Soluble cluster of differentiation 14 levels elevated in bile from gallbladder cancer cases from Shanghai, China.
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ABSTRACT:
SUBMITTER: Brun VL
PROVIDER: S-EPMC8239000 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Apical periodontitis (periapical lesions) is an infection-induced chronic inflammation in the jaw, ultimately resulting in the destruction of apical periodontal tissue. Toll-like receptors (TLRs) are prominent in the initial recognition of pathogens. Our previous study showed that TLR4 signaling is proinflammatory in periapical lesions induced by a polymicrobial endodontic infection. In contrast, the functional role of TLR2 in regulation of periapical tissue destruction is still not fully understood. Using TLR2 deficient (KO), TLR2/TLR4 double deficient (dKO), and wild-type (WT) mice, we demonstrate that TLR2 KO mice are highly responsive to polymicrobial infection-induced periapical lesion caused by over activation of TLR4 signal transduction pathway that resulted in elevation of NF-kB (nuclear factor kappa B) and proinflammatory cytokine production. The altered TLR4 signaling is caused by TLR2 deficiency-dependent elevation of CD14 (cluster of differentiation 14), which is a co-receptor of TLR4. Indeed, neutralization of CD14 strikingly suppresses TLR2 deficiency-dependent inflammation and tissue destruction in vitro and in vivo. Our findings suggest that a network of TLR2, TLR4, and CD14 is a key factor in regulation of polymicrobial dentoalveolar infection and subsequent tissue destruction. Anat Rec, 299:1281-1292, 2016. © 2016 Wiley Periodicals, Inc.
| S-EPMC4982827 | biostudies-literature
Project description:Background:Early diagnosis is important for the timely treatment of gallbladder carcinoma (GBC) patients and may lead to increased survival outcomes. Here, we have applied serological proteome analysis (SERPA), an immunoproteomics approach, for the detection of 'tumor-associated antigens (TAAs) that elicit humoral response' in early stage GBC patients.Methods:Total protein from pooled tumor tissue of GBC patients (n?=?7) was resolved by two-dimensional gel electrophoresis (2-DE) followed by immunoblotting using pooled blood plasma from healthy volunteers (n?=?11) or gallstone disease (GSD) cases (n?=?11) or early stage GBC (Stage I and II) (n?=?5) or GBC stage IIIA (n?=?9). 2-D gel and immunoblot images were acquired and analyzed using PDQuest software to identify immunoreactive spots in GBC cases in comparison to controls. Proteins from immunoreactive spots were identified by liquid chromatography- tandem mass spectrometric analysis (LC-MS/MS). Autoantibody levels for two of the functionally relevant proteins were investigated in individual plasma samples (52 cases and 89 controls) by dot blot assay using recombinant proteins.Results:Image analysis using PDQuest software identified 25 protein spots with significantly high or specific immunoreactivity in GBC cases. Mass spectrometric analysis of 8 corresponding protein spots showing intense immunoreactivity (based on densitometric analysis) in early stage GBC or GBC stage IIIA cases led to the identification of 27 proteins. Some of the identified proteins include ANXA1, HSPD1, CA1, CA2, ALDOA and CTSD. Among the two proteins, namely ANXA1 and HSPD1 verified using a cohort of samples, significantly elevated autoantibody levels against ANXA1 were observed in early stage GBC cases in comparison to healthy volunteers or GSD cases (unpaired t-test, p?<?0.05). Receiver operating characteristic (ROC) curve analysis for ANXA1 showed an Area under the Curve (AUC) of 0.69, with 41.7% sensitivity against a specificity of 89.9% for early stage GBC. IHC analysis for ANXA1 protein showed 'high' expression levels in 72% of GBC cases whereas all the controls showed 'low' expression levels.Conclusions:The study suggests that the ANXA1 autoantibody levels against ANXA1 may be potentially employed for early stage detection of GBC patients. Other proteins could also be explored and verified in a large cohort of clinical samples.
| S-EPMC7709428 | biostudies-literature
Project description: Not available
| S-EPMC10670960 | biostudies-literature
Project description:Background: Recent studies have shown that growth differentiation factor 15 (GDF15), a member of the transforming growth factor-? (TGF-?)/bone morphogenetic protein (BMP) superfamily, plays an important role in appetite, type 2 diabetes, and cardiovascular diseases. Since thyroid hormone has pleiotropic effects on whole-body energy metabolism, we aimed to explore the effect of thyroid hormone on circulating GDF15 levels in humans and GDF15 genes expression in C57BL/6 mice.Methods: A total of 134 hyperthyroid patients and 105 healthy subjects were recruited. Of them, 43 hyperthyroid patients received thionamide treatment for 3 months until euthyroidism. Serum GDF15 levels were determined using the enzyme-linked immunosorbent assay (ELISA) method. To determine the source for the increased circulating GDF15, C57BL/6 mice were treated with T3, and GDF15 gene expressions in the liver, skeletal muscle, brown adipose tissue (BAT), inguinal white adipose tissue (iWAT), epididymal white adipose tissue (eWAT) were analyzed by quantitative real-time polymerase chain reaction (PCR).Results: Serum GDF15 levels were significantly elevated in hyperthyroid patients as compared with healthy subjects (326.06 ± 124.13 vs. 169.24 ± 82.96 pg/mL; P < 0.001). After thionamide treatment, GDF15 levels in hyperthyroid patients declined markedly from 293.27 ± 119.49 to 118.10 ± 71.83 pg/mL (P < 0.001). After adjustment for potential confounders, serum GDF15 levels were independently associated with hyperthyroidism. T3 treatment increased GDF15 expression in the brown adipose tissue of C57BL/6 mice.Conclusions: Serum GDF15 levels were elevated in patients with hyperthyroidism and declined after thionamide treatment. Thyroid hormone treatment upregulated GDF15 expression in mice. Therefore, our results present the clinical relevance of GDF15 in humans under the condition of hyperthyroidism.
| S-EPMC6333670 | biostudies-other
Project description:Background: A deregulated immune system has been implicated in the pathogenesis of post-cardiac arrest syndrome (PCAS). A soluble form of programmed cell death-1 (PD-1) ligand (sPD-L1) has been found at increased levels in cancer and sustained inflammation, thereby deregulating immune functions. Here, we aim to study the possible involvement of sPD-L1 in PCAS. Methods: Thirty out-of-hospital cardiac arrest (OHCA) patients consecutively admitted to the ER of Mie University Hospital were prospectively enrolled. Plasma concentrations of sPD-L1 were measured by an enzyme-linked immunosorbent assay in blood samples of all 30 OHCA patients obtained during cardiopulmonary resuscitation (CPR). In 13 patients who achieved return-of-spontaneous-circulation (ROSC), sPD-L1 levels were also measured daily in the ICU. Results: The plasma concentrations of sPD-L1 in OHCA were significantly increased; in fact, to levels as high as those observed in sepsis. sPD-L1 levels during CPR correlated with reduced peripheral lymphocyte counts and increased C-reactive protein levels. Of 13 ROSC patients, 7 cases survived in the ICU for more than 4 days. A longitudinal analysis of sPD-L1 levels in the 7 ROSC cases revealed that sPD-L1 levels occurred in parallel with organ failure. Conclusions: This study suggests that ischemia- reperfusion during CPR may aberrantly activate immune and endothelial cells to release sPD-L1 into circulation, which may play a role in the pathogenesis of immune exhaustion and organ failures associated with PCAS.
| S-EPMC8468744 | biostudies-literature
Project description:Listeria monocytogenes is a foodborne Gram-positive bacterium causing listeriosis in both animals and humans. It can persist and grow in various environments including conditions countered during saprophytic or intra-host lifestyles. Sigma (σ) subunit of RNA polymerase is a transcriptional factor responsible for guiding the core RNA polymerase and initiating gene expression under normal growth or physiological changes. In L. monocytogenes, there is one housekeeping sigma factor, σA, and four alternative sigma factors σB, σC, σH, and σL. Generally, σA directs expression of genes required for normal growth while alternative σ factors alter gene expression in response to specific conditions (e.g., stress). In this study, we aimed to determine the exclusive role of σA in L. monocytogenes by comparing a wild type strain with its isogenic mutant lacking genes encoding all alternative sigma factors (i.e., sigB, sigC, sigH, and sigL). We further investigated their survival abilities in 6% porcine bile (pH 8.2) mimicking gallbladder bile and their transcriptomics profiles in rich medium (i.e., BHI) and 1% porcine bile. Surprisingly, the results showed that survival abilities of wild type and ΔsigBΔsigCΔsigHΔsigL (or ΔsigBCHL) quadruple mutant strains in 6% bile were similar suggesting a compensatory role for σA. RNA-seq results revealed that bile stimulon of L. monocytogenes wild type contained 66 genes (43 and 23 genes were up- and down-regulated, respectively); however, only 29 genes (five up- and 24 down-regulated by bile) were differentially expressed in ΔsigBCHL. We have shown that bile exposure mediates increased transcription levels of dlt and ilv operons and decreased transcription levels of prfA and heat shock genes in wild type. Furthermore, we identified σA-dependent bile inducible genes that are involved in phosphotransferase systems, chaperones, and transporter systems; these genes appear to contribute to L. monocytogenes cellular homeostasis. As a result, σA seemingly plays a compensatory role in the absence of alternative sigma factors under bile exposure. Our data support that the bile stimulon is prone to facilitate resistance to bile prior to initiated infection.
| S-EPMC6737072 | biostudies-literature
Project description:Background & aimsAs the composition of the bile acid (BA) pool has a major impact on liver pathophysiology, we studied its regulation by the BA receptor Takeda G protein coupled receptor (TGR5), which promotes hepatoprotection against BA overload.MethodsWild-type, total and hepatocyte-specific TGR5-knockout, and TGR5-overexpressing mice were used in: partial (66%) and 89% extended hepatectomies (EHs) upon normal, ursodeoxycholic acid (UDCA)- or cholestyramine (CT)-enriched diet, bile duct ligation (BDL), cholic acid (CA)-enriched diet, and TGR5 agonist (RO) treatments. We thereby studied the impact of TGR5 on: BA composition, liver injury, regeneration and survival. We also performed analyses on the gut microbiota (GM) and gallbladder (GB). Liver BA composition was analysed in patients undergoing major hepatectomy.ResultsThe TGR5-KO hyperhydrophobic BA composition was not directly related to altered BA synthesis, nor to TGR5-KO GM dysbiosis, as supported by hepatocyte-specific KO mice and co-housing experiments, respectively. The TGR5-dependent control of GB dilatation was crucial for BA composition, as determined by experiments including RO treatment and/or cholecystectomy. The poor TGR5-KO post-EH survival rate, related to exacerbated peribiliary necrosis and BA overload, was improved by shifting BAs toward a less toxic composition (CT treatment). After either BDL or a CA-enriched diet with or without cholecystectomy, we found that GB dilatation had strong TGR5-dependent hepatoprotective properties. In patients, a more hydrophobic liver BA composition was correlated with an unfavourable outcome after hepatectomy.ConclusionsBA composition is crucial for hepatoprotection in mice and humans. We indicate TGR5 as a key regulator of BA profile and thereby as a potential hepatoprotective target under BA overload conditions.Lay summaryThrough multiple in vivo experimental approaches in mice, together with a patient study, this work brings some new light on the relationships between biliary homeostasis, gallbladder function, and liver protection. We showed that hepatic bile acid composition is crucial for optimal liver repair, not only in mice, but also in human patients undergoing major hepatectomy.
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Project description:Recent evidence has suggested a role for soluble oligomeric Abeta species in the pathology of Alzheimer's disease (AD). Fibrillar plaque deposits are present in non-demented individuals and levels of soluble Abeta correlate better with cognitive dysfunction in AD and transgenic mouse models. We have previously reported that there are at least two conformationally distinct types of Abeta oligomers: prefibrillar oligomers that are kinetic intermediates in fibril assembly reactions and are specifically recognized by A11 antibody and fibrillar oligomers that may represent fibril seeds or small pieces of fibrils and are recognized by a fibril specific antibody, OC. We have examined the levels of these two types of oligomers in the PBS soluble fraction of brain tissue from control cases, cases with senile degenerative changes (SDC) and AD patients. We found that the levels of soluble fibrillar oligomers detected by OC antibody are significantly elevated in multiple brain regions of AD patients. The elevated fibrillar oligomer levels were found not to be an artifact of tissue homogenization, nor a result of increased Abeta or APP levels. The concentration of fibrillar oligomers in adjacent brain regions of the same patient can vary widely and were not detected in post-mortem cerebrospinal fluid. In contrast, the level of prefibrillar oligomers are variable in both AD and age matched controls, indicating that they are not correlated with cognitive dysfunction and suggesting that they precede dementia in AD. Significant correlations were found between the levels of fibrillar oligomers and cognitive decline (MMSE scores) as well as the neuropathological hallmarks of AD. These results indicate that fibrillar oligomers may play a key role in the pathology of AD and may be a new target for diagnostic and therapeutic development.
| S-EPMC2725199 | biostudies-literature
Project description:To date, no research evaluating the predictive capabilities of soluble programmed cell death-ligand 1 (sPD-L1) in thyroid cancer patients has been performed. We aimed to investigate the prognostic significance of sPD-L1 expression in papillary thyroid cancer (PTC) and to evaluate the association between sPD-L1 levels with tumoural PD-L1 expression and patient outcomes. Pre-treatment levels of serum and plasma sPD-L1 were measured by ELISA in 101 PTC patients. Tissue microarrays were stained with an anti-PD-L1 antibody, clone SP263 (Ventana). The median serum sPD-L1 concentration in PTC patients was significantly higher compared to healthy controls (P = 0.028). An increased incidence of extrathyroidal extension was significantly associated with an elevated serum sPD-L1 level (P = 0.015). Patients with high serum sPD-L1 levels had significantly shorter median disease-free survival (DFS) as compared to those with low sPD-L1 levels (P = 0.011). Following multivariate analysis, serum sPD-L1 was the only statistically significant predictor for DFS. Patients with both positive serum and tumoural PD-L1 expression had a significantly shorter DFS than those in any other subgroup (P = 0.007). Our study is the first to confirm that sPD-L1 concentration is significantly associated with patient outcome in PTC. Soluble PD-L1 may provide clinicians with a non-invasive biomarker that can lessen dependence on tissue biopsies and diagnose aggressive thyroid cancers at a more treatable stage.
| S-EPMC6652242 | biostudies-literature
Project description:TGR5 is a G protein-coupled bile acid receptor present in brown adipose tissue and intestine, where its agonism increases energy expenditure and lowers blood glucose. Thus, it is an attractive drug target for treating human metabolic disease. However, TGR5 is also highly expressed in gallbladder, where its functions are less well characterized. Here, we demonstrate that TGR5 stimulates the filling of the gallbladder with bile. Gallbladder volume was increased in wild-type but not Tgr5(-/-) mice by administration of either the naturally occurring TGR5 agonist, lithocholic acid, or the synthetic TGR5 agonist, INT-777. These effects were independent of fibroblast growth factor 15, an enteric hormone previously shown to stimulate gallbladder filling. Ex vivo analyses using gallbladder tissue showed that TGR5 activation increased cAMP concentrations and caused smooth muscle relaxation in a TGR5-dependent manner. These data reveal a novel, gallbladder-intrinsic mechanism for regulating gallbladder contractility. They further suggest that TGR5 agonists should be assessed for effects on human gallbladder as they are developed for treating metabolic disease.
| S-EPMC3100601 | biostudies-literature