-
Scientific Reports Dec 2021Despite the increased use of medical cannabinoids, the efficacy and safety of the treatment among children remain uncertain. The objective was to study the efficacy and... (Meta-Analysis)
Meta-Analysis
Despite the increased use of medical cannabinoids, the efficacy and safety of the treatment among children remain uncertain. The objective was to study the efficacy and safety of medical cannabinoids in children. The search included studies through 11-May-2020. Selection criteria included studies evaluating efficacy and safety outcomes of medical cannabinoids (tetrahydrocannabinol, cannabidiol and other cannabis derivatives) versus control in children, independently assessed by two reviewers. Eight studies were included, all of which are randomized controlled trials. Cannabidiol is associated with 50% reduction in seizures rate (Relative Risk (RR) = 1.69, 95% CI [1.20-2.36]) and caregiver global impression of change (Median Estimated difference = (- 1), 95%CI [- 1.39-(- 0.60)]) in Dravet syndrome, compared to placebo. While cannabidiol was associated with a reduction in reported seizure events (RR = 0.59, 95% CI [0.36-0.97]), no association was found in products contained also tetrahydrocannabinol (RR = 1.35, 95% CI [0.46-4.03]). Higher dose of cannabidiol was associated with decreased appetite (RR = 2.40, 95% CI [1.39-4.15]). A qualitative assessment suggests that medical cannabinoids might be associated with adverse mental events. In conclusion, cannabidiol is associated with clinical improvement in Dravet syndrome. However, cannabidiol is also associated with decreased appetite. Adverse mental events were reported as well, however, more research should be performed to assess well this outcome.
Topics: Animals; Cannabinoids; Child; Epilepsies, Myoclonic; Humans; Medical Marijuana
PubMed: 34873203
DOI: 10.1038/s41598-021-02770-6 -
Neurobiology of Disease May 2023RecQ helicase family proteins play vital roles in maintaining genome stability, including DNA replication, recombination, and DNA repair. In human cells, there are five...
RecQ helicase family proteins play vital roles in maintaining genome stability, including DNA replication, recombination, and DNA repair. In human cells, there are five RecQ helicases: RECQL1, Bloom syndrome (BLM), Werner syndrome (WRN), RECQL4, and RECQL5. Dysfunction or absence of RecQ proteins is associated with genetic disorders, tumorigenesis, premature aging, and neurodegeneration. The biochemical and biological roles of RecQ helicases are rather well established, however, there is no systematic study comparing the behavioral changes among various RecQ-deficient mice including consequences of exposure to DNA damage. Here, we investigated the effects of ionizing irradiation (IR) on three RecQ-deficient mouse models (RecQ1, WRN and RecQ4). We find abnormal cognitive behavior in RecQ-deficient mice in the absence of IR. Interestingly, RecQ dysfunction impairs social ability and induces depressive-like behavior in mice after a single exposure to IR, suggesting that RecQ proteins play roles in mood and cognition behavior. Further, transcriptomic and metabolomic analyses revealed significant alterations in RecQ-deficient mice, especially after IR exposure. In particular, pathways related to neuronal and microglial functions, DNA damage repair, cell cycle, and reactive oxygen responses were downregulated in the RecQ4 and WRN mice. In addition, increased DNA damage responses were found in RecQ-deficient mice. Notably, two genes, Aldolase Fructose-Bisphosphate B (Aldob) and NADPH Oxidase 4 (Nox4), were differentially expressed in RecQ-deficient mice. Our findings suggest that RecQ dysfunction contributes to social and depressive-like behaviors in mice, and that aldolase activity may be associated with these changes, representing a potential therapeutic target.
Topics: Animals; Humans; Mice; RecQ Helicases; DNA Replication; DNA Repair; DNA Damage; Genomic Instability; Aldehyde-Lyases
PubMed: 36948261
DOI: 10.1016/j.nbd.2023.106092 -
Neuropharmacology Mar 2023Alterations of the brain-gut-microbiome system (BGM) have been implicated in the pathophysiology of irritable bowel syndrome (IBS), yet bowel habit-specific alterations... (Review)
Review
Alterations of the brain-gut-microbiome system (BGM) have been implicated in the pathophysiology of irritable bowel syndrome (IBS), yet bowel habit-specific alterations have not been elucidated. In this cross-sectional study, we apply a systems biology approach to characterize BGM patterns related to predominant bowel habit. Fecal samples and resting state fMRI were obtained from 102 premenopausal women (36 constipation-predominant IBS (IBS-C), 27 diarrhea-predominant IBS (IBS-D), 39 healthy controls (HCs)). Data integration analysis using latent components (DIABLO) was used to integrate data from the phenome, microbiome, metabolome, and resting-state connectome to predict HCs vs IBS-C vs IBS-D. Bloating and visceral sensitivity, distinguishing IBS from HC, were negatively associated with beneficial microbes and connectivity involving the orbitofrontal cortex. This suggests that gut interactions may generate aberrant central autonomic and descending pain pathways in IBS. The connection between IBS symptom duration, key microbes, and caudate connectivity may provide mechanistic insight to the chronicity of pain in IBS. Compared to IBS-C and HCs, IBS-D had higher levels of many key metabolites including tryptophan and phenylalanine, and increased connectivity between the sensorimotor and default mode networks; thus, suggestingan influence on diarrhea, self-related thoughts, and pain perception in IBS-D ('bottom-up' mechanism). IBS-C's microbiome and metabolome resembled HCs, but IBS-C had increased connectivity in the default mode and salience networks compared to IBS-D, which may indicate importance of visceral signals, suggesting a more 'top-down' BGM pathophysiology. These BGM characteristics highlight possible mechanistic differences for variations in the IBS bowel habit phenome. This article is part of the Special Issue on 'Microbiome & the Brain: Mechanisms & Maladies'.
Topics: Humans; Female; Irritable Bowel Syndrome; Gastrointestinal Microbiome; Cross-Sectional Studies; Multiomics; Brain; Diarrhea; Pain
PubMed: 36539012
DOI: 10.1016/j.neuropharm.2022.109381 -
Molecular Metabolism Nov 2023Polyphenols have health-promoting effects, such as improving insulin resistance. Isoxanthohumol (IX), a prenylated flavonoid found in beer hops, has been suggested to...
OBJECTIVE
Polyphenols have health-promoting effects, such as improving insulin resistance. Isoxanthohumol (IX), a prenylated flavonoid found in beer hops, has been suggested to reduce obesity and insulin resistance; however, the mechanism remains unknown.
METHODS
High-fat diet-fed mice were administered IX. We analyzed glucose metabolism, gene expression profiles and histology of liver, epididymal adipose tissue and colon. Lipase activity, fecal lipid profiles and plasma metabolomic analysis were assessed. Fecal 16s rRNA sequencing was obtained and selected bacterial species were used for in vitro studies. Fecal microbiota transplantation and monocolonization were conducted to antibiotic-treated or germ-free (GF) mice.
RESULTS
The administration of IX lowered weight gain, decreased steatohepatitis and improved glucose metabolism. Mechanistically, IX inhibited pancreatic lipase activity and lipid absorption by decreasing the expression of the fatty acid transporter CD36 in the small intestine, which was confirmed by increased lipid excretion in feces. IX administration increased markers of intestinal barrier function, including thickening the mucin layer and increasing caludin-1, a tight-junction related protein in the colon. In contrast, the effects of IX were nullified by antibiotics. As revealed using 16S rRNA sequencing, the microbial community structure changed with a significant increase in the abundance of Akkermansia muciniphila in the IX-treated group. An anaerobic chamber study showed that IX selectively promoted the growth of A. muciniphila while exhibiting antimicrobial activity against some Bacteroides and Clostridium species. To further explore the direct effect of A. muciniphila on lipid and glucose metabolism, we monocolonized either A. muciniphila or Bacteroides thetaiotaomicron to GF mice. A. muciniphila monocolonization decreased CD36 expression in the jejunum and improved glucose metabolism, with decreased levels of multiple classes of fatty acids determined using plasma metabolomic analysis.
CONCLUSIONS
Our study demonstrated that IX prevents obesity and enhances glucose metabolism by inhibiting dietary fat absorption. This mechanism is linked to suppressing pancreatic lipase activity and shifts in microbial composition, notably an increase in A. muciniphila. These highlight new treatment strategies for preventing metabolic syndrome by boosting the gut microbiota with food components.
Topics: Animals; Mice; RNA, Ribosomal, 16S; Insulin Resistance; Obesity; Verrucomicrobia; Diet, High-Fat; Dietary Fats; Glucose; Lipase
PubMed: 37709134
DOI: 10.1016/j.molmet.2023.101797 -
Molecular Cell Jul 2019Genetic recombination in all kingdoms of life initiates when helicases and nucleases process (resect) the free DNA ends to expose single-stranded DNA (ssDNA) overhangs....
Genetic recombination in all kingdoms of life initiates when helicases and nucleases process (resect) the free DNA ends to expose single-stranded DNA (ssDNA) overhangs. Resection regulation in bacteria is programmed by a DNA sequence, but a general mechanism limiting resection in eukaryotes has remained elusive. Using single-molecule imaging of reconstituted human DNA repair factors, we identify phosphorylated RPA (pRPA) as a negative resection regulator. Bloom's syndrome (BLM) helicase together with exonuclease 1 (EXO1) and DNA2 nucleases catalyze kilobase-length DNA resection on nucleosome-coated DNA. The resulting ssDNA is rapidly bound by RPA, which further stimulates DNA resection. RPA is phosphorylated during resection as part of the DNA damage response (DDR). Remarkably, pRPA inhibits DNA resection in cellular assays and in vitro via inhibition of BLM helicase. pRPA suppresses BLM initiation at DNA ends and promotes the intrinsic helicase strand-switching activity. These findings establish that pRPA provides a feedback loop between DNA resection and the DDR.
Topics: Binding Sites; DNA Helicases; DNA Repair Enzymes; DNA, Single-Stranded; Escherichia coli; Exodeoxyribonucleases; Feedback, Physiological; Gene Expression Regulation; Homologous Recombination; Humans; Microscopy, Fluorescence; Nucleosomes; Oligopeptides; Phosphorylation; Protein Binding; RecQ Helicases; Recombinant Fusion Proteins; Replication Protein A; Saccharomyces cerevisiae; Single Molecule Imaging
PubMed: 31153714
DOI: 10.1016/j.molcel.2019.05.005 -
Cureus May 2024Bloom syndrome (BS) is a rare autosomal recessive genetic disorder characterized by photosensitivity, rashes on the nose and cheeks, short stature, and a predisposition...
Bloom syndrome (BS) is a rare autosomal recessive genetic disorder characterized by photosensitivity, rashes on the nose and cheeks, short stature, and a predisposition to develop cancers. In this report, we discuss the diagnosis and management of a 34-year-old Canadian male BS patient, originally from Honduras, who developed B-cell lymphoma and a subsequent non-small cell lung carcinoma (NSCLC). Given the radiosensitivity of the patient due to his BS diagnosis and the early stage of the low-grade B-cell lymphoma, we relied on surveillance as the clinical approach to his management. The treatment for NSCLC was initiated in stage III of the disease and was palliative in intent. Chemotherapy (12 rounds of paclitaxel, with the dosage gradually increasing from 48 mg to 58 mg and finally to 72 mg) was employed to shrink the left upper lobe (LUL) lung mass. Subsequently, radiotherapy (3000 cGY in 20 fractions) was administered to improve symptoms further. The radiotherapy dose schedule was modified given the patient's BS diagnosis to avoid excessive toxicity. The palliative treatment course was well tolerated by the patient and resulted in symptom relief. However, his cancer progressed over the course of the treatment, ultimately resulting in his death 18 months after the initial diagnosis of NSCLC; no autopsy was performed. We believe this report will spur clinicians to engage in fruitful discussions about tailoring chemotherapy and radiation therapy regimens for treating cancer in BS patients.
PubMed: 38860091
DOI: 10.7759/cureus.60107 -
Frontiers in Pediatrics 2020DNA damage response is essential to human physiology. A broad spectrum of pathologies are displayed by individuals carrying monoallelic or biallelic loss-of-function... (Review)
Review
DNA damage response is essential to human physiology. A broad spectrum of pathologies are displayed by individuals carrying monoallelic or biallelic loss-of-function mutations in DNA damage repair genes. DNA repair syndromes with biallelic disturbance of essential DNA damage response pathways manifest early in life with multi-systemic involvement and a high propensity for hematologic and solid cancers, as well as bone marrow failure. In this review, we describe classic biallelic DNA repair cancer syndromes arising from faulty single- and double-strand DNA break repair, as well as dysfunctional DNA helicases. These clinical entities include xeroderma pigmentosum, constitutional mismatch repair deficiency, ataxia telangiectasia, Nijmegen breakage syndrome, deficiencies of DNA ligase IV, NHEJ/Cernunnos, and ERCC6L2, as well as Bloom, Werner, and Rothmund-Thompson syndromes. To give an in-depth understanding of these disorders, we provide historical overview and discuss the interplay between complex biology and heterogeneous clinical manifestations.
PubMed: 33194896
DOI: 10.3389/fped.2020.570084 -
Cell Death & Disease Apr 2022RecQ helicases-also known as the "guardians of the genome"-play crucial roles in genome integrity maintenance through their involvement in various DNA metabolic...
RecQ helicases-also known as the "guardians of the genome"-play crucial roles in genome integrity maintenance through their involvement in various DNA metabolic pathways. Aside from being conserved from bacteria to vertebrates, their importance is also reflected in the fact that in humans impaired function of multiple RecQ helicase orthologs are known to cause severe sets of problems, including Bloom, Werner, or Rothmund-Thomson syndromes. Our aim was to create and characterize a zebrafish (Danio rerio) disease model for Bloom syndrome, a recessive autosomal disorder. In humans, this syndrome is characterized by short stature, skin rashes, reduced fertility, increased risk of carcinogenesis, and shortened life expectancy brought on by genomic instability. We show that zebrafish blm mutants recapitulate major hallmarks of the human disease, such as shortened lifespan and reduced fertility. Moreover, similarly to other factors involved in DNA repair, some functions of zebrafish Blm bear additional importance in germ line development, and consequently in sex differentiation. Unlike fanc genes and rad51, however, blm appears to affect its function independent of tp53. Therefore, our model will be a valuable tool for further understanding the developmental and molecular attributes of this rare disease, along with providing novel insights into the role of genome maintenance proteins in somatic DNA repair and fertility.
Topics: Animals; Bloom Syndrome; Germ Cells; Longevity; RecQ Helicases; Zebrafish
PubMed: 35436990
DOI: 10.1038/s41419-022-04815-8 -
Cell Reports Jun 2023Continued evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is eroding antibody responses elicited by prior vaccination and infection. The...
Continued evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is eroding antibody responses elicited by prior vaccination and infection. The SARS-CoV-2 receptor-binding domain (RBD) E406W mutation abrogates neutralization mediated by the REGEN-COV therapeutic monoclonal antibody (mAb) COVID-19 cocktail and the AZD1061 (COV2-2130) mAb. Here, we show that this mutation remodels the receptor-binding site allosterically, thereby altering the epitopes recognized by these three mAbs and vaccine-elicited neutralizing antibodies while remaining functional. Our results demonstrate the spectacular structural and functional plasticity of the SARS-CoV-2 RBD, which is continuously evolving in emerging SARS-CoV-2 variants, including currently circulating strains that are accumulating mutations in the antigenic sites remodeled by the E406W substitution.
Topics: Humans; SARS-CoV-2; Combined Antibody Therapeutics; COVID-19; Antibodies, Viral; Antibodies, Neutralizing; Antibodies, Monoclonal; Spike Glycoprotein, Coronavirus; Neutralization Tests
PubMed: 37300832
DOI: 10.1016/j.celrep.2023.112621 -
Frontiers in Genetics 2021DNA damage repair response is an important biological process involved in maintaining the fidelity of the genome in eukaryotes and prokaryotes. Several proteins that... (Review)
Review
DNA damage repair response is an important biological process involved in maintaining the fidelity of the genome in eukaryotes and prokaryotes. Several proteins that play a key role in this process have been identified. Alterations in these key proteins have been linked to different diseases including cancer. BLM is a 3'-5' ATP-dependent RecQ DNA helicase that is one of the most essential genome stabilizers involved in the regulation of DNA replication, recombination, and both homologous and non-homologous pathways of double-strand break repair. BLM structure and functions are known to be conserved across many species like yeast, , mouse, and human. Genetic mutations in the BLM gene cause a rare, autosomal recessive disorder, Bloom syndrome (BS). BS is a monogenic disease characterized by genomic instability, premature aging, predisposition to cancer, immunodeficiency, and pulmonary diseases. Hence, these characteristics point toward BLM being a tumor suppressor. However, in addition to mutations, gene undergoes various types of alterations including increase in the copy number, transcript, and protein levels in multiple types of cancers. These results, along with the fact that the lack of wild-type BLM in these cancers has been associated with increased sensitivity to chemotherapeutic drugs, indicate that BLM also has a pro-oncogenic function. While a plethora of studies have reported the effect of gene mutations in various model organisms, there is a dearth in the studies undertaken to investigate the effect of its oncogenic alterations. We propose to rationalize and integrate the dual functions of BLM both as a tumor suppressor and maybe as a proto-oncogene, and enlist the plausible mechanisms of its deregulation in cancers.
PubMed: 33777104
DOI: 10.3389/fgene.2021.634789