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Crohn's disease (CD) is a chronic and progressive inflammatory disease that can involve any part of the gastrointestinal tract. The protective role of dietary polyphenols has been documented in preclinical models of CD. Gut microbiota mediates the metabolism of polyphenols and affects their bioactivity and physiological functions. However, it remains elusive the capacity of microbial polyphenol metabolism in CD patients and healthy controls (HCs) along with its correlation with polyphenols intake and polyphenol-derived metabolites. Thus, we aimed to decode polyphenol metabolism in CD patients through aspects of diet, gut microbiota, and metabolites. Dietary intake analysis revealed that CD patients exhibited decreased intake of polyphenols. Using metagenomic data from two independent clinical cohorts (FAH-SYSU and PRISM), we quantified abundance of polyphenol degradation associated bacteria and functional genes in CD and HCs and observed a lower capacity of flavonoids degradation in gut microbiota residing in CD patients. Furthermore, through analysis of serum metabolites and enterotypes in participants of FAH-SYSU cohort, we observed that CD patients exhibited reduced levels of serum hippuric acid (HA), one of polyphenol-derived metabolites. HA level was higher in healthier enterotypes (characterized by dominance of Ruminococcaceae and Prevotellaceae, dominant by HCs) and positively correlated with multiple polyphenols intake and abundance of bacteria engaged in flavonoids degradation as well as short-chain fatty acid production, which could serve as a biomarker for effective polyphenol metabolism by the gut microbiota and a healthier gut microbial community structure. Overall, our findings provide a foundation for future work exploring the polyphenol-based or microbiota-targeted therapeutic strategies in CD.
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Enfermedad de Crohn , Dieta , Microbioma Gastrointestinal , Polifenoles , Humanos , Enfermedad de Crohn/microbiología , Enfermedad de Crohn/metabolismo , Enfermedad de Crohn/tratamiento farmacológico , Microbioma Gastrointestinal/fisiología , Polifenoles/metabolismo , Femenino , Masculino , Adulto , Hipuratos/metabolismo , Persona de Mediana Edad , Adulto Joven , Bacterias/clasificación , Bacterias/metabolismo , Bacterias/genética , Heces/microbiologíaRESUMEN
Unidirectional transport of liquids has attracted the attention of researchers in recent years for its wide application foreground. However, it is still a challenge to control the spreading of liquid, especially for oils with relatively high viscosity. In this paper, a flexible surface textured with branch-shaped microstructures is proposed. These asymmetric microstructures exhibit excellent unidirectional spreading behaviors for various oils. By suitably stretching the flexible surface to different stretch ratios, the spreading length of the oil droplets can be controlled. Moreover, the ongoing forward spreading of oil droplets can be suspended dynamically when the surface is stretched to 40%. Corresponding mechanism analysis demonstrates that surface stretching can narrow and close the microvalves between adjacent branches, which restrain the flow of the precursor film and the primary droplet. The switchable unidirectional spreading behavior enables the surface with such microstructures to be used for oil transportation, oil-water separation, and controllable lubrication.
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Light-emitting diode (LED)-optical communication is a novel spectrum communication with wide field of view (FOV), light weight, and long-distance free-space capabilities. Due to atmospheric turbulence attenuation and pointing errors caused by long-distance communication, this Letter proposes a multi-pixel channel joint maximum likelihood (JML) reception method using a highly sensitive silicon photomultiplier (SiPM). To evaluate the performance of the SiPM under mobile terminal jittering communication, we analyze the effect of optical transmitting power, pointing errors, and signal-to-noise ratio (SNR) gain on optical communication by comparing JML with signal channel using the maximum likelihood (ML) algorithm. Both simulation analysis and experimental results demonstrate that the proposed JML algorithm to process signals received from SiPM multi-pixel channels can effectively mitigate the impact of pointing errors on the bit error rate (BER) of optical communications by two orders of magnitude at large jitter radians and SNR.
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In general, visible light communication (VLC) uses LEDs as transmitters. However, LEDs can serve as receivers to construct a simple duplex VLC system that uses only two LEDs instead of one LED and one photo-diode (PD). There is a lack of effective equivalent analysis models for characterizing and evaluating the inherent behavioral characteristics of LEDs used as receivers. This paper presents an equivalent analysis model for GaN LEDs as receivers. First, based on the proposed receiving equivalent circuit model, a third-order signal transmission mathematical analysis model is established, revealing the transmission relationship between the photocurrent and output voltage. Further research is conducted on the impact of parameter changes on the bandwidth, and the model can be simplified into a first-order low-pass mathematical analysis model under specific conditions, providing theoretical support for improving the bandwidth of LED receiving applications. The experimental results also confirm the theoretical predictions. This research result holds significant importance for revealing the intrinsic mechanisms and the improved optical communication performance of LEDs for effective reception.
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OBJECTIVES: The aim of this study was to characterise the first complete genome of Porphyromonas pogonae strain PP01-1 of human origin in China. METHODS: The Illumina NovaSeq 6000 (200X coverage) and Nanopore MinION platforms (100× coverage) were used for genome sequencing. A de novo hybrid assembly of short Illumina reads and long MinION reads was performed using Unicycler (v.0.5.0). Genome annotation of PP01-1 was performed using the prokaryotic gene-prediction tool Prokka1.14.6. The genome was further analysed using several bioinformatics tools, including ResFinder, VFDB, VirulenceFinder, Type Strain Genome Server, AntiSMASH, PathogenFinder, MobileElementfinder, CRISPRFinder, and IslandViewer. RESULTS: The assembled circular genome of P. pogonae strain PP01-1 was 2 916 423 bp in length, with a GC content of 41.0%, and no plasmid sequence was detected. A total of 2399 coding sequences were predicted by Prokka. PP01-1 harbours antimicrobial resistance genes blaOXA-347 (ß-lactamase resistance), tet(Q) (tetracycline resistance), and floR (chloramphenicol and florfenicol resistance). CONCLUSIONS: Here, we are the first to report the complete genome of P. pogonae strain PP01-1 of human origin. In this strain, we first identified blaOXA-347 and tet(Q) in P. pogonae, which will pave the way for further analysis that could identify the potential mechanism of antibiotic resistance and virulence factors in P. pogonae.
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Background: GLI3 gene mutations can result in various forms of polysyndactyly, such as Greig cephalopolysyndactyly syndrome (GCPS, MIM: #175700), Pallister-Hall syndrome (PHS, MIM: #146510), and isolated polydactyly (IPD, MIM: #174200, #174700). Reports on IPD-associated GLI3 mutations are rare. In this study, a novel GLI3 mutation was identified in a Chinese family with IPD. Results: We report a family with six members affected by IPD. The family members demonstrated several special phenotypes, including sex differences, abnormal finger joint development, and different polydactyly types. We identified a novel frameshift variant in the GLI3 gene (NM_000168.6: c.1820_1821del, NP_000159.3: p.Tyr607Cysfs*9) by whole-exome sequencing. Further analysis suggested that this mutation was the cause of polydactyly in this family. Conclusions: The discovery of this novel frameshift variant in our study further solidifies the relationship between IPD and GLI3 and expands the previously established spectrum of GLI3 mutations and associated phenotypes.
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This publisher's note contains a correction to Opt. Lett.48, 6468 (2024)10.1364/OL.503007.
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BACKGROUND: Pasteurella multocida is a zoonotic pathogen that mainly causes local skin and soft tissue infections in the human body through cat and dog bites. It rarely causes bacteraemia (or sepsis) and meningitis. We reported a case of septic shock and meningitis caused by P. multocida in a patient without a history of cat and dog bites. CASE PRESENTATION: An 84-year-old male patient was urgently sent to the emergency department after he was found with unclear consciousness for 8 h, accompanied by limb tremors and urinary incontinence. In the subsequent examination, P. multocida was detected in the blood culture and wound secretion samples of the patient. However, it was not detected in the cerebrospinal fluid culture, but its DNA sequence was detected. Therefore, the patient was clearly diagnosed with septic shock and meningitis caused by P. multocida. The patient had no history of cat or dog contact or bite. The patient was subsequently treated with a combination of penicillin G, doxycycline, and ceftriaxone, and he was discharged after 35 days of hospitalisation. CONCLUSION: This report presented a rare case of septic shock and meningitis caused by P. multocida, which was not related to a cat or dog bite. Clinical doctors should consider P. multocida as a possible cause of sepsis or meningitis and should be aware of its potential seriousness even in the absence of animal bites.
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Mordeduras y Picaduras , Meningitis , Infecciones por Pasteurella , Pasteurella multocida , Choque Séptico , Masculino , Humanos , Animales , Perros , Gatos , Anciano de 80 o más Años , Infecciones por Pasteurella/diagnóstico , Infecciones por Pasteurella/tratamiento farmacológico , Choque Séptico/etiología , Choque Séptico/complicaciones , Meningitis/complicaciones , Mordeduras y Picaduras/complicacionesRESUMEN
In the process of synaptic formation, neurons must not only adhere to specific principles when selecting synaptic partners but also possess mechanisms to avoid undesirable connections. Yet, the strategies employed to prevent unwarranted associations have remained largely unknown. In our study, we have identified the pivotal role of combinatorial clustered protocadherin gamma (γ-PCDH) expression in orchestrating synaptic connectivity in the mouse neocortex. Through 5' end single-cell sequencing, we unveiled the intricate combinatorial expression patterns of γ-PCDH variable isoforms within neocortical neurons. Furthermore, our whole-cell patch-clamp recordings demonstrated that as the similarity in this combinatorial pattern among neurons increased, their synaptic connectivity decreased. Our findings elucidate a sophisticated molecular mechanism governing the construction of neural networks in the mouse neocortex.
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Proteínas Relacionadas con las Cadherinas , Neocórtex , Animales , Ratones , Cadherinas/genética , Redes Neurales de la ComputaciónRESUMEN
BACKGROUND: Acute kidney injury (AKI) is common in patients with sepsis and may result in death. Systemic immune inflammation index (SII) is associated with kidney injury, but its predictive value for AKI in patients with sepsis remains unclear. OBJECTIVE: This study aimed to explore the predictive value of SII in sepsis patients with AKI. METHODS: From January 2020 to December 2022, 221 patients with sepsis treated in our hospital were retrospectively collected. The patients were divided into AKI group (n = 61) and control group (n = 160). Clinical characteristics and SII level were compared between the two groups, and the predictive value of SII for the occurrence of AKI was analysed. RESULTS: The SII level (724.72 ± 235.50 vs. 522.38 ± 205.62, p < 0.001), the serum procalcitonin level (8.13 ± 15.52 vs. 4.52 ± 10.34 µg/L, p < 0.001), and the acute physiology and chronic health evaluation II score (14.26 ± 2.90 vs. 11.62 ± 2.26, p < 0.001) significantly increased in the AKI group compared with the control group, whereas the albumin level significantly decreased (30.60 ± 5.41 vs. 32.49 ± 5.31 g/L, p = 0.019). The receiver operating characteristic curve showed that SII was valuable in predicting AKI in patients with sepsis, with an area under the curve of 0.733 (95% confidence interval: 0.657-0.810, p < 0.001). The continuous renal replacement therapy intervention rate (88.52% vs. 0.00%, p < 0.001), the intervention rate of vasoactive drugs (34.43% vs. 3.75%, p < 0.001), and the hospital mortality rate (16.39% vs. 2.50%, p < 0.001) significantly increased in the AKI group compared with the control group. CONCLUSIONS: AKI was associated with poor prognosis in patients with sepsis. SII, procalcitonin and acute physiology and chronic health evaluation II (APACHE II) score were valuable in predicting the occurrence of AKI. SII may serve as a new marker in patients with sepsis.
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Lesión Renal Aguda , Sepsis , Humanos , Pronóstico , Polipéptido alfa Relacionado con Calcitonina , Estudios Retrospectivos , Sepsis/complicaciones , Curva ROC , Lesión Renal Aguda/complicacionesRESUMEN
Intermolecular interactions between drug and co-former are crucial in the formation, release and physical stability of co-amorphous system. However, the interactions remain difficult to investigate with only experimental tools. In this study, intermolecular interactions of co-amorphous curcumin-piperine (i.e., CUR-PIP CM) during formation, dissolution and storage were explored by integrating experimental and modeling techniques. The formed CUR-PIP CM exhibited the strong hydrogen bond interaction between the phenolic OH group of CUR and the CO group of PIP as confirmed by FTIR, ss 13C NMR and molecular dynamics (MD) simulation. In comparison to crystalline CUR, crystalline PIP and their physical mixture, CUR-PIP CM performed significantly increased dissolution accompanied by the synchronized release of CUR and PIP, which arose from the greater interaction energy of H2O-CUR molecules and H2O-PIP molecules than CUR-PIP molecules, breaking the hydrogen bond between CUR and PIP molecules, and then causing a pair-wise solvation of CUR-PIP CM at the molecular level. Furthermore, the stronger intermolecular interaction between CUR and PIP was revealed by higher binding energy of CUR-PIP molecules, which contributed to the excellent physical stability of CUR-PIP CM over amorphous CUR or PIP. The study provides a unique insight into the formation, release and stability of co-amorphous system from MD perspective. Meanwhile, this integrated technique can be used as a practical methodology for the future design of co-amorphous formulations.
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Benzodioxoles , Curcumina , Estabilidad de Medicamentos , Enlace de Hidrógeno , Simulación de Dinámica Molecular , Piperidinas , Alcamidas Poliinsaturadas , Solubilidad , Curcumina/química , Piperidinas/química , Alcamidas Poliinsaturadas/química , Benzodioxoles/química , Liberación de Fármacos , Cristalización/métodos , Espectroscopía Infrarroja por Transformada de Fourier/métodos , Química Farmacéutica/métodos , Espectroscopía de Resonancia Magnética/métodos , AlcaloidesRESUMEN
Background: Acute kidney injury (AKI) is common in patients with sepsis and may result in death. Systemic immune inflammation index (SII) is associated with kidney injury, but its predictive value for AKI in patients with sepsis remains unclear. Objective: This study aimed to explore the predictive value of SII in sepsis patients with AKI. Methods: From January 2020 to December 2022, 221 patients with sepsis treated in our hospital were retrospectively collected. The patients were divided into AKI group (n = 61) and control group (n = 160). Clinical characteristics and SII level were compared between the two groups, and the predictive value of SII for the occurrence of AKI was analysed. Results: The SII level (724.72 ± 235.50 vs. 522.38 ± 205.62, p < 0.001), the serum procalcitonin level (8.13 ± 15.52 vs. 4.52 ± 10.34 µg/L, p < 0.001), and the acute physiology and chronic health evaluation II score (14.26 ± 2.90 vs. 11.62 ± 2.26, p < 0.001) significantly increased in the AKI group compared with the control group, whereas the albumin level significantly decreased (30.60 ± 5.41 vs. 32.49 ± 5.31 g/L, p = 0.019). The receiver operating characteristic curve showed that SII was valuable in predicting AKI in patients with sepsis, with an area under the curve of 0.733 (95% confidence interval: 0.6570.810, p < 0.001). The continuous renal replacement therapy intervention rate (88.52% vs. 0.00%, p < 0.001), the intervention rate of vasoactive drugs (34.43% vs. 3.75%, p < 0.001), and the hospital mortality rate (16.39% vs. 2.50%, p < 0.001) significantly increased in the AKI group compared with the control group. Conclusions: AKI was associated with poor prognosis in patients with sepsis. SII, procalcitonin and acute physiology and chronic health evaluation II (APACHE II) score were valuable in predicting the occurrence of AKI. SII may serve as a new marker in patients with sepsis (AU)
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Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Anciano , Lesión Renal Aguda/sangre , Lesión Renal Aguda/patología , Inflamación , Sepsis , Valor Predictivo de las Pruebas , Estudios RetrospectivosRESUMEN
The industrial Internet of Things (IIoT) environment involves multiple production items, such as robots and automated guided vehicles (AGVs), among others. The practical industrial scenario requires communication of production items while also considering mobile recognition and positioning. Hence the perception approach requires not only combining communications but also realizing the recognition and positioning of multiple communication cells. This Letter proposes a multi-optical cell recognition and positioning framework based on LED image features. The LED images are obtained by a CMOS image sensor. This framework utilizes convolutional neural networks (CNN) to train LED images for recognition between multiple optical cells and locates precise positions through region recognition within the optical cells. The experimental results show that the mean accuracy of the CNN model for two LED cells is above 99%, and the mean accuracy of region recognition within the optical cell is as high as 100%, which is significantly better than other traditional recognition algorithms. Therefore, the proposed framework can provide location-aware services for visible light communication and has a wide application prospect in IIoT.
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In the current visible light communication (VLC) system, a condenser lens is generally used in the front of receiver to achieve a higher data rate, making an extremely narrow field-of-view for the receiver. With the spread of Industrial Internet of Things (IIoT), the communication between mobile terminals is urgently required. A wide-range detecting method for VLC system in IIoT scenario is asked. In this paper, a novel self-adaptive wide-FoV receiver involving reconfigurable intelligent surfaces (RIS) is proposed. The effective detecting range of the receiver can be expanded by dynamically adjusting the incident light directions with the assistance of RIS. Based on the maximum arrived flux criterion, the mathematical model is established and the optimized RIS parameter tuning algorithm is presented. The feasibility and validity of the method are verified by simulation. The results show that the tolerable transceiver offset can be increased to 2â¼4 times as the conventional receiver.
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Solid dispersion (SD) system has been used as an effective formulation strategy to increase in vitro and in vivo performances of poorly water-soluble drugs, such as solubility/dissolution, stability and bioavailability. This review provides a comprehensive SD classification and identifies the most popular amorphous solid dispersions (ASDs). Meanwhile, this review further puts forward the systematic design strategy of satisfactory ASDs in terms of drug properties, carrier selection, preparation methods and stabilization mechanisms. In addition, hot melt extrusion (HME) as the continuous manufacturing technique is described including the principle and structure of HME instrument, key process parameters and production application, in order to guide the scale-up of ASDs and develop more ASD products to the market in pharmaceutical industry.
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Química Farmacéutica , Tecnología de Extrusión de Fusión en Caliente , Química Farmacéutica/métodos , Composición de Medicamentos/métodos , Calor , SolubilidadRESUMEN
Lung inflammation indicated by 18F-labeled fluorodeoxyglucose (FDG) in patients with tuberculosis is associated with disease severity and relapse risk upon treatment completion. We revealed the heterogeneity and intercellular crosstalk in lung tissues with 18F-FDG avidity and adjacent uninvolved tissues from 6 tuberculosis patients by single-cell RNA-sequencing. Tuberculous lungs had an influx of regulatory T cells (Treg), exhausted CD8 T cells, immunosuppressive myeloid cells, conventional DC, plasmacytoid DC, and neutrophils. Immune cells in inflamed lungs showed general up-regulation of ATP synthesis and interferon-mediated signaling. Immunosuppressive myeloid and Treg cells strongly displayed transcriptions of genes related to tuberculosis disease progression. Intensive crosstalk between IL4I1-expressing myeloid cells and Treg cells involving chemokines, costimulatory molecules, and immune checkpoints, some of which are specific in 18F-FDG-avid lungs, were found. Our analysis provides insights into the transcriptomic heterogeneity and cellular crosstalk in pulmonary tuberculosis and guides unveiling cellular and molecular targets for tuberculosis therapy.
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Context: Peripherally inserted central catheters (PICCs) have a high incidence of catheter occlusion, but research exploring the risk factors for such an occlusion for patients in intensive care units (ICUs) is lacking. Objective: The study intended to examine the impact of multiple risk factors on the occurrence of PICC catheter occlusion to find evidence that can help clinical medical staff identify patients at an early stage who are at high risk of a catheter occlusion. Design: The research team performed a retrospective, observational clinical study. Setting: The study took place at a tertiary general hospital, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University in Wenzhou, China. Participants: Participants were 300 patients with a PICC who received treatment in the hospital's adult ICU between January 2019 and April 2022. Groups: According to the time of catheterization, the research team numbered the 1~300 participants and then selected one starting number to divided them into two groups according to the random number table. These two groups were: (1) a training group with 225 participants and (2) validation group with 75 participants. Outcome Measures: The main outcome measure was the evaluation of the factors impacting patients who had had a PICC occlusion during catheter retention, including complete and incomplete occlusions, to build a risk prediction model of PICC occlusion. A secondary outcome measure was the occurrence of extubation of the PICC discharge of the ICU patient. The research team performed a univariate analysis of the training group's data and a multivariate logistic regression analysis of the risk factors. The team: (1) built a risk prediction model of PICC occlusion using the independent risk factors for catheter occlusion for PICC patients in an ICU and (2) used the Hosmer-Lemeshow goodness-of-fit test to test the prediction model. A two tailed using p>0.05 indicated that the model had a good fit. Then, the team applied the model to the validation group and evaluated the model's predictive ability using a receiver operating characteristic (ROC) curve. The team considered an area under the curve (AUC) >0.5 to have predictive value. The larger the area was, the better the predicted value was. The incidence of PICC occlusion in the training group was 18.22%, including 10 participants with complete occlusion and 31 with partial occlusion. The team used the SPSS 22.0 and R software for statistical analysis. Results: The univariate analysis showed that 13 factors were associated with PICC occlusion, including: (1) an age ≥65 years (P < .001), a BMI of ≥24 kg/m2 (P < .001), (2) a BMI of ≥24kg/m2 (P = .002), (3) diabetes (P < .001), (4) stroke (P < .001), (5) hypertension (P < .001), (6) malignant tumors (P < .001), (7) a history of deep vein thrombosis (P < .001), (8) limb activity (P < .001), (10) flushing and sealing pipe frequency of Q8h (P = .035), (11) retention time (P < .001), (12) an increased platelet count (P = .036), (13) blood transfusions (P < .001), and (14) intravenous nutrition (P < .001). The independent risk factors for PICC occlusion included: (1) age ≥65 years-OR=1.224, P = .028; (2) BMI ≥24 kg/m2-OR=1.679, P = .004; (3) diabetes-OR=1.343, P = .017; (4) malignant tumors-OR=2.736, P < .001; (5) blood transfusions-OR=1.947, P < .001), and (6) intravenous nutrition-OR=2.021, P < .001. The frequency of flushing and sealing the pipe (Q8h)-OR=-2.145, P = .002-was a protective factor. In the training group, the area under the curve (AUC) for predicting a PICC occlusion was 0.917. The Hosmer-Lemeshow test of the prediction model showed that no significant differences existed in the test results within the model (χ2 = 5.830, P = .666), indicating that the model passed the internal validation. The ideal and calibration curves of the prediction model were highly coincident, and the model was well calibrated. The Hosmer-Lemeshow test of the validation group showed that no significant differences existed in the test results outside the model, suggesting that the model had high consistency. Conclusions: Age ≥65 years, BMI ≥24 kg/m2, diabetes, malignant tumors, blood transfusions, and intravenous nutrition were independent risk factors for PICC occlusion, while the frequency of flushing and sealing pipe (Q8h) was a protective factor. This prediction model had an outstanding ability to discriminate in identifying patients with a high-risk of PICC occlusion in the ICU.
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Cateterismo Venoso Central , Diabetes Mellitus , Neoplasias , Anciano , Humanos , Cateterismo Venoso Central/efectos adversos , Unidades de Cuidados Intensivos , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Jump and pull-in instability are common nonlinear dynamic behaviors leading to the loss of the performance reliability and structural safety of electrostatic micro gyroscopes. To achieve a better understanding of these initial-sensitive phenomena, the dynamics of a micro gyroscope system considering the nonlinearities of the stiffness and electrostatic forces are explored from a global perspective. Static and dynamic analyses of the system are performed to estimate the threshold of the detecting voltage for static pull-in, and dynamic responses are analyzed in the driving and detecting modes for the case of primary resonance and 1:1 internal resonance. The results show that, when the driving voltage frequency is a bit higher than the natural frequency, a high amplitude of the driving AC voltage may induce the coexistence of bistable periodic responses due to saddle-node bifurcation of the periodic solution. Basins of attraction of bistable attractors provide evidence that disturbance of the initial conditions can trigger a jump between bistable attractors. Moreover, the Melnikov method is applied to discuss the condition for pull-in instability, which can be ascribed to heteroclinic bifurcation. The validity of the prediction is verified using the sequences of safe basins and unsafe zones for dynamic pull-in. It follows that pull-in instability can be caused and aggravated by the increase in the amplitude of the driving AC voltage.
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It has been shown that dexmedetomidine (Dex) could attenuate postoperative cognitive dysfunction (POCD) via targeting circular RNAs (circRNAs). Circ-Shank3 has been found to be involved in the neuroprotective effects of Dex against POCD. However, the role of circ-Shank3 in POCD remains largely unknown. Reverse transcription quantitative PCR (RT-qPCR) was performed to detect circ-Shank3 and miR-140-3p levels in lipopolysaccharide (LPS)-treated microglia BV-2 cells in the absence or presence of Dex. The relationship among circ-Shank3, miR-140-3p and TLR4 was confirmed by dual-luciferase reporter assay. Additionally, Western blot and immunofluorescence (IF) assays were conducted to evaluate TLR4, p65 and Iba-1 or CD11b levels in cells. In this study, we found that Dex notably decreased circ-Shank3 and TLR4 levels and elevated miR-140-3p level in LPS-treated BV2 cells. Mechanistically, circ-Shank3 harbor miR-140-3p, functioning as a miRNA sponge, and then miR-140-3p targeted the 3'-UTR of TLR4. Additionally, Dex treatment significantly reduced TLR4 level and phosphorylation of p65, and decreased the expressions of microglia markers Iba-1 and CD11b in LPS-treated BV2 cells. As expected, silenced circ-Shank3 further reduced TLR4, p65 and Iba-1 and CD11b levels in LPS-treated BV2 cells in the presence of Dex, whereas these phenomena were reversed by miR-140-3p inhibitor. Collectively, our results found that Dex could attenuate the neuroinflammation and microglia activation in BV2 cells exposed to LPS via targeting circ-Shank3/miR-140-3p/TLR4 axis. Our results might shed a new light on the mechanism of Dex for the treatment of POCD.
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Dexmedetomidina , MicroARNs , Humanos , Enfermedades Neuroinflamatorias , Dexmedetomidina/farmacología , Dexmedetomidina/uso terapéutico , Lipopolisacáridos/farmacología , Microglía , Receptor Toll-Like 4 , MicroARNs/genética , Proliferación Celular , ApoptosisRESUMEN
OBJECTIVES: Our aims were to better understand the interplay of diet and gut microbiota in Crohn's disease [CD], taking advantage of a new-onset treatment-naïve CD cohort. We focus on phenylacetylglutamine [PAGln], a diet-derived meta-organismal prothrombotic metabolite. DESIGN: We collected faecal and serum samples from a CD cohort [nâ =â 136] and healthy controls [nâ =â 126] prior to treatment, and quantified serum PAGln using LC-MS/MS. Diet was assessed using food-frequency questionnaires. Mice [C57BL/6] were fed high/low-protein diets and administered dextran sodium sulphate [DSS] to examine plasma PAGly, thrombosis potential, and colitis severity. PAGly or saline was administered to DSS-induced colitis mice, and colitis severity and colonic tissue gene expression were examined. P-selectin and CD40L expression were determined in human platelet-rich plasma [nâ =â 5-6] after exposure to platelet agonists following PAGln priming. Bioinformatic analysis and bacterial culturing identified the main contributor of PAGln in CD. RESULTS: PAGln, a meta-organismal prothrombotic metabolite, is associated with CD. Administration of PAGly exacerbated colitis in a mouse model and upregulated coagulation-related biological processes. Antiplatelet medicine, dipyridamole, attenuated PAGly-enhanced colitis susceptibility. PAGln enhanced platelet activation and CD40L expression in platelet-rich plasma ex vivo. Further study revealed that high dietary protein intake and increased abundance of phenylacetic acid [PAA]-producing Proteobacteria mediated by phenylpyruvate decarboxylase act in concert to cause the elevated PAGln levels in CD patients. CONCLUSION: Taken together, ppdc-carrying Proteobacteria-generated PAGln from dietary protein is associated with CD and exacerbates colitis possibly via platelet-induced coagulation and inflammation These results suggest that PAGln is a potential early diagnostic marker and therapeutic target of CD.