A novel cell-penetrating peptide exerts therapeutic effects against ischemic stroke
2024-01-09
(Press-News.org)
This study is led by Dr. Xing Li and Dr. Yilin Zhao (Department of Anesthesiology, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology). The team's previous research found that the increase in SIRT5 in microglia induced by ischemic stroke causes annexin-A1 (ANXA1) desuccinylation, which decreases ANXA1 membrane recruitment and secretion but promotes ANXA1 nuclear translocation, resulting in the production of proinflammatory mediators and ultimately enhancing neuroinflammation damage. Thus, microglia-specific forced overexpression of SIRT5 worsened ischemic brain injury, whereas downregulation of SIRT5 exhibited neuroprotective and cognitive-preserving effects against ischemic brain injury, which the study was published in Journal of Neuroinflammation (2022;19(1):301). Based on this, a membrane-permeable peptide specifically bound to SIRT5 through a chaperone-mediated autophagy targeting motif (Tat-SIRT5-CTM) was designed and synthesized. In primary microglia, Tat-SIRT5-CTM suppressed the binding of SIRT5 with ANXA1, leading to SIRT5 degradation and thus inhibition of SIRT5-mediated desuccinylation of ANXA1, followed by increased membrane accumulation and secretion of ANXA1. These changes, in turn, alleviated microglia-induced neuroinflammation. "I was excited about it," the first author of the paper Qian Xia says.
They sought to determine the therapeutic effect of this cell-penetrating peptide in mice subjected to ischemic stroke. Following intravenous injection, Tat-SIRT5-CTM could efficiently pass through the blood‒brain barrier. Importantly, systemic administration of Tat-SIRT5-CTM reduced the brain infarct area and neuronal loss, mitigated neurological deficit scores, and improved long-term neurological functions in a mouse model of ischemic stroke. Furthermore, no toxicity was observed when high doses Tat-SIRT5-CTM were injected into nonischemic mice.
The team further indicated that the Tat-SIRT5-CTM inhibits the expression of inflammatory cytokines in microglia after OGD/R or in a mouse model of ischemic stroke. “TUNEL staining showed that microglia or mice treated with Tat-SIRT5-CTM can protect against neuronal damage under OGD/R or MACO/R conditions,” Qian Xia says.
The team also found that the Tat-SIRT5-CTM reduces the infarct volume and mitigates the neurological deficit scores (see left and center images below). “The TTC staining confirmed Tat-SIRT5-CTM successfully reduced the cerebral infarct size, and the modified neurological severity scores demonstrated that Tat-SIRT5-CTM displayed a better neurological score” Qian Xia says.
The researchers finally assess long-term neurobehavioral functions after ischemic brain injury with a battery of behavioral tests. In the rotarod test, the results showed that Tat-SIRT5-CTM-treated mice took longer to fall off the rod and preserves long-term neurobehavioral functions after ischemic brain injury (see below, right image).
"These new exciting results add to growing evidence that promising efficacy of the peptide-directed lysosomal degradation of SIRT5 and suggests it as an effective therapeutic approach for the treatment of ischemic stroke. It was recently proven through a phase 3 clinical trial that a Tat-fused peptide called Nerinetide (NA-1) is not only safe but also effective in preventing ischemic damage to human neurons. We hope that this Tat-SIRT5-CTM peptide can also be successfully translated to the clinic as a new and effective treatment for ischemic stroke in human patients,” Qian Xia says.
This study was funded in part by the National Natural Science Foundation of China, Tongji Hospital (HUST) Foundation for Excellent Young Scientists, and Scientific Research Foundation for the Returned Overseas Chinese Scholars, Tongji Hospital.
See the article:
A cell-penetrating peptide exerts therapeutic effects against ischemic stroke by mediating the lysosomal degradation of sirtuin 5
END
[Attachments] See images for this press release:
ELSE PRESS RELEASES FROM THIS DATE:
2024-01-09
Sensors are essential tools for detecting and analyzing trace molecules in a variety of fields, including environmental monitoring, food safety, and public health. However, developing sensors with high enough sensitivity to detect these tiny amounts of molecules remains a challenge.
One promising approach is surface-enhanced infrared absorption (SEIRA), which uses plasmonic nanostructures to amplify the infrared signals of molecules adsorbed on their surface. Graphene is a particularly promising material for SEIRA because of its high ...
2024-01-09
Ishikawa, Japan -- Amino acids, such as tyrosine and tryptophan, are the fundamental building blocks that make up proteins. These biomolecules have different chemical groups on each end and side chain, and so, have the natural ability to form a chain through the formation of an amide (peptide) bond. However, such linkages are weak and easily degraded under physiological conditions. This is where the Fmoc-protected amino acids come into the picture.
In a new study now, a research team led by Dr. Eijiro Miyako, Associate ...
2024-01-09
This article first identifies the current definition of urban heritage that includes both “old” and “young” monuments. Their protection has also shifted from solely preserving “old” values into a more holistic process to retain “old” values and manage the change in their adaptive reuse to gain “new” values, towards a more people-centered and landscape-based approach. Furthermore, a concept of ecosystem for urban planning and development is introduced, ...
2024-01-09
Alzheimer’s disease (AD) is an age-related neurodegenerative disorder. β-amyloid (Aβ) deposition in the brain is a crucial contributor to the pathogenesis of AD, mitigating excessive cerebral Aβ burden has been considered as a possible therapeutic strategy for AD. Meningeal lymphatic vessels (MLVs) are recently discovered structures responsible for exchanging soluble components between the cerebrospinal fluid and interstitial fluid, and have been proved to be a potential pathway of Aβ drainage.
Researchers at Huazhong University ...
2024-01-09
Love is blind, the saying goes, and thanks to a world-first Australian study, we are now a step closer to understanding why.
It is well known that romantic love changes the brain, releasing the so-called love hormone oxytocin, responsible for the euphoria we feel when falling in love.
Now, researchers from the ANU, University of Canberra and University of South Australia have measured how a part of the brain is responsible for putting our loved one on a pedestal in that first flush of romance.
In the world’s first study investigating the link between the human brain’s behavioural activation ...
2024-01-09
Ammonia is a necessary feedstock to produce nitrogen-based fertilizers, chemicals, pharmaceuticals, and polymers. To date, about 80% of global ammonia is used to produce nitrogen-based fertilizers which relates to 50% of global food production. The global production of ammonia is about 180 million metric tons per year through the carbon-intensive and highly energy-consuming Haber-Bosch process. The high energy consumption, high carbon intensity, and high capital investment of the Haber-Bosch process make the development of environmentally sustainable and affordable routes for ammonia synthesis under ambient conditions more urgent. The electrochemical ammonia ...
2024-01-09
Measuring airborne grass allergen levels instead of pollen counts will be more beneficial for hay fever sufferers as new research shows grass allergen levels are more consistently associated with hay fever symptoms than grass pollen counts.
The research, published today in The Journal of Allergy and Clinical Immunology and led by King’s College London and Imperial College London, shows for the first time that measuring airborne allergen levels will help people with hay fever better control their symptoms.
1 in 4 adults in the UK suffer from hay fever from late-March to September. Symptoms include a runny or blocked ...
2024-01-09
Women with autoimmune disease are more likely to suffer from depression during pregnancy and after childbirth; conversely, women with a history of perinatal depression are at higher risk of developing autoimmune disease, a new study from Karolinska Institutet published in the journal Molecular Psychiatry reports.
In autoimmune disease, the immune system mistakenly attacks the body’s own healthy tissue. Some of the most common autoimmune diseases are gluten intolerance (coeliac disease), autoimmune thyroiditis, rheumatoid ...
2024-01-09
A study of seriously ill patients from academic medical centers across the country has found that nearly a quarter had a delayed or missed diagnosis.
All the patients had either been transferred to the intensive care unit (ICU) after being admitted or died in the hospital. The researchers concluded that three-quarters of these diagnostic errors contributed to temporary or permanent harm, and that diagnostic errors played a role in about one in 15 of the deaths.
The most common errors identified in the study involved delayed rather than missed diagnoses, for example because a specialist was consulted too late or an alternate diagnosis was not considered ...
2024-01-09
LA JOLLA, CA— Ethanol—the compound found in alcoholic beverages—interferes with the normal functioning of a long list of biological molecules, but how each of these interactions contributes to the behavioral effects of alcohol is not fully understood. A guiding, but elusive, goal of researchers is to identify the protein (or proteins) to which ethanol binds that makes some people vulnerable to excessive drinking. Solving this question would point the way to effective therapies for alcohol use disorder, ...
LAST 30 PRESS RELEASES:
[Press-News.org] A novel cell-penetrating peptide exerts therapeutic effects against ischemic stroke
