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LitCovid-sample-CHEBI

{"project":"LitCovid-sample-CHEBI","denotations":[{"id":"T170","span":{"begin":3704,"end":3715},"obj":"Chemical"},{"id":"T171","span":{"begin":6161,"end":6169},"obj":"Chemical"}],"attributes":[{"id":"A170","pred":"chebi_id","subj":"T170","obj":"http://purl.obolibrary.org/obo/CHEBI_48433"},{"id":"A171","pred":"chebi_id","subj":"T171","obj":"http://purl.obolibrary.org/obo/CHEBI_36080"}],"text":"The Controversial Role of ACE2 Expression\nEpidemiological data consistently show that the COVID-19 patients at highest risk of a poor prognosis are males older than 60 years with chronic underlying diseases, mostly hypertension, cardiovascular diseases and type-2 diabetes mellitus. Clinical reports have been rapidly delivered from all over the world, and meta-analyses assessing the prevalence of comorbidities and their impact on prognosis are already available. A meta-analysis pooling data from seven studies following a total number of 1,576 infected patients from hospitals in China found that the most prevalent comorbidities were hypertension (21.1%), diabetes (9.7%), and cardiovascular diseases (8.4%). These increased the risk of developing a more serious disease (i.e., requiring intensive care treatment), with odds ratios ranging from 2.4 (hypertension) to 3.4 (cardiovascular disease) (Yang et al., 2020b). These findings have been confirmed in the analysis performed by the Chinese Center for Disease Control and Prevention in a huge sample of 72314 COVID-19 cases (Epidemiology Working Group for Ncip Epidemic Response and Chinese Center for Disease Control and Prevention, 2020). A study with 1591 Italian patients, similarly, reported a significant association between hypertension and mortality in Intensive Care Unit (63 vs. 40%). This series reported an even higher prevalence of hypertension (49%), diabetes (17%), and cardiovascular disease (21%) (Grasselli et al., 2020). Diabetes has been reported to predict the occurrence of ARDS (HR = 1.44), acute kidney injury (HR = 3.01), septic shock (HR = 1.95), and all-cause mortality (HR = 1.70) (Zhu et al., 2020). Notably, poor glycemic control was significantly associated with worse clinical outcomes, namely multi-organ injuries and higher mortality (Zhu et al., 2020). Obesity has also emerged as an important factor in determining COVID-19 severity. Indeed, obesity was more frequent in patients admitted to critical care for SARS-CoV-2 as compared to the general population; moreover, the BMI was positively related to the need for invasive mechanical ventilation and mortality (Drucker, 2020; Simonnet et al., 2020).\nThe RAAS system is the target of widely used anti-hypertensive drugs, such as ACE-inhibitors (ACEI) and Ang-II type 1 receptor blockers (ARB). Several experimental studies reported that, although not directly affecting ACE2 activity, these drugs are able to upregulate its expression (Ishiyama et al., 2004; Ferrario et al., 2005; Gallagher et al., 2008). Increased expression of ACE2 has also been reported to facilitate SARS-CoV infection in several experimental models and postulated to act in the same way for SARS-CoV-2 (Li et al., 2003; Hofmann et al., 2004; Perrotta et al., 2020).\nHence, following the SARS-CoV-2 outbreak, it has been speculated that the use of ACEI and ARB could increase viral invasion and should therefore be temporarily suspended. This topic has been abundantly debated in the last few months (March–May 2020), with contradictory views (Bavishi et al., 2020; Buckley et al., 2020; Danser et al., 2020; Fang et al., 2020; Huang Z. et al., 2020; Kreutz et al., 2020; Kuster et al., 2020; Mourad and Levy, 2020; Park et al., 2020; Rico-Mesa et al., 2020; Sommerstein et al., 2020; South et al., 2020; Tignanelli et al., 2020; Vaduganathan et al., 2020; Verdecchia et al., 2020b; Zhang P. et al., 2020). As a consequence of this debate, several clinical societies have stated that suspension of ACEI and ARB is not justified on the basis of the present scientific evidence, although a recent BMJ editorial (Aronson and Ferner, 2020) suggested to consider stopping ACE inhibitors or angiotensin receptor blockers in patients with mild hypertension who are at high risk of coronavirus infection.\nOn the other hand, a different viewpoint is based on the intriguing observation that several conditions increasing the risk of viral infection and disease severity are all characterized by a certain degree of ACE2 deficiency. As discussed above (section “Structure of ACE2”) ACE2 deficiency has been suggested to play a significant role in the pathophysiology of hypertension, cardiovascular disease and diabetes. The role of ACE2 expression in the panel of comorbidities correlated to SARS-CoV-2 is a matter of intense still unsolved debate, as brilliantly revised by Shyh et al. (2020) in a very recent paper.\nOn the whole, there is still uncertainty about the relationship between ACE2 density on cell membrane and the fate of SARS-CoV-2 infection. An interesting speculation which could reconcile the two position comes from the hypothesis that while ACE2 is for sure the entry door for the virus, once the infection has evolved, there is the subsequent downregulation of ACE2, responsible for the precipitating of respiratory distress, as showed also in animal models (Kuba et al., 2005).\nIt should be pointed out that the great clinical impact of this issue has encouraged discussions that are largely based on indirect speculations rather than objective data. Data from appropriate clinical trials are still lacking, although a retrospective multicenter study on more than 1,000 patients with COVID-19 and hypertension treated with ACEI or ARB revealed that the use of these drugs was associated with lower mortality from all cause (Bosso et al., 2020).\nA definite conclusion would require specific prospective clinical trials, which are still running: https://clinicaltrials.gov/ct2/show/NCT04312009 is a multi-centered double blind trial with the aim to test the role of ARB in patients with COVID-19 and https://clinicaltrials.gov/ct2/show/NCT04331574 is another trial evaluating the outcome of patients with COVID-19 in therapy with either ACEI and ARBS.\nIn the meanwhile, partial but important information might be obtained by circumscribed experimental and clinical investigations focused some on crucial issues, namely: fate of SARS-CoV-2 infection in human cells manipulated in order to modify ACE2 density; correlation of ACE2 density (in different cell types) and clinical course in human patients; potential role of additional proteins interacting with ACE2, such as the membrane transporter SIT1, which appears to be associated with COVID-19 prognosis and is also affected by anti-hypertensive therapy."}

LitCovid-sample-PD-NCBITaxon

LitCovid-sample-sentences

LitCovid-sample-PD-UBERON

{"project":"LitCovid-sample-PD-UBERON","denotations":[{"id":"T140","span":{"begin":1578,"end":1584},"obj":"Body_part"},{"id":"T141","span":{"begin":1790,"end":1795},"obj":"Body_part"},{"id":"T142","span":{"begin":3829,"end":3833},"obj":"Body_part"}],"attributes":[{"id":"A140","pred":"uberon_id","subj":"T140","obj":"http://purl.obolibrary.org/obo/UBERON_0002113"},{"id":"A141","pred":"uberon_id","subj":"T141","obj":"http://purl.obolibrary.org/obo/UBERON_0000062"},{"id":"A142","pred":"uberon_id","subj":"T142","obj":"http://purl.obolibrary.org/obo/UBERON_0002398"}],"text":"The Controversial Role of ACE2 Expression\nEpidemiological data consistently show that the COVID-19 patients at highest risk of a poor prognosis are males older than 60 years with chronic underlying diseases, mostly hypertension, cardiovascular diseases and type-2 diabetes mellitus. Clinical reports have been rapidly delivered from all over the world, and meta-analyses assessing the prevalence of comorbidities and their impact on prognosis are already available. A meta-analysis pooling data from seven studies following a total number of 1,576 infected patients from hospitals in China found that the most prevalent comorbidities were hypertension (21.1%), diabetes (9.7%), and cardiovascular diseases (8.4%). These increased the risk of developing a more serious disease (i.e., requiring intensive care treatment), with odds ratios ranging from 2.4 (hypertension) to 3.4 (cardiovascular disease) (Yang et al., 2020b). These findings have been confirmed in the analysis performed by the Chinese Center for Disease Control and Prevention in a huge sample of 72314 COVID-19 cases (Epidemiology Working Group for Ncip Epidemic Response and Chinese Center for Disease Control and Prevention, 2020). A study with 1591 Italian patients, similarly, reported a significant association between hypertension and mortality in Intensive Care Unit (63 vs. 40%). This series reported an even higher prevalence of hypertension (49%), diabetes (17%), and cardiovascular disease (21%) (Grasselli et al., 2020). Diabetes has been reported to predict the occurrence of ARDS (HR = 1.44), acute kidney injury (HR = 3.01), septic shock (HR = 1.95), and all-cause mortality (HR = 1.70) (Zhu et al., 2020). Notably, poor glycemic control was significantly associated with worse clinical outcomes, namely multi-organ injuries and higher mortality (Zhu et al., 2020). Obesity has also emerged as an important factor in determining COVID-19 severity. Indeed, obesity was more frequent in patients admitted to critical care for SARS-CoV-2 as compared to the general population; moreover, the BMI was positively related to the need for invasive mechanical ventilation and mortality (Drucker, 2020; Simonnet et al., 2020).\nThe RAAS system is the target of widely used anti-hypertensive drugs, such as ACE-inhibitors (ACEI) and Ang-II type 1 receptor blockers (ARB). Several experimental studies reported that, although not directly affecting ACE2 activity, these drugs are able to upregulate its expression (Ishiyama et al., 2004; Ferrario et al., 2005; Gallagher et al., 2008). Increased expression of ACE2 has also been reported to facilitate SARS-CoV infection in several experimental models and postulated to act in the same way for SARS-CoV-2 (Li et al., 2003; Hofmann et al., 2004; Perrotta et al., 2020).\nHence, following the SARS-CoV-2 outbreak, it has been speculated that the use of ACEI and ARB could increase viral invasion and should therefore be temporarily suspended. This topic has been abundantly debated in the last few months (March–May 2020), with contradictory views (Bavishi et al., 2020; Buckley et al., 2020; Danser et al., 2020; Fang et al., 2020; Huang Z. et al., 2020; Kreutz et al., 2020; Kuster et al., 2020; Mourad and Levy, 2020; Park et al., 2020; Rico-Mesa et al., 2020; Sommerstein et al., 2020; South et al., 2020; Tignanelli et al., 2020; Vaduganathan et al., 2020; Verdecchia et al., 2020b; Zhang P. et al., 2020). As a consequence of this debate, several clinical societies have stated that suspension of ACEI and ARB is not justified on the basis of the present scientific evidence, although a recent BMJ editorial (Aronson and Ferner, 2020) suggested to consider stopping ACE inhibitors or angiotensin receptor blockers in patients with mild hypertension who are at high risk of coronavirus infection.\nOn the other hand, a different viewpoint is based on the intriguing observation that several conditions increasing the risk of viral infection and disease severity are all characterized by a certain degree of ACE2 deficiency. As discussed above (section “Structure of ACE2”) ACE2 deficiency has been suggested to play a significant role in the pathophysiology of hypertension, cardiovascular disease and diabetes. The role of ACE2 expression in the panel of comorbidities correlated to SARS-CoV-2 is a matter of intense still unsolved debate, as brilliantly revised by Shyh et al. (2020) in a very recent paper.\nOn the whole, there is still uncertainty about the relationship between ACE2 density on cell membrane and the fate of SARS-CoV-2 infection. An interesting speculation which could reconcile the two position comes from the hypothesis that while ACE2 is for sure the entry door for the virus, once the infection has evolved, there is the subsequent downregulation of ACE2, responsible for the precipitating of respiratory distress, as showed also in animal models (Kuba et al., 2005).\nIt should be pointed out that the great clinical impact of this issue has encouraged discussions that are largely based on indirect speculations rather than objective data. Data from appropriate clinical trials are still lacking, although a retrospective multicenter study on more than 1,000 patients with COVID-19 and hypertension treated with ACEI or ARB revealed that the use of these drugs was associated with lower mortality from all cause (Bosso et al., 2020).\nA definite conclusion would require specific prospective clinical trials, which are still running: https://clinicaltrials.gov/ct2/show/NCT04312009 is a multi-centered double blind trial with the aim to test the role of ARB in patients with COVID-19 and https://clinicaltrials.gov/ct2/show/NCT04331574 is another trial evaluating the outcome of patients with COVID-19 in therapy with either ACEI and ARBS.\nIn the meanwhile, partial but important information might be obtained by circumscribed experimental and clinical investigations focused some on crucial issues, namely: fate of SARS-CoV-2 infection in human cells manipulated in order to modify ACE2 density; correlation of ACE2 density (in different cell types) and clinical course in human patients; potential role of additional proteins interacting with ACE2, such as the membrane transporter SIT1, which appears to be associated with COVID-19 prognosis and is also affected by anti-hypertensive therapy."}

LitCovid-sample-Pubtator

LitCovid-sample-UniProt

LitCovid-sample-PD-IDO

LitCovid-sample-PD-FMA

{"project":"LitCovid-sample-PD-FMA","denotations":[{"id":"T397","span":{"begin":1578,"end":1584},"obj":"Body_part"},{"id":"T398","span":{"begin":1790,"end":1795},"obj":"Body_part"},{"id":"T399","span":{"begin":3829,"end":3833},"obj":"Body_part"},{"id":"T400","span":{"begin":4516,"end":4529},"obj":"Body_part"},{"id":"T401","span":{"begin":4516,"end":4520},"obj":"Body_part"},{"id":"T402","span":{"begin":5988,"end":5993},"obj":"Body_part"},{"id":"T403","span":{"begin":6081,"end":6085},"obj":"Body_part"},{"id":"T404","span":{"begin":6161,"end":6169},"obj":"Body_part"}],"attributes":[{"id":"A397","pred":"fma_id","subj":"T397","obj":"http://purl.org/sig/ont/fma/fma7203"},{"id":"A399","pred":"fma_id","subj":"T399","obj":"http://purl.org/sig/ont/fma/fma9712"},{"id":"A401","pred":"fma_id","subj":"T401","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A400","pred":"fma_id","subj":"T400","obj":"http://purl.org/sig/ont/fma/fma63841"},{"id":"A398","pred":"fma_id","subj":"T398","obj":"http://purl.org/sig/ont/fma/fma67498"},{"id":"A404","pred":"fma_id","subj":"T404","obj":"http://purl.org/sig/ont/fma/fma67257"},{"id":"A402","pred":"fma_id","subj":"T402","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A403","pred":"fma_id","subj":"T403","obj":"http://purl.org/sig/ont/fma/fma68646"}],"text":"The Controversial Role of ACE2 Expression\nEpidemiological data consistently show that the COVID-19 patients at highest risk of a poor prognosis are males older than 60 years with chronic underlying diseases, mostly hypertension, cardiovascular diseases and type-2 diabetes mellitus. Clinical reports have been rapidly delivered from all over the world, and meta-analyses assessing the prevalence of comorbidities and their impact on prognosis are already available. A meta-analysis pooling data from seven studies following a total number of 1,576 infected patients from hospitals in China found that the most prevalent comorbidities were hypertension (21.1%), diabetes (9.7%), and cardiovascular diseases (8.4%). These increased the risk of developing a more serious disease (i.e., requiring intensive care treatment), with odds ratios ranging from 2.4 (hypertension) to 3.4 (cardiovascular disease) (Yang et al., 2020b). These findings have been confirmed in the analysis performed by the Chinese Center for Disease Control and Prevention in a huge sample of 72314 COVID-19 cases (Epidemiology Working Group for Ncip Epidemic Response and Chinese Center for Disease Control and Prevention, 2020). A study with 1591 Italian patients, similarly, reported a significant association between hypertension and mortality in Intensive Care Unit (63 vs. 40%). This series reported an even higher prevalence of hypertension (49%), diabetes (17%), and cardiovascular disease (21%) (Grasselli et al., 2020). Diabetes has been reported to predict the occurrence of ARDS (HR = 1.44), acute kidney injury (HR = 3.01), septic shock (HR = 1.95), and all-cause mortality (HR = 1.70) (Zhu et al., 2020). Notably, poor glycemic control was significantly associated with worse clinical outcomes, namely multi-organ injuries and higher mortality (Zhu et al., 2020). Obesity has also emerged as an important factor in determining COVID-19 severity. Indeed, obesity was more frequent in patients admitted to critical care for SARS-CoV-2 as compared to the general population; moreover, the BMI was positively related to the need for invasive mechanical ventilation and mortality (Drucker, 2020; Simonnet et al., 2020).\nThe RAAS system is the target of widely used anti-hypertensive drugs, such as ACE-inhibitors (ACEI) and Ang-II type 1 receptor blockers (ARB). Several experimental studies reported that, although not directly affecting ACE2 activity, these drugs are able to upregulate its expression (Ishiyama et al., 2004; Ferrario et al., 2005; Gallagher et al., 2008). Increased expression of ACE2 has also been reported to facilitate SARS-CoV infection in several experimental models and postulated to act in the same way for SARS-CoV-2 (Li et al., 2003; Hofmann et al., 2004; Perrotta et al., 2020).\nHence, following the SARS-CoV-2 outbreak, it has been speculated that the use of ACEI and ARB could increase viral invasion and should therefore be temporarily suspended. This topic has been abundantly debated in the last few months (March–May 2020), with contradictory views (Bavishi et al., 2020; Buckley et al., 2020; Danser et al., 2020; Fang et al., 2020; Huang Z. et al., 2020; Kreutz et al., 2020; Kuster et al., 2020; Mourad and Levy, 2020; Park et al., 2020; Rico-Mesa et al., 2020; Sommerstein et al., 2020; South et al., 2020; Tignanelli et al., 2020; Vaduganathan et al., 2020; Verdecchia et al., 2020b; Zhang P. et al., 2020). As a consequence of this debate, several clinical societies have stated that suspension of ACEI and ARB is not justified on the basis of the present scientific evidence, although a recent BMJ editorial (Aronson and Ferner, 2020) suggested to consider stopping ACE inhibitors or angiotensin receptor blockers in patients with mild hypertension who are at high risk of coronavirus infection.\nOn the other hand, a different viewpoint is based on the intriguing observation that several conditions increasing the risk of viral infection and disease severity are all characterized by a certain degree of ACE2 deficiency. As discussed above (section “Structure of ACE2”) ACE2 deficiency has been suggested to play a significant role in the pathophysiology of hypertension, cardiovascular disease and diabetes. The role of ACE2 expression in the panel of comorbidities correlated to SARS-CoV-2 is a matter of intense still unsolved debate, as brilliantly revised by Shyh et al. (2020) in a very recent paper.\nOn the whole, there is still uncertainty about the relationship between ACE2 density on cell membrane and the fate of SARS-CoV-2 infection. An interesting speculation which could reconcile the two position comes from the hypothesis that while ACE2 is for sure the entry door for the virus, once the infection has evolved, there is the subsequent downregulation of ACE2, responsible for the precipitating of respiratory distress, as showed also in animal models (Kuba et al., 2005).\nIt should be pointed out that the great clinical impact of this issue has encouraged discussions that are largely based on indirect speculations rather than objective data. Data from appropriate clinical trials are still lacking, although a retrospective multicenter study on more than 1,000 patients with COVID-19 and hypertension treated with ACEI or ARB revealed that the use of these drugs was associated with lower mortality from all cause (Bosso et al., 2020).\nA definite conclusion would require specific prospective clinical trials, which are still running: https://clinicaltrials.gov/ct2/show/NCT04312009 is a multi-centered double blind trial with the aim to test the role of ARB in patients with COVID-19 and https://clinicaltrials.gov/ct2/show/NCT04331574 is another trial evaluating the outcome of patients with COVID-19 in therapy with either ACEI and ARBS.\nIn the meanwhile, partial but important information might be obtained by circumscribed experimental and clinical investigations focused some on crucial issues, namely: fate of SARS-CoV-2 infection in human cells manipulated in order to modify ACE2 density; correlation of ACE2 density (in different cell types) and clinical course in human patients; potential role of additional proteins interacting with ACE2, such as the membrane transporter SIT1, which appears to be associated with COVID-19 prognosis and is also affected by anti-hypertensive therapy."}

LitCovid-sample-PD-MONDO

LitCovid-sample-PD-MAT

{"project":"LitCovid-sample-PD-MAT","denotations":[{"id":"T128","span":{"begin":148,"end":153},"obj":"http://purl.obolibrary.org/obo/MAT_0000029"},{"id":"T129","span":{"begin":1578,"end":1584},"obj":"http://purl.obolibrary.org/obo/MAT_0000119"},{"id":"T130","span":{"begin":3829,"end":3833},"obj":"http://purl.obolibrary.org/obo/MAT_0000091"}],"text":"The Controversial Role of ACE2 Expression\nEpidemiological data consistently show that the COVID-19 patients at highest risk of a poor prognosis are males older than 60 years with chronic underlying diseases, mostly hypertension, cardiovascular diseases and type-2 diabetes mellitus. Clinical reports have been rapidly delivered from all over the world, and meta-analyses assessing the prevalence of comorbidities and their impact on prognosis are already available. A meta-analysis pooling data from seven studies following a total number of 1,576 infected patients from hospitals in China found that the most prevalent comorbidities were hypertension (21.1%), diabetes (9.7%), and cardiovascular diseases (8.4%). These increased the risk of developing a more serious disease (i.e., requiring intensive care treatment), with odds ratios ranging from 2.4 (hypertension) to 3.4 (cardiovascular disease) (Yang et al., 2020b). These findings have been confirmed in the analysis performed by the Chinese Center for Disease Control and Prevention in a huge sample of 72314 COVID-19 cases (Epidemiology Working Group for Ncip Epidemic Response and Chinese Center for Disease Control and Prevention, 2020). A study with 1591 Italian patients, similarly, reported a significant association between hypertension and mortality in Intensive Care Unit (63 vs. 40%). This series reported an even higher prevalence of hypertension (49%), diabetes (17%), and cardiovascular disease (21%) (Grasselli et al., 2020). Diabetes has been reported to predict the occurrence of ARDS (HR = 1.44), acute kidney injury (HR = 3.01), septic shock (HR = 1.95), and all-cause mortality (HR = 1.70) (Zhu et al., 2020). Notably, poor glycemic control was significantly associated with worse clinical outcomes, namely multi-organ injuries and higher mortality (Zhu et al., 2020). Obesity has also emerged as an important factor in determining COVID-19 severity. Indeed, obesity was more frequent in patients admitted to critical care for SARS-CoV-2 as compared to the general population; moreover, the BMI was positively related to the need for invasive mechanical ventilation and mortality (Drucker, 2020; Simonnet et al., 2020).\nThe RAAS system is the target of widely used anti-hypertensive drugs, such as ACE-inhibitors (ACEI) and Ang-II type 1 receptor blockers (ARB). Several experimental studies reported that, although not directly affecting ACE2 activity, these drugs are able to upregulate its expression (Ishiyama et al., 2004; Ferrario et al., 2005; Gallagher et al., 2008). Increased expression of ACE2 has also been reported to facilitate SARS-CoV infection in several experimental models and postulated to act in the same way for SARS-CoV-2 (Li et al., 2003; Hofmann et al., 2004; Perrotta et al., 2020).\nHence, following the SARS-CoV-2 outbreak, it has been speculated that the use of ACEI and ARB could increase viral invasion and should therefore be temporarily suspended. This topic has been abundantly debated in the last few months (March–May 2020), with contradictory views (Bavishi et al., 2020; Buckley et al., 2020; Danser et al., 2020; Fang et al., 2020; Huang Z. et al., 2020; Kreutz et al., 2020; Kuster et al., 2020; Mourad and Levy, 2020; Park et al., 2020; Rico-Mesa et al., 2020; Sommerstein et al., 2020; South et al., 2020; Tignanelli et al., 2020; Vaduganathan et al., 2020; Verdecchia et al., 2020b; Zhang P. et al., 2020). As a consequence of this debate, several clinical societies have stated that suspension of ACEI and ARB is not justified on the basis of the present scientific evidence, although a recent BMJ editorial (Aronson and Ferner, 2020) suggested to consider stopping ACE inhibitors or angiotensin receptor blockers in patients with mild hypertension who are at high risk of coronavirus infection.\nOn the other hand, a different viewpoint is based on the intriguing observation that several conditions increasing the risk of viral infection and disease severity are all characterized by a certain degree of ACE2 deficiency. As discussed above (section “Structure of ACE2”) ACE2 deficiency has been suggested to play a significant role in the pathophysiology of hypertension, cardiovascular disease and diabetes. The role of ACE2 expression in the panel of comorbidities correlated to SARS-CoV-2 is a matter of intense still unsolved debate, as brilliantly revised by Shyh et al. (2020) in a very recent paper.\nOn the whole, there is still uncertainty about the relationship between ACE2 density on cell membrane and the fate of SARS-CoV-2 infection. An interesting speculation which could reconcile the two position comes from the hypothesis that while ACE2 is for sure the entry door for the virus, once the infection has evolved, there is the subsequent downregulation of ACE2, responsible for the precipitating of respiratory distress, as showed also in animal models (Kuba et al., 2005).\nIt should be pointed out that the great clinical impact of this issue has encouraged discussions that are largely based on indirect speculations rather than objective data. Data from appropriate clinical trials are still lacking, although a retrospective multicenter study on more than 1,000 patients with COVID-19 and hypertension treated with ACEI or ARB revealed that the use of these drugs was associated with lower mortality from all cause (Bosso et al., 2020).\nA definite conclusion would require specific prospective clinical trials, which are still running: https://clinicaltrials.gov/ct2/show/NCT04312009 is a multi-centered double blind trial with the aim to test the role of ARB in patients with COVID-19 and https://clinicaltrials.gov/ct2/show/NCT04331574 is another trial evaluating the outcome of patients with COVID-19 in therapy with either ACEI and ARBS.\nIn the meanwhile, partial but important information might be obtained by circumscribed experimental and clinical investigations focused some on crucial issues, namely: fate of SARS-CoV-2 infection in human cells manipulated in order to modify ACE2 density; correlation of ACE2 density (in different cell types) and clinical course in human patients; potential role of additional proteins interacting with ACE2, such as the membrane transporter SIT1, which appears to be associated with COVID-19 prognosis and is also affected by anti-hypertensive therapy."}

LitCovid-sample-PD-GO-BP-0

{"project":"LitCovid-sample-PD-GO-BP-0","denotations":[{"id":"T105","span":{"begin":3943,"end":3958},"obj":"http://purl.obolibrary.org/obo/GO_0016032"},{"id":"T106","span":{"begin":6205,"end":6225},"obj":"http://purl.obolibrary.org/obo/GO_0055085"}],"text":"The Controversial Role of ACE2 Expression\nEpidemiological data consistently show that the COVID-19 patients at highest risk of a poor prognosis are males older than 60 years with chronic underlying diseases, mostly hypertension, cardiovascular diseases and type-2 diabetes mellitus. Clinical reports have been rapidly delivered from all over the world, and meta-analyses assessing the prevalence of comorbidities and their impact on prognosis are already available. A meta-analysis pooling data from seven studies following a total number of 1,576 infected patients from hospitals in China found that the most prevalent comorbidities were hypertension (21.1%), diabetes (9.7%), and cardiovascular diseases (8.4%). These increased the risk of developing a more serious disease (i.e., requiring intensive care treatment), with odds ratios ranging from 2.4 (hypertension) to 3.4 (cardiovascular disease) (Yang et al., 2020b). These findings have been confirmed in the analysis performed by the Chinese Center for Disease Control and Prevention in a huge sample of 72314 COVID-19 cases (Epidemiology Working Group for Ncip Epidemic Response and Chinese Center for Disease Control and Prevention, 2020). A study with 1591 Italian patients, similarly, reported a significant association between hypertension and mortality in Intensive Care Unit (63 vs. 40%). This series reported an even higher prevalence of hypertension (49%), diabetes (17%), and cardiovascular disease (21%) (Grasselli et al., 2020). Diabetes has been reported to predict the occurrence of ARDS (HR = 1.44), acute kidney injury (HR = 3.01), septic shock (HR = 1.95), and all-cause mortality (HR = 1.70) (Zhu et al., 2020). Notably, poor glycemic control was significantly associated with worse clinical outcomes, namely multi-organ injuries and higher mortality (Zhu et al., 2020). Obesity has also emerged as an important factor in determining COVID-19 severity. Indeed, obesity was more frequent in patients admitted to critical care for SARS-CoV-2 as compared to the general population; moreover, the BMI was positively related to the need for invasive mechanical ventilation and mortality (Drucker, 2020; Simonnet et al., 2020).\nThe RAAS system is the target of widely used anti-hypertensive drugs, such as ACE-inhibitors (ACEI) and Ang-II type 1 receptor blockers (ARB). Several experimental studies reported that, although not directly affecting ACE2 activity, these drugs are able to upregulate its expression (Ishiyama et al., 2004; Ferrario et al., 2005; Gallagher et al., 2008). Increased expression of ACE2 has also been reported to facilitate SARS-CoV infection in several experimental models and postulated to act in the same way for SARS-CoV-2 (Li et al., 2003; Hofmann et al., 2004; Perrotta et al., 2020).\nHence, following the SARS-CoV-2 outbreak, it has been speculated that the use of ACEI and ARB could increase viral invasion and should therefore be temporarily suspended. This topic has been abundantly debated in the last few months (March–May 2020), with contradictory views (Bavishi et al., 2020; Buckley et al., 2020; Danser et al., 2020; Fang et al., 2020; Huang Z. et al., 2020; Kreutz et al., 2020; Kuster et al., 2020; Mourad and Levy, 2020; Park et al., 2020; Rico-Mesa et al., 2020; Sommerstein et al., 2020; South et al., 2020; Tignanelli et al., 2020; Vaduganathan et al., 2020; Verdecchia et al., 2020b; Zhang P. et al., 2020). As a consequence of this debate, several clinical societies have stated that suspension of ACEI and ARB is not justified on the basis of the present scientific evidence, although a recent BMJ editorial (Aronson and Ferner, 2020) suggested to consider stopping ACE inhibitors or angiotensin receptor blockers in patients with mild hypertension who are at high risk of coronavirus infection.\nOn the other hand, a different viewpoint is based on the intriguing observation that several conditions increasing the risk of viral infection and disease severity are all characterized by a certain degree of ACE2 deficiency. As discussed above (section “Structure of ACE2”) ACE2 deficiency has been suggested to play a significant role in the pathophysiology of hypertension, cardiovascular disease and diabetes. The role of ACE2 expression in the panel of comorbidities correlated to SARS-CoV-2 is a matter of intense still unsolved debate, as brilliantly revised by Shyh et al. (2020) in a very recent paper.\nOn the whole, there is still uncertainty about the relationship between ACE2 density on cell membrane and the fate of SARS-CoV-2 infection. An interesting speculation which could reconcile the two position comes from the hypothesis that while ACE2 is for sure the entry door for the virus, once the infection has evolved, there is the subsequent downregulation of ACE2, responsible for the precipitating of respiratory distress, as showed also in animal models (Kuba et al., 2005).\nIt should be pointed out that the great clinical impact of this issue has encouraged discussions that are largely based on indirect speculations rather than objective data. Data from appropriate clinical trials are still lacking, although a retrospective multicenter study on more than 1,000 patients with COVID-19 and hypertension treated with ACEI or ARB revealed that the use of these drugs was associated with lower mortality from all cause (Bosso et al., 2020).\nA definite conclusion would require specific prospective clinical trials, which are still running: https://clinicaltrials.gov/ct2/show/NCT04312009 is a multi-centered double blind trial with the aim to test the role of ARB in patients with COVID-19 and https://clinicaltrials.gov/ct2/show/NCT04331574 is another trial evaluating the outcome of patients with COVID-19 in therapy with either ACEI and ARBS.\nIn the meanwhile, partial but important information might be obtained by circumscribed experimental and clinical investigations focused some on crucial issues, namely: fate of SARS-CoV-2 infection in human cells manipulated in order to modify ACE2 density; correlation of ACE2 density (in different cell types) and clinical course in human patients; potential role of additional proteins interacting with ACE2, such as the membrane transporter SIT1, which appears to be associated with COVID-19 prognosis and is also affected by anti-hypertensive therapy."}

LitCovid-sample-PD-HP

LitCovid-sample-GO-BP

{"project":"LitCovid-sample-GO-BP","denotations":[{"id":"T107","span":{"begin":3943,"end":3958},"obj":"http://purl.obolibrary.org/obo/GO_0016032"},{"id":"T108","span":{"begin":6205,"end":6225},"obj":"http://purl.obolibrary.org/obo/GO_0055085"}],"text":"The Controversial Role of ACE2 Expression\nEpidemiological data consistently show that the COVID-19 patients at highest risk of a poor prognosis are males older than 60 years with chronic underlying diseases, mostly hypertension, cardiovascular diseases and type-2 diabetes mellitus. Clinical reports have been rapidly delivered from all over the world, and meta-analyses assessing the prevalence of comorbidities and their impact on prognosis are already available. A meta-analysis pooling data from seven studies following a total number of 1,576 infected patients from hospitals in China found that the most prevalent comorbidities were hypertension (21.1%), diabetes (9.7%), and cardiovascular diseases (8.4%). These increased the risk of developing a more serious disease (i.e., requiring intensive care treatment), with odds ratios ranging from 2.4 (hypertension) to 3.4 (cardiovascular disease) (Yang et al., 2020b). These findings have been confirmed in the analysis performed by the Chinese Center for Disease Control and Prevention in a huge sample of 72314 COVID-19 cases (Epidemiology Working Group for Ncip Epidemic Response and Chinese Center for Disease Control and Prevention, 2020). A study with 1591 Italian patients, similarly, reported a significant association between hypertension and mortality in Intensive Care Unit (63 vs. 40%). This series reported an even higher prevalence of hypertension (49%), diabetes (17%), and cardiovascular disease (21%) (Grasselli et al., 2020). Diabetes has been reported to predict the occurrence of ARDS (HR = 1.44), acute kidney injury (HR = 3.01), septic shock (HR = 1.95), and all-cause mortality (HR = 1.70) (Zhu et al., 2020). Notably, poor glycemic control was significantly associated with worse clinical outcomes, namely multi-organ injuries and higher mortality (Zhu et al., 2020). Obesity has also emerged as an important factor in determining COVID-19 severity. Indeed, obesity was more frequent in patients admitted to critical care for SARS-CoV-2 as compared to the general population; moreover, the BMI was positively related to the need for invasive mechanical ventilation and mortality (Drucker, 2020; Simonnet et al., 2020).\nThe RAAS system is the target of widely used anti-hypertensive drugs, such as ACE-inhibitors (ACEI) and Ang-II type 1 receptor blockers (ARB). Several experimental studies reported that, although not directly affecting ACE2 activity, these drugs are able to upregulate its expression (Ishiyama et al., 2004; Ferrario et al., 2005; Gallagher et al., 2008). Increased expression of ACE2 has also been reported to facilitate SARS-CoV infection in several experimental models and postulated to act in the same way for SARS-CoV-2 (Li et al., 2003; Hofmann et al., 2004; Perrotta et al., 2020).\nHence, following the SARS-CoV-2 outbreak, it has been speculated that the use of ACEI and ARB could increase viral invasion and should therefore be temporarily suspended. This topic has been abundantly debated in the last few months (March–May 2020), with contradictory views (Bavishi et al., 2020; Buckley et al., 2020; Danser et al., 2020; Fang et al., 2020; Huang Z. et al., 2020; Kreutz et al., 2020; Kuster et al., 2020; Mourad and Levy, 2020; Park et al., 2020; Rico-Mesa et al., 2020; Sommerstein et al., 2020; South et al., 2020; Tignanelli et al., 2020; Vaduganathan et al., 2020; Verdecchia et al., 2020b; Zhang P. et al., 2020). As a consequence of this debate, several clinical societies have stated that suspension of ACEI and ARB is not justified on the basis of the present scientific evidence, although a recent BMJ editorial (Aronson and Ferner, 2020) suggested to consider stopping ACE inhibitors or angiotensin receptor blockers in patients with mild hypertension who are at high risk of coronavirus infection.\nOn the other hand, a different viewpoint is based on the intriguing observation that several conditions increasing the risk of viral infection and disease severity are all characterized by a certain degree of ACE2 deficiency. As discussed above (section “Structure of ACE2”) ACE2 deficiency has been suggested to play a significant role in the pathophysiology of hypertension, cardiovascular disease and diabetes. The role of ACE2 expression in the panel of comorbidities correlated to SARS-CoV-2 is a matter of intense still unsolved debate, as brilliantly revised by Shyh et al. (2020) in a very recent paper.\nOn the whole, there is still uncertainty about the relationship between ACE2 density on cell membrane and the fate of SARS-CoV-2 infection. An interesting speculation which could reconcile the two position comes from the hypothesis that while ACE2 is for sure the entry door for the virus, once the infection has evolved, there is the subsequent downregulation of ACE2, responsible for the precipitating of respiratory distress, as showed also in animal models (Kuba et al., 2005).\nIt should be pointed out that the great clinical impact of this issue has encouraged discussions that are largely based on indirect speculations rather than objective data. Data from appropriate clinical trials are still lacking, although a retrospective multicenter study on more than 1,000 patients with COVID-19 and hypertension treated with ACEI or ARB revealed that the use of these drugs was associated with lower mortality from all cause (Bosso et al., 2020).\nA definite conclusion would require specific prospective clinical trials, which are still running: https://clinicaltrials.gov/ct2/show/NCT04312009 is a multi-centered double blind trial with the aim to test the role of ARB in patients with COVID-19 and https://clinicaltrials.gov/ct2/show/NCT04331574 is another trial evaluating the outcome of patients with COVID-19 in therapy with either ACEI and ARBS.\nIn the meanwhile, partial but important information might be obtained by circumscribed experimental and clinical investigations focused some on crucial issues, namely: fate of SARS-CoV-2 infection in human cells manipulated in order to modify ACE2 density; correlation of ACE2 density (in different cell types) and clinical course in human patients; potential role of additional proteins interacting with ACE2, such as the membrane transporter SIT1, which appears to be associated with COVID-19 prognosis and is also affected by anti-hypertensive therapy."}

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