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Neurobiology of Disease Mar 2024Transgenic models of familial Alzheimer's disease (AD) serve as valuable tools for probing the molecular mechanisms associated with amyloid-beta (Aβ)-induced pathology.... (Meta-Analysis)
Meta-Analysis Review
Transgenic models of familial Alzheimer's disease (AD) serve as valuable tools for probing the molecular mechanisms associated with amyloid-beta (Aβ)-induced pathology. In this meta-analysis, we sought to evaluate levels of phosphorylated tau (p-tau) and explore potential age-related variations in tau hyperphosphorylation, within mouse models of AD. The PubMed and Scopus databases were searched for studies measuring soluble p-tau in 5xFAD, APP/PSEN1, J20 and APP23 mice. Data were extracted and analyzed using standardized procedures. For the 5xFAD model, the search yielded 36 studies eligible for meta-analysis. Levels of p-tau were higher in 5xFAD mice relative to control, a difference that was evident in both the carboxy-terminal (CT) and proline-rich (PR) domains of tau. Age negatively moderated the relationship between genotype and CT phosphorylated tau in studies using hybrid mice, female mice, and preparations from the neocortex. For the APP/PSEN1 model, the search yielded 27 studies. Analysis showed tau hyperphosphorylation in transgenic vs. control animals, evident in both the CT and PR regions of tau. Age positively moderated the relationship between genotype and PR domain phosphorylated tau in the neocortex of APP/PSEN1 mice. A meta-analysis was not performed for the J20 and APP23 models, due to the limited number of studies measuring p-tau levels in these mice (<10 studies). Although tau is hyperphosphorylated in both 5xFAD and APP/PSEN1 mice, the effects of ageing on p-tau are contingent upon the model being examined. These observations emphasize the importance of tailoring model selection to the appropriate disease stage when considering the relationship between Aβ and tau, and suggest that there are optimal intervention points for the administration of both anti-amyloid and anti-tau therapies.
Topics: Mice; Female; Animals; Alzheimer Disease; Phosphorylation; Amyloid beta-Protein Precursor; Mice, Transgenic; tau Proteins; Amyloid beta-Peptides; Disease Models, Animal
PubMed: 38307366
DOI: 10.1016/j.nbd.2024.106427 -
Heliyon Jan 2024Triple-negative breast cancer stands out as the most aggressive subtype of breast malignancy and is characterized by an unfavourable prognosis. : This systematic review...
Triple-negative breast cancer stands out as the most aggressive subtype of breast malignancy and is characterized by an unfavourable prognosis. : This systematic review summarizes the insights gleaned from metabolomic analyses of individuals afflicted with this cancer variant. The overarching goal was to delineate the molecular alterations associated with triple-negative breast cancer, pinpointing potential therapeutic targets and novel biomarkers. We systematically searched for evidence using the PubMed database and followed the PRISMA and STARLITE guidelines. The search parameters were delimited to articles published within the last 13 years. From an initial pool of 148 scrutinized articles, 17 studies involving 1686 participants were deemed eligible for inclusion. The current body of research shows a paucity of studies, and the available evidence presents conflicting outcomes. Notwithstanding, Pathway Enrichment Analysis identified the urea and glucose-alanine cycles as the most affected metabolic pathways, followed by arginine, proline, and aspartate metabolism. Future investigations need to focus on elucidating which of those metabolites and/or pathways might be reliable candidates for novel therapeutic interventions or reliable biomarkers for diagnosis and prognosis of this subtype of breast cancer.
PubMed: 38187259
DOI: 10.1016/j.heliyon.2023.e23628 -
Nutrients Sep 2023(1) Many studies have attempted to utilize metabolomic approaches to explore potential biomarkers for the early detection of osteoarthritis (OA), but consistent and... (Meta-Analysis)
Meta-Analysis Review
(1) Many studies have attempted to utilize metabolomic approaches to explore potential biomarkers for the early detection of osteoarthritis (OA), but consistent and high-level evidence is still lacking. In this study, we performed a systematic review and meta-analysis of differential small molecule metabolites between OA patients and healthy individuals to screen promising candidates from a large number of samples with the aim of informing future prospective studies. (2) Methods: We searched the EMBASE, the Cochrane Library, PubMed, Web of Science, Wan Fang Data, VIP Date, and CNKI up to 11 August 2022, and selected relevant records based on inclusion criteria. The risk of bias was assessed using the Newcastle-Ottawa quality assessment scale. We performed qualitative synthesis by counting the frequencies of changing directions and conducted meta-analyses using the random effects model and the fixed-effects model to calculate the mean difference and 95% confidence interval. (3) Results: A total of 3798 records were identified and 13 studies with 495 participants were included. In the 13 studies, 132 kinds of small molecule differential metabolites were extracted, 58 increased, 57 decreased and 17 had direction conflicts. Among them, 37 metabolites appeared more than twice. The results of meta-analyses among four studies showed that three metabolites increased, and eight metabolites decreased compared to healthy controls (HC). (4) Conclusions: The main differential metabolites between OA and healthy subjects were amino acids (AAs) and their derivatives, including tryptophan, lysine, leucine, proline, phenylalanine, glutamine, dimethylglycine, citrulline, asparagine, acetylcarnitine and creatinine (muscle metabolic products), which could be potential biomarkers for predicting OA.
Topics: Humans; Prospective Studies; Osteoarthritis; Biomarkers; Bias; Health Status
PubMed: 37836475
DOI: 10.3390/nu15194191 -
Metabolites Sep 2023Response to radiotherapy (RT) includes tissue toxicity, which may involve inflammatory reactions. We aimed to compare changes in metabolic patterns induced at the... (Review)
Review
Response to radiotherapy (RT) includes tissue toxicity, which may involve inflammatory reactions. We aimed to compare changes in metabolic patterns induced at the systemic level by radiation and inflammation itself. Patients treated with RT due to head and neck cancer and patients with inflammation-related diseases located in the corresponding anatomical regions were selected. PubMed and Web of Science databases were searched from 1 January 2000 to 10 August 2023. Twenty-five relevant studies where serum/plasma metabolic profiles were analyzed using different metabolomics approaches were identified. The studies showed different metabolic patterns of acute and chronic inflammatory diseases, yet changes in metabolites linked to the urea cycle and metabolism of arginine and proline were common features of both conditions. Although the reviewed reports showed only a few specific metabolites common for early RT response and inflammatory diseases, partly due to differences in metabolomics approaches, several common metabolic pathways linked to metabolites affected by radiation and inflammation were revealed. They included pathways involved in energy metabolism (e.g., metabolism of ketone bodies, mitochondrial electron transport chain, Warburg effect, citric acid cycle, urea cycle) and metabolism of certain amino acids (Arg, Pro, Gly, Ser, Met, Ala, Glu) and lipids (glycerolipids, branched-chain fatty acids). However, metabolites common for RT and inflammation-related diseases could show opposite patterns of changes. This could be exemplified by the lysophosphatidylcholine to phosphatidylcholine ratio (LPC/PC) that increased during chronic inflammation and decreased during the early phase of response to RT. One should be aware of dynamic metabolic changes during different phases of response to radiation, which involve increased levels of LPC in later phases. Hence, metabolomics studies that would address molecular features of both types of biological responses using comparable analytical and clinical approaches are needed to unravel the complexities of these phenomena, ultimately contributing to a deeper understanding of their impact on biological systems.
PubMed: 37755280
DOI: 10.3390/metabo13091000 -
Genes Aug 2023PSTPIP1 (proline-serine-threonine phosphatase-interactive protein 1)-associated myeloid-related proteinemia inflammatory (PAMI) syndrome, previously known as... (Review)
Review
PSTPIP1 (proline-serine-threonine phosphatase-interactive protein 1)-associated myeloid-related proteinemia inflammatory (PAMI) syndrome, previously known as Hyperzincemia/Hypercalprotectinemia (Hz/Hc) syndrome, is a recently described, rare auto-inflammatory disorder caused by specific deleterious variants in the gene (p.E250K and p.E257K). The disease is characterized by chronic systemic inflammation, cutaneous and osteoarticular manifestations, hepatosplenomegaly, anemia, and neutropenia. Increased blood levels of MRP 8/14 and zinc distinguish this condition from other PSTPIP1-associated inflammatory diseases (PAID). The aim of this systematic review is to provide a comprehensive overview of the disease phenotype, course, treatment, and outcome based on reported cases. This systematic review adheres to the PRISMA guidelines (2020) for reporting. A literature search was performed in Embase, Medline, and Web of Science on 13 October 2022. The quality of the case reports and case series was assessed using the JBI checklists. Out of the 43 included patients with PAMI syndrome, there were 24 females and 19 males. The median age at onset was 3.9 years. The main clinical manifestations included anemia (100%), neutropenia (98%), cutaneous manifestations (74%), osteoarticular manifestations (72%), splenomegaly (70%), growth failure (57%), fever (51%), hepatomegaly (56%), and lymphadenopathy (39%). Systemic inflammation was described in all patients. Marked elevation of zinc and MRP 8/14 blood levels were observed in all tested patients. Response to treatment varied and no consistently effective therapy was identified. The most common therapeutic options were corticosteroids (N = 30), anakinra (N = 13), cyclosporine A (N = 11), canakinumab (N = 6), and anti-TNF (N = 14). Hematopoietic stem cell transplantation has been recently reported to be successful in five patients. Our review highlights the key characteristics of PAMI syndrome and the importance of considering this disease in the differential diagnosis of patients presenting with early-onset systemic inflammation and cytopenia.
Topics: Female; Male; Humans; Tumor Necrosis Factor Inhibitors; Neutropenia; Diagnosis, Differential; Cytoskeletal Proteins; Adaptor Proteins, Signal Transducing
PubMed: 37628706
DOI: 10.3390/genes14081655 -
Frontiers in Molecular Biosciences 2023Systemic sclerosis (SSc) is a chronic autoimmune disease, marked by an unpredictable course, high morbidity, and increased mortality risk that occurs especially in the... (Review)
Review
Systemic sclerosis (SSc) is a chronic autoimmune disease, marked by an unpredictable course, high morbidity, and increased mortality risk that occurs especially in the diffuse and rapidly progressive forms of the disease, characterized by fibrosis of the skin and internal organs and endothelial dysfunction. Recent studies suggest that the identification of altered metabolic pathways may play a key role in understanding the pathophysiology of the disease. Therefore, metabolomics might be pivotal in a better understanding of these pathogenic mechanisms. Through a systematic review of the literature following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Guidelines (PRISMA), searches were done in the PubMed, EMBASE, Web of Science, and Scopus databases from 2000 to September 2022. Three researchers independently reviewed the literature and extracted the data based on predefined inclusion and exclusion criteria. Of the screened studies, 26 fulfilled the inclusion criteria. A total of 151 metabolites were differentially distributed between SSc patients and healthy controls (HC). The main deregulated metabolites were those derived from amino acids, specifically homocysteine (Hcy), proline, alpha-N-phenylacetyl-L-glutamine, glutamine, asymmetric dimethylarginine (ADMA), citrulline and ornithine, kynurenine (Kyn), and tryptophan (Trp), as well as acylcarnitines associated with long-chain fatty acids and tricarboxylic acids such as citrate and succinate. Additionally, differences in metabolic profiling between SSc subtypes were identified. The diffuse cutaneous systemic sclerosis (dcSSc) subtype showed upregulated amino acid-related pathways involved in fibrosis, endothelial dysfunction, and gut dysbiosis. Lastly, potential biomarkers were evaluated for the diagnosis of SSc, the identification of the dcSSc subtype, pulmonary arterial hypertension, and interstitial lung disease. These potential biomarkers are within amino acids, nucleotides, carboxylic acids, and carbohydrate metabolism. The altered metabolite mechanisms identified in this study mostly point to perturbations in amino acid-related pathways, fatty acid beta-oxidation, and in the tricarboxylic acid cycle, possibly associated with inflammation, vascular damage, fibrosis, and gut dysbiosis. Further studies in targeted metabolomics are required to evaluate potential biomarkers for diagnosis, prognosis, and treatment response.
PubMed: 37614441
DOI: 10.3389/fmolb.2023.1215039 -
Frontiers in Endocrinology 2023To compare the effects of five hypoxia-inducible factor-prolyl hydroxylase domain inhibitors (HIF-PHIs), two erythropoiesis-stimulating agents (ESAs), and placebo on... (Meta-Analysis)
Meta-Analysis
Effects of hypoxia-inducible factor-prolyl hydroxylase inhibitors . erythropoiesis-stimulating agents on iron metabolism in non-dialysis-dependent anemic patients with CKD: A network meta-analysis.
OBJECTIVE
To compare the effects of five hypoxia-inducible factor-prolyl hydroxylase domain inhibitors (HIF-PHIs), two erythropoiesis-stimulating agents (ESAs), and placebo on iron metabolism in renal anemia patients with non-dialysis-dependent chronic kidney disease (NDD-CKD).
METHOD
Five electronic databases were searched for studies. Randomized controlled clinical trials comparing HIF-PHIs, ESAs, and placebo in NDD-CKD patients were selected. The statistical program used for network meta-analysis was Stata/SE 15.1. The main outcomes were the change in hepcidin and hemoglobin (Hb) levels. The merits of intervention measures were predicted by the surface under the cumulative ranking curve method.
RESULTS
Of 1,589 original titles screened, data were extracted from 15 trials (3,228 participants). All HIF-PHIs and ESAs showed greater Hb level-raising ability than placebo. Among them, desidustat demonstrated the highest probability of increasing Hb (95.6%). Hepcidin [mean deviation (MD) = -43.42, 95%CI: -47.08 to -39.76], ferritin (MD= -48.56, 95%CI: -55.21 to -41.96), and transferrin saturation (MD = -4.73, 95%CI: -5.52 to -3.94) were decreased, while transferrin (MD = 0.09, 95%CI: 0.01 to 0.18) and total iron-binding capacity (MD = 6.34, 95%CI: 5.71 to 6.96) was increased in HIF-PHIs versus those in ESAs. In addition, this study observed heterogeneity in the ability of HIF-PHIs to decrease hepcidin. Compared with darbepoetin, only daprodustat (MD = -49.09, 95% CI: -98.13 to -0.05) could significantly reduce hepcidin levels. Meanwhile, daprodustat also showed the highest hepcidin-lowering efficacy (84.0%), while placebo was the lowest (8.2%).
CONCLUSION
For NDD-CKD patients, HIF-PHIs could ameliorate functional iron deficiency by promoting iron transport and utilization, which may be achieved by decreasing hepcidin levels. Interestingly, HIF-PHIs had heterogeneous effects on iron metabolism.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=242777, Identifier CRD42021242777.
Topics: Humans; Hepcidins; Hematinics; Prolyl-Hydroxylase Inhibitors; Erythropoiesis; Prolyl Hydroxylases; Network Meta-Analysis; Hypoxia-Inducible Factor-Proline Dioxygenases; Anemia; Transferrin; Renal Insufficiency, Chronic; Iron; Hypoxia; Randomized Controlled Trials as Topic
PubMed: 37008953
DOI: 10.3389/fendo.2023.1131516 -
The Cochrane Database of Systematic... Feb 2023IgA vasculitis (IgAV), previously known as Henoch-Schönlein purpura, is the most common vasculitis of childhood but may also occur in adults. This small vessel... (Review)
Review
BACKGROUND
IgA vasculitis (IgAV), previously known as Henoch-Schönlein purpura, is the most common vasculitis of childhood but may also occur in adults. This small vessel vasculitis is characterised by palpable purpura, abdominal pain, arthritis or arthralgia and kidney involvement. This is an update of a review first published in 2009 and updated in 2015.
OBJECTIVES
To evaluate the benefits and harms of different agents (used singularly or in combination) compared with placebo, no treatment or any other agent for (1) the prevention of severe kidney disease in people with IgAV with or without kidney involvement at onset, (2) the treatment of established severe kidney disease (macroscopic haematuria, proteinuria, nephritic syndrome, nephrotic syndrome with or without acute kidney failure) in IgAV, and (3) the prevention of recurrent episodes of IgAV-associated kidney disease.
SEARCH METHODS
We searched the Cochrane Kidney and Transplant Register of Studies up to 2 February 2023 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.
SELECTION CRITERIA
Randomised controlled trials (RCTs) comparing interventions used to prevent or treat kidney disease in IgAV compared with placebo, no treatment or other agents were included.
DATA COLLECTION AND ANALYSIS
Two authors independently determined study eligibility, assessed the risk of bias and extracted data from each study. Statistical analyses were performed using the random-effects model, and the results were expressed as risk ratio (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes with 95% confidence intervals (CI). Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.
MAIN RESULTS
Twenty studies (1963 enrolled participants) were identified; one three-arm study has been assessed as two studies. Nine studies were at low risk of bias for sequence generation (selection bias), and nine studies were at low risk of bias for allocation concealment (selection bias). Blinding of participants and personnel (performance bias) and outcome assessment (detection bias) was at low risk of bias in four and seven studies, respectively. Nine studies reported complete outcome data (attrition bias), while 10 studies reported expected outcomes, so were at low risk of reporting bias. Five studies were at low risk of other bias. Eleven studies evaluated therapy to prevent persistent kidney disease in IgAV with or without kidney involvement at presentation. There was probably no difference in the risk of persistent kidney disease any time after treatment (5 studies, 746 children: RR 0.74, 95% CI 0.42 to 1.32) or at one, three, six and 12 months in children given prednisone for 14 to 28 days at presentation of IgAV compared with placebo or supportive treatment (moderate certainty evidence). There may be no differences in the risk of any persistent kidney disease with antiplatelet therapy (three studies) or heparin (two studies) in children with or without any kidney disease at study entry, although heparin may reduce the risk of proteinuria by three months compared with placebo or no specific treatment (2 studies, 317 children: RR 0.47, 95% CI 0.31 to 0.73). One study comparing montelukast with placebo found no differences in outcomes as assessed by severity scale scores. Nine studies examined the treatment of severe IgAV-associated kidney disease. In two studies (one involving 56 children and the other involving 54 adults), there may be no differences in efficacy outcomes or adverse effects with cyclophosphamide compared with placebo or supportive treatment. In two studies, there may be no differences in the numbers achieving remission of proteinuria with intravenous (IV) cyclophosphamide compared with mycophenolate mofetil (MMF) (65 children evaluated) or tacrolimus (142 children evaluated). In three small studies comparing cyclosporin with methylprednisolone (15 children), MMF with azathioprine (26 children), or MMF with leflunomide (19 children), it is unclear whether the treatment had any effect on the numbers in remission or the degree of proteinuria between treatment groups because of small numbers of included participants. In one study comparing plasmapheresis, cyclophosphamide and methylprednisolone with cyclophosphamide and methylprednisolone, there may be no difference in the numbers achieving remission. One study compared fosinopril with no specific therapy and reported fosinopril reduced the number of participants with proteinuria. No studies were identified that evaluated the efficacy of therapy on kidney disease in participants with recurrent episodes of IgAV.
AUTHORS' CONCLUSIONS
There are no substantial changes in conclusions from this update compared with the initial review or the previous update despite the addition of five studies. From generally low to moderate certainty evidence, we found that there may be little or no benefit in the use of corticosteroids or antiplatelet agents to prevent persistent kidney disease in children with IgAV in participants with no or minimal kidney involvement at presentation. We did not find any studies which evaluated corticosteroids in children presenting with IgAV and nephritic and/or nephrotic syndrome, although corticosteroids are recommended in such children in guidelines. Though heparin may be effective in reducing proteinuria, this potentially dangerous therapy is not justified to prevent serious kidney disease when few children with IgAV develop severe kidney disease. There may be no benefit of cyclophosphamide compared with no specific treatment or corticosteroids. While there may be no benefit in the efficacy of MMF or tacrolimus compared with IV cyclophosphamide in children or adults with IgAV and severe kidney disease, adverse effects, particularly infections, may be lower in MMF or tacrolimus-treated children. Because of small patient numbers and events leading to imprecision in results, it remains unclear whether cyclosporin, MMF or leflunomide have any role in the treatment of children with IgAV and severe kidney disease. We did not identify any studies which evaluated corticosteroids.
Topics: Adult; Child; Humans; Fosinopril; IgA Vasculitis; Kidney Diseases; Leflunomide; Proteinuria; Tacrolimus; Vasculitis
PubMed: 36853224
DOI: 10.1002/14651858.CD005128.pub4 -
Metabolites Sep 2022Fetal growth restriction (FGR) is a common complication of pregnancy and a significant cause of neonatal morbidity and mortality. The adverse effects of FGR can last... (Review)
Review
Fetal growth restriction (FGR) is a common complication of pregnancy and a significant cause of neonatal morbidity and mortality. The adverse effects of FGR can last throughout the entire lifespan and increase the risks of various diseases in adulthood. However, the etiology and pathogenesis of FGR remain unclear. This study comprehensively reviewed metabolomics studies related with FGR in pregnancy to identify potential metabolic biomarkers and pathways. Relevant articles were searched through two online databases (PubMed and Web of Science) from January 2000 to July 2022. The reported metabolites were systematically compared. Pathway analysis was conducted through the online MetaboAnalyst 5.0 software. For humans, a total of 10 neonatal and 14 maternal studies were included in this review. Several amino acids, such as alanine, valine, and isoleucine, were high frequency metabolites in both neonatal and maternal studies. Meanwhile, several pathways were suggested to be involved in the development of FGR, such as arginine biosynthesis, arginine, and proline metabolism, glyoxylate and dicarboxylate metabolism, and alanine, aspartate, and glutamate metabolism. In addition, we also included 8 animal model studies, in which three frequently reported metabolites (glutamine, phenylalanine, and proline) were also present in human studies. In general, this study summarized several metabolites and metabolic pathways which may help us to better understand the underlying metabolic mechanisms of FGR.
PubMed: 36144264
DOI: 10.3390/metabo12090860 -
Caries Research 2022Salivary proteins play an important role in repairing mechanisms of damaged tissues and the maintenance of oral health. However, there is a dearth of information in the...
Salivary proteins play an important role in repairing mechanisms of damaged tissues and the maintenance of oral health. However, there is a dearth of information in the literature regarding the concentrations of salivary proteins in caries-free (CF) and caries-active (CA) subjects. Hence, this systematic review was conducted to update our previous systematic review published in 2013 that aimed to assess the association between caries and salivary proteins by comparing CF and CA individuals. Thereby, evaluating the possibility of whether salivary proteins can be regarded as biomarkers for caries. An extensive search of studies was conducted using PubMed, EMBASE, Clarivate Analytics' Web of Science, and Elsevier's Scopus between July 2012 and January 2022, without any language restriction. Manual searching in Google Scholar and evaluation of bibliographies of the included studies were also undertaken. The Newcastle-Ottawa Scale was used to assess the risk of bias (RoB) within the included studies. Of 22 included studies, 1,551 human subjects (range: 30-213 participants) were recruited, of which 848 individuals (54.7%) were CA and 703 (45.3%) were CF. Regarding the utilization of DMFT as the caries index, high variability was observed across different articles. A statistically significant increase in the salivary levels of alpha-amylase, acidic proline-rich protein-1, histatin-5, lactoperoxidase, and mucin-1 was found in CA patients, while the salivary levels of carbonic anhydrase 6, proteinase-3, and statherin were observed to be significantly increased in CF subjects. Conflicting results were found regarding the salivary levels of immunoglobulin A and total proteins among CA and CF subjects. The included studies were categorized as low RoB (n = 15), medium RoB (n = 4), and high RoB (n = 3). Due to significant heterogeneity among the included studies, no meta-analysis could be performed. In conclusion, the salivary levels of protein(s) might be a useful biomarker for caries diagnosis, especially alpha-amylase, acidic proline-rich protein-1, histatin-5, lactoperoxidase, mucin-1, carbonic anhydrase 6, proteinase-3, and statherin. However, their diagnostic value must be verified by large-scale prospective studies.
Topics: Humans; Mucin-1; Dental Caries; Histatins; Lactoperoxidase; Prospective Studies; Salivary Proteins and Peptides; Biomarkers; Proline; alpha-Amylases; Peptide Hydrolases
PubMed: 36116431
DOI: 10.1159/000526942