Integrated multi-omics reveal gut microbiota-mediated bile acid metabolism alteration regulating immunotherapy responses to anti-α4ß7-integrin in Crohn's disease.

Gut microbiota and related metabolites are both crucial factors that significantly influence how individuals with Crohn's disease respond to immunotherapy. However, little is known about the interplay among gut microbiota, metabolites, Crohn's disease, and the response to anti-α4ß7-integrin in current studies. Our research utilized 2,4,6-trinitrobenzene sulfonic acid to induce colitis based on the humanized immune system mouse model and employed a combination of whole-genome shotgun metagenomics and non-targeted metabolomics to investigate immunotherapy responses. Additionally, clinical cases with Crohn's disease initiating anti-α4ß7-integrin therapy were evaluated comprehensively. Particularly, 16S-rDNA gene high-throughput sequencing and targeted bile acid metabolomics were conducted at weeks 0, 14, and 54. We found that anti-α4ß7-integrin therapy has shown significant potential for mitigating disease phenotypes in remission-achieving colitis mice. Microbial profiles demonstrated that not only microbial composition but also microbially encoded metabolic pathways could predict immunotherapy responses. Metabonomic signatures revealed that bile acid metabolism alteration, especially elevated secondary bile acids, was a determinant of immunotherapy responses. Especially, the remission mice significantly enriched the proportion of the beneficial Lactobacillus and Clostridium genera, which were correlated with increased gastrointestinal levels of BAs involving lithocholic acid and deoxycholic acid. Moreover, most of the omics features observed in colitis mice were replicated in clinical cases. Notably, anti-α4ß7 integrin provided sustained therapeutic benefits in clinical remitters during follow-up, and long-lasting remission was linked to persistent changes in the microbial-related bile acids. In conclusion, gut microbiota-mediated bile acid metabolism alteration could play a crucial role in regulating immunotherapy responses to anti-α4ß7-integrin in Crohn's disease. Therefore, the identification of prognostic microbial signals facilitates the advancement of targeted probiotics that activate anti-inflammatory bile acid metabolic pathways, thereby improving immunotherapy responses. The integrated multi-omics established in our research provide valuable insights into potential mechanisms that impact treatment responses in complex diseases.

Proteomic profiling of aqueous humor-derived exosomes in Vogt-Koyanagi-Harada disease and Behcet's uveitis.

Vogt-Koyanagi-Harada (VKH) disease and Behcet's uveitis (BU) are the two major vision-threatening uveitis entities. This study performed the first label-free quantitative proteomics on aqueous humor-derived exosomes from 84 patients with VKH or BU to determine their potential roles. Sixty-five differentially expressed proteins (DEPs) and 40 DEPs were detected in the VKH and BU groups, respectively. GO and KEGG analysis showed that DEPs were mainly enriched in the complement-related pathways. The complement C1q subcomponent subunit B (C1QB) was identified as a key exosomal protein, and its expression was significantly increased by western blotting in both diseases. Additionally, the integrated analysis based on the published scRNA-seq data showed that C1QB-containing exosomes were mainly produced by mononuclear macrophages in the anterior segment tissue. Overall, our proteomic profiling highlights that complement-related pathways may be actively involved in the pathogenesis of these two diseases. These pathways may also serve as treatment targets for both diseases.

Long-term remission achieved in a rare case of pyoderma gangrenosum and ulcerative colitis with surgery and postoperative infliximab.

Background Pyoderma gangrenosum (PG) is a rare extraintestinal manifestation of inflammatory bowel disease. In recent years, the use of biologics in PG has been on the rise and has shown promising results. The surgical treatment of PG remains a topic of debate, with limited reports on the use of postoperative biologic therapy. Case reprt: This case report describes a 52-year-old woman who presented with multiple skin ulcers, pus discharge, and bloody diarrhea. The patient was diagnosed with PG with ulcerative colitis based on medical history, ulcer appearance, histopathology, treatment response, and the presence of ulcerative colitis. Surgical intervention was performed to repair the ulcers and amputate the fourth finger and fourth toe of both feet. Additionally, infliximab induction therapy was initiated two weeks after the surgery. The patient's intestinal symptoms demonstrated improvement, and after 10 months of treatment, the lesions were completely healed with no recurrence of skin ulcers. Conclusions This case report highlights a rare instance of successful treatment for PG with ulcerative colitis through a combination of surgery and postoperative infliximab.

Promising derivatives of rutaecarpine with diverse pharmacological activities.

Rutaecarpine (RUT) is a natural pentacyclic indolopyridoquinazolinone alkaloid first isolated from one of the most famous traditional Chinese herbs, Evodia rutaecarpa, which is used for treating a variety of ailments, including headaches, gastrointestinal disorders, postpartum hemorrhage, amenorrhea, difficult menstruation, and other diseases. Accumulating pharmacological studies showed that RUT possesses a wide range of pharmacological effects through different mechanisms. However, its poor physicochemical properties and moderate biological activities have hampered its clinical application. In this regard, the modification of RUT aimed at seeking its derivatives with better physicochemical properties and more potency has been extensively studied. These derivatives exhibit diverse pharmacological activities, including anti-inflammatory, anti-atherogenic, anti-Alzheimer's disease, antitumor, and antifungal activities via a variety of mechanisms, such as inhibiting cyclooxygenase-2 (COX-2), acetylcholine (AChE), phosphodiesterase 4B (PDE4B), phosphodiesterase 5 (PDE5), or topoisomerases (Topos). From this perspective, this paper provides a comprehensive description of RUT derivatives by focusing on their diverse biological activities. This review aims to give an insight into the biological activities of RUT derivatives and encourage further exploration of RUT.

Gut microbiota-related bile acid metabolism-FXR/TGR5 axis impacts the response to anti-α4ß7-integrin therapy in humanized mice with colitis.

The gut microbiota and bile acid metabolism are key determinants of the response of inflammatory bowel disease to biologic therapy. However, the molecular mechanisms underlying the interactions between the response to anti-α4ß7-integrin therapy and the gut microbiota and bile acid metabolism remain unknown. In this research, we investigated the role of gut microbiota-related bile acid metabolism on the response to anti-α4ß7-integrin therapy in a humanized immune system mouse model with colitis induced by 2,4,6-trinitrobenzene sulfonic acid. We found that anti-α4ß7-integrin significantly mitigated intestinal inflammation, pathological symptoms, and gut barrier disruption in remission-achieving colitis mice. Whole-genome shotgun metagenomic sequencing demonstrated that employing baseline microbiome profiles to predict remission and the treatment response was a promising strategy. Antibiotic-mediated gut microbiota depletion and fecal microbiome transplantation revealed that the baseline gut microbiota contained common microbes with anti-inflammatory effects and reduced mucosal barrier damage, improving the treatment response. Targeted metabolomics analysis illustrated that bile acids associated with microbial diversity were involved in colitis remission. Furthermore, the activation effects of the microbiome and bile acids on FXR and TGR5 were evaluated in colitis mice and Caco-2 cells. The findings revealed that the production of gastrointestinal bile acids, particularly CDCA and LCA, further directly promoted the stimulation of FXR and TGR5, significantly improving gut barrier function and suppressing the inflammatory process. Taken together, gut microbiota-related bile acid metabolism-FXR/TGR5 axis may be a potential mechanism for impacting the response to anti-α4ß7-integrin in experimental colitis. Thus, our research provides novel insights into the treatment response in inflammatory bowel disease.

Oxidized quercetin has stronger anti-amyloid activity and anti-aging effect than native form.

Quercetin (QUE) is one of the most widely distributed and used flavonoid. It has many biological activities and pharmacological effect. As a polyhydroxy phenol, QUE is easily oxidized. However, it is unclear how its biology efficacy changes after oxidation. In this study, we prepared QUE oxidation product (QUE-ox) through enzymatic oxidation of QUE. We found the oxidation reduced the antioxidant activity of QUE but increased its anti-amyloid activity in vitro. In C. elegans, oxidation increased the anti-aging effects of QUE. Further experiments showed that both QUE and QUE-ox delayed aging by improving stress resistance, but they have different molecular mechanisms. QUE mainly increased the transcriptional activities of DAF-16 and SKN-1, resulting in the enhancement of expression of oxidative stress resistance genes, and further increased the oxidative resistance in C. elegans. QUE-ox increased the transcriptional activities of DAF-16 and HSF-1 transcription factors to enhance the heat stress resistance. In summary, our study indicated oxidized QUE has stronger anti-amyloid activity and anti-aging effect than native form. This study provides a theoretical basis for the safe and rational application of QUE, especially for its antioxidant, anti-amyloid and anti-aging effects.

Machine-learning defined precision tDCS for improving cognitive function.

BACKGROUND: Transcranial direct current stimulation (tDCS) paired with cognitive training (CT) is widely investigated as a therapeutic tool to enhance cognitive function in older adults with and without neurodegenerative disease. Prior research demonstrates that the level of benefit from tDCS paired with CT varies from person to person, likely due to individual differences in neuroanatomical structure. OBJECTIVE: The current study aims to develop a method to objectively optimize and personalize current dosage to maximize the functional gains of non-invasive brain stimulation. METHODS: A support vector machine (SVM) model was trained to predict treatment response based on computational models of current density in a sample dataset (n = 14). Feature weights of the deployed SVM were used in a weighted Gaussian Mixture Model (GMM) to maximize the likelihood of converting tDCS non-responders to responders by finding the most optimum electrode montage and applied current intensity (optimized models). RESULTS: Current distributions optimized by the proposed SVM-GMM model demonstrated 93% voxel-wise coherence within target brain regions between the originally non-responders and responders. The optimized current distribution in original non-responders was 3.38 standard deviations closer to the current dose of responders compared to the pre-optimized models. Optimized models also achieved an average treatment response likelihood and normalized mutual information of 99.993% and 91.21%, respectively. Following tDCS dose optimization, the SVM model successfully predicted all tDCS non-responders with optimized doses as responders. CONCLUSIONS: The results of this study serve as a foundation for a custom dose optimization strategy towards precision medicine in tDCS to improve outcomes in cognitive decline remediation for older adults.

Comparative efficacy and safety of combination therapy with infliximab for Crohn's disease: a systematic review and network meta-analysis.

PURPOSE: There is not enough information to position medications for the treatment of Crohn's disease (CD). Therefore, using a network meta-analysis and systematic review, we evaluated the efficacy and safety of combination therapy and infliximab (IFX) monotherapy in CD patients. METHODS: We identified randomized controlled trials (RCTs) in CD patients who were given IFX-containing combination therapy versus IFX monotherapy. Induction and maintenance of clinical remission were the efficacy outcomes, while adverse events were the safety outcomes. The surface under cumulative ranking (SUCRA) probabilities was used to assess ranking in the network meta-analysis. RESULTS: In total, 15 RCTs with 1586 CD patients were included in this study. There was no statistical difference between different combination therapies in induction and maintenance of remission. In terms of inducing clinical remission, IFX + EN (SUCRA: 0.91) ranked highest; in terms of maintaining clinical remission, IFX + AZA (SUCRA: 0.85) ranked highest. There was no treatment that was significantly safer than the others. In terms of any adverse events, serious adverse events, serious infections, and infusion/injection-site reactions, IFX + AZA (SUCRA: 0.36, 0.12, 0.19, and 0.24) was ranked lowest for all risks; while IFX + MTX (SUCRA: 0.34, 0.06, 0.13, 0.08, 0.34, and 0.08) was rated lowest for risk of abdominal pain, arthralgia, headache, nausea, pyrexia, and upper respiratory tract infection. CONCLUSION: Indirect comparisons suggested that efficacy and safety of different combination treatments are comparable in CD patients. For maintenance therapies, IFX + AZA was ranked highest for clinical remission and lowest for adverse events. Further head-to-head trials are required.

Effects of methylglyoxal on shrimp tropomyosin structure and allergenicity during thermal processing.

This study aimed to analyze the effect of methylglyoxal (MGO) on the structure and allergenicity of shrimp tropomyosin (TM) during thermal processing. The structural changes were determined by SDS-PAGE, intrinsic fluorescence, circular dichroism, and HPLC-MS/MS. The allergenicity was evaluated by in vitro and in vivo experiments. MGO could cause conformational structural changes in TM during thermal processing. Moreover, the Lys, Arg, Asp, and Gln residues of TM were modified by MGO, which could destroy and/or mask TM epitopes. In addition, TM-MGO samples could lead to lower mediators and cytokines released from RBL-2H3 cells. In vivo, TM-MGO caused a significant reduction in antibodies, histamine, and mast cell protease 1 levels in sera. These results indicate that MGO can modify the allergic epitopes and reduce the allergenicity of shrimp TM during thermal processing. The study will help to understand the changes in the allergenic properties of shrimp products during thermal processing.

Corydalis saxicola Bunting Total Alkaloids ameliorate diet-induced non-alcoholic steatohepatitis by regulating hepatic PI3K/Akt and TLR4/NF-κB pathways in mice.

Corydalis saxicola Bunting (Yanhuanglian), distributed in Southwest China, is mainly used for treatment of hepatitis, oral mucosal erosion, conjunctivitis, dysentery, acute abdominal pain and hemorrhoids in the folk. Corydalis saxicola Bunting Total Alkaloids (CSBTA) are the active ingredients extracted from the root of C. saxicola bunting. Non-alcoholic steatohepatitis (NASH) is the hinge between steatosis and cirrhosis in the spectrum of Non-alcoholic fatty liver disease (NAFLD), which has become one of the most common chronic liver diseases in the world. CSBTA can reduce tumors and brain diseases through anti-inflammatory and antioxidant pathways. Our study was designed to clarify the effects of CSBTA on the HFHC (High fat and high carbohydrate drinking) diet induced mice. In our research, A HFHC diet induced NASH mice model was applied to investigate the effects of CSBTA in vivo and obeticholic acid (OA) was set as positive control. Moreover, the underlying mechanisms were explored by palmitic acid (PA) and lipopolysaccharide (LPS) stimulated HepG2 cells in vitro. The in vivo study illustrated that CSBTA could alleviate mice away from the onset of NASH, and reduce intrahepatocellular lipid accumulation and hepatocyte inflammation under high fat condition. Further in vitro analysis confirmed that CSBTA attenuated inflammation and hepatic lipid accumulation by improving hepatic PI3K/Akt and suppressing hepatic TLR4/NF-κB pathways. In summary, this study demonstrated that CSBTA might be a promising compound for the treatment of NAFLD.

Aptasensors for Staphylococcus aureus Risk Assessment in Food.

Staphylococcus aureus (S. aureus) is the top ordinary pathogen causing epidemic and food poisoning. The authentication of S. aureus has great significance for pathologic diagnosis and food hygiene supervision. Various biosensor methods have been established for identification. This paper reviews the research progress of aptasensors for S. aureus detection, focusing on the classification of aptamer technologies, including optical aptasensors and electrochemical aptasensors. Furthermore, the feasibility and future challenges of S. aureus detection for aptamer assays are discussed. Combining aptasensors with nanomaterials appears to be the developing trend in aptasensors.

Fast water channeling across carbon nanotubes in far infrared terahertz electric fields.

Using molecular dynamics simulations, we investigate systematically the water permeation properties across single-walled carbon nanotubes (SWCNT) in the presence of the terahertz electric field (TEF). With the TEF normal to the nanotube, the fracture of the hydrogen bonds results in the giant peak of net fluxes across the SWCNT with a three-fold enhancement centered around 14 THz. The phenomenon is attributed to the resonant mechanisms, characterized by librational, rotational, and rotation-induced responses of in-tube polar water molecules to the TEF. For the TEF along the symmetry axis of the nanotube, the vortical modes for resonances and consequently the enhancement of net fluxes are greatly suppressed by the alignment of polar water along the symmetry axis, which characterizes the quasi one-dimensional feature of the SWCNT nicely. The resonances of water molecules in the TEF can have potential applications in the high-flux device designs used for various purposes.