A new fluorescent probe for the visualization of progerin.

Hutchinson-Gilford progeria syndrome (HGPS) or progeria is a rare genetic disease that causes premature aging, leading to a drastic reduction in the life expectancy of patients. Progeria is mainly caused by the intracellular accumulation of a defective protein called progerin, generated from a mutation in the LMNA gene. Currently, there is only one approved drug for the treatment of progeria, which has limited efficacy. It is believed that progerin levels are the most important biomarker related to the severity of the disease. However, there is a lack of effective tools to directly visualize progerin in the native cellular models, since the commercially available antibodies are not well suited for the direct visualization of progerin in cells from the mouse model of the disease. In this context, an alternative option for the visualization of a protein relies on the use of fluorescent chemical probes, molecules with affinity and specificity towards a protein. In this work we report the synthesis and characterization of a new fluorescent probe (UCM-23079) that allows for the direct visualization of progerin in cells from the most widely used progeroid mouse model. Thus, UCM-23079 is a new tool compound that could help prioritize potential preclinical therapies towards the final goal of finding a definitive cure for progeria.

Small-Molecule Therapeutic Perspectives for the Treatment of Progeria.

Hutchinson-Gilford progeria syndrome (HGPS), or progeria, is an extremely rare disorder that belongs to the class of laminopathies, diseases characterized by alterations in the genes that encode for the lamin proteins or for their associated interacting proteins. In particular, progeria is caused by a point mutation in the gene that codifies for the lamin A gene. This mutation ultimately leads to the biosynthesis of a mutated version of lamin A called progerin, which accumulates abnormally in the nuclear lamina. This accumulation elicits several alterations at the nuclear, cellular, and tissue levels that are phenotypically reflected in a systemic disorder with important alterations, mainly in the cardiovascular system, bones, skin, and overall growth, which results in premature death at an average age of 14.5 years. In 2020, lonafarnib became the first (and only) FDA approved drug for treating progeria. In this context, the present review focuses on the different therapeutic strategies currently under development, with special attention to the new small molecules described in recent years, which may represent the upcoming first-in-class drugs with new mechanisms of action endowed with effectiveness not only to treat but also to cure progeria.

Serum endocannabinoid levels in suicide attempters: A pilot study.

The search for a biomarker for suicide risk is a longstanding pursuit in clinical psychiatry. Literature addressing the role of endocannabinoids in suicide attempters (SA) is sparse. This cross-sectional study is aimed at comparing 8 AM serum concentrations of 4 endogenous cannabinoids (anandamide, AEA; 2-arachidonoylglycerol, 2-AG; N-palmitoiletanolamida, PEA; and oleoylethanolamide, OEA) in 30 suicide attempters (SA) and 12 psychiatric controls (PC). 8 AM AEA and PEA serum levels were higher in SA compared to PC without controlling for cannabis use (n = 42) (3.58 ± 5.77 vs. 1.62 ± 2.49, F = 3.04, P = 0.089; and 3.31 ± 4.82 vs. 1.21 ± 1.20, F = 6.22, p = 0.017, respectively). Serum ACTH was higher in PC compared to SA (32.11 ± 21.60 vs. 20.05 ± 9.96, F = 9.031, p = 0.0.005). After controlling for cannabis use in the urine test (n = 28), 8 AM AEA and PEA serum levels remained higher in SA compared to PC (4.57 ± 6.38 vs. 0.64 ± 1.11, F = 4.852, P = 0.037; and 4.35 ± 5.46 vs. 1.21 ± 1.25, F = 4.125, p = 0.053, respectively). The present study offers preliminary evidence about the role of AEA and PEA in suicidal behavior (SB). Furthermore, in the context of the mental pain model of SB, our findings suggest that some endocannabinoids may play a role in the pathophysiology of SB. Our pilot study deserves replication by other studies with bigger sample sizes.

Trifluorosulfonylation Cascade in Allenols: Stereocontrolled Synthesis of Bis(triflyl)enones.

Herein, we report investigations embodying the first example of reversal of the native regioselectivity in the reaction of allenols with electrophiles. The effortlessness of C-C bond formation, mild reaction conditions, neither catalysts nor light irradiation, and exquisite selectivity, both in terms of functional-group tolerance and chemo-, site-, and stereo-selectivity, converts this trifluorosulfonylation-rearrangement sequence into an appealing protocol for the preparation of novel functionalized enones. The synthetic utility of this method has been validated by the conversion of the initially prepared bis(triflyl)enones into a variety of bis(triflyl)-functionalized molecules such as 1,3-dienes, allylic alcohols, pyrroles, pyrazoles, and chromenes. Besides, DFT calculations have provided a reliable understanding of observed selectivity.