Tuning Spin-Polarized Lifetime at High Carrier Density through Deformation Potential in Dion-Jacobson-Phase Perovskites.

The control of spin relaxation mechanisms is of great importance for spintronics applications as well as for fundamental studies. Layered metal-halide perovskites represent an emerging class of semiconductors with rich optical spin physics, showing potential for spintronic applications. However, a major hurdle arises in layered metal-halide perovskites with strong spin-orbit coupling, where the spin lifetime becomes extremely short due to D'yakonov-Perel' scattering and Bir-Aronov-Pikus at high carrier density. Using the circularly polarized pump-probe transient reflection technique, we experimentally reveal the important scattering for spin relaxation beyond the electron-hole exchange strength in the Dion-Jacobson (DJ)-type 2D perovskites (3AMP)(MA)n-1PbnI3n+1 [3AMP = 3-(aminomethyl)piperidinium, n = 1-4]. Despite a more than 10-fold increase in carrier concentration, the spin lifetimes for n = 3 and 4 are effectively maintained. We reveal neutral impurity and polar optical phonon scatterings as significant contributors to the momentum relaxation rate. Furthermore, we show that more octahedral distortions induce a larger deformation potential which is reflected on the acoustic phonon properties. Coherent acoustic phonon analysis indicates that the polaronic effect is crucial in achieving control over the scattering mechanism and ensuring spin lifetime protection, highlighting the potential of DJ-phase perovskites for spintronic applications.

The efficient uptake of uranium by amine-functionalized ß-cyclodextrin supported fly ash composite from polluted water.

A novel polyethyleneimine/polydopamine-functionalized ß-cyclodextrin supported fly ash adsorbent (PEI/PDA/ß-CD/FA) had been synthesized to uptake uranium from polluted water. At pH = 5.0 and T = 298 K, the uranium uptake efficiency and capacity of PEI/PDA/ß-CD/FA reached to 98.7 % and 622.8 mg/g, respectively, which were much higher than those of FA (71.4 % and 206.7 mg/g).The excellent uranium uptake properties of PEI/PDA/ß-CD/FA could be explained by three points: (1) using ß-CD as a supporting material could effectively avoid the aggregation of FA and improve the hydrophily of FA; (2) the unique cavity structure of ß-CD could form chelates with uranyl ions; (3) the formation of PEI/PDA co-deposition coating on FA further enhanced the affinity of FA to UO22+. With the presence of interfering ions, the uptake efficiency of PEI/PDA/ß-CD/FA for uranium was still up to 94.5 % after five cycles, indicating the high selectively and recoverability of PEI/PDA/ß-CD/FA. In terms of the results of characterizations, uranium was captured by PEI/PDA/ß-CD/FA via electrostatic attraction, hydrogen bond, coordination and complexation. To sum up, PEI/PDA/ß-CD/FA was expected to be used for actual sewage treatment owing to its excellent uranium uptake efficiency/capacity, selectivity, cycle stability and feasibility of actual application.

Enzymatic modular synthesis of asymmetrically branched human milk oligosaccharides.

Human milk oligosaccharides (HMOs) are intricate glycans that promote healthy growth of infants and have been incorporated into infant formula as food additives. Despite their importance, the limited availability of asymmetrically branched HMOs hinders the exploration of their structure and function relationships. Herein, we report an enzymatic modular strategy for the efficient synthesis of these HMOs. The key branching enzyme for the assembly of branched HMOs, human ß1,6-N-acetylglucosaminyltransferase 2 (GCNT2), was successfully expressed in Pichia pastoris for the first time. Then, it was integrated with six other bacterial glycosyltransferases to establish seven glycosylation modules. Each module comprises a one-pot multi-enzyme (OPME) system for in-situ generation of costly sugar nucleotide donors, combined with a glycosyltransferase for specific glycosylation. This approach enabled the synthesis of 31 branched HMOs and 13 linear HMOs in a stepwise manner with well-programmed synthetic routes. The binding details of these HMOs with related glycan-binding proteins were subsequently elucidated using glycan microarray assays to provide insights into their biological functions. This comprehensive collection of synthetic HMOs not only serves as standards for HMOs structure identification in complex biological samples but also significantly enhances the fields of HMOs glycomics, opening new avenues for biomedical applications.

Anticancer therapy-induced adverse drug reactions in children and preventive and control measures.

In recent years, considerable achievements have been made in pediatric oncology with the innovation and development of antitumor drugs. However, compared to adults, children as a special group have not yet matured fully in terms of liver and kidney function. Moreover, pediatric patients are prone to more adverse drug reactions (ADRs) from the accumulation of antineoplastic drugs due to their smaller body size and larger body surface area. Chemotherapy-related ADRs have become a non-negligible factor that affects cancer remission. To date, studies on ADRs in pediatric cancer patients have emerged internationally, but few systematic summaries are available. Here, we reviewed the various systemic ADRs associated with antitumor drugs in children and adolescent patients, as well as the advances in strategies to cope with ADRs, which consisted of neurotoxicity, hematological toxicity, cardiotoxicity, ADRs of the respiratory system and gastrointestinal system and urinary system, ADRs of the skin and its adnexa, allergic reactions, and other ADRs. For clinicians and researchers, understanding the causes, symptoms, and coping strategies for ADRs caused by anticancer treatments will undoubtedly benefit more children.

Integrative analyses of N6-methyladenosine-associated single-nucleotide polymorphisms (m6A-SNPs) identify tumor suppressor gene AK9 in lung cancer.

N6 -methyladenosine (m6 A) modification has been identified as one of the most important epigenetic regulation mechanisms in the development of human cancers. However, the association between m6 A-associated single-nucleotide polymorphisms (m6 A-SNPs) and lung cancer risk remains largely unknown. Here, we identified m6 A-SNPs and examined the association of these m6 A-SNPs with lung cancer risk in 13,793 lung cancer cases and 14,027 controls. In silico functional annotation was used to identify causal m6 A-SNPs and target genes. Furthermore, methylated RNA immunoprecipitation and quantitative real-time polymerase chain reaction (MeRIP-qPCR) assay was performed to assess the m6 A modification level of different genotypes of the causal SNP. In vitro assays were performed to validate the potential role of the target gene in lung cancer. A total of 8794 m6 A-SNPs were detected, among which 397 SNPs in nine susceptibility loci were associated with lung cancer risk, including six novel loci. Bioinformatics analyses indicated that rs1321328 in 6q21 was located around the m6 A modification site of AK9 and significantly reduced AK9 expression (ß = -0.15, p = 2.78 × 10-8 ). Moreover, AK9 was significantly downregulated in lung cancer tissues than that in adjacent normal tissues of samples from the Cancer Genome Atlas and Nanjing Lung Cancer Cohort. MeRIP-qPCR assay suggested that C allele of rs1321328 could significantly decrease the m6 A modification level of AK9 compared with G allele. In vitro assays verified the tumor-suppressing role of AK9 in lung cancer. These findings shed light on the pathogenic mechanism of lung cancer susceptibility loci linked with m6 A modification.

Oncogenic KRAS effector USP13 promotes metastasis in non-small cell lung cancer through deubiquitinating ß-catenin.

KRAS mutations are frequently detected in non-small cell lung cancers (NSCLCs). Although covalent KRASG12C inhibitors have been developed to treat KRASG12C-mutant cancers, effective treatments are still lacking for other KRAS-mutant NSCLCs. Thus, identifying a KRAS effector that confers poor prognosis would provide an alternative strategy for the treatment of KRAS-driven cancers. Here, we show that KRAS drives expression of deubiquitinase USP13 through Ras-responsive element-binding protein 1 (RREB1). Elevated USP13 promotes KRAS-mutant NSCLC metastasis, which is associated with poor prognosis in NSCLC patients. Mechanistically, USP13 interacts with and removes the K63-linked polyubiquitination of ß-catenin at lysine 508, which enhances the binding between ß-catenin and transcription factor TCF4. Importantly, we identify 2-methoxyestradiol as an effective inhibitor for USP13 from a natural compound library, and it could potently suppress the metastasis of KRAS-mutant NSCLC cells in vitro and in vivo. These findings identify USP13 as a therapeutic target for metastatic NSCLC with KRAS mutations.

Construction of predictive model of interstitial fibrosis and tubular atrophy after kidney transplantation with machine learning algorithms.

Background: Interstitial fibrosis and tubular atrophy (IFTA) are the histopathological manifestations of chronic kidney disease (CKD) and one of the causes of long-term renal loss in transplanted kidneys. Necroptosis as a type of programmed death plays an important role in the development of IFTA, and in the late functional decline and even loss of grafts. In this study, 13 machine learning algorithms were used to construct IFTA diagnostic models based on necroptosis-related genes. Methods: We screened all 162 "kidney transplant"-related cohorts in the GEO database and obtained five data sets (training sets: GSE98320 and GSE76882, validation sets: GSE22459 and GSE53605, and survival set: GSE21374). The training set was constructed after removing batch effects of GSE98320 and GSE76882 by using the SVA package. The differentially expressed gene (DEG) analysis was used to identify necroptosis-related DEGs. A total of 13 machine learning algorithms-LASSO, Ridge, Enet, Stepglm, SVM, glmboost, LDA, plsRglm, random forest, GBM, XGBoost, Naive Bayes, and ANNs-were used to construct 114 IFTA diagnostic models, and the optimal models were screened by the AUC values. Post-transplantation patients were then grouped using consensus clustering, and the different subgroups were further explored using PCA, Kaplan-Meier (KM) survival analysis, functional enrichment analysis, CIBERSOFT, and single-sample Gene Set Enrichment Analysis. Results: A total of 55 necroptosis-related DEGs were identified by taking the intersection of the DEGs and necroptosis-related gene sets. Stepglm[both]+RF is the optimal model with an average AUC of 0.822. A total of four molecular subgroups of renal transplantation patients were obtained by clustering, and significant upregulation of fibrosis-related pathways and upregulation of immune response-related pathways were found in the C4 group, which had poor prognosis. Conclusion: Based on the combination of the 13 machine learning algorithms, we developed 114 IFTA classification models. Furthermore, we tested the top model using two independent data sets from GEO.

0D Pyramid-intercalated 2D Bimetallic Halides with Tunable Electronic Structures and Enhanced Emission under Pressure.

Hybrid metal halides are emerging semiconductors as promising candidates for optoelectronics. The pursuit of hybridizing various dimensions of metal halides remains a desirable yet highly complex endeavor. By utilizing dimension engineering, a diverse array of new materials with intrinsically different electronic and optical properties has been developed. Here, we report a new family of 2D-0D hybrid bimetallic halides, (C6 N2 H14 )2 SbCdCl9 ⋅ 2H2 O (SbCd) and (C6 N2 H14 )2 SbCuCl9 ⋅ 2H2 O (SbCu). These compounds adopt a new layered structure, consisting of alternating 0D square pyramidal [SbCl5 ] and 2D inorganic layers sandwiched by organic layers. SbCd and SbCu have optical band gaps of 3.3 and 2.3 eV, respectively. These compounds exhibit weak photoluminescence (PL) at room temperature, and the PL gradually enhances with decreasing temperature. Density functional theory (DFT) calculations reveal that SbCd and SbCu are direct gap semiconductors, where first-principles band gaps follow the experimental trend. Moreover, given the different pressure responses of 0D and 2D components, these materials exhibit highly tunable electronic structures during compression, where a remarkable 11 times enhancement in PL emission is observed for SbCd at 19 GPa. This work opens new avenues for designing new layered bimetallic halides and further manipulating their structures and optoelectronic properties via pressure.

Nanosecond pulsed cold atmospheric plasma jet suppresses proliferation and migration of human glioblastoma cells via apoptosis promotion and EMT inhibition.

Glioblastoma (GBM) is one of the most aggressive and challenging cancers to treat. Despite extensive research on dozens of cancer cells, including GBM, the effect of cold atmospheric plasma (CAP) on the invasive migration of GBM cells has received limited attention, and the underlying mechanisms remain poorly understood. This study aims to investigate the potential molecular mechanism of ns-CAPJ in inhibiting the invasive migration of human GBM cells. The findings indicate that ns-CAPJ significantly reduces GBM cell invasion and migration, and induces apoptosis in GBM cells. Further mechanistic studies demonstrate a direct correlation between the suppression of the epithelial-mesenchymal transition (EMT) signaling pathway and ns-CAPJ's inhibitory effect on GBM cell invasion and migration. Additionally, combined with the N-acetyl cysteine (NAC, a ROS inhibitor) assay, we found that the ROS stimulated by the ns-CAPJ plays an important role in suppressing the EMT process. This work is expected to provide new insight into understanding the molecular mechanisms of how ns-CAPJ inhibits the proliferation and migration of human GBM cells.

miR-325-3p Reduces Proliferation and Promotes Apoptosis of Gastric Cancer Cells by Inhibiting Human Antigen R.

Human antigen R (HuR), also known as ELAVL1, is a widely expressed RNA-binding protein (RBP) that has a significant impact on the development and advancement of tumors. Our previous study found that 5-fluorouracil (5-FU) may impede the proliferation and increase apoptosis in gastric cancer cells by reducing the nucleocytoplasmic shuttling of HuR. However, how posttranscriptional regulation influences HuR functions in gastric cancer remains to be elucidated. Here, we demonstrated that miR-325-3p has the potential to regulate the expression level of HuR by directly binding to its 3'UTR, which in turn led to a significant reduction in proliferation and an increase in apoptosis in gastric cancer cells. In addition, xenograft experiment showed that knockdown of HuR or overexpression of miR-325-3p group exhibited smaller tumor sizes after transplant of gastric cancer cells into zebrafish larvae. Thus, our findings offer new insights into the pathogenesis of gastric cancer and may potentially assist in identifying novel targets for drug therapy.

Integrative splicing-quantitative-trait-locus analysis reveals risk loci for non-small-cell lung cancer.

Splicing quantitative trait loci (sQTLs) have been demonstrated to contribute to disease etiology by affecting alternative splicing. However, the role of sQTLs in the development of non-small-cell lung cancer (NSCLC) remains unknown. Thus, we performed a genome-wide sQTL study to identify genetic variants that affect alternative splicing in lung tissues from 116 individuals of Chinese ancestry, which resulted in the identification of 1,385 sQTL-harboring genes (sGenes) containing 378,210 significant variant-intron pairs. A comprehensive characterization of these sQTLs showed that they were enriched in actively transcribed regions, genetic regulatory elements, and splicing-factor-binding sites. Moreover, sQTLs were largely distinct from expression quantitative trait loci (eQTLs) and showed significant enrichment in potential risk loci of NSCLC. We also integrated sQTLs into NSCLC GWAS datasets (13,327 affected individuals and 13,328 control individuals) by using splice-transcriptome-wide association study (spTWAS) and identified alternative splicing events in 19 genes that were significantly associated with NSCLC risk. By using functional annotation and experiments, we confirmed an sQTL variant, rs35861926, that reduced the risk of lung adenocarcinoma (rs35861926-T, OR = 0.88, 95% confidence interval [CI]: 0.82-0.93, p = 1.87 × 10-5) by promoting FARP1 exon 20 skipping to downregulate the expression level of the long transcript FARP1-011. Transcript FARP1-011 promoted the migration and proliferation of lung adenocarcinoma cells. Overall, our study provided informative lung sQTL resources and insights into the molecular mechanisms linking sQTL variants to NSCLC risk.

Paravertebral vs Epidural Anesthesia for Video-assisted Thoracoscopic Surgery: A Randomized Trial.

BACKGROUND: The choice of postoperative pain management for patients who experience moderate to severe acute pain after thoracoscopic surgery is debatable. This study aimed to determine whether paravertebral block (PVB) provides more benefits than thoracic epidural analgesia (TEA) for thoracoscopic surgery. METHODS: From February 2020 to April 2022, patients without chronic pain who were scheduled to undergo thoracoscopic surgery were randomly assigned to the PVB group or the TEA group. The visual analogue scale score was used to measure the degree of pain when the patients were at rest or coughing. RESULTS: In total, 176 eligible patients were enrolled in this study. No significant difference in the visual analogue scale score was found between the 2 groups at rest (P = .395) or with coughing (P = .157). Additionally, there was no significant difference in the average pain score between these 2 states (P = .221). The median time for catheter placement in the PVB group was 5 minutes, which was shorter than that (14 minutes) in the TEA group (P < .001). Moreover, the catheter placement failure rate in the PVB group was lower than that in the TEA group (P = .038). The incidence of hypotension (P = .016) and urinary retention (P = .006) in the PVB group was lower than that in the TEA group. CONCLUSIONS: PVB can provide pain relief that is similar to that of TEA but with no additional puncture pain, a shorter catheter placement time, and fewer side effects in patients undergoing video-assisted thoracoscopic surgery.

Radix Paeoniae Alba attenuates Radix Bupleuri-induced hepatotoxicity by modulating gut microbiota to alleviate the inhibition of saikosaponins on glutathione synthetase.

Radix Bupleuri (RB) is commonly used to treat depression, but it can also lead to hepatotoxicity after long-term use. In many anti-depression prescriptions, RB is often used in combination with Radix Paeoniae Alba (RPA) as an herb pair. However, whether RPA can alleviate RB-induced hepatotoxicity remain unclear. In this work, the results confirmed that RB had a dose-dependent antidepressant effect, but the optimal antidepressant dose caused hepatotoxicity. Notably, RPA effectively reversed RB-induced hepatotoxicity. Afterward, the mechanism of RB-induced hepatotoxicity was confirmed. The results showed that saikosaponin A and saikosaponin D could inhibit GSH synthase (GSS) activity in the liver, and further cause liver injury through oxidative stress and nuclear factor kappa B (NF-κB)/NOD-like receptor thermal protein domain associated protein 3 (NLRP3) pathway. Furthermore, the mechanisms by which RPA attenuates RB-induced hepatotoxicity were investigated. The results demonstrated that RPA increased the abundance of intestinal bacteria with glycosidase activity, thereby promoting the conversion of saikosaponins to saikogenins in vivo. Different from saikosaponin A and saikosaponin D, which are directly combined with GSS as an inhibitor, their deglycosylation conversion products saikogenin F and saikogenin G exhibited no GSS binding activity. Based on this, RPA can alleviate the inhibitory effect of saikosaponins on GSS activity to reshape the liver redox balance and further reverse the RB-induced liver inflammatory response by the NF-κB/NLRP3 pathway. In conclusion, the present study suggests that promoting the conversion of saikosaponins by modulating gut microbiota to attenuate the inhibition of GSS is the potential mechanism by which RPA prevents RB-induced hepatotoxicity.

Hybrid Double Perovskite Derived Halides Based on Bi and Alkali Metals (K, Rb): Diverse Structures, Tunable Optical Properties and Second Harmonic Generation Responses.

Double perovskites (DP) have attracted extensive attention due to their rich structures and wide application prospects in the field of optoelectronics. Here, we report 15 new Bi-based double perovskite derived halides with the general formula of A2 BBiX6 (A=organic cationic ligand, B=K or Rb, X=Br or I). These materials are synthesized using organic ligands to coordinate with metal ions with a sp3 oxygen, and diverse structure types have been obtained with distinct dimensionalities and connectivity modes. The optical band gaps of these phases can be tuned by changing the halide, the organic ligand and the alkali metal, varying from 2.0 to 2.9 eV. The bromide phases exhibit increasing photoluminescence (PL) intensity with decreasing temperature, while the PL intensity of iodide phases changes nonmonotonically with temperature. Because the majority of these phases are non-centrosymmetric, second harmonic generation (SHG) responses are also measured for selected non-centrosymmetric materials, showing different particle-size-dependent trends. Our findings give rise to a series of new structural types to the DP family, and provide a powerful synthetic handle for symmetry breaking.

USP12 promotes nonsmall cell lung cancer progression through deubiquitinating and stabilizing RRM2.

RRM2 is the catalytic subunit of ribonucleotide reductase (RNR), which catalyzes de novo synthesis of deoxyribonucleotide triphosphates (dNTPs) and plays critical roles in cancer cell proliferation. RRM2 protein level is controlled by ubiquitination mediated protein degradation system; however, its deubiquitinase has not been identified yet. Here we showed that ubiquitin-specific peptidase 12 (USP12) directly interacts with and deubiquitinates RRM2 in non-small cell lung cancer (NSCLC) cells. Knockdown of USP12 causes DNA replication stress and retards tumor growth in vivo and in vitro. Meanwhile, USP12 protein levels were positively correlated to RRM2 protein levels in human NSCLC tissues. In addition, high expression of USP12 was associated with poor prognosis in NSCLC patients. Therefore, our study reveals that USP12 is a RRM2 regulator and targeting USP12 could be considered as a potential therapeutical strategy for NSCLC treatment.

CYP1B1 inhibits ferroptosis and induces anti-PD-1 resistance by degrading ACSL4 in colorectal cancer.

Immune checkpoint blockade (ICB) is a promising treatment strategy for colorectal cancer (CRC) patients. However, most CRC patients do not response well to ICB therapy. Increasing evidence indicates that ferroptosis plays a critical role in immunotherapy. ICB efficacy may be enhanced by inducing tumor ferroptosis. Cytochrome P450 1B1 (CYP1B1) is a metabolic enzyme that participates in arachidonic acid metabolism. However, the role of CYP1B1 in ferroptosis remains unclear. In this study, we demonstrated that CYP1B1 derived 20-HETE activated the protein kinase C pathway to increase FBXO10 expression, which in turn promoted the ubiquitination and degradation of acyl-CoA synthetase long-chain family member 4 (ACSL4), ultimately inducing tumor cells resistance to ferroptosis. Furthermore, inhibiting CYP1B1 sensitized tumor cells to anti-PD-1 antibody in a mouce model. In addition, CYP1B1 expression was negatively correlated with ACSL4 expression, and high expression indicates poor prognosis in CRC. Taken together, our work identified CYP1B1 as a potential biomarker for enhancing anti-PD-1 therapy in CRC.

One-Dimensional Chiral Copper Iodide Chain-Like Structure Cu4 I4 (R/S-3-quinuclidinol)3 with Near-Unity Photoluminescence Quantum Yield and Efficient Circularly Polarized Luminescence.

Chiral organic-inorganic hybrid metal halide materials have shown great potential for circularly polarized luminescence (CPL) related applications for their tunable structures and efficient emissions. Here, this work combines the highly emissive Cu4 I4 cubane cluster with chiral organic ligand R/S-3-quinuclidinol, to construct a new type of 1D Cu-I chains, namely Cu4 I4 (R/S-3-quinuclidinol)3 , crystallizing in noncentrosymmetric monoclinic P21 space group. These enantiomorphic hybrids exhibit long-term stability and show bright yellow emission with a photoluminescence quantum yield (PLQY) close to 100%. Due to the successful chirality transfer from the chiral ligands to the inorganic backbone, the enantiomers show intriguing chiroptical properties, such as circular dichroism (CD) and CPL. The CPL dissymmetry factor (glum ) is measured to be ≈4 × 10-3 . Time-resolved photoluminescence (PL) measurements show long averaged decay lifetime up to 10 µs. The structural details within the Cu4 I4 reveal the chiral nature of these basic building units, which are significantly different than in the achiral case. This discovery provides new structural insights for the design of high performance CPL materials and their applications in light emitting devices.

Autoimmune pathogenesis, immunosuppressive therapy and pharmacological mechanism in aplastic anemia.

Acquired aplastic anemia (AA) is an autoimmune disease of bone marrow failure mediated by abnormally activated T cells, manifested by severe depletion of hematopoietic stem and progenitor cells (HSPCs) and peripheral blood cells. Due to the limitation of donors for hematopoietic stem cell transplantation, immunosuppressive therapy (IST) is currently an effective first-line treatment. However, a significant proportion of AA patients remain ineligible for IST, relapse, and develop other hematologic malignancies, such as acute myeloid leukemia after IST. Therefore, it is important to elucidate the pathogenic mechanisms of AA and to identify treatable molecular targets, which is an attractive way to improve these outcomes. In this review, we summarize the immune-related pathogenesis of AA, pharmacological targets, and clinical effects of the current mainstream immunosuppressive agents. It provides new insight into the combination of immunosuppressive drugs with multiple targets, as well as the discovery of new druggable targets based on current intervention pathways.

Convergent chemoenzymatic synthesis of O-GalNAc rare cores 5, 7, 8 and their sialylated forms.

All O-GalNAc glycans are derived from 8 cores with 2 or 3 monosaccharides linked via α- or ß-glycosidic bonds. While chemical and chemoenzymatic syntheses of ß-linked cores 1-4 and 6 and derived glycans have been well developed, the preparation of α-linked rare cores 5, 7, and 8 is challenging due to the presence of this 1,2-cis linkage. Meanwhile, the biosynthesis and functional roles of these structures are poorly understood. Herein, we synthesize 3 α-linked rare cores with exclusive α-configuration from a versatile precursor through multifaceted chemical modulations. Efficient regioselective α2-6sialylion of the rare cores was then achieved by Photobacterium damselae α2-6sialyltransferase-catalyzed reactions. These structures, together with ß-linked cores 1-4 and 6, and their sialylated forms, were fabricated into a comprehensive O-GalNAc core microarray to profile the binding of clinically important GalNAc-specific lectins. It is found that only Tn, (sialyl-)core 5, and core 7 are the binders of WFL, VVL, and SBA, while DBA only recognized (sialyl-)core 5, and Jacalin is the only lectin that binds core 8. In addition, activity assays of human α-N-acetylgalactosaminide α2-6sialyltransferases (ST6GalNAcTs) towards the cores suggested that ST6GalNAc1 may be involved in the biosynthesis of previously identified sialyl-core 5 and sialyl-core 8 glycans. In conclusion, we provide efficient routes to access α-linked O-GalNAc rare cores and derived structures, which are valuable tools for functional glycomics studies of mucin O-glycans.

An integrated strategy to study the combination mechanisms of Bupleurum chinense DC and Paeonia lactiflora Pall for treating depression based on correlation analysis between serum chemical components profiles and endogenous metabolites profiles.

ETHNOPHARMACOLOGICAL RELEVANCE: Bupleurum chinense DC-Paeonia lactiflora Pall (BCD-PLP) is a common clinical herb pair in traditional Chinese medicine (TCM) prescriptions commonly used to treat depression. However, its combination mechanisms with its anti-depressive effects remain highly unclear. AIM OF THE STUDY: Here, an effective strategy has been developed to study the combination mechanisms of Bupleurum chinense DC (BCD) and Paeonia lactiflora Pall (PLP) by integrating serum pharmacochemistry analysis, metabolomics technology, and molecular docking technology. MATERIALS AND METHODS: First, the depression model rats were replicated by the chronic unpredictable mild stress (CUMS) procedure, and the difference in the chemical composition in vivo before and after the combination of BCD and PLP was analyzed by integrating background subtraction and multivariate statistical analysis techniques. Then, UPLC/HRMS-based serum metabolomics was performed to analyze the synergistic effect on metabolite regulation before and after the combination of BCD and PLP. Further, the correlation analysis between the differential exogenous chemical components and the differential endogenous metabolites before and after the combination was employed to dissect the combination mechanisms from a global perspective of combining metabolomics and serum pharmacochemistry. Finally, the molecular docking between the differential chemical components and the key metabolic enzymes was applied to verify the regulatory effect of the differential exogenous chemical components on the differential endogenous metabolites. RESULTS: The serum pharmacochemistry analysis results demonstrated that the combination of BCD and PLP could significantly affect the content of 10 components in BCD (including 5 prototype components were significantly decreased and 5 metabolites were significantly increased) and 8 components in PLP (including 4 prototype components and 3 metabolites were significantly increased, 1 metabolite was significantly decreased), which indicated that the combination could enhance BCD prototype components' metabolism and the absorption of the PLP prototype components. Besides, metabolomics results indicated that the BCD-PLP herb pair group significantly reversed more metabolites (8) than BCD and PLP single herb group (5 & 4) and has a stronger regulatory effect on metabolite disorders caused by CUMS. Furthermore, the correlation analysis results suggested that saikogenin F and saikogenin G were significantly positively correlated with the endogenous metabolite itaconate, an endogenous anti-inflammatory metabolite; and benzoic acid was significantly positively correlated with D-serine, an endogenous metabolite with an antidepressant effect. Finally, the molecular docking results further confirmed that the combination of BCD and PLP could affect the activities of cis-aconitic acid decarboxylase and D-amino acid oxidase by increasing the in vivo concentration of saikogenin F and benzoic acid, which further enhances its anti-inflammatory activity and anti-depressive effect. CONCLUSIONS: In this study, an effective strategy has been developed to study the combination mechanisms of BCD and PLP by integrating serum pharmacochemistry analysis, multivariate statistical analysis, metabolomics technology, and molecular docking technology. Based on this strategy, the present study indicated that the combination of BCD and PLP could affect the activities of cis-aconitic acid decarboxylase and D-amino acid oxidase by increasing the concentration of saikogenin F and benzoic acid in vivo, which further enhances its anti-depressive effect. In short, this strategy will provide a reliable method for elucidating the herb-herb compatibility mechanism of TCM.