Could Sumac Be Effective on COVID-19 Treatment?

Introduction

Sumac is an herbal product produced from a bush plant and was commonly consumed as a spice and used for medical treatment for centuries. Sumac is widely produced and used in several regions of the world. Sumac is a plant that belongs to the Rhus genus and has various subspecies that exhibit slight differences based on their region of growth. Literature reveals a plethora of scientific studies focusing on Sumac. The review of these studies and matching their findings with the current clinical findings of COVID-19 infection results with the notion that Sumac could be effective in the treatment of the infection.

The phytochemical structure of Sumac was studied extensively, and it was established that the herb contained tannins, polyphenols, flavonoids, organic acids, and essential oils. Although the structure of the subspecies was acknowledged to hold varying rates of these components, average rates were reported in the literature. Various studies established that Sumac had a free oxygen radical-scavenging effect, a protective effect against liver damage, antihemolytic, leukopenia, and antifibrogenic effects, along with its antiviral, antimicrobial, anti-inflammatory, and antioxidant properties. ¹ Therefore, the present study was founded upon the idea that the expressed effects could be useful in the treatment of COVID-19 infection, hence, it is a significant issue that needs to be addressed.

The COVID-19 infection turned into a pandemic, which resulted in a massive number of deaths worldwide and caused major socioeconomic disruptions with significant impacts on social life. Currently, rigorous research efforts remain intending to clarify the methods and approaches for the treatment of the disease. There is a strong global expectation toward an imminent scientific breakthrough that leads to effective treatment. Therefore, it is essential to initially determine the effective treatment modalities and such promising modalities should be clarified through randomized clinical trials to test whether they are effective.

The main aim in the present review is to examine whether Sumac, which was widely used in the world for therapeutic purposes for centuries and was recognized by a significant portion of communities, could be an effective treatment of COVID-19 infection. Furthermore, convincing discussions on the effectiveness of Sumac for treatment could lead to randomized clinical trials to demonstrate such effectiveness.

Antiviral Effect

SARS-CoV2 virus, which causes COVID-19 infection, is a highly infectious RNA virus. There are no scientific studies on whether Sumac is effective against the SARS-CoV2 virus. On the contrary, the medications currently being used for treatment were directly administered in clinics, without scrutinizing whether they were effective against the novel coronavirus. Subsequently, several medications were identified to be useful during the clinical course of the disease. Yet, there are scientific in vitro and in vivo studies that investigated the antiviral effects of Sumac against several viruses. In a study, bioflavonoids isolated from Sumac were evaluated for their antiviral activities. Sumac presented inhibitory activities against respiratory viruses (influenza A, influenza B, and measles) and herpes viruses (HSV-1, HSV-2, and varicella zoster virus [VZV]). ² Another study found that Sumac extract exhibited significant antiviral activity against fish pathogenic infectious hematopoietic necrosis virus, and viral hemorrhagic septicemia virus. Furthermore, it was considered that Sumac was a potential antiviral therapeutic against fish viral diseases. ³ In a study conducted in 2015, it was established that urushiol obtained from Sumac exhibited reverse transcriptase inhibitory activity for human immunodeficiency virus type 1 (HIV-1). It was specified that Sumac could be used as a biological resource due to such inhibitory activity. ⁴

Another study focusing on HIV found that Sumac extracts exhibited anti-HIV activity due to inhibiting the HIV-1 reverse transcriptase and protease activity. It was also demonstrated that Sumac inhibited the viral load in HIV-infected CEM-GFP (a CD4+ T-lymphocytic reporter cell line expressing green fluorescent protein [GFP] under HIV-1 LTR promoter) cells and human peripheral blood lymphocytes. ⁵ Another study reported that Sumac extract presented strong antiviral activity against HSV-1 and HSV-2. The study also revealed that Sumac extract did not only interact with the viral envelope but also interacted with the surface of the host cells of the viruses, thus, disrupted the ability of the virus to adsorb and penetrate the host cells. ⁶

The above-mentioned studies indicated the antiviral effects of Sumac extracts. The review of the viruses, on which Sumac is effective, such as influenza, HSV-1, HSV-2, VZV, and HIV-1 demonstrated that the common point between these viruses was the fact that they are all enveloped viruses, contain dense lipids in their envelopes, and are sensitive to ether. ⁷ Coronaviruses share the same common features. ⁷ Sumac is likely to affect the lipid layer in the virus envelope, disrupting the adsorption to the host cell and preventing the virus from penetrating the host cell, positively contributing to the infection. Naturally, this hypothesis should be evidenced in future studies. However, its effectiveness on the novel coronavirus (SARS-CoV2) should be clarified first through animal testing and subsequently should be tested through human subjects.

Antihemolytic Effect

One of the main disruptive effects of the SARS-CoV2 virus is the destruction of hemoglobin and erythrocyte and the resulting decrease in the capacity to carry blood oxygen and carbon dioxide. A study compared the differences between the hemogram parameters of several COVID-19 patients at hospitalization and discharge and reported that hemoglobin and hematocrit concentrations of the patients decreased. ⁸ Based on the scientific review by Liu et al., the key molecular steps of SARS-CoV2 were to attack the hemoglobin 1–beta chain, to capture porphyrins, to separate the iron molecule, and to deliver the iron into circulation. Consequently, the total hemoglobin oxygen-binding capacity decreases, resistant hypoxia develops, and multiorgan failure occurs accordingly. ⁹ Preventing such disruptive chain of events would entail a significant success in the treatment against SARS-CoV2. A study on Sumac tannins provides the idea that Sumac could be useful for the scope described above. The study investigated the antihemolytic effect of Sumac tannins and the effect was found to be further related to the modifying effects on the erythrocyte membrane structure. It was determined that Sumac tannins were incorporated into the erythrocyte membrane, transformed the discocytes into echinocytes, and increased the hardness of the hydrophilic region of the lipid bilayer. The findings of the study indicated that embedding Sumac tannins in the erythrocyte membrane altered the physical properties of the membrane and limited its interaction with bacterial toxins. ¹⁰

Anticoagulant Effects

One of the important clinical features of COVID-19 infection is coagulopathy. In a recent cohort study, disseminated intravascular coagulation was found in 71% of patients who died due to COVID-19 infection. ¹¹ COVID-19 infection might result in a tendency toward thrombosis in both venous and arterial circulation due to platelet activation, endothelial dysfunction, and stasis caused by excessive inflammation. ¹² Microvascular thrombosis and venous thromboembolism, which occur due to prothrombotic changes during the COVID-19 infection, increase mortality, and are considered to be the reason for sudden deaths in several patients. Currently, anticoagulants are administered to COVID-19 patients for treatment. However, the method of anticoagulation and the dose of the anticoagulant that needs to be used are still being discussed scientifically. ¹³

The literature review indicates that Sumac can be considered as a protective agent for coagulopathy or for decreasing the tendency of thrombosis in COVID-19 patients. A study isolated 6-Pentadecylsalicylic acid from the extract obtained via the fractionation of Sumac. This extract exhibited antithrombin activity at 50 μg/mL in the amidolytic method. Furthermore, the coagulation test, which measured the thrombin-fibrinogen interaction, yielded prolonged coagulation time in a dose-dependent manner. ¹⁴ Another in vivo study indicated that Sumac extract could prevent the coagulation of human peripheral blood cells. It was also noted that in vivo Sumac extract treatment could restore the delayed blood flow, which occurs due to a high-fat diet, to normal levels in rats. In the concluding remarks of the study, the authors emphasized that the extract had antiplatelet and antiobesity activities and could be used as a functional food component to improve blood circulation. ¹⁵

Anti-Inflammatory Effect

SARS-CoV2 causes a viral infection that results in varying degrees of inflammation severity in patients. The clinical severity of the disease is correlated with the severity of inflammation. Several COVID-19 patients might experience an uncontrolled inflammation that further aggravates the patient's clinical prognosis. Overproduction of proinflammatory cytokines (cytokine storm) observed in patients with severe COVID-19 infection might be associated with acute respiratory distress syndrome. However, the exact pathophysiology and treatment of severe COVID-19 infection remain uncertain. High IL-6 levels in COVID-19 patients were associated with the severity of the infection and increased mortality. ¹⁶ Studies conducted with COVID-19 patients indicate a decrease in white blood cells (WBC) and lymphocyte count and an increase and C-reactive protein (CRP). It was reported that methylprednisolone was added to treatment for 44% of the patients due to severe inflammation. ¹⁷ It was reported that immune-modulating or immunosuppressive treatments such as hydroxychloroquine, interleukin (IL)-6, and IL-1 antagonists, which were widely used in rheumatology, could be considered as treatment options for COVID-19. ¹⁸ A recent study reported that COVID-19 was a systemic infection with a significant effect on the hematopoietic system. Lymphopenia was described as the cardinal laboratory finding with prognostic significance for the infection, and neutrophil/lymphocyte ratio was reported to have a prognostic value in identifying severe cases. The same study indicated that evaluating parameters such as lymphocyte, lactate dehydrogenase (LDH), CRP, and IL-6 might help to diagnose cases that required rapid intervention. ¹⁹ In another study conducted with COVID-19 patients, significantly high levels of neutrophil, CRP, LDH, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and urea and low levels of WBC and serum albumin levels were identified. ²⁰ Early disease CRP levels were higher in Covid-19 patients with severe symptoms. ²¹ It was reported that there was a significant positive correlation between the severity of pneumonia and CRP, erythrocyte sedimentation rate, and LDH. ²²

Sumac could be useful in COVID-19 infection due to its anti-inflammatory effect. Sumac was used as a herbal medicine for the treatment of various inflammatory disorders for centuries.

Anti-inflammatory effects of Sumac were demonstrated in in vitro and in vivo stimulated macrophages. In a study that aimed to investigate whether oral administration of Sumac affected the inflammatory response of the macrophage, it reduced the serum levels of the experimentally induced TNF-a and IL-6. Furthermore, the same study reported that Sumac caused monocyte differentiation through exhibiting selective anti-inflammatory activity without causing overall inhibitory effects on the immune cells. ²³ There exist studies indicating that Sumac decreased the CPR levels, which previously increased due to diabetes, cancer, and atherosclerosis. ²⁴ The findings of a study focusing on Sumac indicated that it had the effect of correcting immunosuppression, which occurred due to chemotherapeutics and was particularly effective for regulating WBC deficiency and lymphopenia. In the same study, Sumac significantly improved myelosuppression due to cisplatin administration to rats. Sumac increased the rats' resistance to the adverse effects in the gastrointestinal tract and bone marrow and exhibited antiemetic properties. ²⁵ In a study, conducted by Lee and Yeo, it was stated that the Sumac had a bidirectional activity that increased COX-2 expression and reduced NO formation, and thereby, modulated inflammation. ²⁶ Such a feature of Sumac that bidirectionally modulates inflammation might provide a highly significant clinical benefit, especially for COVID-19 infection. It can prevent autogenetic breakdown due to severe inflammation and the associated decline in the overall condition of the patients with COVID-19. Another may regulate immune activity by correcting lymphopenia in areas where the immune response is suppressed, such as lymphopenia in some patients. Another effect of Sumac might be regulating the immune activity through improving lymphopenia in areas where the immune response is suppressed.

Antioxidant and Liver-Protective Effect

COVID-19 infection results with severe disease prognosis for ∼15% of the cases and critical for 5%. In severe and critical cases, severe inflammation occasionally deteriorates due to cytokine storm and sepsis, and the overall condition of the patients worsens as they commonly need to be followed up in intensive care units, intubated and connected to a mechanical ventilator. ²⁷ Endothelial dysfunction and subsequent sepsis are highly responsible for the pathophysiology of deterioration in such patients. The main causes of endothelial dysfunction are an increase in free oxygen radicals, increases in levels of nitric oxide, interleukins, and thromboxane A2 and the activation of the complement system. Multiorgan failure, especially liver failure, develops in patients due to tissue damage caused by free oxygen radicals, vascular instability caused by nitric oxide increase, the formation of coagulopathies, and hypoxia. ²⁸ It was identified that concentrations of the liver enzymes ALT and AST, creatinine, creatine kinase, LDH, cardiac troponin I, N-terminal probrain natriuretic peptide, and D-dimer concentrations were high in COVID-19 patients due to hepatitis development. ^29,30 Furthermore, low platelet and fibrinogen levels, high D-dimer levels, and high ferritin levels due to macrophage/hepatocyte activation were detected. ²⁹ A study conducted with COVID-19 patients, who were not admitted to intensive care, indicated prevalent liver damage. It was reported that the size of pulmonary lesions on computed tomography was a predictor of liver function damage. ³¹

The review of the studies focusing on Sumac demonstrated that it had antioxidant and liver-protective effects. A study investigated the protective effects of Sumac ethanolic extract on hydrogen peroxide (H2O2)-induced oxidative stress in human liver cells. The findings of the study indicated that the extract could protect human liver cells against oxidative damage by increasing the antioxidant enzyme levels and regulating the antiapoptotic oxidative stress mechanisms. ³² Another study reported that Sumac extract exhibited strong activity against nitric oxide and reactive oxygen species. Furthermore, the extract significantly regulated the expression of nitric oxide synthase, which prevents the production of nitric oxide at the transcriptional level in active macrophages. ³³ A different study, which focused on the effects of Sumac gall extract noted that it significantly prevented acute liver damage due to carbon tetrachloride in rats. It was indicated that the extract exhibited such effect due to the scavenging of oxygen radicals (Superoxide dismutase-like activity), through dissipating the oxygen radicals in liver cells and serum. ³⁴ Another study investigated the effects and antifibrogenic mechanism of Butein, which is the main component of the Sumac shell, on carbon tetrachloride-induced liver fibrosis in rats. Butein use resulted in a significant decrease in hydroxyproline and malondialdehyde levels in rats. It also reduced tissue inhibitor expression of alpha-1 collagen and metalloproteinase-1 mRNAs in the liver in a dose-dependent manner. ³⁵

Antimalarial Effect

A crucial phase of malaria infection is the phase that malaria parasite plasmodium infects erythrocytes. Erythrocytes are disintegrated after this phase and hemoglobinemia and hemoglobinuria develop. Given the decreased blood hemoglobin ratio, oxygen and carbon dioxide carrying capacity decreases, and hypoxia and dyspnea are observed. The studies focusing on COVID-19 infection reported that 51% of patients had decreased hemoglobin values and 63% increased serum ferritin levels. ³⁶ Several structural and nonstructural proteins isolated from the SARS-CoV2 virus attack the 1-beta chain of hemoglobin and separate the hemoglobin and iron. Hence, porphyrins and heme are formed. Consequently, the process leads to a decrease in hemoglobin, which carries oxygen and carbon dioxide. Serum ferritin levels also increase due to increased heme in the blood. ⁹ Malaria parasite plasmodium and COVID-19 virus are structurally different pathogens; however, chloroquine acts on both pathogens. Chloroquine, which was used as an antimalarial drug for several years, is the most widely accepted and used drug in COVID-19 treatment. Chloroquine accumulates malaria-infected erythrocytes, causes the loss of hemoglobin degradation enzyme, decreases the amino acids necessary for the development of the parasite, and leads to the death of the parasite. It was reported that the therapeutic effect of chloroquine against COVID-19 could be closely related to abnormal hemoglobin metabolism. Chloroquine might inhibit the virus proteins that attack the heme and prevent the binding of surface glycoproteins of the virus to porphyrins. Hence, hypoxia and dyspnea could be alleviated since the hemoglobin structure is protected. ⁹

Sumac has similar antimalarial effects as chloroquine. In vivo and in vitro studies proved the antimalarial activity exhibited by Sumac extracts. In vivo models of rat, testing indicated high malarial parasite clearance and chemo suppression due to Sumac extract administration. ³⁷ A similar study that tested plant combinations in rats reported that Sumac combinations indicated high malaria parasite suppression in vivo. ³⁸ Another study focused on the antimalarial effects of 18 plant extracts and their cytotoxicity in human embryonic lung cells, for the treatment of chloroquine-resistant plasmodium falciparum. It was determined that Sumac extract was one of the two extracts that exhibited antimalarial effects without cytotoxicity, and the other extracts were found to be ineffective. ³⁹ In a previous study, the modifying effects of Sumac tannins on erythrocyte membrane structure were reported. It was identified that Sumac tannins were incorporated into the erythrocyte membrane, leading to the transformation of discocytes into echinocytes and an increase in the hardness of the hydrophilic region of the lipid bilayer. The study findings demonstrated that the Sumac tannins embedded in the erythrocyte membrane alters the physical properties of the membrane and may limit its interaction with bacterial toxins. ¹⁰ The evaluation of the pathophysiological mechanisms of Malaria and COVID-19 infections present certain similarities. Such studies suggest that Sumac extract with antimalarial activity is a significant candidate for testing its effectiveness against COVID-19 infection.

Sumac Toxicity and Possible Side Effects

A plethora of studies demonstrated, through animal and human studies, that the use of Sumac was safe and did not exhibit side effects. A study reported that 30-day long administration of the Sumac extract, with oral concentrations of 312 and 625 mg/kg per day, did not result in any toxicity. ⁴⁰ Another study observed no side effects after administering 3-g Sumac capsules three times a day to diabetic patients for 3 months. ²⁴ Long-term oral use of hot water extract of Sumac was considered safe and could be used daily. A study focusing on the use of hot water extract of Sumac investigated whether the sensation of postexercise muscle pain that occurred in healthy participants after heavy exercise decreased due to Sumac use. The study reported a significant decrease in muscle pain for the experimental group when compared to the placebo-controlled group. Moreover, biochemical parameters, such as creatine kinase, LDH, troponin I, and hydroxyproline were found to be significantly lower. Sumac and placebo groups were switched, and the same results were once more obtained. The study reported no side effects in the groups. ⁴¹ In another study, the safety profile of the Sumac extract was determined. It was found that the extract did not impair the integrity of the intestinal epithelial cell layer, did not significantly decrease Lactobacillus viability, and did not demonstrate any cytotoxic effects on vaginal keratinocytes. ⁵

The extracts mentioned in the reviewed studies were either mentioned as Sumac extracts or as extracts from several subspecies such as coriaria of the rhus genus, verniciflua, and javanica. The present review commonly named the extracts based on the aim of the study. The phytochemical structure in the subspecies was widely studied and relatively small differences were reported. ¹ No lethal dose of cytotoxicity was reported in any of these studies.

The Sumac Dose and Application Recommended For Future Studies

We recommend our treatment protocol proposals based on previous human studies conducted with Sumac. Sumac treatment could be implemented with two methods in Covid-19 patients.

Conclusion

An evaluation of the up to date knowledge, revealed by the clinical studies, on the characteristics of COVID-19 infection, its pathophysiology, clinic, and treatment, suggests that the use of Sumac extracts could be beneficial. Based on the beneficial effects indicated by the scientific studies on Sumac extracts, the present review could be encouraging to investigate its effectiveness for COVID-19 treatment. The authors of the present study believe that the benefits of Sumac extract can be tested by adding the adverse-effect-free Sumac extract to treatment and protecting the existing treatment protocols.