Effects of NAD+ precursors on blood pressure, C-reactive protein concentration and carotid intima-media thickness: A meta-analysis of randomized controlled trials.

BACKGROUND: There are contradictory effects regarding the effect of NAD+ precursor on blood pressure and inflammation. In order to obtain a better viewpoint from them, this study aimed to comprehensively investigate the effects of NAD+ precursor supplementation on blood pressure, C-reactive protein (CRP) and carotid intima-media thickness (CIMT). METHODS: PubMed/MEDLINE, Web of Science, SCOPUS and Embase databases were searched using standard keywords to identify all controlled trials investigating the effects of NAD+ precursor on blood pressure, CRP and CIMT. Pooled weighted mean difference (WMD) and 95% confidence intervals (95% CI) were achieved by random-effects model analysis for the best estimation of outcomes. RESULTS: Twenty-nine articles (with 8664 participants) were included in this article. Results from meta-analyses of RCTs from random-effects models indicated a significant reduction in systolic (SBP) (weighted mean difference (WMD): -2.54 mmHg, p < .001) and diastolic blood pressure (DBP) (WMD: -2.15 mmHg, p < .001), as well as in CRP (WMD: -.93 mg/L, 95% CI -1.47 to -.40, p < .001) concentrations and CIMT (WMD: -.01 mm, 95% CI -.02 to -.00, p = .005) with the NAD+ precursors supplementation compared with the control group. In addition, a greater effect of supplementation with NAD+ precursors in reducing blood pressure (BP) were observed with the highest dose (≥2 g) and duration of the intervention (>12 weeks), as well as with NA supplementation when compared to NE. CONCLUSIONS: Overall, these findings suggest that NAD+ precursor supplementation might have a beneficial effect on cardiovascular risk factors such as BP, CRP concentration and CIMT.

Tandem Synthesis of 2-Azaspiro[4.5]deca-1,6,9-trien-8-ones Based on Tf2O-Promoted Activation of N-(2-Propyn-1-yl) Amides.

Structurally novel 2-azaspiro[4.5]deca-1,6,9-trien-8-ones were synthesized from N-(2-propyn-1-yl) amides and 1,3,5-trimethoxybenzenes by a tandem method consisting of a Tf2O-promoted amide activation and a TfOH-promoted Friedel-Crafts ipso-cyclization. The method offered the first example of using N-(2-propyn-1-yl) amides as substrates in both Tf2O-promoted secondary amide activation and the synthesis of azaspiro[4.5]deca-6,9-diene-8-ones.

Mechanistic Insights into Tf2O-Promoted Electrophilic Activation of 2-Propynamides and a New Synthesis of 2,4-Disubstituted Quinolines.

Direct evidence explaining why 2-propynamides have never been used as substrates in Tf2O-promoted electrophilic activations was obtained. Furthermore, a new method for the synthesis of structurally special 2,4-disubstituted quinolines was developed, by which the substituent at position 2 of quinolines can be diversified easily.

Host Immune Response to Clinical Hypervirulent Klebsiella pneumoniae Pulmonary Infections via Transcriptome Analysis.

Klebsiella pneumoniae (K. pneumoniae), especially those with hypervirulence, is becoming a global concern and posing great threat to human health. Studies on individual immune cells or cytokines have partially revealed the function of the host immune defense against K. pneumoniae pulmonary infection. However, systematic immune response against K. pneumoniae has not been fully elucidated. Herein, we report a transcriptome analysis of the lungs from a mouse pneumonia model infected with a newly isolated K. pneumoniae clinical strain YBQ. Total RNA was isolated from the lungs of mice 48 hours post infection to assess transcriptional alteration of genes. Transcriptome data were analyzed with KEGG, GO, and ICEPOP. Results indicated that upregulated transcription level of numerous cytokines and chemokines was coordinated with remarkably activated ribosome and several critical immune signaling pathways, including IL-17 and TNF signaling pathways. Notably, transcription of cysteine cathepsin inhibitor (stfa1, stfa2, and stfa3) and potential cysteine-type endopeptidase inhibitor (cstdc4, cstdc5, and cstdc6) were upregulated. Results of ICEPOP showed neutrophils functions as the most essential cell type against K. pneumoniae infection. Critical gene alterations were further validated by rt-PCR. Our findings provided a global transcriptional perspective on the mechanisms of host defense against K. pneumoniae infection and revealed some unique responding genes.

Determining the frequency of Streptococcus pneumoniae carriers and its microbial resistance in children.

Streptococcus pneumoniae is a common cause of bacterial infections of the respiratory system, middle ear infection, bacteremia, meningitis, and pneumonia, especially in children. Due to the lack of information about the frequency and resistance of Streptococcus pneumoniae to antibiotics, the present study was performed to determine the frequency of carriers of Streptococcus pneumoniae and its microbial resistance in children. For this purpose, the current descriptive cross-sectional study was conducted from November to March 2020 on 554 children aged 2-12 years in kindergartens and schools. This study collected samples with a sterile swab from the nasopharyngeal region, transported them to the laboratory by a transport medium, and then cultured them on an agar culture medium. After isolation, confirmatory tests and antibiotic susceptibility were performed. The results were analyzed using SPSS16 software and interpreted according to Mann Whitney U and Chi-Square Tests. Streptococcus pneumoniaewas found in 15% of samples, and the antibiotic resistance of the isolates to the antibiotics azithromycin, amoxicillin, rifampicin, amoxicillin-clavulanic acid, trimethoprim/Sulfamethoxazole, and ceftriaxone were 63.9%, 56.6%, 41%, 37.3%, 37.3%, and 3.6%, respectively. Also, 31.1% of the isolates were not resistant to any antibiotics. According to the results, excessive use of antibiotics has led to high resistance to azithromycin, amoxicillin, amoxicillin/clavulanic acid, and trimethoprim/Sulfamethoxazole, which indicates an increased risk of refractory infectious diseases. For this reason, it is necessary to adequately educate physicians and the general public about the overuse of antibiotics.

Development of a chitosan-modified PLGA nanoparticle vaccine for protection against Escherichia coli K1 caused meningitis in mice.

BACKGROUND: Escherichia coli K1 (E. coli K1) caused neonatal meningitis remains a problem, which rises the urgent need for an effective vaccine. Previously, we rationally designed and produced the recombinant protein OmpAVac (Vo), which elicited protective immunity against E. coli K1 infection. However, Vo has limited stability, which hinders its future industrial application. METHOD: Chitosan-modified poly (lactic-co-glycolic acid) (PLGA) nanoparticles were prepared and used as carried for the recombinant Vo. And the safety, stability and immunogenicity of Vo delivered by chitosan-modified PLGA nanoparticles were tested in vitro and in a mouse model of bacteremia. RESULTS: We successfully generated chitosan-modified PLGA nanoparticles for the delivery of recombinant Vo (VoNP). In addition, we found that a freeze-drying procedure increases the stability of the VoNPs without changing the shape, size distribution and encapsulation of the Vo protein. Unlike aluminum adjuvant, the nanoparticles that delivered Vo were immunoprotective in mice even after storage for as long as 180 days. CONCLUSIONS: We identified an effective strategy to improve the stability of Vo to maintain its immunogenicity, which will contribute to the future development of vaccines against E. coli K1.

Construction of Genomic Library and High-Throughput Screening of Pseudomonas aeruginosa Novel Antigens for Potential Vaccines.

Hospital-acquired infections with Pseudomonas aeruginosa have become a great challenge in caring for critically ill and immunocompromised patients. The cause of high mortality is the presence of multi-drug resistant (MDR) strains, which confers a pressing need for vaccines. Although vaccines against P. aeruginosa have been in development for more than several decades, there is no vaccine for patients at present. In this study, we purified genomic DNA of P. aeruginosa from sera of patients affected, constructed genome-wide library with random recombinants, and screened candidate protein antigens by evaluating their protective effects in vivo. After 13-round of screening, 115 reactive recombinants were obtained, among which 13 antigens showed strong immunoreactivity (more than 10% reaction to PcrV, a well-characterized V-antigen of P. aeruginosa). These 13 antigens were: PpiA, PtsP, OprP, CAZ10_34235, HmuU_2, PcaK, CarAd, RecG, YjiR_5, LigD, KinB, RtcA, and PscF. In vivo studies showed that vaccination with PscF protected against lethal P. aeruginosa challenge, and decreased lung inflammation and injury. A genomic library of P. aeruginosa could be constructed in this way for the first time, which could not only screen candidate antigens but also in a high-throughput way. PscF was considered as an ideal promising vaccine candidate for combating P. aeruginosa infection and was supported for further evaluation of its safety and efficacy.

Highly Concentrated Electrolyte towards Enhanced Energy Density and Cycling Life of Dual-Ion Battery.

Dual-ion batteries (DIBs) have attracted much attention owing to their low cost, high voltage, and environmental friendliness. As the source of active ions during the charging/discharging process, the electrolyte plays a critical role in the performance of DIBs, including capacity, energy density, and cycling life. However, most used electrolyte systems based on the LiPF6 salt demonstrate unsatisfactory performance in DIBs. We have successfully developed a 7.5 mol kg-1 lithium bis(fluorosulfonyl)imide (LiFSI) in a carbonate electrolyte system. Compared with diluted electrolytes, this highly concentrated electrolyte exhibits several advantages: 1) enhanced intercalation capacity and cycling stability of the graphite cathode, 2) optimized structural stability of the Al anode, and 3) significantly increased battery energy density. A proof-of-concept DIB based on this concentrated electrolyte exhibits a discharge capacity of 94.0 mAh g-1 at 200 mA g-1 and 96.8 % capacity retention after 500 cycles. By counting both the electrode materials and electrolyte, the energy density of this DIB reaches up to ≈180 Wh kg-1 , which is among the best performances of DIBs reported to date.

The Molecular Mechanism of Sirt1 Signaling Pathway in Brain Injury of Newborn Rats Exposed to Hyperoxia.

The aim of the study was to investigate the changes in the reactive oxygen species (ROS), Sirt1, p53 and acetylated p53 in brain tissue of newborn rats exposed to hyperoxia to clarify the role of Sirt1 signaling pathway in brain injury. Neonate rats were randomly divided into normoxic group and hyperoxic group. Rats in the normoxic group were exposed to room air while the rats in the hyperoxic group were put in a hyperoxic chamber (80 ± 5% oxygen) for 1 to 14 d. Data, including weight growth, the water content of brain tissue, hematoxyline and eosin (H&E) and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (Tunel) stain, ROS expression, the relative expression of Sirt1 mRNA and p53 mRNA, and the protein relative expression of Sirt1, p53 and acetylated p53 were analyzed at 1, 7 and 14 d after exposure. A reduced body weight and increased water content were observed in the brain tissue of hyperoxic group compared to normoxic group. HE staining and Tunel staining of brain tissue suggested that cell damaged after hyperoxic exposure. RT-PCR and Western blot results showed that the expression of Sirt1 in the hyperoxic group was lower than that in the normoxic group while the expression of p53 was higher than that in the normoxic group. In addition, Western blot data indicated acetylated p53 expression was higher in the hyperoxic group. Hyperoxic exposure can lead to brain injury in newborn Sprague-Dawley (SD) rats. These events might be regulated by the Sirt1 pathway, which downregulated the deacetylation of p53.

Theoretical Investigation on the Single Transition-Metal Atom-Decorated Defective MoS2 for Electrocatalytic Ammonia Synthesis.

Using density functional theory calculations, we explored the potential of defective MoS2 sheets decorated with a series of single transition-metal (TM) atoms as electrocatalysts for the N2 reduction reaction (NRR). The computed reaction free-energy profiles reveal that the introduction of embedded single TM atoms significantly reduces the difficulty to break the N≡N triple bond and thus facilitates the activation of inert nitrogen. Onset potential close to -0.6 V could be achieved by anchoring various TMs, such as Sc, Ti, Cu, Hf, Pt, and Zr, and the formation of the second ammonia molecule limits the overall process. The Ti-decorated nanosheet possesses the lowest free-energy change of -0.63 eV for the potential determining step. To better predict the catalysis performance, we introduced a descriptor, φ, which is the product of the number of valence electron and electronegativity of the decorated TM. It shows a good linear relationship between the d-band center and binding energy of nitrogen, except for those metals with less than half-filled d-band. Although the metals in Group IIIB and IVB have strong adsorption interactions with N atoms, the Gibbs free-energy changes for desorption of the second ammonia are unexpectedly low. The selectivity of these systems toward nitrogen reduction reaction (NRR) is also significantly improved. Therefore, those defective MoS2 decorated with Sc, Ti, Zr, and Hf are suggested as promising electrocatalysts for NRR, for their both high efficiency and selectivity.

11B NMR Chemical Shift Predictions via Density Functional Theory and Gauge-Including Atomic Orbital Approach: Applications to Structural Elucidations of Boron-Containing Molecules.

11B nuclear magnetic resonance (NMR) spectroscopy is a useful tool for studies of boron-containing compounds in terms of structural analysis and reaction kinetics monitoring. A computational protocol, which is aimed at an accurate prediction of 11B NMR chemical shifts via linear regression, was proposed based on the density functional theory and the gauge-including atomic orbital approach. Similar to the procedure used for carbon, hydrogen, and nitrogen chemical shift predictions, a database of boron-containing molecules was first compiled. Scaling factors for the linear regression between calculated isotropic shielding constants and experimental chemical shifts were then fitted using eight different levels of theory with both the solvation model based on density and conductor-like polarizable continuum model solvent models. The best method with the two solvent models yields a root-mean-square deviation of about 3.40 and 3.37 ppm, respectively. To explore the capabilities and potential limitations of the developed protocols, classical boron-hydrogen compounds and molecules with representative boron bonding environments were chosen as test cases, and the consistency between experimental values and theoretical predictions was demonstrated.

Ghrelin ameliorates A549 cell apoptosis caused by paraquat via p38-MAPK regulated mitochondrial apoptotic pathway.

Paraquat has relatively strong detrimental effects on humans and animals and can cause acute lung injury with high mortality. Ghrelin is a brain-gut peptide which plays important roles in regulating various physiological processes. This study investigated whether ghrelin could inhibit paraquat-induced lung injuries and attempted to elucidate the possible molecular mechanisms. A549 cells were preincubated with different concentrations of ghrelin and then treated with 200 µM of PQ for 24 h. Then cell survival, apoptosis, cellular oxidative stress and lipid peroxidation of A549 cells were detected after different treatments. Subsequently, we analyzed the mitochondrial membrane potential (ΔΨm) and measured caspase-3 activation in A549 cells. In addition, we investigated the activation of the MAPKs pathway and the function of p38-MAPK within mitochondrial apoptosis. Our study indicated that ghrelin administration improved cell viability and reduced apoptosis of PQ-treated A549 cells dose-dependently. Ghrelin treatment reduced the elevation of ROS and MDA, while improved GSH content in A549 cells after paraquat exposure. Moreover, we found that ghrelin dose-dependently increased ΔΨm and decreased caspase-3 activity. The phosphorylated p38 MAPK and JNK levels elevated following PQ exposure, while the phosphorylation of p38 MAPK decreased following ghrelin pretreatment. p38 MAPK siRNA or SB203580 pretreatment ameliorated PQ-caused cell injury and apoptosis related signals, however, the intracellular ROS production was not affected. N-Acetylcysteine (NAC), a classic antioxidant pretreatment decreased the phosphorylated p38 MAPK level and intracellular ROS production, alleviated cell injury, and inhibited apoptosis. The results showed that p38-MAPK pathway plays an important role in PQ-caused alveolar epithelial cell insult, and ghrelin might attenuate PQ-induced cell injury by inhibiting ROS-induced p38-MAPK modulated mitochondrial apoptotic pathway.

DNA vaccine encoding OmpA and Pal from Acinetobacter baumannii efficiently protects mice against pulmonary infection.

Acinetobacter baumannii (A. baumannii) is an opportunistic pathogen that causes serious infections in the lungs, blood, and brain in critically ill hospital patients, resulting in considerable mortality rates every year. Due to the rapid appearance of multi-drug resistance or even pan-drug resistance isolates, it is becoming more and more difficult to cure A. baumannii infection by traditional antibiotic treatment, alternative strategies are urgently required to combat A. baumannii infection. In this study, we developed a DNA vaccine encoding two antigens from A. baumannii, OmpA and Pal, and the immunogenicity and protective efficacy was further evaluated. The results showed that the DNA vaccine exhibited significant immune protective efficacy against acute A. baumannii infection in a mouse pneumonia model, and cross protective efficacy was observed when immunized mice were challenged with clinical strains of A. baumannii. DNA vaccine immunization induced high level of humoral response and a mixed Th1/Th2/Th17 cellular response, which protect against lethal bacterial challenges by decreased bacterial loads and pathology in the lungs, and reduced level of inflammatory cytokines expression and inflammatory cell infiltration in BALF. These results demonstrated that it is possible to prevent A. baumannii infection by DNA vaccine and both OmpA and Pal could be serve as promising candidate antigens.

Prophylactic and therapeutic protection of human IgG purified from sera containing anti-exotoxin A titers against pneumonia caused by Pseudomonas aeruginosa.

Antibodies are effective alternative tools to combat infections caused by Pseudomonas aeruginosa (PA), especially multi-drug-resistant PA. Thus, to solve the urgent need for an anti-PA antibody drug, we hypothesized that anti-PA intravenous immunoglobulins could be a practical attempt. Exotoxin A (ETA) is one of the most important factors for PA infection and is also a critical target for the development of immune interventions. In this study, a total of 320 sera were collected from healthy volunteers. The concentration of ETA-specific antibodies was determined by a Luminex-based assay and then purified by affinity chromatography. The purified IgGs were able to neutralize the cytotoxicity of ETA in vitro. We showed they had a prophylactic and therapeutic protective effect in PA pneumonia and ETA toxemia models. In addition, administration of nonspecific IgGs also provided partial protection. Collectively, our results provide additional evidence for IVIG-based treatment of infections caused by multi-drug-resistant PA and suggest that patients at high risk of PA pneumonia could be prophylactically treated with anti-ETA IgGs or even with nonspecific IgGs.

Comparative studies of catalytic pathways for Streptococcus pneumoniae sialidases NanA, NanB and NanC.

Streptococcus pneumoniae (S. pneumoniae) is a leading human pathogen, which takes large responsibility for severe otitis media, acute meningitis and septicaemia. It encodes up to three distinct sialidases: NanA, NanB and NanC, which are promising drug targets. Recent experimental studies have shown that these three sialidases might work together up to the ultimate step, where NanA and NanB produce N-acetylneuraminic acid (Neu5Ac) and 2,7-anhydro-Neu5Ac following the functions of sialidase and intramolecular trans-sialidase, whilst NanC carries on a ping-pong mechanism that produces or removes 2-deoxy-2,3-didehydro-Neu5AC. It is intriguing that these sialidases have similar active sites but operate via three distinct reaction pathways. To clarify this issue, herein we present the first systematic computational investigation on the catalytic pathways for S. pneumoniae NanA, NanB and NanC based on combined quantum mechanics/molecular mechanics simulations, and propose the most preferred routes for the three S. pneumoniae sialidases. Our findings support the mechanisms of NanA and NanC that were proposed by previous experimental studies, whereas the role of water in NanB was found to differ slightly from our current understandings. The mechanistic insights obtained from this work are expected to assist in the design of potent inhibitors targeting these key enzymes for therapeutic applications.

Heteroatom-doped MoSe2 Nanosheets with Enhanced Hydrogen Evolution Kinetics for Alkaline Water Splitting.

Electrochemical water splitting for hydrogen generation is a vital part for the prospect of future energy systems, however, the practical utilization relies on the development of highly active and earth-abundant catalysts to boost the energy conversion efficiency as well as reduce the cost. Molybdenum diselenide (MoSe2 ) is a promising nonprecious metal-based electrocatalyst for hydrogen evolution reaction (HER) in acidic media, but it exhibits inferior alkaline HER kinetics in great part due to the sluggish water adsorption/dissociation process. Herein, the alkaline HER kinetics of MoSe2 is substantially accelerated by heteroatom doping with transition metal ions. Specifically, the Ni-doped MoSe2 nanosheets exhibit the most impressive catalytic activity in terms of lower overpotential and larger exchange current density. The density functional theory (DFT) calculation results reveal that Ni/Co doping plays a key role in facilitating water adsorption as well as optimizing hydrogen adsorption. The present work paves a new way to the development of low-cost and efficient electrocatalysts towards alkaline HER.

Diradical Anion of Potassium Aggregate: Reduction of Dimer Boroxide Complex.

Crystalline aggregates containing metal cation clusters "wrapped" by reduced hydrocarbon anions have been presented. Initially, a dimeric complex (2) possessing a bimetallic K2O2 core was synthesized from the reaction between an anthracene substituted boronic acid (2-(anthracen-9-yl)phenyl)(hydroxy)(mesityl)borane (1-H) and KN(SiMe3)2 in THF solution. The B-O bond length (1.281(4) Å) in complex 2 is comparable to those observed in oxoboranes, indicating this may be a double bond, which is supported by its Wiberg bond order (1.9) predicted by density functional theory calculations. Subsequently, potassium aggregate complexes, diradical 3 and dihydro anion 4, were obtained through the reduction reactions of dimeric complex 2 and 1-H, respectively. They exhibit similar K3O2B2 aggregate structures, but differ significantly in the geometry of the anthracene units. Complex 3 features a triplet diradical character with planar anthracene units that carry the unpaired electrons, while the anthracene groups in complex 4 display a puckered structure due to the addition of hydrogen atoms.

The effect of DNA backbone on the triplet mechanism of UV-induced thymine-thymine (6-4) dimer formation.

Density functional theory calculations were carried out to investigate the formation mechanism of the thymine-thymine (6-4) dimer ((6-4)TT), which is one of the main DNA lesions induced by ultraviolet radiation and is closely related to skin cancers. The DNA backbone was found to have nonnegligible effects on the triplet reaction pathway, particularly the reaction steps involving substantial base rotations. The mechanism for the isomerization from (6-4)TT to its Dewar valence isomer (DewarTT) was also explored, confirming the necessity of absorbing a second photon. In addition, the solvation effects were examined and showed considerable influence on the potential energy surface. Graphical Abstract DFT calculations on the influence of DNA backbone on the mechanism of UV-induced thymine-thymine (6-4) dimer formation.

Synthesis of Bis-Cycloborate Olefin and Butatriene Derivatives through the Reduction of Alkynyl-Bridged Diboryl Compounds.

A series of bis-cycloborate olefin and butatriene derivatives were synthesized from alkynyl-bridged diboryl compounds using a simple reduction strategy. In the reduction route of 1,2-bis[2-(dimesitylboranyl)phenyl]ethyne (1), bis-cycloborate olefin (4) to diborate-bridged stilbene (5) can be obtained selectively by varying the reaction temperature. In addition, a thermal isomerization from 4 to 5 was found as a result of the rearrangement of double bonds. The generality of this reaction was further verified in similar reduction reactions. In the direduction of 1,2-bis[8-(dimesitylboranyl)naphthalen-1-yl]ethyne (2), the bis-cycloborate olefin (6) was isolated in high yield and demonstrated no thermal isomerization. In the two-electron reduction of 1,8-bis{[2-(dimesitylboranyl)phenyl]ethynyl}naphthalene (3), the bis-cycloborate butatriene (7) was obtained unexpectedly because of the departure of the naphthyl group. When using Na as the reductant and diethyl ether as the solvent, 1,2-bis[( Z)-2-(dimesitylboranyl)benzylidene]-1,2-dihydroacenaphthylene (8) was isolated after adding 1 or 2 drops of H2O to the reduction reaction filtrates. Meanwhile, the related mechanisms for radical cyclization, thermal isomerization, and formation of bis-cycloborate butatriene were also discussed.

A general two-step one-pot synthesis process of ynones from α-keto acids and 1-iodoalkynes.

A general two-step one-pot synthesis process of ynones was developed by cycloaddition of α-keto acids and 1-iodoalkynes followed by a ring-opening reaction. Its easy conditions and novel mechanism endowed it with two distinctive advantages: iodine-atom bonded to C(sp2) remained intact and α-keto acids became a part of the triple bonds in ynones.