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Humanity’s endeavour towards the mitigation of the consequences of deleterious mutations
(might be) incurring an unforeseen cost, in the long term, on the overall species fitness, through relaxation of selection
Ref: Lynch M “Mutation and Human Exceptionalism: Our Future Genetic Load.” Genetics 202: 869-875 (2016)
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Immunodeficient murine animal models and cultured human cancer cells both serve as test subjects
in the screening of anticancer effects for various chemical compounds resulting in the identification of novel ICD inducers
Immunogenic cell death inducers, cytotoxic agents eliciting such manifestations as the release of HMGB1
other molecular changes include exposure of calreticulin at the cellular surface and lymphosomal ATP secretion
cytotoxic activity - toxicological evaluation
anticancer effects - in human neoplasms
A once compromised immune system by pharmacological intervention
Now sees its antineoplasic agents optimised by anticancer immunosurveillance re-activation
Adaptive immune response against dead cell-associated antigens
Harnessing the cell death signature, triggering ICD apoptotic stimulation
Ref: Sukkurwala AQ et al. “Screening of novel immunogenic cell death inducers within the NCI Mechanistic Diversity Set.” OncoImmunology Vol. 3, Iss.4 (2014)
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Enhanced levels of estrogens in the context of the cellular neurogenesis machinery
Brain development compromised with paracrine signals and unwarranted apoptosis activity
Abnormal development of oestrogeno-dependent reproductive physiological functions
Induced by environmental traces of oestrogen-like chemical contaminations
Environmental estrogens exposure - cellular reproductive foreclosure
Early life exposure to micro-levels of hormone-mimicking toxic pollutants
Leading to a higher incidence of reproductive failures and neurobehavioral mutants
Irreversible epigenetic reprogramming induced by early life exposure to environmental estrogens
Ovarian follicular developmental dysfunction putting a halt to normal reproductive functions
Environmental estrogens exposure - cellular reproductive foreclosure
Chemical contaminants causing the disruption of the estrogen signaling pathway
Endocrine disruptors, abnormal ovarian development is underway
Ref: Cruz G et al. “Long-term effects of early life exposure to environmental estrogens on ovarian function: Role of epigenetics.” J Neuroendocrinol. 26(9): 613-24 (2014)
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Death-receptor, binding the ligand prompting the clustering and formation of a death-inducing signalling complex
Recruitment, by the Fas-associated death domain, of procaspase-8 molecules, proximal activation
A cascade of caspases amplifying pro-apoptotic signals
A crowd of zymogens allowing for the enzymes’mutual cleavage activation
Protein-protein interactions activating upstream caspase initiators
Proteolytically activated apoptotic cell death effectors
Cytochrome c electron carrier, reveals itself to be crucial in cytosolic caspase-9 activation
Pro-apoptotic Bcl-2 inducing the release of the aforementioned, via rupturing of the mitochondrial outer membrane
Procaspase-9 and Apaf-1 forming the apoptosome (complex)
Apoptotic pathway modulated via heat-shock proteins action
Various downstream interactions and multiple subprogram branching
Resulting in cell removal, in an orderly dismantling
Precisely regulated and tightly organized death-inducing pathway; apoptosis
Ref: Hengartner MO “The biochemistry of apoptosis.” Nature 407(6805):770-776 (2000)
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Abnormal immune response, suppression of adaptive immunity
Hypersecretion of cytokines, chemokines and growth factors, all proinflammatory
An observed lack of CD peripheral cells and T-lymphocytes showing low circulating cytokine production
In conjunction with the absence of IFNa2 increase, disrupting the innate immune reaction
cytokine storm - with a significant drop of CD peripheral cells
cytokine storm - EBOLA-induced intracellular hell
Defective early inflammatory responses and lymphocytic apoptosis
DNA fragmentation in peripheral blood cells, reduced interferon levels and necrosis
Drastically lower levels in lymphocytic populations were observed in fatally infected patients
Extremely high levels of circulating inflammatory molecules, dendritic cells' functional impairment
cytokine storm - with a significant loss of T-lymphocyte cells
cytokine storm - EBOLA-induced intracellular hell
Endothelial permeabilization, massive hemorrhagic manifestations
General immune system failure during the acute phase of infection
cytokine storm - with a significant drop of CD peripheral cells
cytokine storm - EBOLA-induced intracellular hell
cytokine storm - with a significant loss of T-lymphocyte cells
cytokine storm - EBOLA-induced intracellular hell
Ref: Paessler S, Walker DH “Pathogenesis of the viral hemorrhagic fevers.” Annual Review of Pathology: Mechanisms of Disease Vol. 8: 411-440 (2013)
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There are many a ways by which cells can be driven into proliferative, cancerous states
A classical model involves changes in DNA sequences, thus causing genomes to mutate
Although most mutations are of no consequences, provided they occur in non-coding regions
Problems may arise when these changes affect key players of DNA-repair or cell cycle regulation
Functional integrity of check point proteins may also be compromised by epigenetic modifications
Normal expression of tumor suppressor genes altered, silenced by aberrant methylation patterns
Repressive chromatin domain formation, from senescence to cell growth, the tables finally have turned
Specific repressing sites’ methylation resulting in transcriptional de-repression
CpG islands gains of methylation promoting cancerous proliferation
Generally senescent cell populations undergoing transcriptional de-repression
Awaiting their re-awakening through aberrant patterns of methylation
Ref: Cruickshanks HA et al. “Senescent cells harbour features of the cancer epigenome.” Nature Cell Biology 15, 1495-1506 (2013)
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Identification of key players in determining cell viability and tumor proliferation
In the context of endoplasmic reticulum stress that triggers the unfolded protein responses
A challenging endeavour / faced with many obstacles / not the least of which being the elucidation
Of precise molecular pathways / involved in tumorigenesis / and cellular proliferation
Blocking the active domain – specific allosteric inhibition
Promoting cell survival – specific allosteric inhibition
Accumulation of unfolded proteins inducing homo-oligomerization
Of a particular kinase/RNase enzyme, splicing the XB1 transcription factor
Abnormal immune system activity / and cellular stress responses / threshold level in substrate degradation
Kinase-inhibiting / RNase attenuators / disrupting oligomerization
Blocking the active domain – specific allosteric inhibition
Promoting cell survival – specific allosteric inhibition
IREalpha unfolded protein sensor, an ineffective target to block the growth of tumors
Tumor cell survival unscathed by the inhibition of the endonuclease domain of this particular transmembrane sensor
Blocking the active domain - specific allosteric inhibition
Promoting cell survival - specific allosteric inhibition
Unfolded protein responses in stress-induced degeneration
Cellular fate under control of small-molecule allosteric modulation
Ref: Ghosh R et al. ”Allosteric Inhibition of the IRE1α RNase Preserves Cell Viability and Function during Endoplasmic Reticulum Stress.” Cell Vol. 158, Iss. 3 pp534-548 (2014)
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8. |
What is necrosis?
01:58
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Necrosis, long thought to be a passive and otherwise chaotic cellular process
Cellular swelling, membrane rupture, loss of intracellular contents
The result of physico-chemical stress, hypoxia, IR, metabolism impairment
It appears that necrosis could be a much more well-orchestrated type of cell death
Precise execution mechanism, signal transduction pathways
Involved in particular developmental process, tissular homeostasis
Ischemia – inadequate oxygen and nutrient supply
Reperfusion – increased cell death following bloodflow restoration
Oxphos inhibition – intracellular ATP depletion
A switch from apoptosis – to necrosis in the presence of apoptotic signalization
Induction of necrosis by ligand-death receptor interaction
TRAIL, Fas, TNFR1, requiring translational inhibition
Blocked caspases, apoptosis prevented, necrotic death initiation
Inflammatory response initiation lead by various pathogen recognition receptors
Exogenous lipopolysaccharide, bacterial RNA, peptidoglycans
Triggering necrotic cell death in various murine and human cellular lineages
Reactive oxygen species – damages resulting in mitochondrial dysfunction
RIP1 – TNF-dependent mitochondrial (re)localization
Immune recognition – phosphatidylserine externalization
Macrophages – necrotic cell clearance by phagocytic engulfment
Ref: Vanlangenakker N et al. “Molecular mechanisms and pathophysiology of necrotic cell death.” Current Molecular Medicine 8(3):207-220. (2008)
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Clustered regularly interspaced short palindromic repeat associated system
An endonuclease complex identified as a part of the immune system of streptococcus pyogenes
A powerful tool in the context of genome editing, gene therapy and gene functional investigation
Yet which still needs to be fully understood in order to minimise unintended mutation and non-specific target recognition
Reprogramming of guiding gRNA sequences
Targeting of a mutated gene of interest
A precise DNA repair mechanism
Potential clinical applications for the CRISPR/Cas9 system
Cultured cells from tripronuclear human zygotes were (ab)used to further investigate the system
Low efficiency in homologous (recombination) directed repair and off-target cleavage observation
Endogenous homologous gene competing with the exogenous donour, causing untoward mutations
Improving the specificity and accuracy of the genome editing method may necessitate years of additional experimentation
Reprogramming of guiding gRNA sequences
Off-target effects, mutations and mosaicism
A not-so precise genome editing mechanism
Potential caveats for the CRISPR/Cas9 system
An otherwise low efficiency of homologous recombination directed repair, due to competing endogenous paralogs and pseudogenes
Combined with off-target cleavage and interfering repair template, mosaic tripronuclear zygotes
hindered by untoward mutations
Ref : Puping L et al. “CRISPR/Cas9-mediated gene editing in human tripronuclear zygotes.” Protein & Cell 6(5): 363–372. (2015)
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Infectious conditions and inflammation displaying a high serum level
Of an endotoxin-induced glycoprotein, the tumor necrosis factor
Found in T & B lymphocytes and natural killer cells
Transduction pathway still not understood fully well
Expressed on the membrane surface, cleaved by proteinases, released in a soluble form
Haemorrhagic necrosis of transplanted sarcomas evidence of pro-inflammatory response
Macrophages, neutrophils and endothelial cells
Cellular necrosis and tissular swelling
A defense against viral or parasitic infections
Turned harmful for the host when in excessive production
Once a glimmer of hope as a chemotherapeutic agent
Contradicted by several cases of metastatic invasion
In direct association with many inflammatory conditions, the tumor necrosis factor
Ref: Bradley JR “TNF-mediated inflammatory disease”. J Pathol 214: 149-160 (2008)
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