• Users Online: 126
  • Print this page
  • Email this page


 
 Table of Contents  
REVIEW ARTICLE
Year : 2022  |  Volume : 9  |  Issue : 1  |  Page : 9

Role of TGF-β Signaling in Coronavirus Disease 2019


1 Department of Nephrology, The Third Affiliated hospital, Southern Medical University, Guangzhou; Departments of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, and Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong Kong, Hong Kong, China
2 Departments of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, and Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong Kong, Hong Kong, China
3 Medical Research Center, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
4 Department of Nephrology, The Third Affiliated hospital, Southern Medical University, Guangzhou, China

Date of Submission06-Feb-2022
Date of Decision03-Mar-2022
Date of Acceptance10-May-2022
Date of Web Publication27-Jul-2022

Correspondence Address:
Hui- Yao Lan
Departments of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong
China
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2773-0387.348713

Rights and Permissions
  Abstract 


Coronavirus disease 2019 (COVID-19) has a broad spectrum of clinical manifestations involving the respiratory, cardiovascular, renal, neuropsychiatric, gastrointestinal, and dermatological systems. Some patients with COVID-19 experience acute infection and post-COVID-19 syndrome. There is increasing evidence that TGF-β signaling plays an important role in the pathogenesis of both acute and chronic COVID-19 infection. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid protein was reported to interact with Smad3, a key downstream mediator of TGF-β signaling, thereby promoting TGF-β1/Smad3 signaling and causing cell death during the acute phase of COVID-19 infection. Because activation of TGF-β/Smad3 signaling has an essential role in multiple organ fibrosis, it is possible that overreactive TGF-β/Smad3 signaling may cause tissue fibrosis in the lung, heart, and kidney after SARS-CoV-2 infection. Thus, not only administration of antiviral drugs and traditional Chinese medicines, but also targeting of TGF-β signaling components, particularly Smad3, with various therapeutic strategies involving OT-101, pirfenidone, and specific Smad3 inhibitors, such as SIS3, may provide novel and specific therapies for COVID-19 patients.

Keywords: Severe acute respiratory syndrome coronavirus 2, coronavirus disease 2019, TGF-β signaling, cell death, fibrosis


How to cite this article:
Chen J, Wu W, Wang W, Tang Y, Lan HY. Role of TGF-β Signaling in Coronavirus Disease 2019. Integr Med Nephrol Androl 2022;9:9

How to cite this URL:
Chen J, Wu W, Wang W, Tang Y, Lan HY. Role of TGF-β Signaling in Coronavirus Disease 2019. Integr Med Nephrol Androl [serial online] 2022 [cited 2022 Aug 14];9:9. Available from: https://journal-imna.com//text.asp?2022/9/1/9/348713




  Introduction Top


In December 2019, a series of patients with pneumonia of unknown cause, now known as coronavirus disease 2019 (COVID-19), were reported for the first time.[1] The pathogen was a new strain of coronavirus, designated severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2). SARS-CoV-2 was identified as an enveloped, non-segmented, positive-sense RNA virus belonging to the β-coronavirus family, together with Middle East Respiratory Syndrome Coronavirus (MERS-CoV) and Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV).[2] After the outbreak, SARS-CoV-2 rapidly spread throughout the world. To date, it has caused more than 390 million infections and more than 5.7 million deaths worldwide.[3]

COVID-19 has a broad spectrum of clinical manifestations from asymptomatic disease to death during the acute phase.[4] Most COVID-19 patients (80%) exhibit a mild clinical syndrome, with symptoms such as fever, fatigue, myalgia, and dry cough.[5],[6] However, severe and critically ill patients may progress to acute respiratory distress syndrome (ARDS), acute kidney injury (AKI), multiple organ dysfunction syndrome (MODS) requiring intensive care, and even death. However, the mechanisms through which COVID-19 causes ARDS, AKI, and MODS remain largely unclear and consequently no specific and effective treatments for COVID-19 are currently available.


  Post-COVID-19 Syndrome Top


Symptoms of myalgia, fatigue, depression, and disordered sleep were observed in SARS-recovered patients during long-term follow-up.[7] Meanwhile, respiratory system- associated symptoms, such as dyspnea, were frequently noted in patients who had recovered from SARS[8] and MERS.[9] As the number of COVID-19 survivors increases, a hidden concern termed post-COVID-19 syndrome is emerging.[10],[11],[12] Long-term follow-up studies are urgently needed to explore the characteristics of post- COVID-19 syndrome. For example, post-COVID-19 syndrome could be a common health problem,[13] and even asymptomatic COVID-19 patients may have post- COVID-19 syndrome.[14],[15] To date, symptoms involving the respiratory, cardiovascular, renal, neuropsychiatric, gastrointestinal, and dermatological systems are known to be present, conferring a heavy burden on health systems.[11],[13] Long-term monitoring and treatment for post-COVID-19 syndrome may be needed.


  TGF-β Signaling in COVID-19 Patients Top


Mammals have three TGF-β isoforms, TGF-β1, TGF-β2, and TGF-β3.[16] TGF-β has also been characterized as latent and active forms. Active TGF-β is released from the latent TGF-β complex after cleavage by proteases like matrix metalloproteinase (MMP) 2 and MMP9.[17],[18] Active TGF-β1 binds to TGF receptor 2 (TGFR2) and subsequently activates TGF receptor 1 (TGFR1) and downstream Smad-dependent (canonical) or Smad- independent (non-canonical) pathways.[16],[19] It has become clear that the TGF-β signaling pathway is a key pathway for regulation of cell apoptosis, proliferation, differentiation, epithelial-mesenchymal transition, and fibrosis.[20]

Similar to patients with SARS[21] and MERS,[22] serum TGF-β levels are significantly elevated in COVID-19 patients and associated with both disease severity and poor clinical outcomes.[23] Indeed, blood TGF-β1 levels are highly elevated at the time of first medical intervention.[24] Blood TGF-β levels are also markedly elevated in severe COVID-19 patients, before decreasing during the convalescence phase.[25] Meanwhile, circulating TGF-β1 levels remain high in post-COVID-19 patients compared with healthy controls.[10] SARS-CoV papain-like protease (PLpro) can significantly increase the TGF-β1 mRNA and protein levels in human promonocytes.[26] A computational analysis of noncoding RNA interactions predicted that the TGF-β signaling pathway is involved in SARS-CoV/CoV-2 infection.[27],[28] A rapid transcriptome analysis of nasopharyngeal swabs confirmed that the TGF-β signaling pathway is significantly upregulated in severe COVID-19 patients.[29] Indeed, SARS-CoV-2 can induce expression of TGF-β family genes in blood monocytes.[30]

TGF-β signaling in COVID-19-associated ARDS and pulmonary fibrosis

SARS-CoV-2 initially infects and replicates in upper respiratory tract epithelial cells, followed by lung epithelial cells, where angiotensin-converting enzyme 2 (ACE2) is highly expressed.[31] Immunohistochemical detection of S protein, N protein,[32],[33] and viral inclusions[34],[35] confirms the presence of SARS-CoV-2 in the lungs of COVID-19 patients. Although most COVID-19 patients manifest a mild respiratory disease, 5%–8% of COVID-19 patients develop ARDS, which is the leading cause of death.[11],[36] There are three major pulmonary pathological changes in COVID-19 patients: 1) reactive epithelial changes and diffuse alveolar damage, 2) microvascular damage, and 3) acute fibrinous and organizing pneumonia and interstitial fibrosis.[37] A report on COVID-19 patients described that 44% have parenchymal injury and 41% have an irregular interface, representing early signs of fibrosis during the acute phase.[38] Radiographic results for COVID-19 patients showed that fibrotic changes are common beyond 7 days after diagnosis,[38] and fibrosis becomes apparent after 3 weeks.[37] A follow-up study on SARS survivors revealed significant impairment of lung function in 23.7% of patients, with 27.8% developing radiographic abnormalities at 12 months after SARS onset.[39] Among children affected by SARS, 32% have radiographic abnormalities, including parenchymal scars, at 12 months after diagnosis.[40] A 15-year follow-up study on SARS survivors revealed that 38% of patients have ground-glass opacity and cord-like consolidation.[8] A study on MERS survivors with a mean follow-up of 43 days also showed that 36% have abnormal radiological findings.[9] Pulmonary fibrosis was identified as one of the sequelae of SARS and MERS.[39] Given that SARS-CoV-2, SARS-CoV-1, and MERS-CoV all belong to the β-coronavirus family, we speculate that pulmonary fibrosis is one of the important features of post-COVID-19 syndrome, because impaired lung function is observed in patients after COVID-19 infection.[41] Lung radiographic abnormalities are common among COVID-19 patients after hospitalization.[42] A 6-month follow-up study on 353 COVID-19 patients with complete chest computed tomographic (CT) imaging showed that more than 45% of patients have GGO, while 16% have irregular lines.[15] Meanwhile, abnormality of CT findings in a follow-up examination is positively associated with disease severity in COVID-19 patients.[15] More than one-third of severe COVID-19 patients develop lung fibrotic- like changes within 6 months after discharge[43]. Compared with the acute phase, 9% of patients have worse radiographic abnormalities during the follow-up period at an average of 54 days.[44] The only option for irreversible lung injury involving pathological end-stage pulmonary fibrosis in COVID-19 patients is lung transplantation.[45] Longer follow-up studies in COVID-19 patients, especially for lung function and radiological findings, are warranted.

It is well known that TGF-β can induce fibroblast proliferation,[46] myofibroblast differentiation,[47],[48] and extracellular matrix (ECM) protein production and deposition.[46],[49] Consequently, TGF-β plays an important role in pulmonary fibrosis. TGF-β was also proven to participate in the early phase of ARDS and to be associated with the development of pulmonary edema.[45] SARS-CoV PLpro was reported to upregulate the mRNA and protein levels of TGF-β1 in lung tissue.[50] SARS-CoV PLpro can also stimulate TGF-β-dependent expression of collagen 1 (Col-1) via non-SMAD pathways in human lung epithelial cells.[51] SARS-CoV nucleocapsid (N) protein was shown to interact with Smad3 to activate the canonical pathway, thereby promoting fibrosis.[52]

In COVID-19 patients, TGF-β expression is increased in the bronchoalveolar lavage (BAL) fluid.[53] A bioinformatics analysis revealed that SARS-CoV-2 infection can increase the mRNA level of TGF-β1, which in turn drives fibrosis in human lung epithelial cells.[54] An immunohistochemical analysis showed that expression of TGF-β1 is significantly increased in lung samples from COVID-19 patients compared with those from H1N1 patients and no lung injury (control) patients.[55] Thus, we predict that TGF-β may be a key mediator of pulmonary fibrosis in COVID-19 patients. As shown in [Figure 1], binding of the SARS-CoV-2 spike (S) protein to ACE2 can directly downregulate ACE2 expression.[56] Because the main function of ACE2 is to convert angiotensin II (Ang II) to Ang 1-7,[57] it is possible that the levels of Ang II are elevated in COVID-19 patients as a result of decreased ACE2, thereby promoting activation of TGF-β/Smad3 signaling via TGF-β-dependent and TGF- β-independent pathways.[58] It is also possible that SARS- CoV-2 infection induces lung infiltration of neutrophils that subsequently release several proteases and active TGF-β.[59] Furthermore, high levels of IL-4/IL-13 can trigger activation of M2 macrophages in the lung tissue of COVID-19 patients.[60] M2 macrophages are known to be a rich source of TGF-β1,[30],[55],[60],[61] which may contribute to TGF-β-mediated lung fibrosis in COVID-19 patients. Importantly, we and other investigators found that the N protein of SARS-CoV-2 can directly interact with Smad3 and promote TGF-β1/Smad3 signaling.[52],[62] Thus, SARS-CoV-2 N protein-induced activation of Smad3 signaling may be a key mechanism for the development of lung fibrosis [Figure 1] and [Figure 2].
Figure 1: Role of TGF-β signaling in COVID-19. After SARS-CoV-2 enters cells via ACE2, its N protein (CoV-2 N) can activate TGF-β signaling directly by binding and promote Smad3-mediated cell death and fibrosis, which can be exacerbated by increased angiotensin II (Ang II) signaling and local inflammatory responses including production of TGF-β by M2 macrophages and release of active TGF-β via PMN-dependent proteases. PMN, polymorphonuclear neutrophil; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Click here to view
Figure 2: TGF-β signaling in COVID-19-associated tissue fibrosis. After SARS-CoV-2 enters cells via ACE2, its N protein (CoV-2 N) can activate TGF-β signaling directly by binding and promote Smad3-mediated fibrosis, which can be further enhanced by non-Smad-dependent TGF-β signaling pathways such as the PI3K/AKT signaling pathway. COVID-19, coronavirus disease 2019; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; ROS, reactive oxygen species; FOXO, forkhead box O; mTOR, mammalian target of rapamycin.

Click here to view


Besides the canonical signaling pathway, phosphatidylinositol 3-kinase (PI3K)/AKT (non-canonical) signaling pathways can also participate in lung fibrosis development in COVID-19 patients.[55] Mammalian target of rapamycin (mTOR) and Forkhead box O (FOXO), as the main downstream targets of the PI3K/AKT pathway, may be involved in the expression of profibrotic genes.[63] Meanwhile, TGF-β1-mediated production of reactive oxygen species (ROS) via NOX4 was proven to participate in the pathogenesis of fibrosis.[64] All of these pathways may be associated with the lung fibrosis observed in COVID-19 patients, as shown in [Figure 2].

TGF-β signaling in COVID-19-associated acute heart injury and cardiac fibrosis

Besides the respiratory system, ACE2 receptors are highly expressed in the heart[65]. Electron microscopy and immunohistochemistry analyses have confirmed the presence of SARS-CoV-2 in the heart.[66] The manifestations of cardiovascular system are common in COVID-19 patients,[67] which include arrhythmia,[68],[69] myocardial injury[69],[70],[71],[72] manifested as elevated cardiac troponin I (cTnI), NT- proBNP, creatine kinase, and lactate dehydrogenase (LDH), and heart failure.[1] The levels of cardiac biomarkers are closely correlated with disease severity in COVID-19 patients[73],[74]. Heart failure also accounts for a significant proportion of deaths in COVID-19 patients during the acute phase of infection.[1],[74] Cardiac magnetic resonance (CMR) imaging shows myocardial inflammation in 60% of recently-recovered COVID-19 patients.[75] Pathologically, mild myocardial edema and atypical interstitial fibrosis with infiltration of inflammatory cells are observed.[76]

Tachycardia is the most common complication in SARS patients during the follow-up period.[77] A 12-year follow- up study on SARS patients revealed that 44% exhibit cardiovascular abnormalities.[78] The similarities between SARS-CoV-1 and SARS-CoV-2 suggest that cardiovascular abnormalities should be carefully monitored in COVID-19 patients during the follow-up period. A 2–3-month follow- up study revealed a high rate of diastolic dysfunction (60%) in COVID-19 patients after hospital discharge.[79] Furthermore, the COMEBAC Study Group reported that 12% of COVID-19 patients have impaired left ventricular ejection fraction (<50%) in the follow-up echocardiography assessment.[42] with all of these patients being ICU survivors. CMR imaging reveals the presence of myocardial edema, fibrosis, and impaired right ventricle function in COVID-19 survivors.[80]

The levels of TGF-β, interstitial Col-1, and Col-3 are elevated in the heart of COVID-19 patients compared with control patients.[81] The mRNA level of TGF-β1 is also upregulated in the left ventricular myocardium of COVID-19 patients with left ventricular fibrosis.[24] The possible mechanisms linking TGF-β signaling and cardiac fibrosis in COVID-19 patients may be similar to those for pulmonary fibrosis, as already discussed and shown in [Figure 2].

TGF-β signaling in COVID-19-associated AKI and renal fibrosis

In addition to the respiratory system and heart, ACE2 is highly expressed in proximal tubule and glomerular parietal epithelial cells in the kidney, based on single-cell RNA sequencing.[82] In COVID-19 patients, SARS-CoV-2 S protein and N protein are detectable in renal tubular epithelial cells (TECs) by immunohistochemistry,[83],[84],[85] while SARS- CoV-2 particles can be observed in TECs and podocyte cells by electron microscopy.[37] The renal manifestations of COVID-19 patients in the acute period are diverse, ranging from proteinuria to hematuria.[86],[87] The incidence of AKI is associated with the severity of COVID-19.[88] Kidney CT findings indicated that inflammation and edema occur in the renal parenchyma of COVID-19 patients.[89] The pathological changes in COVID-19 patients include various degrees of acute tubular injury and collapsing glomerulopathy.[83],[84],[85] Our recent study proved that SARS- CoV-2 N protein induces AKI by causing TEC death through a TGF-β/Smad3-dependent G1 cell cycle arrest mechanism [Figure 3].[62] This was confirmed by protection against SARS-CoV-2 N-induced AKI in mice lacking Smad3.[62] TGF-β/Smad signaling may also play a role in AKI via other cell death signaling pathways, such as receptor-interacting protein kinase (RIPK) protein/mixed- lineage kinase domain-like protein (MLKL)-mediated necroptosis,[90],[91] and TGF-β-inducible early response gene 1 (TIEG1), death-associated protein kinase (DAPK), or p53-induced cell apoptosis.[91],[92] Meanwhile, apoptosis- related protein released from mitochondria upon TGF-β stimulation may also increase the activity of caspase 3.[93] Thus, necroptosis and apoptosis may be the mechanisms related to cell death in COVID-19 patients [Figure 3].
Figure 3: TGF-β signaling in COVID-19-associated cell death. After SARS-CoV-2 enters cells via ACE2, its N protein (CoV-2 N) can activate TGF-β signaling directly by binding and promote Smad3-dependent cell death pathways including p21/p27-mediated G1 cell cycle arrest, RIPK/MLKL-mediated necroptosis, and TIEG1/ DAPK/p53-dependent apoptosis. DAPK, death-associated protein kinase; RIPK, receptor-interacting protein kinase; MLKL, mixed-lineage kinase domain-like protein.

Click here to view


AKI is also observed in patients with SARS and MERS,[94],[95] but few studies have focused on the long-term renal outcomes. In contrast, the long-term renal outcomes in COVID-19 patients have been investigated. A follow-up study on COVID-19 patients compared with non-infected control patients revealed that COVID-19 patients exhibit a decline in estimated glomerular filtration rate (eGFR) that is associated with kidney disease severity at 6 months after AKI.[96] A 9.6-month follow-up study showed a lower eGFR in a group of mainly non-hospitalized COVID-19 patients compared with age, sex, and education-matched control patients.[14] Huang et al.[15] found that 35% COVID-19 patients have reduced kidney function at 6 months after AKI. A 3-month follow-up study on critically ill COVID-19 patients showed that about 10% of AKI patients with renal recovery at the discharge are diagnosed with new-onset chronic kidney disease (CKD), increasing to 44.8% in AKI patients without renal recovery. Furthermore, 5% of COVID-19 survivors need dialysis at 3 months after discharge.[97] In COVID-19 patients diagnosed with AKI requiring kidney replacement therapy, only 62.2% of patients have full renal recovery after a mean follow-up period of 151 days.[98] Based on these studies, development of CKD appears to occur after COVID-19.

Renal fibrosis is a common pathway for CKD. Jansen et al.[99] reported that tubule interstitial fibrosis in COVID-19 patients increases independently of pre-existing CKD. They also observed activation of TGF-β signaling in renal proximal tubular epithelial cells and podocytes in COVID-19 patients. Furthermore, they found that blocking of TGF-β receptor I using SB431542 can ameliorate the Col-1 expression induced by SARS-CoV-2. On the basis of our own study,[62] we predict that SARS-CoV-2 N protein can interact with Smad3 and thus enhance Smad3-mediated renal fibrosis, which may be a key mechanism for CKD development in patients with COVID-19.


  Potential Treatments for COVID-19 Top


Antiviral drugs

Remdesivir

Remdesivir (GS-5734), a prodrug for adenosine analogues, has been shown to act as a broad-spectrum antiviral agent against several RNA viruses, including MERS-CoV[100] and Ebola virus.[101] Based on reports that remdesivir can effectively inhibit SARS-CoV-2 in mouse models and in vitro,[102],[103] it has received approval from the FDA for the treatment of SARS-CoV-2 infection and has shown clinical efficacy, particularly in critically ill patients.[104],[105] However, the mode of intravenous injection has limited its clinical use.

Paxlovid

Paxlovid, a combination of nirmatrelvir (PF-07321332) and ritonavir, is an effective and safe orally bioavailable antiviral drug. Nirmatrelvir binds to SARS-CoV-2 Mpro[106] (main protease; referred to as 3CL protease), which is critical in the replication stage.[107] Ritonavir is used to enhance the therapeutic concentration of nirmatrelvir[108]. Nirmatrelvir was proven to have excellent anti-SARS-CoV-2 activity both in vitro and in animal models.[109] A randomized, double-blind study (RCT) showed that paxlovid can significantly reduce the risk of hospitalization and death in non-hospitalized adults with COVID-19.[110]

Traditional Chinese medicines (TCMs)

TCMs, which are mainly used to treat diseases based on holism and syndrome differentiation, have long been used for the treatment of infectious diseases and have been shown to play indispensable roles in the prevention and treatment of severe epidemic diseases. Several clinical studies have shown that TCMs play significant roles in the treatment of COVID-19.[111],[113] However, the underlying mechanisms of the effects of TCMs in the treatment of COVID-19 remain unclear.

Lianhua Qingwen capsules were preliminarily confirmed to show efficacy in the management of SARS patients, and have been recommended for the treatment of COVID-19 patients.[114] The antiviral activity of LH against SARS-CoV-2 was examined using Vero E6 cells. LH significantly can inhibit the replication of SARS-CoV-2 and reduce the mRNA levels of pro-inflammatory cytokines, including TNF-α, IL-6, MCP-1/ CCL2, and IP-10/CXCL10, suggesting that LH may inhibit the cytokine storm induced by SARS-CoV-2.[115]

Jinhua Qinggan Granules were developed during the 2009 H1N1 influenza pandemic. Network pharmacology and molecular docking techniques revealed that the mechanism of action may be attributed to some of the active constituents, such as kaempferol, baicalein, and oroxylin A, that can bind to SARS-CoV-2 3CL hydrolase and regulate many signaling pathways, including the TNF, PI3K/Akt, and HIF-1 signaling pathways.[116]

Among the TCMs commonly used to treat epidemic diseases, Gancao (Glycyrrhizae Radix Et Rhizoma) and HuangQin (Scutellariae Radix) are administered with high priority. When LigandFit was used to screen for candidate compounds in TCMs, 27 compounds docked with the 3CL hydrolase target and 48 docked with the ACE2 target. The screened compounds were distributed in 27 kinds of TCMs. Among them, Gancao and HuangQin contain the largest amounts of the identified compounds.[117] Thus, Gancao and HuangQin show potential anti-SARS-COV-2 activity by binding to ACE2 and 3CL hydrolase and regulating target genes related to the immune system, inflammation, cellular processes, and endocrine system.[117]

When network pharmacology-based technologies were employed to analyze the mechanisms of action for Chinese herbs in the treatment of COVID-19, 258 compounds and 53 overlapping genes were identified.[118] The key compounds included quercetin, wogonin, luteolin, and oroxylin A. All of these compounds have close associations with IL-6 and contain binding sites for TGF-β.[118] Quercetin is a naturally-abundant flavonoid that is widely distributed in various herbal medicines, especially in the clearing away heat and dampness herbs. In the supercomputer SUMMIT drug-docking screen and expression profiling experiments involving gene set enrichment analyses, quercetin was listed as one of the promising compounds to inhibit SARS-CoV-2 infection.[119] A computational docking model identified that quercetin can bind to either the isolated viral S protein at its host receptor-binding region or the S protein–human ACE2 receptor interface, thus potentially limiting viral recognition of host cells and/or disrupting host–virus interactions.[120] Kyoto encyclopedia of genes and genomes pathway analysis indicated that quercetin may act via several signaling pathways, including the TNF, HIF-1α, TLR, VEGF, and apoptosis- related signaling pathways to effectively treat COVID-19- induced renal injuries.[121] However, most of the research on the mechanisms of action for TCMs in the treatment of COVID-19 has been based on computer-aided systematic approaches, and thus further in vivo and in vitro validation experiments are needed.

Potential treatments for post-COVID-19 syndrome

Trabedersen/AP 12009 (OT-101)

OT-101 is an antisense oligodeoxynucleotide designed to target the mRNA of human TGF-β2.[122] It has been clinically evaluated in patients with advanced solid tumors in a phase I/II study.[123] OT-101 was proven to effectively inhibit tumor growth and metastasis[123],[124]. It also has the ability to overcome chemoresistance.[122] Uckun et al.[125] found that OT-101 suppresses viral replication of SARS-CoV-2 through inhibition of TGF-β, and also prevents the progression of mild ARDS and helps the recovery in COVID-19 patients.

Pirfenidone

Pirfenidone, an orally antifibrotic drug, inhibits conversion of pro-TGF-β to latent TGF-β by blocking furin.[126] Pirfenidone can attenuate TGF-β1-induced expression of fibronectin and α-SMA in human lung fibroblasts,[127] and inhibit the upregulation of Col-I mRNA in a concentration-dependent manner.[128] In a mouse model of bleomycin-induced pulmonary fibrosis, pirfenidone was shown to attenuate the development of fibrosis.[129]

Pirfenidone can reduce the decline in forced vital capacity (FCV) in pulmonary fibrosis patients.[130] It has been approved by the FDA for the treatment of idiopathic pulmonary fibrosis patients since 2014. Based on these findings, pirfenidone may be a safe anti-fibrotic drug to prevent pulmonary fibrosis in SARS-CoV-2 patients by blocking activation of TGF-β. The efficacy and safety of pirfenidone (NCT04282902) in SARS-CoV-2 infection is under investigation.

Smad3 inhibitors

Because Smad3 is a key mediator of TGF-β signaling related to AKI and fibrosis[16] and SARS-CoV-1/2 N protein can bind to Smad3 and promote Smad3 signaling,[52],[62] the development of specific Smad3 inhibitors could be a novel therapeutic strategy for COVID-19-associated AKI and organ fibrosis. This hypothesis was tested in a recent study on SARS-CoV-2 N protein-induced AKI in mice, in which treatment with the Smad3 inhibitor SIS3 was shown to inhibit AKI induced by kidney-specific overexpression of SARS- CoV-2 protein.[62]


  Conclusions Top


The mechanisms underlying COVID-19-associated acute and chronic lung, cardiovascular, and renal injuries remain largely unclear and consequently there are no specific and effective treatment strategies for COVID-19 patients. Based on long-term follow-up studies, post-COVID-19 symptoms remain of concern. Therefore, further studies on COVID-19 survivors with post-COVID-19 symptoms are urgently needed. Because the TGF-β signaling pathway is one of the key pathways involved in the acute and chronic phases of COVID-19, understanding the role and molecular mechanisms of TGF-β signaling in COVID-19 may be the first step toward the development of targeted therapies for patients with COVID-19.

Financial support and sponsorship

This work was supported by the Research Grants Council of Hong Kong (14117418, 14104019, and 14101121), Lui Che Woo Institute of Innovative Medicine (CARE Program), Hong Kong Scholar Program (XJ2019052), National Natural Science Foundation of China (82070709 and 82100723), and Guangdong-Hong Kong-Macao-Joint Labs Program from Guangdong Science and Technology (2019B121205005).

Conflicts of interest

Hui-Yao Lan is a Co-Editor-in-Chief of the journal. The article was subject to the journal’s standard procedures, and peer review was handled independently of this editor and his research groups.



 
  References Top

1.
Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020;395:1054-62.  Back to cited text no. 1
    
2.
Li G, Fan Y, Lai Y, Han T, Li Z, Zhou P, et al. Coronavirus infections and immune responses. J Med Virol 2020;92:424-32.  Back to cited text no. 2
    
3.
Johns Hopkins Coronavirus Resource Center. Available at: https:// coronavirus.jhu.edu. [Last accessed on 2022 Feb 06].  Back to cited text no. 3
    
4.
Gupta A, Madhavan MV, Sehgal K, Nair N, Mahajan S, Sehrawat TS, et al. Extrapulmonary manifestations of COVID-19. Nat Med 2020;26:1017-32.  Back to cited text no. 4
    
5.
Wu Z, McGoogan JM. Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72314 Cases From the Chinese Center for Disease Control and Prevention. JAMA 2020;323:1239- 42.  Back to cited text no. 5
    
6.
Gagliardi I, Patella G, Michael A, Serra R, Provenzano M, Andreucci M. COVID-19 and the Kidney: From Epidemiology to Clinical Practice. J Clin Med 2020;9.  Back to cited text no. 6
    
7.
Moldofsky H, Patcai J. Chronic widespread musculoskeletal pain, fatigue, depression and disordered sleep in chronic post-SARS syndrome; a case-controlled study. BMC Neurol 2011;11:37.  Back to cited text no. 7
    
8.
Zhang P, Li J, Liu H, Han N, Ju J, Kou Y, et al. Correction: Long-term bone and lung consequences associated with hospital-acquired severe acute respiratory syndrome: a 15-year follow-up from a prospective cohort study. Bone Res 2020;8:34.  Back to cited text no. 8
    
9.
Das KM, Lee EY, Singh R, Enani MA, Al Dossari K, Van Gorkom K, et al. Follow-up chest radiographic findings in patients with MERS- CoV after recovery. Indian J Radiol Imaging 2017;27:342-49.  Back to cited text no. 9
[PUBMED]  [Full text]  
10.
Colarusso C, Maglio A, Terlizzi M, Vitale C, Molino A, Pinto A, et al. Post-COVID-19 Patients Who Develop Lung Fibrotic-like Changes Have Lower Circulating Levels of IFN-beta but Higher Levels of IL-1alpha and TGF-beta. Biomedicines 2021;9:1931.  Back to cited text no. 10
    
11.
Oronsky B, Larson C, Hammond TC, Oronsky A, Kesari S, Lybeck M, et al. A Review of Persistent Post-COVID Syndrome (PPCS). Clin Rev Allergy Immunol 2021;1-9.  Back to cited text no. 11
    
12.
Silva Andrade B, Siqueira S, de Assis Soares WR, de Souza Rangel F, Santos NO, Dos Santos Freitas A, et al. Long-COVID and Post-COVID Health Complications: An Up-to-Date Review on Clinical Conditions and Their Possible Molecular Mechanisms. Viruses 2021;13:700.  Back to cited text no. 12
    
13.
Leung TYM, Chan AYL, Chan EW, Chan VY, Chui CSL, Cowling BJ, et al. Short-and potential long-term adverse health outcomes of COVID-19: a rapid review. Emerg Microbes Infect 2020;9:2190-99.  Back to cited text no. 13
    
14.
Petersen EL, Gossling A, Adam G, Aepfelbacher M, Behrendt CA, Cavus E, et al. Multi-organ assessment in mainly non-hospitalized individuals after SARS-CoV-2 infection: The Hamburg City Health Study COVID programme. Eur Heart J 2022;43:1124-37.  Back to cited text no. 14
    
15.
Huang C, Huang L, Wang Y, Li X, Ren L, Gu X, et al. 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study. Lancet 2021;397:220-32.  Back to cited text no. 15
    
16.
Meng XM, Nikolic-Paterson DJ, Lan HY. TGF-beta: the master regulator of fibrosis. Nat Rev Nephrol 2016;12:325-38.  Back to cited text no. 16
    
17.
Robertson IB, Horiguchi M, Zilberberg L, Dabovic B, Hadjiolova K, Rifkin DB. Latent TGF-beta-binding proteins. Matrix Biol 2015;47:44-53.  Back to cited text no. 17
    
18.
Annes JP, Munger JS, Rifkin DB. Making sense of latent TGFbeta activation. J Cell Sci 2003;116:217-24.  Back to cited text no. 18
    
19.
Zhang YE. Non-Smad pathways in TGF-beta signaling. Cell Res 2009;19:128-39.  Back to cited text no. 19
    
20.
Mirzaei H, Faghihloo E. Viruses as key modulators of the TGF-beta pathway; a double-edged sword involved in cancer. Rev Med Virol 2018;28:e1967.  Back to cited text no. 20
    
21.
Lee CH, Chen RF, Liu JW, Yeh WT, Chang JC, Liu PM, et al. Altered p38 mitogen-activated protein kinase expression in different leukocytes with increment of immunosuppressive mediators in patients with severe acute respiratory syndrome. J Immunol 2004;172:7841-7.  Back to cited text no. 21
    
22.
Min CK, Cheon S, Ha NY, Sohn KM, Kim Y, Aigerim A, et al. Comparative and kinetic analysis of viral shedding and immunological responses in MERS patients representing a broad spectrum of disease severity. Sci Rep 2016;6:25359.  Back to cited text no. 22
    
23.
Ghazavi A, Ganji A, Keshavarzian N, Rabiemajd S, Mosayebi G. Cytokine profile and disease severity in patients with COVID-19. Cytokine 2021;137:155323.  Back to cited text no. 23
    
24.
Mustroph J, Hupf J, Baier MJ, Evert K, Brochhausen C, Broeker K, et al. Cardiac Fibrosis Is a Risk Factor for Severe COVID-19. Front Immunol 2021;12:740260.  Back to cited text no. 24
    
25.
Agrati C, Sacchi A, Bordoni V, Cimini E, Notari S, Grassi G, et al. Expansion of myeloid-derived suppressor cells in patients with severe coronavirus disease (COVID-19). Cell Death Differ 2020;27:3196-207.  Back to cited text no. 25
    
26.
Li SW, Yang TC, Wan L, Lin YJ, Tsai FJ, Lai CC, et al. Correlation between TGF-beta1 expression and proteomic profiling induced by severe acute respiratory syndrome coronavirus papain-like protease. Proteomics 2012;12:3193-205.  Back to cited text no. 26
    
27.
Yousefi H, Poursheikhani A, Bahmanpour Z, Vatanmakanian M, Taheri M, Mashouri L, et al. SARS-CoV infection crosstalk with human host cell noncoding-RNA machinery: An in-silico approach. Biomed Pharmacother 2020;130:110548.  Back to cited text no. 27
    
28.
Aydemir MN, Aydemir HB, Korkmaz EM, Budak M, Cekin N, Pinarbasi E. Computationally predicted SARS-COV-2 encoded microRNAs target NFKB, JAK/STAT and TGFB signaling pathways. Gene Rep 2021;22:101012.  Back to cited text no. 28
    
29.
Jain R, Ramaswamy S, Harilal D, Uddin M, Loney T, Nowotny N, et al. Host transcriptomic profiling of COVID-19 patients with mild, moderate, and severe clinical outcomes. Comput Struct Biotechnol J 2021;19:153-60.  Back to cited text no. 29
    
30.
Wendisch D, Dietrich O, Mari T, von Stillfried S, Ibarra IL, Mittermaier M, et al. SARS-CoV-2 infection triggers profibrotic macrophage responses and lung fibrosis. Cell 2021;184:6243-61.  Back to cited text no. 30
    
31.
Barnes CO, Jette CA, Abernathy ME, Dam KA, Esswein SR, Gristick HB, et al. SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies. Nature 2020;588:682-87.  Back to cited text no. 31
    
32.
Magro C, Mulvey JJ, Berlin D, Nuovo G, Salvatore S, Harp J, et al. Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases. Transl Res 2020;220:1-13.  Back to cited text no. 32
    
33.
Zhang H, Zhou P, Wei Y, Yue H, Wang Y, Hu M, et al. Histopathologic Changes and SARS-CoV-2 Immunostaining in the Lung of a Patient With COVID-19. Ann Intern Med 2020;172:629-32.  Back to cited text no. 33
    
34.
Bradley BT, Maioli H, Johnston R, Chaudhry I, Fink S L, Xu H, et al. Histopathology and ultrastructural fndings of fatal COVID-19 infections in Washington State: a case series. Lancet 2020; 396:320-32.  Back to cited text no. 34
    
35.
Tian S, Xiong Y, Liu H, Niu L, Guo J, Liao M, et al. Pathological study of the 2019 novel coronavirus disease (COVID-19) through postmortem core biopsies. Mod Pathol 2020;33:1007-14.  Back to cited text no. 35
    
36.
Osuchowski MF, Winkler MS, Skirecki T, Cajander S, Shankar- Hari M, Lachmann G, et al. The COVID-19 puzzle: deciphering pathophysiology and phenotypes of a new disease entity. Lancet Respir Med 2021;9:622-42.  Back to cited text no. 36
    
37.
Polak SB, Van Gool IC, Cohen D, von der Thusen JH, van Paassen J. A systematic review of pathological findings in COVID-19: a pathophysiological timeline and possible mechanisms of disease progression. Mod Pathol 2020;33:2128-38.  Back to cited text no. 37
    
38.
Yu M, Liu Y, Xu D, Zhang R, Lan L, Xu H. Prediction of the Development of Pulmonary Fibrosis Using Serial Thin-Section CT and Clinical Features in Patients Discharged after Treatment for COVID-19 Pneumonia. Korean J Radiol 2020;21:746-55.  Back to cited text no. 38
    
39.
Hui DS, Joynt GM, Wong KT, Gomersall CD, Li TS, Antonio G, et al. Impact of severe acute respiratory syndrome (SARS) on pulmonary function, functional capacity and quality of life in a cohort of survivors. Thorax 2005;60:401-9.  Back to cited text no. 39
    
40.
Chu WC, Li M, Ng AW, So HK, Lam WW, Lo KL, et al. Thin- Section CT 12 Months After the Diagnosis of Severe Acute Respiratory Syndrome in Pediatric Patients. AJR Am J Roentgenol 2006;186:1707-14.  Back to cited text no. 40
    
41.
Torres-Castro R, Vasconcello-Castillo L, Alsina-Restoy X, Solis- Navarro L, Burgos F, Puppo H, et al. Respiratory function in patients post-infection by COVID-19: a systematic review and meta-analysis. Pulmonology 2021;27:328-37.  Back to cited text no. 41
    
42.
Writing Committee for the COMEBAC Study Group, Morin L, Savale L, Pham T, Colle R, Figueiredo S, et al. Four-Month Clinical Status of a Cohort of Patients After Hospitalization for COVID-19. JAMA 2021;325:1525-34.  Back to cited text no. 42
    
43.
Han X, Fan Y, Alwalid O, Li N, Jia X, Yuan M, et al. Six-month Follow-up Chest CT Findings after Severe COVID-19 Pneumonia. Radiology 2021;299:177-86.  Back to cited text no. 43
    
44.
Mandal S, Barnett J, Brill SE, Brown JS, Denneny EK, Hare SS, et al. ‘Long-COVID’: a cross-sectional study of persisting symptoms, biomarker and imaging abnormalities following hospitalisation for COVID-19. Thorax 2021;76:396-98.  Back to cited text no. 44
    
45.
Dhainaut JF, Charpentier J, Chiche JD. Transforming growth factor- beta: a mediator of cell regulation in acute respiratory distress syndrome. Crit Care Med 2003;31:258-64.  Back to cited text no. 45
    
46.
Xu YD, Hua J, Mui A, O’Connor R, Grotendorst G, Khalil N. Release of biologically active TGF-beta1 by alveolar epithelial cells results in pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 2003;285:527-39.  Back to cited text no. 46
    
47.
Guo W, Shan B, Klingsberg RC, Qin X, Lasky JA. Abrogation of TGF-beta1-induced fibroblast-myofibroblast differentiation by histone deacetylase inhibition. Am J Physiol Lung Cell Mol Physiol 2009;297:864-70.  Back to cited text no. 47
    
48.
Malmstrom J, Lindberg H, Lindberg C, Bratt C, Wieslander E, Delander EL, et al. Transforming growth factor-beta 1 specifically induce proteins involved in the myofibroblast contractile apparatus. Mol Cell Proteomics 2004;3:466-77.  Back to cited text no. 48
    
49.
John AE, Joseph C, Jenkins G, Tatler AL. COVID-19 and pulmonary fibrosis: A potential role for lung epithelial cells and fibroblasts. Immunol Rev 2021;302:228-40.  Back to cited text no. 49
    
50.
Li SW, Wang CY, Jou YJ, Yang TC, Huang SH, Wan L, et al. SARS coronavirus papain-like protease induces Egr-1-dependent up- regulation of TGF-beta1 via ROS/p38 MAPK/STAT3 pathway. Sci Rep 2016;6:25754.  Back to cited text no. 50
    
51.
Wang CY, Lu CY, Li SW, Lai CC, Hua CH, Huang SH, et al. SARS coronavirus papain-like protease up-regulates the collagen expression through non-Samd TGF-beta1 signaling. Virus Res 2017;235:58-66.  Back to cited text no. 51
    
52.
Zhao X, Nicholls JM, Chen YG. Severe acute respiratory syndrome- associated coronavirus nucleocapsid protein interacts with Smad3 and modulates transforming growth factor-beta signaling. J Biol Chem 2008;283:3272-80.  Back to cited text no. 52
    
53.
Xiong Y, Liu Y, Cao L, Wang D, Guo M, Jiang A, et al. Transcriptomic characteristics of bronchoalveolar lavage fluid and peripheral blood mononuclear cells in COVID-19 patients. Emerg Microbes Infect 2020;9:761-70.  Back to cited text no. 53
    
54.
Xu J, Xu X, Jiang L, Dua K, Hansbro PM, Liu G. SARS-CoV-2 induces transcriptional signatures in human lung epithelial cells that promote lung fibrosis. Respir Res 2020;21:182.  Back to cited text no. 54
    
55.
Vaz de Paula CB, Nagashima S, Liberalesso V, Collete M, da Silva FPG, Oricil A GG, et al. COVID-19: Immunohistochemical Analysis of TGF-beta Signaling Pathways in Pulmonary Fibrosis. Int J Mol Sci 2021;23:168.  Back to cited text no. 55
    
56.
Scialo F, Daniele A, Amato F, Pastore L, Matera MG, Cazzola M, et al. ACE2: The Major Cell Entry Receptor for SARS-CoV-2. Lung 2020;198:867-77.  Back to cited text no. 56
    
57.
Santos RAS, Sampaio WO, Alzamora AC, Motta-Santos D, Alenina N, Bader M, et al. The ACE2/Angiotensin-(1-7)/MAS Axis of the Renin-Angiotensin System: Focus on Angiotensin-(1-7). Physiol Rev 2018;98:505-53.  Back to cited text no. 57
    
58.
Liu GX, Li YQ, Huang XR, Wei L, Chen HY, Shi YJ, et al. Disruption of Smad7 promotes ANG II-mediated renal inflammation and fibrosis via Sp1-TGF-beta/Smad3-NFkappaB-dependent mechanisms in mice. PLoS One 2013;8:e53573.  Back to cited text no. 58
    
59.
Chen W. A potential treatment of COVID-19 with TGF-beta blockade. Int J Biol Sci 2020;16:1954-55.  Back to cited text no. 59
    
60.
Vaz de Paula CB, de Azevedo MLV, Nagashima S, Martins APC, Malaquias MAS, Miggiolaro A, et al. IL-4/IL-13 remodeling pathway of COVID-19 lung injury. Sci Rep 2020;10:18689.  Back to cited text no. 60
    
61.
Ribeiro Dos Santos Miggiolaro AF, da Silva Motta Junior J, Busatta Vaz de Paula C, Nagashima S, Alessandra Scaranello Malaquias M, Baena Carstens L, et al. Covid-19 cytokine storm in pulmonary tissue: Anatomopathological and immunohistochemical findings. Respir Med Case Rep 2020;31:101292.  Back to cited text no. 61
    
62.
Wang W, Chen J, Hu D, Pan P, Liang L, Wu W, et al. SARS-CoV-2 N Protein Induces Acute Kidney Injury via Smad3-Dependent G1 Cell Cycle Arrest Mechanism. Adv Sci (Weinh) 2021;e2103248.  Back to cited text no. 62
    
63.
Qin W, Cao L, Massey IY. Role of PI3K/Akt signaling pathway in cardiac fibrosis. Mol Cell Biochem 2021;476:4045-59.  Back to cited text no. 63
    
64.
Richter K, Konzack A, Pihlajaniemi T, Heljasvaara R, Kietzmann T. Redox-fibrosis: Impact of TGFbeta1 on ROS generators, mediators and functional consequences. Redox Biol 2015;6:344-52.  Back to cited text no. 64
    
65.
Oudit GY, Kassiri Z, Jiang C, Liu PP, Poutanen SM, Penninger JM, et al. SARS-coronavirus modulation of myocardial ACE2 expression and inflammation in patients with SARS. Eur J Clin Invest 2009;39:618-25.  Back to cited text no. 65
    
66.
Tavazzi G, Pellegrini C, Maurelli M, Belliato M, Sciutti F, Bottazzi A, et al. Myocardial localization of coronavirus in COVID-19 cardiogenic shock. Eur J Heart Fail 2020;22:911-15.  Back to cited text no. 66
    
67.
Guzik TJ, Mohiddin SA, Dimarco A, Patel V, Savvatis K, Marelli-Berg FM, et al. COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options. Cardiovasc Res 2020;116:1666-87.  Back to cited text no. 67
    
68.
Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA 2020; 323:1061-69.  Back to cited text no. 68
    
69.
Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med 2020;382:1708-20.  Back to cited text no. 69
    
70.
Chen C, Chen C, Yan JT, Zhou N, Zhao JP, Wang DW. Analysis of myocardial injury in patients with COVID-19 and association between concomitant cardiovascular diseases and severity of COVID-19. Zhonghua Xin Xue Guan Bing Za Zhi 2020;48:567-71.  Back to cited text no. 70
    
71.
Zheng YY, Ma YT, Zhang JY, Xie X. COVID-19 and the cardiovascular system. Nat Rev Cardiol 2020;17:259-60.  Back to cited text no. 71
    
72.
Lippi G, Lavie CJ, Sanchis-Gomar F. Cardiac troponin I in patients with coronavirus disease 2019 (COVID-19): Evidence from a meta-analysis. Prog Cardiovasc Dis 2020;63:390-91.  Back to cited text no. 72
    
73.
Zeng JH, Wu WB, Qu JX, Wang Y, Dong CF, Luo YF, et al. Cardiac manifestations of COVID-19 in Shenzhen, China. Infection 2020;48:861-70.  Back to cited text no. 73
    
74.
Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med 2020;46:846-48.  Back to cited text no. 74
    
75.
Puntmann VO, Carerj M L, Wieters I, Fahim M, Arendt C, Hoffmann J, et al. Outcomes of Cardiovascular Magnetic Resonance Imaging in Patients Recently Recovered From Coronavirus Disease 2019 (COVID-19). JAMA Cardiol 2020;5:1265-73.  Back to cited text no. 75
    
76.
Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med 2020;8:420-22.  Back to cited text no. 76
    
77.
Yu CM, Wong RS, Wu EB, Kong SL, Wong J, Yip GW, et al. Cardiovascular complications of severe acute respiratory syndrome. Postgrad Med J 2006;82:140-4.  Back to cited text no. 77
    
78.
Wu Q, Zhou L, Sun X, Yan Z, Hu C, Wu J, et al. Altered Lipid Metabolism in Recovered SARS Patients Twelve Years after Infection. Sci Rep 2017;7:9110.  Back to cited text no. 78
    
79.
Sonnweber T, Sahanic S, Pizzini A, Luger A, Schwabl C, Sonnweber B, et al. Cardiopulmonary recovery after COVID-19: an observational prospective multicentre trial. Eur Respir J 2021;57.  Back to cited text no. 79
    
80.
Huang L, Zhao P, Tang D, Zhu T, Han R, Zhan C, et al. Cardiac Involvement in Patients Recovered From COVID-2019 Identified Using Magnetic Resonance Imaging. JACC Cardiovasc Imaging 2020;13:2330-39.  Back to cited text no. 80
    
81.
Hartmann C, Miggiolaro A, Motta JDS, Baena Carstens L, Busatta Vaz De Paula C, Fagundes Grobe S, et al. The Pathogenesis of COVID-19 Myocardial Injury: An Immunohistochemical Study of Postmortem Biopsies. Front Immunol 2021;12:748417.  Back to cited text no. 81
    
82.
He Q, Mok TN, Yun L, He C, Li J, Pan J. Single-cell RNA sequencing analysis of human kidney reveals the presence of ACE2 receptor: A potential pathway of COVID-19 infection. Mol Genet Genomic Med 2020;8:1442.  Back to cited text no. 82
    
83.
Diao B, Wang C, Wang R, Feng Z, Zhang J, Yang H, et al. Human kidney is a target for novel severe acute respiratory syndrome coronavirus 2 infection. Nat Commun 2021;12:2506.  Back to cited text no. 83
    
84.
Schurink B, Roos E, Radonic T, Barbe E, Bouman CSC, de Boer HH, et al. Viral presence and immunopathology in patients with lethal COVID-19: a prospective autopsy cohort study. Lancet Microbe 2020;1:290-99.  Back to cited text no. 84
    
85.
Su H, Yang M, Wan C, Yi L X, Tang F, Zhu HY, et al. Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China. Kidney Int 2020;98:219-27.  Back to cited text no. 85
    
86.
Cheng Y, Luo R, Wang K, Zhang M, Wang Z, Dong L, et al. Kidney disease is associated with in-hospital death of patients with COVID-19. Kidney Int 2020;97:829-38.  Back to cited text no. 86
    
87.
Yang X, Jin Y, Li R, Zhang Z, Sun R, Chen D. Prevalence and impact of acute renal impairment on COVID-19: a systematic review and meta-analysis. Crit Care 2020;24:356.  Back to cited text no. 87
    
88.
Xu Z, Tang Y, Huang Q, Fu S, Li X, Lin B, et al. Systematic review and subgroup analysis of the incidence of acute kidney injury (AKI) in patients with COVID-19. BMC Nephrol 2021;22:52.  Back to cited text no. 88
    
89.
Li Z,Wu M, Yao J, Guo J, Liao X, Song S, et al. Caution on Kidney Dysfunctions of COVID-19 Patients. 2020. Available at: https:// www.medrxiv.org/content/10.1101/2020.02.08.20021212v2. [Last accessed on 2020 May 27].  Back to cited text no. 89
    
90.
Xu Y, Ma H, Shao J, Wu J, Zhou L, Zhang Z, et al. A Role for Tubular Necroptosis in Cisplatin-Induced AKI. J Am Soc Nephrol 2015;26:2647-58.  Back to cited text no. 90
    
91.
Yang Q, Ren GL, Wei B, Jin J, Huang XR, Shao W, et al. Conditional knockout of TGF-betaRII /Smad2 signals protects against acute renal injury by alleviating cell necroptosis, apoptosis and inflammation. Theranostics 2019;9:8277-93.  Back to cited text no. 91
    
92.
Zhang Y, Alexander PB, Wang X. TGF-beta Family Signaling in the Control of Cell Proliferation and Survival. Cold Spring Harb Perspect Biol 2017;9:a022145.  Back to cited text no. 92
    
93.
Larisch S, Yi Y, Lotan R, Kerner H, Eimerl S, Tony Parks W, et al. A novel mitochondrial septin-like protein, ARTS, mediates apoptosis dependent on its P-loop motif. Nat Cell Biol 2000;2:915-21.  Back to cited text no. 93
    
94.
Chu KH, Tsang WK, Tang CS, Lam MF, Lai FM, To KF, et al. Acute renal impairment in coronavirus-associated severe acute respiratory syndrome. Kidney Int 2005;67:698-705.  Back to cited text no. 94
    
95.
Zhou S, Xu J, Xue C, Yang B, Mao Z, Ong ACM. Coronavirus- associated kidney outcomes in COVID-19, SARS, and MERS: a meta-analysis and systematic review. Ren Fail 2020;43:1-15.  Back to cited text no. 95
    
96.
Bowe B, Xie Y, Xu E, Al-Aly Z. Kidney Outcomes in Long COVID. J Am Soc Nephrol 2021;32:2851-62.  Back to cited text no. 96
    
97.
Lumlertgul N, Pirondini L, Cooney E, Kok W, Gregson J, Camporota L, et al. Acute kidney injury prevalence, progression and long-term outcomes in critically ill patients with COVID-19: a cohort study. Ann Intensive Care 2021;11:123.  Back to cited text no. 97
    
98.
Stockmann H, Hardenberg JB, Aigner A, Hinze C, Gotthardt I, Stier B, et al. High rates of long-term renal recovery in survivors of coronavirus disease 2019-associated acute kidney injury requiring kidney replacement therapy. Kidney Int 2021;99:1021-22.  Back to cited text no. 98
    
99.
Jansen J, Reimer KC, Nagai JS, Varghese FS, Overheul GJ, de Beer M, et al. SARS-CoV-2 infects the human kidney and drives fibrosis in kidney organoids. Cell Stem Cell 2022;29:217-31.  Back to cited text no. 99
    
100.
Sheahan TP, Sims AC, Leist SR, Schafer A, Won J, Brown AJ, et al. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat Commun 2020;11:222.  Back to cited text no. 100
    
101.
Mulangu S, Dodd LE, Davey RT, Jr, Tshiani Mbaya O, Proschan M, Mukadi D, et al. A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics. N Engl J Med 2019;381:2293-303.  Back to cited text no. 101
    
102.
Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 2020;30:269-71.  Back to cited text no. 102
    
103.
Sheahan TP, Sims AC, Zhou S, Graham RL, Pruijssers AJ, Agostini ML, et al. An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice. Sci Transl Med 2020;12:eabb5883.  Back to cited text no. 103
    
104.
Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, et al. Remdesivir for the Treatment of Covid-19-Final Report. N Engl J Med 2020;383:1813-26.  Back to cited text no. 104
    
105.
Grein J, Ohmagari N, Shin D, Diaz G, Asperges E, Castagna A, et al. Compassionate Use of Remdesivir for Patients with Severe Covid-19. N Engl J Med 2020;382:2327-36.  Back to cited text no. 105
    
106.
Ahmad B, Batool M, Ain QU, Kim MS, Choi S. Exploring the Binding Mechanism of PF-07321332 SARS-CoV-2 Protease Inhibitor through Molecular Dynamics and Binding Free Energy Simulations. Int J Mol Sci 2021;22:9124.  Back to cited text no. 106
    
107.
Jin Z, Du X, Xu Y, Deng Y, Liu M, Zhao Y, et al. Structure of M(pro) from SARS-CoV-2 and discovery of its inhibitors. Nature 2020;582: 89-93.  Back to cited text no. 107
    
108.
Hung YP, Lee JC, Chiu CW, Lee CC, Tsai PJ, Hsu IL, et al. Oral Nirmatrelvir/Ritonavir Therapy for COVID-19: The Dawn in the Dark? Antibiotics (Basel) 2022;11:220.  Back to cited text no. 108
    
109.
Owen DR, Allerton CMN, Anderson AS, Aschenbrenner L, Avery M, Berritt S, et al. An oral SARS-CoV-2 M(pro) inhibitor clinical candidate for the treatment of COVID-19. Science 2021;374: 1586-93.  Back to cited text no. 109
    
110.
Drożdżal S, Rosik J, Lechowicz K, Machaj F, Szostak B, Przybyciński J, et al. An update on drugs with therapeutic potential for SARS- CoV-2 (COVID-19) treatment. Drug Resist Updat 2021;59:100794.  Back to cited text no. 110
    
111.
Shi MY, Sun SQ, Zhang W, Zhang X, Xu GH, Chen X, et al. Early therapeutic interventions of traditional Chinese medicine in COVID-19 patients: A retrospective cohort study. J Integr Med 2021;19:226-31.  Back to cited text no. 111
    
112.
Liu M, Gao Y, Yuan Y, Yang K, Shi S, Tian J, et al. Efficacy and safety of herbal medicine (Lianhuaqingwen) for treating COVID-19: A systematic review and meta-analysis. Integr Med Res 2021;10:100644.  Back to cited text no. 112
    
113.
Shu Z, Zhou Y, Chang K, Liu J, Min X, Zhang Q, et al. Clinical features and the traditional Chinese medicine therapeutic characteristics of 293 COVID-19 inpatient cases. Front Med 2020;14:760-75.  Back to cited text no. 113
    
114.
Jia W, Wang C, Wang Y, Pan G, Jiang M, Li Z, et al. Qualitative and quantitative analysis of the major constituents in Chinese medical preparation Lianhua-Qingwen capsule by UPLC-DAD-QTOF-MS. ScientificWorldJournal 2015;2015:731765.  Back to cited text no. 114
    
115.
Li R, Hou Y, Huang J, Pan W, Ma Q, Shi Y, et al. Lianhuaqingwen exerts anti-viral and anti-inflammatory activity against novel coronavirus (SARS-CoV-2). Pharmacol Res 2020;156:104761.  Back to cited text no. 115
    
116.
Chu L, Huang F, Zhang M, Huang B, Wang Y. Current status of traditional Chinese medicine for the treatment of COVID-19 in China. Chin Med 2021;16:63.  Back to cited text no. 116
    
117.
Ren X, Shao XX, Li XX, Jia XH, Song T, Zhou WY, et al. Identifying potential treatments of COVID-19 from Traditional Chinese Medicine (TCM) by using a data-driven approach. J Ethnopharmacol 2020;258:112932.  Back to cited text no. 117
    
118.
Pan HD, Yao XJ, Wang WY, Lau HY, Liu L. Network pharmacological approach for elucidating the mechanisms of traditional Chinese medicine in treating COVID-19 patients. Pharmacol Res 2020;159:105043.  Back to cited text no. 118
    
119.
Glinsky GV. Tripartite Combination of Candidate Pandemic Mitigation Agents: Vitamin D, Quercetin, and Estradiol Manifest Properties of Medicinal Agents for Targeted Mitigation of the COVID-19 Pandemic Defined by Genomics-Guided Tracing of SARS-CoV-2 Targets in Human Cells. Biomedicines 2020;8:129.  Back to cited text no. 119
    
120.
Derosa G, Maffioli P, D’Angelo A, Di Pierro F. A role for quercetin in coronavirus disease 2019 (COVID-19). Phytother Res 2021;35:1230-36.  Back to cited text no. 120
    
121.
Gu YY, Zhang M, Cen H, Wu YF, Lu Z, Lu F, et al. Quercetin as a potential treatment for COVID-19-induced acute kidney injury: Based on network pharmacology and molecular docking study. PLoS One 2021;16:e0245209.  Back to cited text no. 121
    
122.
D’Cruz OJ, Qazi S, Hwang L, Ng K, Trieu V. Impact of targeting transforming growth factor beta-2 with antisense OT-101 on the cytokine and chemokine profile in patients with advanced pancreatic cancer. Onco Targets Ther 2018;11:2779-96.  Back to cited text no. 122
    
123.
Schlingensiepen KH, Jaschinski F, Lang SA, Moser C, Geissler EK, Schlitt HJ, et al. Transforming growth factor-beta 2 gene silencing with trabedersen (AP 12009) in pancreatic cancer. Cancer Sci 2011;102:1193-200.  Back to cited text no. 123
    
124.
Schlingensiepen KH, Schlingensiepen R, Steinbrecher A, Hau P, Bogdahn U, Fischer-Blass B, et al. Targeted tumor therapy with the TGF-beta 2 antisense compound AP 12009. Cytokine Growth Factor Rev 2006;17:129-39.  Back to cited text no. 124
    
125.
Uckun FM, Hwang L, Trieu V. Selectively targeting TGF-β with Trabedersen/OT-101 in treatment of evolving and mild ARDS in COVID-19. Clinical Investigation 2020;10:35-44.  Back to cited text no. 125
    
126.
Hamidi SH, Kadamboor Veethil S, Hamidi SH. Role of pirfenidone in TGF-beta pathways and other inflammatory pathways in acute respiratory syndrome coronavirus 2 (SARS-Cov-2) infection: a theoretical perspective. Pharmacol Rep 2021;73:712-27.  Back to cited text no. 126
    
127.
Stahnke T, Kowtharapu BS, Stachs O, Schmitz KP, Wurm J, Wree A, et al. Suppression of TGF-beta pathway by pirfenidone decreases extracellular matrix deposition in ocular fibroblasts in vitro. PLoS One 2017;12:e0172592.  Back to cited text no. 127
    
128.
Nakayama S, Mukae H, Sakamoto N, Kakugawa T, Yoshioka S, Soda H, et al. Pirfenidone inhibits the expression of HSP47 in TGF- beta1-stimulated human lung fibroblasts. Life Sci 2008;82:210-7.  Back to cited text no. 128
    
129.
Iyer SN, Wild JS, Schiedt MJ, Hyde DM, Margolin SB, Giri SN. Dietary intake of pirfenidone ameliorates bleomycin-induced lung fibrosis in hamsters. J Lab Clin Med 1995;125:779-85.  Back to cited text no. 129
    
130.
King TE Jr, Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, Glassberg MK, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med 2014;370:2083-92.  Back to cited text no. 130
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
   Abstract
    Introduction
Post-COVID-19 Sy...
TGF-β Signa...
Potential Treatm...
    Conclusions
   References
   Article Figures

 Article Access Statistics
    Viewed157    
    Printed16    
    Emailed0    
    PDF Downloaded14    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]