Professors and Graduates from Peking University School of Pharmaceutical Sciences Attending the 67th FIP Congress and CPA Centennial Anniversary

During the first week of September, 2007, the 67th world congress of pharmacy and pharmaceutical sciences,jointly hosted by the International Pharmaceutical Federation (FIP) and the Chinese Pharmaceutical

Advantages of nanocarriers for basic research in the field of traumatic brain injury

A major challenge for the efficient treatment of traumatic brain injury is the need for therapeutic molecules to cross the blood-brain barrier to enter and accumulate in brain tissue.To overcome this problem,researchers have begun to focus on nanocarriers and other brain-targeting drug delivery systems.In this review,we summarize the epidemiology,basic pathophysiology,current clinical treatment,the establishment of models,and the evaluation indicators that are commonly used for traumatic brain injury.We also report the current status of traumatic brain injury when treated with nanocarriers such as liposomes and vesicles.Nanocarriers can overcome a variety of key biological barriers,improve drug bioavailability,increase intracellular penetration and retention time,achieve drug enrichment,control drug release,and achieve brain-targeting drug delivery.However,the application of nanocarriers remains in the basic research stage and has yet to be fully translated to the clinic.

Effects of Maillard reaction and its product AGEs on aging and age-related diseases

Maillard reaction(MR)is a non-enzymatic browning reaction commonly seen in food processing,which occurs between reducing sugars and compounds with amino groups.Despite certain advantages based on Maillard reaction products(MRPs)found in some food for health and storage application have appeared,however,the MR occurring in human physiological environment can produce advanced glycation end products(AGEs)by non-enzymatic modification of macromolecules such as proteins,lipids and nucleic acid,which could change the structure and functional activity of the molecules themselves.In this review,we take AGEs as our main object,on the one hand,discuss physiologic aging,that is,age-dependent covalent cross-linking and modification of proteins such as collagen that occur in eyes and skin containing connective tissue.On the other hand,pathological aging associated with autoimmune and inflammatory diseases,neurodegenerative diseases,diabetes and diabetic nephropathy,cardiovascular diseases and bone degenerative diseases have been mainly proposed.Based on the series of adverse effects of accelerated aging and disease pathologies caused by MRPs,the possible harm caused by some MR can be slowed down or inhibited by artificial drug intervention,dietary pattern and lifestyle control.It also stimulates people's curiosity to continue to explore the potential link between the MR and human aging and health,which should be paid more attention to for the development of life sciences.

Adsorption,in vitro digestion and human gut microbiota regulation characteristics of three Poria cocos polysaccharides

Poria cocos(PC)is a famous traditional Chinese medicine(TCM)and a widely used healthcare ingredient,which has antiobesity,enhancing immunity and improving sleep effects.Traditionally,only water-soluble poria polysaccharide(WSP)is extracted and applied for clinical application,while insoluble polysaccharide(alkali-soluble poria polysaccharide,ASP)is discarded as herb residue.However,the whole PC has also been historically utilized as functional herbal food.Considering the beneficial role of dietary fiber and the traditional use of PC,ASP may also contribute substantially to the therapy function of PC.Compared to WSP,little attention has been paid to ASP and ASP modified product carboxymethyl poria polysaccharide(CMP)which has been used as an antitumor adjuvant drug.In this study,the oil,cholesterol,metal ions and polyphenols adsorption ability,in vitro simulated digestive and the gut microbiota fermentation characteristics of WSP,ASP and CMP were studied to evaluate the functional values of three P.cocos polysaccharides(PCPs).The results showed that all three PCPs had good adsorption capacity on cholesterol,polyphenols and metal ions(Cd^(2+)/Zn^(2+)/Mg^(2+)),among which ASP showed the highest capacity than WSP and CMP.The adsorption capacity of all three PCPs on heavy metal ions(Cd^(2+)/Zn^(2+))was stronger than that of non-heavy metal ions(Mg^(2+));The in vitro digestibility of all three PCPs was very low,but WSP was slightly higher than ASP and CMP;Moreover,the indigestible residue of all three PCPs could improve the richness and diversity of gut microbiota,among which ASP had the greatest influence.In general,ASP and CMP could significantly promote the proliferation of some probiotics and inhibit the growth of some harmful bacteria.The gut microbiota diversity of CMP was reduced,but the richness of probiotics,especially Parabacteroides distasonis was significantly enhanced compared with the ASP group,and the growth of harmful bacteria Klebsiella pneumoniae was inhibited after CMP treatment.The short-chain fatty acids(SCFAs)analysis results showed that all three PCPs could significantly promote the production of acetic acid,propionic acid and the total acid content compared with blank control group,and SCFAs producing activity was positively correlated with the proliferative capacity of probiotics.Taken together,the good adsorption characteristics and gut microbiota regulatory activity of ASP may lay foundation for its lipid-lowering and immune-improving function.Additionally,the probiotic effect of CMP and ASP indicated that except for only use the water extract of PC in clinic,CMP and ASP also can be used in healthcare to take full advantage of this valuable medicine.

Identification of different degrees of processed ginger using GC-IMS combined with machine learning

Ginger,the rhizomes of Zingiber officinale Roscoe,was a wellknown edible plant species commonly used in China,which has pungent flavor[1].Ginger has numerous chemical compounds,such as phenolic constituents,volatile compounds(VOCs),and polysaccharides[2].Among them,VOCs are considered one of the effective compounds in ginger due to their functional properties,including anti-inflammatory,antioxidant,and analgesic[3].

Plastid phylogenomics provides new insights into the systematics,diversification,and biogeography of Cymbidium(Orchidaceae)

Cymbidium(Orchidaceae:Epidendroideae),with around 60 species,is widely-distributed across Southeast Asia,providing a nice system for studying the processes that underlie patterns of biodiversity in the region.However,phylogenetic relationships of Cymbidium have not been well resolved,hampering investigations of species diversification and the biogeographical history of this genus.In this study,we construct a plastome phylogeny of 56 Cymbidium species,with four well-resolved major clades,which provides a framework for biogeographical and diversification rate analyses.Molecular dating and biogeographical analyses show that Cymbidium likely originated in the region spanning northern IndoBurma to the eastern Himalayas during the early Miocene(~21.10 Ma).It then rapidly diversified into four major clades in East Asia within approximately a million years during the middle Miocene.Cymbidium spp.migration to the adjacent regions(Borneo,Philippines,and Sulawesi)primarily occurred during the Pliocene-Pleistocene period.Our analyses indicate that the net diversification rate of Cymbidium has decreased since its origin,and is positively associated with changes in temperature and monsoon intensity.Favorable hydrothermal conditions brought by monsoon intensification in the early Miocene possibly contributed to the initial rapid diversification,after which the net diversification rate was reduced with the cooling climate after the middle Miocene.The transition from epiphytic to terrestrial habits may have enabled adaptation to cooler environments and colonization of northern niches,yet without a significant effect on diversification rates.This study provides new insights into how monsoon activity and temperature changes affected the diversification dynamics of plants in Southeast Asia.

Molecular Mechanisms of Intracellular Delivery of Nanoparticles Monitored by an Enzyme‑Induced Proximity Labeling

Achieving increasingly finely targeted drug delivery to organs,tissues,cells,and even to intracellular biomacromolecules is one of the core goals of nanomedicines.As the delivery destination is refined to cellular and subcellular targets,it is essential to explore the delivery of nanomedicines at the molecular level.However,due to the lack of technical methods,the molecular mechanism of the intracellular delivery of nanomedicines remains unclear to date.Here,we develop an enzyme-induced proximity labeling technology in nanoparticles(nano-EPL)for the real-time monitoring of proteins that interact with intracellular nanomedicines.Poly(lactic-co-glycolic acid)nanoparticles coupled with horseradish peroxidase(HRP)were fabricated as a model(HRP(+)-PNPs)to evaluate the molecular mechanism of nano delivery in macrophages.By adding the labeling probe biotin-phenol and the catalytic substrate H_(2)O_(2)at different time points in cellular delivery,nano-EPL technology was validated for the real-time in situ labeling of proteins interacting with nanoparticles.Nano-EPL achieves the dynamic molecular profiling of 740 proteins to map the intracellular delivery of HRP(+)-PNPs in macrophages over time.Based on dynamic clustering analysis of these proteins,we further discovered that different organelles,including endosomes,lysosomes,the endoplasmic reticulum,and the Golgi apparatus,are involved in delivery with distinct participation timelines.More importantly,the engagement of these organelles differentially affects the drug delivery efficiency,reflecting the spatial–temporal heterogeneity of nano delivery in cells.In summary,these findings highlight a significant methodological advance toward understanding the molecular mechanisms involved in the intracellular delivery of nanomedicines.

In situ injectable hydrogel encapsulating Mn/NO-based immune nano-activator for prevention of postoperative tumor recurrence

Postoperative tumor recurrence remains a predominant cause of treatment failure. In this study, we developed an in situ injectable hydrogel, termed MPB-NO@DOX + ATRA gel, which was locally formed within the tumor resection cavity. The MPB-NO@DOX + ATRA gel was fabricated by mixing a thrombin solution, a fibrinogen solution containing all-trans retinoic acid (ATRA), and a Mn/NO-based immune nano-activator termed MPB-NO@DOX. ATRA promoted the differentiation of cancer stem cells, inhibited cancer cell migration, and affected the polarization of tumor-associated macrophages. The outer MnO2 shell disintegrated due to its reaction with glutathione and hydrogen peroxide in the cytoplasm to release Mn2+ and produce O2, resulting in the release of doxorubicin (DOX). The released DOX entered the nucleus and destroyed DNA, and the fragmented DNA cooperated with Mn2+ to activate the cGAS-STING pathway and stimulate an anti-tumor immune response. In addition, when MPB-NO@DOX was exposed to 808 nm laser irradiation, the Fe-NO bond was broken to release NO, which downregulated the expression of PD-L1 on the surface of tumor cells and reversed the immunosuppressive tumor microenvironment. In conclusion, the MPB-NO@DOX + ATRA gel exhibited excellent anti-tumor efficacy. The results of this study demonstrated the great potential of in situ injectable hydrogels in preventing postoperative tumor recurrence.

Pathogenic contribution of cholesteryl ester accumulation in the brain to neurodegenerative disorders

Cholesteryl esters(CEs) have been increasingly implicated in neurodegenerative disorders such as Alzheimer's disease(AD).Alois Alzheimer noted three prominent neuropathologic features in his original analysis of the AD brain:senile plaques,neurofibrillary tangles,and lipid granule accumulation.Senile plaques,which are aggregates of amyloid-beta(Aβ),and neurofibrillary tangles,which are aggregates of phosphorylated tau,have been regarded as more consistent characteristics of the AD brain compared with lipid granule accumulation and thus have been studied more intensively(Foley,2010).

Immunotherapeutic hydrogel for co-delivery of STAT3 siRNA liposomes and lidocaine hydrochloride for postoperative comprehensive management of NSCLC in a single application

Despite standard treatment for non-small cell lung cancer(NSCLC)being surgical resection,cancer recurrence and complications,such as induction of malignant pleural effusion(MPE)and significant postoperative pain,usually result in treatment failure.In this study,an alginate-based hybrid hydrogel(SOG)is developed that can be injected into the resection surface of the lungs during surgery.Briefly,endoplasmic reticulum-modified liposomes(MSLs)pre-loaded with the signal transducer and activator of transcription 3(STAT3)small interfering RNA and lidocaine hydrochloride are encapsulated in SOG.Once applied,MSLs strongly downregulated STAT3 expression in the tumor microenvironment,resulting in the apoptosis of lung cancer cells and polarization of tumor-associated macrophages towards the M1-like phenotype.Meanwhile,the release of lidocaine hydrochloride(LID)was beneficial for pain relief and natural killer cell activation.Our data demonstrated MSL@LID@SOG not only efficiently inhibited tumor growth but also potently improved the quality of life,including reduced MPE volume and pain relief in orthotopic NSCLC mouse models,even with a single administration.MSL@LID@SOG shows potential for comprehensive clinical management upon tumor resection in NSCLC,and may alter the treatment paradigms for other cancers.

Notopterygium Incisum Extract Promotes Apoptosis by Preventing the Degradation of BIM in Colorectal Cancer

Objective Colorectal cancer(CRC),a prevalent malignancy worldwide,has prompted extensive research into anticancer drugs.Traditional Chinese medicinal materials offer promising avenues for cancer management due to their diverse pharmacological activities.This study investigated the effects of Notopterygium incisum,a traditional Chinese medicine named Qianghuo(QH),on CRC cells and the underlying mechanism.Methods The sulforhodamine B assay and colony formation assay were employed to assess the effect of QH extract on the proliferation of CRC cell lines HCT116 and Caco-2.Propidium iodide(PI)staining was utilized to detect cell cycle progression,and PE Annexin V staining to detect apoptosis.Western blotting was conducted to examine the levels of apoptotic proteins,including B-cell lymphoma 2-interacting mediator of cell death(BIM),B-cell lymphoma 2(Bcl-2),Bcl-2-associated X protein(BAX)and cleaved caspase-3,as well as BIM stability after treatment with the protein synthesis inhibitor cycloheximide.The expression of BAX was suppressed using lentivirus-mediated shRNA to validate the involvement of the BIM/BAX axis in QH-induced apoptosis.The in vivo effects of QH extract on tumor growth were observed using a xenograft model.Lastly,APC^(Min+)mice were used to study the effects of QH extract on primary intestinal tumors.Results QH extract exhibited significant in vitro anti-CRC activities evidenced by the inhibition of cell proliferation,perturbation of cell cycle progression,and induction of apoptosis.Mechanistically,QH extract significantly increased the stability of BIM proteins,which undergo rapid degradation under unstressed conditions.Knockdown of BAX,the downstream effector of BIM,significantly rescued QH-induced apoptosis.Furthermore,the in vitro effect of QH extract was recapitulated in vivo.QH extract significantly inhibited the tumor growth of HCT116 xenografts in nude mice and decreased the number of intestinal polyps in the APC^(Min+)mice.Conclusion QH extract promotes the apoptosis of CRC cells by preventing the degradation of BIM.

The superiority of PMFs on reversing drug resistance of colon cancer and the effect on aerobic glycolysis-ROS-autophagy signaling axis

Background:Polymethoxylatedflavones(PMFs)are compounds present in citrus peels and other Rutaceae plants,which exhibit diverse biological activities,including robust antitumor and antioxidant effects.However,the mechanism of PMFs in reversing drug resistance to colon cancer remains unknown.In the present study,we aimed to investigate the potential connection between the aerobic glycolysis-ROS-autophagy signaling axis and the reversal of PTX resistance in colon cancer by PMFs.Methods:MTT Cell viability assay and colony formation assay were used to investigate the effect of PMFs combined with PTX in reversing HCT8/T cell resistance ex vivo;the mRNA and protein levels of the target were detected by SDS-PAGE(sodium dodecyl sulfate-polyacrylamide gel electrophoresis),quantitative real-timefluorescence polymerase chain reaction(qRT-PCR)and Western blot protein immunoblotting(WB);An HCT8/T cell xenograft model was established to investigate the MDR reversal activity of PMFs in vivo;The extracellular acidification rate(ECAR)and the oxygen consumption rate(OCR)were detected to assess the cellular oxygen consumption rate and glycolytic process.Results:HCT8/T cells demonstrated significant resistance to PTX,up-regulating the expression levels of ABCB1 mRNA,P-gp,LC3-I,and LC3-II protein,and increasing intracellular reactive oxygen species(ROS)content.PMFs mainly contain two active ingredients,nobiletin,and tangeretin,which were able to reverse drug resistance in HCT8/T cells in a concentration-dependent manner.PMFs exhibited high tolerance in the HCT8/T nude mouse model while increasing the sensitivity of PTX-resistant cells and suppressing tumor growth significantly.PMFs combined with PTX reduced extracellular acidification rate(ECAR)and oxygen consumption rate(OCR)in HCT8/T cells.Additionally,PMFs reduced intracellular ROS content,down-regulated the expression levels of autophagy-related proteins LC3-I,LC3-II,Beclin1,and ATG7,and significantly reduced the number of autophagosomes in HCT8/T cells.Conclusions:The present study demonstrated that PMFs could potentially reverse PTX resistance in colon cancer by regulating the aerobic glycolysis-ROS-autophagy signaling axis,which indicated that PMFs would be potential potentiators for future chemotherapeutic agents in colon cancer.

Antitumor effects of a novel photosensitizer-mediated photodynamic therapy and its influence on the cell transcriptome

Photodynamic therapy(PDT)is a promising cancer treatment.This study investigated the antitumor effects and mechanisms of a novel photosensitizer meso-5-[ρ-diethylene triamine pentaacetic acid-aminophenyl]−10,15,20-triphenyl-porphyrin(DTP)mediated PDT(DTP-PDT).Cell viability,reactive oxygen species(ROS),and apoptosis were measured with a Cell Counting Kit-8 assay,DCFH-DA fluorescent probe,and Hoechst staining,respectively.Cell apoptosis-and autophagy-related proteins were examined using western blotting.RNA sequencing was used to screen differentially expressed mRNAs(DERs),and bioinformatic analysis was performed to identify the major biological events after DTP-PDT.Our results show that DTP-PDT inhibited cell growth and induced ROS generation in MCF-7 and SGC7901 cells.The ROS scavenger N-acetyl-L-cysteine(NAC)and the P38 MAPK inhibitor SB203580 alleviated DTP-PDT-induced cytotoxicity.DTP-PDT induced cell apoptosis together with upregulated Bax and downregulated Bcl-2,which could also be inhibited by NAC or SB203580.The level of LC3B-Ⅱ,a marker of autophagy,was increased by DTP-PDT.A total of 3496 DERs were obtained after DTP-PDT.Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses indicated that DERs included those involved in cytosolic ribosomes,the nuclear lumen,protein binding,cell cycle,protein targeting to the endoplasmic reticulum,and ribosomal DNA replication.Disease Ontology and Reactome enrichment analyses indicated that DERs were associated with a variety of cancers and cell cycle checkpoints.Protein-protein interaction results demonstrated that cdk1 and rps27a ranked in the top 10 interacting genes.Therefore,DTP-PDT could inhibit cell growth and induce cell apoptosis and autophagy,partly through ROS and the P38 MAPK signaling pathway.Genes associated with the cell cycle,ribosomes,DNA replication,and protein binding may be the key changes in DTP-PDT-mediated cytotoxicity.

Integrated spatial metabolomics and transcriptomics decipher the hepatoprotection mechanisms of wedelolactone and demethylwedelolactone on non-alcoholic fatty liver disease

Eclipta prostrata L.has been used in traditional medicine and known for its liver-protective properties for centuries.Wedelolactone(WEL)and demethylwedelolactone(DWEL)are the major coumarins found in E.prostrata L.However,the comprehensive characterization of these two compounds on non-alcoholic fatty liver disease(NAFLD)still remains to be explored.Utilizing a well-established zebrafish model of thioacetamide(TAA)-induced liver injury,the present study sought to investigate the impacts and mechanisms of WEL and DWEL on NAFLD through integrative spatial metabolomics with liver-specific transcriptomics analysis.Our results showed that WEL and DWEL significantly improved liver function and reduced the accumulation of fat in the liver.The biodistributions and metabolism of these two compounds in whole-body zebrafish were successfully mapped,and the discriminatory endogenous metabolites reversely regulated by WEL and DWEL treatments were also characterized.Based on spatial metabolomics and transcriptomics,we identified that steroid biosynthesis and fatty acid metabolism are mainly involved in the hepatoprotective effects of WEL instead of DWEL.Our study unveils the distinct mechanism of WEL and DWEL in ameliorating NAFLD,and presents a“multi-omics”platform of spatial metabolomics and liver-specific transcriptomics to develop highly effective compounds for further improved therapy.

Evaluation of the famous classic formula Sanhua decoction based on network pharmacology and multi-component quantitative analysis

Background:Sanhua decoction has significant effects in the treatment of stroke.The study of the Sanhua decoction material benchmark was carried out to analyze the value transfer relationship between the Chinese herbal pieces and the substance benchmark.Methods:Network pharmacology was employed to investigate the potential active components and molecular mechanisms of Sanhua decoction in the treatment of stroke.15 batches of Sanhua decoction lyophilized powder were prepared using traditional formulas and subjected to high-performance liquid chromatography analysis to generate fingerprints of the Sanhua decoction substance benchmarks.Then,a multi-component quantitative analysis method was established,allowing for the simultaneous determination of ten components,to study the transfer of quantity values between pieces and substance benchmarks.Results:60 active ingredients were screened from Sanhua decoction by network pharmacology,of which gallic acid,magnolol honokiol,physcion,and aloe-emodin may have a greater effect than other active components.63 key targets and 134 pathways were predicted as the potential mechanism of Sanhua decoction in treating stroke.The fingerprint similarity of the Sanhua decoction substance benchmarks was found to be good among the 15 batches,confirming the 19 common peaks.The content of the 10 components was basically consistent.The components’transfer rates were within 30%of their respective means.Conclusions:This study provided a comprehensive and reliable strategy for the quality evaluation of Sanhua decoction substance benchmarks and held significant importance in improving its application value.

Based on non-targeted metabolomics for differential components screening of Rosae Chinensis Flos and Rosae Rugosae Flos and their quality evaluation

Background:Rosa chinensis Jacq.and Rosa rugosa Thunb.are not only of ornamental value,but also edible flowers and the flower buds have been listed in the Chinese Pharmacopoeia as traditional medicines.The two plants have some differences in efficacy,but the flower buds are easily confused for similar traits.In addition,large-scale cultivation of ornamental rose flowers may lead to a decrease in the effective components of medicinal roses.Therefore,it is necessary to study the chemical composition and make quality evaluation of Rosae Chinensis Flos(Yueji)and Rosae Rugosae Flos(Meigui).Methods:In this study,40 batches of samples including Meigui and Yueji from different regions in China were collected to establish high-performance liquid chromatography fingerprints.Then,the fingerprints data was analyzed using principal component analysis,hierarchical cluster analysis,and partial least squares discriminant analysis analysis chemometrics to obtain information on intergroup differences,and non-targeted metabolomic techniques were applied to identify and compare chemical compositions of samples which were chosen from groups with large differences.Differential compounds were screened by orthogonal partial least-squares discriminant analysis and S-plot,and finally multi-component quantification was performed to comprehensively evaluate the quality of Yueji and Meigui.Results:The similarity between the fingerprints of 40 batches roses and the reference print R was 0.73 to 0.93,indicating that there were similarities and differences between the samples.Through principal component analysis and hierarchical cluster analysis of fingerprints data,the samples from different origins and varieties were intuitively divided into four groups.Partial least-squares discriminant analysis analysis showed that Meigui and Yueji cluster into two categories and the model was reliable.A total of 89 compounds were identified by high resolution mass spectrometry,mainly were flavonoids and flavonoid glycosides,as well as phenolic acids.Eight differential components were screened out by orthogonal partial least-squares discriminant analysis and S-plot analysis.Quantitative analyses of the eight compounds,including gallic acid,ellagic acid,hyperoside,isoquercitrin,etc.,showed that Yueji was generally richer in phenolic acids and flavonoids than Meigui,and the quality of Yueji from Shandong and Hebei was better.It is worth noting that Xinjiang rose is rich in various components,which is worth focusing on more in-depth research.Conclusion:In this study,the fingerprints of Meigui and Yueji were established.The chemical components information of roses was further improved based on non-targeted metabolomics and mass spectrometry technology.At the same time,eight differential components of Meigui and Yueji were screened out and quantitatively analyzed.The research results provided a scientific basis for the quality control and rational development and utilization of Rosae Chinensis Flos and Rosae Rugosae Flos,and also laid a foundation for the study of their pharmacodynamic material basis.

Circumscription of the East Asia clade (Apiaceae subfamily Apioideae) and the taxonomic placements of several problematic genera

The East Asia(or Physospermopsis) clade was recognized in previous molecular phylogenetic investigations into the higher-level relationships of Apiaceae subfamily Apioideae. The composition of this clade, the phylogenetic relationships among its constituent taxa, and the placement of species previously determined to be problematic have yet to be resolved. Herein, nr DNA ITS sequences were obtained for150 accessions of Apioideae, representing species whose distributions are in East Asia or genera having one or more species included within the East Asia clade. These data, along with published ITS sequences from other Apioideae(for 3678 accessions altogether), were subjected to maximum likelihood and Bayesian inference analyses. The results show that the East Asia clade contains representatives of 11currently recognized genera: Hansenia, Hymenolaena, Keraymonia, Sinolimprichtia, Acronema, Hymenidium, Physospermopsis, Pimpinella, Sinocarum, Tongoloa, and Trachydium. However, the latter seven genera have members falling outside of the East Asia clade, including the generic types of all except Tongoloa. Within the clade, the species comprising these seven genera are widely intermingled, greatly increasing confusion among relationships than previously realized. The problematic species Physospermopsis cuneata is confirmed as falling within the East Asia clade, whereas P. rubrinervis allies with the generic type in tribe Pleurospermeae. Physospermopsis kingdon-wardii is confirmed as a member of the genus Physospermopsis, whereas the generic attributions of P. cuneata and Tongoloa stewardii remain unclear. Two species of Sinocarum(S. filicinum and S. wolffianum) are transferred into the genus Meeboldia. This is the most comprehensive molecular phylogenetic investigation of the East Asia clade to date, and while the results increase systematic understanding of the clade, they also highlight the need for further studies of one of the most taxonomically intractable groups in Apioideae.

Early proactive monitoring of DNA-thioguanine in patients with Crohn’s disease predicts thiopurine-induced late leucopenia in NUDT15/TPMT normal metabolizers

BACKGROUND Thiopurine-induced leucopenia significantly hinders the wide application of thiopurines.Dose optimization guided by nudix hydrolase 15(NUDT15)has significantly reduced the early leucopenia rate,but there are no definitive biomarkers for late risk leucopenia prediction.AIM To determine the predictive value of early monitoring of DNA-thioguanine(DNATG)or 6-thioguanine nucleotides(6TGN)for late leucopenia under a NUDT15-guided thiopurine dosing strategy in patients with Crohn’s disease(CD).METHODS Blood samples were collected within two months after thiopurine initiation for detection of metabolite concentrations.Late leucopenia was defined as a leukocyte count<3.5×10^(9)/L over two months.RESULTS Of 148 patients studied,late leucopenia was observed in 15.6%(17/109)of NUDT15/thiopurine methyltransferase(TPMT)normal and 64.1%(25/39)of intermediate metabolizers.In patients suffering late leucopenia,early DNATG levels were significantly higher than in those who did not develop late leucopenia(P=4.9×10^(-13)).The DNATG threshold of 319.43 fmol/μg DNA could predict late leucopenia in the entire sample with an area under the curve(AUC)of 0.855(sensitivity 83%,specificity 81%),and in NUDT15/TPMT normal metabolizers,the predictive performance of a threshold of 315.72 fmol/μg DNA was much more remarkable with an AUC of 0.902(sensitivity 88%,specificity 85%).6TGN had a relatively poor correlation with late leucopenia whether in the entire sample(P=0.021)or NUDT15/TPMT normal or intermediate metabolizers(P=0.018,P=0.55,respectively).CONCLUSION Proactive therapeutic drug monitoring of DNATG could be an effective strategy to prevent late leucopenia in both NUDT15/TPMT normal and intermediate metabolizers with CD,especially the former.

The marriage of immunomodulatory,angiogenic,and osteogenic capabilities in a piezoelectric hydrogel tissue engineering scafold for military medicine

Background:Most bone-related injuries to grassroots troops are caused by training or accidental injuries.To establish preventive measures to reduce all kinds of trauma and improve the combat effectiveness of grassroots troops,it is imperative to develop new strategies and scafolds to promote bone regeneration.Methods:In this study,a porous piezoelectric hydrogel bone scafold was fabricated by incorporating polydopamine(PDA)-modified ceramic hydroxyapatite(PDA-hydroxyapatite,PHA)and PDA-modified barium titanate(PDABaTiO_(3),PBT)nanoparticles into a chitosan/gelatin(Cs/Gel)matrix.The physical and chemical properties of the Cs/Gel/PHA scafold with 0–10 wt%PBT were analyzed.Cell and animal experiments were performed to characterize the immunomodulatory,angiogenic,and osteogenic capabilities of the piezoelectric hydrogel scafold in vitro and in vivo.Results:The incorporation of BaTiO_(3) into the scafold improved its mechanical properties and increased self-generated electricity.Due to their endogenous piezoelectric stimulation and bioactive constituents,the prepared Cs/Gel/PHA/PBT hydrogels exhibited cytocompatibility as well as immunomodulatory,angiogenic,and osteogenic capabilities;they not only effectively induced macrophage polarization to M2 phenotype but also promoted the migration,tube formation,and angiogenic differentiation of human umbilical vein endothelial cells(HUVECs)and facilitated the migration,osteodifferentiation,and extracellular matrix(ECM)mineralization of MC3T3-E1 cells.The in vivo evaluations showed that these piezoelectric hydrogels with versatile capabilities significantly facilitated new bone formation in a rat large-sized cranial injury model.The underlying molecular mechanism can be partly attributed to the immunomodulation of the Cs/Gel/PHA/PBT hydrogels as shown via transcriptome sequencing analysis,and the PI3K/Akt signaling axis plays an important role in regulating macrophage M2 polarization.Conclusion:The piezoelectric Cs/Gel/PHA/PBT hydrogels developed here with favorable immunomodulation,angiogenesis,and osteogenesis functions may be used as a substitute in periosteum injuries,thereby offering the novel strategy of applying piezoelectric stimulation in bone tissue engineering for the enhancement of combat efectiveness in grassroots troops.

Synergistic effects of three traditional herbs green tea,mulberry leaf and corn silk on glucose uptake level of L6 myoblasts and the hypoglycemic mechanism

Background:Green tea,mulberry leaf and corn silk are traditional herbs used in the prevention and treatment of diabetes in China for a long time,but their synergistic hypoglycemic effects and mechanisms remain unclear.Methods:The effective components of green tea,mulberry leaf and corn silk were extracted and enriched.Mixture design of experiments was used to study the influences of different combinations on the cell viability and glucose uptake level of L6 myoblasts,so as to determine the optimal synergistic hypoglycemic combination.The possible hypoglycemic mechanism of the optimal synergistic combination was explored by cytotoxicity assay,glucose uptake assay,and western blot.Results:Three polyphenol enrichment fractions of the herbs,30%ethanol elution fraction of green tea(GT),50%ethanol elution fraction of mulberry leaf(ML)and 60%ethanol elution fraction of corn silk(CS)were obtained.The antioxidant activities of GT-30%,ML-50%and CS-60%were superior to those of crude extracts,and showed strong potential inα-amylase andα-glucosidase inhibition activities.The optimal synergistic combination of crude extracts G7(crude extract of green tea:crude extract of mulberry leaf:crude extract of corn silk=1:5:3),polyphenol enrichment fractions R3(GT-30%:ML-50%:CS-60%=1:7:1)and monomers X2(epigallocatechin gallate:morusin:formononetin=3:1:2)were selected,respectively.G7,R3,and X2 showed promoting effects on the cell viability and glucose uptake of L6 myoblasts within the detected concentration range.In addition,G7,R3,and X2 could increase the expression levels of p-PI3K/PI3K and p-Akt/Akt in L6 myoblasts,and promote the translocation of Glut4,but G7 and R3 showed more significant effects.Conclusion:The synergistic hypoglycemic effects of green tea,mulberry leaf and corn silk had the characteristics of multiple-components and multiple-targets with p-PI3K/PI3K,p-Akt/Akt and the translocation of Glut4 signal pathways involved.The three traditional herbs might have the potential to be combined used for the prevention and treatment of diabetes based on the synergistic hypoglycemic effects.