New insights into prostate Cancer from the renin-angiotensin-aldosterone system.

Prostate cancer is among the most common malignancies found in men, with multifactorial changes occurring altogether to disrupt the pathophysiology of this gland. The Renin-Angiotensin-Aldosterone System (RAAS) is an extensively studied pathway that has newly attributed fundamental roles in cancer biology that impact cell growth, migration, metastasis, and death. These processes are significantly influenced by various components of the RAAS, including prorenin, AT1R, AT2R, and Ang 1-7/Mas receptors. Although the pathophysiology of prostate cancer is complex, targeting the RAAS shows promise as a therapeutic approach. RAAS dysregulation is evident in prostate cancer, and treatments traditionally used for cardiovascular diseases are being explored for cancer therapy. The RAAS pathway has significant effects on the formation of new blood vessels (angiogenesis), the spread of cancer cells to other parts of the body (metastasis), and cell proliferation. In this pathway, angiotensin II and its receptors have crucial functions. Angiotensin II stimulates angiogenesis and cell proliferation through the AT1R, whereas the AT2R has the opposite effect by inhibiting cell growth. Additional pathways involving ACE2/Ang 1-7/Mas also provide potential targets for therapeutic intervention, mitigating the impact of the traditional ACE/Angiotensin II/AT1R pathway. The components of the RAAS influence multiple signalling pathways, such as Androgen Receptor (AR), NF-κB, and PI3K/AKT/mTOR, which enhances our understanding of how it contributes to the progression of prostate cancer. This also provides new possibilities for therapeutic interventions.

Prospective study of risk factors for community-acquired acute kidney injury.

BACKGROUND AND HYPOTHESIS: Causes and risk factors for community-acquired acute kidney injury (CA-AKI) have not been thoroughly studied. The aim of this study was to examine the risk factors for CA-AKI. METHODS: In this prospective study, we examined serum creatinine from all individuals visiting a university hospital's emergency department (ED) over an 11-month period for the presence of AKI defined according to the KDIGO criteria. Patients with AKI were invited to participate. Randomly selected controls (1:2) were paired according to age, sex, and date of admission. Participants answered questions about their medical history and medication use, including over-the-counter (OTC) drugs. Conditional logistic regression was used to identify factors associated with AKI. RESULTS: Of 602 AKI cases identified, 512 participated in the study. AKI cases were significantly more likely than controls to have used nonsteroidal anti-inflammatory drugs (NSAIDs) (26.0 % vs 18.0 %, p = 0,001) in the week preceding the ED visit, particularly OTC NSAIDs (23.3 % vs 15.9 %, p < 0.001). AKI was associated with a recent history of vomiting (OR 2.52 [95 %CI 1.87-3.39]), diarrhea (1.30 [1.00-1.70]) and urinary retention (1.92 [1.36-2.72]), use of non-selective NSAIDs (1.84, [1.37-2.48]), RAAS blockers (1.63 [1.21-2.19]), and diuretics (1.53 [1.13-2.08]), and a history of diabetes (1.42 [1.04-1.94]), CKD (1.36 [1.01-1.83]) and smoking (1.72 [1.24-2.37]). CONCLUSIONS: Events in the setting of acute illness and medication use, including OTC NSAIDs, may play a greater role in the development of CA-AKI than comorbid conditions. Frequent use of OTC NSAIDs is a concern and should be addressed in view of serious adverse effects.

Omicron-specific ultra-potent SARS-CoV-2 neutralizing antibodies targeting the N1/N2 loop of Spike N-terminal domain.

A multitude of functional mutations continue to emerge on the N-terminal domain (NTD) of the spike protein in SARS-CoV-2 Omicron subvariants. Understanding the immunogenicity of Omicron NTD and the properties of antibodies elicited by it is crucial for comprehending the impact of NTD mutations on viral fitness and guiding vaccine design. In this study, we find that most of NTD-targeting antibodies isolated from individuals with BA.5/BF.7 breakthrough infection (BTI) are ancestral (wildtype or WT)-reactive and non-neutralizing. Surprisingly, we identified five ultra-potent neutralizing antibodies (NAbs) that can only bind to Omicron but not WT NTD. Structural analysis revealed that they bind to a unique epitope on the N1/N2 loop of NTD and interact with the receptor-binding domain (RBD) via the light chain. These Omicron-specific NAbs achieve neutralization through ACE2 competition and blockage of ACE2-mediated S1 shedding. However, BA.2.86 and BA.2.87.1, which carry insertions or deletions on the N1/N2 loop, can evade these antibodies. Together, we provided a detailed map of the NTD-targeting antibody repertoire in the post-Omicron era, demonstrating their vulnerability to NTD mutations enabled by its evolutionary flexibility, despite their potent neutralization. These results revealed the function of the indels in the NTD of BA.2.86/JN.1 sublineage in evading neutralizing antibodies and highlighted the importance of considering the immunogenicity of NTD in vaccine design.

Identification of nitrile-containing isoquinoline-related natural product derivatives as coronavirus entry inhibitors in silico and in vitro.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused millions of infections and deaths worldwide since its emergence in Wuhan, China, in late 2019. Natural product inhibitors targeting the interaction between the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein and human angiotensin-converting enzyme 2 (ACE2), crucial for viral attachment and cellular entry, are of significant interest as potential antiviral agents. In this study a library of nitrile- and sulfur-containing natural product derived compounds were used for virtual drug screening against the RBD of the SARS-CoV-2 spike protein. The top 18 compounds from docking were tested for their efficacy to inhibit virus entry. In vitro experiments revealed that compounds 9, 14, and 15 inhibited SARS-CoV-2 pseudovirus and live virus entry in HEK-ACE2 and Vero E6 host cells at low micromolar IC50 values. Cell viability assays showed these compounds exerted low cytotoxicity towards MRC5, Vero E6, and HEK-ACE2 cell lines. Microscale thermophoresis revealed all three compounds strongly bound to the RBDs of SARS-CoV-2, SARS-CoV-2 XBB, SARS-CoV-1, MERS-CoV, and HCoV-HKU1, with their Kd values increasing as RBD sequence similarity decreased. Molecular docking studies indicated compounds 9, 14, and 15 bound to the SARS-CoV-2 spike protein RBD and interacted with hotspot amino acid residues required for the RBD-ACE2 interaction and cellular infection. These three nitrile-containing candidates, particularly compound 15, should be considered for further development as potential pan-coronavirus entry inhibitors.

Protein-added kefir: biochemical changes in in vitro digestion stages.

BACKGROUND: While yogurt is the leading fermented milk product, kefir is at the top of the beverage scale. Milk proteins, on the other hand, show specific functions that positively affect healthy nutrition due to the bioactive components, that they provide the necessary amino acids for growth and development. RESULTS: In our study, kefir, a functional product enriched with whey proteins, casein and skimmed milk powder, which are the natural components of milk, was produced. Added-protein kefir samples were applied the in vitro digestion protocol, static method. In order to observe different protein behaviors, samples were taken pre-digestion, at 120th minute and at 240th minute of digestion protocol. ACE and Antioxidant capacity determination analyzes were carried out. While ACE inhibition values were in the range of 78.63-90.30% pre-digestion, they changed in the range of 86.97-96.38% after gastrointestinal digestion. It was determined that the ACE inhibition values of the control sample remained at the lowest level at all stages of digestion and that the difference between all of samples was significant (P < 0.05). Antioxidant activity value ranging from 0.3615-0.5512 meq Ascorbic acid/µg before digestion was determined as 1.3796-1.9313 meq Ascorbic acid/µg after gastrointestinal digestion (P < 0.05). CONCLUSION: Kefir samples containing whey protein stand out with their high potential in terms of both antioxidant activity capacity and ACE inhibition activity at all stages of digestion. Considering their therapeutic effects in fermented products, it is thought that whey proteins among milk proteins will be important alternative sources to enrich the protein content in kefir production. © 2024 Society of Chemical Industry.

Perindopril decreases angiotensin-converting enzyme 2 (ACE2) expression in human adipocytes exposed to SARS-CoV-2 S1 spike protein.

The expression of angiotensin-converting enzyme 2 (ACE2) in the adipose tissues of obese patients needs further study, as it may aid infection and serve as a viral reservoir. There has been controversy over whether to use ACE inhibitors to prevent coronavirus disease 2019 (COVID-19) severity. Perindopril, an ACE2 inhibitor, has been proposed; however, its relationship with COVID-19 has not yet been clear. The aim of this study was to investigate the effect of perindopril to reduce the expression of ACE2 and pro-inflammatory cytokine in adipocytes exposed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Enzymatic isolation of adipose tissues was performed from obese male donor patients aged 30-50 years, then exposed it with SARS-CoV-2 S1 spike protein. This study also included human recombinant ACE2 (hrsACE2) as a comparison to perindopril. The expression of ACE2 was evaluated using ELISA. Our data indicated that SARS-CoV-2 Spike protein exposure increased ACE2 expression significantly. Administration of perindopril decreased ACE2 expression (43.37 µg/mL) significantly compared to the positive group (80.31 µg/mL) (p<0.001). Perindopril administration also decreased IL-6 levels significantly compared to positive group (p<0.001). This study highlights that perindopril could reduce the ACE2 expression and pro-inflammatory cytokine levels in adipocytes exposed to SARS-CoV-2 S1 spike protein.

Perindopril and losartan affect ACE-2 and IL- 6 expression in obese rat model.

Obesity has emerged as a worldwide health concern due to its increasing prevalence. Adipocytes have the ability to express angiotensin-converting enzyme 2 receptors (ACE2) and several adipocytokines. These expressions could lead to the activation of a cytokine storm, which in turn promotes the development of cardiovascular diseases. The aim of this study was to investigate the impact of perindopril and losartan exposure on the ACE2 and interleukin 6 (IL-6) levels in adipocyte cells. This study used an in vivo true experimental design utilizing a post-test-only control group. A total of 24 adult male albino rats were divided into four groups, one group served as the non-obese (negative control), while the other three groups were obese: (1) the positive control (untreated obese rats); (2) perindopril group (2 mg/kg BW/day orally for 4 weeks); and (3) losartan group (20 mg/kg BW/day for 4 weeks). Afterwards, the rats were euthanized, and the visceral fat tissue were obtained during dissection. The levels of ACE2 and IL-6 were measured using the enzyme-linked immunosorbent assay (ELISA). Losartan administration in obese rats resulted in a notable elevation in ACE2 levels compared to both the perindopril group (losartan vs perindopril, p=0.011) and the positive control (p=0.004). In addition, the treatment of perindopril and losartan in obese rats resulted in a significant reduction in IL-6 levels when compared to the positive control (perindopril vs positive control, p=0.020; losartan vs positive control, p=0.002, respectively). This study provides insight into the administration of perindopril and losartan, which could suppress the pro-inflammatory (IL-6) but increase the ACE2 levels in adipose tissue.

Role of ACE2 and TMPRSS2 polymorphisms on COVID-19 outcome and disease severity in adult patients: A prospective cohort study in a tertiary hospital, Indonesia.

Coronavirus disease 2019 (COVID-19) has led to a significant number of infections and deaths worldwide, yet its pathogenesis and severity remain incompletely understood. Angiotensin-converting enzyme 2 (ACE2) and transmembrane protease, serine 2 (TMPRSS2), play crucial roles as receptors and molecules responsible for the virus's entry into host cells, initiating the infection process. Their polymorphisms have been extensively studied in relation to COVID-19 severity. The aim of this study was to examine the association of ACE2 (rs2074192) and TMPRSS2 (rs12329760) polymorphisms with COVID-19 outcome and severity. A prospective cohort study was conducted in 2022 at Haji Adam Malik Hospital, Medan, Indonesia. We randomly recruited hospitalized adult patients with COVID-19, confirmed by real-time polymerase chain reaction (RT-PCR). The baseline demographic data, disease severity, underlying disease, comorbidities, and COVID-19 vaccination status were collected. The single-nucleotide polymorphism (SNP) was assessed using TaqMan SNP genotyping assay, and the levels of TMPRSS2 and ACE2 proteins were measured using enzyme-linked immunosorbent assay (ELISA). A total of 151 COVID-19 patients were recruited and there were significant associations between age and severity with mortality outcomes. The age, kidney and lung diseases, and vaccination status were associated with severity levels. The results showed the CC genotype of ACE2 had the highest proportion, followed by TT and CT genotypes among patients, while CT was the most prevalent genotype, followed by CC and TT for TMPRSS2. This study did not find a significant association between ACE2 and TMPRSS2 genetic variants with disease severity and outcome but highlighted a specific association of TMPRSS2 SNP with mortality within the group. In addition, ACE2 concentration was significant different between mild-moderate and severe-critical COVID-19 groups (p=0.033).

Diagnostic Modalities in Heart Failure: A Narrative Review.

Heart failure (HF) can present acutely or progress over time. It can lead to morbidity and mortality affecting 6.5 million Americans over the age of 20. The HF type is described according to the ejection fraction classification, defined as the percentage of blood volume that exits the left ventricle after myocardial contraction, undergoing ejection into the circulation, also called stroke volume, and is proportional to the ejection fraction. Cardiac catheterization is an invasive procedure to evaluate coronary artery disease leading to HF. Several biomarkers are being studied that could lead to early detection of HF and better symptom management. Testing for various biomarkers in the patient's blood is instrumental in confirming the diagnosis and elucidating the etiology of HF. There are various biomarkers elevated in response to increased myocardial stress and volume overload, including B-type natriuretic peptide (BNP) and its N-terminal prohormone BNP. We explored online libraries such as PubMed, Google Scholar, and Cochrane to find relevant articles. Our narrative review aims to extensively shed light on diagnostic modalities and novel techniques for diagnosing HF.

Ropivacaine Administration Suppressed A549 Lung Adenocarcinoma Cell Proliferation and Migration via ACE2 Upregulation and Inhibition of the Wnt1 Pathway.

BACKGROUND: Previous studies have suggested that perioperative anesthesia could have direct impacts on cancer cell biology. The present study investigated the effects of ropivacaine administration on lung adenocarcinoma cells. METHODS: Ropivacaine was administered to A549 cells at concentrations of 0.1, 1, and 6 mM for 2 h. Angiotensin-converting enzyme 2 (ACE2) small interfering RNA (siRNA) transfection was performed 6 h prior to ropivacaine administration. Cell proliferation and migration were assessed with cell counting kit 8 (CCK-8) and a wound healing assay at 0 and 24 h after anesthesia exposure. PCR arrays were performed, followed by PCR validation. RESULTS: Ropivacaine administration inhibited A549 cell proliferation and migration in a concentration-dependent manner, with ACE2 upregulation and HIF1α (hypoxia-inducible factor 1α) downregulation. The anticancer effect of ropivacaine was canceled out via ACE2 siRNA transfection. PCR arrays showed specific gene change patterns in the ropivacaine and respective ACE2-knockdown groups. EGFR (epidermal growth factor receptor), BAX (Bcl-2-associated X protein) and BCL2 (B-cell/CLL lymphoma 2) were suppressed with ropivacaine administration; these effects were reversed via ACE2 siRNA induction. CONCLUSION: Ropivacaine administration inhibited A549 cell biology in conjunction with ACE2 upregulation via the inhibition of the Wnt1 (wingless/Integrated 1) pathway.

Genetic Polymorphisms of Angiotensin-Converting Enzyme 1 (ACE1) and ACE2 Associated With Severe Acute Respiratory Syndrome COVID-19 in the Palestinian Population.

As a key enzyme of the renin-angiotensin system (RAS), angiotensin-converting enzyme 2 (ACE2) is a validated receptor for SARS-CoV-2, linking RAS to COVID-19. Functional ACE1/ACE2 gene polymorphisms likely cause an imbalance in the ACE1/ACE2 ratio, triggering RAS imbalance and may contribute to COVID-19 complications. This study aimed to investigate four single nucleotide polymorphisms (SNPs) of ACE1 and ACE2 genes, three for ACE1 (rs4343, rs4342, rs4341) and one for ACE2 (rs2285666), in patients with COVID-19 among the Palestinian population. A total of 130 blood samples were collected, including 50 negative controls without COVID-19 infection, 50 cases with COVID-19 infection but not hospitalized, and 30 patients with severe COVID-19 infection hospitalized in the intensive care unit. Fragments of the ACE1 and ACE2 genes, including the targeted SNPs, were amplified using multiplex PCR and subsequently genotyped by next-generation sequencing with specific virtual probes. Our results revealed that ACE2 rs2285666 GG genotype carriers were more prevalent in COVID-19 patients compared to the control group (P=0.049), while no statistical differences were observed in the distribution of ACE1 (rs4343, rs4342, rs4341) variants between COVID-19 patients and the control group. GA carriers of ACE2, rs2285666, among cases and ICU groups were at lower risk of getting COVID-19 infection (P=0.002 and P=0.013, respectively), and they were unlikely to develop fatigue (P=0.043), headache (P=0.007), loss of smell (P=0.028), and dyspnea (P=0.005). Age and comorbidities such as hypertension and coronary artery disease (CAD) were independent risk factors for COVID-19 disease. Symptoms of COVID-19 patients such as fatigue, headaches, runny noses, and loss of smell were significantly higher in non-hospitalized cases of COVID-19, while dyspnea was more frequent in the ICU patients. In conclusion, these findings indicate that the ACE2 rs2285666 GG genotype is associated with an increased risk of COVID-19 infection. This association suggests a potential genetic predisposition linked to the ACE2 gene, which may influence the susceptibility and severity of the disease.

Liver ultrasound evaluation of acutely increased liver function tests of COVID-19 hospitalized patients.

Background: The incidence of hepatic abnormalities has been notably higher following the coronavirus disease 2019 (COVID-19) infection, attributed to the virus's entry into cells via angiotensin-converting enzyme 2 (ACE2) surface expression. The gastrointestinal tract's significant ACE2 expression, alongside a lesser degree in the biliary epithelium, has been implicated in gastrointestinal symptoms and liver injury. Purpose: The aim of this study was to determine whether specific ultrasonographic findings in the liver correlate with acute increases in liver function tests (LFTs) among hospitalized patients. Methods: A retrospective analysis was conducted on hospitalized COVID-19 patients at Hazem Mebaireek General Hospital in Qatar, from March 1, 2020, to June 30, 2020. The study focused on patients who experienced acute increases in LFTs, excluding those with chronic liver disease. Ultrasound imaging and patient records were reviewed to gather data. Results: Out of 223 ultrasound studies of COVID-19 patients, 158 met the inclusion criteria. The majority were male, with a mean age of 47.76 ± 13.76 years. Ultrasound results showed 43.7% normal liver parenchyma, while 56.3% exhibited nonspecific abnormalities such as diffuse liver hyperechogenicity (39.2%), enlargement with diffuse hyperechogenicity (12.7%), and other findings (4.4%). The biliary tree was predominantly normal (96.2%), with 3.8% showing abnormalities, including intrahepatic (2.5%) and extrahepatic (1.3%) dilatation. Gallbladder evaluations were normal in 60.1% of cases, with 39.9% showing abnormalities like stones (6.3%), stones with sludge (13.3%), polyps (6.3%), wall thickening (1.9%), and other conditions (12%). A significant correlation was found between abnormal liver parenchyma findings and elevated levels of bilirubin (total and direct) and alkaline phosphatase, with p-values < 0.05. Only aspartate aminotransferase levels showed a significant correlation with biliary tree abnormalities. Conclusion: The most common ultrasonographic finding associated with acute increases in LFTs among hospitalized COVID-19 patients was diffuse liver hyperechogenicity, with or without enlargement. These findings suggest a nonspecific yet significant association with liver function anomalies in the context of COVID-19.

Preparation and Vasodilation Mechanism of Angiotensin-I-Converting Enzyme Inhibitory Peptide from Ulva prolifera Protein.

Ulva prolifera, a type of green algae that can be consumed, was utilized in the production of an angiotensin-I converting enzyme (ACE) inhibitory peptide. The protein from the algae was isolated and subsequently hydrolyzed using a neutral protease. The resulting hydrolysate underwent several processes including Sephadex-G100 filtration chromatography, ultrafiltration, HPLC-Q-TOF-MS analysis, ADMET screening, UV spectrum detection test, molecular docking, and molecular dynamic simulation. Then, the ACE inhibitory peptide named KAF (IC50, 0.63 ± 0.26 µM) was identified. The effectiveness of this peptide in inhibiting ACE can be primarily attributed to two conventional hydrogen bonds. Additionally, it could activate endothelial nitric oxide synthase (eNOS) activity to promote the generation of nitric oxide (NO). Additionally, KAF primarily increased the intracellular calcium (Ca2+) level by acting on L-type Ca2+ channel (LTCC) and the ryanodine receptor (RyR) in the endoplasmic reticulum, and completed the activation of eNOS under the mediation of protein kinase B (Akt) signaling pathway. Our study has confirmed that KAF has the potential to be processed into pharmaceutical candidate functions on vasoconstriction.

Identification of New Angiotensin-Converting Enzyme Inhibitory Peptides Isolated from the Hydrolysate of the Venom of Nemopilema nomurai Jellyfish.

Recently, jellyfish venom has gained attention as a promising reservoir of pharmacologically active compounds, with potential applications in new drug development. In this investigation, novel peptides, isolated from the hydrolysates of Nemopilema nomurai jellyfish venom (NnV), demonstrate potent inhibitory activities against angiotensin-converting enzyme (ACE). Proteolytic enzymes-specifically, papain and protamex-were utilized for the hydrolysis under optimized enzymatic conditions, determined by assessing the degree of hydrolysis through the ninhydrin test. Comparative analyses revealed that papain treatment exhibited a notably higher degree of NnV hydrolysis compared to protamex treatment. ACE inhibitory activity was quantified using ACE kit-WST, indicating a substantial inhibitory effect of 76.31% for the papain-digested NnV crude hydrolysate, which was validated by captopril as a positive control. The separation of the NnV-hydrolysate using DEAE sepharose weak-anion-exchange chromatography revealed nine peaks under a 0-1 M NaCl stepwise gradient, with peak no. 3 displaying the highest ACE inhibition of 96%. The further purification of peak no. 3 through ODS-C18 column reverse-phase high-performance liquid chromatography resulted in five sub-peaks (3.1, 3.2, 3.3, 3.4, and 3.5), among which 3.2 exhibited the most significant inhibitory activity of 95.74%. The subsequent analysis of the active peak (3.2) using MALDI-TOF/MS identified two peptides with distinct molecular weights of 896.48 and 1227.651. The peptide sequence determined by MS/MS analysis revealed them as IVGRPLANG and IGDEPRHQYL. The docking studies of the two ACE-inhibitory peptides for ACE molecule demonstrated a binding affinity of -51.4 ± 2.5 and -62.3 ± 3.3 using the HADDOCK scoring function.

Human placental mesenchymal stem cells transplantation repairs the alveolar epithelial barrier to alleviate lipopolysaccharides-induced acute lung injury.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are accompanied by high mortality rates and few effective treatments. Transplantation of human placental mesenchymal stem cells (hPMSCs) may attenuate ALI and the mechanism is still unclear. Our study aimed to elucidate the potential protective effect and therapeutic mechanism of hPMSCs against lipopolysaccharide (LPS)-induced ALI, An ALI model was induced by tracheal instillation of LPS into wild-type (WT) and angiotensin-converting enzyme 2 (ACE2) knockout (KO) male mice, followed by injection of hPMSCs by tail vein. Treatment with hPMSCs improved pulmonary histopathological injury, reduced pulmonary injury scores, decreased leukocyte count and protein levels in bronchoalveolar lavage fluid(BALF), protected the damaged alveolar epithelial barrier, and reversed LPS-induced upregulation of pro-inflammatory factors Interleukin-6 (IL-6) and Tumor necrosis factor-α(TNF-α) and downregulation of anti-inflammatory factor Interleukin-6(IL-10) in BALF. Moreover, administration of hPMSCs inhibited Angiotensin (Ang)II activation and promoted the expression levels of ACE2 and Ang (1-7) in ALI mice. Pathological damage, inflammation levels, and disruption of alveolar epithelial barrier in ALI mice were elevated after the deletion of ACE2 gene, and the Renin angiotensin system (RAS) imbalance was exacerbated. The therapeutic effect of hPMSCs was significantly reduced in ACE2 KO mice. Our findings suggest that ACE2 plays a key role in hPMSCs repairing the alveolar epithelial barrier to protect against ALI, laying a new foundation for the clinical treatment of ALI.

AlphaFold2 Modeling and Molecular Dynamics Simulations of the Conformational Ensembles for the SARS-CoV-2 Spike Omicron JN.1, KP.2 and KP.3 Variants: Mutational Profiling of Binding Energetics Reveals Epistatic Drivers of the ACE2 Affinity and Escape Hotspots of Antibody Resistance.

The most recent wave of SARS-CoV-2 Omicron variants descending from BA.2 and BA.2.86 exhibited improved viral growth and fitness due to convergent evolution of functional hotspots. These hotspots operate in tandem to optimize both receptor binding for effective infection and immune evasion efficiency, thereby maintaining overall viral fitness. The lack of molecular details on structure, dynamics and binding energetics of the latest FLiRT and FLuQE variants with the ACE2 receptor and antibodies provides a considerable challenge that is explored in this study. We combined AlphaFold2-based atomistic predictions of structures and conformational ensembles of the SARS-CoV-2 spike complexes with the host receptor ACE2 for the most dominant Omicron variants JN.1, KP.1, KP.2 and KP.3 to examine the mechanisms underlying the role of convergent evolution hotspots in balancing ACE2 binding and antibody evasion. Using the ensemble-based mutational scanning of the spike protein residues and computations of binding affinities, we identified binding energy hotspots and characterized the molecular basis underlying epistatic couplings between convergent mutational hotspots. The results suggested the existence of epistatic interactions between convergent mutational sites at L455, F456, Q493 positions that protect and restore ACE2-binding affinity while conferring beneficial immune escape. To examine immune escape mechanisms, we performed structure-based mutational profiling of the spike protein binding with several classes of antibodies that displayed impaired neutralization against BA.2.86, JN.1, KP.2 and KP.3. The results confirmed the experimental data that JN.1, KP.2 and KP.3 harboring the L455S and F456L mutations can significantly impair the neutralizing activity of class 1 monoclonal antibodies, while the epistatic effects mediated by F456L can facilitate the subsequent convergence of Q493E changes to rescue ACE2 binding. Structural and energetic analysis provided a rationale to the experimental results showing that BD55-5840 and BD55-5514 antibodies that bind to different binding epitopes can retain neutralizing efficacy against all examined variants BA.2.86, JN.1, KP.2 and KP.3. The results support the notion that evolution of Omicron variants may favor emergence of lineages with beneficial combinations of mutations involving mediators of epistatic couplings that control balance of high ACE2 affinity and immune evasion.

Use of Herbal Drugs in Cardiovascular Disease- A Review.

Thirty percent of deaths worldwide are caused by cardiovascular disorders (CVDs). As per the WHO data, the number of fatalities due to CVDs is 17.9 million years, and it is projected to cause 22.2 million deaths by 2030. In terms of gender, women die from CVD at a rate of 51% compared to 42% for males. Most people use phytochemicals, a type of traditional medicine derived from plants, either in addition to or instead of commercially available medications to treat and prevent CVD. Phytochemicals are useful in lowering cardiovascular risks, especially for lowering blood cholesterol, lowering obesity-related factors, controlling blood sugar and the consequences of type 2 diabetes, controlling oxidative stress factors and inflammation, and preventing platelet aggregation. Medicinal plants that are widely known for treating CVD include ginseng, ginkgo biloba, ganoderma lucidum, gynostemma pentaphyllum, viridis amaranthus, etc. Plant sterol, flavonoids, polyphenols, sulphur compound and terpenoid are the active phytochemicals present in these plants. The aim of this article is to cover more and more drugs that are used for cardiovascular diseases. In this article, we will learn about the use of different herbal drugs, mechanism of action, phytochemical compounds, side effects, etc. However, more research is required to comprehend the process and particular phytochemicals found in plants that treat CVD.

Role of ACE2 and TMPRSS2 polymorphisms in clinical severity and outcomes of COVID-19 in Egypt.

Background: The clinical presentations of coronavirus disease 2019 (COVID-19) exhibit significant variation, ranging from asymptomatic cases to mortality resulting from severe pneumonia. Host genetics can partially explain this variation. Objective: This study evaluated possible associations between severity and outcome of COVID-19 and single nucleotide polymorphism (SNP) rs2285666 in the ACE2 gene and SNP rs2070788 in the TMPRSS2 gene. Methods: The study included a sample of 100 consecutive adult patients admitted to the COVID-19 Isolation and Intensive Care Units of the Zagazig University Hospitals, Zagazig, Egypt from July 2021 to November 2021. For rs2285666, polymerase chain reaction-restriction fragment length polymorphism was carried out. For rs2070788, real-time polymerase chain reaction was performed. Results: For rs2285666, the GA genotype was the most frequent among female patients (39% [16/41]) and the A genotype was more prevalent among male patients (54.2% [32/59]). For rs2070788, the AA genotype was the most frequent among all patients (46% [46/100]). No rs2285666 or rs2070788 genotypes or allele frequencies had significant associations with either severity or outcomes of patients. Conclusion: This study found no significant associations of COVID-19 severity or outcomes of patients with genotypes or allele frequencies of the rs2285666 SNP in the ACE2 gene or the rs2070788 SNP of the TMPRSS2 gene. The search for other genetic associations with COVID-19 infection is still required. What this study adds: The study reveals that host genetics explain the variation observed in the disease. Specific genetic variants can confer either increased susceptibility or resistance to the disease.

Detection of SARS-CoV-2 binding receptors and miscellaneous targets as well as mucosal surface area of the human lacrimal drainage system.

PURPOSE: Our aim was to evaluate a potential role for the lacrimal drainage system (LDS) as a portal of entry and conduit for SARS-CoV-2 in human infection. We also investigate the mucosal surface area. The relatively long tear contact time in a closed system raises the possibility that this pathway may contribute to the initiation of systemic infection. We looked for expression of ACE2, the main receptor for SARS-CoV-2, as well as cofactors such as TMPRSS2 and other enzymes such as cathepsinB, CD147, elastase1, furin, neuropilin1, neuropilin2, TMPRSS11D and trypsin which also play a role in SARS-CoV-2 infection, in this system. METHODS: Human tissue samples of the draining tear ducts from body donors were analyzed by RT-PCR, Western blot and immunohistochemistry. It is not known whether the respective body donors were Sars-Cov-2 positive at any time; they were negative when they entered the institute. Besides, the draining LDS of body donors were measured to determine the mucosal surface in the lacrimal system. RESULTS: The expression of the main receptor studied, ACE2, cofactors such as TMPRSS2 and other enzymes such as cathepsinB, CD147, elastase1, furin, neuropilin1, neuropilin2, TMPRSS11D and trypsin were all detected at the gene and protein level. The average mucosal surface area of the lacrimal sac and nasolacrimal duct was calculated to be 110 mm2. CONCLUSION: The results show the presence of all analyzed receptors in the efferent LDS. With an average tear passage time of 3 min and a relatively large mucosal surface area, the LDS could therefore be considered as a portal of entry and conduit for SARS-CoV-2. In addition, it represents a surface that should be taken into consideration in the administration of topically applied medication to the ocular surface.

Effects of the ACE2-Ang-(1-7)-Mas axis on gut flora diversity and intestinal metabolites in SuHx mice.

Objective: Pulmonary artery hypertension (PAH) poses a significant challenge due to its limited therapeutic options and high mortality rates. The ACE2-Ang-(1-7)-Mas axis plays a pivotal role in regulating blood pressure and inhibiting myocardial remodeling. However, the precise mechanistic links between the ACE2-Ang-(1-7)-Mas axis and PAH remain poorly understood. This study aimed to elucidate the involvement of the ACE2-Ang-(1-7)-Mas axis in the development of PAH. Methods: PAH was induced in mice using Sugen5416/hypoxia, PAAT/PET ratio and PA were detected using cardiac ultrasound; inflammation related factors such as MCP-1, TNF, IL-10and IL-12p70 were detected in intestines using cytometric bead array (CBA) kits; histopathological and morphological changes in lung and intestinal tissues were assessed via HE staining and Masson staining to evaluate the progression of PAH. Immunohistochemistry and western blotting were employed to determine the expression levels of two tight junction proteins, occludin and ZO-1, in intestinal tissues. Additionally, 16rRNA sequencing and non-targeted metabolomics by LC-MS/MS techniques were utilized to investigate the impact of the ACE2-Ang-(1-7)-Mas axis on microbial diversity and metabolomics of intestinal contents. Results: Activation of the ACE2-Ang-(1-7)-Mas axis improves heart function, reduces intestines inflammatory factors and ameliorates pathological and histological alterations in SuHx mice. This activation notably upregulated the expression of occludin and ZO-1 proteins in intestinal tissues and promoted the proliferation of SCFA-producing bacteria genera, such as g_Candidatus_Saccharimonas. Furthermore, it enhanced the abundance of beneficial metabolites, including tryptophan and butyric acid. Conclusion: The findings suggest that modulation of the ACE2-Ang-(1-7)-Mas axis can alleviate PAH by regulating intestinal microbes and metabolites. These results highlight the potential of the ACE2-Ang-(1-7)-Mas axis as a promising therapeutic target for clinical management of PAH.