Apoptosis and cell growth arrest in A375 human melanoma cells by diorganotin(IV) and triorganotin(IV) complexes of [meso-Tetra(4-sulfonatophenyl)porphine]manganese(III)chloride

In previous studies we have demonstrated that two derivatives of meso-Tetra(4-sulfonatophenyl)porphine (TPPS), (Bu2Sn)2TPPS and (Bu3Sn)4TPPS, cause apoptotic death of A375 melanoma cells and, at lower concentrations, arrest of cell proliferation. In the present study, we examined if the manganese metal inside the porphyrin cavity could improve the efficacy of this class of compounds. Thus, [meso- Tetra(4-sulfonatophenyl)porphine]Mn(III)Cl (=MnTPPS) derivatives, namely (Me2Sn)2MnTPPS, (Bu2Sn)2MnTPPS, (Me3Sn)4MnTPPS and (Bu3Sn)4MnTPPS, were tested on the A375 human melanoma cell line. A cytotoxicity assay showed that (Bu2Sn)2MnTPPS and (Bu3Sn)4MnTPPS were highly cytotoxic by inducing apoptosis in melanoma cells, as shown by DNA fragmentation analysis and by apoptotic nuclei fluorescence, and when used at lower concentrations, they affected only cellular proliferation. An arrest of cell proliferation was also observed with (Me3Sn)4MnTPPS, but at the highest concentrations used. Moreover, the lower concentration of (Bu3Sn)4MnTPPS induced a change in cell morphology, from a polygonal to an elongated and spindle-shaped phenotype, likewise to its cognate (Bu3Sn)4TPPS, previously tested. Western blotting analysis showed indeed that both tributyltin compounds, i.e. (Bu3Sn)4MnTPPS and (Bu3Sn)4TPPS, lowered levels of the major proteins involved in tumorigenesis: ß-catenin, c-myc and snail. We also demonstrated that all compounds entered the cells and localized in the nuclei. In conclusion, our results show that, in spite of the Mn(III) metal introduction, the butyl derivatives always have a higher efficacy than methyl derivatives, and the tributyltin compounds in particular have an interesting effect in vitro on A375 cell proliferation

Clinical Spectrum Time Course in Anti Jo-1 Positive Antisynthetase Syndrome

Anti Jo-1 antibodies are the main markers of the antisynthetase syndrome (ASSD), an autoimmune disease clinically characterized by the occurrence of arthritis, myositis, and interstitial lung disease (ILD). These manifestations usually co-occur (for practical purpose complete forms) in the same patient, but cases with only 1 or 2 of these findings (for practical purpose incomplete forms) have been described. In incomplete forms, the ex novo occurrence of further manifestations is possible, although with frequencies and timing not still defined. The aim of this international, multicenter, retrospective study was to characterize the clinical time course of anti Jo-1 positive ASSD in a large cohort of patients. Included patients should be anti Jo-1 positive and with at least 1 feature between arthritis, myositis, and ILD. We evaluated the differences between complete and incomplete forms, timing of clinical picture appearance and analyzed factors predicting the appearance of further manifestations in incomplete ASSD. Finally, we collected 225 patients (58 males and 167 females) with a median follow-up of 80 months. At the onset, complete ASSD were 44 and incomplete 181. Patients with incomplete ASSD had frequently only 1 of the classic triad findings (110 cases), in particular, isolated arthritis in 54 cases, isolated myositis in 28 cases, and isolated ILD in 28 cases. At the end of follow-up, complete ASSD were 113, incomplete 112. Only 5 patients had an isolated arthritis, only 5 an isolated myositis, and 15 an isolated ILD. During the follow-up, 108 patients with incomplete forms developed further manifestations. Single main feature onset was the main risk factor for the ex novo appearance of further manifestation. ILD was the prevalent ex novo manifestation (74 cases). In conclusion, ASSD is a condition that should be carefully considered in all patients presenting with arthritis, myositis, and ILD, even when isolated. The ex novo appearance of further manifestations in patients with incomplete forms is common, thus indicating the need for an adequate clinical and instrumental follow-up. Furthermore, the study clearly suggested that in ASSD multidisciplinary approach involving Rheumatology, Neurology, Pneumology, and Internal Medicine specialists is mandatory

Racial differences in systemic sclerosis disease presentation: a European Scleroderma Trials and Research group study

Objectives. Racial factors play a significant role in SSc. We evaluated differences in SSc presentations between white patients (WP), Asian patients (AP) and black patients (BP) and analysed the effects of geographical locations.Methods. SSc characteristics of patients from the EUSTAR cohort were cross-sectionally compared across racial groups using survival and multiple logistic regression analyses.Results. The study included 9162 WP, 341 AP and 181 BP. AP developed the first non-RP feature faster than WP but slower than BP. AP were less frequently anti-centromere (ACA; odds ratio (OR) = 0.4, P < 0.001) and more frequently anti-topoisomerase-I autoantibodies (ATA) positive (OR = 1.2, P = 0.068), while BP were less likely to be ACA and ATA positive than were WP [OR(ACA) = 0.3, P < 0.001; OR(ATA) = 0.5, P = 0.020]. AP had less often (OR = 0.7, P = 0.06) and BP more often (OR = 2.7, P < 0.001) diffuse skin involvement than had WP.AP and BP were more likely to have pulmonary hypertension [OR(AP) = 2.6, P < 0.001; OR(BP) = 2.7, P = 0.03 vs WP] and a reduced forced vital capacity [OR(AP) = 2.5, P < 0.001; OR(BP) = 2.4, P < 0.004] than were WP. AP more often had an impaired diffusing capacity of the lung than had BP and WP [OR(AP vs BP) = 1.9, P = 0.038; OR(AP vs WP) = 2.4, P < 0.001]. After RP onset, AP and BP had a higher hazard to die than had WP [hazard ratio (HR) (AP) = 1.6, P = 0.011; HR(BP) = 2.1, P < 0.001].Conclusion. Compared with WP, and mostly independent of geographical location, AP have a faster and earlier disease onset with high prevalences of ATA, pulmonary hypertension and forced vital capacity impairment and higher mortality. BP had the fastest disease onset, a high prevalence of diffuse skin involvement and nominally the highest mortality

Effects of tri-n-butyltin(IV) chloride on neurulation of Ciona intestinalis (Tunicata, Ascidiacea): an ultrastructural study

This paper reports the cytotoxic effects of tri-n-butyltin (IV) chloride, TBTCl, on the neurulation process of the ascidian Ciona intestinalis. Exposure of the embryos at early neurula stage in 10−5 and 10−7 M TBT (IV) chloride solutions for 1–2 h provoked the irreversible arrest of their development. Morphological and ultrastructural observations suggested that most probably there are two principal causes determining the neurulation process block. The first is due to the TBT effects of inhibiting the polymerization and/or degradation of microfilaments and microtubules, proteins that constitute the cytoskeleton. The lack of orientation and extension of both microtubules and microfilaments of actin prevent the shape changes and mobility of neural plate blastomeres indispensable to the neurulation process. The second cause is certainly determined by the ultrastructural modification whichmitochondria undergo. The ultrastructural anomalies showed by these organules are so serious as to impede their proper functionality with consequent inhibition of oxidative phosphorylation and ATP synthesis, remarkable metabolic processes that occur during ascidian neurulation

Diorganotin(IV) N-acetyl-L-cysteinate complexes: Synthesis, solid state, solution phase, DFT and biological investigations.

Diorganotin(IV) complexes of N-acetyl-L-cysteine (H2NAC; (R)-2-acetamido-3-sulfanylpropanoic acid) have been synthesized and their solid and solution-phase structural configurations investigated by FTIR, Mössbauer, 1H, 13C and 119Sn NMR spectroscopy. FTIR results suggested that in R2Sn(IV)NAC (R=Me, Bu, Ph) complexes NAC2− behaves as dianionic tridentate ligand coordinating the tin(IV) atom, through estertype carboxylate, acetate carbonyl oxygen atom and the deprotonated thiolate group. From 119Sn Mössbauer spectroscopy it could be inferred that the tin atom is pentacoordinated, with equatorial R2Sn(IV) trigonal bipyramidal configuration. In DMSO-d6 solution, NMR spectroscopic data showed the coordination of one solvent molecule to tin atom, while the coordination mode of the ligand through the ester-type carboxylate and the deprotonated thiolate group was retained in solution. DFT (Density Functional Theory) study confirmed the proposed structures in solution phase as well as the determination of the most probable stable ring conformation. Biological investigations showed that Bu2SnCl2 and NAC2 induce loss of viability in HCC cells and only moderate effects in non-tumor Chang liver cells. NAC2 showed lower cytotoxic activity than Bu2SnCl2, suggesting that the binding with NAC2− modulates the marked cytotoxic activity exerted by Bu2SnCl2. Therefore, these novel butyl derivatives could represent a new class of anticancer drugs

Sintesi e caratterizzazione allo stato solido ed in soluzione di derivati chinolonici di organostagno(IV)

I chinoloni sono antibiotici, recentemente usati anche come chemioterapici. Tra i derivati dell’acido nalidixico, precursore di tutte le classi di chinoloni, sono stati scelti chinoloni di I e II generazione per la sintesi di derivati di diorganostagno(IV). Questi composti sono stati caratterizzati sia allo stato solido che in soluzione con spettroscopia FT-IR, Mössbauer, 1H NMR, e con spettrometria di massa (ES-MS)

Effects of two organotin(IV)(sulfonato phenyl)porphynates on the MAPKs and on the growth of A375 human melanoma cells

Previously we showed apoptotic induction in A375 human melanoma cells using two complexes of the mesotetra(4-sulfonatophenyl)porphinate (TPPS),(Bu2Sn)2TPPS and (Bu3Sn)4TPPS. To understand how these compounds activate apoptosis in melanoma cells we studied MAPKs and the (Bu2Sn)TPPS and (Bu3Sn)4TPPS cellular uptake. Western blotting experiments showed activated protein kinases ERK 1/2, JNK and p38 in 10 μM (Bu2Sn)2TPPS- and 1 μM (Bu3Sn)4TPPS-treated melanoma cells, which suggests that the three MAP kinases are involved in the apoptotic death of A375-treated cells. By taking advantage of the porphyrin fluorescence, we found a fast concentration of (Bu2Sn)2TPPS and (Bu3Sn)4TPPS in the nucleus and in the nucleoli compared to TPPS. A significantly reduced growth of A375 human melanoma cells was also observed after only 48 h treatment by using 500 nM of (Bu2Sn)2TPPS or 80 nM of (Bu3Sn)4TPPS. A strong slowdown of cell growth and loss of cell-cell interactions were visible by in vitro wound repair assay