Redox Metal-Ligand Cooperativity Enables Robust and Efficient Water Oxidation Catalysis at Neutral pH with Macrocyclic Copper Complexes

Water oxidation catalysis stands out as one of the most important reactions to design practical devices for artificial photosynthesis. Use of late first-row transition metal (TM) complexes provides an excellent platform for the development of inexpensive catalysts with exquisite control on their electronic and structural features via ligand design. However, the difficult access to their high oxidation states and the general labile character of their metal–ligand bonds pose important challenges. Herein, we explore a copper complex (1²⁻) featuring an extended, π-delocalized, tetra-amidate macrocyclic ligand (TAML) as water oxidation catalyst and compare its activity to analogous systems with lower π-delocalization (2²⁻ and 3²⁻). Their characterization evidences a special metal–ligand cooperativity in accommodating the required oxidative equivalents using 1²⁻ that is absent in 2²⁻ and 3²⁻. This consists of charge delocalization promoted by easy access to different electronic states at a narrow energy range, corresponding to either metal-centered or ligand-centered oxidations, which we identify as an essential factor to stabilize the accumulated oxidative charges. This translates into a significant improvement in the catalytic performance of 1²⁻ compared to 2²⁻ and 3²⁻ and leads to one of the most active and robust molecular complexes for water oxidation at neutral pH with a k_(obs) of 140 s⁻¹ at an overpotential of only 200 mV. In contrast, 2²⁻ degrades under oxidative conditions, which we associate to the impossibility of efficiently stabilizing several oxidative equivalents via charge delocalization, resulting in a highly reactive oxidized ligand. Finally, the acyclic structure of 3²⁻ prevents its use at neutral pH due to acidic demetalation, highlighting the importance of the macrocyclic stabilization

Renin angiotensin system and gender differences in dopaminergic degeneration

Background: There are sex differences in dopaminergic degeneration. Men are approximately two times as likely as premenopausal women of the same age to develop Parkinson’s disease (PD). It has been shown that the local renin angiotensin system (RAS) plays a prominent role in sex differences in the development of chronic renal and cardiovascular diseases, and there is a local RAS in the substantia nigra and dopaminergic cell loss is enhanced by angiotensin via type 1 (AT1) receptors. Results: In the present study, we observed that intrastriatal injection of 6-hydroxydopamine induced a marked loss of dopaminergic neurons in the substantia nigra of male rats, which was significantly higher than the loss induced in ovariectomized female rats given estrogen implants (i.e. rats with estrogen). However, the loss of dopaminergic neurons was significantly lower in male rats treated with the AT1 antagonist candesartan, and similar to that observed in female rats with estrogen. The involvement of the RAS in gender differences in dopaminergic degeneration was confirmed with AT1a-null mice lesioned with the dopaminergic neurotoxin MPTP. Significantly higher expression of AT1 receptors, angiotensin converting enzyme activity, and NADPH-oxidase complex activity, and much lower levels of AT2 receptors were observed in male rats than in female rats with estrogen. Conclusions: The results suggest that brain RAS plays a major role in the increased risk of developing PD in men, and that manipulation of brain RAS may be an efficient approach for neuroprotective treatment of PD in men, without the feminizing effects of estrogen.Funding: Spanish Ministry of Science and Innovation, Spanish Ministry of Health (RD06/0010/0013 and CIBERNED), Galician Government (XUGA) and FEDERS

Vibrational and thermal studies of essential oils derived from Cistus ladanifer and Erica arborea shrubs

Producción CientíficaEssential oils from the two most representative shrub species from the Iberian Peninsula (namely Cistus ladanifer L. and Erica arborea L.) have been characterized by Fourier transform infrared spectroscopy (FTIR) and thermoanalytical techniques (TG/DTG and DSC). Vibrational spectra have been compared with those of components of the plants, and with those of oils, gums and resins from other species. The different content in terpenoids of C. ladanifer oil (mainly mono- and sesquiterpenoids) and E. arborea oil (mainly triterpenoids) is reflected in the ATR-FTIR by the position of the bands at around 2873 cm−1, 1730 cm−1 and 1678 cm−1. As regards their thermal behavior, C. ladanifer-derived oil evinced higher thermal stability than that of obtained from E. arborea: the pyrolysis of the former was sensitized at 210°C, whereas for the later it occurred at 143°C. These temperatures are high enough to state that thermolabile constituents such as terpenoids are conserved in the hydrodistillation and that this extraction process ensures the recovery of the main constituents of both essential oils.Programa LIFE+ de la Unión Europea (Proyecto LIFE11 ENV/ ES/000535)Fundação para a Ciência e a Tecnologia (FCT) (Proyecto UID/QUI/UI0313/2013

Angiotensin Type 1 Receptor Antagonists Protect Against Alpha-Synuclein-Induced Neuroinflammation and Dopaminergic Neuron Death

Altres ajuts: This study received funding from the Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas' intramural program (2014/01 and 2017/02), Galician Government (Xunta de Galicia, Consellería de Educación; GRC2014/002), Navarra Government (Departamento de Salud; 046-2017), and Fondo Europeo de Desarrollo Regional (Regional European Development Fund).The loss of dopaminergic neurons and α-synuclein accumulation are major hallmarks of Parkinson's disease (PD), and it has been suggested that a major mechanism of α-synuclein toxicity is microglial activation. The lack of animal models that properly reproduce PD, and particularly the underlying synucleinopathy, has hampered the clarification of PD mechanisms and the development of effective therapies. Here, we used neurospecific adeno-associated viral vectors serotype 9 coding for either the wild-type or mutated forms of human alpha-synuclein (WT and SynA53T, respectively) under the control of a synapsin promoter to further induce a marked dopaminergic neuron loss together with an important microglial neuroinflammatory response. Overexpression of neuronal alpha-synuclein led to increased expression of angiotensin type 1 receptors and NADPH oxidase activity, together with a marked increase in the number of OX-6-positive microglial cells and expression of markers of phagocytic activity (CD68) and classical pro-inflammatory/M1 microglial phenotype markers such as inducible nitric oxide synthase, tumor necrosis factor alpha, interleukin-1β, and IL-6. Moreover, a significant decrease in the expression of markers of immunoregulatory/M2 microglial phenotype such as the enzyme arginase-1 was constantly observed. Interestingly, alpha-synuclein-induced changes in microglial phenotype markers and dopaminergic neuron death were inhibited by simultaneous treatment with the angiotensin type 1 blockers candesartan or telmisartan. Our results suggest the repurposing of candesartan and telmisartan as a neuroprotective strategy for PD

Microglial angiotensin type 2 receptors mediate sex-specific expression of inflammatory cytokines independently of circulating estrogen

Consellería de Cultura, Educación e Ordenación Universitaria, Xunta de Galicia, Grant/Award Numbers: XUGA, ED431C 2018/10, ED431G/05; Instituto de Salud Carlos III, Grant/Award Numbers: PI20/00385, RD16/0011/0016, CIBERNED; Secretaría de Estado de Investigación, Desarrollo e Innovación, Grant/Award Number: RTI2018-098830-B-I00; Regional European Development Fund (FEDER)There are sex differences in microglia, which can maintain sex-related gene expression and functional differences in the absence of circulating sex steroids. The angiotensin type 2 (AT2) receptors mediate anti-inflammatory actions in different tissues, including brain. In mice, we performed RT-PCR analysis of microglia isolated from adult brains and RNA scope in situ hybridization from males, females, ovariectomized females, orchiectomized males and brain masculinized females. We also compared wild type and AT2 knockout mice. The expression of AT2 receptors in microglial cells showed sex differences with much higher AT2 mRNA expression in females than in males, and this was not dependent on circulating gonadal hormones, as observed using ovariectomized females, brain masculinized females and orchiectomized males. These results suggest genomic reasons, possibly related to sex chromosome complement, for sex differences in AT2 expression in microglia, as the AT2 receptor gene is located in the X chromosome. Furthermore, sex differences in expression of AT2 receptors were associated to sex differences in microglial expression of key anti-inflammatory cytokines such as interleukin-10 and pro-inflammatory cytokines such as interleukin-1β and interleukin-6. In conclusion, sex differences in microglial AT2 receptor expression appear as a major factor contributing to sex differences in the neuroinflammatory responses beyond the effects of circulating steroidsThere are sex differences in microglia, which can maintain sex-related gene expression and functional differences in the absence of circulating sex steroids. The angiotensin type 2 (AT2) receptors mediate anti-inflammatory actions in different tissues, including brain. In mice, we performed RT-PCR analysis of microglia isolated from adult brains and RNA scope in situ hybridization from males, females, ovariectomized females, orchiectomized males and brain masculinized females. We also compared wild type and AT2 knockout mice. The expression of AT2 receptors in microglial cells showed sex differences with much higher AT2 mRNA expression in females than in males, and this was not dependent on circulating gonadal hormones, as observed using ovariectomized females, brain masculinized females and orchiectomized males. These results suggest genomic reasons, possibly related to sex chromosome complement, for sex differences in AT2 expression in microglia, as the AT2 receptor gene is located in the X chromosome. Furthermore, sex differences in expression of AT2 receptors were associated to sex differences in microglial expression of key anti-inflammatory cytokines such as interleukin-10 and pro-inflammatory cytokines such as interleukin-1β and interleukin-6. In conclusion, sex differences in microglial AT2 receptor expression appear as a major factor contributing to sex differences in the neuroinflammatory responses beyond the effects of circulating steroidsS

Interaction between angiotensin type 1, type 2, and mas receptors to regulate adult neurogenesis in the brain ventricular–subventricular zone

The renin–angiotensin system (RAS), and particularly its angiotensin type-2 receptors (AT2), have been classically involved in processes of cell proliferation and maturation during development. However, the potential role of RAS in adult neurogenesis in the ventricular-subventricular zone (V-SVZ) and its aging-related alterations have not been investigated. In the present study, we analyzed the role of major RAS receptors on neurogenesis in the V-SVZ of adult mice and rats. In mice, we showed that the increase in proliferation of cells in this neurogenic niche was induced by activation of AT2 receptors but depended partially on the AT2-dependent antagonism of AT1 receptor expression, which restricted proliferation. Furthermore, we observed a functional dependence of AT2 receptor actions on Mas receptors. In rats, where the levels of the AT1 relative to those of AT2 receptor are much lower, pharmacological inhibition of the AT1 receptor alone was sufficient in increasing AT2 receptor levels and proliferation in the V-SVZ. Our data revealed that interactions between RAS receptors play a major role in the regulation of V-SVZ neurogenesis, particularly in proliferation, generation of neuroblasts, and migration to the olfactory bulb, both in young and aged brains, and suggest potential beneficial effects of RAS modulators on neurogenesis.This research was funded by Spanish grants from Ministerio de Economía y Competitividad (BFU2015-70523 and SAF2017-86690-R), Instituto de Salud Carlos III (Retic TERCEL RD16/0011/0016, RD16/0011/0017, and CIBERNED), Galician Government (XUGA, ED431C2018/10; ED431G/05), FEDER (Regional European Development Fund), Generalitat Valenciana (Prometeo 2017-030), and Fundación Emilio Botín-Banco SantanderS

Unravelling the Mechanistic Pathway of the Hydrogen Evolution Reaction Driven by a Cobalt Catalyst

Acord transformatiu CRUE-CSICA cobalt complex bearing a κ-NP ligand is presented (1 or Co(L), where L is (1E,1'E)-1,1'-(pyridine-2,6-diyl)bis(N-(3-(diphenylphosphanyl)propyl)ethan-1-imine). Complex 1 is stable under air at oxidation state Co thanks to the π-acceptor character of the phosphine groups. Electrochemical behavior of 1 reveals a two-electron Co/Co oxidation process and an additional one-electron reduction, which leads to an enhancement in the current due to hydrogen evolution reaction (HER) at E=−1.6 V vs Fc/Fc. In the presence of 1 equiv of bis(trifluoromethane)sulfonimide, 1 forms the cobalt hydride derivative Co(L)-H (2), which has been fully characterized. Further addition of 1 equiv of CoCp* (Cp* is pentamethylcyclopentadienyl) affords the reduced Co(L)-H (2) species, which rapidly forms hydrogen and regenerates the initial Co(L) (1). The spectroscopic characterization of catalytic intermediates together with DFT calculations support an unusual bimolecular homolytic mechanism in the catalytic HER with 1

Small extracellular vesicle targeting of hypothalamic AMPKα1 promotes weight loss in leptin receptor deficient mice

Background and aims: Leptin receptor (LEPR) deficiency promotes severe obesity and metabolic disorders. However, the current therapeutic options against this syndrome are scarce. Methods: db/db mice and their wildtypes were systemically treated with neuronal-targeted small extracellular vesicles (sEVs) harboring a plasmid encoding a dominant negative mutant of AMP-activated protein kinase alpha 1 (AMPKα1-DN) driven by steroidogenic factor 1 (SF1) promoter; this approach allowed to modulate AMPK activity, specifically in SF1 cells of the ventromedial nucleus of the hypothalamus (VMH). Animals were metabolically phenotyped. Results: db/db mice intravenously injected with SF1-AMPKα1-DN loaded sEVs showed a marked feeding-independent weight loss and decreased adiposity, associated with increased sympathetic tone, brown adipose tissue (BAT) thermogenesis and browning of white adipose tissue (WAT).Conclusion: Overall, this evidence indicates that specific modulation of hypothalamic AMPK using a sEV-based technology may be a suitable strategy against genetic forms of obesity, such as LEPR deficiencyMinisterio de Ciencia y Universidades co-funded by the FEDER Program of EU (CD: BFU2017-87721; RN: RTI2018-099413-B-I00 and RED2018-102379-T; ML: RTI2018-101840-B-I00, PID2021-128145NB-I00 and PDC2022-133958-I00). “la Caixa” Foundation (ID100010434), under the agreement LCF/PR/HR19/52160022 (ML); EuroNanoMed III (RA & ML: EURONANOMED2019-050-ENAMEP); European Research Council (RN: ERC Synergy Grant-2019-WATCH-810331)S

Supramolecular Hydrogels Consisting of Nanofibers Increase the Bioavailability of Curcuminoids in Inflammatory Skin Diseases

The low bioavailability of curcuminoids (CCMoids) limits their use in the treatment of inflammatory skin diseases. Our work shows that this constraint can be overcome upon their incorporation into supramolecular hydrogels assembled from a gemini-imidazolium amphiphilic gelator. Three structural CCMoid analogues were used to prepare supramolecular hydrogels, and it was observed that the concentration of both the gelator and CCMoid and the proportion of solvents influence the self-assembly process. Moreover, the mechanical properties of the nanostructured gels were studied to find the optimum gels, which were then further characterized microscopically, and their ability to release the CCMoid was evaluated. The physicochemical properties of the CCMoids play a fundamental role in the interaction with the gelator, influencing not only the gelation but also the morphology at the microscopic level, the mechanical properties, and the biopharmaceutical behavior such as the amount of CCMoid released from the gels. The nanostructured supramolecular hydrogels, which contain the CCMoids at much lower concentrations (μg/mL) in comparison to other products, promote the penetration of the CCMoids within the skin, but not their transdermal permeation, thus preventing any possible systemic effects and representing a safer option for topical administration. As a result, the CCMoid-containing hydrogels can effectively reduce skin inflammation in vivo, proving that these supramolecular systems are excellent alternatives in the treatment of inflammatory skin diseases