Deletion of Smad3 protects against C-reactive protein-induced renal fibrosis and inflammation in obstructive nephropathy.

Introduction and Aims: Elevated plasma levels of C-reactive protein (CRP) are closely associated with progressive renal injury in patients with chronic kidney disease (CKD). Here, we tested a hypothesis that CRP may promote renal fibrosis and inflammation via a TGF-ß/Smad3-dependent mechanism. Methods: Role and mechanisms of TGF-ß/Smad3 in CRP-induced renal fibrosis and inflammation were examined in a mouse model of unilateral ureteral obstruction (UUO) induced in CRP Tg/Smad3 KO mice and in a rat tubular epithelial cell line in which Smad3 gene is stably knocked down (S3KD-NRK52E). Results: We found that mice overexpressing the human CRP gene were largely promoted renal inflammation and fibrosis as evidenced by increasing IL-1ß, TNF-α, MCP-1 expression, F4/80+ macrophages infiltration, and marked accumulation of α-smooth muscle actin (α-SMA), collagen I and fibronectin in the UUO kidney, which were blunted when Smad3 gene was deleted in CRPtg-Smad3KO. Mechanistically, we found that the protection of renal inflammation and fibrosis in the UUO kidney of CRPtg-Smad3KO mice was associated with the inactivation of CD32-NF-κB and TGF-ß/Smad3 signaling. Conclusion: In conclusion, Smad3 deficiency protects against CRP-mediated renal inflammation and fibrosis in the UUO kidney by inactivating CD32-NF-κB and TGF-ß/Smad3 signaling.

Dihydromyricetin promotes apoptosis, suppresses proliferation and tumor necrosis factor-α-mediated nuclear factor kappa-B activation in nasopharyngeal carcinoma CNE-2 cell.

OBJECTIVE: To investigate the efficacy of dihydromyricetin (DMY) on nasopharyngeal carcinoma (NPC) cell proliferation, apoptosis and to reveal the underlying mechanism in vitro experiments. METHODS: The CNE-2 cell line was treated with different concentrations of DMY and the effects of DMY on cell viability and proliferation were evaluated using cell counting kit-8 (CCK-8) assay and plate colony formation assay. Cellular apoptosis was detected by flow cytometry following Annexin V fluorescein isothiocyanate/propidine iodide staining. Nuclei morphology was observed under a fluorescence microscope following Hoechst 333258 staining. The expression of phosphorylated inhibitor of nuclear factor kappa-B kinase subunit beta (p-IKKß), phosphorylated inhibitor of nuclear factor kappa-B kinase subunit alpha (p-IKKα), inhibitor of nuclear factor kappa-B alpha (IκB-α), nuclear factor kappa-B (NF-κB)/p65 was examined by Western blot analysis and the nuclear translocation of NF-κB/p65 was observed using a confocal laser scanning microscopy. RESULTS: DMY inhibited the proliferative capability and colony formation of NPC CNE-2 cells. Meanwhile, DMY induced apoptosis of CNE-2 cells in a dose and time-dependent manner via upregulating B-cell lymphoma-2 associated X, but downregulating B-cell lymphoma-2 and pro-caspase-3. Importantly, we found that DMY suppressed tumor necrosis factor alpha (TNF-α)-mediated NF-κB activation via inhibiting p-IKKß, p-IKKα and blocking NF-κB subunit p65. CONCLUSION: Our experiments demonstrated that DMY had significant antiproliferative and apoptosisinducing effects on CNE-2 cells. Additionally, DMY promoted inactivation of p-IKKß, p-IKKα, and blocked the nuclear translocation of NF-κB subunit p65. These results suggest that DMY may be an important therapeutic approach for NPC.

BTLA associates with increased Foxp3 expression in CD4(+) T cells in dextran sulfate sodium-induced colitis.

Ulcerative colitis (UC) is an inflammatory bowel disease, and its pathogenesis involves a variety of genetic, environmental, and immunological factors such as T helper cells and their secreted cytokines. B and T lymphocyte attenuator (BTLA) is an immunoregulatory receptor that has a strong suppressive effect on T-cell function. However the role of BTLA in UC remains poorly understood. Here we demonstrated that the frequency of BTLA-expressing CD3(+) T cells, especially CD4(+) T cells, increased in blood and mucosa in mice with DSS-induced colitis. The frequency of Foxp3-expressing cells in BTLA+ CD4(+) T cell from lamina propria mononuclear cells (LPMCs) was much higher in DSS-treated mice than that in controls. Similarly, the proportion of IL-17+ cells in BTLA+ CD4(+) T cells from LPMCs in DSS-treated mice is much higher than that in controls, while no perceptible difference for the proportion of IFN-γ+ cells in BTLA+ CD4(+) T cells was noted between DSS-treated mice and controls. Treatment of mesalazine, an anti-ulcerative colitis drug, down-regulated Foxp3 and IL-17 expression in BTLA positive T cells along with attenuated severity for colitis. Our findings indicate that BTLA may be involved in the control of inflammatory responses through increasing Foxp3 expression, rather than attenuating IL-17 production, in DSS-induced colitis.

Elevated HMGB1-related interleukin-6 is associated with dynamic responses of monocytes in patients with active pulmonary tuberculosis.

There were limited studies assessing the role of HMGB1 in TB infection. In this prospective study, we aimed to assess the levels of HMGB1 in plasma or sputum from active pulmonary tuberculosis (APTB) patients positive for Mtb culture test, and to evaluate its relationship with inflammatory cytokines and innate immune cells. A total of 36 sputum Mtb culture positive APTB patients and 32 healthy volunteers (HV) were included. Differentiated THP-1 cells were treated for 6, 12 and 24 hrs with BCG at a multiplicity of infection of 10. The absolute values and percentages of white blood cells (WBC), neutrophils, lymphocytes, and monocytes were detected by an automatic blood analyzer. Levels of HMGB1, IL-6, IL-10 and TNF-α in plasma, sputum, or cell culture supernatant were measured by ELISA. The blood levels of HMGB1, IL-6, IL-10 and TNF-α, the absolute values of WBC, monocytes and neutrophils, and the percentage of monocytes were significant higher in APTB patients than those in HV groups (P < 0.05). The sputum levels of HMGB1, IL-10, and TNF-α were also significantly higher in APTB patients than those in HV groups (P < 0.05). Meanwhile, plasma level of HMGB1, IL-6, and IL-10 in APTB patients were positively correlated with those in sputum (P < 0.05), respectively. IL-6 was positively correlated with HMGB1 both in plasma and sputum of APTB patients (P < 0.05). HMGB1 and IL-6 is positively correlated with the absolute number of monocytes in APTB patients (P < 0.05). BCG induced HMGB1, IL-6, IL-10 and TNF-α production effectively in PMA-treated THP-1 cells. HMGB1 may be used as an attractive biomarker for APTB diagnosis and prognosis and may reflect the inflammatory status of monocytes in patients with APTB.

BTLA exhibits immune memory for αß T cells in patients with active pulmonary tuberculosis.

Despite past extensive studies, the role of B and T lymphocyte attenuator (BTLA) in αß T cells in patients with active pulmonary tuberculosis (ATB) remains poorly understood. Here we demonstrate that BTLA expression on αß T cells is decreased in patients with M. tuberculosis (Mtb) infection. Particularly, BTLA expression levels are likely critical for αß T cells to manifest and maintain an active central memory phenotype with high capacity for secretion of IFN-γ and perforin, which are important for immune memory against TB infection. BTLA(high) αß T cells also exhibited higher capacity in response to Mtb peptide stimulation. In contrast to the role of BTLA played for negative regulation of immune responses, our data in the current studies suggest that BTLA expression on αß T cells is likely associated with protective immune memory against Mtb infection in the setting of patients with active pulmonary tuberculosis. This previous unappreciated role for BTLA may have implications for prevention and treatment of patients with Mtb infection.

Clinicopathological features of an ascending colon mixed adenoneuroendocrine carcinoma with clinical serosal invasion.

Mixed adenoneuroendocrine carcinoma (MANEC) is exceedingly rare with a poor outcome. In this article, we reported a MANEC in a 68-year-old woman with a symptom of abdominal pain and distension. MANEC derived from the ascending colon with highly aggressive behavior. The diagnosis and distinguish of MANEC must base on histological findings and immunohistochemical findings. In this case, microscopic observation showed tumor cells were arranged in conglobate and nested by fibrous tissue with a visible cell atypia and mitotic. NEC-like and exocrine glandular cells were also been seen in a single neoplasm. MANEC tissues were immunopositive for CK, CK20, P53, CK7, CDX-2, Ki-67 (70%+), E-cad, CD56, CEA, Syn, villin and CgA, and immunonegative for CA125, NSE, ER and PR. Here, the patient was treated by surgical operation and was followed-up near 3 months, no local recurrence and distant metastasis.

Embryonal rhabdomyosarcoma of the paranasal sinuses: a case report and review of literature.

Embryonal rhabdomyosarcoma (ERMS) is a rare malignancy with a poor outcome. In this article, we describe a case of ERMS in the paranasal sinuses from a 60-year-old male patient. ERMS derived from the paranasal sinuses is extremely rare. The diagnosis of ERMS must be based on histological findings and immunohistochemical findings. In this case, microscopic observation showed tumor cells were arranged in flocked sheets, cord-like and acinar-like by hyperplastic fibrous tissue. And ERMS tissues were immunopositive for myogenin, desmin, MSA, CD56, vimentin, CD99, Syn and Ki-67 (40%+), and immunonegative for CK, EMA, LCA, GFAP, NSE, S-100, HMB-45 and Melan-A. Here, the patient was treated with multimodal therapy including endoscopic surgery, chemotherapy and radiation, but the patient's postoperative recovery is not too smooth.

A case of mucoepidermoid carcinoma located in the left forearm of a middle-aged pregnant woman.

In this article, we described a mucoepidermoid carcinoma (MEC) located in the left forearm of a 39-year-old pregnant woman. Here, the patient had a superficial tip size apophysis nearly 3 years, which begin to sustained growth after pregnant in 2012, and stopped growth after childbirth. MEC is a rare malignant tumor. Previously reports showed it mainly arise from the salivary, bronchial, thyroid, breast, lacrimal gland and conjunctiva. Here, we reported a case of MEC arising from the forearm gland for the first time. Histological finding showed a cystic and solid tumor in fibrous tissue below the squamous epithelium, and some columnar or cuboidal mucous cells covering on the epidermal cells or mixed with epidermal cells included in the tumor tissues. Also, Focal hyperplasia epidermal cells with round or oval nucleus in center were distributed in small pieces but no keratosis. The tumor tissues were immunopositive for CEA, P63, ki-67 (10%), CK7 and CK5/6, and immunonegative for CK20 and GCDFP-15. This case is a low-grade MEC and the patient's postoperative recovery is smooth.

Nasopharyngeal adenoid cystic carcinoma: a case report and review of the literature.

ACC derived from nasopharyngeal epithelial cells is rare, usually benign. In this article, we reported a nasopharyngeal adenoid cystic carcinoma (NACC) in a 31-year-old woman with a symptom of hoarseness, headache, epistaxis slightly, diplopia, facial numbness and dysphagia near 3 months. A tumor on the right side of the nasopharynx was confirmed by laryngoscope check and MRI of the skull base. Histopathological findings showed that tumor cells were arranged in cord-like or acinar-like by atypical hyperplastic epithelial cells forming a cribriform and tubular pattern, and immunohistochemical findings showed that tumor tissues were immunopositive for p63 (+), CK7 (+), CK19 (+), CK8 (+), CK18 (+), SMA (+), CK (+), p53 (++), S-100 (+) and Ki-67 (5%+), and negative for CD34 (-), CK5/6 (-), CEA (-) and CD117 (-). Patient was treated by surgical operation and radiotherapy, and was followed-up near 10 months, no local recurrence and distant metastasis.

Malignant myoepithelioma of the breast: a case report and review of literature.

In this article, we described a malignant myoepithelioma of the breast (MMB) in a 69-year-old woman. Breast cancer derived from myoepithelial cells is very rare, usually benign. The diagnosis of MMB based on histological and immunohistochemical finding. In this case, the author diagnosed the tumor as MMB, because tumor tissues were immunopositive for 34ßE12, P63, SMA, S-100, CD10, E-Cad and Ki-67, and immunnegative for CK5/6, desmin, ER, PR and C-erbB-2, because tumor tissue showed invasive growth and local hemorrhage or necrosis, suggesting malignant, and also because there was a transition between the tumor cells and hyperplastic myoepithelium of non-tumorous ducts. The patient's postoperative recovery is smooth and regular following of patient is essential.

Ovarian sclerosing stromal tumor in a young woman with ectopic pregnancy: clinical, pathological, and immunohistochemical studies.

In this article, we described an ovarian sclerosing stromal tumor (SST) in a young woman with ectopic pregnancy. It is important to distinguish SST from fibroma, thecoma, and lipoid cell tumors clinically and histologically. Several unique histologic features including pseudolobulation, sclerosis and prominent vascularity are clearly reflected at histopathological findings. The SST cells were immunopositive for CD34, Desmin and SMA, and negative for factor VIII-related antigen, CD31, S-100, ER and PR. The patient's postoperative recovery was smooth and she was discharged after 21 days.

Assessing the role of IL-35 in colorectal cancer progression and prognosis.

Despite the recent realization of Interleukin (IL)-35 in tumorigenesis, its exact impact on colorectal cancer (CRC) progression and prognosis, however, is yet to be elucidated clearly. We thus in the present report conducted comparative analysis of IL-35 levels between CRC patients and matched control subjects. IL-35 is highly expressed in all CRC tissues, which can be detected in vast majority of colorectal cancer cells. IL-35 levels in CRC lysates and serum samples are highly correlated to the severity of malignancy and the clinical stage of tumor. Particularly, a significant reduction for serum IL-35 was noted in patients after surgical resection, indicating that IL-35 promotes CRC progression associated with poor prognosis. Mechanistic study demonstrated a significant correlation between serum IL-35 levels and the number of peripheral regulatory T (Treg) cells in CRC patients, suggesting that IL-35 implicates in CRC pathogenesis probably by inducing Treg cells, while cancer cell-derived IL-35 may also recruit Treg cells into the tumor microenvironment in favor of tumor growth. Together, our data support that IL-35 could be a valuable biomarker for assessing CRC progression and prognosis in clinical settings.