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This study aimed to explore the magnetic resonance cholangiopancreatography (MRCP) manifestations of the pancreaticobiliary ducts and assess pancreatic exocrine function using Secretin-enhanced MRCP (S-MRCP) in dogs with acute edematous pancreatitis (AEP). Twelve (12) dogs were included, with six in the AEP group and six in the control group. The AEP model group underwent a procedure by way of pancreatic duct retrograde injection. The control group underwent the same procedure without infusion. MRCP and S-MRCP were performed identically in both the AEP group and control groups. MRCP was performed pre-surgery and on the 1st, 3rd, and 5th days post-surgery in the AEP group and control groups. The pancreaticobiliary duct diameter was significantly wider in the AEP group compared to the control group (P<0.01) on the 5th day. The S-MRCP images were evaluated on the 3rd day post-surgery at 1, 3, 5, 7, and 11 min after secretin infusion. Compared to the control group, the pancreatic ducts in the AEP group became dilated and branched which appeared, reaching the largest diameters, 3 min postsecretin injection (P<0.01). Eleven minutes after secretin infusion, the degree of duodenal filling in the AEP group was Grade 2, indicating impaired pancreatic exocrine function in dogs with AEP. In conclusion, MRCP provided excellent comprehensive visualization of the pancreatic and hepatobiliary duct systems in dogs with AEP. S-MRCP effectively detected branched pancreatic ducts and impaired pancreatic exocrine in AEP dogs. [ABSTRACT FROM AUTHOR]

Class B G protein-coupled receptors can form dimeric complexes important for high potency biological effects. Here, we apply pharmacological, biochemical, and biophysical techniques to cells and membranes expressing the prototypic secretin receptor (SecR) to gain insights into secretin binding to homo-dimeric and monomeric SecR. Spatial proximity between peptide and receptor residues, probed by disulfide bond formation, demonstrates that the secretin N-terminus moves from adjacent to extracellular loop 3 (ECL3) at wild type SecR toward ECL2 in non-dimerizing mutants. Analysis of fluorescent secretin analogs demonstrates stable engagement of the secretin C-terminal region within the receptor extracellular domain (ECD) for both dimeric and monomeric receptors, while the mid-region exhibits lower mobility while docked at the monomer. Moreover, decoupling of G protein interaction reduces mobility of the peptide mid-region at wild type receptor to levels similar to the mutant, whereas it has no further impact on the monomer. These data support a model of peptide engagement whereby the ability of SecR to dimerize promotes higher conformational dynamics of the peptide-bound receptor ECD and ECLs that likely facilitates more efficient G protein recruitment and activation, consistent with the higher observed functional potency of secretin at wild type SecR relative to the monomeric mutant receptor. GPCRs can form functionally important dimers. Here, authors study impact of dimerization of the secretin receptor on peptide ligand binding and show high receptor conformational dynamics that facilitate G protein recruitment and activation. [ABSTRACT FROM AUTHOR]

MR is a powerful diagnostic tool in the diagnosis and management of most hepatic and pancreatic diseases. Thanks to its multiple sequences, the use of dedicated contrast media and special techniques, it allows a multiparametric approach able to provide both morphological and functional information for many pathological conditions. The knowledge of correct technique is fundamental in order to obtain a correct diagnosis. In this paper, different MR sequences will be illustrated in the evaluation of liver and pancreatic diseases, especially those sequences which provide information not otherwise obtainable with other imaging techniques. Practical MR protocols with the most common indications of MR in the study of the liver and pancreas are provided. [ABSTRACT FROM AUTHOR]

Type 1 diabetes is a disease of the endocrine pancreas; however, it also affects exocrine function. Although most studies have examined the effects of diabetes on acinar cells, much less is known regarding ductal cells, despite their important protective function in the pancreas. Therefore, we investigated the effect of diabetes on ductal function. Diabetes was induced in wild‐type and cystic fibrosis transmembrane conductance regulator (CFTR) knockout mice following an i.p. administration of streptozotocin. Pancreatic ductal fluid and HCO3− secretion were determined using fluid secretion measurements and fluorescence microscopy, respectively. The expression of ion transporters was measured by real‐time PCR and immunohistochemistry. Transmission electron microscopy was used for the morphological characterization of the pancreas. Serum secretin and cholecystokinin levels were measured by an enzyme‐linked immunosorbent assay. Ductal fluid and HCO3− secretion, CFTR activity, and the expression of CFTR, Na+/H+ exchanger‐1, anoctamine‐1 and aquaporin‐1 were significantly elevated in diabetic mice. Acute or chronic glucose treatment did not affect HCO3− secretion, but increased alkalizing transporter activity. Inhibition of CFTR significantly reduced HCO3− secretion in both normal and diabetic mice. Serum levels of secretin and cholecystokinin were unchanged, but the expression of secretin receptors significantly increased in diabetic mice. Diabetes increases fluid and HCO3− secretion in pancreatic ductal cells, which is associated with the increased function of ion and water transporters, particularly CFTR. Key points: There is a lively interaction between the exocrine and endocrine pancreas not only under physiological conditions, but also under pathophysiological conditionsThe most common disease affecting the endocrine part is type‐1 diabetes mellitus (T1DM), which is often associated with pancreatic exocrine insufficiencyCompared with acinar cells, there is considerably less information regarding the effect of diabetes on pancreatic ductal epithelial cells, despite the fact that the large amount of fluid and HCO3− produced by ductal cells is essential for maintaining normal pancreatic functionsDuctal fluid and HCO3− secretion increase in T1DM, in which increased cystic fibrosis transmembrane conductance regulator activation plays a central role.We have identified a novel interaction between T1DM and ductal cells. Presumably, the increased ductal secretion represents a defence mechanism in the prevention of diabetes, but further studies are needed to clarify this issue. [ABSTRACT FROM AUTHOR]

Secretin, though originally discovered as a gut-derived hormone, is recently found to be abundantly expressed in the ventromedial hypothalamus, from which the central neural system controls satiety, energy metabolism, and bone homeostasis. However, the functional significance of secretin in the ventromedial hypothalamus remains unclear. Here we show that the loss of ventromedial hypothalamus-derived secretin leads to osteopenia in male and female mice, which is primarily induced by diminished cAMP response element-binding protein phosphorylation and upregulation in peripheral sympathetic activity. Moreover, the ventromedial hypothalamus-secretin inhibition also contributes to hyperphagia, dysregulated lipogenesis, and impaired thermogenesis, resulting in obesity in male and female mice. Conversely, overexpression of secretin in the ventromedial hypothalamus promotes bone mass accrual in mice of both sexes. Collectively, our findings identify an unappreciated secretin signaling in the central neural system for the regulation of energy and bone metabolism, which may serve as a new target for the clinical management of obesity and osteoporosis. The mechanism by which central secretin regulates metabolism is unclear. Here, the authors show that ventromedial hypothalamus-derived secretin maintains energy and bone homeostasis by controlling food intake and sympathetic nerve activity. [ABSTRACT FROM AUTHOR]

In animal pathogens, assembly of the type III secretion system injectisome requires the presence of so‐called pilotins, small lipoproteins that assist the formation of the secretin ring in the outer membrane. Using a combination of functional assays, interaction studies, proteomics, and live‐cell microscopy, we determined the contribution of the pilotin to the assembly, function, and substrate selectivity of the T3SS and identified potential new downstream roles of pilotin proteins. In absence of its pilotin SctG, Yersinia enterocolitica forms few, largely polar injectisome sorting platforms and needles. Accordingly, most export apparatus subcomplexes are mobile in these strains, suggesting the absence of fully assembled injectisomes. Remarkably, while absence of the pilotin all but prevents export of early T3SS substrates, such as the needle subunits, it has little effect on secretion of late T3SS substrates, including the virulence effectors. We found that although pilotins interact with other injectisome components such as the secretin in the outer membrane, they mostly localize in transient mobile clusters in the bacterial membrane. Together, these findings provide a new view on the role of pilotins in the assembly and function of type III secretion injectisomes. [ABSTRACT FROM AUTHOR]

The extremophile bacterium D. radiodurans boasts a distinctive cell envelope characterized by the regular arrangement of three protein complexes. Among these, the Type II Secretion System (T2SS) stands out as a pivotal structural component. We used cryo-electron microscopy to reveal unique features, such as an unconventional protein belt (DR_1364) around the main secretin (GspD), and a cap (DR_0940) found to be a separated subunit rather than integrated with GspD. Furthermore, a novel region at the N-terminus of the GspD constitutes an additional second gate, supplementing the one typically found in the outer membrane region. This T2SS was found to contribute to envelope integrity, while also playing a role in nucleic acid and nutrient trafficking. Studies on intact cell envelopes show a consistent T2SS structure repetition, highlighting its significance within the cellular framework. [ABSTRACT FROM AUTHOR]

Context: The hormone secretin (SCT) is released from intestinal S cells and acts via the SCT receptor (SCTR). Circulating SCT levels increase after Roux-en-Y gastric bypass surgery and have been associated with massive weight loss and high remission rates of type 2 diabetes (T2D) linked to these operations. Exogenous SCT was recently shown to reduce ad libitum food intake in healthy volunteers. Objective: To understand SCT biology and its potential role in T2D pathophysiology, we examined the intestinal mucosal expression profile of SCT and SCTR and evaluated the density of S cells along the intestinal tract of individuals with T2D and healthy controls. Methods: Using immunohistochemistry and messenger RNA (mRNA) sequencing, we analyzed intestinal mucosa biopsies sampled along the small intestine at 30-cm intervals and from 7 well-defined anatomical sites along the large intestine (during 2 sessions of double-balloon enteroscopy) in 12 individuals with T2D and 12 healthy controls. Results: Both groups exhibited a progressive and similar decrease in SCT and SCTR mRNA expression and S-cell density along the small intestine, with reductions of 14, 100, and 50 times, respectively, in the ileum compared to the duodenum (used as reference). Negligible amounts of SCTR and SCT mRNA, as well as low S-cell density, were found in the large intestine. No significant differences were observed between the groups. Conclusion: SCT and SCTR mRNA expression and S-cell density were abundant in the duodenum and decreased along the small intestine. Very low SCT and SCTR mRNA levels and S-cell numbers were observed in the large intestine, without aberrations in individuals with T2D compared to healthy controls. [ABSTRACT FROM AUTHOR]

Dry eye syndrome, a form of ocular surface inflammation, and chronic ocular pain are common conditions impacting activities of daily living and quality of life. Oxytocin and secretin are peptide hormones that have been shown to synergistically reduce inflammation in various tissues and attenuate the pain response at both the neuron and brain level. The oxytocin receptor (OXTR) and secretin receptor (SCTR) have been found in a wide variety of tissues and organs, including the eye. We reviewed the current literature of in vitro experiments, animal models, and human studies that examine the anti-inflammatory and anti-nociceptive roles of oxytocin and secretin. This review provides an overview of the evidence supporting oxytocin and secretin as the basis for novel treatments of dry eye and ocular pain syndromes.

The gut microbiota plays a vital role in maintaining gastrointestinal homeostasis, however, whether it is influenced by gut hormones remains unknown. Secretin is a well-known gastrointestinal hormone produced by enteroendocrine S cells. This study utilized 16S rRNA amplicon sequencing to characterize the effect of SCT deficiency on the gut microbiota. Our results show that systemic SCT knockout alters the composition and abundance of the mouse gut microbiota but does not affect fecal short-chain fatty acids and lipids concentrations. At the genus level, the abundance of Turicibacter, Bacteroides, Ruminococcu, Romboutsia, Asaccharobacter, and Parasutterella increased in SCT-/- mice, whereas the abundance of Akkermansia and Escherichia decreased. Functional prediction results showed that lack of SCT reduced the abundance of carbohydrate metabolism-related pathways but increased the abundance of linoleic acid metabolism and branched-chain amino acid degradation. Overall, systemic SCT knockout had only minor effects on gut microbiota composition and function in adult male mice fed a standard chow diet.

ABSTRACTIntestinal microbes impact the health of the intestine and organs distal to the gut. Limosilactobacillus reuteri is a human intestinal microbe that promotes normal gut transit, the anti-inflammatory immune system, wound healing, normal social behavior in mice, and prevents bone reabsorption. Oxytocin impacts these functions and oxytocin signaling is required for L. reuteri-mediated wound healing and social behavior; however, the events in the gut leading to oxytocin stimulation and beneficial effects are unknown. Here we report evolutionarily conserved oxytocin production in the intestinal epithelium through analysis of single-cell RNA-Seq datasets and imaging of human and mouse intestinal tissues. Moreover, human intestinal organoids produce oxytocin, demonstrating that the intestinal epithelium is sufficient to produce oxytocin. We find that L. reuteri facilitates oxytocin secretion from human intestinal tissue and human intestinal organoids. Finally, we demonstrate that stimulation of oxytocin secretion by L. reuteri is dependent on the gut hormone secretin, which is produced in enteroendocrine cells, while oxytocin itself is produced in enterocytes. Altogether, this work demonstrates that oxytocin is produced and secreted from enterocytes in the intestinal epithelium in response to secretin stimulated by L. reuteri. This work thereby identifies oxytocin as an intestinal hormone and provides mechanistic insight into avenues by which gut microbes promote host health.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal cancers, and developing an efficient and reliable approach for its early-stage diagnosis is urgently needed. Precancerous lesions of PDAC, such as pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasms (IPMN), arise through multiple steps of driver gene alterations in KRAS, TP53, CDKN2A, SMAD4, or GNAS. Hallmark mutations play a role in tumor initiation and progression, and their detection in bodily fluids is crucial for diagnosis. Recently, liquid biopsy has gained attention as an approach to complement pathological diagnosis, and in addition to mutation signatures in cell-free DNA, cell-free RNA, and extracellular vesicles have been investigated as potential diagnostic and prognostic markers. Integrating such molecular information to revise the diagnostic criteria for pancreatic cancer can enable a better understanding of the pathogenesis underlying inter-patient heterogeneity, such as sensitivity to chemotherapy and disease outcomes. This review discusses the current diagnostic approaches and clinical applications of genetic analysis in pancreatic cancer and diagnostic attempts by liquid biopsy and molecular analyses using pancreatic juice, duodenal fluid, and blood samples. Emerging knowledge in the rapidly advancing liquid biopsy field is promising for molecular profiling and diagnosing pancreatic diseases with significant diversity. [ABSTRACT FROM AUTHOR]

MR is a powerful diagnostic tool in the diagnosis and management of most hepatic and pancreatic diseases. Thanks to its multiple sequences, the use of dedicated contrast media and special techniques, it allows a multiparametric approach able to provide both morphological and functional information for many pathological conditions. The knowledge of correct technique is fundamental in order to obtain a correct diagnosis. In this paper, different MR sequences will be illustrated in the evaluation of liver and pancreatic diseases, especially those sequences which provide information not otherwise obtainable with other imaging techniques. Practical MR protocols with the most common indications of MR in the study of the liver and pancreas are provided.

ABSTRACT Type IVa pili (T4aP) are important for bacterial motility, adhesion, biofilm formation, and virulence. This versatility is based on their cycles of extension, adhesion, and retraction. The conserved T4aP machine (T4aPM) drives these cycles; however, the piliation pattern varies between species. To understand how these patterns are established, we focused on the T4aPM in Myxococcus xanthus that assembles following an outside-in pathway, starting with the polar incorporation of the PilQ secretin forming a multimeric T4aP conduit in the outer membrane. We demonstrate that PilQ recruitment to the nascent poles initiates during cytokinesis, but most are recruited to the new poles in the daughters after the completion of cytokinesis. This recruitment depends on the peptidoglycan-binding AMIN domains in PilQ. Moreover, the pilotin Tgl stimulates PilQ multimerization in the outer membrane, is transiently recruited to the nascent and new poles in a PilQ-dependent manner, and dissociates after the completion of secretin assembly. Altogether, our data support a model whereby PilQ polar recruitment and multimerization occur in two steps: the PilQ AMIN domains bind septal and polar peptidoglycan, thereby enabling polar Tgl localization, which then stimulates secretin multimerization in the outer membrane. Using computational analyses, we provide evidence for a conserved mechanism of T4aPM pilotins whereby the pilotin transiently interacts with the unfolded β-lip of the secretin monomer, i.e., the region that eventually inserts into the outer membrane. Finally, we suggest that the presence/absence of AMIN domain(s) in T4aPM secretins contributes to the different T4aPM localization patterns across bacteria. IMPORTANCE Type IVa pili (T4aP) are widespread bacterial cell surface structures with important functions in motility, surface adhesion, biofilm formation, and virulence. Different bacteria have adapted different piliation patterns. To address how these patterns are established, we focused on the bipolar localization of the T4aP machine in the model organism Myxococcus xanthus by studying the localization of the PilQ secretin, the first component of this machine that assembles at the poles. Based on experiments using a combination of fluorescence microscopy, biochemistry, and computational structural analysis, we propose that PilQ, and specifically its AMIN domains, binds septal and polar peptidoglycan, thereby enabling polar Tgl localization, which then stimulates PilQ multimerization in the outer membrane. We also propose that the presence and absence of AMIN domains in T4aP secretins contribute to the different piliation patterns across bacteria.

The GspD secretin is the outer membrane channel of the bacterial type II secretion system (T2SS) which secrets diverse toxins that cause severe diseases such as diarrhea and cholera. GspD needs to translocate from the inner to the outer membrane to exert its function, and this process is an essential step for T2SS to assemble. Here, we investigate two types of secretins discovered so far in Escherichia coli, GspDα, and GspDβ. By electron cryotomography subtomogram averaging, we determine in situ structures of key intermediate states of GspDα and GspDβ in the translocation process, with resolution ranging from 9 Å to 19 Å. In our results, GspDα and GspDβ present entirely different membrane interaction patterns and ways of transitioning the peptidoglycan layer. From this, we hypothesize two distinct models for the membrane translocation of GspDα and GspDβ, providing a comprehensive perspective on the inner to outer membrane biogenesis of T2SS secretins. In this work the authors investigate two types of secretins in Escherichia coli, GspDα and GspDβ, and report the Cryo-ET in situ structures of their key intermediate states of during the translocation process. Yielding a resolution ranging from 9 Å to 19 Å, the structures allow the identification of different membrane interaction patterns and ways of transitioning the peptidoglycan layer. These results suggest two distinct models for the membrane translocation of GspDα and GspDβ and provide insights into the inner to outer membrane biogenesis of T2SS secretins. [ABSTRACT FROM AUTHOR]

Purpose: Secretin activates brown adipose tissue (BAT) and induces satiation in both mice and humans. However, the exact brain mechanism of this satiety inducing, secretin-mediated gut-BAT-brain axis is largely unknown. Methods and results: In this placebo-controlled, single-blinded neuroimaging study, firstly using [18F]-fluorodeoxyglucose (FDG) PET measures (n = 15), we established that secretin modulated brain glucose consumption through the BAT-brain axis. Predominantly, we found that BAT and caudate glucose uptake levels were negatively correlated (r = -0.54, p = 0.037) during secretin but not placebo condition. Then, using functional magnetic resonance imaging (fMRI; n = 14), we found that secretin improved inhibitory control and downregulated the brain response to appetizing food images. Finally, in a PET-fMRI fusion analysis (n = 10), we disclosed the patterned correspondence between caudate glucose uptake and neuroactivity to reward and inhibition, showing that the secretin-induced neurometabolic coupling patterns promoted satiation. Conclusion: These findings suggest that secretin may modulate the BAT-brain metabolic crosstalk and subsequently the neurometabolic coupling to induce satiation. The study advances our understanding of the secretin signaling in motivated eating behavior and highlights the potential role of secretin in treating eating disorders and obesity. Trial registration: EudraCT no. 2016-002373-35, registered 2 June 2016; Clinical Trials no. NCT03290846, registered 25 September 2017. [ABSTRACT FROM AUTHOR]

Pathological examination by endoscopic ultrasound–fine needle aspiration is not possible in approximately 10% of pancreatic tumor cases. Pancreatic juice cytology (PJC) is considered an alternative diagnostic method. However, its diagnostic capability is insufficient, and PJC has been repeatedly redevised. Serial pancreatic juice aspiration cytological examination (SPACE) and secretin-loaded PJC (S-PJC) have been recently introduced as alternative diagnostic methods. This study aimed to determine the diagnostic capacity and safety of SPACE and S-PJC using a propensity score-matched analysis. The sensitivity, specificity, and accuracy were 75.0%, 100%, and 92.3% for S-PJC, respectively, and 71.4%, 100%, and 92.3% for SPACE, respectively, meaning that there was no significant difference between the groups. Four patients (15.4%) each in the S-PJC and SPACE groups experienced complications, including postendoscopic retrograde cholangiopancreatography, pancreatitis, and cholangitis. Overall, there was no difference in efficacy and safety between the SPACE and S-PJC groups. [ABSTRACT FROM AUTHOR]

Objectives: To develop and validate a radiomics nomogram based on a fully automated pancreas segmentation to assess pancreatic exocrine function. Furthermore, we aimed to compare the performance of the radiomics nomogram with the pancreatic flow output rate (PFR) and conclude on the replacement of secretin-enhanced magnetic resonance cholangiopancreatography (S-MRCP) by the radiomics nomogram for pancreatic exocrine function assessment. Methods: All participants underwent S-MRCP between April 2011 and December 2014 in this retrospective study. PFR was quantified using S-MRCP. Participants were divided into normal and pancreatic exocrine insufficiency (PEI) groups using the cut-off of 200 µg/L of fecal elastase-1. Two prediction models were developed including the clinical and non-enhanced T1-weighted imaging radiomics model. A multivariate logistic regression analysis was conducted to develop the prediction models. The models' performances were determined based on their discrimination, calibration, and clinical utility. Results: A total of 159 participants (mean age ± standard deviation, 45 years ± 14;119 men) included 85 normal and 74 PEI. All the participants were divided into a training set comprising 119 consecutive patients and an independent validation set comprising 40 consecutive patients. The radiomics score was an independent risk factor for PEI (odds ratio = 11.69; p < 0.001). In the validation set, the radiomics nomogram exhibited the highest performance (AUC, 0.92) in PEI prediction, whereas the clinical nomogram and PFR had AUCs of 0.79 and 0.78, respectively. Conclusion: The radiomics nomogram accurately predicted pancreatic exocrine function and outperformed pancreatic flow output rate on S-MRCP in patients with chronic pancreatitis. Key Points: • The clinical nomogram exhibited moderate performance in diagnosing pancreatic exocrine insufficiency. • The radiomics score was an independent risk factor for pancreatic exocrine insufficiency, and every point rise in the rad-score was associated with an 11.69-fold increase in pancreatic exocrine insufficiency risk. • The radiomics nomogram accurately predicted pancreatic exocrine function and outperformed the clinical model and pancreatic flow output rate quantified by secretin-enhanced magnetic resonance cholangiopancreatography on MRI in patients with chronic pancreatitis. [ABSTRACT FROM AUTHOR]

Objective: Obesity is a major global health problem which can be targeted with new mechanistic diverse pharmacological interventions. Here we evaluate a new long-acting secretin receptor agonist as a potential treatment for obesity. Methods: BI-3434 was designed as a secretin analog with stabilized peptide backbone and attached fatty acid-based half-life extension group. The peptide was evaluated in vitro for its ability to stimulate cAMP accumulation in a cell line stably expressing recombinant secretin receptor. On the functional level, stimulation of lipolysis in primary adipocytes after treatment with BI-3434 was determined. The ability of BI-3434 to activate secretin receptor in vivo was assessed in a cAMP reporter CRE-Luc mouse model. Furthermore, a diet-induced obesity mouse model was used to test the effects of BI-3434 on body weight and food intake following repeated daily subcutaneous administration alone and in combination with a GLP-1R agonist. Results: BI-3434 potently activated human secretin receptor. However, lipolysis was only weakly induced in primary murine adipocytes. BI-3434 had an extended half-life compared to endogenous secretin and activated target tissues like pancreas, adipose tissue, and stomach in vivo. BI-3434 did not lower food intake in lean or diet-induced obese mice, but it increased energy expenditure after daily administration. This led to a loss of fat mass, which did not translate in a significant effect on body weight. However, treatment in combination with a GLP-1R agonist led to a synergistic effect on body weight loss. Conclusions: BI-3434 is a highly potent and selective agonist of secretin receptor with an extended pharmacokinetic (PK) profile. Increased energy expenditure after daily treatment with BI-3434 suggests that secretin receptor is involved in metabolic regulation and energy homeostasis. Targeting secretin receptor alone may not be an efficient anti-obesity treatment, but could be combined with anorectic principles like GLP-1R agonists.

To exchange and communicate with their surroundings, bacteria have evolved multiple active and passive mechanisms for trans -envelope transport. Among the pore-forming complexes found in the outer membrane of Gram-negative bacteria, secretins are distinctive homo-oligomeric channels dedicated to the active translocation of voluminous structures such as folded proteins, assembled fibers, virus particles or DNA. Members of the bacterial secretin family share a common cylinder-shaped structure with a gated pore-forming part inserted in the outer membrane, and a periplasmic channel connected to the inner membrane components of the corresponding nanomachine. In this mini-review, we will present what recently determined 3D structures have told us about the mechanisms of translocation through secretins of large substrates to the bacterial surface or in the extracellular milieu. • Secretins are the OM portal of the T2SS, T3SS, T4P and FPE systems. • Secretins form giant pores tailored to the secretion or assembly of large structures. • Secretins consist of a conserved OM C-module and a variable periplasmic N-module. • The channel formed by the C-module is occluded by a flexible central gate (CG). • The N-module connect with the IM components of the respective systems. [ABSTRACT FROM AUTHOR]

Background: Alcohol-related liver disease (ALD) is characterized by ductular reaction (DR), liver inflammation, steatosis, fibrosis, and cirrhosis. The secretin (Sct)/secretin receptor (SR) axis (expressed only by cholangiocytes) regulates liver phenotypes in cholestasis. We evaluated the role of Sct signaling on ALD phenotypes. Methods: We used male wild-type and Sct−/− mice fed a control diet (CD) or ethanol (EtOH) for 8 wk. Changes in liver phenotypes were measured in mice, female/male healthy controls, and patients with alcoholic cirrhosis. Since Cyp4a10 and Cyp4a11/22 regulate EtOH liver metabolism, we measured their expression in mouse/human liver. We evaluated: (i) the immunoreactivity of the lipogenesis enzyme elongation of very-long-chain fatty acids 1 (Elovl, mainly expressed by hepatocytes) in mouse/human liver sections by immunostaining; (ii) the expression of miR-125b (that is downregulated in cholestasis by Sct) in mouse liver by qPCR; and (iii) total bile acid (BA) levels in mouse liver by enzymatic assay, and the mRNA expression of genes regulating BA synthesis (cholesterol 7a-hydroxylase, Cyp27a1, 12a-hydroxylase, Cyp8b1, and oxysterol 7a-hydroxylase, Cyp7b11) and transport (bile salt export pump, Bsep, Na+-taurocholate cotransporting polypeptide, NTCP, and the organic solute transporter alpha (OSTa) in mouse liver by qPCR. Results: In EtOH-fed WT mice there was increased biliary and liver damage compared to control mice, but decreased miR-125b expression, phenotypes that were blunted in EtOH-fed Sct−/− mice. The expression of Cyp4a10 increased in cholangiocytes and hepatocytes from EtOH-fed WT compared to control mice but decreased in EtOH-fed Sct−/− mice. There was increased immunoreactivity of Cyp4a11/22 in patients with alcoholic cirrhosis compared to controls. The expression of miR-125b decreased in EtOH-fed WT mice but returned at normal values in EtOH-fed Sct−/− mice. Elovl1 immunoreactivity increased in patients with alcoholic cirrhosis compared to controls. There was no difference in BA levels between WT mice fed CD or EtOH; BA levels decreased in EtOH-fed Sct−/− compared to EtOH-fed WT mice. There was increased expression of Cyp27a1, Cyp8b1, Cyp7b1, Bsep, NTCP and Osta in total liver from EtOH-fed WT compared to control mice, which decreased in EtOH-fed Sct−/− compared to EtOH-fed WT mice. Conclusions: Targeting Sct/SR signaling may be important for modulating ALD phenotypes. [ABSTRACT FROM AUTHOR]

Innate social investigation behaviors are critical for animal survival and are regulated by both neural circuits and neuroendocrine factors. Our understanding of how neuropeptides regulate social interest, however, is incomplete at the current stage. In this study, we identified the expression of secretin (SCT) in a subpopulation of excitatory neurons in the basolateral amygdala. With distinct molecular and physiological features, BLASCT+ cells projected to the medial prefrontal cortex and were necessary and sufficient for promoting social investigation behaviors, whilst other basolateral amygdala neurons were anxiogenic and antagonized social behaviors. Moreover, the exogenous application of secretin effectively promoted social interest in both healthy and autism spectrum disorder model mice. These results collectively demonstrate a previously unrecognized group of amygdala neurons for mediating social behaviors and suggest promising strategies for social deficits. [ABSTRACT FROM AUTHOR]

Primary biliary cholangitis (PBC) is characterised by ductopenia, ductular reaction, impairment of anion exchanger 2 (AE2) and the 'bicarbonate umbrella'. Ductulo-canalicular junction (DCJ) derangement is hypothesised to promote PBC progression. The secretin (Sct)/secretin receptor (SR) axis regulates cystic fibrosis transmembrane receptor (CFTR) and AE2, thus promoting choleresis. We evaluated the role of Sct/SR signalling on biliary secretory processes and subsequent injury in a late-stage PBC mouse model and human samples. At 32 weeks of age, female and male wild-type and dominant-negative transforming growth factor beta receptor II (late-stage PBC model) mice were treated with Sct for 1 or 8 weeks. Bulk RNA-sequencing was performed in isolated cholangiocytes from mouse models. Biliary Sct/SR/CFTR/AE2 expression and bile bicarbonate levels were reduced in late-stage PBC mouse models and human samples. Sct treatment decreased bile duct loss, ductular reaction, inflammation, and fibrosis in late-stage PBC models. Sct reduced hepatic bile acid levels, modified bile acid composition, and restored the DCJ and 'bicarbonate umbrella'. RNA-sequencing identified that Sct promoted mature epithelial marker expression, specifically anterior grade protein 2 (Agr2). Late-stage PBC models and human samples exhibited reduced biliary mucin 1 levels, which were enhanced by Sct treatment. Loss of Sct/SR signalling in late-stage PBC results in a faulty 'bicarbonate umbrella' and reduced Agr2-mediated mucin production. Sct restores cholangiocyte secretory processes and DCJ formation through enhanced mature cholangiocyte phenotypes and bile duct growth. Sct treatment may be beneficial for individuals with late-stage PBC. Secretin (Sct) regulates biliary proliferation and bicarbonate secretion in cholangiocytes via its receptor, SR, and in mouse models and human samples of late-stage primary biliary cholangitis (PBC), the Sct/SR axis is blunted along with loss of the protective 'bicarbonate umbrella'. We found that both short- and long-term Sct treatment ameliorated ductular reaction, immune cell influx, and liver fibrosis in late-stage PBC mouse models. Importantly, Sct treatment promoted bicarbonate and mucin secretion and hepatic bile acid efflux, thus reducing cholestatic and toxic bile acid-associated injury in late-stage PBC mouse models. Our work perpetuates the hypothesis that PBC pathogenesis hinges on secretory defects, and restoration of secretory processes that promote the 'bicarbonate umbrella' may be important for amelioration of PBC-associated damage. [Display omitted] • The biliary secretin/secretin receptor axis is diminished in late-stage PBC. • Secretin treatment alleviates liver damage in a late-stage PBC model. • Secretin restores the protective 'bicarbonate umbrella' in a late-stage PBC model. • Secretin treatment promotes choleresis and restores ductulo-canalicular junctions. • The secretin/secretin receptor axis promotes mature cholangiocyte differentiation. [ABSTRACT FROM AUTHOR]

The body of mammals harbors two distinct types of adipose tissue: while cells within the white adipose tissue (WAT) store surplus energy as lipids, brown adipose tissue (BAT) is nowadays recognized as the main tissue for transforming chemical energy into heat. This process, referred to as 'non-shivering thermogenesis', is facilitated by the uncoupling of the electron transport across mitochondrial membranes from ATP production. BAT-dependent thermogenesis acts as a safeguarding mechanism under reduced ambient temperature but also plays a critical role in metabolic and energy homeostasis in health and disease. In this review, we summarize the evolutionary structure, function and regulation of the BAT organ under neuronal and hormonal control and discuss its mutual interaction with the central nervous system. We conclude by conceptualizing how better understanding the multifaceted communicative links between the brain and BAT opens avenues for novel therapeutic approaches to treat obesity and related metabolic disorders. [ABSTRACT FROM AUTHOR]

The natural transformation system of the thermophilic bacterium Thermus thermophilus comprises at least 16 competence proteins. Recently we found that the outer membrane (OM) competence protein PilW interacts with the secretin channel, which guides type IV pili (T4P) and potential DNA transporter pseudopili through the OM. Here we have used biochemical techniques to study the interactions of cytoplasmic, inner membrane (IM) and OM components of the DNA transporter in T. thermophilus. We report that PilW is part of a heteropolymeric complex comprising of the cytoplasmic PilM protein, IM proteins PilN, PilO, PilC and the secretin PilQ. Co-purification studies revealed that PilO directly interacts with PilW. In vitro affinity co-purification studies using His-tagged PilC led to the detection of PilC-, PilW-, PilN- and PilO-containing complexes. PilO was identified as direct interaction partner of the polytopic IM protein PilC. PilC was also found to directly interact with the cytoplasmic T4P disassembly ATPase PilT1 thereby triggering PilT1 ATPase activity. This, together with the detection of heteropolymeric PilC complexes which contain PilT1 and the pilins PilA2, PilA4 and PilA5 is in line with the hypothesis that PilC connects the depolymerization ATPase to the base of the pili possibly allowing energy transduction for disassembly of the pilins. [Display omitted] • PilW forms heteropolymeric complexes with PilM, PilN, PilO and PilC • PilO is the direct interaction partner of PilW and PilC and connects the PilW/PilQ complex with the inner membrane platform • PilC interacts with PilM, PilN, PilW, PilN, PilO and PilQ • Macromolecular PilC complexes contain the depolymerization ATPase PilT1 and different pilins [ABSTRACT FROM AUTHOR]

Background: Ductal features alone may not offer high diagnostic sensitivity or most accurate disease severity of chronic pancreatitis (CP)., Purpose: Diagnose CP based on multiparametric MRI and MRCP features., Study Type: Prospective., Population: Between February 2019 and May 2021, 46 control (23 males, 49.3 ± 14.1 years), 45 suspected (20 males, 48.7 ± 12.5 years), and 46 definite (20 males, 53.7 ± 14.6 years) CP patients were enrolled at seven hospitals enrolled in the MINIMAP study. CP classification was based on imaging findings and clinical presentation., Field Strength and Sequences: 1.5 T. T 1 -weighted (T 1 W) spoiled gradient echo, T1 map with variable flip angle, dual-echo Dixon, secretin-enhanced MRCP before and after secretin infusion., Assessment: Dual-echo fat fraction (FF), T 1 relaxation time, extracellular volume (ECV), T 1 signal intensity ratio of the pancreas to the spleen (T 1 score), arterial-to-venous enhancement ratio (AVR), pancreatic tail diameter (PTD), pancreas volume, late gadolinium enhancement, pancreatic ductal elasticity (PDE), and duodenal filling grade of secretin-enhanced MRCP were measured., Statistical Tests: Logistic regression analysis generated CP-MRI and secretin-enhanced CP-SMRI scores. Receiver operating characteristics analysis was used to differentiate definite CP from control. Interobserver agreement was assessed using Lin's concordance correlation coefficient., Results: Compared to control, definite CP cohort showed significantly higher dual-echo FF (7% vs. 11%), lower AVR (1.35 vs. 0.85), smaller PTD (2.5 cm vs. 1.95 cm), higher ECV (28% vs. 38%), and higher incidence of PDE loss (6.5% vs. 50%). With the cut-off of >2.5 CP-MRI score (dual-echo FF, AVR, and PTD) and CP-SMRI score (dual-echo FF, AVR, PTD, and PDE) had cross-validated area under the curves of 0.84 (sensitivity 87%, specificity 68%) and 0.86 (sensitivity 89%, specificity 67%), respectively. Interobserver agreement for both CP-MRI and CP-SMRI scores was 0.74., Conclusion: The CP-MRI and CP-SMRI scores yielded acceptable performance and interobserver agreement for the diagnosis of CP., Evidence Level: 1 TECHNICAL EFFICACY: Stage 2., (© 2024 The Author(s). Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Simple Summary: In human medicine Magnetic resonance imaging (MRI) and MR cholangiopancreatography (MRCP) play a consistent role in the investigation of pancreatic and pancreatic duct disorders. In veterinary medicine the number of studies focused on MR and MRCP for pancreatic disease is scant, and the protocols are not yet standardized. This review will focus on the MRI and MRCP technical aspects of the protocols used for the investigation of pancreatic disease in veterinary medicine. The aim of this review is to elucidate the value and the potential of each MR and MRCP sequence listed in the different protocols, either in canine or feline patients, with the intention to build a valid and solid tool for further innovative studies. Magnetic resonance imaging (MRI) and MR cholangiopancreatography (MRCP) have emerged as non-invasive diagnostic techniques for the diagnosis of pancreatic and pancreatic duct disorders in humans. The number of studies focused on MR and MRCP for pancreatic disease in small animals is very limited. MR has been described for the evaluation of insulinoma in dogs and to investigate pancreatitis in cats. The studies were based on a standard protocol with T2 weighted (w) fast recovery fast spin-echo (FRFSE) with and without fat suppression, T1w FSE pre-contrast and T1w FSE post-contrast with and without fat suppression. MRCP after secretin stimulation has been described in cats to assess the pancreatic ductal system, taking advantage of pulse sequences heavily T2w as rapid acquisition with rapid enhancement (RARE), fast-recovery fast spin-echo (FRFSE) sequences and single-shot fast spin-echo (SSFSE) sequences. In addition to the standard protocol, fast spoiled gradient recalled echo pulse sequences (fSPGR) and volume interpolated 3D gradient-echo T1w pulse sequences pre and post-contrast have also been used in cats, reaching the goal of assessing the biliary tree and the pancreatic duct with the same sequence and in multiple planes. Despite the small amount of data, the results show potential, and the most recent technical innovations, in particular, focused on diffusion MRI and fast acquisition, further support the need for continued evaluation of MRI as an effective instrument for the investigation of pancreatic disease. [ABSTRACT FROM AUTHOR]

Our knowledge of the coordination of intergenerational inheritance and offspring metabolic reprogramming by gastrointestinal endocrine factors is largely unknown. Here, we showed that secretin (SCT), a brain‐gut peptide, is downregulated by overnutrition in pregnant mice and women. More importantly, genetic loss of SCT in the maternal gut results in undesirable phenotypes developed in offspring including enhanced high‐fat diet (HFD)‐induced obesity and attenuated browning of inguinal white adipose tissue (iWAT). Mechanistically, loss of maternal SCT represses iWAT browning in offspring by a global change in genome methylation pattern through upregulation of DNMT1. SCT functions to facilitate ubiquitination and degradation of DNMT1 by activating AMPKα, which contributes to the observed alteration of DNMT1 in progeny. Lastly, we showed that SCT treatment during pregnancy can reduce the development of obesity and improve glucose tolerance and insulin resistance in offspring of HFD‐fed females, suggesting that SCT may serve as a novel biomarker or a strategy for preventing metabolic diseases. Synopsis: Maternal secretin promotes white adipose tissue browning in the offspring by inducing a global change in genome methylation pattern through the DNA methyltransferase DNMT1. Genetic loss of secretin in the maternal gut results in disrupted glucose and lipid homeostasis in the offspring.Maternal secretin promotes white adipose tissue browning in the offspring.Depletion of maternal SCT leads to an AMPKAα dependent increase in DNMT1 protein levels in the white adipose tissue of the offspring.Maternal secretin reprograms white adipose tissue methylation of the offspring. [ABSTRACT FROM AUTHOR]

Bacteriophage M13 assembles its progeny particles in the inner membrane of the host. The major component of the assembly machine is G1p and together with G11p it generates an oligomeric structure with a pore-like inner cavity and an ATP hydrolysing domain. This allows the formation of the phage filament, which assembles multiple copies of the membrane-inserted major coat protein G8p around the extruding single-stranded circular DNA. The phage filament then passes through the G4p secretin that is localized in the outer membrane. Presumably, the inner membrane G1p/G11p and the outer G4p form a common complex. To unravel the structural details of the M13 assembly machine, we purified G1p from infected E. coli cells. The protein was overproduced together with G11p and solubilized from the membrane as a multimeric complex with a size of about 320 kDa. The complex revealed a pore-like structure with an outer diameter of about 12 nm, matching the dimensions of the outer membrane G4p secretin. The function of the M13 assembly machine for phage generation and secretion is discussed. [ABSTRACT FROM AUTHOR]