G-protein-coupled receptors (GPCRs) comprise a large protein superfamily divided into six classes, rhodopsin-like (A), secretin receptor family (B), metabotropic glutamate (C), fungal mating pheromone receptors (D), cyclic AMP receptors (E) and frizzled (F). Until recently, GPCRs signaling was thought to emanate exclusively from the plasma membrane as a response to extracellular stimuli but several studies have challenged this view demonstrating that GPCRs can be present in intracellular localizations, including in the nuclei. A renewed interest in GPCR receptors’ superfamily emerged and intensive research occurred over recent decades, particularly regarding class A GPCRs, but some class B and C have also been explored. Nuclear GPCRs proved to be functional and capable of triggering identical and/or distinct signaling pathways associated with their counterparts on the cell surface bringing new insights into the relevance of nuclear GPCRs and highlighting the nucleus as an autonomous signaling organelle (triggered by GPCRs). Nuclear GPCRs are involved in physiological (namely cell proliferation, transcription, angiogenesis and survival) and disease processes (cancer, cardiovascular diseases, etc.). In this review we summarize emerging evidence on nuclear GPCRs expression/function (with some nuclear GPCRs evidencing atypical/disruptive signaling pathways) in non-communicable disease, thus, bringing nuclear GPCRs as targets to the forefront of debate.

The treatment of hypertension is of major importance to reduce the risk of cardiovascular disease, the leading cause of death worldwide. Angiotensin-converting enzyme (ACE) inhibitors are anti-hypertensive drugs associated with several side effects. Natural products, namely bioactive peptides from brewing by-products, brewers’ spent grain (BSG), and yeast (BSY), are promising alternatives since they can inhibit ACE in vitro. However, the oral intake of these peptides may modify their expected inhibitory effect owing to possible changes in active peptides’ bioavailability, which have not been assessed so far. The goal of this study was to simulate oral administration to evaluate BSG/BSY peptides’ effectiveness by submitting protein hydrolysates sequentially to simulated gastrointestinal digestion, intestinal absorption (Caco-2 cells), and liver metabolism (HepG2 cells). MTT assay was used to assess BSG/BSY protein hydrolysates safeness. The ACE-inhibitory potential of initial and final protein hydrolysates (BSY, BSG, and a new product, MIX) were tested using a fluorometric assay and compared with captopril (1 µM, an ACE-inhibitory drug). Simulation of oral administration greatly increased BSY and MIX protein hydrolysates’ ACE-inhibitory capacity, though final MIX and BSG revealed greater ACE-inhibitory potential than captopril. Notwithstanding, all final protein hydrolysates presented ACE-inhibitory capacity, thus being promising compounds to manage hypertension.

Objectives. To investigate, in initial phases of bladder outlet obstruction (BOO), the urinary ATP levels, the incidence of detrusor underactivity (DU), and if they change after deobstruction. Methods. Adult female Wistar rats submitted to partial BOO (pBOO) and sham-obstruction were used. Cystometry was performed 3 or 15 days after pBOO and fluid was collected from the urethra for ATP determination. Bladders were harvested for morphological evaluation of the urothelium. DU was defined as the average of voiding contractions (VC) of sham-operated animals, with 3 SD at 15 days after the sham surgery. In another group of animals in which pBOO was relieved at 15 days and bladders were let to recover for 15 days, the incidence of DU and ATP levels were also accessed. The KruskalWallis test was followed by Dunns multiple comparisons test, and Spearmans correlation test was used. Results. DU was present in 13 and 67 of the bladders at 3 and 15 days after pBOO, respectively, and in 20 of the bladders at 15 days after deobstruction. ATP levels were significantly lower in DU/pBOO versus sham and non-DU/pBOO rats. A strong positive correlation between ATP levels and VC/min was obtained (r=0.63). DU bladders had extensive areas in which umbrella cells appeared stretched, the width exceeding that presented by sham animals. Conclusions. Low urothelial ATP parallels with a high incidence of DU early after pBOO.

Corema (C.) album is a shrub endemic to the Atlantic coast and has been described as yielding beneficial effects for human health. Nevertheless, studies concerning the bioactivity of C. album leaves are scarce. This study aims at investigating the anticancer potential and mode of action, of an hydroethanolic extract of C. album leaves (ECAL) on triple-negative breast cancer. This is a poor survival breast cancer subtype, owing to its high risk of distant reappearance, metastasis rates and the probability of relapse. The ECAL ability to prevent tumor progression through (i) the inhibition of cell proliferation (cell viability); (ii) the induction of apoptosis (morphological changes, TUNEL assay, caspase-3 cleaved) and (iii) the induction of DNA damage (PARP1 and γH2AX) with (iv) the involvement of NF-κB and of ERK1/2 pathways (AlphaScreen assay) was evaluated. ECAL activated the apoptotic pathway (through caspase-3) along with the inhibition of ERK and NF-κB pathways causing DNA damage and cell death. The large polyphenolic content of ECAL was presumed to be accountable for these effects. The extract of C. album leaves can target multiple pathways and, thus, can block more than one possible means of disease progression, evidencing the anticancer therapeutic potential from a plant source.

Angiotensin-converting enzyme (ACE) inhibitors are anti-hypertensive drugs associated with several side effects. Natural compounds, namely bioactive peptides from brewing by-products—brewer’s spent grain (BSG) and yeast (BSY)—are promising alternatives, as they can inhibit ACE in vitro and are less likely to cause severe side effects, while maintaining therapeutic efficacy. However, the impact of oral administration on peptides’ bioavailability has not been assessed so far. Thus, the aim of this study was to understand in vitro the impact of the oral route on the effectiveness of BSG/BSY peptides as ACE inhibitors. Extracted BSG/BSY proteins were hydrolysed and sequentially subjected to simulated gastrointestinal digestion (INFOGEST), intestinal absorption and liver metabolism (co-culture of Caco-2 and HepG2 cells). MTT assay was used to assess BSG/BSY peptides’ safeness. The ACE-inhibitory potential of initial and final products (BSY, BSG and a mixture 50:50—MIX) at an identical concentration (0.857mg/mL) was measured (fluorometric assay) and compared with Captopril (1 µM, a clinically used ACE-inhibitory drug). Simulation of oral administration increased brewing peptides’ ACE-inhibitory capacity. When comparing the final peptides with captopril, BSY demonstrated identical potency, while BSG showed 22% greater efficacy; the new tested product MIX presented 30% higher inhibition. In conclusion, the current study shows that BSG, BSY and MIX natural peptides derived from the brewing industry enhance their bioactive properties as ACE-inhibitors after oral administration, validating the usefulness of these peptides to reduce the risk of, ameliorate or treat primary hypertension.