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Journal of Personalized Medicine Dec 2023Alongside their long-term effects, post-concussion syndrome (PCS) and mild traumatic brain injuries (mTBI) are significant public health concerns. Currently, there is a... (Review)
Review
BACKGROUND
Alongside their long-term effects, post-concussion syndrome (PCS) and mild traumatic brain injuries (mTBI) are significant public health concerns. Currently, there is a lack of reliable biomarkers for diagnosing and monitoring mTBI and PCS. Exosomes are small extracellular vesicles secreted by cells that have recently emerged as a potential source of biomarkers for mTBI and PCS due to their ability to cross the blood-brain barrier and reflect the pathophysiology of brain injury. In this study, we aimed to investigate the role of salivary exosomal biomarkers in mTBI and PCS.
METHODS
A systematic review using the PRISMA guidelines was conducted, and studies were selected based on their relevance to the topic.
RESULTS
The analyzed studies have shown that exosomal tau, phosphorylated tau (p-tau), amyloid beta (Aβ), and microRNAs (miRNAs) are potential biomarkers for mTBI and PCS. Specifically, elevated levels of exosomal tau and p-tau have been associated with mTBI and PCS as well as repetitive mTBI. Dysregulated exosomal miRNAs have also been observed in individuals with mTBI and PCS. Additionally, exosomal Prion cellular protein (PRPc), coagulation factor XIII (XIIIa), synaptogyrin-3, IL-6, and aquaporins have been identified as promising biomarkers for mTBI and PCS.
CONCLUSION
Salivary exosomal biomarkers have the potential to serve as non-invasive and easily accessible diagnostic and prognostic tools for mTBI and PCS. Further studies are needed to validate these biomarkers and develop standardized protocols for their use in clinical settings. Salivary exosomal biomarkers can improve the diagnosis, monitoring, and treatment of mTBI and PCS, leading to improved patient outcomes.
PubMed: 38248736
DOI: 10.3390/jpm14010035 -
The Journal of Prevention of... 2024In patients with Alzheimer's disease pathophysiological changes of the brain that initiate the onset of Alzheimer's disease include accumulation of amyloid-β plaques... (Review)
Review
In patients with Alzheimer's disease pathophysiological changes of the brain that initiate the onset of Alzheimer's disease include accumulation of amyloid-β plaques and phosphorylation of tau-tangles. A rather recently considered risk factor for the onset of Alzheimer's disease is poor oral health. The aim of this systematic review of the literature was to assess the potential association(s) of oral health as a risk factor for the onset of Alzheimer's disease. After a systematic search of Pubmed, Embase and Web of Science. A total of 1962 studies were assessed, of which 17 studies demonstrated possible associations between oral health diseases and Alzheimer's disease. 4 theories could be distinguished that describe the possible links between oral health and the development or onset of Alzheimer's disease; 1) role of pathogens, 2) role of inflammatory mediators, 3) role of APOE alleles and 4) role of Aβ peptide. The main common denominator of all the theories is the neuroinflammation due to poor oral health. Yet, there is insufficient evidence to prove a link due to the diversity of the designs used and the quality of the study design of the included studies. Therefore, further research is needed to find causal links between oral health and neuroinflammation that possibly can lead to the onset of Alzheimer's disease with the future intention to prevent cognitive decline by better dental care.
Topics: Humans; Alzheimer Disease; Amyloid beta-Peptides; Neuroinflammatory Diseases; Oral Health; Risk Factors
PubMed: 38230738
DOI: 10.14283/jpad.2023.82 -
Frontiers in Pharmacology 2023Intravenous thrombolysis is commonly used in the treatment of acute ischemic stroke damage. The existing thrombolytic drugs still suffer significant shortcomings,...
Intravenous thrombolysis is commonly used in the treatment of acute ischemic stroke damage. The existing thrombolytic drugs still suffer significant shortcomings, including a limited fibrin specificity and bleeding complications. Ferulic acid can directly bind the key thrombus enzymes and target to blood clots, suggesting its thrombolytic potency that may be beneficial with thrombolytic potency for the treatment of acute ischemic stroke damage. The purpose of this systematic review and meta-analysis was to evaluate the efficacy of ferulic acid in the treatment of acute ischemic stroke injury in rats and its potential mechanism of action. We conducted a literature search in six databases, including CNKI, up to July 2023. Sixteen trials were included in the meta-analysis, which demonstrated that ferulic acid significantly reduced infarct size, neurological deficit score, apoptosis index, cleaved caspase-3, and cytochrome C levels (all < 0.05). In addition, ferulic acid significantly increased the levels of phosphorylated Akt, mitochondrial Bcl-xL/Bax, phosphorylated astrocyte PEA15, hippocampal calcium binding protein, and mitochondrial Bcl-2/Bax ratio (all < 0.05). This study demonstrates that ferulic acid protects against acute ischemic stroke injury in rats by inhibiting ischemia-induced excitotoxicity, inflammatory response, and apoptosis.
PubMed: 37927604
DOI: 10.3389/fphar.2023.1278036 -
Journal of Alzheimer's Disease : JAD 2023The negative effects of periodontitis on systemic diseases, including diabetes, cardiovascular diseases, and Alzheimer's disease (AD), have been widely described.
BACKGROUND
The negative effects of periodontitis on systemic diseases, including diabetes, cardiovascular diseases, and Alzheimer's disease (AD), have been widely described.
OBJECTIVE
This systematic review aimed to gather the current understanding of the pathophysiological mechanisms linking periodontitis to AD.
METHODS
An electronic systematic search of the PubMed/MEDLINE, Scopus, and Embase databases was performed using the following PECO question: How can periodontitis or periodontal bacteria influence Alzheimer's disease features?". Only preclinical studies exploring the biological links between periodontitis and AD pathology were included. This study was registered at the International Prospective Register of Systematic Reviews (PROSPERO), and the Syrcle and Camarades protocols were used to assess the risk of bias.
RESULTS
After a systematic screening of titles and abstracts (n = 3,307), thirty-six titles were selected for abstract reading, of which 13 were excluded (k = 1), resulting in the inclusion of 23 articles. Oral or systemic exposure to periodontopathogens or their byproducts is responsible for both in situ brain manifestations and systemic effects. Significant elevated rates of cytokines and amyloid peptides (Aβ) and derivate products were found in both serum and brain. Additionally, in infected animals, hyperphosphorylation of tau protein, hippocampal microgliosis, and neuronal death were observed. Exposure to periodontal infection negatively impairs cognitive behavior, leading to memory decline.
CONCLUSIONS
Systemic inflammation and brain metastatic infections induced by periodontal pathogens contribute to neuroinflammation, amyloidosis, and tau phosphorylation, leading to brain damage and subsequent cognitive impairment.
Topics: Animals; Alzheimer Disease; Systematic Reviews as Topic; Periodontitis; Inflammation; Cognitive Dysfunction
PubMed: 37927257
DOI: 10.3233/JAD-230478 -
PloS One 2023Parkinson's disease (PD) is the fastest-growing neurodegenerative disorder, currently affecting ~7 million people worldwide. PD is clinically and genetically...
Establishing an online resource to facilitate global collaboration and inclusion of underrepresented populations: Experience from the MJFF Global Genetic Parkinson's Disease Project.
Parkinson's disease (PD) is the fastest-growing neurodegenerative disorder, currently affecting ~7 million people worldwide. PD is clinically and genetically heterogeneous, with at least 10% of all cases explained by a monogenic cause or strong genetic risk factor. However, the vast majority of our present data on monogenic PD is based on the investigation of patients of European White ancestry, leaving a large knowledge gap on monogenic PD in underrepresented populations. Gene-targeted therapies are being developed at a fast pace and have started entering clinical trials. In light of these developments, building a global network of centers working on monogenic PD, fostering collaborative research, and establishing a clinical trial-ready cohort is imperative. Based on a systematic review of the English literature on monogenic PD and a successful team science approach, we have built up a network of 59 sites worldwide and have collected information on the availability of data, biomaterials, and facilities. To enable access to this resource and to foster collaboration across centers, as well as between academia and industry, we have developed an interactive map and online tool allowing for a quick overview of available resources, along with an option to filter for specific items of interest. This initiative is currently being merged with the Global Parkinson's Genetics Program (GP2), which will attract additional centers with a focus on underrepresented sites. This growing resource and tool will facilitate collaborative research and impact the development and testing of new therapies for monogenic and potentially for idiopathic PD patients.
Topics: Humans; Parkinson Disease; Palliative Care
PubMed: 37788254
DOI: 10.1371/journal.pone.0292180 -
Molecules (Basel, Switzerland) Aug 2023In drug discovery, protein kinase inhibitors (PKIs) are intensely investigated as drug candidates in different therapeutic areas. While ATP site-directed, non-covalent...
In drug discovery, protein kinase inhibitors (PKIs) are intensely investigated as drug candidates in different therapeutic areas. While ATP site-directed, non-covalent PKIs have long been a focal point in protein kinase (PK) drug discovery, in recent years, there has been increasing interest in allosteric PKIs (APKIs), which are expected to have high kinase selectivity. In addition, as compounds acting by covalent mechanisms experience a renaissance in drug discovery, there is also increasing interest in covalent PKIs (CPKIs). There are various reasons for this increasing interest such as the anticipated high potency, prolonged residence times compared to non-competitive PKIs, and other favorable pharmacokinetic properties. Due to the popularity of PKIs for therapeutic intervention, large numbers of PKIs and large volumes of activity data have accumulated in the public domain, providing a basis for large-scale computational analysis. We have systematically searched for CPKIs containing different reactive groups (warheads) and investigated their potency and promiscuity (multi-PK activity) on the basis of carefully curated activity data. For seven different warheads, sufficiently large numbers of CPKIs were available for detailed follow-up analysis. For only three warheads, the median potency of corresponding CPKIs was significantly higher than of non-covalent PKIs. However, for CKPIs with five of seven warheads, there was a significant increase in the median potency of at least 100-fold compared to PKI analogues without warheads. However, in the analysis of multi-PK activity, there was no general increase in the promiscuity of CPKIs compared to non-covalent PKIs. In addition, we have identified 29 new APKIs in X-ray structures of PK-PKI complexes. Among structurally characterized APKIs, 13 covalent APKIs in complexes with five PKs are currently available, enabling structure-based investigation of PK inhibition by covalent-allosteric mechanisms.
Topics: Protein Kinase Inhibitors; Protein Kinases; Phosphorylation; Drug Discovery
PubMed: 37570774
DOI: 10.3390/molecules28155805 -
Autoimmunity Reviews Sep 2023Psoriatic arthritis (PsA) is an inflammatory complex condition. Posttranslational modifications influence almost all aspects of normal cell biology and pathogenesis. The... (Review)
Review
BACKGROUND AND AIMS
Psoriatic arthritis (PsA) is an inflammatory complex condition. Posttranslational modifications influence almost all aspects of normal cell biology and pathogenesis. The aim of this systematic review was to collect all published evidence regarding posttranslational modifications in PsA, and the main outcome was to evaluate an association between disease outcomes and specific posttranslational modifications in PsA.
METHODS
A systematic electronic search was performed in Medline, PubMed, Cochrane, Virtual Health Library, and Embase databases. A total of 587 articles were identified; 59 were evaluated after removing duplicates and scanning, of which 47 were included. A descriptive analysis was conducted, with results grouped according to the type of posttranslational modification evaluated. The protocol was registered at the PROSPERO database.
RESULTS
Seven posttranslational modifications were identified: citrullination, carbamylation, phosphorylation, glycosylation, acetylation, methylation, and oxidative stress. Anti-citrullinated peptide and anti-carbamylated protein have been evaluated in rheumatoid arthritis. There is now information suggesting that these antibodies may be helpful in improving the diagnosis of PsA and that they may demonstrate a correlation with worse disease progression (erosions, polyarticular involvement, and poor treatment response). Glycosylation was associated with increased inflammation and phosphorylation products related to the expression of SIRT2 and pSTAT3 or the presence of Th17 and cytokine interleukin-22, suggesting a possible therapeutic target.
CONCLUSIONS
Posttranslational modifications often play a key role in modulating protein function in PsA and correlate with disease outcomes. Citrullination, carbamylation, phosphorylation, glycosylation, acetylation, methylation, and oxidative stress were identified as associated with diagnosis and prognosis.
Topics: Humans; Arthritis, Psoriatic; Protein Processing, Post-Translational; Citrullination; Glycosylation; Arthritis, Rheumatoid
PubMed: 37487969
DOI: 10.1016/j.autrev.2023.103393 -
Journal of Genetics and Genomics = Yi... Mar 2024Protein post-translational modifications (PTMs), such as ubiquitination, phosphorylation, and small ubiquitin-like modifier (SUMO)ylation, are crucial for regulating...
Protein post-translational modifications (PTMs), such as ubiquitination, phosphorylation, and small ubiquitin-like modifier (SUMO)ylation, are crucial for regulating protein stability, activity, subcellular localization, and binding with cofactors. Such modifications remarkably increase the variety and complexity of proteomes, which are essential for regulating numerous cellular and physiological processes. The regulation of auxin signaling is finely tuned in time and space to guide various plant growth and development. Accumulating evidence indicates that PTMs play critical roles in auxin signaling regulations. Thus, a thorough and systematic review of the functions of PTMs in auxin signal transduction will improve our profound comprehension of the regulation mechanism of auxin signaling and auxin-mediated various processes. This review discusses the progress of protein ubiquitination, phosphorylation, histone acetylation and methylation, SUMOylation, and S-nitrosylation in the regulation of auxin signaling.
Topics: Indoleacetic Acids; Protein Processing, Post-Translational; Signal Transduction; Sumoylation; Ubiquitination
PubMed: 37451336
DOI: 10.1016/j.jgg.2023.07.002 -
International Journal of Molecular... Jun 2023Through a process termed , platelets cause thrombi to shrink and become more stable. After platelets are activated via inside-out signaling, glycoprotein αIIbβIII...
Through a process termed , platelets cause thrombi to shrink and become more stable. After platelets are activated via inside-out signaling, glycoprotein αIIbβIII binds to fibrinogen and initiates a cascade of intracellular signaling that ends in actin remodeling, which causes the platelet to change its shape. Clot retraction is also important for wound healing. Although the detailed molecular biology of clot retraction is only partially understood, various substances and physiological conditions modulate clot retraction. In this review, we describe some of the current literature pertaining to clot retraction modulators. In addition, we discuss compounds from , , and that diminish clot retraction and have numerous other health benefits. Caffeic acid and diindolylmethane, both common in plants and vegetables, likewise reduce clot retraction, as do all-trans retinoic acid (a vitamin A derivative), two MAP4K inhibitors, and the chemotherapeutic drug Dasatinib. Conversely, the endogenous anticoagulant Protein S (PS) and the matricellular protein secreted modular calcium-binding protein 1 (SMOC1) both enhance clot retraction. Most studies aiming to identify mechanisms of clot retraction modulators have focused on the increased phosphorylation of vasodilator-stimulated phosphoprotein and inositol 1,4,5-triphosphate receptor I and the decreased phosphorylation of various phospholipases (e.g., phospholipase A2 (PLA) and phosphatidylinositol-specific phospholipase Cγ2 (PLCγ), c-Jun N-terminal kinase, and (PI3Ks). One study focused on the decreased phosphorylation of Sarcoma Family Kinases (SFK), and others have focused on increased cAMP levels and the downregulation of inflammatory markers such as thromboxanes, including thromboxane A2 (TXA) and thromboxane B2 (TXB); prostaglandin A2 (PGE2); reactive oxygen species (ROS); and cyclooxygenase (COX) enzyme activity. Additionally, pregnancy, fibrinolysis, and the autoimmune condition systemic lupus erythematosus all seem to affect, or at least have some relation with, clot retraction. All the clot retraction modulators need in-depth study to explain these effects.
Topics: Blood Platelets; Clot Retraction; Phosphorylation; Platelet Aggregation; Signal Transduction
PubMed: 37445780
DOI: 10.3390/ijms241310602 -
Cells Apr 2023With the development of new technologies capable of detecting low concentrations of Alzheimer's disease (AD) relevant biomarkers, the idea of a blood-based diagnosis of... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
With the development of new technologies capable of detecting low concentrations of Alzheimer's disease (AD) relevant biomarkers, the idea of a blood-based diagnosis of AD is nearing reality. This study aims to consider the evidence of total and phosphorylated tau as blood-based biomarkers for mild cognitive impairment (MCI) and AD when compared to healthy controls.
METHODS
Studies published between 1 January 2012 and 1 May 2021 (Embase and MEDLINE databases) measuring plasma/serum levels of tau in AD, MCI, and control cohorts were screened for eligibility, including quality and bias assessment via a modified QUADAS. The meta-analyses comprised 48 studies assessing total tau (t-tau), tau phosphorylated at threonine 181 (p-tau181), and tau phosphorylated at threonine 217 (p-tau217), comparing the ratio of biomarker concentrations in MCI, AD, and cognitively unimpaired (CU) controls.
RESULTS
Plasma/serum p-tau181 (mean effect size, 95% CI, 2.02 (1.76-2.27)) and t-tau (mean effect size, 95% CI, 1.77 (1.49-2.04)) were elevated in AD study participants compared to controls. Plasma/serum p-tau181 (mean effect size, 95% CI, 1.34 (1.20-1.49)) and t-tau (mean effect size, 95% CI, 1.47 (1.26-1.67)) were also elevated with moderate effect size in MCI study participants compared to controls. p-tau217 was also assessed, albeit in a small number of eligible studies, for AD vs. CU (mean effect size, 95% CI, 1.89 (1.86-1.92)) and for MCI vs. CU groups (mean effect size, 95% CI, 4.16 (3.61-4.71)).
CONCLUSIONS
This paper highlights the growing evidence that blood-based tau biomarkers have early diagnostic utility for Alzheimer's disease.
REGISTRATION
PROSPERO No. CRD42020209482.
Topics: Humans; Alzheimer Disease; Biomarkers; Cognitive Dysfunction; tau Proteins
PubMed: 37190093
DOI: 10.3390/cells12081184