key: cord-0836197-2ldnphxa
authors: Santana, Fernanda Paula R.; Thevenard, Fernanda; Gomes, Kaio S.; Taguchi, Laura; Câmara, Niels Olsen S.; Stilhano, Roberta S.; Ureshino, Rodrigo P.; Prado, Carla Maximo; Lago, João Henrique Ghilardi
title: New perspectives on natural flavonoids on COVID‐19‐induced lung injuries
date: 2021-04-29
journal: Phytother Res
DOI: 10.1002/ptr.7131
sha: eb8b4ecf92554e73b417cf43b13555d72cb95b54
doc_id: 836197
cord_uid: 2ldnphxa

The SARS‐CoV‐2 virus, responsible for COVID‐19, spread rapidly worldwide and became a pandemic in 2020. In some patients, the virus remains in the respiratory tract, causing pneumonia, respiratory failure, acute respiratory distress syndrome (ARDS), and sepsis, leading to death. Natural flavonoids (aglycone and glycosides) possess broad biological activities encompassing antiinflammatory, antiviral, antitumoral, antiallergic, antiplatelet, and antioxidant effects. While many studies have focused on the effects of natural flavonoids in experimental models, reports based on clinical trials are still insufficient. In this review, we highlight the effects of flavonoids in controlling pulmonary diseases, particularly the acute respiratory distress syndrome, a consequence of COVID‐19, and their potential use in coronavirus‐related diseases. Furthermore, we also focus on establishing a relationship between biological potential and chemical aspects of related flavonoids and discuss several possible mechanisms of action, pointing out some possible effects on COVID‐19.

since it causes severe respiratory infection, the SARS outbreak in the Guangdong Province of China. Epithelial cells are the primary cells affected by SARS-CoV in the lung, although some studies showed that it can also affect dendritic cells and macrophages and induces proinflammatory cytokines that may contribute to the severe disease (Law et al., 2005; Peiris et al., 2003; Spiegel, Schneider, Weber, Weidmann, & Hufert, 2006) . After 10 years, a novel CoVs appeared in the Middle East in 2012, provoking the Middle East Respiratory

Saudi Arabia and other countries in the Middle East (Zaki, van Boheemen, Bestebroer, Osterhaus, & Fouchier, 2012) . Unlike SARS-CoV, MERS-CoV uses the DPP4 (CD26) receptor to gain entry and effectively replicate in camel cell lines (Raj et al., 2013) .

The first case of COVID-19 was reported in December 2019 in the city of Wuhan, China, and was called the new coronavirus SARS-CoV-2 (Rothan & Byrareddy, 2020) . Many studies suggest that SARS-CoV-2 has arisen in bats, then infected an intermediate host (yet unknown) , and suffered several mutations that allowed the virus to infect humans (Chan et al., 2020; Zhou et al., 2020) . These authors showed that the new virus has 96% genomic similarity compared to the coronavirus residing in bats . Human-to-human transmission occurs through coughing, sneezing, fecal-oral contact, and the virus can trigger respiratory, liver, renal, intestinal, and neurological system complications .

The SARS-CoV-2 has a single-stranded RNA genome with approximately 30 kb. This genetic material is translated into structural and non-structural proteins inside the host cell, determining its shape, life cycle, and virulence (Astuti and Ysrafil, 2020) . In addition to the structures cited, SARS-CoV-2 also has the hemagglutinin esterase (HE) protein in the phospholipid double layer (Chan et al., 2020; Jin et al., 2020) . Several studies point that the host cell angiotensinconverting enzyme 2 (ACE2) is the primary receptor for SARS-CoV-2 cell entry (Astuti and Ysrafil, 2020; Chan et al., 2020; Yan et al., 2020) , as previously observed in SARS-CoV (Li et al., 2003) . ACE2 is expressed in various organs such as the lungs, heart, brain, kidney, stomach, and liver (Hamming et al., 2004; Imai et al., 2005; Jiang, Gao, Lu, & Zhang, 2013; Olszanecki et al., 2009) . Thus, tissue expression and ACE2 distribution are critical for infection and viral tropism. By interacting with ACE2 on cell surfaces, SARS-CoV-2 can connect with high affinity Zhao et al., 2020) , causing a generalized homeostasis imbalance that affects pulmonary, cardiac, circulatory, and renal systems, leading to systemic failure and eventually to patients death . When the virus binds to the ACE2 in the respiratory epithelium, the glycoprotein S inserts two subunits: S1, responsible for viral reach and tropism and S2, responsible for the fusion of the viral cell membrane. For this, the virus needs TMPRSS2 (serine transmembrane protease 2) to activate S glycoproteins in the viral envelope, thus associating SARS-CoV-2 and ACE2 in the lungs (Hoffmann et al., 2020; Wang, Grunewald, & Perlman, 2020) . After membrane fusion, viral RNA replication begins, which proceeds quickly toward cell death, endothelial and epithelial vascular leakage, and pro-inflammatory cytokines release . The viral RNA, identified as PAMPs (pathogen-associated molecular patterns) is detected by Toll-like (TLR) receptors (Birra et al., 2020) and thus starts a cascade, until activation of the nuclear transcription factor κB (NF-κB) and consequent release of several systemic inflammatory mediators occurs in the lungs (Alexopoulou, Holt, Medzhitov, & Flavell, 2001; Wu & Chen, 2014) . When SARS-CoV-2 infection occurs, there is a decrease in ACE2 and an increase in angiotensin II. Reduction of ACE2 is known to be related to alveolar injury and increased vascular permeability (Imai et al., 2005) , and it was confirmed in experimental animal models (Imai, Kuba, & Penninger, 2008; Ye & Liu, 2020) . In addition, angiotensin I (mild vasoconstrictor) is converted by ACE to angiotensin II, a potent vasoconstrictor. ACE2 converts angiotensin II to angiotensin 1-7, known for its vasodilatory effects (Benigni, Cassis, & Remuzzi, 2010) . The ACE2 is also expressed in significant amounts in the pericyte, a mesenchymal cell presented in the endothelium of small vessels, which are essential for endothelial stability. When SARS-CoV-2 attacks the vascular system, there is endothelial imbalance and consequent dysfunction in the microcirculation (Chen, Li, Chen, Feng, & Xiong, 2020) . The autopsy of fatal COVID-19 patients reveals the presence of a microthrombi (Dolhnikoff et al., 2020 ) that can cause the severe form of COVID-19.

Angiotensin II can bind to angiotensin receptors 1 (AT1) and 2 (AT2) that regulate hemodynamic stability and blood pressure (Arendse et al., 2019; Kreutz et al., 2020) . AT1 has a vasoconstrictor effect and accounts for increased vascular permeability inducing inflammation and remodeling (Benigni et al., 2010) . AT2 receptors, on the other hand, have a vasodilatory effect and exert anti-regulatory activity for AT1 (Batenburg, Tom, Schuijt, & Danser, 2005) . One hypothesis is that angiotensin II production through AT1 receptors activates the Janus kinase signal transducer and activator of transcription pathways involved in pro-inflammatory, proliferative, and profibrotic responses and activates other pathways such as reactive oxygen species production, cell growth, and apoptosis (Seif et al., 2020) .

The increase in angiotensin II, on the other hand, was related to increased inflammatory activity due to the vital role of AT1 and the recruitment of immune system cells (Forrester et al., 2018) .

Lung inflammation is one of the characteristics of several lung diseases such as asthma, chronic obstructive lung diseases, and others (Moldoveanu et al., 2009) . However, acute lung inflammation and the ARDS are characterized by an intense inflammation that still kills more than 40% of the patients in the intensive therapy care unit (Bellani et al., 2016) .

Acute lung injury (ALI) is characterized by the recruitment of immune cells, neutrophils, macrophages, and lymphocytes, with a high cytokine production such as IL-6, IL-1β, and TNF-α (Bittencourt-Mernak et al., 2017; Herold, Mayer, & Lohmeyer, 2011) . Currently, several experimental animal models mimic inflammatory findings in ALI, such as intratracheal instillation lipopolysaccharide (LPS), viral infection, and sepsis (Bittencourt-Mernak et al., 2017; Rungsung et al., 2018; Zhang et al., 2017) .

It is described that COVID-19 patient developed a cascade of cytokines and that the immune system often does not respond promptly . This SARS-CoV-2/ACE2 linkage triggers an exaggerated cytokine response, and consequently, an exacerbated inflammatory process, called "cytokine storm" . There is still a dysfunction of the renin-angiotensin system with increased inflammation and vascular permeability, resulting in reduced ACE2 function (Basu, Sarkar, & Maulik, 2020; . Therefore, there is a systemic immune imbalance with significant systemic repercussions.

Respiratory symptoms and pulmonary effects in patients with COVID-19 are the most discussed features related to severity. Three possibilities have been described regarding manifestations of the disease when it affects the respiratory tract of symptomatic patients:

(1) the virus remains in the upper respiratory tract, and due to viral replication, the patient may present symptoms such as sore throat, dry cough, and runny nose; (2) the patient has worsened respiratory symptoms, including dyspnea, hypoxemia, and fever due to the exacerbated immune response; (3) one-third of patients evolve to respiratory failure such as ARDS and need rapid ventilation support (Rothan & Byrareddy, 2020) .

The pathogenesis of COVID-19 is highly complex and involves suppressing host antiviral and innate immune response, induction of oxidative stress followed by hyper inflammation described as the "cytokine storm," causing ALI, tissue fibrosis, and pneumonia. Most patients that recovered from severe COVID-19 showed elevated lung disease severity at days 10-14 after initial symptoms presentations.

The lung lesions can be absorbed in 53.0% of patients during the third week after discharge, with no sequelae. However, about 40% of patients had lung ground-glass opacity (GGO) and fibrous stripe as the main manifestations upon computed tomography images, seen on radiological follow-ups (Pan et al., 2020) .

There is an increase in the cytokines TNF-α, IL-1ß, IL-7, IL-8, IL-9, IL-10, INF-γ, monocyte chemoattractant protein-1, and others (Burgos-Blasco et al., 2020; . Most COVID-19 patients, especially among elderly patients, had marked lymphopenia and increased neutrophils, but T cell counts in severe COVID-19 patients surviving the disease were gradually restored (Akbari et al., 2020; . Some critically ill patients showed higher expressions of IL-1β, IL-6, TNF-α, and other cytokines (Akbari et al., 2020) .

Thus, these inflammatory-related factors might function as a biomarker to monitor the progression of COVID-19 disease.

Some new reports showed that COVID-19 survivors, particularly those developing the severe form, evolved to pulmonary fibrosis (Rogliani et al., 2020; Zhang et al., 2020) . Interestingly, Aloufi et al. (2020) reported that lung fibroblasts isolated from idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease patients express higher levels of ACE2. It suggested that the risk of developing pulmonary fibrosis can be associated with increased expression of ACE2, which occurred in the risk group, involving obesity, heart, and aging disorders (Aloufi et al., 2020) .

As discussed above, viruses commonly encode proteins that inhibit the immune system, promote viral invasion, and pathogenesis.

In this context, flavonoids have been studied for their antiviral effect and inhibition of the virus membrane proteins, preventing cellular invasion (Russo, Moccia, Spagnuolo, Tedesco, & Russo, 2020; Seong, Kim, & Shin, 2018) . Although several studies have shown that different flavonoids are beneficial in controlling respiratory diseases, additional studies of the specific effects of flavonoids on molecular mechanisms in lung diseases are needed.

In this review, we focused on flavonoids described in the literature as having potential biological effects against different coronavirus The leaves of Microcos paniculate, also known as shiral (India, Bengal), has been traditionally used to treat upper airway infections, containing flavonoids such as apigenin C-glycosides (ACGs), vicenin-1 (1), vicenin-2 (2), isoshaftoside (3), shaftoside (4), vitexin (5), isovitexin (6), violanthin (7), and isoviolanthin (8) (Li et al., 2018) . Their effects were measured by cytokine level determination and lung inflammation evaluation in situ. ACGs reduced pulmonary edema and microvascular permeability by down-regulating LPS-induced TNF-α, IL-6, and IL-1β expression. Metabolic profiling showed that this protective effect was due to suppression of TLR4/TRPC signaling pathway activation. As such, ACGs could be further explored to treat ALI and ARDS.

Obtained from Scutellaria baicalensis, baicalin (9) has shown antiapoptosis, antiinflammatory, and antioxidant properties. An in vitro study demonstrated that this compound attenuates oxidative stress and endothelial dysfunction by improving ACE2 activity (Wei et al., 2015) . Improved endothelial function impaired Ang II by promoting endothelial-dependent vasodilation and suppression of human umbilical vein endothelial cells apoptosis. Baicalin decreased the expression of pro-apoptotic protein Bax and cleaved caspase-3, involving an increase of Bcl-2 expression. Baicalin also significantly conversed Ang II to Ang-(1-7) by ACE2 and Mas receptor mRNA expression and protein expression and up-regulation of the PI3K/ AKT/eNOS pathway (Wei et al., 2015) . Astilbin (10), found in Smilax china, shown to diminish LPS-induced ARDS in vivo and in vitro successfully. This effect was determined by regulating pro-inflammatory cytokines TNF-α and IL-6, MAPK phosphorylation inhibition, suppression of proinflammatory enzyme heparinase, and diminished heparin sulphate degradation (Kong et al., 2016) . Glycosylated flavonoids hesperidin (11), naringin (12), and neohesperidin (13), found in different quantities in citrus fruits, were among the compounds subjected to a molecular docking study. The SARS-CoV S protein has a significant binding affinity to the human ACE2 enzyme, considered to be crucial F I G U R E 1 General and subgroup structures of the flavonoids class for virus entrance in host cells (Basu et al., 2020) . Therefore, compounds that bind this enzyme could prevent coronavirus infection.

Rutin (14) The antiinflammatory and antioxidant properties of eriodictyol (20) were also studied in the LPS-induced ALI model. Eriodictyol demonstrated inhibition of proinflammatory cytokine expression and attenuation of oxidative injury by activating the Nrf2 pathway at a dose of 30 mg/kg (Zhu, Guo, Huang, Wu, & Zhang, 2015) . Besides the effects antiinflammatory of narigenin (24), these flavonoids also demonstrated an inhibition of the 3-chymotrypsin-like protease (3CLpro), and reduction of ACE receptors activity (Tutunchi et al., 2020) .

The in vivo protective effect of synthetic flavonoid LFG-500 (25) was shown to inhibit cytokines such as TNF-α, IL-1β, and IL-6 in lung tissues after inducing ALI and inflammation by LPS challenge. In vitro effects were investigated as well, where the cytokine inhibition was also observed, by inhibiting NF-κB activation. In addition, p38 and JNK MAPK pathways were found to be involved in the antiinflammatory properties of compound 25 .

According to a review reporting effects of flavonoids in lung diseases, luteolin (26), pinocembrin (27), and oroxylin-A (28) were described to attenuate LPS-induced ARDS in vivo and in vitro, affecting proinflammatory cytokine concentrations as well as MAPK ad NF-κB pathway activation (Kimata et al., 2000) . In addition, the therapeutic effect of oroxylin-A (28) ameliorated the increased of the white blood cells counts, elevated plasma tumor necrosis factor (TNF)-α, and nitric oxide (NO), increased pulmonary edema, thickened alveolar septa caused by the administration of LPS (Tseng et al., 2012) . In vitro pretreatment with pinocembrin (27) (30) were among those with inhibitory potential against iNOS and NO products. Morin (31) and myricetin (32) were cited for the ability to affect the lipoxygenase enzyme (Havsteen, 2002; O'Leary et al., 2004; Yoon & Baek, 2005) . Flavonoids 26, 29-31 also inhibit the enzyme cyclooxygenase. Furthermore, luteolin, apigenin, and fisetin (33) were shown to inhibit the synthesis of cytokines IL-4 and IL-13 in vitro (Hirano et al., 2004) . Scutellarein (34) and fustin (35) were also among the flavonoids able to inhibit IL-4. Compounds 26, 29, 31, 32, and 34 were reported to have antiinflammatory effects against asthma models and chronic obstructive pulmonary disease (Coutinho, Muzitano, & Costa, 2009; Kim, Son, Chang, & Kang, 2004; O'Leary et al., 2004) . Another study showed that pre-treatment with (Nguyen et al., 2012) . Glycoside flavonoids rhoifolin (44) and pectolinarin (45) were subjected to a molecular docking study and evaluated by Jo, Kim, Shin, and Kim (2020) against 3CL pro . The series of tested compounds showed high inhibitory values with IC 50 of 27.45 and 37.78 μM, respectively. These compounds have an α-Lrhamnopyranosyl β-D-glucopyranoside and L-rhamnopyranosyl β-Dgluco-pyranoside moieties. In addition, these sugar groups attached to position C-7 of the chromen-4-one occupy the S1 and S2 sites and S2

and S30 sites, unlike the two flavonols described above. The higher affinity of rhoifolin (44) may be due to orchestrated binding through S1, S2, and S3 0 sites (Jo et al., 2020) . Studies carried out with roots of (Park et al., 2016) . As observed by the authors, the isoprene unit's length was not relevant for the observed activity. All activities are summarized in Table 2 .

Molecular docking studies developed by Jo et al. (2019) suggested that herbacetin (60) occupies the S1 and S2 sites of MERS-CoV 3CL pro , and the hydroxyl group at C-7 position is essential for S1 binding site. Helichrysetin (61) exhibits relevant inhibitory activity and the authors suggest that the presence of a hydroxyl group at C-4 position is suitable for binding to MERS-CoV 3CL pro (Jo et al., 2019) .

Fractionation of the bioactive extract from Broussonetia papyfera led to the isolation of flavonoids 62-71 (Table 3) 11.6, 12.5, 5.0, 9.5, 9.2, 13.2, 12.7, 14.4, 10.4, and 13 .9 μM, respectively. Compounds 72-76, bearing unusual 3,4-dihydro-2H-pyran structures, were more effective in inhibiting the enzyme than the cyclization precursors (Cho et al., 2013) . This series of compounds allowed the authors to infer that a 3,4-dihydro-2H-pyran moiety is more effective at inhibiting 3CL pro expression than the open ring precursors. The extract from Psoralea corylifolia seeds was subjected to fractionation to afford six related flavonoids (59 and 84-88). (Lung et al., 2020) . In this way, this compound could be considered a lead compound for inhibitors targeting CoVs RdRp (Lung et al., 2020) . A study demonstrated that 3-theaflavin-3-gallate (94) and theaflavin-3,3 0 -digallate (95), both present in black tea, were effective against SARS-CoV 3CL pro , with IC 50 values of 7.0 and 9.5 μM. This suggests that black tea could prevent or alleviate coronavirus infection (Chen et al., 2005) . Studies carried out by Zhuang et al. (2009) with extracts from Cinnamomi cortex describe inhibition in wild-type SARS-CoV (Zhuang et al., 2009) . It was possible to isolate from this extract procyanidin A2 (96), procyanidin B2 (97), and dimer cinnamtannin B1 (98), showing overall moderate inhibitory effects with IC 50 values of 120.7, 161.1, and 32.9 μM, respectively (Zhuang et al., 2009 ).

SARS-CoV N protein envelopes the genomic RNA, and as such, has a crucial role in the virus particle assembly. It may cause apoptosis of the host cells, upregulate the proinflammatory cytokine production and block innate immune responses. In addition, it has a significant role in replication for this virus and is considered a central target for anti-SARS drugs. An inhibitor screening of this protein was performed on a biochip platform, with high sensitivity and rapid response. In this work, (À)-gallocatechin gallate (92) and (À)-catechin gallate (99) showed high activity. Both compounds, at 0.005 μg/mL, diminished the binding affinity in a concentration-dependent manner. More than 40% inhibition was displayed at a concentration of 0.05 μg/mL on the biochip platform for 92 and 99. Other flavonoids including kaempferol (100) and quercetin (15), showed no inhibitory activity at the tested concentrations (Roh, 2012) .

The flavonoids juglanin (101) was shown to inhibit SARS-CoV 3-a-mediated current, with an IC 50 value of 2.5 μM. The activity of this cation-selective channel can be expressed in the infected cells and virus release (Schwarz et al., 2014) .

In summary, flavonoids' favorable effects are related to the antiinflammatory, antioxidant, immunomodulatory, and anti-viral effects, suggesting that flavonoids can be a promising treatment strategy for conventional drugs against COVID-19. (Tutunchi et al., 2020) . structural-activity relationships could be established, especially the methylation of hydroxyl groups at C-7 0 and C-4 0 , which cause a reduction in the inhibitory activity. However, methoxyl at C-7 increases the potency, suggesting that methoxyl groups' position in the structures of these related bioflavonoids is associated with their inhibitory potential of SARS-CoV 3CL pro (Russo et al., 2020; Ryu et al., 2010) .

Considering chalcone derivatives 51-64, the biological effect (SARS-CoV protease inhibitor) seems to be associated with the presence of prenyl unities at different position of C 6 C 3 C 6 moietythis initial analysis also suggested that the presence of hydroxyl group at C-4 0 is important to the activityin addition, it is essential to mention that the acyclic prenyl unity at C-3 seen to be crucial to activity of related compounds since compound 64, a chromene, exhibited reduced potential. A similar profile was observed to prenylated flavanes 66-69 since the effect of compounds, which showed an acyclic unity (66 and 67) were able to inhibit SAR-CoV and MERS-CoV more efficiently in comparison to chromene derivatives 68 and 69. In addition, considering the structures of biflavones 47-50, biflavonols 93-98, and their inhibitory effects of SARS-CoV 3CL pro enzymes, it was observed a positive influence of dimerization (Islam et al., 2020; Ryu et al., 2010) .

Studies using molecular docking showed that rutin, which was approved by NMPA (National Medical Products Administration), exhibited the best effect in the binding affinity to inhibit SARS-CoV-2 compared to other compounds . Some authors have also shown that certain flavonoids can interact with the receptor binding of the SARS-CoV-2 using in silico analysis (Istifli et al., 2020) . In this computational study, the group of flavonoids anthocyanidins, isoflavones, and flavanones showed improved interaction with the target proteins, in special (À)-epicatechin gallate. Basu et al. (2020) also showed that the structure of ACE2 and spike protein fragment 

The authors would like to thank FAPESP, CNPq, and CAPES for financial support. We would like to express our special thanks to Shahin

Shams from the Department of Biomedical Engineering, University of California, Davis, California, USA, who gently revised the manuscript.

The authors have no conflicts of interest to declare related to the data shown on this publication.

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study since it is a review paper ORCID João Henrique Ghilardi Lago https://orcid.org/0000-0002-1193-

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Angiotensin-converting enzyme 2 (ACE2) expression in COPD and IPF fibroblasts-The forgotten cell in COVID-19

Coronavirus main proteinase (3CLpro) structure: Basis for design of anti-SARS drugs

Novel therapeutic approaches targeting the renin-angiotensin system and associated peptides in hypertension and heart failure

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): An overview of viral structure and host response. Diabetes and Metabolic Syndrome

The SARScoronavirus papain-like protease: Structure, function and inhibition by designed antiviral compounds

Molecular docking study of potential phytochemicals and their effects on the complex of SARS-CoV2 spike protein and human ACE2

Angiotensin II type 2 receptor-mediated vasodilation. Focus on bradykinin, NO and endothelium-derived hyperpolarizing factor(s). Vascular Pharmacology

Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries

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Botanical drugs and supplements affecting the immune response in the time of COVID-19: Implications for research and clinical practice

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Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan

Inhibition of SARS-CoV 3C-like protease activity by Theaflavin-3,3 0 -digallate (TF3). Evidence-Based Complementary and Alternative Medicine

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Binding interaction of quercetin-3-β-galactoside and its synthetic derivatives with SARS-CoV 3CLpro: Structure-activity relationship studies reveal salient pharmacophore features

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Angiotensin II signal transduction: An update on mechanisms of physiology and pathophysiology

Anti-inflammatory properties of plant flavonoids. Effects of rutin, quercetin and hesperidin on adjuvant arthritis in rat

The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak-An update on the status. Military

Anti-inflammatory effects of flavonoids: Genistein, kaempferol, quercetin, and daidzein inhibit STAT-1 and NF-kappaB activations, whereas flavone, isorhamnetin, naringenin, and pelargonidin inhibit only NF-kappaB activation along with their inhibitory effects. Mediators of Inflammation

Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis

The biochemistry and medical significance of the flavonoids

Acute lung injury: How macrophages orchestrate resolution of inflammation and tissue repair

Flavonoids such as luteolin, fisetin and apigenin are inhibitors of interleukin-4 and interleukin-13 production by activated human basophils

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The discovery of angiotensinconverting enzyme 2 and its role in acute lung injury in mice

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In silico analysis of the interactions of certain flavonoids with the receptor-binding domain of 2019 novel coronavirus and cellular proteases and their pharmacokinetic properties

ACE2-Ang-(1-7)-Mas axis in brain: A potential target for prevention and treatment of ischemic stroke

Virology, epidemiology, pathogenesis, and control of covid-19

Characteristics of flavonoids as potent MERS-CoV 3C-like protease inhibitors

Inhibition of SARS-CoV 3CL protease by flavonoids

Flavonoids: Biological activities and therapeutic potential

Phenolic phytochemical displaying SARS-CoV papain-like protease inhibition from the seeds of Psoralea corylifolia

Anti-inflammatory plant flavonoids and cellular action mechanisms

Effects of luteolin, quercetin and baicalein on immunoglobulin E-mediated mediator release from human cultured mast cells

Astilbin alleviates LPS-induced ARDS by suppressing MAPK signaling pathway and protecting pulmonary endothelial glycocalyx

Hypertension, the renin-angiotensin system, and the risk of lower respiratory tract infections and lung injury: Implications for COVID-19

Identification, synthesis and evaluation of SARS-CoV and MERS-CoV 3C-like protease inhibitors

Luteolin attenuates the pulmonary inflammatory response involves abilities of antioxidation and inhibition of MAPK and NFκB pathways in mice with endotoxin-induced acute lung injury

Suppression of influenza B virus replication by sakuranetin and mode of its action

Structure-activity association of flavonoids in lung diseases

Chemokine up-regulation in SARS-coronavirus-infected, monocyte-derived human dendritic cells

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SARS-CoV-2 and viral sepsis: Observations and hypotheses

Apigenin C-glycosides of Microcos paniculata protects lipopolysaccharide induced apoptosis and inflammation in acute lung injury through TLR4 signaling pathway

Expression of the SARS-CoV-2 cell receptor gene ACE2 in a wide variety of human tissues

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Anti-SARS coronavirus 3C-like protease effects of Isatis indigotica root and plant-derived phenolic compounds

The potential chemical structure of anti-SARS-CoV-2 RNA-dependent RNA polymerase

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Flavonoid-mediated inhibition of SARS coronavirus 3C-like protease expressed in Pichia pastoris

Flavonoids: A review of probable mechanisms of action and potential applications

Effect of flavonoids and Vitamin E on cyclooxygenase-2 (COX-2) transcription. Mutation Research, Fundamental and Molecular Mechanisms of Mutagenesis

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Flavonoids: An overview

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Evaluation of polyphenols from Broussonetia papyrifera as coronavirus protease inhibitors

Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: A prospective study

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A facile inhibitor screening of SARS coronavirus N protein using nanoparticle-based RNA oligonucleotide

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Roles of flavonoids against coronavirus infection

Biflavonoids from Torreya nucifera displaying SARS-CoV 3CLpro inhibition

Evidences of herbal medicine-derived natural products effects in inflammatory lung diseases

Coronavirus envelope protein: Current knowledge

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Comorbidities in COVID-19: Outcomes in hypertensive cohort and controversies with renin angiotensin system blockers. Diabetes and Metabolic Syndrome

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In vitro and in vivo protection provided by pinocembrin against lipopolysaccharide-induced inflammatory responses

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Interaction of severe acute respiratory syndrome-associated coronavirus with dendritic cells

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Coronaviruses: An updated overview of their replication and pathogenesis

Baicalin attenuates angiotensin II-induced endothelial dysfunction

COVID-19: Attacks the 1-beta chain of hemoglobin and captures the porphyrin to inhibit human heme metabolism

Innate immune sensing and signaling of cytosolic nucleic acids

Inhibitory effects of flavonoids extracted from licorice on lipopolysaccharide-induced acute pulmonary inflammation in mice

Discovery of potential flavonoid inhibitors against COVID-19 3CL proteinase based on virtual screening strategy

Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2

The pathogenesis and treatment of the 'Cytokine Storm' in COVID-19

ACE2 exhibits protective effects against LPSinduced acute lung injury in mice by inhibiting the LPS-TLR4 pathway

MERS, SARS and other coronaviruses as causes of pneumonia

Molecular targets of dietary polyphenols with anti-inflammatory properties

Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia

Discharge may not be the end of treatment: Pay attention to pulmonary fibrosis caused by severe COVID-19

Kaempferol ameliorates H9N2 swine influenza virus-induced acute lung injury by inactivation of TLR4/MyD88-mediated NF-κB and MAPK signaling pathways

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