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Inflammatory bowel diseases (IBD) are chronic inflammatory disorders affecting the digestive tract, including ulcerative colitis and Crohn's disease. Ruscogenin, a prominent steroidal sapogenin present in radix ophiopogon japonicus, has shown a protective effect on attenuating the inflammatory response associated with inflammatory diseases, but the efficacy of ruscogenin in IBD remains unclear. The aim of this study is to explore the effect of ruscogenin on intestinal barrier dysfunction and inflammatory responses as well as the underlying mechanism in ulcerative colitis. A dextran sulfate sodium salt (DSS)-induced C57BL/6 mouse colitis model was employed for the in vivo studies, while in vitro experiments were performed in THP-1 cells and human intestinal epithelial cells involved in inducing inflammatory responses and pyroptosis using LPS/nigericin. The results indicated that ruscogenin treatment attenuated the symptoms of ulcerative colitis, reduced the release of inflammatory cytokines and the expression of pyroptosis-associated proteins, and restored the integrity of the intestinal epithelial barrier in colon tissue in mice. Moreover, ruscogenin inhibited LPS/nigericin-induced pyroptosis in THP-1 cells. Mechanically, ruscogenin inhibited NLRP3 inflammasome activation and canonical pyroptosis, at least in part, through the suppression of the TLR4/NF-κB signaling pathway. These findings might provide new insights and a solid foundation for further exploration into the therapeutic potential of ruscogenin in the treatment of IBD. [ABSTRACT FROM AUTHOR]

Background: Observational studies have indicated associations between inflammatory bowel disease (IBD) and neurodegenerative diseases, including Parkinson's disease (PD). Objective: To evaluate the causal associations of IBD with PD and other selected neurodegenerative disorders using updated data. Methods: Bidirectional two‐sample Mendelian randomization studies using genome‐wide association studies summary statistics of IBD and PD. Results: We found a lack of evidence for the causal association of IBD on PD (odds ratio [OR], 1.014; 95% confidence interval [CI], 0.967–1.063; P = 0.573). Reverse analysis also indicated no evidence of a causal effect for PD on IBD (OR, 0.978; 95% CI, 0.910–1.052; P = 0.549). The causality between IBD and Alzheimer's disease, amyotrophic lateral sclerosis, and multiple sclerosis was unfounded (all P > 0.05). Conclusions: The updated analyses provide no clear evidence for causal associations of IBD with PD or the other three neurodegenerative diseases. Potential confounders might contribute to the previously observed associations, and further investigations are warranted. © 2023 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

The coronavirus disease 2019 (COVID‐19) pandemic has led to a fundamental number of morbidity and mortality worldwide. Glucosamine was indicated to help prevent and control RNA virus infection preclinically, while its potential therapeutic effects on COVID‐19‐related outcomes are largely unknown. To assess the association of habitual glucosamine use with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection, hospital admission, and mortality with COVID‐19 in a large population based cohort. Participants from UK Biobank were reinvited between June and September 2021 to have SARS‐CoV‐2 antibody testing. The associations between glucosamine use and the risk of SARS‐CoV‐2 infection were estimated by logistic regression. Hazard ratios (HRs) and 95% confidence intervals (CIs) for COVID‐19‐related outcomes were calculated using COX proportional hazards model. Furthermore, we carried out propensity‐score matching (PSM) and stratified analyses. At baseline, 42 673 (20.7%) of the 205 704 participants reported as habitual glucosamine users. During median follow‐up of 1.67 years, there were 15 299 cases of SARS‐CoV‐2 infection, 4214 cases of COVID‐19 hospital admission, and 1141 cases of COVID‐19 mortality. The fully adjusted odds ratio of SARS‐CoV‐2 infection with glucosamine use was 0.96 (95% CI: 0.92–1.01). The fully adjusted HR were 0.80 (95% CI: 0.74–0.87) for hospital admission, and 0.81 (95% CI: 0.69–0.95) for mortality. The logistic regression and Cox proportional hazard analyses after PSM yielded consistent results. Our study demonstrated that habitual glucosamine use is associated with reduced risks of hospital admission and death with COVID‐19, but not the incidence of SARS‐CoV‐2 infection. [ABSTRACT FROM AUTHOR]

Ulcerative colitis is a chronic inflammatory bowel disorder that is hard to cure once diagnosed. Bisdemethoxycurcumin has shown positive effects on inflammatory diseases. However, the underlying bioactive interaction between bisdemethoxycurcumin and ulcerative colitis is unclear. The objective of this study was to determine the core target and potential mechanism of action of bisdemethoxycurcumin as a therapy for ulcerative colitis. The public databases were used to identify potential targets for bisdemethoxycurcumin and ulcerative colitis. To investigate the potential mechanisms, the protein-protein interaction network, gene ontology analysis, and Kyoto encyclopedia of genes and genomes analysis have been carried out. Subsequently, experimental verification was conducted to confirm the findings. A total of 132 intersecting genes of bisdemethoxycurcumin, as well as ulcerative coli-tis-related targets, were obtained. SRC, EGFR, AKT1, and PIK3R1 were the targets of highest potential, and the PI3K/Akt and MAPK pathways may be essential for the treatment of ulcerative colitis by bisdemethoxycurcumin. Molecular docking demonstrated that bisdemethoxycurcumin combined well with SRC, EGFR, PIK3R1, and AKT1. Moreover, the in vitro experiments suggested that bisdemethoxycurcumin might reduce LPS-induced pro-inflammatory cytokines levels in RAW264.7 cells by suppressing PI3K/Akt and MAPK pathways. Our study provided a comprehensive overview of the potential targets and molecular mechanism of bisdemethoxycurcumin against ulcerative colitis. Furthermore, it also provided a theoretical basis for the clinical treatment of ulcerative colitis, as well as compelling evidence for further study on the mechanism of bisdemethoxycurcumin in the treatment of ulcerative colitis. [ABSTRACT FROM AUTHOR]

As asymmetric interior permanent magnet synchronous motor (AIPMSM) has excellent performance but complicated topological structure, a novel high-resolution encoding and edge smoothing method is proposed for topology optimization of the asymmetric rotor of interior permanent magnet synchronous motor (IPMSM) in this study. This method aims to solve complex electromagnetic design problems with time-dependent performance through a multi-objective genetic algorithm (MOGA) integrated with a high-resolution encoding and edge smoothing method. The complex structure is represented by a high-resolution image-like matrix and then vectorized by the edge smoothing method. Therefore, the commonly used discrete binary encoded variables related to the finite element (FE) model are replaced with a vectorized topological structure and other control variables. In this sense, high-resolution matrix and edge smoothing methods are used for the first time to represent the rotor topology of AIPMSMs. Compared with the traditional topology optimization method, the proposed method has the advantage of expressing more complex and vectorized topological structures; meanwhile, the obtained performance is accurate and trustworthy using conventional FE simulation. Numerical results show that a stable convergence is achieved with the avoidance of checkerboards and material overlapping. It is shown that the proposed method can find solutions with better performances, in comparison with the reference model. [ABSTRACT FROM AUTHOR]

The demand for fast magnetic field approximation for the optimal design of electromagnetic devices is urgent nowadays. However, due to the lack of a publicly available dataset and the unclear definition of each parameter in the magnetic field dataset, the expansion of data-driven magnetic field approximation is severely limited. This study presents a physics-informed generative adversarial network (PIGAN), as well as a permanent magnet linear synchronous motor (PMLSM)-based magnetic field dataset, for fast magnetic field approximation. It includes the current density, material distribution, electromagnetic material properties, and other parameters of the electric machine. Physics-informed loss functions are utilized in the training process, making the output governed by Maxwell's equation. Different slot-pole combinations of the PMLSM are involved in the dataset to extend the generalization of PIGAN. Some indicators for the further evaluation of magnetic approximation performance, including image-based metrics and calculation methods for the performance of electric motors, are presented in this study. Some challenges of magnetic field approximation using PIGAN are also discussed. The effectiveness of the physics-informed method is verified by comparing the magnetic field approximation results and the performance analysis results of the PMLSM with FEM, and the speed of PIGAN is approximately 40 times faster than that of FEM, while the accuracy is similar. [ABSTRACT FROM AUTHOR]

In this work, a novel general pattern of assisted flux barriers in an asymmetric V-shape interior permanent magnet (AVIPM) machine is presented. The AVIPM machine has a symmetric permanent magnet (PM) structure and an asymmetric rotor core structure to realize the magnetic-field-shifting (MFS) effect. The general pattern can represent four possible types of assisted flux barriers at different positions on the rotor core and the final structure can be automatically determined by using optimization method. The advantage of the proposed optimization pattern is that the optimal design of assisted flux barriers in V-shape interior permanent magnet (VIPM) machines with high torque and low torque ripple can be generated within a short computing time. The proposed optimization method is applied to improve the structure of a conventional 8-pole 48-slot VIPM machine, which is commonly used for driving electric vehicles (EVs). A non-dominated sorting genetic algorithm II (NSGA-II) is used for the global optimization of both a VIPM machine and an AVIPM machine. The electromagnetic performance is computed using a finite element analysis (FEA). Moreover, a frozen permeability (FP) method is applied to perform an accurate separation of PM torque and reluctance torque. The results exhibit that the peak output torque of the AVIPM machine is increased by 8.7% compared to a conventional VIPM machine with the same PM volume due to the notable MFS effect. In the meantime, the AVIPM machine has a better overload capability due to the larger contribution of reluctance torque. Moreover, the proposed machine has high efficiency of over 97%. [ABSTRACT FROM AUTHOR]

Purpose: To compare the treatment zone (TZ) measurements obtained using manual and software‐based methods in orthokeratology (ortho‐k) subjects and explore the TZ characteristics of children with slow and fast axial elongation after ortho‐k. Methods: Data from 69 subjects (aged 7 to <13 years old), who participated in three 24‐month longitudinal orthokeratology studies, showing fast (>0.27 mm, n = 38) and slow (<0.09 mm, n = 31) axial elongation, were retrieved. The TZ after ortho‐k was defined as the central flattened area enclosed by points with no refractive power change. TZ parameters, including decentration, size, width of the peripheral steepened zone (PSZ), central and peripheral refractive power changes and peripheral rate of power change, were determined manually and using python‐based software. TZ parameters were compared between measurement methods and between groups. Results: Almost all TZ parameters measured manually and with the aid of software were significantly different (p < 0.05). Differences in decentration, size and the PSZ width were not clinically significant, but differences (0.45 to 0.92 D) in refractive power change in the PSZ were significant, although intraclass coefficients (0.95 to 0.98) indicated excellent agreement between methods. Significantly greater TZ decentration, smaller TZ size and greater inferior rate of power change (relative to the TZ centre) were observed in slow progressors using both methods, suggesting a potential role of TZ in regulating myopia progression in ortho‐k. Conclusion: TZ measurements using manual and software‐based methods differed significantly and cannot be used interchangeably. The combination of TZ decentration, TZ size and peripheral rate of power change may affect myopia control effect in ortho‐k. [ABSTRACT FROM AUTHOR]

Esophageal adenocarcinoma (EAC) is a highly malignant type of digestive tract cancers with a poor prognosis despite therapeutic advances. Pyroptosis is an inflammatory form of programmed cell death, whereas the role of pyroptosis in EAC remains largely unknown. Herein, we identified a pyroptosis-related five-gene signature that was significantly correlated with the survival of EAC patients in The Cancer Genome Atlas (TCGA) cohort and an independent validation dataset. In addition, a nomogram based on the signature was constructed with novel prognostic values. Moreover, the downregulation of GSDMB within the signature is notably correlated with enhanced DNA methylation. The pyroptosis-related signature might be related to the immune response and regulation of the tumor microenvironment. Several inhibitors including GDC-0879 and PD-0325901 are promising in reversing the altered differentially expressed genes in high-risk patients. Our findings provide insights into the involvement of pyroptosis in EAC progression and are promising in the risk assessment as well as the prognosis for EAC patients in clinical practice. [ABSTRACT FROM AUTHOR]

Emerging evidence suggested that mitophagy may play an important role in the progression of hepatocellular carcinoma (HCC), whereas the association between mitophagy-related genes and HCC patients' prognosis remains unknown. In this study, we aimed to investigate the potential prognostic values of mitophagy-related genes (MRGs) on HCC patients at the genetic level. According to median immunoscore, we categorized HCC patients from TCGA cohort into two immune score groups, while 39 differential expression MRGs were identified. By using univariate analysis, we screened out 18 survival-associated MRGs, and then, the least absolute shrinkage and selection operator (LASSO) analysis was applied to construct a prognosis model that consisted of 9 MRGs (ATG7, ATG9A, BNIP3L, GABARAPL1, HTRA2, MAP1LC3B2, TFE3, TIGAR, and TOMM70). In our prognostic model, overall survival in the high and low-risk groups was significantly different P < 0.001 , and the respective areas under the curve (AUC) of our prognostic model were 0.686 for 3-year survival in the TCGA cohort and 0.776 for 3-year survival in the ICGC cohort. Moreover, we identified the risk score as the independent factor for predicting the HCC patients' prognosis by using single and multifactor analyses, and a nomogram was also constructed for future clinical application. Further functional analyses showed that the immune status between two risk groups was significantly different. Our findings may provide a novel mitophagy-related gene signature, and these will be better used for prognostic prediction in HCC, thus improving patient outcome. [ABSTRACT FROM AUTHOR]

In the past decade, the study of extracellular vesicles (EVs), especially exosomes (50–150 nm) have attracted growing interest in numerous areas of cancer and tissue regeneration due to their unique biological features. A low isolation yield and insufficient targeting abilities limit their therapeutic applicability. Recently, superparamagnetic iron oxide nanoparticles (SPIONs) with magnetic navigation have been exploited to enhance the targeting ability of EVs. To construct targeted EV delivery systems engineered by SPIONs, several groups have pioneered the use of different techniques, such as electroporation, natural incubation, and cell extrusion, to directly internalize SPIONs into EVs. Furthermore, some endogenous ligands, such as transferrins, antibodies, aptamers, and streptavidin, were shown to enable modification of SPIONs, which increases binding with EVs. In this review, we summarized recent advances in targeted EV delivery systems engineered by SPIONs and focused on the key methodological approaches and the current applications of magnetic EVs. This report aims to address the existing challenges and provide comprehensive insights into targeted EV delivery systems. Targeted extracellular vesicle (EV) delivery systems engineered by superparamagnetic iron oxide nanoparticles (SPIONs) have attracted wide attention and research interest in recent years. Such strategies employ external magnet fields to manipulate SPION-functionalized EVs remotely, aiming to enhance their accumulation and penetration in vivo. Although iron oxide nanoparticle laden EVs are interesting, they are controversial at present, hampering the progress in their clinical application. A thorough integration of these studies is needed for an advanced insight and rational design of targeted EV delivery systems. In this review, we summarize the latest advances in the design strategies of targeted EV delivery systems engineered by SPIONs with a focus on their key methodological approaches, current applications, limitation and future perspectives, which may facilitate the development of natural theranostic nanoplatforms. [Display omitted] [ABSTRACT FROM AUTHOR]

In this article, a novel pre-processing method is proposed for magnetic field approximation based on neural networks. The process of calculating magnetic fields based on neural networks is presented first. In order to save the training time and reduce the estimation error, an excitation distance function, which is inspired by an analytical formula of magnetic potential, is proposed to integrate the input data, such as the geometry, excitations, and boundaries. This pre-processing or roughly reduces the dimension of the input layer by three quarters, while the training process is accelerated by a more integrated input layer. Preliminary experiments show that the predicted results by the proposed pre-processing method are close to the ground truth, with a significant reduction of computation time compared with the traditional finite element method (FEM). [ABSTRACT FROM AUTHOR]

This study proposes a novel power supply system that utilises wind power to produce AC and DC power. A special designed generator based on bidirectional flux modulation effect is the key part of the proposed power supply system. The novel power system has a compact structure since the proposed generator has two electric port. There are three essential points that make the proposed system outstanding. One is the contra‐rotating rotors, which will cluster wind power even under low wind speed. Second one is the dual armature winding structure, which will provide AC and DC power simultaneously. There are two electric port in the proposed generator. One port can produce AC power to the non‐sensitive resistive load. The other can provide AC power with different frequency to the rectifier to obtain DC power. The induced voltage due to flux modulation effect can be used to offer AC power, and the induced voltage due to the outer rotor can be used to offer DC power. The voltage frequency of two sets windings is different. The last one is the air gap flux rotation speed amplification due to flux modulation effect. Time stepping finite element method is used to analyse the dynamic performance of the proposed machine. [ABSTRACT FROM AUTHOR]

In this article, an adaptive degrees-of-freedom (DoFs) finite-element method (FEM) is presented to solve the 3-D transient magnetic problems. For time-dependent problems, the error distribution changes over time, and hence mesh coarsening is needed in some regions to keep the number of DoFs small. In this novel h-type adaptive FEM, real mesh coarsening is replaced by an implicit elimination of DoFs, which avoids the following operations after mesh coarsening and the interpolation errors from fine mesh to coarse mesh. The DoFs to be eliminated are constrained by interpolation functions, which are formulated by the master DoFs. To adapt to the 3-D field, a constraint with a variable number of master DoFs and rational coefficients is adopted. The constraints are then integrated into the finite-element (FE) equation in the element level using the slave–master technique, which is followed by a global assembly process. After solving the global FE equation, the solution of constrained DoFs can be recovered from the solution of master DoFs. Several transient problems are computed to showcase the effectiveness of this proposed method. [ABSTRACT FROM AUTHOR]

As an innovative approach to improve the cooling efficiency of fluid, the use of nanofluids has attracted increasing attention in engineering applications. In this paper, the impact on the natural convective heat transfer in disc-type transformer windings due to transformer oil-based nanofluids is studied numerically. A low-voltage winding using nanofluid (SiC/oil) as the coolant is modelled two-dimensionally and simulated by computational fluid dynamics and the multi-phase mixture model. The numerical method is validated with the existing results of transformers using conventional oil cooling, and grid-independence study is carried out for the nanofluid flow. Compared with transformer oil cooling, the temperature of nanofluid cooled winding is significantly reduced, while the temperature trend along the flow direction remains essentially the same. Moreover, the effects of nanofluid on the mass flow rate and the coolant temperature have been taken into consideration in the heat transfer analysis. [ABSTRACT FROM AUTHOR]

An adaptive degrees-of-freedom finite element method (FEM) for 3-dimensional nonlinear magneto-thermal fields is proposed in this article. Both magnetic field and thermal field are discretized using a single FEM mesh, and their degrees of freedom (DoFs) are individually controlled based on the field characteristics. Before solving the algebraic equations, the constrained DoFs are removed using the slave-master technique. The computing time and the storage resources of the second set of FEM mesh are saved while meeting the different requirements on discretization. Data transfer between the thermal and magnetic fields are easily implemented, and mapping errors between different meshes are avoided. To showcase the feasibility and the effectiveness of this method, several numerical examples are tested. [ABSTRACT FROM AUTHOR]

Radiation-induced intestinal injury (RIII) frequently occurs during radiotherapy; however, methods for treating RIII are limited. Ginsenoside Rk1 (RK1) is a substance that is derived from ginseng, and it has several biological activities, such as antiapoptotic, antioxidant and anticancer activities. The present study was designed to investigate the potential protective effect of Rk1 on RIII and the potential mechanisms. The results showed that RK1 treatment significantly improved the survival rate of the irradiated rats and markedly ameliorated the structural injury of the intestinal mucosa observed by histology. Treatment with RK1 significantly alleviated radiation-induced intestinal epithelial cell oxidative stress apoptosis. Moreover, RNA-Seq identified 388 differentially expressed genes (DEGs) and showed that the PI3K-AKT pathway might be a key signaling pathway by which RK1 exerts its therapeutic effects on RIII. The western blotting results showed that the p-PI3K, p-AKT and p-mTOR expression levels, which were increased by radiation, were markedly inhibited by Rk1, and these effects were reversed by IGF-1. The present study demonstrates that Rk1 can alleviate RIII and that the mechanism underlying the antiapoptotic effects of RK1 may involve the suppression of the PI3K/Akt/mTOR pathway. This study provides a promising therapeutic agent for RIII. • Ginsenoside Rk1 ameliorates radiation-induced oxidative stress and apoptosis. • PI3K-AKT might be a key signaling pathway in radiation induced apoptosis. • Providing a promising therapeutic agent for radiation-induced intestinal injury. [ABSTRACT FROM AUTHOR]

For the past two decades, dispute on whether proton pump inhibitor (PPI) leads to digestive tract cancer remains, and emerging studies in recent years still demonstrate inconsistent results, which continues to perpetuate concerns over the safety of PPI use. We performed a systematic review and meta-analysis, with comprehensive evaluation by Bradford Hill criteria of causation, to assess the effect of PPI use on digestive tract cancers. Medline, Embase and Web of Science databases were searched for observational studies published up to 15th January 2021. Pooled relative risks (RRs) were estimated via random effects models. Cumulative defined daily dose- and duration-risk relationships using restricted cubic spline and fractional polynomial models were investigated. Bradford Hill criteria were applied to evaluate causation. PROSPERO Registration: CRD42020211103. Thirty-two publications containing 4,355,254 participants were included. PPI use is associated with an increased risk of overall digestive tract cancers (RR = 1.63, 95% confidence interval (CI) 1.33 to 2.00). PPI use is correlated with increased risks of gastric cancer (RR = 1.78, 95% CI 1.38 to 2.31), pancreatic cancer (RR = 1.72, 95% CI 1.05 to 2.82) and liver cancer (RR = 1.62, 95% CI 1.04 to 2.52), but not of esophageal cancer (RR = 2.06, 95% CI 0.65 to 6.57) and colorectal cancer (RR = 1.24, 95% CI 0.93 to 1.66). The association between PPI and digestive tract cancers is stronger in people with minimal exposure. When cumulative defined daily dose or duration increases, the risks decline and become non-significant. Evaluation by Bradford Hill criteria indicates weak evidence of causation. A causal relationship between PPI use and digestive tract cancers is not supported by the evidence in the current review. Concerns over carcinogenic side-effects of PPI might be unfounded. • Thirty-two studies containing 4.3 million participants are included. • Correlation is evaluated by dose-response analysis and Bradford Hill Criteria. • The risks are non-significant in the highest dose or duration of PPI use. • The causality between PPI use and digestive tract cancers might not be supported. • Dose-response analysis and Bradford Hill Criteria are recommended for interpretation. [ABSTRACT FROM AUTHOR]

Background: Adverse effects of proton pump inhibitors (PPIs) have raised wide concerns. The association of PPIs with influenza is unexplored, while that with pneumonia or COVID-19 remains controversial. Our study aims to evaluate whether PPI use increases the risks of these respiratory infections., Methods: The current study included 160,923 eligible participants at baseline who completed questionnaires on medication use, which included PPI or histamine-2 receptor antagonist (H2RA), from the UK Biobank. Cox proportional hazards regression and propensity score-matching analyses were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs)., Results: Comparisons with H2RA users were tested. PPI use was associated with increased risks of developing influenza (HR 1.32, 95% CI 1.12-1.56) and pneumonia (hazard ratio [HR] 1.42, 95% confidence interval [CI] 1.26-1.59). In contrast, the risk of COVID-19 infection was not significant with regular PPI use (HR 1.08, 95% CI 0.99-1.17), while the risks of severe COVID-19 (HR 1.19. 95% CI 1.11-1.27) and mortality (HR 1.37. 95% CI 1.29-1.46) were increased. However, when compared with H2RA users, PPI users were associated with a higher risk of influenza (HR 1.74, 95% CI 1.19-2.54), but the risks with pneumonia or COVID-19-related outcomes were not evident., Conclusions: PPI users are associated with increased risks of influenza, pneumonia, as well as COVID-19 severity and mortality compared to non-users, while the effects on pneumonia or COVID-19-related outcomes under PPI use were attenuated when compared to the use of H2RAs. Appropriate use of PPIs based on comprehensive evaluation is required., Funding: This work is supported by the National Natural Science Foundation of China (82171698, 82170561, 81300279, 81741067, 82100238), the Program for High-level Foreign Expert Introduction of China (G2022030047L), the Natural Science Foundation for Distinguished Young Scholars of Guangdong Province (2021B1515020003), the Guangdong Basic and Applied Basic Research Foundation (2022A1515012081), the Foreign Distinguished Teacher Program of Guangdong Science and Technology Department (KD0120220129), the Climbing Program of Introduced Talents and High-level Hospital Construction Project of Guangdong Provincial People's Hospital (DFJH201923, DFJH201803, KJ012019099, KJ012021143, KY012021183), and in part by VA Clinical Merit and ASGE clinical research funds (FWL)., Competing Interests: RZ, YM, LZ, DL, RJ, HW, ZZ, QY, JL, FL, CD, WS, HC No competing interests declared, (© 2024, Zeng, Ma, Zhang et al.)

Background: Recently, observational studies have reported that gastroesophageal reflux disease (GERD) is commonly associated with irritable bowel syndrome (IBS), but the causal relationship is unclear., Methods: We conducted a two-sample Mendelian randomization study using summary data from genome-wide association studies (GWASs) to explore a causal relationship between GERD (N cases = 129,080) and IBS (N cases = 4,605) of European ancestry. Furthermore, the inverse-variance weighted (IVW) method and a series of sensitivity analyses were used to assess the accuracy and confidence of our results., Results: We found a significant association of GERD with IBS (NSNP = 74; OR: 1.375; 95% CI: 1.164-1.624; p < 0.001). Reverse MR analysis showed no evidence of a causal association for IBS with GERD (NSNP = 6; OR: 0.996; 95% CI: 0.960-1.034; p = 0.845)., Conclusion: This study provides evidence that the presence of GERD increases the risk of developing IBS, and it is observed from the reverse MR results that IBS did not increase the risk of GERD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wu, Li, Li and Lun.)

Rationale: The therapeutic benefits of bilirubin in the treatment of ulcerative colitis (UC) are considerable, whereas the underlying mechanism of bilirubin on UC remains unclear remains unexplored. In addition, the weak hydrophilicity and toxicity have limited its translational applications. Methods: We have developed a colon dual-targeting nanoparticle, for orally delivering bilirubin through hydrogel encapsulation of hyaluronic acid (HA)-modified poly (lactic-co-glycolic acid) (PLGA) nanoparticles (HA-PLGA Bilirubin ). Confocal microscopy and in vivo imaging were used to evaluate the uptake and the targeted property of HA-PLGA Bilirubin in UC. Immunohistochemistry, immunofluorescence, and transcriptomic analyses were applied to examine the therapeutic effect and potential mechanism of HA-PLGA Bilirubin in UC. Results: Our results indicated that HA-PLGA bilirubin can significantly enhance the release of bilirubin at simulated intestinal pH and demonstrate higher cellular uptake in inflammatory macrophages. Moreover, in vivo biodistribution studies revealed high uptake and retention of HA-PLGA bilirubin in inflamed colon tissue of UC mouse model, resulting in effective recovery of intestinal morphology and barrier function. Importantly, HA-PLGA bilirubin exerted potent therapeutic efficacy against ulcerative colitis through modulating the intestinal epithelial/stem cells regeneration, and the improvement of angiogenesis and inflammation. Furthermore, genome-wide RNA-seq analysis revealed transcriptional reprogramming of immune response genes in colon tissue upon HA-PLGA bilirubin treatment in UC mouse model. Conclusion: Overall, our work provides an efficient colon targeted drug delivery system to potentiate the treatment of ulcerative colitis via modulating intestinal epithelium regeneration and immune response in ulcerative colitis., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Published observational studies have revealed the connection between neurodegenerative disorders and inflammatory bowel disease (IBD), whereas the causal association remains largely unclear. Our study aims to assess the causality and identify the shared genetic architecture between neurodegenerative disorders and IBD. Two-sample Mendelian randomization analyses were performed to assess the causality between IBD and neurodegenerative disorders (amyotrophic lateral sclerosis [ALS], Alzheimer's disease [AD], Parkinson's disease [PD], and multiple sclerosis [MS]). Shared genetic loci, functional interpretation, and transcriptomic profiles were further investigated in ALS and IBD. We identified that genetic predisposition to IBD was suggestively associated with lower odds of ALS (odds ratio [OR] 0.96, 95% confidence interval [CI] 0.94 to 0.99). In contrast, IBD was not genetically associated with an increased risk of AD, PD, or MS (and vice versa). Two shared genetic loci (rs6571361 and rs7154847) were derived, and SCFD1, G2E3, and HEATR5A were further identified as novel risk genes with enriched functions related to membrane trafficking. G2E3 was differentially expressed and significantly correlated with SCFD1 in patients with ALS or IBD. Our study reveals the suggestively protective role of IBD on ALS, and does not support the causality of AD, PD, or MS on IBD (and vice versa). Our findings indicate possible shared genetic architecture and pathways between ALS and IBD. These results provide insights into the pathogenesis and therapeutics of IBD and neurodegenerative disorders.

Introduction: Crohn's disease is characterized of dysregulated inflammatory and immune reactions. The role of the NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome in Crohn's disease remains largely unknown., Methods: The microarray-based transcriptomic data and corresponding clinical information of GSE100833 and GSE16879 were obtained from the Gene Expression Omnibus (GEO) database. Identification of in the NLRP3 inflammasome-related genes and construction of LASSO regression model. Immune landscape analysis was evaluated with ssGSEA. Classification of Crohn's-disease samples based on NLRP3 inflammasome-related genes with ConsensusClusterPlus. Functional enrichment analysis, gene set variation analysis (GSVA) and drug-gene interaction network., Results: The expressions of NLRP3 inflammasome-related genes were increased in diseased tissues, and higher expressions of NLRP3 inflammasome-related genes were correlated with generally enhanced immune cell infiltration, immune-related pathways and human leukocyte antigen (HLA)-gene expressions. The gene-based signature showed well performance in the diagnosis of Crohn's disease. Moreover, consensus clustering identified two Crohn's disease clusters based on NLRP3 inflammasome-related genes, and cluster 2 was with higher expressions of the genes. Cluster 2 demonstrated upregulated activities of immune environment in Crohn's disease. Furthermore, four key hub genes were identified and potential drugs were explored for the treatment of Crohn's disease., Conclusions: Our findings indicate that NLRP3 inflammasome and its related genes could regulate immune cells and responses, as well as involve in the pathogenesis of Crohn's disease from transcriptomic aspects. These findings provide in silico insights into the diagnosis and treatment of Crohn's disease and might assist in the clinical decision-making process., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer HY declared a shared parent affiliation with the author, KC, to the handling editor at the time of the review., (Copyright © 2023 Wu, Zeng, Qiu, Chen, Zhuo, Guo, Xiang, Yang, Jiang, Leung, Lian, Sha and Chen.)

Ulcerative colitis is a chronic inflammatory bowel disorder that is hard to cure once diagnosed. Bisdemethoxycurcumin has shown positive effects on inflammatory diseases. However, the underlying bioactive interaction between bisdemethoxycurcumin and ulcerative colitis is unclear. The objective of this study was to determine the core target and potential mechanism of action of bisdemethoxycurcumin as a therapy for ulcerative colitis. The public databases were used to identify potential targets for bisdemethoxycurcumin and ulcerative colitis. To investigate the potential mechanisms, the protein-protein interaction network, gene ontology analysis, and Kyoto encyclopedia of genes and genomes analysis have been carried out. Subsequently, experimental verification was conducted to confirm the findings. A total of 132 intersecting genes of bisdemethoxycurcumin, as well as ulcerative coli-tis-related targets, were obtained. SRC, EGFR, AKT1, and PIK3R1 were the targets of highest potential, and the PI3K/Akt and MAPK pathways may be essential for the treatment of ulcerative colitis by bisdemethoxycurcumin. Molecular docking demonstrated that bisdemethoxycurcumin combined well with SRC, EGFR, PIK3R1, and AKT1. Moreover, the in vitro experiments suggested that bisdemethoxycurcumin might reduce LPS-induced pro-inflammatory cytokines levels in RAW264.7 cells by suppressing PI3K/Akt and MAPK pathways. Our study provided a comprehensive overview of the potential targets and molecular mechanism of bisdemethoxycurcumin against ulcerative colitis. Furthermore, it also provided a theoretical basis for the clinical treatment of ulcerative colitis, as well as compelling evidence for further study on the mechanism of bisdemethoxycurcumin in the treatment of ulcerative colitis.

Objective: Energy metabolism plays a crucial role in the improvement of heart dysfunction as well as the development of heart failure (HF). The current study is designed to identify energy metabolism-related diagnostic biomarkers for predicting the risk of HF due to myocardial infarction., Methods: Transcriptome sequencing data of HF patients and non-heart failure (NF) people (GSE66360 and GSE59867) were obtained from gene expression omnibus (GEO) database. Energy metabolism-related differentially expressed genes (DEGs) were screened between HF and NF samples. The subtyping consistency analysis was performed to enable the samples to be grouped. The immune infiltration level among subtypes was assessed by single sample gene set enrichment analysis (ssGSEA). Random forest algorithm (RF) and support vector machine (SVM) were applied to identify diagnostic biomarkers, and the receiver operating characteristic curves (ROC) was plotted to validate the accuracy. Predictive nomogram was constructed and validated based on the result of the RF. Drug screening and gene-miRNA network were analyzed to predict the energy metabolism-related drugs and potential molecular mechanism., Results: A total of 22 energy metabolism-related DEGs were identified between HF and NF patients. The clustering analysis showed that HF patients could be classified into two subtypes based on the energy metabolism-related genes, and functional analyses demonstrated that the identified DEGs among two clusters were mainly involved in immune response regulating signaling pathway and lipid and atherosclerosis. ssGSEA analysis revealed that there were significant differences in the infiltration levels of immune cells between two subtypes of HF patients. Random-forest and support vector machine algorithm eventually identified ten diagnostic markers (MEF2D, RXRA, PPARA, FOXO1, PPARD, PPP3CB, MAPK14, CREB1, MEF2A, PRMT1) for risk prediction of HF patients, and the proposed nomogram resulted in good predictive performance (GSE66360, AUC = 0.91; GSE59867, AUC = 0.84) and the clinical usefulness in HF patients. More importantly, 10 drugs and 15 miRNA were predicted as drug target and hub miRNA that associated with energy metabolism-related genes, providing further information on clinical HF treatment., Conclusion: This study identified ten energy metabolism-related diagnostic markers using random forest algorithm, which may help optimize risk stratification and clinical treatment in HF patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chen, Jiang, Huang, Chen, Zeng, Wu, Yang, Guo, Li, Wei, Liao, Tse, Sha and Zhuo.)

Necrotizing enterocolitis (NEC) is one of the most prevalent neonatal gastrointestinal disorders. Despite ongoing breakthroughs in its treatment and prevention, the incidence and mortality associated with NEC remain high. New therapeutic approaches, such as breast milk composition administration, stem cell therapy, immunotherapy, and fecal microbiota transplantation (FMT) have recently evolved the prevention and the treatment of NEC. This study investigated the most recent advances in NEC therapeutic approaches and discussed their applicability to bring new insight to NEC treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wu, Guo, Zhuo, Zeng, Luo, Yang, Li, Jiang, Huang, Sha and Chen.)

Background: Acute myocardial infarction (AMI) is a common cardiovascular disease that has a high mortality. Pyroptosis is a programmed cell death mediated by inflammasome. It remains to be clarified on the expression pattern and risk predictive role of pyroptosis-related genes in AMI., Methods: The gene expression data were extracted from the Gene Expression Omnibus (GEO), and pyroptosis-related genes were obtained from published articles. Pyroptosis-related differential expressed genes were selected between normal and AMI samples and then we explored their immune infiltration level using CIBERSORT. Univariate Cox and LASSO regression were applied to establish a classifier based on pyroptosis-related genes. ROC analysis was utilized to evaluate the classifier., Results: In this study, we obtained 20 pyroptosis-related genes which showed differential expression in AMI and normal samples. Among the differential expressed genes, GZMB was significantly positively associated with activated NK cells (R = 0.71, p < 0.01), while NLRP3 exhibited a negative correlation with resting NK cells (R = -0.66, p < 0.01). 9 genes ( NLRP9, GSDMD, CASP8, AIM2, GPX4, NOD1, NOD2, SCAF11, GSDME ) were eventually identified as a predictive risk classifier for AMI patients. With the classifier, patients at high and low risk could be discriminated. Further external validation showed the high accuracy of the classifier (AUC = 0.75)., Conclusions: Pyroptosis-related genes are closely related to immune infiltration in AMI, and a 9-gene classifier has good performance in predicting the risk of AMI with high accuracy, which could provide a new way for targeted treatment in AMI., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s). Published by IMR Press.)