Targeted glycan degradation potentiates cellular immunotherapy for solid tumors.

Immune cell-based cancer therapies, such as chimeric antigen receptor T (CAR-T)-cell immunotherapy, have demonstrated impressive potency against hematological tumors. However, the efficacy of CAR-T cells against solid tumors remains limited. Herein, we designed tumor-targeting molecule-sialidase conjugates that potently and selectively stripped different sialoglycans from a variety of cancer cells. Desialylation enhanced induced pluripotent stem cell-derived chimeric antigen receptor-macrophage (CAR-iMac) infiltration and activation. Furthermore, the combination of cancer cell desialylation and CAR-iMac adoptive cellular therapy exerted a dramatic therapeutic effect on solid tumors and significantly prolonged the survival of tumor-bearing mice; these effects were mainly dependent on blockade of the checkpoint composed of sialic acid-binding immunoglobulin-like lectin (Siglec)-5 and Siglec-10 on the macrophages, and knockout of the glycoimmune checkpoint receptors could construct a CAR-iMac cell with stronger anticancer activity. This strategy that reverts the immune escape state ("cold tumor") to a sensitive recognition state ("hot tumor") has great significance for enhancing the effect of cellular immunotherapy on solid tumors. Therefore, desialylation combined with CAR-iMac cellular immunotherapy is a promising approach to enhance treatment with cellular immunotherapy and expand the valid indications among solid tumors, which provides inspiration for the development of cellular immunotherapies with glycoimmune checkpoint inhibition for the treatment of human cancer.

Development of an Ion Mobility Spectrometer Based on a Pulsed Photoelectric Effect Ionization Source.

Ion mobility spectrometry (IMS) is a compact and sensitive trace gas analysis instrument that ionizes the sample into ions for detection. Typically, an ion gate is used to cut the continuous ion beam into ion packets for separation and detection. However, commonly used ion gates suffer from complex structures or low ion transmission rates, making the gateless IMS a viable alternative. In this study, an IMS based on a pulsed photoelectric effect ionization source was designed. The photoelectrons were generated by irradiating a photoelectric material with a back-illuminated pulsed xenon lamp. This allows for low-energy photoelectron generation and the production of simple reactant ions (O2-(H2O)n) and thus negative product ions. The photoelectron current generated by this ionization source was analyzed, which can reach an intensity of a few microamperes and can be converted into an ion signal exceeding 10 nA. The introduction of the pulsed photoelectric effect ionization source makes it possible to generate separate ion packets and complete ion injection when a constant electric field is maintained in the ionization region. And with an assisted pulsed electric field in the ionization region, the resolving power of the system can be effectively improved to 1.85 times that of the constant electric field. The IMS developed in this study was used for the detection of common volatile hazardous chemicals, yielding effective results. The detection limit for phenol was below 1 ppb, and the dynamic response range exceeded 1 order of magnitude, which implies the potential applications of this IMS to detect substances with high electron affinity, such as explosives detection in public safety.

FraHMT: A Fragment-Oriented Heterogeneous Graph Molecular Generation Model for Target Proteins.

The molecular generation task stands as a pivotal step in the domains of computational chemistry and drug discovery, aiming to computationally generate molecular structures for specific properties. In contrast to previous models that focused primarily on SMILES strings or molecular graphs, our model placed a special emphasis on the substructure information on molecules, enabling the model to learn richer chemical rules and structure features from fragments and chemical reaction information on molecules. To accomplish this, we fragmented the molecules to construct heterogeneous graph representations based on atom and fragment information. Then our model mapped the heterogeneous graph data into a latent vector space by using an encoder and employed a self-regressive generative model as a decoder for molecular generation. Additionally, we performed transfer learning on the model using a small set of ligand molecules known to be active against the target protein to generate molecules that bind better to the target protein. Experimental results demonstrate that our model is highly competitive with state-of-the-art models. It can generate valid and diverse molecules with favorable physicochemical properties and drug-likeness. Importantly, they produce novel molecules with high docking scores against the target proteins.

Co-occurrence of depressive and anxious symptoms and their influence on self-rated health: a national representative survey among Chinese older adults.

OBJECTIVES: The prevalence of the co-occurrence of depressive and anxious symptoms (CO) and their influence on perceived overall health were not clear in community dwelling Chinese older adults. The aims of the study were to investigate the prevalence of CO and to explore its influence on self-rated health (SRH). METHOD: This study included 12301 individuals aged ≥65 years from the 2018 wave of the Chinese Longitudinal Healthy Longevity Survey (CLHLS), a nationally representative survey of older adults in mainland China. Participants received face-to-face interviews and assessments of depressive symptoms and anxious symptoms via 10-item of the Center for Epidemiologic Studies Depression Scale (CES-D-10) and 7-item Generalized Anxiety Disorder Questionnaire (GAD-7), respectively. SRH was measured by self-reported. A logistic regression model was used to examine the association between CO and SRH after adjusting for confounding variables. RESULTS: The average age was 83.4 (SD: 11.0) years and there were 6576 (53.5%) females. The age- and sex-standardized prevalence of depressive symptoms only (DSO) was 38.6%, anxious symptoms only (ASO) was 1.5%, and CO was 10.8%. Compared with those without depressive and anxious symptoms, the older adults with DSO or ASO were more likely to have significant influence on SRH. And particularly, CO was likely to produce the greatest decrement in the level of SRH. CONCLUSION: CO was not rare in Chinese older adults nationwide. The older adults having CO had increased risk for lower level of SRH than having DSO or ASO. More attention should be given to CO among the older adults.

A regenerable electrochemical sensor for electro-inactive cyclovirobuxine D detection in biological samples.

Based on the pKa determination of cyclovirobuxine D (CVB-D) using the method of potentiometry, we predicted the ionization state of CVB-D at physiological pH. Thus, by taking advantage of the ionization state and consequent non-covalent interactions between protonated CVB-D and deprotonated polymerized bromothymol blue (poly-BTB) under physiological conditions, we developed a simple and reusable electrochemical sensor that contains a poly-BTB/SWNT-modified electrode for electro-inactive CVB-D detection in biological fluids using poly-BTB as both the recognition unit and the electrochemical probe. Upon being immersed in the solution of CVB-D, the poly BTB-based electrode shows a current decrease due to the interaction-driven binding of CVB-D on the electrode surface. The current decrease in the electrochemical sensor toward CVB-D concentration shows a linear relationship in the dynamic ranges of 0.01-1 µM and 1-50 µM with a detection limit of 1.65 nM based on 3σ. The sensor can be easily regenerated through the removal of the binding of CVB-D from the electrode surface by highly negatively charged heparin, and it presents high repeatability with an RSD of less than 4.0% for seven measurements. In animal experiments, the electrochemical sensor was selective and sensitive for CVB-D determination in plasma and liver homogenates. The electrochemical sensor is readily accessible, robust, and cost-effective and holds good promise for more applications in biological and clinical fields associated with CVB-D using less technically demanding and simple operating procedures.

Ultra-Fast Polarity Switching, Non-Radioactive Drift Tube for the Miniaturization of Drift-Time Ion Mobility Spectrometer.

Drift-time ion mobility spectrometer (DT-IMS) is a promising technology for gas detection and analysis in the form of miniaturized instrument. Analytes may exist in the form of positively or negatively charged ions according to their chemical composition and ionization condition, and therefore require both polarity of electric field for the detection. In this work the polarity switching of a drift-time ion mobility spectrometer based on a direct current (DC) corona discharge ionization source was investigated, with novel solutions for both the control of ion shutter and the stabilization of aperture grid. The drift field is established by employing a switchable high voltage power supply and a serial of voltage regulator diode, with optocouplers to drive the ion shutter when the polarity is switched. The potential of aperture grid is stabilized during the polarity switching by the use of four diodes to avoid unnecessary charging cycle of the aperture grid capacitor. Based on the proposed techniques, the developed DT-IMS with 50 mm drift path is able to switch its polarity in 10 ms and acquire mobility spectrum after 10 ms of stabilization. Coupled with a thermal desorption sampler, limit of detection (LoD) of 0.1 ng was achieved for ketamine and TNT. Extra benefits include single calibration substance for both polarities and largely simplified pneumatic design, together with the reduction of second drift tube and its accessories. This work paved the way towards further miniaturization of DT-IMS without compromise of performance.

Detection of Trace Explosives Using a Novel Sample Introduction and Ionization Method.

A novel sample introduction and ionization method for trace explosives detection is proposed and investigated herein, taking into consideration real-world application requirements. A thermal desorption sampling method and dielectric barrier discharge ionization (DBDI) source, with air as the discharge gas, were developed. The counter flow method was adopted firstly into the DBDI source to remove the interference of ozone and other reactive nitrogen oxides. A separated reaction region with an ion guiding electric field was developed for ionization of the sample molecules. Coupled with a homemade miniature digital linear ion trap mass spectrometer, this compact and robust design, with further optimization, has the advantages of soft ionization, a low detection limit, is free of reagent and consumable gas, and is an easy sample introduction. A range of common nitro-based explosives including TNT, 2,4-DNT, NG, RDX, PETN, and HMX has been studied. A linear response in the range of two orders of magnitude with a limit of detection (LOD) of 0.01 ng for TNT has been demonstrated. Application to the detection of real explosives and simulated mixed samples has also been explored. The work paves the path to developing next generation mass spectrometry (MS) based explosive trace detectors (ETDs).

Portable Digital Linear Ion Trap Mass Spectrometer Based on Separate-Region Corona Discharge Ionization Source for On-Site Rapid Detection of Illegal Drugs.

As narcotic control has become worse in the past decade and the death toll of drug abuse hits a record high, there is an increasing demand for on-site rapid detection of illegal drugs. This work developed a portable digital linear ion trap mass spectrometer based on separate-region corona discharge ionization source to meet this need. A separate design of discharge and reaction regions was adopted with filter air as both carrier gas for the analyte and protection of the corona discharge needle. The linear ion trap was driven by a digital waveform with a low voltage (±100 V) to cover a mass range of 50-500 Da with a unit resolution at a scan rate of 10,000 Da/s. Eighteen representative drugs were analyzed, demonstrating excellent qualitative analysis capability. Tandem mass spectrometry (MS/MS) was also performed by ion isolation and collision-induced dissociation (CID) with air as a buffer gas. With cocaine as an example, over two orders of magnitude dynamic range and 10 pg of detection limit were achieved. A single analysis time of less than 10 s was obtained by comparing the information of characteristic ions and product ions with the built-in database. Analysis of a real-world sample further validated the feasibility of the instrument, with the results benchmarked by GC-MS. The developed system has powerful analytical capability without using consumables including solvent and inert gas, meeting the requirements of on-site rapid detection applications.

Evaluation of the effect of Bovis Calculus Artifactus on eight rat liver cytochrome P450 isozymes using LC-MS/MS and cocktail approach.

Bovis Calculus Artifactus (BCA) is the main substitute for natural Calculus bovis, a traditional drug in China used to treat high fever, convulsion, and sore throat. The effect of BCA on cytochrome P450 (CYP) activities is unknown. This study was to investigate the effect of BCA on eight rat hepatic microsomal CYPisozymes to evaluate the potential drug interactions using the cocktail approach.Metabolites of the eight isoform probe substrates of CYP isozymes were quantified by LC-MS/MS. The method was validated by incubating known CYP inhibitors α-naphthoflavone (CYP1A2), thiotepa (CYP2B1), quercetin (CYP2C7), sulfaphenazole (CYP2C6), ticlopidine (CYP2C11), quinidine (CYP2D1), ketoconazole (CYP3A1),4-methylpyrazole (CYP2E1) with individual probe substrate and rat liver microsomes. The formation rates of the corresponding metabolites of the eight probe substrates were determined to evaluate the activity of each isozyme.The results showed that BCA has different degrees of inhibitory effect on four CYP450 isoforms (CYP2C6, CYP2C11, CYP2D1, CYP3A1) (p < 0.05), but no significant influence on CYP1A2, 2B1, 2C7 or 2E1 (p > 0.05). Attention should be paid to the BCA-drug interactions by careful monitoring and appropriate dosage adjustments in the concurrent use of the drugs which are metabolized by CYP1A2, CYP2C19, and CYP3A4. Abbreviations: BCA, bovis calculus artifactus; CYP, cytochrome P450; DDIs, drug-drug interactions; ESI, electrospray ionization; MRM, multiple reaction monitoring; NBC, Natural Bovis Calculus; QC, quality control; T CM, traditional Chinese medicine.

Exploration of severe Covid-19 associated risk factor in China: Meta-analysis of current evidence.

AIM: This meta-analysis aimed to explore potential risk factors for severe Covid-19. METHODS: We systemically and comprehensively retrieved the eligible study evaluating clinical differences between severe vs non-severe Covid-19. Main effect sizes were demographic characteristics, comorbidities, signs and symptoms, laboratory findings as well as radiological features of chest CT. RESULTS: A total of 2566 Covid-19 people (771 in the severe group and 1795 in the non-severe group) from 14 studies were eligible for this meta-analysis. It was demonstrated that older age and males were more likely to have severe Covid-19. Patients with underlying comorbidities, such as hypertension, diabetes, heart disease and COPD were significantly more susceptible to severe Covid-19. Patients with dyspnoea were more likely to be severely ill. Depressed total lymphocytes were observed in this article. Meanwhile, although reticulation (30.8%), intrathoracic lymph node enlargement (20.5%) and pleural effusions (30.8%) were relatively infrequent, meta-analysis revealed that patients with these presentations in chest CT were associated with increased risk of severe Covid-19. CONCLUSIONS: There are significant differences in clinical characteristics between the severe and non-severe Covid-19 patients. Many factors are related to the severity of the disease, which can help clinicians to differentiate severe patients from non-severe patients.

Circular RNAs in renal cell carcinoma: implications for tumorigenesis, diagnosis, and therapy.

Renal cell carcinoma (RCC) is the most common malignant kidney tumor and has a high incidence rate. Circular RNAs (circRNAs) are noncoding RNAs with widespread distribution and diverse cellular functions. They are highly stable and have organ- and tissue-specific expression patterns. CircRNAs have essential functions as microRNA sponges, RNA-binding protein- and transcriptional regulators, and protein translation templates. Recent reports have shown that circRNAs are abnormally expressed in RCC and act as important regulators of RCC carcinogenesis and progression. Moreover, circRNAs have emerged as potential biomarkers for RCC diagnosis and prognosis and targets for developing new treatments. However, further studies are needed to better understand the functions of circRNAs in RCC. In this review, we summarize and discuss the recent research progress on RCC-associated circRNAs, with a focus on their potential for RCC diagnosis and targeted therapy.

Development and validation of a solid-phase competition ELISA based on virus-like particles of foot-and-mouth disease virus serotype A for antibody detection.

Foot-and-mouth disease (FMD), caused by FMD virus (FMDV), is a highly contagious epidemic disease, which is controlled primarily by prophylactic vaccination and serological monitoring after vaccination. Here, we have developed a solid-phase competition ELISA (SPCE) method based on virus-like particles (VLPs) of FMDV serotype A. The use of VLPs in the SPCE assay as a replacement for inactivated FMDV provides a high level of biosafety. The SPCE showed high concordance rates when compared with the virus neutralization test and liquid-phase blocking ELISA for testing clinical serum samples and successive serological monitoring (kappa = 0.925). Thus, this SPCE is an alternative method for post-immunization detection of antibodies against FMDV serotype A, with high specificity and sensitivity.

Integrating brucine with carbon nanotubes toward electrochemical sensing of hydroxylamine.

Based on the intrinsic electrochemical features of brucine integrated with carbon nanotubes (brucine/SWNTs), dimeric quinoid brucine was electrochemically generated by electroactivation of a brucine/SWNTs-modified GC electrode and used as a novel electrocatalyst for efficient electro-oxidation of hydroxylamine (HA). The electrocatalytic activity was investigated with cyclic voltammetry in the range pH 2.0 to pH 11.0, and the best electrocatalytic performance of the electrocatalyst was obtained at pH 10.0. By taking advantage of the electrocatalytic activity of the dimeric quinoid brucine toward HA, we have developed an electrochemical sensor for HA measurements based on a brucine/SWNTS-modified GC electrode using amperometry with the applied potential of + 0.1 V (vs. Ag/AgCl). Under the optimized conditions, the current response toward HA concentration shows a linear relationship in the dynamic ranges of 0.1-10 µM and 10-1000 µM with a detection limit of 0.021 µM based on the 3σ criterion. The sensor was used to assay HA in pharmaceuticals including hydroxyurea tablets and pralidoxime iodide injections with satisfactory results. The spike-and-recovery for samples of tap water (n = 9) and lake water (n = 9) was within 97.17-100.16%. Graphical abstract Schematic illustration of electrochemical sensing of hydroxylamine (HA) enabled by integrating brucine with single-walled carbon nanotube (brucine/SWNTs) based on electro-activation of brucine/SWNTs-modified GC electrode.

Colorectal cancer heterogeneity and targeted therapy: Clinical implications, challenges and solutions for treatment resistance.

Precision medicine is becoming considerably critical in colorectal cancer therapy. Particularly for targeted therapies, the response to anti-EGFR therapy largely varies among individual patients. The mechanisms of anti-EGFR-based regimens resistance have been revealed, for instance, mutations in KRAS, BRAF, and PIK3CA. It is well known that colorectal cancer is a heterogeneous disease, massive evidences indicate that there are intertumour and intratumour heterogeneities in colorectal cancer. Recently, the integrative factor of the genetic, epigenetic and microenvironmental alterations that attribute to CRC heterogeneity is associated with the response to targeted therapies. We review here the possible mechanisms of heterogeneity that influence the anti-EGFR therapy, and mainly focus on the enhancive biomarkers detection to predict the therapy efficiency and select appropriate patients who are most likely to benefit from special targeted therapies, and take advantage of simultaneously blocked the multiple molecules involved in activation of independent of ligands induced EGFR signaling pathway to overcome the resistance to anti-EGFR therapies.

Food withdrawal alters the gut microbiota and metabolome in mice.

Food withdrawal as a health-enhancing measure has beneficial effects on aging, disease prevention, and treatment. However, the cellular and molecular mechanisms involving gut microbial changes and metabolic consequences resulting from food withdrawal have yet to be elucidated. In this study, we subjected lean and obese mice to a dietary intervention that consisted of a 4-d complete food withdrawal and an 8-d 50% food withdrawal, and we studied changes in cecal microbiome and host serum metabolome. The abundance of potentially pathogenic Proteobacteria was decreased and Akkermansia muciniphila was elevated by food withdrawal in mice fed a high-fat diet (HFD). Meanwhile, food withdrawal decreased the abundance of metabolites in branched chain amino acid, lipid, and free fatty acid metabolisms in host serum, more so in HFD mice than in normal mice. Microbial predicted function also showed that food withdrawal decreased the abundance of microbes associated with predicted diseases in the HFD group but not in the normal chow group. Correlation between the microbiome data and metabolomics data revealed a strong association between gut microbial and host metabolic changes in response to food withdrawal. In summary, our results showed that food withdrawal was safer and more metabolically beneficial to HFD-induced obese mice than to normal lean mice, and the beneficial effects were primarily derived from the changes in gut microbiota, which were closely associated with the host metabolome.-Zheng, X., Zhou, K., Zhang, Y., Han, X., Zhao, A., Liu, J., Qu, C., Ge, K., Huang, F., Hernandez, B., Yu, H., Panee, J., Chen, T., Jia, W., Jia, W. Food withdrawal alters the gut microbiota and metabolome in mice.

Peroral Endoscopic Myotomy with the Stag Beetle Knife (SB Knife): Feasibility and Follow-Up.

BACKGROUND Recently, a stag beetle (SB) knife was introduced to reduce the difficulty of peroral endoscopic myotomy (POEM). The objective of this study was to evaluate the efficacy and safety of the SB knife. MATERIAL AND METHODS A total of 71 patients undergoing POEM with the SB knife for esophageal achalasia were included. We used esophagography, manometry, esophagogastroduodenoscopy (EGD), and Eckardt score to assess the utility and safety. RESULTS All cases were completed for POEM. The incidence of adverse events during the operation were 2.8%; however, all cases were treated conservatively. There was a vast improvement in clinical symptoms and endoscopic findings. The average Eckardt score was 6.9 before and 0.6 at 1 year after POEM (p<0.05). The average lower esophageal sphincter (LES) pressure before and 6 months after POEM were 44.34±14.83 mmHg and 19.14±6.74 mmHg (p<0.05), respectively. The average LES relaxation pressure before and 6 months after POEM was 12.11±5.02 mmHg and 3.22±2.29 mmHg (p<0.05), respectively. CONCLUSIONS POEM with the SB Knife is technically efficient and safe in treating achalasia and is associated with favorable short-term outcomes.

The ratio of dihomo-γ-linolenic acid to deoxycholic acid species is a potential biomarker for the metabolic abnormalities in obesity.

Bile acid (BA) signaling regulates fatty acid metabolism. BA dysregulation plays an important role in the development of metabolic disease. However, BAs in relation to fatty acids have not been fully investigated in obesity-related metabolic disorders. A targeted metabolomic measurement of serum BA and free fatty acid profiles was applied to sera of 381 individuals in 2 independent studies. The results showed that the ratio of dihomo-γ-linolenic acid (DGLA) to deoxycholic acid (DCA) species (DCAS) was significantly increased in obese individuals with type 2 diabetes (T2DM) from a case-control study and decreased in the remission group of obese subjects with T2DM after metabolic surgery. The changes were closely associated with their metabolic status. These results were consistently confirmed in both serum and liver of mice with diet-induced obesity, implying that such a metabolic alteration in circulation reflects changes occurring in the liver. In vitro studies of human liver L-02 cell lines under BA treatment revealed that DCA and its conjugated form, TDCA, significantly inhibited mRNA expression of fatty acid transport protein 5 in the presence of DGLA, which was involved in hepatocyte DGLA uptake. Thus, the DGLA:DCAS ratio may be a promising biomarker for metabolic abnormalities in obesity.-Lei, S., Huang, F., Zhao, A., Chen, T., Chen, W., Xie, G., Zheng, X., Zhang, Y., Yu, H., Zhang, P., Rajani, C., Bao, Y., Jia, W., Jia, W. The ratio of dihomo-γ-linolenic acid to deoxycholic acid species is a potential biomarker for the metabolic abnormalities in obesity.

Proteasome Inhibitor Carbobenzoxy-L-Leucyl-L-Leucyl-L-Leucinal (MG132) Enhances Therapeutic Effect of Paclitaxel on Breast Cancer by Inhibiting Nuclear Factor (NF)-κB Signaling.

BACKGROUND Carbobenzoxy-L-leucyl-L-leucyl-L-leucinal (MG132), a peptide aldehyde proteasome inhibitor, can inhibit tumor progression by inactivating nuclear factor (NF)-κB signaling. Paclitaxel (PTX) is part of a routine regimen for the treatment of breast cancer. However, activation of the NF-κB pathway after treatment with PTX confers insensitivity to this drug. This study investigated the potential effect of MG132 as a co-treatment with PTX against breast cancer, and clarifies the underlying molecular mechanisms. MATERIAL AND METHODS Breast cancer cells were treated with PTX, MG132, or PTX plus MG132, and the therapeutic effects were evaluated phenotypically. A mouse model of breast cancer was used to determine the combined effect of PTX plus MG132 in vivo. RESULTS Treatment with PTX plus MG132 suppressed aggressive phenotypes of breast cancer cells more effectively than PTX alone. Consistently, MG132 also enhanced the suppressive effect of PTX on tumor growth in C57BL/6 mice. Significantly, activation of the NF-κB pathway by PTX was attenuated by MG132. CONCLUSIONS Based on our findings, we suggest the application of MG132 in clinical practice in combination with PTX for the treatment of breast cancer.

Bile acid is a significant host factor shaping the gut microbiome of diet-induced obese mice.

BACKGROUND: Intestinal bacteria are known to regulate bile acid (BA) homeostasis via intestinal biotransformation of BAs and stimulation of the expression of fibroblast growth factor 19 through intestinal nuclear farnesoid X receptor (FXR). On the other hand, BAs directly regulate the gut microbiota with their strong antimicrobial activities. It remains unclear, however, how mammalian BAs cross-talk with gut microbiome and shape microbial composition in a dynamic and interactive way. RESULTS: We quantitatively profiled small molecule metabolites derived from host-microbial co-metabolism in mice, demonstrating that BAs were the most significant factor correlated with microbial alterations among all types of endogenous metabolites. A high-fat diet (HFD) intervention resulted in a rapid and significant increase in the intestinal BA pool within 12 h, followed by an alteration in microbial composition at 24 h, providing supporting evidence that BAs are major dietary factors regulating gut microbiota. Feeding mice with BAs along with a normal diet induced an obese phenotype and obesity-associated gut microbial composition, similar to HFD-fed mice. Inhibition of hepatic BA biosynthesis under HFD conditions attenuated the HFD-induced gut microbiome alterations. Both inhibition of BAs and direct suppression of microbiota improved obese phenotypes. CONCLUSIONS: Our study highlights a liver-BA-gut microbiome metabolic axis that drives significant modifications of BA and microbiota compositions capable of triggering metabolic disorders, suggesting new therapeutic strategies targeting BA metabolism for metabolic diseases.

A Microdialysis in Adjuvant Arthritic Rats for Pharmacokinetics⁻Pharmacodynamics Modeling Study of Geniposide with Determination of Drug Concentration and Efficacy Levels in Dialysate.

Microdialysis, a sampling method for pharmacokinetics⁻pharmacodynamics (PK⁻PD) modeling in preclinical and clinical studies, is a convenient in vivo sampling technique. Geniposide (GE), an iridoid glycoside compound, is the major active ingredient of Gardenia jasminoides Ellis fruit which has an anti-inflammatory effect. In this study, an articular cavity microdialysis sampling system for adjuvant arthritic (AA) rats was established to study the effect of GE on the release of prostaglandin E2 (PGE2) in AA rats induced by Freund's complete adjuvant (FCA). An UHPLC-MS/MS method was developed to determine the concentrations of GE and PGE2 in the dialysate. Through the determination of drug concentrations and PGE2 efficacy levels in the dialysate, the developed methods were successfully applied to set up concentration⁻time and effect⁻time profiles followed by PK⁻PD modeling of GE's effect on decreasing PGE2 release after oral administration of GE. The effect was well described by the developed PK⁻PD modeling, indicating that GE may play an anti-inflammatory role via decreasing AA-induced elevated PGE2 levels. In the selection of suitable endogenous small molecules as effect markers, the establishment of AA rat joint-cavity microdialysis is an attractive technique for rational PK⁻PD studies.