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The accumulating data regarding a non-biopsy diagnosis of celiac disease has led to its adoption in certain scenarios, although debate on whether and when to use non-biopsy criteria in clinical practice is ongoing. Despite the growing popularity and evidence basis for a biopsy-free approach to diagnosis in the context of highly elevated serologies, there will continue to be a role for a biopsy in some groups. This review summarizes the current evidence supporting a non-biopsy approach and arguments supporting continued reliance on biopsy, and focuses on opportunities to improve both approaches. [ABSTRACT FROM AUTHOR]

Celiac disease (CeD) is a chronic immune-mediated enteropathy, which occurs in genetically predisposed individuals by the ingestion of gluten proteins present in wheat, barley and rye. The global pooled prevalence of CeD is 0.7% and it has been reported from nations all around the globe and can affect individuals of any age. It has a wide clinical spectrum ranging from being asymptomatic to being symptomatic with severe manifestations. Though initial descriptions of CeD focused on the classical presentation with gastrointestinal manifestations, in recent years it has been found that more patients have non-classical manifestations such as anemia, osteoporosis, increased transaminases, failure to thrive or short stature. The definitive diagnosis of CeD is based on a combination of clinical history, serologic testing with/without examination of duodenal biopsies. The preferred initial serologic test regardless of age for the detection of CeD is the tissue transglutaminase (IgA anti-tTG). Children with a high tTG-IgA (≥10 ULN) AND a positive anti-endomysial IgA antibody (EMA) can be diagnosed to have CeD without the need for duodenal biopsies. The rest should undergo biopsies with at least 4 biopsies from the distal duodenum and at least 1 from the bulb. A correctly orientated biopsy showing increased intraepithelial cells and a villous to crypt ratio of <2 is suggestive of CeD. The management of CeD is a lifelong complete dietary avoidance of gluten. IgA-TGA acts as a surrogate marker for healing of the small-bowel mucosa and should be performed every 6 mo until normalization and then every 12–24 mo thereafter. [ABSTRACT FROM AUTHOR]

Clock gene disruption has been reported in inflammatory and autoimmune diseases. Specifically, it has been shown that clock gene expression is down-regulated in intestinal tissue and peripheral blood mononuclear cells of patients with inflammatory bowel disease (IBD). We aimed to determine the systemic expression of the circadian clock genes in newly diagnosed untreated, young patients with celiac disease (CeD). We prospectively enrolled patients younger than 20 years old who underwent diagnostic endoscopic procedures either for CeD diagnosis or due to other gastrointestinal complaints, at the pediatric and adult gastroenterology units, the Tel Aviv Sourasky Medical Center from 8/2016–8/2022. Demographic data, anthropometric parameters, and endoscopic macroscopic and microscopic findings were obtained. Blood samples were obtained to determine tissue transglutaminase (tTG) and core clock gene (CLOCK , BMAL1 , PER1 , PER2 , CRY1 , CRY2) expression in white blood cells (WBC). Thirty individuals were analyzed (18 with newly diagnosed CeD and 12 controls). Expression of the clock genes CLOCK , BMAL1 , CRY2 , PER1 and PER2 was significantly reduced in CeD patients compared to controls, while CRY1 did not differ between the groups. In conclusion, newly diagnosed, untreated, young patients with CeD have reduced clock gene expression in WBC compared to controls. These results suggest that, in CeD, the inflammatory response is associated with systemic disruption of clock gene expression, as is manifested in other inflammatory and autoimmune diseases. NCT03662646. • Clock gene disruption is seen in inflammatory and autoimmune diseases. • Newly diagnosed patients with celiac disease have reduced clock gene expression. • Celiac disease patients had reduced expression of CLOCK , BMAL1 , CRY2 , PER1 , PER2. • Inflammation in celiac disease is associated with clock gene disruption. [ABSTRACT FROM AUTHOR]

Objectives: To determine the prevalence of celiac disease and its predictors in children with constipation. Methods: A hospital-based cross-sectional comparative study was conducted between November, 2018 to April, 2020. Children aged 1–12 years were screened for the presence of constipation as per ROME IV criteria and designated as cases. Age and sex matched healthy children with normal bowel habits were enrolled as comparison group. Participants underwent a detailed history and examination, and were screened for celiac disease by estimating serum anti-tissue transglutaminase IgA antibody levels (tTG-IgA). Upper gastrointestinal endoscopy and duodenal biopsy were performed in all participants who tested positive on screening (serum tTG-IgA ≥ 20 U/mL). The prevalence of celiac disease and associated factors were compared between the two groups. Results: A total of 460 children (230 in each group) with mean (SD) age 64.08 (37.12) months were enrolled. Twenty-one (4.6%) children screened positive for anti tTG antibodies, among these 15 (75%) children had biopsy features suggestive of celiac disease (Marsh grade III). Children with constipation had significantly higher prevalence of celiac disease (5.65% vs 0.87%, P = 0.004) compared to children without constipation. Wasting and stunting were significantly associated with celiac disease in constipated children (P < 0.001). Conclusion: Children with constipation and associated growth failure have a high prevalence of celiac disease. [ABSTRACT FROM AUTHOR]

Summary: Background: The prevalence of coeliac disease doubled in Finland from 1980 to 2000. Aims: To investigate whether this increase is continuing and if there are specific patient‐related factors predicting the development of coeliac disease at a population level. Methods: We elicited comprehensive health data in the nationwide Health 2000 and Health 2011 surveys. Serum samples were taken for the measurement of tissue transglutaminase antibodies (TGA); subjects who were seropositive were tested for endomysial antibodies (EmA). Coeliac disease was defined either as a reported diagnosis or as positive TGA and EmA. The surveys comprised, respectively, 6379 and 4056 individuals, forming representative samples for 2,946,057 and 2,079,438 Finnish adults. Altogether 3254 individuals participating in both surveys comprised a prospective follow‐up cohort. Results: Prevalence of coeliac disease was 2.12% in 2000 and 2.40% in 2011 (p = 0.156). In the prospective cohort, 16 out of the 3254 (0.49%) subjects developed coeliac disease during follow‐up from 2000 to 2011, with an annual incidence rate of 45 per 100,000 persons. Positive TGA without EmA (OR: 133, 95% CI: 30.3–584), TGA values in the upper normal range (51.1, 16.0–163), and after adjusting for TGA, previous autoimmune co‐morbidity (8.39, 4.98–35.9) in 2000 increased the likelihood of subsequent coeliac disease. Conclusions: The nationwide prevalence of coeliac disease kept on rising from 2.12% in 2000 to 2.40% in 2011 in Finland. Positive TGA without EmA, TGA titres in the upper normal range and a pre‐existing autoimmune disease predisposed to coeliac disease during the 10‐year follow‐up. [ABSTRACT FROM AUTHOR]

Studies are scarce regarding IgG anti-tissue transglutaminase 2 (tTG) normalization in selective IgA deficient (SIgAD) celiac disease (CD) patients after beginning a gluten free diet (GFD). The aim of this study is to analyse the decreasing dynamics of IgG anti-tTG in patients diagnosed with CD who start a GFD. To achieve this objective, IgG and IgA anti-tTG levels at diagnosis and during follow-up in 11 SIgAD CD patients and in 20 IgA competent CD patients were retrospectively evaluated. At diagnosis, statistical differences were not found when comparing IgA anti-tTG levels of IgA competent subjects with IgG anti-tTG levels of SIgAD subjects. Regarding the decreasing dynamics, even though no statistical differences were found (p = 0.06), normalization rates were slower for SIgAD CD patients. After 1 and 2 years on GFD, respectively, only 18.2% and 36.3% of the SIgAD CD patients normalized IgG anti-tTG levels; otherwise, IgA anti-tTG reached values under the reference values in 30% and 80% of the IgA competent patients in the same time-points. Although IgG anti-tTG has demonstrated a high diagnostic efficiency in SIgAD CD pediatric patients, this test does not appear to be as precise for long-term GFD response monitoring as IgA anti-tTG levels in IgA sufficient patients. [ABSTRACT FROM AUTHOR]

Background: Celiac disease (CD) is frequently associated with type I diabetes mellitus (T1D), where its diagnosis may be a challenging task. This study aims to test the usefulness of the double staining immunofluorescence (dsIF) technique for the detection of intestinal anti-tissue transglutaminase specific IgA antibody (tTG-IgA) deposits in CD and T1D children with coexisting CD. Methods: A total of 46 patients (30 cases of CD and 16 cases of T1D with CD) and 16 non-diabetic, non-celiac children were recruited. Endoscopic biopsies were taken and analyzed by light microscopy, quantitative histology (QH), and a dsIF technique. Results: Histologically, villous atrophy was most severe in CD, followed by T1D with CD, while all control biopsies except 1 were normal. QH showed a statistically significant difference in villous height (Vh), crypt depth (CrD), and Vh:CrD ratio between diabetic and non-diabetic patients with CD. dsIF technique could detect tTG-IgA deposits in 85.7% of cases of CD alone and 93.8% of biopsies from diabetic children. Surprisingly, deposits were more extensive in biopsies with minimal villous shortening. Also, all 5 biopsies from T1D patients with normal histology were dsIF positive. Conclusion: In-situ analysis of tTG-IgA immune deposits facilitates the detection of positive serology early-onset CD. Quantitative analysis may be used as an ancillary tool to increase the reliability of histological findings in these patients.

BackgroundCeliac serology has evolved, with the identification of newer antibodies against deamidated gliadin peptides (DGP) [e.g., anti-DGP, immunoglobulin A (IgA), and immunoglobulin G (IgG) types] with sensitivity and specificity in detecting celiac disease (CeD) that are equivalent to anti-tissue transglutaminase [anti-tissue transglutaminase (TTG) IgA]-based tests, particularly in populations with high pretest probability of CeD (prevalence of CeD > 50% of the population under study). This opens the possibility that anti-DGP assays can be used to identify CeD in the general population where the prevalence of CeD is very low (≈1%).ObjectiveThis study aimed (1) to determine the diagnostic performance of DGP antibodies-based serologic assays in identifying CeD during the screening of the general population and (2) to compare the levels of anti-DGP antibodies among CeD patients with mild and severe degrees of enteropathy.MethodsSerology tests for DGP antibodies (DGP-IgA, DGP-IgG, and conjugate TTG/DGP antibodies) were performed on 104 serum samples of positive TTG-IgA (100 confirmed and four potential celiac patients) and a randomly selected 1,000 negative TTG-IgA serum samples collected during mass screening of children (aged 6–15 years) in 2014–2015.ResultsSera from 32 of the 1,000 TTG-IgA negative serum specimens (3.2%) tested positive for one or more of the three anti-DGP serology tests. A total of 13 of the 32 anti-DGP seropositive patients had persistent positive results on follow-up samples in 2020 (1.3%). Eight of the 13 underwent endoscopy with biopsies, and only two had confirmed CeD (both DGP-IgG positive) (0.2%). The sensitivity and specificity of the serology assays were as follows: DGP-IgA (62.7%, 40%), DGP-IgG (80.4%, 100%), and conjugate TTG/DGP (96%, 10%). Based on receiver operating characteristic curves, the area under the curve for DGP-IgG (0.919; 95% CI −0.00406 to 0.114) was comparable to TTG-IgA (0.974; 95% CI 0.924–0.995) (P = 0.0679). Titers of antibodies to DGPs were significantly higher in children with severe intestinal damage than in those in children with mild lesions (P

Circulating uremic toxin indoxyl sulfate (IS), endothelial cell (EC) dysfunction, and decreased nitric oxide (NO) bioavailability are found in chronic kidney disease patients. NO nitrosylates/denitrosylates a specific protein's cysteine residue(s), forming S-nitrosothios (SNOs), and the decreased NO bioavailability could interfere with NO-mediated signaling events. We were interested in investigating the underlying mechanism(s) of the reduced NO and how it would regulate the S-nitrosylation of tissue transglutaminase (TG2) and its substrates on glycolytic, redox and inflammatory responses in normal and IS-induced EC injury. TG2, a therapeutic target for fibrosis, has a Ca2+-dependent transamidase (TGase) that is modulated by S-nitrosylation. We found IS increased oxidative stress, reduced NADPH and GSH levels, and uncoupled eNOS to generate NO. Immunoblot analysis demonstrated the upregulation of an angiotensin-converting enzyme (ACE) and significant downregulation of the beneficial ACE2 isoform that could contribute to oxidative stress in IS-induced injury. An in situ TGase assay demonstrated IS-activated TG2/TGase aminylated eNOS, NFkB, IkBα, PKM2, G6PD, GAPDH, and fibronectin (FN), leading to caspases activation. Except for FN, TGase substrates were all differentially S-nitrosylated either with or without IS but were denitrosylated in the presence of a specific, irreversible TG2/TGase inhibitor ZDON, suggesting ZDON-bound TG2 was not effectively transnitrosylating to TG2/TGase substrates. The data suggest novel roles of TG2 in the aminylation of its substrates and could also potentially function as a Cys-to-Cys S-nitrosylase to exert NO's bioactivity to its substrates and modulate glycolysis, redox, and inflammation in normal and IS-induced EC injury. [ABSTRACT FROM AUTHOR]

Celiac disease (CD) is an immune-mediated enteropathy driven by gluten intake. Presence of tTG-IgA antibodies is important for the diagnosis. However, different tTG-IgA assays are used and test performance may vary. Therefore, a retrospective multicenter study was performed to compare the diagnostic performance of three assays. The fluorescence enzyme-linked immunoassay (FEIA) EliA Celikey IgA (Phadia), the chemiluminescence immunoassays (CLIA) h-tTG IgA QUANTA Flash® (Inova Diagnostics) and the anti-tTG ChLIA IgA (Euroimmun) were compared. Diagnostic samples from CD cases (95 adults; 65 children) and controls (479 adults; 253 children) were included. Samples were blinded and reanalyzed on all platforms. A high quantitative correlation between platforms was found (p<0.0001). Both CLIA were more sensitive (adults 100%; children 100%) compared to the FEIA (adults 88.4%; children 96.6%). Specificity of all assays was high (≥97.6%) with the FEIA having the highest specificity. A cut-off based on receiver operator characteristic analysis (6.5 U/mL) improved the sensitivity of the FEIA (adults 95.8%; children 100%) without affecting specificity. Cut-off values for the CLIA assays did not need further optimization. With the FEIA, 71% of pediatric cases had a tTG-IgA level ≥10× upper limit of normal compared to 91 and 92% with QUANTA Flash and ChLIA, respectively. All platforms have high diagnostic accuracy. The CLIA assays are more sensitive compared to the FEIA assay. A lower cut-off for the FEIA improves diagnostic performance, particularly in adult cases that, as demonstrated in this study, present with lower tTG-IgA levels compared to pediatric cases. [ABSTRACT FROM AUTHOR]

Celiac disease (CD) is frequently associated with type I diabetes mellitus (T1D), where its diagnosis may be a challenging task. This study aims to test the usefulness of the double staining immunofluorescence (dsIF) technique for the detection of intestinal anti-tissue transglutaminase specific IgA antibody (tTG-IgA) deposits in CD and T1D children with coexisting CD. A total of 46 patients (30 cases of CD and 16 cases of T1D with CD) and 16 non-diabetic, non-celiac children were recruited. Endoscopic biopsies were taken and analyzed by light microscopy, quantitative histology (QH), and a dsIF technique. Histologically, villous atrophy was most severe in CD, followed by T1D with CD, while all control biopsies except 1 were normal. QH showed a statistically significant difference in villous height (Vh), crypt depth (CrD), and Vh:CrD ratio between diabetic and non-diabetic patients with CD. dsIF technique could detect tTG-IgA deposits in 85.7% of cases of CD alone and 93.8% of biopsies from diabetic children. Surprisingly, deposits were more extensive in biopsies with minimal villous shortening. Also, all 5 biopsies from T1D patients with normal histology were dsIF positive. In-situ analysis of tTG-IgA immune deposits facilitates the detection of positive serology early-onset CD. Quantitative analysis may be used as an ancillary tool to increase the reliability of histological findings in these patients. [ABSTRACT FROM AUTHOR]

Objective: To investigate the distribution of axial length (AL) and posterior staphyloma (PS) in congenital cataract (CC) patients. The correlation between AL and the concentration of tissue transglutaminase (TGM2) in the aqueous humor (AH) of cataractous eyes was also evaluated. Methods: Cross-sectional data were collected from 499 children with CC who underwent phacoemulsification, anterior vitrectomy, and IOL implantation. AL measured by IOLMaster or A-scan ultrasonography and the presence of PS examined by B-scan ultrasonography were recorded. TGM2 levels in AH of 15 CC patients with normal axial length (NAL) and 15 CC patients with PS or long axial length (LAL) were measured by enzyme-linked immunosorbent assay. Results: The presence of PS in congenital cataractous eyes was 11.02%, and the presence of PS + LAL in congenital cataractous eyes was 29.06%. The AH levels of TGM2 in the cataractous group with NAL were lower than those in the cataractous group with PS or LAL (P

Aim: The present study aims to determine the rate of mucosal recovery and predictors of persistent mucosal damage after gluten free diet (GFD). Background: Celiac disease (CD) is a complex multi-systemic autoimmune disease triggered by exposure to dietary gluten in genetically predisposed individuals. There is still little evidence on the best method for assessing GFD adherence and mucosal recovery during treatment. Methods: The retrospective study included only adult patients (age≥18 years old), with biopsy-proven CD evaluated at a tertiary referral centre between 2016 and 2021. We performed a logistic regression analysis to identify factors associated with partial mucosal recovery (MR) after GFD. We included in the multivariate analysis parameters available at the time of CD diagnosis. Results: A total of 102 patients were enrolled, two thirds were females, median age of 39 years (yrs). The initial biopsy analysis showed different stages of villous atrophy (VA) in 79 (77.4%) cases, while in 23(22.5%) cases showed mild enteropathy (Marsh 1, 2). After at least 12 months of GFD, 26 (25.5%) patients had persistent VA despite good or excellent adherence to GFD. Younger patients (< 35yrs), who showed severe mucosal damage (Marsh 3c lesions) and who had increased anti-gliadin antibody (AGA) levels were at risk for failure to obtain mucosal recovery (MR). Logistic regression analysis demonstrated that complete mucosal atrophy (P=0.007) and high AGA antibody levels (cutoff 129 U/ml, P=0.001) were independent risk factors for lack of mucosal improvement after at least 12 months of GFD. Interestingly, genotype, tTG-IgA antibody levels, or duration of GFD levels did not influence the occurrence of MR. Conclusion: Although AGA seropositivity has lost much of their diagnostic significance in recent years due to the introduction of the more sensitive and specific antibody tests, our study reported that patients aged < 35 yrs, who showed severe mucosal damage (Marsh 3c lesions) and who had increased AGA antibody levels at diagnosis were at risk for failure to obtain MR. The elevated AGA levels at diagnosis could be used as a prognostic tool for assessing MR. [ABSTRACT FROM AUTHOR]

Adhesion G protein-coupled receptors (aGPCRs) represent a distinct family of GPCRs that regulate several developmental and physiological processes. Most aGPCRs undergo GPCR autoproteolysis-inducing domain-mediated protein cleavage, which produces a cryptic tethered agonist (termed Stachel (stinger)), and cleavage-dependent and -independent aGPCR signaling mechanisms have been described. aGPCR G1 (ADGRG1 or G protein-coupled receptor 56 (GPR56)) has pleiotropic functions in the development of multiple organ systems, which has broad implications for human diseases. To date, two natural GPR56 ligands, collagen III and tissue transglutaminase (TG2), and one small-molecule agonist, 3-α-acetoxydihydrodeoxygedunin (3-α-DOG), have been identified, in addition to a synthetic peptide, P19, that contains seven amino acids of the native Stachel sequence. However, the mechanisms by which these natural and small-molecule agonists signal through GPR56 remain unknown. Here we engineered a noncleavable receptor variant that retains signaling competence via the P19 peptide. We demonstrate that both natural and small-molecule agonists can activate only cleaved GPR56. Interestingly, TG2 required both receptor cleavage and the presence of a matrix protein, laminin, to activate GPR56, whereas collagen III and 3-α-DOG signaled without any cofactors. On the other hand, both TG2/laminin and collagen III activate the receptor by dissociating the N-terminal fragment from its C-terminal fragment, enabling activation by the Stachel sequence, whereas P19 and 3-α-DOG initiate downstream signaling without disengaging the N-terminal fragment from its C-terminal fragment. These findings deepen our understanding of how GPR56 signals via natural ligands, and a small-molecule agonist may be broadly applicable to other aGPCR family members.

Aim: To examine the clinical follow up of paediatric coeliac disease and the rate of loss of follow up during childhood, for which data are scarce. Methods: In a cohort of coeliac children diagnosed in 2013–2018 in Gothenburg, Sweden, we retrospectively explored the follow‐up practice of paediatric coeliac disease until June 2021. We used medical records from hospital‐based paediatric gastroenterology and general paediatric outpatient clinics, laboratory records, and questionnaires. Loss of follow up was defined no coeliac disease‐related follow up or tissue transglutaminase test over the past 2 years of study enrolment. Results: We included 162 children (58% girls) aged 7.8–18.2 years (average 12.7). Most participants (76%) were followed at general paediatric outpatient clinics rather than hospital‐based clinics. After 2.3–8.8 (average 5.3) years since diagnosis, 23 patients (14%; 95% confidence interval, 9%–21%) had been lost to follow up. Patients with loss of follow up were more often boys (61% versus 39%, p = 0.08), with a somewhat longer average disease duration of 5.8 versus 5.2 years (p = 0.11). There were no between‐group differences in socio‐economic characteristics and patient‐reported experience measures of coeliac disease care. Conclusion: One in seven coeliac patients may experience loss of follow up during childhood. [ABSTRACT FROM AUTHOR]

Astaxanthin, a natural compound of Haematococcus pluvialis, possesses antioxidant, anti-inflammatory, anti-tumor and immunomodulatory activities. It also represents a potential therapeutic in Alzheimer's disease (AD), that is related to oxidative stress and agglomeration of proteins such as amyloid-beta (Aβ). Aβ is a neurotoxic protein and a substrate of tissue transglutaminase (TG2), an ubiquitary protein involved in AD. Herein, the effect of astaxanthin pretreatment on olfactory ensheathing cells (OECs) exposed to Aβ(1–42) or by Aβ(25–35) or Aβ(35–25), and on TG2 expression were assessed. Vimentin, GFAP, nestin, cyclin D1 and caspase-3 were evaluated. ROS levels and the percentage of cell viability were also detected. In parallel, delayed luminescence (DL) was used to monitor mitochondrial status. ASTA reduced TG2, GFAP and vimentin overexpression, inhibiting cyclin D1 levels and apoptotic pathway activation which induced an increase in the nestin levels. In addition, significant changes in DL intensities were particularly observed in OECs exposed to Aβ toxic fragment (25–35), that completely disappear when OECs were pre-incubated in astaxantin. Therefore, we suggest that ASTA pre-treatment might represent an innovative mechanism to contrast TG2 overexpression in AD. [ABSTRACT FROM AUTHOR]

Background: A strict lifelong gluten-free diet (GFD) remains the only treatment of celiac disease (CD). Adherence to gluten-free diet is best reflected by mucosal healing. Noninvasive tools capable of predicting mucosal recovery in CD patients need to be identified. Aims: To compare the ability of various modalities used to assess compliance to GFD, for predicting persistent mucosal damage in children with CD. Methods: A prospective, single-center, observational study on children with CD on a GFD was conducted between January 2020 and April 2021. Children with CD on GFD were consecutively enrolled and various modalities used to assess adherence to GFD were compared. Results: One hundred and fifty children (Mean age 12.2 ± 3.6 years, 58% Boys) on GFD (Mean duration 6 ± 3.1 years) were enrolled in the study. Persistent mucosal damage was seen in 88% of the enrolled. Fecal gluten immunogenic peptide (GIP) was positive in 87.8% (129/147). Antibodies to tissue transglutaminase (TGA-IgA) and/or deamidated gliadin peptide (DGP) were positive in 32% (48/150) whereas antibody to synthetic neoepitopes of TGA-IgA was positive in 24.8% (37/149). Non-compliance as assessed by local questionnaire, Biagi score, and dietitian detailed interview were 62.7%, 60%, and 75.3%, respectively. Serology had the highest specificity (83%) and fecal GIP had the highest sensitivity (89%). On logistic regression analysis, only non-compliance by Biagi score predicted poor mucosal recovery. Conclusion: Fecal GIP may be sensitive to detect only "one-point dietary transgression." None of the existing modalities used to assess compliance to GFD accurately predict persistent mucosal damage. A subset of patients may develop gluten tolerance. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative disease representing the most prevalent cause of dementia. It is also related to the aberrant amyloid-beta (Aβ) protein deposition in the brain. Since oxidative stress is involved in AD, there is a possible role of antioxidants present in the effected person's diet. Thus, we assessed the effect of the systemic administration of solid lipid nanoparticles (SLNs) to facilitate curcumin (CUR) delivery on TG2 isoform expression levels in Wild Type (WT) and in TgCRND8 (Tg) mice. An experimental model of AD, which expresses two mutated human amyloid precursor protein (APP) genes, was used. Behavioral studies were also performed to evaluate the improvement of cognitive performance and memory function induced by all treatments. The expression levels of Bcl-2, Cyclin-D1, and caspase-3 cleavage were evaluated as well. In this research, for the first time, we demonstrated that the systemic administration of SLNs-CUR, both in WT and in Tg mice, allows one to differently modulate TG2 isoforms, which act either on apoptotic pathway activation or on the ability of the protein to repair cellular damage in the brains of Tg mice. In this study, we also suggest that SLNs-CUR could be an innovative tool for the treatment of AD. [ABSTRACT FROM AUTHOR]

Emerging research has suggested the anticancer potential of tanshinone IIA, the bioactive ingredient isolated from the traditional Chinese herb Salvia miltiorrhiza. However, the molecular mechanism of sodium tanshinone IIA sulfonate (STS) antilung cancer effect is not very clear. In this study, our purpose is to investigate the roles of STS and elongation factor‐2 kinase (eEF‐2K) in regulating the proliferation, migration, and invasion of A549 cells and explore the implicated pathways. We found that STS suppressed A549 cell survival and proliferation in a time‐ and xdose‐dependent manner. Knockdown of eEF‐2K and treatment with STS synergistically exerted antiproliferative, ‐migratory, and ‐invasive effects on A549 cells. These effects were caused by attenuation of the extracellular signal‐regulated kinase (ERK) pathway via inhibition of tissue transglutaminase (TG2). In summary, the inhibition of eEF‐2K synergizes with STS treatment, exerting anticancer effects on lung adenocarcinoma cells through the TG2/ERK signaling pathway, which provides a potential therapeutic target for treating lung adenocarcinoma. [ABSTRACT FROM AUTHOR]

Microbial transglutaminase (mTG) is a frequently consumed processed food additive, and use of its cross-linked complexes is expanding rapidly. It was designated as a processing aid and was granted the generally recognized as safe (GRAS) classification decades ago, thus avoiding thorough assessment according to current criteria of toxicity and public health safety. In contrast to the manufacturer's declarations and claims, mTG and/or its transamidated complexes are proinflammatory, immunogenic, allergenic, pathogenic, and potentially toxic, hence raising concerns for public health. Being a member of the transglutaminase family and functionally imitating the tissue transglutaminase, mTG was recently identified as a potential inducer of celiac disease. Microbial transglutaminase and its docked complexes have numerous detrimental effects. Those harmful aspects are denied by the manufacturers, who claim the enzyme is deactivated when heated or by gastric acidity, and that its covalently linked isopeptide bonds are safe. The present narrative review describes the potential side effects of mTG, highlighting its thermostability and activity over a broad pH range, thus, challenging the manufacturers' and distributers' safety claims. The national food regulatory authorities and the scientific community are urged to reevaluate mTG's GRAS status, prioritizing public health protection against the possible risks associated with this enzyme and its health-damaging consequences., (© The Author(s) 2024. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Circulating uremic toxin indoxyl sulfate (IS), endothelial cell (EC) dysfunction, and decreased nitric oxide (NO) bioavailability are found in chronic kidney disease patients. NO nitrosylates/denitrosylates a specific protein’s cysteine residue(s), forming S-nitrosothios (SNOs), and the decreased NO bioavailability could interfere with NO-mediated signaling events. We were interested in investigating the underlying mechanism(s) of the reduced NO and how it would regulate the S-nitrosylation of tissue transglutaminase (TG2) and its substrates on glycolytic, redox and inflammatory responses in normal and IS-induced EC injury. TG2, a therapeutic target for fibrosis, has a Ca2+-dependent transamidase (TGase) that is modulated by S-nitrosylation. We found IS increased oxidative stress, reduced NADPH and GSH levels, and uncoupled eNOS to generate NO. Immunoblot analysis demonstrated the upregulation of an angiotensin-converting enzyme (ACE) and significant downregulation of the beneficial ACE2 isoform that could contribute to oxidative stress in IS-induced injury. An in situ TGase assay demonstrated IS-activated TG2/TGase aminylated eNOS, NFkB, IkBα, PKM2, G6PD, GAPDH, and fibronectin (FN), leading to caspases activation. Except for FN, TGase substrates were all differentially S-nitrosylated either with or without IS but were denitrosylated in the presence of a specific, irreversible TG2/TGase inhibitor ZDON, suggesting ZDON-bound TG2 was not effectively transnitrosylating to TG2/TGase substrates. The data suggest novel roles of TG2 in the aminylation of its substrates and could also potentially function as a Cys-to-Cys S-nitrosylase to exert NO’s bioactivity to its substrates and modulate glycolysis, redox, and inflammation in normal and IS-induced EC injury.

Tissue transglutaminase (TG2) is a member of the transglutaminase family that catalyzes Ca2+-dependent protein crosslinks and hydrolyzes guanosine 5′-triphosphate (GTP). The conformation and functions of TG2 are regulated by Ca2+ and GTP levels; the TG2 enzymatically active open conformation is modulated by high Ca2+ concentrations, while high intracellular GTP promotes the closed conformation, with inhibition of the TG-ase activity. TG2's unique characteristics and its ubiquitous distribution in the intracellular compartment, coupled with its secretion in the extracellular matrix, contribute to modulate the functions of the protein. Its aberrant expression has been observed in several cancer types where it was linked to metastatic progression, resistance to chemotherapy, stemness, and worse clinical outcomes. The N-terminal domain of TG2 binds to the 42 kDa gelatin-binding domain of fibronectin with high affinity, facilitating the formation of a complex with β-integrins, essential for cellular adhesion to the matrix. This mechanism allows TG2 to interact with key matrix proteins and to regulate epithelial to mesenchymal transition and stemness. Here, we highlight the current knowledge on TG2 involvement in cancer, focusing on its roles translating extracellular cues into activation of oncogenic programs. Improved understanding of these mechanisms could lead to new therapeutic strategies targeting this multi-functional protein. [ABSTRACT FROM AUTHOR]

Problem: Persistent hypoxia and inflammation beyond early pregnancy are involved in a bad outcome because of defective trophoblast invasiveness. Tissue transglutaminase (TG2) coregulates several cell functions. An aberrant expression and/or transamidation activity could contribute to placental dysfunction. Method of study: The first‐trimester trophoblast cell line (Swan‐71) was used to study TG2 expression and cell functions in the absence or presence of inflammatory cytokines (TNF‐α, IL‐1β) or chemical hypoxia (CoCl2). We analyzed The concentration of cytokines in the supernatant by ELISA; Cell migration by scratch assay; NF‐κB activation by detection of nuclear p65 by immunofluorescence or flow cytometry using a Swan‐71 NF‐κB‐hrGFP reporter cell line. Tissue transglutaminase expression was analyzed by immunoblot and confocal microscopy. Expression of spliced mRNA variants of tissue transglutaminase was analyzed by RT‐PCR. Transamidation activity was assessed by flow cytometry using 5‐(biotinamido)‐pentylamine substrate. Results: Chemical hypoxia and TGase inhibition, but not inflammatory stimuli, decreased Swan‐71 migration. IL‐6 production was also decreased by chemical hypoxia, but increased by inflammation. Intracellular TGase activity was increased by all stimuli, but NF‐κB activation was observed only in the presence of proinflammatory cytokines. TG2 expression was decreased by CoCl2 and TNF‐α. Translocation of TG2 and p65 to nuclei was observed only with TNF‐α, without colocalization. Differential relative expression of spliced variants of mRNA was observed between CoCl2 and inflammatory stimuli. Conclusion: The observed decrease in total TG2 expression and relative increase in short variants under hypoxia conditions could contribute to impaired trophoblast invasion and impact on pregnancy outcome. [ABSTRACT FROM AUTHOR]

The latitudinal gradient effect is described for several autoimmune diseases including celiac disease in the United States. However, the association between latitude and global celiac disease prevalence is unknown. We aimed to explore the association between latitude and serology-based celiac disease prevalence through meta-analysis. We searched MEDLINE, Embase, Cochrane, and Scopus databases from their beginning through June 29, 2018, to identify screening studies that targeted a general population sample, used serology-based screening tests, and provided a clear location from which we could assign a latitude. Studies were excluded if sampling was based on symptoms, risk factors, or referral. Study selection and data extraction were performed by independent reviewers. The association measures between latitude and prevalence of serology-based celiac disease were evaluated with random-effects meta-analyses and meta-regression. Of the identified 4667 unique citations, 128 studies were included, with 155 prevalence estimates representing 40 countries. Celiac disease was more prevalent at the higher latitudes of 51° to 60° (relative risk [RR], 1.62; 95% CI, 1.09–2.38) and 61° to 70° (RR, 2.30; 95% CI, 1.36–3.89) compared with the 41° to 50° reference level. No statistically significant difference was observed at lower latitudes. When latitude was treated as continuous, we found a statistically significant association between CD prevalence and latitude overall in the world (RR, 1.03, 95% CI, 1.01–1.05) and a subregional analysis of Europe (RR, 1.05; 95% CI, 1.02–1.07) and North America (RR, 1.1; 95% CI, 1.0–1.2). In this comprehensive review of screening studies, we found that a higher latitude was associated with greater serology-based celiac disease prevalence. [ABSTRACT FROM AUTHOR]

ZED1227 is a small molecule tissue transglutaminase (TG2) inhibitor. The compound selectively binds to the active state of TG2, forming a stable covalent bond with the cysteine in its catalytic center. The molecule was designed for the treatment of celiac disease. Celiac disease is an autoimmune-mediated chronic inflammatory condition of the small intestine affecting about 1–2% of people in Caucasian populations. The autoimmune disease is triggered by dietary gluten. Consumption of staple foods containing wheat, barley, or rye leads to destruction of the small intestinal mucosa in genetically susceptible individuals, and this is accompanied by the generation of characteristic TG2 autoantibodies. TG2 plays a causative role in the pathogenesis of celiac disease. Upon activation by Ca2+, it catalyzes the deamidation of gliadin peptides as well as the crosslinking of gliadin peptides to TG2 itself. These modified biological structures trigger breaking of oral tolerance to gluten, self-tolerance to TG2, and the activation of cytotoxic immune cells in the gut mucosa. Recently, in an exploratory proof-of-concept study, ZED1227 administration clinically validated TG2 as a "druggable" target in celiac disease. Here, we describe the specific features and profiling data of the drug candidate ZED1227. Further, we give an outlook on TG2 inhibition as a therapeutic approach in indications beyond celiac disease. [ABSTRACT FROM AUTHOR]

Aim: The standard serological test to screen for coeliac disease (CD) is tissue transglutaminase (tTG) but some experts recommend including deamidated gliadin peptide (DGP) antibodies for children younger than 3 years old. This study evaluated the utility of DGP-immunoglobulin A (IgA) and DGP-immunoglobulin G (IgG) serologies when screening children younger than 3 years old for CD.Methods: A retrospective chart review was conducted including children 3 years old and under, who had DGP and/or tTG serologies along with duodenal biopsies during their initial diagnostic evaluation. Serology results were compared to the gold-standard histopathology by χ2 to determine the significance of including DGP-IgG/IgA serologies when screening for CD in this age group.Results: We identified 478 patients, 52 who were younger than 3 years old, 43 of whom met inclusion criteria. The positive predictive value (PPV) of the DGP-IgA test was 91.7% whereas, DGP-IgG was 77.8%. When DGP serology was examined in conjunction with tTG-IgA, the PPV with DGP-IgA was 90.9% and with DGP-IgG was 87.5%.Conclusions: In isolation, DGP-IgA provides a high PPV and specificity for CD in children younger than 3 years old, whereas DGP-IgG had a much lower PPV in this age group. When used alone or in conjunction with tTG-IgA, the DGP-IgA test results in a high PPV of 91.7 and 90.9%, respectively. Based on our study, we recommend obtaining both the DGP-IgA and the tTG-IgA serology when screening infants and children younger than 3 years old for coeliac disease. [ABSTRACT FROM AUTHOR]

Abstract Background Kaempferol, a natural flavonoid, exhibits anticancer properties by scavenging reactive oxygen species (ROS). However, increasing evidence has demonstrated that, under certain conditions, kaempferol can inhibit tumor growth by upregulating ROS levels. In this study, we aimed to investigate whether kaempferol effectively suppresses pancreatic cancer through upregulation of ROS, and to explore the underlying molecular mechanism. Methods PANC-1 and Mia PaCa-2 cells were exposed to different concentrations of kaempferol. Cell proliferation and colony formation were evaluated by CCK-8 and colony formation assays. Flow cytometry was performed to assess the ROS levels and cell apoptosis. The mRNA sequencing and KEGG enrichment analysis were performed to identify differentially expressed genes and to reveal significantly enriched signaling pathways in response to kaempferol treatment. Based on biological analysis, we hypothesized that tissue transglutaminase (TGM2) gene was an essential target for kaempferol to induce ROS-related apoptosis in pancreatic cancer. TGM2 was overexpressed by lentivirus vector to verify the effect of TGM2 on the ROS-associated apoptotic signaling pathway. Western blot and qRT-PCR were used to determine the protein and mRNA levels, respectively. The prognostic value of TGM2 was analyzed by Gene Expression Profiling Interactive Analysis (GEPIA) tools based on public data from the TCGA database. Results Kaempferol effectively suppressed pancreatic cancer in vitro and in vivo. Kaempferol promoted apoptosis in vitro by increasing ROS generation, which was involved in Akt/mTOR signaling. TGM2 levels were significantly increased in PDAC tissues compared with normal tissues, and high TGM2 expression was positively correlated with poor prognosis in pancreatic cancer patients. Decreased TGM2 mRNA and protein levels were observed in the cells after treatment with kaempferol. Additionally, TGM2 overexpression downregulated ROS production and inhibited the abovementioned apoptotic signaling pathway. Conclusions Kaempferol induces ROS-dependent apoptosis in pancreatic cancer cells via TGM2-mediated Akt/mTOR signaling, and TGM2 may represent a promising prognostic biomarker for pancreatic cancer.

Background and AimWe sought to correlate two different measures of gut permeability [lactulose:mannitol (L:M) and lactulose:rhamnose (L:R)] to the severity of duodenal histopathology in children with and without elevated antibodies to tissue transglutaminase (tTG). A secondary objective was to correlate gut permeability with celiac disease (CD) serology and indices of inflammation and bacterial product translocation.MethodsWe prospectively randomized children undergoing endoscopy with abnormal (n = 54) and normal (n = 10) concentrations of circulating antibodies to tTG, to either L:M or L:R. Biopsies underwent modified Marsh scoring to measure mucosal injury. Circulating anticore Escherichia coli lipopolysaccharide (LPS) IgG, α-1 acid glycoprotein, LPS-binding protein, and C-reactive protein concentrations were measured by enzyme immunoassays.ResultsOf the 54 cases with positive celiac serology, 31 and 69% had modified Marsh 0/1 scores or ≥3a, respectively. Circulating tTG IgA correlated with the modified Marsh score (p = 0.03). L:R, but not L:M or percent L excreted, differed according to modified Marsh scores (p = 0.01). There was no significant association between any systemic marker of inflammation or gut injury, and modified Marsh scores. Concerningly, most participants had evidence of urinary M before the challenge sugar was administered.ConclusionsL:R, but not L:M, is associated with modified Marsh scores in children undergoing small bowel biopsy for suspected CD. Despite increased intestinal permeability, we see scant evidence of systemic exposure to gut microbes in these children. Gut permeability testing with L:R may predict which patients with abnormal celiac serology will have biopsy evidence for celiac disease and reduce the proportion of such patients undergoing endoscopy whose Marsh scores are ≤1. M should not be used as a monosaccharide for permeability testing in children.

A modern review of highly effective methods for the diagnosis of autoimmune bullous dermatoses are presented. The specificity of the production of autoantibodies underlying bullous dermatoses are described. Considering the severity of the disease and a significant deterioration in the quality of life of patients suffering from bullous dermatoses; the systematization of diagnostic criteria will help improve the prognosis and management of patients; and it will also help optimize work on the development of targeted drugs for the treatment of patients with this pathology.

Introduction: Celiac disease (CD) is a chronic gastrointestinal disorder arising due to gluten sensitivity in susceptible individuals. In India, one person per 100 is suffering from this disease. CD has been reported more in high wheat-consuming areas like northern India. However, the incidence of CD in patients attending tertiary care hospital of Uttarakhand has not yet been reported. Therefore, this study was planned. Materials and Methods: A retrospective study with 603 patients was done at AIIMS Rishikesh in Biochemistry Department. These patients were screened for CD by tissue transglutaminase antibodies (ttgA) levels using enzyme-linked immunosorbent assay method. Percentage of levels of ttgA 4U/ml in male, female adults, and children was calculated. Chi-square test was applied to compare results. Results: Out of 603 patients, 23 (3.81%) had abnormally raised ttgA levels (>4 U/ml). Percentage (15.18%) of ttgA levels in male children was significantly (P = 0.01) higher than 2.56% in female children. Mean + standard deviation (SD) of normal and abnormal ttgA levels in patients was 1.17 + 0.45 versus 66.81 + 34.80 U/ml, respectively. Mean + SD of abnormal ttgA levels in children and adults was 72.84 + 41.91 versus 32.38 + 24.75 U/ml, respectively. There was a statistically significant difference in abnormal ttgA levels among children and adults with children predominantly being higher (P = 0.0235). Conclusion: This study shows that levels of ttgA suggestive of CD in children are higher as compared to adults and more in males than females attending tertiary care hospital of Uttarakhand.

Background: Celiac Disease involves the small intestine patchily affecting more frequently the proximal small bowel but the histological changes have been observed till terminal ileum. Of late in addition to D2, the duodenal bulb (D1 region) biopsies have been found helpful in identifying a small group of patients with CD. Therefore, multiple site biopsies are recommended as histological changes are not uniform throughout small intestine. Methods: During this present 1.5 years prospective study, we evaluated 84 cases of suspected celiac disease with respect to the light microscopy (D1, D2, and D3 biopsy) and serology (anti tTg and or EMA). Histological examination was done according to Modified Marsh grading system. Results: Out of 84 cases with raised anti tTg, the segmental biopsies significantly increased the diagnostic accuracy from 39/44 cases (88.6%) to 43/44 cases (97.7%) and 44/44 cases (100%) when D2 alone, D1 + D2 and D1 + D2 + D3 biopsies were evaluated, respectively. Of the suspected cases of celiac disease patients (tTg > 10 ULN and associated weight loss, diarrhea), additional D3 biopsy increased the diagnostic yield by 2.1%, compared to D1, D2 region biopsy and 6.38% compared to standard D2 biopsy alone. Of the 28 cases (tTg > 10 times ULN + EMA positive and associated weight loss, diarrhea), the potential celiac disease (histologically Type 1/Normal) cases reduced from 28.5% (standard D2 region alone) to 21.4% and 17.8% when additional biopsies were taken from D1 region and D3 region, respectively, and additional D3 biopsy increased the diagnostic yield by 10.8% (compared to standard D2 biopsy alone) and 3.7% (compared to D1 and D2 biopsy). Conclusion: We believe multiple sites duodenal biopsies including D3 region biopsies might increase the diagnostic accuracy of adult celiac disease in addition to sensitive and specific serologic tests.

• 2023 American College of Gastroenterology guidelines recommend a biopsy-free approach for celiac disease diagnosis in children. • Positive predictive value of tissue transglutaminase antibody titers > 10x upper limit of normal is sufficiently high to identify children with celiac disease. • Implementing this approach will significantly reduce the biopsy burden in children. Laboratory testing for celiac disease in pediatric patients integrates serology, genetic susceptibility and duodenal biopsy examination. The 2023 American College of Gastroenterology guidelines recommend a biopsy-free approach in pediatric patients utilizing tissue transglutaminase antibody titers >10 times upper limit of normal and subsequent endomysial antibody seropositivity as sufficient for diagnosis. The objective of this study is to assess the diagnostic accuracy of biopsy-free approach at our pediatric hospital. We conducted a retrospective study involving pediatric patients who underwent biopsy for diagnostic confirmation of celiac disease between May 2019 and May 2023. For these patients, the tissue transglutaminase and endomysial antibody test results were retrieved and performance of biopsy-free approach was assessed using the duodenal histology as the gold standard for celiac disease diagnosis. Tissue transglutaminase antibody titers >10 times upper limit of normal alone demonstrated a positive predictive value of 99% for identifying celiac disease in children. Although endomysial antibody testing is underutilized at our center, its inclusion further improved the predictability to 100 %. Positive predictive value of tissue transglutaminase antibody titers >10 times upper limit of normal is sufficiently high for celiac disease diagnosis in children and may allow for deferral of duodenal biopsy at diagnosis. [ABSTRACT FROM AUTHOR]

Astaxanthin, a natural compound of Haematococcus pluvialis, possesses antioxidant, anti-inflammatory, anti-tumor and immunomodulatory activities. It also represents a potential therapeutic in Alzheimer’s disease (AD), that is related to oxidative stress and agglomeration of proteins such as amyloid-beta (Aβ). Aβ is a neurotoxic protein and a substrate of tissue transglutaminase (TG2), an ubiquitary protein involved in AD. Herein, the effect of astaxanthin pretreatment on olfactory ensheathing cells (OECs) exposed to Aβ(1–42) or by Aβ(25–35) or Aβ(35–25), and on TG2 expression were assessed. Vimentin, GFAP, nestin, cyclin D1 and caspase-3 were evaluated. ROS levels and the percentage of cell viability were also detected. In parallel, delayed luminescence (DL) was used to monitor mitochondrial status. ASTA reduced TG2, GFAP and vimentin overexpression, inhibiting cyclin D1 levels and apoptotic pathway activation which induced an increase in the nestin levels. In addition, significant changes in DL intensities were particularly observed in OECs exposed to Aβ toxic fragment (25–35), that completely disappear when OECs were pre-incubated in astaxantin. Therefore, we suggest that ASTA pre-treatment might represent an innovative mechanism to contrast TG2 overexpression in AD.

Tissue transglutaminase (tTG) is a rather unique GTP-binding/protein crosslinking enzyme that has been shown to play important roles in a number of cellular processes that impact both normal physiology and disease states. This is especially the case in the context of aggressive brain tumors, such as glioblastoma. The diverse roles played by tTG in cancer survival and progression have led to significant interest in recent years in using tTG as a therapeutic target. In this review, we provide a brief overview of the transglutaminase family, and then discuss the primary biochemical activities exhibited by tTG with an emphasis on the role it plays in glioblastoma progression. Finally, we consider current approaches to target tTG which might eventually have clinical impact. Graphical [ABSTRACT FROM AUTHOR]

Consumption of diets high in fat, sugar, and salt (Western diet, WD) is associated with accelerated arterial stiffening, a major independent risk factor for cardiovascular disease (CVD). Women with obesity are more prone to develop arterial stiffening leading to more frequent and severe CVD compared with men. As tissue transglutaminase (TG2) has been implicated in vascular stiffening, our goal herein was to determine the efficacy of cystamine, a nonspecific TG2 inhibitor, at reducing vascular stiffness in female mice chronically fed a WD. Three experimental groups of female mice were created. One was fed regular chow diet (CD) for 43 wk starting at 4 wk of age. The second was fed a WD for the same 43 wk, whereas a third cohort was fed WD, but also received cystamine (216 mg/kg/day) in the drinking water during the last 8 wk on the diet (WD þ C). All vascular stiffness parameters assessed, including aortic pulse wave velocity and the incremental modulus of elasticity of isolated femoral and mesenteric arteries, were significantly increased in WD-versus CD-fed mice, and reduced in WD þ C versus WD-fed mice. These changes coincided with respectively augmented and diminished vascular wall collagen and F-actin content, with no associated effect in blood pressure. In cultured human vascular smooth muscle cells, cystamine reduced TG2 activity, F-actin:G-actin ratio, collagen compaction capacity, and cellular stiffness. We conclude that cystamine treatment represents an effective approach to reduce vascular stiffness in female mice in the setting of WD consumption, likely because of its TG2 inhibitory capacity. [ABSTRACT FROM AUTHOR]

Objectives: Forgoing biopsy for the diagnosis of celiac disease in children with tissue transglutaminase immunoglobulin A (tTG-IgA) levels greater than or equal to 10 times the upper limit of normal (≥10×ULN) has been advocated by the European Society of Paediatric Gastroenterology, Hepatology and Nutrition.Methods: Our retrospective study tested the specificity and positive predictive value (PPV) of the BioPlex 2200 assay (Bio-Rad Laboratories) in diagnosing celiac disease at the ≥10×ULN tTG-IgA threshold, which is ≥150 U/mL (negative <15 U/mL). We used the tTG-IgA and duodenal biopsy results within 6 months following tTG-IgA measurements from 542 patients who had any number of duodenal biopsy fragments, of whom 165 patients had 5 or more tissue fragments. Sensitivity and specificity of the test were calculated using histology as the gold standard for Marsh class 2 and above.Results: For histopathologic findings in the duodenum with Marsh 2 and higher, the specificity and PPV of the BioPlex 2200 at ≥10×ULN tTG-IgA were 99.5% and 95.4% using all biopsies and 97.9% and 94.9% for biopsies with 5 or more tissue fragments.Conclusions: Should clinical considerations preclude endoscopy, the BioPlex 2200 assay at ≥10×ULN TTG-IgA could be considered highly suggestive of disease. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The organophosphate compounds chlorpyrifos (O, O-diethyl O-[3,5,6-trichloro-2-pyridinyl] phosphorothioate, CPF) and phenyl saligenin phosphate (PSP) have been widely implicated in developmental neurotoxicity and neurodegeneration. However, the underlying mechanism remains unclear. Transglutaminase (TG)2 is a calcium ion (Ca2+)-dependent enzyme with an important role in neuronal cell outgrowth and differentiation and in neurotoxin activity and is modulated by organophosphates. MATERIALS AND METHODS: We studied TG2 activity modulation by CPO and PSP during differentiation in C6 glioma cells. We studied the effects of CPO or PSP treatment with or without the TG2 inhibitor Z-DON and identified potential TG2 protein substrates via mass spectrometry. RESULTS: PSP and CPO did not affect cell viability but affected TG2 activity in differentiating cells. Our results indicate that the organophosphate- induced amine incorporation activity of TG2 may have a direct effect on neuronal outgrowth, differentiation, and cell survival by modifying several essential microtubule proteins, including tubulin. Inhibiting TG2 reduced neurite length but not cell survival. CONCLUSIONS: TG2 inhibitors can protect against organophosphate-induced neuropathy and could be used for developing novel therapeutic strategies for treating brain cancer and neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Background: The history of how our knowledge of celiac disease (CD) evolved points to its importance in children. Although it is now appreciated that CD can present at any age, it was originally thought to occur only in children and, if untreated, led to serious consequences. Content: This review includes a brief discussion of small bowel physiology and the pathogenesis of CD. Next, the varied clinical presentations of CD in children are reviewed, including both gastrointestinal and nongastrointestinal manifestations and how these contribute to the difficulty in diagnosis. In addition, information on specific conditions that are associated with CD is presented, particularly as it applies to diagnostic testing of apparently asymptomatic children. The review will also focus on diagnostic testing available for CD and their general performance characteristics. The review will end with a comparison between published guidelines from the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition for diagnosis of pediatric CD. In particular, this review will focus on differences in the incorporation of serologic and genetic testing, and the role of biopsies in the pediatric population. Summary: It is important for laboratorians to understand the evolution of diagnostic guidelines for pediatric CD and how serologic and genetic testing are being applied to and interpreted in this particular patient group. [ABSTRACT FROM AUTHOR]

Cardiovascular disease (CVD)-related mortality and morbidity are among the most critical disease burdens worldwide. CVDs encompass many diseases and involve complex pathogenesis and pathological changes. While research on these diseases has advanced significantly, treatments and their efficacy remain rather limited. New therapeutic strategies and targets must, therefore, be explored. Tissue transglutaminase (TG2) is pivotal to the pathological development of CVDs, including participating in the cross-linking of extracellular proteins, activation of fibroblasts, hypertrophy and apoptosis of cardiomyocytes, proliferation and migration of smooth muscle cells (SMCs), and inflammatory reactions. Regulating TG2 activity and expression could ensure remarkable improvements in disorders like heart failure (HF), pulmonary hypertension (PH), hypertension, and coronary atherosclerosis. In this review, we summarize recent advances in TG2: we discuss its role and mechanisms in the progression of various CVDs and its potential as a diagnostic and therapeutic target.

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Background: Iron deficiency (ID) is one of the most common manifestations of Celiac disease (CD). We aimed to determine whether ID at CD diagnosis affects tissue transglutaminase antibody (TTG) normalization rate among pediatric CD patients adhering to a gluten-free diet (GFD)., Methods: We conducted a retrospective, observational cohort study that enrolled CD subjects aged 2-18y, diagnosed between Jan 2016 and Dec 2020. Demographic and laboratory data were collected at diagnosis and one year after adherence to GFD. ID was determined according to hemoglobin and ferritin levels. We compared CD subjects with and without ID at CD diagnosis in relation to TTG normalization at one year., Results: Our cohort included 118 pediatric CD subjects. At diagnosis, 61 (51.7%) of CD subjects had ID, of whom 27 (44.3%) were female, compared to 46 (80.7%) females in the non-ID group (p<0.001). Median age at CD diagnosis was 5.7y (IQR 4-8.4, range 2-14) and 7.2y (IQR 4.7-10.8, range 0.9-16), and among those with and without ID, respectively (p=0.1). After one year of adherence to GFD, TTG normalization was achieved in 38 (65.5%) and 28 (53.8%) of those with and without ID at CD diagnosis, respectively (p=0.21). However, TTG normalization was achieved in 38 (79.2%) of males compared to 42 (49.4%) of females (p=0.001)., Conclusions: ID at CD diagnosis was not associated with lower rates of TTG normalization at one year among pediatric patients adhering to GFD. However, TTG normalization at one year was significantly more frequent among male subjects compared to females., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Meir Medical Center IRB issued approval MMC-20-0021. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Zifman et al.)

Alzheimer’s disease (AD) is a neurodegenerative disease representing the most prevalent cause of dementia. It is also related to the aberrant amyloid-beta (Aβ) protein deposition in the brain. Since oxidative stress is involved in AD, there is a possible role of antioxidants present in the effected person’s diet. Thus, we assessed the effect of the systemic administration of solid lipid nanoparticles (SLNs) to facilitate curcumin (CUR) delivery on TG2 isoform expression levels in Wild Type (WT) and in TgCRND8 (Tg) mice. An experimental model of AD, which expresses two mutated human amyloid precursor protein (APP) genes, was used. Behavioral studies were also performed to evaluate the improvement of cognitive performance and memory function induced by all treatments. The expression levels of Bcl-2, Cyclin-D1, and caspase-3 cleavage were evaluated as well. In this research, for the first time, we demonstrated that the systemic administration of SLNs-CUR, both in WT and in Tg mice, allows one to differently modulate TG2 isoforms, which act either on apoptotic pathway activation or on the ability of the protein to repair cellular damage in the brains of Tg mice. In this study, we also suggest that SLNs-CUR could be an innovative tool for the treatment of AD.

Background: Kaempferol, a natural flavonoid, exhibits anticancer properties by scavenging reactive oxygen species (ROS). However, increasing evidence has demonstrated that, under certain conditions, kaempferol can inhibit tumor growth by upregulating ROS levels. In this study, we aimed to investigate whether kaempferol effectively suppresses pancreatic cancer through upregulation of ROS, and to explore the underlying molecular mechanism.Methods: PANC-1 and Mia PaCa-2 cells were exposed to different concentrations of kaempferol. Cell proliferation and colony formation were evaluated by CCK-8 and colony formation assays. Flow cytometry was performed to assess the ROS levels and cell apoptosis. The mRNA sequencing and KEGG enrichment analysis were performed to identify differentially expressed genes and to reveal significantly enriched signaling pathways in response to kaempferol treatment. Based on biological analysis, we hypothesized that tissue transglutaminase (TGM2) gene was an essential target for kaempferol to induce ROS-related apoptosis in pancreatic cancer. TGM2 was overexpressed by lentivirus vector to verify the effect of TGM2 on the ROS-associated apoptotic signaling pathway. Western blot and qRT-PCR were used to determine the protein and mRNA levels, respectively. The prognostic value of TGM2 was analyzed by Gene Expression Profiling Interactive Analysis (GEPIA) tools based on public data from the TCGA database.Results: Kaempferol effectively suppressed pancreatic cancer in vitro and in vivo. Kaempferol promoted apoptosis in vitro by increasing ROS generation, which was involved in Akt/mTOR signaling. TGM2 levels were significantly increased in PDAC tissues compared with normal tissues, and high TGM2 expression was positively correlated with poor prognosis in pancreatic cancer patients. Decreased TGM2 mRNA and protein levels were observed in the cells after treatment with kaempferol. Additionally, TGM2 overexpression downregulated ROS production and inhibited the abovementioned apoptotic signaling pathway.Conclusions: Kaempferol induces ROS-dependent apoptosis in pancreatic cancer cells via TGM2-mediated Akt/mTOR signaling, and TGM2 may represent a promising prognostic biomarker for pancreatic cancer. [ABSTRACT FROM AUTHOR]

Transglutaminases (TGs) play important roles in the food industry, pharmacology, and biotechnology, but as protein cross‐linkers, their complexes are stable, resistant, immunogenic, and potentially pathogenic. Many TGs have been characterized, but they operate in narrow temperature and pH range limits. In a research article in this issue, Clemens Furnes and colleagues describe a novel cold‐adapted TG from Atlantic cod, which expands the operating boundaries to a lower temperature and a wider pH. In this accompanying commentary, we discuss how this TG opens new applications in cold environments and can be deactivated by heating. New sources of TGs should be explored in hot environments like hot springs, in order to increase the temperature and widen the pH ranges for human and industrial benefits.