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Background: The renin‐angiotensin system (RAS) has been associated with inflammatory bowel disease (IBD), supporting translational relevance of RAS blockers. Comparability of study design/outcomes is fundamental for data analysis/discussion. Objectives: We aimed at evaluating the heterogeneity among protocols and outcomes to study the effect of angiotensin‐converting enzyme inhibitors or angiotensin receptor blockers in IBD. Methods: This study was performed and reported in accordance with the Cochrane recommendations and PRISMA (PROSPERO‐CRD42022323853). Systematic searches were performed in PubMed, Scopus and Web of Science. Studies that met the inclusion criteria were selected. Quality assessment of the studies was done with the SYRCLES's risk of bias tools for animal studies. Results: Thirty‐five pre‐clinical studies and six clinical studies were included. Chemical induction of colitis was the most used model, but variable doses of the induction agent were reported. All studies reported at least a disease activity index, a macroscopic score, or a histologic assessment, but these scores were methodologically heterogeneous and reported for different characteristics. Great heterogeneity was also found in drug interventions. Inflammatory markers assessed as outcomes were different across studies. Conclusion: Lack of standardization of protocols and outcomes among studies threatens the evidence on how RAS blockers influence IBD outcomes. [ABSTRACT FROM AUTHOR]

In addition to the somatodendritic region, myenteric motoneuron terminals are endowed with nicotinic autoreceptors. We aimed at investigating the effect of nicotinic receptor (nAChR) activation on [3H]-acetylcholine ([3H]-ACh) release from longitudinal muscle-myenteric plexus of the rat ileum and to evaluate whether this could be modulated by adenosine, an endogenous neuromodulator typically operating changes in intracellular cyclic AMP. The nAChR agonist, 1,1-dimethyl-4-phenylpiperazinium (DMPP, 1–30 μM, 3 min) increased [3H]-ACh release in a concentration-dependent manner. DMPP (30 μM)-induced [3H]-ACh outflow was attenuated by hexamethonium (0.1–1 mM), tubocurarine (1–5 μM), or by removing external Ca2+ (plus EGTA, 1 mM). In contrast to veratridine (0.2–10 μM)-induced [3H]-ACh release, the DMPP (30 μM)-induced outflow was resistant to tetrodotoxin (1 μM) and cadmium (0.5 mM). Pretreatment with adenosine deaminase (0.5 U/mL) or with the adenosine A2A-receptor antagonist, ZM 241385 (50 nM), enhanced nAChR-induced transmitter release. Activation of A2A receptors with CGS 21680C (3 nM) reduced the DMPP-induced release of [3H]-ACh. CGS 21680C (3 nM) inhibition was prevented by MDL 12,330A (10 μM, an adenylate cyclase inhibitor) and by H-89 (10 μM, an inhibitor of protein kinase A), but was potentiated by rolipram (300 μM, a phosphodiesterase inhibitor). DMPP-induced transmitter release was decreased by 8-bromo-cyclic AMP (1 mM, a protein kinase A activator), rolipram (300 μM), and forskolin (3 μM, an activator of adenylate cyclase). Both MDL 12,330A (10 μM) and H-89 (10 μM) facilitated DMPP-induced release of [3H]-ACh.The results indicate that nAChR-induced [3H]-ACh release is triggered by the influx of Ca2+, independent of voltage-sensitive calcium channels, presumably directly through nAChRs located on myenteric axon terminals. It was also shown that endogenous adenosine, activating A2A receptors coupled to the adenylate cyclase/cyclic AMP transducing system, is tonically downregulating this nAChR-mediated control of [3H]-ACh release. [Copyright &y& Elsevier]

1: The coexistence of both inhibitory A1 and facilitatory A2 adenosine receptors in the rat myenteric plexus prompted the question of how adenosine activates each receptor subtype to regulate cholinergic neurotransmission. 2: Exogenously applied adenosine (0.3-300?µM) decreased electrically evoked [3H]acetylcholine ([3H]ACh) release. Blocking A1 receptors with 1,3-dipropyl-8-cyclopentylxanthine (10?nM) transformed the inhibitory action of adenosine into a facilitatory effect. Adenosine-induced inhibition was mimicked by the A1 receptor agonist R-N6-phenylisopropyladenosine (0.3?µM), but the A2A agonist CGS 21680C (0.003?µM) produced a contrasting facilitatory effect. 3: Increasing endogenous adenosine levels, by the addition of (1) the adenosine precursor AMP (30-100?µM), (2) the adenosine kinase inhibitor 5'-iodotubercidin (10?µM) or (3) inhibitors of adenosine uptake (dipyridamole, 0.5?µM) and of deamination (erythro-9(2-hydroxy-3-nonyl)adenine, 50?µM), enhanced electrically evoked [3H]ACh release (5?Hz for 40?s). Release facilitation was prevented by adenosine deaminase (ADA, 0.5?U?ml-1) and by the A2A receptor antagonist ZM 241385 (50?nM); these compounds decreased [3H]ACh release by 31±6% (n=7) and 37±10% (n=6), respectively. 4: Although inhibition of ecto-5'-nucleotidase by a,ß-methylene ADP (200?µM) or by concanavalin A (0.1?mg?ml-1) attenuated endogenous adenosine formation from AMP, analysed by HPLC, the corresponding reduction in [3H]ACh release only became evident when stimulation of the myenteric plexus was prolonged to over 250?s. 5: In summary, we found that endogenously generated adenosine plays a predominantly tonic facilitatory effect mediated by prejunctional A2A receptors. Extracellular deamination and cellular uptake may restrict endogenous adenosine actions to the neuro-effector region near the release/production sites.British Journal of Pharmacology (2004) 141, 925-934. doi:10.1038/sj.bjp.0705697 [ABSTRACT FROM AUTHOR]

Background and Aim: Inflammatory bowel disease is challenging to diagnose. Fecal biomarkers offer noninvasive solutions. The renin–angiotensin‐aldosterone system is implicated in intestinal inflammation. Angiotensin‐converting enzyme (ACE) and angiotensin‐converting enzyme 2 (ACE2) regulate its activity, but conflicting findings on these enzymes in colitis require further investigation. We aimed to assess ACE and ACE2 presence and activities in the feces, serum, and colon of 2,4,6‐trinitrobenzene sulfonic acid (TNBS)‐induced rats. Methods: Colitis was induced in male rats by rectal instillation of a 21% ethanolic TNBS solution. After rats' sacrifice, colonic portions, serum, and feces were collected. ACE and ACE2 presence in the feces was analyzed by western Blot, and colonic and serum enzymes' concentrations were quantified using ELISA kits. ACE activity was assessed using Hippuryl‐His‐Leu and Z‐Phe‐His‐Leu as substrates. ACE2 activity was assessed using Mca‐APK (Dnp) as a substrate in the presence and absence of DX600 (ACE2 inhibitor). Results: An ACE isoform of ~70 kDa was found only in the feces of TNBS‐induced rats. ACE concentration was higher than that of ACE2 in the serum and the inflamed colon. ACE N‐domain activity was higher than that of the C‐domain in all matrices. ACE2 activity was higher in the feces of TNBS‐induced animals compared to controls. Conclusion: A 70 kDa ACE isoform only detected in the feces of TNBS‐induced rats may have translational relevance. ACE N‐domain seems to play a significant role in regulating colonic lesions. Further research using human samples is necessary to validate these findings. [ABSTRACT FROM AUTHOR]

Doxorubicin (DOX) and mitoxantrone (MTX) are classical chemotherapeutic agents used in cancer that induce similar clinical cardiotoxic effects, although it is not clear if they share similar underlying molecular mechanisms. We aimed to assess the effects of DOX and MTX on the cardiac remodeling, focusing mainly on metabolism and autophagy. Adult male CD-1 mice received pharmacologically relevant cumulative doses of DOX (18 mg/kg) and MTX (6 mg/kg). Both DOX and MTX disturbed cardiac metabolism, decreasing glycolysis, and increasing the dependency on fatty acids (FA) oxidation, namely, through decreased AMP-activated protein kinase (AMPK) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) content and decreased free carnitine (C0) and increased acetylcarnitine (C2) concentration. Additionally, DOX heavily influenced glycolysis, oxidative metabolism, and amino acids turnover by exclusively decreasing phosphofructokinase (PFKM) and electron transfer flavoprotein-ubiquinone oxidoreductase (ETFDH) content, and the concentration of several amino acids. Conversely, both drugs downregulated autophagy given by the decreased content of autophagy protein 5 (ATG5) and microtubule-associated protein light chain 3 (LC3B), with MTX having also an impact on Beclin1. These results emphasize that DOX and MTX modulate cardiac remodeling differently, despite their clinical similarities, which is of paramount importance for future treatments.

1. The coexistence of both inhibitory A(1) and facilitatory A(2) adenosine receptors in the rat myenteric plexus prompted the question of how adenosine activates each receptor subtype to regulate cholinergic neurotransmission. 2. Exogenously applied adenosine (0.3-300 microm) decreased electrically evoked [(3)H]acetylcholine ([(3)H]ACh) release. Blocking A(1) receptors with 1,3-dipropyl-8-cyclopentylxanthine (10 nm) transformed the inhibitory action of adenosine into a facilitatory effect. Adenosine-induced inhibition was mimicked by the A(1) receptor agonist R-N(6)-phenylisopropyladenosine (0.3 microm), but the A(2A) agonist CGS 21680C (0.003 microm) produced a contrasting facilitatory effect. 3. Increasing endogenous adenosine levels, by the addition of (1) the adenosine precursor AMP (30-100 microm), (2) the adenosine kinase inhibitor 5'-iodotubercidin (10 microm) or (3) inhibitors of adenosine uptake (dipyridamole, 0.5 microm) and of deamination (erythro-9(2-hydroxy-3-nonyl)adenine, 50 microm), enhanced electrically evoked [(3)H]ACh release (5 Hz for 40 s). Release facilitation was prevented by adenosine deaminase (ADA, 0.5 U ml(-1)) and by the A(2A) receptor antagonist ZM 241385 (50 nm); these compounds decreased [(3)H]ACh release by 31+/-6% (n=7) and 37+/-10% (n=6), respectively. 4. Although inhibition of ecto-5'-nucleotidase by alpha,beta-methylene ADP (200 microm) or by concanavalin A (0.1 mg ml(-1)) attenuated endogenous adenosine formation from AMP, analysed by HPLC, the corresponding reduction in [(3)H]ACh release only became evident when stimulation of the myenteric plexus was prolonged to over 250 s. 5. In summary, we found that endogenously generated adenosine plays a predominantly tonic facilitatory effect mediated by prejunctional A(2A) receptors. Extracellular deamination and cellular uptake may restrict endogenous adenosine actions to the neuro-effector region near the release/production sites.