The effect and mechanism of chronic stress on psychosomatic diseases are important topics in stress research.The establishment of animal models to simulate human chronic stress is of great significance to investigations of stress responses,the pathogenesis of related diseases,clinical treatment,and drug development.In this paper,animal models of chronic stress commonly used in China and abroad are reviewed;the classification of stressors,animal selection,model construction,pathological manifestations,and evaluation indexes are summarized;and the advantages and disadvantages and application of various models are discussed.The paper provides a reference for the study and selection of models of chronic stress response.

The Nod-like receptor pyrin domain-associated protein 3(NLRP3)-mediated pyroptosis of pulmonary parenchymal and immune cells plays a key role in the pathogenesis of lung injury during sepsis.NF-κB,JAK2/STAT3 and MAPK signaling pathways are involved in NLRP3-mediated pyroptosis.Targeting NLRP3-pyroptosis and its related signaling pathways,pharmacological interventions with Physalin B,schisandrin,erythropoietin,and physical therapies such as acupuncture at Zusanli and Feishu points,as well as NLRP3-specific inhibitors like ergolide,have all shown effective anti-septic effects in treating lung injuries.This article reviewed the roles and mechanisms of NLRP3-pyroptosis in sepsis-induced lung injury,as well as the experimental progresses made in targeting NLRP3 pyroptosis as a therapy.We aim to highlight the importance of NLRP3-pyroptosis as a target,providing insights for the prevention and treatment of sepsis-induced lung injury.

H 1-antihistamines are widely used in the treatment of various allergic diseases, but there are still many challenges in the safe and rational use of H 1-antihistamines in pediatrics, and there is a lack of guidance on the prescription review of H 1-antihistamines for children.In this paper, suggestions are put forward from the indications, dosage, route of administration, pathophysiological characteristics of children with individual difference and drug interactions, so as to provide reference for clinicians and pharmacists.

Esophageal squamous cell carcinoma (ESCC) is one of the leading causes of cancer death worldwide. It is urgent to develop new drugs to improve the prognosis of ESCC patients. Here, we found benzydamine, a locally acting non-steroidal anti-inflammatory drug, had potent cytotoxic effect on ESCC cells. Benzydamine could suppress ESCC proliferation in vivo and in vitro. In terms of mechanism, CDK2 was identified as a target of benzydamine by molecular docking, pull-down assay and in vitro kinase assay. Specifically, benzydamine inhibited the growth of ESCC cells by inhibiting CDK2 activity and affecting downstream phosphorylation of MCM2, c-Myc and Rb, resulting in cell cycle arrest. Our study illustrates that benzydamine inhibits the growth of ESCC cells by downregulating the CDK2 pathway.
Humans ; Benzydamine ; Esophageal Neoplasms/drug therapy* ; Esophageal Squamous Cell Carcinoma/drug therapy* ; Molecular Docking Simulation ; Phosphorylation ; Cell Proliferation ; Cell Line, Tumor ; Apoptosis ; Cyclin-Dependent Kinase 2

Objective : To explore the method of intraperitoneal injection of allogenic fecal filtrate to establish the rat model of moderate and severe sepsis． Methods: The preparation method of allogeneic fecal filtrate was determined．Allogeneic fecal filtrate of different concentrations (0. 5，1，2 g / kg) was injected intraperitoneally to observe the general situation，survival time and severe degree of sepsis of rats. After determining the optimal concentration，the success rate of the model，serum inflammatory factors，serum concentration of D-lactic acid ( D-LA) and serum intestinal fatty acid binding protein (I-FABP) ，lung function changes，lung，liver and kidney tissue injury were further observed. Results: After intraperitoneal injection of allogenic fecal filtrate for 24 h，the rats of 1 g / kg group presented fever，tachypnea and hypotension，the survival rate was 83. 3% at 24 h and 16. 7% at 48 h， 2 g / kg group rats all died within 24 h，the dose of 1 g / kg was determined for subsequent experiments．Injected fecal filtrate for 24 h，the success rate of the sepsis model was 77. 8% . The levels of interleukin-6 ( IL-6) ，tumor necrosis factor-α ( TNF-α) ，D-LA and I-FABP in serum significantly increased． There were severe edema and bleeding in lung tissue，Pulmonary function appeared respiratory dysfunction，included functional residual capacity (FRC) ，quasi static compliance ( Cdyn) ，forced expiratory volume for the first 100 milliseconds(FEV100) ，peak expiratory flow (PEF) decreased，airway resistance (RI) ，inspiratory capacity (IC) increased．Liver and kidney tissues also showed varying degrees of edema and inflammatory cell infiltration，the levels of alanine aminotransferase (ALT) ，aspartate aminotransferase (AST) ，blood urea nitrogen (BUN) and creatinine ( Cr) in serum significantly increased． Conclusion Intraperitoneal injection of allogenic fecal filtrate ( 1 g / kg) can produce a relative typical septic model in rats.

Objective:To investigate efficacy and safety of topical sirolimus cream in the treatment of superficial vascular malformation in children.Methods:A single-center prospective study was carried out. Children with superficial vascular malformation were enrolled into this study from Vascular Anomalies Clinic, Beijing Children′s Hospital, Capital Medical University from September 2019 to September 2020, and treated with 0.1% sirolimus cream. The efficacy was evaluated according to an international four-level classification system through imaging examination, dermoscopy and subjective evaluation, and adverse reactions during the treatment were monitored. Statistical analysis was carried out by t test, univariate analysis of variance or Fisher′s exact test. Results:A total of 19 children with superficial vascular malformations were enrolled, including 12 males and 7 females, aged 1 - 11.5 years. Fourteen children were diagnosed with vascular and lymphatic malformations, 3 with lymphatic malformations, and 2 with venous malformations. Sixteen children presented with lesions on the lower extremities, 8 were accompanied by pain, 2 presented with ulceration, and 6 had previous treatment history. After 6-month treatment, 3 patients achieved improvement of level Ⅰ, 4 of level Ⅱ, 4 of level Ⅲ, and 8 of level Ⅳ; 16 achieved improvement, and 12 achieved marked improvement. Six patients showed significantly decreased length, thickness and width of lesions after 6 months of treatment (1.83 ± 0.84 cm, 1.00 ± 0.55 cm, 2.25 ± 1.25 cm, respectively) compared with those before treatment (2.40 ± 0.95 cm, 1.35 ± 0.61 cm, 2.50 ± 1.34 cm, t = 5.22, 10.25, 3.73, respectively, all P < 0.05) . Gender, age, medical history and pain sensation did not significantly affect the therapeutic effect (all P > 0.05) , while diagnostic classification of vascular malformations significantly affected the therapeutic effect ( P = 0.008) . Among the 19 children, 2 had mild local burning sensation after the treatment. After 1- and 6-month treatment, the blood concentrations of sirolimus were both below 1.0 ng/ml. Conclusion:Topical sirolimus is effective and safe in the treatment of superficial vascular malformation in children.

N ⁶-methyladenosine (m⁶A) modification is critical for mRNA splicing, nuclear export, stability and translation. Fat mass and obesity-associated protein (FTO), the first identified m⁶A demethylase, is critical for cancer progression. Herein, we developed small-molecule inhibitors of FTO by virtual screening, structural optimization, and bioassay. As a result, two FTO inhibitors namely 18077 and 18097 were identified, which can selectively inhibit demethylase activity of FTO. Specifically, 18097 bound to the active site of FTO and then inhibited cell cycle process and migration of cancer cells. In addition, 18097 reprogrammed the epi-transcriptome of breast cancer cells, particularly for genes related to P53 pathway. 18097 increased the abundance of m⁶A modification of suppressor of cytokine signaling 1 (SOCS1) mRNA, which recruited IGF2BP1 to increase mRNA stability of SOCS1 and subsequently activated the P53 signaling pathway. Further, 18097 suppressed cellular lipogenesis via downregulation of peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT/enhancer-binding protein alpha (C/EBPα), and C/EBPβ. Animal studies confirmed that 18097 can significantly suppress in vivo growth and lung colonization of breast cancer cells. Collectively, we identified that FTO can work as a potential drug target and the small-molecule inhibitor 18097 can serve as a potential agent against breast cancer.

Peptides that are composed of dextrorotary (d)-amino acids have gained increasing attention as a potential therapeutic class. However, our understanding of the in vivo fate of d-peptides is limited. This highlights the need for whole-body, quantitative tracking of d-peptides to better understand how they interact with the living body. Here, we used mouse models to track the movement of a programmed death-ligand 1 (PD-L1)-targeting d-dodecapeptide antagonist (DPA) using positron emission tomography (PET). More specifically, we profiled the metabolic routes of [⁶⁴Cu]DPA and investigated the tumor engagement of [⁶⁴Cu/⁶⁸Ga]DPA in mouse models. Our results revealed that intact [⁶⁴Cu/⁶⁸Ga]DPA was primarily eliminated by the kidneys and had a notable accumulation in tumors. Moreover, a single dose of [⁶⁴Cu]DPA effectively delayed tumor growth and improved the survival of mice. Collectively, these results not only deepen our knowledge of the in vivo fate of d-peptides, but also underscore the utility of d-peptides as radiopharmaceuticals.

Colorectal cancer (CRC) is the second most common cause of cancer-related death in the world. The pro-viral integration site for Moloney murine leukemia virus 1 (PIM1) is a proto-oncogene and belongs to the serine/threonine kinase family, which are involved in cell proliferation, migration, and apoptosis. Fibroblast growth factor receptor 1 (FGFR1) is a tyrosine kinase that has been implicated in cell proliferation, differentiation and migration. Small molecule HCI-48 is a derivative of chalcone, a class of compounds known to possess anti-tumor, anti-inflammatory and antibacterial effects. However, the underlying mechanism of chalcones against colorectal cancer remains unclear. This study reports that HCI-48 mainly targets PIM1 and FGFR1 kinases, thereby eliciting antitumor effects on colorectal cancer growth in vitro and in vivo. HCI-48 inhibited the activity of both PIM1 and FGFR1 kinases in an ATP-dependent manner, as revealed by computational docking models. Cell-based assays showed that HCI-48 inhibited cell proliferation in CRC cells (HCT-15, DLD1, HCT-116 and SW620), and induced cell cycle arrest in the G2/M phase through modulation of cyclin A2. HCI-48 also induced cellular apoptosis, as evidenced by an increase in the expression of apoptosis biomarkers such as cleaved PARP, cleaved caspase 3 and cleaved caspase 7. Moreover, HCI-48 attenuated the activation of downstream components of the PIM1 and FGFR1 signaling pathways. Using patient-derived xenograft (PDX) murine tumor models, we found that treatment with HCI-48 diminished the PDX tumor growth of implanted CRC tissue expressing high protein levels of PIM1 and FGFR1. This study suggests that the inhibitory effect of HCI-48 on colorectal tumor growth is mainly mediated through the dual-targeting of PIM1 and FGFR1 kinases. This work provides a theoretical basis for the future application of HCI-48 in the treatment of clinical CRC.

The key technology of the device for the viviperception of the animal mesenteric microcirculation is to simulate the celiac environment in the device. The technical requirements of the device for microcirculation viviperception are that the observation box should be able to "keep warm, preserve moisture, continually perfuse, and fix the sample"; and the lighting should be "intense", "convergence", and "cool". After actual application, it was found that the newly designed and developed the device by research personnel of Wannan Medical College for the viviperception of the animal mesenteric microcirculation can meet the technical requirements, which is able to "keep warm, preserve moisture, continually perfuse, and fix the sample", and using LED lamp as the microscope light source is "intense", "convergence", and "cool". This device is ingenious and reasonable in design, stable in technology, convenient in operation, and competent in microcirculation viviperception. It solves the technical problem to simulate the celiac environment for mesenteric microcirculation viviperception. The device provides convenience to observe and study the microcirculation, which is worth to be applicated widely.