👤 Sergio Gimenez

Lipoprotein(a) [Lp(a)] is a genetically determined and independent cardiovascular risk factor. Despite its clinical relevance, data on Lp(a) prevalence and impact in Latin America are limited. We aimed to assess the prevalence of elevated Lp(a) and its association with cardiovascular outcomes in a large, multicenter Argentine registry. The GAELp(a) registry included 3000 adults from six Argentine regions. Lp(a) levels were measured using standardized assays; elevated Lp(a) was defined as >50 mg/dL or >125 nmol/L. Clinical, biochemical, and imaging data were collected retrospectively and prospectively. Associations between Lp(a) and major adverse cardiovascular events (MACE) were evaluated with logistic regression in the overall population and stratified by statin use. Elevated Lp(a) was present in 31.4 % of participants, with no sex difference. It was associated with family history of cardiovascular disease, subclinical atherosclerosis, and familial hypercholesterolemia. Patients with elevated Lp(a) had a higher prevalence of coronary artery disease (18.4 % vs. 12.5 %, p < 0.001), peripheral artery disease (4.8 % vs. 2.5 %, p = 0.001), and MACE (21.3 % vs. 14.8 %, p < 0.001). Elevated Lp(a) independently predicted MACE (OR 1.53, 95 % CI: 1.24-1.90, p < 0.001), with stronger associations in statin-naïve individuals (OR 2.18, 95 % CI: 1.17-4.07). ROC analysis showed modest discrimination (AUC 0.57 in nmol/L, 0.59 in mg/dL). Elevated Lp(a) is frequent in Argentina and strongly linked to cardiovascular disease and events. Its predictive value appears greater in statin-naïve patients, highlighting its role as a marker of residual risk. These findings support routine Lp(a) measurement in cardiovascular risk assessment, particularly in regions with high ASCVD burden. Show less

Trypanosoma cruzi, causative agent of Chagas disease (CD), remains a public health problem in Latin America and is emerging in non-endemic areas. Phospholipids (PL) are essential components of biomembranes and their enzymatic modification by phospholipases yields bioactive lipids that modulate immune responses. Anti-PL antibodies have been associated with autoimmune diseases and inflammation, potentially influencing CD pathology by recognising PL and PL-binding proteins. T. cruzi Phospholipase A1 (TcPLA1) hydrolyses membrane PL and participates in parasite-host cell interactions. This study evaluated IgM and IgG antibody responses against phosphatidylcholine, phosphatidylethanolamine, and their derived lysophospholipids (LPL), as well as recombinant TcPLA1, during experimental T. cruzi infection with two strains: RA (high virulence) and K98 (low virulence). It also aimed to predict the recognition capacity of TcPLA1 by CD patients using in silico analysis. Antibody responses were analysed by enzyme-linked immunosorbent assay (ELISA) using different PL and recombinant TcPLA1 as antigens. Lytic activity assays were performed to evaluate the functional impact of anti-PL antibodies. The CHAGASTOPE resource was used to predict TcPLA1 antigenicity. This study identified IgM and IgG antibodies against PL, LPL and TcPLA1 during experimental T. cruzi infection. Different amino acid sequences of TcPLA1 showed stronger antigenic recognition by CD patient's sera. The presence of these antibodies suggests their involvement in the pathogenesis of CD and their potential as markers for disease monitoring and prognosis. Show less

The melanocortin-3 receptor (MC3R) regulates GABA release from agouti-related protein (AgRP) nerve terminals and thus tonically suppresses multiple circuits involved in feeding behavior and energy homeostasis. Here, we examined the role of the MC3R and the melanocortin system in regulating the response to various anorexigenic agents. The genetic deletion or pharmacological inhibition of the MC3R, or subthreshold doses of an MC4R agonist, improved the dose responsiveness to glucagon-like peptide 1 (GLP1) agonists, as assayed by inhibition of food intake and weight loss. An enhanced anorectic response to the acute satiety factors peptide YY (PYY3-36) and cholecystokinin (CCK) and the long-term adipostatic factor leptin demonstrated that increased sensitivity to anorectic agents was a generalized result of MC3R antagonism. We observed enhanced neuronal activation in multiple hypothalamic nuclei using Fos IHC following low-dose liraglutide in MC3R-KO mice (Mc3r-/-), supporting the hypothesis that the MC3R is a negative regulator of circuits that control multiple aspects of feeding behavior. The enhanced anorectic response in Mc3r-/- mice after administration of GLP1 analogs was also independent of the incretin effects and malaise induced by GLP1 receptor (GLP1R) analogs, suggesting that MC3R antagonists or MC4R agonists may have value in enhancing the dose-response range of obesity therapeutics. Show less

Hereditary defects in the function of the Kir7.1 in the retinal pigment epithelium are associated with the ocular diseases retinitis pigmentosa, Leber congenital amaurosis, and snowflake vitreal degeneration. Studies also suggest that Kir7.1 may be regulated by a GPCR, the melanocortin-4 receptor, in certain hypothalamic neurons. We present the first structures of human Kir7.1 and describe the conformational bias displayed by two pathogenic mutations, R162Q and E276A, to provide an explanation for the basis of disease and illuminate the gating pathway. We also demonstrate the structural basis for the blockade of the channel by a small molecule ML418 and demonstrate that channel blockade in vivo activates MC4R neurons in the paraventricular nucleus of the hypothalamus (PVH), inhibiting food intake and inducing weight loss. Preliminary purification, and structural and pharmacological characterization of an in tandem construct of MC4R and Kir7.1 suggests that the fusion protein forms a homotetrameric channel that retains regulation by liganded MC4R molecules. Show less

Most antipsychotic drugs (APDs) induce hyperphagia and weight gain. However, the neural mechanisms are poorly understood, partly due to challenges replicating their metabolic effects in rodents. Here, we report a new mouse model that recapitulates overeating induced by clozapine, a widely prescribed APD. Our study shows that clozapine boosts food intake by inhibiting melanocortin 4 receptor (MC4R) expressing neurons in the paraventricular nucleus of the hypothalamus. Interestingly, neither clozapine nor risperidone, another commonly used APD, affects receptor-ligand binding or the canonical Gαs signaling of MC4R. Instead, they inhibit neuronal activity by enhancing the coupling between MC4R and Kir7.1, leading to the open state of the inwardly rectifying potassium channel. Deletion of Show less

Automated patch clamp recording is a valuable technique in drug discovery and the study of ion channels. It allows for the precise measurement and manipulation of channel currents, providing insights into their function and modulation by drugs or other compounds. The melanocortin 4 receptor (MC4-R) is a G protein-coupled receptor (GPCR) crucial to appetite regulation, energy balance, and body weight. MC4-R signaling is complex and involves interactions with other receptors and neuropeptides in the appetite-regulating circuitry. MC4-Rs, like other GPCRs, are known to modulate ion channels such as Kir7.1, an inward rectifier potassium channel, in response to ligand binding. This modulation is critical for controlling ion flow across the cell membrane, which can influence membrane potential, excitability, and neurotransmission. The MC4-R is the target for the anti-obesity drug Imcivree. However, this drug is known to lack optimal potency and also has side effects. Using high-throughput techniques for studying the MC4-R/Kir7.1 complex allows researchers to rapidly screen many compounds or conditions, aiding the development of drugs that target this system. Additionally, automated patch clamp recording of this receptor-channel complex and its ligands can provide valuable functional and pharmacological insights supporting the development of novel therapeutic strategies. This approach can be generalized to other GPCR-gated ion channel functional complexes, potentially accelerating the pace of research in different fields with the promise to uncover previously unknown aspects of receptor-ion channel interactions. Show less

The melanocortin receptors (MC1R-MC5R) belong to class A G-protein-coupled receptors (GPCRs) and are known to have receptor-specific roles in normal and diseased states. Selectivity for MC4R is of particular interest due to its involvement in various metabolic disorders, including obesity, feeding regulation, and sexual dysfunctions. To further improve the potency and selectivity of MC4R (ant)agonist peptide ligands, we designed and synthesized a series of cyclic peptides based on the recent crystal structure of MC4R in complex with the well-characterized antagonist Show less

The melanocortin-4 receptor (MC4R) is involved in energy homeostasis and is an important drug target for syndromic obesity. We report the structure of the antagonist SHU9119-bound human MC4R at 2.8-angstrom resolution. Ca Show less