[Research status and rapid detection methods of antibiotic residues in agricultural products]. / å†œäº§å“æŠ—ç”Ÿç´ æ®‹ç•™çŽ°çŠ¶åŠå¿«é€Ÿæ£€æµ‹æ–¹æ³•ç ”ç©¶è¿›å±•.

Antibiotics are widely utilized in agriculture for the prevention and treatment of animal diseases. How-ever, the abuse and overuse of antibiotics progressively increase the risks of antibiotic residues and antibiotic resis-tance. The bioaccumulation and biomagnification of antibiotics through food chains will negatively affect ecological safety, and finally threaten human health. There are many shortages of traditional antibiotic detection techniques, such as complex procedures, complicated operation and time consuming, and thus are difficult to meet the demand of instant, efficient and accurate on-site detection. Therefore, it is crucial to develop rapid detection techniques of antibiotics to manage the application of antibiotics in agriculture. We reviewed the utilization, and management of antibiotics in animal husbandry, residual characteristics, and potential hazards of antibiotics in agricultural products, summarized the advancements in rapid detection techniques of antibiotics in agricultural products over the past five years, compared the advantages and disadvantages of different rapid detection techniques, and prospected the future development in this area. This review would provide a valuable reference to the control and point-of-care test of antibiotics in agricultural products.

Pyrroloquinoline quinone production defines the ability of Devosia species to degrade deoxynivalenol.

Deoxynivalenol (DON) is a prevalent mycotoxin that primarily contaminates cereal crops and animal feed, posing a significant risk to human and animal health. In recent years, an increasing number of Devosia strains have been identified as DON degradation bacteria, and significant efforts have been made to explore their potential applications in the food and animal feed industries. However, the characteristics and mechanisms of DON degradation in Devosia strains are still unclear. In this study, we identified a novel DON degrading bacterium, Devosia sp. D-G15 (D-G15), from soil samples. The major degradation products of DON in D-G15 were 3-keto-DON, 3-epi-DON and an unidentified product, compound C. The cell viability assay showed that the DON degradation product of D-G15 revealed significantly reduced toxicity to HEK293T cells compared to DON. Three enzymes for DON degradation were further identified, with G15-DDH converting DON to 3-keto-DON and G15-AKR1/G15-AKR6 reducing 3-keto-DON to 3-epi-DON. Interestingly, genome comparison of Devosia strains showed that the pyrroloquinoline quinone (PQQ) synthesis gene cluster is a unique feature of DON degradation strains. Subsequently, adding PQQ to the cultural media of Devosia strains without PQQ synthesis genes endowed them with DON degradation activity. Furthermore, a novel DON-degrading enzyme G13-DDH (<30% homology with known DON dehydrogenase) was identified from a Devosia strain that lacks PQQ synthesis ability. In summary, a novel DON degrading Devosia strain and its key enzymes were identified, and PQQ production was found as a distinct feature among Devosia strains with DON degradation activity, which is important for developing Devosia strain-based technology in DON detoxification.

Room­Temperature Antisymmetric Magnetoresistance in van der Waals Ferromagnet Fe3GaTe2 Nanosheets.

Van der Waals (vdW) ferromagnetic materials have emerged as a promising platform for the development of 2D spintronic devices. However, studies to date are restricted to vdW ferromagnetic materials with low Curie temperature (Tc) and small magnetic anisotropy. Here, a chemical vapor transport method is developed to synthesize a high-quality room-temperature ferromagnet, Fe3GaTe2 (c-Fe3GaTe2), which boasts a high Tc = 356 K and large perpendicular magnetic anisotropy. Due to the planar symmetry breaking, an unconventional room-temperature antisymmetric magnetoresistance (MR) is first observed in c-Fe3GaTe2 devices with step features, manifesting as three distinctive states of high, intermediate, and low resistance with the sweeping magnetic field. Moreover, the modulation of the antisymmetric MR is demonstrated by controlling the height of the surface steps. This work provides new routes to achieve magnetic random storage and logic devices by utilizing the room-temperature thickness-controlled antisymmetric MR and further design room-temperature 2D spintronic devices based on the vdW ferromagnet c-Fe3GaTe2.

Impact of body mass index on perioperative mortality of acute stanford type A aortic dissection: a systematic review and meta-analysis.

BACKGROUND: Obesity may increase perioperative mortality of acute Stanford type A aortic dissection (ATAAD). However, the available evidence was limited. This study aimed to systematically review published literatures about body mass index (BMI) and perioperative mortality of ATAAD. METHODS: Electronic literature search was conducted in PubMed, Medline, Embase and Cochrane Library databases. All observational studies that investigated BMI and perioperative mortality of ATAAD were included. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using a random-effects model. Meta-regression analysis was performed to assess the effects of different clinical variables on BMI and perioperative mortality of ATAAD. Sensitivity analysis was performed to determine the sources of heterogeneity. Egger's linear regression method and funnel plot were used to determine the publication bias. RESULTS: A total of 12 studies with 5,522 patients were eligible and included in this meta-analysis. Pooled analysis showed that perioperative mortality of ATAAD increased by 22% for each 1 kg/m2 increase in BMI (OR = 1.22, 95% CI: 1.10-1.35). Univariable meta-regression analysis indicated that age and female gender significantly modified the association between BMI and perioperative mortality of ATAAD in a positive manner (meta-regression on age: coefficient = 0.04, P = 0.04; meta-regression on female gender: coefficient = 0.02, P = 0.03). Neither significant heterogeneity nor publication bias were found among included studies. CONCLUSIONS: BMI is closely associated with perioperative mortality of ATAAD. Optimal perioperative management needs to be further explored and individualized for obese patient with ATAAD, especially in elderly and female populations. TRIAL REGISTRATION: PROSPERO (CRD42022358619). BMI and perioperative mortality of ATAAD.

Efficacy of Arthroscopic Discopexy on Condylar Growth in Temporomandibular Joint Anterior Disc Displacement: A Randomized Clinical Trial.

BACKGROUND: Adolescents with temporomandibular joint (TMJ) anterior disc displacement (ADD) frequently develop dentofacial deformities. It is unknown if adjunctive arthroscopic discopexy compared to orthodontic treatment alone increases condylar growth and then improves dentofacial deformity. This study aimed to determine whether arthroscopic discopexy before functional appliance (joint-occlusal treatment) or single functional appliance (occlusal treatment) increases condylar growth and improves dentofacial deformity among adolescents with TMJ ADD. METHODS: A multicenter, randomized, parallel controlled trial was conducted in three centers in China. Adolescents diagnosed with TMJ ADD and dentofacial deformity were enrolled. Eligible participants were randomly assigned to a joint-occlusal group or occlusal group at a ratio of 2:1. MRI, cephalometric radiographs were evaluated at baseline, 8 months and 14 months. The primary outcome was changes in condylar height from 14 months to baseline. Secondary outcomes were changes in skeletal position. RESULTS: A total of 240 patients (14.65±1.88 years of age) were randomized (joint-occlusal group: 160; occlusal group: 80). The overall difference in condylar height between groups was 3.65 mm (95% CI, 3.10 to 4.19; p < 0.001). The between-group differences in condylar height on the left and right sides were 3.60 mm (95% CI, 2.92 to 4.28; p < 0.001) and 3.69 mm (95% CI, 3.06 to 4.32; p < 0.001), respectively. Significant between-group differences were noted in skeletal position (all p < 0.001). CONCLUSIONS: Joint-occlusal treatment can promote condylar growth and improve dentofacial deformity in adolescents after 14 months when compared with single occlusal treatment.

High-throughput identification and determination of antifungal triazoles in human plasma using UPLC-QDa.

Triazoles are common agents for invasive fungal infections, while therapeutic drug monitoring is needed to improve antifungal efficacy and reduce toxicity. This study aimed to exploit a simple and reliable liquid chromatography-mass spectrometry method for high-throughput monitoring of antifungal triazoles in human plasma using UPLC-QDa. Triazoles in plasma were separated by chromatography on a Waters BEH C18 column and detected using positive ions electrospray ionization fitted with single ion recording. M+ for fluconazole (m/z 307.11) and voriconazole (m/z 350.12), M2+ for posaconazole (m/z 351.17), itraconazole (m/z 353.13) and ketoconazole (m/z 266.08, IS) were selected as representative ions in single ion recording mode. The standard curves in plasma showed acceptable linearities over 1.25-40 µg/mL for fluconazole, 0.47-15 µg/mL for posaconazole and 0.39-12.5 µg/mL for voriconazole and itraconazole. The selectivity, specificity, accuracy, precision, recovery, matrix effect, and stability met acceptable practice standards under Food and Drug Administration method validation guidelines. This method was successfully applied to the therapeutic monitoring of triazoles in patients with invasive fungal infections, thereby guiding clinical medication.

The origin of magnetization-caused increment in water oxidation.

Magnetization promoted activity of magnetic catalysts towards the oxygen evolution reaction (OER) has attracted great attention, but remains a puzzle where the increment comes from. Magnetization of a ferromagnetic material only changes its magnetic domain structure. It does not directly change the spin orientation of unpaired electrons in the material. The confusion is that each magnetic domain is a small magnet and theoretically the spin-polarization promoted OER already occurs on these magnetic domains, and thus the enhancement should have been achieved without magnetization. Here, we demonstrate that the enhancement comes from the disappeared domain wall upon magnetization. Magnetization leads to the evolution of the magnetic domain structure, from a multi-domain one to a single domain one, in which the domain wall disappears. The surface occupied by the domain wall is reformatted into one by a single domain, on which the OER follows the spin-facilitated pathways and thus the overall increment on the electrode occurs. This study fills the missing gap for understanding the spin-polarized OER and it further explains the type of ferromagnetic catalysts which can give increment by magnetization.

The prenatal weekly temperature exposure and neonatal congenital heart disease: a large population-based observational study in China.

We aim to explore the link between maternal weekly temperature exposure and CHD in offspring and identify the relative contributions from heat and cold and from moderate and extreme atmospheric temperature. From January 2019 to December 2020, newborns who were diagnosed with CHD by echocardiography in the Network Platform for Congenital Heart Disease (NPCHD) from 11 cities in eastern China were enrolled in the present study. We appraised the exposure lag response relationship between temperature and CHDs in the distributed lag nonlinear model and further probed the pooled estimates by multivariate meta-analysis. We further performed the exposure-response curves in extreme temperature (5th percentile for cold and 95th for hot events). We also delve into the cumulative risk ratios (CRRs) of temperature on CHDs in general and subgroups. In this study, 5904 of 983, 523 infants were diagnosed with CHDs. The temperature-CHD combination performed positive significance in two exposure windows, gestational weeks 10-16 and 26-31, and reached the maximum effect in the 28th week. Compared with extreme cold (5th, 6.14℃), these effects were higher in extreme heat (95th, 29.26℃). The cumulative exposure-response curve showed a steep nonlinear rise in the hot tail but showed non-significance at low temperatures. In this range, the CRRs of temperature showed an increment to a ceiling of 3.781 (95% CI: 1.460-10.723). The temperature- CHD curves for both sex groups showed a general growth trend. No statistical significance was observed between these two groups (P = 0.106). The cumulative effect of the temperature related CHD was significant in regions with lower education levels (maximum CRR was 9.282 (3.019-28.535)). A degree centigrade increase in temperature exposure was associated with the increment of CHD risk in the first and second trimesters, especially in extreme heat. Neonates born in lower education regions were more vulnerable to temperature-related CHDs.

Safety of the 15-valent pneumococcal conjugate vaccine: A phase I clinical trial.

To evaluate the safety of the 15-valent pneumococcal conjugate vaccine (PCV15 (by LvZhu & Co. Ltd)) in healthy infants aged 2 months (minimum to 6 weeks) and 3 months old. This phase I clinical trial enrolled 80 subjects in Laishui County, Hebei Province, China. The total population was divided into 4 age groups on average: 20 adults (≥18 years) and 20 children (1-5 years) all received one vaccine dose; 20 infants (3 months) received the vaccine according to a 3-dose schedule at 0, 1, and 2 months. Twenty infants (2 months, minimum of 6 weeks old) received the vaccine according to a 3-dose schedule of 0, 2, and 4 months. The adverse events (AEs) until 30 days after each dose and serious adverse events (SAEs) until 6 months after the whole dose were reported. The solicited and unsolicited AE frequencies and laboratory indices were similar among the treatment groups. No vaccine-related SAEs were reported. Most vaccine-related adverse events consisting of systemic and local reactions were fever and pain. One hypersensitivity manifested as systemic urticaria that occurred on the third day after the second dose in the 2-month group. The 15-valent pneumococcal conjugate vaccine was generally well tolerated in infants.

Geographical and Socioeconomic Factors Influence the Birth Prevalence of Congenital Heart Disease: A Population-based Cross-sectional Study in Eastern China.

Neonatal congenital heart disease (CHD) is the most common congenital anomaly. As a practical matter of people's livelihood, cardiac ultrasonography was performed on potential CHD children in 11 cities eastern China. In this study, we aimed to document the birth prevalence of CHD and its socioeconomic and geographical distribution, as supported by this public health policy. In this study, the diagnosis of CHD was made based on echocardiography. Geographical and socioeconomic factors were determined by the Statistical Bulletin on National Economic and Social Development (SBNESD). 51857 newborns from the Network Platform for Congenital Heart Disease (NPCHD) from January to December 2019 in 11 cities eastern China were included. The total birth prevalence of CHD was 5.79 per 1000 births. The study on the low-income areas, mountainous areas, areas with low medical institution bed level, and with high qualification of medical personnel reported a signifcantly higher birth prevalence of CHD compared with high-income cities, flat areas, areas with high medical institution bed level, and with low qualification of medical personnel. ASD, VSD, PDA, PS, TOF, atrioventricular septal defect, coarctation of the aorta, TAPVD, TGA and pulmonary atresia are the most frequent subtypes. ASD, VSD, PDA, PS, atrioventricular septal defect, coarctation of the aorta and pulmonary atresia showed a female preponderance, while TOF, TGA and TAPVD showed a male preponderance. Our study gives a relatively realistic prevalence of CHD after cardiac ultrasound examination of newborns suspected positive with CHD. Significant differences across geographical regions, income levels, and health service access were observed. In the future, population-wide cardiac ultrasound screening, prospective birth defect registries, and systematic medical follow-up programs covering the entire eastern or even China are needed to determine the exact birth prevalence.

Global identification of phospho-dependent SCF substrates reveals a FBXO22 phosphodegron and an ERK-FBXO22-BAG3 axis in tumorigenesis.

SKP1-CUL1-F-box (SCF) ubiquitin ligases play fundamental roles in cellular functions. Typically, substrate phosphorylation is required for SCF recognition and subsequent degradation. However, phospho-dependent substrates remain largely unidentified. Here, using quantitative phoshoproteome approach, we performed a system-wide investigation of phospho-dependent SCF substrates. This strategy identified diverse phospho-dependent candidates. Biochemical verification revealed a mechanism by which SCFFBXO22 recognizes the motif XXPpSPXPXX as a conserved phosphodegron to target substrates for destruction. We further demonstrated BAG3, a HSP70 co-chaperone, is a bona fide substrate of SCFFBXO22. FBXO22 mediates BAG3 ubiquitination and degradation that requires ERK-dependent BAG3 phosphorylation at S377. FBXO22 depletion or expression of a stable BAG3 S377A mutant promotes tumor growth via defects in apoptosis and cell cycle progression in vitro and in vivo. In conclusion, our study identified broad phosphorylation-dependent SCF substrates and demonstrated a phosphodegron recognized by FBXO22 and a novel ERK-FBXO22-BAG3 axis involved in tumorigenesis.

Maternal air pollution exposure and neonatal congenital heart disease: A multi-city cross-sectional study in eastern China.

OBJECTIVE: To examine the association between air pollution and neonatal congenital heart disease (CHD), and evaluate the cumulative burden of CHD attributed to above certain level for ambient air pollution exposure. METHODS: We identified newborns who were diagnosed as CHD by echocardiography in Network Platform for Congenital Heart Disease (NPCHD) from January 2019 to December 2020 in 11 cities eastern China. The exposure lag response relationship between air pollutants (PM2.5, PM10, SO2, NO2, CO, and O3) concentration and CHDs was calculated by the distributed lag nonlinear model (DLNM). We further calculated the cumulative risk ratios (CRRs) of each air pollutant above reference concentrations on CHDs. RESULTS: A total of 5904 CHDs from 983, 523 newborns were enrolled in this study. A 10 µg/m3 increase in PM2.5, PM10, SO2, NO2, CO and O3 exposure was associated with an increased risk of higher CHD incident RR = 1.025, 95% CI: 1.016-1.038 for PM2.5 in the third trimester, RR = 1.001, 95% CI: 1.000-1.002 for PM10 in the third trimester, 1.020, 95%CI: 1.004-1.036 for NO2 in the third trimester, RR = 1.001, 95%CI: 1.000-1.002 for O3 in the first trimester, all P value < 0.05). Cumulative effect curves of PM2.5, PM10, SO2, NO2, CO, and O3 were observed as sub-linear with a maximum of 1.876 (95%CI:1.220-2.886), 1.973 (95%CI:1.477,2.637), 2.169 (95%CI:1.347-3.493), 2.902 (95%CI:1.859-4.530), 1.398 (95%CI:1.080-1.809), 2.691 (95%CI:1.705-4.248), respectively. Significant associations were observed for air pollutants and CHDs in cities with higher average education years and babies concepted in cold season. CONCLUSIONS: Our findings could provide growing evidence regarding the adverse health effects of air pollution on CHD, thereby strengthening the hypothesis that air pollutants have harmful impacts on cardiac development. Further studies are needed to verify the associations.

Metabolite Identification in the Preclinical and Clinical Phase of Drug Development.

Metabolite identification plays a critical role in the phases during drug development. Drug metabolites can contribute to efficacy, toxicity, and drug-drug interaction. Thus, the correct identification of metabolites is essential to understand the behavior of drugs in humans. Drug administration authorities (e.g., FDA, EMA, and NMPA) emphasize evaluating the safety of human metabolites with exposure higher than 10% of the total drugrelated components. Many previous reviews have summarized the various methods, tools, and strategies for the appropriate and comprehensive identification of metabolites. In this review, we focus on summarizing the importance of identifying metabolites in the preclinical and clinical phases of drug development. Summarized scenarios include the role of metabolites in pharmacokinetics/pharmacodynamics (PK/PD) analysis, disproportional exposure of metabolites that contribute to drug toxicity, changes in metabolite exposure in renal-impaired patients, covalent tyrosine kinase inhibitors (anticancer drugs), and metabolite identification of drug candidates from natural medicines. This review is aimed to provide meaningful insight into the significant role of metabolite identification in drug development.

Opa1 Prevents Apoptosis and Cisplatin-Induced Ototoxicity in Murine Cochleae.

Optic atrophy1 (OPA1) is crucial for inner mitochondrial membrane (IMM) fusion and essential for maintaining crista structure and mitochondrial morphology. Optic atrophy and hearing impairment are the most prevalent clinical features associated with mutations in the OPA1 gene, but the function of OPA1 in hearing is still unknown. In this study, we examined the ability of Opa1 to protect against cisplatin-induced cochlear cell death in vitro and in vivo. Our results revealed that knockdown of Opa1 affects mitochondrial function in HEI-OC1 and Neuro 2a cells, as evidenced by an elevated reactive oxygen species (ROS) level and reduced mitochondrial membrane potential. The dysfunctional mitochondria release cytochrome c, which triggers apoptosis. Opa1 expression was found to be significantly reduced after cell exposed to cisplatin in HEI-OC1 and Neuro 2a cells. Loss of Opa1 aggravated the apoptosis and mitochondrial dysfunction induced by cisplatin treatment, whereas overexpression of Opa1 alleviated cisplatin-induced cochlear cell death in vitro and in explant. Our results demonstrate that overexpression of Opa1 prevented cisplatin-induced ototoxicity, suggesting that Opa1 may play a vital role in ototoxicity and/or mitochondria-associated cochlear damage.

HBO1 is a versatile histone acyltransferase critical for promoter histone acylations.

Recent studies demonstrate that histones are subjected to a series of short-chain fatty acid modifications that is known as histone acylations. However, the enzymes responsible for histone acylations in vivo are not well characterized. Here, we report that HBO1 is a versatile histone acyltransferase that catalyzes not only histone acetylation but also propionylation, butyrylation and crotonylation both in vivo and in vitro and does so in a JADE or BRPF family scaffold protein-dependent manner. We show that the minimal HBO1/BRPF2 complex can accommodate acetyl-CoA, propionyl-CoA, butyryl-CoA and crotonyl-CoA. Comparison of CBP and HBO1 reveals that they catalyze histone acylations at overlapping as well as distinct sites, with HBO1 being the key enzyme for H3K14 acylations. Genome-wide chromatin immunoprecipitation assay demonstrates that HBO1 is highly enriched at and contributes to bulk histone acylations on the transcriptional start sites of active transcribed genes. HBO1 promoter intensity highly correlates with the level of promoter histone acylation, but has no significant correlation with level of transcription. We also show that HBO1 is associated with a subset of DNA replication origins. Collectively our study establishes HBO1 as a versatile histone acyltransferase that links histone acylations to promoter acylations and selection of DNA replication origins.

Metabolically controlled histone H4K5 acylation/acetylation ratio drives BRD4 genomic distribution.

In addition to acetylation, histones are modified by a series of competing longer-chain acylations. Most of these acylation marks are enriched and co-exist with acetylation on active gene regulatory elements. Their seemingly redundant functions hinder our understanding of histone acylations' specific roles. Here, by using an acute lymphoblastic leukemia (ALL) cell model and blasts from individuals with B-precusor ALL (B-ALL), we demonstrate a role of mitochondrial activity in controlling the histone acylation/acetylation ratio, especially at histone H4 lysine 5 (H4K5). An increase in the ratio of non-acetyl acylations (crotonylation or butyrylation) over acetylation on H4K5 weakens bromodomain containing protein 4 (BRD4) bromodomain-dependent chromatin interaction and enhances BRD4 nuclear mobility and availability for binding transcription start site regions of active genes. Our data suggest that the metabolism-driven control of the histone acetylation/longer-chain acylation(s) ratio could be a common mechanism regulating the bromodomain factors' functional genomic distribution.

Simultaneous determination of forsythin and its major metabolites in human plasma via liquid chromatography-tandem mass spectrometry.

Forsythiae suspensa is widely used in China as a traditional Chinese medicine. Forsythin is extracted from Forsythiae Fructus and has undergone phase II clinical trials as an antipyretic drug in China. The main metabolites of forsythin in human plasma are aglycone sulfate (KD-2-SO3H) and aglycone glucuronide (KD-2-Glc). In the present study, a sensitive and rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and fully validated for the simultaneous analysis of forsythin, KD-2-Glc, and KD-2-SO3H, in human plasma. After precipitating proteins with methanol, these three analytes were separated on a Gemini-C18 column along with teniposide as an internal standard. Mass spectrometry detection, under multiple reaction monitoring, was then carried out in negative mode using the Triple Quad™ 6500+ LC-MS/MS system coupled with an electrospray ionization (ESI) ion source. The transitions of m/z 371.1→356.1 for forsythin, m/z 547.2→356.0 for KD-2-Glc and m/z 451.2→356.2 for KD-2-SO3H were chosen to effectively maintain the balance between selectivity and sensitivity. The developed method was linear over the following concentrations in human plasma samples: 1.00-1000 ng/mL for forsythin, 2.50-2500 ng/mL for KD-2-Glc, and 5.00-5000 ng/mL for KD-2-SO3H. Assays were validated and satisfied the acceptance criteria recommended by the CFDA guidance. Furthermore, this LC-MS/MS method was successfully implemented in a Phase I, first-in-human, dose-escalation pharmacokinetic study among Chinese healthy participants after single oral administration of forsythin tablets.

Vagus nerve plays a pivotal role in CD4+ T cell differentiation during CVB3-induced murine acute myocarditis.

Abnormalities in CD4+ T cell (Th cell) differentiation play an important role in the pathogenesis of viral myocarditis (VMC). Our previous studies demonstrated that activation of the cholinergic anti-inflammatory pathway (CAP) alleviated the inflammatory response. In addition, we observed that right cervical vagotomy aggravates VMC by inhibiting CAP. However, the vagus nerve's effect on differentiation of CD4+ T cells has not been studied in VMC mice to date. In this study, we investigated the effects of cervical vagotomy and the α7nAChR agonist pnu282987 on CD4+ T cell differentiation in a murine myocarditis model (BALB/c) infected with coxsackievirus B3 (CVB3). Splenic CD4+ T cells from CVB3-induced mice obtained and cultured to investigate the potential mechanism of CD4+ T cell differentiation. Each Th cell subset was analyzed by flow cytometry. Our results showed that right cervical vagotomy increased proportions of Th1 and Th17 cells and decreased proportions of Th2 and Treg cells in the spleen. Vagotomy-induced upregulation of T-bet, Ror-γ, IFN-γ, and IL-17 expression while downregulating the expression of Gata3, Foxp3, and IL-4 in the heart. In addition, we observed upregulated levels of proinflammatory cytokines, aggravated myocardial lesions and cellular infiltration, and worsened cardiac function in VMC mice. Pnu282987 administration reversed these outcomes. Furthermore, vagotomy inhibited JAK2-STAT3 activation and enhanced NF-κB activation in splenic CD4+ T cells. The CD4+ T cell differentiation was related to JAK2-STAT3 and NF-κB signal pathways. In conclusion, vagus nerve modulates the inflammatory response by regulating CD4+ T cell differentiation in response to VMC.

Sulfation predominates the pharmacokinetics, metabolism, and excretion of forsythin in humans: major enzymes and transporters identified.

Forsythin extracted from Forsythiae Fructus is widely used to treat fever caused by the common cold or influenza in China, Japan and Korea. The present study aimed to analyze the pharmacokinetics, metabolism and excretion routes of forsythin in humans and determine the major enzymes and transporters involved in these processes. After a single oral administration, forsythin underwent extensive metabolism via hydrolysis and further sulfation. In total, 3 of the 13 metabolites were confirmed by comparison to reference substances, i.e., aglycone M1, M1 sulfate (M2), and M1 glucuronide (M7). Hydrolysis was the initial and main metabolic pathway of the parent compound, followed by extensive sulfation to form M2 and a reduced level of glucuronidation to form M7. In addition, the plasma exposure of M2 and M7 were 86- and 4.2-fold higher than that of forsythin. Within 48 h, ~75.1% of the administered dose was found in urine, with M2 accounting for 71.6%. Further phenotyping experiments revealed that sulfotransferase 1A1 and UDP-glucuronosyltransferase 1A8 were the most active hepatic enzymes involved in the formation of M2 and M7, respectively. The in vitro kinetic study provided direct evidence that M1 showed a preference for sulfation. Sulfated conjugate M2 was identified as a specific substrate of organic anion transporter 3, which could facilitate the renal excretion of M2. Altogether, our study demonstrated that sulfation dominated the metabolism and pharmacokinetics of forsythin, while the sulfate conjugate was excreted mainly in the urine.

Construction and Clinical Translation of Causal Pan-Cancer Gene Score Across Cancer Types.

Pan-cancer strategy, an integrative analysis of different cancer types, can be used to explain oncogenesis and identify biomarkers using a larger statistical power and robustness. Fine-mapping defines the casual loci, whereas genome-wide association studies (GWASs) typically identify thousands of cancer-related loci and not necessarily have a fine-mapping component. In this study, we develop a novel strategy to identify the causal loci using a pan-cancer and fine-mapping assumption, constructing the CAusal Pan-cancER gene (CAPER) score and validating its performance using internal and external validation on 1,287 individuals and 985 cell lines. Summary statistics of 15 cancer types were used to define 54 causal loci in 15 potential genes. Using the Cancer Genome Atlas (TCGA) training set, we constructed the CAPER score and divided cancer patients into two groups. Using the three validation sets, we found that 19 cancer-related variables were statistically significant between the two CAPER score groups and that 81 drugs had significantly different drug sensitivity between the two CAPER score groups. We hope that our strategies for selecting causal genes and for constructing CAPER score would provide valuable clues for guiding the management of different types of cancers.