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2.
Nat Commun ; 15(1): 7761, 2024 Sep 05.
Article de Anglais | MEDLINE | ID: mdl-39237523

RÉSUMÉ

Structure-based virtual screening is a key tool in early drug discovery, with growing interest in the screening of multi-billion chemical compound libraries. However, the success of virtual screening crucially depends on the accuracy of the binding pose and binding affinity predicted by computational docking. Here we develop a highly accurate structure-based virtual screen method, RosettaVS, for predicting docking poses and binding affinities. Our approach outperforms other state-of-the-art methods on a wide range of benchmarks, partially due to our ability to model receptor flexibility. We incorporate this into a new open-source artificial intelligence accelerated virtual screening platform for drug discovery. Using this platform, we screen multi-billion compound libraries against two unrelated targets, a ubiquitin ligase target KLHDC2 and the human voltage-gated sodium channel NaV1.7. For both targets, we discover hit compounds, including seven hits (14% hit rate) to KLHDC2 and four hits (44% hit rate) to NaV1.7, all with single digit micromolar binding affinities. Screening in both cases is completed in less than seven days. Finally, a high resolution X-ray crystallographic structure validates the predicted docking pose for the KLHDC2 ligand complex, demonstrating the effectiveness of our method in lead discovery.


Sujet(s)
Intelligence artificielle , Découverte de médicament , Simulation de docking moléculaire , Découverte de médicament/méthodes , Humains , Canal sodique voltage-dépendant NAV1.7/métabolisme , Canal sodique voltage-dépendant NAV1.7/composition chimique , Liaison aux protéines , Cristallographie aux rayons X , Ligands , Ubiquitin-protein ligases/métabolisme , Ubiquitin-protein ligases/composition chimique , Bibliothèques de petites molécules/composition chimique , Bibliothèques de petites molécules/pharmacologie , Évaluation préclinique de médicament/méthodes
3.
Chem Biodivers ; : e202401224, 2024 Aug 16.
Article de Anglais | MEDLINE | ID: mdl-39149874

RÉSUMÉ

Piper longum L.(PL)  is considered one of the most important species traditionally used for treating various ailments and has indicated the presence of alkaloids, flavonoids, and steroids. In this study, we isolated the chemical compounds of PLleaves,andmeasuredNO, IL-6, iNOS, as well as COX-2 protein levels. In addition, molecular docking analysis were used to further understand anti-inflammation effect of the compounds. We identified one new alkaloid named piperlongumine A (1) with ten known compounds (2-11). The new compound (1) and two other alkaloids 2E)-3-(4-hydroxy-3-methoxyphenyl)-1-(pyrrol-1-yl)propanone (7) and piperchabamide A (8) significantlyreduced NO production in LPS-stimulated RAW 264.7 cells with the IC50 values of 0.97 ± 0.05 mM, 0.91 ± 0.07mM, 1.63 ± 0.14 mM, respectively. Moreover, at concentration of 2 mM, compound 1 inhibited approximately 98 ± 0.64 % of IL-6 secretion, and decreased  iNOS and COX-2 protein level by about 96 and 19 folds compared to LPS treatment alone, respectively. Furthermore, compounds 1, 7, and 8 were predicted to bind and inhibit IL-6, TNF-a, and iNOS, with compound 1 showing the highest binding energy of -7.09 kcal/mol. This study provides new insights for potential anti-inflammatory drug design and warrants further investigation.

4.
Nanophotonics ; 13(18): 3503-3518, 2024 Aug.
Article de Anglais | MEDLINE | ID: mdl-39185487

RÉSUMÉ

Bound states in the continuum have recently been utilized in photonic crystal gratings to achieve strong coupling and ultralow threshold condensation of exciton-polariton quasiparticles with atypical Dirac-like features in their dispersion relation. Here, we develop the single- and many-body theory of these new effective relativistic polaritonic modes and describe their mean-field condensation dynamics facilitated by the interplay between protection from the radiative continuum and negative-mass optical trapping. Our theory accounts for tunable grating parameters giving full control over the diffractive coupling properties between guided polaritons and the radiative continuum, unexplored for polariton condensates. In particular, we discover stable cyclical condensate solutions mimicking a driven-dissipative analog of the zitterbewegung effect characterized by coherent superposition of ballistic and trapped polariton waves. We clarify important distinctions between the polariton nearfield and farfield explaining recent experiments on the emission characteristics of these long lived nonlinear Dirac polaritons.

5.
J Genet Eng Biotechnol ; 22(3): 100404, 2024 Sep.
Article de Anglais | MEDLINE | ID: mdl-39179321

RÉSUMÉ

BACKGROUND: Supplementing probiotics in livestock feed is increasing due to concerns over the potential harm caused by antibiotics and other chemical growth promoters. Several Bacillus sp. have been used as probiotic supplements for livestock. In this study, Bacillus amyloliquefaciens S2.5 was isolated from freshwater and its potential probiotic characteristics were evaluated in vitro. The whole genome of strain S2.5 was sequenced, and its probiotic traits were annotated using bioinformatic tools. RESULTS: Both vegetative cells and spores of strain S2.5 remained stable throughout the 1.5 h of gastric juice and 48 h of intestine simulation. The strain S2.5 harbored the ability to produce glucoamylase, carboxymethyl cellulase, protease, and chitinase. It is also susceptible to all six tested antibiotics. The complete genome sequence shows genes related to acid-bile tolerance, environmental stress resistance, hydrolases, and adhesion to gut mucosa, confirming probiotic traits in the in vitro experiments. CONCLUSIONS: B. amyloliquefaciens S2.5 demonstrated potential probiotic characteristics and its genetic profile in the in vitro experiments. Further in vivo assessments of B. amyloliquefaciens S2.5 on livestock and poultry should be performed to assess its practical application.

6.
Theriogenology ; 228: 30-36, 2024 Oct 15.
Article de Anglais | MEDLINE | ID: mdl-39089072

RÉSUMÉ

Objectives of the current study were to examine the effects of exogenous expression of PGC-1α, which is a transcription factor responsive for controlling mitochondrial DNA (mtDNA) replication, mitochondria quantity control, mitochondrial biogenesis, and reactive oxygen species (ROS) maintenance, in porcine oocytes during in-vitro maturation (IVM) on the developmental competence, as well as mitochondrial quantity and function. Exogenous over-expression of PGC-1α by injection of the mRNA construct into oocytes 20 h after the start of IVM culture significantly increased the copy number of mtDNA in the oocytes, but reduced the incidences of oocytes matured to the metaphase-II stage after the IVM culture for totally 44 h and completely suppressed the early development in vitro to the blastocyst stage following parthenogenetic activation. The exogenous expression of PGC-1α also significantly induced spindle defects and chromosome misalignments. Furthermore, markedly higher ROS levels were observed in the PGC-1α-overexpressed mature oocytes, whereas mRNA level of SOD1, encoded for a ROS scavenging enzyme, was decreased. These results conclude that forced expression of PGC-1α successfully increase mtDNA copy number but led to increased ROS production, evidently by downregulation of SOD1 gene expression, inducement of spindle aberration/chromosomal misalignment, and consequently reduction in the meiotic and developmental competences of porcine oocytes.


Sujet(s)
Techniques de maturation in vitro des ovocytes , Ovocytes , Coactivateur 1-alpha du récepteur gamma activé par les proliférateurs de peroxysomes , Animaux , Femelle , ADN mitochondrial/génétique , ADN mitochondrial/métabolisme , Développement embryonnaire , Régulation de l'expression des gènes au cours du développement , Techniques de maturation in vitro des ovocytes/médecine vétérinaire , Ovocytes/métabolisme , Ovocytes/physiologie , Coactivateur 1-alpha du récepteur gamma activé par les proliférateurs de peroxysomes/génétique , Coactivateur 1-alpha du récepteur gamma activé par les proliférateurs de peroxysomes/métabolisme , Espèces réactives de l'oxygène/métabolisme , Suidae
7.
J Can Dent Assoc ; 90: 3, 2024 Apr.
Article de Anglais | MEDLINE | ID: mdl-39052443

RÉSUMÉ

OBJECTIVES: Although routine dental care is essential for both oral and overall health, in Canada, access to such care is uneven. Those with low or medium income and no workplace dental coverage often face financial barriers in accessing dental care. However, the factors that affect access - income, employer-provided health benefits and public dental care subsidy programs - have changed over the decades. This study examines the net impact of these factors on long-term trends in dental care access among different groups in Canada over the past 5 decades. METHODS: Using data from 1 235 268 respondents to 20 Canadian cross-sectional surveys administered between 1972 and 2017, we estimated the proportion of people who had at least 1 consult with a dental professional over the past 12 months. Prevalence trends by region, age group, education and income level were compared. RESULTS: In each age group, the proportion of people consulting a dental professional at least annually gradually increased over the last 5 decades. During the recession of the early 1990s, a temporary drop in use occurred, particularly among younger age groups. We noted significant regional differences in use among individuals in the same age group: rates were highest in Ontario and British Columbia and lowest in Quebec and the Atlantic provinces. Marked differences in use by level of education and income persisted over the 5 decades. Dental care use was significantly higher among those with higher levels of education and higher incomes. The increase in overall rates of dental care use suggest that an increasing fraction of Canadians have higher incomes or are better educated, or both. Nevertheless, about a third of Canadians ≥ 15 years did not receive dental care in 2015. CONCLUSIONS: Given that dental care is almost wholly privately funded and displays a high degree of income-related inequity, there is an urgent need for policy action to address unequal access to dental care in Canada.


Sujet(s)
Soins dentaires , Accessibilité des services de santé , Humains , Accessibilité des services de santé/statistiques et données numériques , Canada/épidémiologie , Adulte , Adulte d'âge moyen , Études transversales , Soins dentaires/statistiques et données numériques , Soins dentaires/tendances , Femelle , Jeune adulte , Adolescent , Mâle , Sujet âgé , Revenu/statistiques et données numériques
8.
Chem Biodivers ; : e202401161, 2024 Jul 27.
Article de Anglais | MEDLINE | ID: mdl-39073007

RÉSUMÉ

In this study, essential oils and waste hydrosols of leaves of Ocimum tenuiflorum in four different geographical locations were extracted by hydrodistillation method and using gas chromatography / mass spectrometry (GC/MS) for chemical composition analysis. All four essential oil samples contained the main components (E)-ß-caryophyllene (27.8-49.0%), trans-ß-elemene (20.3-37.1%) and eugenol (9.0-44.0%). Three of the four hydrosol samples had eugenol in absolute content (94.5-98.6%), while the remaining hydrosol sample had two main components, elemicin (77.8%) and eugenol (14.2%). Essential oils and hydrosols demonstrated larvicidal activities against four important disease-transmitting mosquito species including Aedes aegypti, Aedes albopictus, Culex quinquefasciatus, and Culex fuscocephala with 24-h LC50 values in the range 15.42-56.01 µg/mL and 53.88-97.80 µg/mL for the essential oils and the hydrosols, respectively. Essential oils and hydrosols strongly inhibited the acetylcholinesterase (AChE) enzyme of electric eels with IC50 values in the range of 25.35-107.19 µg/mL. Microemulsion (ME) can be considered as a sustainable pesticide formulation over 300 days and has improved larvicidal activity compared to free essential oil. The O. tenuiflorum in Vietnam can be considered a low-cost source of eugenol, botanical pesticides that control disease-transmitting mosquitoes, as well as having therapeutic potential to be further investigated.

9.
Nat Prod Res ; : 1-8, 2024 Jul 01.
Article de Anglais | MEDLINE | ID: mdl-38949646

RÉSUMÉ

Recent research has indicated that Panax notoginseng saponins (PNS) extracted from the radix of Panax notoginseng (Burkill) F. H. Chen exert antidepressant effects. This study aimed to assess the antidepressive effects of ginsenoside Rg1 and PNS in a depression model induced by chronic unpredictable mild stress (CUMS). Over a period of three weeks, rats were administered ginsenoside Rg1 at a dose of 30 mg/kg and PNS at dosages ranging from 100 to 200 mg/kg body weight per day. To assess how ginsenoside Rg1 and PNS influence depression-like behaviours in rats, various assessments were conducted, including coat state evaluation, forced swim test, and elevated plus maze test. The levels of cortisol and testosterone in serum samples were analysed using the liquid chromatography-electrospray ionisation tandem mass spectrometry (LC-ESI-MS/MS) method. LC-ESI-MS/MS method provides precise and accurate results. The lower limit of quantification values for cortisol and testosterone were determined as 100 and 2 pg/mL, respectively. Our data demonstrated that both ginsenoside Rg1 and PNS significantly reversed depression-like behaviour in rats by improving coat condition, reducing immobility time in the forced swim test, and increasing time spent in the open arms of the elevated plus maze test. Furthermore, ginsenoside Rg1 and PNS exhibited a regulatory effect on cortisol and testosterone levels in plasma. These findings suggest that ginsenoside Rg1 and PNS may be potential antidepressants in clinical treatment.

10.
Article de Anglais | MEDLINE | ID: mdl-38958657

RÉSUMÉ

Novel Gram-positive, catalase-negative, α-haemolytic cocci were isolated from breast milk samples of healthy mothers living in Hanoi, Vietnam. The 16S rRNA gene sequences of these strains varied by 0-2 nucleotide polymorphisms. The 16S rRNA gene sequence of one strain, designated as BME SL 6.1T, showed the highest similarity to those of Streptococcus salivarius NCTC 8618T (99.4 %), Streptococcus vestibularis ATCC 49124T (99.4 %), and Streptococcus thermophilus ATCC 19258T (99.3 %) in the salivarius group. Whole genome sequencing was performed on three selected strains. Phylogeny based on 631 core genes clustered the three strains into the salivarius group, and the strains were clearly distinct from the other species in this group. The average nucleotide identity (ANI) value of strain BME SL 6.1T exhibited the highest identity with S. salivarius NCTC 8618T (88.4 %), followed by S. vestibularis ATCC 49124T (88.3 %) and S. thermophilus ATCC 19258T (87.4 %). The ANI and digital DNA-DNA hybridization values between strain BME SL 6.1T and other species were below the cut-off value (95 and 70 %, respectively), indicating that it represents a novel species of the genus Streptococcus. The strains were able to produce α-galactosidase and acid from raffinose and melibiose. Therefore, we propose to assign the strains to a new species of the genus Streptococcus as Streptococcus raffinosi sp. nov. The type strain is BME SL 6.1T (=VTCC 12812T=NBRC 116368T).


Sujet(s)
Techniques de typage bactérien , ADN bactérien , Lait humain , Hybridation d'acides nucléiques , Phylogenèse , ARN ribosomique 16S , Analyse de séquence d'ADN , Streptococcus , ARN ribosomique 16S/génétique , Humains , Femelle , ADN bactérien/génétique , Lait humain/microbiologie , Streptococcus/génétique , Streptococcus/isolement et purification , Streptococcus/classification , Vietnam , Séquençage du génome entier
11.
Eur Cardiol ; 19: e05, 2024.
Article de Anglais | MEDLINE | ID: mdl-38983579

RÉSUMÉ

Background: AF is a global health concern, with systemic complications including renal dysfunction. This systematic review and meta-analysis compares the effects of rivaroxaban, a Factor Xa inhibitor, and vitamin K antagonists (VKAs) on renal outcomes in AF patients. Methods: The study protocol is registered in PROSPERO (ID: CRD42023462756). We systematically searched the PubMed, Embase and Cochrane Library databases from 1 January 2017 to 30 June 2023 for real-world studies comparing the effects of rivaroxaban and VKAs on renal outcomes in AF patients, including acute kidney injury, a .30% decrease in estimated glomerular filtration rate, doubling of serum creatinine and worsening renal function. Subgroup analyses targeted diabetes, pre-existing kidney disease, the elderly (age .65 years) and Asian populations. The risk of bias was assessed used the Robins-I tool. HRs and 95% CIs were synthesised through a random-effects model. Two sensitivity analyses were performed, using a fixed-effects model and excluding conference abstracts. Results: We identified 1,666 records. After screening, 14 studies comparing rivaroxaban and VKAs were included. Rivaroxaban exhibited superiority over VKAs in preventing: acute kidney injury (HR 0.68; 95% CI [0.61.0.77]; p<0.00001); a .30% decrease in estimated glomerular filtration rate (HR 0.71; 95% CI [0.60.0.84]; p<0.0001); doubling of serum creatinine (HR 0.50; 95% CI [0.36.0.70]; p<0.0001); and worsening renal function (HR 0.56; 95% CI [0.45.0.69]; p<0.00001). Subgroup and sensitivity analyses consistently confirmed rivaroxaban's favourable effects on renal outcomes in diabetes, pre-existing kidney disease, the elderly and Asian populations. Conclusion: Our findings support the preference of rivaroxaban over VKAs for renal outcomes in AF. The findings endorse rivaroxaban as the preferred anticoagulant to mitigate renal complications, offering clinicians valuable insights for tailored strategies.

12.
Brief Bioinform ; 25(4)2024 May 23.
Article de Anglais | MEDLINE | ID: mdl-38975891

RÉSUMÉ

Unsupervised feature selection is a critical step for efficient and accurate analysis of single-cell RNA-seq data. Previous benchmarks used two different criteria to compare feature selection methods: (i) proportion of ground-truth marker genes included in the selected features and (ii) accuracy of cell clustering using ground-truth cell types. Here, we systematically compare the performance of 11 feature selection methods for both criteria. We first demonstrate the discordance between these criteria and suggest using the latter. We then compare the distribution of selected genes in their means between feature selection methods. We show that lowly expressed genes exhibit seriously high coefficients of variation and are mostly excluded by high-performance methods. In particular, high-deviation- and high-expression-based methods outperform the widely used in Seurat package in clustering cells and data visualization. We further show they also enable a clear separation of the same cell type from different tissues as well as accurate estimation of cell trajectories.


Sujet(s)
Analyse sur cellule unique , Analyse sur cellule unique/méthodes , Analyse de regroupements , Humains , Analyse de profil d'expression de gènes/méthodes , Algorithmes , Biologie informatique/méthodes , Analyse de séquence d'ARN/méthodes , RNA-Seq/méthodes
13.
Toxicol Res ; 40(3): 389-408, 2024 Jul.
Article de Anglais | MEDLINE | ID: mdl-38911537

RÉSUMÉ

Exposure to n-hexane and its metabolite 2,5-hexandione (HD) is a well-known cause of neurotoxicity, particularly in the peripheral nervous system. To date, few studies have focused on the neurotoxic effects of HD on cognitive impairment. Exposure to HD and diabetes mellitus can exacerbate neurotoxicity. There are links among HD, diabetes mellitus, and cognitive impairment; however, the specific mechanisms underlying them remain unclear. Therefore, we aimed to elucidate the neurotoxic effects of HD on cognitive impairment in ob/ob (C57BL/6-Lepem1Shwl/Korl) mice. We found that HD induced cognitive impairment by altering the expression of genes (FN1, AGT, ACTA2, MYH11, MKI67, MET, CTGF, and CD44), miRNAs (mmu-miR15a-5p, mmu-miR-17-5p, and mmu-miR-29a-3p), transcription factors (transcription factor AP-2 alpha [TFAP2A], serum response factor [Srf], and paired box gene 4 [PAX4]), and signaling pathways (ERK/CERB, PI3K/AKT, GSK-3ß/p-tau/amyloid-ß), as well as by causing neuroinflammation (TREM1/DAP12/NF-κB), oxidative stress, and apoptosis. The prevalent use of n-hexane in various industrial applications (for instance, shoe manufacturing, printing inks, paints, and varnishes) suggests that individuals with elevated body weight and glucose levels and those employed in high-risk workplaces have greater probability of cognitive impairment. Therefore, implementing screening strategies for HD-induced cognitive dysfunction is crucial. Supplementary Information: The online version contains supplementary material available at 10.1007/s43188-024-00228-1.

14.
bioRxiv ; 2024 Jun 14.
Article de Anglais | MEDLINE | ID: mdl-38915701

RÉSUMÉ

Purpose: ADP-ribosylation is a post-translational modification involving the transfer of one or more ADP-ribose units from NAD+ to target proteins. Dysregulation of ADP-ribosylation is implicated in neurodegenerative diseases. Here we report a novel homozygous variant in the ADPRS gene (c.545A>G, p.His182Arg) encoding the mono(ADP-ribosyl) hydrolase ARH3 found in 2 patients with childhood-onset neurodegeneration with stress-induced ataxia and seizures (CONDSIAS). Methods: Genetic testing via exome sequencing was used to identify the underlying disease cause in two siblings with developmental delay, seizures, progressive muscle weakness, and respiratory failure following an episodic course. Studies in a cell culture model uncover biochemical and cellular consequences of the identified genetic change. Results: The ARH3 H182R variant affects a highly conserved residue in the active site of ARH3, leading to protein instability, degradation, and reduced expression. ARH3 H182R additionally fails to localize to the nucleus. The combination of reduced expression and mislocalization of ARH3 H182R resulted in accumulation of mono-ADP ribosylated species in cells. Conclusions: The children's clinical course combined with the biochemical characterization of their genetic variant develops our understanding of the pathogenic mechanisms driving CONDSIAS and highlights a critical role for ARH3-regulated ADP ribosylation in nervous system integrity.

15.
Microbiol Spectr ; 12(8): e0095924, 2024 Aug 06.
Article de Anglais | MEDLINE | ID: mdl-38916311

RÉSUMÉ

The pandemic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to evolve to give rise to variants of concern that can escape vaccine-induced immunity. As such, more effective vaccines are urgently needed. In this study, we evaluated virus-like particle (VLP) as a vaccine platform for SARS-CoV-2. The spike, envelope, and membrane proteins of the SARS-CoV-2 Wuhan strain were expressed by a single recombinant baculovirus BacMam and assembled into VLPs in cell culture. The morphology and size of the SARS-CoV-2 VLP as shown by transmission electron microscopy were similar to the authentic SARS-CoV-2 virus particle. In a mouse trial, two intramuscular immunizations of the VLP BacMam with no adjuvant elicited spike-specific binding antibodies in both sera and bronchoalveolar lavage fluids. Importantly, BacMam VLP-vaccinated mouse sera showed neutralization activity against SARS-CoV-2 spike pseudotyped lentivirus. Our results indicated that the SARS-CoV-2 VLP BacMam stimulated spike-specific immune responses with neutralization activity. IMPORTANCE: Although existing vaccines have significantly mitigated the impact of the COVID-19 pandemic, none of the vaccines can induce sterilizing immunity. The spike protein is the main component of all approved vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) due primarily to its ability to induce neutralizing antibodies. The conformation of the spike protein in the vaccine formulation should be critical for the efficacy of a vaccine. By way of closely resembling the authentic virions, virus-like particles (VLPs) should render the spike protein in its natural conformation. To this end, we utilized the baculovirus vector, BacMam, to express virus-like particles consisting of the spike, membrane, and envelope proteins of SARS-CoV-2. We demonstrated the immunogenicity of our VLP vaccine with neutralizing activity. Our data warrant further evaluation of the virus-like particles as a vaccine candidate in protecting against virus challenges.


Sujet(s)
Anticorps neutralisants , Anticorps antiviraux , Baculoviridae , Vaccins contre la COVID-19 , COVID-19 , Souris de lignée BALB C , SARS-CoV-2 , Glycoprotéine de spicule des coronavirus , Vaccins à pseudo-particules virales , Animaux , SARS-CoV-2/immunologie , SARS-CoV-2/génétique , Vaccins à pseudo-particules virales/immunologie , Vaccins à pseudo-particules virales/génétique , Vaccins à pseudo-particules virales/administration et posologie , Baculoviridae/génétique , Baculoviridae/immunologie , Souris , Anticorps antiviraux/immunologie , Anticorps antiviraux/sang , Glycoprotéine de spicule des coronavirus/immunologie , Glycoprotéine de spicule des coronavirus/génétique , Vaccins contre la COVID-19/immunologie , Vaccins contre la COVID-19/administration et posologie , COVID-19/prévention et contrôle , COVID-19/immunologie , Anticorps neutralisants/immunologie , Anticorps neutralisants/sang , Humains , Femelle , Immunogénicité des vaccins , Protéines d'enveloppe des coronavirus/immunologie , Protéines d'enveloppe des coronavirus/génétique , Protéines M des coronavirus
16.
Xenobiotica ; 54(6): 322-341, 2024 Jun.
Article de Anglais | MEDLINE | ID: mdl-38833509

RÉSUMÉ

We aimed to elucidate the toxic effects and biological activities of 3-phenoxybenzoic acid (3PBA) and its metabolite products.Numerous in silico methods were used to identify the toxic effects and biological activities of 3PBA, including PASS online, molecular docking, ADMETlab 2.0, ADMESWISS, MetaTox, and molecular dynamic simulation.Ten metabolite products were identified via Phase II reactions (O-glucuronidation, O-sulfation, and methylation).All of the investigated compounds were followed by Lipinski's rule, indicating that they were stimulants or inducers of hazardous processes.Because of their high gastrointestinal absorption and ability to reach the blood-brain barrier, the studied compounds' physicochemical and pharmacokinetic properties matched existing evidence of harmful effects, including haematemesis, reproductive dysfunction, allergic dermatitis, toxic respiration, and neurotoxicity.The studied compounds have been linked to the apoptotic pathway, the reproductivity system, neuroendocrine disruptors, phospholipid-translocating ATPase inhibitors, and JAK2 expression.An O-glucuronidation metabolite product demonstrated higher binding affinity and interaction with CYP2C9, CYP3A4, caspase 3, and caspase 8 than 3PBA and other metabolite products, whereas metabolite products from methylation were predominant and more toxic.Our in silico findings partly meet the 3Rs principle by minimizing animal testing before more study is needed to identify the detrimental effects of 3PBA on other organs (liver, kidneys).Future research directions may involve experimental validation of in silico predictions, elucidation of molecular mechanisms, and exploration of therapeutic interventions.These findings contribute to our understanding of the toxicological profile of 3PBA and its metabolites, which has implications for risk assessment and regulatory decisions.


Key properties & pharmacokinetics of 3PBA & its metabolites were reportedMetabolite products from methylation were predominant and more toxicMain toxics: haematemesis, reproductive dysfunction, toxic respiration, dermatitis.


Sujet(s)
Benzoates , Simulation numérique , Benzoates/composition chimique , Benzoates/métabolisme , Benzoates/toxicité , Modèles moléculaires , Conformation moléculaire , Phénomènes chimiques , Caspase-3/composition chimique , Caspase-3/métabolisme , Caspase 8/composition chimique , Caspase 8/métabolisme , Sites de fixation des anticorps , Cytochrome P-450 CYP3A/composition chimique , Cytochrome P-450 CYP3A/métabolisme
17.
Mol Cell Proteomics ; 23(8): 100809, 2024 Aug.
Article de Anglais | MEDLINE | ID: mdl-38936775

RÉSUMÉ

Microglia are resident immune cells of the brain and regulate its inflammatory state. In neurodegenerative diseases, microglia transition from a homeostatic state to a state referred to as disease-associated microglia (DAM). DAM express higher levels of proinflammatory signaling molecules, like STAT1 and TLR2, and show transitions in mitochondrial activity toward a more glycolytic response. Inhibition of Kv1.3 decreases the proinflammatory signature of DAM, though how Kv1.3 influences the response is unknown. Our goal was to identify the potential proteins interacting with Kv1.3 during transition to DAM. We utilized TurboID, a biotin ligase, fused to Kv1.3 to evaluate potential interacting proteins with Kv1.3 via mass spectrometry in BV-2 microglia following TLR4-mediated activation. Electrophysiology, Western blotting, and flow cytometry were used to evaluate Kv1.3 channel presence and TurboID biotinylation activity. We hypothesized that Kv1.3 contains domain-specific interactors that vary during a TLR4-induced inflammatory response, some of which are dependent on the PDZ-binding domain on the C terminus. We determined that the N terminus of Kv1.3 is responsible for trafficking Kv1.3 to the cell surface and mitochondria (e.g., NUDC, TIMM50). Whereas, the C terminus interacts with immune signaling proteins in a lipopolysaccharide-induced inflammatory response (e.g., STAT1, TLR2, and C3). There are 70 proteins that rely on the C-terminal PDZ-binding domain to interact with Kv1.3 (e.g., ND3, Snx3, and Sun1). Furthermore, we used Kv1.3 blockade to verify functional coupling between Kv1.3 and interferon-mediated STAT1 activation. Overall, we highlight that the Kv1.3 potassium channel functions beyond conducting the outward flux of potassium ions in an inflammatory context and that Kv1.3 modulates the activity of key immune signaling proteins, such as STAT1 and C3.


Sujet(s)
Canal potassique Kv1.3 , Microglie , Protéomique , Facteur de transcription STAT-1 , Récepteur de type Toll-4 , Canal potassique Kv1.3/métabolisme , Microglie/métabolisme , Animaux , Protéomique/méthodes , Souris , Récepteur de type Toll-4/métabolisme , Facteur de transcription STAT-1/métabolisme , Lignée cellulaire , Récepteur de type Toll-2/métabolisme , Lipopolysaccharides/pharmacologie , Liaison aux protéines
18.
Theriogenology ; 226: 158-166, 2024 Sep 15.
Article de Anglais | MEDLINE | ID: mdl-38901215

RÉSUMÉ

Objectives of the present study were to investigate the characteristics including glucose-6-phosphate dehydrogenase activity, as determined by Brilliant Cresyl Blue (BCB) staining, of suboptimal porcine oocytes and to enhance the meiotic competence of those through pre-culture with cumulus cell masses (CCMs). Percentage of oocyte-cumulus complexes (OCCs) derived from small follicles (SF; <3 mm in diameter) containing the oocytes that were assessed as BCB-negative (BCB-) was significantly higher than those derived from medium follicles (MF; 3-6 mm in diameter). Degrees of dead cumulus cells were significantly higher in OCCs containing BCB- oocytes, regardless of the origin of OCCs (MF vs. SF), than those containing BCB-positive (BCB+) ones. Exposing OCCs containing BCB+ oocytes to the apoptosis inducer, carbonyl cyanide m-chlorophenylhydrazone, for 20 h significantly induced the transition to BCB- and meiotic progression of exposed OCCs were significantly reduced in both SF and MF derived ones. Transit of BCB- oocytes to BCB+ was induced when OCCs were pre-cultured with CCMs of MF derived OCCs containing BCB+ oocytes for 20 h before IVM. This pre-culture also significantly increased the meiotic competence of BCB- oocytes, particularly in SF derived ones. However, reactive oxygen species levels were significantly higher in BCB+ oocytes as compared with BCB- ones, regardless of pre-culture with CCMs, whereas no significant differences were found in the ATP contents among the treatment groups. In conclusion, the BCB result of oocytes could be regulated by the healthy status and content of surrounding cumulus cells and the meiotic competence of suboptimal BCB- porcine oocytes is improved by pre-culture with healthy CCMs.


Sujet(s)
Survie cellulaire , Cellules du cumulus , Méiose , Ovocytes , Oxazines , Animaux , Cellules du cumulus/physiologie , Ovocytes/physiologie , Suidae , Femelle , Techniques de maturation in vitro des ovocytes/médecine vétérinaire , Techniques de maturation in vitro des ovocytes/méthodes , Coloration et marquage/méthodes
19.
Environ Geochem Health ; 46(7): 219, 2024 Jun 07.
Article de Anglais | MEDLINE | ID: mdl-38849667

RÉSUMÉ

This study investigates the removal of amoxicillin micropollutants (AM) from hospital wastewater using CoMoO4-modified graphitic carbon nitride (CMO/gCN). Consequently, CMO/gCN exhibits notable improvements in visible light absorption and electron-hole separation rates compared to unmodified gCN. Besides, CMO/gCN significantly enhances the removal efficiency of AM, attaining an impressive 96.5%, far surpassing the performance of gCN at 48.6%. Moreover, CMO/gCN showcases outstanding reusability, with AM degradation performance exceeding 70% even after undergoing six cycles of reuse. The removal mechanism of AM employing CMO/gCN involves various photoreactions of radicals (•OH, •O2-) and amoxicillin molecules under light assistance. Furthermore, CMO/gCN demonstrates a noteworthy photodegradation efficiency of AM from hospital wastewater, reaching 92.8%, with a near-complete reduction in total organic carbon levels. Detailed discussions on the practical applications of the CMO/gCN photocatalyst for removal of micropollutants from hospital wastewater are provided. These findings underline the considerable potential of CMO/gCN for effectively removing various pollutants in environmental remediation strategies.


Sujet(s)
Amoxicilline , Graphite , Oxydoréduction , Eaux usées , Polluants chimiques de l'eau , Amoxicilline/composition chimique , Eaux usées/composition chimique , Graphite/composition chimique , Polluants chimiques de l'eau/composition chimique , Photolyse , Hôpitaux , Composés de l'azote/composition chimique , Catalyse , Purification de l'eau/méthodes
20.
Clin Chim Acta ; 561: 119819, 2024 Jul 15.
Article de Anglais | MEDLINE | ID: mdl-38901629

RÉSUMÉ

Metabolic syndrome (MetS) represents a significant public health concern due to its association with an increased risk of cardiovascular disease, type 2 diabetes, and other serious health conditions. Despite extensive research, the underlying molecular mechanisms contributing to MetS pathogenesis remain elusive. This review aims to provide a comprehensive overview of the molecular mechanisms linking MetS and cluster of differentiation (CD) markers, which play critical roles in immune regulation and cellular signaling. Through an extensive literature review with a systematic approach, we examine the involvement of various CD markers in MetS development and progression, including their roles in adipose tissue inflammation, insulin resistance, dyslipidemia, and hypertension. Additionally, we discuss potential therapeutic strategies targeting CD markers for the management of MetS. By synthesizing current evidence, this review contributes to a deeper understanding of the complex interplay between immune dysregulation and metabolic dysfunction in MetS, paving the way for the development of novel therapeutic interventions.


Sujet(s)
Syndrome métabolique X , Syndrome métabolique X/métabolisme , Humains , Marqueurs biologiques/métabolisme
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