A self-sustained loop of inflammation-driven inhibition of beige adipogenesis in obesity.

In obesity, inflammation of white adipose tissue (AT) is associated with diminished generation of beige adipocytes ('beige adipogenesis'), a thermogenic and energy-dissipating function mediated by beige adipocytes that express the uncoupling protein UCP1. Here we delineated an inflammation-driven inhibitory mechanism of beige adipogenesis in obesity that required direct adhesive interactions between macrophages and adipocytes mediated by the integrin α4 and its counter-receptor VCAM-1, respectively; expression of the latter was upregulated in obesity. This adhesive interaction reciprocally and concomitantly modulated inflammatory activation of macrophages and downregulation of UCP1 expression dependent on the kinase Erk in adipocytes. Genetic or pharmacological inactivation of the integrin α4 in mice resulted in elevated expression of UCP1 and beige adipogenesis of subcutaneous AT in obesity. Our findings, established in both mouse systems and human systems, reveal a self-sustained cycle of inflammation-driven impairment of beige adipogenesis in obesity.

MicroRNA sequence codes for small extracellular vesicle release and cellular retention.

Exosomes and other small extracellular vesicles (sEVs) provide a unique mode of cell-to-cell communication in which microRNAs (miRNAs) produced and released from one cell are taken up by cells at a distance where they can enact changes in gene expression1-3. However, the mechanism by which miRNAs are sorted into exosomes/sEVs or retained in cells remains largely unknown. Here we demonstrate that miRNAs possess sorting sequences that determine their secretion in sEVs (EXOmotifs) or cellular retention (CELLmotifs) and that different cell types, including white and brown adipocytes, endothelium, liver and muscle, make preferential use of specific sorting sequences, thus defining the sEV miRNA profile of that cell type. Insertion or deletion of these CELLmotifs or EXOmotifs in a miRNA increases or decreases retention in the cell of production or secretion into exosomes/sEVs. Two RNA-binding proteins, Alyref and Fus, are involved in the export of miRNAs carrying one of the strongest EXOmotifs, CGGGAG. Increased miRNA delivery mediated by EXOmotifs leads to enhanced inhibition of target genes in distant cells. Thus, this miRNA code not only provides important insights that link circulating exosomal miRNAs to tissues of origin, but also provides an approach for improved targeting in RNA-mediated therapies.

Reciprocal communication between FAPs and muscle cells via distinct extracellular vesicle miRNAs in muscle regeneration.

Muscle regeneration is a complex process relying on precise teamwork between multiple cell types, including muscle stem cells (MuSCs) and fibroadipogenic progenitors (FAPs). FAPs are also the main source of intramuscular adipose tissue (IMAT). Muscles without FAPs exhibit decreased IMAT infiltration but also deficient muscle regeneration, indicating the importance of FAPs in the repair process. Here, we demonstrate the presence of bidirectional crosstalk between FAPs and MuSCs via their secretion of extracellular vesicles (EVs) containing distinct clusters of miRNAs that is crucial for normal muscle regeneration. Thus, after acute muscle injury, there is activation of FAPs leading to a transient rise in IMAT. These FAPs also release EVs enriched with a selected group of miRNAs, a number of which come from an imprinted region on chromosome 12. The most abundant of these is miR-127-3p, which targets the sphingosine-1-phosphate receptor S1pr3 and activates myogenesis. Indeed, intramuscular injection of EVs from immortalized FAPs speeds regeneration of injured muscle. In late stages of muscle repair, in a feedback loop, MuSCs and their derived myoblasts/myotubes secrete EVs enriched in miR-206-3p and miR-27a/b-3p. The miRNAs repress FAP adipogenesis, allowing full muscle regeneration. Together, the reciprocal communication between FAPs and muscle cells via miRNAs in their secreted EVs plays a critical role in limiting IMAT infiltration while stimulating muscle regeneration, hence providing an important mechanism for skeletal muscle repair and homeostasis.

PAHSAs reduce cellular senescence and protect pancreatic beta cells from metabolic stress through regulation of Mdm2/p53.

Senescence in pancreatic beta cells plays a major role in beta cell dysfunction, which leads to impaired glucose homeostasis and diabetes. Therefore, prevention of beta cell senescence could reduce the risk of diabetes. Treatment of nonobese diabetic (NOD) mice, a model of type 1 autoimmune diabetes (T1D), with palmitic acid hydroxy stearic acids (PAHSAs), a novel class of endogenous lipids with antidiabetic and antiinflammatory effects, delays the onset and reduces the incidence of T1D from 82% with vehicle treatment to 35% with PAHSAs. Here, we show that a major mechanism by which PAHSAs protect islets of the NOD mice is by directly preventing and reversing the initial steps of metabolic stress-induced senescence. In vitro PAHSAs increased Mdm2 expression, which decreases the stability of p53, a key inducer of senescence-related genes. In addition, PAHSAs enhanced expression of protective genes, such as those regulating DNA repair and glutathione metabolism and promoting autophagy. We demonstrate the translational relevance by showing that PAHSAs prevent and reverse early stages of senescence in metabolically stressed human islets by the same Mdm2 mechanism. Thus, a major mechanism for the dramatic effect of PAHSAs in reducing the incidence of type 1 diabetes in NOD mice is decreasing cellular senescence; PAHSAs may have a similar benefit in humans.

Regiodivergent Radical-Relay Alkene Dicarbofunctionalization.

Herein, we report a regiodivergent 1,n-dicarbofunctionalization of unactivated olefins enabled by a Ni-catalyzed radical relay that forges both C(sp3)-C(sp3) and C(sp2)-C(sp3) linkages, even at long-range. Initial studies support an intertwined scenario resulting from the merger of an atom-transfer radical addition (ATRA) and a chain-walking event, with site-selectivity being dictated by a judicious choice of the ligand backbone.

Ring Walking Mediated by Ni-Ni Species as a Vehicle for Enabling Distal C(sp2)-H Functionalization of Aryl Pivalates.

Herein, we report the utilization of Ni-Ni species as a manifold for enabling a "ring-walking" event by dynamic translocation of the metal center over the arene backbone. Experimental and computational studies support a translocation occurring via a 1,2-hydride shift. The synthetic applicability of the method is illustrated in a series of C-C bond formations that occur at distal C(sp2)-H sites of simple aryl pivalates.

Late-Stage C(sp2)-C(sp3) Diversification via Nickel Oxidative Addition Complexes.

Herein, we describe nickel oxidative addition complexes (Ni-OACs) of drug-like molecules as a platform to rapidly generate lead candidates with enhanced C(sp3) fraction. The potential of Ni-OACs to access new chemical space has been assessed not only in C(sp2)-C(sp3) couplings but also in additional bond formations without recourse to specialized ligands and with improved generality when compared to Ni-catalyzed reactions. The development of an automated diversification process further illustrates the robustness of Ni-OACs, thus offering a new gateway to expedite the design-make-test-analyze (DMTA) cycle in drug discovery.

Kinetically-Controlled Ni-Catalyzed Direct Carboxylation of Unactivated Secondary Alkyl Bromides without Chain Walking.

Herein, we report the direct carboxylation of unactivated secondary alkyl bromides enabled by the merger of photoredox and nickel catalysis, a previously inaccessible endeavor in the carboxylation arena. Site-selectivity is dictated by a kinetically controlled insertion of CO2 at the initial C(sp3)-Br site by the rapid formation of Ni(I)-alkyl species, thus avoiding undesired ß-hydride elimination and chain-walking processes. Preliminary mechanistic experiments reveal the subtleties of stereoelectronic effects for guiding the reactivity and site-selectivity.

Unwrapping the structural and functional features of antimicrobial peptides from wasp venoms.

The study of wasp venoms has captured attention due to the presence of a wide variety of active compounds, revealing a diverse array of biological effects. Among these compounds, certain antimicrobial peptides (AMPs) such as mastoparans and chemotactic peptides have emerged as significant players, characterized by their unique amphipathic short linear alpha-helical structure. These peptides exhibit not only antibiotic properties but also a range of other biological activities, which are related to their ability to interact with biological membranes to varying degrees. This review article aims to provide updated insights into the structure/function relationships of AMPs derived from wasp venoms, linking this knowledge to the potential development of innovative treatments against infections.

Barbed versus conventional suture in elective posterior spine surgery.

PURPOSE: Barbed sutures are tissue control devices that can reduce operating room time and costs. We analyzed the utility of barbed sutures in posterior spinal surgery in order to prove non-inferiority to conventional methods for wound closure. METHODS: A cohort of patients undergoing elective posterior spinal surgery in which barbed (prospective) versus conventional sutures (retrospective) were used was analyzed. The primary endpoint was the occurrence of wound healing complications or the need for surgical revision. Secondary endpoints included postoperative stay, readmission rate, and duration and cost of wound closure. RESULT: A total of 483 patients participated in the study, 183 in the Barbed group and 300 in the Conventional group. Wound dehiscence or seroma occurred in 3.8% and 2.7% of the Barbed and Conventional groups, respectively (p = 0.6588). Both superficial (1.6% versus 4.0%, P = 0.2378) and deep infections (2.7% versus 4.7%, p = 0.4124) occurred similarly in both groups. Overall, the rate of re-intervention due to wound healing problems was also similar (4.9% versus 5.3%, p = 0.9906), as well as, total median hospital stay, postoperative stay and 30-day re-admission rates. The average duration of wound closure (1.66 versus 4.16 min per level operated, p < 0.0001) strongly favored the Barbed group. The mean cost of wound closure per patient was higher in the Barbed group (43.23 € versus 22.67 €, p < 0.0001). CONCLUSIONS: In elective posterior spinal procedures, the use of barbed sutures significantly reduced the duration of wound closure. The wound healing process was not hindered and the added cost related to the suture material was small.

Comproportionation and disproportionation in nickel and copper complexes.

Disproportionation and comproportionation reactions have become increasingly important electron transfer events in organometallic chemistry and catalysis. The renewed interest in these reactions is in part attributed to the improved understanding of first-row metals and their ability to occupy odd and even oxidation states. Disproportionation and comproportionation reactions enable metal complexes to shuttle between various oxidation states, a matter of utmost relevance for controlling the speciation and catalytic turnover. In addition, these reactions have a direct impact in the thermodynamic and kinetic stability of the corresponding metal complexes. This review covers the relevance and impact of these processes in electron transfer reactions and provides valuable information about their non-negligible influence in Ni- and Cu-catalysed transformations.

Assessment of an intervention for preventing pediatric overweight and obesity through the World Café technique: A qualitative study.

PURPOSE: To evaluate the self-reported perspectives of participants involved in the Previene Cádiz intervention for preventing pediatric overweight and obesity. DESIGN AND METHODS: This qualitative study collected information through the World Café technique. A purposive sample of 40 participants was used, of which 14 were schoolchildren, 12 were teachers, and 14 were parent volunteers. The data were segmented, and concepts were created and grouped into dimensions and categories. RESULTS: The participants confirmed they had learned new information and behaviors about healthy habits. Parental awareness was considered a crucial and necessary element in changing family habits; therefore, increasing the motivation of family members was deemed a critical task in public health interventions conducted in school settings. DISCUSSION: Despite the suitability of qualitative methodology to evaluate the perceptions of the main players in an educational intervention, scientific literature is scarce. Obtaining information from the educational community about an intervention is not always easy, so the perspectives of teachers, students, and families about the Previene Cádiz intervention through the World Café approach is considered a relevant contribution. CONCLUSIONS: The participants considered the intervention positive in terms of learning and fostering increased knowledge, awareness, and healthy behaviors. PRACTICE IMPLICATIONS: Future interventions should encourage the active participation of all social groups involved, integrating dynamic and collaborative training activities that are acceptable to all participants.

Screening of the Skin-Regenerative Potential of Antimicrobial Peptides: Clavanin A, Clavanin-MO, and Mastoparan-MO.

Skin wound healing is coordinated by a delicate balance between proinflammatory and anti-inflammatory responses, which can be affected by opportunistic pathogens and metabolic or vascular diseases. Several antimicrobial peptides (AMPs) possess immunomodulatory properties, suggesting their potential to support skin wound healing. Here, we evaluated the proregenerative activity of three recently described AMPs (Clavanin A, Clavanin-MO, and Mastoparan-MO). Human primary dermal fibroblasts (hFibs) were used to determine peptide toxicity and their capacity to induce cell proliferation and migration. Furthermore, mRNA analysis was used to investigate the modulation of genes associated with skin regeneration. Subsequently, the regenerative potential of the peptides was further confirmed using an ex vivo organotypic model of human skin (hOSEC)-based lesion. Our results indicate that the three molecules evaluated in this study have regenerative potential at nontoxic doses (i.e., 200 µM for Clavanin-A and Clavanin-MO, and 6.25 µM for Mastoparan-MO). At these concentrations, all peptides promoted the proliferation and migration of hFibs during in vitro assays. Such processes were accompanied by gene expression signatures related to skin regenerative processes, including significantly higher KI67, HAS2 and CXCR4 mRNA levels induced by Clavanin A and Mastoparan-MO. Such findings translated into significantly accelerated wound healing promoted by both Clavanin A and Mastoparan-MO in hOSEC-based lesions. Overall, the data demonstrate the proregenerative properties of these peptides using human experimental skin models, with Mastoparan-MO and Clavanin A showing much greater potential for inducing wound healing compared to Clavanin-MO.

Site-Selective Distal C(sp3)-H Bromination of Aliphatic Amines as a Gateway for Forging Nitrogen-Containing sp3 Architectures.

Herein, we disclose a new strategy that rapidly and reliably incorporates bromine atoms at distal, secondary C(sp3)-H sites in aliphatic amines with an excellent and predictable site-selectivity pattern. The resulting halogenated building blocks serve as versatile linchpins to enable a series of carbon-carbon and carbon-heteroatom bond-formations at remote C(sp3) sites, thus offering a new modular and unified platform that expediates the access to advanced sp3 architectures possessing valuable nitrogen-containing saturated heterocycles of interest in medicinal chemistry settings.

C(sp2)-H Hydroxylation via Catalytic 1,4-Ni Migration with N2O.

Herein, we report a Ni-catalyzed C(sp2)-H hydroxylation of aryl bromides with N2O as an oxygen-atom donor. The reaction is enabled by a 1,4-Ni translocation that results in ipso/ortho difunctionalized products. Regioselectivity and stereocontrol are dictated by a judicious choice of the ligand backbone, thus giving access to either carbonyl or phenol derivatives and offering an opportunity to repurpose hazardous substances en route to valuable oxygen-containing building blocks.

Native Amides as Enabling Vehicles for Forging sp3-sp3 Architectures via Interrupted Deaminative Ni-Catalyzed Chain-Walking.

Herein, we disclose an interrupted deaminative Ni-catalyzed chain-walking strategy that forges sp3-sp3 architectures at remote, yet previously unfunctionalized, methylene sp3 C-H sites enabled by the presence of native amides. This protocol is characterized by its mild conditions and wide scope, including challenging substrate combinations. Site-selectivity can be dictated by a judicious choice of the ligand, thus offering an opportunity to enable sp3-sp3 bond formations that are otherwise inaccessible in conventional chain-walking events.

Remote carboxylation of halogenated aliphatic hydrocarbons with carbon dioxide.

Catalytic carbon-carbon bond formation has enabled the streamlining of synthetic routes when assembling complex molecules. It is particularly important when incorporating saturated hydrocarbons, which are common motifs in petrochemicals and biologically relevant molecules. However, cross-coupling methods that involve alkyl electrophiles result in catalytic bond formation only at specific and previously functionalized sites. Here we describe a catalytic method that is capable of promoting carboxylation reactions at remote and unfunctionalized aliphatic sites with carbon dioxide at atmospheric pressure. The reaction occurs via selective migration of the catalyst along the hydrocarbon side-chain with excellent regio- and chemoselectivity, representing a remarkable reactivity relay when compared with classical cross-coupling reactions. Our results demonstrate that site-selectivity can be switched and controlled, enabling the functionalization of less-reactive positions in the presence of a priori more reactive ones. Furthermore, we show that raw materials obtained in bulk from petroleum processing, such as alkanes and unrefined mixtures of olefins, can be used as substrates. This offers an opportunity to integrate a catalytic platform en route to valuable fatty acids by transforming petroleum-derived feedstocks directly.

Adipose-derived circulating miRNAs regulate gene expression in other tissues.

Adipose tissue is a major site of energy storage and has a role in the regulation of metabolism through the release of adipokines. Here we show that mice with an adipose-tissue-specific knockout of the microRNA (miRNA)-processing enzyme Dicer (ADicerKO), as well as humans with lipodystrophy, exhibit a substantial decrease in levels of circulating exosomal miRNAs. Transplantation of both white and brown adipose tissue-brown especially-into ADicerKO mice restores the level of numerous circulating miRNAs that are associated with an improvement in glucose tolerance and a reduction in hepatic Fgf21 mRNA and circulating FGF21. This gene regulation can be mimicked by the administration of normal, but not ADicerKO, serum exosomes. Expression of a human-specific miRNA in the brown adipose tissue of one mouse in vivo can also regulate its 3' UTR reporter in the liver of another mouse through serum exosomal transfer. Thus, adipose tissue constitutes an important source of circulating exosomal miRNAs, which can regulate gene expression in distant tissues and thereby serve as a previously undescribed form of adipokine.

α-Difluoroalkylation of Benzyl Amines with Trifluoromethylarenes.

An α-difluoroalkylation of benzyl amines with trifluoromethylarenes is disclosed herein. This protocol is characterized by its operational simplicity, excellent chemoselectivity and broad scope-even with advanced synthetic intermediates-, thus offering a new entry point to medicinally-relevant α-difluoroalkylated amines from simple, yet readily accessible, precursors.

Copper-Catalyzed C(sp3 )-Amination of Ketone-Derived Dihydroquinazolinones by Aromatization-Driven C-C Bond Scission.

Herein, we describe the development of a copper-catalyzed C(sp3 )-amination of proaromatic dihydroquinazolinones derived from ketones. The reaction is enabled by the intermediacy of open-shell species arising from homolytic C-C bond-cleavage driven by aromatization. The protocol is characterized by its operational simplicity and generality, including chemical diversification of advanced intermediates.