Preventing COVID-19 Infection by Complementary Medicine and Oral Health

It’s possible that the mechanisms of natural phytotherapeutic remedies used in dental care can prevent the SARS-COV2 virus infection or minimize its clinical manifestations through the modulation of the immune system and counteract viral absorption at the cellular level.

Uncaria Tomentosa and Echinacea are plants with antiviral, antibacterial and immunomodulatory properties. Their main active components are alkaloids, glycosides, triterpenes, polysaccharides which favor immunological, anti-inflammatory, vulnerary activity.

Uncaria Tormetosa acts on a biochemical level as a competitor of the SARS-COV2 virus; Echinacea enhances and modulates the immune response and inhibits viral replication thanks to the flavonoid quercetin.

The use of natural substances could represent a considerable help in countering the coronavirus pandemic. Appropriate clinical studies are desirable to confirm what has been described.

COVID-19 is a disease caused by the SARS-COV-2 virus which can lead to a severe acute respiratory coronavirus syndrome. Today's treatments exist [1-4] but, if not applied with criteria and speed, the coronavirus causes an acute respiratory distress syndrome followed by anemia, acute cardiac injury, and secondary infections [4] with a Fatality Rate of 1,4% [5].

The use of preventive protocols such as distancing, wear the mask and accurate hand hygiene has not prevented a global scaremongering [6-8]. Vaccines effectiveness against contagion was found null, protection against symptomatic infection with the omicron variant rapidly decreases over time after two doses [9-13].

Beyond the already existing allopathic therapies, natural preventive approaches can also be taken into consideration to prevent the disease [14,15].

The coronaviruses, which include COVID 19, are opportunistic infections. Indeed, respiratory viruses infect the human upper respiratory tract, mostly causing mild disease. However, in vulnerable populations, such as neonates, infants, elderly people and immunocompromised individuals, these opportunistic pathogens can also affect the lower respiratory tract, causing more severe disease (e.g., pneumonia) [16].

Furthermore, COVID-19 has oral manifestations of relevant interest in 68% of cases: dysgeusia is the first recognized oral symptom, following ulcer, erosion, bullae, vesicles, pustules, fissured or depapillated tongue, macula, papule, plaque, pigmentation, halitosis, whitish areas, hemorrhagic crust, necrosis, petechiae, swelling, erythema, and spontaneous bleeding. The most common sites of involvement in descending order were the tongue (38%), labial mucosa (26%) and palate (22%).

Oral lesions were nearly equal in both sexes (49% female and 51% male). Older patients with higher severity COVID-19 disease had more diffuse and separate oral lesions. Lack of oral hygiene, opportunistic infections, stress, immunosuppression, vasculitis, and hyperinflammatory response secondary to COVID-19 are the most important predisposing factors for the occurrence of oral lesions [17].

There is sufficient evidence in literature to endorse an association between the presence of periodontal disease and the development and course of respiratory illnesses [18]. There are direct and indirect mechanisms that explain this relationship: from a direct aspiration of periodontal pathogens into the lungs, to the mucosal surfaces’ modification by virulence factors and enzymes released by periodontopathogens that facilitate colonization; or the respiratory epithelium modification via cytokines to promote infection [19].

If periodontal disease is both reflective and deterministic of systemic health [20] some effective natural remedies known and used in the treatment and prevention of periodontitis could also provide valid help in the prevention of viral infections such as SARS-COV-2.

The increase of the immune system, in all its components, should be considered as a prevention of primary importance in the fight against the virus [21].

In this work, some relevant scientific literature concerning two well-known plants in complementary medicine are analyzed: Uncaria Tomentosa (Uncaria T.) also called Una de gato and Echinacea in its variants.

To date, the literature about the interaction of the plant and its chemical components in relation to Covid-19 such as Allium sativum, Camellia sinensis, Zingiber, Nigella sativa, Echinacea spp. Hypericum perforatum, Glycyrrhiza glabra, Scutellaria baicalensis, led to the conclusion that these plants can enhance the immune response [22]. It appears that different types of terpenoids (active chemical components of plants) have promising effects in inhibiting viral replication. In addition, some alkaloid structures (also active chemical components of plants) have strong anti-coronavirus effects. Natural products can inhibit several coronavirus targets such as protein S (Spike protein: allows the virus to anchor itself to human cells via its receptor Angiotensin-converting enzyme 2 (ACE2)) and the replication of viral enzymes such as 3CLpro, PLpro [23] (3-Chymotrypsin-Like proteases and Papain-Like protease: they cleave cellular polyproteins as vital role in viral replication), Helicase [24] (initiates RNA unwinding and potentially contributes to other key functions during viral replication) and RdRp (nonstructural protein 12 RNA-dependent RNA polymerase: viral protein target for antiviral development) [25].

A brief literature analysis was conducted to collect some of the most recent scientific works regarding the specific use of Uncaria T. and Echinacea in the infection of COVID 19 due to their traditional ability to promote overall immune function and to reduce inflammation. These plants have therapeutic indications also in periodontal diseases. The effectiveness of Echinacea has been verified in gingivitis and periodontal disease in combination with sage, peppermint oil, menthol and chamomile [26] and it has been recently proposed as a mouthwash too [27].

Uncaria T. is an anti-inflammatory, antiresorptive, and potential bone anabolic product to be considered as a therapeutic alternative to control bone diseases like periodontitis [28] and to inhibit oral cavity microorganisms [29,30].

The search results are summarized in table 1.

It should be considered that periodontitis, independently of any other pathology, raises IL-6 the same one that is overproduced in COVID 19 disease [31]. Between periodontitis and COVID-19 disease there is the same high expression of ACE-2 and CD147 (also known as extracellular MMP inducer. In periodontitis it has been indicated that regulate the collagenolytic balance [32]) and the similar overexpression of several cytokines [33].

Since the past centuries Uncaria T., also called cat's claw, is a plant considered immunomodulatory by the Curanderos in the South American continent. Many scientific studies confirmed a lot of properties of this phytocomplex [34,35]. Its main components are pentacyclic oxindole alkaloids, glycosides of quinovic acid, polyhydroxylated triterpenes, tannins. The main activity of the drug has been defined as antiphlogistic, immunomodulatory, antiviral.

The antiphlogistic activity seems to be carried out mainly by quinovic acid adjuvanted by alkaloids and procyanidins [36], consequentially Cat's claw inhibits the production of proinflammatory cytokines such as TNF-alpha [37,38].

The ability of its alkaloids to fight the Dengue Virus is recognized [39] as well as the antiviral capabilities [40,41]. Mechanisms of the antiviral activity of the hydroalcoholic extract of Uncaria T. have been elucidated: its alkaloids (pentacyclic alkaloids) induced apoptosis of infected cells and reduced inflammatory mediators such as TNF-α and IFN-α with similar effects to dexamethasone [39] and herpes simplex virus type 1 (HSV-1) [42]. It has recently been demonstrated in an in vitro study that Uncaria T. possesses the anti-HIV property [43].

Disease-active periodontitis contains high loads of reactivated herpesviruses and tends to be associated with latent herpesviruses and with high-titer cytomegalovirus IgG serum antibody [44], that explains the Uncaria T.’ use in medicine and oral diseases especially by gels or mouthwashes [45]. Lima, et al. [28] demonstrated that administration of Uncaria T. extract reduce inflammatory-induced bone loss in periodontitis animal model by means of direct effect on osteoclastogenesis. It not only acts as an antiresorptive agent by inhibiting osteoclasts formation but also osteoclasts function by blocking the expression of Cathepsin K [28] (enzyme that efficiently cleaves type I collagen at the triple helical regions at pH values between 4.5 and 6.6).

Uncaria T. is mentioned in a recent review [46] where twelve therapeutic agents are discussed, they could play a role in the prophylaxis and amelioration symptoms associated with COVID-19 (as adjunctive substances). In this article specific anti-inflammatory capacities are attributed to Uncaria T. in the improvement of symptoms. The initial disease stage occurs at the time of viral inoculation and incubation with symptoms typically nonspecific (e.g., cough, fever, diarrhea). Just before this phase, the strengthening of the immune defenses should be concentrated. The authors advise 800 mg/day in order to inhibits the release of cytokines (IL-, IL-6, IL-8, and TNF-), chemokines (CCL2, CCL3, and CCL5) and the expression of NF-kβ inflammatory enzymes (COX-1, COX-2, PLA2, iNOS) [47,48].

Yepes-Pérez et al. [49] based research on the virus-cell receptor coupling relationship. The SARS-COV-2 "hooks" the target cell through the spike protein, which binds to the specific receptor ACE -2. Structural bioinformatics approaches identified several bioactive compounds of Uncaria T. with potential therapeutic effect by double strong interaction with the interface of RBD-ACE-2 and ACE-2 binding site on the viral spike of SARS-CoV-2 RBD.

The same author publishes a multilevel computational study [50] to evaluate the potential antiviral properties of components of the medicinal herb, focusing on the inhibition of the 3CLpro protease, which is an essential enzyme of SARS-CoV-2, which plays a key role in viral replication and transcription within the cell. The results suggest the potential efficacy of Uncaria T. as a complementary and/or alternative medicine for the treatment of COVID-19.

Main components of Echinacea are alkylamides, alkaloids, polyphenolic compounds, flavonoid glucosides, glycoproteins, essential oils, polyins, polysaccharides and other minor components that are part of the phytocomplex such as betaines, triterpenes, sesquiterpenes, inulin. The main activity of the drug has been defined immunological, anti-inflammatory, and vulnerary [51,52].

Clinical studies have shown that the administration of arabinogalactans (polysaccharide components of Echinacea) favors the increase of lymphocytes, the phagocytic activity of macrophages, enhancing any immune response against bacterial, viral, or other external agents [53].

Echinacea extracts stimulate the immune system and bioavailable alkamides are key players by interacting with immunomodulatory cannabinoid receptors [54].

The most present molecule in Echinacea is Quercetin, the major polyphenolic flavonoid found in various vegetables and fruits, such as berries, lovage, capers, cilantro, dill, apples, and onions [55]. Quercetin is one of the most important plant molecules, showing pharmacological activity such as antiviral, anti‐atopic, pro‐metabolic, and anti-inflammatory effects. Smith and Smith [56] demonstrated for quercetin a theoretical, but significant, capability to interfere with SARS‐CoV‐2 replication as it was identified as ligands for the S protein: ACE2 receptor interface. The quercetin dose‐dependently anti-inflammatory properties decrease the mRNA and protein levels of ICAM‐1(a cell surface glycoprotein expressed at a low basal level in immune, endothelial and epithelial cells, but is up-regulated in response to inflammatory stimulation [57]), IL‐6, IL‐8, and MCP‐1 (Monocyte chemoattractant protein-1) [58]; this mechanism favors the prevention of strong inflammatory cascade triggered during SARS‐CoV‐2 infection, but also the periodontal overproduction of proinflammatory cytokines and matrix metalloproteinases.

Extensive scientific literature describes the potential antiviral role of quercetin administered at very high dosages (1,000 mg/dose) for 12 weeks reducing the days of illness in middle‐aged and elderly subjects [59].

A recent study [60] indicates Echinacea as a bioactive substance against SARS-COV-2 infection.

It shows significant effects via inhibition of the 3CLpro enzyme. The plant has a potent activity against HCoV-229E, SARS-CoV and MERS-CoV with IC50 values of 3.2, 50 and 50 μg/ml respectively.

Flavonoids stand out among the blockers of the ACE2 receptor, but they have also shown anti-replication activities; the inactivation of the viral particles is an effect of Echinacea: the multicomponent extract non-specifically and irreversibly interfere with viral docking receptors to block the infectivity of pathogens and combining with vitamin D, vitamin C, and zinc has been suggested to reduce the risk of infection and death from SARS-CoV-2 [61,62].

There are natural substances capable of increasing the immune system, nature provides a huge reservoir of anti-infective compounds [54]. The Uncaria T. and Echinacea’s immunomodulatory properties, combined with the non-toxicity of these plants, make it advisable to spread the use of these elements of complementary medicine.

Between Periodontitis and SARS-COV-2 infection there are some similar mechanisms which makes the hypothesis of etiopathogenetic correlations plausible [20,31]. Periodontitis has been shown to be a risk factor for: cardiovascular disease, diabetes mellitus, respiratory disease, rheumatoid arthritis and other conditions [63]. Periodontopathic bacteria were found in the bronchoalveolar lavage fluid of patients suffering from pneumonia and the association of periodontitis and diabetes could multiply the risk of pneumonia even in the absence of the SARS-CoV-2 infection [31]. SARS-COV-2 is a respiratory virus that mainly affects the middle-aged and elderly, as well as people with underlying diseases such as hypertension, diabetes, obesity or with heart and kidney problems.

Another similarity is represented by the fact that periodontitis has an excellent prognosis if intercepted early but can cause severe damage to the dentition with delay in therapy; the same pathogenetic mechanism develops for the SARS-COV-2 infection.

Considering the studies, an analysis of the risk of periodontitis cross-referenced with the presence of systemic noncommunicable diseases and with the risk to develop COVID-19 disease or other coronavirus diseases, might suggest the use of natural preventive approaches to help the body to a correct immune-inflammatory response in the fight against both diseases.

Certainly, more basic and clinical investigations into this issue are necessary for effective therapeutic approaches.

Authors declare that there is no financial interest or conflict of interest.

1. Kory P, Meduri GU, Varon J, Iglesias J, Marik PE. Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19. Am J Ther. 2021 Apr 22;28(3):e299-e318. doi: 10.1097/MJT.0000000000001377. Erratum in: Am J Ther. 2021 Nov-Dec 01;28(6):e813. doi: 10.1097/MJT.0000000000001458. PMID: 34375047; PMCID: PMC8088823.
2. Hu GY, Liang CA, Lin PC, Lin CY. Ivermectin's Role in the Prevention of COVID-19: A Systematic Review and Meta-Analysis. J Clin Pharmacol. 2023 Mar;63(3):288-297. doi: 10.1002/jcph.2178. Epub 2022 Dec 10. PMID: 36399336.
3. Akhter J, Quéromès G, Pillai K, Kepenekian V, Badar S, Mekkawy AH, Frobert E, Valle SJ, Morris DL. The Combination of Bromelain and Acetylcysteine (BromAc) Synergistically Inactivates SARS-CoV-2. Viruses. 2021 Mar 6;13(3):425. doi: 10.3390/v13030425. PMID: 33800932; PMCID: PMC7999995.
4. Majid S, Khan MS, Rashid S, Niyaz A, Farooq R, Bhat SA, Wani HA, Qureshi W. COVID-19: Diagnostics, Therapeutic Advances, and Vaccine Development. Curr Clin Microbiol Rep. 2021;8(3):152-166. doi: 10.1007/s40588-021-00157-9. Epub 2021 Feb 15. PMID: 33614398; PMCID: PMC7883962.
5. Sharma A, Ahmad Farouk I, Lal SK. COVID-19: A Review on the Novel Coronavirus Disease Evolution, Transmission, Detection, Control and Prevention. Viruses. 2021 Jan 29;13(2):202. doi: 10.3390/v13020202. PMID: 33572857; PMCID: PMC7911532.
6. Kisielinski K, Giboni P, Prescher A, Klosterhalfen B, Graessel D, Funken S, Kempski O, Hirsch O. Is a Mask That Covers the Mouth and Nose Free from Undesirable Side Effects in Everyday Use and Free of Potential Hazards? Int J Environ Res Public Health. 2021 Apr 20;18(8):4344. doi: 10.3390/ijerph18084344. PMID: 33923935; PMCID: PMC8072811.
7. Jefferson T, Dooley L, Ferroni E, Al-Ansary LA, van Driel ML, Bawazeer GA, Jones MA, Hoffmann TC, Clark J, Beller EM, Glasziou PP, Conly JM. Physical interventions to interrupt or reduce the spread of respiratory viruses. Cochrane Database Syst Rev. 2023 Jan 30;1(1):CD006207. doi: 10.1002/14651858.CD006207.pub6. PMID: 36715243; PMCID: PMC9885521.
8. Allen DW. Covid-19 Lockdown Cost/Benefits: A Critical Assessment of the Literature. Int J Econ Bus. 2022 Jan 2;29(1):1–32.
9. Korosec CS, Farhang-Sardroodi S, Dick DW, Gholami S, Ghaemi MS, Moyles IR, Craig M, Ooi HK, Heffernan JM. Long-term durability of immune responses to the BNT162b2 and mRNA-1273 vaccines based on dosage, age and sex. Sci Rep. 2022 Dec 8;12(1):21232. doi: 10.1038/s41598-022-25134-0. PMID: 36481777; PMCID: PMC9732004.
10. Florentino PTV, Millington T, Cerqueira-Silva T, Robertson C, de Araújo Oliveira V, Júnior JBS, Alves FJO, Penna GO, Vital Katikireddi S, Boaventura VS, Werneck GL, Pearce N, McCowan C, Sullivan C, Agrawal U, Grange Z, Ritchie LD, Simpson CR, Sheikh A, Barreto ML, Rudan I, Barral-Netto M, Paixão ES. Vaccine effectiveness of two-dose BNT162b2 against symptomatic and severe COVID-19 among adolescents in Brazil and Scotland over time: a test-negative case-control study. Lancet Infect Dis. 2022 Nov;22(11):1577-1586. doi: 10.1016/S1473-3099(22)00451-0. Epub 2022 Aug 8. PMID: 35952702; PMCID: PMC9359673.
11. Uschner D, Bott M, Lagarde WH, Keating J, Tapp H, Berry AA, Seals AL, Munawar I, Schieffelin J, Yukich J, Santacatterina M, Gunaratne M, Fette LM, Burke B, Strylewicz G, Edelstein SL, Ahmed A, Miller K, Sanders JW, Herrington D, Weintraub WS, Runyon MS, On Behalf Of The Covid-Community Research Partnership. Breakthrough SARS-CoV-2 Infections after Vaccination in North Carolina. Vaccines (Basel). 2022 Nov 13;10(11):1922. doi: 10.3390/vaccines10111922. PMID: 36423018; PMCID: PMC9695352.
12. Liew J, Gianfrancesco M, Harrison C, Izadi Z, Rush S, Lawson-Tovey S, Jacobsohn L, Ja C, Hyrich KL, Gossec L, Strangfeld A, Carmona L, Schäfer M, Frãzao-Mateus E, Bulina I, Stafford F, Tufan A, Graver C, Yardımcı GK, Zepa J, Al Emadi S, Cook C, Abutiban F, Dey D, Katigbak G, Kaufman L, Kowalski E, Martínez-Martínez MU, Patel NJ, Reyes-Cordero G, Salido E, Smith E, Snow D, Sparks J, Wise L, Bhana S, Gore-Massy M, Grainger R, Hausmann J, Sirotich E, Sufka P, Wallace Z, Machado PM, Robinson PC, Yazdany J. SARS-CoV-2 breakthrough infections among vaccinated individuals with rheumatic disease: results from the COVID-19 Global Rheumatology Alliance provider registry. RMD Open. 2022 Apr;8(1):e002187. doi: 10.1136/rmdopen-2021-002187. PMID: 35387864; PMCID: PMC8987210.
13. Keehner J, Horton LE, Binkin NJ, Laurent LC; SEARCH Alliance; Pride D, Longhurst CA, Abeles SR, Torriani FJ. Resurgence of SARS-CoV-2 Infection in a Highly Vaccinated Health System Workforce. N Engl J Med. 2021 Sep 30;385(14):1330-1332. doi: 10.1056/NEJMc2112981. Epub 2021 Sep 1. PMID: 34469645; PMCID: PMC8451183.
14. Feyaerts AF, Luyten W. Vitamin C as prophylaxis and adjunctive medical treatment for COVID-19? Nutrition. 2020 Nov-Dec;79-80:110948. doi: 10.1016/j.nut.2020.110948. Epub 2020 Jul 25. PMID: 32911430; PMCID: PMC7381407.
15. Szarpak L, Filipiak KJ, Gasecka A, Gawel W, Koziel D, Jaguszewski MJ, Chmielewski J, Gozhenko A, Bielski K, Wroblewski P, Savytskyi I, Szarpak L, Rafique Z. Vitamin D supplementation to treat SARS-CoV-2 positive patients. Evidence from meta-analysis. Cardiol J. 2022;29(2):188-196. doi: 10.5603/CJ.a2021.0122. Epub 2021 Oct 13. PMID: 34642923; PMCID: PMC9007480.
16. Desforges M, Le Coupanec A, Dubeau P, Bourgouin A, Lajoie L, Dubé M, Talbot PJ. Human Coronaviruses and Other Respiratory Viruses: Underestimated Opportunistic Pathogens of the Central Nervous System? Viruses. 2019 Dec 20;12(1):14. doi: 10.3390/v12010014. PMID: 31861926; PMCID: PMC7020001.
17. Iranmanesh B, Khalili M, Amiri R, Zartab H, Aflatoonian M. Oral manifestations of COVID-19 disease: A review article. Dermatol Ther. 2021 Jan;34(1):e14578. doi: 10.1111/dth.14578. Epub 2020 Dec 13. PMID: 33236823; PMCID: PMC7744903.
18. Gomes‐Filho IS, Cruz SSD, Trindade SC, Passos‐Soares JDS, Carvalho‐Filho PC, Figueiredo ACMG, et al. Periodontitis and respiratory diseases: A systematic review with meta‐analysis. Oral Dis. 2020 Mar;26(2):439–46.
19. Sampson V, Kamona N, Sampson A. Could there be a link between oral hygiene and the severity of SARS-CoV-2 infections? Br Dent J. 2020 Jun;228(12):971-975. doi: 10.1038/s41415-020-1747-8. PMID: 32591714; PMCID: PMC7319209.
20. Gupta S, Mohindra R, Singla M, Khera S, Sahni V, Kanta P, Soni RK, Kumar A, Gauba K, Goyal K, Singh MP, Ghosh A, Kajal K, Mahajan V, Bhalla A, Sorsa T, Räisänen I. The clinical association between Periodontitis and COVID-19. Clin Oral Investig. 2022 Feb;26(2):1361-1374. doi: 10.1007/s00784-021-04111-3. Epub 2021 Aug 27. PMID: 34448073; PMCID: PMC8390180.
21. Minich DM, Hanaway PJ. The Functional Medicine Approach to COVID-19: Nutrition and Lifestyle Practices for Strengthening Host Defense. Integr Med (Encinitas). 2020 May 9;19(Suppl 1):54-62. PMID: 33041708; PMCID: PMC7482148.
22. Shahzad F, Anderson D, Najafzadeh M. The Antiviral, Anti-Inflammatory Effects of Natural Medicinal Herbs and Mushrooms and SARS-CoV-2 Infection. Nutrients. 2020 Aug 25;12(9):2573. doi: 10.3390/nu12092573. PMID: 32854262; PMCID: PMC7551890.
23. Cannalire R, Cerchia C, Beccari AR, Di Leva FS, Summa V. Targeting SARS-CoV-2 Proteases and Polymerase for COVID-19 Treatment: State of the Art and Future Opportunities. J Med Chem. 2022 Feb 24;65(4):2716-2746. doi: 10.1021/acs.jmedchem.0c01140. Epub 2020 Nov 13. PMID: 33186044; PMCID: PMC7688049.
24. Grimes SL, Denison MR. The Coronavirus helicase in replication. Virus Res. 2024 Aug;346:199401. doi: 10.1016/j.virusres.2024.199401. Epub 2024 May 31. PMID: 38796132; PMCID: PMC11177069.
25. Boozari M, Hosseinzadeh H. Natural products for COVID-19 prevention and treatment regarding to previous coronavirus infections and novel studies. Phytother Res. 2021 Feb;35(2):864-876. doi: 10.1002/ptr.6873. Epub 2020 Sep 27. PMID: 32985017.
26. Taheri JB, Azimi S, Rafieian N, Zanjani HA. Herbs in dentistry. Int Dent J. 2011 Dec;61(6):287-96. doi: 10.1111/j.1875-595X.2011.00064.x. Epub 2011 Nov 3. PMID: 22117784; PMCID: PMC9374842.
27. Safarabadi M, Ghaznavi-Rad E, Pakniyat A, Rezaie K, Jadidi A. Comparing the Effect of Echinacea and Chlorhexidine Mouthwash on the Microbial Flora of Intubated Patients Admitted to the Intensive Care Unit. Iran J Nurs Midwifery Res. 2017 Nov-Dec;22(6):481-485. doi: 10.4103/ijnmr.IJNMR_92_16. PMID: 29184589; PMCID: PMC5684798.
28. Lima V, Melo IM, Taira TM, Buitrago LYW, Fonteles CSR, Leal LKAM, Souza ASQ, Almeida TS, Costa Filho RND, Moraes MO, Cunha FQ, Fukada SY. Uncaria tomentosa reduces osteoclastic bone loss in vivo. Phytomedicine. 2020 Dec;79:153327. doi: 10.1016/j.phymed.2020.153327. Epub 2020 Sep 2. PMID: 32920290.
29. Ccahuana-Vasquez RA, Santos SS, Koga-Ito CY, Jorge AO. Antimicrobial activity of Uncaria tomentosa against oral human pathogens. Braz Oral Res. 2007 Jan-Mar;21(1):46-50. doi: 10.1590/s1806-83242007000100008. PMID: 17426895.
30. Nedumaran N, Rajasekar A, Venkatakrishnan S, Wajeeha H. An In Vitro Study of Antioxidant, Anti-inflammatory, and Cytotoxic Effects of Echinacea-Mediated Zinc Oxide Nanoparticles. Cureus. 2024 Jul 25;16(7):e65354. doi: 10.7759/cureus.65354. PMID: 39184651; PMCID: PMC11344488.
31. Campisi G, Bizzoca ME, Lo Muzio L. COVID-19 and periodontitis: reflecting on a possible association. Head Face Med. 2021 May 11;17(1):16. doi: 10.1186/s13005-021-00267-1. PMID: 33975613; PMCID: PMC8110692.
32. Lai TM, Kuo PJ, Lin CY, Chin YT, Lin HL, Chiu HC, Fu MMJ, Fu E. CD147 self-regulates matrix metalloproteinase-2 release in gingival fibroblasts after coculturing with U937 monocytic cells. J Periodontol. 2020 May;91(5):651-660. doi: 10.1002/JPER.19-0278. Epub 2019 Oct 21. PMID: 31557319.
33. Wu D, Yang XO. TH17 responses in cytokine storm of COVID-19: An emerging target of JAK2 inhibitor Fedratinib. J Microbiol Immunol Infect. 2020 Jun;53(3):368-370. doi: 10.1016/j.jmii.2020.03.005. Epub 2020 Mar 11. PMID: 32205092; PMCID: PMC7156211.
34. Domingues A, Sartori A, Valente LM, Golim MA, Siani AC, Viero RM. Uncaria tomentosa aqueous-ethanol extract triggers an immunomodulation toward a Th2 cytokine profile. Phytother Res. 2011 Aug;25(8):1229-35. doi: 10.1002/ptr.3549. Epub 2011 Jun 8. PMID: 21656603.
35. Núñez C, Lozada-Requena I, Ysmodes T, Zegarra D, Saldaña F, Aguilar J. Nmunomodulación de Uncaria tomentosa sobre células dendríticas, il-12 y perfil TH1/TH2/TH17 en cáncer de mama [Immunomodulation of Uncaria tomentosa over dendritic cells, il-12 and profile TH1/TH2/TH17 in breast cancer]. Rev Peru Med Exp Salud Publica. 2015 Oct;32(4):643-51. Spanish. PMID: 26732910.
36. Capasso F. Farmacognosia: botanica, chimica e farmacologia delle piante medicinalli. 2nd ed. Milano: Springer; 2011. 489 p.
37. Allen-Hall L, Arnason JT, Cano P, Lafrenie RM. Uncaria tomentosa acts as a potent TNF-alpha inhibitor through NF-kappaB. J Ethnopharmacol. 2010 Feb 17;127(3):685-93. doi: 10.1016/j.jep.2009.12.004. Epub 2009 Dec 6. PMID: 19995599.
38. Villegas Vilchez LF, Ascencios JH, Dooley TP. Prophylaxis and Treatment of Inflammation with Pentacyclic Chemotype of Uncaria tomentosa. Integr Med (Encinitas). 2023 Jul;22(3):22-27. PMID: 37534020; PMCID: PMC10393379.
39. Reis SR, Valente LM, Sampaio AL, Siani AC, Gandini M, Azeredo EL, D'Avila LA, Mazzei JL, Henriques Md, Kubelka CF. Immunomodulating and antiviral activities of Uncaria tomentosa on human monocytes infected with Dengue Virus-2. Int Immunopharmacol. 2008 Mar;8(3):468-76. doi: 10.1016/j.intimp.2007.11.010. Epub 2007 Dec 26. PMID: 18279801.
40. Heitzman ME, Neto CC, Winiarz E, Vaisberg AJ, Hammond GB. Ethnobotany, phytochemistry and pharmacology of Uncaria (Rubiaceae). Phytochemistry. 2005 Jan;66(1):5-29. doi: 10.1016/j.phytochem.2004.10.022. PMID: 15649507.
41. Williams JE. Review of antiviral and immunomodulating properties of plants of the Peruvian rainforest with a particular emphasis on Una de Gato and Sangre de Grado. Altern Med Rev. 2001 Dec;6(6):567-79. PMID: 11804547.
42. Caon T, Kaiser S, Feltrin C, de Carvalho A, Sincero TC, Ortega GG, Simões CM. Antimutagenic and antiherpetic activities of different preparations from Uncaria tomentosa (cat's claw). Food Chem Toxicol. 2014 Apr;66:30-5. doi: 10.1016/j.fct.2014.01.013. Epub 2014 Jan 18. PMID: 24447975.
43. Shahzad M, Chen H, Akhtar T, Rafi A, Zafar MS, Zheng YT. Human immunodeficiency virus: The potential of medicinal plants as antiretroviral therapy. J Med Virol. 2022 Jun;94(6):2669-2674. doi: 10.1002/jmv.27648. Epub 2022 Feb 25. PMID: 35128696.
44. Slots J. Periodontitis: facts, fallacies and the future. Periodontol 2000. 2017 Oct;75(1):7-23. doi: 10.1111/prd.12221. PMID: 28758294.
45. Dioguardi M, Spirito F, Sovereto D, Ballini A, Alovisi M, Lo Muzio L. Application of the Extracts of Uncaria tomentosa in Endodontics and Oral Medicine: Scoping Review. J Clin Med. 2022 Aug 26;11(17):5024. doi: 10.3390/jcm11175024. PMID: 36078953; PMCID: PMC9457483.
46. Ferreira AO, Polonini HC, Dijkers ECF. Postulated Adjuvant Therapeutic Strategies for COVID-19. J Pers Med. 2020 Aug 5;10(3):80. doi: 10.3390/jpm10030080. PMID: 32764275; PMCID: PMC7565841.
47. Aguilar JL, Rojas P, Marcelo A, Plaza A, Bauer R, Reininger E, Klaas CA, Merfort I. Anti-inflammatory activity of two different extracts of Uncaria tomentosa (Rubiaceae). J Ethnopharmacol. 2002 Jul;81(2):271-6. doi: 10.1016/s0378-8741(02)00093-4. PMID: 12065162.
48. Azevedo BC, Morel LJF, Carmona F, Cunha TM, Contini SHT, Delprete PG, Ramalho FS, Crevelin E, Bertoni BW, França SC, Borges MC, Pereira AMS. Aqueous extracts from Uncaria tomentosa (Willd. ex Schult.) DC. reduce bronchial hyperresponsiveness and inflammation in a murine model of asthma. J Ethnopharmacol. 2018 May 23;218:76-89. doi: 10.1016/j.jep.2018.02.013. Epub 2018 Feb 10. PMID: 29432856.
49. Yepes-Pérez AF, Herrera-Calderon O, Quintero-Saumeth J. Uncaria tomentosa (cat's claw): a promising herbal medicine against SARS-CoV-2/ACE-2 junction and SARS-CoV-2 spike protein based on molecular modeling. J Biomol Struct Dyn. 2022 Mar;40(5):2227-2243. doi: 10.1080/07391102.2020.1837676. Epub 2020 Oct 29. PMID: 33118480; PMCID: PMC7657399.
50. Yepes-Pérez AF, Herrera-Calderon O, Sánchez-Aparicio JE, Tiessler-Sala L, Maréchal JD, Cardona-G W. Investigating Potential Inhibitory Effect of Uncaria tomentosa (Cat's Claw) against the Main Protease 3CLpro of SARS-CoV-2 by Molecular Modeling. Evid Based Complement Alternat Med. 2020 Sep 30;2020:4932572. doi: 10.1155/2020/4932572. PMID: 33029165; PMCID: PMC7532411.
51. Sarri Stefano. Uso dei prodotti naturali nelle patologie odontoiatriche. Vol. 1. AriesDue; 2020.
52. Catanzaro M, Corsini E, Rosini M, Racchi M, Lanni C. Immunomodulators Inspired by Nature: A Review on Curcumin and Echinacea. Molecules. 2018 Oct 26;23(11):2778.
53. Choi EM, Kim AJ, Kim YO, Hwang JK. Immunomodulating activity of arabinogalactan and fucoidan in vitro. J Med Food. 2005 Winter;8(4):446-53. doi: 10.1089/jmf.2005.8.446. PMID: 16379554.
54. Hensel A, Bauer R, Heinrich M, Spiegler V, Kayser O, Hempel G, Kraft K. Challenges at the Time of COVID-19: Opportunities and Innovations in Antivirals from Nature. Planta Med. 2020 Jul;86(10):659-664. doi: 10.1055/a-1177-4396. Epub 2020 May 20. PMID: 32434254; PMCID: PMC7356065.
55. Anand David AV, Arulmoli R, Parasuraman S. Overviews of Biological Importance of Quercetin: A Bioactive Flavonoid. Pharmacogn Rev. 2016 Jul-Dec;10(20):84-89. doi: 10.4103/0973-7847.194044. PMID: 28082789; PMCID: PMC5214562.
56. Smith M, Smith JC. Repurposing Therapeutics for COVID-19: Supercomputer-Based Docking to the SARS-CoV-2 Viral Spike Protein and Viral Spike Protein-Human ACE2 Interface. Chemistry. 2020.
57. Bui TM, Wiesolek HL, Sumagin R. ICAM-1: A master regulator of cellular responses in inflammation, injury resolution, and tumorigenesis. J Leukoc Biol. 2020 Sep;108(3):787-799. doi: 10.1002/JLB.2MR0220-549R. Epub 2020 Mar 17. PMID: 32182390; PMCID: PMC7977775.
58. Derosa G, Maffioli P, D'Angelo A, Di Pierro F. A role for quercetin in coronavirus disease 2019 (COVID-19). Phytother Res. 2021 Mar;35(3):1230-1236. doi: 10.1002/ptr.6887. Epub 2020 Oct 9. PMID: 33034398; PMCID: PMC7675685.
59. Heinz SA, Henson DA, Austin MD, Jin F, Nieman DC. Quercetin supplementation and upper respiratory tract infection: A randomized community clinical trial. Pharmacol Res. 2010 Sep;62(3):237-42. doi: 10.1016/j.phrs.2010.05.001. Epub 2010 May 15. PMID: 20478383; PMCID: PMC7128946.
60. Khalifa SAM, Yosri N, El-Mallah MF, Ghonaim R, Guo Z, Musharraf SG, Du M, Khatib A, Xiao J, Saeed A, El-Seedi HHR, Zhao C, Efferth T, El-Seedi HR. Screening for natural and derived bio-active compounds in preclinical and clinical studies: One of the frontlines of fighting the coronaviruses pandemic. Phytomedicine. 2021 May;85:153311. doi: 10.1016/j.phymed.2020.153311. Epub 2020 Aug 29. PMID: 33067112; PMCID: PMC7455571.
61. Llivisaca-Contreras SA, Naranjo-Morán J, Pino-Acosta A, Pieters L, Vanden Berghe W, Manzano P, et al. Plants and Natural Products with Activity against Various Types of Coronaviruses: A Review with Focus on SARS-CoV-2. Molecules. 2021 Jul 5;26(13):4099.
62. Grant WB, Lahore H, McDonnell SL, Baggerly CA, French CB, Aliano JL, Bhattoa HP. Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths. Nutrients. 2020 Apr 2;12(4):988. doi: 10.3390/nu12040988. PMID: 32252338; PMCID: PMC7231123.
63. Yamasaki K, Kawanami T, Yatera K, Fukuda K, Noguchi S, Nagata S, Nishida C, Kido T, Ishimoto H, Taniguchi H, Mukae H. Significance of anaerobes and oral bacteria in community-acquired pneumonia. PLoS One. 2013 May 6;8(5):e63103. doi: 10.1371/journal.pone.0063103. PMID: 23671659; PMCID: PMC3646017.