Study on the Multi-Component Quantitation of Cortex Moutan and Its Intestinal Absorption Characteristics

Cortex Moutan (Paeonia suffruticosa Andr.) is a common traditional Chinese medicine and has been widely used in clinic for 2000 years in China. As sources for this crude drug are always mixed with other species, many cultivars on herbal market may lead to quality instability. Multi-component quantitative analysis is an efficient method to reflect chemical profiles of herb medicine and is always taken as the main method for quality evaluation. So, the aim of this work is to develop analytical method to quantify paeonol, paeoniflorin, gallic acid, oxypaeoniflorin, benzoylpaeoniflorin and paeonolide in Cortex Moutan (CM) to evaluate the chemical qualities of CM from different species or cultivars. Besides, we also study the intestinal absorption characteristics of paeonol and paeoniflorin for further pharmacological evaluation. In the present study, all of the standard markers were performed on an Ecosil C18 (250 mm × 4.6 mm, 5 μM, Lubex Co., Guangzhou, China) with linear gradient elution of 0.2% formic acid water and acetonitrile. The proposed method was applied to analyze 50 batches of samples with acceptable linearity (R2, 0.9995 - 0.9999), precisions (RSD, 0.47% - 2.08%), repeatability (RSD, 039% - 2.63%), stability (RSD, 0.52% - 2.45%), and recovery (RSD, 0.72% - 3.03%) of the six compounds. Furthermore, the Hierarchical Cluster Analysis was applied to classify the 50 samples based on contents of the six compound markers. The results obtained from multi-component quantification of CM clearly indicated that CM originated from P. suffruticosa and P. ostii presented different chemical properties, and that samples from the two materials could be gathered into one branch, respectively, while CM sourced from cultivars of P. suffruticosa showed great variety on chemical quality. The results from Hierarchical Cluster Analysis implied that the established method could be used as a powerful tool for the quality evaluation of CM. The intestinal absorption study indicated that the intestinal absorption activities for paeoniflorin and paeonol showed an increasing absorption with time. Paeonol had lower absorption rate (6.69% - 15.93%) than that of paeoniflorin (19.0% - 30.70%). As a result, the established method is suitable for the quality evaluation of CM. The results of intestinal absorption characteristics of paeonol and paeoniflorin offer an insight for pharmacological evaluation and clinical efficacy research of CM.

Suppressing FXR promotes antiviral effects of bile acids via enhancing the interferon transcription

Bile acids(BAs)are natural metabolites in mammals and have the potential to function as drugs against viral infection.However,the limited understanding of chenodeoxycholic acid(CDCA)receptors and downstream signaling,along with its lower suppression efficiency in inhibiting virus infection limits its clinical application.In this study,we demonstrate that farnesoid X receptor(FXR),the receptor of CDCA,negatively regulates interferon signaling,thereby contributing to the reduced effectiveness of CDCA against virus replication.FXR deficiency or pharmacological inhibition enhances interferon signaling activation to suppress virus infection.Mechanistically,FXR impairs the DNA binding and transcriptional abilities of activated interferon regulatory factor 3(IRF3)through interaction.Reduced IRF3 transcriptional activity by FXReIRF3 interaction significantly undermines the expression of Interferon Beta 1(IFNB1)and the antiviral response of cells,especially upon the CDCA treatment.In FXR-deficient cells,or when combined with Z-guggulsterone(GUGG)treatment,CDCA exhibits a more potent ability to restrict virus infection.Thus,these findings suggest that FXR serves as a limiting factor for CDCA in inhibiting virus replication,which can be attributed to the“signaling-brake”roles of FXR in interferon signaling.Targeting FXR inhibition represents a promising pharmaceutical strategy for the clinical application of BAs metabolites as antiviral drugs.

Pistachio genomes provide insights into nut tree domestication and ZW sex chromosome evolution

Pistachio is a nut crop domesticated in the Fertile Crescent and a dioecious species with ZW sex chromosomes.We sequenced the genomes of Pistacia vera cultivar(cv.)Siirt,the female parent,and P.vera cv.Bagyolu,the male parent.Two chromosome-level reference genomes of pistachio were generated,and Z and W chromosomes were assembled.The ZW chromosomes originated from an autosome following the first inversion,which occurred approximately 8.18 Mya.Three inversion events in the W chromosome led to the formation of a 12.7-Mb(22.8%of the W chromosome)non-recombining region.These W-specific sequences contain several genes of interest that may have played a pivotal role in sex determination and contributed to the initiation and evolution of a ZW sex chromosome system in pistachio.The W-specific genes,including defA,defA-like,DYT1,two PTEN1,and two tandem duplications of six VPS13A paralogs,are strong candidates for sex determination or differentiation.Demographic history analysis of resequenced genomes suggest that cultivated pistachio underwent severe domestication bottlenecks approximately 7640 years ago,dating the domestication event close to the archeological record of pistachio domestication in Iran.We identified 390,211,and 290 potential selective sweeps in 3 cultivar subgroups that underlie agronomic traits such as nut development and quality,grafting success,flowering time shift,and drought tolerance.These findings have improved our understanding of the genomic basis of sex determination/differentiation and horticulturally important traits and will accelerate the improvement of pistachio cultivars and rootstocks.

Single-dose AAV-based vaccine induces a high level of neutralizing antibodies against SARS-CoV-2 in rhesus macaques

Dear Editor,Coronavirus disease 2019(COVID-19)is a highly infectious respiratory disease that continues to pose a serious global public health emergency.The disease shows a high infection rate,long incubation period,and rapidly emerging variants,which have led to its rapid spread worldwide(Krammer 2020).Many vaccines have been developed for the control of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the virus responsible for COVID-19,including vaccines based on messenger RNA(mRNA)(Polack et al.2020),viral vectors(Zhu et al.2020),recombinant proteins(Yang et al.2020),and inactivated SARS-CoV-2(Zhang et al.2021).

Decentralizing access control system for data sharing in smart grid

Smart grid enhances the intelligence of the traditional power grid,which allows sharing varied data such as consumer,production,or energy with service consumers.Due to the untrustworthy networks,there exist potential security threats(e.g.,unauthorized access and modification,malicious data theft)hindering the development of smart grid.While several access control schemes have been proposed for smart grid to achieve sensitive data protection and fine-grained identity management,most of them cannot satisfy the requirements of decentralizing smart grid environment and suffer from key escrow problems.In addition,some existing solutions cannot achieve dynamic user management for lacking the privilege revocation mechanism.In this paper,we propose a decentralizing access control system with user revocation to relieve the above problems.We design a new multiple-authority attribute-based encryption(MABE)scheme to keep data confidentiality and adapt decentralizing smart grid applications.We also compare our proposal with the similar solution from both security and performance.The comparing results show that our access control system can achieve a trade-off among confidentiality,authentication,distribution and efficiency in smart grid.

SKP2 attenuates NF-κB signaling by mediating IKKβ degradation through autophagy

NF-κB signaling controls a large set of physiological processes ranging from inflammatory responses to cell death. Its activation is tightly regulated through controlling the activity and stability of multiple signaling components. Here, we identify that NF-κB activation is suppressed by an F-box protein, S-phase kinase associated protein 2 （SKP2）. SKP2 deficiency enhanced NF-κB activation as well as the production of inflammatory cytokines. In addition, SKP2 potently blocked the NF-κB activation at the κB kinase （IKIO level. Mechanistic study further revealed that SKP2 functions as an adaptor to promote an interaction between active IKKβ and the autophagic cargo receptor p62 to mediate IKKβ degradation via selective autophasy. These findings identify a previously unrecognized role of SKP2 in NF-κB activation by which SKP2 acts as a secondary receptor to assist IKKβ delivery to autophagosomes for degradation in a p62-dependent manner.

Differential expression of FOXO1 during development and myoblast differentiation of Qinchuan cattle and its association analysis with growth traits

Our previous work reported a relationship between FOXO1 mutations and growth of Qinchuan(QC) cattle. Here, we performed differential expression analysis of FOXO1 and its association analysis with growth traits in QC cattle. First, we measured the expression of the FOXO1 gene in nine tissues during three developmental stages. The results showed that FOXO1 was abundantly expressed in tissues of calves but was strongly repressed in adulthood, although there was significant transcription in skeletal muscle. FOXO1 expression showed gradual up-regulation during differentiation of primary bovine skeletal muscle cells.We also identified six SNPs of the bovine FOXO1 gene by sequencing DNA pools of samples from 488 individuals, and association analysis indicated that five SNPs were significantly associated with some growth traits in the QC population. We further analyzed four haplotype combinations of the six SNPs and found significant correlation with body length(P<0.01). In conclusion, FOXO1 participates in bovine myocyte differentiation and expression, and may be a strong candidate as a gene that affects growth traits that could be exploited in a QC cattle breeding program. More generally, our data provide a new theoretical basis for QC beef breeding and beef quality improvement.

The mechanisms of nucleotide actions in insulin resistance

Insulin resistance contributes to metabolic disorders in obesity and type 2 diabetes.In mechanisms of insulin resistance,the roles of glucose,fatty acids,and amino acids have been extensively documented in literature.However,the activities of nucleotides remain to be reviewed comprehensively in the regulation of insulin sensitivity.Nucleotides are well known for their activities in biosynthesis of DNA and RNA as well as their signaling activities in the form of c AMP and c GAMP.Their activities in insulin resistance are dependent on the derivatives and corresponding receptors.ATP and NADH,derivatives of adenosine,inhibit insulin signaling inside cells by downregulation of activities of AMPK and SIRT1,respectively.ATP,ADP and AMP,the well-known energy carriers,regulate cellular responses to insulin outside cells through the purinergic receptors in cell surface.Current evidence suggests that ATP,NADH,c GAMP,and uridine are potential biomarkers of insulin resistance.However,GTP and c GMP are likely the markers of insulin sensitization.Here,studies crossing the biomedical fields are reviewed to characterize nucleotide activities in the regulation of insulin sensitivity.The knowledge brings new insights into the mechanisms of insulin resistance.

Comparison of viral propagation and drug response among SARS-CoV-2 VOCs using replicons capable of recapitulating virion assembly and release

Several variants of concern(VOCs)have emerged since the WIV04 strain of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)was first isolated in January 2020.Due to mutations in the spike(S)protein,these VOCs have evolved to enhance viral infectivity and immune evasion.However,whether mutations of the other viral proteins lead to altered viral propagation and drug resistance remains obscure.The replicon is a noninfectious viral surrogate capable of recapitulating certain steps of the viral life cycle.Although several SARS-CoV-2 replicons have been developed,none of them were derived from emerging VOCs and could only recapitulate viral genome replication and subgenomic RNA(sgRNA)transcription.In this study,SARS-CoV-2 replicons derived from the WIV04 strain and two VOCs(the Beta and Delta variants)were prepared by removing the S gene from their genomes,while other structural genes remained untouched.These replicons not only recapitulate viral genome replication and sgRNA transcription but also support the assembly and release of viral-like particles,as manifested by electron microscopic assays.Thus,the S-deletion replicon could recapitulate virtually all the post-entry steps of the viral life cycle and provides a versatile tool for measuring viral intracellular propagation and screening novel antiviral drugs,including inhibitors of virion assembly and release.Through the quantification of replicon RNA released into the supernatant,we demonstrate that viral intracellular propagation and drug response to remdesivir have not yet substantially changed during the evolution of SARS-CoV-2 from the WIV04 strain to the Beta and Delta VOCs.

Recombinant chimpanzee adenovirus vector vaccine expressing the spike protein provides effective and lasting protection against SARS-CoV-2 infection in mice

SARS-CoV-2 infection is a global public health threat.Vaccines are considered amongst the most important tools to control the SARS-CoV-2 pandemic.As expected,deaths from SARS-CoV-2 infection have dropped dramatically with widespread vaccination.However,there are concerns over the duration of vaccine-induced protection,as well as their effectiveness against emerging variants of concern.Here,we constructed a recombinant chimpanzee adenovirus vectored vaccine expressing the full-length spike of SARS-CoV-2(Ad C68-S).Rapid and high levels of humoral and cellular immune responses were observed after immunization of C57BL/6J mice with one or two doses of Ad C68-S.Notably,neutralizing antibodies were observed up to at least six months after vaccination,without substantial decline.Single or double doses Ad C68-S immunization resulted in lower viral loads in lungs of mice against SARS-CoV-2 challenge both in the short term(21 days)and long-term(6 months).Histopathological examination of Ad C68-S immunized mice lungs showed mild histological abnormalities after SARS-CoV-2 infection.Taken together,this study demonstrates the efficacy and durability of the Ad C68-S vaccine and constitutes a promising candidate for clinical evaluation.

Infection and pathogenesis of the Delta variant of SARS-CoV-2 in Rhesus macaque

Dear Editor,COVID-19 caused by SARS-Co V-2,is still a big threat to human populations around the world.As of Jan 2022,over 292 million cases were reported worldwide with more than 5.4 million deaths.After it was first reported in China in December 2019,the virus kept circulating and evolving and several variants with different transmissibility emerged in different countries and regions(WHO,2021a).