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•Most genes involved in collagen metabolism are upregulated in NSCLC.•High expression of those genes is associated with poor outcome.•In vitro RAS inhibitors led to a dose dependent ...decrease of collagen deposition.•RAS inhibitor intake was associated with improved survival in a large NSCLC cohort.•Our results point towards collagen biosynthesis as a promising target in NSCLC.
The tumor-microenvironment (TME) represents an attractive therapeutic target in NSCLC and plays an important role for efficacy of cancer therapeutics. We hypothesized that upregulation of collagen synthesis might be associated with adverse outcome in NSCLC. Literature evidence suggests that renin-angiotensin system inhibitors (RASi) decrease collagen deposition. Therefore, we aimed to explore the prognostic role of RASi intake and their influence on the TME in NSCLC.
Four publicly available datasets were used to evaluate the impact of key enzymes involved in collagen biosynthesis. To investigate the influence of RASi intake on the TME and prognosis we evaluated a cohort of metastatic NSCLC patients and performed histopathological characterization of the TME. A three-dimensional microtissue in vitro model was developed to define the impact of RASi on collagen synthesis.
Expression of three genes of the collagen synthesis pathway, ALDH18A1, PLOD2 and P4HA1, was upregulated in NSCLC compared to normal lung tissue and linked to shortened overall survival in all investigated cohorts. Together, these genes formed a ‘Collagen Signature’ which represents an independent unfavourable prognostic factor in two NSCLC cohorts and was linked to alterations of the extracellular matrix deposition and cell cycle pathways. In the cohort of metastatic NSCLC, RASi intake was linked to improved overall response rate and survival. Exploratory in vitro experiments revealed that RASi led to a dose dependent reduction of collagen deposition and degradation of three-dimensional lung cancer cell spheroids.
We demonstrate that collagen synthesis is a key upregulated process in the NSCLC TME and its transcriptional readout, the three gene Collagen Signature is independently associated with poor outcome. Pharmacological targeting of this pathways e.g. by RASi bears potential of improving outcome in NSCLC.
Major depressive disorder (MDD) is a highly heterogeneous disorder, which may partly explain why treatment outcome using antidepressants is unsatisfactory. We investigated the onset of depression as ...a possible clinical marker for therapy response prediction in the context of somatic biomarkers blood pressure and plasma electrolyte concentration. 889 MDD patients were divided into early (EO, n = 226), intermediate (IO, n = 493), and late onset (LO, n = 169) patients and were analyzed for differences in socio-demographic and clinical parameters, comorbidities and treatment outcome as well as systolic blood pressure and electrolytes. EO patients more often suffered from a recurrent depression, had more previous depressive episodes, a higher rate of comorbid axis I and II disorders, and more often reported of suicidality (p < 0.001) compared to IO and LO patients. Treatment outcome was not different from IO and LO patients, although LO patients responded faster. EO patients who showed an early non-improvement of depression after 2 weeks of therapy (<20% improvement) had a 4.3-fold higher likelihood to become non-remitter as compared to LO patients with an early improvement. EO patients had significantly lower systolic blood pressure than patients with IO or LO and electrolytes in EO patients were significantly correlated with depression severity. Our results confirm other studies showing an association of an early onset of depression with a slower treatment response. The worse treatment outcome in patients with an additional early non-improvement to antidepressant therapy opens perspectives to develop and test individualized treatment approaches for EO and LO patients in the future, which may be based on differences in autonomic regulation.
Licorice, through the effects of glycyrrhizic acid (GA), raises blood pressure (BP). The World Health Organization has suggested that 100 mg GA/d would be unlikely to cause adverse effects, but of 13 ...previously published studies none have been randomized and controlled and independently quantified the GA content.
Our aim was to analyze the effects on home BP of a daily licorice intake containing 100 mg GA.
Healthy volunteers were randomly assigned to start with either licorice or a control product in a nonblinded, 2 × 2 crossover study. Home BP was measured daily, and blood samples were collected at the end of each 2-wk period.
There were 28 participants and no dropouts. The median age was 24.0 y (interquartile range 22.8–27.0 y). During the licorice compared with control intake period, the systolic home BP increased mean difference: 3.1 mm Hg (95% confidence interval CI: 0.8, 5.4 mm Hg) compared with −0.3 mm Hg (95% CI: −1.8, 1.3 mm Hg); P = 0.018 and renin and aldosterone were suppressed mean change: −30.0% (95% CI: −56.7%, −3.3%) compared with 15.8% (95% CI: −12.8%, 44.4%); P = 0.003; and −45.1% (95% CI: −61.5%, −28.7%) compared with 8.2% (95% CI: −14.7%, 31.1%); P <0.001, respectively. In the quartile of participants with the most pronounced suppression of renin and aldosterone, N-terminal prohormone of brain natriuretic peptide concentration increased during the licorice compared with control period mean change: 204.1% (95% CI: −11.6%, 419.7%) compared with 72.4% (95% CI: −52.2%, 197.1%); P = 0.016.
We found licorice to be more potent than previously known, with significant increases in BP, after a daily intake of only 100 mg GA. Thus, the safe limit of intake of this substance might need to be reconsidered.
This trial was registered at clinicaltrials.gov as NCT05661721 (https://clinicaltrials.gov/study/NCT05661721).
Essential hypertension is a pivotal risk factor for the development of cardiovascular disease (CVD). Hypertensives exhibit greater stress-induced responses in various physiological systems considered ...to contribute to CVD progression. Whether this stress hyperreactivity extends to the adrenal hormone aldosterone has not yet been investigated in essential hypertension. Here, we investigated reactivity of plasma aldosterone to acute psychosocial stress induction in hypertensive and normotensive men. 21 hypertensive men and 25 normotensive controls underwent the standardized Trier-Social-Stress-Test (TSST). We repeatedly assessed plasma aldosterone before and up to 1 h after TSST cessation. Acute psychosocial stress induced significantly greater increases in hypertensives as compared to normotensives (F(3.60, 158.50) = 3.75; p = .008, f = 0.29). Our findings suggest stress-induced hyperreactivity of aldosterone in essential hypertension. Potential implications for stress-related cardiovascular risk remain to be elucidated.
•We found TSST-induced aldosterone increases in hypertensive and normotensive men.•Our results suggest aldosterone hyperreactivity to stress in essential hypertension.•Aldosterone reactivity differed 1 and 10 min after stress cessation between groups.
The renin-angiotensin-aldosterone system (RAAS) plays a relevant role in regulating blood pressure and thus maintaining cardiovascular homeostasis. Although it was recently shown that RAAS parameters ...are responsive to acute psychosocial stress, the psychobiological determinants of the acute stress-induced RAAS activation have not yet been investigated. In a randomized placebo-controlled design, we investigated potential psychological and physiological determinants of the RAAS response and underlying mechanisms.
Fifty-seven young healthy male participants underwent either an acute standardized psychosocial stress test or a nonstress placebo task. We measured aldosterone in plasma and saliva, as well as renin, and the stress-reactive endocrine measures adrenocorticotropic hormone (ACTH), epinephrine, and norepinephrine in plasma at rest, immediately after the task and several times up to 3 hours thereafter. Moreover, we assessed stress-reactive psychological (anticipatory cognitive stress appraisal, mood, physical discomfort) and basal demographic-physiological measures (age, body mass index, blood pressure).
Acute psychosocial stress elicited changes in all assessed endocrine (p values ≤ .028, ηp2 values ≥ 0.07) and stress-reactive psychological measures (p values ≤ .003, ηp2 values ≥ 0.15). The basal parameter body mass index, the stress-reactive endocrine parameters ACTH and norepinephrine, and the psychological parameter anticipatory stress appraisal were identified as determinants of higher RAAS parameter reactivity to acute psychosocial stress. The association between anticipatory cognitive stress appraisal and plasma RAAS measures was fully mediated by ACTH increases (p values ≤ .044, ηp2 values ≥ 0.05).
Cognitive stress appraisal processes seem to modulate RAAS stress reactivity. This points to potential clinical implications for psychoeducative therapeutical interventions targeting stress appraisal processes to reduce endocrine stress reactivity.
The mineralocorticoid hormone aldosterone is a key regulator of the sodium–potassium balance and blood pressure. In excess, aldosterone relates to hypertension and cardiovascular disease (CVD). Here, ...we systematically investigated aldosterone secretion during the day in terms of salivary aldosterone awakening response (AldAR) and salivary aldosterone daytime levels (AldDay) under controlled conditions in participants’ natural environment including assessment of potential confounding variables.
In 40 healthy young men, saliva samples for AldAR were collected immediately after awakening and 15, 30, 45, and 60 min thereafter. AldDay levels were measured in 1 h intervals from 9:00–22:00 h. Analyses were complemented by salivary cortisol assessment. Fluid and food intake was standardized and as potential confounders, we assessed awakening time and sleep duration, age, BMI and MAP, as well as chronic stress.
Awakening was followed by significant increases in salivary aldosterone (p = .004, f= 0.31), returning to baseline levels > 60 min later. Longer sleep duration was associated with lower AldAR (p < .001, f= 0.36). Over the course of the day we observed a continuous decrease of AldDay (p < .001, f= 0.45). Longer sleep duration (p = .097, f= .21), later time of awakening (p < .001, f= .29), and higher chronic stress (p = .041, f= .23) were associated with AldDay characteristics. Circadian aldosterone secretion was positively associated with most cortisol measures.
We observed an awakening response in salivary aldosterone and could confirm a decrease in aldosterone levels during the day, comparable to cortisol. Significant confounders were sleep-related variables and chronic stress. Clinical implications of circadian aldosterone secretion with respect to CVD risk remain to be elucidated.
•Salivary aldosterone showed a response to awakening.•Salivary aldosterone levels decreased over the course of the day.•Sleep duration was associated with the salivary aldosterone awakening response.•Sleep duration, awakening time, and chronic stress related to daytime aldosterone.
Aims Elevated natriuretic peptides (NPs) are associated with an increased cardiovascular risk following acute coronary syndromes (ACSs). However, the therapeutic implications are still undefined. We ...hypothesized that early inhibition of renin–angiotensin–aldosterone system (RAAS) in patients with preserved left ventricular function but elevated NPs but following ACS would reduce haemodynamic stress as reflected by a greater reduction NP compared with placebo. Methods and results AVANT GARDE-TIMI 43 trial, a multinational, double-blind trial, randomized 1101 patients stabilized after ACS without clinical evidence of heart failure or left ventricular function ≤40% but with an increased level of NP 3–10 days after admission to aliskiren, valsartan, their combination, and placebo. The primary endpoint was the change in NT-proBNP from baseline to Week 8. NT-proBNP declined significantly in each treatment arm, including placebo, by Week 8, though there were no differences in the reduction between treatment strategies (42% in placebo, 44% in aliskiren, 39% in valsartan, and 36% in combination arm). Although several subgroups had higher baseline levels of NP and greater reductions over the study period, there were no differences among treatment groups in any subgroup. There were no differences in clinical outcomes but there were more adverse events, including serious events and adverse events leading to early study drug discontinuation, in patients treated with active therapy. Conclusion In this study of a high-risk population with elevated levels of NPs but relatively preserved systolic function and no evidence of heart failure following ACS, there was no evidence for a benefit of early initiation of inhibition of RAAS with valsartan, aliskiren, or their combination compared with placebo with respect to a reduction in NP over 8 weeks of therapy. Moreover, adverse events were reported more frequently in patients assigned to active therapy.
Hypertension is one of the most common disease of the cardiovascular system. Important components of a rational antihypertensive therapy are drugs that block the RAAS. The aim of the study was to ...conduct a comparative evaluation of the effectiveness of blockade of the renin-angiotensin-aldosterone system with drug combinations – aliskiren and amlodipine and combination of ramipril and amlodipine in patients with hypertension and increased body weight. 50 patients with hypertension of stage II, II degree, high and very high risk were involved in the study. Patients were randomized into two groups depending on the received treatment. The first group (25 patients) consisted of patients treated with combined therapy including ramipril and amlodipine, the second group (25 patients) consisted of patients receiving a combination of aliskiren and amlodipine. The control group (25 people) included apparently healthy people. By the 12th week of the study the daily average systolic blood pressure in the first group was 146 (145; 150) mm Hg and 131 (130; 137) mm Hg in the second group, respectively, the daily average diastolic blood pressure was equal to 94 (91; 96) mm Hg in the first group and 81 (80; 82) mm Hg in the second group . By the 12th week of treatment plasma renin levels in the first group was equal to 73 (50; 78) and 15 (14; 27) in the second group, respectively, the level of angiotensin-I in the first group was 6 (4; 7) and 1,4 (1,1; 1,9) in the second group, aldosterone levels in the first group was equal to 134 (132; 145) and 130 (123; 132) in the second group, respectively. It is found that combination of aliskiren and amlodipine have the advantage over the combination of ramipril and amlodipine in achieving of purposeful level of systolic and diastolic blood pressure in patients with hypertension and overweight. The purposeful level of blood pressure reached to 56,6% of patients in group I and 80% of patients in group II to 12th week of the study. Receiving both combinations equally reduces plasma aldosterone levels at the same time receiving a combination of aliskiren and amlodipine accompanied by a decrease in plasma rennin level of 69% and angiotensin-I of 67%, while the combination of ramipril and amlodipine increases of these hormones on 68% and 65% respectively. Thus, using combination of ramipril and amlodipine more effective in patients with low rennin hypertension , patients with normal and high rennin hypertension necessary combination of aliskiren and amlodipine.
The role of inflammation in cardiovascular disease and in hypertensive disease above all, is complex. Several studies confirm that activation of renin-angiotensin-aldosterone system (RAAS), through ...increase in the production of angiotensin II (Ang II), is closely related to local vascular inflammation. Over the BP lowering effects of anti-hypertensive treatments, several ancillary effects for every class may be found, distinguishing the various drugs from one another. Given the pro-inflammatory effects of Ang II and aldosterone, agents that interfere with the components of RAAS, such as ACE inhibitors, Angiotensin Receptor Blockers (ARBs), and mineralocorticoid receptor antagonists (spironolactone or the more selective eplerenone), represent logical therapeutic tools to reduce vascular inflammation and cardiovascular risk, as suggested in large clinical trials in patients with hypertension and diabetes. Regarding ACE inhibitors, actually there is no convincing evidence indicating that ACEi's reduce plasma levels of major inflammatory markers in hypertension models. Lack of evidence concerns especially these inflammation markers, such as fibrinogen of CRP, which are less closely related to atherosclerotic disease and vascular damage and conversely are affected by several more aspecific factors. Results obtained by trials accomplished using ARBs seem to be more univocal to confirm, although to great extent, these is an anti-inflammatory effect of drugs blocking AT1 receptor. In order to strictly study the effects of blockage of RAAS on inflammation, future studies may explore different strategies by, for example, simultaneously acting on the ACE and the AT1 angiotensin receptors.
The coronavirus disease 2019 (COVID-19) pandemic is driven by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which has led to an enormous burden on patient morbidity and ...mortality. The renin-angiotensin-aldosterone system (RAAS) plays a significant role in various pulmonary diseases. Since SARS-CoV-2 utilizes the angiotensin-converting enzyme (ACE)2 receptor to exert its virulence and pathogenicity, the RAAS is of particular importance in COVID 19.
Our preliminary study investigates retrospectively the influence of selected ACE-polymorphisms (I/D location at intron 16 in the B-coding sequence (rs4646994) and A-240T (rs 4291) at the A-promoter) as well as ACE1 and ACE2 serum levels on disease severity and the inflammatory response in inpatients and outpatients with COVID-19.
Our study included 96 outpatients and 88 inpatients (65.9% male, mean age 60 years) with COVID-19 from April to December 2020 in four locations in Germany. Of the hospitalized patients, 88.6% participants were moderately ill (n = 78, 64% male, median age 60 years), and 11.4% participants were severely ill or deceased (n = 10, 90% male, median age 71 years). We found no polymorphism-related difference in disease, in age distribution, time to hospitalization and time of hospitalization for the inpatient group. ACE1 serum levels were significantly increased in the DD compared to the II polymorphism and in the TT compared to the AA polymorphism. There was no significant difference in ACE 1 serum levels l between moderately ill and severely ill patients. However, participants requiring oxygen supplementation had significantly elevated ACE1 levels compared to participants not requiring oxygen, with no difference in ACE2 levels whereas females had significantly higher ACE2 levels.
Although there were no differences in the distribution of ACE polymorphisms in disease severity, we found increased proinflammatory regulation of the RAAS in patients with oxygen demand and increased serum ACE2 levels in women, indicating a possible enhanced anti-inflammatory immune response.
PreBiSeCov: German Clinical Trials Register, DRKS-ID: DRKS00021591, Registered on 27th April 2020.
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