GI hormones and digestive process

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Gut hormones and digestive process

• Dr. wudassie melak
• Assistant professor of internal medicine
• GI fellow at AAU,E thiopia

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Outline of the presentation

• Introduction
• Enteroendocrine cell types
• Regulation of GI function
• Control of gut hormone secretion
• Physiologic actions of gut hormones
• Digestion of carbohydrats, proteins and dietary
  fats

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Introduction

• The GI tract relies on hormones and
  neurotransmitters to integrate signals arising in
  the lumen with whole-body homeostasis
• GI hormones and neurotransmitters are intimately
  involved with every aspect of the digestive
  process including ingestion and absorption of
  nutrients

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Hormones and Transmitters

• Chemical messengers
• The sensory cells of the GI epithelium,
  enteroendocrine cells, as well as neurons of the
  enteric nervous system are the main producers

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GI hormones

• There are more than 30 GI hormones which qualify
  the ff
• stimulation of one organ must cause distant
  response by acting through the blood.
• response must be independent of neural
  stimulation.
• no response in the absence of the secretory
  organ.
• response should be reproducible by applying pure
  amounts of the candidate hormone onto the target
  tissue.

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NTs

• First the candidate molecule must be present
  within a presynaptic neuron.
• Second, the transmitter must be released in
  response to presynaptic depolarization. And,
• Third, specific candidate-receptors must be
  present on the postsynaptic cell.

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Enteroendocrine cells

• Hormone secreting cells in the mucosa of stomach
  , small intestine and colon
• Reside in the mucosa as single cells that are
  scattered among more numerous enterocytes
• Most enteroendocrine cells are oriented with
  their apical surface open to the lumen where they
  are exposed to food and other contents within the
  gut lumen.
• Upon stimulation, enteroendocrine cells release
  from their basolateral surface hormones, which
  enter the paracellular space where they are taken
  up into the blood

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EE cells

• May produce one hormone G cells, S cells
• Produce 5HT and hormones ECF cell
• Produce amine or polypeptide Neuroendocrine
  cells
• Two types
• Closed ex- ECL secretes histamine
• Open ex- G cells

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Enteric neurons

• Are found below the mucosal epithelium
• enteric neurons are not believed to be directly
  exposed to food in the gut.

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Regulation of GI function

• There are 4 forms of signaling in the GI tract
  neurotransmission.
• Enteroendocrine transmitters can be released onto
  their targets in the following manners
• Endocrine
• Paracrine
• Autocrine
• Neurocrine

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Examples

• Endocrine
• Ex- Gastrin, Secretin, PYY
• Paracrine
• Histamine , 5HT,SST
• Autocrine
• TGF a, B
• Neurocrine signaling
• VIP,ACH, neuropeptides, CCK

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GI Hormones
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GI Hormones

• previous belief ? a single enteroendocrine cell
  (EEC) produced only one hormone,
• Now
• EECs produce multiple types of peptide hormones
  and neurotransmitters.
• Stimulation of a single EEC can cause the release
  of multiple transmitters and thereby exert a
  variety of physiological responses

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• Classiifcation by similarity and function
• Gastrin family CCK, Gastrin
• Secretin family Secretin, Glucagon, VIP, GIP
• Others motilin, substance p,

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Gastrin

• The major hormone that stimulates gastric acid
  secretion.
• have growth-promoting effects on the gastric
  mucosa
• The active hormone is generated from a precursor
  peptide called preprogastrin, composed of 101
  AAs, later processed by sequential enzymatic
  cleavage to the two major forms of gastrin
• G34 and G17 and some small forms (14 AA,)

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Sources of gastrin

• Most gastrin is in gastric antrum G cells in
  response to a meal- protein, peptides, and AAs.
• Gastrin release is profoundly influenced by the
  pH of the stomach.
• Fasting and increased gastric acidity inhibit
  gastrin release
• High gastric pH is a strong stimulus
• Smaller amounts from- proximal stomach,
  intestine, colon, and pancreas.
• outside the GI tract, including in the
  hypothalamus, medulla, vagus , adrenal gland,
  respiratory tract, and reproductive organs?
  biological role in these sites is unknown.

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Actions of gastrin

• Stimulaton of gastric acid and pepsin
• trophic effect on the gut mucosal growth
• Stimulates gastric motility
• Release of histamine from ECL cells
• Stimulate insulin secretion after a
• protein meal

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Regulation of gastrin secretion

• Increased

• Decrease secretion

• Luminal
• Peptide AA- tryp,phy gastric distension
• Neural
• Vagal stimulaton via GRP
• Blood
• Ca, epinephrine

• Luminal
• Acid in antrum by direct action on G cells or
  through SST by D cell
• Blood
• Secretin, GIP,VIP, glucagon

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• Hypergastrinemia occurs in
• pathologic states associated with decreased acid
  production, such as atrophic gastritis, PA
• patients on prolonged acid-suppressive
  medications
• stimulation of gastrin production by the alkaline
  pH environment.
• Gastrin-producing tumor, AKA Zollinger-Ellison
  syndrome
• less common cause

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Cholecystokinin

• Secreted by I cells From proximal small intestine
  into the blood following ingestion of a meal, esp
  fat diet
• Also found in nerves in distal ileum and colon,
  neurons in the brain (regulation of food intake)
• Pre pro cck is processed into several fragments
• CCK 8, CCK 22,CCK 33 in response to meal
• CCK 4 enteric and pancreatic nerves
• CCK 8, CCK58 brain
• .

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• The receptors for gastrin and CCK are related and
  constitute the so-called gastrin-CCK receptor
  family.
• CCK-2 receptor is identical to the gastrin
  receptor of the stomach.
• These effects serve to coordinate the ingestion,
  digestion, and absorption of dietary nutrients.
• Ingested fat and protein are the major food
  components that stimulate CCK release

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Actions of CCK

• Major regulator of gallbladder contraction, and
  SOD relaxation
• Regulating meal-stimulated pancreatic secretion
• indirectly through enteropancreatic neurons that
  possess CCK-1 receptors.
• Augment efferent of secretin in producing
  alkaline juice
• Has trophic effects on the pancreas
• Induces satiety and food intake- hypothalamus
• Increase glucagon secretion

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Actions of CCK

• Delays gastric emptying- important in
  coordinating the delivery of food from the
  stomach to the intestine.
• Augment contraction of pyloric sphincter
• Increase secretion of enterokinase
• Increase motility of small int and colon
• Inhibits gastric acid secretion by binding to
  CCK-1 receptors on SST (D) cells in the antrum
  and oxyntic mucosa.
• Somatostatin acts locally to inhibit gastrin
  release from adjacent G cells and directly
  inhibits acid secretion from parietal cells.

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• Through cck receptors
• 1. CCKA- locates in periphery
• 2. CCK B- brain

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• Clinically,
• CCK has been used together with secretin to
  stimulate pancreatic secretion for pancreatic
  function testing.
• It is also used radiographically or
  scintigraphically to evaluate gallbladder
  contractility.
• Low CCK in individuals with celiac disease,
  bulimia nervosa.
• Elevated CCK in some patients with chronic
  pancreatitis presumably because of reduced
  pancreatic enzyme secretion and interruption of
  negative feedback regulation of CCK release.

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Secretin

• Secreted by s cells located deep in mucosal gland
  of Duodenum and jejunum
• In response to protein digestive products, bile
  acid, fatty meal and duodenal acidity-PHlt5
• Acid in the duodenum stimulates alkaline
  pancreatic fluid and bicarbonate secretion,
  leading to neutralization of acidic chyme in the
  intestine, and raises the duodenal pH, thereby
  turning off secretin release (negative
  feedback).
• inhibits gastric acid secretion and intestinal
  motility.
• Acts in concert with CCK,Ach, to stimulate bicarb
  secretion

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• Also causes decreased gastric acid secretion
• Cause pyloric sphincter contraction
• Stimulate growth of exocrine pancreas with cck
• Stimulates liver ductal secretion of bile and
  Produces a watery bile rich in bicarbonate

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• In physiologic concentrations, secretin inhibits
  gastrin release, gastric acid secretion, and
  gastric motility.
• The most common clinical application of secretin
  is in the diagnosis of gastrin-secreting tumors,
  i.e an exaggerated amount of gastrin in response
  to IV secretin, likely caused by specific
  receptors for secretin on tumor cells.
• Inhibited by SST

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Vasoactive Intestinal Polypeptide

• Belongs to a family of GI peptides, including
  secretin and glucagon, that are structurally
  related.
• expressed primarily in neurons of the
  peripheral-enteric and CNS
• An important NT throughout the central and
  peripheral nervous systems
• As a chemical messenger, VIP is released from
  nerve terminals and acts locally on cells bearing
  VIP receptors
• Has wide distribution, effects on many organ
  systems most notably, in the GI tract
• a potent vasodilator that increases blood flow in
  the GI tract and causes smooth muscle relaxation
  and epithelial cell secretion.
• VIP stimulates fluid and electrolyte secretion
  from intestinal epithelium and bile duct
  cholangiocytes
• Increase pancreatic secretion

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• VIP, along with NO, is a primary component of
  nonadrenergic, noncholinergic nerve transmission
  in the gut.
• Intestinal sm muscle relaxation, Longitudinal sm
  m contraction
• neuromodulator of sphincters of the GI tract,
  including the LES and sphincter of Oddi.
• In certain pathologic conditions, such as
  achalasia and Hirschsprung disease, the lack of
  VIP innervation is believed to play a major role
  in defective esophageal relaxation and bowel
  dysmotility, respectively.

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Glucagon

• synthesized and released from pancreatic alpha
  cells and from intestinal endocrine cells of the
  ileum and colon.
• Regulates glucose homeostasis via
  gluconeogenesis, glycogenolysis, and lipolysis,
  and is counterregulatory to insulin.
• The gene for glucagon encodes glucagon-like
  peptides (GLPs).

Enteric factors increasing insulin release
are CCK,GIP.GLP-1, Gucagon
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Glucagon like peptides

• GLP-1 stimulates insulin secretion and augments
  the insulin -releasing effects of glucose on beta
  cell ( Enteroinsular Axis).
• GLP-1 analogs have been developed for the
  treatment of type II diabetes mellitus.
• A long-acting human GLP-1 analog improves beta
  cell function and can lower body weight in
  patients with type II diabetes.
• Incretin hormone
• Produced by L cells in the ileum and colon,
  neurons in hypothalamus and pituitary gland

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Acton of GLP-1
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• GLP-2 is an intestinal growth factor that
  increases villus height, stimulates intestinal
  crypt proliferation, and prevents enterocyte
  apoptosis.
• Based on these actions, GLP-2 agonists are used
  for the treatment of short bowel syndrome.

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Glucose-Dependent Insulinotropic Polypeptide

• produced by K cells in the mucosa of the small
  intestine.
• GIP was discovered because of its ability to
  inhibit gastric acid secretion (enterogastrone
  effect) and was originally termed gastric
  inhibitory polypeptide.
• has potent effects on insulin release that (like
  GLP-1) potentiates glucose-stimulated insulin
  secretion.
• Inactivated by DPP-IV in many tissues and portal
  circulation

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Actions of GIP

• released into the blood in response to ingestion
  of glucose or fat.
• ?Oral glucose can stimulate larger amount of
  insulin than IV glucose
• In the presence of elevated blood glucose levels,
  GIP binds to its receptor on pancreatic beta
  cells leading to insulin secretion.
• its effects on insulin secretion occur only if
  hyperglycemia exists
• GIP does not stimulate insulin release under
  normoglycemic conditions

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• GIP receptors are also expressed on adipocytes,
  through which GIP augments triglyceride storage,
  which may contribute to fat accumulation.
• Based on the insulinotropic properties of GIP,
  coupled with its effects on adipocytes, it has
  been proposed that GIP may play a role in obesity
  and development of insulin resistance associated
  with type II diabetes

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Pancreatic Polypeptide Family

• Includes NPY and peptide tyrosine tyrosine (PYY),
  which were discovered because of the presence of
  a C-terminal tyrosine amide.
• PP is stored and secreted from endocrine cells PP
  cells in pancreatic islets
• NPY is a principal neurotransmitter found in the
  central and peripheral nervous systems.
• PYY has been localized to enteroendocrine cells
  throughout the GI tract. Produced by L cells in
  ileum and colon

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• The PP-PYY-NPY family of peptides functions as
  endocrine, paracrine, and neurocrine transmitters
  in the regulation of a number of actions that
  result from binding to one of five receptor
  subtypes.
• PP inhibits pancreatic exocrine secretion,
  gallbladder contraction, and gut motility.
• Released in response to vagal stimulation,
  gastric distention, fat/AA/glucose in Small bowel

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• PYY inhibits vagally stimulated gastric acid
  secretion and other motor and secretory
  functions.
• Responds to fatty meal, and glucose
• Dec pancreatic bld flow, int motility and meal
  size
• NPY- causes VC/decrease bld flow/, inhibit
  fluid-electrolyte secretion from Small bowel and
  pancreas, decrease GI motility , may stimulate
  feeding

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Substance P

• Substance P belongs to the tachykinin family of
  peptides, which includes neurokinin A and
  neurokinin B.
• The tachykinins are found throughout the
  peripheral and central nervous systems and are
  important mediators of neuropathic inflammation
• Found in myenteric and submucosal plexus
• Stimulated by distension of GI tract
• Increase GI motility spasmogenic effect on GI
  smm ,directly or via Ach releasing myenteric
  neurons
• Decrease bicarb secretion
• Increase intestinal blood flow

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• Substance P has been implicated as a primary
  mediator of neurogenic inflammation.
• In the intestine, Clostridium difficileinitiated
  experimental colitis results from toxin-induced
  release of substance P and consequent activation
  of the NK-1 receptor.
• These inflammatory sequelae can be blocked by
  substance P receptor antagonists.
• Substance P receptors are more abundant in the
  intestine of patients with ulcerative colitis and
  Crohn

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Somatostatin

• Somatostatin initially identified as an inhibitor
  of growth hormone secretion in hypothalamus
• it has been found in almost every organ in the
  body and throughout the GI tract.
• In the gut, somatostatin is produced by D cells
  in the gastric and intestinal mucosa , islets of
  the pancreas, and enteric neurons.
• Somatostatin has a number of pharmacologic
  effects that are mostly inhibitory
• stimulates MMC, possibly through effects on
  motilin

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Sst

• Plays an important role in regulating gastric
  acid secretion.
• A low gastric pH stimulates D cells to secrete
  somatostatin and inhibit gastrin release.
• Reduced gastrin secretion decreases the stimulus
  for acid production and the pH of the stomach
  contents rises.
• Thus some of the inhibitory effects of gastric
  acid on gastrin release are mediated by
  somatostatin.

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Sst

• reduces pepsinogen secretion,
• inhibits pancreatic enzyme fluid, and bicarb
  secretion
• reduces bile flow and GB contraction.
• Somatostatin also reduces intestinal transport of
  nutrients and fluid, reduces splanchnic blood
  flow
• has inhibitory effects on tissue growth and
  proliferation.

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Clinical use of SST and is analogues

• Many endocrine cells possess somatostatin
  receptors and are sensitive to inhibitory
  regulation.
• used to treat conditions of hormone excess
  produced by endocrine tumors, such as acromegaly,
  carcinoid tumors, and islet cell tumors
  (including gastrinomas).
• Dec splanchnic blood flow and portal venous
  pressure ? use in variceal bleeding
• The inhibitory effects on secretion ? to treat
  some forms of diarrhea and reduce fluid output
  from pancreatic fistulas.
• Many endocrine tumors express SST receptors,
  making it possible to use radiolabeled
  somatostatin analogs, such as octreotide, to
  localize even small tumors throughout the body

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Motilin

• Secreted by ECF and M cells of the duodenal
  epithelium
• .
• GI Sm muscle contraction
• Levels increase at interval of 90 minute in the
  interdigestive state
• Motilin is not released by the stimulation of
  food but instead is secreted into the blood in a
  periodic and recurrent pattern that is
  synchronized with the MMC under fasting
  conditions.
• Major regulator of MMCs

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• Secretion inhibited after ingestion
• Agonists to the motilin receptor
• such as erythromycin have pronounced effects on
  GI motility.
• may be useful to treat conditions of impaired
  gastric and intestinal motility
• ?treatment of constipation- predominant IBS.

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Regulation of appetite

• During a meal, ingested nutrients interact with
  cells of the mouth and GI tract.
• Endocrine cells of the stomach and small
  intestine possess receptors that are linked to
  the secretion of GI hormones
• Satiety signals
• Hormones are involved in satiation and regulation
  of insulin secretion

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Effects of GI hormones on feeding

• Suppression of feeing Anorexigenic effect

• Increased feeding
• orexigenic effect

• CCK
• PYY
• GLP-1

• Ghrelin
• NPY

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GHRELIN

• Ghrelin produced by the fundal oxyntic cells
  (P/D1 cells) and is the natural ligand for the GH
  secretagogue receptor.
• lower amounts -in the hypothalamus, pituitary,
  intestine, pancreas, kidney, and placenta.
• When administered centrally or peripherally,
  ghrelin stimulates GH secretion, increases food
  intake, and produces weight gain.
• Circulating ghrelin levels increase during
  periods of fasting or under conditions associated
  with negative energy balance, such as starvation
  or anorexia.
• Ghrelin levels are low after eating and in
  obesity.

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• Ghrelin is a member of the motilin family of
  peptides and, like motilin, ghrelin stimulates
  gastric contraction and enhances stomach
  emptying.
• Serves as a signal for initiation of feeding
• Activates NPY in the arcuate nucleus of the
  hypothalamus, which are involved in the
  regulation of feeding

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Factors influencing Ghrelin secretion

• Increase

• Decrease

• Leptin
• Fasting
• GHRH, thyroid
• Testesterone
• Sleep
• Low BMI
• Anorexia Nervosa

• Food intake
• Glucoe/lipid
• Insulin
• SST
• PYY/PP
• Obesity/high BMI

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Physiologic roles of ghrelin

• Hormonal

• Appetite

• Stimulation of GH secretion
• Synergistic of GHRH
• Dec SST secretion from hypothalamus
• Inc ACTH, PRL,cortisol

• Acting at arcuate nucleus by stimulation of
  NPY/Agouti related peptide? increase appetite

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• Gastric effects

• Other effects

• Increase gastric acid secretion and motility
• Act on vagus which also has GHS receptor
• Increase Epithelial turnover

• Inhibit prroinflamatory cytokines IL1,IL6,TNF
• Anabolic- Increase bone mineral density,
  Adipocity, glucose
• Dec MAP by reducing periph vascular resistance

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Possible clinical uses

• IN GH deficiency , Eating d/os, osteoporosis,
  aging, catabolic states and cachexia
• Gastric bypass patients do not demonstrate the
  premeal increase in plasma ghrelin that is seen
  in normal individuals.
• This lack of ghrelin release may be one of the
  mechanisms contributing to the effectiveness of
  gastric bypass surgery for inducing weight loss.

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Leptin

• Secreted from adipocytes
• Small amounts of leptin are produced by the chief
  cells of the stomach and by the placenta
• primary action is to reduce food intake.
• Five different forms of leptin receptors have
  been reported.
• In hypothalamic nuclei
• Blood levels of leptin increase as obesity
  develops and leptin appears to reflect total fat
  content.

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NEUROTRANSMITTERS
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ACH

• synthesized in cholinergic neurons and is the
  principal regulator of GI motility and pancreatic
  secretion.
• Acetylcholine is stored in nerve terminals and
  released by nerve depolarization.
• binds to postsynaptic muscarinic and/or nicotinic
  receptors.
• Nicotinic receptors belong to a family of
  ligand-gated ion channels and are composed of a,
  ß, ?, d, and e subunits.
• The a subunit mediates postsynaptic membrane
  depolarization following acetylcholine receptor
  binding

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• Muscarinic receptors belong to the heptahelical
  GPCR family. There are five known muscarinic
  cholinergic receptors (M1 to M5).

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Catecholamines

• Include norepinephrine and dopamine.
• NE is synthesized from tyrosine and released from
  postganglionic sympathetic nerve terminals that
  innervate enteric ganglia and blood vessels.
• Tyrosine is converted to dopa by tyrosine
  hydroxylase.
• Dopa is initially converted into dopamine by dopa
  decarboxylase and packaged into secretory
  granules.
• NE is formed from dopamine by the action of
  dopamine ß-hydroxylase in the secretory granule.

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• Adrenergic receptors are G proteincoupled, have
  seven typical membrane-spanning domains, and are
  of two basic types, a and ß.
• a-Adrenergic receptors include a1A, a1B, a2A,
  a2B, a2C, and a2D.
• ß receptors include ß1, ß2, and ß3.
• Norepinephrine signaling is terminated by
  intracellular monoamine oxidase or by rapid
  reuptake by an amine transporter.
• The actions of adrenergic receptor stimulation
  regulate smooth muscle contraction, intestinal
  blood flow, and GI secretion

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Dopamine

• Dopamine is an important mediator of GI
  secretion, absorption, and motility and is the
  predominant catecholamine neurotransmitter of the
  central and peripheral nervous systems.
• In the CNS, dopamine regulates food intake,
  emotions, and endocrine responses and,
  peripherally, controls hormone secretion,
  vascular tone, and GI motility.

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• Has both inhibitory and excitatory effects on the
  GIT
• Dose dependentresponse
• Excitatory response is mediated by presynaptic
  receptors, occurs at a lower agonist
  concentration
• Inhibitory effect , mediated by postsynaptic
  receptors., at higher conc
• Dopamine can activate adrenergic receptors at
  high doses.

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Serotonin

• The GI tract contains gt95 of the total body
  serotonin
• Important in various processes, Including
  epithelial secretion, bowel motility, nausea, and
  emesis.
• Synthesized from tryptophan, an essential amino
  acid, and is converted to its active form in
  nerve terminals
• 7 different serotonin receptor subtypes are found
  on enteric neurons, ECF cells, and GI smooth
  muscle (5-HT1 to 5-HT7).

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Serotonin actions are complex

• SMM contraction through stimulation of
  cholinergic nerves or relaxation by stimulating
  inhibitory NO-containing neurons.
• Serotonin released from mucosal cells stimulates
  sensory neurons,
• Initiating a peristaltic reflex
• Secretion (via 5-HT4 receptors), and
• modulates sensation through activation of 5-HT3
  receptors.

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• Myenteric plexus contains serotoninergic
  interneurons that project to the submucosal
  plexus and ganglia extrinsic to the bowel wall.
• Extrinsic neurons activated by serotonin
  participate in bowel sensation and may be
  responsible for abdominal pain, nausea, and
  symptoms associated with IBS.
• Intrinsic neurons activated by serotonin are
  primary components of the peristaltic and
  secretory reflexes responsible for normal GI
  function.

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Histamine

• Plays a central role in Regulating gastric acid
  secretion and intestinal motility.
• Histamine is produced by ECF cells of the stomach
  and intestine, as well as enteric nerves.
• Histamine is synthesized from L-histidine by
  histidine decarboxylase
• H1 receptors are found on smm and vascular
  endothelial cells,
• mediate many of the allergic responses induced by
  histamine.
• H2 receptors are present on gastric parietal
  cells, SMM, and cardiac myocytes.
• H3 receptors are present in the CNS and GI- ECF
  cells.

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Nitric oxide

• NO is a unique chemical messenger produced from
  L-arginine by the enzyme nitric oxide synthase
  (NOS).
• Three types of NOS.
• Types I and III are also known as endothelial NOS
  and neuronal NOS, respectively, and are active.
• The inducible form of NOS (type II) is apparent
  only when cells become activated by specific
  inflammatory cytokines.
• NOS is often colocalized with VIP neurons of the
  enteric nervous system.

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• NO readily diffuses into adjacent cells
• Many enteric nerves use NO to signal neighboring
  cells and induce epithelial secretion, VD, or
  muscle relaxation.
• NO is also produced by MQ and neutrophils to help
  kill invading organisms.

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Digestive system
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• Digestion and absorption of dietary nutrients
  constitute the primary physiologic function of
  the GI tract
• this includes the 3 major nutrients, namely
  carbohydrates, proteins, and fat, and the
  micronutrients (viamins, menerals and trace
  elements)
• Dietary poly and disaccharides, proteins and fats
  canot be absorbed directly
• Have to be broken down to monosaccharides,
  AA/peptides and FFAs and/or SCF for absorption

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• With some exceptions, Most of water-soluble and
  lipid-soluble vitamins in normal diet are
  absorbed as such without the need for prior
  digestion
• Protein bound vitamins like B12
• Lipid soluble forms

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• Digestion starts in the mouth and stomach, and
  largely in intestine
• Digestion is mostly an enzymatic process mediated
  by several classes of enzymes,
• carbohydrases, proteases and peptidases, and
  lipases, phospholipases, and esterases.
• Also facilitated by physical and mechanical
  events
• Eg- in dietary fat digestion forceful mixing and
  detergent assisted dispersion to promote
  accessibility of the enzymes to their substrates.

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• Two types -Luminal and membrane digestion
• Enterocytes , functional units of intestine , are
  polarized , with a part of their plasma membrane
  facing the intestinal lumen and the rest facing
  the portal circulation.
• ?Hence the BBM and BLM

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The digestive process

• Priming of intestine
• Preparing intestine for the coming chyme
• Secretions from liver/pancreas avail enzymes
• Also neutralize the coming acid rich chyme
• Salivary and gastric secretion is initiated with
  the cephalic phase, triggered by the sight,
  smell,thought of food
• is mediated by the ANS.

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• Nutrients in the GI tract sends additional
  signals for neuroendocrine control
• The parasympathetic innervation of the GI tract
  and pancreas, provided by the vagus nerve, is the
  principal component in this regulatory process
• The mechanoreceptors present in vagal afferent
  fibers are activated by gastric distension,
  sending signals to the brain with regard to meal
  size.
• Chemo-sensitive afferents respond to many of the
  GI hormones (CCK, GLP-1, PYY, ghrelin, and
  serotonin) via their respective cell-surface
  receptors

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Nutrient transport

• The nutrient transporters in the intestinal tract
  are grouped into 2 classes
• active transporters and passive transporters.
• Active transporters are capable of accumulating
  their substrates in cells against a concentration
  gradient whereas
• passive transporters are only capable of
  transferring their substrates down a
  concentration gradient.

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• Five different driving forces operate in the
  absorptive cells of the intestinal tract to
  provide energy for various active transporters
  involved in nutrient absorption
• (1) an inwardly directed Na gradient
• (2) an inwardly directed H gradient
• (3) an inwardly directed Cl- gradient
• (4) an outwardly directed K gradient and
• (5) the membrane potential.
• These driving forces are generated via
• multiple mechanisms, all of
• which rely on the Na/K pump at BLM

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Carbohydrates

• The total amount of carbohydrate in a normal diet
  is 220 to 330 g/day for men and 180 to 230 g/day
  for women.
• Dietary carbohydrate exists in different
  molecular forms polysaccharides, disaccharides,
  and monosaccharides.
• Starch from plant products and glycogen from meat
  are polysaccharides.
• diet also contains carbohydrates in the form of
  fiber, which is neither digestible nor absorbable
  by the human intestine.
• Fiber includes cellulose, hemicellulose, gums,
  pectins, and chitin, all derived from plant
  sources.

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• Digestion starts in mouth by salivary aamylase
  ?ineffective
• Carbo digestion in the small intestine occurs in
  the lumen (luminal digestion) and on the BBM
  (membrane digestion).
• The net result of luminal digestion and membrane
  digestion is to generate monosaccharides
  (glucose, galactose, and fructose) from the
  ingested polys and disaccs, which are then
  absorbed across the enterocyte via selective
  transporters to enter the portal blood.
• Pancreatic a-amylase - only on starch and
  glycogen, no effect on disaccharides.
• Works under neutral PH

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• Membrane digestion, occurs on the external
  surface of the BBM of the intestinal absorptive
  cells
• At least 4 enzymes are involved in membrane
  digestion
• maltase-glucoamylase, s
• ucrase-isomaltase,
• lactase, and
• trehalase
• All of them are integral proteins in the BBM with
  their catalytic sites exposed to the luminal
  surface of the membrane

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• Sequential steps involved in the luminal and
  membrane digestion of dietary polysaccharides and
  disaccharides in the small intestin

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• Glucose and galactose are taken up by the
  enterocytes via an active transport process
• Fructose enters the cells by a passive, but
  facilitated mechanism.
• SGLT1 is responsible for active uptake of glucose
  as well as galactose from the intestinal lumen
  into the cells.

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• Once all 3 monosacchs enter the enterocyte, they
  are exported out into the portal circulation
  across the BLM.
• occurs via GLUT2 ,a low-affinity facilitative
  sugar transporter.
• The low affinity of this transporter is
  physiologically relevant because it dictates that
  the net release of glucose, galactose, and
  fructose from the cells occurs only down their
  concentration gradients
• ( when the intracellular concentrations exceed
  those in the portal)

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• If the digestive process is faulty, dietary
  carbohydrates cannot be digested.
• undigested carbohydrates then reach the colon and
  increase the osmotic pressure leading to
  secretion of water into the lumen resulting in
  abdominal bloating and diarrhea (osmotic
  diarrhea).
• bacteria in the colon hydrolyze and ferment the
  released sugars. And release gas in form of
  hydrogen, leading to flatulence and increased
  appearance of hydrogen in the expired air from
  lungs.

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• Secondary causes of defects in carbohydrate
  digestion in the intestine
• examples celiac disease and ZES.
• Decreased villi and massive acid load from
  gastric chyme inactivating Amylase

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Proteins

• Proteins in the diet serve as the source of
  essential as well as non-essential AAs for
  cellular metabolism.
• Deficiency of dietary protein intake will lead to
  negative nitrogen balance, primarily due to the
  non-availability of the essential AAs.
• Proteins provide approximately 10 to 15 of
  energy intake
• Proteins are digested and absorbed mostly in the
  small intestine with little or no proteins
  entering the colon

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• In contrast to carbs, dietary proteins are only
  partially digested in the lumen of the intestinal
  tract, yielding a mixture of small peptides and
  free AAs, which are absorbed into enterocytes
• Their Digestion into their monomeric units (i.e.,
  free AAs) is completed inside the enterocytes

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Luminal digestion

• begins in the stomach and is initiated by pepsin
• Pepsin is released into the lumen in the form of
  inactive precursor (zymogen) known as pepsinogen.
  
• activated by acidic pH, a process which involves
  changes in protein folding to expose the active
  site of the enzyme.
• Autocatalytic fn of pepsin
• Pepsin is an endoprotease and therefore does not
  generate free AAs but rather produces smaller
  polypeptides

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• Pancreatic proteases major contributors to
  luminal digestion of dietary proteins.
• Three proteases - trypsin, chymotrypsin, and
  elastase and
• Two peptidases - carboxypeptidase A and B.
• Both are released into the pancreatic duct as
  inactive precursors (zymogens)
• trypsinogen, chymotrypsinogen, proelastase, and
  procarboxypeptidases A and B.

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• The first step in this activation process is
  mediated by enteropeptidase, a proteolytic enzyme
  on BBM of the enterocytes in the upper small
  intestine.
• Trypsin, chymotrypsin, and elastase are
  endoproteases, which hydrolyze peptide bonds
  located within the protein substrates,
• Generate smaller peptides, but not free AAs
• carboxypeptidases are exopeptidases, hydrolyze
  peptide bonds located on the carboxyl termini of
  substrates.
• Generate free AAs

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Mne digestion

• The BBM of the enterocytes in the jejunum and
  ileum possesses a battery of peptidases, the most
  important among them being
• aminopeptidase N and carboxypeptidase p (
  exopeptidases), and
• DPP IV, and ACEs.
• End products -consist predominantly of small
  peptides (dip and tripeptides) and, to a smaller
  extent, free AAs.
• are absorbed efficiently across the BBM of the
  absorptive cells in the small intestine

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• The driving force for the process comes from the
  electrochemical H gradient that exists across
  the intestinal BBM, thus highlighting the
  nutritional significance of the microclimate acid
  pH on the luminal surface

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Intracellular Digestion

• Even though dipeptides and tripeptides are
  absorbed into the enterocytes, very little, if
  any, of these small peptides appear in the portal
  circulation, suggesting that they are hydrolyzed
  further inside the cells to free AAs.
• In general,
• peptidases in the BBM prefer oligopeptides
• peptidases in the cytoplasm prefer smaller
  peptides (di and tri peptides) as substrates

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• Defective digestion occurs in diminished
  proteolytic enzymes responsible for luminal
  digestion of the proteins.
• Eg in CF, a genetic disease associated with
  decreased function of the exocrine pancreas with
  defective secretion of pancreatic enzymes,
  including all the proteases
• Digestion of proteins is also compromised in
  patients with genetic absence of the brush-border
  enzyme enteropeptidase

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Fat dietary lipids

• Dietary lipids account one-third of daily caloric
  intake and consist triglycerides (95),
  phospholipids and cholesterol -5.
• Dietary cholesterol comes from animal fat, and
  exists mostly in its free form, with only 10 to
  15 in the form of cholesteryl esters with fatty
  acids.
• Dietary cholesterol is absorbed only partially
  whereas dietary triglycerides are absorbed very
  efficiently in humans.
• The major fatty acids in dietary triglycerides
  are LCFAs (gt14 carbon chain length that may be
  saturated or unsaturated.

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There are several features unique to the
digestion and absorption of dietary fat as it is
insoluble in aqueous medium

• physical forces and detergents (bile acids) are
  needed to disperse dietary fat in the intestinal
  lumen so that enzymes can gain access to the
  molecules for digestion.
• Most dietary fat is digested by enzymes in the
  intestinal lumen prior to uptake into the
  absorptive cells of the small intestine
• Once inside the enterocyte these digested
  components are used to re-synthesize TGs, PLs,
  and CEs and then assembled in a macromolecular
  form before exiting the cell
• Fat digestion products are released into lacteals
  to the lymphatic system

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• MCTs do not undergo digestion in the intestinal -
  are not dependent on bile salts for intestinal
  absorption.
• They simply diffuse across the intestinal
  absorptive cells and enter the portal bloodstream.

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Fat digestion in stomach

• Fat digestion begins in the stomach with gastric
  lipase, which is secreted by chief cells located
  primarily in the fundus.
• Gastric lipase acts efficiently on triglycerides
  containing MCT, and the products of its activity
  are diglycerides and FFA.
• Gastric lipase is responsible for 20 to 30 of
  the luminal digestion of dietary fat, but has no
  activity on phospholipids and cholesteryl esters
• stomach plays a critical role in the
  emulsification of dietary fat and the
  fat-digestion products

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• Emulsification is promoted in the gastric antrum
  by trituration, followed by powerful squirting of
  the contents into the duodenum.
• Transformation in the physical nature of the fat
  in gastric chyme is important for subsequent
  digestion in the small intestine by pancreatic
  lipase.
• Emulsification is also enhanced by FFAs generated
  by the action of gastric lipase.
• The resultant fat droplets in the emulsion are
  stabilized by being coated with phospholipids.

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Intestinal fat digestion

• Pancreatic lipase ( steapsin) is the major enzyme
  responsible for the digestion of triglycerides in
  the small intestine. Works at PH of 8
• it is secreted by the exocrine pancreas in an
  active form
• requires a cofactor, known as colipase- fixes the
  enzyme on the TG( prevent wash away by
  detergents)
• Activation of pro-colipase occurs in the
  intestinal lumen by trypsin
• pancreatic lipase acts on the ester bonds
  associated with carbon atoms 1 and 3 of the
  glycerol moiety, thus generating FFA and
  2-monoglyceride

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• Phospholipase A2 from exocrine pancreas as an
  inactive precursor and is activated in the
  intestinal lumen via limited proteolysis by
  trypsin.
• Cholesteryl esters are digested by a separate
  enzyme known as carboxylic ester hydrolase

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Emulsifier

• bile salts are needed for the activity of
  pancreatic lipase
• Important for micelle formation
• Sodium glycocholate, Taurocholate
• Emulsification decreases surface tension and inc
  surface area of fat globules

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Absorption of lipids

• The products of digestion are incorporated in
  to molecular aggregates to form mixed micells ,
  with the attachment to the hydrophobic tail of
  bile salts
• Spherical particles with the hydrophobic bonds
  interior core and hydrophilic exterior formed
  bile the bile salt

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• The micelle is then taken by the BBM by
  pinocytosis.
• Inside the cells, bile salts are removed
• MCT and SCT directly enter portal vein
• LCT taken to Golgy body, get surrounded by a
  protein coat to form chylomicron, to which MAG,
  PL and chol are bound to
• Then taken to submucosa by exocytosis , then
  taken by lacteals

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triglycerides (8592), phospholipids (612),
cholesterol (13), and proteins (12).
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References

• 1. sleisenger and fordtrans gastrointestinal and
  liver disease,11th edition
• 2. Guyton and hall, textbook of medical
  physiology, 13th ed
• 3. Enteroendocrine Cells Chemosensors in the
  Intestinal Epithelium. Fiona M. Gribble and Frank
  Reimann. Annu. Rev. Physiol. 2016.78277-299

114

• Thank you

115

• Transmitters can be secreted from chemosensory
  cells and neurons through
• Endocrine via the blood eg peptide yy, gastrin,
  secretin
• Paracrine locally in the paracellular space, on
  neighbouring cell eg somatostatin, histamines
  
• Autocrine to act on the samer eleasing cell, or
• synaptic to allow neurotransmission primarily
  used by the enteric nervous system- NEUROCRINE
  SIGNALING
• The most common are peptides such as VIP, or
  small molecules, such as acetylcholine and
  norepinephrine.
• Other molecules, such as NO, can simply diffuse
  across the synaptic cleft to exert an effect on
  the postsynaptic cell.

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Regulation of blood glucose post prandially

• STIMULATE INSULIN RELEASE
• GLP-1, GIP, GRP,
• Cholecystokinin (potentiates amino
  acidstimulated insulin release)
• Gastrin (in presence of amino acids)
• VIP (potentiates glucose-stimulated insulin
  release)
• Pituitary adenylate cyclaseactivating peptide
  (potentiates glucoses timulated insulin release)
• Motilin
• DELAY GASTRIC EMPTYING
• Cholecystokinin, Amylin, Secretin
• INHIBIT GLUCAGON RELEASE
• Amylin

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GI Peptides That Regulate Satiety and Food Intake Reduce Food Intake Increase Food Intake Cholecystokinin (CCK) Ghrelin Glucagon-like peptide-1 Peptide tyrosine tyrosine (PYY3-36) Gastrin-releasing peptide Amylin Apolipoprotein A-IV Somatostatin

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Steps involved in the absorption of fat digestion
products from mixed micelles across the
absorptive cells of the small intestine into the
lymphatics

1. Transfer of fat digestion products across BBM
2. Re-synthesis of TG,PL,CE in SER and formation of
   lipid droplets (yellow dots)
3. Synthesis of aLP B-48 in RER (brown dots)
4. Movement of aLP B-48 from RER to SER to form
   chylomicrons
5. Movement of chylomicrons to cis side of Golgi
6. Budding off chylomicrons on trans side of Golgi
7. Fusion of chylomicrons with BLM and release into
   the intercellular space on the serosal side
8. Entry of chylomicrons into lacteals

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