DCZ0801, a novel compound, induces cell apoptosis and cell cycle arrest via MAPK pathway in multiple myeloma.

Multiple myeloma (MM) is a refractory malignant hematological malignancy, and many therapeutic strategies have been developed to cure patients with MM. DCZ0801 is a compound that consists of oxophenamide and pterostilbene. The role of these compounds in hematological cancers such as MM has yet to be studied. In this study, we explored the potential mechanism of DCZ0801 action, its anti-tumor activity both in vitro and in vivo on MM. This study was carried out via cell cycle proliferation assay, apoptotic analysis, western blot analysis, and examination of xenotransplantation model of tumors. The in vitro studies revealed that DCZ0801 could inhibit cell proliferation and induce apoptosis by regulating both caspase-dependent and mitogen-activated protein kinase signaling pathways, inducing S-phase arrest of the cell cycle related to downregulation of CDK2, cyclin-A2, and CDC25A protein expression. The in vivo studies showed that DCZ0801 could significantly reduce the size of the tumors in nude mice. Our results demonstrated that DCZ0801 may emerge as the new therapeutic option for the patient with MM.

Anti-Inflammatory Effect of IL-37-Producing T-Cell Population in DSS-Induced Chronic Inflammatory Bowel Disease in Mice.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease that is thought to arise in part from abnormal adaptive immune responses against intestinal microbiota. T lymphocytes play significant roles in triggering mucosal inflammation and/or maintaining gut immune homeostasis. It has been demonstrated that IL-37 expresses in a variety of cells and exerts a protective function involved in both innate immunity and adaptive immunity. In the present study, a population of IL-37-producing T-cells was detected in the spleen and mesenteric lymph nodes (MLNs) in IL-37+/+ mice after dextran sodium sulfate (DSS) induction. Adoptive transfer of the T-cells from the spleen of IL-37+/+ mice following DSS treatment partly recovered the body weight, improved the disease activity index (DAI) and macroscopic damage score, and attenuated the intestinal inflammation. In addition, colon shortening, an indirect marker of inflammation, was decreased, consistent with the decreased IFN-γ level and the increased IL-10 level in the colonic tissue. Collectively, our data uncovered a subset of T-lymphocytes expressing IL-37, which represents a potent regulation of immunity and serves as the protective role in chronic IBD.

Ovalbumin induces natural killer cells to secrete Th2 cytokines IL­5 and IL­13 in a mouse model of asthma.

Asthma is a chronic lung disease characterized by an imbalance of T­helper (Th)1/Th2 cells and their cytokine profiles. Natural killer (NK) cells constitute a considerable subset of the lymphocyte population in the lungs, and provide protection against respiratory infection by fungi, bacteria and viruses. However, the mechanism by which NK cells are involved in asthma remains to be fully elucidated. The present study analyzed the dynamic changes of NK cells and their subsets during the development of the ovalbumin (OVA)­induced allergic airway response. Lung tissues were histologically examined for cell infiltration and mucus hypersecretion. The number, activity and cytokine­secreting ability of NK cells was determined by flow cytometry. The results showed that the percentage of NK cells in the lung was decreased following OVA sensitization and challenge. However, NK cells exhibited enhanced activity and secreted more Th2 cytokines (IL­5 and IL­13) following OVA challenge. Furthermore, the proportion of CD11b­ NK subsets increased with the development of asthma, and CD11b­ CD27­ NK cells were the primary NK subset producing Th2 cytokines. These findings suggest that, although NK cells are not the crucial type of lymphocytes involved in asthma, OVA induces NK cells to secrete Th2 cytokines that may be involved in the pathogenesis of asthma.

Establishment of different experimental asthma models in mice.

Asthma is a complex disease. The heterogeneity of airway inflammation during asthma indicates there are different mechanisms involved. In order to further study the mechanisms of asthma, different mouse models were established to mimic corresponding subtypes of asthma in clinic. Eosinophilic asthma was established by intraperitoneal injections of ovalbumin (OVA) on day 0 and day 7, followed by inhalation of aerosolized OVA on days 14-17. Neutrophilic asthma was established by transtracheal administration of a high dose of lipopolysaccharide (LPS; 10 µg) on days 15 and 17 in combination with OVA sensitization and challenge as described previously. Mix-granulocytic asthma was established by transtracheal administration of a low dose of LPS (1 µg) on day 15, in combination with OVA sensitization and challenge as described previously. Compared with healthy controls, increased numbers of eosinophils, elevated levels of T helper (Th)2 cytokines in bronchoalveolar lavage fluid (BALF), and moderated inflammation of lung tissues was observed in eosinophilic asthma. Increased numbers of neutrophils, elevated levels of Th1 and Th17 cytokines in BALF and severe inflammation of lung tissues was observed in neutrophilic asthma. Increased numbers of both eosinophils and neutrophils, elevated levels of Th1, Th2 and Th17 cytokines in BALF and severe inflammation of lung tissues was observed in mix-granulocytic asthma. Airway hyperresponsiveness, increased bronchial mucus secretion, and elevated serum levels of immunoglobin (Ig)E and OVA-IgE were detected in all three asthma models. Dexamethasone reduced the pathogenic symptoms of the mice in eosinophilic asthma, however had no effect on neutrophilic asthma or mix-granulocytic asthma. Each model of asthma established in the present study represents corresponding subtypes of asthma in clinic.

A novel CXCL8-IP10 hybrid protein is effective in blocking pulmonary pathology in a mouse model of Klebsiella pneumoniae infection.

Klebsiella pneumoniae (K. pneumoniae) is a hospital-acquired infectious agent that causes a range of diseases. Herein we have developed a novel CXCL8-IP10 hybrid protein and evaluated its efficacy in an animal model of K. pneumoniae infection. Neutrophil chemotaxis data revealed that CXCL8-IP10 could inhibit human neutrophil chemotactic responses induced by the ELR-CXC chemokine CXCL8. To evaluate the effect of CXCL8-IP10 on K. pneumoniae infection, C57BL/6 mice were challenged with K. pneumoniae followed by treatment with CXCL8-IP10 (500 µg/kg, i.p.), or dexamethasone (0.8 mg/kg, s.c.), or ceftazidime (200 mg/kg, s.c.) individually. CXCL8-IP10, dexamethasone or ceftazidime markedly inhibit Klebsiella-induced pulmonary inflammation as assessed by gross examination and histopathology. Moreover, the chemotactic responses of neutrophils was blocked by CXCL8-IP10 rather than dexamethasone or ceftazidime. Furthermore, the levels of inflammatory factors IL-1ß, IFN-γ and TNF-α were decreased after CXCL8-IP10, dexamethasone or ceftazidime treatment. Together, these results suggest that CXCL8-IP10 may provide a novel strategy for treating K. pneumoniae infection.

Collagenase digestion down-regulates the density of CD27 on lymphocytes.

Collagenases are widely used for tissue digestion in experiments due to their potent hydrolysis of connective tissue. CD27, also known as tumor necrosis factor receptor superfamily 7 (TNFRSF7), is limited to be expressed on the cells of the lymphoid lineage. In our preliminary research, we found that CD27 on NK cells was almost disappeared with the digestion of type I collagenase for 90min. This phenomenon suggests that the process of tissue digestion may affect the density of CD27 on cells. In order to verify this, the lungs of mice were digested with types I and IV collagenase or grinded, respectively. The percentage of CD27(+) cells and the density of CD27 on cells were assayed by flow cytometry. The data presented that the percentage of CD27(+) cells and the density of CD27 on lymphocytes gradually decreased with the time of digestion with type I or IV collagenase. We also detected that the density of CD11b on NK cells was not affected by collagenase digestion. Collectively, the findings of the present study suggest that the collagenase digestion has a selective effect on the density of molecules on cells.