Breaking Barriers: Exploring Neurotransmitters through In Vivo vs. In Vitro Rivalry.

Neurotransmitter analysis plays a pivotal role in diagnosing and managing neurodegenerative diseases, often characterized by disturbances in neurotransmitter systems. However, prevailing methods for quantifying neurotransmitters involve invasive procedures or require bulky imaging equipment, therefore restricting accessibility and posing potential risks to patients. The innovation of compact, in vivo instruments for neurotransmission analysis holds the potential to reshape disease management.

The mechanics of the baby boom: Unveiling the role of the epidemiologic transition.

Recent research on the baby boom and its causes has shown that common explanations, such as the recuperation of births following the Great Depression or Second World War, are not sufficient to account for the phenomenon. However, that research has stressed the role of increasing nuptiality. In this paper, we argue that the increase in survivorship of children and young people that resulted from the epidemiologic transition accounted for a large portion of the increased number of births during the baby boom.

Socio-economic status and fertility decline: Insights from historical transitions in Europe and North America.

The timings of historical fertility transitions in different regions are well understood by demographers, but much less is known regarding their specific features and causes. In the study reported in this paper, we used longitudinal micro-level data for five local populations in Europe and North America to analyse the relationship between socio-economic status and fertility during the fertility transition. Using comparable analytical models and class schemes for each population, we examined the changing socio-economic differences in marital fertility and related these to common theories on fertility behaviour.

Novel oxazolidinone calcitonin gene-related peptide (CGRP) receptor antagonists for the acute treatment of migraine.

In our efforts to develop CGRP receptor antagonists as backups to MK-3207, 2, we employed a scaffold hopping approach to identify a series of novel oxazolidinone-based compounds. The development of a structurally diverse, potent (20, cAMP+HS IC50=0.67 nM), and selective compound (hERG IC50=19 μM) with favorable rodent pharmacokinetics (F=100%, t1/2=7h) is described.

Discovery of MK-1439, an orally bioavailable non-nucleoside reverse transcriptase inhibitor potent against a wide range of resistant mutant HIV viruses.

The optimization of a novel series of non-nucleoside reverse transcriptase inhibitors (NNRTI) led to the identification of pyridone 36. In cell cultures, this new NNRTI shows a superior potency profile against a range of wild type and clinically relevant, resistant mutant HIV viruses. The overall favorable preclinical pharmacokinetic profile of 36 led to the prediction of a once daily low dose regimen in human.

Deficiency of C5L2 increases macrophage infiltration and alters adipose tissue function in mice.

Background: Obesity is considered as a systemic chronic low grade inflammation characterized by increased serum pro-inflammatory proteins and accumulation of macrophages within white adipose tissue (WAT) of obese patients. C5L2, a 7-transmembrane receptor, serves a dual function, binding the lipogenic hormone acylation stimulating protein (ASP), and C5a, involved in innate immunity.

Aim: We evaluated the impact of C5L2 on macrophage infiltration in WAT of wildtype (Ctl) and C5L2 knock-out (C5L2(-/-)) mice over 6, 12 and 24 weeks on a chow diet and moderate diet-induced obesity (DIO) conditions.

Inflammatory markers and adipokines alter adipocyte-derived ASP production through direct and indirect immune interaction.

Obesity and related metabolic diseases are associated with chronic low-grade inflammation, characterized by increased pro-inflammatory proteins. Several studies have demonstrated increases in acylation stimulating protein (ASP) and its precursor protein C3 in obesity, diabetes and dyslipidemia. To evaluate the effects of acute inflammatory factors and adipokines on ASP production and potential mechanisms of action, 3T3-L1 adipocytes were treated for 24 h with adipokines, cytokines, macrophage-conditioned media and direct co-culture with J774 macrophages.

C5L2 and C5aR interaction in adipocytes and macrophages: insights into adipoimmunology.

Obesity is associated with inflammation characterized by increased infiltration of macrophages into adipose tissue. C5aR-like receptor 2 (C5L2) has been identified as a receptor for acylation-stimulating protein (ASP) and the inflammatory factor C5a, which also binds C5aR. The present study examines the effects of ligands ASP and C5a on interactions between the receptors C5L2 and C5aR in 3T3-L1 adipocytes and J774 macrophages.

Differential chemoattractant response in adipocytes and macrophages to the action of acylation stimulating protein.

Obesity is characterized by chronic low-grade inflammation with increased adipose tissue pro-inflammatory cytokine production. Acylation stimulating protein (ASP) stimulates triglyceride synthesis and glucose transport via its receptor C5L2. Circulating ASP is increased in obesity, insulin resistance and metabolic syndrome.

Recombinant acylation stimulating protein administration to C3-/- mice increases insulin resistance via adipocyte inflammatory mechanisms.

Background: Complement 3 (C3), a key component of the innate immune system, is involved in early inflammatory responses. Acylation stimulating protein (ASP; aka C3adesArg), a C3 cleavage product, is produced in adipose tissue and stimulates lipid storage. We hypothesized that, depending on the diet, chronic ASP administration in C3(-/-) mice would affect lipid metabolism and insulin sensitivity via an adaptive adipose tissue inflammatory response.

[Effect of metabolic drugs on the secretion of acylation stimulating protein in 3T3-L1 adipocytes].

Aim: To develop a 3T3-L1 pre-adipocyte model for evaluating the secretion of acylation stimulating protein (ASP) and an ELISA assay for measuring ASP production and investigate the effects and related potential mechanisms of metabolic drugs on the secretion of ASP, and on the complement C3, triglyceride (TG) mass, nonesterified fatty acids (NEFA) release and fatty acid (FA) uptake into adipocytes.

Methods: After differentiated, 3T3-L1 pre-adipocytes were treated with chylomicrons, metformin, rosiglitazone, rimonabant for 48 h. ASP and C3 were measured using a sandwich ELISA.

A new effector of lipid metabolism: complement factor properdin.

Background: The complement system is well known for its role in innate immunity via the classical, the alternative and the lectin pathways, although recent investigations suggest expanding roles in adipose tissue. Properdin stabilizes C3 convertase following alternative complement activation. Properdin is also present in adipose tissue, localized to adipocyte membranes.

[Novel adipokines: links between obesity and atherosclerosis].

Today, cardiovascular diseases (CVD) remain the principal cause of death in industrialized countries and are linked to obesity and metabolic syndrome. Metabolic syndrome is characterized by changes in arterial blood pressure, glucose metabolism, lipid and lipoprotein profiles in addition to inflammation. Adipose tissue produces many cytokines and secretory factors termed adipokines.

Acute injection of ASP in the third ventricle inhibits food intake and locomotor activity in rats.

Acylation-stimulating protein (ASP; also known as C3adesArg) stimulates triglyceride synthesis and glucose transport via interaction with its receptor C5L2, which is expressed peripherally (adipose tissue, muscle) and centrally. Previous studies have shown that ASP-deficient mice (C3KO) and C5L2-deficient mice (C5L2KO) are hyperphagic (59 to 229% increase, P < 0.0001), which is counterbalanced by increased energy expenditure measured as oxygen consumption (Vo(2)) and a lower RQ.

Evaluation of chylomicron effect on ASP production in 3T3-L1 adipocytes.

In the past few years, there has been increasing interest in the production and physiological role of acylation-stimulating protein (ASP), identical to C3adesArg, a product of the alternative complement pathway generated through C3 cleavage. Recent studies in C3 (-/-) mice that are ASP deficient have demonstrated a role for ASP in postprandial triglyceride clearance and fat storage. The aim of the present study was to establish a cell model and sensitive ELISA assay for the evaluation of ASP production using 3T3-L1 adipocytes.

Practical synthesis of a renin inhibitor via a diastereoselective Dieckmann cyclization.

A scalable synthesis of a potent renin inhibitor (1) is described. The absolute stereochemistry is set via an unprecedented diastereoselective Dieckmann cyclization directed by a remote chiral protecting group. This transformation enables preparation of chiral 1,3-[3.

A practical synthesis of 5-lipoxygenase inhibitor MK-0633.

Practical, chromatography-free syntheses of 5-lipoxygenase inhibitor MK-0633 p-toluenesulfonate (1) are described. The first route used an asymmetric zincate addition to ethyl 2,2,2-trifluoropyruvate followed by 1,3,4-oxadiazole formation and reductive amination as key steps. An improved second route features an inexpensive diastereomeric salt resolution of vinyl hydroxy-acid 22 followed by a robust end-game featuring a through-process hydrazide acylation/1,3,4-oxadiazole ring closure/salt formation sequence to afford MK-0633 p-toluenesulfonate (1).

Scalable synthesis of a prostaglandin EP4 receptor antagonist.

The evolution of scalable, economically viable synthetic approaches to the potent and selective prostaglandin EP4 antagonist 1 is presented. The chromatography-free synthesis of multikilogram quantities of 1 using a seven-step sequence (six in the longest linear sequence) is described. This approach has been further modified in an effort to identify a long-term manufacturing route.

Hormone and pharmaceutical regulation of ASP production in 3T3-L1 adipocytes.

Several studies have demonstrated increases in acylation stimulating protein (ASP), and precursor protein C3 in obesity, diabetes and dyslipidemia, however the nature of the regulation is unknown. To evaluate chronic hormonal and pharmaceutical mediated changes in ASP and potential mechanisms, 3T3-L1 adipocytes were treated with physiological concentrations of relevant hormones and drugs currently used in treatment of metabolic diseases for 48 h. Medium ASP production and C3 secretion were evaluated in relation to changes in adipocyte lipid metabolism (cellular triglyceride (TG) mass, non-esterified fatty acid (NEFA) release and real-time FA uptake).

Expression of prostaglandin E synthases in the bovine oviduct.

The oviduct is a specialized organ responsible for the storage and the transport of male and female gametes. It also provides an optimal environment for final gamete maturation, fertilization, and early embryo development. Prostaglandin (PG) E(2) is involved in many female reproductive functions, including ovulation, fertilization, implantation, and parturition.

Recombinant C3adesArg/acylation stimulating protein (ASP) is highly bioactive: a critical evaluation of C5L2 binding and 3T3-L1 adipocyte activation.

C5L2 is a recently identified receptor for C5a/C5adesArg, C3a and C3adesArg (ASP). C5a/C5adesArg bind with high affinity, with no identified activation. By contrast, some studies demonstrate C3a/ASP binding/activation to C5L2; others do not.

Remote electronic control in the regioselective reduction of succinimides: a practical, scalable synthesis of Ep4 antagonist MF-310.

A practical large-scale chromatography-free synthesis of EP4 antagonist MF-310, a potential new treatment for chronic inflammation, is presented. The synthetic route provided MF-310 as its sodium salt in 10 steps and 17% overall yield from commercially available pyridine dicarboxylate 7. The key features of this sequence include a unique regioselective reduction of succinimide 2 controlled by the electronic properties of a remote pyridine ring, preparation of cyclopropane carboxylic acid 3 via a Corey-Chaykovsky cyclopropanation, and a short synthesis of sulfonamide 5.

Practical synthesis of a potent bradykinin B(1) antagonist via enantioselective hydrogenation of a pyridyl N-acyl enamide.

A practical and efficient synthesis of bradykinin B(1) antagonist 1 is described. A convergent strategy was utilized which involved synthesis of three fragments: 3, 6, and 7. Cross coupling of fragments 6 and 7 followed by amidation with 3 enabled efficient synthesis of 1 in 19 steps total, a 35% overall yield from commercially available pyridine 10.

A practical enantioselective synthesis of odanacatib, a potent Cathepsin K inhibitor, via triflate displacement of an alpha-trifluoromethylbenzyl triflate.

An enantioselective synthesis of the Cathepsin K inhibitor odanacatib (MK-0822) 1 is described. The key step involves the novel stereospecific S(N)2 triflate displacement of a chiral alpha-trifluoromethylbenzyl triflate 9a with (S)-gamma-fluoroleucine ethyl ester 3 to generate the required alpha-trifluoromethylbenzyl amino stereocenter. The triflate displacement is achieved in high yield (95%) and minimal loss of stereochemistry.