-
Stem Cell Research & Therapy Apr 2023The efficiency of inducing human embryonic stem cells into NEUROG3+ pancreatic endocrine cells is a bottleneck in stem cell therapy for diabetes. To understand the cell...
The efficiency of inducing human embryonic stem cells into NEUROG3+ pancreatic endocrine cells is a bottleneck in stem cell therapy for diabetes. To understand the cell properties and fate decisions during differentiation, we analyzed the modified induction method using single-cell transcriptome and found that DAPT combined with four factors (4FS): nicotinamide, dexamethasone, forskolin and Alk5 inhibitor II (DAPT + 4FS) increased the expression of NEUROG3 to approximately 34.3%. The increased NEUROG3+ cells were mainly concentrated in Insulin + Glucagon + (INS + GCG+) and SLAC18A1 + Chromogranin A+(SLAC18A1 + CHGA +) populations, indicating that the increased NEUROG3+ cells promoted the differentiation of pancreatic endocrine cells and enterochromaffin-like cells. Single-cell transcriptome analysis provided valuable clues for further screening of pancreatic endocrine cells and differentiation of pancreatic islet cells. The gene set enrichment analysis (GSEA) suggest that we can try to promote the expression of INS + GCG+ population by up-regulating G protein-coupled receptor (GPCR) and mitogen-activated protein kinase signals and down-regulating Wnt, NIK/NF-KappaB and cytokine-mediated signal pathways. We can also try to regulate GPCR signaling through PLCE1, so as to increase the proportion of NEUROG3+ cells in INS+GCG+ populations. To exclude non-pancreatic endocrine cells, ALCAM CD9 could be used as a marker for endocrine populations, and ALCAM CD9CDH1 could remove the SLC18A1 + CHGA+ population.
Topics: Humans; Activated-Leukocyte Cell Adhesion Molecule; Platelet Aggregation Inhibitors; Single-Cell Gene Expression Analysis; Basic Helix-Loop-Helix Transcription Factors; Nerve Tissue Proteins; Cell Differentiation; Glucagon; Endocrine Cells; Vesicular Monoamine Transport Proteins
PubMed: 37098639
DOI: 10.1186/s13287-023-03338-z -
International Journal of Surgery Case... May 2023Gastric neuroendocrine tumors (NETs) are rare neoplasms that originate from enterochromaffin cells in the gastric mucosa and pose a diagnostic dilemma due to their...
INTRODUCTION AND IMPORTANCE
Gastric neuroendocrine tumors (NETs) are rare neoplasms that originate from enterochromaffin cells in the gastric mucosa and pose a diagnostic dilemma due to their non-specific presentation.
CASE PRESENTATION
We present a 79-year-old woman, who came with complaints of abdominal pain associated with loss of pain and appetite. Although on the first look multiple differentials could be listed, upon complete evaluation she was diagnosed to have type III Gastric NET. Histopathology and immunohistochemistry allowed diagnostic confirmation of the disease along with strong clinical suspicion. The patient however succumbed to the illness due to advanced disease and lack of established protocol for its management.
CLINICAL DISCUSSION
The treatment of Gastric NETs primarily involves surgical resection of the tumor and is especially helpful in type I and II cases. For advanced metastatic type III NETs, lines of therapy have not been established although surgical resection can be done if the majority (∼90 %) of the tumor is resectable. Patients should be given a choice in decision making and newer drug therapies should always be considered.
CONCLUSION
Since gastric NETs are a rarer cause of abdominal pain, it can often be overlooked in favor of other, more common differentials. One should be aware of this disease and the newer diagnostic methods to have any sort of clinical suspicion when presented with such a scenario. The management of the condition although not been established, novel therapies should be considered if the tumor is not resectable.
PubMed: 37087934
DOI: 10.1016/j.ijscr.2023.108238 -
Gut Microbes 2023Dietary fibers/probiotics may relieve constipation via optimizing gut microbiome, yet with limited trial-based evidences. We aimed to evaluate the effects of formulas... (Randomized Controlled Trial)
Randomized Controlled Trial
Dietary fibers/probiotics may relieve constipation via optimizing gut microbiome, yet with limited trial-based evidences. We aimed to evaluate the effects of formulas with dietary fibers or probiotics on functional constipation symptoms, and to identify modulations of gut microbiota of relevance. We conducted a 4-week double-blinded randomized placebo-controlled trial in 250 adults with functional constipation. Intervention: A: polydextrose; B: psyllium husk; C: wheat bran + psyllium husk; D: subsp. HN019 + HN001; Placebo: maltodextrin. Oligosaccharides were also included in group A to D. 16S rRNA sequencing was used to assess the gut microbiota at weeks 0, 2, and 4. A total of 242 participants completed the study. No time-by-group effect was observed for bowel movement frequency (BMF), Bristol stool scale score (BSS), and degree of defecation straining (DDS), while BSS showed mean increases of 0.95-1.05 in group A to D (all < 0.05), but not significantly changed in placebo ( = 0.170), and 4-week change of BSS showed similarly superior effects of the interventions as compared placebo. Group D showed a marginal reduction in plasma 5-hydroxytryptamine. Group A resulted in a higher abundance than placebo at week 2 and 4. Fourteen genera showed intervention-specific increasing or decreasing trends continuously, among which showed increasing trends in groups B and C, associated with BMF increase. Random forest models identified specific baseline microbial genera panels predicting intervention responders. In conclusion, we found that the dietary fibers or probiotics may relieve hard stool, with intervention-specific changes in gut microbiota relevant to constipation relief. Baseline gut microbiota may predispose the intervention responsiveness. number, NCT04667884.
Topics: Adult; Humans; Dietary Fiber; Gastrointestinal Microbiome; Psyllium; RNA, Ribosomal, 16S; Constipation; Probiotics; Bifidobacterium animalis; Gastrointestinal Diseases; Double-Blind Method
PubMed: 37078654
DOI: 10.1080/19490976.2023.2197837 -
FASEB Journal : Official Publication of... May 2023The Multiple Endocrine Neoplasia I (MEN1) locus encodes the protein MENIN, which functions as a tumor suppressor protein in neuroendocrine tissues. Gastrinomas are... (Review)
Review
The Multiple Endocrine Neoplasia I (MEN1) locus encodes the protein MENIN, which functions as a tumor suppressor protein in neuroendocrine tissues. Gastrinomas are neuroendocrine neoplasms that overproduce the hormone gastrin and can arise sporadically or as part of the MEN1 syndrome, in which mutations in the MEN1 gene lead to loss or inactivation of MENIN protein. Gastrin is a peptide hormone that is primarily synthesized in the gastric antrum and stimulates the secretion of histamine from enterochromaffin-like (ECL) cells and subsequently acid from parietal cells in the gastric corpus. In addition, gastrin exerts a mitogenic function primarily on ECL cells and progenitor cells in the gastric isthmus. Current studies seek to understand how MEN1 mutations generate a mutant MENIN protein that abrogates its tumor suppressor function. Mutations in the MEN1 gene are broadly distributed throughout its nine protein-coding exons, making it difficult to correlate protein structure with its function. Although disruption of the Men1 locus in mice causes functional neuroendocrine tumors in the pituitary and pancreas, gastrinomas do not develop in these transgenic animal models. Prior studies of human gastrinomas suggest that tissue-specific microenvironmental cues in the submucosal foregut may contribute to tumorigenesis by reprogramming of epithelial cells toward the neuroendocrine phenotype. Accordingly, recent studies suggest that neural crest-derived cells are also sensitive to reprogramming when MEN1 is deleted or mutated. Thus, the goal of this report is to review our current understanding of how MENIN modulates gastrin gene expression while highlighting its role in the prevention/suppression of neuroendocrine cell transformation.
Topics: Humans; Animals; Mice; Gastrinoma; Gastrins; Multiple Endocrine Neoplasia Type 1; Transcription Factors; Pancreatic Neoplasms; Gene Expression; Proto-Oncogene Proteins
PubMed: 37078545
DOI: 10.1096/fj.202201809RR -
BioRxiv : the Preprint Server For... Apr 2023Small bowel neuroendocrine tumors (SBNETs) originate from enterochromaffin cells in the intestine which synthesize and secrete serotonin. SBNETs express high levels of...
Small bowel neuroendocrine tumors (SBNETs) originate from enterochromaffin cells in the intestine which synthesize and secrete serotonin. SBNETs express high levels of tryptophan hydroxylase 1 (Tph1), a key enzyme in serotonin biosynthesis. Patients with high serotonin level may develop carcinoid syndrome, which can be treated with somatostatin analogues and the Tph1 inhibitor telotristat ethyl in severe cases. Although the active drug telotristat can efficiently reduce serotonin levels, its effect on tumor growth is unclear. This study determined the effect of serotonin inhibition on tumor cell growth and . The levels of Tph1 in various neuroendocrine neoplasms (NENs) were determined and the biological effects of Tph1 inhibition and using genetic and pharmacologic approaches was tested. Gene and protein expression analyses were performed on patient tumors and cancer cell lines. shRNAs targeting were used to create stable knockdown in BON cells. Control and knockdown lines were assessed for their growth rates and , angiogenesis potential, serotonin levels, endothelial cell tube formation, tumor weight, and tumor vascularity. is highly expressed in SBNETs and many cancer types. knockdown cells and telotristat treated cells showed similar growth rates as control cells . However, knockdown cells formed smaller tumors and tumors were less vascularized. Although Tph1 inhibition with telotristat showed no effect on tumor cell growth , Tph1 inhibition reduced tumor formation . Serotonin inhibition in combination with other therapies is a promising new avenue for targeting metabolic vulnerabilities in NENs.
PubMed: 37066322
DOI: 10.1101/2023.04.07.536013 -
International Journal of Nanomedicine 2023The widespread use of zinc oxide nanoparticles (ZnONPs) has raised concerns about its potential toxicity. Melatonin is a neurohormone with tremendous anti-toxic effects....
PURPOSE
The widespread use of zinc oxide nanoparticles (ZnONPs) has raised concerns about its potential toxicity. Melatonin is a neurohormone with tremendous anti-toxic effects. The enterochromaffin cells are an essential source of melatonin in vivo. However, studies on the effects of ZnONPs on endogenous melatonin are minimal. In the present study, we aimed to investigate the effects of ZnONPs exposure on gut-derived melatonin.
METHODS
In the present study, 64 adult male mice were randomly and equally divided into four groups, and each group was exposed to ZnONPs (0, 6.5, 13, 26 mg/kg/day) for 30 days. Subsequently, the neurobehavioral changes were observed. The effects of ZnONPs on the expression of melatonin-related genes arylalkylamine N-acetyltransferase (), melatonin receptor1A (/), melatonin receptor1B (/), and neuropeptide Y () on melatonin synthesis and secretion in duodenum, jejunum, ileum and colon during day and night were also assessed.
RESULTS
The results revealed that oral exposure to ZnONPs induced impairments of locomotor activity and anxiety-like behavior in adult mice during the day. The transcriptional analysis of brain tissues revealed that exposure to ZnONPs caused profound effects on genes and transcriptional signaling pathways associated with melatonin synthesis and metabolic processes during the day and night. We also observed that, in the duodenum, jejunum, ileum and colon sites, ZnONPs resulted in a significant reduction in the expression of the gut-derived melatonin rate-limiting enzyme , the membrane receptors and and during the day and night.
CONCLUSION
Taken together, this is the first study shows that oral exposure to ZnONPs interferes with melatonin synthesis and secretion in different intestinal segments of adult mice. These findings will provide novelty insights into the neurotoxic mechanisms of ZnONPs and suggest an alternative strategy for the prevention of ZnONP neurotoxicity.
Topics: Male; Mice; Animals; Zinc Oxide; Melatonin; Nanoparticles
PubMed: 37057188
DOI: 10.2147/IJN.S386240 -
Journal of Neuroendocrinology Nov 2023Throughout the 20th Century, regulatory peptide discovery advanced from the identification of gut hormones to the extraction and characterization of hypothalamic... (Review)
Review
Throughout the 20th Century, regulatory peptide discovery advanced from the identification of gut hormones to the extraction and characterization of hypothalamic hypophysiotropic factors, and to the isolation and cloning of multiple brain neuropeptides. These discoveries were followed by the discovery of G-protein-coupled and other membrane receptors for these peptides. Subsequently, the systems physiology associated with some of these multiple regulatory peptides and receptors has been comprehensively elucidated and has led to improved therapeutics and diagnostics and their approval by the US Food and Drug Administration. In light of this wealth of information and further potential, it is truly a time of renaissance for regulatory peptides. In this perspective, we review what we have learned from the pioneers in exemplified fields of gut peptides, such as cholecystokinin, enterochromaffin-like-cell peptides, and glucagon, from the trailblazing studies on the key stress hormone, corticotropin-releasing factor, as well as from more recently characterized relaxin-family peptides and receptors. The historical viewpoints are based on our understanding of these topics in light of the earliest phases of research and on subsequent studies and the evolution of knowledge, aiming to sharpen our vision of the current state-of-the-art and those studies that should be prioritized in the future.
Topics: Neuropeptides; Corticotropin-Releasing Hormone; Cholecystokinin; Relaxin; Glucagon
PubMed: 37053148
DOI: 10.1111/jne.13251 -
Iranian Journal of Basic Medical... 2023To examine the effect and potential mechanism of electroacupuncture (EA) pretreatment in spatial learning, memory, gut microbiota, and JNK signaling in...
OBJECTIVES
To examine the effect and potential mechanism of electroacupuncture (EA) pretreatment in spatial learning, memory, gut microbiota, and JNK signaling in D-galactose-induced AD-like rats.
MATERIALS AND METHODS
The AD-like rat model was generated by intraperitoneal injection of D-galactose. Morris water maze was used to determine spatial learning and memory ability, Real-time PCR to determine intestinal flora levels, ELISA to determine tryptophan (Trp) and 5-HT levels in the colon and hippocampal tissues, immunofluorescence to determine 5-HT levels in enterochromaffin cells (ECs), and immunoblotting to determine JNK signaling protein levels in hippocampal tissues.
RESULTS
Electroacupuncture pretreatment significantly reduced escape latency and prolonged exploration time in the target quadrant, and significantly increased the relative DNA abundance of and . Meanwhile, electroacupuncture pretreatment also reduced colonic 5-HT levels and increased hippocampal 5-HT levels. Moreover, electroacupuncture pretreatment significantly inhibited hippocampal JNK pathway-related protein expression, including 5-HT6R, JNK, p-JUNK, c-JUN, and p-c-Jun. And the combination of GV20 and ST36 was more effective than single acupoints.
CONCLUSION
Electroacupuncture pretreatment improved the learning and memory ability of D-galactose-induced AD-like model rats, changed the gut microbiota composition, and the mechanism may be related to the gut-brain axis and the JNK signaling pathway. In addition, the combination of GV20 and ST36 could further enhance the efficacy.
PubMed: 37051108
DOI: 10.22038/IJBMS.2023.66954.14683 -
Developmental Cell May 2023Pancreatic islet cells derived from human pluripotent stem cells hold great promise for modeling and treating diabetes. Differences between stem-cell-derived and primary...
Pancreatic islet cells derived from human pluripotent stem cells hold great promise for modeling and treating diabetes. Differences between stem-cell-derived and primary islets remain, but molecular insights to inform improvements are limited. Here, we acquire single-cell transcriptomes and accessible chromatin profiles during in vitro islet differentiation and pancreas from childhood and adult donors for comparison. We delineate major cell types, define their regulomes, and describe spatiotemporal gene regulatory relationships between transcription factors. CDX2 emerged as a regulator of enterochromaffin-like cells, which we show resemble a transient, previously unrecognized, serotonin-producing pre-β cell population in fetal pancreas, arguing against a proposed non-pancreatic origin. Furthermore, we observe insufficient activation of signal-dependent transcriptional programs during in vitro β cell maturation and identify sex hormones as drivers of β cell proliferation in childhood. Altogether, our analysis provides a comprehensive understanding of cell fate acquisition in stem-cell-derived islets and a framework for manipulating cell identities and maturity.
Topics: Adult; Humans; Islets of Langerhans; Pancreas; Cell Differentiation; Insulin-Secreting Cells; Pluripotent Stem Cells
PubMed: 37040771
DOI: 10.1016/j.devcel.2023.03.011 -
Translational Cancer Research Mar 2023Neuroendocrine tumors of the small intestine are uncommon, but at the same time they are the most frequent subtype of neuroendocrine tumor in the gastrointestinal...
BACKGROUND
Neuroendocrine tumors of the small intestine are uncommon, but at the same time they are the most frequent subtype of neuroendocrine tumor in the gastrointestinal system. They originate from enterochromaffin cells, which are involved in the creation of serotonin. This asymptomatic characteristic in the initial presentation is usually why these tumors are discovered at a late stage, sometimes in association with symptomatic metastatic disease.
CASE DESCRIPTION
We present a case-report of a 52-year-old gentleman with a suggestive family history of hereditary cancer syndrome (mother with lung cancer and maternal uncle with colon cancer at the age of 40 years old). The patient was diagnosed with rectal cancer and he received neoadjuvant chemotherapy with short-course radiotherapy followed by a robotic low anterior resection with diverting loop ileostomy. Following closure of his ileostomy, the pathology report of the ileostomy resection specimen showed a 1.1 cm neuroendocrine tumor with negative margins.
CONCLUSIONS
This extraordinary unusual presentation could be very fortuity for the patient, who in every other opportunity just found this neuroendocrine tumor after advanced or maybe metastatic diseases.
PubMed: 37033359
DOI: 10.21037/tcr-22-2270