Colorectal cancer (CRC) is one of the most common malignancies worldwide. Inflammation contributes to cancer development and inflammatory bowel disease is an important risk factor for CRC. The aim of ...this study is to assess whether a widely used probiotic
can modulate the NLRP3 inflammasome and protect against colitis and colitis-associated CRC. We studied the effect of heat-killed cells of
on NLRP3 inflammasome activation in THP-1-derived macrophages. Pretreatment of
or NLRP3 siRNA can inhibit NLRP3 inflammasome activation in macrophages in response to fecal content or commensal microbes,
or
, according to the reduction of caspase-1 activation and IL-1β maturation. Mechanistically,
attenuates the phagocytosis that is required for the full activation of the NLRP3 inflammasome. In in vivo mouse experiments,
can ameliorate the severity of intestinal inflammation and thereby protect mice from dextran sodium sulfate (DSS)-induced colitis and the formation of CRC in wild type mice. On the other hand,
cannot prevent DSS-induced colitis in NLRP3 knockout mice. Our findings indicate that application of the inactivated probiotic,
, may be a useful and safe strategy for attenuation of NLRP3-mediated colitis and inflammation-associated colon carcinogenesis.
The etiology and pathogenesis of interstitial cystitis/bladder pain syndrome (IC/BPS) are unclear. Chronic inflammation is considered the main pathology of IC/BPS. This study measured the serum ...c-reactive protein (CRP), nerve growth factor (NGF) and pro-inflammatory cytokine/chemokine interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and IL-8 expression in patients with IC/BPS to elucidate the involvement of systemic inflammation in IC/BPS.
Serum samples were collected from 30 IC/BPS patients and 26 control subjects. The concentrations of serum nerve growth factor (NGF), IL-1β, IL-6, TNF-α, and IL-8 were quantified using a bead-based, human serum adipokine panel kit. Serum C-reactive protein (CRP) was also assessed. Differences of serum CRP, NGF, IL-1β, IL-6, TNF-α, and IL-8 levels between the IC/BPS patients and controls were compared, and correlations between CRP and pro-inflammatory cytokines and chemokine were also evaluated.
The results showed that CRP level (p = 0.031), NGF (p = 0.015) and pro-inflammatory cytokines/chemokine IL-1β, IL-6, TNF-α, and IL-8 levels were significantly higher in the patients with IC/BPS than among controls (all p<0.001). Significant associations were observed between IL-1β and IL-8 (p<0.001), IL-6 and CRP (p = 0.01), IL-6 and IL-8 (p = 0.02), and IL-6 and TNF-α (p = 0.03).
Increased pro-inflammatory cytokines/chemokine (IL-1β, IL-6, TNF-α, and IL-8) expression in the sera of IC/BPS patients implies not only mast cell activation, but also that other inflammatory mediators play important roles in the pathogenesis of IC/BPS. Thus, for some patients, IC/BPS is considered a chronic inflammatory disease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Photodissociation of acetaldehyde (CH3CHO) by UV excitation involves interwoven multiple reaction pathways, including nonradiative decay, isomerization, transition-state pathway, roaming, and other ...dissociation mechanisms. Recently, we employed picosecond time-resolved, pair-correlated product imaging in a study of acetaldehyde photodissociation at 267 nm to disentangle those competing mechanisms and to elucidate the possible roaming pathways ( Yang, C. H. ; Chem. Sci. 2020, 11, 6423−6430 ). Here, we complement the pair-correlated product speed distribution of CO(v = 0) at the high-j side of the CO rotational state distribution in the CO + CH4 channel and detail the two-dimensional data analysis of the time-resolved images. As a result, extensive comparisons with other studies can be made and the branching fractions of the previously assigned TScc(S0), non-TScc(S0), and CI(S1/S0) pathways for the CO(v = 0) + CH4 molecular channel are evaluated to be 0.74 ± 0.08, 0.15 ± 0.02, and 0.11 ± 0.02, respectively. Together with the macroscopic branching ratio between the molecular (CO + CH4) and radical (CH3 + HCO) channels at 267 nm from the literature, a global view of the microscopic pathways can then be delineated, which provides invaluable insights and should pave the way for further studies of this interesting system.
Objective
To evaluate early retinal microvascular abnormalities in patients with chronic kidney disease (CKD) via optical coherence tomography angiography.
Methods
A cross‐sectional study. Two ...hundred patients with CKD stage ≧3 were enrolled in the CKD group, and 50 age‐matched healthy subjects were enrolled in the control group. Main outcome measures were the differences in parafoveal vessel densities in the superficial vascular plexus (SVP) and deep vascular plexus (DVP) between the CKD and control groups.
Results
The mean ages were 62.7 ± 10.1 in the CKD group and 61.9 ± 9.7 (P = 0.622) in the control group. The CKD group had reduced parafoveal vessel densities in SVP (46.7 ± 4.3 vs 49.7 ± 2.9, P < 0.001) and DVP (50.1 ± 4.1 vs 52. 6 ± 2.9, P < 0.001) when compared to those of the control group. In multiple linear regression models, age, diabetes, estimated glomerular filtration rate, and use of anti‐hypertensive drugs were factors associated with vessel density in SVP, whereas age, diabetes, and smoking were factors associated with vessel density in DVP.
Conclusion
Patients with CKD had reduced vessel densities in parafoveal SVP and DVP, as compared to that of control subjects. Microvasculature in the different retinal layers may be affected by different systemic factors.
Abstract The blood–brain barrier (BBB) can be temporarily and locally opened by focused ultrasound (FUS) in the presence of circulating microbubbles (MBs). Currently, contrast-enhanced magnetic ...resonance imaging (CE-MRI) is used to monitor contrast agent leakage to verify BBB-opening and infer drug deposition. However, despite being administered concurrently, MBs, therapeutic agent, and contrast agent have distinct pharmacodynamic behaviors, thus complicating the quantification and optimization of BBB-opening and drug delivery. Here we propose multifunctional MBs loaded with therapeutic agent (doxorubicin; DOX) and conjugated with superparamagnetic iron oxide (SPIO) nanoparticles. These DOX-SPIO-MBs were designed to concurrently open the BBB and perform drug delivery upon FUS exposure, act as dual MRI and ultrasound contrast agent, and allow magnetic targeting (MT) to achieve enhanced drug delivery. We performed burst-tone FUS after injection of DOX-SPIO-MBs, followed by MT with an external magnet attached to the scalp in a rat glioma model. Animals were monitored by T2-weighted MRI and susceptibility weighted imaging and the concentration of SPIO particles was determined by spin–spin relaxivity. We found that DOX-SPIO-MBs were stable and provided significant superparamagnetic/acoustic properties for imaging. BBB-opening and drug delivery were achieved concurrently during the FUS exposure. In addition, MT increased local SPIO deposition in tumor regions by 22.4%. Our findings suggest that DOX-SPIO-MBs with FUS could be an excellent theranostic tool for future image-guided drug delivery to brain tumors.
The Fusarium solani species complex (FSSC) comprises fungal pathogens responsible for mortality in a diverse range of animals and plants, but their genome diversity and transcriptome responses in ...animal pathogenicity remain to be elucidated. We sequenced, assembled and annotated six chromosome-level FSSC clade 3 genomes of aquatic animal and plant host origins. We established a pathosystem and investigated the expression data of F. falciforme and F. keratoplasticum in Chinese softshell turtle (Pelodiscus sinensis) host. Comparative analyses between the FSSC genomes revealed a spectrum of conservation patterns in chromosomes categorised into three compartments: core, fast-core (FC), and lineage-specific (LS). LS chromosomes contribute to variations in genomes size, with up to 42.2% of variations between F. vanettenii strains. Each chromosome compartment varied in structural architectures, with FC and LS chromosomes contain higher proportions of repetitive elements with genes enriched in functions related to pathogenicity and niche expansion. We identified differences in both selection in the coding sequences and DNA methylation levels between genome features and chromosome compartments which suggest a multi-speed evolution that can be traced back to the last common ancestor of Fusarium. We further demonstrated that F. falciforme and F. keratoplasticum are opportunistic pathogens by inoculating P. sinensis eggs and identified differentially expressed genes also associated with plant pathogenicity. These included the most upregulated genes encoding the CFEM (Common in Fungal Extracellular Membrane) domain. The high-quality genome assemblies provided new insights into the evolution of FSSC chromosomes, which also serve as a resource for studies of fungal genome evolution and pathogenesis. This study also establishes an animal model for fungal pathogens of trans-kingdom hosts.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Activation of the Nod-like receptor 3 (NLRP3) inflammasome is important for activation of innate immune responses, but improper and excessive activation can cause inflammatory disease. We previously ...showed that glycolysis, a metabolic pathway that converts glucose into pyruvate, is essential for NLRP3 inflammasome activation in macrophages. Here, we investigated the role of metabolic pathways downstream glycolysis - lactic acid fermentation and pyruvate oxidation-in activation of the NLRP3 inflammasome. Using pharmacological or genetic approaches, we show that decreasing lactic acid fermentation by inhibiting lactate dehydrogenase reduced caspase-1 activation and IL-1β maturation in response to various NLRP3 inflammasome agonists such as nigericin, ATP, monosodium urate (MSU) crystals, or alum, indicating that lactic acid fermentation is required for NLRP3 inflammasome activation. Inhibition of lactate dehydrogenase with GSK2837808A reduced lactate production and activity of the NLRP3 inflammasome regulator, phosphorylated protein kinase R (PKR), but did not reduce the common trigger of NLRP3 inflammasome, potassium efflux, or reactive oxygen species (ROS) production. By contrast, decreasing the activity of pyruvate oxidation by depletion of either mitochondrial pyruvate carrier 2 (MPC2) or pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1) enhanced NLRP3 inflammasome activation, suggesting that inhibition of mitochondrial pyruvate transport enhanced lactic acid fermentation. Moreover, treatment with GSK2837808A reduced MSU-mediated peritonitis in mice, a disease model used for studying the consequences of NLRP3 inflammasome activation. Our results suggest that lactic acid fermentation is important for NLRP3 inflammasome activation, while pyruvate oxidation is not. Thus, reprograming pyruvate metabolism in mitochondria and in the cytoplasm should be considered as a novel strategy for the treatment of NLRP3 inflammasome-associated diseases.
The prevalence of type 2 diabetes (T2D) has increased dramatically in recent decades, and there are increasing indications that dementia is related to T2D. Previous attempts to analyze such ...relationships principally relied on traditional multiple linear regression (MLR). However, recently developed machine learning methods (Mach-L) outperform MLR in capturing non-linear relationships. The present study applied four different Mach-L methods to analyze the relationships between risk factors and cognitive function in older T2D patients, seeking to compare the accuracy between MLR and Mach-L in predicting cognitive function and to rank the importance of risks factors for impaired cognitive function in T2D.
We recruited older T2D between 60-95 years old without other major comorbidities. Demographic factors and biochemistry data were used as independent variables and cognitive function assessment (CFA) was conducted using the Montreal Cognitive Assessment as an independent variable. In addition to traditional MLR, we applied random forest (RF), stochastic gradient boosting (SGB), Naïve Byer's classifier (NB) and eXtreme gradient boosting (XGBoost).
Totally, the test cohort consisted of 197 T2D (98 men and 99 women). Results showed that all ML methods outperformed MLR, with symmetric mean absolute percentage errors for MLR, RF, SGB, NB and XGBoost respectively of 0.61, 0.599, 0.606, 0.599 and 0.2139. Education level, age, frailty score, fasting plasma glucose and body mass index were identified as key factors in descending order of importance.
In conclusion, our study demonstrated that RF, SGB, NB and XGBoost are more accurate than MLR for predicting CFA score, and identify education level, age, frailty score, fasting plasma glucose, body fat and body mass index as important risk factors in an older Chinese T2D cohort.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The roaming mechanism, an unconventional reaction path, was discovered more than a decade ago in the studies of formaldehyde photodissociation, H
2
CO → H
2
+ CO. Since then, observations of roaming ...have been claimed in numerous photochemical processes. A closer examination of the presented data, however, revealed that evidence for roaming is not always unequivocal, and some of the conclusions could be misleading. We report here an in-depth, joint experimental and theoretical study of the title reaction. By tracking the time-evolution of the pair-correlated product state distributions, we decipher the competing, interwoven reaction pathways that lead to the radical (CH
3
+ HCO) and molecular (CH
4
+ CO) products. Possible roaming pathways are then elucidated and a more precise descriptor of the phenomenon is delineated.
Unraveling the entangled multi-channel dissociation pathways by a two-dimensional, time and product pair-correlation, measurement and
ab initio
calculations.
Objectives
To investigate the anticancer effects and underlying mechanisms of surfactin on human oral squamous cell carcinoma (OSCC).
Materials and Methods
The capacity of surfactin to induce ...apoptosis, autophagy, and cell cycle arrest of two different human OSCC cell lines was investigated by cell viability, acridine orange staining, and cell cycle regulatory protein expression, respectively. The signaling network underlying these processes were determined by the analysis of reactive oxygen species (ROS) generation, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, endoplasmic reticulum (ER) stress‐related protein levels, calcium release, mitogen‐activated protein kinases activation, and cell cycle regulatory protein expression through corresponding reagents and experiments under various experimental conditions using specific pharmaceutical inhibitors or small interfering RNAs.
Results
Surfactin was able to induce apoptosis through NADPH oxidase/ROS/ER stress/calcium‐downregulated extracellular signal‐regulated kinases 1/2 pathway. Surfactin could also lead to autophagy that shared the common regulatory signals with apoptosis pathway until calcium node. Cell cycle arrest at G2/M phase caused by surfactin was demonstrated through p53 and p21 accumulation combined p34cdc2, phosphorylated p34cdc2, and cyclin B1 inhibition, which was regulated by NADPH oxidase‐derived ROS.
Conclusion
Surfactin could induce apoptosis, autophagy, and cell cycle arrest in ROS‐dependent manner, suggesting a multifaced anticancer agent for OSCC.
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