Development in the Study of Natural Killer Cells for Malignant Peritoneal Mesothelioma Treatment.

Malignant peritoneal mesothelioma (MPeM) is a rare primary malignant tumor originating from peritoneal mesothelial cells. Insufficient specificity of the symptoms and their frequent reappearance following surgery make it challenging to diagnose, creating a need for more efficient treatment options. Natural killer cells (NK cells) are part of the innate immune system and are classified as lymphoid cells. Under the regulation of activating and inhibiting receptors, NK cells secrete various cytokines to exert cytotoxic effects and participate in antiforeign body, antiviral, and antitumor activities. This review provides a comprehensive summary of the specific alterations observed in NK cells following MPeM treatment, including changes in cell number, subpopulation distribution, active receptors, and cytotoxicity. In addition, we summarize the impact of various therapeutic interventions, such as chemotherapy, immunotherapy, and targeted therapy, on NK cell function post-MPeM treatment.

Drug sensitivity tumor cell clusters in malignant peritoneal mesothelioma.

BACKGROUND: To explore the most effective adjuvant chemotherapy regimen for malignant peritoneal mesothelioma (MPM) through patient derived tumor-like cell clusters (PTC) drug sensitivity test. METHODS: PTC were cultured in vitro with intraoperative specimens, and drug sensitivity test was performed to calculate the most effective chemotherapy regimen for MPM. The patients were divided into conventional and individualized chemotherapy group according to whether they received PTC drug testing. Univariate and multivariate analyses were conducted to identify independent prognostic factors. RESULTS: Among 186 MPM patients included, 63 underwent PTC culture and drug sensitivity test. The results showed that the most effective chemotherapy regimen was oxaliplatin + gemcitabine. After propensity score matching, a total of 64 patients were enrolled in the following study, including 32 patients receiving individualized chemotherapy guided by PTC drug results as group 1 and 32 patients receiving conventional chemotherapy as group 2. Survival analysis showed that the median OS of group 1 was not reached, significantly longer than that of group 2 (23.5 months) (p < 0.05). CONCLUSIONS: Compared with conventional chemotherapy, individualized chemotherapy guided by PTC drug sensitivity tests can prolong patient survival, and oxaliplatin + gemcitabine + apatinib could be the optimal adjuvant treatment regimen for MPM.

Molecular properties, structure, neurotrophic and anti-inflammatory activities of cultured secondary metabolites from the cultures of the mushroom Cyathus striatus CBPFE A06.

Two previously undescribed natural cyathane diterpenoids Me-dentifragilin A (1) and Epi-neocyathin O (2), and three known cyathane diterpenoids 3-5, cyathin O, neocyathin P, and cyathin I, were isolated from the rice medium of the Cyathus striatus CBPFE A06. Their structures were established by NMR spectra, and HR-ESI-MS. Compounds 1-5 displayed encouraging neurotrophic activity in PC-12 cells at doses of 5 µM. Meanwhile, 1-5 significantly inhibited LPS-induced NO generation in BV2 cells with the IC50 values ranging from 2.44 ± 0.16 to 4.33 ± 0.32 µM. Western blot analysis showed that 2 and 4 inhibited the expression of genes involved in nitric oxide (NO) production. Molecular docking revealed that five residues of inducible NO synthase (iNOS) are key residues affecting the interaction of 2 and 4 with iNOS. This study enriches the structural diversity of cyathane diterpenes and adds to the evidence that cyathane diterpenes prevent and treat neurodegenerative diseases.

Essential oil from the roots of Paeonia lactiflora pall. has protective effect against corticosterone-induced depression in mice via modulation of PI3K/Akt signaling pathway.

For thousands of years, the roots of Paeonia lactiflora Pall (PLP) has been considered by traditional Chinese medicine as a drug that can improve mental or emotional disorders, including depression, anxiety and affective disorders. Unfortunately, the research on the mechanism of action and active ingredients of this beneficial drug is not comprehensive. This study focused on the activity of essential oil from PLP (EOP), systematically studied the antidepressant effect of EOP for the first time, and discussed the potential mechanism of its antidepressant effect. In this study, we used a mouse model of corticosterone (CORT)-induced depression, and found that EOP had a significant antidepressant effect on the symptoms of CORT-induced depression in mice, and significantly down-regulated the levels of CRH, ACTH and cortisol in the brain tissues of mice. In addition, we found that EOP treatment alleviated CORT-induced hippocampal neuron injury in mice In vitro experiments. It was also found that EOP could inhibit CORT-induced apoptosis and improve the proliferation ability and cell viability of PC12 cells. Further, with the help of network analysis, it was revealed that PI3K-Akt might be one of the main signaling pathways of EOP against CORT-induced hippocampal neuron apoptosis. In this study, we also found that EOP up-regulated the phosphorylation of PI3K and Akt in CORT-induced mouse hippocampal neurons and PC12 cells, and promoted the nuclear transcription of Nrf2 in CORT-induced PC12 cells. In conclusion, with the integrated approach, we demonstrated that EOP exerted anti-apoptotic effects on hippocampal neurons through PI3K/Akt/Nrf2 signaling pathway.

Association of high PM2.5 levels with short-term and medium-term lung function recovery in patients with pulmonary lobectomy.

The association between exposure to ambient fine particulate matter with an aerodynamic diameter of ≤ 2.5 µm (PM2.5) and short- and medium-term lung function recovery (LFR) in patients undergoing lobectomy remains uncertain. This study investigated the associations between PM2.5 concentrations and LFR in adult patients (n = 526) who underwent video-assisted thoracoscopic (VATS) lobectomy in Guangzhou, China between January 2018 and June 2021. All patients underwent at least two spirometry tests. Environmental PM2.5 concentrations in the same period were collected from the nearest monitoring station. A multiple linear regression (MLR) model was employed to investigate the associations between changes in PM2.5 concentrations and LFR in patients who underwent lobectomy after adjusting for potential confounders. We assessed short- and medium-term LFR in patients who underwent lobectomy. The three- and 6-month average PM2.5 concentrations in each patient's residential area were divided into regional mild pollution (PM2.5 <25 µg/m3), moderate pollution (25 µg/m3 ≤ PM2.5 <35 µg/m3), and severe pollution (35 µg/m3 ≤ PM2.5) periods. The MLR model confirmed that PM2.5 was an independent risk factor affecting short-term forced lung capacity (FVC), forced expiratory volume in 1 s (FEV1), and maximum expiratory flow at 50% vital capacity (MEF50) recovery (adjusted P = 0.041, 0.014, 0.016, respectively). The MLR model confirmed that PM2.5 was an independent risk factor affecting medium-term MEF50 recovery (adjusted P = 0.046). Compared with the moderate and severe pollution periods, the short- and medium-term LFR (FVC, FEV1, MEF50) of patients in the mild pollution period were faster and better (P < 0.001, P < 0.001, P < 0.001, P = 0.048, P = 0.010, P = 0.013, respectively). Thus, exposure to high PM2.5 levels was associated with significantly reduced speed and degree of short- and medium-term LFR in patients who underwent lobectomy.

Moderate Dose Irradiation Induces DNA Damage and Impairments of Barrier and Host Defense in Nasal Epithelial Cells in vitro.

Purpose: Radiotherapy (RT) is the mainstay treatment for head and neck cancers. However, chronic and recurrent upper respiratory tract infections and inflammation have been commonly reported in patients post-RT. The underlying mechanisms remain poorly understood. Method and Materials: We used a well-established model of human nasal epithelial cells (hNECs) that forms a pseudostratified layer in the air-liquid interface (ALI) and exposed it to single or repeated moderate dose γ-irradiation (1Gy). We assessed the DNA damage and evaluated the biological properties of hNECs at different time points post-RT. Further, we explored the host immunity alterations in irradiated hNECs with polyinosinic-polycytidylic acid sodium salt (poly [I:C]) and lipopolysaccharides (LPS). Results: IR induced DNA double strand breaks (DSBs) and triggered DNA damage response in hNECs. Repeated IR significantly reduced basal cell proliferation with low expression of p63/KRT5 and Ki67, induced cilia loss and inhibited mucus secretion. In addition, IR decreased ZO-1 expression and caused a significant decline in the transepithelial electrical resistance (TEER). Moreover, hyperreactive response against pathogen invasion and disrupted epithelial host defense can be observed in hNECs exposed to repeated IR. Conclusion: Our study suggests that IR induced prolonged structural and functional impairments of hNECs may contribute to patients post-RT with increased risk of developing chronic and recurrent upper respiratory tract infection and inflammation.

Association of carotid artery geometries with middle cerebral artery atherosclerosis.

BACKGROUND AND AIMS: Evidence shows that artery geometries play a role in atherogenesis by influencing blood flow dynamics. However, whether upstream artery geometries influence downstream atherosclerosis remains unclear. We aimed to investigate whether carotid artery geometries were associated with middle cerebral artery (MCA) atherosclerosis. METHODS: We reviewed our institutional database of 3-dimensional head-neck combined high-resolution magnetic resonance imaging. The carotid artery geometries, carotid atherosclerosis, MCA configurations, and MCA atherosclerosis were examined. The associations between carotid artery geometry and MCA atherosclerosis were also analyzed. A final model integrating carotid artery geometries was established, and the incremental diagnostic value was evaluated and compared to a basic model that included only traditional risk factors. RESULTS: Among the 575 artery units of the ipsilateral carotid artery and MCA, the artery units with MCA plaques (n = 273) were associated with a larger bifurcation angle (odds ratio [OR], 1.138 per 10-degree increase; 95% confidential interval [CI], 1.023-1.264) and kinking-type extracranial internal carotid artery (ICA; OR, 2.193; 95%CI, 1.283-3.748) compared with those without MCA plaques (n = 302). These associations were independent of traditional risk factors, carotid atherosclerosis, and MCA configuration. A larger carotid bifurcation angle was also associated with tandem ICA and MCA atherosclerosis (OR, 1.211 per 10-degree increase; 95%CI, 1.110-1.321). The incremental diagnostic value of carotid artery geometry to traditional risk factors was revealed by comparing the area under the curves of the two diagnostic models (basic model, 0.673 vs. final model, 0.701; p = 0.016). CONCLUSIONS: Carotid artery geometries are independently associated with ipsilateral MCA atherosclerosis, providing new insights into the pathophysiology of intracranial atherosclerosis.

ZIF-8 with cationic defects toward efficient 125I2 uptake for in vitro radiotherapy of colon cancer.

Introducing 2,3-dimethyl-1H-imidazol-3-ium iodide (Dmim) as a monodentate ligand during the preparation of ZIF-8 yields ZIF-8 + (50) and ZIF-8 + (38) with cationic 'missing linker' defects. ZIF-8 + (38) adsorbs 125I2 and the resulting radioactive host-guest complex exhibits in vitro cytotoxicity comparable to that of Na125I against colon cancer cell line CT26.

High-Survival Rate After Microinjection of Mouse Oocytes and Early Embryos With mRNA by Combining a Tip Pipette and Piezoelectric-Assisted Micromanipulator.

Utilizing microinjection to introduce biological molecules such as DNA, mRNA, siRNA, and proteins into the cell is well established to study oocyte maturation and early embryo development in vitro. However, microinjection is an empirical technology. The cellular survival after microinjection is mainly dependent on the operator, and an experienced operator should be trained for a long time, from several months to years. Optimizing the microinjection to be highly efficient and quickly learned should be helpful for new operators and some newly established laboratories. Here, we combined the tip pipette and piezo-assisted micromanipulator to microinject the oocyte and early embryos at different stages of mouse. The results showed that the survival rate after microinjection was more than 85% for cumulus-oocyte complex, germinal vesicle oocyte, two-cell, and four-cell embryos, and close to 100% for MII oocyte and zygotes. The high-rate survival of microinjection can save many experimental samples. Thus, it should be helpful in studying some rare animal models such as aging and conditional gene knockout mice. Furthermore, our protocol is much easier to learn for new operators, who can usually master the method proficiently after several training times. Therefore, we would like to publicly share this experience, which will help some novices master microinjection skillfully and save many laboratory animals.

A narrative review of research progress on FoxM1 in breast cancer carcinogenesis and therapeutics.

OBJECTIVE: The purpose of this review is to clarify the potential roles of forkhead box transcription factor M1 (FoxM1) in the occurrence and progression of breast cancer, as well as the predictive value of FoxM1 as a prognostic biomarker and potential therapeutic target for breast cancer. BACKGROUND: Breast cancer, well-known as a molecularly heterogeneous cancer, is still one of the most frequently diagnosed malignant tumors among females worldwide. Tumor recurrence and metastasis are the central causes of high mortality in breast cancer patients. Many factors contribute to the occurrence and progression of breast cancer, including FoxM1. FoxM1, widely regarded as a classic proliferation-related transcription factor, plays pivotal roles in the occurrence, proliferation, invasion, migration, drug resistance, and epithelial-mesenchymal transition (EMT) processes of multiple human tumors including breast cancer. METHODS: The PubMed database was searched for articles published in English from February 2008 to May 2021 using related keywords such as "forkhead box transcription factor M1", "human breast cancer", "FoxM1", and "human tumor". About 90 research papers and reports written in English were identified, most of which were published after 2015. These papers mainly concentrated on the functions of FoxM1 in the occurrence, development, drug resistance, and treatment of human breast cancer. CONCLUSIONS: Considering that the abnormal expression of FoxM1 plays a significant role in the proliferation, invasion, metastasis, and chemotherapy drug resistance of breast cancer, and its overexpression is closely correlated with the unfavorable clinicopathological characteristics of breast tumor patients, it is considerably important to comprehend the regulatory mechanism of FoxM1 in breast cancer. This will provide strong evidence for FoxM1 as a potential biomarker for the targeted treatment and prognostic evaluation of breast cancer patients.

Blocking Effect of Demethylzeylasteral on the Interaction between Human ACE2 Protein and SARS-CoV-2 RBD Protein Discovered Using SPR Technology.

The novel coronavirus disease (2019-nCoV) has been affecting global health since the end of 2019, and there is no sign that the epidemic is abating. Targeting the interaction between the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein and the human angiotensin-converting enzyme 2 (ACE2) receptor is a promising therapeutic strategy. In this study, surface plasmon resonance (SPR) was used as the primary method to screen a library of 960 compounds. A compound 02B05 (demethylzeylasteral, CAS number: 107316-88-1) that had high affinities for S-RBD and ACE2 was discovered, and binding affinities (KD, µM) of 02B05-ACE2 and 02B05-S-RBD were 1.736 and 1.039 µM, respectively. The results of a competition experiment showed that 02B05 could effectively block the binding of S-RBD to ACE2 protein. Furthermore, pseudovirus infection assay revealed that 02B05 could inhibit entry of SARS-CoV-2 pseudovirus into 293T cells to a certain extent at nontoxic concentration. The compoundobtained in this study serve as references for the design of drugs which have potential in the treatment of COVID-19 and can thus accelerate the process of developing effective drugs to treat SARS-CoV-2 infections.

Mechanistic Insight into pH-Dependent Luminol Chemiluminescence in Aqueous Solution.

Luminol is one of the best known chemiluminescent cyclic hydrazides used in basic solution. Owing to the complexity of luminol oxidation, the mechanism of luminol chemiluminescence (CL), especially in aqueous solution, has not yet been fully elucidated. Recent theoretical computations have confirmed that luminol CL originates from the chemiexcitation of a 1,2-dioxane-3,6-dione dianion (CP2-). This seems to be inconsistent with the luminol oxidation in aqueous solutions, where only the decomposition of a monoanionic peroxyketal (L-OOH) is confirmed to yield CL. In this work, we theoretically investigated the complete decomposition of L-OOH and the pKa of key intermediates in aqueous solutions using (time-dependent) density functional theory. L-OOH first cyclizes to an endoperoxide monoanion (EP-). When pH < pKa (EP-), EP- directly decomposes by a retro-Diels-Alder (rDA) reaction to an aminophthalate monoanion (AP-) without CL activity. Moreover, when pH > pKa (EP-), EP- deprotonates to dianionic EP2-, which rapidly eliminates N2 to CP2-, inducing chemiexcitation. This conclusion is supported by the pKa (EP-) ≈ 8 estimated in this work, which is consistent with the pH-dependent profile of luminol CL observed in previous experiments. Thus, the pH-dependent CL determined by the acidity of endoperoxides may provide a theoretical basis to design new cyclic hydrazides with CL activity at different pH.

The clinical value of head-neck joint high-resolution vessel wall imaging in ischemic stroke.

BACKGROUND AND PURPOSE: To study the feasibility and clinical utility of head-neck joint high-resolution vessel wall imaging (HNJ-VWI) in the assessment of ischemic stroke. METHODS: We reviewed our institutional HNJ-VWI database. Patients with transient ischemic attack (TIA) or ischemic stroke were included. Abnormal findings of intracranial and/or extracranial artery were assessed on three-dimensional time-of-flight magnetic resonance angiography (3D TOF MRA) and HNJ-VWI modified from high-resolution 3D T1 sequence and classified into three groups including intracranial, extracranial and coexisting based on the locations. Etiologies of stroke were recorded according to Trial of Org 10172 in Acute Stroke Treatment criteria. RESULTS: One hundred and ten consecutive patients were studied. 3D TOF MRA displayed 71.8% (79/110, based on patients) abnormal arteries (stenosis or occlusion) , while HNJ-VWI displayed 96.3% (106/110) abnormal arteries (plaque,wall thickness and occlusion) including four isolated extracranial lesions and ten coexisting lesions. The etiologies of TIA/ischemic stroke included large artery atherosclerosis (80 cases), cerebral small vessel disease (6 cases), cardiogenic (2 cases), dissection (6 cases), vasculitis (4 cases), moyamoya disease (6 cases), others (2 cases) and undetermined (4 cases). For patients with atherosclerosis stroke, re-infarctions were more common in coexisting group than intracranial group (extracranial vs. intracranial vs coexisting: 0% vs. 9.1% vs. 43.7%, p = 0.001). CONCLUSIONS: HNJ-VWI is a feasible and valuable technique in assessment of ischemic stroke by detecting extracranial and intracranial artery abnormalities with one-step scan.

Tritiated Water Induces Toxicity in Human Umbilical Vein Vascular Endothelial Cells via IL8.

We aimed to determine the toxic effects of tritiated water (HTO) on 12 generations (T1-T12) of human umbilical vein vascular endothelial cells (HUVECs) and elucidate the underlying mechanisms. We evaluated cellular senescence, interleukin (IL) 8 concentrations, and angiogenesis using ß-galactosidase staining, enzyme-linked immunosorbent assay, and in vitro assays, respectively. The adhesion properties of contaminated cells and differentially expressed genes were assessed using the xCELLigence RTCA SP system and gene chip analysis, respectively. We found that long-term exposure to low levels of HTO can reduce the adhesion of HUVECs to the cellular matrix as well as their angiogenic capacity, while increasing their permeability, senescence, and adhesion to monocytes. Interleukin 8 activated the p38 and Epidermal Growth Factor Receptor (EGFR) pathways in HTO-treated cells and hence was identified as a key candidate of biomarker. The present study clarified the toxicity of HTO in vascular endothelial cells and identified IL8 as a novel protective target with important theoretical and practical values.

Adaptively capturing the heterogeneity of expression for cancer biomarker identification.

BACKGROUND: Identifying cancer biomarkers from transcriptomics data is of importance to cancer research. However, transcriptomics data are often complex and heterogeneous, which complicates the identification of cancer biomarkers in practice. Currently, the heterogeneity still remains a challenge for detecting subtle but consistent changes of gene expression in cancer cells. RESULTS: In this paper, we propose to adaptively capture the heterogeneity of expression across samples in a gene regulation space instead of in a gene expression space. Specifically, we transform gene expression profiles into gene regulation profiles and mathematically formulate gene regulation probabilities (GRPs)-based statistics for characterizing differential expression of genes between tumor and normal tissues. Finally, an unbiased estimator (aGRP) of GRPs is devised that can interrogate and adaptively capture the heterogeneity of gene expression. We also derived an asymptotical significance analysis procedure for the new statistic. Since no parameter needs to be preset, aGRP is easy and friendly to use for researchers without computer programming background. We evaluated the proposed method on both simulated data and real-world data and compared with previous methods. Experimental results demonstrated the superior performance of the proposed method in exploring the heterogeneity of expression for capturing subtle but consistent alterations of gene expression in cancer. CONCLUSIONS: Expression heterogeneity largely influences the performance of cancer biomarker identification from transcriptomics data. Models are needed that efficiently deal with the expression heterogeneity. The proposed method can be a standalone tool due to its capacity of adaptively capturing the sample heterogeneity and the simplicity in use. SOFTWARE AVAILABILITY: The source code of aGRP can be downloaded from https://github.com/hqwang126/aGRP .

Testing the utility of DNA barcodes and a preliminary phylogenetic framework for Chinese freshwater mussels (Bivalvia: Unionidae) from the middle and lower Yangtze River.

The middle and lower portions of the Yangtze River basin is the most species-rich region for freshwater mussels in Asia. The management and conservation of the taxa in this region has been greatly hampered by the lack of a well-developed phylogeny and species-level taxonomic framework. In this study, we tested the utility of two mitochondrial genes commonly used as DNA barcodes: the first subunit of the cytochrome oxidase c gene (COI) and the first subunit of the NADH dehydrogenase gene (ND1) for 34 putative species representing 15 genera, and also generated phylogenetic hypotheses for Chinese unionids based on the combined dataset of the two mitochondrial genes. The results showed that both loci performed well as barcodes for species identification, but the ND1 sequences provided better resolution when compared to COI. Based on the two-locus dataset, Bayesian Inference (BI) and Maximum Likelihood (ML) phylogenetic analyses indicated 3 of the 15 genera of Chinese freshwater mussels examined were polyphyletic. Additionally, the analyses placed the 15 genera into 3 subfamilies: Unioninae (Aculamprotula, Cuneopsis, Nodularia and Schistodesmus), Gonideninae (Lamprotula, Solenaia and Ptychorhychus) and Anodontinae (Cristaria, Arconaia, Acuticosta, Lanceolaria, Anemina and Sinoanodonta). Our results contradict previous taxonomic classification that placed the genera Arconaia, Acuticosta and Lanceolaria in the Unioninae. This study represents one of the first attempts to develop a molecular phylogenetic framework for the Chinese members of the Unionidae and will provide a basis for future research on the evolution, ecology, and conservation of Chinese freshwater mussels.

Bone marrow mesenchymal stem cells ameliorate lung injury through anti-inflammatory and antibacterial effect in COPD mice.

The anti-inflammatory and antibacterial mechanisms of bone marrow mesenchymal stem cells (MSCs) ameliorating lung injury in chronic obstructive pulmonary disease (COPD) mice induced by cigarette smoke and Haemophilus Parainfluenza (HPi) were studied. The experiment was divided into four groups in vivo: control group, COPD group, COPD+HPi group, and COPD+HPi+MSCs group. The indexes of emphysematous changes, inflammatory reaction and lung injury score, and antibacterial effects were evaluated in all groups. As compared with control group, emphysematous changes were significantly aggravated in COPD group, COPD+HPi group and COPD+HPi+MSCs group (P<0.01), the expression of necrosis factor-kappaB (NF-κB) signal pathway and proinflammatory cytokines in bronchoalveolar lavage fluid (BALF) were increased (P<0.01), and the phagocytic activity of alveolar macrophages was downregulated (P<0.01). As compared with COPD group, lung injury score, inflammatory cells and proinflammatory cytokines were significantly increased in the BALF of COPD+HPi group and COPD+HPi+MSCs group (P<0.01). As compared with COPD+HPi group, the expression of tumor necrosis factor-α stimulated protein/gene 6 (TSG-6) was increased, the NF-κB signal pathway was depressed, proinflammatory cytokine was significantly reduced, the anti-inflammatory cytokine IL-10 was increased, and lung injury score was significantly reduced in COPD+HPi+MSCs group. Meanwhile, the phagocytic activity of alveolar macrophages was significantly enhanced and bacterial counts in the lung were decreased. The results indicated cigarette smoke caused emphysematous changes in mice and the phagocytic activity of alveolar macrophages was decreased. The lung injury of acute exacerbation of COPD mice induced by cigarette smoke and HPi was alleviated through MSCs transplantation, which may be attributed to the fact that MSCs could promote macrophages into anti-inflammatory phenotype through secreting TSG-6, inhibit NF-кB signaling pathway, and reduce inflammatory response through reducing proinflammatory cytokines and promoting the expression of the anti-inflammatory cytokine. Simultaneously, MSCs could enhance phagocytic activity of macrophages and bacterial clearance. Meanwhile, we detected anti-inflammatory and antibacterial activity of macrophages regulated by MSCs in vitro. As compared with RAW264.7+HPi+CSE group, the expression of NF-кB p65, IL-1ß, IL-6 and TNF-α was significantly reduced, and the phagocytic activity of macrophages was significantly increased in RAW264.7+HPi+CSE+MSCs group (P<0.01). The result indicated the macrophages co-cultured with MSCs may inhibit NF-кB signaling pathway and promote phagocytosis by paracrine mechanism.

Bone Marrow Mesenchymal Stem Cells Ameliorate Lung Injury through Anti-inflammatory and Antibacterial Effect in COPD Mice / 华中科技大学学报（医学）（英德文版）

The anti-inflammatory and antibacterial mechanisms of bone marrow mesenchymal stem cells (MSCs) ameliorating lung injury in chronic obstructive pulmonary disease (COPD) mice induced by cigarette smoke and Haemophilus Parainfluenza (HPi) were studied.The experiment was divided into four groups in vivo:control group,COPD group,COPD+HPi group,and COPD+HPi+MSCs group.The indexes of emphysematous changes,inflammatory reaction and lung injury score,and antibacterial effects were evaluated in all groups.As compared with control group,emphysematous changes were significantly aggravated in COPD group,COPD+HPi group and COPD+HPi+MSCs group (P＜0.01),the expression of necrosis factor-kappaB (NF-κB) signal pathway and proinflammatory cytokines in bronchoalveolar lavage fluid (BALF) were increased (P＜0.01),and the phagocytic activity of alveolar macrophages was downregulated (P＜0.01).As compared with COPD group,lung injury score,inflammatory cells and proinflammatory cytokines were significantly increased in the BALF of COPD+HPi group and COPD+HPi+MSCs group (P＜0.01).As compared with COPD+HPi group,the expression of tumor necrosis factor-α stimulated protein/gene 6 (TSG-6) was increased,the NF-κB signal pathway was depressed,proinflammatory cytokine was significantly reduced,the anti-inflammatory cytokine IL-10 was increased,and lung injury score was significantly reduced in COPD+HPi+MSCs group.Meanwhile,the phagocytic activity of alveolar macrophages was significantly enhanced and bacterial counts in the lung were decreased.The results indicated cigarette smoke caused emphysematous changes in mice and the phagocytic activity of alveolar macrophages was decreased.The lung injury of acute exacerbation of COPD mice induced by cigarette smoke and HPi was alleviated through MSCs transplantation,which may be attributed to the fact that MSCs could promote macrophages into anti-inflammatory phenotype through secreting TSG-6,inhibit NF-κB signaling pathway,and reduce inflammatory response through reducing proinflammatory cytokines and promoting the expression of the anti-inflammatory cytokine.Simultaneously,MSCs could enhance phagocytic activity of macrophages and bacterial clearance.Meanwhile,we detected anti-inflammatory and antibacterial activity of macrophages regulated by MSCs in vitro.As compared with RAW264.7+HPi+CSE group,the expression of NF-κB p65,IL-1β,IL-6 and TNF-α was significantly reduced,and the phagocytic activity of macrophages was significantly increased in RAW264.7+HPi+CSE+MSCs group (P＜0.01).The result indicated the macrophages co-cultured with MSCs may inhibit NF-κB signaling pathway and promote phagocytosis by paracrine mechanism.

Structure and mechanism of the unique C2 domain of Aida.

Axin interactor, dorsalization-associated (Aida) was identified as a regulatory factor that utilizes its C-terminal region to interact with axis formation inhibitor (Axin). Aida abrogates the Axin-mediated Jun N-terminal kinase activation required for proper dorsalization during zebrafish embryonic development, and thus functions as a proventralization factor. Here, we report the structure of Aida C-terminal fragments, which adopt a conventional C2 domain topology. We also demonstrate that Aida can specifically bind to phosphoinositides in a Ca(2+) -independent manner, and is able to associate with the cell membrane via a novel positively charged surface, namely a basic loop. Mutation of the positively charged patch on the basic loop leads to destabilization of the Aida-membrane association or disruption of the Aida-Axin interaction, resulting in impaired Jun N-terminal kinase inhibition. Together, our findings provide a molecular basis for C2 domain-mediated Aida-membrane and Aida-Axin associations. DATABASE: The atomic coordinates and structure factors of the mouse Aida C2 domain (code: 2QZ5) and the zebrafish Aida C2 domain (code: 2QZQ) have been deposited in the Protein Data Bank (http://www.rcsb.org/) STRUCTURED DIGITAL ABSTRACT: AIDA physically interacts with Axin by anti tag coimmunoprecipitation (View interaction).