*3.1.1 Evidence of ginger's anti-COVID-19 properties*

SARS-CoV-2-related papain-like protease (PLpro) cleaves polyprotein a/b (PP a/b) at different sites yielding several proteins needing for viral survival and replication (**Figure 2**) [17]. SARS-CoV-2-related PLpro also interferes with type I IFN anti-virus response [17]. In order to successfully suppress virus multiplication and survival, anti-SARS-CoV-2 medications should target PLpro. [18]. According to the findings of a study conducted in Saudi Arabia, COVID-19 patients' consumption of ginger increased from 36.2% prior to infection to 57.6% after infection. The proportion of patients admitted to the hospital for COVID 19 treatment was also lower (28.0%) among ginger users than among nonusers (38.0%) [19]. A few examples of cured COVID-19 patients were recorded in a Bangladesh study, who drank home medicines using ginger in blends of various herbs with or without further treatments [20]. A few cases of COVID-19 were treated with home remedies including ginger in combination with other herbs improved disease symptoms, according to the findings of a Tunisian study [21]. In certain African countries, renowned treatments involving ginger in combinations with other herbs were also utilized to treat COVID-19 [22]. In compared to those treated with a normal protocol using hydroxy-chloroquine alone, the results of an Iranian clinical trial study show that combining outpatients with probable COVID-19, ginger and Echinacea alleviated some of their clinical symptoms (breath shortness, coughing, and muscular discomfort) [23]. Ginger may help patients with pulmonary problems such ARDS (Acute respiratory distress syndrome), fibrosis, lung and pneumonia, as well as sepsis, which are all indications seen in COVID-19. Overall, the evidence suggests that more high-quality controlled trials are needed to validate ginger's benefit and safety in COVID-19 patients. In Iran, a clinical investigation is underway in which 84 COVID-19 patients were randomly assigned to two groups, each with 42 participants, including intervention and control groups [24]. The intervention group will receive standard treatment plus 1000 mg ginger three times daily for seven days, whereas the control group will receive normal treatment plus placebo tablets at the same dose and schedule for seven days [16].

#### **Figure 2.**

*COVID-19 pathogenesis is influenced by SARS-CoV-2 and inflammation. SARS-CoV-2 infects tissues that express ACE2, causing necrosis, pyroptosis and apoptosis, as well as inflammation. Infected macrophages with SARS-CoV-2 release a variety of cytokines and chemokines, causing tissue inflammation and a cytokine stormTLRs and inflammasomes can be activated by SARS-CoV-2, resulting in an increase in inflammatory responses and tissue damage. Ginger can enhance antiviral immune responses and have direct anti-SARS-CoV-2 effects, as well as interfere with inflammatory responses mediated by macrophages, TLRs, and inflammasomes. Abbreviations: ALI: Acute lung injury; ACE2: Angiotensin-converting enzyme 2; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; ARDS: Acute respiratory distress syndrome; TLR: Toll-like receptor; IL: Interleukin [16].*
