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Journal of Pharmacy & Bioallied Sciences Feb 2024Alteration in the various markers is seen in diabetic nephropathy (DN). In the current research, four different markers were evaluated and were examined for their...
INTRODUCTION
Alteration in the various markers is seen in diabetic nephropathy (DN). In the current research, four different markers were evaluated and were examined for their diagnostic value in the nephropathic type 2 diabetes patients.
METHODS
A prospective clinical trial was piloted with diabetic male subjects with nephropathy. The subjects were followed up for 9 months. Thirty subjects were recruited as type 2 diabetes mellitus patients without nephropathy as controls. The interventional groups were grouped again as microalbuminuria, normoalbuminuria, and hyperfiltration. All of them underwent testing for urinary biomarkers like urine protein, ACR, HbA1C, and estimated glomerular filtration rate (eGFR). Correlation and logistic regression were used to compare all diagnostic tests across various groupings.
RESULTS
The greatest area under curve (AUC) values were .90 and .91 for AGT and AGT/Cr, respectively. The AUC, specificity, sensitivity, and cut-off value of AGT/Cr were, respectively, .91, 85%, 91%, and 4.36 mg/g. When using urine as the cut-off, the sensitivity was 42 and 100 for ACR and eGFR both. All other biomarkers had lower values than the AGT. Less than. 50 was evident for NGAL/Cr and NAGL.
CONCLUSIONS
To identify DN, before the initiation of the albuminuria, compared to other diagnostic markers, urinary AGT demonstrated a greater diagnostic value. Further research is suggested to corroborate the findings.
PubMed: 38595634
DOI: 10.4103/jpbs.jpbs_494_23 -
Physiological Reports Mar 2024With climate change, selection for water efficiency and heat resilience are vitally important. We undertook this study to determine the effect of chronic cyclic heat...
With climate change, selection for water efficiency and heat resilience are vitally important. We undertook this study to determine the effect of chronic cyclic heat stress (HS) on the hypothalamic expression profile of water homeostasis-associated markers in high (HWE)- and low (LWE)-water efficient chicken lines. HS significantly elevated core body temperatures of both lines. However, the amplitude was higher by 0.5-1°C in HWE compared to their LWE counterparts. HWE line drank significantly less water than LWE during both thermoneutral (TN) and HS conditions, and HS increased water intake in both lines with pronounced magnitude in LWE birds. HWE had better feed conversion ratio (FCR), water conversion ratio (WCR), and water to feed intake ratio. At the molecular level, the overall hypothalamic expression of aquaporins (AQP8 and AQP12), arginine vasopressin (AVP) and its related receptor AVP2R, angiotensinogen (AGT), angiotensin II receptor type 1 (AT1), and calbindin 2 (CALB2) were significantly lower; however, CALB1 mRNA and AQP2 protein levels were higher in HWE compared to LWE line. Compared to TN conditions, HS exposure significantly increased mRNA abundances of AQPs (8, 12), AVPR1a, natriuretic peptide A (NPPA), angiotensin I-converting enzyme (ACE), CALB1 and 2, and transient receptor potential cation channel subfamily V member 1 and 4 (TRPV1 and TRPV4) as well as the protein levels of AQP2, however it decreased that of AQP4 gene expression. A significant line by environment interaction was observed in several hypothalamic genes. Heat stress significantly upregulated AQP2 and SCT at mRNA levels and AQP1 and AQP3 at both mRNA and protein levels, but it downregulated that of AQP4 protein only in LWE birds. In HWE broilers, however, HS upregulated the hypothalamic expression of renin (REN) and AVPR1b genes and AQP5 proteins, but it downregulated that of AQP3 protein. The hypothalamic expression of AQP (5, 7, 10, and 11) genes was increased by HS in both chicken lines. In summary, this is the first report showing improvement of growth performances in HWE birds. The hypothalamic expression of several genes was affected in a line- and/or environment-dependent manner, revealing potential molecular signatures for water efficiency and/or heat tolerance in chickens.
Topics: Animals; Chickens; Aquaporin 2; Water; Hot Temperature; Heat-Shock Response; RNA, Messenger
PubMed: 38467563
DOI: 10.14814/phy2.15972 -
Prague Medical Report 2024There is little data regarding the impact of renin-angiotensin system (RAS) gene polymorphisms on tuberculosis. The current study designed to survey the possible...
There is little data regarding the impact of renin-angiotensin system (RAS) gene polymorphisms on tuberculosis. The current study designed to survey the possible association between RAS polymorphisms and the risk of pulmonary tuberculosis (PTB) in a sample of the southeast Iranian population. This case-control study was done on 170 PTB patients and 170 healthy subjects. The AGT rs699 C>T, ACE rs4341 C>G and AT1R rs5186 C>A variants were genotyped using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) and ACE rs4646994 (287bp I/D) variant by PCR method. Regarding AT1R rs5186 A>C polymorphism, the findings revealed that AC genotype and C allele significantly decreased the risk of PTB (OR=0.39, 95% CI=0.22-0.67, p=0.001, and OR=0.53, 95% CI=0.25-0.72, p=0.002, C vs. A, respectively). The TC genotype and C allele of AGT rs699 T>C significantly associated with decreased the risk of PTB (OR=0.45, 95% CI=0.28-0.74, p=0.002, TC vs. TT and OR=0.51, 95% CI=0.32-0.80, p=0.005, C vs. T, respectively). The ID genotype of ACE 287bp I/D significantly increased the risk of PTB (OR=1.88, 95% CI=1.12-3.17, p=0.017). Our finding did not support an association between ACE rs4341 C>G variant and the risk of PTB. In summary, the findings revealed an association between AT1R rs5186 A>C, AGT rs699 T>C and ACE 287bp I/D polymorphisms and the risk of PTB in a sample of the southeast Iranian population. Further investigation with higher sample sizes and diverse ethnicities are required to confirm our findings.
Topics: Humans; Angiotensinogen; Case-Control Studies; Genetic Predisposition to Disease; Genotype; Iran; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Tuberculosis, Pulmonary
PubMed: 38380450
DOI: 10.14712/23362936.2024.1 -
Journal of the... 2023The renin-angiotensin system (RAS) is the main target of neurohumoral therapy in heart failure with reduced ejection fraction (HFrEF) effectively reducing mortality....
Renin Trajectories and Outcome in Stable Heart Failure with Reduced Ejection Fraction (HFrEF) on Contemporary Therapy: A Monocentric Study from an Austrian Tertiary Hospital Outpatient Clinic.
INTRODUCTION
The renin-angiotensin system (RAS) is the main target of neurohumoral therapy in heart failure with reduced ejection fraction (HFrEF) effectively reducing mortality. Reasonably, renin might serve as a biomarker for risk prediction and therapy response. Renin indeed bears some additional value to clinical risk models, albeit the effect is not pronounced. Whether assessing renin trajectories can overcome the weaknesses of single renin measurements has not been reported.
METHODS
A total of 505 patients with stable HFrEF were enrolled prospectively and followed through routine clinical visits. Active plasma renin concentration was documented up to 5 years. Changes in renin were analyzed throughout the disease course, and survival was compared for different renin trajectories within the first year.
RESULTS
Baseline renin levels were not related to all-cause mortality (crude HR for an increase of 100 iE/ml: 1.01 (95% CI: 0.99-1.02), = 0.414) but associated with unplanned HF hospitalizations (crude HR: 1.01 (95% CI: 1.00-1.02), = 0.015). Renin increased during the disease course from baseline to 1-year and 2-year FUP (122.7 vs. 185.6 IU/ml, = 0.039, and 122.7 vs. 258.5 IU/ml, = 0.001). Both survival and unplanned HF hospitalization rates were comparable for different renin trajectories at 1-year FUP ( = 0.546, = 0.357).
CONCLUSIONS
Intriguingly, renin is not a good biomarker to indicate prognosis in HF, while renin trajectories over a 1-year period do not have an additional value. Rapid physiologic plasma renin variations, but also opposing effects of angiotensinogen-derived metabolites under presence of RAS blockade, might obscure the predictive ability of renin.
Topics: Humans; Heart Failure; Renin; Stroke Volume; Austria; Disease Progression; Biomarkers; Hospitalization
PubMed: 37941680
DOI: 10.1155/2023/8883145 -
Cells Apr 2024Glioblastoma is a highly aggressive disease with poor survival outcomes. An emerging body of literature links the role of the renin-angiotensin system (RAS), well-known...
Glioblastoma is a highly aggressive disease with poor survival outcomes. An emerging body of literature links the role of the renin-angiotensin system (RAS), well-known for its function in the cardiovascular system, to the progression of cancers. We studied the expression of RAS-related genes (, , , , , and ) in The Cancer Genome Atlas (TCGA) glioblastoma cohort, their relationship to patient survival, and association with tumour microenvironment pathways. The expression of RAS genes was then examined in 12 patient-derived glioblastoma cell lines treated with chemoradiation. In cases of glioblastoma within the TCGA, , , , and had consistent expressions across samples, while and were lowly expressed. High expression of was independently associated with lower progression-free survival (PFS) ( = 0.01) and had a non-significant trend for overall survival (OS) after multivariate analysis ( = 0.095). The combined expression of RAS receptors (, , and ) was positively associated with gene pathways involved in hypoxia, microvasculature, stem cell plasticity, and the molecular characterisation of glioblastoma subtypes. In patient-derived glioblastoma cell lines, and were upregulated after chemoradiotherapy and correlated with an increase in expression. This data suggests the RAS is correlated with changes in the tumour microenvironment and associated with glioblastoma survival outcomes.
Topics: Humans; Renin-Angiotensin System; Up-Regulation; Glioblastoma; Tumor Microenvironment; Receptors, Cell Surface; Prorenin Receptor
PubMed: 38607073
DOI: 10.3390/cells13070634 -
Frontiers in Pharmacology 2024Acinar ductal metaplasia (ADM) is among the earliest initiating events in pancreatic ductal adenocarcinoma (PDAC) development. We developed a novel morphology-based...
Acinar ductal metaplasia (ADM) is among the earliest initiating events in pancreatic ductal adenocarcinoma (PDAC) development. We developed a novel morphology-based screen using organoids from wildtype and (Cre) mice to discover epigenetic modulators that inhibit or reverse pancreatic ADM more effectively than the broad-spectrum HDAC inhibitor trichostatin A (TSA). Of the 144 compounds screened, nine hits and two additional natural product HDAC inhibitors were validated by dose-response analysis. The class I HDAC inhibitors apicidin and FK228, and the histone methyltransferase inhibitor chaetocin demonstrated pronounced ADM inhibition and reversal without inducing significant cytotoxicity at 1 µM. Thioester prodrug class I HDAC inhibitor largazole attenuated ADM while its disulfide homodimer was effective in both ADM inhibition and reversal. Prioritized compounds were validated for ADM reversal in ; LSL- (KC) mouse organoids using both morphological and molecular endpoints. Molecular index analysis of ADM reversal in KC mouse organoids demonstrated improved activity compared to TSA. Improved prodrug stability translated into a stronger phenotypic and molecular response. RNA-sequencing indicated that angiotensinogen was the top inhibited pathway during ADM reversal. Our findings demonstrate a unique epigenetic mechanism and suggest that the phenotypic screen developed here may be applied to discover potential treatments for PDAC.
PubMed: 38510657
DOI: 10.3389/fphar.2024.1335246 -
JNMA; Journal of the Nepal Medical... Nov 2023Chronic lithium toxicity is a potentially serious side effect on patients taking lithium for a prolonged period with the diagnosis of mood disorders. The toxicity is...
UNLABELLED
Chronic lithium toxicity is a potentially serious side effect on patients taking lithium for a prolonged period with the diagnosis of mood disorders. The toxicity is even higher in patients taking drugs that interfere with the metabolism of lithium like angiotensin receptor blockers and in older patients with reduced kidney function. In this report, we present the case of a 62-year-old woman who presented to the emergency department with symptoms including loose stools, generalised body weakness, slurred speech, coarse hand tremors, and dystonia persisting for fifteen days. She had been under lithium therapy for bipolar type 1 disorder for 15 years before experiencing these symptoms, which emerged shortly after the addition of telmisartan (angiotensinogen receptor blocker) for hypertension.
KEYWORDS
angiotensin receptor blocker; bipolar disorder; case reports; lithium; telmisartan.
Topics: Female; Humans; Aged; Middle Aged; Lithium; Angiotensin Receptor Antagonists; Telmisartan; Bipolar Disorder; Antidepressive Agents
PubMed: 38289730
DOI: 10.31729/jnma.8346 -
Journal of Pharmacological Sciences Apr 202411β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) plays an important role in regulating the expression of glucocorticoid actions in target tissues. Overexpression of...
11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) plays an important role in regulating the expression of glucocorticoid actions in target tissues. Overexpression of 11β-HSD1 in mouse adipose tissue causes a metabolic syndrome-like phenotype, leading to hypertension. Although, many 11β-HSD1 inhibitors have been studied, few have shown a clear ameliorative effect against hypertension. We investigated whether JTT-654, a novel 11β-HSD1 inhibitor, ameliorated hypertension and elucidated the underlying mechanisms. JTT-654 showed inhibitory effects on angiotensinogen production in cortisone-treated 3T3-L1 adipocytes and in a rat model. JTT-654 improved hypertension not only in cortisone-treated rats and spontaneously hypertensive rats (SHR), but also in SHR/NDmcr-cp rats. In the SHR study, JTT-654 and losartan showed the same degree of antihypertensive efficacy. In addition, JTT-654 ameliorated diabetic nephropathy by suppressing renal angiotensinogen production in SHR/NDmcr-cp rats. These effects of JTT-654 were independent of its insulin-sensitizing effects, and similar effects were not observed for pioglitazone, an insulin sensitizer. Moreover, JTT-654 did not affect normotension or hypothalamus-pituitary-adrenal (HPA) axis function in normal Sprague-Dawley rats. Our results indicate that JTT-654 ameliorates hypertension and diabetic nephropathy by inhibiting 11β-HSD1 in the adipose tissue, liver, and kidney.
Topics: Mice; Rats; Animals; 11-beta-Hydroxysteroid Dehydrogenase Type 1; Diabetic Nephropathies; Cortisone; Angiotensinogen; Rats, Sprague-Dawley; Insulin; Kidney; Hypertension; Diabetes Mellitus
PubMed: 38485342
DOI: 10.1016/j.jphs.2024.02.001 -
Journal of Cellular and Molecular... Apr 2024In the last decade, extensive attention has been paid to the uremic toxin indoxyl sulphate (IS) as an inducer of cardiac fibroblast (cFib) activation and cardiac...
In the last decade, extensive attention has been paid to the uremic toxin indoxyl sulphate (IS) as an inducer of cardiac fibroblast (cFib) activation and cardiac fibrosis in chronic kidney disease. At cellular level, IS engages aryl hydrocarbon receptor (AhR) and regulates many biological functions. We analysed how AhR inhibition by CH-223191 (CH) and overexpression of non-functional (dominant negative, DN) nuclear factor-erythroid-2-related factor 2 (NRF2), a transcription factor recruited by AhR, modulate the response of neonatal mouse (nm) cFib to IS. We also evaluated nm-cardiomyocytes after incubation with the conditioned medium (CM) of IS±CH-treated nm-cFib. IS induced activation, collagen synthesis, TLR4 and-downstream-MCP-1, and the genes encoding angiotensinogen, angiotensin-converting enzyme, angiotensin type 1 receptor (AT1r) and neprilysin (Nepr) in nm-cFib. CH antagonized IS-initiated nm-cFib activation, but did not affect or even magnified the other features. IS promoted NRF2 nuclear translocation and expression the NRF2 target Nqo1. Both pre-incubation with CH and transfection of DN-NRF2 resulted in loss of NRF2 nuclear localization. Moreover, DN-NRF2 overexpression led to greater TLR4 and MCP-1 levels following exposure to IS. The CM of IS-primed nm-cFib and to a larger extent the CM of IS+CH-treated nm-cFib upregulated AT1r, Nepr and TNFα and myostatin genes in nm-cardiomyocytes. Hence, IS triggers pro-inflammatory activation of nm-cFib partly via AhR, and AhR-NRF2 counteract it. Strategies other than AhR inhibition are needed to target IS detrimental actions on cardiac cells.
Topics: Mice; Animals; Indican; Signal Transduction; Receptors, Aryl Hydrocarbon; NF-E2-Related Factor 2; Toll-Like Receptor 4; Fibroblasts
PubMed: 38506079
DOI: 10.1111/jcmm.18192 -
Journal of Personalized Medicine Feb 2024Hypertension, characterized by elevated pressure, poses a significant health risk. Recent studies in Jordan highlight high hypertension rates, emphasizing the need for...
BACKGROUND
Hypertension, characterized by elevated pressure, poses a significant health risk. Recent studies in Jordan highlight high hypertension rates, emphasizing the need for genetic investigations to comprehend essential hypertension determinants. The gene, part of the Renin Angiotensin System, is linked to blood pressure regulation. Limited information exists on the frequency of this polymorphism among Jordanian hypertensive patients.
AIMS
This study explores the association between the polymorphism and essential hypertension in Jordan.
METHODS
A cross-sectional study with 435 participants (199 hypertensive, 236 non-hypertensive) was conducted at the University of Jordan Hospital. Blood pressure was measured, and genetic analysis of the polymorphism was completed using the PCR-RFLP technique. Chi-square and -tests were used for comparisons using SPSS software.
RESULTS
Hypertensive patients exhibited significantly higher weight, BMI, and blood pressure. Genotyping results showed no significant difference ( > 0.05, ) in polymorphism distribution between control and patient groups. In addition, allele frequencies showed comparable patterns ( > 0.05, ). All genotype frequencies showed no deviation from the Hardy-Weinberg equation ( > 0.05, ).
CONCLUSIONS
The genetic polymorphism is not more prevalent among hypertensive patients in Jordan, although the average weight and BMI among hypertensive patients is higher than the non-hypertensive participants. Obesity can be addressed as a potential risk factor for essential hypertension in Jordan. In addition, it is recommended to find out the influence of the genetic polymorphism on the response of antihypertensive drugs among hypertensive patients in Jordan.
PubMed: 38541014
DOI: 10.3390/jpm14030273