Cardioprotection and lifespan extension by the natural polyamine spermidine

Aging is associated with an increased risk of cardiovascular disease and death. Here we show that oral supplementation of the natural polyamine spermidine extends the lifespan of mice and exerts cardioprotective effects, reducing cardiac hypertrophy and preserving diastolic function in old mice. Spermidine feeding enhanced cardiac autophagy, mitophagy and mitochondrial respiration, and it also improved the mechano-elastical properties of cardiomyocytes in vivo, coinciding with increased titin phosphorylation and suppressed subclinical inflammation. Spermidine feeding failed to provide cardioprotection in mice that lack the autophagy-related protein Atg5 in cardiomyocytes. In Dahl salt-sensitive rats that were fed a high-salt diet, a model for hypertension-induced congestive heart failure, spermidine feeding reduced systemic blood pressure, increased titin phosphorylation and prevented cardiac hypertrophy and a decline in diastolic function, thus delaying the progression to heart failure. In humans, high levels of dietary spermidine, as assessed from food questionnaires, correlated with reduced blood pressure and a lower incidence of cardiovascular disease. Our results suggest a new and feasible strategy for protection against cardiovascular disease

Stronger Cytotoxicity for Cancer Cells Than for Fast Proliferating Human Stem Cells by Rationally Designed Dinuclear Complexes

Schwarzbich S, Horstmann Nee Gruschka C, Simon J, et al. Stronger Cytotoxicity for Cancer Cells Than for Fast Proliferating Human Stem Cells by Rationally Designed Dinuclear Complexes. Inorganic chemistry. 2020;59(19):14464–14477.Cytostatic metallo-drugs mostly bind to the nucleobases of DNA. A new family of dinuclear transition metal complexes was rationally designed to selectively target the phosphate diesters of the DNA backbone by covalent bonding. The synthesis and characterization of the first dinuclear NiII2 complex of this family are presented, and its DNA binding and interference with DNA synthesis in polymerase chain reaction (PCR) are investigated and compared to those of the analogous CuII2 complex. The NiII2 complex also binds to DNA but forms fewer intermolecular DNA cross-links, while it interferes with DNA synthesis in PCR at lower concentrations than CuII2. To simulate possible competing phosphate-based ligands in vivo, these effects have been studied for both complexes with 100-200-fold excesses of phosphate and ATP, which provided no disturbance. The cytotoxicity of both complexes has been studied for human cancer cells and human stem cells with similar rates of proliferation. CuII2 shows the lowest IC50 values and a remarkable preference for killing the cancer cells. Three different assays show that the CuII2 complex induces apoptosis in cancer cells. These results are discussed to gain insight into the mechanisms of action and demonstrate the potential of this family of dinuclear complexes as anticancer drugs acting by a new binding target

Rational design of a cytotoxic dinuclear Cu2 complex that binds by molecular recognition at two neighboring phosphates of the DNA backbone

Jany T, Moreth A, Gruschka C, et al. Rational design of a cytotoxic dinuclear Cu2 complex that binds by molecular recognition at two neighboring phosphates of the DNA backbone. Inorganic chemistry. 2015;54(6):2679-2690.The mechanism of the cytotoxic function of cisplatin and related anticancer drugs is based on their binding to the nucleobases of DNA. The development of new classes of anticancer drugs requires establishing other binding modes. Therefore, we performed a rational design for complexes that target two neighboring phosphates of the DNA backbone by molecular recognition resulting in a family of dinuclear complexes based on 2,7-disubstituted 1,8-naphthalenediol. This rigid backbone preorganizes the two metal ions for molecular recognition at the distance of two neighboring phosphates in DNA of 6-7 Å. Additionally, bulky chelating pendant arms in the 2,7-position impede nucleobase complexation by steric hindrance. We successfully synthesized the Cu(II)2 complex of the designed family of dinuclear complexes and studied its binding to dsDNA by independent ensemble and single-molecule methods like gel electrophoresis, precipitation, and titration experiments followed by UV-vis spectroscopy, atomic force microscopy (AFM), as well as optical tweezers (OT) and magnetic tweezers (MT) DNA stretching. The observed irreversible binding of our dinuclear Cu(II)2 complex to dsDNA leads to a blocking of DNA synthesis as studied by polymerase chain reactions and cytotoxicity for human cancer cells

Rational Design of a Cytotoxic Dinuclear Cu₂ Complex That Binds by Molecular Recognition at Two Neighboring Phosphates of the DNA Backbone

The mechanism of the cytotoxic function of cisplatin and related anticancer drugs is based on their binding to the nucleobases of DNA. The development of new classes of anticancer drugs requires establishing other binding modes. Therefore, we performed a rational design for complexes that target two neighboring phosphates of the DNA backbone by molecular recognition resulting in a family of dinuclear complexes based on 2,7-disubstituted 1,8-naphthalenediol. This rigid backbone preorganizes the two metal ions for molecular recognition at the distance of two neighboring phosphates in DNA of 6–7 Å. Additionally, bulky chelating pendant arms in the 2,7-position impede nucleobase complexation by steric hindrance. We successfully synthesized the Cu^II₂ complex of the designed family of dinuclear complexes and studied its binding to dsDNA by independent ensemble and single-molecule methods like gel electrophoresis, precipitation, and titration experiments followed by UV–vis spectroscopy, atomic force microscopy (AFM), as well as optical tweezers (OT) and magnetic tweezers (MT) DNA stretching. The observed irreversible binding of our dinuclear Cu^II₂ complex to dsDNA leads to a blocking of DNA synthesis as studied by polymerase chain reactions and cytotoxicity for human cancer cells

Rational Design of a Cytotoxic Dinuclear Cu₂ Complex That Binds by Molecular Recognition at Two Neighboring Phosphates of the DNA Backbone

The mechanism of the cytotoxic function of cisplatin and related anticancer drugs is based on their binding to the nucleobases of DNA. The development of new classes of anticancer drugs requires establishing other binding modes. Therefore, we performed a rational design for complexes that target two neighboring phosphates of the DNA backbone by molecular recognition resulting in a family of dinuclear complexes based on 2,7-disubstituted 1,8-naphthalenediol. This rigid backbone preorganizes the two metal ions for molecular recognition at the distance of two neighboring phosphates in DNA of 6–7 Å. Additionally, bulky chelating pendant arms in the 2,7-position impede nucleobase complexation by steric hindrance. We successfully synthesized the Cu^II₂ complex of the designed family of dinuclear complexes and studied its binding to dsDNA by independent ensemble and single-molecule methods like gel electrophoresis, precipitation, and titration experiments followed by UV–vis spectroscopy, atomic force microscopy (AFM), as well as optical tweezers (OT) and magnetic tweezers (MT) DNA stretching. The observed irreversible binding of our dinuclear Cu^II₂ complex to dsDNA leads to a blocking of DNA synthesis as studied by polymerase chain reactions and cytotoxicity for human cancer cells

Rational Design of a Cytotoxic Dinuclear Cu₂ Complex That Binds by Molecular Recognition at Two Neighboring Phosphates of the DNA Backbone

The mechanism of the cytotoxic function of cisplatin and related anticancer drugs is based on their binding to the nucleobases of DNA. The development of new classes of anticancer drugs requires establishing other binding modes. Therefore, we performed a rational design for complexes that target two neighboring phosphates of the DNA backbone by molecular recognition resulting in a family of dinuclear complexes based on 2,7-disubstituted 1,8-naphthalenediol. This rigid backbone preorganizes the two metal ions for molecular recognition at the distance of two neighboring phosphates in DNA of 6–7 Å. Additionally, bulky chelating pendant arms in the 2,7-position impede nucleobase complexation by steric hindrance. We successfully synthesized the Cu^II₂ complex of the designed family of dinuclear complexes and studied its binding to dsDNA by independent ensemble and single-molecule methods like gel electrophoresis, precipitation, and titration experiments followed by UV–vis spectroscopy, atomic force microscopy (AFM), as well as optical tweezers (OT) and magnetic tweezers (MT) DNA stretching. The observed irreversible binding of our dinuclear Cu^II₂ complex to dsDNA leads to a blocking of DNA synthesis as studied by polymerase chain reactions and cytotoxicity for human cancer cells

Pleiotropic functions for transcription factor zscan10.

The transcription factor Zscan10 had been attributed a role as a pluripotency factor in embryonic stem cells based on its interaction with Oct4 and Sox2 in in vitro assays. Here we suggest a potential role of Zscan10 in controlling progenitor cell populations in vivo. Mice homozygous for a Zscan10 mutation exhibit reduced weight, mild hypoplasia in the spleen, heart and long bones and phenocopy an eye malformation previously described for Sox2 hypomorphs. Phenotypic abnormalities are supported by the nature of Zscan10 expression in midgestation embryos and adults suggesting a role for Zscan10 in either maintaining progenitor cell subpopulation or impacting on fate choice decisions thereof

Pleiotropic Functions for Transcription Factor Zscan10

10.1371/journal.pone.0104568PLoS ONE98e10456

Small eye phenotype in <i>Zscan10</i> homozygous mutant mice.

<p>Lateral (A) and frontal (B) view of adult mutant (left) and wild type (right) mice. Lateral view of right eye of a wild type (C) and mutant (D) adult female. (E) Eye size measurements by laser interference biometry revealed significantly reduced axial eye length in mutants of both sexes (p<0.001). Anterior eye investigation by Scheimpflug imaging indicated significantly increased mean lens density between controls and mutants for left eyes in males (p = 0.002) (F) and right eyes in females (p = 0.016) (G). Virtual drum vision testing showed a reduced response with borderline significance in female mutants (p = 0.034) (H). (E) to (H) are displayed as boxplot split by sex and genotype. Outliers are indicated by open circles.</p

Organ weight determined in pathology screen.

<p>(A) Normalized liver weight is significantly increased in male mutant mice (P = 0.008). (B) Absolute spleen weight is significantly reduced in mutant mice of both genders. (C) Normalized spleen weight is significantly reduced in female mutant mice (P = 0.002). (D) Absolute heart weight is significantly reduced in female mutant mice (p = 0.003). (E) Normalized heart weight is significantly reduced in female mutant mice (p = 0.016). All results demonstrated as boxplot with strip chart, split by sex and genotype. For tibia length refer to <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0104568#pone-0104568-g001" target="_blank">Figure 1F</a>. Points are individual animals; circles represent females (f); diamonds represent males (m) of <i>Zscan10</i> homozygous mutants (mut) and wild type littermates (con). Line within the boxplot represents median. Box represents the 25% and 75% quantile. Asterix represents the mean. Circled points: Values outside the upper whisker (min(max(x), 75% quantile +1.5*IQR) and outside the lower whisker (max(min(x), 25% quantile+1.5*IQR)  =  outliers. IQR  =  interquartile range (75% quantile–25% quantile).</p