TGF-alpha Research Articles

Protein Biomarkers of New-Onset Heart Failure: Insights From the Heart Omics and Ageing Cohort, the Atherosclerosis Risk in Communities Study, and the Framingham Heart Study.

We sought to identify protein biomarkers of new-onset heart failure (HF) in 3 independent cohorts (HOMAGE cohort [Heart Omics and Ageing], ARIC study [Atherosclerosis Risk in Communities], and FHS [Framingham Heart Study]) and assess if and to what extent they improve HF risk prediction compared to clinical risk factors alone. A nested case-control design was used with cases (incident HF) and controls (without HF) matched on age and sex within each cohort. Plasma concentrations of 276 proteins were measured at baseline in ARIC (250 cases/250 controls), FHS (191/191), and HOMAGE cohort (562/871). In single protein analysis, after adjusting for matching variables and clinical risk factors (and correcting for multiple testing), 62 proteins were associated with incident HF in ARIC, 16 in FHS, and 116 in HOMAGE cohort. Proteins associated with incident HF in all cohorts were BNP (brain natriuretic peptide), NT-proBNP (N-terminal pro-B-type natriuretic peptide), eukaryotic translation initiation factor 4E-BP1 (4E-binding protein 1), hepatocyte growth factor (HGF), Gal-9 (galectin-9), TGF-alpha (transforming growth factor alpha), THBS2 (thrombospondin-2), and U-PAR (urokinase plasminogen activator surface receptor). The increment in C-index for incident HF based on a multiprotein biomarker approach, in addition to clinical risk factors and NT-proBNP, was 11.1% (7.5%-14.7%) in ARIC, 5.9% (2.6%-9.2%) in FHS, and 7.5% (5.4%-9.5%) in HOMAGE cohort, all P<0.001), each of which was a larger increase than that for NT-proBNP on top of clinical risk factors. Complex network analysis revealed a number of overrepresented pathways related to inflammation (eg, tumor necrosis factor and interleukin) and remodeling (eg, extracellular matrix and apoptosis). A multiprotein biomarker approach improves prediction of incident HF when added to natriuretic peptides and clinical risk factors.

Arterial wall inflammation assessed by 18F-FDG-PET/CT is higher in individuals with Type 1 diabetes and associated with circulating inflammatory proteins.

The article investigates whether chronic hyperglycaemia in Type 1 diabetes (T1D) is associated with a proinflammatory immune signature and with arterial wall inflammation, driving the development of atherosclerosis. Patients with T1D (n = 41), and healthy age-, sex-, and body mass index-matched controls (n = 20) were recruited. Arterial wall inflammation and haematopoietic activity were measured with 2'-deoxy-2'-(18F)-fluoro-D-glucose (18F-FDG) positron emission tomography/computed tomography. In addition, flow cytometry of circulating leucocytes was performed as well as targeted proteomics to measure circulating inflammatory markers. 18F-FDG uptake in the wall of the abdominal aorta, carotid arteries, and iliac arteries was higher in T1D compared with that in the healthy controls. Also, 18F-FDG uptake in the bone marrow and spleen was higher in patients with T1D. CCR2 and CD36 expressions on circulating monocytes were higher in patients with T1D, as well as several circulating inflammatory proteins. In addition, several circulating inflammatory markers (osteoprotegerin, transforming growth factor-alpha, CX3CL1, and colony-stimulating factor-1) displayed a positive correlation with FDG uptake. Within T1D, no differences were found between people with a high and low HbA1c. These findings strengthen the concept that chronic hyperglycaemia in T1D induces inflammatory changes that fuel arterial wall inflammation leading to atherosclerosis. The degree of hyperglycaemia appears to play a minor role in driving this inflammatory response in patients with T1D.

The role of polymorphism of candidate genes in the development of knee osteoarthritis in men of the Central Chernozem region of Russia

Knee osteoarthritis (OA) is a disease resulting from the interaction of many local and systemic risk factors, among which an important role is played by genetic (hereditary) factors. This disease affects both men and women, but there are certain differences in the development and progression of the disease in different sexes.Aim: To study associations of polymorphic loci of candidate genes with the risk of developing knee ОА in the male population of the Central Chernozem region of Russia.Material and Methods. The study sample included 410 men (208 patients with knee OA and 202 controls). Ten polymorphic loci of candidate genes were genotyped: rs2820436 and rs2820443 LYPLAL1, rs3771501 TGFA, rs11177 GNL3, rs6976 GLT8D1, rs1060105 and rs56116847 SBNO1, rs6499244 NFAT5, rs34195470 WWP2, rs143384 GDF5. The study of associations of polymorphic genetic loci with the development of the disease was carried out by the method of logistic regression, taking into account covariates (age, BMI). The MB-MDR method was used to study intergenic interactions of polymorphisms associated with the disease.Results and Discussion. It was found that nine out of ten polymorphic loci of candidate genes (with the exception of rs6976 GLT8D1) are associated with the formation of knee OA in men in four models of interlocus interactions (pperm ≤ 0.024). The rs3771501 TGFA polymorphic locus (included in three of the four most significant models of gene-gene interactions) demonstrates the greatest contribution to the development of the disease in men. Independent effects of the studied polymorphic loci of candidate genes in the development of knee OA in men have not been identified (р &gt; 0,05).Conclusion. Polymorphic loci rs2820436 and rs2820443 LYPLAL1, rs3771501 TGFA, rs11177 GNL3, rs6976 GLT8D1, rs1060105 and rs56116847 SBNO1, rs6499244 NFAT5, rs34195470 WWP2, rs143384 GDF5 involved in the development of knee osteoarthritis in men in four models of intergenic interactions. Among the studied loci, rs3771501 of the TGFA gene has the greatest contribution to disease susceptibility.

Cell-Based Sensors for the Detection of EGF and EGF-Stimulated Ca2+ Signaling

Epidermal growth factor (EGF)-mediated activation of EGF receptors (EGFRs) has become an important target in drug development due to the implication of EGFR-mediated cellular signaling in cancer development. While various in vitro approaches are developed for monitoring EGF-EGFR interactions, they have several limitations. Herein, we describe a live cell-based sensor system that can be used to monitor the interaction of EGF and EGFR as well as the subsequent signaling events. The design of the EGF-detecting sensor cells is based on the split-intein-mediated conditional protein trans-cleavage reaction (CPC). CPC is triggered by the presence of the target (EGF) to activate a signal peptide that translocates the fluorescent cargo to the target cellular location (mitochondria). The developed sensor cell demonstrated excellent sensitivity with a fast response time. It was also successfully used to detect an agonist and antagonist of EGFR (transforming growth factor-α and Cetuximab, respectively), demonstrating excellent specificity and capability of screening the analytes based on their function. The usage of sensor cells was then expanded from merely detecting the presence of target to monitoring the target-mediated signaling cascade, by exploiting previously developed Ca2+-detecting sensor cells. These sensor cells provide a useful platform for monitoring EGF-EGFR interaction, for screening EGFR effectors, and for studying downstream cellular signaling cascades.

Circ_0006667 contributes to high glucose-induced retinal pigment epithelial cell dysfunction by mediating miR-7-5p/TGFA axis in diabetic retinopathy.

Diabetic retinopathy (DR) is a common complication of diabetes mellitus and it can lead to visual impairment and blindness. The loss of retinal pigment epithelial (RPE) cells is associated with the etiology of DR. Moreover, dysregulated circular RNAs (circRNAs) are implicated in DR progression. Therefore, this project aims to explore the role and potential mechanism of circ_0006667 in DR. RPE cells (ARPE-19) were stimulated with high glucose (33mM; HG group) for 24h to establish the DR cell model. Circ_0006667, microRNA-7-5p (miR-7-5p), and transforming growth factor alpha (TGFA) expression was determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Cell viability, proliferation, and apoptosis were analyzed by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), 5-ethynyl-2'-deoxyuridine (EdU), and flow cytometry. CyclinD1, Cleaved-caspase-3, and TGFA protein levels were detected using western blot. Using Circinteractome and starBase analysis, the binding miR-7-5p and circ_0006667 or TGFA was predicted, and then validated using dual-luciferase reporter and RNA Immunoprecipitation (RIP). Circ_0006667 expression was up-regulated in DR patients and HG-induced ARPE-19 cells. HG stimulation suppressed ARPE-19 cell proliferation and promoted cell apoptosis and inflammation, which were alleviated via circ_0006667 silence. Circ_0006667 acted as a molecular sponge for miR-7-5p, and circ_0006667 absence-mediated protective effects in HG-induced ARPE-19 cells were largely overturned by the interference of miR-7-5p. miR-7-5p directly targeted TGFA, and miR-7-5p overexpression protected ARPE-19 cells from HG-induced dysfunction largely by down-regulating TGFA. Circ_0006667 can up-regulate the expression of TGFA by sponging miR-7-5p in ARPE-19 cells. Circ_0006667 silencing protected ARPE-19 cells from HG-induced dysfunction by mediating miR-7-5p/TGFA axis.

Ectodomain shedding of EGFR ligands serves as an activation readout for TRP channels.

Transient receptor potential (TRP) channels are activated by various extracellular and intracellular stimuli and are involved in many physiological events. Because compounds that act on TRP channels are potential candidates for therapeutic agents, a simple method for evaluating TRP channel activation is needed. In this study, we demonstrated that a transforming growth factor alpha (TGFα) shedding assay, previously developed for detecting G-protein-coupled receptor (GPCR) activation, can also detect TRP channel activation. This assay is a low-cost, easily accessible method that requires only an absorbance microplate reader. Mechanistically, TRP-channel-triggered TGFα shedding is achieved by both of a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) and 17 (ADAM17), whereas the GPCR-induced TGFα shedding response depends solely on ADAM17. This difference may be the result of qualitative or quantitative differences in intracellular Ca2+ kinetics between TRP channels and GPCRs. Use of epidermal growth factor (EGF) and betacellulin (BTC), substrates of ADAM10, improved the specificity of the shedding assay by reducing background responses mediated by endogenously expressed GPCRs. This assay for TRP channel measurement will not only facilitate the high-throughput screening of TRP channel ligands but also contribute to understanding the roles played by TRP channels as regulators of membrane protein ectodomain shedding.

A Dedicated 21-Plex Proximity Extension Assay Panel for High-Sensitivity Protein Biomarker Detection Using Microdialysis in Severe Traumatic Brain Injury: The Next Step in Precision Medicine?

Cerebral protein profiling in traumatic brain injury (TBI) is needed to better comprehend secondary injury pathways. Cerebral microdialysis (CMD), in combination with the proximity extension assay (PEA) technique, has great potential in this field. By using PEA, we have previously screened >500 proteins from CMD samples collected from TBI patients. In this study, we customized a PEA panel prototype of 21 selected candidate protein biomarkers, involved in inflammation (13), neuroplasticity/-repair (six), and axonal injury (two). The aim was to study their temporal dynamics and relation to age, structural injury, and clinical outcome. Ten patients with severe TBI and CMD monitoring, who were treated in the Neurointensive Care Unit, Uppsala University Hospital, Sweden, were included. Hourly CMD samples were collected for up to 7 days after trauma and analyzed with the 21-plex PEA panel. Seventeen of the 21 proteins from the CMD sample analyses showed significantly different mean levels between days. Early peaks (within 48 h) were noted with interleukin (IL)-1β, IL-6, IL-8, granulocyte colony-stimulating factor, transforming growth factor alpha, brevican, junctional adhesion molecule B, and neurocan. C-X-C motif chemokine ligand 10 peaked after 3 days. Late peaks (>5 days) were noted with interleukin-1 receptor antagonist (IL-1ra), monocyte chemoattractant protein (MCP)-2, MCP-3, urokinase-type plasminogen activator, Dickkopf-related protein 1, and DRAXIN. IL-8, neurofilament heavy chain, and TAU were biphasic. Age (above/below 22 years) interacted with the temporal dynamics of IL-6, IL-1ra, vascular endothelial growth factor, MCP-3, and TAU. There was no association between radiological injury (Marshall grade) or clinical outcome (Extended Glasgow Outcome Scale) with the protein expression pattern. The PEA method is a highly sensitive molecular tool for protein profiling from cerebral tissue in TBI. The novel TBI dedicated 21-plex panel showed marked regulation of proteins belonging to the inflammation, plasticity/repair, and axonal injury families. The method may enable important insights into complex injury processes on a molecular level that may be of value in future efforts to tailor pharmacological TBI trials to better address specific disease processes and optimize timing of treatments.

Galectin-14 promotes hepatocellular carcinoma tumor growth via enhancing heparan sulfate proteoglycan modification.

Hepatocellular carcinoma (HCC) is a highly heterogeneous malignancy and lacks effective treatment. Bulk-sequencing of different gene transcripts by comparing HCC tissues and adjacent normal tissues provides some clues for investigating the mechanisms or identifying potential targets for tumor progression. However, genes that are exclusively expressed in a subpopulation of HCC may not be enriched or detected through such a screening. In the current study, we performed a single cell-clone-based screening and identified galectin-14 as an essential molecule in the regulation of tumor growth. The aberrant expression of galectin-14 was significantly associated with a poor overall survival of liver cancer patients with database analysis. Knocking down galectin-14 inhibited the proliferation of tumor growth, whereas overexpressing galectin-14 promoted tumor growth in vivo. Non-targeted metabolomics analysis indicated that knocking down galectin-14 decreased glycometabolism; specifically that glycoside synthesis was significantly changed. Further study found that galectin-14 promoted the expression of cell surface heparan sulfate proteoglycans (HSPGs) that functioned as co-receptors, thereby increasing the responsiveness of HCC cells to growth factors, such as epidermal growth factor and transforming growth factor-alpha. In conclusion, the current study identifies a novel HCC-specific molecule galectin-14, which increases the expression of cell surface HSPGs and the uptake of growth factors to promote HCC cell proliferation.

Autocrine EGF and TGF-α promote primary and acquired resistance to ALK/c-Met kinase inhibitors in non-small-cell lung cancer.

Drug resistance severely limits the clinical therapeutic value of molecularly targeted drugs. Growth factors gain a tremendous amount of focus due to the ability to promote drug resistance in non-small-cell lung cancer (NSCLC). However, whether tumor cells themselves can mediate drug resistance by secreting growth factors needs further clarification. Here, we first screened growth factors to identify autocrine epidermal growth factor (EGF) and transforming growth factor alpha (TGF-α) that caused primary resistance to the ALK inhibitor TAE684 in H3122 cells and the c-MET-specific inhibitor SGX-523 in EBC-1 cells. Next, we discovered increased autocrine production of EGF and TGF-α in established acquired resistant H3122/TR and EBC-1/SR cells. Importantly, overexpression of EGF and TGF-α in two NSCLC cell lines produced resistance to TAE684 and SGX-523. Clinically, NSCLC patients with high expression of EGF and TGF-α developed primary resistance to crizotinib. Mechanistically, autocrine EGF and TGF-α activated EGFR signaling pathways to survive targeted c-Met and ALK inhibition. Furthermore, combined treatment with gefitinib circumvented EGF- and TGF-α-mediated primary and acquired resistance to TAE684/SGX-523. Taken together, these results suggested increased autocrine EGF and TGF-α conferred primary and acquired resistance to ALK/c-Met kinase inhibitors in NSCLC.

Polymorphism of LYPLAL1 and TGFA Genes Associated With Progression of Knee Osteoarthritis in Residents Central Chernozem Region of Russia

Background. Кnee osteoarthritis (OA) is a multifactorial disease in which genetic factors play an important role. The share of the hereditary component in the development of OA, according to various literature sources, ranges from 40 to 65%. Кnee OA is a progressive disease that leads to a decrease in the quality of life and disability.&#x0D; The study aimed to evaluate the role of polymorphic markers of candidate genes rs2820436 and rs2820443 LYPLAL1, rs3771501 TGFA, rs11177 GNL3, rs6976 GLT8D1 in the progression of knee OA in the population of the Central Chernozem Region of Russia.&#x0D; Methods. The study was performed in a case-control design on a sample of 500 patients with knee OA. Case patients with III-IV stages of the disease according to KellgrenLawrence (n = 325), control (individuals who do not have the analyzed sign III-IV stages of the disease) patients with stage II (n = 175). Genotyping of five single nucleotide polymorphisms (SNPs) of candidate genes was performed using the polymerase chain reaction method for DNA synthesis. The study of the associations of the studied polymorphic loci, the calculation of haplotype frequencies and the analysis of their relationship with the progression of knee OA was carried out by the method of logistic regression in the program PLINK v 2.050.&#x0D; Results. Significant associations with the progression of OA of the knee were established for allelic variant A rs2820436 of LYPLAL1 gene according to allelic (OR = 1.48, p = 0.010, pperm = 0.012), additive (OR = 1.58, p = 0.009, pperm = 0.010), dominant (OR = 1.61, p = 0.024, pperm = 0.030) genetic models and A/A genotype of the same polymorphism (OR = 2.53, p = 0.041). The genotypes C/C rs2820436 LYPLAL1 (OR = 0.67, p = 0.043), A/G rs3771501 TGFA (OR = 0.67, p = 0.042) have a protective role in the progression of the disease. It was found that the frequency of the AC haplotype of haploblock rs2820436-rs2820443 in the group of patients with III-IV stages of the disease was significantly higher than in patients with stage II (OR = 1.83, p = 0.002, pperm = 0.002). The identified molecular genetic markers rs2820436 and rs2820443 of LYPLAL1 gene, rs3771501 of TGFA gene are associated both with the risk of developing OA according to previous genome-wide studies and, according to our data, are associated with the progression of knee OA.&#x0D; Conclusions. Genetic risk factors for the development of knee OA of III-IV radiological stages are allelic variant A and genotype A/A rs2820436 of LYPLAL1 gene, haplotype AC of haploblock rs2820436-rs2820443 in the population of the Central Chernozem Region of Russia. Genotypes C/C rs2820436 of LYPLAL1 gene and A/G rs3771501 of TGFA gene have a protective value in the progression of this disease.

LncRNA HOTTIP promotes inflammatory response in acute gouty arthritis via miR-101-3p/BRD4 axis.

Acute gouty arthritis (AGA) is characterized by the accumulation of pro-inflammatory factors. This research aimed to examine the regulation of long non-coding RNA HOXA distal transcript antisense RNA (HOTTIP) in AGA on inflammation and its potential mechanisms. Serum levels of HOTTIP in AGA patients were examined by reverse-transcription quantitative polymerase chain reaction. The receiver operating characteristic curve was performed in the diagnosis of AGA patients. Monosodium urate (MSU) stimulation of THP-1-derived macrophages was used to establish an in vitro AGA model. Enzyme-linked immunosorbent assay was carried out to assess the levels of pro-inflammatory cytokines. Pearson correlation was applied to examine the correlation. RNA immunoprecipitation assay and dual-luciferase reporter assay were employed to identify the targeting relationship between miR-101-3p and HOTTIP or bromodomain-containing 4 (BRD4). HOTTIP and BRD4 were statistically overexpressed in AGA patients compared with controls, while miR-101-3p was reduced (P < 0.05). Serum HOTTIP can significantly distinguish AGA patients from healthy controls. HOTTIP bound with miR-101-3p then augmented BRD4 via a competing endogenous RNA mechanism. Additionally, HOTTIP levels were elevated in a dose-dependent manner by MSU (P < 0.05). Weakened HOTTIP significantly inhibited MSU-induced release of pro-inflammatory factors interleukin (IL)-1β, IL-8, and transforming growth factor-α in macrophages (P < 0.05), but this inhibition was reversed by silencing miR-101-3p (P < 0.05). In short, HOTTIP contributes to inflammation via miR-101-3p/BRD4 axis, and serves as a new diagnostic biomarker. This study offers a renewed perspective on the diagnosis and treatment of AGA.

Lentigo melanoma associated with Leser–Trélat syndrome

LeserTrlat syndrome is characterized by the sudden appearance of a large amount of elements of seborrheic keratosis. The syndrome is associated with the development of malignant tumors of internal organs. The reason for the development of the syndrome is probably the production of cytokines by cells of malignant tumors of internal organs (transforming growth factor alpha (TGF-), epidermal growth factor (EGF), etc.) endogenous mediators that affect the proliferation of keratinocytes and cause rapid growth of seborrheic keratosis. Currently, the question of the paraneoplastic nature of multiple seborrheic keratosis remains open. The article presents the observation of an 82-year-old patient with lentigo-melanoma, who developed multiple elements of seborrheic keratosis within a short time, discusses the question of how in this case it is possible to consider this as a paraneoplastic process. This case is interesting for the atypical clinical picture of seborrheic keratosis and the association with lentigo-melanoma.

Ionizing Radiation and Estrogen Affecting Growth Factor Genes in an Experimental Breast Cancer Model.

Genes associated with growth factors were previously analyzed in a radiation- and estrogen-induced experimental breast cancer model. Such in vitro experimental breast cancer model was developed by exposure of the immortalized human breast epithelial cell line, MCF-10F, to low doses of high linear energy transfer (LET) α particle radiation (150 keV/μm) and subsequent growth in the presence or absence of 17β-estradiol. The MCF-10F cell line was analyzed in different stages of transformation after being irradiated with either a single 60 cGy dose or 60/60 cGy doses of alpha particles. In the present report, the profiling of differentially expressed genes associated with growth factors was analyzed in their relationship with clinical parameters. Thus, the results indicated that Fibroblast growth factor2 gene expression levels were higher in cells transformed by radiation or in the presence of ionizing radiation; whereas the fibroblast growth factor-binding protein 1gene expression was higher in the tumor cell line derived from this model. Such expressions were coincident with higher values in normal than malignant tissues and with estrogen receptor (ER) negative samples for both gene types. The results also showed that transforming growth factor alpha gene expression was higher in the tumor cell line than the tumorigenic A5 and the transformed A3 cell line, whereas the transforming growth factor beta receptor 3 gene expression was higher in A3 and A5 than in Tumor2 cell lines and the untreated controls and the E cell lines. Such gene expression was accompanied by results indicating negative and positive receptors for transforming growth factor alpha and the transforming growth factor beta receptor 3, respectively. Such expressions were low in malignant tissues when compared with benign ones. Furthermore, Fibroblast growth factor2, the fibroblast growth factor-binding protein 1, transforming growth factor alpha, the transforming growth factor beta receptor 3, and the insulin growth factor receptor gene expressions were found to be present in all BRCA patients that are BRCA-Basal, BRCA-LumA, and BRCA-LumB, except in BRCA-Her2 patients. The results also indicated that the insulin growth factor receptor gene expression was higher in the tumor cell line Tumor2 than in Alpha3 cells transformed by ionizing radiation only; then, the insulin growth factor receptor was higher in the A5 than E cell line. The insulin growth factor receptor gene expression was higher in breast cancer than in normal tissues in breast cancer patients. Furthermore, Fibroblast growth factor2, the fibroblast growth factor-binding protein 1, transforming growth factor alpha, the transforming growth factor beta receptor 3, and the insulin growth factor receptor gene expression levels were in stages 3 and 4 of breast cancer patients. It can be concluded that, by using gene technology and molecular information, it is possible to improve therapy and reduce the side effects of therapeutic radiation use. Knowing the different genes involved in breast cancer will make possible the improvement of clinical chemotherapy.

Chlorogenic acid improves growth performance of weaned rabbits via modulating the intestinal epithelium functions and intestinal microbiota.

This study was conducted to investigate the impacts of chlorogenic acid (CGA) on growth performance, intestinal permeability, intestinal digestion and absorption-related enzyme activities, immune responses, antioxidant capacity and cecum microbial composition in weaned rabbits. One hundred and sixty weaned rabbits were allotted to four treatment groups and fed with a basal diet or a basal diet supplemented with 400, 800, or 1,600 mg/kg CGA, respectively. After a 35-d trial, rabbits on the 800 mg/kg CGA-supplemented group had higher (p < 0.05) ADG and lower (p < 0.05) F/G than those in control (CON) group. According to the result of growth performance, eight rabbits per group were randomly selected from the CON group and 800 mg/kg CGA group to collect serum, intestinal tissue samples and cecum chyme samples. Results showed that compared with the CON group, supplementation with 800 mg/kg CGA decreased (p < 0.05) levels of D-lactate, diamine oxidase, IL-1β, IL-6, and malondialdehyde (MDA), and increased IL-10 concentration in the serum; increased (p < 0.05) jejunal ratio of villus height to crypt depth, enhanced (p < 0.05) activities of maltase and sucrase, increased (p < 0.05) concentrations of IL-10, T-AOC, MHCII and transforming growth factor-α, and decreased (p < 0.05) levels of TNF-α and MDA in the jejunum of weaned rabbits. In addition, results of high-throughput sequencing showed that CGA supplementation elevated (p < 0.05) microbial diversity and richness, and increased (p < 0.05) the abundances of butyrate-producing bacteria (including genera V9D2013_group, Monoglobus, Papillibacter, UCG-005, and Ruminococcus). These results indicated that dietary supplementation with 800 mg/kg CGA could improve the growth performance of weaned rabbits by enhancing intestinal structural integrity, improving the intestinal epithelium functions, and modulating the composition and diversity of gut microbiota.

Red blood cell distribution width derivatives in alcohol-related liver cirrhosis and metabolic-associated fatty liver disease

BACKGROUNDLooking for undiscovered blood markers of liver fibrosis and steatosis still remains an issue worth exploring. There are still plenty of unresolved issues related to the actual role of hematological indices as potential markers of liver function.AIMTo study red blood cell distribution width (RDW), RDW-to-platelet ratio (RPR) and RDW-to-lymphocyte ratio (RLR) in alcohol-related liver cirrhosis (ALC) and metabolic-associated fatty liver disease (MAFLD).METHODSThe study group was composed of 302 people: 142 patients with ALC and 92 with MAFLD; 68 persons were included as controls. RDW, RPR and RLR were measured in each person. Indirect and direct parameters of liver fibrosis were also assessed [aspartate transaminase to alkaline transaminase ratio, aspartate transaminase to platelet ratio index (APRI), fibrosis-4 (FIB-4), gamma-glutamyl transpeptidase to platelet ratio (GPR), procollagen I carboxyterminal propeptide, procollagen III aminoterminal propeptide, transforming growth factor-α, platelet-derived growth factor AB, laminin]. MELD score in ALC patients and non-alcoholic fatty liver disease (NAFLD) fibrosis score together with BARD score were obtained in the MAFLD group. The achieved results were compared to controls. Then a correlation between assessed markers was done. Diagnostic value of each investigated parameter and its suggested cut-off in the research group were evaluated with area under the curve (AUC).RESULTSRDW, RPR and RLR values turned out to be significantly higher in ALC and MAFLD groups compared to controls (ALC: P < 0.0001; NAFLD: P < 0.05, P < 0.0001 and P < 0.0001, respectively). RPR correlated positively with MELD score (P < 0.01) and indirect indices of liver fibrosis (FIB-4 and GPR; P < 0.0001) in ALC patients; negative correlations were found between PDGF-AB and both: RDW and RPR (P < 0.01 and P < 0.0001, respectively). RPR correlated positively with NAFLD fibrosis score and APRI (P < 0.0001) in the MAFLD group; a positive relationship was observed between RDW and FIB-4, too (P < 0.05). AUC values and suggested cut-offs for RDW, RPR and RLR in ALC patients were: 0.912 (> 14.2%), 0.965 (> 0.075) and 0.914 (> 8.684), respectively. AUC values and suggested cut-offs for RDW, RPR and RLR in MAFLD patients were: 0.606 (> 12.8%), 0.724 (> 0.047) and 0.691 (> 6.25), respectively.CONCLUSIONRDW with its derivatives appear to be valuable diagnostic markers in patients with ALC. They can also be associated with a deterioration of liver function in this group.

Effects of dietary Bopu powder supplementation on intestinal development and microbiota in broiler chickens.

This study aimed to investigate the effect of dietary supplementation with Bopu powder on intestinal development and bacterial community composition in broiler chickens. A total of 486 1-day-old arbor acres broilers were fed a basal diet (CON group), a basal diet supplemented with 50 mg/kg aureomycin (AB group), or a basal diet supplemented with 40 mg/kg Bopu powder (BP group). The results showed that the BP group had significantly lower serum tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, and diamine oxidase concentrations and had significantly higher serum IL-10 concentrations than CON group (p < 0.05). Groups AB and BP had a significantly higher weight per unit length of the small intestine and villus height than the CON group (p < 0.05), and BP group had a significantly higher ratio of villus height to crypt depth than groups CON and AB (p < 0.05). Compared to the CON group, dietary Bopu powder or aureomycin supplementation significantly increased transforming growth factor-α concentration and mRNA expressions of zonula occludens-1 (ZO-1) and occludin, and decreased intestinal mucosal concentrations of TNF-α, IL-6, IL-10, caspase-3, and caspase-8 and mRNA expressions of nuclear factor-kappa-B and Bax/Bcl-2 ratio in the intestinal mucosa (p < 0.05). Meanwhile, BP group had significantly higher ZO-1, secretory immunoglobulin A, interferon-γ concentrations, and mRNA expressions of glucose transporter type-2 and sirtuin-1, and significantly lower IL-1β concentration than groups CON and AB in intestinal mucosa (p < 0.05). Dietary Bopu powder supplementation significantly increased the concentration of trefoil factor family member and mRNA expressions of superoxide dismutase-1 and bcl-2 associated X, and significantly reduced casepase-9 concentration and myeloid differentiation primary response-88 expression in the intestinal mucosa of broiler chickens relative to CON group (p < 0.05). Moreover, results of high-throughput sequencing showed that broilers in the BP group had microbial community structure distinct from that in CON group, and the addition of Bopu powder increased the abundances of Faecalibacterium and Colidextribacter (p < 0.05). Therefore, our study suggests a synergic response of intestinal development and microbiota to the Bopu powder, and provides a theoretical basis as a potential substitute for antibiotics.

S3634 Menetrier Disease: A Case Report

Introduction: Menetrier disease is a rare form of protein-losing gastropathy that is characterized by enlarged mucosal folds in the proximal part of the stomach. Although it is generally self-limited in children, adult patients are at increased risk of malignancies, thromboembolic phenomenon, and gastric outlet obstruction. Considering the high risk of morbidity and mortality, prompt diagnosis and management are needed. We present a rare case of Menetrier disease, occurring in a postpartum female patient. Case Description/Methods: A 25-year-old female patient presented with nausea and abdominal cramping, diarrhea and weight loss of 9 kg five weeks after delivering her 3rd child. These symptoms were followed by anasarca. Her laboratory tests showed hypoalbuminemia of 1.5 g/dl, low total protein level of 3.4 g/dl, elevated urine protein-to-creatinine ratio of 0.8, and elevated random urine protein of 16 mg/dl with otherwise normal labs (e.g., complete blood count, comprehensive metabolic panel). An esophagogastroduodenoscopy revealed markedly diffuse thick folds in the gastric fundus, body and antrum (Figure A). Antral mucosa and antral-fundic transition zone mucosa showed foveolar hyperplasia with negative Helicobacter pylori and cytomegalovirus (CMV) staining (Figure B). She was treated with IV antiemetics, IV albumin and furosemide and started on a pureed, high-protein diet which resulted in a significant improvement in her symptoms. Discussion: Although the pathophysiology of Menetrier disease is unclear, it has been associated with CMV infection in children and H. Pylori in adults. One hypothesis contributes the etiopathogenesis to an overexpression of the transforming growth factor-alpha. It commonly presents in male adult patients with epigastric pain, fatigue, weight loss, edema or/and vomiting. The diagnosis can be made based on histopathology showing extreme foveolar hyperplasia and atrophic changes in glandular epithelium. Moreover, endoscopy or barium study showing markedly enlarged gastric rugae along with laboratory findings of lymphopenia and reduced globulin, albumin, alpha-1-antitrypsin, cholesterol, ceruloplasmin and fibrinogen levels are indicative of this disease. Supportive treatment involves high-protein diet, proton pump inhibitors, and replacement of micronutrients. Treatment of H. pylori, CMV, and medications like octreotide or cetuximab showed improvement in disease progression in some patients.Figure 1.: Marked enlarged gastric rugae on endoscopy (A) and foveolar hyperplasia on biopsy (B).

Inflammatory biomarkers after an exercise intervention in childhood acute lymphoblastic leukemia survivors.

Cancer survivors show increased risk for non-communicable diseases and chronic low-grade inflammation characterizes the development of such diseases. We investigated inflammatory plasma protein profiles of survivors of childhood acute lymphoblastic leukemia (ALL) in comparison to healthy controls and after an intervention with a home-based exercise program. Survivors of childhood ALL aged 16-30 years (n = 21) with a median age at diagnosis 4.9 (1.6-12.9) years and a median time of 15.9 years from diagnosis, and sex- and age-matched healthy controls (n = 21) were studied. Stored plasma samples were analyzed with Olink's 92-protein-wide Inflammation panel in 21 ALL long-term survivors at baseline, after a previous 16-week home-based exercise intervention (n = 17) and in 21 age- and sex-matched controls at baseline. Protein expression levels were compared between the groups. Inflammatory protein levels did not differ between the survivors and controls at baseline. Significantly reduced levels after the intervention were found in 11 proteins related to either vascular inflammation, insulin resistance, or both: tumor necrosis factor superfamily member 14 (TNFSF14), oncostatin M (OSM), monocyte chemoattractant protein 1 (MCP-1), MCP-2, fibroblast growth factor 21 (FGF-21), chemokine (C-C motif) ligand 4 (CCL4), transforming growth factor alpha (TGF-α), tumor necrosis factor-related apoptosis-inducing ligand 10 (TRAIL), adenosine deaminase (ADA), chemokine (C-X-C motif) ligand 6 (CXCL6), and latency-associated peptide transforming growth factor beta 1 (LAP TGF-β1). The ALL survivors were not significantly more affected by inflammation than controls at baseline. The survivors' 16-week exercise intervention led to significant reduction in inflammatory protein levels. Physical exercise should be promoted for survivors of childhood cancer.

Association of Body Mass Index, Blood Pressure, and Interictal Serum Levels of Cytokines in Migraine with and without Aura.

The aim of the study was to clarify correlations between body mass index (BMI), blood pressure (BP), and serum levels of cytokines in female migraine patients. A total of 14 migraineurs with aura, and 12 without aura during their interictal period were compared with 25 controls. Interleukin-8 (IL-8), soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), matrix metalloproteinase-9 (MMP-9), interferon gamma (IFN-γ), monocyte chemoattractant protein-1 (MCP-1), transforming growth factor alpha (TGF-α), and plasminogen activator inhibitor-1 (PAI-1) were measured. Migraineurs have elevated levels of IL-8, but decreased serum levels of PAI-1 and sICAM-1 during the interictal period, regardless of aura. BMI correlates with BP, and also with IFN-γ and MMP-9 only in patients with aura. There are three correlations in migraine patients with aura that are absent in patients without aura: between IL-8 and PAI-1; MMP-9 and IL-8; and IL-8 and sICAM-1. Migraineurs without aura, on the other hand, have correlations that patients with aura do not have (between PAI-1 and MCP-1, sICAM-1; between MMP-9 and sICAM-1, MCP-1; between TGF-α and PAI-1, MMP-9, sICAM-1; between sICAM-1 and MMP-9, PAI-1, MCP-1; as well as between sVCAM-1 and MCP-1). PAI-1, TGF, and MMP-9 could be used as biomarkers to distinguish migraineurs from healthy individuals.

Effects of dietary daidzein supplementation on reproductive performance, immunity, and antioxidative capacity of New Zealand White does

This study was conducted to explore the effects of dietary daidzein (DA) supplementation on reproductive functions in rabbit does. A total of 200 New Zealand White does were randomly assigned to four groups and fed a basal diet with no DA (control, CON) or the basal diet supplemented with 85 (DA85), 170 (DA170), and 340 (DA340) mg DA/kg throughout the gestation. Results showed that DA elevated individual embryo weight at 19 days of gestation. DA supplementation at 170 mg/kg also elevated the individual and litter birth weight at parturition (P < 0.05). DA supplementation at 170 and 340 mg/kg elevated the serum concentrations of estrogen and IGF-I at 19 days of gestation (P < 0.05), and elevated the concentrations of leptin and high-density lipoprotein cholesterol (HDL-C) at parturition (P < 0.05). DA increased the serum concentration of IgG, but decreased the concentrations of tumour necrosis factor-α (TNF-α) and malonic dialdehyde (MDA) (P < 0.05). DA supplementation at 170 mg/kg increased the serum activities of glutathione peroxidase (GSH-Px) and catalase (CAT) at parturition (P < 0.05). Moreover, DA elevated the expression levels of critical genes related to reproductive functions such as the progesterone receptor (PGR), estrogen receptor-β (ESRRB), and transforming growth factor-α (TGF-α) in the uterus (P < 0.05). DA supplementation at a moderate dose (170 mg/kg) also elevated the expression levels of epidermal growth factor receptor (EGFR) and nuclear receptor subfamily 5 group A member 2 (NR5A2) in the placenta (P < 0.05). These results suggested that DA can improve the reproductive performance of does, which was associated with elevated serum hormones, immunity and antioxidant capacity, as well as the expression levels of critical genes related to reproductive functions.