Role of protein deimination in cardiovascular diseases: potential new avenues for diagnostic and prognostic biomarkers.

INTRODUCTION: Arginine deimination (citrullination) is a post-translational modification catalyzed by a family of peptidyl arginine deiminase (PAD) enzymes. Cell-based functional studies and animal models have manifested the key role of PADs in various cardiovascular diseases (CVDs). AREA COVERED: This review summarizes the past 10 years of knowledge on the role of PADs in CVD pathogenesis. It focuses on the PAD functions and diverse citrullinated proteins in cardiovascular conditions like deep vein thrombosis, ischemia/reperfusion, and atherosclerosis. Identification of PAD isoforms and citrullinated targets are essential for directing diagnosis and clinical intervention. Finally, anti-citrullinated protein antibodies (ACPAs) are addressed as an independent risk factor for cardiovascular events. EXPERT OPINION: PAD is an unique family of enzymes that permanently converts amino acid arginine to amino acid citrulline in protein . Overexpression or increased activity of PAD has been observed in various CVDs with acute and chronic inflammation as the background. Importantly, far beyond being simply involved in forming neutrophil extracellular traps (NETs), accumulating evidence indicated PAD activation as a trigger for numerous processes, such as transcriptional regulation, endothelial dysfunction, and thrombus formation. In summary, the findings so far have testified the important role of deimination in cardiovascular biology, while more basic and translational studies are essential for further exploration.

Spatial Compartmentalization of Cobalt Phosphide in P-Doped Dual Carbon Shells for Efficient Alkaline Overall Water Splitting.

Highly durable and earth-abundant bifunctional catalysts with low cell voltage are desirable for alkaline overall water splitting in the industrial fields. Herein, a novel carbon-based CoP hybrid with spatial compartmentalization of CoP nanoparticles (NPs) in P-doped dual carbon shells is achieved via a cheap Co-glycerate-template strategy. Benefitted from the uniform atomic blending of Co2+ ions in the Co-glycerate precursors, CoP NPs in situ formed in the confined space with NaH2PO2 as phosphorus source during the annealing process; meanwhile, glycerate suffered carbonization and transformed into P-doped dual carbon shells during the annealing process, including interior thin carbon coating, closely encircled CoP NP, and peripheral hollow carbon sphere loading a lot of CoP NPs. Not only does spatial compartmentalization of CoP NPs avoid the aggregation and expose more active sites but also P-doped dual carbon shells improve the conductivity and durability of the catalyst. As expected, the optimized hybrid exhibits outstanding electrocatalytic activities in alkaline media, such as hydrogen evolution reaction (HER) overpotential of 101 mV, oxygen evolution reaction (OER) overpotential of 280 mV, and a low cell voltage of 1.66 V to deliver a current density of 10 mA cm-2. Moreover, durability and stability are greatly improved under harsh electrochemical conditions. The current strategy shades new insight into the development of carbon-based transition metal phosphides (TMP) catalysts for electrocatalysis applications.

Preparation of a Phenolic-Resin-Based Polymer Sponge Composed of Intertwined Nanofibers with Tunable Wettability for High-Efficiency Separation of Oil-Water Emulsions.

Nowadays, as the combination of water pollution and water shortage causes severe environmental and social issues, the special wettable materials, which can be selectively wetted by either water or oil, attract tremendous attention for high-efficiency separation of oil-water mixtures. Herein, we prepare a phenolic-resin-based sponge composed of intertwined nanofibers via a simple hydrothermal method. The wettability of the as-prepared polymer is tuned readily by controlling only the hydrothermal temperature. In the case of the hydrothermal temperature below 210 °C, the polymer sponge demonstrates superhydrophilic and underwater superoleophobic properties, affording the separation of oil-in-water emulsions. However, as the hydrothermal temperature increases above 220 °C, the resulting bulk phenolic-resin-based material becomes superhydrophobic and underoil superhydrophobic, realizing a high filtration flux of 6147 L m-2 h-1 for the separation of water-in-oil emulsions driven by an external pressure of 40 kPa. This provides a feasible platform for future practical applications. The wettability transition depending on the hydrothermal temperature is discussed in terms of the reaction mechanism. In addition, the stability and breakthrough pressure are also addressed from the viewpoints of thermodynamic and fluid mechanics, respectively.

Low Cost and Reliable Electrochemical Sensor for Rutin Detection Based on Au Nanoparticles-Loaded ZnS Nanocomposites.

Facile preparation of electrode modified materials with low-cost nanocomposites is an important step to develop highly active electrochemical sensors for mass-market applications. Here we fabricated Au nanoparticles (AuNPs)-loaded ZnS nanocomposites for the sensitive determination of rutin due to the cooperative amplification of the conductivity and catalytic activity of AuNPs on ZnS spheres resulting from the high loading ratio of AuNPs on ZnS spheres. Under the optimal conditions, the developed sensor based on AuNPs-loaded ZnS nanocomposites exhibited excellent electrocatalytic activity towards rutin in a linear range from 1 × 10-7 mol/L to 2 × 10-5 mol/L with a limit of detection of 15.3 nM at a signal-to-noise ratio of 3. Furthermore, the proposed method gave satisfactory results for rutin determination in pharmaceutical tablets, which offer promising potential for rutin electrochemical analysis in serum monitoring or Chinese medical analysis owing to its simplicity, low cost, high sensitivity and good stability.

Pancreatic ß-Cell Death due to Pdx-1 Deficiency Requires Multi-BH Domain Protein Bax but Not Bak.

Diabetes develops in Pdx1-haploinsufficient mice due to an increase in ß-cell death leading to reduced ß-cell mass and decreased insulin secretion. Knockdown of Pdx1 gene expression in mouse MIN6 insulinoma cells induced apoptotic cell death with an increase in Bax activation and knockdown of Bax reduced apoptotic ß-cell death. In Pdx1 haploinsufficient mice, Bax ablation in ß-cells increased ß-cell mass, decreased the number of TUNEL positive cells and improved glucose tolerance after glucose challenge. These changes were not observed with Bak ablation in Pdx1-haploinsufficient mice. These results suggest that Bax mediates ß-cell apoptosis in Pdx1-deficient diabetes.

Identification of Ssm1b, a novel modifier of DNA methylation, and its expression during mouse embryogenesis.

The strain-specific modifier Ssm1 is responsible for the strain-dependent methylation of particular E. coli gpt-containing transgenic sequences. Here, we identify Ssm1 as the KRAB-zinc finger (ZF) gene 2610305D13Rik located on distal chromosome 4. Ssm1b is a member of a gene family with an unusual array of three ZFs. Ssm1 family members in C57BL/6 (B6) and DBA/2 (D2) mice have various amino acid changes in their ZF domain and in the linker between the KRAB and ZF domains. Ssm1b is expressed up to E8.5; its target transgene gains partial methylation by this stage as well. At E9.5, Ssm1b mRNA is no longer expressed but by then its target has become completely methylated. By contrast, in D2 embryos the transgene is essentially unmethylated. Methylation during B6 embryonic development depends on Dnmt3b but not Mecp2. In differentiating B6 embryonic stem cells methylation spreads from gpt to a co-integrated neo gene that has a similarly high CpG content as gpt, but neo alone is not methylated. In adult B6 mice, Ssm1b is expressed in ovaries, but in other organs only other members of the Ssm1 family are expressed. Interestingly, the transgene becomes methylated when crossed into some, but not other, wild mice that were kept outbred in the laboratory. Thus, polymorphisms for the methylation patterns seen among laboratory inbred strains are also found in a free-living population. This may imply that mice that do not have the Ssm1b gene may use another member of the Ssm1 family to control the potentially harmful expression of certain endogenous or exogenous genes.

Dynamic behavior of water droplet impact on microtextured surfaces: the effect of geometrical parameters on anisotropic wetting and the maximum spreading diameter.

Textured silicon surfaces decorated by square arrays of pillars with adjustable pitch were fabricated. The wetting behavior, especially for direction-dependent water contact angles on textured silicon surfaces after silanization, was investigated by incorporating the contact line fraction into a modified Wenzel model. Also, the effect of geometrical parameters on the anisotropic wetting behavior of water was examined with respect to water droplet impact on the textured surface. Moreover, the maximum spreading factor was studied theoretically in terms of energy conservation, allowing for surface topography and viscous friction of the liquid flowing among the arrays of the posts. Theoretical models were found to be in good agreement with experimental data.

Clinical Efficacy and Safety Analysis of PD-1/PD-L1 Inhibitor vs. Chemotherapy in the Treatment of Advanced Non-Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis.

Objective: To systematically evaluate the efficacy and safety of pembrolizumab (PD-1/PD-L inhibitor) and adjuvant chemotherapy to treat NSCLC and provide evidence-based reference for clinical use. Methods: By searching the Cochrane Library, EMBASE, PubMed, and Web of Science, according to the inclusion criteria, literature selection, data extraction, and quality evaluation were carried out for the included literature. The I 2 test was used to evaluate heterogeneity between studies, and the meta-analysis was performed using RevMan 5.3 software provided by Cochrane. Results: Finally, 14 relevant documents meeting the standards were included. It is a statistical difference in one-year survival rate [OR = 1.50, 95% CI (1.28, 1.76), P < 0.00001, I 2 = 0%, Z = 4.99]; overall response rate[OR =1.57, 95% CI (1.29, 1.90), P < 0.00001, I 2 = 0%, Z = 4.58]; progression-free survival [OR = 2.99, 95% CI (2.29, 3.91), P < 0.00001, I 2 = 26%, Z = 8.00]; and overall survival [OR = 1.38, 95% CI (1.07, 1.78), P = 0.01, I 2 = 46%, Z = 2.50] and reduces the incidence of adverse drug reactions [OR = 2.54, 95% CI (1.99, 3.25), P < 0.00001, I 2 = 69%, Z = 7.43]. Conclusion: Pembrolizumab adjuvant chemotherapy is effective in the treatment of advanced NSCLC, but attention should be paid to the occurrence of adverse reactions in clinical. Due to the limitations of the methodology included in the study, this conclusion required more validation of large-sample RCT.

Two dimensional Ni2P/CdS photocatalyst for boosting hydrogen production under visible light irradiation.

Two-dimensional (2D) semiconductor materials have attracted considerable attention in the field of photocatalysis due to the high interfacial charge separation efficiency and abundant surface active sites. Herein, we have fabricated 2D/2D sheets of Ni2P/CdS heterostructure for photocatalytic H2 evolution. The microscopic and photocatalytic activity results suggested that Ni2P nanosheets were coupled with snowflake CdS. The optimal hydrogen production rate reached 58.33 mmol h-1 g-1 (QE = 34.38%, λ = 420 nm) over 5 wt% Ni2P, which is equivalent to that of 1 wt% Pt/CdS. Compared with pure CdS, Ni2P/CdS presented lower fluorescence intensity and stronger photocurrent density, which demonstrated that the 2D/2D Ni2P/CdS heterojunction photocatalyst significantly improved the separation efficiency of photogenerated electrons and holes. The excellent performance of Ni2P/CdS clearly indicated that Ni2P was an excellent cocatalyst and could provide abundant active sites for hydrogen evolution.

Ultrathin Ni(OH)2 nanosheets: a new strategy for cocatalyst design on CdS surfaces for photocatalytic hydrogen generation.

Ultrathin metal materials exhibit quantum size and surface effects that give rise to unique catalytic properties. In this paper, we report a facile liquid synthesis method for polyvinylpyrrolidone (PVP, K30) capped ultrathin Ni(OH)2 nanosheets with lamellar structure. The as-prepared ultrathin Ni(OH)2 nanosheets coupled with CdS nanorods exhibit excellent activity in hydrogen generation from water splitting under visible light. The H2 evolution rate of Ni(OH)2/CdS, 40.18 mmol h-1 gCat. -1 with a quantum efficiency of 66.1% at 420 nm, is ca. 1.5 times that of Pt/CdS with an optimal loading amount (1.25 wt%) under the same reaction conditions. Considering the cost of photocatalysts, the ultrathin Ni(OH)2 nanosheet coupled CdS photocatalyst may have a promising commercial application in photocatalytic hydrogen production.

Critical role for the Tsc1-mTORC1 pathway in ß-cell mass in Pdx1-deficient mice.

Mutations in the pancreatic duodenal homeobox (PDX1) gene are associated with diabetes in humans. Pdx1-haploinsufficient mice also develop diabetes, but the molecular mechanism is unknown. To this end, we knocked down Pdx1 gene expression in mouse MIN6 insulinoma cells. Pdx1 suppression not only increased apoptotic cell death but also decreased cell proliferation, which was associated with a decrease in activity of mechanistic target of rapamycin complex 1 (mTORC1). We found that in Pdx1-deficient mice, tuberous sclerosis 1 (Tsc1) ablation in pancreatic ß-cells restores ß-cell mass, increases ß-cell proliferation and size, decreases the number of TUNEL-positive cells and restores glucose tolerance after glucose challenge. In addition, Tsc1 ablation in pancreatic ß-cells increases phosphorylation of initiation factor 4E-binding protein 1 (4E-BP1) phosphorylation and 40S ribosomal protein S6, two downstream targets of mTORC1 indicating that Tsc1 mediates mTORC1 downregulation induced by Pdx1 suppression. These results suggest that the Tsc1-mTORC1 pathway plays an important role in mediating the decrease in ß-cell proliferation and growth and the reduction in ß-cell mass that occurs in Pdx1-deficient diabetes. Thus, mTORC1 may be target for therapeutic interventions in diabetes associated with reductions in ß-cell mass.

Pt-Ni x alloy nanoparticles: a new strategy for cocatalyst design on a CdS surface for photo-catalytic hydrogen generation.

Solar photocatalytic water splitting for the production of hydrogen has been a core aspect for decades. A highly active and durable photocatalyst is crucial for the success of the renewable hydrogen economy. To date, the development of highly effective photocatalysts has been seen by the contemporary research community as a grand challenge. Thus, herein we put forward a sincere attempt to use a Pt-Ni x alloy nanoparticle (NP) cocatalyst loaded CdS photocatalyst ((Pt-Ni x )/CdS) for photocatalytic hydrogen production under visible light. The Pt-Ni x alloy NP cocatalyst was synthesized using a one-pot solvothermal method. The cocatalyst nanoparticles were deposited onto the surface of CdS, forming a Pt-Ni x /CdS photocatalyst. Photocatalytic hydrogen production was carried out using a 300 W Xe light equipped with a 420 nm cut-off filter. The H2 evolution rate of the Pt-Ni3/CdS photocatalyst can reach a value as high as 48.96 mmol h-1 g-1 catalyst, with a quantum efficiency of 44.0% at 420 nm. The experimental results indicate that this Pt-Ni3/CdS photocatalyst is a prospective candidate for solar hydrogen generation from water-splitting.

Mammary epithelium-specific inactivation of V-ATPase reduces stiffness of extracellular matrix and enhances metastasis of breast cancer.

Extracellular matrix (ECM) critically impacts tumor progression and is influenced by both cancer and host tissue cells. While our understanding of cancer cell ECM remodeling is widespread, the importance of host tissue ECM, which provides initial congenial environment for primary tumor formation, is partly understood. Here, we report a novel role of epithelial cell-associated vacuolar ATPase 'a2' isoform (a2V) in regulating breast tissue ECM stiffness to control metastasis. Using a mammary gland-specific a2V-knockout model, we show that in the absence of a2V, breast tumors exhibit atypically soft tumor phenotype, less tumor rigidity, and necrotic tumor microenvironment. These tumors contain a decreased number of cancer cells at primary tumor site, but showed extensive metastases compared to control. Nanomechanical evaluation of normal breast tissues revealed a decrease in stiffness and collagen content in ECM of a2V-deleted breast tissues. Mechanistically, inhibition of a2V expression caused dispersed Golgi morphology with relocation of glycosyltransferase enzymes to early endosomes in mammary epithelial cells. This resulted in defective glycosylation of ECM proteins and production of compromised ECM that further influenced tumor metastasis. Clinically, in patients with cancer, low a2V expression levels in normal breast tissue correlated with lymph node metastasis. Thus, using a new knockout mouse model, we have identified a2V expression in epithelial cells as a key requirement for proper ECM formation in breast tissue and its expression levels can significantly modulate breast tumor dissemination. Evaluation of a2V expression in normal breast tissues can help in identifying patients with high risk of developing metastases.

BH3-only molecule Bim mediates ß-cell death in IRS2 deficiency.

Irs2-deficient mice develop type 2-like diabetes due to a reduction in ß-cell mass and a failure of pancreatic islets to undergo compensatory hyperplasia in response to insulin resistance. In order to define the molecular mechanisms, we knocked down Irs2 gene expression in mouse MIN6 insulinoma cells. Insulin receptor substrate 2 (IRS2) suppression induced apoptotic cell death, which was associated with an increase in expression of the BH3-only molecule Bim. Knockdown (KD) of Bim reduced apoptotic ß-cell death induced by IRS2 suppression. In Irs2-deficient mice, Bim ablation restored ß-cell mass, decreased the number of TUNEL-positive cells, and restored normal glucose tolerance after glucose challenge. FoxO1 mediates Bim upregulation induced by IRS2 suppression, and FoxO1 KD partially inhibits ß-cell death induced by IRS2 suppression. These results suggest that Bim plays an important role in mediating the increase in ß-cell apoptosis and the reduction in ß-cell mass that occurs in IRS2-deficient diabetes.

Role of BH3-only molecules Bim and Puma in ß-cell death in Pdx1 deficiency.

Mutations in pancreatic duodenal homeobox-1 (PDX1) are associated with diabetes in humans. Pdx1-haploinsufficient mice develop diabetes due to an increase in ß-cell death leading to reduced ß-cell mass. For definition of the molecular link between Pdx1 deficiency and ß-cell death, Pdx1-haploinsufficient mice in which the genes for the BH3-only molecules Bim and Puma had been ablated were studied on a high-fat diet. Compared with Pdx1(+/-) mice, animals haploinsufficient for both Pdx1 and Bim or Puma genes showed improved glucose tolerance, enhanced ß-cell mass, and reduction in the number of TUNEL-positive cells in islets. These results suggest that Bim and Puma ablation improves ß-cell survival in Pdx1(+/-) mice. For exploration of the mechanisms responsible for these findings, Pdx1 gene expression was knocked down in mouse MIN6 insulinoma cells resulting in apoptotic cell death that was found to be associated with increased expression of BH3-only molecules Bim and Puma. If the upregulation of Bim and Puma that occurs during Pdx1 suppression was prevented, apoptotic ß-cell death was reduced in vitro. These results suggest that Bim and Puma play an important role in ß-cell apoptosis in Pdx1-deficient diabetes.

[Relationship of IL-6 and IL-8 secretion in epithelial ovarian cancer cell lines with their sensitivity to tamoxifen as well as MAPK, Akt and estrogen receptor phosphorylation].

AIM: To investigate the relationship of IL-6 and IL-8 secretion in four epithelial ovarian cancer cell lines (A2780, CAOV-3, SKOV-3 and ES-2) with their sensitivity to tamoxifen (TAM) as well as MAPK, Akt and estrogen receptor (ER) phosphorylation, and to explore the mechanism of endocrine therapy resistance caused by IL-6 and IL-8 in ovarian cancer cells. METHODS: Reverse transcription polymerase chain reaction (RT-PCR) and enzyme linked immunosorbent assay (ELISA) were performed to analyze the expression of IL-6 and IL-8. MTT assay was carried out to examine the response of ovarian cancer cells to TAM. Western blot was used to detect phosphorylated MAPK, Akt and ER. RESULTS: Except A2780 cells, three other ovarian cancer cells constitutively expressed IL-6 and IL-8. The mRNA levels of IL-6 and IL-8 correlated with their protein levels in four ovarian cancer cells. The four ovarian cancer cells showed different response to TAM. A2780 cells was the most responsive, whereas CAOV-3, SKOV-3 and ES-2 cells were TAM-resistant to a different degree. There was a notable difference in phosphorylated MAPK, Akt and ER (serine 118 and 167) among the four ovarian cancer cells. CONCLUSION: Autocrine production of IL-6 and IL-8 in epithelial ovarian cancer cell lines is inversely associated with cell response to TAM, and positively associated with phosphorylated MAPK, Akt and ER.

[Comparative study of the protective immunity activated by antigens of adult worms and muscle larvae of Trichinella spiralis].

AIM: To compare the immune protective effects of the mice immunized by antigens derived from adult worms and muscle larvae of Trichinella spiralis. METHODS: The adult worm and muscle larvae antigens of Trichinella spiralis were prepared and two groups of mice (adult worm antigen group and muscle larvae antigen group) were immunized with them, respectively. After 10 days of the final vaccination, the mice in each group were challenged with infective larvae of Trichinella spiralis. The number of intestinal adult worms and muscle larvae were examined and their reduction rate was calculated. Meanwhile, the level of serum IgG in each group was detected by ELISA. RESULTS: Compared with control group, the number of intestinal adult worms and muscle larvae in adult worm group and muscle larvae antigen group was lower(P<0.05) and number of intestinal adult worms and muscle larvae in adult worm antigen group was at the lowest(P<0.01). When the mice in the two groups were challenged with infective larvae of Trichinella spiralis, the titer of serum IgG detected on the same day was higher than that before they were vaccinated with the antigens(P<0.01, P<0.05) and it was also higher than that in control group(P<0.01, P<0.05). The level of serum IgG of the mice detected on the day when they were challenged with infective larvae of Trichinella spiralis was significantly higher than that before the mice were vaccinated and it was also higher than that in adult worm antigen group(P<0.01). CONCLUSION: Both the adult worm and muscle larvae antigens of Trichinella spiralis can stimulate mice to produce protective immunity and the mice immunized with adult worm antigens have stronger resistance to the subsequent challenge infection.