Recent advances have improved our understanding of the renin‐angiotensin system (RAS). These have included the recognition that angiotensin (Ang)‐(1‐7) is a biologically active product of the RAS ...cascade. The identification of the ACE homologue ACE2, which forms Ang‐(1‐7) from Ang II, and the GPCR Mas as an Ang‐(1‐7) receptor have provided the necessary biochemical and molecular background and tools to study the biological significance of Ang‐(1‐7). Most available evidence supports a counter‐regulatory role for Ang‐(1‐7) by opposing many actions of Ang II on AT1 receptors, especially vasoconstriction and proliferation. Many studies have now shown that Ang‐(1‐7) by acting via Mas receptor exerts inhibitory effects on inflammation and on vascular and cellular growth mechanisms. Ang‐(1‐7) has also been shown to reduce key signalling pathways and molecules thought to be relevant for fibrogenesis. Here, we review recent findings related to the function of the ACE2/Ang‐(1‐7)/Mas axis and focus on the role of this axis in modifying processes associated with acute and chronic inflammation, including leukocyte influx, fibrogenesis and proliferation of certain cell types. More attention will be given to the involvement of the ACE2/Ang‐(1‐7)/Mas axis in the context of renal disease because of the known relevance of the RAS for the function of this organ and for the regulation of kidney inflammation and fibrosis. Taken together, this knowledge may help in paving the way for the development of novel treatments for chronic inflammatory and renal diseases.
Recent advances have improved our understanding of the renin‐angiotensin system (
RAS
). These have included the recognition that angiotensin (
A
ng)‐(1‐7) is a biologically active product of the
RAS
...cascade. The identification of the
ACE
homologue
ACE2
, which forms
A
ng‐(1‐7) from
A
ng
II
, and the
GPCR M
as as an
A
ng‐(1‐7) receptor have provided the necessary biochemical and molecular background and tools to study the biological significance of
A
ng‐(1‐7). Most available evidence supports a counter‐regulatory role for
A
ng‐(1‐7) by opposing many actions of
A
ng
II
on
AT
1
receptors, especially vasoconstriction and proliferation. Many studies have now shown that
A
ng‐(1‐7) by acting via
M
as receptor exerts inhibitory effects on inflammation and on vascular and cellular growth mechanisms.
A
ng‐(1‐7) has also been shown to reduce key signalling pathways and molecules thought to be relevant for fibrogenesis. Here, we review recent findings related to the function of the
ACE2
/
A
ng‐(1‐7)/
M
as axis and focus on the role of this axis in modifying processes associated with acute and chronic inflammation, including leukocyte influx, fibrogenesis and proliferation of certain cell types. More attention will be given to the involvement of the
ACE2
/
A
ng‐(1‐7)/
M
as axis in the context of renal disease because of the known relevance of the
RAS
for the function of this organ and for the regulation of kidney inflammation and fibrosis. Taken together, this knowledge may help in paving the way for the development of novel treatments for chronic inflammatory and renal diseases.
The ATP-sensitive potassium channel blocker glibenclamide prevents renal ischemia/reperfusion injury in rats.
Renal ischemia/reperfusion (I/R) is a complex neutrophil-mediated syndrome. ...Adenosine-triphosphate (ATP)-sensitive potassium (KATP) channels are involved in neutrophil migration in vivo. In the present study, we have investigated the effects of glibenclamide, a KATP channel blocker, in renal I/R injury in rats.
The left kidney of the rats was excised through a flank incision and ischemia was performed in the contralateral kidney by total interruption of renal artery flow for 45 minutes. Renal perfusion was reestablished, and the kidney and lungs were removed for analysis of vascular permeability, neutrophil accumulation, and content of cytokines tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-10 4 and 24 hours later. Renal function was assessed by measuring creatinine, Na+, and K+ levels in the plasma and by determination of creatinine clearance. Drugs were administered subcutaneously after the onset of ischemia.
Reperfusion of the ischemic kidney induced local (kidney) and remote (lung) inflammatory injury and marked renal dysfunction. Glibenclamide (20 mg/kg) significantly inhibited the reperfusion-associated increase in vascular permeability, neutrophil accumulation, increase in TNF-α levels and nuclear factor-κB (NF-κB) translocation. These inhibitory effects were noticed in the kidney and lungs. Moreover, glibenclamide markedly ameliorated the renal dysfunction at 4 and 24 hours.
Treatment with glibenclamide is associated with inhibition of neutrophil recruitment and amelioration of renal dysfunction following renal I/R. Glibenclamide may have a therapeutic role in the treatment of renal I/R injury, such as after renal transplantation.
Obesity is a metabolic disorder that predisposes patients to numerous diseases and has become a major global public-health concern. Animal models of diet-induced obesity (DIO) are frequently used to ...study obesity, but which DIO model most accurately reflects the pathology of human obesity remains unclear. In this study, we designed a diet based on the human Western diet (WD) and compared it with the cafeteria diet (CAF) and high-fat diet (HFD) in order to evaluate which diet most closely mirrors human obesity.
Wistar rats were fed four different diets (WD, CAF, HFD and a low-fat diet) for 18 weeks. Metabolic parameters and gut microbiota changes were then characterized.
Rats fed the four different diets exhibited completely different phenotypes, highlighting the importance of diet selection. This study also revealed that WD most effectively induced obesity and obesity-related disorders, and thus proved to be a robust model of human obesity. Moreover, WD-fed rats developed obesity and obesity-related comorbidities independent of major alterations in gut microbiota composition (dysbiosis), whereas CAF-fed rats developed the greatest dysbiosis independent of obesity. We also characterized gut microbiota after feeding on these four different diets and identified five genera that might be involved in the pathogenesis of obesity.
These data suggest that diet, and not the obese state, was the major driving force behind gut microbiota changes. Moreover, the marked dysbiosis observed in CAF-fed rats might have resulted from the presence of several additives present in the CAF diet, or even a lack of essential vitamins and minerals. Based on our findings, we recommend the use of the prototypic WD (designed here) in DIO models. Conversely, CAF could be used to investigate the effects of excessive consumption of industrially produced and highly processed foods, which are characteristic of Western society.
Some studies have suggested that ursodeoxycholic acid (UDCA) may have a chemopreventive effect on the development of colorectal neoplasia in patients with ulcerative colitis (UC) and primary ...sclerosing cholangitis (PSC). We examined the effects of high-dose (28-30 mg/kg/day) UDCA on the development of colorectal neoplasia in patients with UC and PSC.
Patients with UC and PSC enrolled in a prior, multicenter randomized placebo-controlled trial of high-dose UDCA were evaluated for the development of colorectal neoplasia. Patients with UC and PSC who received UDCA were compared with those who received placebo. We reviewed the pathology and colonoscopy reports for the development of low-grade or high-grade dysplasia or colorectal cancer.
Fifty-six subjects were followed for a total of 235 patient years. Baseline characteristics (including duration of PSC and UC, medications, patient age, family history of colorectal cancer, and smoking status) were similar for both the groups. Patients who received high-dose UDCA had a significantly higher risk of developing colorectal neoplasia (dysplasia and cancer) during the study compared with those who received placebo (hazard ratio: 4.44, 95% confidence interval: 1.30-20.10, P=0.02).
Long-term use of high-dose UDCA is associated with an increased risk of colorectal neoplasia in patients with UC and PSC.
Purpose
To assess bone microarchitecture in maxillary sites grafted with autogenous or xenogenous grafts as well as to demonstrate the usefulness of microCT in dental implant research.
Materials and ...Methods
Samples (n = 12) consisting of titanium fixation screws covered by at least 0.5–1 mm of human bone were obtained from 17 sites grafted with autogenous or xenogenous materials and prepared for microCT scanning and conventional histology. Bone histomorphometric parameters were evaluated in three distinct regions (graft region, transitional region, and native bone region). Three‐dimensional (3D) bone‐to‐implant contact (BIC) calculation was performed using microCT data. Histological sections were used to calculate two‐dimensional (2D) BIC percentages, which were compared with values obtained from 2D microCT images.
Results
Histomorphometric parameters varied according to the type of graft used, but sites reconstructed with autogenous bone showed higher mean values in general. In autograft samples, indices for parameters such as Tb.Th and Tb.Sp were significantly different when the native bone region was compared to the graft region. While a higher mean 3D BIC was found in the native bone region for both graft materials, significant BIC differences were absent when graft types were compared. The 2D BIC percentages obtained from histological and microCT images were similar.
Conclusions
Autografts outperformed the xenogenous material used in this study concerning the histomorphometric parameters assessed. While graft type did not seem to influence 3D BIC, the native bone region showed the highest BIC percentages when compared to the other regions in both graft groups. In addition, 2D BIC ratios were similar regardless of graft material or image source (histological sections x microCT slices). Taken together, our findings suggest that microCT is an effective tool for 2D and 3D histomorphometric and BIC assessments in dental implant research.
Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of young adults that is associated with significant morbidity and mortality. No effective medical therapy is available. ...Minocycline has been found to exert biological effects independent of its antimicrobial properties, including anti-inflammatory activities such as inhibition of inducible nitric oxide synthase, upregulation of interleukin 10, and direct suppressive effect on B- and T-cell function. Minocycline may also inhibit cell death pathways by reducing both proapoptotic and proinflammatory enzyme activation. We sought to investigate the safety and efficacy of minocycline among patients with PSC.
We evaluated the efficacy of minocycline in patients with PSC in a pilot study. Sixteen patients with PSC were enrolled. Minocycline, 100 mg orally twice daily, was given for 1 year.
A statistically significant improvement in serum alkaline phosphatase activity (330 U/l vs. 265 U/l, P=0.04) and Mayo risk score (0.55 vs. 0.02, P=0.05) occurred with treatment. Serum bilirubin and albumin remained essentially unchanged while on treatment.
The results of this pilot study indicate that minocycline is reasonably well tolerated and potentially effective in patients with PSC. These findings might be explained by the anti-inflammatory and antiapoptotic properties of minocycline. Though the data presented are too preliminary to support the clinical use of minocycline in the treatment of PSC at this time, its use should be further investigated.
When savannas in Latin America are brought into cultivation, rice (Oryza sativa L.) can be sown with the perennial grasses palisadegrass Brachiaria brizantha (Hochst. ex A. Rich) Stapf and ...signalgrass (B. decumbens Stapf) to harvest a grain crop while establishing a pasture to suppress weeds and provide grazing in subsequent years. However, these Brachiaria spp. can reduce upland rice yields. Rice cultivars need to be competitive with Brachiaria spp. to maintain yields but must allow Brachiaria spp. sufficient growth for pasture establishment. Field studies were conducted during 1994 and 1995 on a Typic Haplustox oxisol soil in the Eastern Plains of Colombia to evaluate the competitiveness of upland rice cultivars and to identify rice traits for competitiveness. Ten (1994) and 14 (1995) upland rice cultivars were grown with and without signalgrass in 1994 and palisadegrass in 1995. Rice cultivars differed substantially in their competitiveness. Rice yield losses ranged from 18 to 55%, and Brachiaria aboveground biomass ranged from 1.4 to 3.2 Mg ha−1 dry mass. Competition for light was critical; rice photon flux density interception, leaf area index ≥45 d after emergence (DAE), and number of tillers (≥60 DAE) were correlated with competitiveness. No tradeoff between high yield potential and competitiveness was detected in these upland rice cultivars. Early maturity of rice is a desired characteristic for the rice–Brachiaria spp. association. The development of more‐competitive cultivars appears to be a viable approach for reducing herbicide dependency and improving profitability of Latin American rice–pasture intercropping systems.
Four adult dairy cows in which a diagnosis of left-displaced abomasum (LDA) had been made underwent a 1-step laparoscopic abomasopexy (LA). The technique was performed with each cow positioned in ...dorsal recumbency. Two laparoscopic portals were created in the right paramedian area to identify the abomasum and direct insertion of the steel trocar and cannula into the abomasal lumen. A stainless steel toggle pin (with 2 lengths of suture attached to its midpoint) was inserted via the cannula into the abomasal lumen while the excess suture material remained exterior to the abdomen. The abomasum was deflated, and the excess suture material was withdrawn up to a preset marker on the suture to position the abomasum adjacent to the body wall. The suture was then tied to secure the abomasum in place. By use of this 1-step LA technique, LDA was successfully corrected in all 4 cows. The procedure is minimally invasive and allows viewing of the abomasum for correct positioning and fixation; it can be accomplished with the speed associated with the blind roll-and-tack technique. The 1-step LA technique may reduce the incidence of complications associated with traditional laparotomy and the blind roll-and-tack technique and could be a useful alternative procedure for the treatment of LDA in dairy cows.
PDF
