Sterile inflammation as a factor in human male infertility: Involvement of Toll like receptor 2, biglycan and peritubular cells

Changes in the wall of seminiferous tubules in men with impaired spermatogenesis imply sterile inflammation of the testis. We tested the hypothesis that the cells forming the wall of seminiferous tubules, human testicular peritubular cells (HTPCs), orchestrate inflammatory events and that Toll like receptors (TLRs) and danger signals from the extracellular matrix (ECM) of this wall are involved. In cultured HTPCs we detected TLRs, including TLR2. A TLR-2 ligand (PAM) augmented interleukin 6 (IL-6), monocyte chemo-attractant protein-1 (MCP-1) and pentraxin 3 (PTX3) in HTPCs. The ECM-derived proteoglycan biglycan (BGN) is secreted by HTPCs and may be a TLR2-ligand at HTPCs. In support, recombinant human BGN increased PTX3, MCP-1 and IL-6 in HTPCs. Variable endogenous BGN levels in HTPCs derived from different men and differences in BGN levels in the tubular wall in infertile men were observed. In testes of a systemic mouse model for male infertility, testicular sterile inflammation and elevated estradiol (E2) levels, BGN was also elevated. Hence we studied the role of E2 in HTPCs and observed that E2 elevated the levels of BGN. The anti-estrogen ICI 182,780 blocked this action. We conclude that TLR2 and BGN contribute to sterile inflammation and infertility in man

Sterile inflammation as a factor in human male infertility: Involvement of Toll like receptor 2, biglycan and peritubular cells

Changes in the wall of seminiferous tubules in men with impaired spermatogenesis imply sterile inflammation of the testis. We tested the hypothesis that the cells forming the wall of seminiferous tubules, human testicular peritubular cells (HTPCs), orchestrate inflammatory events and that Toll like receptors (TLRs) and danger signals from the extracellular matrix (ECM) of this wall are involved. In cultured HTPCs we detected TLRs, including TLR2. A TLR-2 ligand (PAM) augmented interleukin 6 (IL-6), monocyte chemo-attractant protein-1 (MCP-1) and pentraxin 3 (PTX3) in HTPCs. The ECM-derived proteoglycan biglycan (BGN) is secreted by HTPCs and may be a TLR2-ligand at HTPCs. In support, recombinant human BGN increased PTX3, MCP-1 and IL-6 in HTPCs. Variable endogenous BGN levels in HTPCs derived from different men and differences in BGN levels in the tubular wall in infertile men were observed. In testes of a systemic mouse model for male infertility, testicular sterile inflammation and elevated estradiol (E2) levels, BGN was also elevated. Hence we studied the role of E2 in HTPCs and observed that E2 elevated the levels of BGN. The anti-estrogen ICI 182,780 blocked this action. We conclude that TLR2 and BGN contribute to sterile inflammation and infertility in man

Proučavanje 194Ir uhvatom termičkih neutrona I (d, p) reakcijom

Levels of 194Ir were studied using thermal neutron capture reaction. A pair spectrometer was used to measure the high-energy γ-ray spectrum from thermal-neutron capture in enriched 193Ir target over the energy range 4640 - 6100 keV. The low-energy γ-radiation from the reaction was studied with crystal diffraction spectrometers, and conversion electrons were observed with magnetic spectrometers. The high-sensitivity measurements at the Grenoble reactor, evaluated for transition energies up to 500 keV, are compared with lower-sensitivity measurements at the Wuerenlingen and Salaspils reactors. The comparison helped to obtain reliable isotopic identification for a number of 194Ir lines. The multipolarity admixtures for 29 γ-transitions were determined on the basis of conversion lines from different electron subshells. Prompt and delayed γ-γ coincidences were measured using semiconductor and scintillation detectors. The 193Ir(d,p) high-resolution spectra, observed with a magnetic spectrometer, are given. All these data contributed to establishing a detailed level scheme of 194Ir. Additional data and the interpretation of the results in terms of current models will be presented in a forthcoming paper.Proučavala su se stanja u 194Ir reakcijama 193Ir(n, γ) i 193Ir(d, p). Mjerenja uhvata termičkih neutrona načinjena su uz reaktore u Grenoblu, Wuerenlingenu i Salapsisu. Za mjerenja γ-zračenja visoke energije upotrebljavao se spektrometar parova, a za niske energije difraktometar. Konverzijske elektrone se mjerilo magnetskim spektrometrom. Mjerenja reakcije (d, p) visokog razlučivanja izvedena su magnetskim spektrometrom. Usporedbe tih mjerenja omogućile su pouzdano izotopno prepoznavanje prijelaza u 194 Ir, a spektri konverzijskih elektrona i određivanje multipolnosti prijelaza. Dobiveni su podaci osnova sheme raspada 194Ir

Proučavanje 194Ir uhvatom termičkih neutrona I (d, p) reakcijom

Levels of 194Ir were studied using thermal neutron capture reaction. A pair spectrometer was used to measure the high-energy γ-ray spectrum from thermal-neutron capture in enriched 193Ir target over the energy range 4640 - 6100 keV. The low-energy γ-radiation from the reaction was studied with crystal diffraction spectrometers, and conversion electrons were observed with magnetic spectrometers. The high-sensitivity measurements at the Grenoble reactor, evaluated for transition energies up to 500 keV, are compared with lower-sensitivity measurements at the Wuerenlingen and Salaspils reactors. The comparison helped to obtain reliable isotopic identification for a number of 194Ir lines. The multipolarity admixtures for 29 γ-transitions were determined on the basis of conversion lines from different electron subshells. Prompt and delayed γ-γ coincidences were measured using semiconductor and scintillation detectors. The 193Ir(d,p) high-resolution spectra, observed with a magnetic spectrometer, are given. All these data contributed to establishing a detailed level scheme of 194Ir. Additional data and the interpretation of the results in terms of current models will be presented in a forthcoming paper.Proučavala su se stanja u 194Ir reakcijama 193Ir(n, γ) i 193Ir(d, p). Mjerenja uhvata termičkih neutrona načinjena su uz reaktore u Grenoblu, Wuerenlingenu i Salapsisu. Za mjerenja γ-zračenja visoke energije upotrebljavao se spektrometar parova, a za niske energije difraktometar. Konverzijske elektrone se mjerilo magnetskim spektrometrom. Mjerenja reakcije (d, p) visokog razlučivanja izvedena su magnetskim spektrometrom. Usporedbe tih mjerenja omogućile su pouzdano izotopno prepoznavanje prijelaza u 194 Ir, a spektri konverzijskih elektrona i određivanje multipolnosti prijelaza. Dobiveni su podaci osnova sheme raspada 194Ir

Study of ^194 Ir via thermal neutron capture and (d,p) reactions

Levels of ^194 Ir were studied using thermal neutron capture reaction. A pair spectrometer was used to measure the high-energy gamma-ray spectrum from thermal-neutron capture in enriched ^193 Ir target over the energy range 4640 - 6100 keV. The low-energy gamma-radiation from the reaction was studied with crystal diffraction spectrometers, and conversion electrons were observed with magnetic spectrometers. The high-sensitivity measurements at the Grenoble reactor, evaluated for transition energies up to 500 keV, are compared with lower-sensitivity measurements at the Wuerenlingen and Salaspils reactors. The comparison helped to obtain reliable isotopic identification for a number of ^194 Ir lines. The multipolarity admixtures for 29 gamma-transitions were determined on the basis of conversion lines from different electron subshells. Prompt and delayed gamma-gamma coincidences were measured using semiconductor and scintillation detectors. The ^193 Ir(d,p) high-resolution spectra, observed with a magnetic spectrometer, are given. All these data contributed to establishing a detailed level scheme of ^194 Ir. Additional data and the interpretation of the results in terms of current models will be presented in a forthcoming paper

Modulating endothelial adhesion and migration impacts stem cell therapies efficacy

Background: Limited knowledge of stem cell therapies‘ mechanisms of action hampers their sustainable implementation into the clinic. Specifically, the interactions of transplanted stem cells with the host vasculature and its implications for their therapeutic efficacy are not elucidated. We tested whether adhesion receptors and chemokine receptors on stem cells can be functionally modulated, and consequently if such modulation may substantially affect therapeutically relevant stem cell interactions with the host endothelium. Methods: We investigated the effects of cationic molecule polyethylenimine (PEI) treatment with or without nanoparticles on the functions of adhesion receptors and chemokine receptors of human bone marrow-derived Mesenchymal Stem Cells (MSC). Analyses included MSC functions in vitro, as well as homing and therapeutic efficacy in rodent models of central nervous system´s pathologies in vivo. Findings: PEI treatment did not affect viability, immunomodulation or differentiation potential of MSC, but increased the CCR4 expression and functionally blocked their adhesion receptors, thus decreasing their adhesion capacity in vitro. Intravenously applied in a rat model of brain injury, the homing rate of PEI-MSC in the brain was highly increased with decreased numbers of adherent PEI-MSC in the lung vasculature. Moreover, in comparison to untreated MSC, PEI-MSC featured increased tumour directed migration in a mouse glioblastoma model, and superior therapeutic efficacy in a murine model of stroke. Interpretation: Balanced stem cell adhesion and migration in different parts of the vasculature and tissues together with the local microenvironment impacts their therapeutic efficacy. Funding: Robert Bosch Stiftung, IZEPHA grant, EU grant 7 FP Healt

Nuclear translocation of haeme oxygenase-1 is associated to prostate cancer

The role of oxidative stress in prostate cancer has been increasingly recognised. Acute and chronic inflammations generate reactive oxygen species that result in damage to cellular structures. Haeme oxygenase-1 (HO-1) has cytoprotective effects against oxidative damage. We hypothesise that modulation of HO-1 expression may be involved in the process of prostate carcinogenesis and prostate cancer progression. We thus studied HO-1 expression and localisation in 85 samples of organ-confined primary prostate cancer obtained via radical prostatectomy (Gleason grades 4–9) and in 39 specimens of benign prostatic hyperplasia (BPH). We assessed HO-1 expression by immunohistochemical staining. No significant difference was observed in the cytoplasmic positive reactivity among tumours (84%), non-neoplastic surrounding parenchyma (89%), or BPH samples (87%) (P=0.53). Haeme oxygenase-1 immunostaining was detected in the nuclei of prostate cancer cells in 55 of 85 (65%) patients but less often in non-neoplastic surrounding parenchyma (30 of 85, 35%) or in BPH (9 of 39, 23%) (P<0.0001). Immunocytochemical and western blot analysis showed HO-1 only in the cytoplasmic compartment of PC3 and LNCaP prostate cancer cell lines. Treatment with hemin, a well-known specific inducer of HO-1, led to clear nuclear localisation of HO-1 in both cell lines and highly induced HO-1 expression in both cellular compartments. These findings have demonstrated, for the first time, that HO-1 expression and nuclear localisation can define a new subgroup of prostate cancer primary tumours and that the modulation of HO-1 expression and its nuclear translocation could represent new avenues for therapy