CCL2 as a potential therapeutic target for clear cell renal cell carcinoma

We previously reported that the pVHL-atypical PKC-JunB pathway contributed to promotion of cell invasiveness and angiogenesis in clear cell renal cell carcinoma (ccRCC), and we detected chemokine (C-C motif) ligand-2 (CCL2) as one of downstream effectors of JunB. CCL2 plays a critical role in tumorigenesis in other types of cancer, but its role in ccRCC remains unclear. In this study, we investigated the roles and therapeutic potential of CCL2 in ccRCC. Immunohistochemical analysis of CCL2 expression for ccRCC specimens showed that upregulation of CCL2 expression correlated with clinical stage, overall survival, and macrophage infiltration. For functional analysis of CCL2 in ccRCC cells, we generated subclones of WT8 cells that overexpressed CCL2 and subclones 786-O cells in which CCL2 expression was knocked down. Although CCL2 expression did not affect cell proliferation in vitro, CCL2 overexpression enhanced and CCL2 knockdown suppressed tumor growth, angiogenesis, and macrophage infiltration in vivo. We then depleted macrophages from tumor xenografts by administration of clodronate liposomes to confirm the role of macrophages in ccRCC. Depletion of macrophages suppressed tumor growth and angiogenesis. To examine the effect of inhibiting CCL2 activity in ccRCC, we administered CCL2 neutralizing antibody to primary RCC xenografts established from patient surgical specimens. Inhibition of CCL2 activity resulted in significant suppression of tumor growth, angiogenesis, and macrophage infiltration. These results suggest that CCL2 is involved in angiogenesis and macrophage infiltration in ccRCC, and that CCL2 could be a potential therapeutic target for ccRCC

Heterogeneous fibroblasts underlie age-dependent tertiary lymphoid tissues in the kidney

Acute kidney injury (AKI) is a common clinical condition defined as a rapid decline in kidney function. AKI is a global health burden, estimated to cause 2 million deaths annually worldwide. Unlike AKI in the young, which is reversible, AKI in the elderly often leads to end-stage renal disease, and the mechanism that prevents kidney repair in the elderly is unclear. Here we demonstrate that aged but not young mice developed multiple tertiary lymphoid tissues (TLTs) in the kidney after AKI. TLT size was associated with impaired renal function and increased expression of proinflammatory cytokines and homeostatic chemokines, indicating a possible contribution of TLTs to sustained inflammation after injury. Notably, resident fibroblasts from a single lineage diversified into p75 neurotrophin receptor(+) (p75NTR(+)) fibroblasts and homeostatic chemokine-producing fibroblasts inside TLTs, and retinoic acid-producing fibroblasts around TLTs. Deletion of CD4(+) cells as well as late administration of dexamethasone abolished TLTs and improved renal outcomes. Importantly, aged but not young human kidneys also formed TLTs that had cellular and molecular components similar to those of mouse TLTs. Therefore, the inhibition of TLT formation may offer a novel therapeutic strategy for AKI in the elderly.</p

Discovery of New Hydrothermal Activity and Chemosynthetic Fauna on the Central Indian Ridge at 18°–20°S

Indian Ocean hydrothermal vents are believed to represent a novel biogeographic province, and are host to many novel genera and families of animals, potentially indigenous to Indian Ocean hydrothermal systems. In particular, since its discovery in 2001, much attention has been paid to a so-called ‘scaly-foot’ gastropod because of its unique iron-sulfide-coated dermal sclerites and the chemosynthetic symbioses in its various tissues. Despite increasing interest in the faunal assemblages at Indian Ocean hydrothermal vents, only two hydrothermal vent fields have been investigated in the Indian Ocean. Here we report two newly discovered hydrothermal vent fields, the Dodo and Solitaire fields, which are located in the Central Indian Ridge (CIR) segments 16 and 15, respectively. Chemosynthetic faunal communities at the Dodo field are emaciated in size and composition. In contrast, at the Solitaire field, we observed faunal communities that potentially contained almost all genera found at CIR hydrothermal environments to date, and even identified previously unreported taxa. Moreover, a new morphotype of ‘scaly-foot’ gastropod has been found at the Solitaire field. The newly discovered ‘scaly-foot’ gastropod has similar morphological and anatomical features to the previously reported type that inhabits the Kairei field, and both types of ‘scaly-foot’ gastropods genetically belong to the same species according to analyses of their COI gene and nuclear SSU rRNA gene sequences. However, the new morphotype completely lacks an iron-sulfide coating on the sclerites, which had been believed to be a novel feature restricted to ‘scaly-foot’ gastropods. Our new findings at the two newly discovered hydrothermal vent sites provide important insights into the biodiversity and biogeography of vent-endemic ecosystems in the Indian Ocean

The phytotherapeutic agent, eviprostat, suppresses stromal proliferation and inflammation even after establishment of nonbacterial prostatitis in the rat prostate

Objective To evaluate the effect of phytotherapeutic agent, Eviprostat, administered after the establishment of nonbacterial prostatitis (NBP) on the stroma-to-epithelium ratio (S/E ratio), inflammatory scores, tissue macrophage infiltration, and cytokines and chemokines levels in prostate tissue and urine.Materials and methods Ten-month-old male Wistar rats were castrated and exposed to 17-beta-isomer of estradiol for 30 days to induce NBP. Twenty-five NBP rats were divided into 5 groups: (1) NBP (0) rats sacrificed immediately after the establishment of NBP; (2,3) NBP (30)/control (CTL) and NBP (30)/Eviprostat (EVI) rats fed without or with 0.1% Eviprostat under estradiol-free for 30 days, respectively; and (4,5) NBP (60)/CTL and NBP (60)/EVI rats fed without or with 0.1% Eviprostat under estradiol-free for 60 days, respectively. The S/E ratio, inflammatory scores, and the number of macrophage infiltration in the prostate were assessed. Concentrations of cytokines and chemokines in prostatic tissue and urine were measured by enzyme-linked immunosorbent assay.Results The S/E ratio was significantly increased with time until 60 days under estradiol-free condition (P <.001). The S/E ratio and the inflammatory scores in NBP (60)/EVI was significantly lower than that of NBP (60)/CTL (P <.001, and P = .022, respectively). The mean tissue concentration of chemokine ligand 2 (CCL2)/monocyte chemoattractant protein-1 (MCP-1) in NBP (60)/CTL was significantly higher than that in NBP (0) (P = .016), whereas, there was no difference between NBP (60)/EVI and NBP (0). Furthermore, urinary CCL2/MCP-1 was significantly decreased in NBP (60)/EVI as compared with NBP (0) (P = .028).Conclusion Eviprostat suppresses the stromal proliferation and inflammation in the rat prostate after the establishment of NBP at least partly owing to inhibitory effect on CCL2/MCP-1 production in the prostate

Expression and Role of GPR87 in Urothelial Carcinoma of the Bladder

The orphan GPR87 has recently been matched with its ligand LPA, which is a lipid mediator with multiple physiological functions, including cancer cell proliferation. This study aimed to clarify the role of GPR87 in urothelial carcinoma of the bladder. GPR87 expression was assessed in seven human bladder cancer cell lines. A replication-deficient recombinant adenoviral vector expressing shRNA targeting GPR87 (Ad-shGPR87), was constructed. Gene silencing was carried out using Ad-shGPR87. Immunohistochemical analysis was performed for transurethral resection of bladder tumor samples from 71 patients with non-muscle-invasive bladder cancer. We observed GPR87 expression in five of the seven cell lines, and silencing GPR87 gene expression significantly reduced cell viability. GPR87 expression was positive in 38 (54%) of 71 tumors. Ki-67 index was associated with positive GPR87 staining status (p < 0.0001). Patients with GPR87-positive tumors had shorter intravesical recurrence-free survival than those with GPR87-negative tumors (p = 0.010). Multivariate analysis revealed that GPR87 staining status was an independent prognostic parameter for intravesical recurrence (p = 0.041). Progression from non-muscle-invasive to muscle-invasive tumor was more frequently observed in patients with GPR87-positive tumors, although this trend did not reach statistical significance (p = 0.056). These results warrant further prospective studies to clarify the role of GPR87 expression in intravesical recurrence and progression in bladder cancer

Geological background of the Kairei and Edmond hydrothermal fields along the Central Indian Ridge : Implications for the distinct chemistry between their vent fluids

Hydrogen-rich hydrothermal areas, such as those in the Indian Ocean, may have had an influence on early evolution of life on Earth and thus have attracted interest because they may be a proxy for ancient ecosystems. The Kairei and Edmond hydrothermal fields in the Indian Ocean are separated by 160 km, but exhibit distinct fluid chemistry: Kairei fluids are hydrogen-rich; Edmond fluids are hydrogen-poor. At this region, the Central Indian Ridge shows an intermediate spreading rate, 48 mm year−1 as full rate, where the hydrothemal fields occur. Kairei field vent fluids show persistently high concentrations of H2. The Kairei field seems to be unique among hydrogen-enriched hydrothermal regions: most similar hydrogen-rich hydrothermal activity occurs along slowly spreading ridge, <40 mm year−1. The geological and tectonic aspects of the Kairei and Edmond hydrothermal fields were studied to try to elucidate geological constraints on hydrogen production. Visual observations of the seafloor near Kairei from a submersible revealed olivine-rich plutonic rocks with olivine gabbro-troctolite-dunite assemblages exposed within 15 km of the vent field, with serpentinized ultramafic mantle rocks on the Oceanic Core Complex (OCC). The OCC area might be a recharge zone of Kairei hydrothermal activity producing H2-rich vent fluids. The chaotic seafloor within 30 km of the Kairei field reflects a magma-starved condition persisting there for 1 Myr. Asymmetric geomagnetic and gravity anomalies near the Kairei field can be used to infer that patchy olivine-rich intrusions are scattered within mantle ultramafics, where infiltrated seawater reacts with magma and ultramafic rocks or olivine-rich rocks. The heterogeneous uppermost lithosphere containing shallow olivine-rich rock facies surrounding the Kairei field provides abundant H2 into the vent fluid through serpentinization. The hydrogen-rich Kairei field is hosted by basalt, with mafic-ultramafic olivine-rich lithology; the ordinary, hydrogen-poor Edmond field is hosted by a normal basaltic lithology. The contrasting geochemical signatures of the two fields reported here can also be found in ancient rocks from a juvenile Earth. This suggests that lithology-controlled generation of hydrogen may have operated for a long time and be relevant to the origin of life on Earth