FAAH inhibition can indirectly enhance endocannabinoid signaling to therapeutic levels, effectively preventing or slowing its progression of Alzheimer's disease (AD). Hence, the search for effective dual FAAH/cholinesterase inhibitors is considerable need for disease-modifying therapies. To this aim, we designed, synthesized, and tested three series of natural phenol carbamates. The majority of carbamates proved to be potent on a single target, amongst them, compound D12 containing paeonol motif was identified as an effective dual BuChE/FAAH inhibitor, with well-balanced nanomolar activity (IC₅₀ = 81 and 400 nM for hBuChE and hFFAH, respectively). D12 possessed BBB penetrating ability, benign safety, neuroprotection and pseudo-irreversible BuChE inhibition (K_d = 2.11 μM, k₂ = 2.27 min^-1), showing good drug-like properties. D12 also modulated the BV2 microglial polarization to inhibit neuroinflammation. In vivo study verified that D12 improved Aβ_1-41-induced learning impairments in AD mouse model for both short- and long-term memory responses. Thus, the dual activity of D12 could lead to a potentially more effective treatment for the counteraction of AD progression.

2024-12-01·Applied Microbiology and Biotechnology

Preparation and application of fluorescent monoclonal antibodies recognizing goat CD4+CD25+ regulatory T cells

Article

作者: Gao, Shikong ; Yang, Haoyue ; Jiang, Yuecai ; Hu, Jiajin ; Chen, Dekun ; Ma, Wentao ; Wang, Yunpeng

AbstractRegulatory T cells (Tregs) are a subset of T cells participating in a variety of diseases including mycoplasmal pneumonia, contagious ecthyma, and so on. The role of Tregs in goat contagious ecthyma is not completely understood due to the lack of species-specific antibodies. Here, we developed a combination of CD4 and CD25 fluorescence monoclonal antibodies (mAb) to recognize goat Tregs and assessed its utility in flow cytometry, immunofluorescence staining. Using immunofluorescence staining, we found that the frequency of Treg cells was positively correlated with the viral load during orf virus infection. These antibodies could serve as important tools to monitor Tregs during orf virus infection in goats.Key points• A combination of fluorescent mAbs (C11 and D12) was prepared for the detection of goat Tregs.• C11 and D12 are effective in flow cytometry, immunofluorescence staining, and C11 has excellent species specificity.• The frequency of Treg cells was positively correlated with the viral load during orf virus infection.

2022-12-01·BMC Geriatrics

Validation of the Dyspnoea-12 and Multidimensional Dyspnea profile among older Swedish men in the population

Article

作者: Ekström, Magnus ; Olsson, Max

AbstractBackgroundThe Dyspnoea-12 (D12) and Multidimensional dyspnea profile (MDP) are commonly used instruments for assessing multiple dimensions of breathlessness but have not been validated in older people in the population. The aim of this study was to validate the D12 and MDP in 73-years old men in terms of the instruments’ underlying factor structures, internal consistency, and validity.MethodsA postal survey was sent out to a population sample of 73-years old men (n = 1,193) in southern Sweden. The two-factor structures were evaluated with confirmatory factor analysis, internal consistency with Cronbach's alpha, and validity using Pearson´s correlations with validated scales of breathlessness, anxiety, depression, fatigue, physical/mental quality of life, body mass index (BMI), and cardiorespiratory disease.ResultsA total 684 men were included. Respiratory and cardiovascular disease were reported by 17% and 38%, respectively. For D12 and MDP, the proposed two-factor structure was not fully confirmed in this population. Internal consistency was excellent for all D12 and MDP domain scores (Cronbach's alpha scores > 0.92), and the instruments’ domains showed concurrent validity with other breathlessness scales, and discriminant validity with anxiety, depression, physical/mental quality of life, BMI, and cardiorespiratory disease.ConclusionsIn a population sample of 73-years old men, the D12 and MDP had good psychometrical properties in terms of reliability and validity, which supports that the instruments are valid for use in population studies of older men.

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