-
Frontiers in Aging Neuroscience 2023Many lines of evidence suggest that mitochondria have a central role in aging-related neurodegenerative diseases, such as Alzheimer's disease (AD). Mitochondrial...
Many lines of evidence suggest that mitochondria have a central role in aging-related neurodegenerative diseases, such as Alzheimer's disease (AD). Mitochondrial dysfunction, cerebral energy dysmetabolism and oxidative damage increase with age, and are early event in AD pathophysiology and may precede amyloid beta (Aβ) plaques. probes of mitochondrial function and energy metabolism are therefore crucial to characterize the bioenergetic abnormalities underlying AD risk, and their relationship to pathophysiology and cognition. A majority of the research conducted in humans have used F-fluoro-deoxygluose (FDG) PET to image cerebral glucose metabolism (CMRglc), but key information regarding oxidative phosphorylation (OXPHOS), the process which generates 90% of the energy for the brain, cannot be assessed with this method. Thus, there is a crucial need for imaging tools to measure mitochondrial processes and OXPHOS in the human brain. Phosphorus-magnetic resonance spectroscopy (P-MRS) is a non-invasive method which allows for the measurement of OXPHOS-related high-energy phosphates (HEP), including phosphocreatine (PCr), adenosine triphosphate (ATP), and inorganic phosphate (Pi), in addition to potential of hydrogen (pH), as well as components of phospholipid metabolism, such as phosphomonoesters (PMEs) and phosphodiesters (PDEs). Herein, we provide a systematic review of the existing literature utilizing the P-MRS methodology during the normal aging process and in patients with mild cognitive impairment (MCI) and AD, with an additional focus on individuals at risk for AD. We discuss the strengths and limitations of the technique, in addition to considering future directions toward validating the use of P-MRS measures as biomarkers for the early detection of AD.
PubMed: 37273652
DOI: 10.3389/fnagi.2023.1183228 -
Journal of Cellular Physiology Jul 2022Pemphigus vulgaris (PV) is a potentially fatal autoimmune blistering disease characterized by cell-cell detachment (or acantholysis) and blister formation. While the... (Review)
Review
Pemphigus vulgaris (PV) is a potentially fatal autoimmune blistering disease characterized by cell-cell detachment (or acantholysis) and blister formation. While the signaling mechanisms that associate with skin/mucosal blistering are being elucidated, specific treatment strategies targeting PV-specific pathomechanisms, particularly kinase signaling, have yet to be established. Hence, the aim of this review was to systematically evaluate molecules in the class of kinases that are essential for acantholysis and blister formation and are therefore candidates for targeted therapy. English articles from PubMed and Scopus databases were searched, and included in vitro, in vivo, and human studies that investigated the role of kinases in PV. We selected studies, extracted data and assessed risk of bias in duplicates and the results were reported according to the methodology outlined by the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). The risk of bias assessment was performed on in vivo studies utilizing SYRCLE's risk of bias tool. Thirty-five studies were included that satisfied the pathogenicity criterion of kinases in PV, the vast majority being experimental models that used PV sera (n = 13) and PV-IgG (n = 22). Inhibition of kinase activity (p38MAPK, PKC, TK, c-Src, EGFR, ERK, mTOR, BTK, and CDK2) was achieved mostly by pharmacological means. Overall, we found substantial evidence that kinase inhibition reduced PV-associated phosphorylation events and keratinocyte disassociation, prevented acantholysis, and blocked blister formation. However, the scarce adherence to standardized reporting systems and the experimental protocols/models used did limit the internal and external validity of these studies. In summary, this systematic review highlighted the pathogenic intracellular events mediated by kinases in PV acantholysis and presented kinase signaling as a promising avenue for translational research. In particular, the molecules identified and discussed in this study represent potential candidates for the development of mechanism-based interventions in PV.
Topics: Acantholysis; Autoantibodies; Blister; Humans; Immunoglobulin G; Keratinocytes; Pemphigus; Phosphorylation
PubMed: 35616233
DOI: 10.1002/jcp.30784 -
European Urology Feb 2013There is increasing evidence for the role of altered metabolism in the pathogenesis of renal cancer. (Review)
Review
CONTEXT
There is increasing evidence for the role of altered metabolism in the pathogenesis of renal cancer.
OBJECTIVE
This review characterizes the metabolic effects of genes and signaling pathways commonly implicated in renal cancer.
EVIDENCE ACQUISITION
A systematic review of the literature was performed using PubMed. The search strategy included the following terms: renal cancer, metabolism, HIF, VHL.
EVIDENCE SYNTHESIS
Significant progress has been made in the understanding of the metabolic derangements present in renal cancer. These findings have been derived through translational, in vitro, and in vivo studies. To date, the most well-characterized metabolic features of renal cancer are linked to von Hippel-Lindau (VHL) loss. VHL loss and the ensuing increase in the expression of hypoxia-inducible factor affect several metabolic pathways, including glycolysis and oxidative phosphorylation. Collectively, these changes promote a glycolytic metabolic phenotype in renal cancer. In addition, other histologic subtypes of renal cancer are also notable for metabolic derangements that are directly related to the causative genes.
CONCLUSIONS
Current knowledge of the genetics of renal cancer has led to significant understanding of the metabolism of this malignancy. Further studies of the metabolic basis of renal cell carcinoma should provide the foundation for the development of new treatment approaches and development of novel biomarkers.
Topics: Basic Helix-Loop-Helix Transcription Factors; Carcinoma, Renal Cell; Gene Expression Regulation, Neoplastic; Glycolysis; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Kidney Neoplasms; Oxidative Phosphorylation; Signal Transduction; Von Hippel-Lindau Tumor Suppressor Protein
PubMed: 23063455
DOI: 10.1016/j.eururo.2012.09.054 -
Journal of Cachexia, Sarcopenia and... Jun 2024Proliferating cancer cells shift their metabolism towards glycolysis, even in the presence of oxygen, to especially generate glycolytic intermediates as substrates for...
BACKGROUND
Proliferating cancer cells shift their metabolism towards glycolysis, even in the presence of oxygen, to especially generate glycolytic intermediates as substrates for anabolic reactions. We hypothesize that a similar metabolic remodelling occurs during skeletal muscle hypertrophy.
METHODS
We used mass spectrometry in hypertrophying C2C12 myotubes in vitro and plantaris mouse muscle in vivo and assessed metabolomic changes and the incorporation of the [U-C]glucose tracer. We performed enzyme inhibition of the key serine synthesis pathway enzyme phosphoglycerate dehydrogenase (Phgdh) for further mechanistic analysis and conducted a systematic review to align any changes in metabolomics during muscle growth with published findings. Finally, the UK Biobank was used to link the findings to population level.
RESULTS
The metabolomics analysis in myotubes revealed insulin-like growth factor-1 (IGF-1)-induced altered metabolite concentrations in anabolic pathways such as pentose phosphate (ribose-5-phosphate/ribulose-5-phosphate: +40%; P = 0.01) and serine synthesis pathway (serine: -36.8%; P = 0.009). Like the hypertrophy stimulation with IGF-1 in myotubes in vitro, the concentration of the dipeptide l-carnosine was decreased by 26.6% (P = 0.001) during skeletal muscle growth in vivo. However, phosphorylated sugar (glucose-6-phosphate, fructose-6-phosphate or glucose-1-phosphate) decreased by 32.2% (P = 0.004) in the overloaded muscle in vivo while increasing in the IGF-1-stimulated myotubes in vitro. The systematic review revealed that 10 metabolites linked to muscle hypertrophy were directly associated with glycolysis and its interconnected anabolic pathways. We demonstrated that labelled carbon from [U-C]glucose is increasingly incorporated by ~13% (P = 0.001) into the non-essential amino acids in hypertrophying myotubes, which is accompanied by an increased depletion of media serine (P = 0.006). The inhibition of Phgdh suppressed muscle protein synthesis in growing myotubes by 58.1% (P < 0.001), highlighting the importance of the serine synthesis pathway for maintaining muscle size. Utilizing data from the UK Biobank (n = 450 243), we then discerned genetic variations linked to the serine synthesis pathway (PHGDH and PSPH) and to its downstream enzyme (SHMT1), revealing their association with appendicular lean mass in humans (P < 5.0e-8).
CONCLUSIONS
Understanding the mechanisms that regulate skeletal muscle mass will help in developing effective treatments for muscle weakness. Our results provide evidence for the metabolic rewiring of glycolytic intermediates into anabolic pathways during muscle growth, such as in serine synthesis.
Topics: Glucose; Muscle, Skeletal; Animals; Mice; Humans; Hypertrophy; Muscle Fibers, Skeletal; Insulin-Like Growth Factor I; Metabolomics
PubMed: 38742477
DOI: 10.1002/jcsm.13468 -
Journal of Ovarian Research Nov 2021STAT3 and p-STAT3 are often overexpressed in various human tumours and participate in cancer development and progression. However, whether STAT3/p-STAT3 expression is... (Meta-Analysis)
Meta-Analysis
PURPOSE
STAT3 and p-STAT3 are often overexpressed in various human tumours and participate in cancer development and progression. However, whether STAT3/p-STAT3 expression is associated with clinicopathologic characteristics and has prognostic significance for people suffering from ovarian cancer remains controversial. We conducted a systematic review and meta-analyses to clarify the associations between STAT3/p-STAT3 expression and clinicopathologic characteristics and prognostic factors of ovarian cancer.
METHODS
A systematic electronic search in the PubMed, Embase, CNKI, and Wanfang databases was conducted to identify relevant articles published before 3 April 2021. All statistical analyses were performed using Stata 15.1.
RESULTS
We included 16 eligible studies incorporating 1747 ovarian cancer patients. The expression of STAT3/p-STAT3 was upregulated in ovarian cancer samples versus normal ovarian tissue, benign tumours and borderline tumours (OR = 10.14, p < 0.00001; OR = 9.08, P < 0.00001; OR = 4.01, p < 0.00001, respectively). STAT3/p-STAT3 overexpression was significantly correlated with FIGO stage (I-II vs. III-IV) (OR = 0.36, p < 0.00001), tumour grade (G1 + G2 vs. G3) (OR = 0.55; p = 0.001) and lymph node metastasis (yes vs. no) (OR = 3.39; p < 0.00001). High STAT3/p-STAT3 expression was correlated with poorer prognosis of ovarian cancer patients for both overall survival (OS) (HR = 1.67, p < 0.00001) and progression-free survival (PFS) (HR = 1.40, p = 0.007).
CONCLUSION
The present meta-analysis indicated that high STAT3/p-STAT3 expression is likely predictive of an unfavourable prognosis in ovarian cancer patients. Nonetheless, prospective trials are required to confirm these associations.
Topics: Biomarkers, Tumor; Female; Humans; Lymphatic Metastasis; Neoplasm Grading; Neoplasm Staging; Ovarian Neoplasms; Phosphorylation; Prognosis; Progression-Free Survival; STAT3 Transcription Factor; Survival Rate
PubMed: 34789292
DOI: 10.1186/s13048-021-00918-6 -
Frontiers in Pharmacology 2022Pulmonary fibrosis (PF) is a lung disease with no curative drug, characterized by a progressive decrease in lung function. Metformin (MET) is a hypoglycemic agent with...
Pulmonary fibrosis (PF) is a lung disease with no curative drug, characterized by a progressive decrease in lung function. Metformin (MET) is a hypoglycemic agent with the advantages of high safety and low cost and has been used in several trials to treat fibrotic diseases. This study aimed to explore the efficacy and safety of MET in treating PF and elaborate on its mechanism. Eight databases were searched for animal trials of MET for PF from the time of database creation until 1 March 2022. The risk of bias quality assessment of the included studies was conducted using SYRCLE's risk of bias assessment. Pulmonary inflammation and fibrosis scores were the primary outcomes of this study. Hydroxyproline (HYP), type I collagen (collagen I), α-smooth muscle actin (α-SMA), transforming growth factor-β (TGF-β), Smad, AMP-activated protein kinase (AMPK), and extracellular signal-regulated kinase (ERK) protein expression in lung tissues and animal mortality were secondary outcomes. Effect magnitudes were combined and calculated using Revman 5.3 and Stata 16.0 to assess the efficacy and safety of MET in animal models of PF. Inter-study heterogeneity was examined using the or Q test, and publication bias was assessed using funnel plots and Egger's test. A total of 19 studies involving 368 animals were included, with a mean risk of bias of 5.9. The meta-analysis showed that MET significantly suppressed the level of inflammation and degree of PF in the lung tissue of the PF animal model. MET also reduced the content of HYP, collagen I, α-SMA, and TGF-β and phosphorylation levels of Smad2, Smad3, p-smad2/3/smad2/3, ERK1/2, and p-ERK1/2/ERK1/2 in lung tissues. MET also elevated AMPK/p-AMPK levels in lung tissues and significantly reduced animal mortality. The results of this study suggest that MET has a protective effect on lung tissues in PF animal models and may be a potential therapeutic candidate for PF treatment. https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=327285, identifier CRD42022327285.
PubMed: 36147352
DOI: 10.3389/fphar.2022.948101 -
British Journal of Clinical Pharmacology Aug 2015Currently, treatment for Alzheimer's disease (AD) focuses on the cholinergic hypothesis and provides limited symptomatic effects. Research currently focuses on other... (Review)
Review
AIMS
Currently, treatment for Alzheimer's disease (AD) focuses on the cholinergic hypothesis and provides limited symptomatic effects. Research currently focuses on other factors that are thought to contribute to AD development such as tau proteins and Aβ deposits, and how modification of the associated pathology affects outcomes in patients. This systematic review summarizes and appraises the evidence for the emerging drugs affecting Aβ and tau pathology in AD.
METHODS
A comprehensive, systematic online database search was conducted using the databases ScienceDirect and PubMed to include original research articles. A systematic review was conducted following a minimum set of standards, as outlined by The PRISMA Group . Specific inclusion and exclusion criteria were followed and studies fitting the criteria were selected. No human trials were included in this review. In vitro and in vivo AD models were used to assess efficacy to ensure studied agents were emerging targets without large bodies of evidence.
RESULTS
The majority of studies showed statistically significant improvement (P < 0.05) of Aβ and/or tau pathology, or cognitive effects. Many studies conducted in AD animal models have shown a reduction in Aβ peptide burden and a reduction in tau phosphorylation post-intervention. This has the potential to reduce plaque formation and neuronal degeneration.
CONCLUSIONS
There are many emerging targets showing promising results in the effort to modify the pathological effects associated with AD. Many of the trials also provided evidence of the clinical effects of such drugs reducing pathological outcomes, which was often demonstrated as an improvement of cognition.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Clinical Trials as Topic; Cognition; Drug Discovery; Drug Evaluation, Preclinical; Humans; Neuroprotective Agents; tau Proteins
PubMed: 25753046
DOI: 10.1111/bcp.12621 -
Fluids and Barriers of the CNS May 2017The purpose of this systematic review and meta-analysis was to evaluate the performance of cerebrospinal fluid (CSF) beta amyloid 42 (Aβ42), total tau (t-tau), and... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
The purpose of this systematic review and meta-analysis was to evaluate the performance of cerebrospinal fluid (CSF) beta amyloid 42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau) as potential diagnostic biomarkers for idiopathic normal-pressure hydrocephalus (iNPH) and to assess their utility indistinguishing patients with iNPH from those with Alzheimer disease (AD) and healthy normal controls.
METHODS
Studies were identified by searching PubMed, Embase, the Cochrane Library, Web of Science, Chinese National Knowledge Infrastructure (CNKI), Wanfang Chinese Periodical Database, VIP Chinese database, and Chinese Bio-medicine Database (CBM) before August 2016. The standardized mean difference (SMD) and 95% confidence interval (CI), comparing CSF Aβ42, t-tau, and p-tau levels between iNPH, AD and healthy controls, were calculated using random-effects models. Subgroup analyses were created according to ethnicity (Caucasian or Asian) and CSF type (lumbar or ventricular), and the publication bias was estimated using Egger's test and the Begg's test.
RESULTS
A total of 10 studies including 413 patients with iNPH, 186 patients with AD and 147 healthy controls were included in this systematic review and meta-analysis. The concentrations of CSF t-tau, and p-tau were significantly lower in iNPH patients compared to AD (SMD = -1.26, 95% CI -1.95 to -0.57, P = 0.0004; SMD = -1.54, 95% CI -2.34 to -0.74, P = 0.0002, respectively) and lower than healthy controls (SMD = -0.80, 95% CI -1.50 to -0.09, P = 0.03; SMD = -1.12, 95% CI -1.38 to -0.86, P < 0.00001, respectively). Patients with iNPH had significantly lower Aβ42 levels compared with controls (SMD = -1.14, 95% CI -1.74 to -0.55, P = 0.0002), and slightly higher Aβ42 levels compared with AD patients (SMD = 0.32, 95% CI 0.00-0.63, P = 0.05). Subgroup analyses showed that the outcomes may have been influenced by ethnicity and CSF source. Compared to AD, overall sensitivity in differentiating iNPH was 0.813 (95% CI 0.636-0.928) for Aβ42, 0.828 (95% CI 0.732-0.900) for t-tau, 0.943 (95% CI 0.871-0.981) for p-tau. Relative to AD, overall specificity in differentiating iNPH was 0.506 (95% CI 0.393-0.619) for Aβ42, 0.842 (95% CI 0.756-0.907) for t-tau, 0.851 (95% CI 0.767-0.914) for p-tau.
CONCLUSION
The results of our meta-analysis suggest that iNPH may be associated with significantly reduced levels of CSF Aβ42, t-tau and p-tau compared to the healthy normal state. Compared to AD, both t-tau and p-tau were significantly decreased in iNPH, but CSF Aβ42 was slightly increased. Prospective studies are needed to further assess the clinical utility of these and other CSF biomarkers in assisting in the diagnosis of iNPH and differentiating it from AD and other neurodegenerative disorders.
Topics: Amyloid beta-Peptides; Databases, Bibliographic; Diagnosis, Differential; Humans; Hydrocephalus, Normal Pressure; Peptide Fragments; Phosphorylation; tau Proteins
PubMed: 28486988
DOI: 10.1186/s12987-017-0062-5 -
Journal of Pharmacy & Bioallied Sciences Aug 2020Diabetes mellitus is an endocrinal disorder affecting worldwide and the disease incidence is rising alarmingly high. The effects of diabetes on tooth development are... (Review)
Review
Diabetes mellitus is an endocrinal disorder affecting worldwide and the disease incidence is rising alarmingly high. The effects of diabetes on tooth development are explored by limited studies and their molecular insights are very rarely studied. This systematic review is aimed to provide the best scientific literature source on the molecular insights into odontogenesis in hyperglycemic environment caused by diabetes mellitus or by maternal diabetes on the offspring. The literature search was conducted on the databases, namely PubMed, PubMed Central, Cochrane, and Scopus. The original studies exploring the alterations in the molecular pathways of odontogenesis in diabetes mellitus were selected. Data were extracted, chosen, and evaluated by two independent researchers. At the end of thorough data search, four articles were eligible for the review. Three articles brought out the molecular pathways involved in the offspring of gestational diabetes through animal models. Fourth article was an study, which treated the stem cells in hyperglycemic environment and drafted the molecular pathway. The altered molecular pathways in dental epithelial stem cells (DESCs), dental papilla cells (DPCs), and stem cells from apical papilla were studied and empowered with statistical analysis. Thus with this systematic review, we conclude that apurinic/apyrimidinic endonuclease1 downregulation causing deoxyribonucleic acid hypermethylation and gene silencing, activation of toll-like receptor-4/nuclear factor kappa B (TLR4/NF-κB) pathway are involved in suppressing cell proliferation and accelerated apoptosis in DESCs in high glucose environment. DPCs are suppressed from odonto differentiation by activation of TLR4 signaling and resulting inhibition of SMAD1/5/9 phosphorylation in diabetic condition. NF-κB pathway activation causes decreased cell proliferation and enhanced differentiation in apical papilla stem cells in hyperglycemia. Further studies targeting various stages of odontogenesis can reveal more molecular insight.
PubMed: 33149430
DOI: 10.4103/jpbs.JPBS_159_20 -
Frontiers in Pharmacology 2023Alzheimer's disease (AD) is a degenerative disease of the nervous system. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), a drug used to treat type 2 diabetes,...
Alzheimer's disease (AD) is a degenerative disease of the nervous system. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), a drug used to treat type 2 diabetes, have been shown to have neuroprotective effects. This systematic review and meta-analysis evaluated the effects and potential mechanisms of GLP-1 RAs in AD animal models. 26 studies were included by searching relevant studies from seven databases according to a predefined search strategy and inclusion criteria. Methodological quality was assessed using SYRCLE's risk of bias tool, and statistical analysis was performed using ReviewManger 5.3. The results showed that, in terms of behavioral tests, GLP-1 RAs could improve the learning and memory abilities of AD rodents; in terms of pathology, GLP-1 RAs could reduce Aβ deposition and phosphorylated tau levels in the brains of AD rodents. The therapeutic potential of GLP-1 RAs in AD involves a range of mechanisms that work synergistically to enhance the alleviation of various pathological manifestations associated with the condition. A total of five clinical trials were retrieved from ClinicalTrials.gov. More large-scale and high-quality preclinical trials should be conducted to more accurately assess the therapeutic effects of GLP-1 RAs on AD.
PubMed: 37771725
DOI: 10.3389/fphar.2023.1205207