NLRP3 Phosphorylation Is an Essential Priming Event for Inflammasome Activation.

Many infections and stress signals can rapidly activate the NLRP3 inflammasome to elicit robust inflammatory responses. This activation requires a priming step, which is thought to be mainly for upregulating NLRP3 transcription. However, recent studies report that the NLRP3 inflammasome can be activated independently of transcription, suggesting that the priming process has unknown essential regulatory steps. Here, we report that JNK1-mediated NLRP3 phosphorylation at S194 is a critical priming event and is essential for NLRP3 inflammasome activation. We show that NLRP3 inflammasome activation is disrupted in NLRP3-S194A knockin mice. JNK1-mediated NLRP3 S194 phosphorylation is critical for NLRP3 deubiquitination and facilitates its self-association and the subsequent inflammasome assembly. Importantly, we demonstrate that blocking S194 phosphorylation prevents NLRP3 inflammasome activation in cryopyrin-associated periodic syndromes (CAPS). Thus, our study reveals a key priming molecular event that is a prerequisite for NLRP3 inflammasome activation. Inhibiting NLRP3 phosphorylation could be an effective treatment for NLRP3-related diseases.

Capillary zone electrophoresis-high field asymmetric ion mobility spectrometry-tandem mass spectrometry for top-down characterization of histone proteoforms.

Characterization of histone proteoforms with various post-translational modifications (PTMs) is critical for a better understanding of functions of histone proteoforms in epigenetic control of gene expression. Mass spectrometry (MS)-based top-down proteomics (TDP) is a valuable approach for delineating histone proteoforms because it can provide us with a bird's-eye view of histone proteoforms carrying diverse combinations of PTMs. Here, we present the first example of coupling capillary zone electrophoresis (CZE), ion mobility spectrometry (IMS), and MS for online multi-dimensional separations of histone proteoforms. Our CZE-high-field asymmetric waveform IMS (FAIMS)-MS/MS platform identified 366 (ProSight PD) and 602 (TopPIC) histone proteoforms from a commercial calf histone sample using a low microgram amount of histone sample as the starting material. CZE-FAIMS-MS/MS improved the number of histone proteoform identifications by about 3 folds compared to CZE-MS/MS alone (without FAIMS). The results indicate that CZE-FAIMS-MS/MS could be a useful tool for comprehensive characterization of histone proteoforms with high sensitivity.

Pilot Evaluation of the Long-Term Reproducibility of Capillary Zone Electrophoresis-Tandem Mass Spectrometry for Top-Down Proteomics of a Complex Proteome Sample.

Mass spectrometry (MS)-based top-down proteomics (TDP) has revolutionized biological research by measuring intact proteoforms in cells, tissues, and biofluids. Capillary zone electrophoresis-tandem MS (CZE-MS/MS) is a valuable technique for TDP, offering a high peak capacity and sensitivity for proteoform separation and detection. However, the long-term reproducibility of CZE-MS/MS in TDP remains unstudied, which is a crucial aspect for large-scale studies. This work investigated the long-term qualitative and quantitative reproducibility of CZE-MS/MS for TDP for the first time, focusing on a yeast cell lysate. Over 1000 proteoforms were identified per run across 62 runs using one linear polyacrylamide (LPA)-coated separation capillary, highlighting the robustness of the CZE-MS/MS technique. However, substantial decreases in proteoform intensity and identification were observed after some initial runs due to proteoform adsorption onto the capillary inner wall. To address this issue, we developed an efficient capillary cleanup procedure using diluted ammonium hydroxide, achieving high qualitative and quantitative reproducibility for the yeast sample across at least 23 runs. The data underscore the capability of CZE-MS/MS for large-scale quantitative TDP of complex samples, signaling its readiness for deployment in broad biological applications. The MS RAW files were deposited in ProteomeXchange Consortium with the data set identifier of PXD046651.

Resource-Efficient Direct Characterization of General Density Matrix.

Sequential weak measurements allow for the direct extraction of individual density-matrix elements, rather than relying on global reconstruction of the entire density matrix, which opens a new avenue for the characterization of quantum systems. Nevertheless, extending the sequential scheme to multiqudit quantum systems is challenging due to the requirement of multiple coupling processes for each qudit and the lack of appropriate precision evaluation. To address these issues, we propose a resource-efficient scheme (RES) that directly characterizes the density matrix of general multiqudit systems while optimizing measurements and establishing a feasible estimation analysis. In the RES, an efficient observable of the quantum system is constructed such that a single meter state coupled to each qudit is sufficient to extract the corresponding density-matrix element. An appropriate model based on the statistical distribution of errors is utilized to evaluate the precision and feasibility of the scheme. We have experimentally applied the RES to the direct characterization of general single-photon qutrit states and two-photon entangled states. The results show that the RES outperforms sequential schemes in terms of efficiency and precision in both weak- and strong-coupling scenarios. This Letter sheds new light on the practical characterization of large-scale quantum systems and the investigation of their nonclassical properties.

UPLC/Q-TOF-MS-based metabolomics and molecular docking analysis of Bifidobacterium adolescentis exposure to levofloxacin.

Antibiotic-associated diarrhea is a common adverse reaction caused by the widespread use of antibiotics. The decrease in probiotics is one of the reasons why antibiotics cause drug-induced diarrhea. However, few studies have addressed the intrinsic mechanism of antibiotics inhibiting probiotics. To investigate the underlying mechanism of levofloxacin against Bifidobacterium adolescentis, we used a metabolomics mass spectrometry-based approach and molecular docking analysis for a levofloxacin-induced B. adolescentis injury model. The results showed that levofloxacin reduced the survival rate of B. adolescentis and decreased the number of B. adolescentis. The untargeted metabolomics analysis identified 27 potential biomarkers, and many of these metabolites are involved in energy metabolism, amino acid metabolism and the lipid metabolism pathway. Molecular docking showed that levofloxacin can bind with aminoacyl-tRNA synthetase and lactic acid dehydrogenase. This result provides a novel insight into the mechanism of the adverse reactions of levofloxacin.

Causal effects of life course adiposity on temporomandibular disorders: A Mendelian randomization study.

BACKGROUND: Previous studies investigated the associations between obesity and temporomandibular disorders (TMDs), but the evidence for the causal inferences was unclear. OBJECTIVE: We aimed to investigate the causal link between life course adiposity and TMDs. METHODS: Mendelian randomization (MR) studies were performed using genetic instruments for birth weight (BW) (N = 261 932), childhood body mass index (BMI) (N = 39 620), childhood body size (N = 454 718), adult BMI (N = 99 998), body fat percentage (N = 454 633) and TMDs (N = 211 023). We assessed the overall effect of each life course adiposity factor via inverse-variance weighted (IVW), weighted median, and MR-Egger methods and performed extensive sensitivity analyses. Additionally, multivariable MR was conducted to evaluate the direct and indirect effects of childhood BMI on TMDs while accounting for BW and adult BMI, and vice versa. RESULTS: Univariable MR analyses revealed a causal effect of low childhood adiposity on an increased risk of TMDs (childhood BMI: IVW OR: 0.65, 95% CI: 0.54-0.78, p < .001; childhood body size: IVW OR: 0.56, 95% CI: 0.43-0.73, p < .001). No causal association existed between genetically predicted BW, adult BMI, or body fat percentage and TMDs. In the multivariable MR analyses, the effects of childhood BMI on TMDs occurrence remained significant and direct, even after adjusting for BW and adult BMI (multivariable IVW OR: 0.78, 95% CI: 0.61-0.99, p = .048). No pleiotropy and heterogeneity were detected (p > .05). CONCLUSION: Low childhood BMI might causally increase the risk of TMDs through a direct pathway.

Causal effects of educational attainment on temporomandibular disorders and the mediating pathways: A Mendelian randomization study.

BACKGROUND: As one of the most important indicators of socioeconomic status, educational attainment (EA) exhibits a strong association with temporomandibular disorders (TMDs). Despite this link, there is a lack of evidence regarding the causal role of EA in either facilitating or preventing TMDs. OBJECTIVE: This study aimed to investigate the causal effect of education on TMDs and explore potential mediating pathways. METHODS: Utilizing summary statistics from genome-wide association studies on years of schooling (N = 766 345) and TMDs (N = 211 023), we conducted Mendelian randomization (MR) to assess the overall effect of education. Additionally, a two-step MR approach was employed to evaluate 30 potential mediators and calculate the mediation proportions in the association. Comprehensive sensitivity analyses were used to verify the robustness, heterogeneity, and pleiotropy. RESULTS: Univariable MR analyses revealed a causal effect of lower EA on an increased risk of TMDs (OR: 0.53, 95% CI: 0.43-0.66, p < .001). Five out of 30 modifiable factors were identified as causal mediators in the associations of EA with TMDs, including feeling nervous (mediation proportion: 11.6%), feeling tense (10.2%), depression (9.6%), feeling worry (7.6%) and daily smoking (8.9%). Meanwhile, no pleiotropy was detected in the analyses (p > .05). CONCLUSION: Our findings supported that higher EA has a protective effect on the onset of TMDs, with partial mediation by psychological disorders and daily smoking. Interventions on these factors thus have the potential of substantially reducing the burden of TMDs attributed to low education.

The Even Shorter Almost Perfect Scale: Psychometric Evaluation and Cross-National Implications for Psychological Outcomes.

Short empirically-supported scales or individual items are preferred in comprehensive surveys, brief screeners, and experience sampling studies. To that end, we examined the Short Almost Perfect Scale (SAPS) to evaluate empirical support for the interchangeability of items to measure perfectionistic strivings (Standards) and perfectionistic concerns (Discrepancy). Based on a large and diverse sample (N = 1,103) and tests of tau-equivalence (equal factor loadings) for each respective set of items, Study 1 advanced a subset of SAPS items to measure Standards (2 items) and Discrepancy (3 items). Cross-sectional gender and race/ethnicity invariance were supported, and in structural equations analyses, the SAPS5 factors were significantly associated with depression, state anxiety, life satisfaction, and gratitude. Study 2 cross-validated Study 1 measurement and structural findings with a new U.S. sample (N = 803). The three items representing the Discrepancy (perfectionistic concerns) factor also were supported in a cross-national comparison between the U.S. sample and a scale development sample in New Zealand (N = 3,921). For the most part, across both studies and all analyses, the three Discrepancy items were empirically interchangeable indicators of perfectionistic concerns and comparably strong predictors of psychological outcomes, supporting their use in studies or other contexts with space or time restrictions for measurement.

Protective effects of oyster polypeptide on cyclophosphamide-induced immunosuppressed rats.

BACKGROUND: Oyster polypeptide (OP) is a mixture of oligopeptides extracted from oysters through enzyme lysis, separation, and purification. It is associated with immunomodulatory effects, but the underlying mechanisms are not known. This study therefore combined proton nuclear magnetic resonance (1H-NMR) urinary metabolomics and 16S rRNA gene sequencing of the gut microbiome to determine the immunoprotective mechanisms of OP in rats subjected to cyclophosphamide-induced immunosuppression. RESULTS: Oyster polypeptide restored the body weight and the structure of spleen and thymus in rats with cyclophosphamide-induced immunosuppression. It upregulated the levels of white blood cells (WBCs), hemoglobin (HGB), platelets (PLT), red blood cells (RBCs), immunoglobulin G (IgG), immunoglobulin M (IgM), cytokines such as interleukin­6 (IL-6) and tumor necrosis factor-α (TNF-α), and increased the numbers of CD3+ and CD4+ T cells in the immunosuppressed rats. The 1H-NMR metabolomics results showed that OP significantly reversed the levels of ten metabolites in urine, including 2-oxoglutarate, citrate, dimethylamine, taurine, N-phenylacetylglycine, alanine, betaine, creatinine, uracil, and benzoate. The 16S rRNA gene sequencing results showed that OP restored the gut microbiome homeostasis by increasing the abundance of beneficial bacteria and reducing the abundance of pathogenic bacteria. Finally, a combination of metabolomics and microbiomics found that the metabolism of taurine and hypotaurine, and the metabolism of alanine, aspartate, and glutamate were disturbed, but these metabolic pathways were restored by OP. CONCLUSION: This study demonstrated that OP had immunoprotective effects in rats with cyclophosphamide-induced immunosuppression by restoring key metabolic pathways and the gut microbiome homeostasis. Our findings provide a framework for further research into the immunoregulatory mechanisms of OP and its potential use in drugs and nutritional supplements. © 2024 Society of Chemical Industry.

Causal relationship between hypothyroidism and temporomandibular disorders: evidence from complementary genetic methods.

BACKGROUND: The role of thyroid health in temporomandibular disorders (TMDs) has been emphasized in observational studies. However, whether the causation exists is unclear, and controversy remains about which specific disorder, such as hypothyroidism or hyperthyroidism, is destructive in TMDs. This study aims to investigate the overall and specific causal effects of various thyroid conditions on TMDs. METHODS: Mendelian randomization (MR) studies were performed using genetic instruments for thyrotropin (TSH, N = 119,715), free thyroxine (fT4, N = 49,269), hypothyroidism (N = 410,141), hyperthyroidism (N = 460,499), and TMDs (N = 211,023). We assessed the overall effect of each thyroid factor via inverse-variance weighted (IVW), weighted median, and MR-Egger methods, and performed extensive sensitivity analyses. Additionally, multivariable MR was conducted to evaluate the direct or indirect effects of hypothyroidism on TMDs whilst accounting for TSH, fT4 and hyperthyroidism, and vice versa. RESULTS: Univariable MR analyses revealed a causal effect of hypothyroidism on an increased risk of TMDs (IVW OR: 1.12, 95% CI: 1.05-1.20, p = 0.001). No significant association between genetically predicted hyperthyroidism, TSH, or fT4 and TMDs. In the multivariable MR analyses, the effects of hypothyroidism on TMDs occurrence remained significant even after adjSusting for TSH, fT4 and hyperthyroidism (multivariable IVW OR: 1.10, 95% CI: 1.03-1.17, p = 0.006). No pleiotropy and heterogeneity were detected in the analyses (p > 0.05). CONCLUSIONS: Hypothyroidism might causally increase the risk of TMDs through a direct pathway, highlighting the critical role of managing thyroid health in the prevention of TMDs. Clinicians should give heightened attention to patients with hypothyroidism when seeking medical advice for temporomandibular discomfort. However, caution is warranted due to the potential confounders, pleiotropy, and selection bias in the MR study.

Glutamatergic neurons in lateral hypothalamus play a vital role in acupuncture preconditioning to alleviate MIRI.

Myocardial ischemia-reperfusion injury (MIRI) has high morbidity and mortality worldwide. Increasing evidence has shown that electroacupuncture (EA) plays a critical role in alleviating MIRI. The aim of this study is to investigate whether glutamatergic neurons in the lateral hypothalamus (LH) have vital effect on MIRI as well as the underlying mechanism during the EA pretreatment. The MIRI model was established by ligating the left anterior descending (LAD) coronary artery for 30 min followed by reperfusion for 2 h. Chemogenetics, electrocardiogram (ECG) recording, ELISA, multichannel physiology recording, and immunofluorescence staining methods were combined to demonstrate that firing frequencies of neurons in the LH and expression of c-Fos decreased by EA pretreatment. Meanwhile, EA preconditioning significantly reduced the percentage of infarct size and the levels of cardiac troponin I (cTnI) and creatine kinase isoenzymes (CK-MB) were similar to inhibition of glutamatergic neurons in LH, also attenuated morphology of myocardial tissue was induced by MIRI. However, activation of glutamatergic neurons in LH weakened the above effects of EA pretreatment.NEW & NOTEWORTHY This study demonstrates that EA preconditioning can attenuate myocardial injury for MIRI, which is similar to inhibition of glutamatergic neurons in LH. However, chemical activation of glutamatergic neurons in LH attenuates the protective effect of EA pretreatment. These findings help better understand the mechanisms of EA to regulate cardiac function.

Coupling High-Field Asymmetric Waveform Ion Mobility Spectrometry with Capillary Zone Electrophoresis-Tandem Mass Spectrometry for Top-Down Proteomics.

Capillary zone electrophoresis-tandem mass spectrometry (CZE-MS/MS) has emerged as an essential technique for top-down proteomics (TDP), providing superior separation efficiency and high detection sensitivity for proteoform analysis. Here, we aimed to further enhance the performance of CZE-MS/MS for TDP via coupling online gas-phase proteoform fractionation using high-field asymmetric waveform ion mobility spectrometry (FAIMS). When the compensation voltage (CV) of FAIMS was changed from -50 to 30 V, the median mass of identified proteoforms increased from less than 10 kDa to about 30 kDa, suggesting that FAIMS can efficiently fractionate proteoforms by their size. CZE-FAIMS-MS/MS boosted the number of proteoform identifications from a yeast sample by nearly 3-fold relative to CZE-MS/MS alone. It particularly benefited the identification of relatively large proteoforms, improving the number of proteoforms in a mass range of 20-45 kDa by 6-fold compared to CZE-MS/MS alone. FAIMS fractionation gained nearly 20-fold better signal-to-noise ratios of randomly selected proteoforms than no FAIMS. We expect that CZE-FAIMS-MS/MS will be a useful tool for further advancing the sensitivity and coverage of TDP. This work shows the first example of coupling CE with ion mobility spectrometry (IMS) for TDP.

Capillary Zone Electrophoresis-Tandem Mass Spectrometry for Top-Down Proteomics of Mouse Brain Integral Membrane Proteins.

Mass spectrometry (MS)-based top-down characterization of integral membrane proteins (IMPs) is crucial for understanding their functions in biological processes. However, it is technically challenging due to their low solubility in typical MS-compatible buffers. In this work, for the first time, we developed an efficient capillary zone electrophoresis (CZE)-tandem MS (MS/MS) method for the top-down proteomics (TDP) of IMPs enriched from mouse brains. Our technique employs a sample buffer containing 30% (v/v) formic acid and 60% (v/v) methanol for solubilizing IMPs and utilizes a separation buffer of 30% (v/v) acetic acid and 30% (v/v) methanol for maintaining the solubility of IMPs during CZE separation. Single-shot CZE-MS/MS identified 51 IMP proteoforms from the mouse brain sample. Coupling size exclusion chromatography (SEC) to CZE-MS/MS enabled the identification of 276 IMP proteoforms from the mouse brain sample containing 1-4 transmembrane domains. This proof-of-concept work demonstrates the high potential of CZE-MS/MS for the large-scale TDP of IMPs.

Pilot investigation of magnetic nanoparticle-based immobilized metal affinity chromatography for efficient enrichment of phosphoproteoforms for mass spectrometry-based top-down proteomics.

Protein phosphorylation is a vital and common post-translational modification (PTM) in cells, modulating various biological processes and diseases. Comprehensive top-down proteomics of phosphorylated proteoforms (phosphoproteoforms) in cells and tissues is essential for a better understanding of the roles of protein phosphorylation in fundamental biological processes and diseases. Mass spectrometry (MS)-based top-down proteomics of phosphoproteoforms remains challenging due to their relatively low abundance. Herein, we investigated magnetic nanoparticle-based immobilized metal affinity chromatography (IMAC, Ti4+, and Fe3+) for selective enrichment of phosphoproteoforms for MS-based top-down proteomics. The IMAC method achieved reproducible and highly efficient enrichment of phosphoproteoforms from simple and complex protein mixtures. It outperformed one commercial phosphoprotein enrichment kit regarding the capture efficiency and recovery of phosphoproteins. Reversed-phase liquid chromatography (RPLC)-tandem mass spectrometry (MS/MS) analyses of yeast cell lysates after IMAC (Ti4+ or Fe3+) enrichment produced roughly 100% more phosphoproteoform identifications compared to without IMAC enrichment. Importantly, the phosphoproteoforms identified after Ti4+-IMAC or Fe3+-IMAC enrichment correspond to proteins with much lower overall abundance compared to that identified without the IMAC treatment. We also revealed that Ti4+-IMAC and Fe3+-IMAC could enrich different pools of phosphoproteoforms from complex proteomes and the combination of those two methods will be useful for further improving the phosphoproteoform coverage from complex samples. The results clearly demonstrate the value of our magnetic nanoparticle-based Ti4+-IMAC and Fe3+-IMAC for advancing top-down MS characterization of phosphoproteoforms in complex biological systems.

Hardness and superconductivity in tetragonal LiB4 and NaB4.

Boron-based compounds have triggered substantial attention due to their multifunctional properties, incorporating excellent hardness and superconductivity. While tetragonal metal borides LiB4 and NaB4 with BaAl4-type structure and striking clathrate boron motif have been induced under compression, there is still a lack of deep understanding of their potential properties at ambient pressure. We herein conduct a comprehensive study on I4/mmm-structured LiB4 and NaB4 under ambient pressure via first-principles calculations. Remarkably, both LiB4 and NaB4 are found to possess high Vickers hardness of 39 GPa, which is ascribed to the robust boron framework with strong covalency. Furthermore, their high hardness values together with distinguished stability make them highly potential superhard materials. Meanwhile, electron-phonon coupling analysis reveals that both LiB4 and NaB4 are conventional phonon-mediated superconductors, with critical temperatures of 6 and 8 K at 1 atmosphere pressure (atm), respectively, mainly arising from the coupling of B 2p electronic states and the low-frequency phonon modes associated with Li-, Na-, and B-derived vibrations. This work provides valuable insights into the mechanical and superconducting behaviors of metal borides and will boost further studies of emergent borides with multiple functionalities.

Metabolomics and molecular docking analysis of antibiotic exposure in Bifidobacterium adolescentis.

Bifidobacterium adolescentis is a probiotic. This research aimed to investigate the mechanism of antibiotics led to decrease in the number of B. adolescentis. The metabolomics approach was employed to explore the effects of amoxicillin on metabolism of B.adolescentis, while MTT assay and scanning electron microscopy were applied to analyse changes in viability and morphology of bacteria. Molecular docking was used to illuminate the mechanism by which amoxicillin acts on a complex molecular network. The results showed that increasing the concentration of amoxicillin led to a gradual decrease in the number of live bacteria. Untargeted metabolomics analysis identified 11 metabolites that change as a result of amoxicillin exposure. Many of these metabolites are involved in arginine and proline metabolism, glutathione metabolism, arginine biosynthesis, cysteine, and methionine metabolism, and tyrosine and phenylalanine metabolism. Molecular docking revealed that amoxicillin had a good binding effect on the proteins AGR1, ODC1, GPX1, GSH, MAT2A, and CBS. Overall, this research provides potential targets for screening probiotic regulatory factors and lays a theoretical foundation for the elucidation of its mechanisms.

Comprehensive analysis on subchondral bone marrow lesions of human osteoarthritis by integrating bulk and single-cell transcriptomes.

OBJECTIVE: This study aims to demonstrate the cellular composition and underlying mechanisms in subchondral bone marrow lesions (BMLs) of knee osteoarthritis (OA). METHODS: BMLs were assessed by MRI Osteoarthritis Knee Score (MOAKS)≥2. Bulk RNA-sequencing (bulk-seq) and BML-specific differentially expressed genes (DEGs) analysis were performed among subchondral bone samples (including OA-BML=3, paired OA-NBML=3; non-OA=3). The hub genes of BMLs were identified by verifying in independent datasets and multiple bioinformatic analyses. To further estimate cell-type composition of subchondral bone, we utilized two newly developed deconvolution algorithms (MuSiC, MCP-counter) in transcriptomic datasets, based on signatures from open-accessed single-cell RNA sequencing (scRNA-seq). Finally, competing endogenous RNA (ceRNA) and transcription factor (TF) networks were constructed through multiple predictive databases, and validated by public non-coding RNA profiles. RESULTS: A total of 86 BML-specific DEGs (up 79, down 7) were identified. IL11 and VCAN were identified as core hub genes. The "has-miR-424-5p/lncRNA PVT1" was determined as crucial network, targeting IL11 and VCAN, respectively. More importantly, two deconvolution algorithms produced approximate estimations of cell-type composition, and the cluster of heterotopic-chondrocyte was discovered abundant in BMLs, and positively correlated with the expression of hub genes. CONCLUSION: IL11 and VCAN were identified as the core hub genes of BMLs, and their molecular networks were determined as well. We profiled the characteristics of subchondral bone at single-cell level and determined that the heterotopic-chondrocyte was abundant in BMLs and was closely linked to IL11 and VCAN. Our study may provide new insights into the microenvironment and pathological molecular mechanism of BMLs, and could lead to novel therapeutic strategies.

Impact of inflammatory factors, hemoglobin A1c, and platelet parameters in gestational diabetes mellitus.

PURPOSE: The aim of this study was to evaluate the relationship among inflammatory cytokines including hypersensitive C-reactive protein (hs-CRP) and interleukin-6 (IL-6), glycated hemoglobin A1c (HbA1c), and platelet distribution width (PDW) in women with gestational diabetes mellitus (GDM). METHODS: Data on 191 pregnant women (96 women with GDM; 95 healthy controls) were extracted from routine prenatal examination records in Nanjing, China. Fasting concentrations of hs-CRP, IL-6, HbA1c, blood cell indices, and glucose at 24-28th gestational weeks were determined. RESULTS: The levels of hs-CRP, IL-6, FPG, PG1h, PG2h, HbA1c, RBC, and PDW significantly were increased (P < 0.05) in GDM group. hs-CRP had a positive correlation with HbA1c and PLT (P < 0.05). The odds ratios of HbA1c and PDW were 7.817 (95% CI 1.921-31.816, P = 0.004) and 1.523 (95% CI 1.158-2.002, P = 0.003), respectively. Furthermore, AUC of the combined diagnosis of GDM including HbA1c, FPG, and PDW reached 0.754, with specificity of 80.0% and sensitivity of 60.4%. CONCLUSION: Our findings support that elevated levels of hs-CRP, IL-6, HbA1c, and PDW at 24-28th gestational weeks even within the conventional normal range, may be implicated in the pathogenesis of GDM and their evaluation should be part of prenatal care routine.

Preventive effect of tilapia skin collagen hydrolysates on ulcerative colitis mice based on metabonomic and 16 S rRNA gene sequencing.

BACKGROUND: Tilapia skin collagen hydrolysates (TSCHs) are the product of enzymatic hydrolysis of collagen, which is mainly extracted from tilapia skin. The components of TSCHs have recently been reported to play a preventive role in dextran sulfate sodium (DSS)-induced ulcerative colitis (UC). However, it has not been illustrated whether TSCHs can prevent against DSS-induced UC via the gut microbiota and its derived metabolites. RESULTS: TSCHs are mainly composed of amino acids, which have similar characteristics to collagen, with most having a molecular weight below 5 kDa. In a mouse model of UC, TSCHs had no toxic effect at a dose of 60 g kg-1 and could reduce body weight changes, colon length, histopathological changes and score, and the level of the serum inflammatory cytokine interleukin (IL)-6. Concurrently, 16 S rRNA sequencing showed that TSCHs significantly reduced the abundance of Bacteroidetes and Proteobacteria at the phylum level and norank_f__Muribaculaceae and Escherichia-Shigella at the genus level, while they increased the abundance of Firmicutes at the phylum level and Lachnoclostridium, Allobaculum, Enterorhabdus, and unclassified__f__Ruminococcaceae at the genus level. Target metabolomic analysis showed that TSCHs elevated the concentration of total acid, acetic acid, propanoic acid, and butanoic acid, but reduced isovaleric acid concentrations. Moreover, Pearson correlation analysis revealed that Allobaculum, unclassified_Ruminococcaceae, and Enterorhabdus were positively correlated with acetic acid and butyric acid, but not Escherichia-Shigella. CONCLUSION: These findings suggest that TSCHs can prevent UC by modulating gut microbial and microbiota-derived metabolites. © 2023 Society of Chemical Industry.

[Mechanism of Danggui Sini Decoction in improving kidney injury caused by blood stasis syndrome based on metabolomics and network pharmacology].

This article analyzed the mechanism of Danggui Sini Decoction(DSD) in improving kidney injury caused by blood stasis syndrome(BSS) in rats. Firstly, 32 female SD rats were randomly divided into the following four groups: a normal group and a BSS group, both receiving an equal amount of distilled water by gavage; a normal+DSD group and a BSS+DSD group, both receiving 5.103 g·kg~(-1) DSD orally for a total of 14 days. Daily cold water bath was given to establish the BSS model, and on the 14th day, BSS rats were subcutaneously injected with 0.8 mg·kg~(-1) adrenaline. Normal rats were subjected to the water bath at 37 ℃ and injected with an equal volume of distilled water. After the experiment, 24-hour urine, serum, and kidney samples were collected for metabolomic analysis, biochemical measurements, and hematoxylin-eosin(HE) staining. The study then employed ~1H-NMR metabolomic technology to reveal the metabolic network regulated by DSD in improving BSS-induced kidney injury and used network pharmacology to preliminarily elucidate the key targets of the effectiveness of DSD. Pathological and biochemical analysis showed that DSD intervention significantly reduced inflammation and abnormal levels of blood creatinine, blood urea nitrogen, and urine protein in the kidneys. Metabolomic analysis indicated that DSD attenuated BSS-induced kidney injury primarily by regulating 10 differential metabolites and three major metabolic pathways(taurine and hypotaurine metabolism, citrate cycle, and acetaldehyde and dicarboxylic acid metabolism). Network pharmacology analysis suggested that the protective effect of DSD against BSS-induced kidney injury might be related to two key genes, ATP citrate lyase(ACLY) and nitric oxide synthase 2(NOS2), and two main metabolic pathways, i.e., arginine biosynthesis, and arginine and proline metabolism. This study, from the perspective of network regulation, provides initial insights and evidence into the mechanism of DSD in improving kidney injury induced by BSS, offering a basis for further investigation into the molecular mechanisms underlying its efficacy.