Age-linked lung pathology is reduced by immunotherapeutic targeting of isoDGR protein damage DOI Open Access
Pazhanichamy Kalailingam,

Khalilatul‐Hanisah Mohd‐Kahliab,

SoFong Cam Ngan

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Aug. 14, 2023

Abstract Aging is a significant contributor to chronic lung disorders, yet the precise molecular mechanisms remain elusive. This study investigates impact of isoDGR motif accumulation, form protein damage, on age-related pathology using both mouse models and human tissues. We utilized Pcmt1-/-mice, lacking repair enzyme, treated them with motif-specific antibodies, employing range techniques including histology, RNA sequencing, imaging, functional analyses. Human tissue microarrays (TMA) were also employed assess associations aging fibrosis. The revealed notable isoDGR-modified accumulation in blood vessels accompanied by low-grade inflammation, variable pulmonary edema, reduced lifespan. buildup triggered mitochondrial ribosomal dysfunction, as well cellular senescence apoptosis, contributing damage. Treatment anti-isoDGR antibodies suppressed TLR pathway activity, alleviated cytokine-driven restored mtDNA expression, led vivo. Similarly, exposure endothelial cells fibronectin hindered oxygen consumption, escalated reactive species, disrupted acidification; these effects reversed antibodies. TMA experiments further positive correlation between isoDGR-protein levels CD68+ macrophage infiltration fibrosis In conclusion, this underscores role isoDGR-damaged proteins utilizing Targeting isoDGR-specific emerges promising therapeutic avenue for addressing disorders elderly population.

Language: Английский

The heterocellular heart: identities, interactions, and implications for cardiology DOI Creative Commons
Achim Lother, Peter Köhl

Basic Research in Cardiology, Journal Year: 2023, Volume and Issue: 118(1)

Published: July 26, 2023

The heterocellular nature of the heart has been receiving increasing attention in recent years. In addition to cardiomyocytes as prototypical cell type heart, non-myocytes such endothelial cells, fibroblasts, or immune cells are coming more into focus. rise single-cell sequencing technologies enables identification ever subtle differences and reignited question what defines a cell's identity. Here we provide an overview major cardiac types, describe their roles homeostasis, outline findings on non-canonical functions that may be relevance for cardiology. We highlight modes biochemical biophysical interactions between different types discuss potential implications basic research therapeutic interventions.

Language: Английский

Citations

28
Pericytes in the brain and heart: functional roles and response to ischaemia and reperfusion DOI Creative Commons
Turgay Dalkara, Leif Østergaard, Gerd Heusch

et al.

Cardiovascular Research, Journal Year: 2024, Volume and Issue: unknown

Published: July 26, 2024

In the last 20 years there has been a revolution in our understanding of how blood flow is regulated many tissues. Whereas it used to be thought that essentially all control occurred at arteriole level, now recognised capillary by contractile pericytes plays key role both regulating physiologically and reducing clinically-relevant pathological conditions. this article we compare contrast brain cardiac regulate cerebral coronary flow, focusing mainly on events ischemia. The beds differ dramatically morphology, yet cases pericyte-mediated constriction restricting after ischemia possibly other We conclude with suggestions for therapeutic approaches relaxing pericytes, which may prove useful long term pericyte-induced

Language: Английский

Citations

6
A pathogenic role for IL-10 signalling in capillary stalling and cognitive impairment in type 1 diabetes DOI Creative Commons

Sorabh Sharma,

Manjinder S. Cheema, Patrick Reeson

et al.

Nature Metabolism, Journal Year: 2024, Volume and Issue: 6(11), P. 2082 - 2099

Published: Nov. 4, 2024

Vascular pathology is associated with cognitive impairment in diseases such as type 1 diabetes; however, how capillary flow affected and the underlying mechanisms remain elusive. Here we show that capillaries diabetic mouse brain both sexes are prone to stalling, blocks consisting primarily of erythrocytes branches off ascending venules. Screening for circulating inflammatory cytokines revealed persistently high levels interleukin-10 (IL-10) mice. Contrary expectation, stimulating IL-10 signalling increased obstruction, whereas inhibiting receptors neutralizing antibodies or endothelial specific knockdown mice reversed these impairments. Chronic treatment receptor improved cerebral blood flow, flux diameter, downregulated haemostasis cell adhesion-related gene expression, deficits. These data suggest has an unexpected pathogenic role microcirculatory defects diabetes. Interleukin-10 promotes formation a model

Language: Английский

Citations

4
Immunotherapeutic targeting of aging‐associated isoDGR motif in chronic lung inflammation DOI Creative Commons
Pazhanichamy Kalailingam, SoFong Cam Ngan,

Ranjith Iyappan

et al.

Aging Cell, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 5, 2025

Accumulation of damaged biomolecules in body tissues is the primary cause aging and age-related chronic diseases. Since this damage often occurs spontaneously, it has traditionally been regarded as untreatable, with typical therapeutic strategies targeting genes or enzymes being ineffective domain. In report, we demonstrate that an antibody isoDGR motif lung tissue can guide immune clearance harmful proteins vivo, effectively reducing age-linked inflammation. We observed age-dependent accumulation human tissues, well 8-fold increase isoDGR-damaged fibrotic compared healthy tissue. This was accompanied by marked infiltration CD68+/CD11b + macrophages, consistent a role for promoting therefore assessed function mice were either naturally aged lacked repair enzyme. IsoDGR-protein mouse strongly correlated inflammation, pulmonary edema, hypoxemia. also induced mitochondrial ribosomal dysfunction, addition to features cellular senescence, thereby contributing progressive over time. Importantly, treatment anti-isoDGR able reduce these molecular disease significantly reduced pathology vivo.

Language: Английский

Citations

0
Analysis of Brain Tissue Poroelastic Properties Using Multiscale Modelling DOI Creative Commons

Abbas Shabudin,

Mohd Jamil Mohamed Mokhtarudin,

Nik Abdullah Nik Mohamed

et al.

IIUM Engineering Journal, Journal Year: 2025, Volume and Issue: 26(1), P. 437 - 449

Published: Jan. 10, 2025

Mathematical models are developed to further understand ischaemic stroke formation and achieve treatment effectiveness. The existing poroelastic model of the brain assumed as a homogenized structure with uniform capillary distribution. This paper describes use multiscale modeling technique known asymptotic expansion homogenization (AEH) derive new tissue. consists governing macroscale effective parameters determined from microscale cell equations. equations solved on representative volume element (RVE) comprising tissue embedded capillary. Here, effect tortuosity radius parameters, which hydraulic conductivity interstitial space (K G), homogenous Biot's coefficient blood (?c? ?t?), Young's modulus Poisson's ratio investigated. From results, it is found that percentage difference K 97.98% increasing tortuosity, suggests significantly influenced by shape In contrast, G only 0.25%, showing unaffected Meanwhile, ?c? ?t decrease increase respectively. Both E ? not affected for each just 0.14% 0.03%, terms radius, increases decreases radius. while ?t? shows opposite trend. differences 18.26% 14.55% observed E? ?, respectively, implying both conclusion, including capillaries in affects parameters. Hence, important properties capillary, size, should be carefully emphasized so accurate findings can obtained when solving brain. ABSTRAK: Model matematik dibangunkan untuk mendapatkan pemahaman lanjut tentang pembentukan strok iskemia supaya keberkesanan rawatan dapat dicapai. poroelastik otak yang sedia ada menganggap sebagai struktur homogen dengan taburan kapilari seragam. Makalah ini menerangkan penggunaan teknik pemodelan multiskala dikenali penghomogenan pengembangan asimtotik (PPA) memperoleh baharu tisu otak. terdiri daripada satu set skala makro pentadbir parameter berkesan ditentukan persamaan sel mikro. Persamaan mikro diselesaikan pada unsur isipadu perwakilan tertanam. Di sini, kesan kelikuan dan jejari berkesan, iaitu kekonduksian hidraulik ruang celahan pekali Biot bagi darah Young (E) nisbah Poisson (?), akan diselidiki. Daripada keputusan diperoleh, didapati perbezaan peratusan ialah peningkatan kelikuan, menunjukkan bahawa dipengaruhi oleh bentuk secara signifikan. Manakala hanyalah ia tidak kelikuan. Sementara itu, masing-masing menurun meningkat Kedua-dua terjejas ketara kerana setiap hanya 0.03%. Dari segi pula, bertambah berkurangan pertambahan jejari. ?c jejari, manakala sebaliknya. Peratusan diperhatikan kedua-dua kapilari. Kesimpulannya, kemasukan dalam mempunyai terhadap berkesan. Oleh sifat penting termasuk saiz harus ditekankan teliti penemuan tepat boleh diperolehi apabila menyelesaikan

Citations

0
Navigating Complexity in Postural Orthostatic Tachycardia Syndrome DOI Creative Commons
Hui‐Qi Qu, Hákon Hákonarson

Biomedicines, Journal Year: 2024, Volume and Issue: 12(8), P. 1911 - 1911

Published: Aug. 20, 2024

Postural Orthostatic Tachycardia Syndrome (POTS) affects up to 1% of the US population, predominantly women, and is characterized by a complex, elusive etiology heterogeneous phenotypes. This review delves into intricate physiology POTS, decoding roles sinoatrial node, autonomic nervous system, fluid dynamics, interplay between immune endocrine systems. It further examines key contributing factors such as dysautonomia, thoracic hypovolemia, neuropathies, sympathetic denervation, autoimmune responses, associations with conditions small-fiber neuropathy mast cell activation syndrome. Given numerous mysteries surrounding we also cautiously bring attention node myocardial function, particularly in how heart responds stress despite exhibiting normal cardiac phenotype at rest. The potential genomic research elucidating underlying mechanisms POTS emphasized, suggesting this valuable approach that likely improve our understanding genetic underpinnings POTS. introduces tentative classification system for etiological which seeks capture condition's diverse aspects categorizing various acknowledging co-occurring conditions. classification, while aiming enhance optimize treatment targets, presented preliminary model needing study refinement. underscores ongoing need unravel complexities develop targeted therapies can patient outcomes.

Language: Английский

Citations

3
Endothelial structure contributes to heterogeneity in brain capillary diameter DOI Creative Commons
Sheridan Sargent, Stephanie Bonney, Yuandong Li

et al.

Vascular Biology, Journal Year: 2023, Volume and Issue: 5(1)

Published: Jan. 1, 2023

The high metabolic demand of brain tissue is supported by a constant supply blood flow through dense microvascular networks. Capillaries are the smallest class vessels in and their lumens vary diameter between ~2 5 μm. This range plays significant role optimizing resistance, cell distribution, oxygen extraction. control capillary has largely been ascribed to pericyte contractility, but it remains unclear if architecture endothelial wall also contributes diameter. Here, we use public, large-scale volume electron microscopy data from mouse cortex (MICrONS Explorer, Cortical mm 3 ) examine how number, thickness, coverage relates lumen size. We find that transitional near penetrating arteriole ascending venule composed two six interlocked cells, while capillaries intervening these zones either one or with roughly equal proportions. luminal area on average slightly larger segments cells vs cell. However, this difference insufficient explain full diameters seen vivo . suggests both structure other influences, including tone, contribute basal optimized perfusion capillaries.

Language: Английский

Citations

9
A pathogenic role for IL-10 signalling in capillary stalling and cognitive impairment in type 1 diabetes DOI Creative Commons

Sorabh Sharma,

Manjinder S. Cheema,

Kelly A. Tennant

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 2, 2024

Abstract Vascular pathology is associated with cognitive impairment in diseases such as type 1 diabetes, but precisely how capillary flow affected and the underlying mechanisms remain elusive. Here we show that capillaries diabetic mouse brain are prone to stalling, blocks composed primarily of erythrocyte plugs branches off penetrating venules. Increased obstructions were evident both sexes only partially reversed by insulin. Screening for circulating inflammatory cytokines revealed persistently high levels interleukin-10 (IL-10) mice. Contrary expectation, stimulating IL-10 signalling increased obstructions, whereas inhibiting receptors neutralizing antibodies or endothelial specific knockdown mice, these impairments. Chronic IL-10R blocking antibody treatment mice also improved stimulus evoked cerebral blood flow, widths lower-order deficits. These data suggest plays an unexpected pathogenic role microcirculatory defects impairment.

Language: Английский

Citations

2
Post-stroke hippocampal neurogenesis is impaired by microvascular dysfunction and PI3K signaling in cerebral amyloid angiopathy DOI Creative Commons
Olivia M. Osborne, Manav Daftari, Oandy Naranjo

et al.

Cell Reports, Journal Year: 2024, Volume and Issue: 43(10), P. 114848 - 114848

Published: Oct. 1, 2024

Ischemic stroke and cerebral amyloid angiopathy (CAA) pose significant challenges in an aging population, particularly post-stroke recovery. Using the 5xFAD mouse model, we explore relationship between CAA, ischemic stroke, tissue We hypothesize that amyloid-beta accumulation worsens outcomes by inducing blood-brain barrier (BBB) dysfunction, leading to impaired neurogenesis. Our findings show CAA exacerbates outcomes, with mice exhibiting constricted BBB microvessels, reduced blood flow, Transcriptional analysis shows endothelial cells neural progenitor (NPCs) hippocampus exhibit differential gene expression response specifically targeting phosphatidylinositol 3-kinase (PI3K) pathway. In vitro experiments human NPCs validate these findings, showing disruption of CXCL12-PIK3C2A-CREB3L2 axis impairs Notably, PI3K pathway activation restores neurogenesis, highlighting a potential therapeutic approach. These results suggest combined induces microvascular dysfunction aberrant neurogenesis through this specific

Language: Английский

Citations

1
Editorial: The role of pericytes in physiology and pathophysiology DOI Creative Commons
Shaun L. Sandow, Sean M. Wilson, M. Dennis Leo

et al.

Frontiers in Physiology, Journal Year: 2023, Volume and Issue: 14

Published: Oct. 20, 2023

EDITORIAL article Front. Physiol., 20 October 2023Sec. Cell Physiology Volume 14 - 2023 | https://doi.org/10.3389/fphys.2023.1306031

Language: Английский

Citations

2