There has been a significant shift in the perception of hypertension as an important contributor to the global disease burden. Approximately 6 % and 8 % of pregnancies are affected by hypertension, which can adversely affect the mother and the fetus. Furthermore, a hypertensive individual is at increased risk of developing kidney disease, arterial hardening, eye damage, and strokes. Using angiotensin receptor blockers (ARBs) is widespread in treating hypertension, heart failure, coronary artery disease, and diabetic nephropathy. Despite this, some ARBs have limited use due to their poor oral bioavailability and water solubility. To tackle this, a variety of nanoparticle (NP)-based systems, such as polymeric NPs (i. e., dendrimers), polymeric micelles, polymer-drug conjugates, lipid NPs, nanoemulsions, self-emulsifying drug delivery systems (SEDDS), solid lipid NPs (SLNs), nanostructured lipid carriers (NLCs), carbon-based nanocarriers, inorganic NPs, and nanocrystals, have been recently developed for efficient delivery of losartan, Valsartan (Val), Olmesartan (OLM), Telmisartan (TEL), Candesartan, Eprosartan, Irbesartan, and Azilsartan to target cells. This review article provides a literature-based comparison of the various classes of ARBs, their mechanisms of action, and an overview of the nanoformulations developed for ARB delivery and successfully applied to managing hypertension, diabetic complications, and other conditions.

Traumatic brain injuries (TBIs) are among the most important clinical and research areas in neurosurgery, owing to their devastating effects and high prevalence. Over the last few decades, there has been increasing research on the complex pathophysiology of TBI and secondary injuries following TBI. A growing body of evidence has shown that the renin-angiotensin system (RAS), a well-known cardiovascular regulatory pathway, plays a role in TBI pathophysiology. Acknowledging these complex and poorly understood pathways and their role in TBI could help design new clinical trials involving drugs that alter the RAS network, most notably angiotensin receptor blockers and angiotensin-converting enzyme inhibitors. This study aimed to briefly review the molecular, animal, and human studies on these drugs in TBI and provide a clear vision for researchers to fill knowledge gaps in the future.

Oral manifestations of COVID-19 are amongst the most obscure and ill-reported. Of these, angina bullosa haemorrhagica is amongst the rarest. Only 2 cases of angina bullosa haemorrhagica in COVID-19 patients have been reported in literature. Angina bullosa haemorrhagica (ABH) is an enigmatic, abstruse condition represented by sudden onset of painful subepithelial, mucosal blood-filled vesicles and bullae in the oral cavity. It is not attributed to any systemic conditions, blood dyscracias or other well-known dermatological pathologies. The occurrence of these lesions in patients of COVID-19 suggests that the underlying pathology of the latter may predispose to ABH and thus help in shedding some light onto the pathogenesis of this obscure disease. Herein we present 2 cases of ABH in patients of COVID-19 within a few weeks of the resolution of the latter. Both patients reported that they had never had this condition before and that this was the first presentation of the symptom. A review of literature shows that the etiopathogenesis of ABH is ambiguous at best and that the pathology underlying the oral manifestation of COVID-19 may well be applicable to ABH as well. Various mechanisms have been proposed to cause oral manifestations in COVID-19 patients. These include imbalance in the RAS pathway causing mucosal disruption, immune dysregulation, deranged cellular immune mechanism and disruption of local immune mechanisms. Since ABH has been reported in COVID 19, it is plausible that some of the mechanisms underlying the pathogenesis of oral manifestations may explain the pathogenesis of ABH.

The aim of this study is to analyze the latest evidence on the effects of losartan or Ang II receptor antagonists on cartilage repair, with a focus on their clinical relevance.
The PubMed, Embase, and Cochrane Library databases were searched up to November 12th 2021 to evaluate the effects of losartan or Ang II receptor antagonists on cartilage repair in in vitro studies and in vivo animal studies. Study design, sample characteristics, treatment type, duration, and outcomes were analyzed. The risk of bias and the quality of the eligible studies were assessed using the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) risk of bias assessment tool and Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies (CAMARADES).
A total of 12 studies were included in this systematic review. Of the 12 eligible studies, two studies were in vitro human studies, three studies were in vitro animal studies, one study was an in vitro human and animal study, and six studies were in vivo animal studies. The risk bias and quality assessments were predominantly classified as moderate. Since meta-analysis was difficult due to differences in treatment type, dosage, route of administration, and method of outcome assessment among the eligible studies, qualitative evaluation was conducted for each study.
Both in vitro and in vivo studies provide evidence to demonstrate beneficial effects of Ang II receptor antagonists on osteoarthritis and cartilage defect models across animal species.

COVID‑19 patients with severe infection have been observed to have elevated auto‑antibodies (AAs) against angiotensin II receptor type 1 (AT1R) and endothelin (ET) 1 receptor type A (ETAR), compared with healthy controls and patients with favorable (mild) infection. AT1R and ETAR are G protein‑coupled receptors, located on vascular smooth muscle cells, fibroblasts, immune and endothelial cells, and are activated by angiotensin II (Ang II) and ET1 respectively. AAs that are specific for these receptors have a functional role similar to the natural ligands, but with a more prolonged vasoconstrictive effect. They also induce the production of fibroblast collagen, the release of reactive oxygen species and the secretion of proinflammatory cytokines (including IL‑6, IL‑8 and TNF‑α) by immune cells. Despite the presence of AAs in severe COVID‑19 infected patients, their contribution and implication in the severity of the disease is still not well understood and further studies are warranted. The present review described the major vascular homeostasis systems [ET and renin‑angiotensin‑aldosterone system (RAAS)], the vital regulative role of nitric oxide, the AAs, and finally the administration of angiotensin II receptor blockers (ARBs), so as to provide more insight into the interplay that exists among these components and their contribution to the severity, prognosis and possible treatment of COVID‑19.

Obstructive sleep apnea is a chronic, sleep-related breathing disorder, which is an independent risk factor for cardiovascular disease. The renin-angiotensin-aldosterone system regulates salt and water homeostasis, blood pressure, and cardiovascular remodelling. Elevated aldosterone levels are associated with excess morbidity and mortality. We aimed to analyse the influence and implications of renin-angiotensin-aldosterone system derangement in individuals with and without obstructive sleep apnea. We pooled data from 20 relevant studies involving 2828 participants (1554 with obstructive sleep apnea, 1274 without obstructive sleep apnea). The study outcomes were the levels of renin-angiotensin-aldosterone system hormones, blood pressure and heart rate. Patients with obstructive sleep apnea had higher levels of plasma renin activity (pooled wmd+ 0.25 [95% confidence interval 0.04-0.46], p = 0.0219), plasma aldosterone (pooled wmd+ 30.79 [95% confidence interval 1.05-60.53], p = 0.0424), angiotensin II (pooled wmd+ 5.19 [95% confidence interval 3.11-7.27], p < 0.001), systolic (pooled wmd+ 5.87 [95% confidence interval 1.42-10.32], p = 0.0098) and diastolic (pooled wmd+ 3.40 [95% confidence interval 0.86-5.94], p = 0.0086) blood pressure, and heart rate (pooled wmd+ 3.83 [95% confidence interval 1.57-6.01], p = 0.0009) compared with those without obstructive sleep apnea. The elevation remained significant (except for renin levels) when studies involving patients with resistant hypertension were removed. Sub-group analysis demonstrated that levels of angiotensin II were significantly higher only among the Asian population with obstructive sleep apnea compared with those without obstructive sleep apnea. Body mass index accounted for less than 10% of the between-study variance in elevation of the renin-angiotensin-aldosterone system parameters. Patients with obstructive sleep apnea have higher levels of renin-angiotensin-aldosterone system hormones, blood pressure and heart rate compared with those without obstructive sleep apnea, which remains significant even among patients without resistant hypertension.

The activation of the Renin Angiotensin System (RAS) is required during pregnancy and it seems that RAS dysfunction has some important effects on pathological pregnancy conditions, including preeclampsia (PE). The objective of this review is to summarize and to discuss the role of the RAS in normal pregnancy and in PE. We found evidence that the RAS is important for the evolution of pregnancy under physiological conditions and plays an important role in the pathogenesis of PE. In normal gestation, almost all circulating components of RAS are increased and there is a general state of non-reactivity to the vasoconstrictor actions of Angiotensin (Ang) II. In PE, changes in the circulating levels of RAS components occur, especially with an intense decrease in the levels of Ang I, Ang II and Ang-(1-7). Our findings endorse the idea that PE is a disease whose cornerstone relies on altered placental physiology. There are high tissue levels of Ang II type 1 receptor (AT1R) in the musculature of the blood vessels and in the placenta, generating a state of increased sensitivity to the vasoconstrictor action of Ang II. AT1R autoantibodies (AT1R-AA) might be one of the key points for the vicious cycle of PE, as these molecules are synthesized in situations of hypoxia and enhance placental vasoconstriction, causing even more hypoxia. Further studies are needed to investigate the role of circulating RAS, uteroplacental RAS and local RAS molecules from other tissues related to the pathogenesis of PE.

BACKGROUND: Much research shows that blood calcidiol (25(OH)D3) levels correlate strongly with SARS-CoV-2 infection severity. There is open discussion regarding whether low D3 is caused by the infection or if deficiency negatively affects immune defense. The aim of this study was to collect further evidence on this topic.
METHODS: Systematic literature search was performed to identify retrospective cohort as well as clinical studies on COVID-19 mortality rates versus D3 blood levels. Mortality rates from clinical studies were corrected for age, sex, and diabetes. Data were analyzed using correlation and linear regression.
RESULTS: One population study and seven clinical studies were identified, which reported D3 blood levels preinfection or on the day of hospital admission. The two independent datasets showed a negative Pearson correlation of D3 levels and mortality risk (r(17) = -0.4154, p = 0.0770/r(13) = -0.4886, p = 0.0646). For the combined data, median (IQR) D3 levels were 23.2 ng/mL (17.4-26.8), and a significant Pearson correlation was observed (r(32) = -0.3989, p = 0.0194). Regression suggested a theoretical point of zero mortality at approximately 50 ng/mL D3.
CONCLUSIONS: The datasets provide strong evidence that low D3 is a predictor rather than just a side effect of the infection. Despite ongoing vaccinations, we recommend raising serum 25(OH)D levels to above 50 ng/mL to prevent or mitigate new outbreaks due to escape mutations or decreasing antibody activity.

Ischemia with no obstructive coronary artery disease (INOCA) is a common diagnosis with a higher prevalence in women compared to men. Despite the absence of obstructive coronary artery disease and no structural heart disease, INOCA is associated with major adverse cardiovascular outcomes as well a significant contributor to angina and related disability. A major feature of INOCA is coronary microvascular dysfunction (CMD), which can be detected by non-invasive imaging and invasive coronary physiology assessments in humans. CMD is associated with epicardial endothelial-dependent and -independent dysfunction, diffuse atherosclerosis, and left-ventricular hypertrophy, all of which lead to insufficient blood flow to the myocardium. Inflammatory and oxidative stress signaling, upregulation of the renin-angiotensin-aldosterone system and adrenergic receptor signaling are major drivers of CMD. Treatment of CMD centers around addressing cardiovascular risk factors; however, there are limited treatment options for those who do not respond to traditional anti-anginal therapies. In this review, we highlight the ability of berry-derived polyphenols to modulate those pathways. The evidence supports the need for future clinical trials to investigate the effectiveness of berries and their polyphenols in the treatment of CMD in INOCA patients.

Heerfordt\'s syndrome is a rare manifestation of sarcoidosis combining uveitis, parotidomegaly, facial paralysis and fever in its classic form. It is an active form of the disease whose diagnosis is facilitated by salivary gland biopsy. We conducted clinical observation of a 17-year-old female patient with uveitis, right parotidomegaly and right facial paralysis characterized by violent onset. After laboratory tests and imaging exam (parotid ultrasound), biopsy of minor salivary glands established the diagnosis of sarcoidosis. A pre-therapeutic assessment allowed for the initiation of oral corticosteroid therapy with favorable outcome and total remission. Heerfordt\'s syndrome is a rare clinical form of sarcoidosis, with favorable outcome in most cases. Specific diagnostic approach (excluding differential diagnoses, especially the incomplete forms) is necessary, based on therapeutic advances in this area.