Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 588
Filter
1.
Pharmaceutics ; 16(7)2024 Jul 08.
Article in English | MEDLINE | ID: mdl-39065608

ABSTRACT

In diabetic ulcers, an increased secretion of human neutrophil elastase (HNE) and bacterial infections play crucial roles in hindering healing. Considering that, the present study proposed the development of multi-action polycaprolactone (PCL)/polyethylene glycol (PEG) electrospun fibers incorporating elastase-targeting peptides, AAPV and WAAPV, via blending. Characterization confirmed WAAPV's efficacy in regulating proteolytic enzymes by inhibiting HNE. The engineered fibers, particularly those containing PEG, exhibited optimal wettability but an accelerated degradation that was mitigated with the peptide's inclusion, thus promoting a sustained peptide release over 24 h. Peptide loading was verified indirectly through thermal stability and hydration capacity studies (hydrophobic bonding between PCL and WAAPV and hydrophilic affinities between PCL/PEG and AAPV) and determined at ≈51.1 µg/cm2 and ≈46.0 µg/cm2 for AAPV and ≈48.5 µg/cm2 and ≈51.3 µg/cm2 for WAAPV, respectively, for PCL and PCL/PEG. Both AAPV and WAAPV effectively inhibited HNE, with PEG potentially enhancing this effect by interacting with the peptides and generating detectable peptide-PEG complexes (≈10% inhibition with PCL + peptide fibers after 6 h of incubation, and ≈20% with PCL/PEG + peptide fibers after 4 h incubation). Peptide-loaded fibers demonstrated antibacterial efficacy against Staphylococcus aureus (up to ≈78% inhibition) and Escherichia coli (up to ≈66% inhibition), with peak effectiveness observed after 4 and 2 h of incubation, respectively. This study provides initial insights into the WAAPV's potential for inhibiting HNE and bacteria activities, showing promise for applications in diabetic ulcer management.

2.
Microbes Infect ; : 105400, 2024 Jul 26.
Article in English | MEDLINE | ID: mdl-39069117

ABSTRACT

Infection by SARS-CoV-2 is associated with uncontrolled inflammatory response during COVID-19 severe disease, in which monocytes are one of the main sources of pro-inflammatory mediators leading to acute respiratory distress syndrome. Extracellular vesicles (EVs) from different cells play important roles during SARS-CoV-2 infection, but investigations describing the involvement of EVs from primary human monocyte-derived macrophages (MDM) on the regulation of this infection are not available. Here, we describe the effects of EVs released by MDM stimulated with the neuropeptides VIP and PACAP on SARS-CoV-2-infected monocytes. MDM-derived EVs were isolated by differential centrifugation of medium collected from cells cultured for 24 h in serum-reduced conditions. Based on morphological properties, we distinguished two subpopulations of MDM-EVs, namely large (LEV) and small EVs (SEV). We found that MDM-derived EVs stimulated with the neuropeptides inhibited SARS-CoV-2 RNA synthesis/replication in monocytes, protected these cells from virus-induced cytopathic effects and reduced the production of pro-inflammatory mediators. In addition, EVs derived from VIP- and PACAP-treated MDM prevented the SARS-CoV-2-induced NF-κB activation. Overall, our findings suggest that MDM-EVs are endowed with immunoregulatory properties that might contribute to the antiviral and anti-inflammatory responses in SARS-CoV-2-infected monocytes and expand our knowledge of EV effects during COVID-19 pathogenesis.

3.
Lasers Med Sci ; 39(1): 189, 2024 Jul 23.
Article in English | MEDLINE | ID: mdl-39039318

ABSTRACT

To evaluate the effectiveness of photobiomodulation (PBM) in conjunction with an aerobic exercise program (AEP) on the level of pain and quality of life of women with fibromyalgia (FM). METHODS: A double-blinded randomized controlled trial in which 51 participants with FM were allocated into 4 groups: control group (CG) (n = 12); active PBM group (APG) (n = 12); AEP and placebo PBM group (EPPG) (n = 13); AEP and active PBM group (EAPG) (n = 14). AEP was performed on an ergometric bicycle; and a PBM (with an increase dosage regime) [20 J, 32 J and 40 J] was applied using a cluster device. Both interventions were performed twice a week for 12 weeks. A mixed generalized model analysis was performed, evaluating the time (initial and final) and group (EAPG, EPPG, APG and CG) interaction. All analyses were based on intent-to-treat for a significance level of p ≤ 0.05. RESULTS: The intra-group analysis demonstrated that all treated groups presented a significant improvement in the level of pain and quality of life comparing the initial and final evaluation (p < 0.05). Values for SF-36 and 6-minute walk test increased significant in intragroup analysis for EPPG comparing the initial and final evaluation. No intergroup differences were observed. CONCLUSIONS: Both exercised and PBM irradiated volunteers present improvements in the variables analyzed. However, further studies should be performed, with other PBM parameters to determine the best regime of irradiation to optimize the positive effects of physical exercises in FM patients.


Subject(s)
Exercise , Fibromyalgia , Low-Level Light Therapy , Quality of Life , Humans , Female , Fibromyalgia/radiotherapy , Fibromyalgia/therapy , Fibromyalgia/psychology , Fibromyalgia/physiopathology , Low-Level Light Therapy/methods , Double-Blind Method , Adult , Middle Aged , Exercise/physiology , Exercise Therapy/methods , Pain Measurement , Treatment Outcome , Pain/radiotherapy , Pain/etiology
4.
Ann Bot ; 2024 Jun 02.
Article in English | MEDLINE | ID: mdl-38824400

ABSTRACT

BACKGROUND AND AIMS: Pleistocene climatic oscillations, characterized by arid (interglacial) and pluvial (glacial) phases, have profoundly impacted the floras of Mediterranean climates. Our study investigates the hypothesis that these climatic extremes have promoted phases of range expansion and contraction in the Eriosyce sect. Neoporteria, resulting in pronounced genetic structuring and restricted gene flow. METHODS: Utilizing nuclear microsatellite markers, we genotyped 251 individuals across 18 populations, encompassing all 14 species and one subspecies within the Eriosyce sect. Neoporteria. Additionally, Species Distribution Models (SDMs) were employed to reconstruct past (Last Interglacial, Last Glacial Maximum, Mid-Holocene) and current potential distribution patterns, aiming to delineate the climatic influences on species' range dynamics. KEY RESULTS: The gene flow analysis disclosed disparate levels of genetic interchange among species, with marked restrictions observed between entities that are geographically or ecologically separated. Notably, E. subgibbosa from Hualpen emerged as genetically distinct, warranting its exclusion for clearer genetic clustering into north, central, and south clusters. The SDMs corroborated these findings, showing marked range expansions during warmer periods and contractions during colder times, indicating significant shifts in distribution patterns in response to climatic changes. CONCLUSIONS: Our findings emphasize the critical role of Pleistocene climatic fluctuations in driving the dynamic patterns of range expansions and contractions that have led to geographic isolation and speciation within the Eriosyce sect. Neoporteria. Even in the face of ongoing gene flow, these climate-driven processes have played a pivotal role in sculpting the species' genetic architecture and diversity. This study elucidates the complex interplay between climatic variability and evolutionary dynamics among Mediterranean cacti in central Chile, highlighting the necessity of considering historical climatic millenial oscillations in conservation and evolutionary biology studies.

5.
Proc Natl Acad Sci U S A ; 121(22): e2314166121, 2024 May 28.
Article in English | MEDLINE | ID: mdl-38768348

ABSTRACT

The nonstructural protein 1 (Nsp1) of SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) is a virulence factor that targets multiple cellular pathways to inhibit host gene expression and antiviral response. However, the underlying mechanisms of the various Nsp1-mediated functions and their contributions to SARS-CoV-2 virulence remain unclear. Among the targets of Nsp1 is the mRNA (messenger ribonucleic acid) export receptor NXF1-NXT1, which mediates nuclear export of mRNAs from the nucleus to the cytoplasm. Based on Nsp1 crystal structure, we generated mutants on Nsp1 surfaces and identified an acidic N-terminal patch that is critical for interaction with NXF1-NXT1. Photoactivatable Nsp1 probe reveals the RNA Recognition Motif (RRM) domain of NXF1 as an Nsp1 N-terminal binding site. By mutating the Nsp1 N-terminal acidic patch, we identified a separation-of-function mutant of Nsp1 that retains its translation inhibitory function but substantially loses its interaction with NXF1 and reverts Nsp1-mediated mRNA export inhibition. We then generated a recombinant (r)SARS-CoV-2 mutant on the Nsp1 N-terminal acidic patch and found that this surface is key to promote NXF1 binding and inhibition of host mRNA nuclear export, viral replication, and pathogenicity in vivo. Thus, these findings provide a mechanistic understanding of Nsp1-mediated mRNA export inhibition and establish the importance of this pathway in the virulence of SARS-CoV-2.


Subject(s)
Active Transport, Cell Nucleus , COVID-19 , Nucleocytoplasmic Transport Proteins , RNA, Messenger , RNA-Binding Proteins , SARS-CoV-2 , Viral Nonstructural Proteins , Humans , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , SARS-CoV-2/genetics , Viral Nonstructural Proteins/metabolism , Viral Nonstructural Proteins/genetics , Viral Nonstructural Proteins/chemistry , RNA, Messenger/genetics , RNA, Messenger/metabolism , Nucleocytoplasmic Transport Proteins/metabolism , Nucleocytoplasmic Transport Proteins/genetics , Animals , COVID-19/virology , COVID-19/metabolism , RNA-Binding Proteins/metabolism , RNA-Binding Proteins/genetics , Virus Replication , Cell Nucleus/metabolism , Vero Cells , Virulence , Chlorocebus aethiops , HEK293 Cells
6.
Eur J Cell Biol ; 103(2): 151419, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38763048

ABSTRACT

Nuclear receptor Nur77 plays a pivotal role in immune regulation across various tissues, influencing pro-inflammatory signaling pathways and cellular metabolism. While cellular mechanics have been implicated in inflammation, the contribution of Nur77 to these mechanical processes remains elusive. Macrophages exhibit remarkable plasticity in their morphology and mechanics, enabling them to adapt and execute essential inflammatory functions, such as navigating through inflamed tissue and pathogen engulfment. However, the precise regulatory mechanisms governing these dynamic changes in macrophage mechanics during inflammation remain poorly understood. To establish the potential correlation of Nur77 with cellular mechanics, we compared bone marrow-derived macrophages (BMDMs) from wild-type (WT) and Nur77-deficient (Nur77-KO) mice and employed cytoskeletal imaging, single-cell acoustic force spectroscopy (AFS), migration and phagocytosis assays, and RNA-sequencing. Our findings reveal that Nur77-KO BMDMs exhibit changes to their actin networks compared to WT BMDMs, which is associated with a stiffer and more rigid phenotype. Subsequent in vitro experiments validated our observations, showcasing that Nur77 deficiency leads to enhanced migration, reduced adhesion, and increased phagocytic activity. The transcriptomics data confirmed altered mechanics-related pathways in Nur77-deficient macrophage that are accompanied by a robust pro-inflammatory phenotype. Utilizing previously obtained ChIP-data, we revealed that Nur77 directly targets differentially expressed genes associated with cellular mechanics. In conclusion, while Nur77 is recognized for its role in reducing inflammation of macrophages by inhibiting the expression of pro-inflammatory genes, our study identifies a novel regulatory mechanism where Nur77 governs macrophage inflammation through the modulation of expression of genes involved in cellular mechanics. Our findings suggest that immune regulation by Nur77 may be partially mediated through alterations in cellular mechanics, highlighting a potential avenue for therapeutic targeting.


Subject(s)
Macrophages , Mice, Knockout , Nuclear Receptor Subfamily 4, Group A, Member 1 , Nuclear Receptor Subfamily 4, Group A, Member 1/metabolism , Nuclear Receptor Subfamily 4, Group A, Member 1/genetics , Animals , Macrophages/metabolism , Macrophages/immunology , Mice , Mice, Inbred C57BL , Phagocytosis , Cell Movement , Inflammation/metabolism
7.
Clin Nutr ESPEN ; 61: 8-14, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38777477

ABSTRACT

BACKGROUND & AIMS: Low-grade systemic inflammation (LGSI) is critical to developing many chronic diseases. In turn, it has been shown that the diet can modulate favorably or unfavorably the inflammatory status. Thus, evaluating the diet from appropriate approaches is fundamental; to do so, there are different proposals for dietary indexes. We aimed to: (i) investigate the association between three well-known dietary indexes and LGSI biomarkers; (ii) test these associations individually or in combination with an indicator of ultra-processed foods (UFPs) intake. (iii) as an additional aim, hypothesizing that all the indexes should be capable of identifying the inflammatory potential of diet, we tested the hypothesis that these indexes agree and correlate with each other. METHODS: Cross-sectional population-based data of adults and older persons (n = 583). Dietary data were obtained through two non-consecutive 24-h dietary recalls (24HDR) and calculated for Dietary Inflammatory Index (DII), Mediterranean-Style Dietary Pattern Score (MSDPS); Brazilian Healthy Eating Index - Revised (BHEI-R) and energy ingested from UPFs (UPFs ratio). An LGSI score was created from some plasma inflammatory biomarkers [C-Reactive Protein (CRP), tumor necrosis factor-alpha (TNF-α), and adiponectin]. Logistic and linear regression models tested the associations between dietary indexes and LGSI score. RESULTS: The MSDPS and DII were significantly associated with our inflammatory score, but the BHEI-R did not. Including UPFs in regression models did not increase the strength of these associations. CONCLUSIONS: From the three scores, the dietary inflammatory index and the Mediterranean-style dietary pattern score (MSDPS) were the ones that showed significant association with the inflammatory biomarker. The combination of the indexes with a ratio of UPF intake did not increase the significance of our analyses. The best agreement between the indexes was found between MSDPS and UPFs ratio; the only pair of indexes considered concordant and correlated was the BHEI-R and DII.


Subject(s)
Biomarkers , C-Reactive Protein , Inflammation , Humans , Inflammation/blood , Cross-Sectional Studies , Male , Female , Biomarkers/blood , Middle Aged , Aged , C-Reactive Protein/metabolism , Adult , Diet , Diet, Mediterranean , Brazil , Tumor Necrosis Factor-alpha/blood , Fast Foods/adverse effects , Energy Intake , Diet, Healthy , Adiponectin/blood , Food, Processed
8.
Yale J Biol Med ; 97(1): 49-65, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38559460

ABSTRACT

Objective: to evaluate the effect of prenatal care (PC) on perinatal outcomes of pregnant women with diabetes mellitus (DM). Methods: systematic review developed according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 guidelines and conducted through the population, intervention, control, and outcomes (PICO) strategy. Clinical trials and observational studies were selected, with adult pregnant women, single-fetus pregnancy, diagnosis of DM, or gestational DM and who had received PC and/or nutritional therapy (NT). The search was carried out in PubMed, Scopus, and BIREME databases. The quality of the studies was evaluated using the tools of the National Heart, Lung and Blood Institute-National Institutes of Health (NHLBI-NIH). Results: We identified 5972 records, of which 15 (n=47 420 pregnant women) met the eligibility criteria. The most recurrent outcomes were glycemic control (14 studies; n=9096 participants), hypertensive disorders of pregnancy (2; n=39 282), prematurity (6; n=40 163), large for gestational age newborns (4; n=1556), fetal macrosomia (birth weight >4kg) (6; n=2980) and intensive care unit admission (4; n=2022). Conclusions: The findings suggest that PC interferes with the perinatal outcome, being able to reduce the risks of complications associated with this comorbidity through early intervention, especially when the NT is an integral part of this assistance.


Subject(s)
Pregnancy Outcome , Prenatal Care , Humans , Pregnancy , Female , Prenatal Care/methods , Pregnancy Outcome/epidemiology , Diabetes, Gestational/epidemiology , Pregnancy in Diabetics/epidemiology , Pregnancy in Diabetics/therapy , Infant, Newborn , Adult
9.
BMC Res Notes ; 17(1): 121, 2024 Apr 29.
Article in English | MEDLINE | ID: mdl-38679724

ABSTRACT

Cri Du Chat syndrome, or 5p- syndrome, is characterized by a terminal or interstitial deletion on the short arm of chromosome 5 that causes variable clinical manifestations, including high-pitched cry in newborns, delayed growth, and global development. Different cytogenomic rearrangements, family history, and environmental factors may hinder the genotype-phenotype association. Thus, the phenotypic variability of this syndrome may not be limited only to variations in gene structure, such as deletions and duplications. It is possible that other mechanisms related to the activation or inactivation of promoters and/or exons of actively transcribed genes, such as DNA methylation are involved. Therefore, we studied the genome-wide methylation status profile of peripheral blood samples from fifteen patients with Cri du Chat Syndrome and nine control samples through the array method to look for Differentially Methylated Regions. We found that Differentially Methylated Regions outside the 5p region are mainly associated with regulating gene transcription, splicing, and chromatin remodeling. Most biological pathways are related to transcription, histone and chromatin binding, spliceosome and ribosomal complex, and RNA processing. Our results suggest that changes in the 5p region can cause an imbalance in other chromosomal regions capable of affecting gene modulation and thus explain the phenotypic differences in patients with 5p-.


Subject(s)
Cri-du-Chat Syndrome , DNA Methylation , Phenotype , Humans , DNA Methylation/genetics , Female , Cri-du-Chat Syndrome/genetics , Male , Chromosomes, Human, Pair 5/genetics , Child, Preschool , Infant , Child
10.
Health Res Policy Syst ; 22(1): 46, 2024 Apr 11.
Article in English | MEDLINE | ID: mdl-38605301

ABSTRACT

BACKGROUND: Mexico and other low- and middle-income countries (LMICs) present a growing burden of non-communicable diseases (NCDs), with gender-differentiated risk factors and access to prevention, diagnosis and care. However, the political agenda in LMICs as it relates to health and gender is primarily focused on sexual and reproductive health rights and preventing violence against women. This research article analyses public policies related to gender and NCDs, identifying political challenges in the current response to women's health needs, and opportunities to promote interventions that recognize the role of gender in NCDs and NCD care in Mexico. METHODS: We carried out a political mapping and stakeholder analysis during July-October of 2022, based on structured desk research and interviews with eighteen key stakeholders related to healthcare, gender and NCDs in Mexico. We used the PolicyMaker V5 software to identify obstacles and opportunities to promote interventions that recognize the role of gender in NCDs and NCD care, from the perspective of the political stakeholders interviewed. RESULTS: We found as a political obstacle that policies and stakeholders addressing NCDs do not take a gender perspective, while policies and stakeholders addressing gender equality do not adequately consider NCDs. The gendered social and economic aspects of the NCD burden are not widely understood, and the multi-sectoral approach needed to address these aspects is lacking. Economic obstacles show that budget cuts exacerbated by the pandemic are a significant obstacle to social protection mechanisms to support those caring for people living with NCDs. CONCLUSIONS: Moving towards an effective, equity-promoting health and social protection system requires the government to adopt an intersectoral, gender-based approach to the prevention and control of NCDs and the burden of NCD care. Despite significant resource constraints, policy innovation may be possible given the willingness among some stakeholders to collaborate, particularly in the labour and legal sectors. However, care will be needed to ensure the implementation of new policies has a positive impact on both gender equity and health outcomes. Research on successful approaches in other contexts can help to identify relevant learnings for Mexico.


Subject(s)
Health Policy , Noncommunicable Diseases , Humans , Female , Noncommunicable Diseases/epidemiology , Noncommunicable Diseases/prevention & control , Mexico , Health Services Accessibility , Human Rights
11.
Epilepsy Behav ; 154: 109706, 2024 May.
Article in English | MEDLINE | ID: mdl-38518671

ABSTRACT

Non-human primates (NHPs) have played a crucial role in our understanding of epilepsy, given their striking similarities with humans. Through their use, we have gained a deeper understanding of the neurophysiology and pathophysiology of epileptic seizures, and they have proven invaluable allies in developing anti-seizure therapies. This review explores the history of NHPs as natural models of epilepsy, discusses the findings obtained after exposure to various chemoconvulsant drugs and focal electrical stimulation protocols that helped uncover important mechanisms related to epilepsy, examines diverse treatments to prevent and manage epilepsy, and addresses essential ethical issues in research. In this review, we aim to emphasize the important role of NHPs in epilepsy research and summarize the benefits and challenges associated with their use as models.


Subject(s)
Epilepsy , Primates , Animals , Humans , Disease Models, Animal , Epilepsy/physiopathology
12.
Mol Biol Cell ; 35(5): ar62, 2024 May 01.
Article in English | MEDLINE | ID: mdl-38507240

ABSTRACT

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) accessory protein Orf6 works as an interferon antagonist, in part, by inhibiting the nuclear import activated p-STAT1, an activator of interferon-stimulated genes, and the export of the poly(A) RNA. Insight into the transport regulatory function of Orf6 has come from the observation that Orf6 binds to the nuclear pore complex (NPC) components: Rae1 and Nup98. To gain further insight into the mechanism of Orf6-mediated transport inhibition, we examined the role of Rae1 and Nup98. We show that Rae1 alone is not necessary to support p-STAT1 import or nuclear export of poly(A) RNA. Moreover, the loss of Rae1 suppresses the transport inhibitory activity of Orf6. We propose that the Rae1/Nup98 complex strategically positions Orf6 within the NPC where it alters FG-Nup interactions and their ability to support nuclear transport. In addition, we show that Rae1 is required for normal viral protein production during SARS-CoV-2 infection presumably through its role in supporting Orf6 function.


Subject(s)
Active Transport, Cell Nucleus , COVID-19 , Nuclear Pore , Nucleocytoplasmic Transport Proteins , SARS-CoV-2 , Humans , COVID-19/metabolism , Interferons/metabolism , Nuclear Pore/metabolism , Nuclear Pore Complex Proteins/metabolism , Nucleocytoplasmic Transport Proteins/metabolism , RNA, Messenger/metabolism , SARS-CoV-2/metabolism , Viral Proteins/metabolism , Nuclear Matrix-Associated Proteins/metabolism
13.
Polymers (Basel) ; 16(5)2024 Feb 22.
Article in English | MEDLINE | ID: mdl-38475286

ABSTRACT

With the increasing demand for lighter, more environmentally friendly, and affordable solutions in the mobility sector, designers and engineers are actively promoting the use of innovative integral dissimilar structures. In this field, friction stir-based technologies offer unique advantages compared with conventional joining technologies, such as mechanical fastening and adhesive bonding, which recently demonstrated promising results. In this study, an aluminum alloy and a glass fiber-reinforced polymer were friction stir joined in an overlap configuration. To assess the main effects, interactions, and influence of processing parameters on the mechanical strength and processing temperature of the fabricated joints, a full factorial design study with three factors and two levels was carried out. The design of experiments resulted in statistical models with excellent fit to the experimental data, enabling a thorough understanding of the influence of rotational speed, travel speed, and tool tilt angle on dissimilar metal-to-polymer friction stir composite joints. The mechanical strength of the composite joints ranged from 1708.1 ± 45.5 N to 3414.2 ± 317.1, while the processing temperature was between 203.6 ± 10.7 °C and 251.5 ± 9.7.

14.
Zootaxa ; 5415(4): 543-551, 2024 Feb 23.
Article in English | MEDLINE | ID: mdl-38480184

ABSTRACT

Two new species of the South American genus Kinrentius are described and illustrated. Kinrentius catuaba sp. nov. from Brazil (Acre, Amazonas and Rondnia states) can be distinguished by the male pygofer with multidentate anteroventral and posteroventral processes with short dentiform processes between them and aedeagus with dorsal projection forming a distinct process and apex with paired apical processes, each subrectangular, with apical margin irregularly serrated in caudal view. Kinrentius peruvianus sp. nov. from Peru (Cusco and Madre de Dios departments) has short male pygofer posteroventral processes and aedeagus more robust and parallel sided in dorsal view, with paired apical processes, each subquadrate, with apical portion weekly sclerotized, and apical margin approximately straight and slightly serrate in caudal view. A taxonomic key to males and a distribution map of all four species of the genus are provided.


Subject(s)
Hemiptera , Male , Animals
15.
Neurotox Res ; 42(1): 14, 2024 Feb 13.
Article in English | MEDLINE | ID: mdl-38349488

ABSTRACT

Recent studies have demonstrated that cannabinoids are potentially effective in the treatment of various neurological conditions, and cannabidiol (CBD), one of the most studied compounds, has been proposed as a non-toxic option. However, the adverse effects of CBD on neurodevelopmental processes have rarely been studied in cell culture systems. To better understand CBD's influence on neurodevelopment, we exposed neural progenitor cells (NPCs) to different concentrations of CBD (1 µM, 5 µM, and 10 µM). We assessed the morphology, migration, differentiation, cell death, and gene expression in 2D and 3D bioprinted models to stimulate physiological conditions more effectively. Our results showed that CBD was more toxic at higher concentrations (5 µM and 10 µM) and affected the viability of NPCs than at lower concentrations (1 µM), in both 2D and 3D models. Moreover, our study revealed that higher concentrations of CBD drastically reduced the size of neurospheres and the number of NPCs within neurospheres, impaired the morphology and mobility of neurons and astrocytes after differentiation, and reduced neurite sprouting. Interestingly, we also found that CBD alters cellular metabolism by influencing the expression of glycolytic and ß-oxidative enzymes in the early and late stages of metabolic pathways. Therefore, our study demonstrated that higher concentrations of CBD promote important changes in cellular functions that are crucial during CNS development.


Subject(s)
Cannabidiol , Neurotoxicity Syndromes , Humans , Cannabidiol/toxicity , Neurons , Astrocytes , Carbidopa
16.
Clin Cancer Res ; 30(10): 2017-2024, 2024 May 15.
Article in English | MEDLINE | ID: mdl-38266167

ABSTRACT

In this commentary, we advance the notion that mutant KRAS (mKRAS) is an ideal tumor neoantigen that is amenable for targeting by the adaptive immune system. Recent progress highlights key advances on various fronts that validate mKRAS as a molecular target and support further pursuit as an immunological target. Because mKRAS is an intracellular membrane localized protein and not normally expressed on the cell surface, we surmise that proteasome degradation will generate short peptides that bind to HLA class I (HLA-I) molecules in the endoplasmic reticulum for transport through the Golgi for display on the cell surface. T-cell receptors (TCR)αß and antibodies have been isolated that specifically recognize mKRAS encoded epitope(s) or haptenated-mKRAS peptides in the context of HLA-I on tumor cells. Case reports using adoptive T-cell therapy provide proof of principle that KRAS G12D can be successfully targeted by the immune system in patients with cancer. Among the challenges facing investigators is the requirement of precision medicine to identify and match patients to available mKRAS peptide/HLA therapeutics and to increase the population coverage by targeting additional mKRAS epitopes. Ultimately, we envision mKRAS-directed immunotherapy as an effective treatment option for selected patients that will complement and perhaps synergize with small-molecule mKRAS inhibitors and targeted mKRAS degraders.


Subject(s)
Antigens, Neoplasm , Immunotherapy , Mutation , Neoplasms , Proto-Oncogene Proteins p21(ras) , Humans , Proto-Oncogene Proteins p21(ras)/genetics , Proto-Oncogene Proteins p21(ras)/immunology , Neoplasms/therapy , Neoplasms/immunology , Neoplasms/genetics , Immunotherapy/methods , Antigens, Neoplasm/immunology , Antigens, Neoplasm/genetics , Molecular Targeted Therapy
17.
Int J Ophthalmol ; 17(1): 144-156, 2024.
Article in English | MEDLINE | ID: mdl-38239949

ABSTRACT

AIM: To provide a comprehensive and more representative national data on the disease, especially on treatment options and outcomes, and to determine access of retinoblastoma patients from Luzon, Visayas and Mindanao to eye care, and determine if access is associated with delay in consultation, staging and outcomes. METHODS: Cohort study of retinoblastoma patients seen in eleven institutions located in the three major areas of the Philippines namely Luzon, Vizayas and Mindanao from 2010-2020. RESULTS: Totally 636 patients, involving 821 eyes, were included. Majority (57%) were from Luzon and were seen in institutions in Luzon (72%). Annually, 58±10 new cases were seen with 71% having unilateral disease. Median delay of consultation remained long at 9 (3, 17)mo, longest in patients with unilateral disease (P<0.02) and those from the Visayas (P<0.003). Based on the International Retinoblastoma Staging System, only 35% of patients had Stage 1 while 47% already had extraocular disease. Enucleation was the most common treatment received by 484 patients while intravenous chemotherapy was received by 469. There were 250 (39%) patients alive, 195 (31%) dead, 85 (13%) abandoned, 17 (3%) refused and 89 (14%) with no data. CONCLUSION: This study presents the largest cohort of retinoblastoma patients in the Philippines in terms of patients' and participating institutions' number and geographical location and type of institution (private and public). It also presents more comprehensive data on the treatments used and outcomes (survival, globe salvage, and vision retention rates). Delay in consultation was still long among patients leading to advanced disease stage and lower survival rate. Despite increasing capacity to diagnose and manage retinoblastoma in the country, the delay of consultation remains long primarily due to accessibility issues to eye care institutions especially in the Visayas and financial concerns. The delay was still significant that overall survival rate remain low.

18.
PhytoKeys ; 237: 117-139, 2024.
Article in English | MEDLINE | ID: mdl-38292077

ABSTRACT

Chile's distinctive flora, geographical isolation, and complex topography collectively contribute to a notable endemic species diversity, particularly within central regions identified as critical areas for biodiversity conservation. The cactus genus Eriosyce, as currently circumscribed, encompasses seven sections, with Eriosycesect.Horridocatus presenting a notably complex species group. This study investigates the E.curvispina complex, a member of the Notocacteae tribe common in central Chile, by incorporating new populations and examining phylogenetic relationships using four plastid and one nuclear molecular marker. The phylogenetic analysis of sampled individuals identified nine independent lineages, each warranting recognition at the species rank. Despite minimal morphological differences among taxa, morphological characters were utilized to support and stabilize the DNA-based phylogenetic hypothesis. The results highlight the high taxonomic diversity in these cactus lineages and have implications for the classification of the E.curvispina complex, including new combinations and proposals of conservation status.


ResumenLa flora distintiva de Chile, su aislamiento geográfico y topografía compleja contribuyen colectivamente a una notable diversidad de especies endémicas, particularmente dentro de las regiones centrales identificadas como áreas críticas para la conservación de la biodiversidad. El género de cactus Eriosyce, tal como está circunscrito actualmente, abarca siete secciones, presentando Eriosycesect.Horridocatus un grupo de especies notablemente complejo. Este estudio investiga el complejo E.curvispina, un miembro de la tribu Notocacteae común en Chile central, incorporando nuevas poblaciones y examinando las relaciones filogenéticas utilizando cuatro marcadores moleculares del cloroplasto y uno nuclear. El análisis filogenético de las poblaciones muestreadas identificó nueve linajes independientes, cada uno mereciendo reconocimiento a nivel de especie. A pesar de las mínimas diferencias morfológicas entre los taxones, se utilizaron caracteres morfológicos para apoyar y estabilizar la filogenia basada en ADN. Los resultados resaltan la alta diversidad taxonómica en estos linajes de cactus y tienen implicaciones para la clasificación del complejo E.curvispina, incluyendo nuevas combinaciones y propuestas de estado de conservación.

19.
Environ Toxicol Chem ; 43(2): 374-384, 2024 Feb.
Article in English | MEDLINE | ID: mdl-37933775

ABSTRACT

Cigarette butts (CBs) are the most common type of beach litter worldwide and contain a complex mixture of chemicals. Given the recent interest in this emerging problem, it is important to assess the toxicity of CB leachates to a range of species from different regions, sensitivities, and ecological traits. We evaluated the waterborne toxicity of smoked CB to tropical invertebrates. Leachates were prepared in the laboratory and characterized for trace elements (Mn, Fe, Co, Ni, Cu, Zn, As, Cd, and Pb), ammonia nitrogen, and polycyclic aromatic hydrocarbons. Then a set of toxicity tests with marine invertebrates was performed as follows: the brine shrimp Artemia sp. (nontoxic); the amphipod Tiburonella viscana (median lethal concentration [LC50] of 0.038 CB/L); the tanaid Monokalliapseudes schubarti (LC50 of 0.126 CB/L); the copepods Tisbe biminiensis (median effect concentration [EC50] of 0.038 CB/L) and Nitokra sp. (EC50 of 0.009 CB/L); pluteus stage larvae of the sea urchin Echinometra lucunter (EC50 of 0.152 CB/L); the sand dollar Mellita quinquiesperforata (EC50 of 0.054 CB/L); and D-stage larvae of the mussel Perna perna (EC50 of 0.005 CB/L). The predicted no-effect concentration was estimated using species sensitivity distribution, producing a 5th percentile hazard concentration of 0.015 CB/L. This preliminary threshold allowed us to estimate the potential impact of a single CB to 67 L of seawater via leaching, contributing to the advancement of knowledge regarding the contamination, toxicity, and ecological risks of cigarette waste. Environ Toxicol Chem 2024;43:374-384. © 2023 SETAC.


Subject(s)
Invertebrates , Tobacco Products , Animals , Tobacco Products/toxicity , Aquatic Organisms , Toxicity Tests , Larva
20.
Small ; 20(19): e2307045, 2024 May.
Article in English | MEDLINE | ID: mdl-38100142

ABSTRACT

Since WHO has declared the COVID-19 outbreak a global pandemic, nearly seven million deaths have been reported. This efficient spread of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is facilitated by the ability of the spike glycoprotein to bind multiple cell membrane receptors. Although ACE2 is identified as the main receptor for SARS-CoV-2, other receptors could play a role in viral entry. Among others, C-type lectins such as DC-SIGN are identified as efficient trans-receptor for SARS-CoV-2 infection, so the use of glycomimetics to inhibit the infection through the DC-SIGN blockade is an encouraging approach. In this regard, multivalent nanostructures based on glycosylated [60]fullerenes linked to a central porphyrin scaffold have been designed and tested against DC-SIGN-mediated SARS-CoV-2 infection. First results show an outstanding inhibition of the trans-infection up to 90%. In addition, a deeper understanding of nanostructure-receptor binding is achieved through microscopy techniques, high-resolution NMR experiments, Quartz Crystal Microbalance experiments, and molecular dynamic simulations.


Subject(s)
Cell Adhesion Molecules , Fullerenes , Lectins, C-Type , Porphyrins , Receptors, Cell Surface , SARS-CoV-2 , Humans , Cell Adhesion Molecules/metabolism , Cell Adhesion Molecules/antagonists & inhibitors , COVID-19/virology , COVID-19 Drug Treatment , Fullerenes/chemistry , Fullerenes/pharmacology , Lectins, C-Type/metabolism , Lectins, C-Type/antagonists & inhibitors , Molecular Dynamics Simulation , Porphyrins/chemistry , Porphyrins/pharmacology , Protein Binding , Receptors, Cell Surface/metabolism , Receptors, Cell Surface/antagonists & inhibitors , SARS-CoV-2/drug effects , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Spike Glycoprotein, Coronavirus/chemistry
SELECTION OF CITATIONS
SEARCH DETAIL