Search

Abstract The renin-angiotensin system (RAS) constitutes one of the principal mechanisms to maintain hemodynamic and fluid homeostasis. However, most research until now on RAS primarily focuses on its relationship with hypertension and its role in critically ill hypotensive populations is not well understood. With the approval of angiotensin II (Ang II) in the United States and Europe, following a phase 3 randomized controlled trial showing efficacy in catecholamine-resistant vasodilatory shock, there is growing interest in RAS in critically ill patients. Among the fundamental components of RAS, renin acts as the initial stimulus for the entire system. In the context of hypotension, its release increases in response to low blood pressure sensed by renal baroreceptors and attenuated negative Ang II feedback loop. Thus, elevated renin could reflect disease severity and predict poor outcomes. Studies investigating this hypothesis have validated the prognostic accuracy of renin in various critically ill populations, with several reports indicating its superiority to lactate for mortality prediction. Accordingly, renin reduction has been used to assess the effectiveness of Ang II administration. Furthermore, renin holds potential to identify patients who might benefit from Ang II treatment, potentially paving the way for personalized vasopressor management. Despite these promising data, most available evidence is derived from retrospective analysis and necessitates prospective confirmation. The absence of a rapid, point-of-care and reliable renin assay presents another hurdle to its integration into routine clinical practice. This narrative review aims to describe the current understanding and future directions of renin as a biomarker during resuscitation of critically ill patients.

Abstract Brown adipocytes are potential therapeutic targets for the prevention of obesity-associated metabolic diseases because they consume circulating glucose and fatty acids for heat production. Angiotensin II (Ang II) peptide is involved in the pathogenesis of obesity- and cold-induced hypertension; however, the mechanism underlying the direct effects of Ang II on human brown adipocytes remains unclear. Our transcriptome analysis of chemical compound-induced brown adipocytes (ciBAs) showed that the Ang II type 1 receptor (AGTR1), but not AGTR2 and MAS1 receptors, was expressed. The Ang II/AGTR1 axis downregulated the expression of mitochondrial uncoupling protein 1 (UCP1). The simultaneous treatment with β-adrenergic receptor agonists and Ang II attenuated UCP1 expression, triglyceride lipolysis, and cAMP levels, although cAMP response element-binding protein (CREB) phosphorylation was enhanced by Ang II mainly through the protein kinase C pathway. Despite reduced lipolysis, both coupled and uncoupled mitochondrial respiration was enhanced in Ang II-treated ciBAs. Instead, glycolysis and glucose uptake were robustly activated upon treatment with Ang II without a comprehensive transcriptional change in glucose metabolic genes. Elevated mitochondrial energy status induced by Ang II was likely associated with UCP1 repression. Our findings suggest that the Ang II/AGTR1 axis participates in mitochondrial thermogenic functions via glycolysis.

The proliferation of vascular smooth muscle cells (VSMCs) induced by hyperglycemia plays a pivotal role in the development of atherosclerosis and restenosis. This study aims to examine the impact of angiotensin II (Ang II) and high glucose on VSMC proliferation and the phosphorylation status of key signalling proteins, specifically ERK1/2, Akt, and STAT3. Furthermore, we assess the inhibitory effects of resveratrol, a polyphenolic compound, on these signalling pathways.

Abstract Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly contagious virus that uses angiotensin converting enzyme 2 (ACE2), a pivotal member of the renin–angiotensin system (RAS), as its cell-entry receptor. Another member of the RAS, angiotensin II (Ang II), is the major biologically active component in this system. There is growing evidence suggesting that serum miRNAs could serve as prognostic biomarkers for SARS-CoV-2 infection and regulate ACE2 expression. Therefore, the aim of this study is to evaluate the changes in the serum levels of sACE2 and Ang II, as well as the expression level of miR-141-3p and miR-421 in SARS-CoV-2 positive and negative subjects. Methods In the present study, the serum levels of sACE2 and Ang II were measured in 94 SARS-CoV-2 positive patients and 94 SARS-CoV-2 negative subjects with some symptoms similar to those of SARS-CoV-2 positive patients using the ELISA method. In addition, the expression level of miR-141-3p and miR-421 as ACE2 regulators and biomarkers was evaluated using quantitative real-time PCR (qRT-PCR) method. Results The mean serum sACE2 concentration in the SARS-CoV-2-positive group was 3.268 ± 0.410 ng/ml, whereas in the SARS-CoV-2 negative group, it was 3.564 ± 0.437 ng/ml. Additionally, the mean serum Ang II level in the SARS-CoV-2 positive and negative groups were 60.67 ± 6.192 ng/L and 67.97 ± 6.837 ng/L, respectively. However, there was no significant difference in the serum levels of sACE2 (P value: 0.516) and Ang II (P value: 0.134) between the SARS-CoV-2 positive and negative groups. Meanwhile, our findings indicated that the expression levels of miR-141-3p and miR-421 in SARS-CoV-2 positive group were significantly lower and higher than SARS-CoV-2 negative group, respectively (P value

Abstract Background Data to support the use of specific vasopressors in septic shock are limited. Since angiotensin II (AT2) was approved by the Food and Drug Administration in 2017, multiple mechanistically distinct vasopressors are available to treat septic shock, but minimal data exist regarding which patients are most likely to benefit from each agent. Renin and dipeptidyl peptidase 3 (DPP3) are components of the renin–angiotensin–aldosterone system which have been shown to outperform lactate in predicting sepsis prognosis, and preliminary data suggest they could prove useful as biomarkers to guide AT2 use in septic shock. Methods The DARK-Sepsis trial is an investigator-initiated industry-funded, open-label, single-center randomized controlled trial of the use of AT2 versus standard of care (SOC) vasopressor therapy in patients admitted to the intensive care unit (ICU) with vasodilatory shock requiring norepinephrine ≥ 0.1 mcg/kg/min. In both groups, a series of renin and DPP3 levels will be obtained over the first 24 h of treatment with AT2 or SOC. The primary study outcome will be the ability of these biomarkers to predict response to vasopressor therapy, as measured by change in total norepinephrine equivalent dose of vasopressors at 3 h post-drug initiation or the equivalent timepoint in the SOC arm. To determine if the ability to predict vasopressor response is specific to AT2 therapy, the primary analysis will be the ability of baseline renin and DPP3 levels to predict vasopressor response adjusted for treatment arm (AT2 versus control) and Sequential Organ Failure Assessment (SOFA) scores. Secondary outcomes will include rates of acute kidney injury, need for mechanical ventilation and kidney replacement therapy, lengths of stay in the ICU and hospital, ICU and hospital mortality, and rates of prespecified adverse events. Discussion With an armamentarium of mechanistically distinct vasopressor agents now available, sub-phenotyping patients using biomarkers has the potential to improve septic shock outcomes by enabling treatment of the correct patient with the correct vasopressor at the correct time. However, this approach requires validation in a large definitive multicenter trial. The data generated through the DARK-Sepsis study will prove crucial to the optimal design and patient enrichment of such a pivotal trial. Trial registration ClinicalTrials.gov NCT05824767. Registered on April 24, 2023.

It has been our pleasure to have been able to develop two special issues within the International Journal of Molecular Sciences: (1) Renin-Angiotensin-Aldosterone System in Pathologies and (2) Renin-Angiotensin-Aldosterone System in Metabolism & Disease [...].

Aortic aneurysms are prevalent and severe vascular diseases with high mortality from unpredicted ruptures, while the only treatment option is surgical correction of large aneurysms with considerable risk. We have shown that folic acid (FA) is highly effective in alleviating development of aneurysms although not sufficient to completely attenuate aneurysm formation. Here, we examined therapeutic effects on aneurysms of combining FA with Nifedipine as novel and potentially more effective oral medication. Oral administration with FA (15 mg/kg/day) significantly reduced incidence of AAA from 85.71% to 18.75% in Ang II-infused apolipoprotein E (apoE) null mice, while combination of FA with Nifedipine (1.5, 5.0 or 20 mg/kg/day) substantially and completely further reduced incidence of AAA to 12.5%, 11.76% and 0.00% respectively in a dose-dependent manner. The combinatory therapy substantially and completely further alleviated enlargement of abdominal aortas defined by ultrasound, vascular remodeling characterized by elastin degradation and adventitial hypertrophy, as well as aortic superoxide production and eNOS uncoupling activity also in a dose-dependent manner, with combination of FA with 20 mg/kg/day Nifedipine attenuating all of these features by 100% to control levels. Aortic NO and H4B bioavailabilities were also dose-dependently further improved by combining FA with Nifedipine. These data establish entirely innovative and robust therapeutic regime of FA combined with Nifedipine for the treatment of aortic aneurysms. The comminatory therapy can serve as a first-in-class and most effective oral medication for aortic aneurysms, which can be rapidly translated into clinical practice to revolutionize management of the devastating vascular diseases of aortic aneurysms known as silent killers.

The renin-angiotensin system (RAS) constitutes one of the principal mechanisms to maintain hemodynamic and fluid homeostasis. However, most research until now on RAS primarily focuses on its relationship with hypertension and its role in critically ill hypotensive populations is not well understood. With the approval of angiotensin II (Ang II) in the United States and Europe, following a phase 3 randomized controlled trial showing efficacy in catecholamine-resistant vasodilatory shock, there is growing interest in RAS in critically ill patients. Among the fundamental components of RAS, renin acts as the initial stimulus for the entire system. In the context of hypotension, its release increases in response to low blood pressure sensed by renal baroreceptors and attenuated negative Ang II feedback loop. Thus, elevated renin could reflect disease severity and predict poor outcomes. Studies investigating this hypothesis have validated the prognostic accuracy of renin in various critically ill populations, with several reports indicating its superiority to lactate for mortality prediction. Accordingly, renin reduction has been used to assess the effectiveness of Ang II administration. Furthermore, renin holds potential to identify patients who might benefit from Ang II treatment, potentially paving the way for personalized vasopressor management. Despite these promising data, most available evidence is derived from retrospective analysis and necessitates prospective confirmation. The absence of a rapid, point-of-care and reliable renin assay presents another hurdle to its integration into routine clinical practice. This narrative review aims to describe the current understanding and future directions of renin as a biomarker during resuscitation of critically ill patients. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder, with more than half of the patients developing lupus nephritis (LN), which significantly contributes to chronic kidney disease (CKD) and end-stage renal disease (ESRD). The treatment of lupus nephritis has always been challenging. Tacrolimus (TAC), an effective immunosuppressant, has been increasingly used in the treatment of LN in recent years. This review aims to explore the mechanisms of action of tacrolimus in treating LN. Firstly, we briefly introduce the pharmacological properties of tacrolimus, including its role as a calcineurin (CaN) inhibitor, exerting immunosuppressive effects by inhibiting T cell activation and cytokine production. Subsequently, we focus on various other immunomodulatory mechanisms of tacrolimus in LN therapy, including its effects on T cells, B cells, and immune cells in kidney. Particularly, we emphasize tacrolimus' regulatory effect on inflammatory mediators and its importance in modulating the Th1/Th2 and Th17/Treg balance. Additionally, we review its effects on actin cytoskeleton, angiotensin II (Ang II)-specific vascular contraction, and P-glycoprotein activity, summarizing its impacts on non-immune mechanisms. Finally, we summarize the efficacy and safety of tacrolimus in clinical studies and trials. Although some studies have shown significant efficacy of tacrolimus in treating LN, its safety remains a challenge. We outline the potential adverse reactions of long-term tacrolimus use and provide suggestions on effectively monitoring and managing these adverse reactions in clinical practice. In general, tacrolimus, as a novel immunosuppressant, holds promising prospects for treating LN. Of course, further research is needed to better understand its therapeutic mechanisms and ensure its safety and efficacy in clinical practice. [ABSTRACT FROM AUTHOR]

Amphetamine (AMPH) exposure induces behavioural and neurochemical sensitization observed in rodents as hyperlocomotion and increased dopamine release in response to a subsequent dose. Brain Angiotensin II modulates dopaminergic neurotransmission through its AT1 receptors (AT1‐R), positively regulating striatal dopamine synthesis and release. This work aims to evaluate the AT1‐R role in the development and maintenance of AMPH‐induced sensitization. Also, the AT1‐R involvement in striatal dopamine reuptake was analysed. The sensitization protocol consisted of daily AMPH administration for 5 days and tested 21 days after withdrawal. An AT1‐R antagonist, candesartan, was administered before or after AMPH exposure to evaluate the participation of AT1‐R in the development and maintenance of sensitization, respectively. Sensitization was evaluated by locomotor activity and c‐Fos immunostaining. Changes in dopamine reuptake kinetics were evaluated 1 day after AT1‐R blockade withdrawal treatment, with or without the addition of AMPH in vitro. The social interaction test was performed as another behavioural output. Repeated AMPH exposure induced behavioural and neurochemical sensitization, which was prevented and reversed by candesartan. The AT1‐R blockade increased the dopamine reuptake kinetics. Neither the AMPH administration nor the AT1‐R blockade altered the performance of social interaction. Our results highlight the AT1‐R's crucial role in AMPH sensitization. The enhancement of dopamine reuptake kinetics induced by the AT1‐R blockade might attenuate the neuroadaptive changes that lead to AMPH sensitization and its self‐perpetuation. Therefore, AT1‐R is a prominent candidate as a target for pharmacological treatment of pathologies related to dopamine imbalance, including drug addiction and schizophrenia. [ABSTRACT FROM AUTHOR]

Olmesartan medoxomil (OLM) is a selective angiotensin II receptor antagonist used in the treatment of hypertension. Its therapeutic potential is limited by its poor water solubility, leading to poor bioavailability. Encapsulation of the drug substance by two methylated cyclodextrins, namely randomly methylated β-cyclodextrin (RM-β-CD) and heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin (TM-β-CD), was carried out to overcome the limitation related to OLM solubility, which, in turn, is expected to result in an improved biopharmaceutical profile. Supramolecular entities were evaluated by means of thermoanalytical techniques (TG—thermogravimetry; DTG—derivative thermogravimetry), spectroscopic methods including powder X-ray diffractometry (PXRD), universal-attenuated total reflectance Fourier-transform infrared (UATR-FTIR) and UV spectroscopy, saturation solubility studies, and by a theoretical approach using molecular modeling. The phase solubility method reveals an AL-type diagram for both inclusion complexes, indicating a stoichiometry ratio of 1:1. The values of the apparent stability constant indicate the higher stability of the host–guest system OLM/RM-β-CD. The physicochemical properties of the binary systems are different from those of the parent compounds, emphasizing the formation of inclusion complexes between the drug and CDs when the kneading method was used. The molecular encapsulation of OLM in RM-β-CD led to an increase in drug solubility, thus the supramolecular adduct can be the subject of further research to design a new pharmaceutical formulation containing OLM, with improved bioavailability. [ABSTRACT FROM AUTHOR]

The three striatins (STRN, STRN3, STRN4) form the core of STRiatin-/nteracting Phosphatase and Kinase (STRIPAK) complexes. These place protein phosphatase 2A (PP2A) in proximity to protein kinases thereby restraining kinase activity and regulating key cellular processes. Our aim was to establish if striatins play a significant role in cardiac remodelling associated with cardiac hypertrophy and heart failure. All striatins were expressed in control human hearts, with up-regulation of STRN and STRN3 in failing hearts. We used mice with global heterozygote gene deletion to assess the roles of STRN and STRN3 in cardiac remodelling induced by angiotensin II (AngII; 7 days). Using echocardiography, we detected no differences in baseline cardiac function or dimensions in STRN+/- or STRN3+/-male mice (8 weeks) compared with wild-type littermates. Heterozygous gene deletion did not affect cardiac function in mice treated with AngII, but the increase in left ventricle mass induced by AngII was inhibited in STRN+/- (but not STRN3+/-) mice. Histological staining indicated that cardiomyocyte hypertrophy was inhibited. To assess the role of STRN in car-diomyocytes, we converted the STRN knockout line for inducible cardiomyocyte-specific gene deletion. There was no effect of cardiomyocyte STRN knockout on cardiac function or dimensions, but the increase in left ventricle mass induced by AngII was inhibited. This resulted from inhibition of cardiomyocyte hypertrophy and cardiac fibrosis. The data indicate that cardiomyocyte striatin is required for early remodelling of the heart by AngII and identify the striatin-based STRIPAK system as a signalling paradigm in the development of pathological cardiac hypertrophy. [ABSTRACT FROM AUTHOR]

Brown adipocytes are potential therapeutic targets for the prevention of obesity-associated metabolic diseases because they consume circulating glucose and fatty acids for heat production. Angiotensin II (Ang II) peptide is involved in the pathogenesis of obesity- and cold-induced hypertension; however, the mechanism underlying the direct effects of Ang II on human brown adipocytes remains unclear. Our transcriptome analysis of chemical compound-induced brown adipocytes (ciBAs) showed that the Ang II type 1 receptor (AGTR1), but not AGTR2 and MAS1 receptors, was expressed. The Ang II/AGTR1 axis downregulated the expression of mitochondrial uncoupling protein 1 (UCP1). The simultaneous treatment with β-adrenergic receptor agonists and Ang II attenuated UCP1 expression, triglyceride lipolysis, and cAMP levels, although cAMP response element-binding protein (CREB) phosphorylation was enhanced by Ang II mainly through the protein kinase C pathway. Despite reduced lipolysis, both coupled and uncoupled mitochondrial respiration was enhanced in Ang II-treated ciBAs. Instead, glycolysis and glucose uptake were robustly activated upon treatment with Ang II without a comprehensive transcriptional change in glucose metabolic genes. Elevated mitochondrial energy status induced by Ang II was likely associated with UCP1 repression. Our findings suggest that the Ang II/AGTR1 axis participates in mitochondrial thermogenic functions via glycolysis. [ABSTRACT FROM AUTHOR]

Ongoing cardiomyocyte injury is a major mechanism in the progression of heart failure, particularly in dystrophic hearts. Due to the poor regenerative capacity of the adult heart, cardiomyocyte death results in the permanent loss of functional myocardium. Understanding the factors contributing to myocyte injury is essential for the development of effective heart failure therapies. As a model of persistent cardiac injury, we examined mice lacking β-sarcoglycan (β-SG), a key component of the dystrophin glycoprotein complex (DGC). The loss of the sarcoglycan complex markedly compromises sarcolemmal integrity in this β-SG−/− model. Our studies aim to characterize the mechanisms underlying dramatic sex differences in susceptibility to cardiac injury in β-SG−/− mice. Male β-SG−/− hearts display significantly greater myocardial injury and death following isoproterenol-induced cardiac stress than female β-SG−/− hearts. This protection of females was independent of ovarian hormones. Male β-SG−/− hearts displayed increased susceptibility to exogenous oxidative stress and were significantly protected by angiotensin II type 1 receptor (AT 1 R) antagonism. Increasing general antioxidative defenses or increasing the levels of S -nitrosylation both provided protection to the hearts of β-SG−/− male mice. Here we demonstrate that increased susceptibility to oxidative damage leads to an AT 1 R-mediated amplification of workload-induced myocardial injury in male β-SG−/− mice. Improving oxidative defenses, specifically by increasing S -nitrosylation, provided protection to the male β-SG−/− heart from workload-induced injury. These studies describe a unique susceptibility of the male heart to injury and may contribute to the sex differences in other forms of cardiac injury. [Display omitted] • Male mice with a dystrophic mutation are more susceptible to myocardial injury. • Female protection from dystrophic injury is not mediated by ovarian hormones. • Males and females have distinct transcriptional responses to dystrophic mutations. • Dystrophic males are more susceptible to exogenous oxidative stress. • Improving oxidative defenses protects males, but not females. [ABSTRACT FROM AUTHOR]

Cardiac pain is an index of cardiac ischemia that helps the detection of cardiac hypoxia and adjustment of activity in the sufferer. Drivers and thresholds of cardiac pain markedly differ in different subjects and can oscillate in the same individual, showing a distinct circadian rhythmicity and clinical picture. In patients with syndrome X or silent ischemia, cardiac pain intensity may cause neurogenic stress that potentiates the cardiac work and intensifies the cardiac hypoxia and discomfort of the patient. The reasons for individual differences in cardiac pain sensation are not fully understood. Thus far, most attention has been focused on inappropriate regulation of the heart by the autonomic nervous system, autacoids, and cardiovascular hormones. Herein, we summarize evidence showing that the autonomic nervous system regulates cardiac pain sensation in cooperation with vasopressin (AVP). AVP is an essential analgesic compound and it exerts its antinociceptive function through actions in the brain (the periaqueductal gray, caudate nucleus, nucleus raphe magnus), spinal cord, and heart and coronary vessels. Vasopressin acts directly by means of V1 and V2 receptors as well as through multiple interactions with the autonomic nervous system and cardiovascular hormones, in particular, angiotensin II and endothelin. The pain regulatory effects of the autonomic nervous system and vasopressin are significantly impaired in cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Introduction: This study aimed to explore the function of miR-135a in the progress of atrial fibrosis and the mechanism of miR-135a/SIRT1 (sirtuin 1) in human cardiac fibroblasts and mouse cardiac fibroblasts (MCFs) mediating the regulation of atrial fibrosis by mitochondrial oxidative respiration function. Methods: Using Ang II (angiotensin II) to induce fibrosis in HCFs (human corneal fibroblasts) and MCF (Michigan Cancer Foundation, MCF) cells in vitro, the miRNA-seq results of previous studies were validated. Proliferative and invasive ability of HCFs and MCFs was detected by Cell Counting Kit-8 assay (CCK-8) and scratch experiment after overexpressing miR-135a in HCFs and MCF cells. Protein and mRNA expression was tested using Western blot and qPCR. The target of miR-135a was verified as SIRT1 by a luciferase reporter assay and the activities of the mitochondrial respiratory enzyme complexes I, II, III, and IV were determined colorimetrically. The activities of malondialdehyde, reactive oxygen species, and superoxide dismutase in cells were detected with enzyme-linked immunosorbent assay (ELISA). Results: miR-135a expression was elevated in HCFs and MCFs cells in the Ang II group than control group. Overexpression of miR-135a could promote the proliferation, migration, oxidative stress, as well as fibrosis of cardiac fibroblasts and suppresses mitochondrial activity. In addition, we found SIRT1 was a target gene of miR-135a. What is more, the findings showed miR-135a promoted fibrosis in HCFs and MCFs cells acting through regulation of SIRT1. Conclusions: miR-135a mediates mitochondrial oxidative respiratory function through SIRT1 to regulate atrial fibrosis. [ABSTRACT FROM AUTHOR]

Antibodies to angiotensin II type 1 receptor (AT1R‐Abs) are among the most well‐studied non‐HLA antibodies in renal transplantation. These antibodies have been shown to be common in pediatric kidney transplantation and associated with antibody‐mediated rejection (AMR), vascular inflammation, development of human leukocyte donor‐specific antibodies (HLA DSA), and allograft loss. As AT1R‐Ab testing becomes more readily accessible, evidence to guide clinical practice for testing and treating AT1R‐Ab positivity in pediatric kidney transplant recipients remains limited. This review discusses the clinical complexities of evaluating AT1R‐Abs given the current available evidence. [ABSTRACT FROM AUTHOR]

Chronic angiotensin II (ANG II) infusion is an experimental model that induces hypertension in rodents. The natriuresis, diuresis, and blood pressure responses differ between males and females. This is perhaps not unexpected, given the rodent kidney, which plays a key role in blood pressure regulation, exhibits marked sex differences. Under normotensive conditions, compared with males, the female rat nephron exhibits lower Naþ/Hþ exchanger 3 (NHE3) activity along the proximal tubule but higher Naþ transporter activities along the distal segments. ANG II infusion-induced hypertension induces a pressure natriuretic response that reduces NHE3 activity and shifts Naþ transport capacity downstream. The goals of this study were to apply a computational model of epithelial transport along a rat nephron 1) to understand how a 14-day ANG II infusion impacts segmental electrolyte transport in male and female rat nephrons and 2) to identify and explain any sex differences in the effects of loop diuretics, thiazide diuretics, and Kþ-sparing diuretics. Model simulations suggest that the NHE3 downregulation in the proximal tubule is a major contributor to natriuresis and diuresis in hypertension, with the effects stronger in males. All three diuretics are predicted to induce stronger natriuretic and diuretic effects under hypertension compared with normotension, with relative increases in sodium excretion higher in hypertensive females than in males. The stronger natriuretic responses can be explained by the downstream shift of Naþ transport load in hypertension and by the larger distal transport load in females, both of which limit the ability of the distal segments to further elevate their Naþ transport. [ABSTRACT FROM AUTHOR]

Cardiovascular outcome in Marfan syndrome (MFS) patients most prominently depends on aortic aneurysm progression with subsequent aortic dissection. Angiotensin II receptor blockers (ARBs) prevent aneurysm formation in MFS mouse models. In patients, ARBs only slow down aortic dilation. Downstream signalling from the angiotensin II type 1 receptor (AT1R) is mediated by G proteins and β-arrestin recruitment. AT1R also interacts with the monocyte chemoattractant protein-1 (MCP-1) receptor, resulting in inflammation. In this study, we explore the targeting of β-arrestin signalling in MFS mice by administering TRV027. Furthermore, because high doses of the ARB losartan, which has been proven beneficial in MFS, cannot be achieved in humans, we investigate a potential additive effect by combining lower concentrations of losartan (25 mg/kg/day and 5 mg/kg/day) with barbadin, a β-arrestin blocker, and DMX20, a C-C chemokine receptor type 2 (CCR2) blocker. A high dose of losartan (50 mg/kg/day) slowed down aneurysm progression compared to untreated MFS mice (1.73 ± 0.12 vs. 1.96 ± 0.08 mm, p = 0.0033). TRV027, the combination of barbadin with losartan (25 mg/kg/day), and DMX-200 (90 mg/kg/day) with a low dose of losartan (5 mg/kg/day) did not show a significant beneficial effect. Our results confirm that while losartan effectively halts aneurysm formation in Fbn1C1041G/+ MFS mice, neither TRV027 alone nor any of the other compounds combined with lower doses of losartan demonstrate a notable impact on aneurysm advancement. It appears that complete blockade of AT1R function, achieved by administrating a high dosage of losartan, may be necessary for inhibiting aneurysm progression in MFS. [ABSTRACT FROM AUTHOR]

Investigating the role of podocytes in proteinuric disease is imperative to address the increasing global burden of chronic kidney disease (CKD). Studies strongly implicate increased levels of monocyte chemoattractant protein-1 (MCP-1/CCL2) in proteinuric CKD. Since podocytes express the receptor for MCP-1 (i.e., CCR2), we hypothesized that podocyte-specific MCP-1 production in response to stimuli could activate its receptor in an autocrine manner, leading to further podocyte injury. To test this hypothesis, we generated podocyte-specific MCP-1 knockout mice (Podo-Mcp-1fl/fl) and exposed them to proteinuric injury induced by either angiotensin II (Ang II; 1.5 mg/kg/d, osmotic minipump) or Adriamycin (Adr; 18 mg/kg, intravenous bolus). At baseline, there were no between-group differences in body weight, histology, albuminuria, and podocyte markers. After 28 days, there were no between-group differences in survival, change in body weight, albuminuria, kidney function, glomerular injury, and tubulointerstitial fibrosis. The lack of protection in the knockout mice suggests that podocyte-specific MCP-1 production is not a major contributor to either Ang II- or Adr-induced glomerular disease, implicating that another cell type is the source of pathogenic MCP-1 production in CKD. [ABSTRACT FROM AUTHOR]

Objectives WCK 4282 is a novel combination of cefepime 2 g and tazobactam 2 g being developed for the treatment of infections caused by piperacillin/tazobactam-resistant ESBL infections. The dosing regimen for cefepime/tazobactam needs to be optimized to generate adequate exposures to treat infections caused by ESBL-producing pathogens resistant to both cefepime and piperacillin/tazobactam. Methods We developed pharmacokinetic population models of cefepime and tazobactam to evaluate the optimal dose adjustments in patients, including those with augmented renal clearance as well as various degrees of renal impairment, and also for those on intermittent haemodialysis. Optimal doses for various degrees of renal function were identified by determining the PTA for a range of MICs. To cover ESBL-producing pathogens with an cefepime/tazobactam MIC of 16 mg/L, a dosing regimen of 2 g q8h infused over 1.5 h resulted in a combined PTA of 99% for the mean murine 1 log10-kill target for the cefepime/tazobactam combination. Results We found that to adjust for renal function, doses need to be reduced to 1 g q8h, 500 mg q8h and 500 mg q12h for patients with CLCR of 30–59, 15–29 and 8–14 mL/min (as well as patients with intermittent haemodialysis), respectively. In patients with high to augmented CLR (estimated CLCR 120–180 mL/min), a prolonged 4 h infusion of standard dose is required. Conclusions The suggested dosing regimens will result in exposures of cefepime and tazobactam that would be adequate for infections caused by ESBL-producing pathogens with a cefepime/tazobactam MICs up to 16 mg/L. [ABSTRACT FROM AUTHOR]

In our previous studies, we showed that the generation of ovarian tumors in NSG mice (immune-compromised) resulted in the induction of muscle and cardiac cachexia, and treatment with withaferin A (WFA; a steroidal lactone) attenuated both muscle and cardiac cachexia. However, our studies could not address if these restorations by WFA were mediated by its anti-tumorigenic properties that might, in turn, reduce the tumor burden or WFA's direct, inherent anti-cachectic properties. To address this important issue, in our present study, we used a cachectic model induced by the continuous infusion of Ang II by implanting osmotic pumps in immunocompetent C57BL/6 mice. The continuous infusion of Ang II resulted in the loss of the normal functions of the left ventricle (LV) (both systolic and diastolic), including a significant reduction in fractional shortening, an increase in heart weight and LV wall thickness, and the development of cardiac hypertrophy. The infusion of Ang II also resulted in the development of cardiac fibrosis, and significant increases in the expression levels of genes (ANP, BNP, and MHCβ) associated with cardiac hypertrophy and the chemical staining of the collagen abundance as an indication of fibrosis. In addition, Ang II caused a significant increase in expression levels of inflammatory cytokines (IL-6, IL-17, MIP-2, and IFNγ), NLRP3 inflammasomes, AT1 receptor, and a decrease in AT2 receptor. Treatment with WFA rescued the LV functions and heart hypertrophy and fibrosis. Our results demonstrated, for the first time, that, while WFA has anti-tumorigenic properties, it also ameliorates the cardiac dysfunction induced by Ang II, suggesting that it could be an anticachectic agent that induces direct effects on cardiac muscles. [ABSTRACT FROM AUTHOR]

Vascular smooth muscle cells (VSMCs) play a key role in aortic aneurysm formation. Bone morphogenetic proteins (BMPs) have been implicated as important regulators of VSMC phenotype, and dysregulation of the BMP pathway has been shown to be associated with vascular diseases. The aim of this study was to investigate for the first time the effects of BMP-4 on the VSMC phenotype and to understand its role in the development of thoracic aortic aneurysms (TAAs). Using the angiotensin II (AngII) osmotic pump model in mice, aortas from mice with VSMC-specific BMP-4 deficiency showed changes similar to AngII-infused aortas, characterised by a loss of contractile markers, increased fibrosis, and activation of matrix metalloproteinase 9. When BMP-4 deficiency was combined with AngII infusion, there was a significantly higher rate of apoptosis and aortic dilatation. In vitro, VSMCs with mRNA silencing of BMP-4 displayed a dedifferentiated phenotype with activated canonical BMP signalling. In contrast, BMP-2-deficient VSMCs exhibited the opposite phenotype. The compensatory regulation between BMP-2 and BMP-4, with BMP-4 promoting the contractile phenotype, appeared to be independent of the canonical signalling pathway. Taken together, these results demonstrate the impact of VSMC-specific BMP-4 deficiency on TAA development. [ABSTRACT FROM AUTHOR]

Background: Post-streptococcal glomerulonephritis (PSGN) is a consequence of the infection by group A beta-hemolytic streptococcus. During this infection, various immunological processes generated by streptococcal antigens are triggered, such as the induction of antibodies and immune complexes. This activation of the immune system involves both innate and acquired immunity. The immunological events that occur at the renal level lead to kidney damage with chronic renal failure as well as resolution of the pathological process (in most cases). Summary: Angiotensin II (Ang II) is a molecule with vasopressor and pro-inflammatory capacities, being an important factor in various inflammatory processes. During PSGN some events are defined that make Ang II conceivable as a molecule involved in the inflammatory processes during the disease. Conclusion: This review is focused on defining which reported events would be related to the presence of this hormone in PSGN. [ABSTRACT FROM AUTHOR]

To celebrate 100 years of American Heart Association-supported cardiovascular disease research, this review article highlights milestone papers that have significantly contributed to the current understanding of the signaling mechanisms driving hypertension and associated cardiovascular disorders. This article also includes a few of the future research directions arising from these critical findings. To accomplish this important mission, 4 principal investigators gathered their efforts to cover distinct yet intricately related areas of signaling mechanisms pertaining to the pathogenesis of hypertension. The renin-angiotensin system, canonical and novel contractile and vasodilatory pathways in the resistance vasculature, vascular smooth muscle regulation by membrane channels, and noncanonical regulation of blood pressure and vascular function will be described and discussed as major subjects. [ABSTRACT FROM AUTHOR]

The early myocardial response of hypertension is an elevation of angiotensin‐II (Ang‐II) concentration, leading to heart failure and cardiac hypertrophy. This hypertrophic event of the heart is mediated by the interaction of Ang type 1 receptors (AT‐R1), thereby modulating NADPH oxidase activity in cardiomyocytes, which alters redox status in cardiomyocytes. Ellagic acid (EA) has anti‐inflammatory and anti‐oxidative capacities. Thus, EA has potential preventive effects on cardiovascular diseases and diabetes. In the last decades, because the protective effect of EA on Ang‐II‐induced hypertrophic responses is unclear, this study aims to investigate the protective effect of EA in cardiomyocytes. H9c2 cells were treated to Ang‐II 1 μM for 24 h to induce cellular damage. We found that EA protected against Ang‐II‐increased cell surface area and pro‐hypertrophic gene expression in H9c2. EA reduced Ang‐II‐caused AT‐R1 upregulation, thereby inhibiting oxidative stress NADPH oxidase activation. EA mitigated Ang‐II‐enhanced p38 and extracellular‐signal‐regulated kinase (ERK) phosphorylation. Moreover, EA treatment under Ang‐II stimulation also reversed NF‐κB activity and iNOS expression. This study shows that EA protects against Ang‐II‐induced myocardial hypertrophy and attenuates oxidative stress through reactive oxygen species‐mediated mitogen‐activated protein kinase signaling pathways in H9c2 cells. Thus, EA may be an effective compound for preventing Ang‐II‐induced myocardial hypertrophy. [ABSTRACT FROM AUTHOR]

BACKGROUND Abdominal aortic aneurysm (AAA) is an arterial disease characterized by dilatation of the aortic wall. It has been suggested that neutrophil counts and neutrophil elastase activity are associated with AAA. We investigated whether a neutrophil elastase (NE) inhibitor, sivelestat (Siv), had a protective effect against angiotensin II (AngII)-induced AAAs. METHODS Male apolipoprotein E-deficient mice were assigned into three groups: Vehicle + saline, AngII + saline, and AngII + Siv. All mice were administered intraperitoneally with either Siv or vehicle twice daily after AngII infusion. RESULTS In the 4-week AngII infusion study, plasma NE concentration (P  = 0.041) and its activity (P  = 0.011) were elevated by AngII. These increases were attenuated by Siv (concentration: P  = 0.010, activity: P  = 0.027). Further, plasma elastase activity was closely correlated with aortic width (R  = 0.6976, P  < 0.001). In the 1-week AngII infusion study, plasma and tissue elastase activity increased by AngII (plasma: P  = 0.034, tissue: P  < 0.001), but were reduced by Siv (plasma: P  = 0.014, tissue: P  = 0.024). AngII increased aortic width (P  = 0.011) but was attenuated by co-administration of Siv (P  = 0.022). Moreover, Siv decreased the incidence of AAAs (P  = 0.009). Elastin fragmentation induced by AngII was reduced by Siv. Many inflammatory cells that were either CD68 or Gr-1 positive were observed in the AngII + saline group, whereas few inflammatory cells were accumulated in the AngII + Siv group. MMP-2 and MMP-9 were enhanced by AngII, but were reduced by Siv. In vitro , MMP-2 activity was induced by human NE (medium: P  < 0.001, cells: P  = 0.001), which was attenuated by co-incubation of Siv in medium (P  < 0.001) and protein of human aortic smooth muscle cells (P  = 0.001). CONCLUSIONS Siv attenuated AngII-induced AAA through the inhibition of NE. [ABSTRACT FROM AUTHOR]

As a main extraction compound from Scutellaria baicalensis Georgi, Baicalin exhibits various biological activities. However, the underlying mechanism of Baicalin on hypertension‐induced heart injury remains unclear. In vivo, mice were infused with angiotensin II (Ang II; 500 ng/kg/min) or saline using osmotic pumps, followed by intragastrically administrated with Baicalin (5 mg/kg/day) for 4 weeks. In vitro, H9C2 cells were stimulated with Ang II (1 μM) and treated with Baicalin (12.5, 25 and 50 μM). Baicalin treatment significantly attenuated the decrease in left ventricular ejection fraction and left ventricular fractional shortening, increase in left ventricular mass, left ventricular systolic volume and left ventricular diastolic volume of Ang II infused mice. Moreover, Baicalin treatment reversed 314 differentially expressed transcripts in the cardiac tissues of Ang II infused mice, and enriched multiple enriched signalling pathways (including apoptosis, autophagy, AMPK/mTOR signalling pathway). Consistently, Baicalin treatment significantly alleviated Ang II‐induced cell apoptosis in vivo and in vitro. Baicalin treatment reversed the up‐regulation of Bax, cleaved‐caspase 3, cleaved‐caspase 9, and the down‐regulation of Bcl‐2. Meanwhile, Baicalin treatment alleviated Ang II‐induced increase of autophagosomes, restored autophagic flux, and down‐regulated LC3II, Beclin 1, as well as up‐regulated SQSTM1/p62 expression. Furthermore, autophagy inhibitor 3‐methyladenine treatment alleviated the increase of autophagosomes and the up‐regulation of Beclin 1, LC3II, Bax, cleaved‐caspase 3, cleaved‐caspase 9, down‐regulation of SQSTM1/p62 and Bcl‐2 expression after Ang II treated, which similar to co‐treatment with Baicalin. Baicalin treatment reduced the ratio of p‐AMPK/AMPK, while increased the ratio of p‐mTOR/mTOR. Baicalin alleviated Ang II‐induced cardiomyocyte apoptosis and autophagy, which might be related to the inhibition of the AMPK/mTOR pathway. [ABSTRACT FROM AUTHOR]

An abdominal aortic aneurysm (AAA) is a life-threatening cardiovascular disease. We identified plasma insulin-like growth factor 1 (IGF1) as an independent risk factor in patients with AAA by correlating plasma IGF1 with risk. Smooth muscle cell– or fibroblast-specific knockout of Igf1r, the gene encoding the IGF1 receptor (IGF1R), attenuated AAA formation in two mouse models of AAA induced by angiotensin II infusion or CaCl2 treatment. IGF1R was activated in aortic aneurysm samples from human patients and mice with AAA. Systemic administration of IGF1C, a peptide fragment of IGF1, 2 weeks after disease development inhibited AAA progression in mice. Decreased AAA formation was linked to competitive inhibition of IGF1 binding to its receptor by IGF1C and modulation of downstream alpha serine/threonine protein kinase (AKT)/mammalian target of rapamycin signaling. Localized application of an IGF1C-loaded hydrogel was developed to reduce the side effects observed after systemic administration of IGF1C or IGF1R antagonists in the CaCl2-induced AAA mouse model. The inhibitory effect of the IGF1C-loaded hydrogel administered at disease onset on AAA formation was further evaluated in a guinea pig-to-rat xenograft model and in a sheep-to-minipig xenograft model of AAA formation. The therapeutic efficacy of IGF1C for treating AAA was tested through extravascular delivery in the sheep-to-minipig model with AAA established for 2 weeks. Percutaneous injection of the IGF1C-loaded hydrogel around the AAA resulted in improved vessel flow dynamics in the minipig aorta. These findings suggest that extravascular administration of IGF1R antagonists may have translational potential for treating AAA. Editor's summary: An abdominal aortic aneurysm (AAA) is life threatening and has limited therapeutic options. Wei et al. showed that localized inhibition of insulin-like growth factor 1 receptor (IGF1R) protected against AAA. Humans with AAA had increased IGF1 and IGF1R in aortic tissue. In mice treated with angiotensin II infusion or calcium chloride to induce AAA, IGF1R was increased, and genetic deletion of Igf1r in smooth muscle cells or fibroblasts decreased AAA pathology. IGF1C, a peptide fragment of IGF1, inhibited IGF1R in human cells in culture and in the two mouse models, resulting in decreased AAA pathology. In both a rat and minipig model of aorta xenotransplantation to induce AAA, the application of a hydrogel containing IGF1C to the aorta decreased AAA pathology. Inhibiting IGF1R in AAA may be a treatment for slowing AAA. —Brandon Berry [ABSTRACT FROM AUTHOR]

Copyright of Journal of China Medical University is the property of Journal of China Medical University Editorial Office and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: Flavin monooxygenases (FMOs) are enzymes responsible for the oxidation of a broad spectrum of exogenous and endogenous amines. There is increasing evidence that trimethylamine (TMA), a compound produced by gut bacteria and also recognized as an industrial pollutant, contributes to cardiovascular diseases. FMOs convert TMA into trimethylamine oxide (TMAO), which is an emerging marker of cardiovascular risk. This study hypothesized that blood pressure phenotypes in rats might be associated with variations in the expression of FMOs. Methods: The expression of FMO1, FMO3, and FMO5 was evaluated in the kidneys, liver, lungs, small intestine, and large intestine of normotensive male Wistar-Kyoto rats (WKY) and two distinct hypertensive ratmodels: spontaneously hypertensive rats (SHRs) and WKY rats with angiotensin II-induced hypertension (WKY-ANG). Plasma concentrations of TMA and TMAO were measured at baseline and after intravenous administration of TMA using liquid chromatography-mass spectrometry (LC-MS). Results: We found that the expression of FMOs in WKY, SHR, andWKY-ANGrats was in the descending order of FMO3 > FMO1 >> FMO5. The highest expression of FMOs was observed in the liver. Notably, SHRs exhibited a significantly elevated expression of FMO3 in the liver compared to WKY and WKY-ANG rats. Additionally, the plasma TMAO/TMA ratio was significantly higher in SHRs than in WKY rats. Conclusion: SHRs demonstrate enhanced expression of FMO3 and a higher plasma TMAO/TMA ratio. The variability in the expression of FMOs and the metabolism of amines might contribute to the hypertensive phenotype observed in SHRs. [ABSTRACT FROM AUTHOR]

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly contagious virus that uses angiotensin converting enzyme 2 (ACE2), a pivotal member of the renin–angiotensin system (RAS), as its cell-entry receptor. Another member of the RAS, angiotensin II (Ang II), is the major biologically active component in this system. There is growing evidence suggesting that serum miRNAs could serve as prognostic biomarkers for SARS-CoV-2 infection and regulate ACE2 expression. Therefore, the aim of this study is to evaluate the changes in the serum levels of sACE2 and Ang II, as well as the expression level of miR-141-3p and miR-421 in SARS-CoV-2 positive and negative subjects. Methods: In the present study, the serum levels of sACE2 and Ang II were measured in 94 SARS-CoV-2 positive patients and 94 SARS-CoV-2 negative subjects with some symptoms similar to those of SARS-CoV-2 positive patients using the ELISA method. In addition, the expression level of miR-141-3p and miR-421 as ACE2 regulators and biomarkers was evaluated using quantitative real-time PCR (qRT-PCR) method. Results: The mean serum sACE2 concentration in the SARS-CoV-2-positive group was 3.268 ± 0.410 ng/ml, whereas in the SARS-CoV-2 negative group, it was 3.564 ± 0.437 ng/ml. Additionally, the mean serum Ang II level in the SARS-CoV-2 positive and negative groups were 60.67 ± 6.192 ng/L and 67.97 ± 6.837 ng/L, respectively. However, there was no significant difference in the serum levels of sACE2 (P value: 0.516) and Ang II (P value: 0.134) between the SARS-CoV-2 positive and negative groups. Meanwhile, our findings indicated that the expression levels of miR-141-3p and miR-421 in SARS-CoV-2 positive group were significantly lower and higher than SARS-CoV-2 negative group, respectively (P value < 0.001). Conclusions: Taken together, the results of this study showed that the serum levels of sACE2 and Ang II in SARS-CoV-2 positive and negative subjects were not significantly different, but the expression levels of miR-141-3p and miR-421 were altered in SARS-CoV-2 positive patients which need more investigation to be used as biomarkers for COVID-19 diagnosis. [ABSTRACT FROM AUTHOR]

This article discusses various aspects of cardiovascular research, including the role of SERCA2a and Mfn2 in cardiac microvascular ischemic injury, the impact of SERCA2a on mitochondrial fusion and hypoxic injury in cardiac microvascular endothelial cells, the involvement of Mfn2 in cardiac ischemic injury and cardioprotection, the role of mitochondrial dynamics in Charcot-Marie-Tooth type 2A, and the importance of understanding the molecular mechanisms of cell death and the role of mitochondria in various diseases. The article also provides a list of references for further research on cardiovascular topics. [Extracted from the article]

Cardiac remodeling is the primary pathological feature of chronic heart failure (HF). Exploring the characteristics of cardiac remodeling in the very early stages of HF and identifying targets for intervention are essential for discovering novel mechanisms and therapeutic strategies. Silent mating type information regulation 2 homolog 3 (SIRT3), as a major mitochondrial nicotinamide adenine dinucleotide (NAD)-dependent deacetylase, is required for mitochondrial metabolism. However, whether SIRT3 plays a role in cardiac remodeling by regulating the biosynthesis of mitochondrial cardiolipin (CL) is unknown. In this study, we induced pressure overload in wild-type (WT) and SIRT3 knockout (SIRT3−/−) mice via transverse aortic constriction (TAC). Compared with WT mouse hearts, the hearts of SIRT3−/− mice exhibited more-pronounced cardiac remodeling and fibrosis, greater reactive oxygen species (ROS) production, decreased mitochondrial-membrane potential (ΔΨm), and abnormal mitochondrial morphology after TAC. Furthermore, SIRT3 deletion aggravated TAC-induced decrease in total CL content, which might be associated with the downregulation of the CL synthesis related enzymes cardiolipin synthase 1 (CRLS1) and phospholipid-lysophospholipid transacylase (TAFAZZIN). In our in vitro experiments, SIRT3 overexpression prevented angiotensin II (AngII)- induced aberrant mitochondrial function, CL biosynthesis disorder, and peroxisome proliferator-activated receptor gamma (PPARγ) downregulation in cardiomyocytes; meanwhile, SIRT3 knockdown exacerbated these effects. Moreover, the addition of GW9662, a PPARγ antagonist, partially counteracted the beneficial effects of SIRT3 overexpression. In conclusion, SIRT3 regulated PPARγ-mediated CL biosynthesis, maintained the structure and function of mitochondria, and thereby protected the myocardium against cardiac remodeling. [ABSTRACT FROM AUTHOR]

Metformin (MET) is a drug used in the treatment of type 2 diabetes due to its insulin receptor sensitizing properties and anti-hepatic gluconeogenesis effect. One of the comorbidities in diabetes is the depression. This review aimed at summarizing the results of the available MET, depression and diabetes studies to clarify the possible role of MET in the depression during diabetes. A bibliographic search on PubMed, Embase, PsycINFO, Web of Science, Cochrane Central for studies referring to MET, depression and diabetes. Several studies have associated depression to the chronic inflammation that characterizes diabetes. Additionally MET is an anti-inflammatory molecule that generally acts by activating AMPK and inhibiting the NF-kB factor. In the context of diabetes, MET can act directly as an anti-inflammatory drug as well as inhibiting other pro-inflammatory molecules. In this regard, MET may inhibit the pro-inflammatory effects of angiotensin II. By facilitating the action of insulin and reducing hepatic gluconeogenesis, MET reduces circulating glucose levels, decreasing the formation of advanced glycation end products and therefore inflammation. During diabetes, the gut microbiota and the permeability of the intestinal barrier are altered, causing high levels of circulating lipopolysaccharides (LPS), which induce inflammation. MET can normalize the microbiota and the intestinal barrier permeability reducing the levels of LPS and inflammation. Clinical and experimental studies show the anti-depressant effect of MET mediated by different mechanisms both at the peripheral level and in the central nervous system. Therefore, MET as an anti-inflammatory drug can decrease symptoms of depression and represents a therapeutic approach to improve the psychological state of patients with diabetes. Additionally, insulin also has an anti-inflammatory effect that could act together with MET. Metformin (MET) is capable of decreasing inflammation and depression mediated by insulin receptor sensitization, decreased serum glucose levels, inhibition of neoglucogenesis, inhibition of angiotensin II (Ang II), normalization of gut microbiota and intestinal permeabilization and inhibition of NF-kB factor. [Display omitted] • Metformin (MET) is a drug with anti-inflammatory properties used in diabetes and metabolic syndrome. • Diabetes curses with manifestations of clinical depression. • Depression has been related to inflammatory processes. • MET with its anti-inflammatory property and inhibition of other pro-inflammatory molecules can improve depression in diabetes. [ABSTRACT FROM AUTHOR]

This document is a list of references for scientific articles on the topic of antioxidants and their role in health and disease. The articles cover various aspects such as lipid metabolism, neuroprotection, mitochondrial function, and therapeutic applications in conditions like cerebral ischemia-reperfusion injury and liver fibrosis. It serves as a valuable resource for library patrons conducting research on antioxidants. [Extracted from the article]

The coronavirus disease 2019 (COVID-19) pandemic has caused significant morbidity and mortality. Spike messenger RNA (mRNA)–based vaccines against severe acute respiratory syndrome coronavirus 2 may contribute to immune-mediated injuries. Here we present a case of a previously healthy 47-year-old man, who developed progressive jaundice 2 weeks after receiving his 3rd COVID-19 vaccination (1st mRNA-based vaccine). Apart from elevated serum total bilirubin levels (peaked at >70 mg/dL), deteriorating renal (blood urea nitrogen: peak, 108.5 mg/dL; creatinine: peak, 6 mg/dL) and exocrine pancreas (amylase: peak, 1717 U/L; lipase: peak, 5784 U/L) profiles were also seen. Vanishing bile duct syndrome characterized by ductopenia and cholangiocyte vacuolation, positive C4d deposition, and high titer of anti-angiotensin II type 1 receptor antibody consistently explain the overall antibody-mediated pathogenesis resembling antibody-mediated "rejection" in the solid organ transplant setting. Corticosteroids and plasmapheresis were administered, leading to gradual resolution of the symptoms, and the jaundice completely resolved 2 months later. In conclusion, we reported a case of antibody-mediated multiorgan injury after an mRNA COVID-19 vaccine, characterized by severe cholangiopathy. The patient recovered with corticosteroids and plasmapheresis, and long-term follow-up is necessary. [ABSTRACT FROM AUTHOR]

Aortic dissection (AD) is the most catastrophic vascular disease with a high mortality rate. Trimethylamine N-oxide (TMAO), a gut microbial metabolite, has been implicated in the pathogenesis of cardiovascular diseases. However, the role of TMAO in AD and the underlying mechanisms remain unclear. This study aimed to explore the effects of TMAO on AD. Plasma and fecal samples from patients with AD and healthy individuals were collected to analyze TMAO levels and gut microbial species, respectively. The plasma levels of TMAO were significantly higher in 253 AD patients compared with those in 98 healthy subjects (3.47, interquartile range (IQR): 2.33 to 5.18 μM vs. 1.85, IQR: 1.40 to 3.35 μM; p < 0.001). High plasma TMAO levels were positively associated with AD severity. An increase in the relative abundance of TMA-producing genera in patients with AD was revealed using 16S rRNA sequencing. In the angiotensin II or β-aminopropionitrile-induced rodent model of AD, mice fed a TMAO-supplemented diet were more likely to develop AD compared to mice fed a normal diet. Conversely, TMAO depletion mitigated AD formation in the BAPN model. RNA sequencing of aortic endothelial cells isolated from mice administered TMAO revealed significant upregulation of genes involved in inflammatory pathways. The in vitro experiments verified that TMAO promotes endothelial dysfunction and activates nuclear factor (NF)-κB signaling. The in vivo BAPN-induced AD model confirmed that TMAO increased aortic inflammation. Our study demonstrates that the gut microbial metabolite TMAO aggravates the development of AD at least in part by inducing endothelial dysfunction and inflammation. This study provides new insights into the etiology of AD and ideas for its management. [Display omitted] • Plasma levels of TMAO were significantly higher in AD patients compared with those in healthy subjects. • TMAO aggravates the development of AD. • TMAO induces EC dysfunction and activates the NF-κB signaling pathway. • Gut microbiota may be a new therapeutic target in AD. [ABSTRACT FROM AUTHOR]

Aim: Protein disulfide isomerases (PDIs) are involved in platelet aggregation and intravascular thrombosis, but their role in regulating endothelial function is unclear. Here, we characterized the involvement of vascular PDIA1 in angiotensin II (Ang II)‐induced endothelial dysfunction in mice. Methods: Endothelial dysfunction was induced in C57BL/6JCmd male mice via Ang II subcutaneous infusion, and PDIA1 was inhibited with bepristat. Endothelial function was assessed in vivo with magnetic resonance imaging and ex vivo with a myography, while arterial stiffness was measured as pulse wave velocity. Nitric oxide (NO) bioavailability was measured in the aorta (spin‐trapping electron paramagnetic resonance) and plasma (NO2− and NO3− levels). Oxidative stress, eNOS uncoupling (DHE‐based aorta staining), and thrombin activity (thrombin–antithrombin complex; calibrated automated thrombography) were evaluated. Results: The inhibition of PDIA1 by bepristat in Ang II‐treated mice prevented the impairment of NO‐dependent vasodilation in the aorta as evidenced by the response to acetylcholine in vivo, increased systemic NO bioavailability and the aortic NO production, and decreased vascular stiffness. Bepristat's effect on NO‐dependent function was recapitulated ex vivo in Ang II‐induced endothelial dysfunction in isolated aorta. Furthermore, bepristat diminished the Ang II‐induced eNOS uncoupling and overproduction of ROS without affecting thrombin activity. Conclusion: In Ang II‐treated mice, the inhibition of PDIA1 normalized the NO‐ROS balance, prevented endothelial eNOS uncoupling, and, thereby, improved vascular function. These results indicate the importance of vascular PDIA1 in regulating endothelial function, but further studies are needed to elucidate the details of the mechanisms involved. [ABSTRACT FROM AUTHOR]

Objective: Chronic kidney disease (CKD) is a progressive disorder characterized by intricate structural and functional alterations in the kidneys, attributable to diverse causative factors. Notably, the therapeutic promise of miR-145-5p in addressing renal pathologies has been discerned. This investigation seeks to elucidate the functional role of miR-145-5p in injured kidneys by subjecting human glomerular mesangial cells (HGMCs) to stimulation with Angiotensin II (AngII). Materials and Methods: Cellular viability and the levels of inflammatory mediators were evaluated utilizing Cell Counting Kit-8 (CCK-8), quantitative real-time polymerase chain reaction (qRT-PCR), and western blot methodologies, both in the presence of AngII incubation and in scenarios of miR-145p overexpression and downregulation. Furthermore, the cell cycle dynamics were elucidated through Fluorescence-activated Cell Sorting (FACS) analysis. Results: AngII incubation induced an upregulation of miR-145-5p and inflammatory factors including Intercellular Adhesion Molecule 1 (ICAM-1), Interleukin 6 (IL-6), Interleukin 8 (IL-8), and Interleukin 1β (IL-1β). Additionally, it elevated the expression of Cyclin A2, Cyclin D1, and the G2/M cell cycle ratio. Conversely, inhibition of miR-145-5p heightened the levels of inflammatory factors and cell cycle regulators induced by AngII incubation. Reduced expression of miR-145-5p correlated with a downregulation of Interleukin 10 (IL-10) expression, concurrently promoting HGMC proliferation under AngII stimulation. Moreover, ectopic miR-145-5p expression demonstrated a reduction in inflammatory factors, cell cyclin regulators, G2/M cell cycle ratio, and overall proliferation. Conclusion: MiR-145-5p exhibited inhibitory effects on the inflammatory response and proliferation induced by Angiotensin II in HGMCs, showcasing its potential as a therapeutic avenue for the treatment of kidney injury. [ABSTRACT FROM AUTHOR]

Orthostatic intolerance is a broad term that represents a spectrum of dysautonomic disorders, including postural orthostatic tachycardia syndrome (POTS) and orthostatic hypotension (OH), as manifestations of severe autonomic failure. While the etiology of orthostatic intolerance has not yet fully been uncovered, it has been associated with multiple underlying pathological processes, including peripheral neuropathy, altered renin–aldosterone levels, hypovolemia, and autoimmune processes. Studies have implicated adrenergic, cholinergic, and angiotensin II type I autoantibodies in the pathogenesis of orthostatic intolerance. Several case series have demonstrated that immunomodulation therapy resulted in favorable outcomes, improving autonomic symptoms in POTS and OH. In this review, we highlight the contemporary literature detailing the association of autoimmunity with POTS and OH. [ABSTRACT FROM AUTHOR]

Backgrounds: People with solitary functioning kidneys (SFK) are prone to renal failure with time. Accordingly, local renin angiotensin system (RAS) and renal functions in subjects with SFK may act differently compared to normal condition. This study was designed to determine the renal hemodynamics responses to angiotensin II (Ang. II) in SFK male and female rats. Methods: Fifty to sixty-day-old male and female Wistar rats were subjected to unilateral renal artery obstruction, and 28 days later basal renal hemodynamic responses to Ang. II were examined in SFK groups compared to sham groups. Results: The findings indicated lower renal vascular resistance (RVR) and renal blood flow (RBF) responses to Ang. II in male SFK compared to sham group. Such observation was not seen in female animals. Conclusions: An increase in renal metabolism due to hyperfunction, especially in SFK male rats, may cause a decrease in RVR. Moreover, the lower RBF response to Ang. II may be related to alteration to Ang. II receptors in the remnant kidneys in SFK rats. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the effect of remifentanil in clinical anesthesia and postoperative intravenous analgesia. Methods: A retrospective analysis was conducted on the medical records of 100 patients who received remifentanil for anesthesia and postoperative intravenous analgesia at Zibo Center Hospital, Zibo, China from February 2020 to February 2023. The patients were divided into study and control groups comprising 50 patients in each group. The study group received remifentanil intravenously (8 g/kg) while the control group received fentanyl (3 - 4 µg/kg). Heart rate (HR), mean arterial pressure (MAP), and Bispectral Index (BIS) were monitored 5 min before anesthesia (T1), 10 min after (T2), 40 min after (T3), and 5 min before the end of surgery (T4). The levels of blood glucose (Glu), angiotensin II (Ang II), and cortisol (Cor) were measured at T1, T2, T3, and T4. Analgesic and sedative effects were evaluated 3, 12 and 24 h after surgery using the visual analog scale (VAS) and Ramsay sedation score. Results: At T1, T2, T3, and T4, there were no significant differences in HR, MAP, and BIS between the two groups (p > 0.05), while the levels of Glu, Ang II, and Cor in study group were significantly lower (p < 0.05). At 3, 12 and 24 h after surgery, VAS score in the study group was significantly lower, while Ramsay's analgesia score was significantly higher (p < 0.05). Total effectiveness was significantly higher in the study group (p < 0.05). Recovery time for orientation, spontaneous breathing, awakening, stay in the recovery room, and incidence of adverse reactions were significantly lower in study group (p < 0.05). Conclusion: The use of remifentanil for postoperative intravenous analgesia significantly lowers stress response, sedation and improves recovery time. It is, therefore, effective, and produces lower adverse effects than fentanyl. Large-scale investigation to determine the impact of confounding factors on the outcome of fentanyl/remifentanil combination is required. [ABSTRACT FROM AUTHOR]

Introduction: Calcium channel blockers (CCB) are a leading cause of ingestion-associated fatality. Angiotensin-converting enzyme inhibitor (ACEi) overdose as part of co-ingestion is common and associated with refractory shock. Treatment options to manage this profound vasoplegia are limited. We describe the first case of use of newly formulated Angiotensin II for treatment of severe ACEi and CCB poisoning. Case Report: A 57-year-old man presented after suicide attempt by ingesting 20 tablets each of amlodipine 10 mg and benazepril 20 mg. His hypotension was initially managed with 35 mL/kg of crystalloid, norepinephrine, and hyperinsulinemic euglycemic therapy (HIET). His hemodynamics further deteriorated, and he developed lactic acidosis, electrolyte derangements, and renal dysfunction. Further complications of his ingestion included cardiac arrest, subsequent requirement for emergency cricothyrotomy, and renal replacement therapy. Maximal hemodynamic support with HIET therapy insulin drip 4.4 units/kg/hour, norepinephrine 2 mcg/kg/min, epinephrine 1 mcg/kg/min, vasopressin.06 units/hour, and intravenous lipid emulsion was unsuccessful. Ang II was started and titrated to maximal doses with dramatic improvement in hemodynamics. Within hours of starting Ang II, epinephrine was stopped and norepinephrine decreased by 50%. He was downgraded from the intensive care unit without any ongoing end-organ dysfunction. Discussion: Isolated CCB overdoses have high complication rates and well-established treatments. Therefore, management of CCB and ACEi co-ingestion is typically driven by CCB poisoning algorithm. There are multiple reports of CCB and ACEi co-ingestions causing treatment-refractory shock. Therapeutic options are limited by toxicities and availability of salvage therapies. Ang II is a safe and highly effective option to manage these patients. [ABSTRACT FROM AUTHOR]