Presentation prepared for a Talk on Nobel Prize Winning Research by Semenza, Kaelin and Ratcliffe in the field of Medicine and Physiology in the year 2019 Talk was organized by Department of Molecular Biology and Biotechnology, Cotton University, Guwahati This slide was suceeded by previously presented slides upon history and the basic systemic and biological pathways involved in hypoxia and HIF-1 discovery

1. Rise of a new molecular aspect of
medicine
PRESENTING BEFORE YOU
BY-
MONOSWI CHAKRABORTY
UG-BIOTECHNOLOGY,5th SEM
DEPT. OF MBBT

2.  Investigations On Tumour Hypoxia
 Hypoxia Inducing Factor-1 (HIF-1) protein
 Role of HIF-1 in Wound Healing
 Role of HIF-1 in Chronic Kidney Diseases,
Anaemia and Cardiovascular diseases
 Blood Doping

3. Investigations On Tumour
Hypoxia
-Anatomy, causes and clinical
consequences

4. Anatomy and micro-environment of
Solid tumours

5. Comparative analysis of O2-concentrations
in varied regions of tumorigenic tissues
and its healthy counterparts

6. Causes of Tumour Hypoxia
angiogenesis

7. Tumour Hypoxia and its adaptation
mechanism
O2

8. How does HIF matter to cancer cell?

9. Clinical Consequences of Tumour
Hypoxia
The hypoxic microenvironment shields the therapeutic effects
and accelerates tumour growth(HIF-1 should be knock down)
Primary tumours in hypoxic microenvironments tend to enter
blood stream and travels to new site to form secondary tumour
EMT occurs

10. Lets delve deeper………

11. -the potential panacea of
ClinicalWorld

12. HIF-1 protein: The next Elixir of Life
Lets draw an analogy where,
 HIF-1a : The Supervisor
 Cell/Tissue : The company
 Nucleus : Supervisor’s office where
he transcripts/orders for manufacturing
products
 Erythropoetins(EPO): Worker’s in the
company
 RBC’s: Products
 O2 : Money

13. Basic purpose of the protein?
• Aerobic life sustains upon the 21%
of O2 that is available in the
atmosphere.
• Absence of O2: Leads to Oxidative
stress producing free radicals of O2
and ROS(Reactive Oxygen Species)
• Free radicals or ROS damages
surrounding proteins, lipids and
especially DNA.
• Thus, the basic purpose of HIF-1 is
to prevent the organism from
losing 02 contents thereby lowering
defects in cellular function.
21% O2 in
atmosphere
Free
radicals
ROS
DNA damage

14. HIF-1 and its paralogs HIF-2/HIF-3
• Understanding the cellular pathways that mediate recovery from hypoxia is critical
for developing novel therapeutic approaches for cardiovascular diseases and
cancer (Marcin Serocki, 2018)
• The master regulators of oxygen homeostasis that control angiogenesis during
hypoxia are hypoxia-inducible factors (HIFs).
• HIF-1 and HIF-2 function as transcriptional regulators and have both unique and
overlapping target genes, whereas the role of HIF-3 is less clear.
• HIF-1 governs the acute adaptation to hypoxia, whereas HIF-2 and HIF-3
expressions begin during chronic hypoxia in human endothelium.
• When HIF-1 levels decline, HIF-2 and HIF-3 increase. This switch from HIF-1 to HIF-
2 and HIF-3 signaling is required in order to adapt the endothelium to prolonged
hypoxia.

15. miRNA mediated HIF Switch: A potent
therapeutic possibility
• Recently, the miRNAs have been
shown to play critical roles in the
hypoxia response pathways.
(Anna Janaszak-Jasiecka, 2018)
• These classes of RNAs provide
therapeutic possibilities to
selectively target HIFs and thus
modulate the HIF switch.
• Several antagomiR(reduction)
and agomiR (mimic)-based
miRNA(overexpression)
therapeutics are currently in
development
miR-155 +miR-429: Reduce HIF-1α level,
transition to HIF-2 and HIF-3 signaling
miR-210 +miR-429: HIF-3α accumulation

16. But, What is an miRNA?

17. Prolyl hydroxylase inhibitors (PHI’s)- a
promising drug in clinical development

18. Role of HIF-1-PHI’s in Wound
Healing:
Scope and significance

19. Present and Future prospects of HIF-1-
PHI based wound healing
• Recent Advances: Positive regulators
of HIF-1, such as prolyl-4-hydroxylase
inhibitors, have been shown to be
beneficial in enhancing diabetic
ischemic wound closure and are
currently undergoing clinical trials for
treatment of several human-
ischemia-based conditions.
• Future Directions: Counteracting the
detrimental effects of excessive or
deficient HIF-1 signaling by
modulating HIF-1 expression may
improve future management of
poorly healing wounds.

20. Role of HIF-1-PHI’s in Chronic
Kidney Diseases
-Potent tool to fight Anaemia and
Cardiovascular diseases

21. Mechanism of HIF and PHI action in
battling Anaemia and Cardiovascular
diseases.

22. Advances in Clinical trial
• Cardiovascular disease is a common and serious complication in
patients with chronic kidney disease (CKD).
• One of the fundamental functions of the cardiovascular system is
oxygen delivery, therefore cardiovascular disease inherently is
linked to insufficient tissue oxygenation.
• Advances in our knowledge of cellular oxygen sensing by a family
of prolyl hydroxylases (PHDs) and their role in regulating hypoxia-
inducible factors (HIFs) have led to the discovery of PHD inhibitors
as HIF stabilizers.
• Several small-molecule PHD inhibitors are currently in clinical trials
for the treatment of anemia in CKD.

23. Are you sometimes in need of
instant energy???
---and your packet of glucose isn’t
working…..

24. Blood Doping
• Blood doping is the practice of
boosting the number of red blood
cells in the bloodstream in order to
enhance athletic performance.
• Because such blood cells
carry oxygen from the lungs to
the muscles, a higher concentration
in the blood can improve an
athlete’s aerobic capacity (VO2 max)
and endurance.
• Many methods of blood doping are
illegal, particularly in professional
sports. Blood doping is carried out by
injecting already collected blood back
into the persons system.

25. Recombinant EPO and HIF stabilizers
as potent Blood doping methods
• EPO was first developed to
counteract the effects of
chemotherapy and radiation therapy
for cancer patients
• a glycoprotein hormone produced by
the interstitial fibroblasts in the
kidney that signal for erythropoiesis
in bone marrow. The increased
activity of a Hemocytoblast (RBC
stem cell) allows the blood to have a
greater carrying capacity for oxygen.
• Because of its physiological side
effects, particularly increased
hematocrit, EPO has become a drug
with abuse potential by professional
and amateur cyclists.
• HIF stabilizers as used by cyclists in
combination with cobalt
chloride/desferrioxamine stimulate and
de-regulate the natural production of
erythropoietin hormone
• The combination of drugs consistently
releases EPO due to increased
transcription at the cellular level.

26. Credits and References
• Cormac T. Taylor; Mitochondria and cellular oxygen sensing in the HIF pathway. Biochem J 1
January 2008; 409 (1): 19–26
• Thomas P. Keeley and Giovanni E. Mann, Defining Physiological Normoxia for Improved
Translation of Cell Physiology to Animal Models and Humans, Physiological
Reviews, 10.1152/physrev.00041.2017, 99, 1, (161-234), (2019).
• Wang GL & Semenza GL ( 1993 ). General involvement of hypoxia‐inducible factor 1 in
transcriptional response to hypoxia . Proc Natl Acad Sci U S A 90 , 4304 – 4308
• https://www.editage.com/insights/the-fight-against-cancer-the-promise-of-hif-1-inhibitors
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4696033/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5855611/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4005494/
• https://link.springer.com/article/10.1007/s10456-018-9600-2
• https://www.sciencedirect.com/science/article/abs/pii/S0270929518300275
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1828868/
• Image taken: NC Denko (2008), Nature Reviews Cancer ;8:705
: Jones and Thompson (2009), Genes and Development 23:537
: AK Lectures
:https://youtu.be/WBwy1fEuE34
:https://youtu.be/gGe8nm0XKBo

27. THANK YOU ALL FOR YOUR PATIENCE
Presented by :
Abhinaba Bhattacharjee
Deepa Das
Monoswi Chakraborty
Dept. of Molecular Biology
and Biotechnology
COTTON UNIVERSITY