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Brain : a Journal of Neurology Nov 2023Geographical variations in the incidence and prevalence of multiple sclerosis have been reported globally. Latitude as a surrogate for exposure to ultraviolet radiation...
Geographical variations in the incidence and prevalence of multiple sclerosis have been reported globally. Latitude as a surrogate for exposure to ultraviolet radiation but also other lifestyle and environmental factors are regarded as drivers of this variation. No previous studies evaluated geographical variation in the risk of secondary progressive multiple sclerosis, an advanced form of multiple sclerosis that is characterized by steady accrual of irreversible disability. We evaluated differences in the risk of secondary progressive multiple sclerosis in relation to latitude and country of residence, modified by high-to-moderate efficacy immunotherapy in a geographically diverse cohort of patients with relapsing-remitting multiple sclerosis. The study included relapsing-remitting multiple sclerosis patients from the global MSBase registry with at least one recorded assessment of disability. Secondary progressive multiple sclerosis was identified as per clinician diagnosis. Sensitivity analyses used the operationalized definition of secondary progressive multiple sclerosis and the Swedish decision tree algorithm. A proportional hazards model was used to estimate the cumulative risk of secondary progressive multiple sclerosis by country of residence (latitude), adjusted for sex, age at disease onset, time from onset to relapsing-remitting phase, disability (Multiple Sclerosis Severity Score) and relapse activity at study inclusion, national multiple sclerosis prevalence, government health expenditure, and proportion of time treated with high-to-moderate efficacy disease-modifying therapy. Geographical variation in time from relapsing-remitting phase to secondary progressive phase of multiple sclerosis was modelled through a proportional hazards model with spatially correlated frailties. We included 51 126 patients (72% female) from 27 countries. The median survival time from relapsing-remitting phase to secondary progressive multiple sclerosis among all patients was 39 (95% confidence interval: 37 to 43) years. Higher latitude [median hazard ratio = 1.21, 95% credible interval (1.16, 1.26)], higher national multiple sclerosis prevalence [1.07 (1.03, 1.11)], male sex [1.30 (1.22, 1.39)], older age at onset [1.35 (1.30, 1.39)], higher disability [2.40 (2.34, 2.47)] and frequent relapses [1.18 (1.15, 1.21)] at inclusion were associated with increased hazard of secondary progressive multiple sclerosis. Higher proportion of time on high-to-moderate efficacy therapy substantially reduced the hazard of secondary progressive multiple sclerosis [0.76 (0.73, 0.79)] and reduced the effect of latitude [interaction: 0.95 (0.92, 0.99)]. At the country-level, patients in Oman, Tunisia, Iran and Canada had higher risks of secondary progressive multiple sclerosis relative to the other studied regions. Higher latitude of residence is associated with a higher probability of developing secondary progressive multiple sclerosis. High-to-moderate efficacy immunotherapy can mitigate some of this geographically co-determined risk.
Topics: Humans; Multiple Sclerosis, Chronic Progressive; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Ultraviolet Rays; Disease Progression; Neoplasm Recurrence, Local
PubMed: 37369086
DOI: 10.1093/brain/awad218 -
Medicine Sep 2023According to current research, the primary active ingredients of Radix Astragali (RA), such as saponins, flavonoids, and polysaccharides, play an important role in...
According to current research, the primary active ingredients of Radix Astragali (RA), such as saponins, flavonoids, and polysaccharides, play an important role in anti-inflammatory effects. However, the exact molecular mechanism underlying the action was not elucidated to date. Our research attempted to determine the active components in RA and to investigate the interaction between the active components and targets involved in the anti-inflammation activity by network pharmacology and molecular docking. The active components and targets of RA were screened out by TCMSP. Thereafter, through the "anti-inflammation effect" and "inflammation" as the keywords, disease targets were obtained from the GeneCards database. The PPI network was constructed with Cytoscape 3.8.0 software to screen core targets. The GO function and KEGG analysis were enriched and analyzed through the Metascape platform, obtaining the 3-dimensional view of the core targets from the PDB database, and then, performing molecular docking in AutoDock Vina, a heatmap was constructed using the binding free energies in GraphPad Prism 8. The Discovery Studio software was used for docking analysis, and eventually, the docking results were visualized. We also explored the targets and signaling pathways of Astragaloside IV acting on anti-inflammatory effects via constructing compound-disease-target-pathway network. 18 active components and 45 targets of RA were screened out. The main anti-inflammatory active components of RA were quercetin, Astragaloside IV, kaempferol, 7-O-methylisomucronulatol, and formononetin, and the strongly interacting core proteins were TNF, IL6, IL1B, TLR4, CXCL8, CCL2, IL10, VEGFA, and MMP9. The signal pathways mainly involved include Lipid and atherosclerosis, IL-17 signaling pathway, Chagas disease, leishmaniasis, and TNF signaling pathway. Moreover, molecular docking showed that the 2 most active compounds, Astragaloside IV and kaempferol, could efficiently bind with the targets TNF, TLR4, and IL10. Astragaloside IV may play a part in anti-inflammatory effects through pathways such as HIF-1 signaling pathway, Inflammatory bowel disease and Hepatitis B ect. RA exhibits the characteristic of multicomponent and multitarget synergistic effects in exerting anti-inflammatory effects and the effective component of RA is Astragaloside IV, targeting TNF, TLR4, and IL10.
Topics: Humans; Molecular Docking Simulation; Network Pharmacology; Kaempferols; Interleukin-10; Toll-Like Receptor 4; Anti-Inflammatory Agents
PubMed: 37657026
DOI: 10.1097/MD.0000000000034945 -
Thoracic Cancer Oct 2023The aim of this study was to explore the function and mechanism of circular RNA (circRNA) matrix metallopeptidase 1 (circMMP1) in the progression of esophageal squamous...
BACKGROUND
The aim of this study was to explore the function and mechanism of circular RNA (circRNA) matrix metallopeptidase 1 (circMMP1) in the progression of esophageal squamous cell carcinoma (ESCC).
METHODS
CircMMP1 expression was detected by quantitative real-time PCR (qRT-PCR), and its relationship with the prognosis of ESCC patients was evaluated by Kaplan-Meier analysis. Cells were transfected using corresponding plasmids, and the cell proliferation activity, migration and invasion capabilities in vitro were assessed. The protein level in tissues and cells was analyzed using western blotting. RNA pulldown, dual-luciferase reporter assay and RNA immunoprecipitation assay were performed in ESCC cells to detect the interaction between circMMP1 and miR-671-5p, or the correlation between miR-671-5p and ANO1. Xenograft tumor experiment was carried out to uncover the function of circMMP1 in vivo.
RESULTS
The high level of circMMP1 in tumor tissues was associated with poor prognoses of ESCC patients. Knockdown of circMMP1 suppressed ESCC cell proliferation, migration and invasion in vitro. MiR-671-5p was the target of circMMP1 and mediated the inhibition effect of circMMP1 on ESCC cells. CircMMP1 targeted miR-671-5p to regulate ANO1 expression, which was downstream of miR-671-5p. Overexpression of ANO1 weakened tumor-repressive function of circMMP1 knockdown in ESCC cells. Moreover, silencing of circMMP1 impeded ESCC tumor growth in vivo.
CONCLUSION
Our study provided novel evidence that circMMP1 accelerated ESCC progression by acting as a miR-671-5p sponge to enhance ANO1 expression.
Topics: Humans; Esophageal Squamous Cell Carcinoma; Esophageal Neoplasms; MicroRNAs; Cell Proliferation; Prognosis; Cell Line, Tumor; Gene Expression Regulation, Neoplastic
PubMed: 37635445
DOI: 10.1111/1759-7714.15078 -
Life Science Alliance Dec 2023Primary cilia are cellular surface projections enriched in receptors and signaling molecules, acting as signaling hubs that respond to stimuli. Malfunctions in primary...
Primary cilia are cellular surface projections enriched in receptors and signaling molecules, acting as signaling hubs that respond to stimuli. Malfunctions in primary cilia have been linked to human diseases, including retinopathies and ocular defects. Here, we focus on TMEM107, a protein localized to the transition zone of primary cilia. TMEM107 mutations were found in patients with Joubert and Meckel-Gruber syndromes. A mouse model lacking exhibited eye defects such as anophthalmia and microphthalmia, affecting retina differentiation. expression during prenatal mouse development correlated with phenotype occurrence, with enhanced expression in differentiating retina and optic stalk. TMEM107 deficiency in retinal organoids resulted in the loss of primary cilia, down-regulation of retina-specific genes, and cyst formation. Knocking out TMEM107 in human ARPE-19 cells prevented primary cilia formation and impaired response to agonist treatment because of ectopic activation of the SHH pathway. Our data suggest TMEM107 plays a crucial role in early vertebrate eye development and ciliogenesis in the differentiating retina.
Topics: Female; Pregnancy; Humans; Mice; Animals; Membrane Proteins; Retina; Polycystic Kidney Diseases; Retinitis Pigmentosa; Ciliary Motility Disorders
PubMed: 37863656
DOI: 10.26508/lsa.202302073 -
Psychiatria Polska Oct 2023We present a case of a 32-years-old female patient diagnosed with paranoid schizophrenia for many years who has developed neuroleptic malignant syndrome (NMS) as a... (Review)
Review
We present a case of a 32-years-old female patient diagnosed with paranoid schizophrenia for many years who has developed neuroleptic malignant syndrome (NMS) as a result of long-acting antipsychotic's injection. Since the initial ineffectiveness of benzodiazepines, the course of electroconvulsive therapy (ECT) has been carried out. In spite of the initial promising response to ECT 3 weeks after the admission her somatic and mental state deteriorated greatly, that was hardly explicable solely by the potential loss of effectiveness of ECT or laboratory tests. Diagnostics extended with imaging tests and gynecological examination revealed the connective tissue-covered cap of a popular multivitamin supplement in patient's vagina. During the following deepened interview, she admitted that in fact 6 months ago a piece had gotten stuck while masturbating. However due to the sense of shame and subjective lack of disturbing symptoms she had left it unsaid. One month after the evacuation of the foreign body she has been discharged from the hospital remaining the full remission. The presented case shows that inflammation in the body can complicate catatonia and NMS, causing a non-specific course and difficulties in diagnosis and treatment. In some patients, the inflammatory process may be caused by a foreign body located in various natural orifices in the body. It appears significant in the group of psychiatric patients. Once again it highlights the tremendous role of meticulously conducted interview including the patient's autoerotic life.
Topics: Humans; Female; Adult; Masturbation; Neuroleptic Malignant Syndrome; Benzodiazepines; Electroconvulsive Therapy; Foreign Bodies; Antipsychotic Agents; Catatonia
PubMed: 36542768
DOI: 10.12740/PP/OnlineFirst/138338 -
Microscopic and Biopharmaceutical Evaluation of Emulsion and Self-Emulsifying Oil with Cyclosporine.Pharmaceuticals (Basel, Switzerland) Dec 2023Among the currently available commercial eye drops with cyclosporine A (Cs) there is a lack of long-acting dosage forms and products with a concentration of the drug...
Among the currently available commercial eye drops with cyclosporine A (Cs) there is a lack of long-acting dosage forms and products with a concentration of the drug substance higher than 0.1%, although Cs is widely used in ophthalmology. The aim of the research was to conduct the microscopic and biopharmaceutical evaluation of two formulations, an emulsion (EM) and a self-emulsifying oil (SEO), both with 0.5% of Cs, proposed for use in eye drops, and the comparison of both. SEO eye drops with Cs or any other drug substance are currently not available as marketed products, and the highest concentration of Cs in the ocular emulsion is only 0.1%. The microscopic evaluation of the emulsion and the SEO after emulsification with water was carried out using a high-resolution digital microscopy. The properties of both preparations were compared using the high dynamic range function or optical shadow effect mode. Images in the 3D composition mode were also recorded. The study of the Cs formulations was performed on male albino rabbits. The eye tolerance of the preparations was assessed using the ocular irritation test, which is a modified Draize test. carriers (without the drug substance) were also subjected to irritation testing. The concentration of Cs in the tissues (cornea and conjunctiva) and fluids (tear fluid and aqueous humor) of the rabbit eye was determined after multiple instillations of Cs-EM or Cs-SEO. The tested preparations were compared using the digital microscopy technique, which highlights the features of the formulations and eliminates the risk of unnoticeable properties that are difficult to observe in classical optical microscopy. Both tested Cs-loaded formulations are classified as practically non-irritating. There were also no significant differences when testing the carriers. After a topical administration, Cs was widely distributed in all tissues (e.g., in cornea 1.3 ng/mg and 1.0 ng/mg) and fluids of the eye (e.g., in tear fluid 11.6 µg/mL and 4.3 µg/mL), after the administration of Cs-SEO and Cs-EM, respectively. The obtained results allow us to recognize both tested formulations, the emulsion and the self-emulsifying oil with 0.5% Cs content, as carriers safe for ophthalmic use and effective in delivering the drug substance to the structures of the eye.
PubMed: 38139839
DOI: 10.3390/ph16121713 -
Frontiers in Plant Science 2023Silicon-based defenses deter insect herbivores in many cultivated and wild grass species. Furthermore, in some of these species, silicon (Si) uptake and defense can be...
Silicon-based defenses deter insect herbivores in many cultivated and wild grass species. Furthermore, in some of these species, silicon (Si) uptake and defense can be induced by herbivory. Tropical trees also take up Si and leaf Si concentrations vary greatly across and within species. As herbivory is a major driver of seedling mortality and niche differentiation of tropical tree species, understanding anti-herbivore defenses is pivotal. Yet, whether silicon is a constitutive and inducible herbivory defense in tropical forest tree species remains unknown. We grew seedlings of eight tropical tree species in a full factorial experiment, including two levels of plant-available soil Si concentrations (-Si/+Si) and a simulated herbivory treatment (-H/+H). The simulated herbivory treatment was a combination of clipping and application of methyl jasmonate. We then carried out multiple-choice feeding trials, separately for each tree species, in which leaves of each treatment combination were offered to a generalist caterpillar (). Leaf damage was assessed. Three species showed a significant decrease in leaf damage under high compared to low Si conditions (by up to 72%), consistent with our expectation of Si-based defenses acting in tropical tree species. In one species, leaf damage was increased by increasing soil Si and in four species, no effect of soil Si on leaf damage was observed. Opposite to our expectation of Si uptake and defense being inducible by herbivory damage, simulated herbivory increased leaf damage in two species. Furthermore, simulated herbivory reduced Si concentrations in one species. Our results showed that tropical tree seedlings can be better defended when growing in Si-rich compared to Si-poor soils, and that the effects of Si on plant defense vary strongly across species. Furthermore, Si-based defenses may not be inducible in tropical tree species. Overall, constitutive Si-based defense should be considered part of the vast array of anti-herbivore defenses of tropical tree species. Our finding that Si-based defenses are highly species-specific combined with the fact that herbivory is a major driver of mortality in tropical tree seedling, suggests that variation in soil Si concentrations may have pervasive consequences for regeneration and performance across tropical tree species.
PubMed: 37900768
DOI: 10.3389/fpls.2023.1250868 -
Cardiovascular Diabetology Aug 2023Agonism at the receptor for the glucose-dependent insulinotropic polypeptide (GIPR) is a key component of the novel unimolecular GIPR:GLP-1R co-agonists, which are among...
BACKGROUND
Agonism at the receptor for the glucose-dependent insulinotropic polypeptide (GIPR) is a key component of the novel unimolecular GIPR:GLP-1R co-agonists, which are among the most promising drugs in clinical development for the treatment of obesity and type 2 diabetes. The therapeutic effect of chronic GIPR agonism to treat dyslipidemia and thus to reduce the cardiovascular disease risk independently of body weight loss has not been explored yet.
METHODS
After 8 weeks on western diet, LDL receptor knockout (LDLR-/-) male mice were treated with daily subcutaneous injections of long-acting acylated GIP analog (acyl-GIP; 10nmol/kg body weight) for 28 days. Body weight, food intake, whole-body composition were monitored throughout the study. Fasting blood glucose and intraperitoneal glucose tolerance test (ipGTT) were determined on day 21 of the study. Circulating lipid levels, lipoprotein profiles and atherosclerotic lesion size was assessed at the end of the study. Acyl-GIP effects on fat depots were determined by histology and transcriptomics.
RESULTS
Herein we found that treatment with acyl-GIP reduced dyslipidemia and atherogenesis in male LDLR-/- mice. Acyl-GIP administration resulted in smaller adipocytes within the inguinal fat depot and RNAseq analysis of the latter revealed that acyl-GIP may improve dyslipidemia by directly modulating lipid metabolism in this fat depot.
CONCLUSIONS
This study identified an unanticipated efficacy of chronic GIPR agonism to improve dyslipidemia and cardiovascular disease independently of body weight loss, indicating that treatment with acyl-GIP may be a novel approach to alleviate cardiometabolic disease.
Topics: Male; Animals; Mice; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Atherosclerosis; Dyslipidemias; Body Weight; Weight Loss
PubMed: 37592302
DOI: 10.1186/s12933-023-01940-2 -
The Journal of Antimicrobial... Nov 2023The COVID-19 pandemic saw unprecedented resources and funds driven into research for the development, and subsequent rapid distribution, of vaccines, diagnostics and...
The COVID-19 pandemic saw unprecedented resources and funds driven into research for the development, and subsequent rapid distribution, of vaccines, diagnostics and directly acting antivirals (DAAs). DAAs have undeniably prevented progression and life-threatening conditions in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, there are concerns of antimicrobial resistance (AMR), antiviral resistance specifically, for DAAs. To preserve activity of DAAs for COVID-19 therapy, as well as detect possible mutations conferring resistance, antimicrobial stewardship and surveillance were rapidly implemented in England. This paper expands on the ubiquitous ongoing public health activities carried out in England, including epidemiologic, virologic and genomic surveillance, to support the stewardship of DAAs and assess the deployment, safety, effectiveness and resistance potential of these novel and repurposed therapeutics.
Topics: Humans; COVID-19; SARS-CoV-2; Anti-Bacterial Agents; Pandemics; Antiviral Agents; Drug Resistance, Bacterial; England
PubMed: 37995354
DOI: 10.1093/jac/dkad314 -
Cancers Dec 2023Anticancer peptides are short and structurally heterogeneous aminoacidic chains, which display selective cytotoxicity mostly against tumor cells, but not healthy cells,... (Review)
Review
Anticancer peptides are short and structurally heterogeneous aminoacidic chains, which display selective cytotoxicity mostly against tumor cells, but not healthy cells, based on their different cell surface properties. Their anti-tumoral activity is carried out through interference with intracellular homeostasis, such as plasmalemma integrity, cell cycle control, enzymatic activities and mitochondrial functions, ultimately acting as angiogenesis-, drug resistance- and metastasis-inhibiting agents, immune stimulators, differentiation inducers and necrosis or extrinsic/intrinsic apoptosis promoters. The marine environment features an ever-growing level of biodiversity, and seas and oceans are poorly exploited mines in terms of natural products of biomedical interest. Adaptation processes to extreme and competitive environmental conditions led marine species to produce unique metabolites as a chemical strategy to allow inter-individual signalization and ensure survival against predators, infectious agents or UV radiation. These natural metabolites have found broad use in various applications in healthcare management, due to their anticancer, anti-angiogenic, anti-inflammatory and regeneration abilities. The aim of this review is to pick selected studies that report on the isolation of marine animal-derived peptides and the identification of their anticancer activity in in vitro cultures of cancer cells, and list them with respect to the taxonomical hierarchy of the source organism.
PubMed: 38201464
DOI: 10.3390/cancers16010036