Class notes - Molecular Regulations of Health and Disease

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Samenvatting - Class notes - Molecular Regulations of Health and Disease

  • 1441749600 Molecular regulation of energy and nutrient metabolism

  • What is the difference between a tumour and a cancer? Also explain the difference in metabolism. 
    A tumour can be benign, pre-malignant or malignant or can represent a lesion with no cancerous potential. 

    A cancer is by definition malignant (neoplasm). 
  • What are the 5 differences between cancer cells and normal cells? 
    1. Cancer cells are immortal and can grow indefinitely. 

    2. Cancer cells diplay sufficiency in growth signals. They display lower growth signal requirements. In a tissue medium cancer cells require much less serum than normal cells. 

    3. Cancer cells are invasive and have properties that support invasion and metastasis. 

    4. Cancer cells are resistant to apoptosis.

    5. Cancer cells have an altered nutrient and energy metabolism.
  • Give 5 examples of how cancer cells can be invasive.
    1. Cancer cells have loss of contact inhibition. Normal cells in a culture stop growing when their plasma membranes come into contact with one another, cancer cells do not. 

    2. Cancer cells have reduced cellular adhesion. They stick less to each other than normal cells do. In a mixed origin, normal cells if the same origin stick together. This is not the case for cancer cells. 

    3. Cancer cells have loss of anchorage dependence. Where most cells need to be attached to a rigid substrate (be anchored to grow), transformed cells can grow even when they are not attached to a substrate.

    4. Cancer cells have less organized, more mobile surface proteins. Possibly related to a de-differentiated state.

    5. Cancer cells show an altered secreted protein profile. Cancer cells have an increased secretion of proteolytic enzymes, which facilitates cell migration and invasiveness. 
  • Name two examples how cancer cell nutrient and energy metabolism is altered. 
    1. Cancer cells show an increased rate of glycolysis. There is an increased uptake of glucose and a corresponding increase in lactic acid production in cells of solid tumours. Increased glucose uptake can be used to diagnose specific cancers with PET imaging. 

    2. Cancer cells have a more negative surface charge of the cell membrane and sustained angiogenesis. A more negative cell surface facilitates uptake of nutrients just like angiogenesis.
  • What are the 6 Hallmarks of cancer? And what 2 Hallmarks were later added? Explain the Hallmarks!
    1.  Sustaining proliferative signalling
    2. Evading growth suppressors
    3. Resisting cell death
    4. Enabling replicative immortality
    5. Inducing angiogenesis
    6. Activating invasion and metastasis

    Later added:
    7. Evading immune destruction
    8. Reprogramming of energy metabolism
  • 1441836000 1.2: Mitochondria

  • Draw a mitochondria and explain: what does what?
    See reader, page 17. 
  • What is the main function of mitochondria? And what is the main function of mitochondria in cancer cells?
    In normal cells; the production of ATP is the main function of mitochondria. 
    1. They produce ATP.
    2. They respond to cellular energy demand.
    3. They have a regulatory role in the balanced use of energy substrates. 
    4. ""  """"                                                                      in the urea cycle.
    5. ""                                                                             in calcium homeostasis.
    6. "" in amino acid metabolism. 
    7. They are essential for heme and iron-sulphur cluster biosynthesis.
    8. They mediate apoptosis.
    9. They mediate innate immune defence.
    10. Oxidative signalling are produced in the mitochondria and play a role in several of its functions. 
  • Explain: glycolytic metabolism. 
    1. The end product can be two molecules of pyruvate (or lactate), these enter in to mitochondria.
    2. Pyruvate goes into the TCA cycle with the help of fatty acid oxidation. This happens because acetyl CoA (derived from pyruvate, FA and AA breakdown) is broken down to generate CO2. 
    3. This causes NAD+ to reduce to NADH and FAD.

    These intermediated provide electrons to the Electron Transport Complexes.
  • Explain: Electron Transport Complexes.
    This repiratory chain consists of a series of enzyme systems coupled together and that are described as: Complex I (NADH dehydrogenase), II (succinate dehydrogenase), III (cytochrome c reductase), IV (cytochrome c oxidase) and V. 

    Electrons are transferred from NADH to complex I or from FADH (succinate) to complex II. 
    Then the electrons are transferred to ubisemiquinone which shuttles them to complex III. From Complex II aswell. 
    Cytochrome c shuttles them to complex IV.
    Here the electrons are transferred to oxygen to form H2O. The use of oxygen is called respiration. 
  • 1442786400 Microbiota in health and disease lecture 1

  • Why is the small intestine a harsh environment for microbes? And the stomach?
    The small intestine is harsh because it has a fast transit time of food components - only a few hours max. Furthermore bile is present and digestive digestive enzymes.

    The stomach has a very acidic pH and also a very fast transit time (30 min). Only acidic microbes can survive this environment.
  • Which 3 components are important for the regulation of health and disease in and interact in the GI-tract?
    1. Diet and Food
    2. GI-tract microbes
    3. Human host

    GI-tract microbes convert non-digested food components and produce certain vitamins, SCFA and are involved in immune modulation.

    The human host digests and takes up food components and produce antimicrobial peptides and endogenous substrate and are therefore important for the immune respons.
  • Name all the compartments of the small intestine.
    Duodenum (relatively low in microbiota), jejenum and last ileum.
  • Why is collecting microbes from the small intestine difficult?
    It is very invasive to achieve microbiota, it is very inaccessible. Most information comes from sudden death individuals or collected from ileostomy patients (no colon). Collection via catheter or surgery is possible, but very invasive.
  • Why is the small intestine largely driven by rapid uptake and conversion of simple sugars?
    These sugars can be used by other members of this community such as Veillonella and butyrate producers. Microbiota in the small human intestine are therefore maintained.
  • Why is the colon the fermentation 'vessel' of the human GI tract?
    Because it has a slow transit time and food components that have escaped digestion in the small intestine can be converted by microbes into components that can be absorbed.
  • Explain the model of bacterial life in the large intestine.
    See lecture 2.1, slide 20
  • Explain the model of bacterial life in the small intestine.
    See lecture 2.1, slide 17
  • Name some functions of GI tract bacteria.
    - Fermentation of indigestible carbohydrates.
    - Development GI tract structure and immune system.
    - Resistance against pathogens.
    - Improved metabolite absorption.
    - Production SCFA.
    - Production of vitamins.
    - Deconjugation bile acids.
  • Why is protein fermentation often considered to have a negative impact on our colonic tissue?
    The fermentation of proteins will result in the production of branched SCFA, but also in hazardous components, such as ammonia and sulfide, amines and phenolic compounds.
  • Which 3 bacterial phyla are most dominant in the human colon?
    1. Firmicutes
    2. Bacteroidetes
    3. Actinobacteria
  • Name from the following phyla whether they are Gram-/+, most common genera and main functions; Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria.
    1. Firmicutes are low G+C Gram positives. Clostridium, Eubacterium, Ruminococcus and Lactobacillus are genera. It converts carbohydrates, lactate and/or acetate into butyrate.

    2. Bacteroidetes, Gram-negative, most common genera; Bacteroides and Prevotella. They degrade complex carbohydrates.

    3. The actinobacteria are G+C Gram positive bacteria, most well-known is the Bifidobacterium which produces lactic acid and is a beneficial microbe and used in biotic products.

    4. Proteobacteria is a Gram-negative phylum which contains typical sulfate-reducing bacteria and (opportunistic) pathogens, such as; Salmonella, Helicobacter and Campylobacter. Most common is E. coli.

    Furthermore there is Verrucomicrobia which is recently discovered. An example is the Akkermansia Muciniphila.
  • What common features can be said about newborn babies with respect to the microbiotal composition?
    The first microbes are already entering after the first cry through contact wit hthe mother and their environment. The first microbes are facultative anaerobes which convert the oxic environment present in the GI tract into a strictly anoxic environment.
    Immediately afterwards, strict anaerobes start to colonize, bifidobacteria are in general dominantly present.
    After weaning, the numbers of bifidobacteria decline and the microbiota function seems to become less chaotic.
  • Is microbiota similar in time/individuals?
    Relatively stable in time, but very host-specific. Probably genetic factors play a role, but also environment.
  • Explain "Dollo's law of irreversibility".
    An organism cannot return to a previous stage that has already been realized in the rank of its ancestors, indicating that once a common ancestor has lost methane production in the intestine, it will not reappear in descendants.
  • There is an unique composition vs. universal functions of microbiotica. Explain the three hypotheses correlated with this. Also give drawbacks of each theory.
    1. Common core theory. We all share a common core of microbiota. Dominant species are core species and perform general functions, rare species are individual specific. However, observations are not consistent and it also depends on the phylogenetic level you look at.

    2. Different species can have similar functions. There are more bacteria that can exert the same functions, and this hypothesis could explain why the diverse community of the GI tract is resilient with respect to factors that can disturb the ecosystem.

    3. Enterotypes. A recent paper can divide individuals in three distinct eneterotypes, which are not dependent on age, countrey, gender and health status. Each enterotype is characterized by specific co- and anti-correlations between microbes and the gut. This indicates that the enterotypes are driven by groups of species that contribute to the preferred community composition.
    Drawback: it was shown that enterotypes are associated with long-term dietary habits. However they could not detect enterotype 3. Enterotypes can change over time so they are not linked to fixed human features.
  • Why seems enterotypes like a feasible hypothesis?
    It supports the diagnostics for diseases associated with the GI tract microbiota. Enterotype 3 is very prominent in IBS. Further research needs to be done.
  • Name some disorders that have been associated to GI tract microbiota.
    Allergy, Autism, Cardiovascular disease, Clostridium difficile infection, Crohn's Disease, Eczema, IBD, IBS, Metabolic Syndrome, Obesity, Type 1+2 Diabetes, Ulcerative Colitis.
  • What was the result when they compared conventional mice with germ-free mice in relation to obesity?
    Conventional mice have higher body fat percentage, lower calory intake, higher metabolis rate compared to germ free mice. The obese phenotype/microbiota are transferable to germ-free mice.
  • What is the difference in Bacteriodetes/Firmicutes ratio between lean and obese mice?
    Obese mice have higher Firmicutes and less Bacteroidetes compared to lean mice.
  • What are the proposed mechanisms of the impact of microbiota on obesity?
    1. Suppression of fasting-induced adipose factor -> triglyceride accumulation in adipocytes.

    2. Inactivation AMP activated protein kinase -> suppression FAO.

    3. Signalling microbiota -> promoting low grade pro-inflammatory state.

    4. Production SCFA -> energy fuel and regulating transit time and bowel movement via G-protein receptors and enteroendocrine peptide YY.
  • Please explain the link between obesity and insulin sensitivity.
    See lecture 2.1, slide 60.
  • What are the three subtypes of IBS?
    IBS-D: Diarrhea predominant
    IBS-C: Constipation predominant
    IBS-N: Mixed defecation (most common)
  • What did O'Mahony and colleagues demonstrated? And Kajander et al?
    That a Bifidobacterium infantis-based probiotic resulted in a significant reduction of IBS symptom scores.
    It is thought that this strain modulated the immune response in IBS parients by normalizing cytokine IL10/IL12 ratio, which was found abnormal in IBS population.

    Kajander found that an intervention with multispecies probiotic significantly decreased IBS symptoms. Micorbiota composition was stabilized.
  • There is no uniform correlation between microbiota and IBS in different studies. Name 6 possible explanations.
    1. IBS is a heterogenous disorder.
    2. Number of subjects per study is limited.
    3. Single snaphop of microbiota vs chronic characteristic IBS -> more samples in time are needed.
    4. Improvement subtyping of IBS patients needed.
    5. Enterotype-specific impact?
    6. Microbiota analytic tools are different.
  • How can C. difficile be harmful and what treatment has a high succesrate?
    It can be harmful when it increases in number, low levels are not harmful. Transplantation of the microbiota has a high success rate.
  • Name a model for the impact of bacteria.
    See lecture 2.1, slide 79
  • What are some common features of microbiota in health and disease?
    - Multifactorial, etiology unclear.
    - Composition microbiota often reduced in diversity and unstable in disease.
    - Composition microbiota different in structure compared to healthy individuals.
    - Difficult to assign specific microbes to disease.
    1. studies have different contradicting observations.
    2. in case of correlation; microbe cause or consequence of disease?
    3. confounders (use medication etc)
    - Microbiota transplantation outcome?
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What is the difference between a tumour and a cancer? Also explain the difference in metabolism. 
1
What are the 5 differences between cancer cells and normal cells? 
1
Give 5 examples of how cancer cells can be invasive.
1
Name two examples how cancer cell nutrient and energy metabolism is altered. 
1
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