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Biomolecules Aug 2022α-synuclein is a core component of Lewy bodies, one of the pathological hallmarks of Parkinson's disease. Aggregated α-synuclein can impair both synaptic functioning... (Review)
Review
α-synuclein is a core component of Lewy bodies, one of the pathological hallmarks of Parkinson's disease. Aggregated α-synuclein can impair both synaptic functioning and axonal transport. However, understanding the pathological role that α-synuclein plays at a cellular level is complicated as existing findings are multifaceted and dependent on the mutation, the species, and the quantity of the protein that is involved. This systematic review aims to stratify the research findings to develop a more comprehensive understanding of the role of aggregated α-synuclein on synaptic and axonal proteins in Parkinson's disease models. A literature search of the PubMed, Scopus, and Web of Science databases was conducted and a total of 39 studies were included for analysis. The review provides evidence for the dysregulation or redistribution of synaptic and axonal proteins due to α-synuclein toxicity. However, due to the high quantity of variables that were used in the research investigations, it was challenging to ascertain exactly what effect α-synuclein has on the expression of the proteins. A more standardized experimental approach regarding the variables that are employed in future studies is crucial so that existing literature can be consolidated. New research involving aggregated α-synuclein at the synapse and regarding axonal transport could be advantageous in guiding new treatment solutions.
Topics: Axons; Humans; Lewy Bodies; Parkinson Disease; Synapses; alpha-Synuclein
PubMed: 36139038
DOI: 10.3390/biom12091199 -
BMC Genomics Aug 2022The histidine metabolism and transport (his) genes are controlled by a variety of RNA-dependent regulatory systems among diverse taxonomic groups of bacteria including...
BACKGROUND
The histidine metabolism and transport (his) genes are controlled by a variety of RNA-dependent regulatory systems among diverse taxonomic groups of bacteria including T-box riboswitches in Firmicutes and Actinobacteria and RNA attenuators in Proteobacteria. Using a comparative genomic approach, we previously identified a novel DNA-binding transcription factor (named HisR) that controls the histidine metabolism genes in diverse Gram-positive bacteria from the Firmicutes phylum.
RESULTS
Here we report the identification of HisR-binding sites within the regulatory regions of the histidine metabolism and transport genes in 395 genomes representing the Bacilli, Clostridia, Negativicutes, and Tissierellia classes of Firmicutes, as well as in 97 other HisR-encoding genomes from the Actinobacteria, Proteobacteria, and Synergistetes phyla. HisR belongs to the TrpR family of transcription factors, and their predicted DNA binding motifs have a similar 20-bp palindromic structure but distinct lineage-specific consensus sequences. The predicted HisR-binding motif was validated in vitro using DNA binding assays with purified protein from the human gut bacterium Ruminococcus gnavus. To fill a knowledge gap in the regulation of histidine metabolism genes in Firmicutes genomes that lack a hisR repressor gene, we systematically searched their upstream regions for potential RNA regulatory elements. As result, we identified 158 T-box riboswitches preceding the histidine biosynthesis and/or transport genes in 129 Firmicutes genomes. Finally, novel candidate RNA attenuators were identified upstream of the histidine biosynthesis operons in six species from the Bacillus cereus group, as well as in five Eubacteriales and six Erysipelotrichales species.
CONCLUSIONS
The obtained distribution of the HisR transcription factor and two RNA-mediated regulatory mechanisms for histidine metabolism genes across over 600 species of Firmicutes is discussed from functional and evolutionary points of view.
Topics: Actinobacteria; Bacteria; DNA; Gene Expression Regulation, Bacterial; Gram-Positive Bacteria; Histidine; Humans; Phylogeny; Riboswitch; Transcription Factors
PubMed: 36008760
DOI: 10.1186/s12864-022-08796-y -
BMC Geriatrics Aug 2022Healthy aging relies on mitochondrial functioning because this organelle provides energy and diminishes oxidative stress. Single nucleotide polymorphisms (SNPs) in...
INTRODUCTION
Healthy aging relies on mitochondrial functioning because this organelle provides energy and diminishes oxidative stress. Single nucleotide polymorphisms (SNPs) in TOMM40, a critical gene that produces the outer membrane protein TOM40 of mitochondria, have been associated with mitochondrial dysfunction and neurodegenerative processes. Yet it is not clear whether or how the mitochondria may impact human longevity. We conducted this review to ascertain which SNPs have been associated with markers of healthy aging.
METHODS
Using the PRISMA methodology, we conducted a systematic review on PubMed and Embase databases to identify associations between TOMM40 SNPs and measures of longevity and healthy aging.
RESULTS
Twenty-four articles were selected. The TOMM40 SNPs rs2075650 and rs10524523 were the two most commonly identified and studied SNPs associated with longevity. The outcomes associated with the TOMM40 SNPs were changes in BMI, brain integrity, cognitive functions, altered inflammatory network, vulnerability to vascular risk factors, and longevity.
DISCUSSIONS
Our systematic review identified multiple TOMM40 SNPs potentially associated with healthy aging. Additional research can help to understand mechanisms in aging, including resilience, prevention of disease, and adaptation to the environment.
Topics: Aging; Healthy Aging; Humans; Longevity; Membrane Transport Proteins; Mitochondrial Precursor Protein Import Complex Proteins; Polymorphism, Single Nucleotide
PubMed: 35964003
DOI: 10.1186/s12877-022-03337-4 -
Molecules (Basel, Switzerland) May 2022Bile acids (BAs) are important steroidal molecules with a rapidly growing span of applications across a variety of fields such as supramolecular chemistry, pharmacy, and... (Review)
Review
Bile acids (BAs) are important steroidal molecules with a rapidly growing span of applications across a variety of fields such as supramolecular chemistry, pharmacy, and biomedicine. This work provides a systematic review on their transport processes within the enterohepatic circulation and related processes. The focus is laid on the description of specific or less-specific BA transport proteins and their localization. Initially, the reader is provided with essential information about BAs' properties, their systemic flow, metabolism, and functions. Later, the transport processes are described in detail and schematically illustrated, moving step by step from the liver via bile ducts to the gallbladder, small intestine, and colon; this description is accompanied by descriptions of major proteins known to be involved in BA transport. Spillage of BAs into systemic circulation and urine excretion are also discussed. Finally, the review also points out some of the less-studied areas of the enterohepatic circulation, which can be crucial for the development of BA-related drugs, prodrugs, and drug carrier systems.
Topics: Bile Acids and Salts; Bile Ducts; Carrier Proteins; Enterohepatic Circulation; Liver
PubMed: 35566302
DOI: 10.3390/molecules27092961 -
Neural Regeneration Research Nov 2022Blood exosomes, which are extracellular vesicles secreted by living cells into the circulating blood, are regarded as a relatively noninvasive novel tool for monitoring... (Review)
Review
Blood exosomes, which are extracellular vesicles secreted by living cells into the circulating blood, are regarded as a relatively noninvasive novel tool for monitoring brain physiology and disease states. An increasing number of blood cargo-loaded exosomes are emerging as potential biomarkers for preclinical and clinical Alzheimer's disease. Therefore, we conducted a meta-analysis and systematic review of molecular biomarkers derived from blood exosomes to comprehensively analyze their diagnostic performance in preclinical Alzheimer's disease, mild cognitive impairment, and Alzheimer's disease. We performed a literature search in PubMed, Web of Science, Embase, and Cochrane Library from their inception to August 15, 2020. The research subjects mainly included Alzheimer's disease, mild cognitive impairment, and preclinical Alzheimer's disease. We identified 34 observational studies, of which 15 were included in the quantitative analysis (Newcastle-Ottawa Scale score 5.87 points) and 19 were used in the qualitative analysis. The meta-analysis results showed that core biomarkers including Aβ, P-T181-tau, P-S396-tau, and T-tau were increased in blood neuron-derived exosomes of preclinical Alzheimer's disease, mild cognitive impairment, and Alzheimer's disease patients. Molecules related to additional risk factors that are involved in neuroinflammation (C1q), metabolism disorder (P-S312-IRS-1), neurotrophic deficiency (HGF), vascular injury (VEGF-D), and autophagy-lysosomal system dysfunction (cathepsin D) were also increased. At the gene level, the differential expression of transcription-related factors (REST) and microRNAs (miR-132) also affects RNA splicing, transport, and translation. These pathological changes contribute to neural loss and synaptic dysfunction. The data confirm that the above-mentioned core molecules and additional risk-related factors in blood exosomes can serve as candidate biomarkers for preclinical and clinical Alzheimer's disease. These findings support further development of exosome biomarkers for a clinical blood test for Alzheimer's disease. This meta-analysis was registered at the International Prospective Register of Systematic Reviews (Registration No. CRD4200173498, 28/04/2020).
PubMed: 35535875
DOI: 10.4103/1673-5374.335832 -
Frontiers in Pharmacology 2022Potassium ion (K) channels are pore-forming transmembrane proteins that control the transport of K ions. Medicinal plants are widely used as complementary therapies for... (Review)
Review
Potassium ion (K) channels are pore-forming transmembrane proteins that control the transport of K ions. Medicinal plants are widely used as complementary therapies for several disorders. Studies have shown that the modulation of K channels is most likely involved in various pharmacological effects of medicinal plants. This review aimed to evaluate the modulatory effects of medicinal plants and their active constituents on K channels under pathological conditions. This systematic review was prepared according to the Preferred Reporting Items for the Systematic Reviews and Meta-analyses (PRISMA) 2020 guideline. Four databases, including PubMed, Web of Science, embase, and Scopus, were searched. We identified 687 studies from these databases, from which we selected 13 studies for the review by using the Population, Intervention, Comparison, Outcomes, Study (PICOS) tool. The results of the 13 selected studies showed a modulatory effect of medicinal plants or their active constituents on ATP-sensitive potassium channels (K), and small (SK) and large (BK) conductance calcium-activated K channels in several pathological conditions such as nociception, brain ischemia, seizure, diabetes, gastric ulcer, myocardial ischemia-reperfusion, and hypertension via possible involvement of the nitric oxide/cyclic GMP pathway and protein kinase. K channels should be considered as significant therapeutic milestones in the treatment of several diseases. We believe that understanding the mechanism behind the interaction of medicinal plants with K channels can facilitate drug development for the treatment of various K channel-related disorders.
PubMed: 35273505
DOI: 10.3389/fphar.2022.831963 -
Journal of Pharmacy & Pharmaceutical... 2022This narrative review explores the currently published studies that have evaluated tenapanor for the treatment of hyperphosphatemia in end-stage kidney disease (ESKD)...
PURPOSE
This narrative review explores the currently published studies that have evaluated tenapanor for the treatment of hyperphosphatemia in end-stage kidney disease (ESKD) patients on hemodialysis. This medication's new phosphate lowering mechanism of action reduces intestinal phosphate absorption predominantly through reduction of passive paracellular phosphate flux by inhibition of the sodium/hydrogen exporter isoform 3 (NHE3). Tenapanor additionally prevents active transcellular phosphate absorption compensation by decreasing the expression of sodium phosphorus 2b transport protein (NaPi2b).
METHODS
A comprehensive search of the literature was conducted using PubMed and ClinicalTrials.gov search engines. The search term "tenapanor hyperphosphatemia" was used for study retrieval. Results were limited to studies published in the English language and excluded review articles. Human, animal, and in vitro studies were included. No date range was specified.
RESULTS
A total of 11 primary studies were identified and included in this review, the largest human study of which enrolled 236 patients. Each study is presented in table format along with measured end points.
CONCLUSIONS
Tenapanor is the first drug in its class that lowers hyperphosphatemia in ESKD patients through a novel mechanism of action involving paracellular inactive transport. Although more studies are needed, early results indicate that tenapanor may have a place in managing hyperphosphatemia in ESKD patients both as monotherapy and as an adjunct to existing phosphate binder therapy.
Topics: Animals; Biological Transport, Active; Cytochrome P-450 Enzyme Inhibitors; Drug Interactions; Humans; Hyperphosphatemia; Intestinal Absorption; Isoquinolines; Kidney Failure, Chronic; Phosphates; Rats; Sodium-Hydrogen Exchanger 3; Sulfonamides
PubMed: 35041802
DOI: 10.18433/jpps32284 -
Urologic Oncology May 2022Determining meta-analysis of transcriptional profiling of muscle-invasive bladder cancer (MIBC) through Gene Expression Omnibus (GEO) datasets has not been investigated.... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Determining meta-analysis of transcriptional profiling of muscle-invasive bladder cancer (MIBC) through Gene Expression Omnibus (GEO) datasets has not been investigated. This study aims to define gene expression profiles in MIBC and to identify potential candidate genes and pathways.
OBJECTIVES
To review and evaluate gene expression studies in MIBC through publicly available RNA sequencing (RNA-Seq) and microarray data in order to identify potential prognostic and therapeutic targets for MIBC.
METHODS
A systematic literature search of the Ovid MEDLINE, PubMed, and Wiley Cochrane Central Register of Controlled Trials databases was performed using the terms "gene," "gene expression," and "bladder cancer" January 1, 1990 through March 2021 focused on populations with MIBC.
RESULTS
In the final analysis, GEO datasets were included. Fixed effect model was employed in the meta-analysis. Gene networking connections and gene-set functional analyses of the identified genes as differentially expressed in MIBC were performed using ImaGEO and GeneMANIA software. A heatmap for the upregulated and downregulated genes was generated along with the correlated pathways.
CONCLUSION
A total of 9 genes were reported in this analysis. Six genes were reported as upregulated (ProTα, SPINT1, UBE2E1, RAB25, KPNB1, HDAC1) and 3 genes as downregulated (NUP188, IPO13, NUP124). Genes were found to be involved in "ubiquitin mediated proteolysis," "protein processing in endoplasmic reticulum," "transcriptional misregulation in cancer," and "RNA transport" pathways.
Topics: Female; Gene Expression Profiling; Gene Regulatory Networks; Humans; Male; Muscles; Neoplasm Invasiveness; Prognosis; Urinary Bladder Neoplasms; rab GTP-Binding Proteins
PubMed: 35039218
DOI: 10.1016/j.urolonc.2021.11.003 -
Molecules (Basel, Switzerland) Dec 2021Proliferating cancer cells have high energy demands, which is mainly obtained through glycolysis. The transmembrane trafficking of lactate, a major metabolite produced... (Meta-Analysis)
Meta-Analysis
Proliferating cancer cells have high energy demands, which is mainly obtained through glycolysis. The transmembrane trafficking of lactate, a major metabolite produced by glycolytic cancer cells, relies on monocarboxylate transporters (MCTs). MCT1 optimally imports lactate, although it can work bidirectionally, and its activity has been linked to cancer aggressiveness and poor outcomes. AZD3965, a specific MCT1 inhibitor, was tested both in vitro and in vivo, with encouraging results; a phase I clinical trial has already been undertaken. Thus, analysis of the experimental evidence using AZD3965 in different cancer types could give valuable information for its clinical use. This systematic review aimed to assess the in vivo anticancer activity of AZD3965 either alone (monotherapy) or with other interventions (combination therapy). Study search was performed in nine different databases using the keywords "AZD3965 in vivo" as search terms. The results show that AZD3965 successfully decreased tumor growth and promoted intracellular lactate accumulation, which confirmed its effectiveness, especially in combined therapy. These results support the setup of clinical trials, but other important findings, namely AZD3965 enhanced activity when given in combination with other therapies, or MCT4-induced treatment resistance, should be further considered in the clinical trial design to improve therapy response.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Disease Management; Disease Progression; Drug Evaluation, Preclinical; Energy Metabolism; Glycolysis; Humans; Lactic Acid; Monocarboxylic Acid Transporters; Neoplasms; Pyrimidinones; Signal Transduction; Symporters; Thiophenes; Tumor Microenvironment; Warburg Effect, Oncologic; Xenograft Model Antitumor Assays
PubMed: 35011413
DOI: 10.3390/molecules27010181 -
Nutrients Nov 2021Several observational studies have examined vitamin D pathway polymorphisms and their association with type 1 diabetes (T1D) susceptibility, with inconclusive results.... (Meta-Analysis)
Meta-Analysis
Several observational studies have examined vitamin D pathway polymorphisms and their association with type 1 diabetes (T1D) susceptibility, with inconclusive results. We aimed to perform a systematic review and meta-analysis assessing associations between selected variants affecting 25-hydroxyvitamin D [25(OH)D] and T1D risk. We conducted a systematic search of Medline, Embase, Web of Science and OpenGWAS updated in April 2021. The following keywords "vitamin D" and/or "single nucleotide polymorphisms (SNPs)" and "T1D" were selected to identify relevant articles. Seven SNPs (or their proxies) in six genes were analysed: rs10741657, (low frequency) rs117913124, rs12785878, rs3755967, rs17216707, rs10745742 and rs8018720. Seven case-control and three cohort studies were eligible for quantitative synthesis ( = 10). Meta-analysis results suggested no association with T1D (range of pooled ORs for all SNPs: 0.97-1.02; > 0.01). Heterogeneity was found in rs12785878 (I: 64.8%, = 0.02). Sensitivity analysis showed exclusion of any single study did not alter the overall pooled effect. No association with T1D was observed among a Caucasian subgroup. In conclusion, the evidence from the meta-analysis indicates a null association between selected variants affecting serum 25(OH)D concentrations and T1D.
Topics: Adolescent; Adult; Amidohydrolases; Carbon-Nitrogen Ligases with Glutamine as Amide-N-Donor; Child; Child, Preschool; Cholestanetriol 26-Monooxygenase; Cohort Studies; Cytochrome P450 Family 2; Diabetes Mellitus, Type 1; Female; Genetic Predisposition to Disease; Humans; Male; Oxidoreductases Acting on CH-CH Group Donors; Polymorphism, Single Nucleotide; Receptors, Calcitriol; Vesicular Transport Proteins; Vitamin D; Vitamin D Deficiency; Vitamin D-Binding Protein; Vitamin D3 24-Hydroxylase; Young Adult
PubMed: 34959812
DOI: 10.3390/nu13124260