The considerable increase in the occupation of coastal areas requires strategies to conceive and apply hazard prevention and mitigation measures, especially in coastlines with sea cliffs where mass ...movements are more likely to occur. To predict the potential of sea cliff failures and identify the more unstable cliff sections, analytical, physical and/or statistical tools can enable the assessment of cliff failure susceptibility, which is a progress towards a better understanding of sea cliff failure hazard assessment and mapping.
In this study, statistical approaches for the assessment of sea cliff failure susceptibility and definition of safety set-back lines located landwards of the cliff top crest were adopted, in the coast located to northeast of Peniche, between Baleal and the Óbidos lagoon, in the western coast of Portugal. For the susceptibility assessment, the logistic regression was used to correlate a set of predictive factors, obtained from thematic maps of geology (lithology, structure, faults), geomorphology (cliff height, slope angle, exposure, curvature, toe protection) and wave action, with an inventory of cliff failures that caused cliff top retreat, compiled from aerial photographs from 1947 to 2010. This method enabled the production of cliff failure susceptibility models using terrain units with different sizes, encompassing cliff crest length segments of 50 m, 20 m, and 10 m. The ordinal logistic regression was applied for the setback lines definition.
The modeling results were analyzed using diagnostic measures and external validation, with each model being validated against the cliff instability inventory which indicated very good statistical performance and allowed the production of reliable susceptibility maps.
The application of such statistical techniques enables estimation of the degree of susceptibility for cliff failures at regional scales of analysis, and assists the definition of cliff setback lines, which provide answers to planning and hazard prevention problems of coastal areas with sea cliffs.
•Sea cliff hazard mapping using statistical methods allows better coastal management.•Statistical sea cliff failure hazard assessment and mapping•Probabilistic sea cliff top set back areas definition•Quantitative tool for sea cliffs planning and management
One classical feature of cancer cells is their metabolic acquisition of a highly glycolytic phenotype. Carbon monoxide (CO), one of the products of the cytoprotective molecule heme oxygenase-1 (HO-1) ...in cancer cells, has been implicated in carcinogenesis and therapeutic resistance. However, the functional contributions of CO and HO-1 to these processes are poorly defined. In human prostate cancers, we found that HO-1 was nuclear localized in malignant cells, with low enzymatic activity in moderately differentiated tumors correlating with relatively worse clinical outcomes. Exposure to CO sensitized prostate cancer cells but not normal cells to chemotherapy, with growth arrest and apoptosis induced in vivo in part through mitotic catastrophe. CO targeted mitochondria activity in cancer cells as evidenced by higher oxygen consumption, free radical generation, and mitochondrial collapse. Collectively, our findings indicated that CO transiently induces an anti-Warburg effect by rapidly fueling cancer cell bioenergetics, ultimately resulting in metabolic exhaustion.
A few ruthenium based metal carbonyl complexes, e.g. CORM-2 and CORM-3, have therapeutic activity attributed to their ability to deliver CO to biological targets. In this work, a series of related ...complexes with the formula Ru(CO)3Cl2L (L = DMSO (3), L-H3CSO(CH2)2CH(NH2)CO2H) (6a); D,L-H3CSO(CH2)2CH(NH2)CO2H (6b); 3-NC5H4(CH2)2SO3Na (7); 4-NC5H4(CH2)2SO3Na (8); PTA (9); DAPTA (10); H3CS(CH2)2CH(OH)CO2H (11); CNCMe2CO2Me (12); CNCMeEtCO2Me (13); CN(c-C3H4)CO2Et) (14)) were designed, synthesized and studied. The effects of L on their stability, CO release profile, cytotoxicity and anti-inflammatory properties are described. The stability in aqueous solution depends on the nature of L as shown using HPLC and LC-MS studies. The isocyanide derivatives are the least stable complexes, and the S-bound methionine oxide derivative is the more stable one. The complexes do not release CO gas to the headspace, but release CO2 instead. X-ray diffraction of crystals of the model protein Hen Egg White Lysozyme soaked with 6b (4UWN) and 8 (4UWN) shows the addition of Ru(II)(CO)(H2O)4 at the His15 binding site. Soakings with 7(4UWN) produced the metallacarboxylate Ru(COOH)(CO)(H2O)3(+) bound to the His15 site. The aqueous chemistry of these complexes is governed by the water-gas shift reaction initiated with the nucleophilic attack of HO(-) on coordinated CO. DFT calculations show this addition to be essentially barrierless. The complexes have low cytotoxicity and low hemolytic indices. Following i.v. administration of CORM-3, the in vivo bio-distribution of CO differs from that obtained with CO inhalation or with heme oxygenase stimulation. A mechanism for CO transport and delivery from these complexes is proposed.
The complex fac-Mo(CO)(3)(histidinate)Na has been reported to be an effective CO-Releasing Molecule in vivo, eliciting therapeutic effects in several animal models of disease. The CO releasing ...profile of this complex in different settings both in vitro and in vivo reveals that the compound can readily liberate all of its three CO equivalents under biological conditions. The compound has low toxicity and cytotoxicity and is not hemolytic. CO release is accompanied by a decrease in arterial blood pressure following administration in vivo. We studied its behavior in solution and upon the interaction with proteins. Reactive oxygen species (ROS) generation upon exposure to air and polyoxomolybdate formation in soaks with lysozyme crystals were observed as processes ensuing from the decomposition of the complex and the release of CO.
The discovery of the biological effects of carbon monoxide (CO) in recent years strongly suggests that CO could find applications as a therapeutic agent. CO is a highly toxic gas when used at ...industrial doses, due in part to its binding affinity to hemoglobin. Since hemoglobin binds CO with the highest affinity in vivo, it also constitutes a major barrier to the delivery of CO to tissues in need of therapy. A method of delivering CO that can bypass hemoglobin is the use of pro-drugs or CO carriers, called CO-releasing molecules (CO-RMs) that become activated and release CO in tissues in need of treatment. Organometallic carbonyl complexes are best suited to play the role of CO carriers, and indeed the natural CO carrier molecules hemoglobin and myoglobin belong to this class of chemical compounds. Here we describe the preparation of novel molybdenum CO-RMs of general formula Mo(CO)3(CNCR′R″CO2R‴)3 (R′, R″ = H, Me, iPr, CH2Ph, CO2Li, −CH2CH2–, −CH2(CH2)3CH2–; R‴ = H, Li), which present favorable druglike characteristics, have low toxicity, and demonstrate specific CO delivery to the liver in the treatment of acetaminophen (APAP)-induced acute liver failure in mice.
Cationic liposomes for gene delivery Simões, Sérgio; Filipe, Ana; Faneca, Henrique ...
Expert opinion on drug delivery
2, Številka:
2
Journal Article
Recenzirano
Cationic liposome-DNA complexes (lipoplexes) constitute a potentially viable alternative to viral vectors for the delivery of therapeutic genes. This review will focus on various parameters governing ...lipoplex biological activity, from their mode of formation to in vivo behaviour. Particular emphasis is given to the mechanism of interaction of lipoplexes with cells, in an attempt to dissect the different barriers that need to be surpassed for efficient gene expression to occur. Aspects related to new trends in the formulation of lipid-based gene delivery systems aiming at overcoming some of their limitations will be covered. Finally, examples illustrating the potential of cationic liposomes in clinical applications will be provided.
A few ruthenium based metal carbonyl complexes,
e.g.
CORM-2 and CORM-3, have therapeutic activity attributed to their ability to deliver CO to biological targets. In this work, a series of related ...complexes with the formula Ru(CO)
3
Cl
2
L (L = DMSO (
3
),
l
-H
3
CSO(CH
2
)
2
CH(NH
2
)CO
2
H) (
6a
);
d
,
l
-H
3
CSO(CH
2
)
2
CH(NH
2
)CO
2
H (
6b
); 3-NC
5
H
4
(CH
2
)
2
SO
3
Na (
7
); 4-NC
5
H
4
(CH
2
)
2
SO
3
Na (
8
); PTA (
9
); DAPTA (
10
); H
3
CS(CH
2
)
2
CH(OH)CO
2
H (
11
); CNCMe
2
CO
2
Me (
12
); CNCMeEtCO
2
Me (
13
); CN(
c
-C
3
H
4
)CO
2
Et) (
14
)) were designed, synthesized and studied. The effects of L on their stability, CO release profile, cytotoxicity and anti-inflammatory properties are described. The stability in aqueous solution depends on the nature of L as shown using HPLC and LC-MS studies. The isocyanide derivatives are the least stable complexes, and the S-bound methionine oxide derivative is the more stable one. The complexes do not release CO gas to the headspace, but release CO
2
instead. X-ray diffraction of crystals of the model protein Hen Egg White Lysozyme soaked with
6b
(
4UWN
) and
8
(
4UWV
) shows the addition of Ru
II
(CO)(H
2
O)
4
at the His15 binding site. Soakings with
7
(
4UWU
) produced the metallacarboxylate Ru(COOH)(CO)(H
2
O)
3
+
bound to the His15 site. The aqueous chemistry of these complexes is governed by the water-gas shift reaction initiated with the nucleophilic attack of HO
−
on coordinated CO. DFT calculations show this addition to be essentially barrierless. The complexes have low cytotoxicity and low hemolytic indices. Following i.v. administration of CORM-3, the
in vivo
bio-distribution of CO differs from that obtained with CO inhalation or with heme oxygenase stimulation. A mechanism for CO transport and delivery from these complexes is proposed.
Water-gas shift chemistry modulates aqueous stability and protein interactions of Ru(CO)
3
Cl
2
L CORMs.
A few ruthenium based metal carbonyl complexes, e.g. CORM-2 and CORM-3, have therapeutic activity attributed to their ability to deliver CO to biological targets. In this work, a series of related ...complexes with the formula Ru(CO) 3 Cl 2 L (L = DMSO ( 3 ), l -H 3 CSO(CH 2 ) 2 CH(NH 2 )CO 2 H) ( 6a ); d , l -H 3 CSO(CH 2 ) 2 CH(NH 2 )CO 2 H ( 6b ); 3-NC 5 H 4 (CH 2 ) 2 SO 3 Na ( 7 ); 4-NC 5 H 4 (CH 2 ) 2 SO 3 Na ( 8 ); PTA ( 9 ); DAPTA ( 10 ); H 3 CS(CH 2 ) 2 CH(OH)CO 2 H ( 11 ); CNCMe 2 CO 2 Me ( 12 ); CNCMeEtCO 2 Me ( 13 ); CN( c -C 3 H 4 )CO 2 Et) ( 14 )) were designed, synthesized and studied. The effects of L on their stability, CO release profile, cytotoxicity and anti-inflammatory properties are described. The stability in aqueous solution depends on the nature of L as shown using HPLC and LC-MS studies. The isocyanide derivatives are the least stable complexes, and the S-bound methionine oxide derivative is the more stable one. The complexes do not release CO gas to the headspace, but release CO 2 instead. X-ray diffraction of crystals of the model protein Hen Egg White Lysozyme soaked with 6b (4UWN) and 8 (4UWV) shows the addition of Ru II (CO)(H 2 O) 4 at the His15 binding site. Soakings with 7 (4UWU) produced the metallacarboxylate Ru(COOH)(CO)(H 2 O) 3 + bound to the His15 site. The aqueous chemistry of these complexes is governed by the water–gas shift reaction initiated with the nucleophilic attack of HO − on coordinated CO. DFT calculations show this addition to be essentially barrierless. The complexes have low cytotoxicity and low hemolytic indices. Following i.v. administration of CORM-3, the in vivo bio-distribution of CO differs from that obtained with CO inhalation or with heme oxygenase stimulation. A mechanism for CO transport and delivery from these complexes is proposed.
A few ruthenium based metal carbonyl complexes, e.g. CORM-2 and CORM-3, have therapeutic activity attributed to their ability to deliver CO to biological targets. In this work, a series of related ...complexes with the formula Ru(CO) sub(3)Cl sub(2)L (L = DMSO (3), l-H sub(3)CSO(CH sub(2)) sub(2)CH(NH sub(2))CO sub(2)H) (6a); d,l-H sub(3)CSO(CH sub(2)) sub(2)CH(NH sub(2))CO sub(2)H (6b); 3-NC sub(5)H sub(4)(CH sub( 2)) sub(2)SO sub(3)Na (7); 4-NC sub(5)H sub(4)(CH sub( 2)) sub(2)SO sub(3)Na (8); PTA (9); DAPTA (10); H sub(3)CS(CH sub(2)) sub(2 )CH(OH)CO sub(2)H (11); CNCMe sub(2)CO sub(2)Me (12); CNCMeEtCO sub(2)Me (13); CN(c-C sub(3)H sub(4))CO sub(2)Et) (14)) were designed, synthesized and studied. The effects of L on their stability, CO release profile, cytotoxicity and anti-inflammatory properties are described. The stability in aqueous solution depends on the nature of L as shown using HPLC and LC-MS studies. The isocyanide derivatives are the least stable complexes, and the S-bound methionine oxide derivative is the more stable one. The complexes do not release CO gas to the headspace, but release CO sub(2) instead. X-ray diffraction of crystals of the model protein Hen Egg White Lysozyme soaked with 6b (4UWN) and 8 (4UWV) shows the addition of Ru super(II)(CO)(H sub(2)O) sub(4) at the His15 binding site. Soakings with 7 (4UWU) produced the metallacarboxylate Ru(COOH)(CO)(H sub(2)O) sub(3) super(+) bound to the His15 site. The aqueous chemistry of these complexes is governed by the water-gas shift reaction initiated with the nucleophilic attack of HO super(-) on coordinated CO. DFT calculations show this addition to be essentially barrierless. The complexes have low cytotoxicity and low hemolytic indices. Following i.v. administration of CORM-3, the in vivo bio-distribution of CO differs from that obtained with CO inhalation or with heme oxygenase stimulation. A mechanism for CO transport and delivery from these complexes is proposed.
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