Percutaneous Coronary Intervention of Left Main Disease: Outcome After 1-year Follow-up at a Tertiary Hospital in Vietnam.

Background: Left main (LM) coronary artery disease (CAD) is a severe condition that can lead to severe outcomes. Treatment options include medication, coronary artery bypass graft surgery (CABG) and percutaneous coronary intervention (PCI). Recent advancements in PCI techniques position it as a viable alternative to CABG for LM revascularisation. Methods: This prospective observational study evaluated outcomes after PCI for LM CAD, encompassing in-hospital and post-discharge mortality, in a single-centre registry in Vietnam. Results: Our research involved 59 patients who underwent PCI for LM lesions, with an average age of 66.7 ±1.5 years, who were divided into two groups based on presentation diagnosis - acute coronary syndrome or chronic coronary syndrome. After PCI, one individual was diagnosed with contrast-induced nephropathy and one with cardiac shock. There were two cases of in-hospital mortality in the acute coronary syndrome group and one in the chronic coronary syndrome group giving a rate of major adverse cardiac and cerebrovascular events (MACCE) of 5.1%. After a 12-month follow-up, the MACCE rate increased to 18.6%. Triple vessel coronary artery disease and troponin I elevation exhibited significant associations with adverse in-hospital outcomes (p<0.05). Conclusion: PCI for LM coronary artery disease is considered a safe treatment option, demonstrating relatively favourable in-hospital and mid-term outcomes. It presents a viable alternative for patients in need of revascularisation, particularly in cases where CABG is not the preferred choice. Clinical indicators, such as triple vessel coronary artery disease and elevated troponin I levels, may serve as predictors of adverse outcomes during hospitalisation.

The use of artificial intelligence in induced pluripotent stem cell-based technology over 10-year period: A systematic scoping review.

BACKGROUND: Stem cell research, particularly in the domain of induced pluripotent stem cell (iPSC) technology, has shown significant progress. The integration of artificial intelligence (AI), especially machine learning (ML) and deep learning (DL), has played a pivotal role in refining iPSC classification, monitoring cell functionality, and conducting genetic analysis. These enhancements are broadening the applications of iPSC technology in disease modelling, drug screening, and regenerative medicine. This review aims to explore the role of AI in the advancement of iPSC research. METHODS: In December 2023, data were collected from three electronic databases (PubMed, Web of Science, and Science Direct) to investigate the application of AI technology in iPSC processing. RESULTS: This systematic scoping review encompassed 79 studies that met the inclusion criteria. The number of research studies in this area has increased over time, with the United States emerging as a leading contributor in this field. AI technologies have been diversely applied in iPSC technology, encompassing the classification of cell types, assessment of disease-specific phenotypes in iPSC-derived cells, and the facilitation of drug screening using iPSC. The precision of AI methodologies has improved significantly in recent years, creating a foundation for future advancements in iPSC-based technologies. CONCLUSIONS: Our review offers insights into the role of AI in regenerative and personalized medicine, highlighting both challenges and opportunities. Although still in its early stages, AI technologies show significant promise in advancing our understanding of disease progression and development, paving the way for future clinical applications.

The radical scavenging activity of monocaffeoylquinic acids: the role of neighboring hydroxyl groups and pH levels.

Caffeoylquinic acids (CQAs) are well-known antioxidants. However, a key aspect of their radical scavenging activity - the mechanism of action - has not been addressed in detail thus far. Here we report on a computational study of the mechanism of activity of CQAs in scavenging hydroperoxyl radicals. In water at physiological pH, the CQAs demonstrated ≈ 104 times higher HOO˙ antiradical activity than in lipid medium (k(lipid) ≈ 104 M-1 s-1). The activity in the aqueous solution was determined by the hydrogen transfer mechanism of the adjacent hydroxyl group (O6'-H) of the dianion states (Γ = 93.2-95.2%), while the single electron transfer reaction of these species contributed 4.8-6.8% to the total rate constants. The kinetics estimated by the calculations are consistent with experimental findings in water (pH = 7.5), yielding a kcalculated/kexperimental = 2.4, reinforcing the reliability and precision of the computational method and demonstrating its utility for evaluating radical reactions in silico. The results also revealed the pH dependence of the HOO˙ scavenging activity of the CQAs; activity was comparable for all compounds below pH 3, however at higher pH values 5CQA reacted with the HOO˙ with lower activity than 3CQA or 4CQA. It was also found that CQAs are less active than Trolox below pH 4.7, however over pH 5.0 they showed higher activity than the reference. The CQAs had the best HOO˙ antiradical activity at pH values between 5.0 and 8.6. Therefore, in the physiological environment, the hydroperoxyl antiradical capacity of CQAs exhibits similarity to renowned natural antioxidants including resveratrol, ascorbic acid, and Trolox.

Induced Pluripotent Stem Cell-Derived Cardiomyocytes Therapy for Ischemic Heart Disease in Animal Model: A Meta-Analysis.

Ischemic heart disease (IHD) poses a significant challenge in cardiovascular health, with current treatments showing limited success. Induced pluripotent derived-cardiomyocyte (iPSC-CM) therapy within regenerative medicine offers potential for IHD patients, although its clinical impacts remain uncertain. This study utilizes meta-analysis to assess iPSC-CM outcomes in terms of efficacy and safety in IHD animal model studies. A meta-analysis encompassing PUBMED, ScienceDirect, Web of Science, and the Cochrane Library databases, from inception until October 2023, investigated iPSC therapy effects on cardiac function and safety outcomes. Among 51 eligible studies involving 1012 animals, despite substantial heterogeneity, the iPSC-CM transplantation improved left ventricular ejection fraction (LVEF) by 8.23% (95% CI, 7.15 to 9.32%; p < 0.001) compared to control groups. Additionally, cell-based treatment reduced the left ventricle fibrosis area and showed a tendency to reduce left ventricular end-systolic volume (LVESV) and end-diastolic volume (LVEDV). No significant differences emerged in mortality and arrhythmia risk between iPSC-CM treatment and control groups. In conclusion, this meta-analysis indicates iPSC-CM therapy's promise as a safe and beneficial intervention for enhancing heart function in IHD. However, due to observed heterogeneity, the efficacy of this treatment must be further explored through large randomized controlled trials based on rigorous research design.

The Theoretical and Experimental Insights into the Radical Scavenging Activity of Rubiadin.

Rubiadin (RBD), an anthraquinone derivative, is obtained from Rubia cordifolia, a plant species classified under the Rubiaceae family. Rubiadin has proven beneficial properties, such as anticancer, neuroprotective, anti-inflammatory, and antidiabetic activity. The antioxidant activity of this molecule was suggested by some experimental results but has not been clearly established thus far. In this study, we employ DFT calculations to comprehensively assess the mechanism and kinetics of the HO•/HOO• radical scavenging activity of this compound in relation to solvents. RBD showed moderate HO• radical scavenging activity, with rate constants of 2.95 × 108 and 1.82 × 1010 M-1 s-1 in lipid and polar media, respectively. In the aqueous solution, the compound exhibited remarkable superoxide anion radical scavenging activity (k = 4.93 × 108 M-1 s-1) but modest HOO• antiradical activity. RBD also showed promising antiradical activity against a variety of radicals (CCl3O•, CCl3OO•, NO2, SO4•-, and N3•), while experimental and computational results confirmed that RBD has moderate activity in DPPH/ABTS•+ assays. Thus, RBD is predicted to be a good, albeit selective, radical scavenger.

A Comprehensive Study of the Radical Scavenging Activity of Rosmarinic Acid.

Rosmarinic acid (RA) is reported in separate studies to be either an inducer or reliever of oxidative stress, and this contradiction has not been resolved. In this study, we present a comprehensive examination of the radical scavenging activity of RA using density functional theory calculations in comparison with experimental data. In model physiological media, RA exhibited strong HO• radical scavenging activity with overall rate constant values of 2.89 × 1010 and 3.86 × 109 M-1 s-1. RA is anticipated to exhibit excellent scavenging properties for HOO• in an aqueous environment (koverall = 3.18 × 108 M-1 s-1, ≈2446 times of Trolox) following the hydrogen transfer and single electron transfer pathways of the dianion state. The neutral form of the activity is equally noteworthy in a lipid environment (koverall = 3.16 × 104 M-1 s-1) by the formal hydrogen transfer mechanism of the O6(7,15,16)-H bonds. Chelation with RA may prevent Cu(II) from reduction by the ascorbic acid anion (AA-), hence blocking the OIL-1 pathway, suggesting that RA in an aqueous environment also serves as an OIL-1 antioxidant. The computational findings exhibit strong concurrence with the experimental observations, indicating that RA possesses a significant efficacy as a radical scavenger in physiological environments.

Antiradical Activity of Lignans from Cleistanthus sumatranus: Theoretical Insights into the Mechanism, Kinetics, and Solvent Effects.

Sumatranus lignans (SL) isolated from Cleistanthus sumatranus have demonstrated bioactivities, e.g., they were shown to exhibit immunosuppressive properties in previous research. Their structure suggests potential antioxidant activity that has not attracted any attention thus far. Consistently, a comprehensive analysis of the antioxidant activity of these compounds is highly desirable with the view of prospective medical applications. In this work, the mechanism and kinetics of the antiradical properties of SL against hydroperoxyl radicals were studied by using calculations based on density functional theory (DFT). In the lipid medium, it was discovered that SL reacted with HOO• through the formal hydrogen transfer mechanism with a rate constant of 101-105 M-1 s-1, whereas in aqueous media, the activity primarily occurred through the sequential proton loss electron transfer mechanism with rate constants of 102-108 M-1 s-1. In both lipidic and aqueous environments, the antiradical activity of compounds 6 and 7 exceeds that of resveratrol, ascorbic acid, and Trolox. These substances are therefore predicted to be good radical scavengers in physiological environments.

Human tauopathy strains defined by phosphorylation in R1-R2 repeat domains of tau.

Distinctive post-translational modifications (PTM) characterize tau inclusions found in tauopathy patients. Using detergent-insoluble tau isolated from Alzheimer's disease (AD-tau) or Progressive Supranuclear Palsy (PSP-tau) patients, we provide insights into whether phosphorylation of critical residues determine templated tau seeding. Our initial data with phosphorylation-ablating mutations (Ser/Thr → Ala) on select sites of P301L tau showed no changes in seeding efficacy by AD-tau or PSP-tau. Interestingly, when specific sites in the R1-R2 repeat domains (Ser262/Thr263/Ser289/Ser305) were mutated to phosphorylation-mimicking amino acid Glu, it substantially reduced the seeding efficiency of AD-tau, but not PSP-tau seeds. The resultant detergent-insoluble tau shows deficient phosphorylation on AT8, AT100, AT180 and PHF1 epitopes, indicating inter-domain cooperativity. We further identify Ser305 as a critical determinant of AD-tau-specific seeding, whereby the phospho-mimicking Ser305Glu tau abrogates seeding by AD-tau but not PSP-tau. This suggests that phosphorylation on Ser305 could be related to the formation of disease-specific tau strains. Our results highlight the existence of a phospho-PTM code in tau seeding and further demonstrate the distinctive nature of this code in 4R tauopathies.

The alkoxy radical polymerization of N-vinylpyrrolidone in organic solvents: theoretical insight into the mechanism and kinetics.

Poly(N-vinylpyrrolidone) (PVP) is a polymer with many applications in cosmetic, pharmaceutical, and biomedical formulations due to its minimal toxicity. PVP can be synthesized through radical polymerization in organic solvents; this well-known industrial process is thoroughly characterized experimentally, however, quantum chemical modeling of the process is scarce: the mechanism and kinetics have not been thoroughly investigated yet. In this work, the mechanism and kinetics of the alkoxy radical polymerization of N-vinylpyrrolidone in organic solvents, namely isopropanol (IP) and toluene (TL), were successfully modeled by computational chemistry. The initiator radicals di-tert-butyl peroxide (TBO˙) and dicumyl peroxide (CMO˙) as well as the solvents isopropanol and toluene, were shown to be capable of assisting in the initiation reactions. The rate constant was influenced by the combination of initiators and solvent and the values of the rate constant of propagation were approximately 101-103 M-1 s-1. The radical polymerization of NVP with dicumyl peroxide as an initiator was comparable to that of di-tert-butyl peroxide in all of the examined organic solvents, whereas the solvents had less of an effect.

Study of the Mechanism and Kinetics of the Radical Scavenging Activity of 2-Mercaptoimidazole.

2-Mercaptoimidazole (2MI) is related to natural ovothiols that are recognized as powerful radical scavengers. Yet, despite early reports of its potent antioxidant properties, 2MI received little attention. Specifically, its radical scavenging activity against typical free radicals like HO• and HOO• has not yet been studied in terms of its mechanism and kinetics. In this project, density functional theory (DFT) simulations were used to assess the antiradical activity of 2MI. Calculations indicate that 2MI can demonstrate anti-HO• activity in both lipid and aqueous environments (koverall of 1.05 × 1010 and 2.07 × 1010 M-1 s-1, respectively). The calculated kinetics is extremely close to the experimental data in water (pH = 7.0), resulting in a kcalculated/kexperimental ratio of 1.73, validating the accuracy of the computational method and its usefulness for assessing radical scavenging activity in silico. In lipid media, the HOO• radical scavenging activity of 2MI is faster than that of common typical natural scavengers such as ascorbic acid, Trolox, and trans-resveratrol; hence, 2MI is a powerful radical scavenger in nonpolar media.

Humanized APOE genotypes influence lifespan independently of tau aggregation in the P301S mouse model of tauopathy.

Apolipoprotein (APOE) E4 isoform is a major risk factor of Alzheimer's disease and contributes to metabolic and neuropathological abnormalities during brain aging. To provide insights into whether APOE4 genotype is related to tau-associated neurodegeneration, we have generated human P301S mutant tau transgenic mice (PS19) that carry humanized APOE alleles (APOE2, APOE3 or APOE4). In aging mice that succumbed to paralysis, PS19 mice homozygous for APOE3 had the longest lifespan when compared to APOE4 and APOE2 homozygous mice (APOE3 > APOE4 ~ APOE2). Heterozygous mice with one human APOE and one mouse Apoe allele did not show any variations in lifespan. At end-stage, PS19 mice homozygous for APOE3 and APOE4 showed equivalent levels of phosphorylated tau burden, inflammation levels and ventricular volumes. Compared to these cohorts, PS19 mice homozygous for APOE2 showed lower induction of phosphorylation on selective epitopes, though the effect sizes were small and variable. In spite of this, the APOE2 cohort showed shorter lifespan relative to APOE3 homozygous mice. None of the cohorts accumulated appreciable levels of phosphorylated tau compartmentalized in the insoluble cell fraction. RNAseq analysis showed that the induction of immune gene expression was comparable across all the APOE genotypes in PS19 mice. Notably, the APOE4 homozygous mice showed additional induction of transcripts corresponding to the Alzheimer's disease-related plaque-induced gene signature. In human Alzheimer's disease brain tissues, we found no direct correlation between higher burden of phosphorylated tau and APOE4 genotype. As expected, there was a strong correlation between phosphorylated tau burden with amyloid deposition in APOE4-positive Alzheimer's disease cases. Overall, our results indicate that APOE3 genotype may confer some resilience to tauopathy, while APOE4 and APOE2 may act through multiple pathways to increase the pathogenicity in the context of tauopathy.

Feruloylmonotropeins: promising natural antioxidants in Paederia scandens.

Paederia scandens (Lour.) is a widely used medicinal herb in Vietnam, China, India, and Japan for the treatment of a variety of conditions, including toothache, chest pains, piles, and spleen inflammation. There is broad interest in identifying the composition of its extracts and confirming their numerous biological activities, including anti-nociceptive, antiviral, and anticancer properties. Two iridoid glucosides obtained from the MeOH extract of P. scandens, 6'-O-E-feruloylmonotropein (6-FMT) and 10'-O-E-feruloylmonotropein (10-FMT), are potential antioxidants based on their structure. In this study, the hydroperoxyl scavenging activity of 6-FMT and 10-FMT was examined in silico by using density functional theory. These FMTs are predicted to be weak antioxidants in non-polar environments, whereas a good HOO˙ scavenging activity is expected in polar environments (pH = 7.4) with k overall = 3.66 × 107 M-1 s-1 and 9.45 × 106 M-1 s-1, respectively. This activity is better than many common antioxidants such as trolox and nearly equivalent to ascorbic acid and resveratrol. The hydroperoxyl scavenging activity was exerted mainly by the di-anion form of FMTs in water at physiological pH following the single electron transfer mechanism. The results suggest that FMTs are promising natural antioxidants in aqueous physiological environments.

Reactions of nicotine and the hydroxyl radical in the environment: Theoretical insights into the mechanism, kinetics and products.

Nicotine (NCT) is a prevalent and highly poisonous tobacco alkaloid found in wastewater discharge. Advanced oxidative processes (AOP) are radical interactions between harmful pollutants and ambient free radicals that, theoretically, result in less toxic compounds. For a better understanding of the chemical transformations and long-term environmental effects of toxic discharges, the study of these processes is crucial. Here, quantum chemical calculations are used to investigate the AOP of the NCT in aqueous and lipidic environments. It was found that NCT interacted with HO• in polar and nonpolar media, with an overall rate constant koverall = 106 - 1010 M-1 s-1. The computed kinetic data are reasonably accurate as seen by the comparison with the experimental rate constant in water (pH = 7.0), which results in a kcalculated/kexperimetal ratio of 1.4. The hydrogen transfer (C7, C9, C12)-single electron transfer pathways are the main mechanisms for the HO• + NCT reaction in pentyl ethanoate solvent to form the cations as the primary products of the two-step reaction. However, in aqueous environments, the degradation of NCT by HO• radicals increases with increasing pH levels. It is predicted that oxidation products are less toxic than nicotine itself, especially in an aqueous environment with a pH < 7.0.

Large-Scale Synthesis of Nanosilica from Silica Sand for Plant Stimulant Applications.

Nanosilica is a versatile nanomaterial suitable as, e.g., drug carriers in medicine, fillers in polymers, and fertilizer/pesticide carriers and potentially a bioavailable source of silicon in agriculture. The enhanced biological activity of nanosilica over quartz sand has been noted before; it is directly related to the altered physicochemical properties of the nanoparticles compared to those of the bulk material. Therefore, it is feasible to use nanosilica as a form of plant stimulant. Nanosilica synthesis is a relatively cheap routine process on the laboratory scale; however, it is not easily scalable. Largely for this reason, studies of nanosilica fertilizers are scarce. This study will focus on industrial-scale silica nanoparticle production and the application of nanosilica as a plant stimulant in maize. A variant of the sol-gel method is used to successfully synthesize nanosilica particles starting from silica sand. The resulting particles are in the size range of 16-37 nm with great purity. The potential of nanosilica as a plant stimulant is demonstrated with the increased quantity and quality of maize crops.

The radical scavenging activity of glycozolidol in physiological environments: a quantum chemical study.

Glycozolidol was isolated from the root of Glycosmis pentaphylla (6-hydroxy-2-methoxy-3-methylcarbazole, GLD). This molecule attracted considerable interest due to its beneficial biological activities that likely stem from its antioxidant activity; yet, the radical scavenging action of GLD has not been investigated thus far. In this study, DFT calculations were used to estimate the radical scavenging activity of GLD against a variety of biologically significant radical species in physiological environments. The findings demonstrated that GLD exerts significant antiradical activity in water at pH = 7.40 and in pentyl ethanoate (as a model of lipidic media) with k overall = 8.23 × 106 and 3.53 × 104 M-1 s-1, respectively. In aqueous solution, the sequential proton-loss electron transfer mechanism made the highest contribution to the activity, whereas in nonpolar solvents the formal hydrogen transfer mechanism dominated the activity. GLD is predicted to have strong antiradical activity against CH3O˙, CH3OO˙, CCl3OO˙, NO2, SO4˙-, DPPH and ABTS+˙ k app ≈ 109 M-1 s-1 and k f ≈ 106 M-1 s-1. The results suggest that GLD is a good radical scavenger in physiological environments.

Synthesis and evaluation of the antioxidant activity of 3-pyrroline-2-ones: experimental and theoretical insights.

The heterocyclic γ-lactam ring 2-pyrrolidinone has four carbon atoms and one nitrogen atom. Among the group of derivatives of 2-pyrrolidinones, 1,5-dihydro-2H-pyrrol-2-ones, also known as 3-pyrroline-2-ones, play a significant structural role in a variety of bioactive natural compounds. In this study, three-component reactions were used to successfully synthesize six polysubstituted 3-hydroxy-3-pyrroline-2-one derivatives. The antioxidant activity of the compounds was tested by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, identifying 4-ethoxycarbonyl-3-hydroxy-5-(4-methylphenyl)-1-phenyl-3-pyrroline-2-one (4b) as the most promising radical scavenger. Quantum chemistry calculations of the thermodynamics and kinetics of the radical scavenging activity also suggest that 4b is an effective HO˙ radical scavenger, with k overall values of 2.05 × 109 and 1.54 × 1010 M-1 s-1 in pentyl ethanoate and water, respectively. On the other hand, 4b could not scavenge hydroperoxyl radicals in either media. The ability of 4b to scavenge hydroxyl radicals in polar and non-polar environments is comparable to that of conventional antioxidants such as melatonin, gallic acid, indole-3-carbinol, ramalin, or Trolox. Thus 4b may be classed as a promising HO˙ radical scavenger in the physiological environment.

MhcII Regulates Transmission of α-Synuclein-Seeded Pathology in Mice.

MHCII molecules, expressed by professional antigen-presenting cells (APCs) such as T cells and B cells, are hypothesized to play a key role in the response of cellular immunity to α-synuclein (α-syn). However, the role of cellular immunity in the neuroanatomic transmission of α-syn pre-formed fibrillar (PFF) seeds is undetermined. To illuminate whether cellular immunity influences the transmission of α-syn seeds from the periphery into the CNS, we injected preformed α-syn PFFs in the hindlimb of the Line M83 transgenic mouse model of synucleinopathy lacking MhcII. We showed that a complete deficiency in MhcII accelerated the appearance of seeded α-syn pathology and shortened the lifespan of the PFF-seeded M83 mice. To characterize whether B-cell and T-cell inherent MhcII function underlies this accelerated response to PFF seeding, we next injected α-syn PFFs in Rag1-/- mice which completely lacked these mature lymphocytes. There was no alteration in the lifespan or burden of endstage α-syn pathology in the PFF-seeded, Rag1-deficient M83+/- mice. Together, these results suggested that MhcII function on immune cells other than these classical APCs is potentially involved in the propagation of α-syn in this model of experimental synucleinopathy. We focused on microglia next, finding that while microglial burden was significantly upregulated in PFF-seeded, MhcII-deficient mice relative to controls, the microglial activation marker Cd68 was reduced in these mice, suggesting that these microglia were not responsive. Additional analysis of the CNS showed the early appearance of the neurotoxic astrocyte A1 signature and the induction of the Ifnγ-inducible anti-viral response mediated by MhcI in the MhcII-deficient, PFF-seeded mice. Overall, our data suggest that the loss of MhcII function leads to a dysfunctional response in non-classical APCs and that this response could potentially play a role in determining PFF-induced pathology. Collectively, our results identify the critical role of MhcII function in synucleinopathies induced by α-syn prion seeds.

A Potent Antioxidant Sesquiterpene, Abelsaginol, from Abelmoschus sagittifolius: Experimental and Theoretical Insights.

The sesquiterpenoid compound abelsaginol (AS) was successfully isolated from Abelmoschus sagittifolius for the first time. The compound was identified using NMR and MS data. The antioxidant activity of AS was also evaluated both theoretically and experimentally. AS was found to be a weak HOO• radical scavenger in organic solvents such as pentyl ethanoate and dimethyl sulfoxide (k overall = ∼ 102 M-1 s-1), in a good agreement with the results of the 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) assay. However, AS exhibited good HOO• antiradical activity in water at pH 7.40 (k overall = 9.00 × 106 M-1 s-1) through the single-electron transfer mechanism of the anion state. Further calculations also demonstrated that AS could exert good to moderate activity against CH3O•, CH3OO•, CCl3OO•, NO2, and SO4 •- radicals, with k f values from 4.00 × 103 to 1.52 × 107 M-1 s-1. However, AS exerted much lower activity against HO•, CCl3O•, NO, O2 •-, and N3 • radicals under the studied conditions. In general, the activity of AS in water at pH 7.40 is higher than that of Trolox or butylated hydroxytoluene, which are common reference antioxidants. Thus, in an aqueous physiological milieu, AS is a promising natural antioxidant.

Deletion of Abi3/Gngt2 influences age-progressive amyloid ß and tau pathologies in distinctive ways.

BACKGROUND: The S209F variant of Abelson Interactor Protein 3 (ABI3) increases risk for Alzheimer's disease (AD), but little is known about its function in relation to AD pathogenesis. METHODS: Here, we use a mouse model that is deficient in Abi3 locus to study how the loss of function of Abi3 impacts two cardinal neuropathological hallmarks of AD-amyloid ß plaques and tau pathology. Our study employs extensive neuropathological and transcriptomic characterization using transgenic mouse models and adeno-associated virus-mediated gene targeting strategies. RESULTS: Analysis of bulk RNAseq data confirmed age-progressive increase in Abi3 levels in rodent models of AD-type amyloidosis and upregulation in AD patients relative to healthy controls. Using RNAscope in situ hybridization, we localized the cellular distribution of Abi3 in mouse and human brains, finding that Abi3 is expressed in both microglial and non-microglial cells. Next, we evaluated Abi3-/- mice and document that both Abi3 and its overlapping gene, Gngt2, are disrupted in these mice. Using multiple transcriptomic datasets, we show that expression of Abi3 and Gngt2 are tightly correlated in rodent models of AD and human brains, suggesting a tight co-expression relationship. RNAseq of the Abi3-Gngt2-/- mice revealed upregulation of Trem2, Plcg2, and Tyrobp, concomitant with induction of an AD-associated neurodegenerative signature, even in the absence of AD-typical neuropathology. In APP mice, loss of Abi3-Gngt2 resulted in a gene dose- and age-dependent reduction in Aß deposition. Additionally, in Abi3-Gngt2-/- mice, expression of a pro-aggregant form of human tau exacerbated tauopathy and astrocytosis. Further, using in vitro culture assays, we show that the AD-associated S209F mutation alters the extent of ABI3 phosphorylation. CONCLUSIONS: These data provide an important experimental framework for understanding the role of Abi3-Gngt2 function and early inflammatory gliosis in AD. Our studies also demonstrate that inflammatory gliosis could have opposing effects on amyloid and tau pathology, highlighting the unpredictability of targeting immune pathways in AD.

The hydroperoxyl radical scavenging activity of natural hydroxybenzoic acids in oil and aqueous environments: Insights into the mechanism and kinetics.

Foods that contain hydroxybenzoic acid derivatives (HBA) include red fruits, black radish, onion, and potato peel. HBA are widely known for their anti-inflammatory, anti-cancer, and especially antioxidant capabilities; however, a comprehensive study of the mechanism and kinetics of the antiradical action of these compounds has not been performed. Here, we report a study on the mechanisms and kinetics of hydroperoxyl radical scavenging activity of HBA by density functional theory (DFT) calculations. According to the results, HBA exert low HOO• antiradical activity in the nonpolar environment with overall rate constants in the range of koverall = 5.90 × 10-6 - 4.10 × 103 M-1 s-1. However, most HBA exhibit significant HOO• antiradical activity (koverall = 105 - 108 M-1 s-1) by the single electron transfer (SET) reaction of the phenoxide anions in water at physiological pH. The overall rate constant increases with increasing pH values in the majority of the substances studied. At pH ≤ 4, gentisic acid had the best HOO• antiradical activity (log(koverall) = 3.7-4.8), however at pH > 4, the largest HOO• radical scavenging activity (log(koverall) = 4.8-9.8) was almost exclusively found for gallic and syringic acids. Salicylic and 5-sulphosalicylic acids have the lowest antiradical activity across most of the pH range. The activities of the majority of the acids in this study are faster than the reference compound Trolox. Thus, in the aqueous physiological environment, these HBA are good natural antioxidants.