Fatores de mobilidade sustentável: um estudo nas cidades do norte gaúcho

Os estudos de mobilidade urbana tornam-se fundamentais para a criação de novas políticas públicas voltadas à funcionalidade adequada e ao deslocamento populacional em escala global. Diante desta perspectiva, este estudo analisa as diferentes concepções de mobilidade urbana voltadas aos padrões de sustentabilidade com base nos 27 manuscritos selecionados de um total 1.320 fontes, encontradas nas bases vinculadas às bases da Web of Science, utilizando o método PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). Além disso, a pesquisa abordou as cidade de Erechim/RS, Marau/RS e Passo Fundo/RS, através da análise dos fatores como: número de carros, evolução demográfica, renda per capita e o transporte de passageiros. Os dados revelam que a pandemia da Covid-19, impactou significativamente no transporte público, reduzindo em 45% o número de passageiros em Erechim, 30% em Marau e 25% em Passo Fundo. Em contraste, o número de veículos e a população continuaram crescendo, evidenciando os desafios da mobilidade sustentável

Maternal nicotine exposure leads to decreased cardiac protein disulfide isomerase and impaired mitochondrial function in male rat offspring.

Smoking throughout pregnancy can lead to complications during gestation, parturition and neonatal development. Thus, nicotine replacement therapies are a popular alternative thought to be safer than cigarettes. However, recent studies in rodents suggest that fetal and neonatal nicotine exposure alone results in cardiac dysfunction and high blood pressure. While it is well known that perinatal nicotine exposure causes increased congenital abnormalities, the mechanisms underlying longer-term deficits in cardiac function are not completely understood. Recently, our laboratory demonstrated that nicotine impairs placental protein disulfide isomerase (PDI) triggering an increase in endoplasmic reticulum stress, leading us to hypothesize that this may also occur in the heart. At 3 months of age, nicotine-exposed offspring had 45% decreased PDI levels in the absence of endoplasmic reticulum stress. Given the association of PDI and superoxide dismutase enzymes, we further observed that antioxidant superoxide dismutase-2 levels were reduced by 32% in these offspring concomitant with a 26-49% decrease in mitochondrial complex proteins (I, II, IV and V) and tissue inhibitor of metalloproteinase-4, a critical matrix metalloprotease for cardiac contractility and health. Collectively, this study suggests that perinatal nicotine exposure decreases PDI, which can promote oxidative damage and mitochondrial damage, associated with a premature decline in cardiac function

Palladium(II) complexes of tridentate bis(benzazole) ligands: Structural, substitution kinetics, DNA interactions and cytotoxicity studies.

Reactions of 2,6-bis(benzimidazol-2-yl)pyridine (L1), 2,6-bis(benzoxazol-2-yl)pyridine (L2), and 2,6-bis(benzothiazol-2-yl)pyridine (L3) with [Pd(NCMe)2Cl2] in the presence of NaBF4 afforded the corresponding Pd(II) complexes, [Pd(L1)Cl]BF4, PdL1; [Pd(L2)Cl]BF4, PdL2; [Pd(L3)Cl]BF4, PdL3; respectively, while reaction of bis[(1H-benzimidazol-2-yl)methyl]amine (L4) with [Pd(NCMe)2Cl2] afforded complex [Pd(L4)Cl]Cl, PdL4. Characterisation of the complexes was accomplished using NMR, IR, MS, elemental analyses and single crystal X-ray crystallography. Ligand substitution kinetics of these complexes by biological nucleophiles thiourea (Tu), L-methionine (L-Met) and guanosine 5'-diphosphate disodium salt (5-GMP) were examined under pseudo-first order conditions. The reactivity of the complexes decreased in the order: PdL1 > PdL2 > PdL3 > PdL4, ascribed to electronic effects. Density functional theory (DFT) supported this trend. Studies of interaction of the Pd(II) complexes with calf thymus DNA (CT-DNA) revealed strong binding affinities via intercalative binding mode. Molecular docking studies established associative non-covalent interactions between the Pd complexes and DNA. The in vitro cytotoxic activities of PdL1-PdL4 were assessed in cancer cell lines HeLa and MRC5-SV2 and a normal cell line MRC-5, using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. PdL1 exhibited cytotoxic potency and selectivity against HeLa cell that was comparable to cisplatin's. Complex PdL1, unlike cisplatin, did not significantly induce caspase-dependent apoptosis

Characterization of the anticancer properties of ruthenium-derived compounds: mode of action, optimization and development of experimental tools.

Platinum-based compounds are widely used anticancer drugs, despite severe side effects and drug-resistance phenomena. Over the past few years, a new class of platinum-free metal-based compounds, called RDCs (ruthenium-derived compounds), has been introduced with the aim of overcoming these issues. RDCs, in particular RDC11, have shown interesting and peculiar biological properties: a good anticancer activity in vivo, a reduced toxicity on healthy tissues and the ability to induce apoptosis through the induction of the CHOP/DDIT3 protein via a DNA-independent mechanism. Indeed, in contrast to platinum-based drugs, it has been suggested that ruthenium derivatives could exert their cytotoxicity independently from DNA interaction and through direct modulation of the activity of redox enzymes. In our study, we have compared the relative activity of platinum (cisplatin) and ruthenium (RDC11) derivatives on the HIF-1 and mTOR pathways, two pathways that are sensitive to the cellular metabolism. We showed that, unlike cisplatin, RDC11 was able to decrease HIF-1α and HIF-1β protein levels in normoxic and hypoxic conditions, leading to the reduction of the expression of HIF-1 target genes, such as VEGF and GLUT1. We have demonstrated that HIF-1α protein levels downregulation involves a complex mechanism associating changes in HIF-1α protein stability, HIF1α mRNA translation and synthesis. As mTOR controls HIF-1α translation, we analyzed the regulation of this pathway. We showed that, in contrast to cisplatin, RDC11 reduced the phosphorylation of the ribosomal protein S6 and Akt on specific sites that are markers for the activity of the mTORC1 and the mTORC2 complexes of mTOR. This observation correlates with a reduction in mRNA levels of RICTOR and RAPTOR, two components of mTOR. Finally, we showed that the inhibitory effect of RDC11 on the HIF-1 and mTOR pathways is consistent with its ability to reduce angiogenesis and potentiate the antitumor activity of the mTOR inhibitor rapamycin in vivo. Altogether, our results showed that ruthenium-derived compounds strongly impact metabolic pathways. In parallel with the identification of RDCs direct targets, a structure/activity analysis to ameliorate the chemical and pharmacological features of RDCs, has been started. We have demonstrated that by changing ligands around the ruthenium center, it is possible to modulate several parameters, such as the redox value and the lipophilic/hydrophilic status, which might influence the ability of RDCs to enter the cells, to interact with intracellular targets and to alter their functions, as well as to modify their pharmacokinetic and distribution properties into the tissues. We have shown that the optimized RDCs reduce tumor growth in different mouse models and that they are more potent inducers of cancer cell death through the production of reactive oxygen species and activation of caspase 8, while retaining their ability to induce CHOP/DDIT3. The fact that RDC11 was able to target molecular pathways (such as HIF-1α and Akt) directly involved in the development of the metastatic process, led us to wonder whether it could exert an antimetastatic effect. The study of the antimetastatic effects of RDCs prompted us to undertake a further and separate study aimed to set up a model suitable for in vitro tests on chemicals endowed with the capacity to selectively target tumor metastases than being un-selective cytotoxics. We have set up the cell culture conditions suitable to recreate in vitro the metastatization of colorectal cancer cells towards the liver, the preferential site of metastatic colorectal carcinoma, in a model of bioreactor called “plastic mouse”. We have demonstrated that the three different cell lines selected for our study can growth in the same environment, without undergoing modifications in viability and morphology, thus representing a good model for our purpose. In conclusion, the results obtained during my PhD thesis have allowed us to identify a novel mechanism of action of RDC11, which is different from that of classical metal-based drugs, pointing out that platinum and ruthenium-based molecules can act differently, even if the latter was initially designed to mimic cisplatin. The second study has demonstrated the importance that the modifications of the ligands around the ruthenium center play in modulating the cytotoxicity and selectivity of the new generated RDCs towards different cancer types. This can be explained by their ability to interfere with different pathways crucial for cancer metabolism. Finally, we have made a breakthrough in developing an experimental tool to study the metastatic process in vitro. The plastic mouse will be useful in the future to screen potential antimetastatic molecules.I derivati del platino sono ampiamente utilizzati come farmaci antitumorali, nonostante i gravi effetti collaterali e i fenomeni di farmaco-resistenza. Nel corso degli ultimi anni, una nuova classe di composti contenenti un metallo diverso dal platino, chiamati RDCs (ruthenium-derived compounds), è stata introdotta con lo scopo di superare queste limitazioni. Gli RDCs, e in particolare RDC11, hanno mostrato interessanti e peculiari proprietà biologiche: una buona attività antitumorale in vivo, una ridotta tossicità sui tessuti sani e la capacità di indurre l'apoptosi attraverso un meccanismo DNA-indipendente che implica l'induzione della via di segnalazione di CHOP/DDIT3. Contrariamente ai farmaci a base di platino, è stato suggerito che i derivati di rutenio possano esercitare la loro citotossicità indipendentemente dall’interazione con il DNA e attraverso la modulazione diretta dell'attività di enzimi ossido-riduttivi. In questo studio, abbiamo confrontato l'attività dei derivati del platino (cisplatino) e rutenio (RDC11) sulle vie di segnalazione di HIF-1 e mTOR, due vie sensibili al metabolismo cellulare. Abbiamo dimostrato come, a differenza del cisplatino, RDC11 sia in grado di diminuire i livelli di espressione delle proteine HIF-1α e HIF-1β in condizioni di normossia e ipossia, portando alla riduzione dell'espressione dei geni bersaglio di HIF-1α, come VEGF e GLUT1. Abbiamo dimostrato che la down-regulation dei livelli proteici di HIF-1α implica un complesso meccanismo che associa le variazioni della stabilità proteica di HIF-1α con la traduzione dell'mRNA di HIF-1α e la sua sintesi. Dal momento che mTOR controlla la traduzione di HIF-1α, abbiamo analizzato la regolazione di questa via da parte di RDC11. Abbiamo dimostrato che, diversamente dal cisplatino, RDC11 riduce la fosforilazione della proteina ribosomiale S6 e Akt su siti specifici che sono i marcatori per l'attività dei complessi mTORC1 e mTORC2 di mTOR. Questa osservazione è correlata con una riduzione dei livelli di mRNA di RICTOR e RAPTOR, due componenti di mTOR. Infine, abbiamo dimostrato come l'effetto inibitorio di RDC11 sulle vie di HIF-1 e mTOR sia coerente con la sua capacità di ridurre l'angiogenesi e di potenziare l'attività antitumorale della rapamicina, inibitore di mTOR, in vivo. Complessivamente, i nostri risultati hanno dimostrato che i derivati del rutenio hanno un forte impatto su diverse vie metaboliche. In parallelo all'individuazione dei target diretti degli RDCs, è stato avviata un’analisi struttura/attività con lo scopo di migliorare le caratteristiche chimiche e farmacologiche di questi composti. Abbiamo dimostrato come, variando i ligandi attorno all’atomo di rutenio, sia possibile modulare diversi parametri, come il valore redox e lo stato di lipofilicità/idrofilicità, si possa influenzare la capacità degli RDCs di entrare nelle cellule, di interagire con i bersagli intracellulari e di alterare le loro funzioni, così come di modificare le loro proprietà farmacocinetiche e la distribuzione nei tessuti. Abbiamo dimostrato che gli RDCs ottimizzati riducono la crescita tumorale in diversi modelli murini e che sono più potenti induttori del processo apoptotico nelle cellule tumorali attraverso la produzione di specie reattive dell'ossigeno e l'attivazione della caspasi 8, pur mantenendo la loro capacità di indurre la via di CHOP/DDIT3. Il fatto che RDC11 agisca su vie di segnalazione cellulare (come quella di HIF-1α e Akt) direttamente coinvolte nella regolazione del processo metastatico, ci ha indotti a pensare ad un suo possibile effetto su tale processo. Per tale ragione, abbiamo intrapreso uno studio separato al fine di definire un modello cellulare in vitro per testare nuove molecole potenzialmente capaci di bersagliare in maniera selettiva le metastasi tumorali, piuttosto che essere dei composti citotossici non selettivi. Abbiamo creato le condizioni di coltura cellulare ideali per riprodurre in vitro la metastatizzazione di cellule tumorali colorettali verso il fegato, il sito preferenziale del carcinoma colorettale metastatico, in un prototipo di bioreattore chiamato "plastic mouse". Abbiamo dimostrato che le tre diverse linee cellulari selezionate per il nostro studio sono in grado di crescere nel medesimo ambiente, senza subire modifiche della vitalità e morfologia, rappresentando così un buon modello per il nostro obiettivo. In conclusione, i risultati ottenuti durante la mia tesi di dottorato ci hanno permesso di identificare un nuovo meccanismo d'azione di RDC11, diverso da quello dei classici farmaci contenenti un metallo, sottolineando che i derivati del platino e del rutenio possano agire diversamente, anche se questi ultimi sono stati inizialmente progettati per imitare il cisplatino. Il secondo studio ha dimostrato l'importanza che le modificazioni dei ligandi attorno all’atomo di rutenio svolgono nel modulare la citotossicità e la selettività dei nuovi RDCs verso diversi tipi di tumori. Questo può essere spiegato grazie alla loro capacità di interferire con diverse vie di segnalazione, cruciali per il metabolismo delle cellule tumorali. Infine, abbiamo compiuto un passo avanti nello sviluppo di uno prototipo sperimentale per studiare il processo metastatico in vitro. Il plastic mouse risulterà utile in futuro per lo screening di potenziali farmaci antimetastatici

Caractérisation des propriétés anticancéreuses des composés dérivés du ruthénium : mode d'action, optimisation et développement d’outils expérimentaux.

Au cours des dernières années, une nouvelle classe de composés anticancéreux à base de ruthénium, appelés RDCs (Ruthenium-Derived Compounds), a été développé pour dépasser les limitations des agents chimiothérapiques contenants du platine. Contrairement à ces derniers, l’activité anticancéreuse des RDCs est en partie indépendante de l'interaction avec l'ADN. L’objectif principal de ma thèse a été ainsi de comprendre les mécanismes moléculaires quiinter viennent dans l’action anticancéreuse et antimétastatique des RDCs au-delà du dommage à l’ADN.J’ai démontré que le RDC11, contrairement au cisplatine, affecte les voies de signalisation de HIF-1 et mTOR, deux voies qui jouent un rôle clé dans le métabolisme cellulaire et qui sont souvent altérées dans les cellules cancéreuses.En parallèle, j’ai effectué un analyse structure/activité pour sélectionner des nouveaux RDCs ayant meilleures propriétés chimiques et pharmacologiques que le RDC11. Cette étude a permis d’identifier deux nouveaux RDCs qui réduisent la croissance tumorale in vivo avec un dosage beaucoup plus faible que le RDC11 et qui induisent la mort des cellules cancéreuses par une surproduction d'espèces réactives de l'oxygène et par l'activation de la caspase8. En conclusion, mes travaux ont conduit à l’identification de nouveaux mécanismes à la base de l’activité anticancéreuse du RDC11 qui pourraient expliquer certaines différences entre le mode d’action du RDC11 et du cisplatine. De plus, ils ont permis de sélectionner deux nouveaux RDCs plus efficaces que le RDC11. Ces résultat sont un impact important pour le développement de nouvelles thérapies anticancéreuses ou antimétastatiques.In recent years, a new class of anticancer ruthenium-based drugs, called RDCs (Ruthenium-Derived Compounds), has been developed to overcome the limitations of classic platinum chemotherapeutics. Unlike the latter, the anticancer activity of RDCs is in part independent of DNA interaction. Therefore, the main objective of my thesis work was to elucidate the molecular mechanisms involved in RDCs anticancer and antimetastatic activity beyond DNA damage. I demonstrated that RDC11, unlike cisplatin, affects the HIF-1 and mTOR signaling pathways, two pathways that play a key role in cellular metabolism and that are frequently altered in cancer cells. In parallel, I performed a structure/activity analysis to select new RDCs endowed with better chemical and pharmacological properties than RDC11. This study allowed to identify two novel RDCs that reduce tumor growth in vivo at much lower doses than RDC11 and that induce cancer cell death by an overproduction of reactive oxygen species and activation of caspase 8. In conclusion, my work led to the identification of new mechanisms underlying the anticancer activity of RDC11 that could explain some of the differences between the mode of action of RDC11 and cisplatin. In addition, it allowed to select two novel RDCs which are more effective than RDC11. These results have a significant impact on the development of new anticancer or antimetastatic therapies

Caractérisation des propriétés anticancéreuses des composés dérivés du ruthénium : mode d'action, optimisation et développement d’outils expérimentaux.

Au cours des dernières années, une nouvelle classe de composés anticancéreux à base de ruthénium, appelés RDCs (Ruthenium-Derived Compounds), a été développé pour dépasser les limitations des agents chimiothérapiques contenants du platine. Contrairement à ces derniers, l’activité anticancéreuse des RDCs est en partie indépendante de l'interaction avec l'ADN. L’objectif principal de ma thèse a été ainsi de comprendre les mécanismes moléculaires quiinter viennent dans l’action anticancéreuse et antimétastatique des RDCs au-delà du dommage à l’ADN.J’ai démontré que le RDC11, contrairement au cisplatine, affecte les voies de signalisation de HIF-1 et mTOR, deux voies qui jouent un rôle clé dans le métabolisme cellulaire et qui sont souvent altérées dans les cellules cancéreuses.En parallèle, j’ai effectué un analyse structure/activité pour sélectionner des nouveaux RDCs ayant meilleures propriétés chimiques et pharmacologiques que le RDC11. Cette étude a permis d’identifier deux nouveaux RDCs qui réduisent la croissance tumorale in vivo avec un dosage beaucoup plus faible que le RDC11 et qui induisent la mort des cellules cancéreuses par une surproduction d'espèces réactives de l'oxygène et par l'activation de la caspase8. En conclusion, mes travaux ont conduit à l’identification de nouveaux mécanismes à la base de l’activité anticancéreuse du RDC11 qui pourraient expliquer certaines différences entre le mode d’action du RDC11 et du cisplatine. De plus, ils ont permis de sélectionner deux nouveaux RDCs plus efficaces que le RDC11. Ces résultat sont un impact important pour le développement de nouvelles thérapies anticancéreuses ou antimétastatiques.In recent years, a new class of anticancer ruthenium-based drugs, called RDCs (Ruthenium-Derived Compounds), has been developed to overcome the limitations of classic platinum chemotherapeutics. Unlike the latter, the anticancer activity of RDCs is in part independent of DNA interaction. Therefore, the main objective of my thesis work was to elucidate the molecular mechanisms involved in RDCs anticancer and antimetastatic activity beyond DNA damage. I demonstrated that RDC11, unlike cisplatin, affects the HIF-1 and mTOR signaling pathways, two pathways that play a key role in cellular metabolism and that are frequently altered in cancer cells. In parallel, I performed a structure/activity analysis to select new RDCs endowed with better chemical and pharmacological properties than RDC11. This study allowed to identify two novel RDCs that reduce tumor growth in vivo at much lower doses than RDC11 and that induce cancer cell death by an overproduction of reactive oxygen species and activation of caspase 8. In conclusion, my work led to the identification of new mechanisms underlying the anticancer activity of RDC11 that could explain some of the differences between the mode of action of RDC11 and cisplatin. In addition, it allowed to select two novel RDCs which are more effective than RDC11. These results have a significant impact on the development of new anticancer or antimetastatic therapies

Caractérisation des propriétés anticancéreuses des composés dérivés du ruthénium (mode d'action, optimisation et développement d outils expérimentaux.)

Au cours des dernières années, une nouvelle classe de composés anticancéreux à base de ruthénium, appelés RDCs (Ruthenium-Derived Compounds), a été développé pour dépasser les limitations des agents chimiothérapiques contenants du platine. Contrairement à ces derniers, l activité anticancéreuse des RDCs est en partie indépendante de l'interaction avec l'ADN. L objectif principal de ma thèse a été ainsi de comprendre les mécanismes moléculaires quiinter viennent dans l action anticancéreuse et antimétastatique des RDCs au-delà du dommage à l ADN.J ai démontré que le RDC11, contrairement au cisplatine, affecte les voies de signalisation de HIF-1 et mTOR, deux voies qui jouent un rôle clé dans le métabolisme cellulaire et qui sont souvent altérées dans les cellules cancéreuses.En parallèle, j ai effectué un analyse structure/activité pour sélectionner des nouveaux RDCs ayant meilleures propriétés chimiques et pharmacologiques que le RDC11. Cette étude a permis d identifier deux nouveaux RDCs qui réduisent la croissance tumorale in vivo avec un dosage beaucoup plus faible que le RDC11 et qui induisent la mort des cellules cancéreuses par une surproduction d'espèces réactives de l'oxygène et par l'activation de la caspase8. En conclusion, mes travaux ont conduit à l identification de nouveaux mécanismes à la base de l activité anticancéreuse du RDC11 qui pourraient expliquer certaines différences entre le mode d action du RDC11 et du cisplatine. De plus, ils ont permis de sélectionner deux nouveaux RDCs plus efficaces que le RDC11. Ces résultat sont un impact important pour le développement de nouvelles thérapies anticancéreuses ou antimétastatiques.In recent years, a new class of anticancer ruthenium-based drugs, called RDCs (Ruthenium-Derived Compounds), has been developed to overcome the limitations of classic platinum chemotherapeutics. Unlike the latter, the anticancer activity of RDCs is in part independent of DNA interaction. Therefore, the main objective of my thesis work was to elucidate the molecular mechanisms involved in RDCs anticancer and antimetastatic activity beyond DNA damage. I demonstrated that RDC11, unlike cisplatin, affects the HIF-1 and mTOR signaling pathways, two pathways that play a key role in cellular metabolism and that are frequently altered in cancer cells. In parallel, I performed a structure/activity analysis to select new RDCs endowed with better chemical and pharmacological properties than RDC11. This study allowed to identify two novel RDCs that reduce tumor growth in vivo at much lower doses than RDC11 and that induce cancer cell death by an overproduction of reactive oxygen species and activation of caspase 8. In conclusion, my work led to the identification of new mechanisms underlying the anticancer activity of RDC11 that could explain some of the differences between the mode of action of RDC11 and cisplatin. In addition, it allowed to select two novel RDCs which are more effective than RDC11. These results have a significant impact on the development of new anticancer or antimetastatic therapies.STRASBOURG-Bib.electronique 063 (674829902) / SudocSudocFranceF

MutSignatures: an R package for extraction and analysis of cancer mutational signatures

Cancer cells accumulate somatic mutations as result of DNA damage, inaccurate repair and other mechanisms. Different genetic instability processes result in characteristic non-random patterns of DNA mutations, also known as mutational signatures. We developed mutSignatures, an integrated R-based computational framework aimed at deciphering DNA mutational signatures. Our software provides advanced functions for importing DNA variants, computing mutation types, and extracting mutational signatures via non-negative matrix factorization. Specifically, mutSignatures accepts multiple types of input data, is compatible with non-human genomes, and supports the analysis of non-standard mutation types, such as tetra-nucleotide mutation types. We applied mutSignatures to analyze somatic mutations found in smoking-related cancer datasets. We characterized mutational signatures that were consistent with those reported before in independent investigations. Our work demonstrates that selected mutational signatures correlated with specific clinical and molecular features across different cancer types, and revealed complementarity of specific mutational patterns that has not previously been identified. In conclusion, we propose mutSignatures as a powerful open-source tool for detecting the molecular determinants of cancer and gathering insights into cancer biology and treatment