Effects of Broussonetia papyrifera (L.) L'Hér. ex Vent. fruits water extract on hippocampal neurogenesis in the treatment of APP/PS1 transgenic mice.

Background: Adult neurogenesis plays an important role in repairing damaged neurons and improving cognitive impairment in Alzheimer's disease (AD). B. Papyrifera (L.) L'Hér. ex Vent. fruits (BL), a traditional Chinese medicine for tonifying the kidney, has been reported to improve cognitive function in AD mice, but the underlying mechanisms have not been clearly illuminated. This study aimed to provide an overview of the differential compounds in the brain of APP/PS1 mice after BL water extract (BLWE) treatment through metabolomics technology and to elucidate whether the therapeutic effect and mechanism are through the enhancement of neurogenesis. Methods: APP/PS1 transgenic mice were treated with different doses of BLWE. After 6 weeks of intragastric injection, the therapeutic effects of BLWE on APP/PS1 transgenic mice were determined by the Morris water maze test, immunohistochemistry, hematoxylin & eosin and Nissl staining, enzyme-linked immunosorbent assay and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. Subsequently, metabolomics technology was used to analyze the regulatory effect of BLWE on differential compounds in the brain of APP/PS1 mice, and on this basis, its molecular mechanism of BLWE was screened. Finally, the protein expression of the Wnt/ß-catenin signaling pathway was detected by Western blotting. Results: After BLWE treatment, the learning and memory function of APP/PS1 mice were significantly improved, which was related to the increase in the number of Nestin+/BrdU+ and NeuN+/BrdU+ cells, and the decrease in the number of apoptotic cells in the hippocampus. BLWE treatment could also up-regulate the expression of synapse-associated proteins. Moreover, BLWE could modulate endogenous metabolic compounds in the brains of AD mice, including N-acetyl-aspartate, glutamine, etc. Furthermore, BLWE inhibited the phosphorylation of Tyr216-GSK-3ß and ß-catenin protein while increased CyclinD1 protein expression. Conclusion: We demonstrated that BLWE can enhance neural stem cells proliferation and improve neurogenesis, thereby efficiently repairing damaged neurons in the hippocampus and ameliorating cognitive impairment in APP/PS1 transgenic mice. The mechanism is at least partly through activating the Wnt/ß-catenin signaling pathway.

Effect of Cd on Mechanical Properties of Al-Si-Cu-Mg Alloys under Different Multi-Stage Solution Heat Treatment.

Multi-stage heat treatment is an important method to improve the mechanical properties of Al-Si-Cu-Mg aluminum alloys. In this paper, the multi-stage heat treatment was carried out for the Cd-free and Cd-containing alloys. The experimental results show that the addition of Cd promoted the precipitation of Q″ and θ″, which led to the formation of a large number of fine, dispersed precipitates and a higher yield strength (YS) and ultimate tensile strength (UTS) for the Cd-containing alloys. The addition of Cd also altered the optimal heat treatment parameters. For the Cd-free alloys, the Cu-rich phase fully dissolved after three-stage heat treatment, and the YS and UTS of the three-stage heat-treated alloys were higher than their two-stage heat-treated counterparts. For the Cd-containing alloys, the three-stage heat treatment led to the precipitation of Cd-rich low melting point phases, caused defects, and reduced the mechanical properties of the alloy. The size and volume fractions of the precipitates were significantly less than those of the alloys after two-stage heat treatment and the strength of the alloys decreased. Therefore, the solution time should be strictly controlled for Cd-containing Al-Si-Cu-Mg alloys.

Correlation between focal lesion sites and language deficits in the acute phase of post-stroke aphasia.

INTRODUCTION: Focal lesion sites can predict the language function of patients with aphasia during the subacute or chronic phases. However, the relationship between focal lesion sites and language deficits in the acute phase remains unclear. Therefore, our study aimed to investigate the relationship between focal lesion sites and fluency, auditory comprehension, repetition and naming deficits in patients with acute aphasia to further understand the pathophysiological mechanism of aphasia. MATERIAL AND METHODS: We included a total of 52 patients with acute aphasia who had their first-ever stroke between June 2018 and June 2021 to investigate the association between focal lesion sites and fluency, auditory comprehension, repetition and naming deficits. Language function was assessed by the Western Aphasia Battery scale within one month of onset. The lesion sites were independently assessed by three professional speech and language pathologists according to the main sulcus of the brain within 1-2 days after stroke. RESULTS: Lesions involving the superior temporal gyrus, middle frontal gyrus, inferior frontal gyrus, precentral gyrus, postcentral gyrus, supramarginal gyrus, angular gyrus and insula were significantly associated with low fluency. Lesions involving the superior temporal gyrus, middle temporal gyrus, inferior temporal gyrus, middle frontal gyrus, inferior frontal gyrus, supramarginal gyrus and angular gyrus significantly resulted in auditory comprehension impairment. Lesions involving the superior temporal gyrus, middle temporal gyrus, middle frontal gyrus, inferior frontal gyrus, precentral gyrus, postcentral gyrus, supramarginal gyrus, angular gyrus and insula significantly resulted in repetition and naming deficits. CONCLUSIONS: Our study suggests that focal lesion sites could lead to different language function impairments in the acute phase of post-stroke aphasia, which adds to our understanding of speech pathology and provides a direction for future research and treatment.

A Novel Blockade CD47 Antibody With Therapeutic Potential for Cancer.

Macrophages as components of the innate immune system play a critical role in antitumor responses. Strategies for targeting CD47 are becoming a hot spot for cancer therapy. The expression of CD47 is exercised by macrophages to make a distinction between "self" or "nonself." Anti-CD47 antibodies block the interaction between macrophage signal regulatory protein-α (SIRPα) and tumor surface CD47. In this study, we report and assess a novel anti-CD47 blocking antibody named 2C8, which exhibits high affinity and tremendous anticancer effects. More concretely, 2C8 significantly induces macrophages, including protumorigenic subtype M2 macrophages killing tumor cells in vitro, and is revealed to be more effective than commercially available anti-CD47 mAb B6H12.2. In vivo, 2C8 controls tumor growth and extends survival of xenograft mice. The antitumor ability of 2C8 might be applicable to many other cancers. The generation of a novel CD47 antibody contributes to consolidating clinical interest in targeting macrophages for the treatment of malignancy and, moreover, as a supplement therapy when patients are resistant or refractory to other checkpoint therapies or relapse after such treatments.

An Engineered Fusion Protein Anti-CD19(Fab)-LDM Effectively Inhibits ADR-Resistant B Cell Lymphoma.

The 5-year survival rate of patients with B cell lymphoma is about 50% after initial diagnosis, mainly because of resistance to chemotherapy. Hence, it is necessary to understand the mechanism of chemo-resistance and to explore novel methods to circumvent multidrug resistance. Previously, we showed that an engineered cytotoxic fusion protein anti-CD19(Fab)-LDM (lidamycin), can induce apoptosis of B-lymphoma cells. Herein, we successfully established an adriamycin (ADR)-resistant B cell lymphoma cell line BJAB/ADR. The mRNA and protein level of ATP-binding cassette subfamily B member 1 (ABCB1) were significantly overexpressed in BJAB/ADR cells. Increased efflux function of ABCB1 was observed by analyzing intracellular accumulation and efflux of Rhodamine 123. The efflux of Rhodamine 123 could be significantly ameliorated by verapamil. Treatment with anti-CD19(Fab)-LDM at different concentrations induced cytotoxic response of BJAB/ADR cells similar to that of the sensitive cells. In vivo studies showed that anti-CD19(Fab)-LDM had better antitumor effect in BJAB and BJAB/ADR cell lymphoma xenografts compared with ADR or LDM treatment alone. Taken together, anti-CD19(Fab)-LDM can effectively inhibit the growth of BJAB/ADR cells both in vitro and in vivo. Anti-CD19(Fab)-LDM could be a promising molecule for the treatment of drug resistant cancers.

Bispecific CD3-HAC carried by E1A-engineered mesenchymal stromal cells against metastatic breast cancer by blocking PD-L1 and activating T cells.

BACKGROUND: PD-1/PD-L1 blockade can confer durable benefits in the treatment of metastatic cancers, but the response rate remains modest and potential adverse effects occur sometimes. Concentrating immunotherapeutic agents at the site of disease was believed to break local immune tolerance and reduce systemic toxicity. E1A-engineered mesenchymal stromal cell (MSC.E1A) was an attractive transfer system that preferentially homing and treating cancer metastasis, through which the tumor cells were modified by locally replicated adenoviruses to release CD3-HAC, a bifunctional fusion protein that anti-CD3 scfv linked with high-affinity consensus (HAC) PD-1. Subsequently, CD3-HAC, wbich was bound on PD-L1-positive breast cancer cells, recruited T cells to exhibit a potent antitumor immunity incombination with immune checkpoint blockade. METHODS: We constructed the CD3-HAC gene driven by human telomerase reverse transcriptase (hTERT) promoter into an adenoviral vector and the E1A gene into the lentiviral vector. The homing property of MSCs in vivo was analyzed with firefly luciferase-labeled MSCs (MSC.Luc) by bioluminescent imaging (BLI). The cytotoxicity of T cells induced by CD3-HAC towards PD-L1-positive cells was detected in vitro and in vivo in combination with 5-FU. RESULTS: Our data suggest that CD3-HAC could specifically bind to PD-L1-positive tumor cells and induce lymphocyte-mediated lysis effectively both in vitro and in vivo. The intervention with HAC diminished the effects of PD-1/PD-L1 axis on T cells exposed to MDA-MB-231 cells and increased lymphocytes activation. MSCs infected by AdCD3-HAC followed by LentiR.E1A could specially migrate to metastasis of breast cancer and produce adenoviruses in the tumor sites. Furthermore, treatment with MSC.CD3-HAC.E1A in combination with 5-FU significantly inhibited the tumor growth in mice. CONCLUSIONS: This adenovirus-loaded MSC.E1A system provides a promising strategy for the identification and elimination of metastasis with locally released immuno-modulator.