Vascular dementia (VD) results from accumulated damage in the vascular system, which is characterized by progressive impairments in memory and cognition and is second only to Alzheimer's disease (AD) ...in prevalence among all types of dementia. In contrast to AD, there is no FDA-approved treatment for VD owing to its multiple etiologies. In this study, we investigated whether CZ-7, a new derivative of Claulansine F (Clau F) with verified neuroprotective activity in vitro, could ameliorate the cognitive impairment of rats with permanent occlusion of bilateral common carotid arteries (2VO) and its potential mechanisms of action. The 2VO rats were orally administered CZ-7 (10, 20, 40 mg/kg) from day 27 to day 53 post-surgery. Morris water maze tests conducted at day 48-51 revealed that CZ-7 administration significantly reduced the escape latency in 2VO rats. After the rats were sacrificed on day 53, morphological studies using Nissl and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining showed that administration of CZ-7 markedly attenuated the pathological changes in CA1-CA3 area of the hippocampus, including neuronal cell loss, nuclear shrinkage, and dark staining of neurons, and significantly decreased the chronic cerebral hypoperfusion-induced cell loss. Klüver-Barrera staining study revealed that CZ-7 administration significantly improved the white matter lesions. 8-OHdG and reactive oxygen species (ROS) immunofluorescent analyses showed that CZ-7 administration significantly decreased oxidative stress in CA1-CA3 area of the hippocampus. Finally, we found that the CZ-7-improved oxidative stress might be mediated via the Nrf2 pathway, evidenced by the double immunofluorescent staining of Nrf2 and the elevation of expression levels of oxidative stress proteins HO-1 and NQO1. In conclusion, CZ-7 has therapeutic potential for VD by alleviating oxidative stress injury through Nrf2-mediated antioxidant responses.
An effective approach for discovering small molecular inhibitors is the residues-oriented strategy based on enzyme analysis. In this study, we employed a rational approach to design and synthesize a ...library of butenolide analogues (
Ia-f
and
IIa-f
) targeting Trp107, utilizing reported piperonyl butenolide as lead compound. Notably, the most compounds
IIa-f
(R
2
= NO
2
) exhibited slightly higher inhibitory potency against
Of
ChtI compared to compounds
Ia-f
(R
2
= Br). Molecular mechanism studies unveiled a crucial hydrogen bond interaction between the NO
2
group and Trp107, explaining the enhanced binding affinities. Compounds
IIe
and
IIf
, both bearing NO
2
on the benzene ring at the R
2
position, displayed the highest inhibitory activity, with
K
i
values of 0.87 and 0.68
μ
M, respectively. Our findings highlight the potential of designing inhibitors with high enzymatic activity by structurally optimizing compounds based on the distinct interaction modes with crucial residues in the binding cavity of
Of
ChtI.
Epidermolysis bullosa acquisita (EBA) is a rare chronic subepidermal bullous autoimmune disease. The occurrence of acquired hemophilia A (AHA) is low and so the coexistence of EBA and AHA is ...extremely rare. We herein described a case of EBA coexisting with AHA and a case of EBA coexisting with AHA and hepatitis B. These EBA may be related to the pathogenesis of AHA. In this study, we analyzed the clinical features in the two Chinese cases of EBA coexisting with AHA, and found esophageal hemorrhage and hematemesis were the main symptoms of both patients. Cyclosporin, prednisone and lamivudine effectively control EBA with AHA and hepatitis B. The dose of cyclosporin should be more than 4 mg/kg per day and the period of treatment should be longer than 5 months to reduce the risk of EBA co‐occurring with AHA.
The discovery of room-temperature ferromagnetism in van der Waals (vdW) materials opens new avenues for exploring low-dimensional magnetism and its applications in spintronics. Recently, the ...observation of the room-temperature topological Hall effect in the vdW ferromagnet Fe3GaTe2 suggests the possible existence of room-temperature skyrmions, yet skyrmions have not been directly observed. In this study, real-space imaging was employed to investigate the domain evolution of the labyrinth and skyrmion structure. First, Néel-type skyrmions can be created at room temperature. In addition, the influence of flake thickness and external magnetic field (during field cooling) on both labyrinth domains and the skyrmion lattice is unveiled. Due to the competition between magnetic anisotropy and dipole interactions, the specimen thickness significantly influences the density of skyrmions. These findings demonstrate that Fe3GaTe2 can host room-temperature skyrmions of various sizes, opening up avenues for further study of magnetic topological textures at room temperature.
Ten undescribed C12 polyketide phialocetones A-J, featuring twelve-, six- and five-membered lactone moieties, were isolated from a rhizospheric soil-derived Phialocephala sp. YUD18001 associated with ...Gastrodia elata. Their structures were established by NMR spectroscopic analysis and HRMS, while their absolute configurations were determined by computational methods and chemical reactions. All isolated compounds were evaluated for their anti-inflammatory and cytotoxic activities. As a result, phialocetone D exhibited moderate effects against NO production in lipopolysaccharide (LPS)-induced RAW264.7 cells with an IC50 value of 14.77 μM, while phialocetone E showed cytotoxicity against HL-60 and SW480 cell lines with IC50 values of 19.04 and 10.22 μM, respectively.
Ten undescribed C12 polyketide phialocetones were isolated from a rhizospheric soil-derived Phialocephala sp. YUD18001 associated with Gastrodia elata. Display omitted
•Ten undescribed C12 lactones were isolated from Phialocephala sp. YUD18001.•The lactones were divided into three types, including 12-, 6- and 5-membered ring.•Some of the lactones showed significant biological activities.
Abstract. Reduced bone formation in patients with T-cell acute lymphoblastic leukemia (T-ALL) may be related to the interaction between tumour cells and bone marrow stromal cells (BMSCs). The miRNAs ...in extracellular vesicles derived from leukemia cells play an essential role in regulating the function of BMSCs; however, the regulatory mechanisms remain unclear. The expression of miR-34a-5p in T-ALL patients and cells was measured by quantitative real-time PCR. BMSCs were co-cultured with extracellular vesicles isolated from T-ALL cells in mineralization medium. The osteogenic differentiation of BMSCs was evaluated by Alizarin Red S staining, alkaline phosphatase (ALP) staining, and detection of osteogenic differentiation markers. A dual-luciferase reporter assay was performed to confirm the targeting relationship between miR-34a-5p and Wnt family member 1 (WNT1). MiR-34a-5p expression was upregulated in T-ALL patients and Jurkat cells. After BMSCs were co-cultured with extracellular vesicles derived from T-ALL cells, osteogenic differentiation of BMSCs was inhibited, and bone mineralization and ALP activity were decreased compared to those of control cells. MiR-34a-5p knockdown in T-ALL cells restored osteogenic differentiation of BMSCs co-cultured with extracellular vesicles. In addition, miR-34a-5p targets and negatively regulates WNT1 expression. In conclusion, our results demonstrated that knockdown of miR-34a-5p in extracellular vesicles derived from T-ALL cells promoted osteogenic differentiation of BMSCs by regulating WNT1.
Eliminating malaria and preventing re-establishment of malaria transmission in border areas requires universal coverage of malaria surveillance and a rapid response to any threats (i.e. malaria cues) ...of re-establishing transmission.
Strategy 1: Intensive interventions within 2.5 km-wide perimeter along the border to prevent border-spill malaria. The area within 2.5 km along the international border is the travel radius of anopheline mosquitoes. Comprehensive interventions should include: (1) proactive and passive case detection, (2) intensive vector surveillance, (3) evidence-based vector control, and (4) evidence-based preventative treatment with anti-malarial drugs. Strategy 2: Community-based malaria detection and screening of migrants and travellers in frontier townships. Un-permitted travellers cross borders frequently and present in frontier townships. Maintenance of intensified malaria surveillance should include: (1) passive malaria detection in the township hospitals, (2) seek assistance from villager leaders and health workers to monitor cross border travellers, and refer febrile patients to the township hospitals and (3) the county's Centre for Disease Control and Prevention maintain regular proactive case detection. Strategy 3: Universal coverage of malaria surveillance to detect malaria cues. Passive detection should be consolidated into the normal health service. Health services personnel should remain vigilant to ensure universal coverage of malaria detection and react promptly to any malaria cues. Strategy + 1: Strong collaborative support with neighbouring countries. Based on the agreement between the two countries, integrated control strategies should be carried out to reduce malaria burden for both countries. There should be a clear focus on the border areas between neighbouring countries.
The 3 + 1 strategy is an experience summary of border malaria control and elimination, and then contributed to malaria elimination in Yunnan's border areas, China. Nevertheless, Yunnan still has remaining challenges of re-establishment of malaria transmission in the border areas, and the 3 + 1 strategy should still be carried out.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A multifunctional nanosystem with Fe2+-chelated ultra-uniform polydopamine shell was prepared from photosensitizer-loaded hollow silica mesoporous nanoparticle. The nanosystem enabled efficient ...anti-tumor effect through synergetic photodynamic therapy (PDT) and photothermal (PT)-enhanced chemodynamic therapy (CDT) while maintaining skin safety.
Display omitted
•An ultra-uniform polydopamine (PDA) shell was controllably synthesized on photosensitizer-loaded hollow silica mesoporous nanoparticles (NPs) via photo-generated 1O2.•The light-absorbing PDA shell with felicitous thickness endowed the multifunctional NPs with negligible skin phototoxicity while maintaining moderate 1O2 generation ability.•Owing to high metal-ion affinity and photothermal (PT) conversion of PDA shell, the multifunctional NPs exhibited PT-enhanced •OH generation (Fenton reaction).•Synergetic 638 nm PDT and 808 nm PT-enhanced CDT produced effective inhibition of not only tumor growth but also tumor metastasis.
Although photodynamic therapy (PDT) has been extensively studied as an established modality of cancer treatment, it still suffers from a few clinical limitations, such as skin phototoxicity and tumor hypoxia. To circumvent these hurdles, hollow silica mesoporous nanoparticles (HMSNs) loaded with photosensitizers were employed as the nanoplatform to construct multifunctional nanoparticles (NPs). Specifically, an ultra-uniform polydopamine (PDA) shell was highly controlled grown around HMSNs by photogenerated outwards-diffused 1O2, followed by conjugation of folic acid-poly(ethylene glycol) and chelation of Fe2+ ions. Thanks to the optimal thickness of light-absorbing PDA shell, the multifunctional NPs exhibited not only negligible skin phototoxicity but also efficient 1O2 generation and photothermal (PT)-enhanced •OH generation upon respective photoirradiation. Anti-tumor therapy was then performed on both 4 T1 tumor cells and tumor-bearing mice by the combination of 638 nm PDT and 808 nm PT-enhanced chemodynamic therapy (CDT). As a result, high therapeutic efficacy was achieved compared to single-modality therapy, with a cell inhibitory rate of 86% and tumor growth inhibition of 70.4% respectively. More interestingly, tumor metastasis was effectively inhibited by the synergetic treatment. These results convincingly demonstrate that our multifunctional NPs are very promising skin-safe PDT agents combined with CDT for efficient tumor therapy.
CeO2 is an important energy storage material that can be used in solid fuel cells. Adding citric acid can improve the particle distribution of the pyrolytic preparation of CeO2 inside the reactor. ...Through Fluent, this paper investigated the pyrolysis preparation of CeO2 with the addition of citric acid by adopting the Eulerian multiphase flow model, component transportation model, and standard k-ε turbulence model. The experimental and simulation results suggest that the addition of citric acid can alter the pressure, temperature, and component distributions inside the reactor. When the mass fraction of O2 is 0.3, the concentration distribution effect of the CeO2 component is optimal and its conversation rate is the highest. When the mass fraction of citric acid is 0.04, the concentration distribution effect of the CeO2 component is the best, as witnessed by the high CeO2 concentration at the exit. It was found that an O2 content of 30 wt % and citric acid content of 4 wt % were optimal operating conditions for this technology.
An unusual and highly effective asymmetric annulation of nitrosoarenes with hydroxymaleimides catalyzed by a chiral bifunctional amine squaramide catalyst has been disclosed. A wide range of highly ...fused chiral N-hydroxyindolines with two consecutive quaternary stereocenters and multifunctional groups were directly and effectively prepared in excellent yields (up to >99%) with complete regioselective cyclization and excellent stereoselectivities (up to >99:1 dr and >99% ee). The efficiency and potentials of the new reaction and the target chiral entities were well demonstrated by delicate transformations into a series of new chiral indolines.
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