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ACS Omega Jun 2024Improving the sensitivity of the fluorescence method for the detection of bioactive molecules is crucial in biochemical analysis. In this work, an ultrasensitive sensing...
Improving the sensitivity of the fluorescence method for the detection of bioactive molecules is crucial in biochemical analysis. In this work, an ultrasensitive sensing strategy was constructed for the detection of ascorbic acid (AA) using high-quality 3-mercaptopropionic acid-capped CdSe/CdS/ZnS quantum dots (MPA-CdSe/CdS/ZnS QDs) as the fluorescent probe. The prepared water-soluble QDs exhibited a high photoluminescence quantum yield (PL QY) of up to 96%. Further, the fluorescence intensity of the QDs was intensively quenched through the dynamic quenching of Ag ions due to an efficient photoinduced electron transfer progress. While the existence of AA before adding Ag ions, Ag ions were reduced. Thus, the interaction of the QDs and Ag ions was destroyed, which led to the fluorescence distinct recovery. The detection limit of AA could be as low as 0.2 nM using this sensing system. Additionally, most relevant small molecules and physiological ions had no influence on the analysis of AA. Satisfactory results were obtained in orange beverages, showing its great potential as a meaningful platform for highly sensitive and selective AA sensing for clinical analysis.
PubMed: 38947783
DOI: 10.1021/acsomega.4c01045 -
IScience Jun 2024Drug efflux transporters are a major determinant of drug efficacy and toxicity. A canonical example is P-glycoprotein (P-gp), an efflux transporter that controls the...
Drug efflux transporters are a major determinant of drug efficacy and toxicity. A canonical example is P-glycoprotein (P-gp), an efflux transporter that controls the intestinal absorption of diverse compounds. Despite a rich literature on the dietary and pharmaceutical compounds that impact P-gp activity, its sensitivity to gut microbial metabolites remains an open question. Surprisingly, we found that the cardiac drug-metabolizing gut Actinobacterium increases drug absorption in mice. Experiments in cell culture revealed that produces a soluble factor that post-translationally inhibits P-gp ATPase efflux activity. P-gp inhibition is conserved in the family but absent in other Actinobacteria. Comparative genomics identified genes associated with P-gp inhibition. Finally, activity-guided biochemical fractionation coupled to metabolomics implicated a group of small polar metabolites with P-gp inhibitory activity. These results highlight the importance of considering the broader relevance of the gut microbiome for drug disposition beyond first-pass metabolism.
PubMed: 38947502
DOI: 10.1016/j.isci.2024.110122 -
World Journal of Gastroenterology Jun 2024In this editorial we comment on the article by Agatsuma published in the . They suggest policies for more effective colorectal screening. Screening is the main policy...
In this editorial we comment on the article by Agatsuma published in the . They suggest policies for more effective colorectal screening. Screening is the main policy that has led to lower mortality rates in later years among the population that was eligible for screening. Colonoscopy is the gold standard tool for screening and has preventive effects by removing precancerous or early malignant polyps. However, colonoscopy is an invasive process, and fecal tests such as the current hemoglobin immunodetection were developed, followed by endoscopy, as the general tool for population screening, avoiding logistical and economic problems. Even so, participation and adherence rates are low. Different screening options are being developed with the idea that if people could choose between the ones that best suit them, participation in population-based screening programs would increase. Blood tests, such as a recent one that detects cell-free DNA shed by tumors called circulating tumor DNA, showed a similar accuracy rate to stool tests for cancer, but were less sensitive for advanced precancerous lesions. At the time when the crosstalk between the immune system and cancer was being established as a new hallmark of cancer, novel immune system-related biomarkers and information on patients' immune parameters, such as cell counts of different immune populations, were studied for the early detection of colorectal cancer, since they could be effective in asymptomatic people, appearing earlier in the adenoma-carcinoma development compared to the presence of fecal blood. sCD26, for example, detected 80.37% of advanced adenomas. To reach as many eligible people as possible, starting at an earlier age than current programs, the direction could be to apply tests based on blood, urine or salivary fluid to samples taken during routine visits to the primary health system.
Topics: Humans; Colorectal Neoplasms; Early Detection of Cancer; Colonoscopy; Mass Screening; Biomarkers, Tumor; Occult Blood; Feces; Adenoma
PubMed: 38947291
DOI: 10.3748/wjg.v30.i22.2849 -
Research Square Jun 2024Nosebleeds and intracranial hemorrhage from brain arteriovenous malformations (bAVMs) are among the most devastating symptoms of patients with hereditary hemorrhagic...
Nosebleeds and intracranial hemorrhage from brain arteriovenous malformations (bAVMs) are among the most devastating symptoms of patients with hereditary hemorrhagic telangiectasis (HHT). All available managements have limitations. We showed that intravenous delivery of soluble FMS-related tyrosine kinase 1 using an adeno-associated viral vector (AAV9-sFLT1) reduced bAVM severity of deficient mice. However, minor liver inflammation and growth arrest in young mice were observed. To identify AAV variants and delivery methods that can best transduce brain and nasal tissue with an optimal transduction profile, we compared 3 engineered AAV capsids (AAV.cc47, AAV.cc84 and AAV1RX) with AAV9. A single-stranded CBA promoter driven tdTomato transgene was packaged in these capsids and delivered intravenously (i.v.) or intranasally (i.n.) to wild-type mice. A CMV promoter driven transgene was packaged into AAV.cc84 and delivered to PdgfbiCre; mice through i.v. injection followed by brain AVM induction. Transduced cells in different organs, vessel density and abnormal vessels in the bAVMs, and liver inflammation were analyzed histologically. Liver and kidney function were measured enzymatically. Compared to other viral vectors, AAV.cc84, after i.v. delivery, transduced a high percentage of brain ECs and few hepatocytes; whereas after i.n. delivery, AAV.cc84 transduced ECs and perivascular cells in the brain, and ECs, epithelial cells, and skeletal muscles in the nose with minimum hepatocyte transduction. No changes to liver or kidney function were detected. Delivery of AAV.cc84-Alk1 through i.v. to PdgfbiCre; mice reduced bAVM severity. In summary, we propose that AAV.cc84-Alk1 is a promising candidate for developing gene therapy in HHT patients.
PubMed: 38947073
DOI: 10.21203/rs.3.rs-4469011/v1 -
MedRxiv : the Preprint Server For... Jun 2024Plasma p-tau217 and Tau-PET are strong prognostic biomarkers in Alzheimer's disease (AD), but their relative performance in predicting future cognitive decline among...
Plasma p-tau217 and Tau-PET are strong prognostic biomarkers in Alzheimer's disease (AD), but their relative performance in predicting future cognitive decline among cognitively unimpaired (CU) individuals is unclear. In this head-to-head comparison study including 9 cohorts and 1534 individuals, we found that plasma p-tau217 and medial temporal lobe Tau-PET signal showed similar associations with cognitive decline on a global cognitive composite test (R =0.32 vs R =0.32, p =0.812) and with progression to mild cognitive impairment (Hazard ratio[HR] =1.56[1.43-1.70] vs HR =1.63[1.50-1.77], p =0.627). Combined plasma and PET models were superior to the single biomarker models (R =0.36, p<0.01). Furthermore, sequential selection using plasma p-tau217 and then Tau-PET reduced the number of participants required for a clinical trial by 94%, compared to a 75% reduction when using plasma p-tau217 alone. We conclude that plasma p-tau217 and Tau-PET showed similar performance for predicting future cognitive decline in CU individuals, and their sequential use (i.e., plasma p-tau217 followed by Tau-PET in a subset with high plasma p-tau217) is useful for screening in clinical trials in preclinical AD.
PubMed: 38947004
DOI: 10.1101/2024.06.12.24308824 -
Research Square Jun 2024Tauopathies, including Alzheimer's disease (AD) and Frontotemporal Dementia (FTD), are histopathologically defined by the aggregation of hyperphosphorylated pathological...
Virus-like particle (VLP)-based vaccine targeting tau phosphorylated at Ser396/Ser404 (PHF1) site outperforms phosphorylated S199/S202 (AT8) site in reducing tau pathology and restoring cognitive deficits in the rTg4510 mouse model of tauopathy.
Tauopathies, including Alzheimer's disease (AD) and Frontotemporal Dementia (FTD), are histopathologically defined by the aggregation of hyperphosphorylated pathological tau (pTau) as neurofibrillary tangles in the brain. Site-specific phosphorylation of tau occurs early in the disease process and correlates with progressive cognitive decline, thus serving as targetable pathological epitopes for immunotherapeutic development. Previously, we developed a vaccine (Qβ-pT181) displaying phosphorylated Thr181 tau peptides on the surface of a Qβ bacteriophage virus-like particle (VLP) that induced robust antibody responses, cleared pathological tau, and rescued memory deficits in a transgenic mouse model of tauopathy. Here we report the characterization and comparison of two additional Qβ VLP-based vaccines targeting the dual phosphorylation sites Ser199/Ser202 (Qβ-AT8) and Ser396/Ser404 (Qβ-PHF1). Both Qβ-AT8 and Qβ-PHF1 vaccines elicited high-titer antibody responses against their pTau epitopes. However, only Qβ-PHF1 rescued cognitive deficits, reduced soluble and insoluble pathological tau, and reactive microgliosis in a 4-month rTg4510 model of FTD. Both sera from Qβ-AT8 and Qβ-PHF1 vaccinated mice were specifically reactive to tau pathology in human AD post-mortem brain sections. These studies further support the use of VLP-based immunotherapies to target pTau in AD and related tauopathies and provide potential insight into the clinical efficacy of various pTau epitopes in the development of immunotherapeutics.
PubMed: 38946961
DOI: 10.21203/rs.3.rs-4390998/v1 -
Saudi Journal of Biological Sciences Aug 2024Human Rotavirus (HRV) is the causative pathogen of severe acute enteric infections that cause mortality among children worldwide. This study focuses on developing a new...
Human Rotavirus (HRV) is the causative pathogen of severe acute enteric infections that cause mortality among children worldwide. This study focuses on developing a new and effective treatment for rotavirus infection using an extract from Saccharomyces cerevisiae, aiming to make this treatment easily accessible to everyone. 15 antigens and 26 antibodies were detected in serum and stool using ELISA. The titers of HRVq1, HRVq2, HRVC1, and HRVC2 on Vero cells were determined to be 1.2x10, 3.0x10, 4.2x10, and 7.5x10 (Plaque forming unit, PFU/ml) four days after infection, respectively. The HRVq1 isolate induced cytopathic effects, i.e., forming multinucleated, rounded, enlarged, and expanding gigantic cells. RT-PCR identified this isolate, and the accession number 2691714 was assigned to GeneBank. The molecular docking analysis revealed that nonstructural proteins (NSPs) NSP1, NSP2, NSP3, NSP4, NSP5, and NSP6 exhibited significant binding with RNA. NSP2 demonstrated the highest binding affinity and the lowest binding energy (-8.9 kcal/mol). This affinity was maintained via hydrophobic interactions and hydrogen bonds spanning in length from 1.12 Å to 3.11 Å. The ADMET and bioactivity predictions indicated that the yeast extract possessed ideal solubility, was nontoxic, and did not cause cancer. The inhibitory constant values predicted for the extract in the presence of HRV vital proteins varied from 5.32 to 7.45 mM, indicating its potential as a viable drug candidate. extract could be utilized as a dietary supplement to combat HRV as an alternative dietary supplement.
PubMed: 38946847
DOI: 10.1016/j.sjbs.2024.104031 -
RSC Advances Jun 2024Complexes tris((1-ferrocenyl-1-1,2,3-triazol-4-yl)methyl)amine (3), bis((1-ferrocenyl-1-1,2,3-triazol-4-yl)methyl)amine (6),...
Complexes tris((1-ferrocenyl-1-1,2,3-triazol-4-yl)methyl)amine (3), bis((1-ferrocenyl-1-1,2,3-triazol-4-yl)methyl)amine (6), bis((1-ferrocenyl-1-1,2,3-triazol-4-yl)methyl)ether (7), and 1-ferrocenyl-1-1,2,3-triazol-4-yl)methanamine (9) were synthesized using the copper-catalyzed click reaction. Complexes 3, 6, 7, and 9 were characterized using NMR (H and {H}) and IR spectroscopy, elemental analysis, and mass spectrometry. Structures of 3, 7, and 9 in the solid state were determined using single-crystal X-ray diffraction. It was found that the triazole rings were planar and slightly twisted with respect to the cyclopentadienyl groups attached to them. Chains and 3D network structures were observed due to the presence of π⋯π and C-H⋯N interactions between the cyclopentadienyl and triazole ligands. A reversible redox behavior of the Fc groups between 239 and 257 mV with multicycle stability was characteristic for all the compounds, revealing that the electrochemically generated species Fc remained soluble in dichloromethane. Electrochemical sensor tests demonstrated the applicability of all the complexes to enhance the quantification sensing behavior of the screen-printed carbon electrode (SPCE) toward Cd, Pb, and Cu ions.
PubMed: 38946768
DOI: 10.1039/d4ra04023f -
Natural Product Research Jul 2024The natural product ambergris is only found rarely on beaches, as jetsam. Even more scarce, or even absent, are accounts of flotsam ambergris. Here, we report the...
The natural product ambergris is only found rarely on beaches, as jetsam. Even more scarce, or even absent, are accounts of flotsam ambergris. Here, we report the chemical analysis of a rare, large piece (>100kg) of flotsam found in the Atlantic in 2019. About 95% of subsamples from the outside of the coprolith was soluble in dichloromethane. Of this, FTIR spectroscopy, APCI-MS and GC-MS indicated the presence of ambrein. Radiocarbon dating indicated that the sample was post 1950s in age. The C/C isotope ratio (-22.5 ‰) was typical of those reported to date for whale 'body' ambergris. Metals of ambergris have hardly been reported previously. The distribution found here for the flotsam, was dominated by copper and zinc, which is similar to that of several squid species. This is also consistent with the presence of squid beaks in the coprolith. Squid are a major prey species of sperm whales.
PubMed: 38946693
DOI: 10.1080/14786419.2024.2361863 -
Journal of Materials Chemistry. B Jul 2024Water-soluble graphene quantum dots (GQDs) have recently exhibited considerable potential for diverse biomedical applications owing to their exceptional optical and... (Review)
Review
Water-soluble graphene quantum dots (GQDs) have recently exhibited considerable potential for diverse biomedical applications owing to their exceptional optical and chemical properties. However, the pronounced heterogeneity in the composition, size, and morphology of GQDs poses challenges for a comprehensive understanding of the intricate correlation between their structural attributes and functional properties. This variability also introduces complexities in scaling the production processes and addressing safety considerations. Light and sound have firmly established their role in clinical applications as pivotal energy sources for minimally invasive therapeutic interventions. Given the limited penetration depth of light, photodynamic therapy (PDT) predominantly targets superficial conditions such as dermatological disorders, head and neck malignancies, ocular ailments, and early-stage esophageal cancer. Conversely, ultrasound-based sonodynamic therapy (SDT) capitalizes on its superior ability to propagate and focus ultrasound within biological tissues, enabling a diverse range of therapeutic applications, including the management of gliomas, breast cancer, hematological tumors, and modulation of the blood-brain barrier (BBB). Considering the advancements in theranostic and precision therapies, reevaluating these conventional energy sources and their associated sensitizers is imperative. This review introduces three prevalent treatment modalities that harness light and sound stimuli: PDT, SDT, and a synergistic approach that integrates PDT and SDT. This study delineated the therapeutic dynamics and contemporary designs of sensitizers tailored to these modalities. By exploring the historical context of the field and elucidating the latest design strategies, this review underscores the pivotal role of GQDs in propelling the evolution of PDT and SDT. This aspires to stimulate researchers to develop "multimodal" therapies integrating both light and sound stimuli.
PubMed: 38946657
DOI: 10.1039/d4tb00767k