-
Neurology Jun 2019CNS small vessel disease (CSVD) causes 25% of strokes and contributes to 45% of dementia cases. Prevalence increases with age, affecting about 5% of people aged 50 years... (Review)
Review
CNS small vessel disease (CSVD) causes 25% of strokes and contributes to 45% of dementia cases. Prevalence increases with age, affecting about 5% of people aged 50 years to almost 100% of people older than 90 years. Known causes and risk factors include age, hypertension, branch atheromatous disease, cerebral amyloid angiopathy, radiation exposure, immune-mediated vasculitides, certain infections, and several genetic diseases. CSVD can be asymptomatic; however, depending on location, lesions can cause mild cognitive dysfunction, dementia, mood disorders, motor and gait dysfunction, and urinary incontinence. CSVD is diagnosed on the basis of brain imaging biomarkers, including recent small subcortical infarcts, white matter hyperintensities, lacunes, cerebral microbleeds, enlarged perivascular spaces, and cerebral atrophy. Advanced imaging modalities can detect signs of disease even earlier than current standard imaging techniques. Diffusion tensor imaging can identify altered white matter connectivity, and blood oxygenation level-dependent imaging can identify decreased vascular reactivity. Pathogenesis is thought to begin with an etiologically specific insult, with or without genetic predisposition, which results in dysfunction of the neurovascular unit. Uncertainties regarding pathogenesis have delayed development of effective treatment. The most widely accepted approach to treatment is to intensively control well-established vascular risk factors, of which hypertension is the most important. With better understanding of pathogenesis, specific therapies may emerge. Early identification of pathologic characteristics with advanced imaging provides an opportunity to forestall progression before emergence of symptoms.
Topics: Antihypertensive Agents; CADASIL; Cerebral Amyloid Angiopathy; Cerebral Small Vessel Diseases; Dementia; Diffusion Magnetic Resonance Imaging; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Magnetic Resonance Imaging; Platelet Aggregation Inhibitors; Stroke, Lacunar
PubMed: 31142635
DOI: 10.1212/WNL.0000000000007654 -
Health Physics Nov 2022With rapid technical advances, ionizing radiation has been put into wider application in ordinary living, with the worst cytological effect on the human body being cell... (Review)
Review
With rapid technical advances, ionizing radiation has been put into wider application in ordinary living, with the worst cytological effect on the human body being cell death. Moreover, according to the Nomenclature Committee on Cell Death, the method of radiation-induced cell death, usually classified as interphase and proliferative death, undergoes more detailed classifications oriented by its molecular mechanism. Elaborating its mode and molecular mechanism is crucial for the protection and treatment of radiation injury, as well as the radiotherapy and recovery of tumors. Varying with the changes of the radiation dose and the environment, the diverse targets and pathways of ionizing radiation result in various cell deaths. This review focuses on classifications of radiation-induced cell death and its molecular mechanism. We also examine the main characteristics of ionizing radiation-induced cell death. The modes of radiation-induced cell death can be classified as apoptosis, necrosis, autophagy-dependent cell death, pyroptosis, ferroptosis, immunogenic cell death, and non-lethal processes. Once the dose is high enough, radiation effects mostly appear as destructiveness ("destructiveness" is used to describe a situation in which cells do not have the opportunity to undergo a routine death process, in which case high-dose radiation works like a physical attack). This breaks up or even shatters cells, making it difficult to find responses of the cell itself. Due to diversities concerning cell phenotypes, phases of cell cycle, radiation dose, and even cellular subregions, various methods of cell death occur, which are difficult to identify and classify. Additionally, the existence of common initial activation and signaling molecules among all kinds of cell deaths, as well as sophisticated crossways in cellular molecules, makes it more laborious to distinguish and classify various cell deaths.
Topics: Apoptosis; Cell Death; Humans; Neoplasms; Radiation, Ionizing; Signal Transduction
PubMed: 36069830
DOI: 10.1097/HP.0000000000001601 -
International Journal of Radiation... May 2021As part of the American Association of Physicists in Medicine Working Group on Stereotactic Body Radiotherapy investigating normal tissue complication probability (NTCP)... (Review)
Review
PURPOSE
As part of the American Association of Physicists in Medicine Working Group on Stereotactic Body Radiotherapy investigating normal tissue complication probability (NTCP) after hypofractionated radiation therapy, data from published reports (PubMed indexed 1995-2018) were pooled to identify dosimetric and clinical predictors of radiation-induced brain toxicity after single-fraction stereotactic radiosurgery (SRS) or fractionated stereotactic radiosurgery (fSRS).
METHODS AND MATERIALS
Eligible studies provided NTCPs for the endpoints of radionecrosis, edema, or symptoms after cranial SRS/fSRS and quantitative dose-volume metrics. Studies of patients with only glioma, meningioma, vestibular schwannoma, or brainstem targets were excluded. The data summary and analyses focused on arteriovenous malformations (AVM) and brain metastases.
RESULTS
Data from 51 reports are summarized. There was wide variability in reported rates of radionecrosis. Available data for SRS/fSRS for brain metastases were more amenable to NTCP modeling than AVM data. In the setting of brain metastases, SRS/fSRS-associated radionecrosis can be difficult to differentiate from tumor progression. For single-fraction SRS to brain metastases, tissue volumes (including target volumes) receiving 12 Gy (V12) of 5 cm, 10 cm, or >15 cm were associated with risks of symptomatic radionecrosis of approximately 10%, 15%, and 20%, respectively. SRS for AVM was associated with modestly lower rates of symptomatic radionecrosis for equivalent V12. For brain metastases, brain plus target volume V20 (3-fractions) or V24 (5-fractions) <20 cm was associated with <10% risk of any necrosis or edema, and <4% risk of radionecrosis requiring resection.
CONCLUSIONS
The risk of radionecrosis after SRS and fSRS can be modeled as a function of dose and volume treated. The use of fSRS appears to reduce risks of radionecrosis for larger treatment volumes relative to SRS. More standardized dosimetric and toxicity reporting is needed to facilitate future pooled analyses that can refine predictive models of brain toxicity risks.
Topics: Antineoplastic Agents; Brain; Brain Edema; Brain Neoplasms; Brain Stem; Disease Progression; Humans; Immune Checkpoint Inhibitors; Intracranial Arteriovenous Malformations; Models, Biological; Models, Theoretical; Necrosis; Organs at Risk; Probability; Radiation Dose Hypofractionation; Radiation Injuries; Radiation Tolerance; Radiosurgery; Radiotherapy Dosage; Re-Irradiation
PubMed: 32921513
DOI: 10.1016/j.ijrobp.2020.08.013 -
ACS Nano Oct 2019Human dermal fibroblasts (HDFs), the main cell population of the dermis, gradually lose their ability to produce collagen and renew intercellular matrix with aging. One...
Human dermal fibroblasts (HDFs), the main cell population of the dermis, gradually lose their ability to produce collagen and renew intercellular matrix with aging. One clinical application for the autologous trans-dermis injection of HDFs that has been approved by the Food and Drug Administration aims to refine facial contours and slow down skin aging. However, the autologous HDFs used vary in quality according to the state of patients and due to many passages they undergo during expansion. In this study, factors and exosomes derived from three-dimensional spheroids (3D HDF-XOs) and the monolayer culture of HDFs (2D HDF-XOs) were collected and compared. 3D HDF-XOs expressed a significantly higher level of tissue inhibitor of metalloproteinases-1 (TIMP-1) and differentially expressed miRNA cargos compared with 2D HDF-XOs. Next, the efficacy of 3D HDF-XOs in inducing collagen synthesis and antiaging was demonstrated and in a nude mouse photoaging model. A needle-free injector was used to administer exosome treatments. 3D HDF-XOs caused increased procollagen type I expression and a significant decrease in MMP-1 expression, mainly through the downregulation of tumor necrosis factor-alpha (TNF-α) and the upregulation of transforming growth factor beta (TGF-β). In addition, the 3D-HDF-XOs group showed a higher level of dermal collagen deposition than bone marrow mesenchymal stem cell-derived exosomes. These results indicate that exosomes from 3D cultured HDF spheroids have anti-skin-aging properties and the potential to prevent and treat cutaneous aging.
Topics: Animals; Biopolymers; Cell Proliferation; Cells, Cultured; Enzyme-Linked Immunosorbent Assay; Exosomes; Fibroblasts; Humans; Mice; Mice, Nude; Skin; Skin Aging; Spheroids, Cellular; Tissue Inhibitor of Metalloproteinase-1; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Ultraviolet Rays; Wound Healing
PubMed: 31449388
DOI: 10.1021/acsnano.9b04384 -
Cell Death & Disease Oct 2023Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of fatty deposits in the inner walls of vessels. These plaques restrict blood flow... (Review)
Review
Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of fatty deposits in the inner walls of vessels. These plaques restrict blood flow and lead to complications such as heart attack or stroke. The development of atherosclerosis is influenced by a variety of factors, including age, genetics, lifestyle, and underlying health conditions such as high blood pressure or diabetes. Atherosclerotic plaques in stable form are characterized by slow growth, which leads to luminal stenosis, with low embolic potential or in unstable form, which contributes to high risk for thrombotic and embolic complications with rapid clinical onset. In this complex scenario of atherosclerosis, macrophages participate in the whole process, including the initiation, growth and eventually rupture and wound healing stages of artery plaque formation. Macrophages in plaques exhibit high heterogeneity and plasticity, which affect the evolving plaque microenvironment, e.g., leading to excessive lipid accumulation, cytokine hyperactivation, hypoxia, apoptosis and necroptosis. The metabolic and functional transitions of plaque macrophages in response to plaque microenvironmental factors not only influence ongoing and imminent inflammatory responses within the lesions but also directly dictate atherosclerotic progression or regression. In this review, we discuss the origin of macrophages within plaques, their phenotypic diversity, metabolic shifts, and fate and the roles they play in the dynamic progression of atherosclerosis. It also describes how macrophages interact with other plaque cells, particularly T cells. Ultimately, targeting pathways involved in macrophage polarization may lead to innovative and promising approaches for precision medicine. Further insights into the landscape and biological features of macrophages within atherosclerotic plaques may offer valuable information for optimizing future clinical treatment for atherosclerosis by targeting macrophages.
Topics: Humans; Plaque, Atherosclerotic; Atherosclerosis; Macrophages; Apoptosis; Myocardial Infarction
PubMed: 37863894
DOI: 10.1038/s41419-023-06206-z -
Molecular Therapy : the Journal of the... Jan 2022Exercise training benefits the heart. The knowledge of post-transcription regulation, especially RNA editing, in hearts remain rare. ADAR2 is an enzyme that edits...
Exercise training benefits the heart. The knowledge of post-transcription regulation, especially RNA editing, in hearts remain rare. ADAR2 is an enzyme that edits adenosine to inosine nucleotides in double-stranded RNA, and RNA editing is associated with many human diseases. We found that ADAR2 was upregulated in hearts during exercise training. AAV9-mediated cardiac-specific ADAR2 overexpression attenuated acute myocardial infarction (AMI), MI remodeling, and doxorubicin (DOX)-induced cardiotoxicity. In vitro, overexpression of ADAR2 inhibited DOX-induced cardiomyocyte (CM) apoptosis. but it could also induce neonatal rat CM proliferation. Mechanistically, ADAR2 could regulate the abundance of mature miR-34a in CMs. Regulations of miR-34a or its target genes (Sirt1, Cyclin D1, and Bcl2) could affect the pro-proliferation and anti-apoptosis effects of ADAR2 on CMs. These data demonstrated that exercise-induced ADAR2 protects the heart from MI and DOX-induced cardiotoxicity. Our work suggests that ADAR2 overexpression or a post-transcriptional associated RNA editing via ADAR2 may be a promising therapeutic strategy for heart diseases.
Topics: Animals; Apoptosis; Cardiotoxicity; Doxorubicin; MicroRNAs; Myocardial Infarction; Myocytes, Cardiac; Rats
PubMed: 34274534
DOI: 10.1016/j.ymthe.2021.07.004 -
Journal of the American Heart... Sep 2019Background Sex-specific criteria are recommended for the diagnosis of myocardial infarction, but the impact of these on presenting characteristics is unknown. Methods... (Clinical Trial)
Clinical Trial Comparative Study
Background Sex-specific criteria are recommended for the diagnosis of myocardial infarction, but the impact of these on presenting characteristics is unknown. Methods and Results We evaluated patient-reported symptoms in 1941 patients (39% women) with suspected acute coronary syndrome attending the emergency department in a substudy of a prospective trial. Standardized criteria defined typical and atypical presentations based on pain nature, location, radiation, and additional symptoms. Diagnosis of myocardial infarction was adjudicated using a high-sensitivity cardiac troponin I assay with sex-specific thresholds (>16 ng/L women, >34 ng/L men). Patients identified who were missed by the contemporary assay with a uniform threshold (≥50 ng/L) were reclassified by this approach. Type 1 myocardial infarction was diagnosed in 16% (184/1185) of men and 12% (90/756) of women, with 9 (5%) men and 27 (30%) women reclassified using high-sensitivity cardiac troponin I and sex-specific thresholds. Chest pain was the presenting symptom in 91% (1081/1185) of men and 92% (698/756) of women. Typical symptoms were more common in women than in men with myocardial infarction (77% [69/90] versus 59% [109/184]; P=0.007), and differences were similar in those reclassified (74% [20/27] versus 44% [4/9]; P=0.22). The presence of ≥3 typical features was associated with a positive likelihood ratio for the diagnosis of myocardial infarction in women (positive likelihood ratio, 1.18; 95% CI, 1.03-1.31) but not in men (positive likelihood ratio 1.09; 95% CI, 0.96-1.24). Conclusions Typical symptoms are more common and have greater predictive value in women than in men with myocardial infarction whether or not they are diagnosed using sex-specific criteria. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier NCT01852123.
Topics: Acute Coronary Syndrome; Aged; Angina Pectoris; Biomarkers; Female; Health Status Disparities; Humans; Male; Middle Aged; Myocardial Infarction; Pain Measurement; Predictive Value of Tests; Prospective Studies; Reproducibility of Results; Scotland; Sex Factors; Symptom Assessment; Troponin I
PubMed: 31431112
DOI: 10.1161/JAHA.119.012307 -
Nature Biomedical Engineering Apr 2020Environmental factors are the largest contributors to cardiovascular disease. Here we show that cardiac organoids that incorporate an oxygen-diffusion gradient and that...
Environmental factors are the largest contributors to cardiovascular disease. Here we show that cardiac organoids that incorporate an oxygen-diffusion gradient and that are stimulated with the neurotransmitter noradrenaline model the structure of the human heart after myocardial infarction (by mimicking the infarcted, border and remote zones), and recapitulate hallmarks of myocardial infarction (in particular, pathological metabolic shifts, fibrosis and calcium handling) at the transcriptomic, structural and functional levels. We also show that the organoids can model hypoxia-enhanced doxorubicin cardiotoxicity. Human organoids that model diseases with non-genetic pathological factors could help with drug screening and development.
Topics: Cardiotoxicity; Drug Development; Drug Evaluation, Preclinical; Heart; Humans; Models, Cardiovascular; Myocardial Infarction; Organoids; Oxygen
PubMed: 32284552
DOI: 10.1038/s41551-020-0539-4 -
Oxidative Medicine and Cellular... 2021Radiation-induced brain necrosis (RBN) is a serious complication of intracranial as well as skull base tumors after radiotherapy. In the past, due to the lack of... (Review)
Review
Radiation-induced brain necrosis (RBN) is a serious complication of intracranial as well as skull base tumors after radiotherapy. In the past, due to the lack of effective treatment, radiation brain necrosis was considered to be progressive and irreversible. With better understanding in histopathology and neuroimaging, the occurrence and development of RBN have been gradually clarified, and new treatment methods are constantly emerging. In recent years, some scholars have tried to treat RBN with bevacizumab, nerve growth factor, and gangliosides and have achieved similar results. Some cases of brain necrosis can be repairable and reversible. We aimed to summarize the incidence, pathogenesis, and treatment of RBN.
Topics: Brain Neoplasms; Humans; Necrosis; Radiation Injuries
PubMed: 34976300
DOI: 10.1155/2021/4793517 -
Frontiers in Immunology 2024The heightened risk of ionizing radiation exposure, stemming from radiation accidents and potential acts of terrorism, has spurred growing interests in devising... (Review)
Review
The heightened risk of ionizing radiation exposure, stemming from radiation accidents and potential acts of terrorism, has spurred growing interests in devising effective countermeasures against radiation injury. High-dose ionizing radiation exposure triggers acute radiation syndrome (ARS), manifesting as hematopoietic, gastrointestinal, and neurovascular ARS. Hematopoietic ARS typically presents with neutropenia and thrombocytopenia, while gastrointestinal ARS results in intestinal mucosal injury, often culminating in lethal sepsis and gastrointestinal bleeding. This deleterious impact can be attributed to radiation-induced DNA damage and oxidative stress, leading to various forms of cell death, such as apoptosis, necrosis and ferroptosis. Damage-associated molecular patterns (DAMPs) are intrinsic molecules released by cells undergoing injury or in the process of dying, either through passive or active pathways. These molecules then interact with pattern recognition receptors, triggering inflammatory responses. Such a cascade of events ultimately results in further tissue and organ damage, contributing to the elevated mortality rate. Notably, infection and sepsis often develop in ARS cases, further increasing the release of DAMPs. Given that lethal sepsis stands as a major contributor to the mortality in ARS, DAMPs hold the potential to function as mediators, exacerbating radiation-induced organ injury and consequently worsening overall survival. This review describes the intricate mechanisms underlying radiation-induced release of DAMPs. Furthermore, it discusses the detrimental effects of DAMPs on the immune system and explores potential DAMP-targeting therapeutic strategies to alleviate radiation-induced injury.
Topics: Humans; Receptors, Pattern Recognition; Acute Radiation Syndrome; Cell Death; Sepsis
PubMed: 38333215
DOI: 10.3389/fimmu.2024.1353990