XI'AN,
China, March 29, 2023 /PRNewswire/ -- The burden
of cardiovascular, metabolic, and neurological diseases (including
ischemic heart disease, stroke, diabetes, and Parkinson's disease)
is particularly high, and these conditions affect millions around
the world annually. In order to develop effective treatment
strategies against these diseases, it is important to delineate the
cellular and molecular pathways that contribute to their
development. Three pre-clinical studies published in Volume 13
Issue 2 of Journal of Pharmaceutical Analysis have done just
that.
The first study, published on December 5,
2022, focused on myocardial infarction (MI), better known as
a heart attack. Given that the repair of damaged heart tissue
following MI is crucial for maintaining cardiac function and
prolonging patient survival, the study explored the mechanisms
underlying this process. It focused on elucidating the role of a
post-translational modification called SUMOylation and the response
of cardiac cells to the lack of SUMO1, a key protein involved in
this modification. The study revealed that mutant mice who lack
SUMO1 show aggravated systolic dysfunction and infarct size after
MI. Single-nucleus RNA sequencing and in vitro studies were
conducted in three cell types: cardiomyocytes (heart muscle cells),
fibroblasts (which provide collagen and connective tissue for heart
cells), and endothelial cells (which line the blood vessels). The
authors sum up their findings: "The findings revealed that SUMO1
overexpression and deletion in different cell types have different
effects on cardiac recovery following MI. However, its
cardiomyocyte-specific overexpression can have cardiac
benefits." Hence, modulating SUMO1 expression in different
heart cell types could enable the treatment of MI.
The second study examined the mechanisms underlying a link
between diabetes and Parkinson's disease. One key finding was that
high glucose levels in the brain microenvironment contributed to
the increased risk of Parkinson's disease in patients with
diabetes. Interestingly, the researchers found that high glucose
levels enhance the neurotoxic effects of the neurotoxin
6-hydroxydopamine (6-OHDA) in motor neurons. Metabolomic analysis
revealed that high glucose levels impair neuronal energy generation
pathways, promoting mitochondrial loss and neuronal death. These
effects are mediated by a protein called pyruvate kinase M2 (PKM2),
which is involved in glucose metabolism. Interestingly, blocking
this protein could prevent neuronal damage and reduce the risk of
Parkinson's disease in diabetic rats. "Therefore," one
author says, "the targeted inhibition of PKM2 could offer a new
tool for preventing the development of Parkinson's disease in
people with diabetes."
The final study explored the potential of a potent antioxidant,
celastrol, in mitigating oxidative damage after ischemic stroke.
The results of this study, which was published on January 7, 2023, attested to the potential of
celastrol in exerting antioxidative effects on astrocytes, a type
of brain cell, after ischemic stroke. They showed that celastrol
treatment leads to an increase in the expression of a protein
called Nrf2 by targeting Nedd4, an enzyme. Liquid
chromatography-tandem mass spectrometry revealed that celastrol
directly bound to Nedd4, releasing Nrf2 from Nedd4 in astrocytes.
Celastrol also blocked the Nedd4-induced increase in astrocytic
reactive oxygen species following ischemic injury. Accordingly,
celastrol inhibited oxidative stress and astrocyte activation,
preventing damage to nerve processes (axons) and apoptosis of
neurons. The authors of this study believe that "celastrol could
be a potential therapeutic agent for stroke."
The findings from this series of studies open up new therapeutic
doors and provide hope for the development of better disease
management strategies.
Reference
Title of original paper: SUMO1 regulates
post-infarct cardiac repair based on cellular heterogeneity
Journal: Journal of Pharmaceutical Analysis
DOI:
https://doi.org/10.1016/j.jpha.2022.11.010
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