Angiotensin-converting Enzyme Levels Research Articles

Rare manifestations of sarcoidosis in a young boy

Sarcoidosis is a chronic multisystem granulomatous disease of unknown etiology. It is rare in young children. A 9-year-old boy presented with failure to thrive, skin rashes, persistent fever and respiratory symptoms since 5 years of age. Blood investigations done showed elevated serum calcium and angiotensin converting enzyme (ACE) levels and biopsy of the rashes on the left shin revealed non-caseating granulomatous lesion. Computed tomography (CT) of chest revealed interstitial lung disease (ILD) and examination of eyes showed bilateral uveitis. He also had sensorineural hearing impairment, nephrocalcinosis and short stature. The patient was treated with oral steroids and mycophenolate mofetil. At follow up there was improvement in his systemic features including rashes and arthritis. Early detection, diagnosis and appropriate treatment of sarcoidosis are vital for disease control and to avoid morbidity.

ACE2: the node connecting the lung cancer and COVID-19.

Angiotensin-converting Enzyme 2 (ACE2) collaborates with Angiotensin (Ang) 1-7 and Mas receptors to establish the ACE2-Ang (1-7)-Mas receptor axis. ACE2 impacts lung function and can cause lung injury due to its inflammatory effects. Additionally, ACE2 contributes to pulmonary vasculature dysfunction, resulting in pulmonary hypertension. In addition, ACE2 is a receptor for coronavirus entry into host cells, leading to coronavirus infection. Lung cancer, one of the most common respiratory diseases worldwide, has a high rate of infection. Elevated levels of ACE2 in lung cancer patients, which increase the risk of SARS-CoV-2 infection and severe disease, have been demonstrated in clinical studies and by molecular mechanisms. The association between lung cancer and SARS-CoV-2 is closely linked to ACE2. This review examines the basic pathophysiological role of ACE2 in the lung, the long-term effects of SARS-CoV-2 infection on lung function, the development of pulmonary fibrosis, chronic inflammation in long-term COVID patients, and the clinical research and mechanisms underlying the increased susceptibility of lung cancer patients to the virus. Possible mechanisms of lung cancer in SARS-CoV-2-infected individuals and the potential role of ACE2 in this process are also explored in this review. The role of ACE2 as a therapeutic target in the novel coronavirus infection process is also summarized. This will help to inform prevention and treatment of long-term pulmonary complications in patients.

The expression of renin-angiotensin system components in human carotid plaque

Background/Aim. The renin-angiotensin system (RAS) is linked to the development of atherosclerosis (As), including its initiation and progression. Besides the well-known angio-tensin-converting enzyme (ACE), two newer RAS family members are related to vascular remodeling - ACE2 as a homolog of ACE and collectrin [transmembrane protein 27 (TMEM27)] as a homolog of ACE2. Up to now, a limited number of studies have examined the expression of these RAS components in advanced carotid plaque (CP) tissue based on the sex of the patients and plaque phenotypes (PPs). There are two ultrasonographically defined PPs - the hypoechogenic plaque (HoP) and the hyperechogenic plaque (HerP) phenotype. The aim of the study was to investigate whether there was a correlation between the expression of RAS components in the CP and the sex and PPs of patients. Methods. We examined 74 patients with advanced CP who underwent carotid endarterectomy. The intraplaque expression of RAS components was determined with the real-time polymerase chain reaction, using the TaqMan? gene expression assays and Western blot. A two-way ANOVA followed by a post-hoc Tukey test was performed for the statistical analysis of results. Results. No interaction was recorded between the sex of the patients and PPs in influencing the relative expression of ACE and TMEM27 messenger RNA (mRNA) (p > 0.05). In 56.06% of plaque samples, no expression of ACE2 mRNA was detected. Among the plaques where ACE2 mRNA expression was detected, its expression level was higher in females with the HoP phenotype compared to females with the HerP phenotype (p < 0.001). In patients with the HoP phenotype, females had higher expression of ACE2 mRNA than males (p < 0.05). In the male study group, ACE protein levels were significantly lower in the HoP phenotype compared to the HerP phenotype (p < 0.001). Fe-males with the HoP phenotype had significantly higher ACE protein levels than males with the HoP phenotype (p < 0.0001). Conclusion. Our results revealed alterations in the expression levels of ACE and ACE2, at the mRNA and protein levels, in advanced carotid As. These alterations are impacted by sex and PP and may indicate a switch from the balanced RAS/ACE/ACE2 axis in the healthy blood vessel to the unbalanced axis in vascular remodeling due to As.

TARGETED IMMUNOTHERAPY FOR HEPATOCELLULAR CARCINOMA: A CLINICAL CASE

Relevance: Hepatocellular carcinoma (HCC) is the most common malignant tumor of the liver. HCC is one of the most important problems of the oncology service of Kazakhstan, as it has a progressive course, late detection, low survival, and unfavorable prognosis.
 The study aimed to evaluate the use of targeted immunotherapy in treating hepatocellular carcinoma in a clinical example.
 Methods: The paper presents a clinical case of targeted immunotherapy in combination with Atezolizumab 1200 mg + Bevacizumab 800 mg, once every 3 weeks, in treating HCC in the Regional Oncology Center in Kyzylorda.
 Results: The first symptoms of liver damage appeared in 2018, at which time HCC was discovered. Viral hepatitis B was diagnosed in 2016. MRI OBP from 15.08.20: a picture of the right lobe of the liver in S5 – 9×7×6 cm, in S3 – 3.7 cm, in S7 – 3.0 cm, in S8 – 2.5 cm. During the follow-up examination (July 2021), the enzyme immunoassay revealed a high angiotensin-converting enzyme (ACE) level of 450.56 IU/ml; the abdominal CT scan showed no deterioration. Later, despite the therapy, ACE increased rapidly: 2,595.3 IU/ml (August 2021) and 2,142.25 IU/ml (September 2021), and the therapy was changed to Regorafenib. ACE continued to rise to 4,405 IU/ml (November 2021) and 18,005 IU/ml (December 2021). A control abdominal CT scan showed a moderate reduction in the size of the tumor.
 Taking into account a steady ACE increase, in February 2022, the patient was recommended therapy with Atezolizumab and Bevacizumab. In January 2023, the patient has already received 13 courses, and ACE continued to decrease: 1,932 IU/ml (January 2023), 53.38 IU/ml (February 2023), 16.07 IU/ml (March 2023), and the abdominal CT scan showed positive dynamics.
 Conclusion: Targeted immunotherapy showed its effectiveness in the described case of inoperable HCC and allowed the patient to continue living, working, and leading an active lifestyle for more than 18 months.

Report two case of lymphangioleiomyomatosis (LAM) with presentation of recurrent pneumothorax

Pulmonary Lymphangioleiomyomatosis (LAM) is a rare and female-dominant disease and associated with smooth muscle cell proliferation, (LAM) which presents with diffuse progressive destruction of the pulmonary parenchyma. The incidence is less than 1 per million, which results in cystic lung disease and presente commonly with dyspnea and pneumothorax. Work up for diagnosis and exclusion other disease as: Sjögren’s syndrome type A, B and mazement of angiotensin-converting enzyme (ACE) levels, alpha-1-antitrypsin levels, and vascular endothelial growth factor (VEGF) anti bodies. Definitive diagnosis limited only to tissue sampling. No effective treatments are currently proposed for this disease. Two 49 and 39year-old woman who was referred with recurrent pneumothorax, after thoracotomy and resection, diagnosed was made with pulmonary Lymphangioleiomyomatosis. After pulmonary Lymphangioleiomyomatosis was performed, they treated with anti-estrogen therapy and symptomatic supportive care. In follow up pneumothorax was not occurred again. Pulmonary Lymphangioleiomyomatosis is a very rare disease that cannot be effectively cured.

Effect of SARS-CoV-2 spike protein exposure on ACE2 and interleukin 6 productions in human adipocytes: An in-vitro study.

Since adipocytes play a crucial role in pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection due to their interaction with angiotensin-converting enzyme 2 (ACE2) and interleukin 6 (IL-6), obesity is associated with an increased risk of coronavirus disease 2019 (COVID-19) mortality. Discovery of ACE2 as a SARS-CoV-2 receptor raises a controversy about whether to use ACE inhibitors (ACEIs) could be an optional therapy to prevent cytokine storms. Studies assessing the expressions of ACE2 and IL-6 upon exposure to SARS-CoV-2 is therefore important as a basis for therapeutical trials in the future. The aim of this study was to determine the effect of SARS-CoV-2 spike protein exposure on the production of ACE2 and IL-6 in adipocyte cells. Adipocytes were collected from abdominal adipose tissues of healthy and obese 45-year-old male donor having neither a history of SARS-CoV-2 infection nor COVID-19 vaccination. After being stained using the oil red O protocol, the viable adipocytes were then exposed to S1 subunit of SARS-CoV-2 spike protein. The levels of ACE2 and IL-6 were then examined using the enzyme-linked immunosorbent assay (ELISA). The results showed significant increase of ACE2 (90.22 µg/mL) and IL-6 level (60.01 µg/mL) in human adipocytes upon exposure compared to unexposed control cells (ACE2 13.33 µg/mL; IL-6 21.33 µg/mL), both comparisons had p<0.001). This study provides insight into the basic mechanism of severe COVID-19 symptoms in obese patients and provides a basic information of the potential of ACE inhibitors as an optional therapy for COVID-19 patients with obesity.

TARGETED IMMUNOTHERAPY FOR HEPATOCELLULAR CARCINOMA:&#x0D; A CLINICAL CASE

Relevance: Hepatocellular carcinoma (HCC) is the most common malignant tumor of the liver. HCC is one of the most important problems&#x0D; of the oncology service of Kazakhstan, as it has a progressive course, late detection, low survival, and unfavorable prognosis.&#x0D; The study aimed to evaluate the use of targeted immunotherapy in treating hepatocellular carcinoma in a clinical example.&#x0D; Methods: The paper presents a clinical case of targeted immunotherapy in combination with Atezolizumab 1200 mg + Bevacizumab 800 mg,&#x0D; once every 3 weeks, in treating HCC in the Regional Oncology Center in Kyzylorda.&#x0D; Results: The first symptoms of liver damage appeared in 2018, at which time HCC was discovered. Viral hepatitis B was diagnosed in 2016.&#x0D; MRI OBP from 15.08.20: a picture of the right lobe of the liver in S5 – 9×7×6 cm, in S3 – 3.7 cm, in S7 – 3.0 cm, in S8 – 2.5 cm. During the follow-up&#x0D; examination (July 2021), the enzyme immunoassay revealed a high angiotensin-converting enzyme (ACE) level of 450.56 IU/ml; the abdominal CT&#x0D; scan showed no deterioration. Later, despite the therapy, ACE increased rapidly: 2,595.3 IU/ml (August 2021) and 2,142.25 IU/ml (September 2021),&#x0D; and the therapy was changed to Regorafenib. ACE continued to rise to 4,405 IU/ml (November 2021) and 18,005 IU/ml (December 2021). A control&#x0D; abdominal CT scan showed a moderate reduction in the size of the tumor.&#x0D; Taking into account a steady ACE increase, in February 2022, the patient was recommended therapy with Atezolizumab and Bevacizumab. In&#x0D; January 2023, the patient has already received 13 courses, and ACE continued to decrease: 1,932 IU/ml (January 2023), 53.38 IU/ml (February&#x0D; 2023), 16.07 IU/ml (March 2023), and the abdominal CT scan showed positive dynamics.&#x0D; Conclusion: Targeted immunotherapy showed its effectiveness in the described case of inoperable HCC and allowed the patient to continue&#x0D; living, working, and leading an active lifestyle for more than 18 months.

A case of hepatosplenic sarcoidosis accompanied by hypercalcemia.

We present a case diagnosed with hepatosplenic sarcoidosis with hypercalcemia. Elevated liver enzymes and hypercalcemia were detected in the patient who was admitted to the hospital with abdominal pain and dyspnea. Abdominal dynamic magnetic resonance imaging (MRI) showed diffuse, multiple, nodular hyperintense lesions on T2 weighted. Multinuclear giant cells and lymphocytic portal inflammation were seen in the patient's liver biopsy, whose angiotensin-converting enzyme level was high, and hepatosplenic sarcoidosis was diagnosed. Shortness of breath, abdominal pain, and calcium level improved with methylprednisolone treatment.

Exploring the implications of blocking renin-angiotensin-aldosterone system and fibroblast growth factor 23 in early left ventricular hypertrophy without chronic kidney disease.

Whether fibroblast growth factor 23 (FGF23) directly induces left ventricular hypertrophy (LVH) remains controversial. Recent studies showed an association between FGF23 and the renin-angiotensin-aldosterone system (RAAS). The aim of this study was to investigate changes in FGF23 levels and RAAS parameters and their influences on LVH. In the first experiment, male C57BL/6J mice were divided into sham and transverse aortic constriction (TAC) groups. The TAC group underwent TAC at 8 weeks of age. At 1, 2, 3, and 4 weeks after TAC, the mice were sacrificed, and blood and urine samples were obtained. Cardiac expressions of FGF23 and RAAS-related factors were evaluated, and cardiac histological analyses were performed. In the second experiment, the sham and TAC groups were treated with vehicle, angiotensin-converting enzyme (ACE) inhibitor, or FGF receptor 4 (FGFR4) inhibitor and then evaluated in the same way as in the first experiment. In the early stage of LVH without chronic kidney disease, serum FGF23 levels did not change but cardiac FGF23 expression significantly increased along with LVH progression. Moreover, serum aldosterone and cardiac ACE levels were significantly elevated, and cardiac ACE2 levels were significantly decreased. ACE inhibitor did not change serum FGF23 levels but significantly decreased cardiac FGF23 levels with improvements in LVH and RAAS-related factors, while FGFR4 inhibitor did not change the values. Not serum FGF23 but cardiac FGF23 levels and RAAS parameters significantly changed in the early stage of LVH without chronic kidney disease. RAAS blockade might be more crucial than FGF23 blockade for preventing LVH progression in this condition.

Eye Washing Downregulated Angiotensin-Converting Enzyme 2 in Conjunctival Tissue Samples from Smokers.

This study aimed to (1) determine whether the expression of angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 is increased in tobacco smokers, which potentially increases their susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and (2) assess whether eye rinsing can reduce susceptibility. This prospective study included 20 eyes of 10 smokers and 18 eyes of nine healthy non-smokers (control) for reverse-transcription polymerase chain reaction. This study also included 28 eyes of 14 smokers and 16 eyes of eight healthy non-smokers (control) for enzyme-linked immunosorbent assay. Tear and impression cytology samples were collected from the right eye of each patient. The left eye was then rinsed for 30 s, and after 5 min, the tear and impression cytology samples were collected in the same manner. The expression of the ACE2 gene was significantly higher in the conjunctiva of smokers (n = 17; median 3.07 copies/ng of total RNA) than in those of non-smokers (n = 17; median 1.92 copies/ng of total RNA, p = 0.003). Further, mRNA expression and protein levels of ACE2 were weakly correlated in smokers (r = 0.49). ACE2 protein levels in Schirmer's strip samples were significantly reduced from 5051 to 3202 pg/mL after eye washing (n = 10; p = 0.001). Ocular surface cells are susceptible to SARS-CoV-2 infection. Smoking may be a risk factor for SARS-CoV-2 infection, and eye rinsing may reduce the risk of infection.

ACE2 knockout hinders SARS-CoV-2 propagation in iPS cell-derived airway and alveolar epithelial cells.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, continues to spread around the world with serious cases and deaths. It has also been suggested that different genetic variants in the human genome affect both the susceptibility to infection and severity of disease in COVID-19 patients. Angiotensin-converting enzyme 2 (ACE2) has been identified as a cell surface receptor for SARS-CoV and SARS-CoV-2 entry into cells. The construction of an experimental model system using human iPS cells would enable further studies of the association between viral characteristics and genetic variants. Airway and alveolar epithelial cells are cell types of the lung that express high levels of ACE2 and are suitable for in vitro infection experiments. Here, we show that human iPS cell-derived airway and alveolar epithelial cells are highly susceptible to viral infection of SARS-CoV-2. Using gene knockout with CRISPR-Cas9 in human iPS cells we demonstrate that ACE2 plays an essential role in the airway and alveolar epithelial cell entry of SARS-CoV-2 in vitro. Replication of SARS-CoV-2 was strongly suppressed in ACE2 knockout (KO) lung cells. Our model system based on human iPS cell-derived lung cells may be applied to understand the molecular biology regulating viral respiratory infection leading to potential therapeutic developments for COVID-19 and the prevention of future pandemics.

Lepra Reactions: Mimickers and Mirror to Unmask Complex Cases of Leprosy

Abstract Leprosy is a silent disease with protean manifestations, especially during lepra reactions (LRs). Cases with atypical leprosy or LR simulate a number of conditions misdiagnosed frequently. Here, three classical cases of leprosy are reported for their complex presentation. Leprosy was hidden in Case 1 due to co-existing diabetes. COVID vaccination induced LR unmasked all leprosy lesions, which were extensive, large, bizarre and spreading to various immune zones. Case 2 presented with high-grade fever, tachycardia, generalized erythema and body aches. A detailed workup unveiled his leprosy with a rare presentation of Type 1 lepra reaction (T1LR) with erythroderma and severe systemic symptoms. Case 3 mimicked sarcoidosis and lupus erythematosus (LE) on routine workup. She had facial lesions in the malar area, photosensitivity, joint pains, raised angiotensin-converting enzyme (ACE) levels and positive anti-nuclear antibodies. Peri-appendageal granulomas on histopathology and therapeutic response to multidrug therapy helped in the early diagnosis of leprosy.

Hippophae rhamnoides Prevents Oleic Acid-Induced Acute Respiratory Distress Syndrome by Releasing Acetylcholinesterase Activity and Mitigation of Angiotensin-Converting Enzyme Level.

Hippophae rhamnoides exhibit a wide variety of medicinal and pharmacological effects. The present study aims to determine the role of ethanol extract of H. rhamnoides on oleic acid (OA)-induced acute respiratory distress syndrome (ARDS) in rats. Male rats were randomly divided into the following groups: (I) Control, (II) OA, and (III) OA+H. rhamnoides. H. rhamnoides extract (500 mg/kg) was given orally for 2 weeks before OA in Group III. Levels of total antioxidant capacity, total oxidant status (TOS), myeloperoxidase (MPO), mitogen-activated protein kinase (MAPK), acetylcholinesterase (AChE), and angiotensin-converting enzyme (ACE) were quantified by enzyme-linked immunosorbent assay (ELISA). Real time quantitative polymerase chain reaction was utilized to evaluate the expression of nuclear factor kappa B (NF-κB), tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and matrix metalloproteinase 2 (MMP2). Also, Caspase-3 immunostaining and expression were performed to evaluate apoptosis. Compared with the OA group, there was a significantly decrease in the levels of MPO, TOS, MAPK, and ACE and in the expression of NF-κB, TNF-α, IL-6, MMP2, and Caspase-3 in the H. rhamnoides administration group. Moreover, the activity of AChE and level of TAS were substantially higher in the H. rhamnoides administration compared with the OA group. The findings in the study suggest that the protective effect of H. rhamnoides pretreatment may act through inhibition of the ACE activity, releasing AChE, regulation of inflammatory cytokine levels, and suppression of apoptotic process in ARDS.

Engineered Nanovesicles Expressing Bispecific Single Chain Variable Fragments to Protect against SARS-CoV-2 Infection.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in high morbidity and mortality rates worldwide. Although the epidemic has been controlled in many areas and numerous patients have been successfully treated, the risk of reinfection persists due to the low neutralizing antibody titers and weak immune response. To provide long-term immune protection for infected patients, novel bispecific CB6/dendritic cell (DC)-specific intercellular adhesion molecule 3-grabbing nonintegrin (SIGN) nanovesicles (NVs) were constructed to target both the SARS-CoV-2 spike protein (S) and the DC receptors for virus neutralization and immune activation. Herein, we designed NVs expressing both CB6 and DC-SIGN single chain variable fragments (scFvs) on the surface to block SARS-CoV-2 invasion and activate DC function. Monophosphoryl lipid A (MPLA) was loaded into the CB6/DC-SIGN NVs as an adjuvant to promote this process. The CB6/DC-SIGN NVs prevented a pseudovirus expressing the S protein from infecting the target cells expressing high levels of angiotensin-converting enzyme 2 in vitro. Additionally, CB6/DC-SIGN NVs admixed with S-expressing pseudoviruses activated the DCs, which was promoted by the adjuvant MPLA loaded in the NVs. Using a mouse model, we also confirmed that the CB6/DC-SIGN NVs effectively improved the neutralizing antibody titer and inhibited the growth of tumors expressing the S protein after 3 weeks of treatment. This potential NV-based treatment not only exerts a blocking effect by binding the S protein in the short term but may also provide patients with long-term protection against secondary infections.

Sambou Bamboo salt™ down-regulates the expression levels of angiotensin-converting enzyme 2 in activated human mast cells.

Mast cells have a detrimental impact on coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Sambou Bamboo salt™ (BS) suppresses mast cell-mediated inflammatory response and enhances immunity. In this study, we investigated the regulatory effects of BS on expression of angiotensin-converting enzyme 2 (ACE2) and transmembrane protease/serine subfamily member 2 (TMPRSS2) in human mast cell line (HMC)-1 cells. BS resulted in significant reductions in expression levels of ACE2 and TMPRSS2 in activated HMC-1 cells. Levels of tryptase were reduced by BS. In addition, BS blocked activation of activator protein 1 (AP-1), c-Jun NH2-terminal kinases (JNK), p38, and phosphatidylinositide-3-kinase (PI3K) in activated HMC-1 cells. Therefore, these results show that BS reduces levels of ACE2, TMPRSS2, and tryptase by inhibiting AP-1/JNK/p38/PI3K signaling pathways in mast cells. These findings can serve as valuable foundational data for the development of therapeutic agents aimed at preventing SARS-CoV-2 infection.

Losartan Has a Comparable Effect to Human Recombinant ACE2 in Reducing Interleukin-6 (IL-6) Levels on Human Adipocytes Exposed to SARS-CoV-2 Spike Protein

BACKGROUND: High angiotensin-converting enzyme 2 (ACE2) expression in adipocyte cells facilitates the initiation of SARS-CoV-2 infection and triggers a cytokine storm. This finding suggests that obesity is an independent risk factor for the severity of the symptoms caused by COVID-19. The use of cardiovascular medications that focus on ACE2, such as angiotensin II receptor blockers, remains controversial, and their effects on inflammatory cytokine production and ACE2 expression in cells, especially adipocytes, remain inconsistent.METHODS: The human adipocytes were isolated from obese donor subcutaneous adipose tissue and infected with the subunit S1 spike protein from SARS-Cov-2. The adipocytes were later treated with either hrsACE2 or losartan. The levels of ACE2 and inflammatory cytokines interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α were measured using enzyme linked immunosorbent assay (ELISA). ACE2 and S1 spike protein binding assays were also performed. RESULTS: ACE2, IL-6, and TNF-α levels were significantly increased in human adipocyte cells infected with SARS-Cov-2 but not IL-1β. There was a statistically significant positive correlation between ACE2 and IL-6 (r=0.878, p&lt;0.001). Administration of losartan and hrsACE2 was shown to reduce ACE2 levels and its binding to the SARS-CoV-2 S1 spike protein, and IL-6 levels were statistically significant, but had no significant effect on IL-1β or TNF-α levels.CONCLUSION: This study shows that the administration of losartan in COVID-19 may not be harmful, but instead has a protective effect similar to that of hrsACE2 in preventing a cytokine storm, especially IL-6.KEYWORDS: obesity, SARS-CoV-2, losartan, IL-6, ACE2

Serum Level of Ceruloplasmin, Angiotensin-Converting Enzyme and Transferrin as Markers of Severity in SARS-CoV-2 Infection in Patients with Type 2 Diabetes

The aim of this study was to analyze other possible new markers of severity, at hospital admission, that can be assessed in patients with type 2 diabetes and a SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection. Our study included 90 subjects: 45 patients with type 2 diabetes mellitus infected with the SARS-CoV-2 virus, and 45 healthy persons as controls. The serum level of ceruloplasmin at hospital admission was statistically significant and directly correlated with the severity of COVID-19 (coronavirus disease) (p = 0.037) and with the serum level of IL-6 (interleukin 6) (p = 0.0001). Ceruloplasmin was statistically significant and inversely correlated with the serum iron level (p = 0.0001). However, we observed that ACE (angiotensin-converting enzyme) decreased in severe forms of SARS-CoV-2 infections in patients with type 2 diabetes (p = 0.001). Moreover, the decrease in ACE levels was correlated with an increase in IL-6 levels in these patients (p = 0.001). IL-6 increases were statistically significant and inversely correlated with serum iron, transferrin, and ACE levels. There was a noticed decreasing tendency of the transferrin depending on the severity of the COVID-19 infection (p = 0.0001). In addition to the known severity factors in the context of infection with the new coronavirus, increased concentrations of ceruloplasmin and decreased concentrations of ACE and transferrin may represent new markers of COVID-19 severity in patients with type 2 diabetes. These parameters, if analyzed upon admission to the hospital, could better inform health professionals about the evolution towards more severe forms of SARS-CoV-2 infections.

Anisomeles indica Extracts and Their Constituents Suppress the Protein Expression of ACE2 and TMPRSS2 In Vivo and In Vitro.

Coronavirus disease 2019 (COVID-19), stemming from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has had a profound global impact. This highly contagious pneumonia remains a significant ongoing threat. Uncertainties persist about the virus's effects on human health, underscoring the need for treatments and prevention. Current research highlights angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) as key targets against SARS-CoV-2. The virus relies on ACE2 to enter cells and TMPRSS2 to activate its spike protein. Inhibiting ACE2 and TMPRSS2 expression can help prevent and treat SARS-CoV-2 infections. Anisomeles indica (L.) Kuntze, a medicinal plant in traditional Chinese medicine, shows various promising pharmacological properties. In this study, ethanolic extracts of A. indica were examined both in vivo (250 and 500 μM) and in vitro (500 μM). Through Western blotting analysis, a significant reduction in the expression levels of ACE2 and TMPRSS2 proteins was observed in HepG2 (human hepatocellular carcinoma) cells and HEK 293T (human embryonic kidney) cell lines without inducing cellular damage. The principal constituents of A. indica, namely, ovatodiolide (5 and 10 μM), anisomlic acid (5 and 10 μM), and apigenin (12.5 and 25 μM), were also found to produce the same effect. Furthermore, immunohistochemical analysis of mouse liver, kidney, and lung tissues demonstrated a decrease in ACE2 and TMPRSS2 protein expression levels. Consequently, this article suggests that A. indica and its constituents have the potential to reduce ACE2 and TMPRSS2 protein expression levels, thus aiding in the prevention of SARS-CoV-2 infections.

Evaluation of the Relationship Between Serum miR-200b-3p and miR-214-3p Expression Levels with Soluble ACE2 and TMPRSS2 in COVID-19 Patients.

The emergence and rapid global spread of the coronavirus disease 2019 (COVID-19) has presented a significant global health challenge. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects human host cells through the interaction of angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2), which serve as main regulators for viral entry. Specifically, ACE2 and TMPRSS2 genes are influenced by two microRNAs: miR-200b-3p and miR-214-3p, respectively. The objective of this study was to explore the association between the serum levels of miR-200b-3p and miR-214-3p and the presence of circulating ACE2 and TMPRSS2 in severe and non-severe cases of COVID-19. This study sought to examine the potential utility of microRNAs as biomarkers for assessing disease severity and progression. Additionally, the study aimed to elucidate the interplay between microRNAs and the ACE2 and TMPRSS2 proteins, which play crucial roles in facilitating SARS-CoV-2 viral entry and infection. This practical-foundational study involved the collection of samples from 61 hospitalized patients with confirmed COVID-19 and 31 healthy individuals. Subsequently, the enzyme-linked immunosorbent assay (ELISA) technique was utilized to measure the concentrations of ACE2 and TMPRSS2 in the blood samples. Additionally, the expression levels of serum miR-200b-3p and miR-214-3p were analyzed using real-time polymerase chain reaction (PCR). The statistical analysis of the data was conducted using GraphPad Prism software (version 8.02) and SPSS software (version 19.0), ensuring the accurate interpretation of results. The findings revealed significant increases in the peripheral blood concentrations of ACE2 and TMPRSS2 in patients with non-severe COVID-19, compared to healthy individuals (P < 0.001 and P < 0.01, respectively). Similarly, patients with severe COVID-19 exhibited higher serum levels of ACE2 and TMPRSS2 than healthy subjects (P < 0.0001). Additionally, the serum levels of miR-200b-3p and miR-214-3p were decreased in both non-severe and severe COVID-19 patients, compared to healthy individuals (P < 0.01 and P < 0.0001, respectively). Moreover, a decrease in the serum levels of both miR-200b-3p and miR-214-3p was observed in patients with severe COVID-19, compared to those with non-severe cases (P < 0.001). Furthermore, this study identified a negative correlation between miR-200b-3p and ACE2 serum levels and between miR-214-3p and TMPRSS2 peripheral blood levels. The above-mentioned findings suggest that miR-200b-3p and miR-214-3p might be potential biomarkers for disease severity and prognosis in COVID-19 patients.

Effect of tofacitinib therapy on angiotensin converting enzyme activity in rheumatoid arthritis.

The Renin-Angiotensin-Aldosterone system (RAAS) has been implicated in the regulation of the cardiovascular system and linked to rheumatoid arthritis (RA). Little information has become available on the effects of Janus kinase (JAK) inhibition on RAAS. Here we studied the effects of 12-month tofacitinib treatment on angiotensin converting enzyme (ACE), ACE2 production and ACE/ACE2 ratios in RA along with numerous other biomarkers. Thirty RA patients were treated with tofacitinib in this prospective study. Serum ACE concentrations were assessed by ELISA. ACE2 activity was determined by a specific quenched fluorescent substrate. ACE/ACE2 ratios were calculated. We also determined common carotid intima-media thickness (ccIMT), brachial artery flow-mediated vasodilation (FMD) and carotid-femoral pulse-wave velocity (cfPWV) by ultrasound. C-reactive protein (CRP), rheumatoid factor (RF) and anti-citrullinated protein autoantibodies (ACPA) were also determined. All measurements were performed at baseline, as well as after 6 and 12 months of tofacitinib treatment. After the dropout of 4 patients, 26 completed the study. Tofacitinib treatment increased ACE levels after 6 and 12 months, while ACE2 activity only transiently increased at 6 months. The ACE/ACE2 ratio increased after 1 year of therapy (p < 0.05). Logistic regression analyses identified correlations between ACE, ACE2 or ACE/ACE2 ratios and RF at various time points. Baseline disease duration also correlated with erythrocyte sedimentation rate (ESR) (p < 0.05). One-year changes of ACE or ACE2 were determined by tofacitinib treatment plus ACPA or RF, respectively (p < 0.05). JAK inhibition increases serum ACE and ACE/ACE2 ratio in RA. Baseline inflammation (ESR), disease duration and ACPA, as well as RF levels at various time points can be coupled to the regulation of ACE/ACE2 ratio. The effect of tofacitinib on RAAS provides a plausible explanation for the cardiovascular effects of JAK inhibition in RA.