Introduction

The worldwide outbreak of the Coronavirus Disease 2019 (COVID-19) towards the end of 2019 is significantly disrupting various human activities, especially within the healthcare sector.1,2 It is a respiratory condition caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection. People grappling with chronic conditions such as Diabetes Mellitus (DM) often have an elevated mortality rate, a phenomenon attributed to the effects of COVID-19 on the immune system. Additionally, the novel coronavirus targets essential organs including the lungs, brain, kidneys, and heart. These repercussions are implicated in the heightened vulnerability and comorbidity observed in people with chronic illnesses who contract COVID-19.3 The COVID-19 pandemic has impacted daily life not only through infections but also through lockdowns and restrictions. These changes have disrupted lifestyle routines, particularly affecting diabetic patients by complicating blood glucose control and overall health.4,5

DM is a syndrome characterized by signs and symptoms of prolonged high blood glucose.6 According to the 2019 International Diabetes Federation report, the global prevalence of DM is 463 million people, with projections expected to reach 578 million by 2030 and 700 million by 2045. It is estimated that approximately 20% to 50% of COVID-19 patients have DM, a rate significantly higher than the global incidence of the disease.7

In SARS-CoV-2 infection, the host cell plays a crucial role in cross-species transmission. After the host is exposed to the virus, the spike proteins on the surface of SARS-CoV-2 attach to cells that express specific receptors. The protease of the host cell then breaks down the spike protein, enabling the virus to penetrate the cell and replicate.8,9 Angiotensin-converting enzyme-2 (ACE-2) has been recognized as a primary receptor for both SARS-CoV and SARS-CoV-2. It is extensively expressed in various tissues, including the respiratory tract, intestines, kidneys, heart, brain neurons, arterial and venous endothelium, pancreas, and immune cells.8,10

COVID-19 initially became a pandemic in March 2020, and until early November 2021, it has infected 254 million people worldwide and has a two-way relationship with DM. Patients with COVID-19 have also shown severe metabolic complications from pre-existing DM, including hyperosmolarity and diabetic ketoacidosis requiring high doses of insulin. In Italy, the mortality rate among COVID-19 patients with DM is 36%.11 The relation between infection and DM has long been recognized clinically. Diabetes impairs the immune system, making individuals more susceptible to infections like COVID-19.12 It also promotes chronic inflammation, increasing the risk of a severe cytokine storm. Diabetic patients have higher levels of ACE2 receptors, which SARS-CoV-2 uses to enter cells, and this is linked to altered glucose metabolism.13 Additionally, diabetes causes endothelial dysfunction and raises the risk of blood clots, further complicating COVID-19 outcomes.14,15

Although significant progress has been made in developing anti-SARS-CoV-2 inhibitors, many of these drugs need to be evaluated in terms of side effects or pharmacoeconomics aspect. Ritonavir has numerous drug-drug interactions that necessitate careful evaluation before use,11,16 and Paxlovid is costly, priced at $530 for each 5-day treatment course.17 In addition, before the development and widespread distribution of COVID-19 vaccines and in the absence of specific antiviral therapies, especially among DM patients, there was heightened interest in alternative and complementary treatments, including herbal medicines. Some herbal medicines were proposed as potential complementary therapy based on antiviral and anti-inflammatory properties. Herbal medicines, which have a long history in traditional medicine, have the potential to aid in symptom relief, enhance recovery, and strengthen the immune system. While no herbal remedy has been consistently proven effective for treating COVID-19, recent studies have identified promising candidates.18–20 Some natural compounds, especially flavonoids, may block viral entry by modulating the ACE2 receptor through the spike-RBD/TMPRSS2/ACE2 axis.21 Additionally, several herbs have multi-functional effects, offering antiviral, anti-inflammatory, antidiabetic, and immunomodulatory benefits.18–20The main objective of this review was to examine the scientific evidence of herbal medicines used as complementary therapy in DM patients with COVID-19 complications. This review discusses the potency of herbal medicines in in-vivo and in-vitro studies using animal and human models.

Methods

The articles were selected based on the inclusion criteria formulated, including journals published in the last 15 years (2008–2023), written in Indonesian and English, available as full-text articles and abstracts. The keywords used were “herbal medicines”, “COVID-19”, “DM”, “antidiabetics”, “antiviral”, and “anti-inflammatory”.

After determining the article search criteria, a search was performed using a predetermined database. The next step was to select articles from the 138 obtained according to the topic and study questions. The article selection mechanism was performed by formulating inclusion criteria. Meanwhile, non-English, reviews, unrelated studies, were excluded. After sorting the articles according to the inclusion criteria, a screening was conducted to re-check whether the contents of the 93 selected articles were in accordance with the pre-set study questions. The 25 articles which satisfied the inclusion criteria were then analyzed. In addition, a screening chart for the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Scoping Review (PRISMA) (Figure 1).

Figure 1 PRISMA Chart.

Results and Discussion COVID-19 Effects on Diabetes Mellitus

COVID-19 infects almost all ages but the currently available data show that the elderly and people with comorbidities have a higher risk and worse complications. These comorbidities include hypertension, DM, cardiovascular disease, and chronic lung disease. COVID-19 is found in about 8% of cases, especially in patients with DM. The worldwide outbreak of COVID-19 started at the end of 2019, significantly disrupting various human activities, especially within the healthcare sector.1,2 Not only the infection of COVID-19 itself, but lockdowns have also influenced dietary habits, leading to higher glucose intake, as well as increased stress and depression, which can trigger systemic inflammation. Given these challenges, herbal and nutritional interventions may provide supportive benefits by helping manage diabetes and enhancing immune function, potentially helping diabetic individuals better cope with COVID-19 risks.4,5,22

The relation between infection and DM has long been recognized clinically. Infections, primarily pneumonia and influenza, are often found in older people with T2DM.16 However, it remains debatable whether DM increases susceptibility and the outcome of infection or whether cardiovascular and renal diseases are the primary factors at play.

DM is a long-term inflammatory condition marked by various metabolic and vascular disorders that can impact our response to infections. Elevated blood glucose levels and insulin resistance increase the synthesis of advanced glycated end products and pro-inflammatory cytokines, which play a role in mediating tissue inflammation.12 This inflammatory process could be the underlying mechanism for the increased susceptibility to infections and poorer outcomes. DM patients are generally characterized by elevated levels of pro-inflammatory cytokines, such as C-reactive proteins (CRP) and interleukin-6 (IL-6). Additionally, these patients show increased coagulation activity, indicated by higher concentrations of d-dimer, which correlates with disease severity.14,15

In a study conducted in China, 39 SARS-CoV patients without a history of DM, who did not receive steroid treatment, were compared to 39 matched healthy siblings. The results showed that 20 patients developed DM during hospital stay. In addition, immunostaining for ACE-2 is also commonly found in pancreatic islets, suggesting SARS-CoV can also damage pancreatic islets, causing DM due to insulin deficiency.23 Although additional evidence is required, pancreatic damage may also occur and could have a more severe impact on DM patients with COVID-19.

WHO announced therapeutic recommendations for therapeutics in September 2021, including casirivimab and imdevimab for neutralizing monoclonal antibodies, IL-6 receptor blockers, and systemic corticosteroids.24,25 There is currently no data on the best management strategies for DM patients infected with SARS-CoV-2 or for COVID-19 patients experiencing glycemic decompensation. Therefore, it is necessary to consider alternative interventions, including herbal or traditional medicines, as supplementary options to conventional DM therapy for COVID-19 patients.

Herbal Medicines as Complementary Therapy in Diabetes Patients with COVID-19

According to the World Health Organization (WHO), traditional medicines refer to the knowledge, skills, and practices rooted in the theories, beliefs, and experiences of various cultures, used for maintaining health and for the prevention, diagnosis, enhancement, or treatment of physical and mental diseases.26 Traditional Chinese Medicine (TCM) is a significant example of how ancient and accumulated knowledge is used in a holistic approach within contemporary healthcare.27 Most TCM consists of a single plant or a mixture of various herbal medicines widely known to have many pharmacological activities. Sambiloto (Andrographis paniculata) extract is an example of herbal medicines with pharmacological activity including antidiabetic, antibacterial, antiviral, anti-inflammatory, and immunomodulator often used as an alternative DM therapy.

In 2003, TCM was used to treat various viral infections, including SARS, Middle East Respiratory Syndrome (MERS), Asian lineage avian influenza A (H7N9), avian influenza A (H1N1), Ebola virus, and others.28 TCM has also been advocated as a remedy for COVID-19 in the “New Coronavirus Pneumonia Diagnosis and Treatment Plan” (Trial Version Five).28 Nourishment and herbs demonstrate antiviral and immunomodulatory activities, for instance, Aloe vera, Ganoderma lucidum (lingzhi mushroom), Panax ginseng (ginseng), and Scutellaria baicalensis (Chinese skullcap) have demonstrated immunomodulatory properties.29 The actions selectively stimulate cytokines, enhancing the ability to kill abnormal cells by intensifying macrophage actions and activating lymphocytes. Furthermore, wheat bran, rice bran, Echinacea purpurea, Plumbago zeylanica (Ceylon leadwort), Lawsonia alba (hina), and Cissampelos pareira Linn (velvetleaf) have been studied for the ability to enhance immunomodulatory properties by promoting phagocytosis. Eucalyptus essential oil has also been reported for the ability to enhance the innate cell-mediated immune response and may serve as an immunoregulatory agent against viruses responsible for infectious diseases.30,31

Since the spread of coronavirus, especially COVID-19, allopathic therapy has been used to cure 99 patients in Wuhan Jinyintan Hospital including intravenous immunoglobulin (27%), oxygen (75%), antiviral (76%), and antibiotic (71%).32 The US Food and Drug Administration (FDA) has not yet approved any specific drug for COVID-19 therapy. However, many studies continuously discover effective COVID-19 therapy using herbal medicines known for antiviral, anti-inflammatory, immunomodulatory, and antidiabetic activity. These herbal medicines could serve as complementary therapy for DM patients facing complications related to COVID-19.

A specific antiviral treatment for COVID-19 has not yet been determined.33 Therefore, several approaches have been suggested, such as using convalescent plasma and interferon (IFN), together with IL-6 receptor inhibitors to reduce the cytokine storm.34 Chloroquine and hydroxychloroquine also play roles in inhibiting endocytosis-mediated viral entry, endosomal acidification, and ACE-2 glycosylation.35–37 Ivermectin also inhibits the nuclear transport of viral proteins.38,39 On June 17, 2020, WHO announced to stop using chloroquine and hydroxychloroquine for COVID-19 therapy. This recommendation was founded on six trials with 6000 participants who were not infected with SARS-CoV-2, as well as 30 trials with more than 10,000 COVID-19 patients. WHO reported that Chloroquine and hydroxychloroquine did not lower mortality rates, and may even heighten the risk of heart rhythm issues, kidney damage, blood and lymph disorders, liver complications, and failures. These drugs are safe for use in patients with malaria or autoimmune diseases, but not COVID-19.24,37,40

Antivirals targeting protease inhibitor proteins and nucleotide or nucleoside analogs that work to block viral RNA synthesis have been recognized for treating SARS-CoV-2 infection.41–44 Nucleoside analogs are a class of drugs that inhibit reverse transcription and represent some of the most effective antiviral agents for fighting SARS-CoV-2 infection.45 The antiviral and antidiabetic effects of herbal medicines, particularly quercetin, against influenza and SARS-CoV viruses have been validated through the inhibition of SARS-CoV 3-chymotrypsin-like protease (3CLpro) expression in Pichia pastoris.46,47

Anti-Inflammatory and Immunomodulatory Activity of Herbal Medicines in COVID-19 and Patients with Diabetes

Patients with DM are more susceptible to bacteria or viral infections and have a more severe disease course than non-diabetic people.48 Previous studies showed an increased risk of COVID-19 severity in patients with T2DM along with a higher rate of morbidity and mortality.49–52 Some mechanisms that trigger this increasing severity are DM-associated endothelial dysfunction, decreased viral immunity, and a compromised immune system.53,54 A population-based cohort study reported a rise in COVID-19-related deaths among DM patients (both type 1 and type 2) compared to the period before the pandemic.55

SARS-CoV-2 infection affects multi-organ systems and influences ACE-2 receptor expression. Recent studies reported that viral infection of pancreatic endocrine and exocrine cells caused changes in morphology, translation mechanism, and functional aspects of the pancreas, leading to impaired insulin secretion.56,57 Inflammatory responses were also linked to increased blood glucose levels. The activities of macrophages and monocytes in the immune response and viral infection resulted in a worse prognosis for COVID-19 patients. An in-vitro study reported increased viral load, as well as ACE-2 and interleukin expression in DM patients infected with SARS-CoV-2.58 Clinical data also reported increased glucose levels, cytokines, and immune responses. DM patients with COVID-19 show an increased proportion of T-helper cells, a lower percentage of T-cytotoxic cells, as well as higher serum levels of IL-2, IL-6, IL-10, and IFN-γ.59

Maintaining blood glucose levels within the normal range can enhance the prognosis and survival rate.50 However, when selecting a glucose-lowering agent for DM patients with COVID-19, it is necessary to consider clinical factors, comorbidities, and the mechanisms of concomitant drugs administered to treat other symptoms. The absence of an optimal drug for DM and the diminished effectiveness of oral medications are currently concerns for disease progression. Although these drugs are essential in managing DM, the reduced efficacy in maintaining glucose homeostasis over time and the associated side effects have restricted use.60 In this context, plant extracts and plant-derived compounds that possess antioxidant and immunomodulatory properties could act as a complementary or alternative therapy to help reduce and/or prevent complications related to congenital DM.20,61

Except for respiratory failure, critically ill COVID-19 patients share features in common with previous studies. One feature is having a very high inflammatory parameter, including CRP, pro-inflammatory cytokines such as IL-6, IL-8, Tumor necrosis factor alpha (TNF-α) and others, immune system destruction indicated by spleen and lymph node atrophy, and reduction of lymphocytes in lymphoid organs.62,63 Meanwhile, herbal medicines, which have anti-inflammatory and immunomodulatory activities such as Panax ginseng, inhibit cytokine production and viral replication, bio-inflammatory marker production and heighten immunity by increasing antibodies in the body. Centella asiatica has various pharmacological activities, including antihyperglycemic effects in obese diabetic rats, anti-inflammatory and analgesic activity based on chemical-induced animal behavior tests, as well as therapeutic activity on liver and kidney enzymes associated with oxidation of glucose and amino acids affected by DM. This plant significantly reduced renal levels of malondialdehyde (33%), IFN-γ (42%) and TNF-α (78%). Treatment with Centella asiatica also significantly enhanced the antioxidant status of the kidneys and brain in obese diabetic rats.64

Herbal medicines currently remain a favorite alternative and complementary therapy in many countries, along with allopathic therapy. Although herbal medicines can be complementary therapy in DM and COVID-19 patients, further studies are needed regarding efficacy, effectiveness, dosage, and toxicity. While reviewing the effectiveness of therapy, efficacy, and side effects of using herbal medicines in DM patients with COVID-19 complications, it is also necessary to monitor blood glucose levels closely and thoroughly to avoid drug interactions that can worsen symptoms and other unwanted outcomes.65

Although hyperglycemia is typically the primary concern, other factors should not be ignored. These include the possibility of a hypoglycemic reaction resulting from the interaction between drug therapy, the symptoms often experienced by DM patients, and COVID-19 viral pathogenesis. Therefore, it is also necessary to develop careful and effective therapeutic formulations along with strict and optimal glucose level measurements for DM patients infected with COVID-19 to obtain the desired results.

Some studies reported that using insulin can decrease severity and mortality rates. These results were due to the anti-inflammatory and immunomodulatory activity as well as decreased blood glucose levels in DM patients66,67 However, other studies claimed that insulin administration could worsen the clinical profile of DM patients with COVID-19. This condition correlated with poor prognosis caused by insulin-mediated inhibition of disintegrin and metalloproteinase domain-containing protein 17 (ADAM17), facilitating proteolytic cleavage and release of the active ectodomain of ACE-2. Therefore, it elevated the activities of ACE-2 in SARS-CoV-2 infection.68,69

Recent studies reported decreasing mortality rates among DM patients infected with SARS-CoV-2 who were administered metformin to maintain blood glucose levels. This decrease was potentially due to the mammalian target of rapamycin (mTOR) inhibitory effects of metformin.70 Studies have suggested that metformin may interfere with the interaction between host cells and viral proteins regulating replication, assembly, and pathogenesis.71,72 The immunomodulatory mechanisms of metformin are inhibiting monocyte-macrophage differentiation, pro-inflammatory expression of activated macrophages, as well as differentiation of T-cells into regulatory and memory T-cells. However, some issues arose when the FDA recalled metformin in 2020. The concern was related to nitrosamine impurity findings in some metformin extended-release products. These results caused many patients to find natural and effective alternatives to metformin with similar active components.73 Some active components that can replace metformin are berberine and N-acetyl-cysteine (NAC).

Table 1 shows some herbal medicines with antidiabetic properties as well as other pharmacological activities related to COVID-19. Although this review provides preliminary data on the medicinal plants that can be used as complementary therapy for DM patients with COVID-19 complications, it did not discuss safety profiles, potential side effects, or interactions of herbal medicines with conventional medications due to limited references on the mentioned topic. Some other herbal medicines showed antidiabetic effects and can be used as alternatives for DM patients with COVID-19 complications (Table 1).

Table 1 Potential Herbal Medicines That Could Be Used as Complementary Therapy for DM Patients with COVID-19 Complications

Among the various herbal medicines discussed in this review, several have shown promising potential as complementary therapy for COVID-19 patients with DM complications. However, determining the most effective is challenging due to the differences in methodologies, designs, and experimental conditions used across the studies. The variability in dosages, models (animal vs human), and outcome measures further complicates direct comparisons between herbal medicines.

Our study is limited to in vitro and in vivo models, which, while providing valuable insights, may not fully translate to humans due to physiological and metabolic differences. These differences can impact drug dosage, bioavailability, and effectiveness in human applications. Recent human studies on certain herbal products, such as curcumin and propolis, show promise against COVID-19 and diabetes (DM), but data remain limited.21 Observational studies on other herbs, including Echinacea purpurea, turmeric (Curcuma longa), Nigella sativa, and Zingiber officinale, suggest potential as adjuvant therapies for COVID-19.100 Therefore, further human studies—specifically clinical trials—are needed to confirm the efficacy, optimal dosages, and safety of these herbal treatments. This study could serve as preliminary research for future human investigations.

Conclusion

In conclusion, the limited efficacy of available allopathic medicines against COVID-19 highlights the need for alternative or complementary approaches. Current literature provides substantial evidence that herbal medicines may serve as potential adjunct therapies for managing complications in diabetes mellitus (DM) patients with COVID-19. Promising candidates include Andrographis paniculata, Ageratum conyzoides, Artocarpus altilis, Centella asiatica, Momordica charantia, Persea gratissima, Phyllanthus urinaria, Physalis angulata, Tinospora cordifolia, Zingiber zerumbet, Fibraurea tinctoria, Allium cepa, and Allium sativum. These herbal medicines may play a role as complementary preventive and adjunct therapies. To translate these findings into clinical practice, further experimental validation and clinical trials are essential to establish their efficacy and safety in COVID-19 patients with DM. Additionally, exploring their mechanisms of action, optimal dosing, and potential interactions with standard treatments would provide critical insights for integrating herbal medicines into comprehensive therapeutic strategies. This research direction could significantly enhance patient outcomes and broaden the scope of integrative medicine in managing COVID-19 and its complications.

Acknowledgments

The authors would like to thank the Rector of Universitas Padjadjaran for facilitating the APC via the Directorate of Research and Community Engagement.

Disclosure

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

1. jin ZJ, Dong X, yuan CY, et al. Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China. Allergy: European Journal of Allergy and Clinical Immunology. 2020;75(7). doi:10.1111/all.14238

2. Di Gennaro F, Pizzol D, Marotta C, et al. Coronavirus diseases (COVID-19) current status and future perspectives: a narrative review. Int J Environ Res Public Health. 2020;17(8):2690. doi:10.3390/ijerph17082690

3. Ajebli M, Amssayef A, Akdad M, et al. Chronic diseases and COVID-19: a review. Endocr Metab Immune Disord Drug Targets. 2021;21(10):1781–1803. doi:10.2174/1871530320666201201110148

4. Zhao Z, Li L, Sang Y. The COVID-19 pandemic increased poor lifestyles and worsen mental health: a systematic review. Am J Transl Res. 2023;15:3060–3066.

5. Lim S, Kong APS, Tuomilehto J. Influence of COVID-19 pandemic and related quarantine procedures on metabolic risk. Prim Care Diabetes. 2021;15(5):745–750. doi:10.1016/j.pcd.2021.07.008

6. Zimmet P, Alberti KG, Magliano DJ, Bennett PH. Diabetes mellitus statistics on prevalence and mortality: facts and fallacies. Nat Rev Endocrinol. 2016;12(10):616–622. doi:10.1038/nrendo.2016.105

7. Bornstein SR, Rubino F, Khunti K, et al. Practical recommendations for the management of diabetes in patients withCOVID-19. Lancet Diabetes Endocrinol. 2020;8(6):546–550. doi:10.1016/S2213-8587(20)30152-2

8. Letko M, Marzi A, Munster V. Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses. Nat Microbiol. 2020;5:562–569. doi:10.1038/s41564-020-0688-y

9. Latarissa IR, Barliana MI, Meiliana A, Lestari K. Potential of quinine sulfate for COVID-19 treatment and its safety profile: review. Clin Pharmacol. 2021;13:225–234. doi:10.2147/CPAA.S331660

10. Li W, Moore MJ, Vasilieva N, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARScoronavirus. Nature. 2003;426(6965):450–454. doi:10.1038/nature02145

11. Onder G, Rezza G, Brusaferro S. Case-fatality rate and characteristics of patients dying in relation to COVID-19 in Italy. JAMA. 2020;323(18):1775–1776. doi:10.1001/jama.2020.4683

12. Petrie JR, Guzik TJ, Touyz RM. Diabetes, hypertension, and cardiovascular disease: clinical insights and vascular mechanisms. Canadian Journal of Cardiology. 2018;34(5):575–584. doi:10.1016/j.cjca.2017.12.005

13. Lu Y, Xing C, Lv X, et al. Changes of ACE2 in different glucose metabolites and its relationship with COVID-19. Medicine. 2022;101(41):e31102. doi:10.1097/MD.0000000000031102

14. Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382(18):1708–1720. doi:10.1056/NEJMoa2002032

15. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054–1062. doi:10.1016/S0140-6736(20)30566-3

16. Li S, Wang J, Zhang B, Li X, Liu Y. Diabetes mellitus and cause-specific mortality: a population-based study. Diabetes Metab J. 2019;43(3):319–341. doi:10.4093/dmj.2018.0060

17. Yang L, Wang Z. Bench-to-bedside: innovation of small molecule anti-SARS-CoV-2 drugs in China. Eur J Med Chem. 2023;257:115503. doi:10.1016/J.EJMECH.2023.115503

18. Wang Z, Yang L. The Therapeutic Potential of Natural Dietary Flavonoids against SARS-CoV-2 Infection. Nutrients. 2023;15(15). doi:10.3390/NU15153443

19. Lestari K, Babikian H, Kulsum ID, et al. The combination of Gardenia jasminoides, Boswellia serrata, Commiphora myrrha, Foeniculum vulgarae, and Daucus carota essential oil blend improved the inflammatory and clinical status in respiratory tract infection of COVID-19 patients: a multicentre, randomized, open-label, controlled trial. The Indonesian Biomedical Journal. 2024;16(3):237–247. doi:10.18585/INABJ.V16I3.3023

20. Latarissa IR, Meiliana A, Sormin IP, et al. The efficacy of herbal medicines on the length of stay and negative conversion time/rate outcomes in patients with COVID-19: a systematic review. Front Pharmacol. 2024;15:1383359. doi:10.3389/FPHAR.2024.1383359

21. Yusuf AP, ye ZJ, Quan LJ, Muhammad A, Abubakar MB. Herbal medications and natural products for patients with covid-19 and diabetes mellitus: potentials and challenges. Phytomedicine Plus. 2022;2(3):100280. doi:10.1016/j.phyplu.2022.100280

22. Szajnoga D, Perenc H, Jakubiak GK, Cieślar G, Ćwieląg-Drabek M. Consumption of meats and fish in Poland during the COVID-19 lockdown period. Nutrients. 2024;16(9):1318. doi:10.3390/nu16091318

23. Yang JK, Lin SS, Ji XJ, Guo LM. Binding of SARS coronavirus to its receptor damages islets and causes acute diabetes. Acta Diabetol. 2010;47(3):193–199. doi:10.1007/s00592-009-0109-4

24. World Health Organization (WHO). WHO therapeutics and COVID-19: living guideline. World Health Organisation. 2022:128.

25. Agarwal A, Hunt B, Stegemann M, et al. A living WHO guideline on drugs for covid-19. BMJ. 2020;370:m3379. doi:10.1136/bmj.m3379

26. World Health Organization. Traditional and complementary medicine in primary health care. 2018:1–16.

27. Wang Z, Yang L. Chinese herbal medicine: fighting SARS-CoV-2 infection on all fronts. J Ethnopharmacol. 2021;270. doi:10.1016/J.JEP.2021.113869

28. Luo Y, Wang CZ, Hesse-Fong J, Lin JG, Yuan CS. Application of Chinese Medicine in Acute and Critical Medical Conditions. Am J Chin Med (Gard City N Y). 2019;47(6):1223–1235. doi:10.1142/S0192415X19500629

29. Wang SX, Wang Y, Lu YB, et al. Diagnosis and treatment of novel coronavirus pneumonia based on the theory of traditional Chinese medicine. J Integr Med. 2020;18(4):275–283. doi:10.1016/j.joim.2020.04.001

30. Serafino A, Vallebona P, Andreola F, et al. Stimulatory effect of Eucalyptus essential oil on innate cell-mediated immune response. BMC Immunol. 2008;9:1–16. doi:10.1186/1471-2172-9-17

31. Sadlon AE, Lamson DW. Immune-modifying and antimicrobial effects of Eucalyptus oil and simple inhalation devices. Altern Med Rev. 2010;15(1):33–47.

32. Peng X, Xu X, Li Y, Cheng L, Zhou X, Ren B. Transmission routes of 2019-nCoV and controls in dental practice. Int J Oral Sci. 2020;12(1). doi:10.1038/s41368-020-0075-9

33. Wang Z, Yang L. Broad-spectrum prodrugs with anti-SARS-CoV-2 activities: strategies, benefits, and challenges. J Med Virol. 2022;94(4):1373–1390. doi:10.1002/JMV.27517

34. Keam S, Megawati D, Patel SK, Tiwari R, Dhama K, Harapan H. Immunopathology and immunotherapeutic strategies in severe acute respiratory syndrome coronavirus 2 infection. Rev Med Virol. 2020;30(5):e2123. doi:10.1002/rmv.2123

35. Liu J, Cao R, Xu M, et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov. 2020;6(1):6–9. doi:10.1038/s41421-020-0156-0

36. Colson P, Rolain JM, Raoult D. Chloroquine for the 2019 novel coronavirus SARS-CoV-2. Int J Antimicrob Agents. 2020;55(3):105923. doi:10.1016/j.ijantimicag.2020.105923

37. Latarissa IR, Barliana MI, Meiliana A, et al. Efficacy of quinine sulfate in patients with mild-to-moderate COVID-19:A randomized controlled trial. The Indonesian Biomedical Journal. 2023;15(6):366–374. doi:10.18585/INABJ.V15I6.2543

38. Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 2020;178:104787. doi:10.1016/j.antiviral.2020.104787

39. Choudhary R, Sharma AK. Potential use of hydroxychloroquine, ivermectin and azithromycin drugs infighting COVID-19: trends, scope and relevance. New Microbes New Infect. 2020;35:100684. doi:10.1016/j.nmni.2020.100684

40. WHO. Drugs to prevent COVID-19: living guideline. World Health Organization. 2023:1–23.

41. Wang J. Fast identification of possible drug treatment of coronavirus disease-19(COVID-19) through computational drug repurposing study. J Chem Inf Model. 2020;60(6):3277–3286. doi:10.1021/acs.jcim.0c00179

42. Hall DCJ, Ji HF. A search for medications to treat COVID-19 via in silico molecular docking models of the SARS-CoV-2 spike glycoprotein and 3CL protease. Travel Med Infect Dis. 2020;35:101646. doi:10.1016/j.tmaid.2020.101646

43. Ribavirin EAA, Remdesivir S. Galidesivir, and Tenofovir against SARS-CoV-2RNA dependent RNA polymerase (RdRp): a molecular docking study. Life Sci. 2020;253:117592. doi:10.1016/j.lfs.2020.117592

44. Wu F, Zhao S, Yu B, et al. A new coronavirus associated with human respiratory disease in China. Nature. 2020;579(7798):265–269. doi:10.1038/s41586-020-2008-3

45. Wang Z, Yang L, Zhao XE. Co-crystallization and structure determination: an effective direction for anti-SARS-CoV-2 drug discovery. Comput Struct Biotechnol J. 2021;19:4684–4701. doi:10.1016/j.csbj.2021.08.029

46. Nguyen TTH, Woo HJ, Kang HK, et al. Flavonoid-mediated inhibition of SARS coronavirus 3C-like protease expressed inPichia pastoris. Biotechnol Lett. 2012;34(5):831–838. doi:10.1007/s10529-011-0845-8

47. Lu R, Zhao X, Li J, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. The Lancet. 2020;395(10224):565–574. doi:10.1016/S0140-6736(20)30251-8

48. Kulcsar KA, Coleman CM, Beck SE, Frieman MB. Comorbid diabetes results in immune dysregulation and enhanced disease severity following MERS-CoV infection. JCI Insight. 2019;4(20). doi:10.1172/jci.insight.131774

49. Erener S. Diabetes, infection risk and COVID-19. Mol Metab. 2020;39:101044. doi:10.1016/j.molmet.2020.101044

50. Zhu L, She ZG, Cheng X, et al. Association of blood glucose control and outcomes in patients with COVID-19 andPre-existing type 2 diabetes. Cell Metab. 2020;31(6):1068–1077.e3. doi:10.1016/j.cmet.2020.04.021

51. Samuel SM, Varghese E, Büsselberg D. Therapeutic potential of metformin in COVID-19: reasoning for its protectiveRole. Trends Microbiol. 2021;29(10):894–907. doi:10.1016/j.tim.2021.03.004

52. Gregory JM, Slaughter JC, Duffus SH, et al. COVID-19 severity is tripled in the diabetes community: a prospective analysis of the pandemic’s impact in type 1 and type 2 diabetes. Diabetes Care. 2021;44(2):526–532. doi:10.2337/dc20-2260

53. Lisco G, De Tullio A, Giagulli VA, Guastamacchia E, De Pergola G, Triggiani V. Hypothesized mechanisms explaining poor prognosis in type 2 diabetes patients with COVID-19: a review. Endocrine. 2020;70(3):441–453. doi:10.1007/s12020-020-02444-9

54. Teuwen LA, Geldhof V, Pasut A, Carmeliet P. COVID-19: the vasculature unleashed. Nat Rev Immunol. 2020;20(7):389–391. doi:10.1038/s41577-020-0343-0

55. Holman N, Knighton P, Kar P, et al. Risk factors for COVID-19-related mortality in people with type 1 and type 2 diabetes in England: a population-based cohort study. Lancet Diabetes Endocrinol. 2020;8(10):823–833. doi:10.1016/S2213-8587(20)30271-0

56. Müller JA, Groß R, Conzelmann C, et al. SARS-CoV-2 infects and replicates in cells of the human endocrine and exocrine pancreas. Nat Metab. 2021;3(2):149–165. doi:10.1038/s42255-021-00347-1

57. Yang L, Han Y, Nilsson-Payant BE, et al. A human pluripotent stem cell-based platform to study SARS-CoV-2 tropism and model virus infection in human cells and organoids. Cell Stem Cell. 2020;27(1):125–136.e7. doi:10.1016/j.stem.2020.06.015

58. Codo AC, Davanzo GG, de B ML, et al. Elevated glucose levels favor SARS-CoV-2 infection and monocyte response through a HIF-1α/glycolysis-dependent axis. Cell Metab. 2020;32(3):437–446.e5. doi:10.1016/j.cmet.2020.07.007

59. Zheng M, Wang X, Guo H, et al. The cytokine profiles and immune response are increased in COVID-19 patients withType 2 diabetes mellitus. J Diabetes Res. 2021;2021:9526701. doi:10.1155/2021/9526701

60. Bowen ME, Rothman RL. Multidisciplinary management of type 2 diabetes in children and adolescents. J Multidiscip Healthc. 2010;3:113–124. doi:10.2147/jmdh.s7840

61. Nasri H, Shirzad H, Baradaran A, Rafieian-Kopaei M. Antioxidant plants and diabetes mellitus. J Res Med Sci. 2015;20(5):491–502. doi:10.4103/1735-1995.163977

62. Tabatabaei-Malazy O, Abdollahi M, Larijani B. Beneficial effects of anti-oxidative herbal medicines in diabetic patients infected with COVID-19: a hypothesis. Diabetes Metab Syndr Obes. 2020;13:3113–3116. doi:10.2147/DMSO.S264824

63. Latarissa IR, Rendrayani F, Iftinan GN, et al. The Efficacy of Oral/Intravenous Corticosteroid Use in COVID-19 Patients: A Systematic Review. J Exp Pharmacol. 2024;16:39371262. doi:10.2147/JEP.S484596

64. Masola B, Oguntibeju OO, Oyenihi AB. Centella asiatica ameliorates diabetes-induced stress in rat tissues via influences on antioxidants and inflammatory cytokines. Biomed Pharmacother. 2018;101:447–457. doi:10.1016/j.biopha.2018.02.115

65. Lisni I, Latarissa IR, Andalusia LR, Lestari K. Drug interaction detection and glycemic control – telepharmacy’s role in diabetes management: before-after study. Pharmacia. 2024;71:1–8. doi:10.3897/PHARMACIA.71.E123313

66. Sun Q, Li J, Gao F. New insights into insulin: the anti-inflammatory effect and its clinical relevance. World J Diabetes. 2014;5(2):89–96. doi:10.4239/wjd.v5.i2.89

67. Sardu C, D’Onofrio N, Balestrieri ML, et al. Outcomes in patients with hyperglycemia affected by COVID-19: can we do more on glycemic control? Diabetes Care. 2020;43(7):1408–1415. doi:10.2337/dc20-0723

68. Chen Y, Yang D, Cheng B, et al. Clinical characteristics and outcomes of patients with diabetes and COVID-19 inAssociation with glucose-lowering medication. Diabetes Care. 2020;43(7):1399–1407. doi:10.2337/dc20-0660

69. Salem ESB, Grobe N, Elased KM. Insulin treatment attenuates renal ADAM17 and ACE2 shedding in diabetic Akita mice. Am J Physiol Renal Physiol. 2014;306(6):F629–39. doi:10.1152/ajprenal.00516.2013

70. Lally MA, Tsoukas P, Halladay CW, O’Neill E, Gravenstein S, Rudolph JL. Metformin is associated with decreased 30-day mortality among nursing home residents infected with SARS-CoV2. J Am Med Dir Assoc. 2021;22(1):193–198. doi:10.1016/j.jamda.2020.10.031

71. Samuel S, Satheesh N, Ghosh S, et al. Treatment with a combination of metformin and 2-deoxyglucose upregulates thrombospondin-1 in microvascular endothelial cells: implications in anti-angiogenic cancer therapy. Cancers (Basel). 2019;11:1737. doi:10.3390/cancers11111737

72. Sharma S, Ray A, Sadasivam B. Metformin in COVID-19: a possible role beyond diabetes. Diabetes Res Clin Pract. 2020;164:108183. doi:10.1016/j.diabres.2020.108183

73. FDA alerts patients and health care professionals to nitrosamine impurity findings in certain metformin extended-release products | FDA. Available from: https://www.fda.gov/news-events/press-announcements/fda-alerts-patients-and-health-care-professionals-nitrosamine-impurity-findings-certain-metformin. Accessed December13, 2023.

74. Nugroho AE, Andrie M, Warditiani NK, Siswanto E, Pramono S, Lukitaningsih E. Antidiabetic and antihiperlipidemic effect of Andrographis paniculata (Burm. f.)Nees and andrographolide in high-fructose-fat-fed rats. Indian J Pharmacol. 2012;44(3):377–381. doi:10.4103/0253-7613.96343

75. Chao WW, Kuo YH, Lin BF. Anti-inflammatory activity of new compounds from Andrographis paniculata by NF-kappaB transactivation inhibition. J Agric Food Chem. 2010;58(4):2505–2512. doi:10.1021/jf903629j

76. Nyunaï N, Njikam N, Abdennebi EH, Mbafor JT, Lamnaouer D. Hypoglycaemic and antihyperglycaemic activity of Ageratum conyzoides L. in rats. Afr J Tradit Complement Altern Med. 2009;6(2):123–130.

77. Faqueti LG, Brieudes V, Halabalaki M, et al. Antinociceptive and anti-inflammatory activities of standardized extract of polymethoxyflavones from Ageratum conyzoides. J Ethnopharmacol. 2016;194:369–377. doi:10.1016/j.jep.2016.09.025

78. Indrowati M, Pratiwi R, Rumiyati A, Astuti P. Levels of blood glucose and insulin expression of beta-cells inStreptozotocin-induced diabetic rats treated with ethanolic extract of Artocarpus altilis Leaves and GABA. Pak J Biol Sci. 2017;20(1):28–35. doi:10.3923/pjbs.2017.28.35

79. Hafid A, Chie U, Permanasari A, et al. Antiviral activity of the dichloromethane extracts from Artocarpus heterophyllus leaves against Hepatitis C Virus. Asian Pac J Trop Biomed. 2017;7:633–639. doi:10.1016/j.apjtb.2017.06.003

80. Riasari H, Nurlalela S, Gumilang G. Anti-inflammatory activity of Artocarpus altilis (Parkinson) fosberg in Wistar Male Rats. Pharmacology and Clinical Pharmacy Research. 2019;4:22. doi:10.15416/pcpr.v4i1.21397

81. Mishra A, Gautam S, Pal S, et al. Effect of Momordica charantia fruits on streptozotocin-induced diabetes mellitus and its associated complications. Int J Pharm Pharm Sci. 2015;7:356–363.

82. Nerurkar PV, Orias D, Soares N, Kumar M, Nerurkar VR. Momordica charantia (bitter melon) modulates adipose tissue inflammasome gene expression and adipose-gut inflammatory cross talk in high-fat diet (HFD)-fed mice. Journal of Nutritional Biochemistry. 2019;68:16–32. doi:10.1016/j.jnutbio.2019.03.003

83. Pongthanapisith V, Ikuta K, Puthavathana P, Leelamanit W. Antiviral protein of Momordica charantia L. Inhibits different subtypes ofInfluenza A. Evid Based Complement Alternat Med. 2013;2013:729081. doi:10.1155/2013/729081

84. Athaydes BR, Alves GM, de AALEM, et al. Avocado seeds (Persea americana Mill.) prevents indomethacin-induced gastric ulcer in mice. Food Research International. 2019;119:751–760. doi:10.1016/j.foodres.2018.10.057

85. Ahmed N, Tcheng M, Roma A, et al. Avocatin B protects against lipotoxicity and improves insulin sensitivity in diet-induced obesity. Mol Nutr Food Res. 2019;63(24):e1900688. doi:10.1002/mnfr.201900688

86. Cheng HY, Yang CM, Lin TC, Lin LT, Chiang LC, Lin CC. Excoecarianin, isolated from Phyllanthus urinaria Linnea, inhibits herpes simplex virus type 2 infection through inactivation of viral particles. Evidence Based Complem Alter Med. 2011;2011: 259103. doi:10.1093/ecam/nep157

87. Gunawan-puteri MDPT, Kato E, Kawabata J. α -Amylase inhibitors from an Indonesian medicinal herb. Phyllanthus Urinaria. 2012;606–609. doi:10.1002/jsfa.4615

88. Cheng HY, Yang CM, Lin TC, Lin LT, Chiang LC, Excoecarianin LCC. Isolated from Phyllanthus urinaria Linnea, inhibits herpes SimplexVirus type 2 infection through inactivation of viral particles. Evid Based Complement Alternat Med. 2011;2011:259103. doi:10.1093/ecam/nep157

89. Sun CP, Qiu CY, Yuan T, et al. Antiproliferative and anti-inflammatory withanolides from physalis angulata. J Nat Prod. 2016;79(6):1586–1597. doi:10.1021/acs.jnatprod.6b00094

90. Adewoye EO, Oguntola MA, Ige AO. Anti-oxidative and Reno-restorative effects of physalis angulata (whole plant extract) in alloxan-induced diabetic male Wistar rats. Afr J Med Med Sci. 2016;45(1):99–108.

91. Lestari K, Ridho A, Nurcayani N, Ramadhania Z, Barliana M. Stevia rebaudiana bertoni leaves extract as a nutraceutical with hypoglycemic activity in diabetic rats. The Indonesian Biomedical Journal. 2019;11. doi:10.18585/inabj.v11i2.686

92. Latarissa IR, Barliana MI, Lestari K. A comprehensive review of stevia rebaudiana bertoni effects on human health and its mechanism. Journal of Advanced Pharmacy Education & Research. 2020;10(2):91–95.

93. Cho BO, Ryu HW, So Y, et al. Anti-inflammatory effect of austroinulin and 6-O-acetyl-austroinulin from Stevia rebaudiana in lipopolysaccharide-stimulated RAW264.7 macrophages. Food Chem Toxicol. 2013;62:638–644. doi:10.1016/j.fct.2013.09.011

94. Hussain L, Akash MSH, Ain NU, Rehman K, Ibrahim M. The Analgesic, Anti-Inflammatory and Anti-Pyretic Activities of Tinospora cordifolia. Adv Clin Exp Med. 2015;24(6):957–964. doi:10.17219/acem/27909

95. Sharma BR, Park CM, Kim HA, Kim HJ, Rhyu DY. Tinospora cordifolia preserves pancreatic beta cells and enhances glucose uptake in adipocytes to regulate glucose metabolism in diabetic rats. Phytother Res. 2019;33(10):2765–2774. doi:10.1002/ptr.6462

96. Ajish KR, Antu KA, Riya MP, et al. Studies on α-glucosidase, aldose reductase and glycation inhibitory properties of sesquiterpenes and flavonoids of Zingiber zerumbet Smith. Nat Prod Res. 2015;29(10):947–952. doi:10.1080/14786419.2014.956741

97. Haque MA, Jantan I, Harikrishnan H, Ghazalee S Standardized extract of Zingiber zerumbet suppresses LPS-induced pro-inflammatory responses through NF-ΚB, MAPK and PI3K-Akt signaling pathways in U937 macrophages. Phytomedicine. 2019;54: 195–205. doi:10.1016/j.phymed.2018.09.183

98. Utami R, Sandi NH, Hasti S, Delvia S. Uji aktivitas antidiabetes ekstrak etanol dari akar dan batang tumbuhan Sekunyit (Fibraurea Tinctoria Lour) [Antidiabetic activity test of ethanol extract from the roots and stems of Sekunyit plant (Fibraurea tinctoria Lour)]. Indonesian. Jurnal Farmasi Indonesia ■. 2015;7(4):216–222.

99. de RLR, Kaga O, AK BPO, et al. Beneficial effects of N-acetylcysteine on hepatic oxidative stress in streptozotocin-induced diabetic rats. Can J Physiol Pharmacol. 2018;96(4):412–418. doi:10.1139/cjpp-2017-0559

100. Komariah M, Amirah S, Maulana S, et al. The efficacy of herbs as complementary and alternative therapy in recovery and clinical outcome among people with COVID-19: a systematic review, meta-analysis, and meta-regression. Ther Clin Risk Manag. 2023;19:611–627. doi:10.2147/TCRM.S405507