Diabetic nephropathy (DN) involves damage associated to hyperglycemia and oxidative stress. Renal fibrosis is a major pathologic feature of DN. The aim of this study was to evaluate anti-fibrogenic ...and renoprotective effects of all-trans retinoic acid (ATRA) in isolated glomeruli and proximal tubules of diabetic rats. Diabetes was induced by single injection of streptozotocin (STZ, 60 mg/Kg). ATRA (1 mg/Kg) was administered daily by gavage, from days 3-21 after STZ injection. ATRA attenuated kidney injury through the reduction of proteinuria, renal hypertrophy, increase in natriuresis, as well as early markers of damage such as β2-microglobulin, kidney injury molecule-1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL). The following parameters increased: macrophage infiltration, localization of alpha-smooth muscle actin (αSMA)-positive cells in renal tissue, and pro-fibrotic proteins such as transforming growth factor-β (TGF-β1), laminin beta 1 (LAM-β1), and collagens IV and I. Remarkably, ATRA treatment ameliorated these alterations and attenuated expression and nuclear translocation of Smad3, with increment of glomerular and tubular Smad7. The diabetic condition decreased expression of retinoic acid receptor alpha (RAR-α) through phosphorylation in serine residues mediated by the activation of c-Jun N-terminal kinase (JNK). ATRA administration restored the expression of RAR-α and inhibited direct interactions of JNK/RAR-α. ATRA prevented fibrogenesis through down-regulation of TGF-β1/Smad3 signaling.
Progressive hepatic damage and fibrosis are major features of chronic liver diseases of different etiology, yet the underlying molecular mechanisms remain to be fully defined. N-RAS, a member of the ...RAS family of small guanine nucleotide-binding proteins also encompassing the highly homologous H-RAS and K-RAS isoforms, was previously reported to modulate cell death and renal fibrosis; however, its role in liver damage and fibrogenesis remains unknown. Here, we approached this question by using N-RAS deficient (N-RAS
) mice and two experimental models of liver injury and fibrosis, namely carbon tetrachloride (CCl
) intoxication and bile duct ligation (BDL). In wild-type (N-RAS
) mice both hepatotoxic procedures augmented N-RAS expression in the liver. Compared to N-RAS
counterparts, N-RAS
mice subjected to either CCl
or BDL showed exacerbated liver injury and fibrosis, which was associated with enhanced hepatic stellate cell (HSC) activation and leukocyte infiltration in the damaged liver. At the molecular level, after CCl
or BDL, N-RAS
livers exhibited augmented expression of necroptotic death markers along with JNK1/2 hyperactivation. In line with this, N-RAS ablation in a human hepatocytic cell line resulted in enhanced activation of JNK and necroptosis mediators in response to cell death stimuli. Of note, loss of hepatic N-RAS expression was characteristic of chronic liver disease patients with fibrosis. Collectively, our study unveils a novel role for N-RAS as a negative controller of the progression of liver injury and fibrogenesis, by critically downregulating signaling pathways leading to hepatocyte necroptosis. Furthermore, it suggests that N-RAS may be of potential clinical value as prognostic biomarker of progressive fibrotic liver damage, or as a novel therapeutic target for the treatment of chronic liver disease.
Abstract Objective The primary aim was to search for lower doses of Bacillus Calmette-Guerin (BCG) that are effective and have lower toxicity. Methods A low dose of BCG 27 mg was compared with BCG ...13.5 mg, using mitomycin C (MMC) 30 mg as the third arm of comparison. A total of 430 patients with intermediate-risk superficial bladder cancer were randomised into three groups. Instillations were repeated once a week for 6 wk followed by another six instillations given once every 2 wk during 12 wk. Results There was a significantly longer disease-free interval for BCG 27 mg versus MMC 30 mg ( p = 0.006). There were no statistically significant differences between BCG 27 mg and BCG 13.5 mg ( p = 0.165) or between BCG 13.5 mg and MMC 30 mg ( p = 0.183). Cox proportional hazards regression showed that disease-free interval in the multivariate analysis was significantly better for primary disease and treatment with BCG 27 mg. There were no significant differences among the three groups with regards to time to progression and cancer-specific survival time. Local and systemic toxicity were higher in both BCG treatment groups. Conclusions One third of the standard dose, BCG 27 mg, seems to be the minimum effective dose as adjuvant treatment for intermediate-risk superficial bladder cancer, being more effective than MMC 30 mg. One sixth of the standard dose, BCG 13.5 mg, has the same efficacy as MMC 30 mg but it is more toxic.
Abstract only
Potentilla indica
(Jacks.) Th. Wolf (Rosaceae) also known as mock strawberry, to which medicinal properties are attributed related to oxidative stress and chronic inflammation. A ...methanolic extract was obtained from the mature fruits of
P. indica
, and methanolic and chloroformic fractions of the extract were obtained by liquid‐liquid fractionation. The chloroformic fraction (1 mg/mL) presented the highest antioxidant activity by
in vitro
methods, 67.90% (TAC), 67.25% (DPPH) and 44.51% (ABTS). The anti‐inflammatory activity was tested using the carrageenan‐induced paw edema model in male Wistar albino rats (400 g). Ibuprofen was used as standard drug at concentration of 25 mg/kg of body weight. The methanolic extract and chloroformic fraction (dissolved in DMSO 5%) were administered topically and orally (by 28 days) at doses of 0.1, 1 and 10 mg/kg of body weight (50 μL). Control animals received an equal volume of vehicle. Edema was induced with 1% carrageenan to all the groups after four hour of treatments, and paw thickness was checked at 1, 2, 3, 4, and 8 h. Topical administration of the chloroformic fraction (1 mg/kg) decreased by 77.7% in paw thickness, and with oral administration decreased by 72% in paw thickness. The chloroformic fraction of methanolic extract of
P. indica
fruits had a high antioxidant activity and significantly decreased the inflammatory reactions induced by carrageenan.
Support or Funding Information
Support grant from CIC‐UMSNH (2.10 to RSG).
Non-alcoholic fatty liver disease (NAFLD) is the main cause of liver diseases in Spain and the incidence is raising due to the outbreak of type 2 diabetes and obesity. This CPG suggests ...recommendation about diagnosis, mainly non-invasive biomarkers, and clinical management of this entity. Life-style modifications to achieve weight loss is the main target in the management of NAFLD. Low caloric Mediterranean diet and 200 minutes/week of aerobic exercise are encouraged. In non-responders patients with morbid obesity, bariatric surgery or metabolic endoscopy could be indicated. Pharmacological therapy is indicated in patients with NASH and fibrosis and non-responders to weight loss measures. NAFLD could influence liver transplantation, as a growing indication, the impact of steatosis in the graft viability, de novo NAFLD rate after OLT and a raised cardiovascular risk that modify the management of this entity. The current CPG was the result of the First Spanish NAFLD meeting in Seville.
Abstract
Background
Hyperkalaemia is a common condition in patients with comorbidities such as chronic kidney disease (CKD) or congestive heart failure (HF). Moreover, severe hyperkalaemia is a ...potentially life-threatening condition that is associated with a higher risk of adverse clinical events such as ventricular arrhythmias and sudden cardiac death. Currently, data regarding the prognostic implications of chronic hyperkalaemia are available; however, information about the long-term clinical consequences after an episode of severe hyperkalaemia remains scarce. The objective of this study was to evaluate the association between the trajectory of potassium measurements in patients with acute hyperkalaemia and long-term all-cause mortality.
Methods
This is a retrospective observational study that included patients with acute severe hyperkalaemia potassium (K) >6 mEq/L without haemolysis in the emergency room of Dr Peset University Hospital in Valencia, Spain searching the lab database from January 2016 to March 2017. The multivariable-adjusted association of serum potassium with mortality was assessed by using comprehensive state-of-the-art regression methods that can accommodate time-dependent exposure modelling.
Results
We found 172 episodes of acute hyperkalaemia in 160 patients in the emergency room. The mean ± standard deviation age of the sample was 77 ± 12 years and 60.5% were males. The most frequent comorbidities were CKD (71.2%), HF (35%) and diabetes mellitus (56.9%). Only 11.9% of the patients were on chronic dialysis. A quarter of the patients did not have previous CKD, making hyperkalaemia an unpredictable life-threatening complication. During the acute episode, mean potassium and estimated glomerular filtration rate (eGFR) were 6.6 ± 0.6 (range 6.1–9.2) mEq/L and 23 ± 16 (range 2–84) mL/min/1.73 m2, respectively. After a median (interquartile range) follow-up of 17.3 (2.2–23.7) months, 68 patients died (42.5%). Recurrences of hyperkalaemia (K >5.5 mEq/L) were detected in 39.5% of the patients who were monitored during follow-up. We found that previous potassium levels during an acute severe hyperkalaemia episode were not predictors of mortality. Conversely, the post-discharge longitudinal trajectories of potassium were able to predict all-cause mortality (overall P = 0.0015). The effect of transitioning from hyperkalaemia to normokalaemia (K >5.5 mEq/L to K ≤5.5 mEq/L) after the acute episode was significant, and inversely associated with the risk of mortality.
Conclusions
Potassium levels prior to a severe hyperkalaemic event do not predict mortality. Conversely, following an episode of acute severe hyperkalaemia, serial kinetics of potassium trajectories predict the risk of death. Further evidence is needed to confirm these findings and clarify the optimal long-term management of these patients.
We determined if a third of the dose of intravesical bacillus Calmette-Guerin (BCG) has the same efficacy than a standard dose for decreasing the risk of recurrence and progression after ...transurethral resection in patients with superficial high risk (stages T1G3 and carcinoma in situ) bladder cancer. Also, we evaluated toxic side effects.
A total of 155 patients with a mean age ± SD of 67 ± 10.1 years with superficial bladder cancer, including stages T1G3 in 90, a Tis primary tumor in 23 and associated Tis disease in 42, were enrolled and randomly assigned to be treated after transurethral resection of all visible lesions with intravesical BCG, Connaught strain (weekly × 6 and fortnightly × 6 thereafter) with the standard dose of 81 mg or with the decreased dose of 27 mg.
Median followup was 61 months (range 3 to 102). Disease recurred in 32 patients (39%) treated with the standard dose and in 33 (45%) treated with the decreased dose. Median time to recurrence was not attained in the standard dose arm and it was 63 months in the decreased dose arm. Kaplan-Meier estimates for time to recurrence did not reveal differences between the 2 doses (p = 0.405). Tumor progressed in 20 patients (24.7%) with the standard dose and in 19 (26%) with the decreased dose. Four patients (6.1%) with Tis had local extension into the prostatic urethra and ducts, including 3 (8.3%) treated with the standard dose and 1 (3.4%) treated with the decreased dose. Median time to progression was not attained in either arm. Kaplan-Meier estimates for time to progression did not differ significantly (p = 0.7997). Deferred cystectomy for progression was performed in 7 patients (8.4%) treated with the standard dose and in 7 (9.5%) of those treated with the decreased dose. Subgroup analysis by patient age, tumor status, number, size and T stage (T1G3 vs Tis) did not differ significantly. The groups did not differ in disease specific mortality, which was 12.2% in the standard dose arm and 16.4% in the decreased dose arm. Mean disease specific survival ± SE was 86.96 ± 4.14 and 83.73 ± 4.73 months, respectively.
Our results suggest that a 3-fold decreased dose of intravesical BCG is as effective as the standard dose against progression in patients with high risk stages T1G3 and Tis superficial bladder carcinoma but with significantly less toxicity.
Aim
To investigate the geographic patterns and ecological correlates in the geographic distribution of the most common tree dispersal modes in Amazonia (endozoochory, synzoochory, anemochory and ...hydrochory). We examined if the proportional abundance of these dispersal modes could be explained by the availability of dispersal agents (disperser‐availability hypothesis) and/or the availability of resources for constructing zoochorous fruits (resource‐availability hypothesis).
Time period
Tree‐inventory plots established between 1934 and 2019.
Major taxa studied
Trees with a diameter at breast height (DBH) ≥ 9.55 cm.
Location
Amazonia, here defined as the lowland rain forests of the Amazon River basin and the Guiana Shield.
Methods
We assigned dispersal modes to a total of 5433 species and morphospecies within 1877 tree‐inventory plots across terra‐firme, seasonally flooded, and permanently flooded forests. We investigated geographic patterns in the proportional abundance of dispersal modes. We performed an abundance‐weighted mean pairwise distance (MPD) test and fit generalized linear models (GLMs) to explain the geographic distribution of dispersal modes.
Results
Anemochory was significantly, positively associated with mean annual wind speed, and hydrochory was significantly higher in flooded forests. Dispersal modes did not consistently show significant associations with the availability of resources for constructing zoochorous fruits. A lower dissimilarity in dispersal modes, resulting from a higher dominance of endozoochory, occurred in terra‐firme forests (excluding podzols) compared to flooded forests.
Main conclusions
The disperser‐availability hypothesis was well supported for abiotic dispersal modes (anemochory and hydrochory). The availability of resources for constructing zoochorous fruits seems an unlikely explanation for the distribution of dispersal modes in Amazonia. The association between frugivores and the proportional abundance of zoochory requires further research, as tree recruitment not only depends on dispersal vectors but also on conditions that favour or limit seedling recruitment across forest types.
The REAC-TAVI (Assessment of platelet REACtivity after Transcatheter Aortic Valve Implantation) trial enrolled patients with aortic stenosis (AS) undergoing transcatheter aortic valve replacement ...(TAVR) pre-treated with aspirin + clopidogrel, aimed to compare the efficacy of clopidogrel and ticagrelor in suppressing high platelet reactivity (HPR) after TAVI.
Current recommendations support short-term use of aspirin + clopidogrel for patients with severe AS undergoing TAVR despite the lack of compelling evidence.
This was a prospective, randomized, multicenter investigation. Platelet reactivity was measured at 6 different time points with the VerifyNow assay (Accriva Diagnostics, San Diego, California). HPR was defined as (P2Y
reaction units (PRU) ≥208. Patients with HPR before TAVR were randomized to either aspirin + ticagrelor or aspirin + clopidogrel for 3 months. Patients without HPR continued with aspirin + clopidogrel (registry cohort). The primary endpoint was non-HPR status (PRU <208) in ≥70% of patients treated with ticagrelor at 90 days post-TAVR.
A total of 68 patients were included. Of these, 48 (71%) had HPR (PRU 273 ± 09) and were randomized to aspirin + ticagrelor (n = 24, PRU 277 ± 08) or continued with aspirin + clopidogrel (n = 24, PRU 269 ± 49). The remaining 20 patients (29%) without HPR (PRU 133 ± 12) were included in the registry. Overall, platelet reactivity across all the study time points after TAVR was lower in patients randomized to ticagrelor compared with those treated with clopidogrel, including those enrolled in the registry (p < 0.001). The primary endpoint was achieved in 100% of patients with ticagrelor compared with 21% with clopidogrel (p < 0.001). Interestingly, 33% of clopidogrel responder patients at baseline developed HPR status during the first month after TAVR.
HPR to clopidogrel is present in a considerable number of patients with AS undergoing TAVR. Ticagrelor achieves a better and faster effect, providing sustained suppression of HPR to these patients. (Platelet Reactivity After TAVI: A Multicenter Pilot Study REAC-TAVI; NCT02224066).
Capsicum pubescens is the least studied domesticated chili pepper, specifically in its antioxidant activity and hypoglycemic properties. It is cultivated on a small scale in family gardens and ...greenhouses in the central Mexico to the mid elevation Andes of Peru and Bolivia, where it probably originated. The fruits are called “peron” (pear‐shaped and yellow) or “manzano” (apple‐shaped and red) in Mexico and “rocoto” in Peru. In this research, the hypoglycemic effect of the methanolic extract of immature yellow chili fruit of C. pubescens (peron chili pepper), administered orally (100 μL) to diabetic rats treated with 40 mg of streptozotocin (STZ)/kg of body weight, was evaluated over 60 days in three doses (0.1, 1 and 10 mg/kg). During this time, the body weight and glucose levels were obtained every ten days and at 60 days, the rats were sacrificed (NOM‐062‐ZOO‐1999), determining the levels of blood glucose, urea, creatinine, uric acid, triacylglycerides, total lipids, total cholesterol and HDL‐cholesterol. In normoglycemic (non‐diabetic) rats, the extract did not show a negative effect on the parameters determined, maintaining blood glucose levels (90 mg/dL) and body weight (436.6 g) without significant differences in the three doses probed. However, in the diabetic rats treated with the extract, there was a significant decrease in the levels of blood glucose (<110 mg/dL), uric acid, creatinine, triacylglycerides and total lipids, and a tendency to lower cholesterol levels total and cholesterol‐HDL doses‐dependent. These results demonstrate the hypoglycemic effect of the methanolic extract of immature fruits of the yellow genotype of C. pubescens, as well as a protective effect of kidney and liver damage, mainly at a dose of 10 mg/kg.
Support or Funding Information
Grants: Financial support grant from CONACYT (ACC) and CIC/UMSNH (Project 2.10 RSG).
This is from the Experimental Biology 2019 Meeting. There is no full text article associated with this published in The FASEB Journal.
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