Autism Spectrum Disorders (ASDs) are reported as a group of neurodevelopmental disorders. The structural changes of brain regions including the hippocampus were widely reported in autistic patients and mouse models with dysfunction of ASD risk genes, but the underlying mechanisms are not fully understood. Here, we report that deletion of Trio, a high-susceptibility gene of ASDs, causes a postnatal dentate gyrus (DG) hypoplasia with a zigzagged suprapyramidal blade, and the Trio-deficient mice display autism-like behaviors. The impaired morphogenesis of DG is mainly caused by disturbing the postnatal distribution of postmitotic granule cells (GCs), which further results in a migration deficit of neural progenitors. Furthermore, we reveal that Trio plays different roles in various excitatory neural cells by spatial transcriptomic sequencing, especially the role of regulating the migration of postmitotic GCs. In summary, our findings provide evidence of cellular mechanisms that Trio is involved in postnatal DG morphogenesis.
Animals ; Dentate Gyrus/metabolism* ; Mice ; Morphogenesis/physiology* ; Neurons/pathology* ; Cell Movement ; Mice, Inbred C57BL ; Autism Spectrum Disorder/pathology* ; Mice, Knockout ; Neural Stem Cells ; Male ; Neurogenesis ; Autistic Disorder/genetics*

Syncytial giant cells (SGCs) are epithelial giant cells with multiple uniform and similar nuclei. Clear cell renal cell carcinoma (ccRCC) with SGCs is a rare microscopic morphology. A 70-year-old man was admitted to hospital with multiple nodules in both lungs found by chest CT examination 2 weeks before. A left renal carcinoma with lung metastasis was considered by PET-CT. Cytoreductive nephrectomy was performed, and postoperative pathological diagnosis confirmed ccRCC with SGCs of the left renal. Combined immunotherapy and targeted therapies were administered. There was no disease progression during follow-up period of 28 months.

Diabetic macular edema (DME) is the most threatening complication of diabetic retinopathy that affects visual function, which is characterized by intractability and recurrent attacks. Currently, the clinical routine treatments for DME mainly include intravitreal injection, grid laser photocoagulation in the macular area, subthreshold micropulse laser, periocular corticosteroid injection, and vitrectomy. Although conventional treatments are effective for some patients, persistent, refractory, and recurrent DME remains a clinical challenge that needs to be urgently addressed. In recent years, clinical studies have found that certain combination therapies are superior to monotherapy, which can not only restore the anatomical structure of the macular area and effectively reduce macular edema but also improve visual function to some extent while reducing the number of treatments and the overall cost. This makes up for the shortcomings of single treatment modalities and is highly anticipated in the clinical setting. However, the application of combination therapy in clinical practice is relatively short, and its safety and long-term effectiveness need further exploration. Currently, new drugs, new formulations, and new therapeutic targets are still under research and development to address different mechanisms of DME occurrence and development, such as anti-vascular endothelial growth factor agents designed to anchor repetitive sequence proteins with stronger inhibition of vascular leakage, multiple growth factor inhibitors, anti-inflammatory agents, and stem cell therapy. With the continuous improvement of the combination application of existing drugs and treatments and the development of new drugs and treatment technologies, personalized treatment for DME will become possible.

ObjectiveTo explore the anti-gout effect and mechanism of Derris eriocarpa extract by network pharmacological analysis combined with in vivo and in vitro experimental verification. MethodThe chemical components and candidate targets of D. eriocarpa were obtained from the database. The key targets and potential active components of D. eriocarpa in the treatment of gout were screened by the protein-protein interaction analysis， and then the Gene Ontology （GO） functional annotation and Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway enrichment were performed for the key targets. A mouse model of hyperuricemia was established by intraperitoneal injection of hypoxanthine to observe the effect of D. eriocarpa alcohol extract on hyperuricemia. A rat model of gouty inflammation induced by the injection of microcrystalline sodium urate crystals into the foot and plantar was used to observe the effect of D. eriocarpa alcohol extract on gouty inflammation. A xylene-induced acute inflammation model was established to observe the anti-inflammatory effect of D. eriocarpa alcohol extract. The hot plate test and twisting test were performed to observe the pain-relieving effect of D. eriocarpa. The lipopolysaccharide （LPS）-induced RAW264.7 cells were used to study the anti-gout effect and mechanism of D. eriocarpa alcohol extract. ResultA total of 12 key targets and 15 potential active components were obtained from the D. eriocarpa-component-gout target network. The emodin， betulinic acid， and medicarpin endowed D. eriocarpa with anti-hyperuricemia， anti-inflammatory， and pain-relieving effects by acting on Toll-like receptor 4 （TLR4）， NOD-like reception protein 3 （NLRP3）， and nuclear factor （NF）-κB. Compared with the control group， the model groups showed elevated serum uric acid level in mice （P<0.01）， increased swelling degree of rats （P<0.05， P<0.01）， alleviated the auricular swelling of mice （P<0.05）， reduced the twisting times of mice （P<0.05， P<0.01）， and increased the hot plate pain threshold （P<0.05）. Moreover， the model group showed up-regulated mRNA level of TLR4 and protein levels of TLR4， NF-κB， and NLRP3 in cells （P<0.01）， and elevated levels of TLR4 and NF-κB in the cell supernatant （P<0.05， P<0.01）. Compared with the model group， the alcoholic extracts （20， 10， 5 g·kg^-1） of D. eriocarpa lowered the serum uric acid level in hyperuricemic mice （P<0.01）， inhibited foot and plantar swelling in rats （P<0.05， P<0.01）， down-regulated the mRNA level of TLR4 and the protein levels of TLR4， NF-κB， NLRP3 in cells， and lowered the levels of TLR4， TNF-α， NF-κB， and IL-6 in cell supernatants （P<0.05， P<0.01）. ConclusionD. eriocarpa alcohol extract may exert the anti-gout， anti-inflammatory， and pain-relieving effects by regulating the TLR4/NF-κB/NLRP3 signaling pathway.

【Objective】 To investigate the effect of isoliquiritigenin on inflammatory response of vascular endothelial cells and whether the regulatory effect of isoliquiritigenin on inflammation is mediated by histone deacetylase 3 (HDAC3). 【Methods】 Human umbilical vein endothelial cells (HUVECs) were cultured in vitro and treated with LPS, different concentrations of isoliquiritigenin and HDAC3 specific inhibitor, respectively. Real-time PCR and Western blotting were used to detect the mRNA and protein expressions of inflammatory cytokines and HDAC3. Male C57BL/6J mice were randomly divided into vehicle group and isoliquiritigenin treatment group. The vascular inflammation model of C57BL/6J mice was established by ligation of the left carotid arteries. The mRNA expressions of inflammatory cytokines and HDAC3 in the carotid arteries of mice were detected by Real-time PCR. A molecular docking study was performed to investigate the interaction between isoliquiritigenin and HDAC3. 【Results】 Compared with the vehicle group, isoliquiritigenin reduced the mRNA expressions of inflammatory cytokines NLRP3, IL-1β, IL-18, MCP-1 and ICAM-1 and decreased the expression of HDAC3 mRNA and protein in HUVECs stimulated with LPS. In addition, isoliquiritigenin also decreased the mRNA expressions of NLRP3, IL-1β and HDAC3 in carotid arteries of ligated C57BL/6J mice. The docking of isoliquiritigenin in the active site of HDAC3 showed that isoliquiritigenin might act through HDAC3. Furthermore, HDAC3 specific inhibitor RGFP966 further promoted the inhibitory effect of isoliquiritigenin on the expression of inflammatory cytokines in vascular endothelial cells. 【Conclusion】 These results suggest that isoliquiritigenin suppresses the inflammatory response of vascular endothelial cells via HDAC3.

The radial migration of cortical pyramidal neurons (PNs) during corticogenesis is necessary for establishing a multilayered cerebral cortex. Neuronal migration defects are considered a critical etiology of neurodevelopmental disorders, including autism spectrum disorders (ASDs), schizophrenia, epilepsy, and intellectual disability (ID). TRIO is a high-risk candidate gene for ASDs and ID. However, its role in embryonic radial migration and the etiology of ASDs and ID are not fully understood. In this study, we found that the in vivo conditional knockout or in utero knockout of Trio in excitatory precursors in the neocortex caused aberrant polarity and halted the migration of late-born PNs. Further investigation of the underlying mechanism revealed that the interaction of the Trio N-terminal SH3 domain with Myosin X mediated the adherence of migrating neurons to radial glial fibers through regulating the membrane location of neuronal cadherin (N-cadherin). Also, independent or synergistic overexpression of RAC1 and RHOA showed different phenotypic recoveries of the abnormal neuronal migration by affecting the morphological transition and/or the glial fiber-dependent locomotion. Taken together, our findings clarify a novel mechanism of Trio in regulating N-cadherin cell surface expression via the interaction of Myosin X with its N-terminal SH3 domain. These results suggest the vital roles of the guanine nucleotide exchange factor 1 (GEF1) and GEF2 domains in regulating radial migration by activating their Rho GTPase effectors in both distinct and cooperative manners, which might be associated with the abnormal phenotypes in neurodevelopmental disorders.
Autism Spectrum Disorder/metabolism* ; Cell Movement/genetics* ; Humans ; Interneurons/metabolism* ; Neurodevelopmental Disorders/genetics* ; Neurons/metabolism* ; Rho Guanine Nucleotide Exchange Factors/genetics*

Objective : To establish a mouse model of acute pseudomembranous stomatitis and to observe the effect of photoactivated disinfection (PAD) on the removal of Candida albicans in vivo, and initially explore the feasibility of this technology in the treatment of acute pseudomembranous stomatitis. Methods: Six-week-old male ICR mice were selected and immunized with 1 × 107CFU/mL Candida albicans solution on the backs of the tongues of immunosuppressed mice. Thirty model mice with acute pseudomembranous stomatitis were successfully established and randomly divided into a control group and a photoactivated disinfection group, with 15 mice in each group. Mice in the photoactivated disinfection group were coated with 1 mg/mL toluidine blue solution on the back of the tongue, incubated for 1 min and irradiated with 750 mW LED red light for 1 min. Immediately after treatment, the tongue fungal load was measured in the photoactivated disinfection group and the control group. Tongue fungal load was measured again 48 h later, and tongue histopathological examination was performed in both groups. Results : Forty-eight hours after PAD treatment, the white pseudomembrane on the back of the tongue in the photoactivated group was significantly less than the control group. The fungal load on the dorsum of the tongue in the treatment group was significantly lower than the control group immediately and 48 h after treatment for PAD, and the difference was statistically significant (P<0.05). Forty-eight hours after PAD treatment, HE staining showed that the epithelial structure of the PAD group was more regular than the control group, and no microabscesses were observed. PAS staining showed that the number of mycelia in the PAD group was significantly less than the control group. Mycelia occasionally invaded the keratinized layer but did not penetrate into the upper cortex. Conclusion PAD significantly removed Candida albicans from the tongues of mice with acute pseudomembranous Candida stomatitis.

Objective:To systematic review the efficacy and safety of external application of traditional Chinese medicine on treatment of breast cancer related lymphedema.Methods:CNKI, Wanfang Data, VIP, Sino-Med, The Cochrane Library, PubMed, Web of Science were searched for related randomized controlled trials, the retrieval time was from inception to May 25, 2020. Two researchers independently screened and evaluated the included studies. Meta-analysis was performed by RevMan 5.4 software.Results:A total of 16 studies involving 1 315 patients with breast cancer related lymphedema were included, and the methodological quality of the included studies was not high. Compared with conventional treatment, external application of traditional Chinese medicine combined with conventional treatment had advantages in improving the total efficiency( P<0.01) and quality of life( P<0.01), reducing pain( P<0.01) and improving upper limb function( P<0.01), without obvious adverse reactions( P>0.05), but there was no improvement in depression( P>0.05). Compared with conventional treatment, external application of traditional Chinese medicine could improve the total efficiency( P<0.01). Compared with placebo sticker combined with conventional treatment, external application of traditional Chinese medicine combined with conventional treatment can reduce circumference( P<0.05) and reduce pain( P<0.01), without obvious adverse reactions( P>0.05). Conclusions:Available evidence suggests that external application of traditional Chinese medicine may be a potential treatment method for breast cancer related lymphedema. Due to the poor methodological quality of the included studies, high-quality randomized controlled trials are still needed.

Objective:In this study, we established a reliable surgical procedure of lung ischaemia-reperfusion(IR) injury in rats. The research progress of different lung IR injury models and application value was also discussed.Methods:Twenty-eight adult SD rats were randomly divided into SHAM group and lung IR injury group(IR group), 14 rats in each group. In IR group, rats underwent tracheotomy under general anesthesia and received mechanical ventilation. Chest was opened in supine position, and pulmonary hilum was blocked for 30 minutes then the occlusion was removed. Samples were harvested after reperfusion for 45minutes. Rats in SHAM group received surgery and exposure of the right pulmonary artery, and experienced the same amount of time before the chest closed. Arterial blood gas was extracted postoperatively. Gross view of the lungs and pathological changes were observed, and the dry/wet ratio(W/D) was determined. Protein level of pro-inflammatory factors, markers in oxidative stress pathway, and endothelial functional markers in lung were tested by western blot analysis.Results:In IR group, there was pink foamy secretion in the airway, and the lungs exhibited signs of edema and congestion. In IR group, the alveolitis score was significantly increased, the W/D ratio was also increased, p38MAPK and NF-κB signaling pathways were activated, and the expression of TNF-α was significantly increased, while the expression of eNOS was significantly decreased.Conclusion:Left hilum clamping and bilateral reperfusion injury in lung is a practical animal model, it is a simple, low-cost and repeatable animal model for further studies. No microsurgical instruments were required during the procedure. Lung IR injury is characterized by oxidative stress response, inflammatory response and endothelial cell dysfunction.

Objective:To investigate the relationship between serum matrix metalloproteinase-9 (MMP-9) level and the location and severity of bleeding in patients with cerebral microbleeds(CMBs).Methods:A total of 60 CMBs patients admitted to the Department of Neurology of the First Affiliated Hospital of the Xinxiang Medical University from January 2019 to August 2020 were selected as subjects as the CMBs group, and 60 healthy controls without nervous system diseases in outpatient physical examination during the same period were selected as the control group. The clinical data and biochemical indicators of the two groups were collected. Serum MMP-9 levels were measured by enzyme linked immunosorbent assay (ELISA). According to susceptibility weighted imaging (SWI), CMBs patients were divided into grade 1 group ( n=24), grade 2 group ( n=19) and grade 3 group ( n=17), and according to the micro analytical rating scale (MARS), the CMBs patients were divided into the lobar group ( n=19), the deep or infratentorial group ( n=17) and the mixed group ( n=24).The relationship between serum MMP-9 level and the location and severity of CMBs was analyzed. SPSS 19.0 software was used for data statistical analysis.One-way ANOVA, t-test and rank sum test were used for comparison. Logistic regression analysis was used to analyze the influencing factors. Pearson correlation analysis and Spearman correlation analysis were used for correlation analysis. Results:The level of MMP-9 in CMBs group was significantly higher than that in control group (208.13(142.25, 285.88) μg/L, 149.50(93.40, 186.51)μg/L), and the difference was statistically significant ( P<0.05). Serum MMP-9 level was a risk factor of CMBs ( β=1.322, OR=3.750, 95% CI=2.038-7.997, P=0.002). The difference of level of MMP-9 in different severity of CMBs was statistically significant (147.55(109.25, 266.47)μg/L, 242.12(147.55, 288.80)μg/L, 270.42(203.43, 364.27)μg/L, P=0.017). Serum MMP-9 level was positively correlated with the number of CMBs ( r=0.371, P=0.003). The difference of MMP-9 level of CMBs in different locations were statistically significant (249.77(158.43, 338.46)μg/L, 188.83(138.52, 243.15)μg/L, 210.65(144.25, 255.78)μg/L, P=0.013). The increased serum MMP-9 level was a risk factor for CMBs( β=0.401, OR=1.122, 95% CI=1.004-1.204, P=0.036). Conclusion:The increased level of serum MMP-9 may be a risk factor of CMBs, especially for CMBs in cerebral lobesand, and the level of MMP-9 is positively correlated with the severity of CMBs.