Intercellular Signaling Pathways as Therapeutic Targets for Vascular Dementia Repair.

Vascular dementia (VaD) is a white matter ischemic disease and the second-leading cause of dementia, with no direct therapy. Within the lesion site, cell-cell interactions dictate the trajectory towards disease progression or repair. To elucidate the underlying intercellular signaling pathways, a VaD mouse model was developed for transcriptomic and functional studies. The mouse VaD transcriptome was integrated with a human VaD snRNA-Seq dataset. A custom-made database encompassing 4053 human and 2032 mouse ligand-receptor (L-R) interactions identified significantly altered pathways shared between human and mouse VaD. Two intercellular L-R systems, Serpine2-Lrp1 and CD39-A3AR, were selected for mechanistic study as both the ligand and receptor were dysregulated in VaD. Decreased Seprine2 expression enhances OPC differentiation in VaD repair. A clinically relevant drug that reverses the loss of CD39-A3AR function promotes tissue and behavioral recovery in the VaD model. This study presents novel intercellular signaling targets and may open new avenues for VaD therapies.

Perceived Effectiveness, Safety, and Attitudes Toward the Use of Nucleic Tests of SARS-CoV-2 Among Clinicians and General Public in China.

Objective: To assess whether there is a knowledge gap about the use of test kits for residents and to explore the knowledge, attitudes, and practices of using test kits in China during the coronavirus disease 2019 (COVID-19) epidemic. Method: An online-based, nationwide, and cross-sectional study was conducted. A total of 1,167 respondents were recruited from June 19 to July 2, 2020. All participants completed a validated questionnaire written in Chinese. Electronic consent was obtained from all participants upon their agreement to commence the questionnaire. Perceived efficacy, safety, and their attitudes toward the use of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing kits were measured. Result: The majority of the study respondents were female [749 (64.2%)], aged 31-40 years old [372 (31.9%)], and located in mainland China [1,137 (97.4%)]. The majority of the respondents held a positive view toward the introduction of the fast-track approval policy for novel coronavirus testing products (6.16 ± 1.30) as well as toward putting more investment in scientific research and biomedicine to improve the detection accuracy of detection kits (5.94 ± 1.55) in China. The respondents valued the detection accuracy more as opposed to the detection time of the testing kits (4.66 ± 2.00), whereas few participants agreed that in the research and development process, detection accuracy could be sacrificed to speed up production and coverage capacity (3.02 ± 2.04). Conclusion: The majority of the participants have a basic knowledge of the detection methods of the SARS-CoV-2 virus and the types of test kits, as well as great confidence in China's domestic production of test kits and decisions. However, how basic knowledge, high compliance, and positive attitudes play a role in easing the tension of the pandemic still remains unknown.

Inactivation of tumor suppressor gene Clusterin leads to hyperactivation of TAK1-NF-κB signaling axis in lung cancer cells and denotes a therapeutic opportunity.

Purpose: Clinical success of precision medicine is severely limited by de novo or acquired drug resistance. It remains a clinically unmet need to treat these patients. Tumor suppressor genes (TSGs) play a critical role in tumorigenesis and impact the therapeutic effect of various treatments. Experimental Design: Using clinical data, in vitro cell line data and in vivo mouse model data, we revealed the tumor suppressive role of Clusterin in lung cancer. We also delineated the signaling cascade elicited by loss of function of CLU in NSCLC cells and tested precision medicine for CLU deficient lung cancers. Results:CLU is a potent and clinically relevant TSG in lung cancer. Mechanistically, CLU inhibits TGFBR1 to recruit TRAF6/TAB2/TAK1 complex and thus inhibits activation of TAK1- NF-κB signaling axis. Lung cancer cells with loss of function of CLU show exquisite sensitivity to TAK1 inhibitors. Importantly, we show that a significant portion of Kras mutation positive NSCLC patients are concurrently deficient of CLU and that TAK1 kinase inhibitor synergizes with existing drugs to treat this portion of lung cancers patients. Conclusions: Combinational treatment with TAK1 inhibitor and MEK1/2 inhibitor effectively shrank Kras mutation positive and CLU deficient NSCLC tumors. Moreover, we put forward a concept that loss of function of a TSG rewires signaling network and thereby creates an Achilles' heel in tumor cells which could be exploited in precision medicine.

GATA6 Exerts Potent Lung Cancer Suppressive Function by Inducing Cell Senescence.

Lung cancer is the leading cause of cancer-related deaths worldwide. Tumor suppressor genes (TSGs) play a critical role in restricting tumorigenesis and impact the therapeutic effect of various treatments. However, TSGs remain to be systemically determined in lung cancer. Here, we identified GATA6 as a potent lung cancer TSG. GATA6 inhibited lung cancer cell growth in vitro and tumorigenesis in vivo. Mechanistically, GATA6 upregulated p53 and p21 mRNA while it inhibited AKT activation to stabilize p21 protein, thus inducing lung cancer cell senescence. Furthermore, we showed that ectopic expression of GATA6 led to dramatic slowdown of growth rate of established lung tumor xenograft in vivo.

Anti-Atherosclerosis Effect of Angong Niuhuang Pill via Regulating Th17/Treg Immune Balance and Inhibiting Chronic Inflammatory on ApoE-/- Mice Model of Early and Mid-Term Atherosclerosis.

Angong Niuhuang Pill (ANP) is a well-known patented Chinese medicine which is used for hundreds of years for treating the central nervous system diseases. Atherosclerosis is a poly-aetiological chronic inflammatory vascular disease. Preventing inflammation is fundamental for treating atherosclerosis in early stages. In this study, we investigated the protective effects and possible mechanisms of ANP action on a high-fat diet induced early and mid-term atherosclerosis ApoE-/- mice. The effects of ANP were compared with accepted drug simvastatin. Twelve male C57BL/6J mice were used as the control group, and 60 male ApoE-/- mice were randomly divided into five groups: Model group, Simvastatin group, Low-, Medium-, and High-dose ANP group these groups received, respectively, saline, simvastatin (3.0mg/kg), low-dose ANP (0.25 g/kg), medium-dose ANP (0.50 g/kg), and high-dose ANP (1.0 g/kg), once every other day for 10 weeks. After administration, serum biochemical indices were detected by the automatic biochemical analyzer, the concentrations of IL-6 and IL-10 in the serum were assayed by ELISA, expression levels of IL-1ß, TNF-α, MMP-2, MMP-9, CCL2, and its receptor CCR2 in the full-length aorta, and expression levels of transcription factors Foxp3, RORγt in the spleen were assayed via western blotting and RT-qPCR. Flow cytometry was used to analyze Th17 cells and Treg cells. Pathological and histological analysis was completed on aortic root. ANP decreased LDL/HDL ratio, concentrations of IL-6 while increased IL-10 in serum. Moreover, ANP down-regulated the expression levels of IL-1ß, TNF-α, MMP-2, MMP-9, CCL2, and CCR2 receptor in the full-length aorta. In addition, ANP decreased Th17 cells and expression levels of transcription factor RORγt, increased Treg cells and expression levels of transcription factor Foxp3. ANP decreased content of collagen fibers and infiltration of inflammatory cells in the aortic root. In conclusion, we demonstrated that ANP has anti-atherosclerosis effects on a high-fat diet induced ApoE-/- mice early and mid-term AS model via regulating Th17/Treg balance, inhibiting chronic inflammation, reducing plaque collagen fibers, and reducing inflammatory cells infiltration, to exert its multi-channel multi-target anti-early and mid-term AS effects.