A cyclopalladated complex interacts with mitochondrial membrane thiol-groups and induces the apoptotic intrinsic pathway in murine and cisplatin-resistant human tumor cells

<p>Abstract</p> <p>Background</p> <p>Systemic therapy for cancer metastatic lesions is difficult and generally renders a poor clinical response. Structural analogs of cisplatin, the most widely used synthetic metal complexes, show toxic side-effects and tumor cell resistance. Recently, palladium complexes with increased stability are being investigated to circumvent these limitations, and a biphosphinic cyclopalladated complex {Pd₂[<it>S_(-)</it>C², N-dmpa]₂(μ-dppe)Cl₂} named C7a efficiently controls the subcutaneous development of B16F10-Nex2 murine melanoma in syngeneic mice. Presently, we investigated the melanoma cell killing mechanism induced by C7a, and extended preclinical studies.</p> <p>Methods</p> <p>B16F10-Nex2 cells were treated <it>in vitro </it>with C7a in the presence/absence of DTT, and several parameters related to apoptosis induction were evaluated. Preclinical studies were performed, and mice were endovenously inoculated with B16F10-Nex2 cells, intraperitoneally treated with C7a, and lung metastatic nodules were counted. The cytotoxic effects and the respiratory metabolism were also determined in human tumor cell lines treated <it>in vitro </it>with C7a.</p> <p>Results</p> <p>Cyclopalladated complex interacts with thiol groups on the mitochondrial membrane proteins, causes dissipation of the mitochondrial membrane potential, and induces Bax translocation from the cytosol to mitochondria, colocalizing with a mitochondrial tracker. C7a also induced an increase in cytosolic calcium concentration, mainly from intracellular compartments, and a significant decrease in the ATP levels. Activation of effector caspases, chromatin condensation and DNA degradation, suggested that C7a activates the apoptotic intrinsic pathway in murine melanoma cells. In the preclinical studies, the C7a complex protected against murine metastatic melanoma and induced death in several human tumor cell lineages <it>in vitro</it>, including cisplatin-resistant ones. The mitochondria-dependent cell death was also induced by C7a in human tumor cells.</p> <p>Conclusions</p> <p>The cyclopalladated C7a complex is an effective chemotherapeutic anticancer compound against primary and metastatic murine and human tumors, including cisplatin-resistant cells, inducing apoptotic cell death via the intrinsic pathway.</p

MAMMALS IN PORTUGAL : A data set of terrestrial, volant, and marine mammal occurrences in P ortugal

Mammals are threatened worldwide, with 26% of all species being includedin the IUCN threatened categories. This overall pattern is primarily associatedwith habitat loss or degradation, and human persecution for terrestrial mam-mals, and pollution, open net fishing, climate change, and prey depletion formarine mammals. Mammals play a key role in maintaining ecosystems func-tionality and resilience, and therefore information on their distribution is cru-cial to delineate and support conservation actions. MAMMALS INPORTUGAL is a publicly available data set compiling unpublishedgeoreferenced occurrence records of 92 terrestrial, volant, and marine mam-mals in mainland Portugal and archipelagos of the Azores and Madeira thatincludes 105,026 data entries between 1873 and 2021 (72% of the data occur-ring in 2000 and 2021). The methods used to collect the data were: live obser-vations/captures (43%), sign surveys (35%), camera trapping (16%),bioacoustics surveys (4%) and radiotracking, and inquiries that represent lessthan 1% of the records. The data set includes 13 types of records: (1) burrowsjsoil moundsjtunnel, (2) capture, (3) colony, (4) dead animaljhairjskullsjjaws, (5) genetic confirmation, (6) inquiries, (7) observation of live animal (8),observation in shelters, (9) photo trappingjvideo, (10) predators dietjpelletsjpine cones/nuts, (11) scatjtrackjditch, (12) telemetry and (13) vocalizationjecholocation. The spatial uncertainty of most records ranges between 0 and100 m (76%). Rodentia (n=31,573) has the highest number of records followedby Chiroptera (n=18,857), Carnivora (n=18,594), Lagomorpha (n=17,496),Cetartiodactyla (n=11,568) and Eulipotyphla (n=7008). The data setincludes records of species classified by the IUCN as threatened(e.g.,Oryctolagus cuniculus[n=12,159],Monachus monachus[n=1,512],andLynx pardinus[n=197]). We believe that this data set may stimulate thepublication of other European countries data sets that would certainly contrib-ute to ecology and conservation-related research, and therefore assisting onthe development of more accurate and tailored conservation managementstrategies for each species. There are no copyright restrictions; please cite thisdata paper when the data are used in publications.info:eu-repo/semantics/publishedVersio

Mammals in Portugal: a data set of terrestrial, volant, and marine mammal occurrences in Portugal

Mammals are threatened worldwide, with ~26% of all species being included in the IUCN threatened categories. This overall pattern is primarily associated with habitat loss or degradation, and human persecution for terrestrial mammals, and pollution, open net fishing, climate change, and prey depletion for marine mammals. Mammals play a key role in maintaining ecosystems functionality and resilience, and therefore information on their distribution is crucial to delineate and support conservation actions. MAMMALS IN PORTUGAL is a publicly available data set compiling unpublished georeferenced occurrence records of 92 terrestrial, volant, and marine mammals in mainland Portugal and archipelagos of the Azores and Madeira that includes 105,026 data entries between 1873 and 2021 (72% of the data occurring in 2000 and 2021). The methods used to collect the data were: live observations/captures (43%), sign surveys (35%), camera trapping (16%), bioacoustics surveys (4%) and radiotracking, and inquiries that represent less than 1% of the records. The data set includes 13 types of records: (1) burrows | soil mounds | tunnel, (2) capture, (3) colony, (4) dead animal | hair | skulls | jaws, (5) genetic confirmation, (6) inquiries, (7) observation of live animal (8), observation in shelters, (9) photo trapping | video, (10) predators diet | pellets | pine cones/nuts, (11) scat | track | ditch, (12) telemetry and (13) vocalization | echolocation. The spatial uncertainty of most records ranges between 0 and 100 m (76%). Rodentia (n =31,573) has the highest number of records followed by Chiroptera (n = 18,857), Carnivora (n = 18,594), Lagomorpha (n = 17,496), Cetartiodactyla (n = 11,568) and Eulipotyphla (n = 7008). The data set includes records of species classified by the IUCN as threatened (e.g., Oryctolagus cuniculus [n = 12,159], Monachus monachus [n = 1,512], and Lynx pardinus [n = 197]). We believe that this data set may stimulate the publication of other European countries data sets that would certainly contribute to ecology and conservation-related research, and therefore assisting on the development of more accurate and tailored conservation management strategies for each species. There are no copyright restrictions; please cite this data paper when the data are used in publications

Tailored Viral-like Particles as Drivers of Medical Breakthroughs

Despite the recognized potential of nanoparticles, only a few formulations have progressed to clinical trials, and an even smaller number have been approved by the regulatory authorities and marketed. Virus-like particles (VLPs) have emerged as promising alternatives to conventional nanoparticles due to their safety, biocompatibility, immunogenicity, structural stability, scalability, and versatility. Furthermore, VLPs can be surface-functionalized with small molecules to improve circulation half-life and target specificity. Through the functionalization and coating of VLPs, it is possible to optimize the response properties to a given stimulus, such as heat, pH, an alternating magnetic field, or even enzymes. Surface functionalization can also modulate other properties, such as biocompatibility, stability, and specificity, deeming VLPs as potential vaccine candidates or delivery systems. This review aims to address the different types of surface functionalization of VLPs, highlighting the more recent cutting-edge technologies that have been explored for the design of tailored VLPs, their importance, and their consequent applicability in the medical field

Effects of the social security reform in colombia on equity to access and use of health services

In order to evaluate the effects of the new health system upon the equity to access and use of the health services, two cross sections of the population were compared: before Law 100 of 1993, which created the General System for Social Security in Health-SGSSS-, and after the law was passed. The changes in the distribution of an indicator of equity in access to health care services, the affiliation to the General System for Social Security in Health, were assessed. Additionally, two groups were compared in the 1997 cross section, affiliated and non-affiliated to the SGSSS, in order to assess the changes in the equity of use of hospital services and health care services in general. The results obtained show that between 1993 and 1997 the coverage of the SGSSS increased from 23% to 57%. This increase in coverage was more dramatic amongst the poorest sectors of the population: in the homes of people in the lowest tenth percentile of income the coverage increased from 3.1% to 43.7%, and the index of concentration of affiliation to the SGSSS decreased by half: from 0.34 to 0.17. By contrast, the indicators of concentration corresponding to the use of health services varied very little even after the adjustments by age, gender and needs. These results suggest a positive impact of the SGSSS on the inequities of access to health services, but the effects upon the inequities of use of health services are not clear.Para evaluar los efectos del nuevo sistema de salud sobre la equidad en el acceso y la utilización de los servicios de salud, se compararon dos cortes transversales de la población antes de la Ley 100 de 1993 que creó el Sistema General de Seguridad Social en Salud-SGSSS y después de la misma. Se evaluaron los cambios en la distribución de un indicador de equidad en el acceso a los servicios de salud: afiliación al SGSSS; adicionalmente, se compararon dos grupos de población en el corte de 1997, afiliados y no afiliados al SGSSS, con el fin de evaluar los cambios en la distribución de dos indicadores de equidad en la utilización de servicios: hospitalización y uso de servicios de salud en general. Los resultados obtenidos, revelan que entre 1993 y 1997, la cobertura del SGSSS aumentó del 23 % al 57 %. El aumento en la cobertura fue más dramático entre los segmentos más pobres de la población: en los hogares del primer decil de ingresos la cobertura aumentó del 3,1 % al 43,7 %, y el índice de concentración en la distribución de la afiliación al SGSSS se redujo a la mitad: del 0,34 a 0,17. En cambio, los indicadores de concentración correspondientes a la utilización de servicios variaron muy poco inclusive luego del ajuste hecho por edad, género y necesidades. Estos resultados sugieren un impacto positivo del SGSSS sobre las inequidades en el acceso, pero los efectos sobre las inequidades en la utilización de los servicios de salud no son claros

Ent-7 alpha-acetoxytrachyloban-18-oic acid and ent-7 alpha-hydroxytrachyloban-18-oic acid from Xylopia langsdorfiana A. St-Hil. & Tul. modulate K+ and Ca2+ channels to reduce cytosolic calcium concentration on guinea pig ileum

In this study we investigated the mechanism underlying the spasmolytic action of ent-7 alpha-acetoxytrachyloban- 18-oic acid (trachylobane-360) and ent-7 alpha-hydroxytrachyloban-18-oic acid (trachylobane-318), diterpenes obtained from Xylopia langsdorfiana, on guinea pig ileum. Both compounds inhibited histamine-induced cumulative contractions (slope=3.5 +/- 0.9 and 4.4 +/- 0.7) that suggests a noncompetitive antagonism to histaminergic receptors. CaCl2-induced contractions were nonparallelly and concentration-dependently reduced by both diterpenes, indicating blockade of calcium influx through voltage-dependent calcium channels (Ca-v). the Ca-v participation was confirmed since both trachylobanes equipotently relaxed ileum pre-contracted with S-(-)-Bay K8644 (EC50=3.5 +/- 0.7x10-(5) and 1.1 +/- 0.2x10-(5) M) and KCl (EC50=5.5 +/- 0.3x10-(5) and 1.4 +/- 0.2x10-(5) M). K+ channels participation was confirmed since diterpene-induced relaxation curves were significantly shifted to right in the presence of 5 mM tetraethylammonium (TEA(+)) (EC50=0.5 +/- 0.04x10-(4) and 2.0 +/- 0.5x10-(5) M). ATP-sensitive K+ channel (K-ATP), voltage activated K+ channels (K-V), small conductance calcium-activated K+ channels (SKCa) or big conductance calciuma-ctivated K+ channels (BKCa) did not seem to participate of trachylobane-360 spasmolytic action. However trachylobane-318 modulated positively K-ATP, K-V and SKCa (EC50=1.1 +/- 0.3x10-(5), 0.7 +/- 0.2x10-(5) and 0.7 +/- 0.2x10-(5) M), but not BKCa. A fluorescence analysis technique confirmed the decrease of cytosolic calcium concentration ([Ca2+](c)) induced by both trachylobanes in ileal myocytes. in conclusion, trachylobane-360 and trachylobane-318 induced spasmolytic activity by K+ channel positive modulation and Ca2+ channel blockade, which results in [Ca2+](c) reduction at cellular level leading to smooth muscle relaxation. (C) 2011 Published by Elsevier B. V.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)FAPESQ-PBUniv Fed Paraiba, Lab Tecnol Farmaceut Prof Delby Fernandes de Mede, BR-58051970 Joao Pessoa, Paraiba, BrazilUniv Fed Piaui, Dept Bioquim & Farmacol, Teresina, Piaui, BrazilUniv Fed Paraiba, Dept Ciencias Farmaceut, BR-58051970 Joao Pessoa, Paraiba, BrazilUniversidade Federal de São Paulo, São Paulo, BrazilUniversidade Federal de São Paulo, São Paulo, BrazilWeb of Scienc