Interferon Pathways and Coronavirus Drug Targets

Interferon Pathways and Coronavirus Drug Targets

(From Potential Antiviral Agents for Coronaviruses: Compounds, Herbal Products, and Drug Targets)

  • Some plus-strand RNA viruses encode proteins with macrodomains (Kuri et al., 2011).
  • These domains have ADP-ribose-1″-phosphatase (ADRP) activity and/or bind poly (ADP-ribose), poly(A) or poly(G).
  • Macrodomain-related ADRP activities may be involved in viral escape from the innate immune responses.
  • Mutants of SARS-CoV and human coronavirus 229E (HCoV-229E) have been developed.
  • These mutants with ADRP-deficient macrodomains had higher sensitivity to the antiviral activities of interferon-α (Kuri et al., 2011).
  • In addition, the SARS-CoV could block interferon (IFN)-dependent signaling pathways.
  • The pathways are the primary steps of antiviral responses (Wathelet et al., 2007).
  • The SARS-CoV nonstructural protein 1 (nsp1) may be a virulence and pathogenic factor that supports viral replication.
  • Expression of nsp1 may block IFN-dependent signaling (Wathelet et al., 2007).
  • The viral protein nsp1 may be a potential antiviral drug target.

References:

Kuri, T., Eriksson, K. K., Putics, A., Züst, R., Snijder, E. J., Davidson, A. D., Siddell, S. G., Thiel, V., Ziebuhr, J., & Weber, F. (2011). The ADP-ribose-1’’-monophosphatase domains of severe acute respiratory syndrome coronavirus and human coronavirus 229E mediate resistance to antiviral interferon responses. The Journal of General Virology, 92(Pt 8), 1899–1905.

Wathelet, M. G., Orr, M., Frieman, M. B., & Baric, R. S. (2007). Severe acute respiratory syndrome coronavirus evades antiviral signaling: Role of nsp1 and rational design of an attenuated strain. Journal of Virology, 81(21), 11620–11633.

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The Spike Protein, ACE2, and Coronaviruses

The Spike Protein, ACE2, and Coronaviruses

(From Potential Antiviral Agents for Coronaviruses: Compounds, Herbal Products, and Drug Targets)

  • It is important to understand the SARS-CoV genome, evolution and lifecycle.
  • The spike (S) protein of the SARS-CoV is essential in viral entry into host cells (Simmons et al., 2013).
  • Host cell proteases cleave and activate the spike (S) protein of the SARS-CoV.
  • Cathepsins and type II transmembrane serine proteases are crucial cellular activators of SARS-CoV for viral infectivity.
  • Emerging coronaviruses may use these enzymes to enhance their spread (Simmons et al., 2013).
  • This is done through interacting with cellular receptors for membrane fusion (Keng et al., 2005).
  • This mechanism can be the major target of neutralizing antibodies and important for the development of vaccines.
  • Antibodies may recognize the mature form of the S protein on the cell surface (Keng et al., 2005).
  • The anti-SDelta10 antibody targeting the S amino acid residues with heptad repeat 2 may have neutralizing effects.
  • The S region with neutralizing epitopes is critical for the virus entry into cells, and may be drug/vaccine targets (Keng et al., 2005).
  • In addition, the angiotensin-converting enzyme 2 (ACE2) is a receptor for the SARS-CoV entry process (Kuhn et al., 2007).
  • In summary, two potential drug targets are the SARS-CoV spike protein and ACE2.
  • Potential drugs can be developed against these targets to block SARS-CoV replication and cellular entry (Kuhn et al., 2007).

References:

Keng, C.-T., Zhang, A., Shen, S., Lip, K.-M., Fielding, B. C., Tan, T. H. P., Chou, C.-F., Loh, C. B., Wang, S., Fu, J., Yang, X., Lim, S. G., Hong, W., & Tan, Y.-J. (2005). Amino acids 1055 to 1192 in the S2 region of severe acute respiratory syndrome coronavirus S protein induce neutralizing antibodies: Implications for the development of vaccines and antiviral agents. Journal of Virology, 79(6), 3289–3296.

Kuhn, J. H., Li, W., Radoshitzky, S. R., Choe, H., & Farzan, M. (2007). Severe acute respiratory syndrome coronavirus entry as a target of antiviral therapies. Antiviral Therapy, 12(4 Pt B), 639–650.

Simmons, G., Zmora, P., Gierer, S., Heurich, A., & Pöhlmann, S. (2013). Proteolytic activation of the SARS-coronavirus spike protein: Cutting enzymes at the cutting edge of antiviral research. Antiviral Research, 100(3), 605–614.

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Host Factors and Antiviral Targets


Host Factors and Antiviral Targets

(From Potential Antiviral Agents for Coronaviruses: Compounds, Herbal Products, and Drug Targets)

  • Host factors associated with SARS-CoV replication need to be investigated (de Wilde et al., 2015).
  • These factors include the innate immune response and the metabolism of complex lipids that are involved in SARS-CoV infection.
  • The early secretory pathways are essential for SARS-CoV replication.
  • Protein kinases are crucial regulators of cellular functions.
  • The knockdown of protein kinases may reveal factors and pathways associated with virus replication.
  • Depletion of the antiviral double-stranded RNA-activated protein kinase (PKR) promoted virus replication.
  • Cyclin-dependent kinase 6 (CDK6) has been found as an antiviral host factor in SARS-CoV replication (de Wilde et al., 2015).
  • The pro- and antiviral host factors and pathways of viral replication are important for finding drug targets.

References:

de Wilde, A. H., Wannee, K. F., Scholte, F. E. M., Goeman, J. J., Ten Dijke, P., Snijder, E. J., Kikkert, M., & van Hemert, M. J. (2015). A Kinome-Wide Small Interfering RNA Screen Identifies Proviral and Antiviral Host Factors in Severe Acute Respiratory Syndrome Coronavirus Replication, Including Double-Stranded RNA-Activated Protein Kinase and Early Secretory Pathway Proteins. Journal of Virology, 89(16), 8318–8333.

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Saikosaponins and Coronaviruses

Saikosaponins

(From Potential Antiviral Agents for Coronaviruses: Compounds, Herbal Products, and Drug Targets)

  • Saikosaponins are oleanane derivatives including glucosides (Cheng et al., 2006).
  • Saikosaponins are extracted from plants such as Bupleurum spp., Heteromorpha spp. and Scrophularia scorodonia.
  • Saikosaponins have anti-inflammatory activities with anti-hepatitis, anti-nephritis, and antihepatoma effects.
  • They may also have immunomodulation and antibacterial functions.
  • The potential anti-coronaviral effects of saikosaponins (A, B2, C and D) have been tested.
  • The saikosaponins A and B2 showed no cytotoxic effects on target cells.
  • Saikosaponin B2 had the strongest suppressing effects on viral attachment and penetration (Cheng et al., 2006).
  • Saikosaponin B2 may have anti-coronaviral effects in the early stage of viral replication.

References:

Cheng, P.-W., Ng, L.-T., Chiang, L.-C., & Lin, C.-C. (2006). Antiviral effects of saikosaponins on human coronavirus 229E in vitro. Clinical and Experimental Pharmacology & Physiology, 33(7), 612–616.

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Antiviral Compounds and Human Coronavirus OC43

Antiviral Compounds and Human Coronavirus OC43

(From Potential Antiviral Agents for Coronaviruses: Compounds, Herbal Products, and Drug Targets)

  • Stephania tetrandra and Menispermaceae contain the bis-benzylisoquinoline alkaloids tetrandrine (TET) (Kim et al., 2019).
  • They also have fangchinoline (FAN) and cepharanthine (CEP).
  • These compounds have anticancer and anti-inflammatory effects.
  • They may also have antiviral activities against human coronaviruses.
  • The antiviral activities of TET, FAN, and CEP were examined in HCoV-OC43-infected human lung cells.
  • These compounds suppressed virus-caused cell death during the early stages of viral infection.
  • TET, FAN, and CEP treatment inhibited the viral replication, and viral S and N protein expressions (Kim et al., 2019).
  • TET, FAN, and CEP may be potential natural antiviral products for the prevention and therapy of HCoV-OC43 infections.

References:

Kim, D. E., Min, J. S., Jang, M. S., Lee, J. Y., Shin, Y. S., Song, J. H., Kim, H. R., Kim, S., Jin, Y.-H., & Kwon, S. (2019). Natural Bis-Benzylisoquinoline Alkaloids-Tetrandrine, Fangchinoline, and Cepharanthine, Inhibit Human Coronavirus OC43 Infection of MRC-5 Human Lung Cells. Biomolecules, 9(11).

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Herbal Extracts May Inhibit Coronavirus Replication

Herbal Extracts May Inhibit Coronavirus Replication

(From Potential Antiviral Agents for Coronaviruses: Compounds, Herbal Products, and Drug Targets)

  • Medicinal herbal extracts have been screened for their antiviral effects on coronavirus replication (Kim et al., 2008; Kim et al., 2010).
  • The extracts may suppress the replication of mouse hepatitis virus A59 (MHV-A59) and the intracellular RNA and protein expression.
  • They may also suppress porcine epidemic diarrhea virus (PEDV) (Kim et al., 2008).
  • These herbs include Cimicifuga rhizoma, Meliae cortex, Coptidis rhizoma, Phellodendron cortex and Sophora subprostrata radix.
  • These extracts may reduce PEDV and vesicular stomatitis virus (VSV) production (Kim et al., 2008).
  • The herbal extracts may suppress MHV replication and may become candidates for anti-coronavirus therapeutics.
  • Acanthopanacis cortex and Torilis fructus may decrease intracellular viral RNA levels and inhibit viral proteins (Kim et al., 2010).  
  • The extracts may inhibit the replication of the John Howard Mueller strain of MHV and vesicular stomatitis virus.
  • Sanguisorbae radix may inhibit coronavirus production and protein synthesis.
  • Acanthopanacis cortex and Torilis fructus may promote cyclooxygenase-2 expression.
  • They may activate extracellular signal-related kinase (ERK) and p38 or ERK alone, respectively.
  • Sophorae radix, Acanthopanacis cortex, Sanguisorbae radix and Torilis fructus may have anti-coronavirus effects (Kim et al., 2010).

References:

Kim, H.-Y., Eo, E.-Y., Park, H., Kim, Y.-C., Park, S., Shin, H.-J., & Kim, K. (2010). Medicinal herbal extracts of Sophorae radix, Acanthopanacis cortex, Sanguisorbae radix and Torilis fructus inhibit coronavirus replication in vitro. Antiviral Therapy, 15(5), 697–709.

Kim, H.-Y., Shin, H.-S., Park, H., Kim, Y.-C., Yun, Y. G., Park, S., Shin, H.-J., & Kim, K. (2008). In vitro inhibition of coronavirus replications by the traditionally used medicinal herbal extracts, Cimicifuga rhizoma, Meliae cortex, Coptidis rhizoma, and Phellodendron cortex. Journal of Clinical Virology: The Official Publication of the Pan American Society for Clinical Virology, 41(2), 122–128.

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Antiviral Flavonoids from Houttuynia Cordata

Antiviral Flavonoids from Houttuynia Cordata

(From Potential Antiviral Agents for Coronaviruses: Compounds, Herbal Products, and Drug Targets)

  • The ethyl acetate (EA) fraction of Houttuynia cordata (H. cordata) Thunb. (Saururaceae) may have antiviral effects.
  • It may be used against coronaviruses and dengue virus (DENV) (Chiow et al., 2016).
  • H. cordata has flavonoids including quercetin, quercitrin and rutin.
  • The antiviral effects of H. cordata and flavonoids were tested against mouse hepatitis virus (MHV) and DENV type 2 (DENV-2).
  • The EA fraction of H. cordata suppressed viral infectivity up to 6 days.
  • The EA fraction did not cause acute toxicity in mice.
  • Some flavonoids showed weak antiviral effects, e.g., quercetin suppressed both MHV and DENV-2 (Chiow et al., 2016).  
  • Quercitrin suppressed DENV-2 but not MHV, but rutin did not inhibit either virus.
  • The combination of quercetin and quercitrin promoted anti-DENV-2 effects with decreased cytotoxicity.
  • The synergistic activities of the flavonoid combination were weaker than that of the EA fraction.
  • The flavonoids and the EA fraction of H. cordata may be antiviral against coronaviruses and dengue infections (Chiow et al., 2016).

References:

Chiow, K. H., Phoon, M. C., Putti, T., Tan, B. K. H., & Chow, V. T. (2016). Evaluation of antiviral activities of Houttuynia cordata Thunb. Extract, quercetin, quercetrin and cinanserin on murine coronavirus and dengue virus infection. Asian Pacific Journal of Tropical Medicine, 9(1), 1–7.

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Sabadinine, Houttuynia Cordata, and Coronaviruses

Sabadinine and Houttuynia Cordata

(From Potential Antiviral Agents for Coronaviruses: Compounds, Herbal Products, and Drug Targets)

  • The replication of CoVs relies on proteolytic processing (Toney et al., 2004).
  • The major proteinase, 3C-like protease (3CLpro), may become a target for anti-SARS drugs.
  • A study used molecular docking into the active site of 3CLpro, looking for non-peptidyl inhibitors (Toney et al., 2004).
  • A potential antiviral compound was found to be sabadinine extracted from a natural herb (Toney et al., 2004).
  • Moreover, Houttuynia cordata Thunb. (Saururaceae)(HC) is an herb that has been used to treat pneumonia (Lau et al., 2008).
  • HC water extract enhanced the proportions of CD4(+) and CD8(+) T cells.
  • It may promote the production of IL-2 and IL-10 by mouse splenic lymphocytes (Lau et al., 2008).
  • HC may also inhibit 3CLpro and RNA-dependent RNA polymerase (RdRp) of SARS-CoV.
  • Oral acute toxicity tests showed that HC was non-toxic for oral administration (Lau et al., 2008).
  • HC extracts may be useful for the development of antiviral agents for SARS.

References:

Lau, K.-M., Lee, K.-M., Koon, C.-M., Cheung, C. S.-F., Lau, C.-P., Ho, H.-M., Lee, M. Y.-H., Au, S. W.-N., Cheng, C. H.-K., Lau, C. B.-S., Tsui, S. K.-W., Wan, D. C.-C., Waye, M. M.-Y., Wong, K.-B., Wong, C.-K., Lam, C. W.-K., Leung, P.-C., & Fung, K.-P. (2008). Immunomodulatory and anti-SARS activities of Houttuynia cordata. Journal of Ethnopharmacology, 118(1), 79–85.

Toney, J. H., Navas-Martín, S., Weiss, S. R., & Koeller, A. (2004). Sabadinine: A potential non-peptide anti-severe acute-respiratory-syndrome agent identified using structure-aided design. Journal of Medicinal Chemistry, 47(5), 1079–1080.

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Glycyrrhizin, Cinnamomi Cortex, and Toona Sinensis Roem

Glycyrrhizin, Cinnamomi Cortex, and Toona Sinensis Roem

(From Potential Antiviral Agents for Coronaviruses: Compounds, Herbal Products, and Drug Targets)

  • Glycyrrhizin (GL) may suppress SARS-CoV replication (Hoever et al., 2005).
  • The insertion of 2-acetamido-beta-d-glucopyranosylamine into the GL glycoside chain increased the antiviral effects to 10-fold higher.
  • Amides and conjugates of GL with two amino acid residues and a free 30-COOH function increased the effects up to 70-fold higher.
  • However, they caused higher cytotoxicity with lower selectivity index (Hoever et al., 2005).
  • In addition, the butanol fraction of Cinnamomi Cortex (CC/Fr.2) may suppress SARS-CoV (Zhuang et al., 2009).
  • It may also inhibit HIV/SARS-CoV S pseudovirus infections.
  • The compounds from CC such as procyanidin A2 and procyanidin B1 may have moderate antiviral effects (Zhuang et al., 2009).
  • CC/Fr.2 could block the clathrin-dependent endocytosis pathway and suppress the internalization of transferrin receptor.
  • CC/Fr.2 may have the antiviral activities for SARS-CoV by blocking endocytosis (Zhuang et al., 2009).
  • Moreover, TSL-1, the extract from Toona sinensis Roem (Cedrela sinensis; TSR), may also inhibit SARS-CoV (Chen et al., 2008).

References:

Chen, C.-J., Michaelis, M., Hsu, H.-K., Tsai, C.-C., Yang, K. D., Wu, Y.-C., Cinatl, J., & Doerr, H. W. (2008). Toona sinensis Roem tender leaf extract inhibits SARS coronavirus replication. Journal of Ethnopharmacology, 120(1), 108–111.

Hoever, G., Baltina, L., Michaelis, M., Kondratenko, R., Baltina, L., Tolstikov, G. A., Doerr, H. W., & Cinatl, J. (2005). Antiviral activity of glycyrrhizic acid derivatives against SARS-coronavirus. Journal of Medicinal Chemistry, 48(4), 1256–1259.

Zhuang, M., Jiang, H., Suzuki, Y., Li, X., Xiao, P., Tanaka, T., Ling, H., Yang, B., Saitoh, H., Zhang, L., Qin, C., Sugamura, K., & Hattori, T. (2009). Procyanidins and butanol extract of Cinnamomi Cortex inhibit SARS-CoV infection. Antiviral Research, 82(1), 73–81.

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The Antiviral Flavonoids for SARS-CoV and HCV

The Antiviral Flavonoids for SARS-CoV and HCV

(From Potential Antiviral Agents for Coronaviruses: Compounds, Herbal Products, and Drug Targets)

  • Aryl diketoacid (ADK) has antiviral effects that can be improved by adding an aromatic arylmethyl substituent (Park et al., 2012).
  • A natural flavonoid quercetin has a 3,5-dihydroxychromone pharmacophore.
  • It is in association with the 1,3-diketoacid moiety of the ADK (Park et al., 2012).
  • It is necessary to examine the antiviral effects of the quercetin derivatives with an arylmethyl group attached.
  • Some 7-O-arylmethylquercetin derivatives with aromatic substituents were assessed for their antiviral effects (Park et al., 2012).
  • The effects were examined against the SARS-CoV and hepatitis C virus (HCV).
  • Aromatic substituents improved the effects of the 7-O-arylmethylquercetin derivatives against SCV and HCV (Park et al., 2012).

References:

Park, H. R., Yoon, H., Kim, M. K., Lee, S. D., & Chong, Y. (2012). Synthesis and antiviral evaluation of 7-O-arylmethylquercetin derivatives against SARS-associated coronavirus (SCV) and hepatitis C virus (HCV). Archives of Pharmacal Research, 35(1), 77–85.

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Emodin and the SARS Coronavirus

Emodin and the SARS Coronavirus

(From Potential Antiviral Agents for Coronaviruses: Compounds, Herbal Products, and Drug Targets)

  • SARS-CoV spike (S) protein is a type I membrane-bound protein (Ho et al., 2007).
  • It has an elemental role for the viral attachment to the host cell receptor angiotensin-converting enzyme 2 (ACE2).
  • The screening of 312 medicinal herbs found three herbs of the family Polygonaceae with potential antiviral effects (Ho et al., 2007).
  • The herbs suppressed the interactions between the S protein and ACE2.
  • The three herbs were:
    • Radix et Rhizoma Rhei (the root tubers of Rheum officinale Baill.);
    • Radix Polygoni multiflori (the root tubers of Polygonum multiflorum Thunb.);
    • Caulis Polygoni multiflori (the vines of P. multiflorum Thunb.).
  • Emodin is an anthraquinone compound extracted from genus Rheum and Polygonum.
  • Emodin inhibited the S protein and ACE2 interaction in a dose-dependent way.
  • It also suppressed the infectivity of S protein-pseudotyped retrovirus.
  • Emodin may become a potential antiviral agent for the therapy of SARS (Ho et al., 2007).

References:

Ho, T.-Y., Wu, S.-L., Chen, J.-C., Li, C.-C., & Hsiang, C.-Y. (2007). Emodin blocks the SARS coronavirus spike protein and angiotensin-converting enzyme 2 interaction. Antiviral Research, 74(2), 92–101.

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Antiviral Herbal Compounds for SARS-CoV Ion Channels

Antiviral Herbal Compounds for SARS-CoV Ion Channels

(From Potential Antiviral Agents for Coronaviruses: Compounds, Herbal Products, and Drug Targets)

  • The protein coded by the open-reading-frame 3a of SARS coronavirus may form a cation-selective channel (Schwarz et al., 2014).
  • The channel is important in virus release.
  • Drugs that suppress the ion channel may suppress virus release.
  • Many herbal products with anticancer effects may also have antiviral activities.
  • Such herbal products include the flavonols kaempferol, kaempferol glycosides, and acylated kaempferol glucoside derivatives.
  • These herbal products may block the 3a channel.
  • The most effective one may be the glycoside juglanin (with an arabinose residue) for blocking the 3a-mediated current.
  • Kaempferol derivatives with rhamnose residue may also have antiviral effects (Schwarz et al., 2014).
  • Coronaviral ion channels can be antiviral drug targets, e.g., the 3a channel proteins may be inhibited by kaempferol glycosides.

References:

Schwarz, S., Sauter, D., Wang, K., Zhang, R., Sun, B., Karioti, A., Bilia, A. R., Efferth, T., & Schwarz, W. (2014). Kaempferol derivatives as antiviral drugs against the 3a channel protein of coronavirus. Planta Medica, 80(2–3), 177–182.

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The Antiviral Compound for MERS-CoV

The Antiviral Compound for MERS-CoV

(From Potential Antiviral Agents for Coronaviruses: Compounds, Herbal Products, and Drug Targets)

  • A type of nucleoside analogues may be similar to the natural nucleosides that can block viral replication (Agostini et al., 2019).
  • Potent antiviral effects of a broad-spectrum ribonucleoside analogue, β-d-N4-hydroxycytidine (NHC) have been identified.
  • Studies found that viral proofreading activity did not influence the sensitivity to NHC inhibition (Agostini et al., 2019).
  • The finding refers to the interaction between a nucleoside analogue inhibitor and the CoV replicase.  
  • However, mutagenic nucleoside analogues including ribavirin and 5-fluorouracil may be ineffective.
  • This may be caused by the proofreading activity of the viral 3’-5’ exoribonuclease (ExoN).
  • NHC may inhibit multiple viruses including murine hepatitis virus (MHV) and Middle East respiratory syndrome CoV (MERS-CoV).
  • NHC may evade or overcome ExoN activity.
  • NHC inhibited MHV in the early stages of infection.
  • Further development of NHC may be helpful for finding broad-spectrum antivirals of CoV infections (Agostini et al., 2019).

References:

Agostini, M. L., Pruijssers, A. J., Chappell, J. D., Gribble, J., Lu, X., Andres, E. L., Bluemling, G. R., Lockwood, M. A., Sheahan, T. P., Sims, A. C., Natchus, M. G., Saindane, M., Kolykhalov, A. A., Painter, G. R., Baric, R. S., & Denison, M. R. (2019). Small-Molecule Antiviral β-d-N4-Hydroxycytidine Inhibits a Proofreading-Intact Coronavirus with a High Genetic Barrier to Resistance. Journal of Virology, 93(24).

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Structural Analysis for Antiviral Compounds

Structural Analysis for Antiviral Compounds

(From Potential Antiviral Agents for Coronaviruses: Compounds, Herbal Products, and Drug Targets)

  • The coronavirus main protease (M(pro)) is critical in viral gene expression (Xue et al., 2008).
  • The viral replication through the proteolytic processing of replicase polyproteins may be a potential antiviral target.
  • The crystal structures of infectious bronchitis virus (IBV) M(pro) and SARS-CoV M(pro) mutant (H41A) are important.
  • The structures of the N-terminal autocleavage substrate are also critical.
  • These structures can be used to describe the structural flexibility and substrate binding of M(pro).
  • A monomeric form of IBV M(pro) was identified in CoV M(pro) structures.
  • A comparison of these M(pro) structures may be helpful for the design of substrate-based inhibitors targeting CoV M(pro)s.
  • A Michael acceptor inhibitor (N3) was co-crystallized with IBV M(pro) and led to inactivation of IBV M(pro).
  • The structure-based optimization of N3 has led to compounds N27 and H16 that may inhibit SARS-CoV M(pro) (Xue et al., 2008).

A Potential Antiviral Molecule for SARS-CoV and Ebola

(From Potential Antiviral Agents for Coronaviruses: Compounds, Herbal Products, and Drug Targets)

  • SARS-CoV and Ebola, Hendra, and Nipah viruses belong to different viral families.
  • These viruses need cathepsin L for entering their target cells (Elshabrawy et al., 2014).
  • The viral glycoproteins are primed by protease cleavage before fusing with the host cell membrane (Elshabrawy et al., 2014).
  • A high-throughput assay has been used to identify small molecules that can prevent cathepsin L cleavage of viral glycoproteins.
  • A broad-spectrum small molecule was able to inhibit the cathepsin L-mediated cleavage and the entry of glycoprotein pseudotypes.
  • The small molecule may be a candidate as a broad-spectrum antiviral drug against these viruses (Elshabrawy et al., 2014).

References:

Elshabrawy, H. A., Fan, J., Haddad, C. S., Ratia, K., Broder, C. C., Caffrey, M., & Prabhakar, B. S. (2014). Identification of a broad-spectrum antiviral small molecule against severe acute respiratory syndrome coronavirus and Ebola, Hendra, and Nipah viruses by using a novel high-throughput screening assay. Journal of Virology, 88(8), 4353–4365. https://doi.org/10.1128/JVI.03050-13

Xue, X., Yu, H., Yang, H., Xue, F., Wu, Z., Shen, W., Li, J., Zhou, Z., Ding, Y., Zhao, Q., Zhang, X. C., Liao, M., Bartlam, M., & Rao, Z. (2008). Structures of two coronavirus main proteases: Implications for substrate binding and antiviral drug design. Journal of Virology, 82(5), 2515–2527. https://doi.org/10.1128/JVI.02114-07

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Potential Antiviral Compounds for Coronaviruses: Tests and Screenings

Potential Antiviral Compounds for Coronaviruses: Tests and Screenings

(From Potential Antiviral Agents for Coronaviruses: Compounds, Herbal Products, and Drug Targets)

  • Some agents inhibiting coronaviral replication have been investigated (Golda and Pyrc, 2008).
  • The potential antiviral agents include (Golda and Pyrc, 2008):
    • Carbohydrate-binding agents;
    • Neutralizing antibodies;
    • Drugs targeting the coronaviral envelope protein.
  • Real-time PCR has been used for testing antivirals against Lassa virus, SARS coronavirus, and Ebola virus (Günther et al., 2004).
  • A small-scale screening found a class of imidazole nucleoside/nucleotide analogues with antiviral activities against Lassa virus.
  • The analogues had dinitrile or diester groups at the imidazole 4,5-positions (Günther et al., 2004).
  • Many of these had an acyclic sugar or sugar phosphonate moiety at the imidazole 1-position.
  • The compounds also suppressed the replications of SARS and Ebola viruses (Günther et al., 2004).
  • These compounds may be useful for the development of broad-spectrum drugs against viruses.

References:

Golda, A., & Pyrc, K. (2008). Recent antiviral strategies against human coronavirus-related respiratory illnesses. Current Opinion in Pulmonary Medicine, 14(3), 248–253. https://doi.org/10.1097/MCP.0b013e3282f7646f

Günther, S., Asper, M., Röser, C., Luna, L. K. S., Drosten, C., Becker-Ziaja, B., Borowski, P., Chen, H.-M., & Hosmane, R. S. (2004). Application of real-time PCR for testing antiviral compounds against Lassa virus, SARS coronavirus and Ebola virus in vitro. Antiviral Research, 63(3), 209–215. https://doi.org/10.1016/j.antiviral.2004.05.001

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Antiviral Antibodies, Immunity, and Coronaviruses

Antiviral Antibodies and Coronaviruses

(From Potential Antiviral Agents for Coronaviruses: Compounds, Herbal Products, and Drug Targets)

  • Mutations in virus-derived CD8 T-cell epitopes may abolish cytotoxic T-lymphocyte (CTL) recognition (Butler et al., 2007).
  • The mutations may block virus clearance in coronavirus-infected hosts.
  • These “CTL escape variant viruses” may lead to disease progression and elevated disease severity.
  • Antiviral antibody-mediated inhibition of virus replication and subsequent virus clearance may help prevent the CTL escape.
  • B-cell-deficient mice may shelter the CTL escape and would not eliminate infectious viruses effectively (Butler et al., 2007).
  • Antiviral antibodies are crucial for the protection from the CTL escape variant viruses.

Antiviral Immunity and Coronavirus Vaccine Vectors

(From Potential Antiviral Agents for Coronaviruses: Compounds, Herbal Products, and Drug Targets)

  • Effective vaccination against infectious viruses relies on specific antigens targeting dendritic cells (DCs).
  • Vaccine vectors may help with the delivery of antigens to antigen-presenting cells (APCs) (Cervantes-Barragan et al., 2010).
  • Vaccine vectors derived from attenuated murine coronavirus genomes were produced to express epitopes.
  • These epitopes can be from the lymphocytic choriomeningitis virus glycoprotein or human Melan-A.
  • They can be combined with the immunostimulatory cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF).
  • These vectors may selectively target DCs and lead to vector-mediated antigen expression and the maturation of DCs.
  • Single application of low vector doses may cause strong and long-term cytotoxic T-cell responses.
  • Such responses may enable protective antiviral and antitumor immune functions.
  • The DCs transduced with Melan-A-recombinant virus may activate tumor-specific CD8(+) T cells (Cervantes-Barragan et al., 2010).
  • Such a vaccine platform can be used to transport antigens and immunostimulatory cytokines to DCs to enable protective immunity.

References:

Butler, N. S., Dandekar, A. A., & Perlman, S. (2007). Antiviral antibodies are necessary to prevent cytotoxic T-lymphocyte escape in mice infected with a coronavirus. Journal of Virology, 81(24), 13291–13298. https://doi.org/10.1128/JVI.01580-07

Cervantes-Barragan, L., Züst, R., Maier, R., Sierro, S., Janda, J., Levy, F., Speiser, D., Romero, P., Rohrlich, P.-S., Ludewig, B., & Thiel, V. (2010). Dendritic cell-specific antigen delivery by coronavirus vaccine vectors induces long-lasting protective antiviral and antitumor immunity. MBio, 1(4). https://doi.org/10.1128/mBio.00171-10

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Potential Antiviral Agents for SARS and Various Coronaviruses

Indomethacin for Various Coronaviruses

(From Potential Antiviral Agents for Coronaviruses: Compounds, Herbal Products, and Drug Targets)

  • Cyclopentenone cyclooxygenase (COX) metabolites have been found to be useful targets against RNA viruses (Amici et al., 2006).
  • The COX inhibitor indomethacin (INDO) may have antiviral effects against SARS-CoV and canine coronavirus (CCoV).
  • INDO may inhibit the viral RNA synthesis and replication.
  • The antiviral effects of INDO have been tested in CCoV-infected dogs (Amici et al., 2006).
  • INDO has both anti-inflammatory and antiviral effects with potentials for the treatment of SARS and other coronaviruses.

P-PMOs for Murine Hepatitis Virus (MHV)

(From Potential Antiviral Agents for Coronaviruses: Compounds, Herbal Products, and Drug Targets)

  • The antiviral effects of peptide-conjugated antisense phosphorodiamidate morpholino oligomers (P-PMOs) were examined.
  • P-PMOs were tested for several strains of murine hepatitis virus (MHV) (Burrer et al., 2007).
  • One of the P-PMOs (5TERM) complementary to the 5’ terminus of the genomic RNA was found effective against six strains of MHV.
  • The 5TERM P-PMO therapy decreased viral titers in target organs and protected from virus-induced tissue damages in mouse models.
  • The prophylactic 5TERM P-PMO therapy alleviated weight loss caused by infections and prolonged survival.
  • However, 5TERM P-PMO was not protective in the cases of high-dose viral infections followed by delayed treatment.
  • P-PMO may have toxic effects in late-stage diseased mice (Burrer et al., 2007).  
  • With its antiviral effects, further development of P-PMO may provide treatments for a broad spectrum of coronavirus infections.

Potential Antiviral Agents for Hepatitis C Virus and SARS

(From Potential Antiviral Agents for Coronaviruses: Compounds, Herbal Products, and Drug Targets)

  • The 5-hydroxychromone (5b-5g) may be a potential antiviral agent with anti-hepatitis C virus (HCV) effects (Kim et al., 2011).
  • Some of the derivatives 5b-5f were found effective against SARS-associated coronavirus (SCV).
  • The 5b-5f were effective against both NTPase and helicase activities of the target enzymes of SCV.
  • The 3-iodobenzyloxy-substituted derivative 5e had the most potent activity against HCV and SCV.
  • Such platform structures may be useful for the design of multi-targets or broad-spectrum antiviral drugs (Kim et al., 2011).

References:

Amici, C., Di Caro, A., Ciucci, A., Chiappa, L., Castilletti, C., Martella, V., Decaro, N., Buonavoglia, C., Capobianchi, M. R., & Santoro, M. G. (2006). Indomethacin has a potent antiviral activity against SARS coronavirus. Antiviral Therapy, 11(8), 1021–1030.

Burrer, R., Neuman, B. W., Ting, J. P. C., Stein, D. A., Moulton, H. M., Iversen, P. L., Kuhn, P., & Buchmeier, M. J. (2007). Antiviral effects of antisense morpholino oligomers in murine coronavirus infection models. Journal of Virology, 81(11), 5637–5648. https://doi.org/10.1128/JVI.02360-06

Kim, M. K., Yu, M.-S., Park, H. R., Kim, K. B., Lee, C., Cho, S. Y., Kang, J., Yoon, H., Kim, D.-E., Choo, H., Jeong, Y.-J., & Chong, Y. (2011). 2,6-Bis-arylmethyloxy-5-hydroxychromones with antiviral activity against both hepatitis C virus (HCV) and SARS-associated coronavirus (SCV). European Journal of Medicinal Chemistry, 46(11), 5698–5704. https://doi.org/10.1016/j.ejmech.2011.09.005

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Remdesivir and Chloroquine as Potential Broad-Spectrum Antiviral Drugs

Remdesivir As A Potential Broad-Spectrum Antiviral Drug

(From Potential Antiviral Agents for Coronavirus-es: Compounds, Herbal Products, and Drug Targets)

  • The nucleoside analogue GS-5734 (remdesivir) has been found to inhibit human and zoonotic CoVs (Agostini et al., 2018).
  • GS-5734 may inhibit murine hepatitis virus (MHV), SARS-CoV and MERS-CoV.
  • GS-5734 could be a broad-spectrum drug to protect against current and novel CoVs.
  • The effects of nucleoside-based therapeutics may be blocked by a proofreading exoribonuclease (ExoN), e.g., the CoV nsp14 ExoN.
  • To solve the problem, a group β-2a CoV was added to the nucleotide prodrug remdesivir (GS-5734).
  • Higher and nontoxic concentrations of GS-5734 may help overcome the viral resistance.
  • Further development of GS-5734 has the potential to make it as an effective pan-CoV antiviral agent (Agostini et al., 2018).        

The Broad-Spectrum Antiviral Effects of Chloroquine

(From Potential Antiviral Agents for Coronavirus-es: Compounds, Herbal Products, and Drug Targets)

  • HCoVs including HCoV-OC43 may cause 15 to 30% of mild upper respiratory tract infections (Keyaerts et al., 2009).
  • Chloroquine has been used for its antimalarial functions, and may inhibit HCoV-OC43 replication.
  • Chloroquine may also prevent HCoV-OC43-induced death in newborn mice given through maternal milk.
  • The high survival rate occurred when the mother mice were given the drug with 15 mg/kg of body weight/day.
  • Survival rates declined in a dose-dependent manner, with 88% survival when treated with 5 mg/kg and 13% survival with 1 mg/kg.
  • Chloroquine has been found effective against HCoV-OC43 infection in mice as a potential drug (Keyaerts et al., 2009).

References:

Agostini, M. L., Andres, E. L., Sims, A. C., Graham, R. L., Sheahan, T. P., Lu, X., Smith, E. C., Case, J. B., Feng, J. Y., Jordan, R., Ray, A. S., Cihlar, T., Siegel, D., Mackman, R. L., Clarke, M. O., Baric, R. S., & Denison, M. R. (2018). Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease. MBio, 9(2). https://doi.org/10.1128/mBio.00221-18

Keyaerts, E., Li, S., Vijgen, L., Rysman, E., Verbeeck, J., Van Ranst, M., & Maes, P. (2009). Antiviral activity of chloroquine against human coronavirus OC43 infection in newborn mice. Antimicrobial Agents and Chemotherapy, 53(8), 3416–3421. https://doi.org/10.1128/AAC.01509-08

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Broad-Spectrum Antiviral Drugs for Coronaviruses

Broad-Spectrum Antiviral Drugs for Coronaviruses

(From Potential Antiviral Agents for Coronavirus-es: Compounds, Herbal Products, and Drug Targets)

  • Broad-spectrum antiviral drugs may lower the vulnerability of public health systems to the coronavirus pandemic.
  • Broad-spectrum antiviral drugs are needed to
    • Combat the emergence of novel coronaviruses, e.g., COVID-19;
    • Prevent the re-emergence of SARS-CoV, its mutants, and other related viruses;
    • Combat the continuance of MERS-CoV infections (Totura and Bavari, 2019).
  • Experiences from SARS and MERS outbreaks have revealed the demands for drugs with pan-coronavirus antiviral activities.

Antiviral Strategies for Coronaviruses

(From Potential Antiviral Agents for Coronavirus-es: Compounds, Herbal Products, and Drug Targets)

  • Nucleoside analogues may have antiviral effects against SARS-CoV (Chu et al., 2006).
  • Methods can be developed to antagonize viral nonstructural proteins (Totura and Bavari, 2019).
  • Agents can be designed to neutralize structural proteins of the coronaviruses.
  • Approaches can be developed to modulate essential host elements of viral infections.

References:

Chu, C. K., Gadthula, S., Chen, X., Choo, H., Olgen, S., Barnard, D. L., & Sidwell, R. W. (2006). Antiviral activity of nucleoside analogues against SARS-coronavirus (SARS-coV). Antiviral Chemistry & Chemotherapy, 17(5), 285–289. https://doi.org/10.1177/095632020601700506

Totura, A. L., & Bavari, S. (2019). Broad-spectrum coronavirus antiviral drug discovery. Expert Opinion on Drug Discovery, 14(4), 397–412. https://doi.org/10.1080/17460441.2019.1581171

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About Coronaviruses (CoVs)

About Coronaviruses (CoVs) (From Potential Antiviral Agents for Coronavirus-es: Compounds, Herbal Products, and Drug Targets)

  • Coronaviruses (CoVs) may lead to lethal infections, but currently no effective antiviral therapeutics or vaccines are available.
  • The pandemic of the deadly coronavirus disease 2019 (COVID-19) is a reminder that such coronaviruses can emerge at any time.
  • COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
  • Novel human coronaviruses (HCoVs) may lead to severe respiratory tract infections such as bronchiolitis and pneumonia.
  • More than 15 years have passed since the severe acute respiratory syndrome coronavirus (SARS-CoV) emerged from China.
  • SARS is an acute respiratory disease with high morbidity and mortality.
  • The Middle East respiratory syndrome coronavirus (MERS-CoV) is another fatal zoonotic virus (Totura and Bavari, 2019).
  • These coronaviruses can cause Acute Respiratory Distress Syndrome (ARDS) and renal failure.
  • They are highly transmissible and can spread from person-to-person through close contact (Totura and Bavari, 2019).

References:

Totura, A. L., & Bavari, S. (2019). Broad-spectrum coronavirus antiviral drug discovery. Expert Opinion on Drug Discovery, 14(4), 397–412. https://doi.org/10.1080/17460441.2019.1581171

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Studies about Antiviral Drugs for Coronaviruses


The Antiviral Remdesivir and the Coronavirus SARS-CoV

Agostini, M. L., Andres, E. L., Sims, A. C., Graham, R. L., Sheahan, T. P., Lu, X., Smith, E. C., Case, J. B., Feng, J. Y., Jordan, R., Ray, A. S., Cihlar, T., Siegel, D., Mackman, R. L., Clarke, M. O., Baric, R. S., & Denison, M. R. (2018). Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease. MBio, 9(2). https://doi.org/10.1128/mBio.00221-18

The Antiviral Compound β-d-N4-Hydroxycytidine and the Coronavirus MERS-CoV

Agostini, M. L., Pruijssers, A. J., Chappell, J. D., Gribble, J., Lu, X., Andres, E. L., Bluemling, G. R., Lockwood, M. A., Sheahan, T. P., Sims, A. C., Natchus, M. G., Saindane, M., Kolykhalov, A. A., Painter, G. R., Baric, R. S., & Denison, M. R. (2019). Small-Molecule Antiviral β-d-N4-Hydroxycytidine Inhibits a Proofreading-Intact Coronavirus with a High Genetic Barrier to Resistance. Journal of Virology, 93(24). https://doi.org/10.1128/JVI.01348-19

The Antiviral Indomethacin and the Coronavirus SARS-CoV

Amici, C., Di Caro, A., Ciucci, A., Chiappa, L., Castilletti, C., Martella, V., Decaro, N., Buonavoglia, C., Capobianchi, M. R., & Santoro, M. G. (2006). Indomethacin has a potent antiviral activity against SARS coronavirus. Antiviral Therapy, 11(8), 1021–1030.

The Antiviral Effects of P-PMOs

Burrer, R., Neuman, B. W., Ting, J. P. C., Stein, D. A., Moulton, H. M., Iversen, P. L., Kuhn, P., & Buchmeier, M. J. (2007). Antiviral effects of antisense morpholino oligomers in murine coronavirus infection models. Journal of Virology, 81(11), 5637–5648. https://doi.org/10.1128/JVI.02360-06

Antiviral Flavonoids and DENV

Chiow, K. H., Phoon, M. C., Putti, T., Tan, B. K. H., & Chow, V. T. (2016). Evaluation of antiviral activities of Houttuynia cordata Thunb. Extract, quercetin, quercetrin and cinanserin on murine coronavirus and dengue virus infection. Asian Pacific Journal of Tropical Medicine, 9(1), 1–7. https://doi.org/10.1016/j.apjtm.2015.12.002

Nucleoside Analogues and SARS-CoV

Chu, C. K., Gadthula, S., Chen, X., Choo, H., Olgen, S., Barnard, D. L., & Sidwell, R. W. (2006). Antiviral activity of nucleoside analogues against SARS-coronavirus (SARS-coV). Antiviral Chemistry & Chemotherapy, 17(5), 285–289. https://doi.org/10.1177/095632020601700506

The Antiviral Effects of Common Household Disinfectants for SARS-CoV

Dellanno, C., Vega, Q., & Boesenberg, D. (2009). The antiviral action of common household disinfectants and antiseptics against murine hepatitis virus, a potential surrogate for SARS coronavirus. American Journal of Infection Control, 37(8), 649–652. https://doi.org/10.1016/j.ajic.2009.03.012

A Potential Antiviral Molecule for SARS-CoV and Ebola

Elshabrawy, H. A., Fan, J., Haddad, C. S., Ratia, K., Broder, C. C., Caffrey, M., & Prabhakar, B. S. (2014). Identification of a broad-spectrum antiviral small molecule against severe acute respiratory syndrome coronavirus and Ebola, Hendra, and Nipah viruses by using a novel high-throughput screening assay. Journal of Virology, 88(8), 4353–4365. https://doi.org/10.1128/JVI.03050-13

The Antiviral Effects of Glycyrrhizin and SARS-CoV

Hoever, G., Baltina, L., Michaelis, M., Kondratenko, R., Baltina, L., Tolstikov, G. A., Doerr, H. W., & Cinatl, J. (2005). Antiviral activity of glycyrrhizic acid derivatives against SARS-coronavirus. Journal of Medicinal Chemistry, 48(4), 1256–1259. https://doi.org/10.1021/jm0493008

Antiviral Effects of Chloroquine for the Coronavirus OC43

Keyaerts, E., Li, S., Vijgen, L., Rysman, E., Verbeeck, J., Van Ranst, M., & Maes, P. (2009). Antiviral activity of chloroquine against human coronavirus OC43 infection in newborn mice. Antimicrobial Agents and Chemotherapy, 53(8), 3416–3421. https://doi.org/10.1128/AAC.01509-08

Antiviral Herbal Compounds for SARS

Schwarz, S., Sauter, D., Wang, K., Zhang, R., Sun, B., Karioti, A., Bilia, A. R., Efferth, T., & Schwarz, W. (2014). Kaempferol derivatives as antiviral drugs against the 3a channel protein of coronavirus. Planta Medica, 80(2–3), 177–182. https://doi.org/10.1055/s-0033-1360277

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Resources for Studying the 2019-nCoV Coronavirus (COVID-19): Databases and Tools

Resources for Studying the 2019-nCoV Coronavirus (COVID-19): Databases and Tools

  • “human coronaviruses such as …endemic human coronaviruses (HCoV) can persist on inanimate surfaces like metal, glass or plastic for up to 9 days…”

From Persistence of coronaviruses on inanimate surfaces and their inactivation with biocidal agents (https://www.journalofhospitalinfection.com/article/S0195-6701(20)30046-3/fulltext)

Including the sequence data and the BLAST tool.

  • Coronavirus COVID-19 Global Cases by Johns Hopkins CSSE:

https://gisanddata.maps.arcgis.com/apps/opsdashboard/index.html#/bda7594740fd40299423467b48e9ecf6

Bioinformatics Analysis: Genes Identified in the 2019-nCoV Coronavirus (COVID-19)

  • E (envelope protein [Wuhan seafood market pneumonia virus])
  • M (membrane glycoprotein [Wuhan seafood market pneumonia virus])
  • N (nucleocapsid phosphoprotein [Wuhan seafood market pneumonia virus])
  • orf1ab (orf1a polyprotein;orf1ab polyprotein [Wuhan seafood market pneumonia virus])
  • ORF3a (ORF3a protein [Wuhan seafood market pneumonia virus])
  • ORF6 (ORF6 protein [Wuhan seafood market pneumonia virus])
  • ORF7a (ORF7a protein [Wuhan seafood market pneumonia virus])
  • ORF7b (ORF7b [Wuhan seafood market pneumonia virus])
  • ORF8 (ORF8 protein [Wuhan seafood market pneumonia virus])
  • ORF10 (ORF10 protein [Wuhan seafood market pneumonia virus])
  • S (surface glycoprotein [Wuhan seafood market pneumonia virus])

Publications about the 2019-nCoV Coronavirus (COVID-19)

Transmission and Epidemiology of 2019-nCoV (COVID-19)

  • Backer, J. A., Klinkenberg, D., & Wallinga, J. (2020). Incubation period of 2019 novel coronavirus (2019-nCoV) infections among travellers from Wuhan, China, 20-28 January 2020. Euro Surveillance: Bulletin Europeen Sur Les Maladies Transmissibles = European Communicable Disease Bulletin, 25(5). https://doi.org/10.2807/1560-7917.ES.2020.25.5.2000062
  • Giovanetti, M., Benvenuto, D., Angeletti, S., & Ciccozzi, M. (2020). The first two cases of 2019-nCoV in Italy: Where they come from? Journal of Medical Virology. https://doi.org/10.1002/jmv.25699
  • Habibzadeh, P., & Stoneman, E. K. (2020). The Novel Coronavirus: A Bird’s Eye View. The International Journal of Occupational and Environmental Medicine, 11(2), 65–71. https://doi.org/10.15171/ijoem.2020.1921
  • Holshue, M. L., DeBolt, C., Lindquist, S., Lofy, K. H., Wiesman, J., Bruce, H., Spitters, C., Ericson, K., Wilkerson, S., Tural, A., Diaz, G., Cohn, A., Fox, L., Patel, A., Gerber, S. I., Kim, L., Tong, S., Lu, X., Lindstrom, S., … Washington State 2019-nCoV Case Investigation Team. (2020). First Case of 2019 Novel Coronavirus in the United States. The New England Journal of Medicine. https://doi.org/10.1056/NEJMoa2001191
  • Nishiura, H., Jung, S.-M., Linton, N. M., Kinoshita, R., Yang, Y., Hayashi, K., Kobayashi, T., Yuan, B., & Akhmetzhanov, A. R. (2020). The Extent of Transmission of Novel Coronavirus in Wuhan, China, 2020. Journal of Clinical Medicine, 9(2). https://doi.org/10.3390/jcm9020330
  • Nishiura, H., Kobayashi, T., Yang, Y., Hayashi, K., Miyama, T., Kinoshita, R., Linton, N. M., Jung, S.-M., Yuan, B., Suzuki, A., & Akhmetzhanov, A. R. (2020). The Rate of Underascertainment of Novel Coronavirus (2019-nCoV) Infection: Estimation Using Japanese Passengers Data on Evacuation Flights. Journal of Clinical Medicine, 9(2). https://doi.org/10.3390/jcm9020419
  • Patel, A., Jernigan, D. B., & 2019-nCoV CDC Response Team. (2020). Initial Public Health Response and Interim Clinical Guidance for the 2019 Novel Coronavirus Outbreak—United States, December 31, 2019-February 4, 2020. MMWR. Morbidity and Mortality Weekly Report, 69(5), 140–146. https://doi.org/10.15585/mmwr.mm6905e1
  • Riou, J., & Althaus, C. L. (2020). Pattern of early human-to-human transmission of Wuhan 2019 novel coronavirus (2019-nCoV), December 2019 to January 2020. Euro Surveillance: Bulletin Europeen Sur Les Maladies Transmissibles = European Communicable Disease Bulletin, 25(4). https://doi.org/10.2807/1560-7917.ES.2020.25.4.2000058
  • Ryu, S., Chun, B. C., & Korean Society of Epidemiology 2019-nCoV Task Force Team. (2020). An interim review of the epidemiological characteristics of 2019 novel coronavirus. Epidemiology and Health, 42, e2020006. https://doi.org/10.4178/epih.e2020006
  • Wu, J. T., Leung, K., & Leung, G. M. (2020). Nowcasting and forecasting the potential domestic and international spread of the 2019-nCoV outbreak originating in Wuhan, China: A modelling study. Lancet (London, England). https://doi.org/10.1016/S0140-6736(20)30260-9
  • Wu, P., Hao, X., Lau, E. H. Y., Wong, J. Y., Leung, K. S. M., Wu, J. T., Cowling, B. J., & Leung, G. M. (2020). Real-time tentative assessment of the epidemiological characteristics of novel coronavirus infections in Wuhan, China, as at 22 January 2020. Euro Surveillance: Bulletin Europeen Sur Les Maladies Transmissibles = European Communicable Disease Bulletin, 25(3). https://doi.org/10.2807/1560-7917.ES.2020.25.3.2000044

Virus Evolution and Molecular Studies of 2019-nCoV (COVID-19)

  • Benvenuto, D., Giovanetti, M., Ciccozzi, A., Spoto, S., Angeletti, S., & Ciccozzi, M. (2020). The 2019-new coronavirus epidemic: Evidence for virus evolution. Journal of Medical Virology. https://doi.org/10.1002/jmv.25688
  • Benvenuto, D., Giovanetti, M., Salemi, M., Prosperi, M., De Flora, C., Junior Alcantara, L. C., Angeletti, S., & Ciccozzi, M. (2020). The global spread of 2019-nCoV: A molecular evolutionary analysis. Pathogens and Global Health, 1–4. https://doi.org/10.1080/20477724.2020.1725339
  • Ceraolo, C., & Giorgi, F. M. (2020). Genomic variance of the 2019-nCoV coronavirus. Journal of Medical Virology. https://doi.org/10.1002/jmv.25700

Detection and Diagnosis of 2019-nCoV (COVID-19)

  • Corman, V. M., Landt, O., Kaiser, M., Molenkamp, R., Meijer, A., Chu, D. K., Bleicker, T., Brünink, S., Schneider, J., Schmidt, M. L., Mulders, D. G., Haagmans, B. L., van der Veer, B., van den Brink, S., Wijsman, L., Goderski, G., Romette, J.-L., Ellis, J., Zambon, M., … Drosten, C. (2020). Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR. Euro Surveillance: Bulletin Europeen Sur Les Maladies Transmissibles = European Communicable Disease Bulletin, 25(3). https://doi.org/10.2807/1560-7917.ES.2020.25.3.2000045
  • Kampf, G., Todt, D., Pfaender, S., & Steinmann, E. (2020). Persistence of coronaviruses on inanimate surfaces and its inactivation with biocidal agents. The Journal of Hospital Infection. https://doi.org/10.1016/j.jhin.2020.01.022
  • Phan, T. (2020). Novel coronavirus: From discovery to clinical diagnostics. Infection, Genetics and Evolution: Journal of Molecular Epidemiology and Evolutionary Genetics in Infectious Diseases, 79, 104211. https://doi.org/10.1016/j.meegid.2020.104211
  • Quilty, B. J., Clifford, S., Cmmid nCoV Working Group, null, Flasche, S., & Eggo, R. M. (2020). Effectiveness of airport screening at detecting travellers infected with novel coronavirus (2019-nCoV). Euro Surveillance: Bulletin Europeen Sur Les Maladies Transmissibles = European Communicable Disease Bulletin, 25(5). https://doi.org/10.2807/1560-7917.ES.2020.25.5.2000080
  • To, K. K.-W., Tsang, O. T.-Y., Chik-Yan Yip, C., Chan, K.-H., Wu, T.-C., Chan, J. M. C., Leung, W.-S., Chik, T. S.-H., Choi, C. Y.-C., Kandamby, D. H., Lung, D. C., Tam, A. R., Poon, R. W.-S., Fung, A. Y.-F., Hung, I. F.-N., Cheng, V. C.-C., Chan, J. F.-W., & Yuen, K.-Y. (2020). Consistent detection of 2019 novel coronavirus in saliva. Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America. https://doi.org/10.1093/cid/ciaa149
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Metabolomics of Obesity: Gut Microbiota

Recent Development in Metabolomics of Obesity: Gut Microbiota and Metabolic Syndrome

Abu Bakar, M. H., Sarmidi, M. R., Cheng, K.-K., Ali Khan, A., Suan, C. L., Zaman Huri, H., & Yaakob, H. (2015). Metabolomics – the complementary field in systems biology: A review on obesity and type 2 diabetes. Molecular BioSystems, 11(7), 1742–1774. https://doi.org/10.1039/c5mb00158g

Aguilar-Salinas, C. A., & Viveros-Ruiz, T. (2019). Recent advances in managing/understanding the metabolic syndrome. F1000Research, 8. https://doi.org/10.12688/f1000research.17122.1

Aw, W., & Fukuda, S. (2015). Toward the comprehensive understanding of the gut ecosystem via metabolomics-based integrated omics approach. Seminars in Immunopathology, 37(1), 5–16. https://doi.org/10.1007/s00281-014-0456-2

Heinken, A., & Thiele, I. (2015). Systems biology of host-microbe metabolomics. Wiley Interdisciplinary Reviews. Systems Biology and Medicine, 7(4), 195–219. https://doi.org/10.1002/wsbm.1301

Hoek, M. J. A. van, & Merks, R. M. H. (2017). Emergence of microbial diversity due to cross-feeding interactions in a spatial model of gut microbial metabolism. BMC Systems Biology, 11(1), 56. https://doi.org/10.1186/s12918-017-0430-4

Jaitin, D. A., Adlung, L., Thaiss, C. A., Weiner, A., Li, B., Descamps, H., … Amit, I. (2019). Lipid-Associated Macrophages Control Metabolic Homeostasis in a Trem2-Dependent Manner. Cell, 178(3), 686-698.e14. https://doi.org/10.1016/j.cell.2019.05.054

Kieffer, D. A., Piccolo, B. D., Marco, M. L., Kim, E. B., Goodson, M. L., Keenan, M. J., … Adams, S. H. (2016). Mice Fed a High-Fat Diet Supplemented with Resistant Starch Display Marked Shifts in the Liver Metabolome Concurrent with Altered Gut Bacteria. The Journal of Nutrition, 146(12), 2476–2490. https://doi.org/10.3945/jn.116.238931

Mathur, S. K., Tiwari, P., Gupta, S., Gupta, N., Nimesh, S., Medicherla, K. M., & Suravajhala, P. (2018). Genetics of Lipodystrophy: Can It Help in Understanding the Pathophysiology of Metabolic Syndrome? Biomolecules, 8(3). https://doi.org/10.3390/biom8030047

Meijnikman, A. S., Gerdes, V. E., Nieuwdorp, M., & Herrema, H. (2018). Evaluating Causality of Gut Microbiota in Obesity and Diabetes in Humans. Endocrine Reviews, 39(2), 133–153. https://doi.org/10.1210/er.2017-00192

Wang, J., Ma, M. C. J., Mennie, A. K., Pettus, J. M., Xu, Y., Lin, L., … Kwitek, A. E. (2015). Systems biology with high-throughput sequencing reveals genetic mechanisms underlying the metabolic syndrome in the Lyon hypertensive rat. Circulation. Cardiovascular Genetics, 8(2), 316–326. https://doi.org/10.1161/CIRCGENETICS.114.000520

Wu, H., Tremaroli, V., & Bäckhed, F. (2015). Linking Microbiota to Human Diseases: A Systems Biology Perspective. Trends in Endocrinology and Metabolism: TEM, 26(12), 758–770. https://doi.org/10.1016/j.tem.2015.09.011

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Biomarkers Database: Obesity in Different Populations

Park, B.-Y., Hong, J., & Park, H. (2017). Neuroimaging biomarkers to associate obesity and negative emotions. Scientific Reports, 7(1), 7664. https://doi.org/10.1038/s41598-017-08272-8

Pecht, T., Gutman-Tirosh, A., Bashan, N., & Rudich, A. (2014). Peripheral blood leucocyte subclasses as potential biomarkers of adipose tissue inflammation and obesity subphenotypes in humans. Obesity Reviews: An Official Journal of the International Association for the Study of Obesity, 15(4), 322–337. https://doi.org/10.1111/obr.12133

Pescador, N., Pérez-Barba, M., Ibarra, J. M., Corbatón, A., Martínez-Larrad, M. T., & Serrano-Ríos, M. (2013). Serum circulating microRNA profiling for identification of potential type 2 diabetes and obesity biomarkers. PloS One, 8(10), e77251. https://doi.org/10.1371/journal.pone.0077251

Petrásová, D., Bertková, I., Petrásová, M., Hijová, E., Mareková, M., Babinská, I., … HepaMeta Team. (2014). Biomarkers associated with obesity and overweight in the Roma population residing in eastern Slovakia. Central European Journal of Public Health, 22 Suppl, S18-21. https://doi.org/10.21101/cejph.a3896

Pinheiro Volp, A. C., Santos Silva, F. C., & Bressan, J. (2015). Hepatic inflammatory biomarkers and its link with obesity and chronic diseases. Nutricion Hospitalaria, 31(5), 1947–1956. https://doi.org/10.3305/nh.2015.31.5.8525

Porter Starr, K. N., Orenduff, M., McDonald, S. R., Mulder, H., Sloane, R., Pieper, C. F., & Bales, C. W. (2019). Influence of Weight Reduction and Enhanced Protein Intake on Biomarkers of Inflammation in Older Adults with Obesity. Journal of Nutrition in Gerontology and Geriatrics, 38(1), 33–49. https://doi.org/10.1080/21551197.2018.1564200

Randell, E. W., Twells, L. K., Gregory, D. M., Lester, K. K., Daneshtalab, N., Dillon, C., … Boone, D. (2018). Pre-operative and post-operative changes in CRP and other biomarkers sensitive to inflammatory status in patients with severe obesity undergoing laparoscopic sleeve gastrectomy. Clinical Biochemistry, 52, 13–19. https://doi.org/10.1016/j.clinbiochem.2017.10.010

Rashad, N. M., El-Shabrawy, R. M., Sabry, H. M., Fathy, H. A., Said, D., & Yousef, M. S. (2018). Interleukin-6 and hs-CRP as Early Diagnostic Biomarkers for Obesity-Related Peripheral Polyneuropathy in Non-Diabetic Patients. The Egyptian Journal of Immunology, 25(2), 153–165.

Rauschert, S., Uhl, O., Koletzko, B., & Hellmuth, C. (2014). Metabolomic biomarkers for obesity in humans: a short review. Annals of Nutrition & Metabolism, 64(3–4), 314–324. https://doi.org/10.1159/000365040

Recker, E. N., Brogden, K. A., Avila-Ortiz, G., Fischer, C. L., Pagan-Rivera, K., Dawson, D. V., … Elangovan, S. (2015). Novel biomarkers of periodontitis and/or obesity in saliva-An exploratory analysis. Archives of Oral Biology, 60(10), 1503–1509. https://doi.org/10.1016/j.archoralbio.2015.07.006

Ribeiro, C., Dourado, G., & Cesar, T. (2017). Orange juice allied to a reduced-calorie diet results in weight loss and ameliorates obesity-related biomarkers: A randomized controlled trial. Nutrition (Burbank, Los Angeles County, Calif.), 38, 13–19. https://doi.org/10.1016/j.nut.2016.12.020

Rivera, P., Martos-Moreno, G. Á., Barrios, V., Suárez, J., Pavón, F. J., Chowen, J. A., … Argente, J. (2019). A novel approach to childhood obesity: circulating chemokines and growth factors as biomarkers of insulin resistance. Pediatric Obesity, 14(3), e12473. https://doi.org/10.1111/ijpo.12473

Rodríguez-Rivera, C., Pérez-García, C., Muñoz-Rodríguez, J. R., Vicente-Rodríguez, M., Polo, F., Ford, R.-M., … Alguacil, L. F. (2019). Proteomic Identification of Biomarkers Associated with Eating Control and Bariatric Surgery Outcomes in Patients with Morbid Obesity. World Journal of Surgery, 43(3), 744–750. https://doi.org/10.1007/s00268-018-4851-z

Sandhu, R. K., Ezekowitz, J. A., Hijazi, Z., Westerbergh, J., Aulin, J., Alexander, J. H., … Wallentin, L. (2018). Obesity paradox on outcome in atrial fibrillation maintained even considering the prognostic influence of biomarkers: insights from the ARISTOTLE trial. Open Heart, 5(2), e000908. https://doi.org/10.1136/openhrt-2018-000908

Santilli, F., Guagnano, M. T., Vazzana, N., La Barba, S., & Davi, G. (2015). Oxidative stress drivers and modulators in obesity and cardiovascular disease: from biomarkers to therapeutic approach. Current Medicinal Chemistry, 22(5), 582–595.

Schlesinger, S., Herder, C., Kannenberg, J. M., Huth, C., Carstensen-Kirberg, M., Rathmann, W., … Ziegler, D. (2019). General and Abdominal Obesity and Incident Distal Sensorimotor Polyneuropathy: Insights Into Inflammatory Biomarkers as Potential Mediators in the KORA F4/FF4 Cohort. Diabetes Care, 42(2), 240–247. https://doi.org/10.2337/dc18-1842

Scrivo, R., Vasile, M., Müller-Ladner, U., Neumann, E., & Valesini, G. (2013). Rheumatic diseases and obesity: adipocytokines as potential comorbidity biomarkers for cardiovascular diseases. Mediators of Inflammation, 2013, 808125. https://doi.org/10.1155/2013/808125

Selma, M. V., González-Sarrías, A., Salas-Salvadó, J., Andrés-Lacueva, C., Alasalvar, C., Örem, A., … Espín, J. C. (2018). The gut microbiota metabolism of pomegranate or walnut ellagitannins yields two urolithin-metabotypes that correlate with cardiometabolic risk biomarkers: Comparison between normoweight, overweight-obesity and metabolic syndrome. Clinical Nutrition (Edinburgh, Scotland), 37(3), 897–905. https://doi.org/10.1016/j.clnu.2017.03.012

Serra, M. C., Beavers, D. P., Henderson, R. M., Kelleher, J. L., Kiel, J. R., & Beavers, K. M. (2019). Effects of a Hypocaloric, Nutritionally Complete, Higher Protein Meal Plan on Regional Body Fat and Cardiometabolic Biomarkers in Older Adults with Obesity. Annals of Nutrition & Metabolism, 74(2), 149–155. https://doi.org/10.1159/000497066

Shaver, L. N., Beavers, D. P., Kiel, J., Kritchevsky, S. B., & Beavers, K. M. (2018). Effect of Intentional Weight Loss on Mortality Biomarkers in Older Adults With Obesity. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences. https://doi.org/10.1093/gerona/gly192

Shen, S.-H., Shen, S.-Y., Liou, T.-H., Hsu, M.-I., Chang, Y. I., Cheng, C.-Y., … Tzeng, C.-R. (2015). Obesity and inflammatory biomarkers in women with polycystic ovary syndrome. European Journal of Obstetrics, Gynecology, and Reproductive Biology, 192, 66–71. https://doi.org/10.1016/j.ejogrb.2015.06.022

Shin, Y. H., Kim, K. E., Lee, Y.-J., Nam, J.-H., Hong, Y. M., & Shin, H.-J. (2014). Associations of matrix metalloproteinase (MMP)-8, MMP-9, and their inhibitor, tissue inhibitor of metalloproteinase-1, with obesity-related biomarkers in apparently healthy adolescent boys. Korean Journal of Pediatrics, 57(12), 526–532. https://doi.org/10.3345/kjp.2014.57.12.526

Socha, P., Hellmuth, C., Gruszfeld, D., Demmelmair, H., Rzehak, P., Grote, V., … European Childhood Obesity Trial Study Group. (2016). Endocrine and Metabolic Biomarkers Predicting Early Childhood Obesity Risk. Nestle Nutrition Institute Workshop Series, 85, 81–88. https://doi.org/10.1159/000439489

Tenório, T. R. S., Balagopal, P. B., Andersen, L. B., Ritti-Dias, R. M., Hill, J. O., Lofrano-Prado, M. C., & Prado, W. L. (2018). Effect of Low- Versus High-Intensity Exercise Training on Biomarkers of Inflammation and Endothelial Dysfunction in Adolescents With Obesity: A 6-Month Randomized Exercise Intervention Study. Pediatric Exercise Science, 30(1), 96–105. https://doi.org/10.1123/pes.2017-0067

Tolusso, B., Gigante, M. R., Alivernini, S., Petricca, L., Fedele, A. L., Di Mario, C., … Gremese, E. (2018). Chemerin and PEDF Are Metaflammation-Related Biomarkers of Disease Activity and Obesity in Rheumatoid Arthritis. Frontiers in Medicine, 5, 207. https://doi.org/10.3389/fmed.2018.00207

Torres-Perez, E., Valero, M., Garcia-Rodriguez, B., Gonzalez-Irazabal, Y., Calmarza, P., Calvo-Ruata, L., … Arbones-Mainar, J. M. (2015). The FAT expandability (FATe) Project: Biomarkers to determine the limit of expansion and the complications of obesity. Cardiovascular Diabetology, 14, 40. https://doi.org/10.1186/s12933-015-0203-6

Tsai, C.-L., Huang, T.-H., & Tsai, M.-C. (2017). Neurocognitive performances of visuospatial attention and the correlations with metabolic and inflammatory biomarkers in adults with obesity. Experimental Physiology, 102(12), 1683–1699. https://doi.org/10.1113/EP086624

Tulipani, S., Palau-Rodriguez, M., Miñarro Alonso, A., Cardona, F., Marco-Ramell, A., Zonja, B., … Andres-Lacueva, C. (2016). Biomarkers of Morbid Obesity and Prediabetes by Metabolomic Profiling of Human Discordant Phenotypes. Clinica Chimica Acta; International Journal of Clinical Chemistry, 463, 53–61. https://doi.org/10.1016/j.cca.2016.10.005

Vasquez, M. M., Hu, C., Roe, D. J., Chen, Z., Halonen, M., & Guerra, S. (2016). Least absolute shrinkage and selection operator type methods for the identification of serum biomarkers of overweight and obesity: simulation and application. BMC Medical Research Methodology, 16(1), 154. https://doi.org/10.1186/s12874-016-0254-8

Vernarelli, J. A., Mitchell, D. C., Rolls, B. J., & Hartman, T. J. (2015). Dietary energy density is associated with obesity and other biomarkers of chronic disease in US adults. European Journal of Nutrition, 54(1), 59–65. https://doi.org/10.1007/s00394-014-0685-0

Vernini, J. M., Moreli, J. B., Costa, R. A. A., Negrato, C. A., Rudge, M. V. C., & Calderon, I. M. P. (2016). Maternal adipokines and insulin as biomarkers of pregnancies complicated by overweight and obesity. Diabetology & Metabolic Syndrome, 8(1), 68. https://doi.org/10.1186/s13098-016-0184-y

Vigna, L., Vassalle, C., Tirelli, A. S., Gori, F., Tomaino, L., Sabatino, L., & Bamonti, F. (2017). Gender-related association between uric acid, homocysteine, γ-glutamyltransferase, inflammatory biomarkers and metabolic syndrome in subjects affected by obesity. Biomarkers in Medicine. https://doi.org/10.2217/bmm-2017-0072

Vurbic, D., Harder, V. S., Redner, R. R., Lopez, A. A., Phillips, J. K., & Higgins, S. T. (2015). Co-occurring obesity and smoking among U.S. women of reproductive age: Associations with educational attainment and health biomarkers and outcomes. Preventive Medicine, 80, 60–66. https://doi.org/10.1016/j.ypmed.2015.05.020

Wiseman, A. J., Lynch, B. M., Cameron, A. J., & Dunstan, D. W. (2014). Associations of change in television viewing time with biomarkers of postmenopausal breast cancer risk: the Australian Diabetes, Obesity and Lifestyle Study. Cancer Causes & Control: CCC, 25(10), 1309–1319. https://doi.org/10.1007/s10552-014-0433-z

Yassour, M., Lim, M. Y., Yun, H. S., Tickle, T. L., Sung, J., Song, Y.-M., … Huttenhower, C. (2016). Sub-clinical detection of gut microbial biomarkers of obesity and type 2 diabetes. Genome Medicine, 8(1), 17. https://doi.org/10.1186/s13073-016-0271-6

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Biomarkers Database: Obesity, Cognition, and Inflammation

Garcia-Mazcorro, J. F., Mills, D. A., Murphy, K., & Noratto, G. (2018). Effect of barley supplementation on the fecal microbiota, caecal biochemistry, and key biomarkers of obesity and inflammation in obese db/db mice. European Journal of Nutrition, 57(7), 2513–2528. https://doi.org/10.1007/s00394-017-1523-y

Ghosh, S., Murinova, L., Trnovec, T., Loffredo, C. A., Washington, K., Mitra, P. S., & Dutta, S. K. (2014). Biomarkers linking PCB exposure and obesity. Current Pharmaceutical Biotechnology, 15(11), 1058–1068.

Goguet-Rubio, P., Klug, R. L., Sharma, D. L., Srikanthan, K., Puri, N., Lakhani, V. H., … Sodhi, K. (2017). Existence of a Strong Correlation of Biomarkers and miRNA in Females with Metabolic Syndrome and Obesity in a Population of West Virginia. International Journal of Medical Sciences, 14(6), 543–553. https://doi.org/10.7150/ijms.18988

Hawkins, M. a. W., Colaizzi, J., Gunstad, J., Hughes, J. W., Mullins, L. L., Betts, N., … Lovallo, W. R. (2018). Cognitive and Self-regulatory Mechanisms of Obesity Study (COSMOS): Study protocol for a randomized controlled weight loss trial examining change in biomarkers, cognition, and self-regulation across two behavioral treatments. Contemporary Clinical Trials, 66, 20–27. https://doi.org/10.1016/j.cct.2017.12.010

Hilger-Kolb, J., Bosle, C., Motoc, I., & Hoffmann, K. (2017). Associations between dietary factors and obesity-related biomarkers in healthy children and adolescents – a systematic review. Nutrition Journal, 16(1), 85. https://doi.org/10.1186/s12937-017-0300-3

Hulsmans, M., & Holvoet, P. (2013). MicroRNAs as early biomarkers in obesity and related metabolic and cardiovascular diseases. Current Pharmaceutical Design, 19(32), 5704–5717.

Indumathy, J., Pal, G. K., Pal, P., Ananthanarayanan, P. H., Parija, S. C., Balachander, J., & Dutta, T. K. (2015). Association of sympathovagal imbalance with obesity indices, and abnormal metabolic biomarkers and cardiovascular parameters. Obesity Research & Clinical Practice, 9(1), 55–66. https://doi.org/10.1016/j.orcp.2014.01.007

Iwasaki, M., Le Marchand, L., Franke, A. A., Hamada, G. S., Miyajima, N. T., Sharma, S., … Tsugane, S. (2016). Comparison of plasma levels of obesity-related biomarkers among Japanese populations in Tokyo, Japan, São Paulo, Brazil, and Hawaii, USA. European Journal of Cancer Prevention: The Official Journal of the European Cancer Prevention Organisation (ECP), 25(1), 41–49. https://doi.org/10.1097/CEJ.0000000000000123

Jacobs, C. A., Vranceanu, A.-M., Thompson, K. L., & Lattermann, C. (2018). Rapid Progression of Knee Pain and Osteoarthritis Biomarkers Greatest for Patients with Combined Obesity and Depression: Data from the Osteoarthritis Initiative. Cartilage, 1947603518777577. https://doi.org/10.1177/1947603518777577

Ji, Y., Park, S., Chung, Y., Kim, B., Park, H., Huang, E., … Holzapfel, W. H. (2019). Amelioration of obesity-related biomarkers by Lactobacillus sakei CJLS03 in a high-fat diet-induced obese murine model. Scientific Reports, 9(1), 6821. https://doi.org/10.1038/s41598-019-43092-y

Kannan, S., Acosta, L. M., Acevedo-Garcia, D., Divjan, A., Bracero, L. A., Perzanowski, M. S., & Chew, G. L. (2013). Sociocultural characteristics, obesity and inflammatory biomarkers in Puerto Rican toddlers born in New York City. Pediatric Allergy and Immunology: Official Publication of the European Society of Pediatric Allergy and Immunology, 24(5), 487–492. https://doi.org/10.1111/pai.12084

Katsareli, E. A., & Dedoussis, G. V. (2014). Biomarkers in the field of obesity and its related comorbidities. Expert Opinion on Therapeutic Targets, 18(4), 385–401. https://doi.org/10.1517/14728222.2014.882321

Kim, D.-H., Kim, H., Jeong, D., Kang, I.-B., Chon, J.-W., Kim, H.-S., … Seo, K.-H. (2017). Kefir alleviates obesity and hepatic steatosis in high-fat diet-fed mice by modulation of gut microbiota and mycobiota: targeted and untargeted community analysis with correlation of biomarkers. The Journal of Nutritional Biochemistry, 44, 35–43. https://doi.org/10.1016/j.jnutbio.2017.02.014

Lafortuna, C. L., Tovar, A. R., Rastelli, F., Tabozzi, S. A., Caramenti, M., Orozco-Ruiz, X., … Bertoli, G. (2017). Clinical, functional, behavioural and epigenomic biomarkers of obesity. Frontiers in Bioscience (Landmark Edition), 22, 1655–1681.

Levy, E., Saenger, A. K., Steffes, M. W., & Delvin, E. (2017). Pediatric Obesity and Cardiometabolic Disorders: Risk Factors and Biomarkers. EJIFCC, 28(1), 6–24.

Lloret-Linares, C., Miyauchi, E., Luo, H., Labat, L., Bouillot, J.-L., Poitou, C., … Declèves, X. (2016). Oral Morphine Pharmacokinetic in Obesity: The Role of P-Glycoprotein, MRP2, MRP3, UGT2B7, and CYP3A4 Jejunal Contents and Obesity-Associated Biomarkers. Molecular Pharmaceutics, 13(3), 766–773. https://doi.org/10.1021/acs.molpharmaceut.5b00656

Lorente-Cebrián, S., González-Muniesa, P., Milagro, F. I., & Martínez, J. A. (2019). MicroRNAs and other non-coding RNAs in adipose tissue and obesity: emerging roles as biomarkers and therapeutic targets. Clinical Science (London, England: 1979), 133(1), 23–40. https://doi.org/10.1042/CS20180890

Lubrano, C., Valacchi, G., Specchia, P., Gnessi, L., Rubanenko, E. P., Shuginina, E. A., … De Luca, C. (2015). Integrated Haematological Profiles of Redox Status, Lipid, and Inflammatory Protein Biomarkers in Benign Obesity and Unhealthy Obesity with Metabolic Syndrome. Oxidative Medicine and Cellular Longevity, 2015, 490613. https://doi.org/10.1155/2015/490613

Luciano, R., Barraco, G. M., Muraca, M., Ottino, S., Spreghini, M. R., Sforza, R. W., … Manco, M. (2015). Biomarkers of Alzheimer disease, insulin resistance, and obesity in childhood. Pediatrics, 135(6), 1074–1081. https://doi.org/10.1542/peds.2014-2391

MacKintosh, M. L., Derbyshire, A. E., McVey, R. J., Bolton, J., Nickkho-Amiry, M., Higgins, C. L., … Crosbie, E. J. (2019). The impact of obesity and bariatric surgery on circulating and tissue biomarkers of endometrial cancer risk. International Journal of Cancer, 144(3), 641–650. https://doi.org/10.1002/ijc.31913

Marcondes, J. P. de C., Andrade, P. F. B., Sávio, A. L. V., Silveira, M. A. D., Rudge, M. V. C., & Salvadori, D. M. F. (2018). BCL2 and miR-181a transcriptional alterations in umbilical-cord blood cells can be putative biomarkers for obesity. Mutation Research. Genetic Toxicology and Environmental Mutagenesis, 836(Pt B), 90–96. https://doi.org/10.1016/j.mrgentox.2018.06.009

Miller, A. L., Lee, H. J., & Lumeng, J. C. (2015). Obesity-associated biomarkers and executive function in children. Pediatric Research, 77(1–2), 143–147. https://doi.org/10.1038/pr.2014.158

Montilla, M., Santi, M. J., Carrozas, M. A., & Ruiz, F. A. (2014). Biomarkers of the prothrombotic state in abdominal obesity. Nutricion Hospitalaria, 31(3), 1059–1066. https://doi.org/10.3305/nh.2015.31.3.8168

Mozafarizadeh, M., Mohammadi, M., Sadeghi, S., Hadizadeh, M., Talebzade, T., & Houshmand, M. (2019). Evaluation of FTO rs9939609 and MC4R rs17782313 Polymorphisms as Prognostic Biomarkers of Obesity: A Population-based Cross-sectional Study. Oman Medical Journal, 34(1), 56–62. https://doi.org/10.5001/omj.2019.09

Nasr, H. B., Dimassi, S., M’hadhbi, R., Debbabi, H., Kortas, M., Tabka, Z., & Chahed, K. (2016). Functional G894T (rs1799983) polymorphism and intron-4 VNTR variant of nitric oxide synthase (NOS3) gene are susceptibility biomarkers of obesity among Tunisians. Obesity Research & Clinical Practice, 10(4), 465–475. https://doi.org/10.1016/j.orcp.2015.04.008

Netto, B. D. M., Bettini, S. C., Clemente, A. P. G., Ferreira, J. P. de C., Boritza, K., Souza, S. de F., … Dâmaso, A. R. (2015). Roux-en-Y gastric bypass decreases pro-inflammatory and thrombotic biomarkers in individuals with extreme obesity. Obesity Surgery, 25(6), 1010–1018. https://doi.org/10.1007/s11695-014-1484-7

Nimptsch, K., Konigorski, S., & Pischon, T. (2019). Diagnosis of obesity and use of obesity biomarkers in science and clinical medicine. Metabolism: Clinical and Experimental, 92, 61–70. https://doi.org/10.1016/j.metabol.2018.12.006

Nimptsch, K., & Pischon, T. (2016). Obesity Biomarkers, Metabolism and Risk of Cancer: An Epidemiological Perspective. Recent Results in Cancer Research. Fortschritte Der Krebsforschung. Progres Dans Les Recherches Sur Le Cancer, 208, 199–217. https://doi.org/10.1007/978-3-319-42542-9_11

Olza, J., Ruperez, A. I., Gil-Campos, M., Leis, R., Fernandez-Orth, D., Tojo, R., … Aguilera, C. M. (2013). Influence of FTO variants on obesity, inflammation and cardiovascular disease risk biomarkers in Spanish children: a case-control multicentre study. BMC Medical Genetics, 14, 123. https://doi.org/10.1186/1471-2350-14-123

O’Neil, C. E., Nicklas, T. A., Rampersaud, G. C., & Fulgoni, V. L. (2012). 100% orange juice consumption is associated with better diet quality, improved nutrient adequacy, decreased risk for obesity, and improved biomarkers of health in adults: National Health and Nutrition Examination Survey, 2003-2006. Nutrition Journal, 11, 107. https://doi.org/10.1186/1475-2891-11-107

Osadnik, T., Bujak, K., Osadnik, K., Czarnecka, H., Pawlas, N., Reguła, R., … Gąsior, M. (2019). Novel inflammatory biomarkers may reflect subclinical inflammation in young healthy adults with obesity. Endokrynologia Polska, 70(2), 135–142. https://doi.org/10.5603/EP.a2019.0002

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