3D printed biopolymer/black phosphorus nanoscaffolds for bone implants: A review.

Bone implantation is one of the recognized and effective means of treating bone defects, but osteoporosis and bone tumor-related bone abnormalities have a series of problems such as susceptibility to infection, difficulty in healing, and poor therapeutic effect, which poses a great challenge to clinical medicine. Three-dimensional things may be printed using 3D printing. Researchers can feed materials through the printer layer by layer to create the desired shape for a 3D structure. It is widely employed in the healing of bone defects, and it is an improved form of additive manufacturing technology with prospective future applications. This review's objective is to provide an overview of the findings reports pertaining to 3D printing biopolymers in recent years, provide an overview of biopolymer materials and their composites with black phosphorus for 3D printing bone implants, and the characterization methods of composite materials are also summarized. In addition, summarizes 3D printing methods based on ink printing and laser printing, pointing out their special features and advantages, and provide a combination strategy of photothermal therapy and bone regeneration materials for black phosphorus-based materials. Finally, the associations between bone implant materials and immune cells, the bio-environment, as well as the 3D printing bone implants prospects are outlined.

Primary aldosteronism with postoperative elevation of aldosterone treated effectively by finerenone: A case report.

The authors report a case of primary aldosteronism (PA) with postoperative elevation of aldosterone treated effectively by finerenone. The patient was a hypertensive man with a 30-year history of hypertension and sustained an acute myocardial infarction 5 years ago. Bilateral adrenal nodules with hyperplasia were detected and PA was confirmed. His blood potassium, direct renin concentration, and aldosterone level returned to normal after surgery of right adrenalectomy. However, 1 year after surgery, he experienced a decrease in blood potassium and an increase in aldosterone. A saline infusion test revealed an aldosterone level of 124.47 pg/mL. The patient consented to treatment with finerenone. His aldosterone and potassium levels and blood pressure have been controlled well during follow-up. This case highlights the need to screen for secondary hypertension as early as possible. Finerenone may be effective for patients with PA who are not candidates for surgery and those not relieved after surgery.

Design, synthesis and biological evaluation of tanshinone IIA derivatives as NLRP3 inflammasome inhibitors.

Natural product structures have long provided valuable pharmacophores and even candidates for drug discovery. Tanshinone scaffold showed moderately inhibitory activity in NLRP3 inflammasome/IL-1ß pathway. Herein, we designed a series of derivatives on different regions of Tanshinone IIA (TNA) scaffold. The biological evaluation identified compound T10, a scaffold hybrid of TNA and salicylic acid, as a potent NLRP3 inflammasome inhibitor. Mechanistically, T10 inhibits the production of ROS and prevents NLRP3 inflammasome-dependent IL-1ß production. In addition, treatment with T10 significantly attenuated inflammatory response in DSS-induced peritonitis. Our work describes a potential tanshinone-based derivative, which needs to be further structurally optimized as NLRP3 inflammasome inhibitors for treating inflammatory disorders.

The microbiome, resistome, and their co-evolution in sewage at a hospital for infectious diseases in Shanghai, China.

The emergence of antibiotic-resistant bacteria (ARB) caused by the overuse of antibiotics severely threatens human health. Hospital sewage may be a key transmission hub for ARB. However, the complex link between the microbiome and resistomeresistance in hospital sewage remains unclear. In this study, metagenomic assembly and binning methods were used to investigate the microbial community, resistome, and association of antibiotic resistance genes (ARGs) with ARB in sewage from 10 representative sites (outpatient building, surgery building, internal medicine buildings [IMB1-4], staff dormitory, laboratory animal building, tuberculosis building [TBB], and hospital wastewater treatment plant) of a hospital in Shanghai from June 2021 to February 2022. A total of 252 ARG subtypes, belonging to 17 antibiotic classes, were identified. The relative abundance of KPC-2 was higher at IMBs and TBB than at other sites. Of the ARG-carrying contigs, 47.3%-62.6% were associated with mobile genetic elements, and the proportion of plasmid-associated ARGs was significantly higher than that of chromosome-associated ARGs. Although a similar microbiome composition was shared, certain bacteria were enriched at different sites. Potential pathogens Enterococcus B faecium and Klebsiella pneumoniae were primarily enriched in IMB2 and IMB4, respectively. The same ARGs were identified in diverse bacterial hosts (especially pathogenic bacteria), and accordingly, the latter possessed multiple ARGs. Furthermore, gene flow was frequently observed in the sewage of different buildings. The results provide crucial information on the characterization profiles of resistomes in hospital sewage in Shanghai.IMPORTANCEEnvironmental antibiotic resistance genes (ARGs) play a critical role in the emergence and spread of antimicrobial resistance, which poses a global health threat. Wastewater from healthcare facilities serves as a significant reservoir for ARGs. Here, we characterized the microbial community along with the resistome (comprising all antibiotic resistance genes) in wastewater from a specialized hospital for infectious diseases in Shanghai. Potential pathogenic bacteria (e.g., Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Enterococcus B faecium) were frequently detected in hospital wastewater and carried multiple ARGs. A complex link between microbiome and resistome was observed in the wastewater of this hospital. The monitoring of ARGs and antibiotic-resistant bacteria (ARB) in hospital wastewater might be of great significance for preventing the spread of ARB.

Oxidative degradation and possible interactions of coexisting decabromodiphenyl ether (BDE-209) on polystyrene microplastics in UV/chlorine process.

This work was to investigate the transformation of coexisting decabromodiphenyl ether (BDE-209) on microplastics and their possible interactions in UV/chlorine process. Compared with pristine microplastics, the highly aged polystyrene (PS) showed an inhibitory effect on degradation of BDE-209. Increasing initial concentration of BDE-209 on PS inhibited degradation, while the chlorine concentration and pH did not affect the final degradation efficiency. Moreover, the presence of NO3-, SO42-, HCO3- and HA in water was unfavorable for BDE-209 degradation. According to the experimental and calculation results, the contribution to the degradation of BDE-209 was ranked as direct photolysis > HO• > •Cl in the UV/ chlorine system. Chlorination products released by PS during UV/chlorination were detected. Four possible reaction pathways of BDE-209 were proposed, which mainly involved debromination, hydroxylation, chlorine substitution, cleavage of ether bond, and intramolecular elimination of HBr. It was worth noting that PS microplastics not only inhibited the degradation of BDE-209, but also affected the type and abundance of its transformation products. Meanwhile, interaction products of PS and BDE-209 were determined, which was attributed to reactions of PS-derived radicals with •Br/•C6Br5 and •Cl. Results of toxicity evaluation showed that the introduction of carbon-halogen bonds, especially C-Br bond, increased the toxicity of chain scission products of PS. This work provides some new insights into transformation, interaction, and associated ecological risks of coexisting microplastics and surface adsorbed contaminants in the UV/chlorine process of drinking water treatment plants (DWTPs) and wastewater treatment plants (WWTPs).

Rapid point-of-care detection of BK virus in urine by an HFman probe-based loop-mediated isothermal amplification assay and a finger-driven microfluidic chip.

Background: BK virus (BKV)-associated nephropathy (BKVN) is one of the leading causes of renal dysfunction and graft loss in renal transplant recipients. Early monitoring of BKV in urine is crucial to minimize the deleterious effects caused by this virus on preservation of graft function. Methods: We report a simple, rapid, sensitive loop-mediated isothermal amplification (LAMP) assay using an HFman probe for detecting BKV in urine. To evaluate the performance of the assay, a comparison of the HFman probe-based LAMP (HF-LAMP) assay with two qPCR assays was performed using urine samples from 132 HIV-1 infected individuals. We further evaluated the performance of HF-LAMP directly using the urine samples from these HIV-1 infected individuals and 30 kidney transplant recipients without DNA extraction. Furthermore, we combined the HF-LAMP assay with a portable finger-driven microfluidic chip for point-of-care testing (POCT). Results: The assay has high specificity and sensitivity with a limit of detection (LOD) of 12 copies/reaction and can be completed within 30 min. When the DNA was extracted, the HF-LAMP assay showed an equivalent and potentially even higher sensitivity (93.5%) than the qPCR assays (74.2-87.1%) for 132 urine samples from HIV-1 infected individuals. The HF-LAMP assay can be applied in an extraction-free format and can be completed within 45 min using a simple heat block. Although some decreased performance was seen on urine samples from HIV-1 infected individuals, the sensitivity, specificity, and accuracy of the extraction-free BKV HF-LAMP assay were 95%, 100%, and 96.7% for 30 clinical urine samples from kidney transplant recipients, respectively. Conclusion: The assay has high specificity and sensitivity. Combined with a portable finger-driven microfluidic chip for easy detection, this method shows great potential for POCT detection of BKV.

Bone-marrow derived cells do not contribute to new beta-cells in the inflamed pancreas.

The contribution of bone-marrow derived cells (BMCs) to a newly formed beta-cell population in adults is controversial. Previous studies have only used models of bone marrow transplantation from sex-mismatched donors (or other models of genetic labeling) into recipient animals that had undergone irradiation. This approach suffers from the significant shortcoming of the off-target effects of irradiation. Partial pancreatic duct ligation (PDL) is a mouse model of acute pancreatitis with a modest increase in beta-cell number. However, the possibility that recruited BMCs in the inflamed pancreas may convert into beta-cells has not been examined. Here, we used an irradiation-free model to track the fate of the BMCs from the donor mice. A ROSA-mTmG red fluorescent mouse was surgically joined to an INS1Cre knock-in mouse by parabiosis to establish a mixed circulation. PDL was then performed in the INS1Cre mice 2 weeks after parabiosis, which was one week after establishment of the stable blood chimera. The contribution of red cells from ROSA-mTmG mice to beta-cells in INS1Cre mouse was evaluated based on red fluorescence, while cell fusion was evaluated by the presence of green fluorescence in beta-cells. We did not detect any red or green insulin+ cells in the INS1Cre mice, suggesting that there was no contribution of BMCs to the newly formed beta-cells, either by direct differentiation, or by cell fusion. Thus, the contribution of BMCs to beta-cells in the inflamed pancreas should be minimal, if any.

Insight into the photodegradation and universal interactive products of 2,2',4,4'-tetrabromodiphenyl ether on three microplastics.

The transformation process of contaminants on microplastics (MPs) exposed to sunlight has attracted increasing attention. However, the interactions between them are typically disregarded; therefore, this work investigated the photodegradation of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) on three MPs (polystyrene (PS), polypropylene (PP) and polyethylene (PE)) and the interactions between these two. The inhibition of aged PS on the elimination of BDE-47 was due to light shielding, while aged PP and PE increased the degradation rate. More hydroxyl radicals (HO•) was detected in the PS system, which resulted in the higher degradation rate of BDE-47 on PS. A total of 33 different products were identified and four reaction pathways were presented, and the reaction mechanisms mainly included debromination, hydroxylation, carbon-oxygen-bond breaking and interactive reactions. The Ecological Structure Activity Relationship (ECOSAR) and Toxicity Estimation Software Tool (TEST) programs were used to evaluate the toxicity of reaction products, and the results indicated that even though BDE-47 was the most toxic, the interaction products were still toxic or harmful to aquatic organisms. This study provides significant information on the photodegradation of contaminants on common microplastics and their interaction, which cannot be ignored.

BERT-PPII: The Polyproline Type II Helix Structure Prediction Model Based on BERT and Multichannel CNN.

Predicting the polyproline type II (PPII) helix structure is crucial important in many research areas, such as the protein folding mechanisms, the drug targets, and the protein functions. However, many existing PPII helix prediction algorithms encode the protein sequence information in a single way, which causes the insufficient learning of protein sequence feature information. To improve the protein sequence encoding performance, this paper proposes a BERT-based PPII helix structure prediction algorithm (BERT-PPII), which learns the protein sequence information based on the BERT model. The BERT model's CLS vector can fairly fuse sample's each amino acid residue information. Thus, we utilize the CLS vector as the global feature to represent the sample's global contextual information. As the interactions among the protein chains' local amino acid residues have an important influence on the formation of PPII helix, we utilize the CNN to extract local amino acid residues' features which can further enhance the information expression of protein sequence samples. In this paper, we fuse the CLS vectors with CNN local features to improve the performance of predicting PPII structure. Compared to the state-of-the-art PPIIPRED method, the experimental results on the unbalanced dataset show that the proposed method improves the accuracy value by 1% on the strict dataset and 2% on the less strict dataset. Correspondingly, the results on the balanced dataset show that the AUCs of the proposed method are 0.826 on the strict dataset and 0.785 on less strict datasets, respectively. For the independent test set, the proposed method has the AUC value of 0.827 on the strict dataset and 0.783 on the less strict dataset. The above experimental results have proved that the proposed BERT-PPII method can achieve a superior performance of predicting the PPII helix.

Green Tea Polyphenols Prevent Early Vascular Aging Induced by High-Fat Diet via Promoting Autophagy in Young Adult Rats.

OBJECTIVE: Epidemiology studies indicate that green tea polyphenols (GTP) perform a protective effect on cardiovascular diseases, but the underlying mechanisms are complex. The present study aimed to investigate the effect of GTP on high-fat diets (HFD) induced-early vascular aging. METHODS: Six-week young adult Wistar rats were fed with standard chow or HFD in the presence and absence of GTP (200 mg/kg body weight) for 18 weeks. In vitro experiment, human umbilical vascular endothelial cells (HUVECs) were treated with palmitic acid (PA) and GTP. RESULTS: The results showed that GTP alleviated the disorganized arterial wall and the increased intima-media thickness induced by HFD. In addition, the vascular oxidative injury was suppressed following GTP treatment. Furthermore, GTP elevated the ratio of LC3-II/LC3-I and suppressed expression of p62/SQSTM1, and restored SIRT3 expression in the aorta of HFD rats. Consistently, in cultured HUVECs, GTP inhibited cell senescence indicated by SA-ß-gal and promoted endothelial autophagy compared with the PA treatment group. The activity of SIRT3 was specifically inhibited by 3-TYP, and the protective effect of GTP was consequently abolished. CONCLUSION: The findings indicated that GTP protected against early vascular senescence in young HFD rats via ameliorating oxidative injury and promoting autophagy which was partially regulated by the SIRT3 pathway.

Level of von Willebrand factor to assess the occurrence and prognosis of acute myocardial infarction.

BACKGROUND: To observe and compare the differences in von Willebrand factor antigen (vWF:Ag) levels between patients with acute myocardial infarction (AMI) and healthy residents, and to determine whether this measure can be used to evaluate the incidence of AMI and whether or not to undertake cardiac bypass surgery. METHODS: A retrospective analysis was conducted using the clinical data of 110 patients with acute cardiovascular disease without bypass (no bypass group), 351 patients with AMI and bypass (bypass group), and 60 healthy volunteers (healthy group) who underwent physical examination between July 2018 and May 2019 in Tianjin Chest Hospital. The plasma vWF:Ag was measured and the receiver operating characteristic (ROC) curve was utilized to critically assess its efficacy in determining the occurrence and prognosis of AMI, and the Chi-square test was used to evaluate the correlation between vWF:Ag and clinicopathological factors. RESULTS: The plasma vWF:Ag was 201% (139%, 250%) in the bypass group, 118% (107%, 134%) in the non-bypass group, and 95.5% (85.25%, 102.75%) in the control group, and the differences were statistically significant (P<0.05). The component status of the plasma vWF:Ag used in the bypass group was greater as compared to that of the normal group (P<0.05) and the non-bypass group (P<0.05). The area under the ROC curve of plasma vWF:Ag level was 0.797 (95% CI: 0.749-0.845). When the medical decision level of plasma vWF:Ag was set at 155.5%, the sensitivity and specificity of predicting AMI were 68.9% and 86.7%, respectively. The levels of plasma vWF:Ag in patients with AMI were correlated with hypertension, diabetes, age, and history of cerebral infarction (P<0.05). CONCLUSIONS: The plasma vWF level can predict the occurrence of AMI and provides guidance for cardiac bypass surgery.

LncRNA CBR3-AS1 potentiates Wnt/ß-catenin signaling to regulate lung adenocarcinoma cells proliferation, migration and invasion.

BACKGROUND: Long non-coding RNAs (lncRNAs) are pervasively transcribed in genome and emerging as a new player in tumorigenesis due to their functions in transcriptional, posttranscriptional and epigenetic mechanisms of gene regulation. As the most frequent malignancy and the foremost source of cancer mortality, lung cancer is a heterogeneous disorder. The most common type of lung cancer is Non-small cell lung cancer (NSCLC), occupying 85% of the total cases, and the main subtypes of NSCLC include lung adenocarcinoma (LAD), large cell carcinoma (LCC), and lung squamous cell carcinoma (LSCC). Recently, numerous lncRNAs have been reported to be strongly linked to NSCLC. In the present study, we found that a new lncRNA CBR3-AS1 is highly expressed in lung cancer. In addition, we also examined the expression of lncRNA CBR3-AS1 in 60 of LADs, 40 of LCCs and 40 of LSCCs patient samples, finding that CBR3-AS1 was specificity highly expressed in LAD cancer tissues. Mechanically, we discovered that CBR3-AS1 could regulate the proliferation, migration and invasion of LAD cells through targeting Wnt/ß-catenin signaling. METHODS: Real-time PCR, RNA-pulldown, RIP, western blotting, lentivirus transfection, luciferase reporter assays, cell proliferation assays, colony formation assays, wound healing scratch assays and transwell assays were employed to examine the relationship between lncRNA CBR3-AS1 and its regulation of Wnt/ß-catenin signaling in LAD cells. RESULTS: LncRNA CBR3-AS1 is highly-expressed in LAD and cell lines. LncRNA CBR3-AS1 shows physical association with ß-catenin. CBR3-AS1 could facilitate Wnt/ß-catenin signaling activation thought promoting nuclear localization of ß-catenin. CBR3-AS1 promotes LAD cell proliferation, migration and invasion by targeting Wnt/ß-catenin signaling. CONCLUSION: It can be found that a new functional lncRNA CBR3-AS1 could promote nuclear localization of ß-catenin so as to facilitate Wnt/ß-catenin signaling activation and regulate the proliferation, migration and invasion of LAD cells.

Portable integrated digital PCR system for the point-of-care quantification of BK virus from urine samples.

This paper presents a portable integrated digital PCR (PI-dPCR) system with a self-partitioning SlipChip (sp-SlipChip) microfluidic device for the quantitative analysis of BK virus (BKV) viral load directly from raw urine samples. Digital PCR is an accurate nucleic acid quantification method with single-molecule sensitivity, but the complexity of the instrument and the limited integration of the operation workflow greatly limit its application in clinical diagnostics, especially point-of-care testing (PoCT). Our PI-dPCR system has a small footprint, is lightweight, and is fully integrated with the thermal control and fluorescence imaging modules. Unlike the traditional SlipChip device, which requires the precise overlapping of microfeatures on the contacting surfaces to establish the fluidic loading path, this sp-SlipChip device utilizes microchannels with alternating depth and width for fluidic manipulation. This system can quantify BKV directly from raw urine samples with a simple "sample-to-digital-result" operation workflow without complex nucleic acid extraction and purification steps. The current design of the system provides a dynamic range of 3.0 × 104 to 1.5 × 108 copies/mL of BKV DNA in clinical urine samples within 2 h. We tested the system for the quantification of BKV viral load in thirty archived urine samples from kidney transplantation recipients and twelve additional samples from six patients before and after the adjustment of immunosuppressive treatment. This integrated system provides a promising method for both the detection and monitoring of viral infection in a point-of-care setting.

The crosstalk between platelets and body fat: A reverse translational study.

BACKGROUND & AIMS: Our previous study found that platelet counts were positively associated with body fat percentage in human. In the present study, we conducted a reverse translational study to explore the role of platelets in modulating pre-adipocyte proliferation in mice. METHODS: Mouse pre-adipocyte cell line (3T3-L1) and human pre-adipocytes harvested from female subcutaneous fat were used. Pre-adipocytes were co-cultured with platelets or platelet releasate, which were isolated from mice or humans. The cell viability and proliferative ability of the pre-adipocytes were examined by MTT and flow cytometry assays. Western blotting analysis was used to determine the phosphorylation levels of proteins in the mTOR pathway. RESULTS: The number of platelets in the adipose tissues from obese mice was significantly higher than that from lean mice. Platelets and collagen-activated platelet releasate stimulated the proliferation of human pre-adipocytes and 3T3-L1 cells in vitro. Besides, platelets from obese mice were more potent in stimulating pre-adipocyte proliferation than those from lean control mice. Mechanistically, platelets enhanced pre-adipocyte proliferation through the acceleration of cell cycle progression from G0/G1 to S phase cell cycle progression. At the molecular level, platelets promoted pre-adipocyte proliferation through mTOR pathway-mediated upregulation of cyclin D1 expression. CONCLUSION: In conclusion, platelets and platelet releasate play an important role in the proliferation of pre-adipocytes. Our study may provide new clues and the molecular mechanism of the causal pathways between platelets and body fat to explain the finding we observed in population study.

Discovery of a novel selective water-soluble SMAD3 inhibitor as an antitumor agent.

Targeting the SMAD3 protein is an attractive therapeutic strategy for treating cancer, as it avoids the potential toxicities due to targeting the TGF-ß signaling pathway upstream. Compound SIS3 was the first selective SMAD3 inhibitor developed that had acceptable activity, but its poor water solubility limited its development. Here, a series of SIS3 analogs was created to investigate the structure-activity relationship for inhibiting the activation of SMAD3. On the basis of this SAR, further optimization generated a water-soluble compound, 16d, which was capable of effectively blocking SMAD3 activation in vitro and had similar NK cell-mediated anticancer effects in vivo to its parent SIS3. This study not only provided a preferable lead compound, 16d, for further drug discovery or a potential tool to study SMAD3 biology, but also proved the effectiveness of our strategy for water-solubility driven optimization.

Enhanced oxidative degradation of decabromodiphenyl ether in soil by coupling Fenton-persulfate processes: Insights into degradation products and reaction mechanisms.

Decabromodiphenyl ether (BDE-209) has extreme hydrophobicity, which results in its significant accumulation in soil, sediments and other solid materials. In this work, an oxidation method coupling Fenton with persulfate (PS) was proposed for the effective degradation of BDE-209 adsorbed on solid surfaces. After adding 0.1 M PS to the Fenton system at 1.0 h, the removal rate of BDE-209 was significantly increased from 62.2% to 94.0%. The degradation of BDE-209 in various soil samples was also investigated by the coupling Fenton-PS method. Removal efficiency of 73.4-95.8% was obtained, suggesting that this coupling method was feasible in real application. According to the radical scavenging experiments, •OH dominated the overall reaction of BDE-209 in the coupling system. Meanwhile, the enhanced removal was attributed to the generation of SO4•- from the catalytic decomposition of PS. The calculated energy barriers for SO4•- attacking on the carbons were smaller than •OH initiated reactions, which further confirmed that SO4•- plays a role in the accelerated removal of BDE-209. The initial attack of BDE-209 by SO4•- generated the SO4•- adducts, which may undergo debromination or CO bond cleavage reaction together with subsequent hydroxyl substitution to form the primary product OH-Nona-BDEs and pentabromophenol. Under the successive attack of radicals, these primary products were further transformed into lower-brominated hydroxylation products and bromophenols via direct debromination and hydroxyl substitution reaction. This work provides an economical and effective method for treating BDE-209 contaminated soils and samples.

Placental growth factor in beta cells plays an essential role in gestational beta-cell growth.

OBJECTIVE: Pancreatic beta cells proliferate in response to metabolic requirements during pregnancy, while failure of this response may cause gestational diabetes. A member of the vascular endothelial growth factor family, placental growth factor (PlGF), typically plays a role in metabolic disorder and pathological circumstance. The expression and function of PlGF in the endocrine pancreas have not been reported and are addressed in the current study. RESEARCH DESIGN AND METHODS: PlGF levels in beta cells were determined by immunostaining or ELISA in purified beta cells in non-pregnant and pregnant adult mice. An adeno-associated virus (AAV) serotype 8 carrying a shRNA for PlGF under the control of a rat insulin promoter (AAV-rat insulin promoter (RIP)-short hairpin small interfering RNA for PlGF (shPlGF)) was prepared and infused into mouse pancreas through the pancreatic duct to specifically knock down PlGF in beta cells, and its effects on beta-cell growth were determined by beta-cell proliferation, beta-cell mass and insulin release. A macrophage-depleting reagent, clodronate, was coapplied into AAV-treated mice to study crosstalk between beta cells and macrophages. RESULTS: PlGF is exclusively produced by beta cells in the adult mouse pancreas. Moreover, PlGF expression in beta cells was significantly increased during pregnancy. Intraductal infusion of AAV-RIP-shPlGF specifically knocked down PlGF in beta cells, resulting in compromised beta-cell proliferation, reduced growth in beta-cell mass and impaired glucose tolerance during pregnancy. Mechanistically, PlGF depletion in beta cells reduced islet infiltration of trophic macrophages, which appeared to be essential for gestational beta-cell growth. CONCLUSIONS: Our study suggests that increased expression of PlGF in beta cells may trigger gestational beta-cell growth through recruited macrophages.

Role of Resveratrol on Indoxyl Sulfate-Induced Endothelial Hyperpermeability via Aryl Hydrocarbon Receptor (AHR)/Src-Dependent Pathway.

Resveratrol (RES), a dietary polyphenol compound, has been shown to possess health benefits due to its anti-inflammatory, antioxidative, and antiatherosclerosis properties. Tryptophan metabolite-derived indoxyl sulfate (IS) is identified as one of the uremic toxins and physiological endogenous ligand/activator of aryl hydrocarbon receptor (AHR), associated with atherosclerosis in chronic kidney disease (CKD) patients. Studies have shown that a high serum level of IS causes deleterious effects on health primarily by inducing oxidative stress and endothelial dysfunction. However, the precise mechanisms are still unclear. Here, we investigated the underlying mechanism of IS effect on endothelial permeability and the role of RES on IS-induced endothelial hyperpermeability via the AHR/Src-dependent pathway. Bovine aorta endothelial cells (BAECs) were cultured and incubated with IS in the presence or absence of RES, and transendothelial electrical resistance (TEER) and permeability of cells were measured. Alongside, AHR, Src kinase, and Vascular Endothelial Cadherin (VE-Cadherin) activation were examined. Our data showed that IS reduced TEER of cells resulting in increased permeability. VE-Cadherin, a vital regulator of endothelial permeability, was also significantly activated in response to IS, which appeared to be associated with changes of endothelial permeability and AHR/Src kinase. Interestingly, in this setting, RES reversed the effect of IS and inhibited the increased activation of Src induced by IS-activated AHR and modulated VE-Cadherin and permeability. CH223191, an inhibitor of AHR, significantly inhibits IS-induced endothelial hyperpermeability. Further analysis with treatment of PP2, an inhibitor of Src abolishing Src activation, suggests downstream factors. All our data indicated that IS upregulated the AHR/Src kinase pathway, and increased endothelial permeability and phosphorylation of VE-Cadherin may be represented and provide new strategies for addressing protective properties of RES against Src kinase involved in AHR-mediated endothelial hyperpermeability. The findings may be crucial for managing diseases in which endothelial permeability is compromised, and the dietary polyphenols are involved.

IFN-stimulated P2Y13 protects mice from viral infection by suppressing the cAMP/EPAC1 signaling pathway.

Among the most important sensors of extracellular danger signals, purinergic receptors have been demonstrated to play crucial roles in host defense against infection. However, the function of P2 receptors in viral infection has been little explored. Here we demonstrated that P2Y13 and its ligand ADP play an important role in protecting hosts from viral infections. First, we demonstrate that P2Y13, as a typical interferon-stimulated gene, is induced together with extracellular ADP during viral infection. Most importantly, extracellular ADP restricts the replication of different kinds of viruses, including vesicular stomatitis virus, Newcastle disease virus, herpes simplex virus 1, and murine leukemia virus. This kind of protection is dependent on P2Y13 but not P2Y1 or P2Y12, which are also considered as receptors for ADP. Furthermore, cyclic adenosine monophosphate and EPAC1 are downregulated by extracellular ADP through the P2Y13-coupled Gi alpha subunit. Accordingly, inhibition or deletion of EPAC1 significantly eliminates ADP/P2Y13-mediated antiviral activities. Taken together, our results show that P2Y13 and ADP play pivotal roles in the clearance of invaded virus and have the potential as antiviral targets.

Effects of green tea polyphenols on trace metals level of rats on food restriction and high-fat diet.

Little evidence showed the interplay between tea and diet in the regulation of trace metal. Here, we examined the effects of green tea polyphenols (GTPs) on the level of trace elements (TEs) in rats on food restriction or high-fat diet. Thirty-six rats (Wistar, male) were randomly divided into 6 groups and fed on standard diet, food restriction and high-fat diet with or without GTPs (200 mg/kg bw/day) supplementation, respectively. Levels of vanadium (V), manganese (Mn), iron (Fe), copper (Cu), zinc (Zn), selenium (Se), molybdenum (Mo) and cobalt (Co) in feed, whole blood, femur and urine were measured by inductively coupled plasma mass spectrometry (ICP-MS). Blood glucose, total cholesterol (TC), triglycerides (TG), high and low density lipoprotein-cholesterol (LDL-C, HDL-C) in serum were determined. Decreased daily intakes of TEs were observed in rats on food restriction and high-fat diet. Decreased whole blood level of Zn, femur level of Co and increase urinary excretion of Se were observed in rats fed on high-fat diet. GTPs altered the whole blood level of several TEs in rats on food restriction (V, Zn, Co) or high-fat diet (V, Se), respectively, but not in rats fed on standard diet. The level of several TEs in femur and the daily urinary excretion of V and Mo were altered by GTPs in rats on all of the three diets. In addition, rats fed on high-fat diet developed dyslipidemia, which was ameliorated by GTPs. The data indicated that diet status played a role in the effects of GTPs on TEs and lipid metabolism, and trace elements may play a role in the modulation of lipid metabolic disturbances by high-fat diet and GTPs.