Complement hyperactivation and thrombotic microangiopathy are closely associated with severe COVID-19. Endothelial dysfunction is a key mechanism underlying thrombotic microangiopathy. To address the relationship between endothelial injury, complement activation and thrombotic microangiopathy of severe COVID-19, we wonder whether, and if so, what and how SARS-CoV-2 factors make endothelial cells (ECs) sensitive to complement-mediated cytotoxicity. We revealed that multiple SARS-CoV-2 proteins enhanced complement-mediated cytotoxicity to ECs by inhibiting membrane complement regulatory proteins (CRPs) and enhancing the deposition of complement-recognizing component FCN1. By screening with CRISPR/Cas9-gRNA libraries, we identified that ADAMTS9, SYAP1, and HIGD1A as intrinsic regulators of CD59 on ECs, which were inhibited by the SARS-CoV-2 M, NSP16, and ORF9b proteins. IFN-γ, GM-CSF, and IFN-α upregulated CD55 and CD59, while IFN-γ antagonized the inhibition of CD59 by the three SARS-CoV-2 proteins. So, the deficiency of IFN-γ weakened the protection of ECs by CRPs against complement-mediated injury which may be enhanced during infection. Our findings illustrated the regulation of protection against complement-mediated attack on self-cells by SARS-CoV-2 infection and immune responses, providing insights into endothelial injury, thrombotic microangiopathy, and potential targets for treating severe COVID-19.

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has led to a significant burden on global healthcare systems. COVID-19-induced acute kidney injury (AKI) is among one of the complications, that has emerged as a critical and frequent condition in COVID-19 patients. This AKI among COVID-19 patients is associated with poor outcomes, and high mortality rates, especially in those with severe AKI or requiring renal replacement therapy. COVID-19-induced AKI represents a significant complication with complex pathophysiology and multifactorial risk factors. Indeed, several pathophysiological mechanisms, including direct viral invasion of renal cells, systemic inflammation, endothelial and thrombotic abnormalities as well as nephrotoxic drugs and rhabdomyolysis are believed to underlie this condition. Moreover, histopathological and immunohistopathological findings commonly observed in postmortem studies include acute tubular necrosis, glomerular injury, and the presence of viral particles within renal tissue and urine. Identified risk factors for developing AKI vary among studies, depending on regions, underlying conditions, and the severity of the disease. Moreover, histopathological and immunohistopathological findings commonly observed in postmortem studies include show acute tubular necrosis, glomerular injury, and viral particles within renal tissue and urine. While, identified risk factors for developing AKI vary among studies, according to regions, underlying conditions, and the gravity of the disease. This narrative review aims to synthesize current knowledge on the incidence, pathophysiology, risk factors, histopathology, and outcomes of AKI induced by COVID-19.

The Angiotensin-converting enzyme 2 (ACE2) receptor, crucial for coronavirus recognition of host cells, is a key target for therapeutic intervention against SARS-CoV-2 and related coronaviruses. Therefore, thoroughly investigating the interaction mechanism between ACE2 and the Spike protein (S protein), as well as developing targeted inhibitors based on this mechanism, is vital for effectively controlling the spread of SARS-CoV-2 and preventing potential future pandemics caused by other coronaviruses.

This article comprehensively reviews the mechanisms underlying ACE2-S protein interaction that facilitate SARS-CoV-2 entry into host cells. It also analyzes the patent landscape regarding inhibitors targeting the ACE2-S interface since 2019.

In the 5 years since the outbreak of SARS-CoV-2, numerous methods and design strategies have been employed to develop innovative therapeutics against coronaviruses. Among these approaches, inhibitors targeting both the ACE2 receptor and the S protein have gained significant interest due to their potential in blocking various coronaviruses. Despite facing challenges similar to other protein-protein interaction inhibitors, progress has been made in developing these inhibitors through virtual screening, covalent protein binding, and peptide modification strategies. However, obstacles persist in clinical translation, necessitating a multidisciplinary strategy that integrates state-of-the-art methodologies to optimize S-ACE2 interface-targeted drug discovery.

Basal cell carcinoma (BCC) is the most prevalent human neoplasm, with constantly increasing annual incidence. Despite its slow growth, BCC is locally invasive and, if left untreated, can cause severe complications, including metastasis and death. The renin-angiotensin system (RAS) plays a key role in electrolyte balance, atrial pressure, tissue development, homeostasis, and inflammation, but also in cancer development. After binding to its type 1 receptor (AT1R), angiotensin II (ANGII), the system's principal hormonal effector, regulates cancer pathways spanning from the formation of the initial cancer cell to the construction and nutrition of the tumor microenvironment, angiogenesis, proliferation, and metastasis. Although the role of RAS in the development of skin pathologies has not been widely researched, RAS-targeting antihypertensive medications have been shown to have a chemoprotective effect against BCC. Based on those findings, our group conducted a series of genetic association studies to investigate the association between common functional variations in key genes related to ANGII production (AGT, ACE, ACE2, AT1R, AT2R, and CMA1) and the risk of BCC occurrence. This review provides a summary of the current understanding of the ANGII involvement in BCC development. The reliable and easily assessed pool of genetic biomarkers may be used for predictive testing and prevention purposes in high-risk individuals.

Stress, infections, and psychological and social well-being can affect the reproductive system. Activation of the hypothalamic-pituitary-adrenal axis can disrupt ovarian cyclicity. Estrogens can modulate stress responsiveness and mood. Thus, understanding this interaction and how it modulates the menstrual cycle is crucial for women's reproductive health.

The objective of this study was to analyze the influence of a stressor, a period of the Covid-19 pandemic when there were no vaccines available yet, on the psychological state of women aged 18 to 45 years; as well as the influence of mental health on the menstrual cycle, considering the influence of age and hormonal contraceptives.

Online questionnaire using the Google Forms platform was used.

There is a high prevalence of the onset of new psychosocial symptoms. Moreover, most women reported some type of change in their menstrual cycles. The women who were using hormonal contraceptives demonstrated a higher frequency of spotting and menstrual color alterations, while women without hormonal contraceptives demonstrated a higher frequency of cycle duration and menstrual odor alterations. Women without hormonal contraceptives were more susceptible to the development of psychosocial symptoms. Younger adult women were more affected by menstrual changes and psychosocial symptoms. Close to 90% of women who reported several psychosocial symptoms had changes in their menstrual cycles.

These data suggest the impact of stressors, such as a period of the pandemic, on mental health and menstrual cycles, and younger adult women can be more susceptible. This reflects the relationship between mental and reproductive health.

Alterations in the classical Renin-Angiotensin Aldosterone System (RAAS) have been described during septic shock and are associated with patient outcomes. Since the alternative RAAS has also been reported to be altered in critically ill patients, and given that the RAAS can be modulated by specific therapeutics, such as angiotensin II, understanding its pathophysiology is of primary interest.

To describe the alterations in the classical and alternative RAAS during septic shock in comparison with healthy controls.

This prospective, monocentric, controlled study enrolled 20 patients fulfilling the septic shock diagnosis, as defined by the Sepsis-3 criteria, along with 30 controls. The main exclusion criteria were the use of any prior medication modifying the RAAS, prior liver failure (Child-Pugh score > 9), or chronic kidney disease (estimated glomerular filtration rate < 30 ml/min/1.73 m²). Equilibrium concentrations of RAAS peptides were analyzed using a liquid chromatography-mass spectrometry method from heparinized plasma. Circulating angiotensin-converting enzyme (cACE), cACE type 2 (cACE2) activities, and circulating dipeptidyl peptidase 3 (cDPP3) concentrations were assessed. Values were measured at diagnosis, 6 h after diagnosis and on days 1 and 3. The main timepoint of interest was 6 h after diagnosis. Values 6 h after diagnosis were compared to 30 controls.

In septic shock patients, increased concentrations of the main peptides of the classical and alternative RAAS were observed compared to controls, particularly angiotensin I (Ang I) and angiotensin-(1-7) (Ang-(1-7)). Additionally, there was a significant increase in the Ang I/Ang II ratio (1.16 [0.74-3.31] vs. 0.34 [0.25-0.43], p < 0.05) and the Ang-(1-7)/Ang II ratio (0.15 [0.08-1.30] vs. 0.03 [0.02-0.04], p < 0.05). We also observed a significant reduction in cACE activity (3.38 [2.29-6.8] vs. 7.89 [6.39-9.05] nmol Ang II/L/h), an increase in cACE2 activity (814 [669-1987] vs. 214 [132-293] pmol Ang-(1-7)/L/h), and increased cDPP3 concentrations (54.6 [35-142.2] ng/mL vs. 13.7 [11.9-15.4] ng/mL, all p < 0.05).

Septic shock was associated with increased Ang I/Ang II and Ang-(1-7)/Ang II ratios, along with reduced cACE activity, increased cACE2 activity, and elevated cDPP3 concentrations compared to healthy controls.

The renin-angiotensin system (RAS) plays a pivotal role in regulating blood volume, systemic vascular resistance, and electrolyte balance, serving as a key component of cardiovascular health. Recent findings highlight the role of angiotensin II (Ang II) in inducing autophagy through angiotensin II receptor type 1 (AT1R). Autophagy, a process of self-degradation and turnover of cellular components, is a homeostatic response that eliminates superfluous materials. Abnormal autophagy promotes cardiomyocyte loss and is critical in hypertrophy and heart failure progression. The RAS's non-canonical axis, which includes the angiotensin 1-9 peptide [Ang-(1-9)], has an anti-hypertrophic effect in cardiomyocytes via an unknown mechanism. In the present study, we aimed to elucidate the effect of Ang-(1-9) on cardiomyocyte autophagy.

We isolated and cultured neonatal ventricular cardiomyocytes and then co-treated them with Ang-(1-9) in the presence of chloroquine (CQ), Ang-II, and chemical inhibitors of different signaling pathways. After treatment, total RNA and protein extracts were obtained to analyze the abundance of different autophagy markers. Likewise, cells were fixed, and autophagy was analyzed through epifluorescence microscopy.

Our findings show that CQ leads to a reduction in autophagy markers, such as microtubule-associated protein 1 light chain 3-II (LC3-II) and total LC3, suggesting Ang-(1-9)'s regulatory role in basal autophagy levels. Furthermore, Ang-(1-9) opposes Ang-II-induced autophagy and induces the phosphorylation of the S234 residue of Beclin-1 (BCN1) via an angiotensin II receptor type 2 (AT2R)/Akt-dependent pathway.

This reduction of Ang-II-induced autophagy by Ang-(1-9) unveils a novel aspect of its action, potentially contributing to its cardioprotective effects.

Particulate matter 2.5 (PM2.5) pollution and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic are the greatest environmental health issues worldwide. Several statistics revealed the significant positive correlation between the morbidity of coronavirus disease-19 (COVID-19) and the levels of air pollution. Nevertheless, there is no direct experimental evidence to indicate the effect of PM2.5 exposure on SARS-CoV-2 infection. The objective of this study was to evaluate whether the infection of SARS-CoV-2 affected by PM2.5 through angiotensin-converting enzyme II (ACE2) expression enhances and investigate the function of ACE2 in lung injury induced by PM2.5. An animal model of PM2.5-induced lung injury was established using wild-type (WT, C57BL/6), human ACE2 transgenic (K18-hACE2 TG), and murine ACE2 gene knockout (mACE2 KO) mice. The results indicate that PM2.5 exposure facilitates SARS-CoV-2 infection through inducing ACE2 expression in vitro (10 μg/mL) and in vivo (6.25 mg/kg/day in 50 μL saline). The levels of ACE, inflammatory cytokines, and mitogen-activated protein kinase (MAPK) proteins in WT, K18-hACE TG and mACE2 KO mice were significantly increased after PM2.5 instillation. The severest PM2.5-induced lung damage was observed in mACE2 KO mice. In summary, ACE2 plays a double-edged sword role in lung injury, PM2.5 exposure contributed to SARS-CoV-2 infection through inducing ACE2 expression, but ACE2 also protected pulmonary inflammation from PM2.5 challenge.

The COVID-19 pandemic has profoundly affected human health; however, the mechanisms underlying its impact on metabolic and vascular systems remain incompletely understood. Clinical evidence suggests that SARS-CoV-2 directly disrupts vascular homeostasis, with perfusion abnormalities observed in various tissues. The pancreatic islet, a key endocrine miniorgan reliant on its microvasculature for optimal function, may be particularly vulnerable. Studies have proposed a link between SARS-CoV-2 infection and islet dysfunction, but the mechanisms remain unclear. Here, we investigated how SARS-CoV-2 spike S1 protein affects human islet microvascular function. Using confocal microscopy and living pancreas slices from organ donors without diabetes, we show that a SARS-CoV-2 spike S1 recombinant protein activates pericytes, key regulators of islet capillary diameter and β-cell function, and induces capillary constriction. These effects are driven by a loss of ACE2 from pericytes' plasma membrane, impairing ACE2 activity and increasing local angiotensin II levels. Our findings highlight islet pericyte dysfunction as a potential contributor to the diabetogenic effects of SARS-CoV-2 and offer new insights into the mechanisms linking COVID-19, vascular dysfunction, and diabetes.

Different components of the renin-angiotensin system are expressed by vascular cells in human pancreatic islets. The islet microvasculature is responsive to vasoactive angiotensin peptides. This pancreatic renin-angiotensin system is targeted upon incubation with a SARS-CoV-2 spike recombinant protein. SARS-CoV-2 spike activates pericytes and constricts capillaries in human islets. Islet vascular dysfunction could contribute to dysglycemia in some patients with COVID-19.

Clinical outcomes resulting from SARS-CoV-2 infection vary widely, ranging from asymptomatic cases to the development of mild to severe respiratory illness, and in some instances, chronic lingering disease and mortality. The underlying biological mechanisms driving this wide spectrum of pathogenicity among certain individuals and demographics remain elusive. Autoantibodies have emerged as potential contributors to the severity of COVID-19. Although preliminary reports have suggested the induction of antibodies targeting Angiotensin-Converting Enzyme II (ACE2) post-infection, this assertion lacks confirmation in large-scale studies. In this study, our objective is to comprehensively characterize and quantify the prevalence and expression levels of autoantibodies directed against ACE2 in a sizable cohort (n = 464). Our findings reveal that ACE2-reactive IgM antibodies are the most prevalent, with an overall seroprevalence of 18.8%, followed by IgG at 10.3% and IgA at 6.3%. Longitudinal analysis of individuals with multiple blood draws showed stable ACE2 IgG and IgA levels over time. Upon stratifying individuals based on molecular testing for SARS-CoV-2 or serological evidence of past infection, no significant differences were observed between groups. Functional assessment of ACE2 autoantibodies demonstrated that they are non-neutralizing and failed to inhibit spike-ACE2 interaction or affect the enzymatic activity of ACE2. Our results highlight that ACE2 autoantibodies are prevalent in the general population and were not induced by SARS-CoV-2 infection in our cohort. Notably, we found no substantiated evidence supporting a direct role for ACE2 autoantibodies in SARS-CoV-2 pathogenesis.

The Food and Drug Administration (FDA) recently approved renal denervation to treat resistant hypertension. This procedure is a minimally invasive procedure that starts by placing a catheter in the renal artery. This catheter is used to send either radiofrequency heat or ultrasound waves to burn the superficial nerves surrounding the renal arteries while making certain no damage happens to the renal arteries themselves. This procedure is done after a renal angiogram to ensure patency of the renal artery. Each radiofrequency ablation will take 1-2 minutes, depending on the device used. The radiofrequency balloon generator requires one single application of the radiofrequency pulse. The radiofrequency generator that uses a catheter tube will need more than one pulse. The second approved option uses ultrasound to generate an electrical signal that is converted into ultrasound vibration, that occurs at the distal end of the catheter. This vibration heats the system around the nerves, disrupting the superficial nerves that communicate with the central nervous system. This will result in lowering the blood pressure. We will review the studies that led to FDA approval, and the current guidelines for use. The FDA now approves both devices.

Background/Objectives: The SARS-CoV-2's high mutations and replication rates contribute to its high infectivity and resistance to current vaccinations and treatments. The primary cause of resistance to most current treatments aligns within the coding regions for the spike S protein of SARS-CoV-2 that has mutated. As a potential novel immunotherapy, we generated a novel fusion protein composed of a soluble ACE2 (sACE2) linked to llama-derived anti-CD16 that targets different variants of spike proteins and enhances natural killer cells to target infected cells. Methods: Here, we generated a novel sACE2-AntiCD16VHH fusion protein using a Gly4Ser linker, synthesized and cloned into the pLVX-EF1alpha-IRES-Puro vector, and further expressed in ExpiCHO-S cells and purified using Ni+NTA chromatography. Results: The fusion protein significantly blocked SARS-CoV-2 alpha, beta, delta, gamma, and omicron S-proteins binding and activating angiotensin-converting enzyme receptor-2 (ACE2) on ACE2-expressing RAW-Blue macrophage cells and the secretion of several key inflammatory cytokines, G-CSF, MIP-1A, and MCP-1, implicated in the cytokine release storm (CRS). The sACE2-Anti-CD16VHH fusion protein also bridged NK cells to ACE2-expressing human lung carcinoma A549 cells and significantly activated NK-dependent cytotoxicity. Conclusions: The findings show that a VHH directed against CD16 could be an excellent candidate to be linked to soluble ACE2 to generate a bi-specific molecule (sACE2-AntiCD16VHH) suitable for bridging effector cells and infected target cells to inhibit SARS-CoV-2 variant spike proteins binding to the ACE2 receptor in the RAW-Blue cell line and pro-inflammatory cytokines and to activate natural killer cell cytotoxicity.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters host cells via the angiotensin-converting enzyme 2 (ACE2) receptor. Mounting evidence has indicated the presence of hepatic SARS-CoV-2 infection and liver injury in patients with coronavirus disease 2019 (COVID-19). Understanding the mechanisms of hepatic SARS-CoV-2 infection is crucial for addressing COVID-19-related liver pathology and developing targeted therapies. This editorial discusses the significance of ACE2 in hepatic SARS-CoV-2 infection, drawing on the research by Jacobs et al. Their findings indicate that hepatic ACE2 expression, frequency of hepatic SARS-CoV-2 infection, and severity of liver injury are elevated in patients with pre-existing chronic liver diseases. These data suggest that hepatic ACE2 could be a promising therapeutic target for COVID-19.

Diabetic cardiomyopathy (DCM) is a cardiac complication specific to individuals with diabetes. It is defined as abnormalities of myocardial structure and function in diabetic patients who do not exhibit any obvious coronary artery disease, hypertensive heart disease, valvular heart disease, or inherited cardiomyopathy. A significant cardiovascular protective factor identified recently is angiotensin-converting enzyme 2 (ACE2), which is a rising star in the renin angiotensin system (RAS) and is responsible for the onset and progression of DCM. Nonetheless, there is not a comprehensive review outlining ACE2's effect on DCM. From the perspective of the pathogenesis of DCM, this review summarizes the myocardial protective role of ACE2 in the aspects of alleviating myocardial structure and dysfunction, correcting energy metabolism disorders, and restoring vascular function. Concurrently, we propose the connections between ACE2 and underlying signaling pathways, including ADAM17, Apelin/APJ, and Nrf2. Additionally, we highlight ACE2-related pharmaceutical treatment options and clinical application prospects for preventing and managing DCM. Further and underlying research is extensively required to completely comprehend the principal pathophysiological mechanism of DCM and the distinctive function of ACE2, switching experimental findings into clinical practice and identifying efficient therapeutic approaches.

Severe acute respiratory symptom coronavirus 2 (SARS-CoV-2) infection occurs via the attachment of the spike (S) protein's receptor binding domain (RBD) to human ACE2 (hACE2). Natural polymorphisms in hACE2, particularly at the interface, may alter RBD-hACE2 interactions, potentially affecting viral infectivity across populations. This study identified the effects of six naturally occurring hACE2 polymorphisms with high allele frequency in the African population (S19P, K26R, M82I, K341R, N546D and D597Q) on the interaction with the S protein RBD of the BA.4/5 Omicron sub-lineage through post-molecular dynamics (MD), inter-protein interaction and dynamic residue network (DRN) analyses. Inter-protein interaction analysis suggested that the K26R variation, with the highest interactions, aligns with reports of enhanced RBD binding and increased SARS-CoV-2 susceptibility. Conversely, S19P, showing the fewest interactions and largest inter-protein distances, agrees with studies indicating it hinders RBD binding. The hACE2 M82I substitution destabilized RBD-hACE2 interactions, reducing contact frequency from 92 (WT) to 27. The K341R hACE2 variant, located distally, had allosteric effects that increased RBD-hACE2 contacts compared to WThACE2. This polymorphism has been linked to enhanced affinity for Alpha, Beta and Delta lineages. DRN analyses revealed that hACE2 polymorphisms may alter the interaction networks, especially in key residues involved in enzyme activity and RBD binding. Notably, S19P may weaken hACE2-RBD interactions, while M82I showed reduced centrality of zinc and chloride-coordinating residues, hinting at impaired communication pathways. Overall, our findings show that hACE2 polymorphisms affect S BA.4/5 RBD stability and modulate spike RBD-hACE2 interactions, potentially influencing SARS-CoV-2 infectivity-key insights for vaccine and therapeutic development.

The human angiotensin converting enzyme 2 (ACE2) gene encodes a type I transmembrane protein, which is homologous to angiotensin I-converting enzyme (ACE) and belongs to the angiotensin-converting enzyme family of dipeptidyl carboxypeptidases. As highlighted by the COVID-19 pandemic, ACE2 is not only crucial for the renin-angiotensin-aldosterone system (RAAS), but also displays great affinity with the SARS-CoV-2 spike protein, representing the major receptor of the virus. Given the significance of ACE2 in COVID-19, especially among cancer patients, the present study aims to explore the transcriptional landscape of ACE2 in human cancer and non-cancerous cell lines through the design and implementation of a custom targeted long-read sequencing approach. Bioinformatics analysis of the massive parallel sequencing data led to the identification of novel ACE2 mRNA splice variants (ACE2 sv.7-sv.12) that demonstrate previously uncharacterized exon-skipping events as well as 5' and/or 3' alternative splice sites. Demultiplexing of the sequencing data elucidated the differential expression profile of the identified splice variants in multiple human cell types, whereas in silico analysis suggests that some of the novel splice variants could produce truncated ACE2 isoforms with altered functionalities, potentially influencing their interaction with the SARS-CoV-2 spike protein. In summary, our study sheds light on the complex alternative splicing landscape of the ACE2 gene in cancer cell lines, revealing novel splice variants that could have significant implications for SARS-CoV-2 susceptibility in cancer patients. These findings contribute to the increased understanding of ACE2's role in COVID-19 and highlight the importance of considering alternative splicing as a key factor in viral pathogenesis. Undoubtably, further research is needed to explore the functional roles of these variants and their potential as therapeutic targets in the ongoing fight against COVID-19.

ACE2 (angiotensin-converting enzyme 2) is a monocarboxypeptidase that cleaves Ang II (angiotensin II) among other substrates. ACE2 is present in the cell membrane of many organs, most abundantly in epithelial cells of kidney proximal tubules and the small intestine, and also exists in soluble forms in plasma and body fluids. Membrane-bound ACE2 exerts a renoprotective action by metabolizing Ang II and therefore attenuating the undesirable actions of excess Ang II. Therefore, soluble ACE2, by downregulating this peptide, may exert a therapeutic action. Our laboratory has designed ACE2 truncates that pass the glomerular filtration barrier to target the kidney renin-angiotensin system directly and, therefore, compensate for loss of kidney membrane-bound ACE2. Membrane-bound ACE2 is also the essential receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Soluble ACE2 proteins have been studied as a way to intercept SARS-CoV-2 from binding to membrane-bound ACE2 and prevent cell entry of SARS-CoV-2 altogether. We bioengineered a soluble ACE2 protein, termed ACE2 618-DDC-ABD, with increased binding affinity for SARS-CoV-2 and prolonged duration of action, which, when administered intranasally, provides near-complete protection from lethality in k18hACE2 mice infected with different SARS-CoV-2 variants. The main advantage of soluble ACE2 proteins for the neutralization of SARS-CoV-2 is their immediate onset of action and universality for current and future emerging SARS-CoV-2 variants. It is notable that ACE2 is critically involved in 2 dissimilar functions: as a receptor for cell entry of many coronaviruses and as an enzyme in the metabolism of Ang II, and yet in both cases, it is a therapeutic target.

This study aimed to elucidate the distinctions between the expression levels of angiotensin-converting enzyme (ACE) and ACE2, as well as their genetic polymorphisms, in patients with acute aortic dissection (AD) and coronary heart disease (CHD).

A cohort of 86 patients was enrolled, comprising 34 individuals with acute AD (encompassing Stanford types A and B), 18 with ascending aortic aneurysm, 21 with CHD, and 13 healthy controls. Aortic tissue samples were procured from 44 patients during surgical interventions.

Statistically significant differences were observed in ACE and ACE2 expression levels among the ascending aortic aneurysm, CHD, and control groups (p < 0.05). However, the expression of ACE messenger ribonucleic acid (mRNA) in the aortic wall was significantly higher in the AD group than in the ascending aortic aneurysm and CHD groups (p < 0.05). Additionally, the expression of ACE2 mRNA and the ACE/ACE2 ratio in the aortic wall were significantly different in the AD group compared with the ascending aortic aneurysm and CHD groups (p < 0.05).

Plasma ACE levels, and the gene expressions of ACE and ACE2, are markedly reduced in patients with acute AD. The observed imbalance in ACE and ACE2 expressions may play a pivotal role in the pathogenesis of AD.

Coronavirus Disease 2019, caused by severe acute respiratory coronavirus 2, has been an ever-evolving disease and pandemic, profoundly impacting clinical care, drug treatments, and understanding. In response to this global health crisis, there has been an unprecedented increase in research exploring new and repurposed drugs and advancing available clinical interventions and treatments. Given the widespread interest in this topic, this review aims to provide a current summary-for interested professionals not specializing in COVID-19-of the clinical characteristics, recommended treatments, vaccines, prevention strategies, and epidemiology of COVID-19. The review also offers a historical perspective on the pandemic to enhance understanding.

A 61-year-old man with chronic renal failure had an embolic stroke of undetermined source that was treated with warfarin. Five weeks later, the patient contracted coronavirus disease (COVID-19). Six days after the onset of COVID-19, high blood pressure (>200 ‍mmHg) and consciousness disturbance were reported. CT demonstrated symmetrical hypodensity areas in the bilateral cerebellar hemispheres. MRI revealed hyperintensity lesions in the bilateral cerebellar hemispheres and pons on the T2-weighted and fluid-attenuated inversion recovery images. Moreover, cerebellar lesions appeared as hyperintensity areas on apparent diffusion coefficient mapping. Based on these findings, a diagnosis of posterior reversible encephalopathy syndrome (PRES) was made. The patient was treated with antihypertensive drugs, and the consciousness level improved gradually. MRI after one month showed that the lesions had disappeared. PRES should be considered if the brain CT of patients with COVID-19 shows a low-density lesion, especially in patients with risk factors for PRES such as chronic renal failure or hypertension.

Successful ovulation is essential for natural conception and fertility. Defects in the ovulatory process are associated with various conditions of infertility or subfertility in women. However, our understanding of the intra-ovarian biochemical mechanisms underlying this process in women has lagged compared to our understanding of animal models. This has been largely due to the limited availability of human ovarian samples that can be used to examine changes across the ovulatory period and delineate the underlying cellular/molecular mechanisms in women. Despite this challenge, steady progress has been made to improve our knowledge of the ovulatory process in women by: (i) collecting granulosa cells across the IVF interval, (ii) creating a novel approach to collecting follicular cells and tissues across the periovulatory period from normally cycling women, and (iii) developing unique in vitro models to examine the LH surge or hCG administration-induced ovulatory changes in gene expression, the regulatory mechanisms underlying the ovulatory changes, and the specific functions of the ovulatory factors.

The objective of this review is to summarize findings generated using in vivo and in vitro models of human ovulation, with the goal of providing new insights into the mechanisms underlying the ovulatory process in women.

This review is based on the authors' own studies and a search of the relevant literature on human ovulation to date using PubMed search terms such as 'human ovulation EGF-signaling', 'human ovulation steroidogenesis', 'human ovulation transcription factor', 'human ovulation prostaglandin', 'human ovulation proteinase', 'human ovulation angiogenesis' 'human ovulation chemokine', 'human ovulatory disorder', 'human granulosa cell culture'. Our approach includes comparing the data from the authors' studies with the existing microarray or RNA-seq datasets generated using ovarian cells obtained throughout the ovulatory period from humans, monkeys, and mice.

Current findings from studies using in vivo and in vitro models demonstrate that the LH surge or hCG administration increases the expression of ovulatory mediators, including EGF-like factors, steroids, transcription factors, prostaglandins, proteolytic systems, and other autocrine and paracrine factors, similar to those observed in other animal models such as rodents, ruminants, and monkeys. However, the specific ovulatory factors induced, their expression pattern, and their regulatory mechanisms vary among different species. These species-specific differences stress the necessity of utilizing human samples to delineate the mechanisms underlying the ovulatory process in women.

The data from human ovulation in vivo and in vitro models have begun to fill the gaps in our understanding of the ovulatory process in women. Further efforts are needed to discover novel ovulatory factors. One approach to address these gaps is to improve existing in vitro models to more closely mimic in vivo ovulatory conditions in humans. This is critically important as the knowledge obtained from these human studies can be translated directly to aid in the diagnosis of ovulation-associated pathological conditions, for the development of more effective treatment to help women with anovulatory infertility or, conversely, to better manage ovulation for contraceptive purposes.

N/A.

SARS-CoV-2 virus infects cells by engaging with ACE2 requiring protease TMPRSS2. ACE2 is highly expressed in kidneys. Predictors for severe disease are high age and male sex. We hypothesized that ACE2 and TMPRSS2 proteins are more abundant (1) in males and with increasing age in kidney and (2) in urine and extracellular vesicles (EVs) from male patients with COVID-19 and (3) SARS-CoV-2 is present in urine and EVs during infection. Kidney cortex samples from patients subjected to cancer nephrectomy (male/female; < 50 years/˃75 years, n = 24; ˃80 years, n = 15) were analyzed for ACE2 and TMPRSS2 protein levels. Urine from patients hospitalized with SARS-CoV-2 infection was analyzed for ACE2 and TMPRSS2. uEVs were used for immunoblotting and SARS-CoV-2 mRNA and antigen detection. Tissue ACE2 and TMPRSS2 protein levels did not change with age. ACE2 was not more abundant in male kidneys in any age group. ACE2 protein was associated with proximal tubule apical membranes in cortex. TMPRSS2 was observed predominantly in the medulla. ACE2 was elevated significantly in uEVs and urine from patients with COVID-19 with no sex difference compared with urine from controls w/wo albuminuria. TMPRSS2 was elevated in uEVs from males compared to female. ACE2 and TMPRSS2 did not co-localize in uEVs/apical membranes. SARS-CoV-2 nucleoprotein and mRNA were not detected in urine. Higher kidney ACE2 protein abundance is unlikely to explain higher susceptibility to SARS-CoV-2 infection in males. Kidney tubular cells appear not highly susceptible to SARS-CoV-2 infection. Loss of ACE2 into urine in COVID could impact susceptibility and angiotensin metabolism.

The renin-angiotensin system (RAS) is becoming increasingly recognised as a biochemical pathway relevant to the development and progression of Alzheimer's disease (AD). RAS involvement in AD was initially linked to AD via numerous genetic association studies and more recent Genome-Wide Association Studies (GWAS), and in some cases in relation to classical hallmarks of AD pathology. Since these initial findings, which will be summarised here, several complementary areas of research are converging in support of what has been proposed as the Angiotensin Hypothesis for Alzheimer's disease. This hypothesis proposes how the RAS and disease-associated changes to the normal balance between opposing regulatory pathways within RAS warrant careful consideration in the pathogenesis of AD and its pathology. We discuss some of these in relation to RAS-targeting therapeutics, originally developed for the treatment of cardiovascular conditions, and how they might be repurposed as interventions for AD.

Heparan sulfate (HS) linear polysaccharide glycosaminoglycan compound is linked to components from the cell surface and the extracellular matrix. HS mediates SARS-CoV-2 infection through spike protein binding to cell surface receptors and is required to bind ACE2, prompting the need for electronic structure and molecular docking evaluation of this core system to exploit this attachment in developing new derivatives. Therefore, we have studied five molecules based on HS using molecular docking and electronic structure analysis. Non-covalent interaction analysis shows hydrogen bonding and van der Waals interactions in the binding to RBD-ACE2 interface and 3CLpro. SDM3 and SDM1 molecules present the lowest gap, including solvent effect under 154.6 kcal/mol, and exhibit the most reactivity behavior in this group, potentially leading to enhanced interaction in docking studies.

Heparan sulfate and four derivatives were optimized using B3LYP functional with two basis sets 6-31 + G(d,p) and def2SVP. Electronic structure was used to explore the main interactions and the reactivity of these molecules, and these optimized structures were used in the molecular docking study against 3CLpro, RBD, and ACE2.

Angiotensin-converting enzyme-2 (ACE2) acts as a key regulatory molecule and important therapeutic target in the pathological remodeling of numerous organs and diseases. In this study, a rapid, simple, and efficient synthetic route with a catalytic, 18F-for-Cl (18F/Cl) exchange scheme was designed for the preparation of 18F-labeled MLN-4760, and its targeting ability was investigated in a humanized ACE2 mouse model.

A novel 18F-labeled MLN-4760 radioligand, abbreviated as 18F-MLN-4760, was successfully synthesized by the 18F/Cl exchange-labeling, and was purified by SepPak C18 columns with a radiochemical yield of 30% and a radiochemical purity of 29.89%. Target distribution of 18F-MLN-4760 in several organs with high ACE2 expression was observed by PET imaging with good stability over 120 min. The biodistribution data showed that the uptake of 18F-MLN-4760 in ACE2-overexpressing organs and tissues was highly specific, and immunohistochemistry confirmed the same results of ACE2 expression and biodistribution in the major organs (heart, liver, lungs, and kidneys). There was a good correlation between the uptake in the organs with high ACE2 expression and ACE2 expression levels (r = 0.935).

18F-MLN-4760 was successfully synthesized via 18F/Cl exchange under phase transfer catalysis, and served as a potential probe for ACE2-targeted PET imaging.

Cardiomyopathy constitutes a global health burden. It refers to myocardial injury that causes alterations in cardiac structure and function, ultimately leading to heart failure. Currently, there is no definitive treatment for cardiomyopathy. This is because existing treatments primarily focus on drug interventions to attenuate symptoms rather than addressing the underlying causes of the disease. Notably, the cardiomyocyte loss is one of the key risk factors for cardiomyopathy. This loss can occur through various mechanisms such as metabolic disturbances, cardiac stress (e.g., oxidative stress), apoptosis as well as cell death resulting from disorders in autophagic flux, etc. Sirtuins (SIRTs) are categorized as class III histone deacetylases, with their enzyme activity primarily reliant on the substrate nicotinamide adenine dinucleotide (NAD (+)). Among them, Sirtuin 1 (SIRT1) is the most intensively studied in the cardiovascular system. Forkhead O transcription factors (FOXOs) are the downstream effectors of SIRT1. Several reports have shown that SIRT1 can form a signaling pathway with FOXOs in myocardial tissue, and this pathway plays a key regulatory role in cell loss. Thus, this review describes the basic mechanism of SIRT1-FOXOs in inhibiting cardiomyocyte loss and its favorable role in cardiomyopathy. Additionally, we summarized the SIRT1-FOXOs related regulation factor and prospects the SIRT1-FOXOs potential clinical application, which provide reference for the development of cardiomyopathy treatment.

The present investigation assesses ursodeoxycholic acid's efficacy (UDCA) as an ACE2 activator against gamma irradiation through activating the renin-angiotensin system's (RAS) beneficial axis, ACE2/Ang-(1-7)/Mas1 via its profitable influence on inflammation, oxidative stress, and neuronal damage caused by irradiation (IRR). Four groups of rats were treated as follows: control group, group receiving UDCA (100 mg/kg/day) for 14 days by gavage, group irradiated at 6 Gy, and group receiving UDCA post-irradiation for 14 days. The results revealed that gamma-irradiation (6 Gy) caused a substantial drop in the cerebral ACE2/Ang-(1-7)/Mas1 axis and remarkably increased the expression of cerebral inflammatory mediators: tumor necrosis factor-α (TNF-α), nuclear factor kappa-B (NF-κB), interleukin-6 (IL-6) and interleukin-1β (IL-1β) combined with significant elevation in cyclooxygenase-II (COX-II), (NADPH) oxidases (NOX4), lipooxygenase (LOX) activities and nitric oxide (NO) content. Moreover, it greatly enhanced the reduction in N-methyl-d-aspartate (NMDA) level, while dramatically increasing gamma-aminobutyric acid (GABA) level and neuronal nitric oxide synthases (nNOS) enzyme activity in cerebral tissue homogenate. Irradiated rats' brain sections underwent histological investigation using hematoxylin and eosin staining, which revealed cellular damage and a pathological appearance. The administration of UDCA inverts these unusual alterations. In conclusion, UDCA treatment efficiently normalizes the above-mentioned pathological abnormalities and avoids the development of IRR-associated neurological dysfunction by upregulating the beneficial axis of RAS in the brain. Hence, ursodeoxycholic acid presents a novel option for patient care during radiotherapy.

The renin-angiotensin system (RAS) is a crucial factor in chronic kidney disease (CKD) progression, affecting renal function and contributing significantly to renal tissue inflammation and fibrosis. Activation of the classical ACE/Ang II/AT1 axis exacerbates renal damage, while the ACE2/Ang-(1-7)/Mas axis has shown promise in reducing CKD progression in numerous animal models. Recently, the ACE2/Ang-(1-7)/Mas axis has emerged as a promising target for CKD interventions. This review provides a comprehensive review of the pivotal role of this axis in CKD pathogenesis and systematically examines various molecules and pharmaceutical agents targeting this pathway. This review aims to elucidate potential strategies for delaying or halting CKD progression, offering patients more effective treatment options.

The intricate physiological and pathological diversity of the Renin-Angiotensin-Aldosterone System (RAAS) underpins its role in maintaining bodily equilibrium. This paper delves into the classical axis (Renin-ACE-Ang II-AT1R axis), the protective arm (ACE2-Ang (1-7)-MasR axis), the prorenin-PRR-MAP kinases ERK1/2 axis, and the Ang IV-AT4R-IRAP cascade of RAAS, examining their functions in both physiological and pathological states. The dysregulation or hyperactivation of RAAS is intricately linked to numerous diseases, including cardiovascular disease (CVD), renal damage, metabolic disease, eye disease, Gastrointestinal disease, nervous system and reproductive system diseases. This paper explores the pathological mechanisms of RAAS in detail, highlighting its significant role in disease progression. Currently, in addition to traditional drugs like ACEI, ARB, and MRA, several novel therapeutics have emerged, such as angiotensin receptor-enkephalinase inhibitors, nonsteroidal mineralocorticoid receptor antagonists, aldosterone synthase inhibitors, aminopeptidase A inhibitors, and angiotensinogen inhibitors. These have shown potential efficacy and application prospects in various clinical trials for related diseases. Through an in-depth analysis of RAAS, this paper aims to provide crucial insights into its complex physiological and pathological mechanisms and offer valuable guidance for developing new therapeutic approaches. This comprehensive discussion is expected to advance the RAAS research field and provide innovative ideas and directions for future clinical treatment strategies.

The angiotensin-converting enzyme-2 (ACE2) is a transmembrane glycoprotein, consisting of two segments: a large carboxypeptidase catalytic domain and a small transmembrane collectrin-like segment. This protein plays an essential role in blood pressure regulation, transforming the peptides angiotensin-I and angiotensin-II (vasoconstrictors) into angiotensin-1-9 and angiotensin-1-7 (vasodilators). During the COVID-19 pandemic, ACE2 became best known as the receptor of the S-protein of SARS-CoV-2 coronavirus. The purpose of the following research is to reconstruct the 3D structure of the catalytic domain of the rabbit enzyme rACE2 using its primary amino acid sequence, and then to compare it with the human analog hACE2. For this purpose, we have calculated the electric properties and thermodynamic stability of the two protein globules employing computer programs for protein electrostatics. The analysis of the amino acid content and sequence demonstrates an 85% identity between the two polypeptide chains. The 3D alignment of the catalytic domains of the two enzymes shows coincidence of the α-helix segments, and a small difference in two unstructured segments of the chain. The electric charge of the catalytic domain of rACE2, determined by 70 positively chargeable amino acid residues, 114 negatively chargeable ones, and two positive charges of the Zn2+ atom in the active center exceeds that of hACE2 by one positively and four negatively chargeable groups; however, in 3D conformation, their isoelectric points pI 5.21 coincide. The surface electrostatic potential is similarly distributed on the surface of the two catalytic globules, but it strongly depends on the pH of the extracellular medium: it is almost positive at pH 5.0 but strongly negative at pH 7.4. The pH dependence of the electrostatic component of the free energy discloses that the 3D structure of the two enzymes is maximally stable at pH 6.5. The high similarity in the 3D structure, as well as in the electrostatic and thermodynamic properties, suggests that rabbit can be successfully used as an animal model to study blood pressure regulation and coronavirus infection, and the results can be extrapolated to humans.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) not only posed major health and economic burdens to international societies but also threatens patients with comorbidities and underlying autoimmune disorders, including Crohn's disease (CD) patients. As the vaccinated population is gradually relieved from the stress of the latest omicron variant of SARS-CoV-2 due to competent immune responses, the anxiety of CD patients, especially those on immunosuppressive treatment, has not subsided. Whether the use of immunosuppressants for remission of CD outweighs the potential risk of severe coronavirus disease 2019 (COVID-19) has long been discussed. Thus, for the best benefit of CD patients, our primary goal in this study was to navigate the clinical management of CD during the COVID pandemic. Herein, we summarized COVID-19 outcomes of CD patients treated with immunosuppressive agents from multiple cohort studies and also investigated possible mechanisms of how SARS-CoV-2 impacts the host immunity with special consideration of CD patients. We first looked into the SARS-CoV-2-related immunopathology, including lymphocytopenia, T-cell exhaustion, cytokine storms, and their possible molecular interactions, and then focused on mechanistic actions of gastrointestinal systems, including interruption of tryptophan absorption, development of dysbiosis, and consequent local and systemic inflammation. Given challenges in managing CD, we summarized up-to-date clinical and molecular evidence to help physicians adjust therapeutic strategies to achieve the best clinical outcomes for CD patients.

The Coronavirus disease 2019 (COVID-19) pandemic has led to a global health crisis, including ocular symptoms, primarily targeting the Angiotensin-Converting Enzyme 2 (ACE2) receptor. PM2.5 air pollution may increase infection risk by altering ACE2 expression. Silicon Dioxide (SiO2) and carbon black (CB), major components of PM2.5 from sands and vehicle emissions, were studied for their effects on ACE2 and Transmembrane Protease Serine 2 (TMPRSS2) expression in corneal and conjunctival cells, and ocular tissues. Human corneal epithelial cells (HCECs) and conjunctival epithelial cells (HCjECs) were exposed to nanoparticles (NPs) for 24 hours, assessing viability via WST-8 assay. TNF-α, IL-6, and IL-1β levels in the medium were measured. An in vivo rat study administered NPs via eye drops, with Rose Bengal staining to evaluate damage. ACE2, TMPRSS2, and Angiotensin II (AngII) protein expressions were quantified by Western blot. ACE2 expression in HCjECs increased with NP exposure, while it decreased in HCECs. CB exposure increased TNF-α, IL-6, and IL-1β levels in HCECs. In vivo, corneal exposure to CB decreased ACE2 expression, whereas conjunctival exposure to SiO2 increased ACE2 expression. These changes suggest that SiO2 exposure may increase the risk of COVID-19 through the ocular surface, while CB exposure may decrease it.

The dysregulation of Angiotensin-converting enzyme 2 (ACE2) in central nervous system is believed associates with COVID-19 induced cognitive dysfunction. However, the detailed mechanism remains largely unknown. In this study, we performed a comprehensive system genetics analysis on hippocampal ACE2 based on BXD mice panel. Expression quantitative trait loci (eQTLs) mapping showed that Ace2 was strongly trans-regulated, and the elevation of Ace2 expression level was significantly correlated with impaired cognitive functions. Further Gene co-expression analysis showed that Ace2 may be correlated with the membrane proteins in Calcium signaling pathway. Further, qRT-PCR confirmed that SARS-CoV-2 spike S1 protein upregulated ACE2 expression together with eight membrane proteins in Calcium Signaling pathway. Moreover, such elevation can be attenuated by recombinant ACE2. Collectively, our findings revealed a potential mechanism of Ace2 in cognitive dysfunction, which could be beneficial for COVID-19-induced cognitive dysfunction prevention and potential treatment.

SARS-CoV-2 mainly infects the respiratory tract but can also target other organs, including the central nervous system. While it was recently shown that cells of the blood-brain-barrier are permissive to SARS-CoV-2 infection in vitro, it remains debated whether neurons can be infected. In this study, we demonstrate that vesicular stomatitis virus particles pseudotyped with the spike protein of SARS-CoV-2 variants WT, Alpha, Delta and Omicron enter the neuronal model cell line SH-SY5Y. Cell biological analyses of the pseudo-virus treated cultures showed marked alterations in microtubules of SH-SY5Y cells. Because the changes in β-tubulin occurred in most cells, but only few were infected, we further asked whether interaction of the cells with spike protein might be sufficient to cause molecular and structural changes. For this, SH-SY5Y cells were incubated with trimeric spike proteins for time intervals of up to 24 h. CellProfiler™-based image analyses revealed changes in the intensities of microtubule staining in spike protein-incubated cells. Furthermore, expression of the spike protein-processing protease cathepsin L was found to be up-regulated by wild type, Alpha and Delta spike protein pseudotypes and cathepsin L was found to be secreted from spike protein-treated cells. We conclude that the mere interaction of the SARS-CoV-2 with neuronal cells can affect cellular architecture and proteolytic capacities. The molecular mechanisms underlying SARS-CoV-2 spike protein induced cytoskeletal changes in neuronal cells remain elusive and require future studies.

The angiotensin-converting enzyme 2 (ACE2), which is expressed in cerebral vascular endothelial cells (CVECs), has been currently identified as a functional receptor for SARS-CoV-2.

We specifically induced injury to ACE2-expressing CVECs in mice and evaluated the effects of such targeted damage through magnetic resonance imaging (MRI) and cognitive behavioral tests. In parallel, we recruited a single-center cohort of COVID-19 survivors and further assessed their brain microvascular injury based on cognition and emotional scales, cranial MRI scans, and blood proteomic measurements.

Here, we show an array of pathological and behavioral alterations characteristic of cerebral small vessel disease (CSVD) in mice that targeted damage to ACE2-expressing CVECs, and COVID-19 survivors. These CSVD-like manifestations persist for at least 7 months post-recovery from COVID-19.

Our findings suggest that SARS-CoV-2 may induce cerebral small vessel damage with persistent sequelae, underscoring the imperative for heightened clinical vigilance in mitigating or treating SARS-CoV-2-mediated cerebral endothelial injury throughout infection and convalescence.

Cerebral small vessel disease-associated changes were observed after targeted damage to angiotensin-converting enzyme 2-expressing cerebral vascular endothelial cells. SARS-CoV-2 may induce cerebral small vessel damage with persistent sequelae. Clinical vigilance is needed in preventing SARS-CoV-2-induced cerebral endothelial damage during infection and recovery.

SARS-CoV-2 infection is considered as a multi-organ disease, and several studies highlighted the relevance of the virus infection in the induction of vascular injury and tissue morphological alterations, including placenta. In this study, immunohistochemical analyses were carried out on placenta samples derived from women with COVID-19 infection at delivery (SARS-CoV-2 PCR+) or women healed from a COVID-19 infection (SARS-CoV-2 negative at delivery, SARS-CoV-2 PCR-) or women who gave birth before 2019 (Control). Angiotensin Converting Enzyme 2 (ACE2) receptor, Cluster of differentiation 147 (CD147), endothelial CD34 marker, Vascular Endothelial Growth Factor (VEGF) and total Microtubule-associated protein 1 Light Chain 3B marker (LC3B) were investigated in parallel with SPIKE protein by standard IHC. Multiplexed Immunohistochemical Consecutive Staining on Single Slide (MICSSS) was used to examine antigen co-expression in the same specimen. SPIKE protein was detected in villi and decidua from women with ongoing infection, with no significant differences in SPIKE staining between both biopsy sites. VEGF was significantly increased in SARS-CoV-2 PCR + biopsies compared to control and SARS-CoV-2 PCR- samples, and MICSSS method showed the co-localization of SPIKE with VEGF and CD34. The induction of autophagy, as suggested by the LC3B increase in SARS-CoV-2 PCR + biopsies and the co-expression of LC3B with SPIKE protein, may explain one of the different mechanisms by which placenta may react to infection. These data could provide important information on the impact that SARS-CoV-2 may have on the placenta and mother-to-fetus transmission.

The Spike protein mutation severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to decreased protective effect of various vaccines and mAbs, suggesting that blocking SARS-CoV-2 infection by targeting host factors would make the therapy more resilient against virus mutations. Angiotensin-converting enzyme 2 (ACE2) is the host receptor of SARS-CoV-2 and its variants, as well as many other coronaviruses. Downregulation of ACE2 expression in the respiratory tract may prevent viral infection. Antisense oligonucleotides (ASOs) can be rationally designed on the basis of sequence data, require no delivery system, and can be administered locally.

We sought to design ASOs that can block SARS-CoV-2 by downregulating ACE2 in human airway.

ACE2-targeting ASOs were designed using a bioinformatic method and screened in cell lines. Human primary nasal epithelial cells cultured at the air-liquid interface and humanized ACE2 mice were used to detect the ACE2 reduction levels and the safety of ASOs. ASO-pretreated nasal epithelial cells and mice were infected and then used to detect the viral infection levels.

ASOs reduced ACE2 expression on mRNA and protein level in cell lines and in human nasal epithelial cells. Furthermore, they efficiently suppressed virus replication of 3 different SARS-CoV-2 variants in human nasal epithelial cells. In vivo, ASOs also downregulated human ACE2 in humanized ACE2 mice and thereby reduced viral load, histopathologic changes in lungs, and increased survival of mice.

ACE2-targeting ASOs can effectively block SARS-CoV-2 infection. Our study provides a new approach for blocking SARS-CoV-2 and other ACE2-targeting virus in high-risk populations.

Glaucoma, a leading cause of blindness worldwide, encompasses a group of pathological conditions affecting the optic nerve and is characterized by progressive retinal ganglion cell loss, cupping of the optic nerve head, and distinct visual field defects. While elevated intraocular pressure (IOP) is the main risk factor for glaucoma, many patients do not have elevated IOP. Consequently, other risk factors, such as ocular blood flow abnormalities and immunological factors, have been implicated in its pathophysiology. Traditional therapeutic strategies primarily aim to reduce IOP, but there is growing interest in developing novel treatment approaches to improve disease management and reduce the high rates of severe visual impairment. In this context, targeting the ocular renin-angiotensin-aldosterone system (RAAS) has been found as a potential curative strategy. The RAAS contributes to glaucoma development through key effectors such as prorenin, angiotensin II, and aldosterone. Recent evidence has highlighted the potential of using RAAS modulators to combat glaucoma, yielding encouraging results. Our study aims to explore the molecular pathways linking the ocular RAAS and glaucoma, summarizing recent advances that elucidate the role of the RAAS in triggering oxidative stress, inflammation, and remodelling in the pathogenesis of glaucoma. Additionally, we will present emerging therapeutic approaches that utilize RAAS modulators and antioxidants to slow the progression of glaucoma.