The aim of this study is to review the role of renin-angiotensin in skin regeneration and wound healing with a focus on molecular mechanisms. Angiotensin receptor type 1 (AT1R) are abundant in the wounded area, and thus, lead to the activation of ERK, STAT1, and STAT3 which can lead to epidermal self-renewal. The expression of Renin Angiotensin System (RAS) components was significantly lower in wounds caused by burning, rather than intact skin, noting that RAS is involved in the re-epithelialization of skin. ERK, STAT and STAT3 are the targets of Ang II, indicating that RAS active components are involved in fibroblast, stem cells and keratinocyte migration. The effect of inhibiting the RAS on wound healing is context-dependent. On one hand, it is suggested that inhibiting RAS during this phase may slow down wound healing speed. On the other hand, studies have shown that RAS inhibition in this phase can lead to α-SMA activation, ultimately accelerating the wound healing process. Most of the investigations indicate that the inhibition of RAS with Angiotensin Receptor Blockers (ARBs) and Angiotensin Converting Enzyme (ACE) plays a significant role in tissue remodeling in the last phase of wound healing. It has been shown that the inhibition of RAS can inhibit scar formation and fibrosis through the downregulation of inflammatory and fibrogenic agents, such as TGF-β, SMAD2/3, and TAK1, PDGF-BB, and HSP47. To sum up, that local administration of RAS regulators might lead to less scar formation and inflammation in the last phase of wound closure.

Activation of the renin-angiotensin-aldosterone system (RAAS) plays an important pathophysiological role in hypertension. Increased mRNA levels of the angiotensinogen angiotensin-converting enzyme, angiotensin type 1 receptor gene, Agtr1a, and the aldosterone synthase gene, CYP11B2, have been reported in the heart, blood vessels, and kidneys in salt-sensitive hypertension. However, the mechanism of gene regulation in each component of the RAAS in cardiovascular and renal tissues is unclear. Epigenetic mechanisms, which are important for regulating gene expression, include DNA methylation, histone post-translational modifications, and microRNA (miRNA) regulation. A close association exists between low DNA methylation at CEBP-binding sites and increased AGT expression in visceral adipose tissue and the heart of salt-sensitive hypertensive rats. Several miRNAs influence AGT expression and are associated with cardiovascular diseases. Expression of both ACE and ACE2 genes is regulated by DNA methylation, histone modifications, and miRNAs. Expression of both angiotensinogen and CYP11B2 is reversibly regulated by epigenetic modifications and is related to salt-sensitive hypertension. The mineralocorticoid receptor (MR) exists in cardiovascular and renal tissues, in which many miRNAs influence expression and contribute to the pathogenesis of hypertension. Expression of the 11beta-hydroxysteroid dehydrogenase type 2 (HSD11B2) gene is also regulated by methylation and miRNAs. Epigenetic regulation of renal and vascular HSD11B2 is an important pathogenetic mechanism for salt-sensitive hypertension.

Gastrointestinal disorders dysregulate the biochemical environment of the gastrointestinal tract by altering pH conditions during the gastric phase of digestion or by reducing the secretion of pancreatin during the intestinal part of the process. Ingested functional food could therefore lose some of its health-promoting potential apart from its nutritional value. In this work, we aimed to manufacture bread marked by decreased gluten content, using a commercial or laboratory sourdough, that could be appropriate for patients afflicted with wheat allergy, hypertension and pancreatic malfunctions. A reference sample (no sourdough) was prepared alongside wheat and wheat-rye bread samples-produced with either commercial or laboratory sourdough (L. plantarum BS, L. brevis 1269, L. sanfranciscensis 20663). We measured the QQQPP allergen content (ELISA) in bread extracts digested in vitro and determined how these extracted components affect the level of active angiotensin and alpha amylase (spectrophotometry). We then elucidated how these properties changed when physiological digestion conditions (pH and pancreatin activity) were disturbed to mimic gastric hyperacidity, hypochlorhydria or exocrine pancreatic insufficiency. The key finding was that every tested type of bread produced with laboratory sourdough exhibited pronounced angiotensin-converting enzyme inhibition. The effect was preserved even in dysregulated digestive conditions. The use of laboratory sourdough prevented an increase in allergenicity when pancreatin was restricted as opposed to the commercial sourdough, which surpassed the reference sample reading at 50% pancreatin. No statistically consistent link was reported when the inhibition of alpha amylase was assayed. In conclusion, functional bread manufactured with sourdough composed of L. plantarum BS, L. brevis 1269, and L. sanfranciscensis 20663 was shown to be potentially capable of contributing to the treatment against hypertension as evidenced by in vitro research. It was also moderately safer with regard to its allergenicity.

Sepsis and atherosclerotic cardiovascular disease (ASCVD) are major health challenges involving complex processes like inflammation, renin-angiotensin system (RAS) dysregulation, and thrombosis. Despite distinct clinical symptoms, both conditions share mechanisms mediated by bradykinin. This review explores bradykinin\'s role in inflammation, RAS modulation, and thrombosis in sepsis and ASCVD. In sepsis, variable kininogen-bradykinin levels may correlate with disease severity and progression, though the effect of bradykinin receptor modulation on inflammation remains uncertain. RAS activation is present in both diseases, with sepsis showing variable or low levels of Ang II, ACE, and ACE2, while ASCVD consistently exhibits elevated levels. Bradykinin may act as a mediator for ACE2 and AT2 receptor effects in RAS regulation. It may influence clotting and fibrinolysis in sepsis-associated coagulopathy, but evidence for an antithrombotic effect in ASCVD is insufficient. Understanding bradykinin\'s role in these shared pathologies could guide therapeutic and monitoring strategies and inform future research.

Blood pressure (BP) displays a circadian rhythm and disruptions in this pattern elevate cardiovascular risk. While both central and peripheral clock genes are implicated in these processes, the importance of vascular clock genes is not fully understood. BP, vascular reactivity, and the renin-angiotensin-aldosterone system display overt sex differences, but whether changes in circadian patterns underlie these differences is unknown. Therefore, we hypothesized that circadian rhythms and vascular clock genes would differ across sex and would be blunted by Ang II-induced hypertension. Ang II infusion elevated BP and disrupted circadian patterns similarly in both males and females. In females, an impact on heart rate and locomotor activity was revealed, while in males hypertension suppressed baroreflex sensitivity. A marked disruption in the vascular expression patterns of Per1 and Bmal1 were noted in both sexes. Vascular expression of the G protein-coupled estrogen receptor (Gper1) also showed diurnal synchronization in both sexes that was similar to that of Per1 and Per2 and disrupted by hypertension. In contrast, vascular expression of Esr1 showed a diurnal rhythm and hypertension-induced disruption only in females. This study shows a strikingly similar impact of hypertension on BP rhythmicity, vascular clock genes, and vascular estrogen receptor expression in both sexes. We identified a greater impact of hypertension on locomotor activity and heart rate in females and on baroreflex sensitivity in males and also revealed a diurnal regulation of vascular estrogen receptors. These insights highlight the intricate ties between circadian biology, sex differences, and cardiovascular regulation.

Sepsis is a life-threatening situation that ultimately affects cardiac function, leading to cardiomyopathy and myocardial injury as a result of uncontrolled response to infection.Till now, there is limited effective treatment to rescue those cases. Thus, novel therapeutic strategies should be identified to achieve better outcomes for septic patients. For the first time, we aimed to evaluate the effect of sacubitril/valsartan (Sac/Val) on sepsis-induced cardiac injury. Wistar male adult albino rats were randomly divided into four groups; Group I received the vehicle; Group II was given the vehicle plus 1 ml saline containing viable Escherichia coli (E. coli) (2.1 × 109 cfu) by intraperitoneal (i.p.) injection on the 1st and 2nd days; Group III received i.p. injection as group II plus oral administration of Sac/Val (30 mg/kg/day) and Nitro- ω-L-arginine (L-NNA) (25 mg/kg/day) for 7 days. Group IV was administered i.p. injection as group II plus oral administration of Sac/Val (30 mg/kg/day) for 7 days. Our data (n = 10) revealed successful induction of sepsis as it showed a significant increase in the measured cardiac enzymes, malondialdehyde (MDA), angiotensin II (Ang II), neprilysin, inflammasome, caspase 1, interleukin (IL)1β, and caspase 3 with cardiac histopathological changes, but there was a significant decrease in the antioxidants and blood pressure (BP). Co-administration of Sac/Val could obviously improve these changes. Interestingly, L-NNA given group showed a decrease in the cardioprotective effect of Sac/Val. Sac/Val could ameliorate sepsis induced cardiac damage via inhibition of Ang II and neprilysin with anti-inflammatory, anti-oxidant and anti-apoptotic properties.

The objective of the present work is to examine from a new perspective the existence of causal factors not predicted by the classical theory that thirst and sodium appetite are two distinct motivations. For example, we ask why water deprivation induces sodium appetite, thirst is not \"water appetite\", and intracellular dehydration potentially causes sodium appetite. Contrary to the classical theory, we suggest that thirst first, and sodium appetite second, designate a temporal sequence underlying the same motivation. The single motivation becomes an \"intervenient variable\" a concept borrowed from the literature, fully explained in the text, between causes of dehydration (extracellular, intracellular, or both together), and respective behavioral responses subserved by hindbrain-dependent inhibition (e.g., lateral parabrachial nucleus) and forebrain facilitation (e.g., angiotensin II). A corollary is homology between rat sodium appetite and marine teleost thirst-like motivation that we name \"protodipsia\". The homology argument rests on similarities between behavior (salty water intake) and respective neuroanatomical as well as functional mechanisms. Tetrapod origin in a marine environment provides additional support for the homology. The single motivation hypothesis is also consistent with ingestive behaviors in nature given similarities (e.g., thirst producing brackish water intake) between the behavior of the laboratory rat and wild animals, rodents included. The hypotheses of single motivation and homology might explain why hyperosmotic rats, or eventually any other hyperosmotic tetrapod, shows paradoxical signs of sodium appetite. They might also explain how ingestive behaviors determined by dehydration and subserved by hindbrain inhibitory mechanisms contributed to tetrapod transition from sea to land.

Nitric oxide (NO) is widely recognized for its role in regulating renal function and blood pressure. However, the precise mechanisms by which NO affects renal epithelial cells remain understudied. Our previous research has shown that NO signaling in glomerular podocytes can be initiated by Angiotensin II (Ang II) but not by ATP. This study aims to elucidate the crucial interplay between the renin-angiotensin system (RAS) and NO production in podocytes. To conduct our research, we utilized cultured human podocytes and freshly isolated rat glomeruli. A variety of RAS peptides were employed, alongside confocal microscopy, to detect NO production and NO/Ca2+ crosstalk. Dynamic changes in the podocyte cytoskeleton, mediated by RAS-NO intracellular signaling, were observed using fluorescent labeling for F-actin and scanning probe microscopy. The experiments demonstrated that Ang II and Ang III generated high levels of NO through the activation of the Angiotensin II Type 2 Receptor (AT2R). We did not detect functional MAS receptor presence in podocytes, and the moderate NO response to Ang 1-7 was also mediated through AT2R. Furthermore, NO production impacted intracellular Ca2+ signaling and correlated with an increase in podocyte volume and growth. Scanning probe experiments revealed that AT2R activation and the corresponding NO generation are responsible for the protrusion of podocyte lamellipodia. Taken together, our data indicate that AT2R activation enhances NO production in podocytes and subsequently mediates changes in Ca2+ signaling and podocyte volume dynamics. These mechanisms may play a significant role in both physiological and pathophysiological interactions between the RAS and podocytes.

Pancreatic ductal adenocarcinoma (PDAC) remains a dreadful disease with poor prognosis. While the prognosis of colorectal carcinoma (CRC) is better than that of PDAC, it still is the second-leading cause of cancer deaths worldwide. Recently, a (methyl)lanthionine-stabilized, highly receptor-specific agonist of galanin subtype 2 (GAL2) receptor inhibited the growth of GAL2 receptor-expressing patient-derived xenografts (PDX) of pancreatic cancer. Furthermore, a lanthionine-constrained agonist of angiotensin II type 2 (AT2) receptor inhibited PDX of colorectal cancer in mice. Stimulation of GAL2 receptor may modulate immune surveillance and inhibits PDAC via cell cycle inhibition and apoptosis. Consistent with GAL2 receptor-mediated tumor inhibition, for PDAC, survival is much higher for patients with high GAL2 receptor expression. Importantly, a (methyl)lanthionine-stabilized GAL2 receptor-specific agonist enhances expression of GAL2 receptor, not only in PDAC-PDX but also in healthy tissue indicating therapeutic and preventive potentials for GAL2 receptor agonists. AT2 receptor is interacting with four tumor suppressor proteins, Src homology phosphatase 1, Src homology phosphatase 2, Promyelocytic Leukemia Zinc Finger protein and Microtuble-Associated Scaffold Protein1, the latter also known as Angiotensin-II type 2 receptor-Interacting Protein. Pathways linked to these tumor suppressor proteins may enhance immune surveillance, prevent carcinogenesis, counter proliferation and stimulate apoptosis. Taken together, current data are prompting the hypothesis of a prophylactic treatment option with stable, specific and safe agonists of GAL2 receptor and AT2 receptor to prevent the emergence of pancreatic and colorectal cancer in individuals at risk.

OBJECTIVE: Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to reduce the risk of cardiovascular events independently of glycemic control. However, the possibility that SGLT2 inhibitors improve vascular restenosis is unknown. The aim of this study was to examine whether dapagliflozin could prevent neointima thickening following balloon injury and, if so, to determine the underlying mechanisms.
METHODS: Saline, dapagliflozin (1.5 mg/kg/day), or losartan (30 mg/kg/day) was administered orally for five weeks to male Wistar rats. Balloon injury of the left carotid artery was performed a week after starting the treatment and rats were sacrificed 4 weeks later. The extent of neointima was assessed by histomorphometric and immunofluorescence staining analyses. Vascular reactivity was assessed on injured and non-injured carotid artery rings, changes of target factors by immunofluorescence, RT-qPCR, and histochemistry.
RESULTS: Dapagliflozin and losartan treatments reduced neointima thickening by 32 % and 27 %, respectively. Blunted contractile responses to phenylephrine and relaxations to acetylcholine and down-regulation of eNOS were observed in the injured arteries. RT-qPCR investigations indicated an increased in gene expression of inflammatory (IL-1beta, VCAM-1), oxidative (p47phox, p22phox) and fibrotic (TGF-beta1) markers in the injured carotid. While these changes were not affected by dapagliflozin, increased levels of AT1R and NTPDase1 (CD39) and decreased levels of ENPP1 were observed in the restenotic carotid artery of the dapagliflozin group.
CONCLUSIONS: Dapagliflozin effectively reduced neointimal thickening. The present data suggest that dapagliflozin prevents restenosis through interfering with angiotensin and/or extracellular nucleotides signaling. SGLT2 represents potential new target for limiting vascular restenosis.