The rational design of AT1 receptor antagonists represents a pivotal approach in the development of therapeutic agents targeting cardiovascular pathophysiology. Sartans, a class of compounds engineered to inhibit the binding and activation of Angiotensin II on the AT1 receptor, have demonstrated significant clinical efficacy. This review explores the multifaceted role of sartans in mitigating hypertension and related complications. We highlight the integration of crystallography, computational simulations, and NMR spectroscopy to elucidate sartan-AT1 receptor interactions, providing a foundation for the next-generation antagonist design. The review also delves into the challenges posed by the high lipophilicity and suboptimal bioavailability of sartans, emphasizing advancements in nanotechnology and novel drug delivery systems. Additionally, we discuss the impact of lipid bilayers on the AT1 receptor conformation and drug binding, underscoring the importance of the lipidic environment in receptor-drug interactions. We suggest that optimizing drug design to account for these factors could enhance the therapeutic potential of AT1 receptor antagonists, paving the way for improved cardiovascular health outcomes.

The renin-angiotensin system (RAS) is known to affect diverse physiological processes that affect the functioning of many key organs. Angiotensin-converting enzyme (ACE) modulates a variety of bioactive peptides associated with pain. ACE inhibitors (ACEis) have found applications in the treatment of cardiovascular, kidney, neurological and metabolic disorders. However, ACEis also tend to display undesirable effects, resulting in increased pain sensitization and mechanical allodynia. In this review, we provide comprehensive discussion of preclinical and clinical studies involving the evaluation of various clinically approved ACEis. With the emerging knowledge of additional factors involved in RAS signaling and the indistinct pharmacological role of ACE substrates in pain, extensive studies are still required to elucidate the mechanistic role of ACE in pain perception.

Several risk factors are associated with the chronic evolution of migraine. Clinical and preclinical studies have provided data about the role of hypertension (HT) as one of the potential modifiable risk factors of chronic migraine (CM). This review is focused on the biological and clinical evidence supporting common mechanisms underlying HT and migraine and the potential role of HT in the transition from episodic to chronic migraine.

We conducted a narrative review from a literature search covering the available evidence from studies investigating: i) the role of HT in the transition to CM in clinical practice; ii) the biological mechanisms potentially underpinning the association between HT and evolution to CM; iii) the role of antihypertensive medications in migraine prophylaxis.

HT proved to be at the base of multiple mechanisms underlying migraine and migraine chronicization. Endothelial dysfunction, blood-brain barrier alterations, calcitonin gene-related peptide signaling, and renin-angiotensin-aldosterone system dysregulation are involved in the worsening effect of HT on migraine frequency, and the role of HT in the transition to CM is supported by clinical observations.

The observed evidence supports HT contribution to CM evolution due to shared pathophysiologic mechanisms. While a bidirectional influence appears to be ascertained, data are still lacking about the one-way role of HT as direct risk factor for CM transition. Further research is needed to confirm a causal role of HT in this process.

Yangxue Qingnao Granules (YXQN) is a Chinese patent medicine that has been commonly used in the clinical treatment of migraine.

To assess the efficacy and safety of YXQN alone for the treatment of migraine.

We searched 10 databases to identify relevant randomized controlled trials (RCTs) published before September 2022. Two review authors independently searched and screened the literature, extracted the data, and assessed the methodological quality of the studies using criteria from ROB 2.0, and analyzed the data using Review Manager 5.4 software.

A total of 12 RCTs including 767 participants with migraine met the selection criteria. We divided these studies into comparisons of YXQN with placebo, routine treatment drugs, and other Chinese patent medicines. The meta-analysis showed the following: (1) Efficacy: The YXQN group outperformed the placebo group [relative risk (RR) = 0.29, 95% confidence interval (95%CI): 0.15-0.43, P < 0.00001], routine treatment group (RR = 0.18, 95%CI: 0.09-0.27, P < 0.0001), and Chinese patent medicine group (RR = 0.27, 95%CI: 0.13-0.41, P < 0.001); (2) frequency of headache: There was a significant difference between YXQN vs placebo [mean difference (MD) = -1.25, 95%CI: -1.60 to -0.90, P < 0.00001], routine treatment drugs (MD = -0.85, 95%CI: -1.15 to -0.56, P < 0.00001), and Chinese patent medicine (MD = -0.91, 95%CI: -1.35 to -0.46, P < 0.0001); (3) headache duration: We found great heterogeneity between studies, with no differences between YXQN and placebo (MD = -0.61, 95%CI: -1.53 to -0.31, P = 0.19) and routine treatment drugs (MD = -0.22, 95%CI: -0.89 to 0.46, P < 0.53). YXQN was more effective than other Chinese patent medicines in reducing headache duration (MD = -1.24, 95%CI: -1.70 to -0.77, P < 0.00001); and (4) headache severity: There was no significant difference between YXQN vs placebo (MD = -1.67, 95%CI: -3.52 to 0.19, P = 0.08), routine treatment drugs (MD = -0.53, 95%CI: -2.02 to 0.96, P = 0.68), and other Chinese patent medicines (MD = -0.49, 95%CI: -2.83 to 1.85, P = 0.68). Mild gastrointestinal adverse reactions were reported in three cases.

This study revealed that YXQN is effective and safe for treatment of migraine.

The mRNA SARS-CoV-2 vaccines were brought to market in response to the public health crises of Covid-19. The utilization of mRNA vaccines in the context of infectious disease has no precedent. The many alterations in the vaccine mRNA hide the mRNA from cellular defenses and promote a longer biological half-life and high production of spike protein. However, the immune response to the vaccine is very different from that to a SARS-CoV-2 infection. In this paper, we present evidence that vaccination induces a profound impairment in type I interferon signaling, which has diverse adverse consequences to human health. Immune cells that have taken up the vaccine nanoparticles release into circulation large numbers of exosomes containing spike protein along with critical microRNAs that induce a signaling response in recipient cells at distant sites. We also identify potential profound disturbances in regulatory control of protein synthesis and cancer surveillance. These disturbances potentially have a causal link to neurodegenerative disease, myocarditis, immune thrombocytopenia, Bell's palsy, liver disease, impaired adaptive immunity, impaired DNA damage response and tumorigenesis. We show evidence from the VAERS database supporting our hypothesis. We believe a comprehensive risk/benefit assessment of the mRNA vaccines questions them as positive contributors to public health.

Coronavirus disease 2019 (COVID-19) has emerged as a potentially severe disease, especially for individuals presenting with certain underlying medical conditions. We analyzed the rates of comorbidities and symptoms to reveal the potential severity of the pandemic in Volos, one of the most air-polluted cities in Greece. Environmental and health-related predictors for SARS-CoV-2 infection were investigated. A web-based questionnaire was disseminated through social media in the first half of March 2021 during a five-month strict lockdown. Sociodemographic data, preexisting medical conditions, frequency of clinical symptoms, and COVID-19 information were recorded. The study population consisted of 2000 responders. Four-fifths of the participants reported comorbidities that could increase vulnerability to severe COVID-19. Respiratory symptoms were reported from the unemployed and from retirees, and cold-related symptoms were reported in the education sector and in undergraduates. Women and younger generations shaped social vulnerability to respiratory infections similar to the elderly. SARS-CoV-2 infection was reported in 3.7% of the study population. Common headache (OR 2; CI 1189-3013; p = 0.007) and prior pneumonia (OR 1.9; CI 1024-2898; p = 0.04) were significant predictors for susceptibility to SARS-CoV-2 infection. The importance of monitoring society through community-based questionnaires is highlighted, for predicting and preventing future widespread transmission of infectious diseases.

Disability from migraine has a profound impact on the world's economy. Research has been ongoing to identify biomarkers to aid in diagnosis and treatment.

The aim of this study was to highlight the purported diagnostic and therapeutic migraine biomarkers and their role in precision medicine.

A comprehensive literature search was conducted using PubMed, Google Scholar, and clinicaltrials.gov using keywords: "migraine" OR "headache" combined with "biomarkers" OR "marker." Other keywords included "serum," "cerebral spinal fluid," "inflammatory," and "neuroimaging."

After a review of 88 papers, we find the literature supports numerous biomarkers in the diagnosis of migraine. Therapeutic biomarkers, while not as extensively published, highlight calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating peptide-38 (PACAP-38) as biomarkers with the most substantiated clinical relevance. Genetic markers mainly focusing on gene mutations with resultant biochemical alterations continue to be studied and show promise.

Although there are several proposed biomarkers for migraine, continued research is needed to substantiate their role in clinical practice.

Primary headache is a common malady that is often under-recognized and frequently inadequately managed in spite of the fact that it affects up to 95 % of the population in a lifetime. Many forms of headache, including episodic tension and migraine headaches, if properly diagnosed, are reasonably amenable to treatment, but a smaller, though not insignificant, percent of the population suffer daily from a chronic, intractable form of headache that destroys one's productivity and quality of life. These patients are frequently seen in neurological practices at a point when treatment options are limited and largely ineffective. In the following review, we will discuss mechanisms drawn from recent studies that address the transition from acute to chronic pain that may apply to the transformation from episodic to chronic daily headaches which may offer opportunities for preempting headache transformation.

In the present case-control study, we investigated the correlation between the common ACE insertion/deletion (I/D) polymorphism and migraine.

Genotyping of the ACE I/D variant was performed in 502 Caucasian patients with migraine and 323 age-, sex- and race/ethnicity-matched healthy controls. We investigated associations between ACE genetic variants and sociodemographic and/or clinical features of migraineurs.

We found a significant association between ACE insertion/insertion (I/I) polymorphism and lower use of pharmacological prophylaxis in migraine patients with aura and in those with chronic migraine. Moreover, ACE I/I polymorphism was significantly more common in migraine patients with aura who had a negative family history of migraine.

Our data suggest that although the ACE I/D polymorphism is not a direct risk factor for migraine, the ACE I/I genotype may influence the clinical feature of this disease being associated with reduced use of prophylactic agents in patients with migraine with aura and in those with chronic migraine.

The focus of this review is to review potential diagnostic and therapeutic biomarkers associated with migraine.

Migraine headache is a common disease that affects millions of individuals worldwide. Although well-accepted diagnostic criteria exist for migraine, it is still a complex disorder that remains both underdiagnosed and misdiagnosed. The causes of migraine are likely a mix of genetic, epigenetic, and environmental factors that, together with the individual's life history, translate into the observed clinical heterogeneity. Inherent clinical heterogeneity is an obstacle in developing more effective treatments. The lack of appropriate biomarkers is also an impediment to developing more effective therapeutic/preventive approaches. Ultimately, biomarkers may facilitate the goal of individualized medicine by enabling clinicians to more accurately diagnose and treat migraine and other types of headache.

A comprehensive review was conducted of PubMed citations containing the key word "marker" OR "biomarker" combined with "migraine" OR "headache." Other key words included "serum," "saliva," "cerebrospinal fluid," "genes," "blood," and "inflammation." The only restriction was English-language publication. The abstracts of all articles meeting these criteria were reviewed, and full text was retrieved and examined for relevant references.

Data from human studies have begun to identify genetic mutations/polymorphisms and altered levels of specific proinflammatory and neuromodulatory molecules that strongly correlate with migraine as well as symptom severity. Results from a smaller number of studies have identified parameters, such as the neuropeptide calcitonin gene-related peptide (CGRP), which are significantly associated with response to specific treatments for acute migraine attacks and prophylaxis. Epigenetic mechanisms may also be involved in the development of migraine, and understanding environmentally induced genetic changes associated with this disease may eventually guide the development of therapies capable of reversing these pathophysiological changes in gene function.

The understanding of the etiology of migraine is incomplete. Although the identification and validation of biomarkers has greatly advanced diagnostic precision and measures of therapeutic efficacy in other diseases, there are no currently accepted biomarkers for chronic or episodic migraine. However, the continued investigation and identification of genetic, epigenetic, and molecular biomarkers is likely to facilitate the goal of individualizing medicine by enabling clinicians to more accurately diagnose and treat migraine and other headache disorders.

In the present study, we have investigated the anti-nociceptive and anti-allodynic activity of the renin inhibitor, aliskiren, in various pain models. The anti-nociceptive activity of aliskiren was investigated in chemically-induced pain, orofacial pain and centrally mediated pain models. Anti-allodynic activity was evaluated in post-operative and neuropathic pain models. The levels of TNF-α and IL-6 were measured in homogenates of hind paw as markers of inflammation in formalin injected mice. Intraperitoneal administration of aliskiren (1-50mg/kg) showed anti-nociceptive activity in the writhing test, formalin hind paw test, capsaicin induced pain, and orofacial pain tests in ICR mice in a dose dependent manner. Aliskiren (50mg/kg, i.p.) reduced levels of TNF-α and IL-6 in hind paw homogenates of formalin-injected mice. Aliskiren (50mg/kg, i.p.) did not show any analgesic activity in hot-plate and tail-flick tests, indicating the absence of centrally mediated anti-nociceptive effects. On the other hand, intra-plantar administration of aliskiren (0.1, 0.5 and 1mg) showed analgesic activity in rat formalin tests, indicating a locally mediated effect. Aliskiren (30-100mg/kg, i.p.) showed anti-allodynic activity in post-operative pain and chronic constriction injury-induced neuropathic pain in Sprague Dawley rats. This data suggests that aliskiren may have the potential to be used as an anti-nociceptive and anti-allodynic agent.

The present study was designed to investigate the potential of aliskiren, a direct renin inhibitor, in chronic constriction injury (CCI)-induced neuropathic pain in rats. Neuropathic pain was induced by placing four loose ligatures around the sciatic nerve. Acetone drop, von Frey hair, pin-prick and hot plate tests were performed to assess cold allodynia, mechanical allodynia, mechanical and heat hyperalgesia, respectively. The levels of Tumor necrosis factor-alpha (TNF-α) were measured in the sciatic nerve as an inflammatory marker. CCI was associated with the development of cold allodynia, mechanical allodynia, mechanical and heat hyperalgesia along with a rise in the levels of Tumor necrosis factor-alpha (TNF-α). Administration of aliskiren (25 or 50 mg/kg intraperitoneal (i.p.)) for 14 days in CCI-subjected rats significantly attenuated CCI-induced pain-related behavior and rise in TNF-α level. It may be concluded that aliskiren-mediated anti-inflammatory actions may be responsible for its beneficial effects in neuropathic pain in rats.