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Signal Transduction and Targeted Therapy Feb 2021The abnormal regulation of alternative splicing is usually accompanied by the occurrence and development of tumors, which would produce multiple different isoforms and...
The abnormal regulation of alternative splicing is usually accompanied by the occurrence and development of tumors, which would produce multiple different isoforms and diversify protein expression. The aim of the present study was to conduct a systematic review in order to describe the regulatory mechanisms of alternative splicing, as well as its functions in tumor cells, from proliferation and apoptosis to invasion and metastasis, and from angiogenesis to metabolism. The abnormal splicing events contributed to tumor progression as oncogenic drivers and/or bystander factors. The alterations in splicing factors detected in tumors and other mis-splicing events (i.e., long non-coding and circular RNAs) in tumorigenesis were also included. The findings of recent therapeutic approaches targeting splicing catalysis and splicing regulatory proteins to modulate pathogenically spliced events (including tumor-specific neo-antigens for cancer immunotherapy) were introduced. The emerging RNA-based strategies for the treatment of cancer with abnormally alternative splicing isoforms were also discussed. However, further studies are still required to address the association between alternative splicing and cancer in more detail.
Topics: Alternative Splicing; Carcinogenesis; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; RNA Splicing; RNA Splicing Factors; RNA, Circular
PubMed: 33623018
DOI: 10.1038/s41392-021-00486-7 -
Frontiers in Bioscience (Landmark... Jan 2022p38 MAPK (mitogen-activated protein kinases) family proteins (α, β, γ and δ) are key inflammatory kinases and play an important role in relaying and processing...
p38 MAPK (mitogen-activated protein kinases) family proteins (α, β, γ and δ) are key inflammatory kinases and play an important role in relaying and processing intrinsic and extrinsic signals in response to inflammation, stress, and oncogene to regulate cell growth, cell death and cell transformation. Recent studies in genetic mouse models revealed that p38α in epithelial cells mostly suppresses whereas in immune cells it promotes inflammation and inflammation-associated oncogenesis. On the contrary, p38γ and p38δ signaling in immune and epithelial cells is both pro-inflammatory and oncogenic. This review summarizes recent discoveries in this field, discusses possible associated mechanisms, and highlights potentials of systemically targeting isoform-specific p38 MAPKs. Understanding of p38 MAPK isoform-specific and cell/tissue- and perhaps stage-dependent effects and their integrated regulated activity in inflammation and in inflammation-associated oncogenesis is essential for effectively targeting this group of kinases for therapeutic intervention.
Topics: Animals; Carcinogenesis; Inflammation; Mice; Mitogen-Activated Protein Kinases; Protein Isoforms; p38 Mitogen-Activated Protein Kinases
PubMed: 35090336
DOI: 10.31083/j.fbl2701031 -
Advances in Clinical Chemistry 2023There is a need for blood biomarkers to detect individuals at different Alzheimer's disease (AD) stages because obtaining cerebrospinal fluid-based biomarkers is...
There is a need for blood biomarkers to detect individuals at different Alzheimer's disease (AD) stages because obtaining cerebrospinal fluid-based biomarkers is invasive and costly. Plasma phosphorylated tau proteins (p-tau) have shown potential as such biomarkers. This systematic review was conducted according to the PRISMA guidelines and aimed to determine whether quantification of plasma tau phosphorylated at threonine 181 (p-tau181), threonine 217 (p-tau217) and threonine 231 (p-tau231) is informative in the diagnosis of AD. All p-tau isoforms increase as a function of Aβ-accumulation and discriminate healthy individuals from those at preclinical AD stages with high accuracy. P-tau231 increases earliest, followed by p-tau181 and p-tau217. In advanced stages, all p-tau isoforms are associated with the clinical classification of AD and increase with disease severity, with the greatest increase seen for p-tau217. This is also reflected by a better correlation of p-tau217 with Aβ scans, whereas both, p-tau217 and p-tau181 correlated equally with tau scans. However, at the very advanced stages, p-tau181 begins to plateau, which may mirror the trajectory of the Aβ pathology and indicate an association with a more intermediate risk of AD. Across the AD continuum, the incremental increase in all biomarkers is associated with structural changes in widespread brain regions and underlying cognitive decline. Furthermore, all isoforms differentiate AD from non-AD neurodegenerative disorders, making them specific for AD. Incorporating p-tau181, p-tau217 and p-tau231 in clinical use requires further studies to examine ideal cut-points and harmonize assays.
Topics: Humans; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Cognitive Dysfunction; Protein Isoforms; tau Proteins; Threonine
PubMed: 37852722
DOI: 10.1016/bs.acc.2023.05.001 -
Neuropathology and Applied Neurobiology Jun 2023Becker muscular dystrophy (BMD) and Duchenne muscular dystrophy (DMD) are associated with intelligence quotients (IQs) lower than the normative values, and it is... (Meta-Analysis)
Meta-Analysis Review
AIMS
Becker muscular dystrophy (BMD) and Duchenne muscular dystrophy (DMD) are associated with intelligence quotients (IQs) lower than the normative values, and it is suggested that IQ is negatively correlated with the number of affected isoforms (i.e., Dp427, Dp140 and Dp71). Therefore, the objective of this meta-analysis was to estimate the IQ, and the IQ-genotype association according to the altered dystrophin isoforms, in the population with BMD or DMD.
METHODS
A systematic search in Medline, Web of Science, Scopus and the Cochrane Library was conducted from inception to March 2023. Observational studies that determined the IQ and/or the IQ by genotype in the population with BMD or DMD were included. Meta-analyses of IQ, IQ by genotype and IQ-genotype association by comparing IQ according to the genotype were conducted. The results are shown as the mean/mean differences and 95% confidence intervals.
RESULTS
Fifty-one studies were included. The IQ in BMD was 89.92 (85.84, 94.01) and in DMD was 84.61 (82.97, 86.26). Moreover, the IQ for Dp427-/Dp140+/Dp71+ and Dp427-/Dp140-/Dp71+ was 90.62 (86.72, 94.53) and 80.73 (67.49, 93.98) in BMD, while the IQ for Dp427-/Dp140+/Dp71+, Dp427-/Dp140-/Dp71+ and Dp427-/Dp140-/Dp71- was 93.05 (89.42, 96.67), 81.78 (77.23, 86.32) and 49.19 (40.47, 57.90) in DMD. Finally, in DMD, Dp427-/Dp140-/Dp71+ vs Dp427-/Dp140+/Dp71+ and Dp427-/Dp140-/Dp71- vs Dp427-/Dp140-/Dp71+ were associated with -10.73 (-14.66, -6.81) and -36.14 (-48.87, -23.41) points, respectively.
CONCLUSIONS
The IQ in BMD and DMD was lower than the normative values. Moreover, in DMD, there is a synergistic association between the number of affected isoforms and IQ.
Topics: Humans; Dystrophin; Muscular Dystrophy, Duchenne; Protein Isoforms; Intelligence
PubMed: 37312416
DOI: 10.1111/nan.12914 -
Experimental Gerontology Oct 2021The excessive deposition of β-amyloid proteins (Aβ) is directly correlated with the establishment and development of Alzheimer's Disease (AD). Current treatments for... (Meta-Analysis)
Meta-Analysis Review
The excessive deposition of β-amyloid proteins (Aβ) is directly correlated with the establishment and development of Alzheimer's Disease (AD). Current treatments for AD only reduce symptoms instead of acting on Aβ, the primary etiological agent. Hence, the anti-amyloid effect of regular exercise has been widely investigated as an alternative therapy. This systematic review and meta-analysis examined the anti-amyloid effect of regular physical exercise in animal models of AD. The search was conducted on the electronic databases Pubmed, Embase, Scopus and Web of Science without data limitation and using the following describers: "amyloid beta" (OR senile plaque OR amyloid plaque) and "exercise" (OR physical activity OR training). The risk of bias was evaluated using the SYRCLE's tool. Meta-analyses were conducted using models of random continuous effects. A total of 36 studies were selected and most used: transgenic mice (n = 29), treadmill training, duration of 12 weeks (interval of 4 to 28 weeks), rate of 60 min/day (interval of 30 min and up until free access) and speed of 12 m/min (interval of 3.2 to 32 m/min). The hippocampus and cortex were the most frequently investigated regions. Meta-analysis demonstrated a decrease in Aβ with greater effect in unspecified isoforms Meta-analysis demonstrated a decrease in Aβ with greater effect in unspecified isoforms (N = 4; SMD = -2.71, IC 95%: -3.59, -1.84, p < 0.00001, Q2 = 3.38, I2 = 11%) and Aβ (N = 21; SMD = -1.94, IC 95%: -2.37, -1.51, p < 0.00001, Q2 = 33,37, I2 = 40%). Concerning training, greater effect was found with: 1) swimming (N = 4; SMD = -1.98, IC 95%: -3,28 - -0,68, p = 0.003, Q2 = 9.74, I2 = 69%), 2) moderate intensity (N = 4; SMD = -2.03, IC 95%: -3.31 - -0.75, p < 0.005, Q = 12.68, I = 76%); 3) duration up to six weeks (N = 6; N = 6; SMD = -2.35, IC 95%: -3.15 - -1.55, p < 0.00001, Q = 8.38, I = 40%); 4) young animals (SMD = -2.00, IC 95%: -2.59 - -1.42, p < 0.00001, Q = 24.90, I = 52%); 5) in the amygdala region (N = 1; SMD = -8.56, IC 95%: -12.88 - -4.23, p = 0.0001) and females (N = 4; SMD = -2.14, IC 95%: -3.48 - -0.79, p = 0.002, Q = 10.31, I = 71%). However, the reduction of Aβ was associated with decrease of amyloidogenic pathway and increase of non-amyloidogenic. Hence, regular physical exercise demonstrated anti-amyloid effect in experimental models of AD through positive alterations in APP processing through different signaling pathways.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Disease Models, Animal; Exercise; Female; Mice; Mice, Transgenic; Models, Theoretical; Plaque, Amyloid
PubMed: 34339821
DOI: 10.1016/j.exger.2021.111502 -
BioMed Research International 2013The Ena/VASP (enabled/vasodilator stimulated phosphoprotein) family includes the binding actin proteins such as mammalian Ena (Mena), VASP, and Ena-VASP-like. It is... (Review)
Review
The Ena/VASP (enabled/vasodilator stimulated phosphoprotein) family includes the binding actin proteins such as mammalian Ena (Mena), VASP, and Ena-VASP-like. It is known that the perturbation of actin cycle could determine alteration in the mobility of cells and in consequence of organogenesis. Few recent studies have revealed that Mena protein could play a role in breast or pancreatic carcinogenesis. Based on our researches, we observed that the intensity of Mena expression increased from premalignant to malignant lesions in some organs such as large bowel, stomach, cervix, and salivary glands. These findings prove that Mena could be a marker of premalignant epithelial lesions. In premalignant lesions, it could be helpful to define more accurately the risk for malignant transformation. In malignant tumors, correlation of expression of its splice variants could indicate metastatic behavior. In conclusion, we consider that it is necessary to analyze the expression of Mena splice variants in a higher number of cases, in different epithelial lesions, and also in experimental studies to define its exact role in carcinogenesis and also its possible prognostic and predictive values.
Topics: Actins; Alternative Splicing; Carcinogenesis; DNA-Binding Proteins; Embryonic Development; Humans; Microfilament Proteins; Neoplasm Invasiveness; Protein Binding; Protein Isoforms
PubMed: 23956979
DOI: 10.1155/2013/365192 -
Heart, Lung & Circulation Aug 2015Aldehyde dehydrogenase 1 (ALDH1) has been identified as a putative cancer stem cell (CSC) marker in lung cancer. However, the clinicopathological and prognostic value of... (Meta-Analysis)
Meta-Analysis Review
PURPOSE
Aldehyde dehydrogenase 1 (ALDH1) has been identified as a putative cancer stem cell (CSC) marker in lung cancer. However, the clinicopathological and prognostic value of this protein in lung cancer patients remains controversial. Thus, we performed a systematic review and meta-analysis of studies assessing the clinical and prognostic significance of ALDH1 expression in lung cancer.
METHODS
An identification and review of publications assessing clinical or prognostic significance of ALDH1 expression in lung cancer until September 1, 2014 was undertaken. A meta-analysis was performed to clarify the association between ALDH1 expression and clinical outcomes.
RESULTS
A total of 14 publications met the criteria and comprised 1926 cases. Analysis of these data showed that ALDH1 expression was not significantly associated with the patient age (OR = 0.82, 95% confidence interval [CI]: 0.45-1.50, P=0.52), tumour size (OR=0.68, 95% CI: 0.22-2.06, P=0.49), smoking status (OR=1.37, 95% CI: 0.85-2.22, P=0.19), or tumour grade (OR=1.65, 95% CI: 0.83-3.26, P=0.15). However, in the identified studies, ALDH1 expression was highly correlated with lymph node metastasis (OR=1.97, 95% CI: 1.16-3.34, P=0.01), tumour TNM staging (OR=1.68, 95% CI 1.28-2.22, P=0.0002), decreased overall survival (relative risk [RR]: 1.97,95% CI: 1.16-3.34, P =0.01) and decreased disease free survival (RR: 1.63, 95% CI: 1.01-2.64, P=0.05).
CONCLUSIONS
This meta-analysis shows ALDH1 expression in lung cancer is connected with decreased overall and disease free survival and thus marks a worse prognosis.
Topics: Aldehyde Dehydrogenase 1 Family; Disease-Free Survival; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Isoenzymes; Lung Neoplasms; Neoplasm Proteins; Neoplastic Stem Cells; Retinal Dehydrogenase; Survival Rate
PubMed: 25921687
DOI: 10.1016/j.hlc.2015.03.021 -
Frontiers in Neuroscience 2021To review the available evidence on sensitivity and specificity of anti-NF155 antibody detection in diagnosing a specific subset of patients with chronic inflammatory...
To review the available evidence on sensitivity and specificity of anti-NF155 antibody detection in diagnosing a specific subset of patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and to calculate the frequencies of different autoantibodies to paranodal proteins. Diagnosis of CIDP relies on clinical and neurophysiologic criteria and lacks useful diagnostic biomarkers. A subset of CIDP patients exhibit atypical clinical phenotypes and impaired response to conventional treatments. These patients were reported as having autoantibodies targeting paranodal protein neurofascin isoform 155 (NF155), contactin-1 (CNTN1), and contactin-associated protein-1 (CASPR1). Here, we conducted a meta-analysis to summarize evidence on the diagnostic and prognostic value of these autoantibodies, especially for anti-NF155 antibody. We searched the following electronic bibliographic databases: PubMed, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science. Eligible studies provided information to calculate the frequencies of anti-NF155 antibody and anti-CNTN1 antibody, the sensitivity and specificity of anti-NF155 antibody, and the incidence of improvement and deterioration among anti-NF155 antibody seropositive CIDP patients. Heterogeneity was assessed using Q and statistics. The pooled frequency of anti-NF155 autoantibody across 14 studies was 7% [95% confidence interval (CI): 0.05-0.10] with high heterogeneity; the overall pooled sensitivity and specificity of anti-NF155 antibody for the diagnosis of a specific subgroup of CIDP patients were 0.45 (95% CI: 0.29-0.63) and 0.93 (95% CI: 0.86-0.97), respectively. For diagnosing of a specific subset of CIDP characterized by poor response to intravenous immunoglobulin (IVIg), we found a moderate sensitivity and a high specificity. The anti-NF155 antibody test should be used as a confirmatory test rather than a screening test. PROSPERO, identifier: CRD42020203385 and CRD42020190789.
PubMed: 34108854
DOI: 10.3389/fnins.2021.637336 -
Developmental Medicine and Child... Jun 2023To estimate the global prevalence of intellectual developmental disorder (IDD) and the IDD prevalence-genotype association in Becker muscular dystrophy (BMD) or Duchenne... (Meta-Analysis)
Meta-Analysis Review
AIM
To estimate the global prevalence of intellectual developmental disorder (IDD) and the IDD prevalence-genotype association in Becker muscular dystrophy (BMD) or Duchenne muscular dystrophy (DMD) according to the affected isoforms of the DMD gene: Dp427, Dp140, Dp71.
METHOD
Systematic searches in MEDLINE, Scopus, Web of Science, and the Cochrane Library were conducted from inception of each database to March 2022. Observational studies that determined the prevalence of IDD in the population with BMD or DMD were included. Meta-analyses of IDD prevalence and prevalence ratios of the IDD-genotype association were conducted.
RESULTS
Forty-nine studies were included. The prevalence of IDD in BMD was 8.0% (95% confidence interval 5.0-11.0), and in DMD it was 22.0% (18.0-27.0). Meta-analyses of IDD-genotype association showed a deleterious association between IDD and the number of isoforms affected in DMD, with a prevalence ratio = 0.43 (0.28-0.64) and 0.17 (0.09-0.34) for Dp140 /Dp71 versus Dp140 /Dp71 and Dp140 /Dp71 versus Dp140 /Dp71 comparisons respectively. However, in BMD, there was no association for Dp140 /Dp71 versus Dp140 /Dp71 .
INTERPRETATION
There is a high prevalence of IDD in BMD and DMD. Moreover, the number of isoforms affected is strongly and negatively associated with the prevalence of IDD in DMD.
WHAT THIS PAPER ADDS
The global prevalence of intellectual developmental disorder (IDD) was 8% in Becker muscular dystrophy and 22% in Duchenne muscular dystrophy (DMD). The global prevalence of IDD in DMD was 12%, 29%, and 84% in participants with Dp427 /Dp140 /Dp71 , Dp427 /Dp140 /Dp71 , and Dp427 /Dp140 /Dp71 genotypes respectively. In DMD, 12% and 22% of participants had abnormal performance IQ and verbal IQ values respectively.
Topics: Child; Humans; Muscular Dystrophy, Duchenne; Dystrophin; Developmental Disabilities; Prevalence; Intellectual Disability; Protein Isoforms
PubMed: 36440509
DOI: 10.1111/dmcn.15481 -
Biochemistry. Biokhimiia Jan 2024Mutations that disrupt the function of the DNA/RNA-binding protein FUS could cause amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. One of the... (Review)
Review
Mutations that disrupt the function of the DNA/RNA-binding protein FUS could cause amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. One of the key features in ALS pathogenesis is the formation of insoluble protein aggregates containing aberrant isoforms of the FUS protein in the cytoplasm of upper and lower motor neurons. Reproduction of human pathology in animal models is the main tool for studying FUS-associated pathology and searching for potential therapeutic agents for ALS treatment. In this review, we provide a systematic analysis of the role of FUS protein in ALS pathogenesis and an overview of the results of modelling FUS-proteinopathy in animals.
Topics: Animals; Humans; Amyotrophic Lateral Sclerosis; RNA-Binding Protein FUS; Motor Neurons; Cytoplasm; Mutation; Disease Models, Animal
PubMed: 38621743
DOI: 10.1134/S0006297924140037