemical properties was generally insignificantly different through changes between two vegetation types. Pearson correlation analysis showed that there was close relationship between soil physical and chemical properties, therein, TOC content in the study area was positively and significantly related to TN (P < 0.01), NO3⁻-N (P < 0.01, and NH4⁺-N (P < 0.05) contents, respectively. Both the TN and TOC contents were significantly negatively related to sand content (P < 0.01), while was significantly positively related to clay content (P < 0.01), indicating that high sand content cou ld pormote poro9sity and permeability of soil and then accelerate the degradation rate of organic matters in soils. In addition, the results of RDA indicated that TOC and NH4⁺-N contents increased with increasing the height and coverage of the tree layer. Soil TP and NO3⁻-N contents increased with increasing the plant diameter at breast height (DBH) of the tree layer and coverage of the herb layer. Meanwhile, with the increase of elevation gradient, the content of soil NH4⁺-N presented an increasing trend, indicating that soil properties were significantly influenced by the effects of community structure and elevation gradient in the study area.

Advances in research and development of universal influenza vaccines / 病毒学报

Vaccination is the primary strategy for the prevention and control of pandemic influenza. Because influenza virus is highly variable across strains, universal influenza vaccines need to be developed to address this problem. This review describes the research progress in conserved epitopes of influenza virus, the advances in the research and development of universal influenza vaccines based on the relatively conserved sequences of NP, M2e, HA2, and headless HA, the mechanisms of cross-protection, and the methods to improve cross-protection.

An overview of the pharmacokinetics of polymer-based nanoassemblies and nanoparticles.

Advancements in the design and synthesis of polymer-based nanoassemblies and nanoparticles, combined with achievements in nanotechnology and medicine, have resulted in remarkable applications of polymer nanosystems in the areas of nanomedicine and pharmaceutical sciences. However, a complete understanding of the absorption, distribution, metabolism, and elimination (ADME) processes of such polymer nanosystems in living systems has not been achieved. The influences of the pharmacokinetic parameters of polymer nanomaterials on the ADME processes are reviewed in this article, with discussions of the absorption and transportation of polymer nanoparticles across biological barriers, the factors affecting the bodily distribution of polymer nanocarriers, the transformation of polymer nanomaterials in vivo, the elimination pathway of polymer nanoparticles from biological systems, and perspectives of future pharmacokinetics and safety investigations of polymer-based nanoassemblies. A full and better understanding of the pharmacokinetic parameters of polymer-based nanomaterials is of vital importance in developing polymer nanosystems with optimal pharmacokinetics and biological safety for applications in nanomedicine and the pharmaceutical industry.

Folate-modified poly(2-ethyl-2-oxazoline) as hydrophilic corona in polymeric micelles for enhanced intracellular doxorubicin delivery.

The transmembrane transport of drug loaded micelles to intracellular compartment is quite crucial for efficient drug delivery. In the current study, we investigated the cellular internalization and anticancer activity of doxorubicin loaded micelles with folate modified stealthy PEOz corona. Folate-decorated micelles incorporating doxorubicin were characterized for particle size, degree of folate decoration, drug loading content and encapsulation efficiency, morphology, and surface charge. The targeting capability and cell viability were assessed using HeLa, KB, A549 and MCF-7/ADR cell lines. In vitro study clearly illustrated the folate receptor (FR) mediated targeting of FA modified micelles to FR-positive human HeLa, KB and MCF-7/ADR cells, while specific delivery to FR-negative A549 cells was not apparently increased at the same experimental conditions. Cytotoxicity assay showed 60% and 58% decrease in IC50 values for HeLa and KB cells, while only a slight decrease for A549 cells, following treatment with folate modified formulations. The enhanced intracellular delivery of FA modified micelles in MCF-7/ADR cells was also observed. In vivo antitumor tests revealed DOX entrapped FA-PEOz-PCL micelles effectively inhibited the tumor growth and reduced the toxicity to mice compared with free DOX. The current study showed that the targeted nano-vector improved cytotoxicity of DOX and suggested that this novel PEOz endowed stealthy micelle system held great promise in tumor targeted therapy.

[Ecological risk assessment of dam construction for terrestrial plant species in middle reach of Lancangjiang River, Southwest China].

Taking the surrounding areas of Xiaowan Reservoir in the middle reach of Lancangjiang River as study area, and based on the vegetation investigation at three sites including electricity transmission area (site 1), electricity-transfer substation and roadsides to the substation (site 2), and emigration area (site 3) in 1997 (before dam construction), another investigation was conducted on the vegetation composition, plant coverage, and dominant species at the same sites in 2010 (after dam construction), aimed to evaluate the ecological risk of the dam construction for the terrestrial plant species in middle reach of Lancangjiang River. There was an obvious difference in the summed dominance ratio of dominant species at the three sites before and after the dam construction. According the types of species (dominant and non-dominant species) and the changes of plant dominance, the ecological risk (ER) for the plant species was categorized into 0 to IV, i.e., no or extremely low ecological risk (0), low ecological risk (I), medium ecological risk (II), high ecological risk (III), and extremely high ecological risk (IV). As affected by the dam construction, the majority of the species were at ER III, and a few species were at ER IV. The percentage of the plant species at ER III and ER IV at site 3 was higher than that at sites 1 and 2. The decrease or loss of native plants and the increase of alien or invasive plants were the major ecological risks caused by the dam construction. Effective protection strategies should be adopted to mitigate the ecological risk of the dam construction for the terrestrial plants at species level.