This is the slide show I presented Vaccines R&D 2023 Baltimore, USA i Nov 8, 2023

1. A Homeostatic Approach to COVID-19; preserving physiological boundaries of RAS
by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant

2. Reza Nejat, M. D., FCCM,
Anesthesiology and Critical Care Dept., Laleh Hospital,
Anti-Doping, Nutrition and Metabolism Consultant, World Powerlifting Ltd., Eurasia Division (Asia, Iran),
Melbourne, Australia,
Former Assistant Professor, SBMU,
N1

3. Slide 2
N1 reviewer, 8/26/2023

4. by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
A Homeostatic Approach to COVID-19;
preserving physiological boundaries of RAS
HOMEOSTASIS
Coined by Walter B.
Cannon
Self regulating processes
maintaining the internal
stability and function of
organisms facing constant
changes of their external
environment
Endow the organism with
buffering protective
mechanisms:
Required for free independent life
Billman, G. E., Frontiers in Physiology, 2020: p.200

5. by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
A Homeostatic Approach to COVID-19;
preserving physiological boundaries of RAS
 HOMEOSTASIS:
 Intricate network of activators
and inhibitors
 Modification of these network:
 Activates latent metabolic
or signaling pathways
 Induces unpredicted
interactions
 Deviates the set points

6. by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
A Homeostatic Approach to COVID-19;
preserving physiological boundaries of RAS
Oldstone, M.B., et al., Science, 1982. 218: p. 1125-1127

7. by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
A Homeostatic Approach to COVID-19;
preserving physiological boundaries of RAS
Kotzamanis, K., et al., Medical Microbiol Immunol, 2015. 204: p.
395-407

8. by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
A Homeostatic Approach to COVID-19;
preserving physiological boundaries of RAS
Immunopathologic dyshomeostatic
characteristics of severe COVID-19
 Impaired production of IFN-I,
 Overwhelming Inflammatory
reactions,
 Lymphopenia ,
 Lymphocytic exhaustion,
 Delayed triggering of adaptive
immunity,

9. by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
A Homeostatic Approach to COVID-19;
preserving physiological boundaries of RAS
Nejat, R., M.F. Torshizi, and D.J. Najafi, Vaccines, 2023. 11(2): p. 204

10. by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
A Homeostatic Approach to COVID-19;
preserving physiological boundaries of RAS
Nejat, R., M.F. Torshizi, and D.J. Najafi, Vaccines, 2023. 11(2): p. 204

11. by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
A Homeostatic Approach to COVID-19;
preserving physiological boundaries of RAS
RAS components and inflammation
 Ang II receptor was found on
 human mononuclear cells (1978)
 Mϕ in granuloma induced by
schistosoma egg (1984)
 Ang I, Ang II, ACE were found in
 Hepatic granuloma induced by
schistosoma egg (1981, 1983)
 Pretreatment with captopril
 Decreased Granuloma induced by
BCG (1982)
 Chemoattractant effect of Ang II
 Rat peritoneal Mϕ (1980, 1983)

12. by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
A Homeostatic Approach to COVID-19;
preserving physiological boundaries of RAS
 Systemic RAS
 Endocrine system
BP regulation
Water and electrolyte balance
 Local tissue RAS (1971)
 Multiple paracrine/autocrine
effects:
 Cell growth, proliferation,
differentiation, migration, apoptosis
 Oxidative metabolism,
 Adipogenesis

13. by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
A Homeostatic Approach to COVID-19;
preserving physiological boundaries of RAS
 Intra-cellular RAS
 Found in some types of cells (?)
 De novo synthesis (high glucose)
 Cellular uptake
 nucleus and cytoplasm
 Intracrine effects
 Mediated by AT1R and AT2R
 Growth of VSMC
 Cell proliferation (PI3K, ERK)
 Increase [Ca2+]i
♣ Influx from EC
♣ From intracellular stores

14. by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
A Homeostatic Approach to COVID-19;
preserving physiological boundaries of RAS
Ang II increases: (pro-inflammatory effects)
Adhesion molecules (ICAM, VCAM),
Cytokines (TNF-α, IL-6, CRP),
Chemokines (MCP-1, IL-8, MIF),
Ang II interrupts:
Insulin anti-inflammatory effects
Ang II promotes:
Prothrombotic state (PAI-1),
Oxidative stress (NADPH oxidase)
Dandona, P., et al., Journal of human hypertension, 2007. 21(1): p. 20-27

15. by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
A Homeostatic Approach to COVID-19;
preserving physiological boundaries of RAS
Angiotensin receptor blockers
Suppress pro-inflammatory mediators,
(TNF-α, IL-6, MCP-1, PAI-1)
Increase I ĸB (inhibitor of NF-ĸB),
Decreases CRP,
Downregulates ROS,
Reduce insulin resistance
modest PPAR-γ activity
Increase adiponectin
Dandona, P., et al., Journal of human hypertension, 2007. 21(1): p. 20-27

16. by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
A Homeostatic Approach to COVID-19;
preserving physiological boundaries of RAS
 RAS components in Human T
and NK cells, DC and
Monocytes:
 Renin and Renin Receptor,
 Angiotensinogen,
 ACE
 Angiotensin I (Ang I),
 Angiotensin II (Ang II),
Jurewicz, M., et al. Journal of the American Society of
Nephrology, 2007. 18(4): p. 1093-1102.

17. by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
A Homeostatic Approach to COVID-19;
preserving physiological boundaries of RAS
Jurewicz, M., et al. Journal of the American Society of
Nephrology, 2007. 18(4): p. 1093-1102.
 Ang II and its precursors:
 Shows mitogenic properties
CD8+ T and NK(presence)
 Stimulate TCR-specific cells
proliferation
 AT1R, AT2R are involved,
 Another unidentified Ang II
receptor???

18. by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
A Homeostatic Approach to COVID-19;
preserving physiological boundaries of RAS
Jurewicz, M., et al. Journal of the American Society of
Nephrology, 2007. 18(4): p. 1093-1102.
 Ang II
 ratio of IFN-γ/IL-4
 Th1/Th2 cytokines,
 Type I Mϕ
 RANTES
♣ Shows chemotactic
properties

19. by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
A Homeostatic Approach to COVID-19;
preserving physiological boundaries of RAS
T cells and ACE2 expression
 T cells express ACE2 molecules (almost
1000)
 When activated, T cells express more ACE2
molecules
 SARS-CoV-2 replication post-entry into T cells
is restricted and does not produce
infectious virus
Welch, J.L., et al., The Journal of Infectious Diseases,
2022. 225(5): p. 810-819

20. by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
A Homeostatic Approach to COVID-19;
preserving physiological boundaries of RAS
 Ang II stimulates (in DCs):
 Maturation,
 Migration,
 Cytokine secretion
 DC-mediated T cell proliferation
 Through NF-kB/ERK1-2/STAT1
pathway
Meng, Y., et al., Cellular Physiology and Biochemistry,
2017. 42(4): p. 1550-1558

21. by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
A Homeostatic Approach to COVID-19;
preserving physiological boundaries of RAS
 Endogenous Ang II:
 produced in T cells,
 Activates T cells,
 Induces TNF-α
 through NOX- mediated
ROS production
Hoch, N.E., et al., Am. J. Physiology-Regulatory, Integrative
and Comparative Physiology, 2009. 296(2): p. R208-R216

22. by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
A Homeostatic Approach to COVID-19;
preserving physiological boundaries of RAS
Hoch, N.E., et al., Am. J. Physiology-Regulatory, Integrative
and Comparative Physiology, 2009. 296(2): p. R208-R216
 Endogenous Ang II:
 Slightly more in CD4+ than
CD8+
 AT1R and AT2R both contribute
to TNF-α production
 Losartan (AT1R antagonist),
 PD123319 (AT2R antagonist)*,
 decrease TNF-α by 30%

23. by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
A Homeostatic Approach to COVID-19;
preserving physiological boundaries of RAS
 Endogenous Ang II:
 Induces mitochondrial oxidative
damage
 Nox/PKC pathway
 Increase ROS
 Activation of mitoKATP
channels
 Diminished NO availability
Doughan, A.K., et al., Circulation research, 2008. 102(4): p. 488-496.

24. by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
A Homeostatic Approach to COVID-19;
preserving physiological boundaries of RAS
 Endogenous Ang II:
 Inhibits alveolar fluid clearance
 dysregulates ENaC expression
via AT1 receptors,
 contribute to alveolar filling
and pulmonary edema in
LPS-induced ALI
Deng, J., et al., Canadian respiratory journal, 2012. 19: p. 311-318

25. by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
A Homeostatic Approach to COVID-19;
preserving physiological boundaries of RAS
March 2020
A video clip was uploaded in youtube:
https://youtu.be/kpyDrxw1kAI
“Losartan may subside ARDS in COVID-
19”
A case report of a patient with COVID-
19 in whom serial Lung CT scan
showed improvement of lung density
improved with losartan.

26. by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
A Homeostatic Approach to COVID-19;
preserving physiological boundaries of RAS
An in Silico study and a review
SARS-CoV-2 infection:
 Downregulation of ACE2
 Overzealous activation of local and
cellular Ang II/AT1R/Nox
Losartan (AT1R antagonist) and Imatinib:
 “we have demonstrated that
losartan and imatinib could distort
the binding site of SARSCoV2 RBD
to ACE2.”

27. by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
A Homeostatic Approach to COVID-19;
preserving physiological boundaries of RAS
An in Silico study and a review
SARS-CoV-2 infection:
 Downregulation of ACE2
 Overzealous activation of local and
cellular Ang II/AT1R/Nox
Losartan (AT1R antagonist) and Imatinib:
 “we have demonstrated that
losartan and imatinib could distort
the binding site of SARSCoV2 RBD
to ACE2.”

28. by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
A Homeostatic Approach to COVID-19;
preserving physiological boundaries of RAS
An in vitro cell culture study
Losartan (AT1R antagonist)
 “Importantly, losartan treatment of
Vero E6 cells prior to and after
SARS-CoV-2 infection inhibited the
virus replication.”

29. by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
A Homeostatic Approach to COVID-19;
preserving physiological boundaries of RAS
Conclusion
Considering the dyshomeostatic impact of
viral infections on host cells preserving
homeostatic balance of RAS in patients
with COVID-19 seems quite rational to be
considered as a promising therapeutic
strategy.
Thank you for your patience
You may kindly find me through
rezanejat@yahoo.com