Potential Involvement of M1 Macrophage and VLA4/VCAM-1 Pathway in the Valvular Damage Due to Rheumatic Heart Disease.

BACKGROUND: Rheumatic heart disease (RHD) is caused by inflammatory cells mistakenly attacking the heart valve due to Group A Streptococcus (GAS) infection, but it is still unclear which cells or genes are involved in the process of inflammatory cells infiltrating the valve. Inflammatory infiltration into the target tissue requires an increase in the expression of phosphorylated vascular endothelial-cadherin (p-VE-cad), p-VE-cad can increase the endothelial permeability and promote the migration of inflammatory cells across the endothelium. P-VE-cad is potentially regulated by RAS-related C3 botulinum substrate 1 (RAC1), together with phosphorylated proline-rich tyrosine kinase 2 (p-PYK2). While RAC1/p-PYK2/p-VE-cad is triggered by the activation of vascular cell adhesion molecule-1 (VCAM-1). VCAM-1 is related to M1 macrophages adhering to the endothelium via very late antigen 4 (VLA4). Inflammatory infiltration into the valve is extremely important in the early pathogenesis of RHD. However, there is no relevant research on whether M1/VLA4/VCAM-1/RAC1/p-PYK2/p-VE-cad is involved in RHD; therefore, what we explored in this study was whether M1/VLA4/VCAM-1/RAC1/p-PYK2/p-VE-cad is involved. METHODS: We established a rat model of RHD and a cell model of M1 macrophage and endothelial cell cocultivation. Subsequently, we measured the degree of inflammatory cell infiltration, the levels of IL-6/IL-17, the degree of fibrosis (COL3/1), and the expression levels of fibrosis markers (FSP1, COL1A1 and COL3A1) in the heart valves of RHD rats. Additionally, we detected the expression of M1/M2 macrophage biomarkers in rat model and cell model, as well as the expression of M1/VLA4/VCAM-1/RAC1/p-PYK2/p-VE-cad. We also tested the changes in endothelial permeability after coculturing M1 macrophages and endothelial cells. RESULTS: Compared to those in the control group, the levels of inflammatory cell infiltration and fibrotic factors in the heart valves of RHD rats were significantly higher; the expression of M1 macrophage biomarkers (iNOS, CD86 and TNF-α) in RHD rats was significantly higher; and significantly higher than the expression of M2 macrophage biomarkers (Arg1 and TGF-ß). And the expression levels of VLA4/VCAM-1 and RAC1/p-PYK2/p-VE-cad in the hearts of RHD rats were significantly higher. At the cellular level, after coculturing M1 macrophages with endothelial cells, the expression levels of VLA4/VCAM-1 and RAC1/p-PYK2/p-VE-cad were significantly higher, and the permeability of the endothelium was significantly greater due to cocultivation with M1 macrophages. CONCLUSIONS: All the results suggested that M1 macrophages and the VLA4/VCAM-1 pathway are potentially involved in the process of inflammatory infiltration in RHD.

Network pharmacology and in vivo experiment-based strategy for investigating the mechanism of chronic prostatitis/chronic pelvic pain syndrome in QianLieJinDan tablets.

Background: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common urinary system disease that is prone to recurrence. It typically leads to varying degrees of pelvic pain and discomfort, as well as symptoms related to the urinary system in affected patients. QianLieJinDan tablets (QLJD), a traditional Chinese medicine, have shown promising therapeutic effects on CP/CPPS in clinical practice, but the underlying mechanisms of QLJD in treating CP/CPPS have not been determined. Objective: To reveal the phytochemical characterization and multitarget mechanism of QLJD on CP/CPPS. Methods: The concentrations of the components of QLJD were determined using UHPLC-Q Exactive Orbitrap-MS. Utilizing network pharmacology approaches, the potential components, targets, and pathways involved in the treatment of CP/CPPS caused by QLJD were screened. Molecular docking calculations were employed to assess the affinity between the components of the QLJD and potential targets, revealing the optimal molecular conformation and binding site. Finally, the therapeutic efficacy and potential underlying mechanisms of QLJD were investigated through pharmacological experiments. Results: In this study, a total of 35 components targeting 29 CP-related genes were identified, among which quercetin, baicalin, icariin, luteolin, and gallic acid were the major constituents. Enrichment analysis revealed that the potential targets were involved mainly in the regulation of cytokines, cell proliferation and apoptosis, and the oxidative stress response and were primarily associated with the cytokine‒cytokine receptor interaction pathway, the IL-17 signaling pathway, the Th17 cell differentiation pathway, and the JAK-STAT signaling pathway. In vivo experiments demonstrated that QLJD effectively attenuated the infiltration of CD3+ T cells and the expression of ROS in a CP/CPPS model rat prostate tissue. Furthermore, through the inhibition of IL-6 and STAT3 expression, QLJD reduced the differentiation of Th17 cells, thereby ameliorating pathological injury and prostatic index in prostate tissue. Conclusion: The potential of QLJD as an anti-CP/CPPS agent lies in its ability to interfere with the expression of IL-6 and STAT3, inhibit Th17 cell differentiation, reduce inflammatory cell infiltration in rat prostate tissue, and alleviate oxidative stress damage through its multi-component, multi-target, and multi-pathway effects.

Effect of curcumin nanoparticles on proliferation and migration of mouse airway smooth muscle cells and airway inflammatory infiltration.

Curcumin (CUR) possesses the capability to inhibit various inflammatory factors, exert anti-inflammatory effects, and alleviate asthma attacks; however, its hydrophobicity and instability significantly impede its clinical application. In this study, we synthesized CUR-loaded nanoparticles (CUR-NPs) and evaluated their impact on the proliferation, migration, and inflammatory infiltration of mouse airway smooth muscle cells (ASMCs), while investigating their underlying mechanisms. To achieve this objective, ASMCs were isolated from BALB/c mice and subjected to TGF-ß1-induced cell proliferation and migration. Our findings demonstrate that CUR-NPs effectively regulate the release of CUR within cells with superior intracellular uptake compared to free CUR. The CCK-8 assay results indicate that the blank carrier does not exhibit any cytotoxic effects on cells, thus rendering the impact of the carrier itself negligible. The TGF-ß1 group exhibited a significant increase in cell proliferation, whereas treatment with CUR-NPs significantly suppressed TGF-ß1-induced cell proliferation. The findings from both the cell scratch assay and transwell assay demonstrated that TGF-ß1 substantially enhanced cell migration, while CUR-NPs treatment effectively attenuated TGF-ß1-induced cell migration. The Western blot analysis demonstrated a substantial increase in the expression levels of TGF-ß1, p-STAT3, and CTGF in ASMCs following treatment with TGF-ß1 when compared to the control group. Nevertheless, this effect was effectively counteracted upon administration of CUR-NPs. Furthermore, an asthma mouse model was successfully established and CUR-NPs were administered through tail vein injection. The serum levels of TGF-ß1 and the expression levels of TGF-ß1, p-STAT3, and CTGF proteins in the lung tissue of mice in the model group exhibited significant increases compared to those in the control group. However, CUR-NPs treatment effectively attenuated this change. Our research findings suggest that CUR-NPs possess inhibitory effects on ASMC proliferation, migration, and inflammatory infiltration by suppressing activation of the TGF-ß1/p-STAT3/CTGF signaling pathway, thereby facilitating inhibition of airway remodeling.

Targeting brain-peripheral immune responses for secondary brain injury after ischemic and hemorrhagic stroke.

The notion that the central nervous system is an immunologically immune-exempt organ has changed over the past two decades, with increasing evidence of strong links and interactions between the central nervous system and the peripheral immune system, both in the healthy state and after ischemic and hemorrhagic stroke. Although primary injury after stroke is certainly important, the limited therapeutic efficacy, poor neurological prognosis and high mortality have led researchers to realize that secondary injury and damage may also play important roles in influencing long-term neurological prognosis and mortality and that the neuroinflammatory process in secondary injury is one of the most important influences on disease progression. Here, we summarize the interactions of the central nervous system with the peripheral immune system after ischemic and hemorrhagic stroke, in particular, how the central nervous system activates and recruits peripheral immune components, and we review recent advances in corresponding therapeutic approaches and clinical studies, emphasizing the importance of the role of the peripheral immune system in ischemic and hemorrhagic stroke.

Clinical value of TAM receptor tyrosine kinase and ligands in evaluating disease severity of acute pancreatitis / 中华胰腺病杂志

Objective:To investigate the clinical value of Tyro3/Axl/Mertk (TAM) receptor tyrosine kinase and ligands in severity evaluation for acute pancreatitis (AP).Methods:The peripheral blood and clinical data of 27 patients with AP admitted in the Department of Gastroenterology of Shanghai General Hospital from February 2020 to July 2022 were prospectively selected. The patients were divided in to mild AP group (MAP, n=13), moderately severe AP (MSAP, n=10) and severe AP group (SAP, n=4) according to the 2012-revised Atlanta classification for AP. Another 10 healthy normal subjects were selected as the control group. The general information, biochemical indicators and blood cell analysis of the patients were recorded, and the levels of serum Gas6, protein S and soluble Axl (sAxl) were measured by ELISA. Linear regression equations were used to analyze the correlation of serum Gas6, protein S and sAxl levels with the white blood cell (WBC) counts, neutrophil percentages, lymphocyte percentages, and monocyte percentages of each group, and to assess the clinical value of Gas6, protein S and sAxl in predicting the severity of AP patients. Results:Compared with the control group, the serum Gas6 level [(31.3±13.0)ng/ml vs (21.2±2.6)ng/ml], protein S level [(24.4±11.3)μg/ml vs (17.7±3.4)μg/ml], and sAxl level [(9.0±4.4)ng/ml vs (6.6±1.3)ng/ml] were significantly higher in the AP group. The Gas6 level was significantly higher in the SAP group (54.1±13.7 ng/ml) than in the MAP group (31.0±9.4 ng/ml) and the MSAP group (25.2±8.9 ng/ml), and the differences were statistically significant (all P value <0.05). The Gas6 level was significantly positively correlated with the WBC count ( r=0.1733) and neutrophils percentage ( r=0.4424), and negatively correlated with lymphocyte percentage(r=-0.363), with statistically significant differences (all P value <0.05). The levels of protein S and sAXL were positively correlated WBC count and neutrophil percentage, and negatively correlated with monocyte percentage and lymphocyte percentage, but the differences were not statistically significant. Conclusions:The serum levels of Gas6 increase significantly with the severity grading of AP, which may serve as a relatively good predictor for the early severity assessment of AP.

Diagnostic study of actinic cheilitis by reflectance confocal microscopy / 口腔疾病防治

Objective @#To explore the clinical application value of reflectance confocal microscopy(RCM) in the diagnosis of actinic cheilitis(AC).@*Methods@#After approval by the hospital ethics committee and informed consent given by the patients, from October 2020 to July 2022, 17 patients who were diagnosed with actinic cheilitis in the Ninth People's Hospital affiliated with Shanghai Jiao Tong University School of Medicine were retrospectively analyzed. The white keratotic lesions of the lips were scanned with reflectance confocal microscopy, and the image characteristics were summarized and analyzed, including epithelial hyperplasia/atrophy, hyperkeratosis, inflammatory cell infiltration, blood vessel dilatation, solar elastosis, atypical keratinocytes, widening of intercellular spaces, degeneration of basal cell layer, and pigmentation. We used the sample compliance rate to measure the correlation between RCM parameters and histopathological diagnostic criteria for AC and kappa concordance analysis to calculate the concordance between RCM and pathological diagnosis. @* Results@# Under RCM, the sample correct rates for epithelial hyperplasia/atrophy, hyperkeratosis, inflammatory cell infiltration, vasodilation, and solar elastosis were 76.5%, 100%, 100%, 64.7%, and 70.6%, the sample accuracy compared with pathological diagnosis was 82.4%, 47.1%, 94.1%, 88.2% and 76.5%, respectively. We also observed that 100%, 88.2%, 76.5%, and 88.2% of AC patients showed RCM features of atypical keratinocytes, widening of intercellular spaces, degeneration of the basal cell layer, and pigmentation, respectively. The kappa value of hyperkeratosis and inflammatory cell infiltration was 1. The kappa value of blood vessel dilatation was 0.645. @* Conclusion @#Reflectance confocal microscopy is noninvasive and versatile and has clinical application value in the diagnosis of actinic cheilitis.

Effect of azitromycin on Th17/Treg balance in bronchiolitis obliterans mice after lung transplantation / 器官移植

Objective To evaluate the effect of azitromycin upon the bronchiolitis obliterans and T helper (Th)17/regulatory T cell (Treg) balance after lung transplantation. Methods Twenty-four specific pathogen free(SPF) C57BL/6 mice were used as the donors and 48 Balb/c mice were utilized as the recipients. The Balb/c mice were randomly divided into the control (C group), azitromycin control (Cazm group), transplantation (T group) and transplantation + azitromycin groups (Tazm group), 12 mice in each group. In the T and Tazm groups, heterotopic tracheal transplantation models were established to simulate bronchiolitis obliterans after lung transplantation. From 1 d post-transplantation, intragastric administration of azitromycin was given at a dose of 30 mg/kg three times per week in the Cazm and Tazm groups. At 14 and 28 d after transplantation, the transplanted trachea was removed and peripheral blood was collected. The tracheal sample was prepared for hematoxylin-eosin (HE) staining for pathological observation. The expression levels of ROR-γt and Foxp3 messenger ribonucleic acid (mRNA) in the peripheral blood were quantitatively measured by reverse transcription polymerase chain reaction (RT-PCR). The variation in the related cytokines levels of Th17 cells and Treg in the plasma was detected by enzyme linked immunosorbent assay (ELISA). Results After heterotopic tracheal transplantation, compared with the C group, thetracheal occlusion accompanied with inflammatory infiltration was observed in the T and Tazm groups. The severity of relevant symptoms in the Tazm group was slighter than that in the T group. Compared with the T group, the expression level of ROR-γt mRNA in the Tazm group was significantly down-regulated (P<0.05). No statistical significance was identified in the expression of Foxp3 mRNA between two groups (P>0.05). Compared with the T group, the levels of interleukin (IL)-6 and IL-17 cytokines in the Tazm group were significantly down-regulated (all P<0.05). Conclusions Persistent therapy of azitromycin can delay the progression of bronchiolitis obliterans after transplantation, which is probably associated with inhibiting Th17 cell differentiation and inflammation.

The indications and therapeutic strategies of multivisceral resection for locally advanced colorectal cancer / 中国癌症杂志

The only possible cure for patients with locally advanced colorectal cancer is multivisceral resection. With the development of oncological surgery techniques and various types of targeted cancer therapy drugs, treatment modality of multidisciplinary team has been proposed and implemented. How to choose the optimal treatment strategy is a common problem.

Anti-apoptosis and anti-inflammatory effect of osthole in mice following stab wound injury / 中国药理学通报

Aim To investigate the effects of osthol on cell apoptosis and inflammatory cell infiltration after brain stab wound injury in mice. Methods The mice underwent the stab wound injury by a needle, then were randomly divided into sham operation group, model group, osthol 10, 20, 30 mg · kg-1 treatment group. The main examinations included mice brain wa-ter content; the apoptotic cytokines Bax, Bcl-2, Caspase-3 mRNA expression were assessed by PT-PCR; immunohistochemistry staining was used to de-tect neutrophils (MPO) and microglia (Iba-1) infiltra-tion and Caspase-3 positive cell expression around in-jured lesions. Results Treatment with osthole 20, 30 mg·kg-1 group significantly reduced the water content in injured brain, improved the ratio of Bax/Bcl-2, and reduced the expression of apoptosis cytokine Caspase-3 mRNA. Osthole 30 mg·kg-1 treatment group obvious-ly reduced the infiltration of neutrophils and microglial cells and significantly reduced the number of apoptotic cells around the injured cerebral cortex. Conclusion Osthole has therapeutic effect on stab wound injury in mice, and the possible mechanism may be by reducing the infiltration of inflammatory cells and reducing apop-totic cells.

Correlation analysis of acute pancreatitis retroperitoneal clearance CT in-flammatory infiltration degree and clinical severity / 中国现代医生

Objective To study the correlation of patients with acute pancreatitis gap retroperitoneal inflammatory in-filtration CT and clinical severity. Methods 236 cases of acute pancreatitis from June 2010 to June 2012 were collected for treatment, comparatively analyzed and compared clinical severity of inflammatory infiltration of acute pancreatitis and retroperitoneal gap though CT examination. Results A total of 236 cases of patients were selected and 196 cases of patients with varying degrees of post-gap involving the peritoneum, 88 cases of mild acute pancreatitis, mainly involv-ing the next pre-renal clearance, 66 cases of severe acute pancreatitis type 1, while involving the perirenal space next stage renal clearance in front to the main level II infiltration, 82 cases of severe acute type 2 pancreatitis, involved the perirenal space, before clearance and clearance, renal infiltration beside kidney. CT inflammatory infiltration and retroperitoneal gap clinical severity was positively correlated (r=0.7797, P=0.001). Conclusion CT retroperitoneal in-flammatory infiltration gap, especially next to the renal clearance of involvement often reflect the clinical severity of acute pancreatitis.

Clinical, imaging and pathological features of intracerebral inflammatory pseudotumour (report of 1 case) / 临床神经病学杂志

Objective To investigate the clinical,imaging (CT and MRI) and pathological features of intracerebral inflammatory pseudotumour. Methods The clinical, neuroimaging and neuropathological data of a patient with intracerebral inflammatory pseudotumour were analyzed retrospectively. Results The manifestations of this patient included headache, nausea, vomiting, fever and seizures. Brain MRI showed abnormal high T1 and T2 signals in the right frontal lobe and midline shift. The resection pathology showed brain tissue swelling, loss of normal neuron outline, massive inflammatory infiltrations in perivascular spaces. Although the patient was treated with operation, dehydration and antibiotics, he died eventually.Conclusions Intracerebral inflammatory pseudotumour is an unusual disease in clinical practice. This disease is diagnosed mainly depended upon pathological examinations because of no specific clinical and imaging manifestations. The prognosis is not good although operative treatment is performed.