Melatonin therapy reverses lead exposure-induced testicular damage in rats despite the lack of effect on serum testosterone levels.

Lead (Pb) exposure induces testicular damage and infertility. The aim of this study was to analyze and compare the therapeutic effects of antioxidants or vitamin D and calcium, which have previously been shown to reduce the toxic effects of Pb co-exposure, in rats. Rats were exposed to Pb for 28 days and subsequently treated with antioxidant (melatonin, silymarin), vitamin D and calcium (VitDCa) or a combination (melatonin or silymarin with VitDCa) for 28 days. Control groups included untreated rats (no Pb exposure or therapy), rats exposed only to melatonin or silymarin and rats exposed to Pb without post exposure therapy. Pb exposure induced testicular damage, increased blood lead level (BLL) and reduced serum testosterone level (STL). Rats exposed to Pb and left untreated for 28 days showed persistent pathological testicular alterations. The two treatments that were most effective in reversing pathological testis damage and restoring spermatogenesis were melatonin and silymarin. However, silymarin and melatonin treatment resulted in significantly different serum testosterone levels in rats. Whereas melatonin therapy reduced serum testosterone to levels lower than those in control rats, silymarin increased serum testosterone to levels higher than those in controls. Our pathological analysis of testes revealed that melatonin promoted spermatogenesis and regression of Pb exposure-induced degenerative changes, despite the associated reduction in serum testosterone levels. This result suggests that circulating testosterone may not have an important role in spermatogenesis. Collectively, our results suggest that melatonin and silymarin are effective therapies against the toxic effects Pb exposure in the male reproductive system.

The peptide bond rupture mechanism in the serine proteases: an in silico study based on sequential scale models.

Given the importance of serine proteases for biochemical processes, we have studied the peptide bond rupture mechanism using three sequential scale models as representations of the KLK5 enzyme (a protein overexpressed in ovarian cancer). The first model contains the basic functional groups of the residues that conform to the catalytic triad present in serine proteases; the second model contains some additional residues and, finally, the last representation includes all atoms of the KLK5 protein together with 10.000 explicit water molecules. This separation into three scale models allows us to separate the intrinsic reactivity of the catalytic triad from the process taking place in the enzyme. The methodologies employed in this work include full DFT calculations with a dielectric continuum in the first two models and a multi-level setup with a Quantum Mechanics/Molecular Mechanics (QM/MM) partition in the whole protein system. Our results show that the peptide-bond rupture mechanism is a stepwise process involving two proton transfer reactions. The rate-determining step is the second proton transfer from the imidazole group to the amidic nitrogen of the substrate. In addition, we find that the simplest model does not provide accurate results compared to the full protein system. This can be attributed to the electronic stabilization conferred by the residues around the reaction site. Interestingly, the energy profile obtained with the second scale model with additional residues shows the same trends as the full system and could therefore be considered an appropriate model system. It could be used for studying the peptide bond rupture mechanism in case full QM/MM calculations cannot be performed, or as a rapid tool for screening purposes.

Modeling Adsorption of CO2 in Rutile Metallic Oxide Surfaces: Implications in CO2 Catalysis.

CO2 is the most abundant greenhouse gas, and for this reason, it is the main target for finding solutions to climatic change. A strategy of environmental remediation is the transformation of CO2 to an aggregated value product to generate a carbon-neutral cycle. CO2 reduction is a great challenge because of the large C=O dissociation energy, ~179 kcal/mol. Heterogeneous photocatalysis is a strategy to address this issue, where the adsorption process is the fundamental step. The focus of this work is the role of adsorption in CO2 reduction by means of modeling the CO2 adsorption in rutile metallic oxides (TiO2, GeO2, SnO2, IrO2 and PbO2) using Density Functional Theory (DFT) and periodic DFT methods. The comparison of adsorption on different metal oxides forming the same type of crystal structure allowed us to observe the influence of the metal in the adsorption process. In the same way, we performed a comparison of the adsorption capability between two different surface planes, (001) and (110). Two CO2 configurations were observed, linear and folded: the folded conformations were observed in TiO2, GeO2 and SnO2, while the linear conformations were present in IrO2 and PbO2. The largest adsorption efficiency was displayed by the (001) surface planes. The CO2 linear and folded configurations were related to the interaction of the oxygen on the metallic surface with the adsorbate carbon, and the linear conformations were associated with the physisorption and folded configurations with chemisorption. TiO2 was the material with the best performance for CO2 interactions during the adsorption.

Antiradical properties of curcumin, caffeic acid phenethyl ester, and chicoric acid: a DFT study.

The antiradical properties and possible mechanisms of action of the tautomers of curcumin, caffeic acid phenethyl ester (CAPE), and chicoric acid (CA) have been studied within density functional theory (DFT). We calculated global chemical reactivity descriptors from conceptual DFT, pKa, bioavailability, and toxicity to evaluate the antiradical properties and characterize these species. Our final level of theory is the M06-2X functional with the 6-31 + G* basis set; we selected this level after performing a benchmark calibration and validation among different levels. Solvent effects were modeled via the continuum solvation model based on density (SMD). We used water and pentyl ethanoate as solvents to simulate the physiological conditions. The free radical scavenger capacity was analyzed for three possible oxidative stress mechanisms: single electron transfer (SET), hydrogen atom transfer (HAT), and xanthine oxidase (XO) inhibition. The results indicate that neutral curcumin, CA, and CAPE behave as antireductants. The most favorable mechanism turns out to be HAT, where CA and CAPE stand out. In conclusion, our DFT study strongly indicates that neutral curcumin, CAPE, and CA would very likely perform well as antiradical drugs with recommended therapeutic use, supported by their non-toxic nature.

Association between lead source exposure and blood lead levels in some lead manufacturing countries: A systematic review and meta-analysis.

Lead is one of the 10 most toxic chemicals of greatest concern for its effects on public health. Predominantly, in undeveloped countries, high blood lead levels (BLLs) persist in the population. To develop intervention strategies that may reduce lead exposure in populations, it is a priority to know the sources of lead pollution. The objective of this critical review and meta-analysis is to assess whether there is an association between different sources of lead exposure and the mean difference in blood lead levels in people exposed. To identify the major lead source exposure, a statistical analysis was performed on selection studies. This investigation reveals the limited information available on the sources of lead in Mexico and other lead producer countries, such as Croatia, Ecuador, Brazil, South Korea, India, Nigeria, Turkey, and China. Meta-analysis could be performed only in battery, smelting mining, and glazed ceramic workers. Battery manufacturing workers have the highest mean difference level of lead in their blood worldwide. Mexico has the second highest mean difference BLL in battery workers in the world. An interesting difference between the mean difference in BLL in mining workers from uncontrolled industry (-39.38) and controlled industry (-5.68) was found. This difference highlighted the success of applying strict control of lead sources and community education to reduce BLL and its potential harmful effects on human health and the environment. Children living near mining sites have the highest mean difference BLL (-11.1). This analysis may aid in assessing the source of lead exposure associated with a range of BLLs in people. Furthermore, this review highlights several social and cultural patterns associated with lead exposure and lead levels in control populations. These results could help to develop international lead regulations and appropriate public health guidelines to protect people around the world.

Correlation between urinary KIM-1 and kidney protein expression of p-ERK following damage in rats exposed to gentamicin or lead acetate.

Kidney injury molecule-1 (KIM-1) is a membrane receptor upregulated in the proximal tubule cells following various types of kidney injuries. Notably, studies have suggested a correlation between KIM-1 expression and extracellular signal-regulated kinase (ERK) activation. In this study, we aimed to investigate the association between the kidney overexpression pattern of cytoplasmic phosphorylated-ERK (p-ERK) protein and increased urinary KIM-1 levels in rats exposed to gentamicin or lead acetate, both at the end of toxic exposure and after a 4-week recovery period. Although other proteins were evaluated, only kidney overexpression of cytoplasmic p-ERK protein correlated with increased urinary KIM-1 levels. For both toxic substances, the increased urinary KIM-1 levels corresponded with kidney inflammation. Our results suggest that KIM-1 and p-ERK share a common mechanism in kidney injury mediated by both toxic substances that induce proximal tubule damage.

Design of Fluorescent Coumarin-Hydroxamic Acid Derivatives as Inhibitors of HDACs: Synthesis, Anti-Proliferative Evaluation and Docking Studies.

Coumarin-hydroxamic acid derivatives 7a-k were herein designed with a dual purpose: as antiproliferative agents and fluorescent probes. The compounds were synthesized in moderate yields (30-87%) through a simple methodology, biological evaluation was carried out on prostate (PC3) and breast cancer (BT-474 and MDA-MB-231) cell lines to determine the effects on cell proliferation and gene expression. For compounds 7c, 7e, 7f, 7i and 7j the inhibition of cancer cell proliferation was similar to that found with the reference compound at a comparable concentration (10 µM), in addition, their molecular docking studies performed on histone deacetylases 1, 6 and 8 showed strong binding to the respective active sites. In most cases, antiproliferative activity was accompanied by greater levels of cyclin-dependent kinase inhibitor p21, downregulation of the p53 tumor suppressor gene, and regulation of cyclin D1 gene expression. We conclude that compounds 7c, 7e, 7f, 7i and 7j may be considered as potential anticancer agents, considering their antiproliferative properties, their effect on the regulation of the genes, as well as their capacity to dock to the active sites. The fluorescent properties of compound 7j and 7k suggest that they can provide further insight into the mechanism of action.

Binding of Pb-Melatonin and Pb-(Melatonin-metabolites) complexes with DMT1 and ZIP8: implications for lead detoxification.

We have applied the docking methodology to characterize the binding modes of the divalent metal transporter 1 (DMT1) and the zinc transporter 8 (ZIP8) protein channels with: melatonin, some melatonin metabolites, and a few lead complexes of melatonin and its metabolites, in three different coordination modes (mono-coordinated, bi-coordinated and tri-coordinated). Our results show that bi-coordinated and tri-coordinated lead complexes prefer to bind inside the central region of ZIP8. Moreover, the interaction strength is larger compared with that of the free melatonin and melatonin metabolites. On the other hand, the binding modes with DMT1 of such complexes display lower binding energies, compared with the free melatonin and melatonin metabolites. Our results suggest that ZIP8 plays a major role in the translocation of Pb, bi or tri coordinated, when melatonin metabolites are present. Finally, we have characterized the binding modes responsible for the ZIP8 large affinities, found in bi-coordinated and tri-coordinated lead complexes. Our results show that such interactions are greater, because of an increase of the number of hydrogen bonds, the number and intensity of electrostatic interactions, and the interaction overlay degree in each binding mode. Our results give insight into the importance of the ZIP8 channel on lead transport and a possible elimination mechanism in lead detoxification processes. Graphical abstract .

Computational study of metal complexes formed with EDTA, melatonin, and its main metabolites: implications in lead intoxication and clues to a plausible alternative treatment.

Melatonin has been proposed as an alternative treatment to the usage of EDTA for lead intoxication. In this computational paper, since previous work has not systematically studied the complexes that may be formed in the existing and proposed treatments, we study 45 possible complexes that we suggest may be formed between Pb and some essential metals with melatonin, melatonin metabolites, and EDTA, analyzing the stability and viability of these through the Gibbs free energy of complexation (ΔΔG), molecular orbitals, and energy decomposition analysis at the DFT level of theory PBE/TZ2P. Our findings show that most complexes present exergonic energies of reaction, and thus spontaneous complex formation. In addition, we show that the AMK and 3OHM melatonin metabolites possess electronic and thermodynamic properties adequate to act as lead trapping molecules due to the lower Pauli repulsion energies involved in the complexes they form and their large negative values of ΔΔG. Therefore, it is shown that both melatonin and some of its metabolites may be employed in a viable treatment for lead intoxication through formation of stable Pb-complexes. Graphical abstract Metal complexes formed with EDTA, melatonin, and its main metabolites.

Effects of lead and lead-melatonin exposure on protein and gene expression of metal transporters, proteins and the copper/zinc ratio in rats.

Human lead (Pb) exposure induces many adverse health effects, including some related to lead accumulation in organs. Although lead bio-distribution in the body has been described, the molecular mechanism underlying distribution and excretion is not well understood. The transport of essential and toxic metals is principally mediated by proteins. How lead affects the expression of metal transporter proteins in the principal metal excretory organs, i.e., the liver and kidney, is unknown. Considering that co-administration of melatonin and lead reduces the toxic effects of lead and lead levels in the blood in vivo, we examined how lead and co-administration of lead and melatonin affect the gene and protein expression of metal transporter proteins (ZIP8, ZIP14, CTR1 and DMT1) in these organs. Rats were exposed intraperitoneally to lead or lead-melatonin. Our results show that Pb exposure induces changes in the protein and gene expression of ZIP8, ZIP14 and CTR1. Alterations in the copper/zinc ratio found in the blood, liver and kidney were likely related to these changes. With DMT1 expression (gene and protein), a positive correlation was found with lead levels in the kidney. Co-administration of melatonin and lead reduced lead-induced DMT1 expression through an unknown mechanism. This effect of melatonin relates to reduced lead levels in the blood and kidney. The metal transport protein function and our results suggest that DMT1 likely contributes to lead accumulation in organs. These data further elucidate the effects of lead on Cu and Zn and the molecular mechanism underlying lead bio-distribution in animals.

Synthesis of azepino[4,5-b]indol-4-ones via MCR/free radical cyclization and in vitro-in silico studies as 5-Ht6R ligands.

A series of nine new 3-acetamide-azepino[4,5-b]indol-4-ones were synthesized in two steps: (i) multicomponent reaction (Ugi-4CR/SN2) and (ii) free radical-mediated cyclization. These compounds, along with their tetrazole-based analogs, were studied in vitro to assess their binding with the 5-hydroxytryptamine type 6 receptor (5-Ht6R). The 3-acetamide-azepino[4,5-b]indol-4-ones displayed moderate affinity, whereas the 3-tetrazolylmethyl-azepino[4,5-b]indol-4-ones affinity values are lower. However, one of the 3-acetamide-azepino[4,5-b]indol-4-ones exhibited a hit value of Ki (211.2nM) to the 5-Ht6R. Minimal-energy structures of one cis-amide and its tetrazole-based analog (calculated by means of the Density Functional Theory) were analyzed to assess some interesting bioisosterism aspects. Interactions and binding energies between all products and the 5-Ht6R were calculated through in silico molecular couplings. Finally, a QSAR model was proposed using the results of the in vitro assays.

In vitro and in silico evaluation of twelve newly-synthesized 1-acetamide-5-methoxy-2-oxindoles as 5-Ht7 receptor ligands.

Based on in vitro studies of twelve newly-synthesized 1-acetamide-5-methoxy-2-oxindoles as 5-Ht7 receptor ligands, Structure Affinity Relationship (SAR) and Quantitative Structure Affinity Relationship model (QSAR) are provided. Also, a ligand-based pharmacophore model is proposed through molecular docking techniques and Nucleus Independent Chemical Shift DFT calculations (NICS).

Melatonin reduces lead levels in blood, brain and bone and increases lead excretion in rats subjected to subacute lead treatment.

Melatonin, a hormone known for its effects on free radical scavenging and antioxidant activity, can reduce lead toxicity in vivo and in vitro.We examined the effects of melatonin on lead bio-distribution. Rats were intraperitoneally injected with lead acetate (10, 15 or 20mg/kg/day) with or without melatonin (10mg/kg/day) daily for 10 days. In rats intoxicated with the highest lead doses, those treated with melatonin had lower lead levels in blood and higher levels in urine and feces than those treated with lead alone, suggesting that melatonin increases lead excretion. To explore the mechanism underlying this effect, we first assessed whether lead/melatonin complexes were formed directly. Electronic density functional (DFT) calculations showed that a lead/melatonin complex is energetically feasible; however, UV spectroscopy and NMR analysis showed no evidence of such complexes. Next, we examined the liver mRNA levels of metallothioneins (MT) 1 and 2. Melatonin cotreatment increased the MT2 mRNA expression in the liver of rats that received the highest doses of lead. The potential effects of MTs on the tissue distribution and excretion of lead are not well understood. This is the first report to suggest that melatonin directly affects lead levels in organisms exposed to subacute lead intoxication.

Unraveling the origin of the relative stabilities of group 14 M2N2(2+) (M, N = C, Si, Ge, Sn, and Pb) isomer clusters.

We analyze the molecular structure, relative stability, and aromaticity of the lowest-lying isomers of group 14 M2N2(2+) (M and N = C, Si, and Ge) clusters. We use the gradient embedded genetic algorithm to make an exhaustive search for all possible isomers. Group 14 M2N2(2+) clusters are isoelectronic with the previously studied group 13 M2N2(2-) (M and N = B, Al, and Ga) clusters that includes Al4(2-), the archetypal all-metal aromatic molecule. In the two groups of clusters, the cyclic isomers present both σ- and π-aromaticity. However, at variance with group 13 M2N2(2-) clusters, the linear isomer of group 14 M2N2(2+) is the most stable for two of the clusters (C2Si2(2+) and C2Ge2(2+)) , and it is isoenergetic with the cyclic D(4h) isomer in the case of C4(2+). Energy decomposition analyses of the lowest-lying isomers and the calculated magnetic- and electronic-based aromaticity criteria of the cyclic isomers help to understand the nature of the bonding and the origin of the stability of the global minima. Finally, for completeness, we have also analyzed the structure and stability of the heavier Sn and Pb group 14 M2N2(2+) analogues.

Synthesis of 3-tetrazolylmethyl-azepino[4,5-b]indol-4-ones in two reaction steps: (Ugi-azide/N-acylation/SN2)/free radical cyclization and docking studies to a 5-Ht(6) model.

A series of nine novel 3-tetrazolylmethyl-azepino[4,5-b]indol-4-ones were prepared in moderate to good overall yields in only two reaction steps. The first step consisted of a one-pot sequential process of an Ugi-azide multicomponent reaction, N-acylation and SN2 to give the xanthates. The second step was an intramolecular cyclization under free radical conditions. Also, their binding modes have been modelled using docking techniques.

Tuning aromaticity in trigonal alkaline earth metal clusters and their alkali metal salts.

In this work, we analyze the geometry and electronic structure of the [X(n)M(3)](n-2) species (M = Be, Mg, and Ca; X = Li, Na, and K; n = 0, 1, and 2), with special emphasis on the electron delocalization properties and aromaticity of the cyclo-[M(3)](2-) unit. The cyclo-[M(3)](2-) ring is held together through a three-center two-electron bond of sigma-character. Interestingly, the interaction of these small clusters with alkali metals stabilizes the cyclo-[M(3)](2-) ring and leads to a change from sigma-aromaticity in the bound state of the cyclo-[M(3)](2-) to pi-aromaticity in the XM(3) (-) and X(2)M(3) metallic clusters. Our results also show that the aromaticity of the cyclo-[M(3)](2-) unit in the X(2)M(3) metallic clusters depends on the nature of X and M. Moreover, we explored the possibility for tuning the aromaticity by simply moving X perpendicularly to the center of the M(3) ring. The Na(2)Mg(3), Li(2)Mg(3), and X(2)Ca(3) clusters undergo drastic aromaticity alterations when changing the distance from X to the center of the M(3) ring, whereas X(2)Be(3) and K(2)Mg(3) keep its aromaticity relatively constant along this process.

Coordination and haptotropic migration of Cr(CO)3 in polycyclic aromatic hydrocarbons: the effect of the size and the curvature of the substrate.

In this work, we study the reaction mechanism of the tricarbonylchromium complex haptotropic rearrangement between two six-membered rings arranged like in naphthalene of four polycyclic aromatic hydrocarbons (PAHs). It has been found that the reaction mechanism of this haptotropic migration can either occur in a single step or stepwise depending on the interaction between the orbitals of the Cr(CO)3 and the PAH fragments. Our results show that the size of the cyclic system favors the metal migration whereas the curvature of the organic substrate tends to slow down the rearrangement. We discuss the key factors that help to explain this behavior through orbital and energy decomposition analysis.

Dinuclear copper(I) complexes with hexaaza macrocyclic dinucleating ligands: structure and dynamic properties.

The synthesis and structural and spectroscopic characterization of a family of copper(I) complexes, containing a dinucleating hexaaza macrocyclic ligand, of general formula [Cu(2)(L)(X)(2)](2+) (L = Me2p, Me2m, Me3p, or Me3m; X = MeCN, n-PrCN, CO, t-BuNC, or PPh(3)) is described. This family of complexes contains ligands that differ from one another in the number of methylenic units linking the tertiary amines and in the meta or para substitution of their aromatic rings. The structural characterization in the solid-state includes a single-crystal X-ray diffraction analysis of [Cu(2)(Me2p)(CO)(2)](2+) and of [Cu(2)(Me2m)(t-BuNC)(2)](2+). In solution, those complexes are structurally characterized through NMR spectroscopy that also allows us to put forward and establish their fluxional behavior. Theoretical calculations at the DFT level have also been performed in order to further analyze the relative energy of the different potential isomers as well as to gain insight into their chemical properties. Finally, the influence of the hexaaza ligands over different structural aspects as well as on its potential chemical reactivity is discussed.

Structural, electronic, and magnetic consequences of O-carbonyl vs O-alkoxy ester coordination in new dicopper complexes containing the Cu2(mu-Cl)2 core.

The complexes [Cu2(mu-Cl)2(Cl)2(L)2] (L = dialkylpyridine-2,6-dicarboxylate; R = Et, L = depc, 1; R = i-Pr, L = dppc, 2) have been prepared and their magnetic properties studied. The crystal structures of complexes 1 and 2 have been solved. Compound 1 belongs to the P space group with Z = 2, a = 8.3020(10) A, b = 9.2050(10) A, c = 10.065(2) A, alpha = 99.040(10), beta = 100.810(10), and gamma = 106.502(10) whereas 2 belongs to the C2/c space group with Z = 8, a = 11.6360(10) A, b = 25.906(3) A, c = 11.76579(10) A, and beta = 107.900(10). The different alkyl ester substitutes produce substantial structural and electronic differences. The Cu2Cl2 core geometry is planar for 1 whereas it adopts a butterfly shape in the case of 2. Furthermore, in 2 the dppc ligand coordinates only by the carbonyl oxygen atoms whereas in 1 the depc ligand coordinates through carbonyl and alkoxy oxygen atoms. Magnetic susceptibility data show a ferromagnetic coupling between the two Cu(II) centers in both cases (J = 39.9(6) cm(-1) for 1, and J = 51.3(5) cm(-1) for 2) with very weak antiferromagnetic interactions (J ' = -0.59 cm(-1) and -0.57 cm(-1) for 1 and 2, respectively). Theoretical calculations at the extended Hückel level have also been carried out to further understand the electronic nature of complexes 1 and 2.

CdS nanoparticles modified to chalcogen sites: new supramolecular complexes, butterfly bridging, and related optical effects.

All present approaches to surface modification of nanoparticles (NPs) with organic ligands exploit metal (cadmium) sites as anchor points. To obtain efficient interaction of NP surface with p-orbitals of organic chromophores, we utilize the chalcogen (sulfur) sites on the NP surface. These sites present several advantages stemming from a stronger interaction of their atomic orbitals with both modifier and NP core. The chalcogen modification of CdS was achieved by using a mixed ligand (2,2'-bipyridyl-N,N')(malonato-O,O')-copper(II) monohydrate complex. The weak monodentate ligands (water) are replaced by a copper-sulfur bond during the modification reaction. The structure of the product was investigated by optical spectroscopy, electron spin resonance, and nuclear magnetic resonance. The modified NP can be described as a few tens (<40) of (2,2'-bipyridyl-N,N')(malonato-O,O')-copper units attached to the CdS core. Steady-state and time-resolved luminescence measurements, molecular orbital calculations, and UPS data indicate that delocalized surface states enveloping the surface chalcogen atoms of NP, transition metal, and p-orbitals of the bipyridine ligand are present in the synthesized species. The delocalized states are made possible due to the bridging of p-levels of sulfur and pi-orbitals of bipyridine by butterfly d-orbitals of the transition metal atom placed between them. Chalcogen-modified NP can be considered as a new member of the family of supramolecular compounds based on transition metal complexes. Both NP and metal complex parts of the prepared supramolecules are very versatile structural units, and new molecular constructs of similar design, in which quantum effects of NPs are combined with optical properties of transition metal complexes, can be obtained with different NPs and metal complexes.