CRISPR/Cas9-based therapeutics face significant challenges in penetrating the dense microenvironment of solid tumors, resulting in insufficient gene editing and compromised treatment efficacy. Current nanostrategies, which mainly focus on the paracellular pathway attempted to improve gene editing performance, whereas their efficiency remains uneven in the heterogenous extracellular matrix. Here, the nanoCRISPR system is prepared with self-cascading mechanisms for gene editing-mediated robust apoptosis and transcellular penetration. NanoCRISPR unlocks its self-cascade capability within the matrix metallopeptidase 2-enriched tumor microenvironment, initiating the transcellular penetration. By facilitating cellular uptake, nanoCRISPR triggers robust apoptosis in edited malignancies, promoting further transcellular penetration and amplifying gene editing in neighboring tumor cells. Benefiting from self-cascade between robust apoptosis and transcellular penetration, nanoCRISPR demonstrates continuous gene transfection/tumor killing performance (transfection/apoptosis efficiency: 1st round: 85%/84.2%; 2nd round: 48%/27%) and homogeneous penetration. In xenograft tumor-bearing mice, nanoCRISPR treatment achieves remarkable anti-tumor efficacy (∼83%) and significant survival benefits with minimal toxicity. This strategy presents a promising paradigm emphasizing transcellular penetration to enhance the effectiveness of CRISPR-based antitumor therapeutics.

Objective:To study the growth inhibition of Thunberg Fritillary extract on non-small cell lung cancer.Methods:The Thunberg Fritillary extract was prepared and characterized by UPLC-QE/MS.Replicated Lewis lung carcinoma ectopic tumor-bear-ing mouse model,yeast injection induced acute inflammation,compared the effect of Thunberg Fritillary extract combination with acute inflammation on the growth,tumor volume and tumor suppression rate of Lewis lung carcinoma mice,and determine the content of inflammatory factors by the flow CBA method(IL-6,IL-1β,IL-1α,IL-10,IL-27,IL-17A,IL-12p70,IL-23,TNF-α,IFN-γ,IFN-β,GM-CSF,MCP-1).Results:The inhibition of Lewis lung carcinoma mice was similar to that of cisplatin alone,and the tumor suppression rate was 35%;the tumor suppression rate of Thunberg Fritillary extract combined with acute inflammatory stimulation of yeast was 62%,1.8 times that of cisplatin alone.The decrease in the expressions of cytokines IL-23,MCP-1 after acute inflammatory stimulation in yeast was associated with tumor suppression;while the increased expressions of IL-6,IL-1β,IL-1α,IL-10,IL-27,IL-17A,IL-12p70,TNF-α,IFN-γ,IFN-β and GM-CSF cytokines were associated with tumor suppression.Conclusion:The Thun-berg Fritillary extract combination with acute inflammation can play a positive role against non-small cell lung cancer,which will pro-vide new research ideas and methods for the prevention and treatment of non-small cell lung cancer.

Objective:To study the growth inhibition of Thunberg Fritillary extract on non-small cell lung cancer.Methods:The Thunberg Fritillary extract was prepared and characterized by UPLC-QE/MS.Replicated Lewis lung carcinoma ectopic tumor-bear-ing mouse model,yeast injection induced acute inflammation,compared the effect of Thunberg Fritillary extract combination with acute inflammation on the growth,tumor volume and tumor suppression rate of Lewis lung carcinoma mice,and determine the content of inflammatory factors by the flow CBA method(IL-6,IL-1β,IL-1α,IL-10,IL-27,IL-17A,IL-12p70,IL-23,TNF-α,IFN-γ,IFN-β,GM-CSF,MCP-1).Results:The inhibition of Lewis lung carcinoma mice was similar to that of cisplatin alone,and the tumor suppression rate was 35%;the tumor suppression rate of Thunberg Fritillary extract combined with acute inflammatory stimulation of yeast was 62%,1.8 times that of cisplatin alone.The decrease in the expressions of cytokines IL-23,MCP-1 after acute inflammatory stimulation in yeast was associated with tumor suppression;while the increased expressions of IL-6,IL-1β,IL-1α,IL-10,IL-27,IL-17A,IL-12p70,TNF-α,IFN-γ,IFN-β and GM-CSF cytokines were associated with tumor suppression.Conclusion:The Thun-berg Fritillary extract combination with acute inflammation can play a positive role against non-small cell lung cancer,which will pro-vide new research ideas and methods for the prevention and treatment of non-small cell lung cancer.

Objective:To investigate the influence of different test conditions on the particle size distribution of elemene emulsion injection measured by laser light scattering method.Methods:The method of particle size deter-mination of elemene emulsion injection was explored.The test conditions were as follows:shading rate 5％-10％,absorption rate 0.000 1-0.1,refractive index1.52-1.54,mixing speed 800-1 600 r·min-1,balance time 0.5-1 min.After the methodology verification,3 batches of elemene emulsion injection were taken and deter-mined on the Bettersize 2600 laser particle size distribution instrument(wet method).Results:Measurement results of 3 batches of samples:d(0.1),d(0.5),d(0.9),d(0.99)were 252,251,213 nm;354,351,316 nm;543,532,476 nm;979,953,887 nm.Conclusion:This test method can be used to determine the particle size distribution of elemene emulsion injection with good reproducibility.

Cirrhotic portal hypertension (CPH) is a manifestation of decompensated liver cirrhosis, with ascites, portal collateral circulation formation, hypersplenism and splenomegaly as the typical clinical symptoms. In recent years, the incidence of CPH has been increasing year by year, and the treatment of CPH has gradually become a hot issue in medical research. In order to further explore the diagnosis and treatment scheme of CPH. We briefly describe the pathophysiological mechanism and diagnosis of CPH, and the current situation of CPH treatment and the new progress of internal and external treatment were reviewed.

Objective:To predict the mechanism of Panacis Quinquefolii Radix- Acori Tatarinowii Rhizoma (PQ-AT) in the treatment of diabetes encephalopathy (DE) using network pharmacology combined with molecular docking; To conduct experimental verification.Methods:The active components and targets of PQ and AT were screened by TCMSP database. The GeneCards and Disgenet were used to collect DE related target genes. String database and Cytoscape software were used to structure PPI network and perform visualization analysis. The common targets were imported into Metascape platform for GO annotation and KEGG enrichment analysis. Molecular docking was used to verify the binding ability of active components to core targets. Rats were randomly divided into a blank group, a model group, and a low-dose group of PQ-AT (1.08 g/kg), a high-dose group of PQ-AT (2.16 g/kg), and a metformin group (0.18 g/kg) using a random number table. To establish the rat model of diabetes encephalopathy, intraperitoneal injection of streptozotocin was used in addition to the blank group. After a 12-week drug intervention, TNF-α and Cyclooxygenase-2 (PTGS2) protein expression in the cerebral cortex of rats was detected using Western blot.Results:A total of 26 active components in PQ-AT and 107 related targets of DE were obtained, mainly including TNF, JUN, and PTSG2, which were mainly concentrated in TNF signaling pathway, cancer and other signal pathways. Molecular docking showed that the main active components of PQ-AT had relatively stable binding activity with TNF-α and PTGS2. Western blot results shows that compared with the model group, the expressions of PTGS2 and TNF-α significantly decreased in each administration group ( P<0.05 or P<0.01). Conclusion:PQ-AT can act on TNF, CASP3, JUN, STAT3, PTGS2 and other core targets to regulate signal pathways such as TNF, and inhibit inflammatory reaction to achieve the effect of treating DE.

Objective:To investigate the influence of collaborative psychological nursing on the quality of life and psychology of non-Hodgkin lymphoma (NHL) patients and their caregivers.Methods:Eighty NHL patients and 80 caregivers in the Affiliated Hospital of Inner Mongolia Medical University from February 2018 to February 2019 were selected, and the patients were divided into observation group 1 (40 patients) and control group 1 (40 patients) according to the random number table method, and the caregivers were divided into observation group 2 (40 caregivers) and control group 2 (40 caregivers). Control group 1 was given routine nursing, and observation group 1 was given collaborative psychological nursing on the basis of routine nursing. The World Health Organization Quality of Life (WHOQOL)-BREF was used to compare the quality of life of two groups of patients and two groups of caregivers. Self-rating anxiety scale (SAS) and self-rating depression scale (SDS) were used to compare the psychological states of two groups of patients and two groups of caregivers.Results:Compared with control group 1, the observation group 1 had lower SAS and SDS scores after nursing [(40±6) points vs. (44±6) points, t = 5.12, P = 0.014; (46±4) points vs. (52±4) points, t = 3.22, P = 0.031] and higher WHOQOL-BREF scores [(87.2±2.1) points vs. (65.0±2.5) points, t = 8.55, P = 0.018]. Compared with control group 2, the observation group 2 had lower SAS and SDS scores after nursing [(37±4) points vs. (40±4) points, t = 3.21, P = 0.021; (44±4) points vs. (49±3) points, t = 2.37, P = 0.032] and higher WHOQOL-BREF scores [(84.0±2.5) points vs. (79.5±2.7) points, t = 3.28, P=0.015]. Compared with before nursing, SAS and SDS of each group decreased after nursing, while WHOQOL-BREF scores increased, and all differences were statistically significant (all P < 0.05). Conclusions:Collaborative psychological nursing can effectively improve the quality of life and mental resilience score of NHL patients and their caregivers.

Objective:To explore the effect of macrophage-derived exosomes on the activation of hepatic stellate cells and its possible mechanism.Methods:Differential ultracentrifugation was used to extract macrophage exosomes. The exosomes were co-cultured with the mouse hepatic stellate cell line JS1, and a control group was established with phosphate buffered saline (PBS). Cell immunofluorescence was used to observe the expressional conditions of F-actin. Cell counting kit-8 (CCK8) was used to detect the survival rate of JS1 cells in the two groups. The activation indices of JS1 cells [collagen type Ⅰ (Col Ⅰ) and α-smooth muscle actin (α-SMA)] and its key signal pathway activation index expression level [transforming growth factor (TGF)-β1/Smads, platelet-derived growth factor (PDGF)] in the two groups were determined using Western blot and RT-PCR. Data comparison between two groups was performed using an independent sample t-test.Results:The membrane structure of exosomes was clearly observed by transmission electron microscopy. The expression of exosome marker proteins CD63 and CD81 was positive, suggesting that exosomes were successfully extracted. Exosomes were co-cultured with JS1 cells. Compared with the PBS control group, there was no statistically significant difference in the proliferation rate of JS1 cells in the exosomes group ( P＞0.05). The expression of F-actin was significantly increased in the exosome group. The mRNA and protein expression levels of α-SMA and ColⅠwere significantly increased in exosome group JS1 cells (all P＜0.05). The mRNA relative expression levels of α-SMA in PBS and exosome group were 0.25±0.07 and 1.43±0.19, respectively, while that of ColⅠ was 1.03±0.04 and 1.57±0.06, respectively. The mRNA and protein expressions of PDGF were significantly increased in exosome group JS1 cells ( P＜0.05). The mRNA relative expression levels of PDGF in the PBS group and exosome group were 0.27±0.04 and 1.65±0.12, respectively. There were no statistically significant differences in the mRNA and protein expressions of TGF-β1, Smad2 and Smad3 between the two groups ( P＞0.05). Conclusion:Macrophage-derived exosomes significantly promote the activation of hepatic stellate cells. JS1 cells may be the underlying mechanism for the up-regulation of PDGF expression.

Although the functions of metabolic enzymes and nuclear receptors in controlling physiological homeostasis have been established, their crosstalk in modulating metabolic disease has not been explored. Genetic ablation of the xenobiotic-metabolizing cytochrome P450 enzyme CYP2E1 in mice markedly induced adipose browning and increased energy expenditure to improve obesity. CYP2E1 deficiency activated the expression of hepatic peroxisome proliferator-activated receptor alpha (PPARα) target genes, including fibroblast growth factor (FGF) 21, that upon release from the liver, enhanced adipose browning and energy expenditure to decrease obesity. Nineteen metabolites were increased in Cyp2e1-null mice as revealed by global untargeted metabolomics, among which four compounds, lysophosphatidylcholine and three polyunsaturated fatty acids were found to be directly metabolized by CYP2E1 and to serve as PPARα agonists, thus explaining how CYP2E1 deficiency causes hepatic PPARα activation through increasing cellular levels of endogenous PPARα agonists. Translationally, a CYP2E1 inhibitor was found to activate the PPARα-FGF21-beige adipose axis and decrease obesity in wild-type mice, but not in liver-specific Ppara-null mice. The present results establish a metabolic crosstalk between PPARα and CYP2E1 that supports the potential for a novel anti-obesity strategy of activating adipose tissue browning by targeting the CYP2E1 to modulate endogenous metabolites beyond its canonical role in xenobiotic-metabolism.

Abstract Allostatic load (AL) is related to stress. Adverse childhood experiences(ACEs), as a common stress in childhood, can make a serious and lasting impact on it. Allostatic load can reflect the wear and tear of an individual s physiological system. This article mainly reviews the functional changes of several systems of AL who have experienced ACEs, including neuroendocrine, metabolism, immune, and cardiovascular systems, as well as the different effects of the occurrence time and subtypes of ACES on AL, providing some theoretical basis for the development of early intervention plans in the future and reducing the occurrence and development of deleterious outcomes.