Abstract
In December 2019, a novel coronavirus SARS CoV-2 caused COVID-19 in more than 200 countries. The infection had high mortality and morbidity rates with no specific approved antiviral drugs. Isolation, appropriate hygiene measures, and treatment were the most efficient ways to prevent infections. Interestingly, plants, sponges, corals, and microorganisms remain a plentiful source of natural bio-actives for treating different human illnesses and COVID-19. We herein retrieved literature from PubMed.gov, ScienceDirect, and Google Scholar relevant to anti-COVID-19 metabolites by searching with the keywords "SARS-CoV-2" and "Bio-actives from plants/marine invertebrates/microbes" till November 2023. The study briefly covered SARS-CoV-2, its variants, therapeutics, and intervention for COVID-19 infection. This study also aimed to develop low-calorie probiotic-rich fermented ginger beer and fruit juices to use as an immunity booster to fight against multiple viral infections. Only literature pertinent to the topic was included, and those not available as full text and duplicate sources with similar titles and content were excluded. The comprehensive findings of the present study are essential to make national-level policy decisions on both beneficiaries of natural bio-actives to improve health by consuming herbal low-calorie fermented products during such needy hours.
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1 Introduction
Coronaviruses (CoV) belong to Nidovirales within the family Coronaviridae and have a crown-like appearance. It is an enveloped spherical virus with a single-stranded, positive-sense RNA genome. Spike protein is the most prominent feature of coronaviruses. Four groups of CoV, i.e., alpha, beta (originated from bats and rodents), gamma (previously referred to as coronavirus groups 1, 2, and 3), and delta (originated from avian species) have been reported. CoV is highly contagious and rapidly spread by inhalation and ingesting aerosols containing virus particles, resulting in common clinical symptoms of coughing and sneezing [1]. Specifically, they cause respiratory disorders, gastroenteritis, and central nervous system infection in many avian and mammalian hosts. CoV in humans is believed to have arisen from mammalian coronavirus, specifically the bat coronavirus [2]. In the early 1960s, six different CoV strains were known to infect humans, including HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1 (Fig. 1). While coronavirus causing Middle East Respiratory Syndrome (MERS-CoV) and Sever Acute Respiratory Syndrome (SARS-CoV) were reported in the past two decades infecting a large number of people. The novel CoV accountable for ‘COVID- 19’ pandemic is caused by beta-coronavirus. The virus's genome is fully sequenced and appears to be the most similar strain in bats. It is named SARS-coronavirus-2 (SARS-CoV-2). SARS-CoV-2 symptoms showed cough, fever, dyspnea, headache, and myalgia. Overall, SARS-CoV-2 is less pathogenic but spreads more than SARS-CoV and MERS-CoV. In December 2019, the first case of SARS-CoV-2 was reported in Wuhan, China. The COVID-19 wave has taken a severe toll across the globe. In particular, India's first wave of SARS-CoV-2 infection began in late January 2020 with a total of 11 million cases and 0.157 million deaths over nine months [2]. Repurposing the existing knowledge on plant and natural products based on traditional remedies for different infections could be a relief and a better choice for the already burdened healthcare system [9, 10]. Worldwide, particularly from China, Japan, and India, and also some regions of African populations, use herbal-based remedies for different kinds of diseases mainly due to their easy availability and relatively low cost. In China, the National Health Commission has permitted the use of herb-based and Western remedies as an alternate therapy for COVID-19 [11]. Recently, a research group in India studied the efficacy of Fifatrol and Amrytavir for curtailing COVID-19 symptoms, especially against the Omicron variant of SARS-CoV-2 [12]. In another study, a natural ayurvedic poly-herbal immunity booster, Ayush Kwath, was approved by the Ministry of Ayush, India, and has been used as a prophylactic measure against SARS-CoV-2 infection [13].
Ginger (Zingiber officinale) is one the herbal spices that has over 400 bio-active compounds and exhibits various therapeutic biological activities such as antimicrobial, antioxidant, anti-inflammatory, anti-tumor, antifungal, anti-migraine, anti-diabetic, anti-obesity, anti-emetic, anti-nausea, immuno-modulatory, hypo-cholesterolemic, hepato-protective effects along with anti-viral property. Studies have been reported on the protective role of ginger against acute respiratory distress syndrome, which is the prime cause of patient mortality with severe COVID-19 infection [14, 15]. Moreover, active components such as shogaol and gingerol interfere with the spike protein of the SARS-CoV-2 and angiotensin-converting enzyme 2 of the host [16].
Amidst COVID-19, fermented food consumption has increased worldwide due to its additional nutrient supplement and health benefits. Fermented food increases nutrients' bioavailability and provides viable microbes of potential biological activity, boosting immunity [17]. It has been reported that fermented ginger reduced neuron cell loss and synaptic disorder than non-fermented ginger [18]. The natural fermentation process using starter culture in ginger bugs has resulted in a homogeneous product with improved nutritional and sensory characteristics [19, 20]. Concerning fermented fruit beverages, pineapple, and watermelon are suitable substrates for producing probiotic juice enriched with Lactobacillus sp. and Bifidobacterium sp. They can be potential alternative functional food matrices. The characteristics of such probiotic drinks primarily depend on microbial strain, fermentable sugars, and protein content. These nutritional supplements improve health status by boosting immunity and protection from different diseases [21, 22]. However, detailed clinical research is essential to fully understand the mechanism of fermented-based traditional natural medicine and its role in fighting against SARS-CoV-2 infection.
The present study provides an overview of the biological potential of different natural formulations and products derived from microbes, invertebrates, and plants against SARS-CoV-2. It underlines its antiviral properties in an effort to deliberate these resources as a valuable and effective alternative for the prevention and treatment of COVID-19. Additionally, we aimed to produce and characterize probiotic ginger beer and fruit juices through natural fermentation to use as an immunity booster during COVID-19 and other types of viral infections.
2 SARS-COV-2: structure and its variants
SARS-CoV-2 is a beta-type coronavirus proposed by the name nCoV-19 (COVID-19). It has a specific gene sequence that differentiates it from previously sequenced coronaviruses but has 88% shared identity with SARS-CoV and 50% with MERS-CoV. Phylogenetic analysis revealed that the SARS-CoV-2 strain has evolved from bats. Till now, no confirmed report on the intermediate host(s) of SARS-CoV-2 has been detected. COVID-19 has passed from bats to pangolins to humans in the Wuhan, China's local seafood market in 2019. Direct viral transmission from bat to human is also reported. However, this worldwide pandemic spreads through droplets or direct contact between humans and is highly contagious [1]. Coronavirus has around 20 kb genome with replicase gene consisting of single-stranded positive-sense RNA with a 5' cap and 3' poly A tail encoding 16 non-structural proteins (proteins like Nsp1, Nsp3, Nsp5, Nsp7, Nsp10, Nsp12, Nsp13, Nsp14 and Nsp15) [23]. These proteins play a crucial role in virus-mediated infections. The replicase gene encodes for open reading frames rep1a and rep1b open reading frames, which express the polyproteins pp1a and pp1ab, respectively. Structural proteins such as Spike (S), Nucleocapsid (N), Matrix (M), Envelope (E) (Fig. 2a), and accessory proteins are encoded by the rest of the genome. S proteins are glycosylated proteins (~ 150 kDa) consisting of N-terminal S1 and C-terminal S2 domain, which make easy recognition, attachment, and entry of the virus into the host cell; M protein (~ 30 kDa) is a dimer with three domains aids in giving shape and viral budding; E protein (~ 8–12 kDa) is transmembrane protein present in limited quantities for CoV assembly; and N phosphoprotein (45–50 kDa) for allowing the viral RNA inside the virion and other virus-protein-mediated processes. These structural and non-structural proteins are the critical targets for various drugs and bio-active compounds used chiefly with other inhibitors of the viral replication cycle. Additionally, interspersed and/or overlap** genes within open reading frames encode other accessory proteins [2].
Structure and variants of SARS-CoV-2
Multiple variants of the SARS-CoV-2 are circulating throughout the world and are categorized into Variant of Interest (VOI), Variant of Concern (VOC), and Variant of High Consequence (VOHC). According to Global Variant Reports, the United States is circulating the variants of interest like B.1.526, B.1.526.1, B.1.525, and P.2 and variants of concern such as B.1.1.7, B.1.351, P.1, B.1.427, and B.1.429. However, no variants of high consequence have been identified (Fig. 2b). The increasing number of COVID-19 cases is due to the easy and quick spread of these variants, leading to more hospitalizations and deaths. Implementing Standard Operating Procedures (SOPs) will aid in preventing the infection against the virus. Additionally, increasing public health mitigation strategies like the use of masks, hand hygiene, vaccination, physical distancing, isolation, and quarantine are of primary importance. The second wave progressed with more infectious variants of SARS-CoV-2 (alpha variant and delta variant) which followed from mid-February 2021. During this period, an increased surge in the mucormycosis associated with COVID-19 cases was observed in India. This condition was frequently seen in highly immunocompromised individuals with severely life-threatening situations [24]. The third wave of SARS-CoV-2 infection in India was reported in the last week of November 2021 and became widespread in less than three weeks in the previous week of December 2021. During this time, the progression was observed for the Omicron variant, which has mutated into other types of variants [7]. One such variant, B.1.1.529, has been discovered in South Africa and was highlighted across all six World Health Organization (WHO) regions [25]. Till December 2023, India has reported approximately 43.5 million COVID cases, second to the US, and around 524,600 deaths after the US and Brazil (https://covid19.who.int/).
3 Prevention and therapeutic intervention for SARS-CoV-2 infection: general overview
Preventing SARS-CoV-2 virus pathogenesis is a significant step in controlling the COVID-19 pandemic. The containment of the infected patients has been recommended to avoid transmission. However, it is difficult to impose the isolation of infected patients and poses many social issues. Masks have been in extensive demand to prevent the spread of this viral infection. The medical masks avoid direct exposure to respiratory droplets from infected patients (symptomatic patients). Regular hand washing is a straightforward and effective measure to regulate virus transmission. Other practices include covering the mouth and nose when coughing and sneezing to prevent the virus spread. Generally, one should avoid close contact with those who show symptoms such as coughing and sneezing [26].
3.1 Vaccines and chemical drugs
According to the data reported in a recent review, ∼66 vaccines are being developed globally, with ∼170 candidates in pre-clinical trial experiments [2]. Interestingly, at least one National regulatory body has approved the use of ten newly developed vaccines, which fall under significant mRNA categories: inactivated virus vaccines, non-replicating viral vector vaccines, and peptide vaccines [2]. India launched the COVID-19 vaccination on January 16, 2021, with over 12,130,881,147 vaccine doses have been administered among the population (Table 1) (https://www.bbc.com/news/world-asia-india-56345591; https://covid19.who.int/). Although vaccines play an essential role in COVID-19 treatment, they are less effective and require an extended period of development and time for global population vaccination. Since then, the administration of interventional chemical drugs to reduce viral load, cytokine storm, and inflammation, along with the management of COVID-19 symptoms, have been practiced over the course of the pandemic. A variety of therapeutics are available under the Food Drug and Administration (FDA), which has granted Emergency Use Authorization (EUA) for the management of COVID-19 (Food and Drug Administration). These include anti-viral drugs (e.g., Remdesivir), anti-SARS-CoV-2 monoclonal antibodies (e.g., Bamlanivimab/Etesevimab, Casirivimab/Imdevimab), anti-inflammatory drugs (e.g., Dexamethasone), immuno-modulator agents (e.g., Baricitinib, Tocilizumab). Remdesivir is a potential anti-viral drug against SARS-CoV and MERS-CoV when clinically tried in grown cells and mice models. Remdesivir has effectively inhibited virus infection in Vero E6 and Huh-7 human liver cancer cells susceptible to SARS-CoV-2. Favipiravir has undergone clinical trials to treat COVID-19 infection and inhibits RNA-dependent polymerase RNA (RdRp). HIV protease inhibitors such as Lopinavir and Ritonavir and a combination of Oseltamivir are used to improve the status of COVID-19 patients. Baricitinib is used for the treatment of pneumonia in COVID-19 patients. Convalescent plasma and monoclonal antibodies improve the survival rate of the patients with SARS-CoV-2. Interestingly, humanized monoclonal antibodies such as Leronlimab and an RNA polymerase inhibitor, i.e., Galidesivir, have shown survival benefits in many deadly virus infections [8, 27, 28]. Additionally, anti-malarial drugs, chloroquine (CQ) and hydroxychloroquine (HCQ) have shown anti-SARS-CoV-2 activity under clinical treatments [27]. However, later, it was found that the death rate was twice that of the patients who did not take the dose of these drugs [2]. Considering the time factor as a major hurdle between the synthesis and administration of new vaccine formulations and drugs [9], there is a growing demand for repurposing preapproved drugs to treat various viral infections. This is possible due to the high availability of pharmacodynamic and pharmacokinetic data generated for broad-spectrum antiviral medicines [29]. Different studies have been proposed for repurposing drugs such as metformin, baricitinib, cenicriviroc, and phosphodiesterase 5 inhibitors for the symptom management associated with COVID-19 and its newer variants [9, 30, 31]. However, the clinical utility of using these treatments is specific and is based on the risk factors and severity of illness. Thus, it is clear that other drugs and natural products derived from natural origin with much higher efficacy against COVID-19 are the need of the hour, offering an alternative approach to the treatment.
3.2 Natural products and bio-actives against SARS-CoV-2: immunity enhancer
The human body's immune system plays a pivotal role in protecting our health against various infections. It has been reported that an older person with a suppressed immune system is more prone to be affected by COVID-19. Scientific evidence shows that proper diet and adequate nutrient intake are the first choices to boost immunity and prevent COVID-19 infection [6]. Further, the degree of immunological dysfunction in COVID-19 patients was related to the disease severity. Nutrients rich in vitamins, metal ions and omega-3 fatty acids have shown beneficial effects in eliminating SARS-CoV-2 viral load and hospitalization. It has been well-documented that COVID-19 has drastically altered the dietary patterns of every individual. According to epidemiologic research, increased consumption of herbals, fruits, and vegetables has improved overall life span and reduced the risk of cancers, diabetes mellitus, cardiovascular issues, and increased weight. This is due to essential anti-inflammatory compounds such as vitamins, carotenoids and polyphenols [14, 32,33,34]. Interestingly, nutraceuticals rich in probiotics, vitamin D, vitamin C, Zn, curcumin, cinnamaldehyde, selenium, quercetin, lactoferrin, etc., have been shown to boost immunity by antioxidant, anti-inflammatory, and antiviral activities. This led to symptoms associated with infection, such as pain, fever, loss of appetite, dry cough, malaise, nausea, vomiting, diarrhea, dyspnea, and other respiratory symptoms [35]. It has been reported that an appropriate combination of some of these nutrients as a food supplement helps prevent virus spread, prevent disease progression, suppress hyper-inflammation, and provide prophylactic and therapeutic support against SARS-CoV-2 infection [36, 37]. Several research works have shown that micronutrients (Fe, Zn, Se, Cu, and folate) and macronutrients (omega-3 fatty acids, eicosatetraenoic acid, and docosahexaenoic acid) inhibit viral replication and boost the immunity of the body by increasing the antibody production. They mediate cellular immunity by activating cytokines and chemokines [6]. These natural supplements inhibit the viral infection by one of the several mechanisms as highlighted in Fig. 3.
Mechanistic inhibition of SARS-CoV-2 by some representative natural probiotic and prebiotic supplements
Recently, natural products derived from microbes and marine invertebrates have been known to interact with the S protein of SARS-CoV-2, inhibiting COVID-19 infection. This is useful for drug discovery to treat COVID-19 and other diseases in the near future [6]. Globally, maximally natural products from medicinal plants have been reported to show effectiveness under laboratory clinical experiments on SARS-CoV-2, inhibiting the virus growth and multiplication [2, 6, 10, 12, 13, 38]. Specifically, herbal medicines have proved to alleviate the effects of SARS-CoV-2 [10, 39, 40]. Herbal medicine interacts with SARS-CoV-2 pathogenesis by inhibiting replication and entry of the virus into the host cells. Some of the antiviral medicinal plant species belonging to Allium, Curcuma, Citrus, Cinchona, Echinacea, Mentha, Nigella, and Orange are reported as the most desirable fruit or herbs usually consumed in the form of decoction for COVID-19 management [32, 41]. For instance, the antiviral effects of polyphenols are mediated by direct inhibitory effects on virus replication or through the induction of immunomodulatory responses [42, 43]. Overall, we proposed that bio-actives from microbes, plants, and animals are potent in boosting immunity along with the specific activity of proteins of the virus, thereby inhibiting their invasiveness in the human body (Fig. 4).
Proposed general mechanism of action of bio-actives derived from microbes, plants and invertebrates on SARS-CoV-2
4 Recent advancement in In-silico computational approach for drug discovery against COVID-19
Although significant efforts have been made in drug development for appropriate COVID-19 medication over the years, only ~ 13% have shown success in clinical trials, with a maximum percentage having faced attrition problems. This is due to a need for more process optimization during drug development and low features concerning distribution, absorption, metabolism, excretion, and toxicity. Different research organizations and pharmaceutical corporations have taken a leading step in using computer-aided drug discovery for rapid development processes with relatively low costs and preventing failures at the final stage. This strategy helps the researchers use rational drug design to better interact between target protein and ligand by understanding the binding affinity and molecular interaction. Furthermore, there are leading discoveries in medicinal research for drug development due to the availability of supercomputing facilities, improved programs, algorithms, parallel processing, and tools [44]. Moreover, recent research studies have targeted 3CLpro/Mpro of SARS-CoV-2 thus inhibiting infection. Supporting this, Tallei et al. [45] aimed at predicting ability of bio-active compounds derived from plants to inhibit the spike and Mpro proteins using molecular docking studies. Their results revealed better docking pose for compounds from plants than antiretroviral and antimalarial drugs. Although results are preliminary, the study can be further investigated in-vivo and laboratory as chief natural compounds against SARS-CoV-2. Recently, Rahman et al. [6] reviewed computational techniques to determine the possible anti-COVID-19 agents from plant metabolites. The study has also highlighted the in-silico method to choose the most effective drug among terpenoids, alkaloids, flavonoids, polyphenols, and terpenoids against SARS-CoV-2 main protease [6].
5 Methodology
A literature review on the topic was identified through the following databases: PubMed.gov, Google Scholar and Science Direct. In all these listed databases, broad search terms/keyword “SARS-CoV-2” were paired with ‘bio-actives. Initially, extensive screening was used to establish a list of peer-reviewed research articles that were the primary source of the research topic. Initially, a basic search of assistive technology efficacy was used from the article titles and research data derived from databases with the search basis. The search terms selected for this literary analysis consisted of keywords combined in various ways with " + " commands to obtain the most narrowly defined and relevant articles from December 2019 to November 2023. Most of the terms were generated from the initial Google Scholar search, combined with results from the various database searches. For example, the keyword ‘SARS-CoV-2’ was combined with 'Bio-actives, ' which was then paired with plants, animals, microorganisms, and marine organisms. Sources were analyzed according to the inclusion and exclusion criteria. Data inclusion criteria include: (a) Sources need to be in line with the purpose of the literature review based on the research questions of the article, (b) Sources must be from primary source research and any sources that focused on secondary source research were removed, (c) Source had to be from peer-reviewed journal sources. Data exclusion criteria includes: (a) Duplicate titles or similar contents, (b) Report on antiviral properties other than SARS-CoV-2, c) Chemical or synthetic compounds of not natural origin. Examination of journals that would be characteristic of their respective field were selected and used for further studies. Also, chemical structures of some representative bio-actives from plants, invertebrates and microbes were drawn using Chem-Draw Ultra 8.0 (Cambridge, MA 02140). Further, we aimed to produce probiotic-rich fermented ginger beer and fruit drink of low-caloric value using the pre-existing knowledge based on the properties of different medicinal herbs and nutritious fruits in treating various viral and bacterial infections.
5.1 Production of probiotic-rich fermented ginger beer and fruit juices
5.1.1 Procurement of ginger and fruits
Ginger and fruits (watermelon and pineapples) of 2 kg each were collected from the local market of Ponda-Goa, India. For characterization, ginger was washed twice, chopped along with the peel, sun-dried, ground to a fine powder and stored in air-tight containers for further use. The powder sample was then examined for texture, color, odor and taste. The presence of organic functional groups in ginger was determined using Fourier Transform Infra-Red spectroscopic analysis (FTIR) (IR Prestige, Shimadzu). Watermelon and pineapples were washed, peeled and chopped into pieces and kept in clean containers until further use.
5.1.2 Natural fermentation process for the production of ginger beer
For the preparation of ginger bugs, fresh ginger rhizomes were rinsed twice with clean water and dried at room temperature for 30 min. The rhizomes were then grated using a motor and pestle, and a sample (10%, w/v) was weighed and added to 500 mL of clean water containing 10% (w/v) crystal sugar in 2 l of the glass container. The mixture was stirred to allow sugar dissolution and uniform distribution of the grated ginger. The content was covered with a cotton cloth, secured tightly with rubber bands, and kept for yeast growth for 24 h. Ginger bugs allow the growth of natural yeast (Saccharomyces pyriformis) residing in the skin to ferment the ginger and lemon mixture. This ginger bug was then fed daily with 5% (w/v) grated ginger and 4% (w/v) of sugar for 5 days to allow the fermentation process (Fig. 5a). Aliquots from the container on each day were removed to analyze the pH of the mixture. For beer production, 150 g of fresh ginger was crushed and added to 2 L of boiled water, followed by 150 g of sugar and 100 g of jaggery in a container. The content was kept at low flame for 10 min and allowed to cool at room temperature. After that, 100 mL of lemon juice was added and inoculated with 100 mL of gingerbug. The mixture was stirred well and sieved using a muslin cotton cloth. The filtrate (~ 2200 mL) was distributed equally in four clean sterile bottles of 1 L capacity, providing proper headspace, and stored at room temperature for 14 days. (Fig. 5b). After fermentation, the content was filtered and stored at 4℃ for further use. Aliquots from the container were removed at 0, 7, and 14 days for pH analysis. Further, the functional groups associated with the components of the fermented beer were detected by using FTIR in the range of 4000–400 cm−1. The ingredients and the requirements used for the preparation of beer are listed in Table 2. Furthermore, sensory evaluation of ginger beer was performed using the hedonic rating test with 20 selected panelists (n = 20, 10 women and 10 men aged between 20 and 50 years) using preferred attribute elimination (PAE) after 14 days. Each panelist was asked to evaluate taste, fizz, aroma, color, and overall acceptability by giving a score according to a 9-point hedonic scale. The ratings were: 9- Like extremely, 8- Like very much, 7- Like moderately, 6- Like slightly, 5- Neither like nor dislike, 4- Dislike slightly, 3- Dislike moderately, 2- Dislike very much and 1- Dislike extremely. The elicited responses for each attribute were written and grouped into categories in consensus by the selected panelists. The panelist excluded attributes having difficulty in evaluation or the same meaning. The results obtained were computed into means.
Flow sheet for preparation of ginger bug (a) and ginger beer (b)
5.1.3 Natural fermentation process for production of watermelon and pineapple fruit juice
Fermented watermelon juice was prepared by homogenizing the pieces in an electronic mixture. The juice was strained in a glass bottle to which 100 g of organic sugar was added, followed by 150 g of the chopped ginger plug, increasing the growth of Lactobacillus and Bifidobacterium species. Finally, lemon juice extracted from 30 g of lemons and a 25 g spoonful of salt was added. The content was boiled, cooled and mixed with 500 mL of water. Pineapple pieces were ground in an electronic mixture to prepare fermented pineapple fruit juice. The juice was strained in a glass bottle to which 400 g organic sugar, 5 g pepper powder, and 25 g spoonful salt were added. The content was boiled, cooled, and mixed with 500 mL water. Each content of fruit juice (watermelon and pineapple) was separately filled in the bottle and was then tightly closed with proper headspace and shaken thoroughly to mix the ingredients. The bottles were kept at room temperature for 12 days for fermentation. Table 2 gives the details of the ingredients required for the preparation of probiotic watermelon and pineapple juice. Further, after 12 days, aliquots from each fermented watermelon and pineapple juice were serially diluted and spread plated on Ragosa agar media to isolate probiotic bacteria. The plates were incubated at 37℃ in the BOD incubator. After 24 h, plates were monitored for viable colonies and noted down the colony characteristics. The distinct colonies were selected and purified by repeated streaking on the same agar medium. The purified isolates from fermented watermelon and pineapple juice were designated as WMJS (watermelon juice strain) and PAJS (pineapple juice strain). Further, the isolates were characterized using morphology and checked for utilization of carbon and nitrogen sources.
6 Findings with discussion
The present study deals with the comprehensive findings of already published data on bio-actives from microbes, marine invertebrates, and plants against SARS-CoV-2 and explores the future direction of natural bio-active research in the medical field. The attempt was also made to prepare fermented ginger beer and fruit drinks as plausible approaches as immunity boosters against viral infection. A literature search in the databases yielded published reports on natural bio-actives from plants, marine invertebrates and microorganisms, and COVID-19, which, upon applying inclusion and exclusion criteria, led to the selection of a few articles of interest related to the study. The inclusion of the most of the articles was done based on careful assessment of data pertaining to only SARS-CoV-2, therapeutics used during COVID-19, recent advancement in re-purposing drugs and future scope for natural bio-actives from microorganisms towards the identification of the molecule that can be used in the management of the corona virus. Additionally, the mode of action of active components from herbal plants of Indian origin as well as possible clinical trials are discussed. Figure 6 depicts a detailed flow chart of the literature review process of identification, inclusion, and exclusion criteria used for analyses.
Flow diagram for literature search and selection criteria
6.1 General mechanism of action of natural bio-actives on SARS-CoV-2
The emergence of the COVID-19 worldwide pandemic has focused on the urgent need for the research and development of new drugs and vaccines to tackle the pathogenesis of SARS-CoV-2. Most of the vaccines developed against COVID-19 are injected via intramuscular route stimulating humoral and cell-mediated immune response. Surprisingly, Dhama et al. [46] developed intranasal vaccines against SARS-CoV-2 which showed promising ability to induce antibody and cell-mediated immunity along with stimulation of protective mucosal immunity. This type of vaccine is easy to administer and prevent SARS-CoV-2 virus infection, replication and transmission. Even with the discovery of effective vaccines, few drugs are currently available in the market to treat COVID-19 symptoms. Natural products constitute diverse structures and chemical classes and offer an excellent resource for drug discovery. Many natural products from plants belonging to flavonoids and terpenes target papain-like proteases of SARS-CoV and inhibit its growth [2]. Interestingly, natural bio-active derived from marine organisms and microbes also have preventive and therapeutic promise [6]. Biochemically, microbes, plants and marine organisms are a source of glycosides, cyanogenic glycosides, anthraquinone glycosides, glucosinolates, saponins, flavonoids, furocoumarins, naphthodianthrones, proanthocyanidins, phenylpropanoids, mono and sesquiterpenoids, diterpenoids, alkaloids, tropane alkaloids, pyrrolizidine alkaloids, isoquinoline alkaloids, methylxanthine alkaloids, pseudoalkaloids, resins, tannins, lignin, proteins, peptides etc. Preliminary data in the previous reports suggested the direct action of natural bio-active compounds on SARS-CoV-2 entry or fusion, virus coat, reverse transcriptase, viral protease, and viral release. Additionally, natural products block SARS-CoV-2 entry, stop viral replication, block viral survival in host cells and boost the host immune response [2]. However, these results are still preliminary, with only a few studies assessing the direct activity of the virus. Therefore, it necessitates develo** and analyzing such natural bio-active on animal models before starting the clinical trials. The representative examples from plants, microbes, and marine invertebrates are depicted in Fig. 7.
Structures of some representative bio-active derivatives. a Plants; b Marine invertebrates and c, Microbes
6.2 Natural products and bio-actives against SARS-CoV-2
6.2.1 Natural bio-actives from microorganisms
Natural bio-actives obtained from microorganisms belonging to bacteria, fungi and cyanobacteria are usually unique in their chemical diversity. Interestingly, ~ 53% of natural-products-based drugs from microbial sources are approved by the FDA and possess antiviral properties. Recently, a semisynthetic pentacyclic- sixteen-membered-lactone-anti-parasitic-drug ivermectin isolated from Streptomyces avermitilis was effective against SARS-CoV-2. Considering the potential of microorganisms and the urgent need to deploy new drugs against COVID-19, in-silico techniques have gained much attention in drug discovery based on virtual screening, docking, bioinformatics, and molecular dynamics [47]. Sayed et al. [47] documented Anthrobenzoxoconone, Citriquinochroman, Holyrine B, Proximicin C, Pityriacitrin B, Penimethavone as potential candidates through molecular dynamic simulations against SARS-CoV-2. These microbial-derived metabolites are potential inhibitors of SARS-CoV-2 protease verified using docking and molecular dynamic simulations (MDS) analysis. The following section gives a brief overview on the bio-actives derived from bacteria, fungi and cyanobacteria as potential inhibitors against SARS-CoV-2.
6.2.2 Bio-actives from bacteria
6.2.2.1 Bio-surfactants
Bio-surfactants are surface active bio-molecules produced by several microorganisms with broad applications and unique properties such as anti-inflammatory and anti-viral properties. Biosurfactants regulate the attachment and detachment of microorganisms from the surfaces. It interacts and inactivates the viruses by various physiochemical reactions and disrupts the membrane and structure of the virus. The antiviral activity of BSs has been patented for treating multiple viral infections. Due to its amphiphilic nature, biosurfactants interact with SARS-CoV-2’s lipid bilayer and denature the genome, thus killing the virus [48].
6.2.2.2 Probiotics and prebiotics
Probiotics are live microorganisms usually found in fermented foods such as cheese, pickles, and yogurt. The probiotics help in reducing the symptoms of lactose intolerance, preventing allergic disease with improvements in lactose digestion, maintaining intestinal pH, preventing ischemic heart syndrome, reducing blood cholesterol levels, producing vitamin B, improving the bioavailability of dietary calcium, and boosting immunity. Probiotics include various species of bacteria and yeast. This includes Bifidobacterium, Bacillus, Escherichia, Enterococcus, Lactococcus, Leuconostoc, Lactobacillus, Pediococcus, Propionibacterium, Streptococcus, Sporolactobacillus, Saccharomyces etc. Consumption of fermented foods by infants, children, adults, and older people significantly reduces upper respiratory tract and gastrointestinal infections. Probiotics can prevent COVID-19 by maintaining the human gastrointestinal (GI) or lung microbiota. On the other hand, prebiotics are non-digestible food ingredients that beneficially affect the host by selectively stimulating the growth and activity of bacteria living in the colon. Prebiotics can be delivered to the intestine by oral administration into microbially colonized body sites or directly to the vaginal tract and skin. They include fructans, oligosaccharides, arabinooligosaccharides, isomaltooligosaccharides, xylooligosaccharides resistant starch, lactosucrose, lactobionic acid, galatomannan psyllium polyphenols and polyunsaturated fatty acids. Gut microbial metabolites such as desaminotyrosine, butyrate, and bile acid are known to prevent COVID-19 by inhibiting viral replication or improving immunity. Prebiotics have an excellent potential effect against COVID-19 by increasing probiotic development and survivability. In addition, prebiotics can directly impact GI symptoms caused by COVID-19 by inhibiting the ACE enzyme [49].
6.2.2.3 Glucocorticoid
Methylprednisolone is one of the glucocorticoids efficiently produced by the dehydrogenation of cortisone by Corynebacterium simplex when grown in a nutrient medium with cortisone and yeast extract. It is a prednisolone derivative of glucocorticoid, which has undergone two clinical trials in 2020 against SARS-CoV-2 (ClinicalTrials.gov; NCT04273321; NCT04244591) [3]. A docking study by Zahran et al. [50] discussed the anti-corona activity of tirandamycins isolated from marine-derived Streptomyces. This inhibits the SARS-CoV-2 methyltransferase (nsp16) enzyme. In addition, alteramide A obtained from the extract of Alteromonas sp. associated with sponge Halichondria okadai has shown promising results against RNA-dependent RNA polymerase (RdRp).
6.2.3 Bio-actives from fungi
Fungal metabolites possess anti-viral properties making up more than 90% of naturally occurring antibiotics and compounds. Pyranonigrins A belong to the family of anti-oxidative compounds produced by Aspergillus niger and showed potent inhibitory potential against the main protease (Mpro) expressed in COVID-19 and utilized to prevent cardiovascular diseases associated with COVID-19 [51]. As reviewed by Khalifa et al. [3], fingolimod is a metabolite from the fungus Isaria sinclairii. It was tested in 30 COVID-19 patients in China, which act via modulating sphingosine-1-phosphate receptors (ClinicalTrials.gov; NCT04280588).
6.2.4 Bio-actives from algae and cyanobacteria
Micro and macro-algae are photosynthetic and unicellular organisms that adapt to adverse environmental conditions such as extreme temperature, photooxidation, high or low salinity, and osmotic stress. They have recently been used as a source of bioactive compounds such as phycocyanin, lutein, vitamins (E, B12, and K1), polyunsaturated fatty acids, polysaccharides, and phenolics [6]. Phycocyanobilins (PCBs) are blue phycobilins with tetrapyrrole chromophores present in cyanobacteria such as Rhodhophytes. These pigments possess anti-viral, anti-oxidant, and NADPH-oxidase inhibitory activity. Phycocyanobilin exhibited high affinity towards main protease and the RNA-dependant RNA polymerase. Phycocyanobilins from cyanobacteria Spirulina sp. were reported to treat RNA virus infection. Also, allophycocyanin demonstrated potent activity against enterovirus 71. The pigment neutralizes the cytopathic effects of the viral infection and delays the viral RNA synthesis [52].
6.2.5 Bio-actives from invertebrates
Besides unicellular and multicellular microorganisms, marine invertebrate organisms such as sponges, echinoderms, soft corals, bryozoans, ophiuras, and tunnels serve as an excellent source for discovering new pharmacological compounds. Marine sponges include Aplysinidae sp., Theonella swinhoei, Petrosia strongylophora sp, Axinella cf. Corrugate, Theonella swinhoei, Theonella aff. Mirabilis, Plakortis halichondroides; while soft coral like Pterogorgia citrina, Formosan gorgonian and Briareum are known to produce bio-active compounds [53]. Marine-derived bio-actives such as alkaloids, peptides, flavonoids, phlorotannins, terpenoids, lectins, lipids, and polysaccharides invade coronavirus at the penetration stage. A potent antiviral agent was isolated from the Ascidian aplidium albicans and is under clinical trials in COVID-19 patients [54].
6.3 Bio-actives from fruits and vegetables
Interestingly, Fruit and vegetables are primary sources of antioxidant vitamins. Antioxidants control oxidative reactions, which primarily cause degenerative diseases, including cardiovascular diseases, cancer, early cataracts, etc. Vitamin C, vitamin E and carotenoids are collectively known as the antioxidants of vitamins. The individual or synergistic use of these vitamins helps to prevent oxidative stress. Considering the functional phenolic bio-actives, polyphenols produced by plants act as guards to protect them from photosynthetic stress. Among 8000 different polyphenols reported, anthocyanin, flavanols, flavones, flavan-3-ol and flavanones are considered the most abundant and essential polyphenols. Dietary polyphenols are of great interest as they can affect numerous cellular processes like gene expression, apoptosis, platelet aggregation, and intercellular signaling that can have anti-carcinogenic effects. Polyphenols also possess antioxidant, anti-inflammatory, antimicrobial, and cardioprotective activities and play a significant role in the prevention of neurodegenerative diseases and diabetes. The occurrence of polyphenols and vitamins in fruits such as watermelons and pineapples is responsible for the hydrophilic antioxidant activity [55, 56].
6.4 Bio-actives from medicinal plants of Indian origin
Considering the current scenario of ever-increasing different types of cells and immunity associated disorders or diseases, Indian medicines developed using traditional methods plays a pivotal role in the management of the overall global healthcare system. These include ayurveda, homeopathy, naturopathy, Siddha, Unani, and yoga, which are conventionally practiced to prevent and cure different infections. Overall, approximately 25,000 different herb-based preparations and extracts have been employed in South Asia as components of traditional medicine [11]. Recently, a decoction of three medicinal plants, maricha, lavanga, and sunthi, has been suggested for COVID-19 patients, alleviating airway hypersensitivity and increasing the humoral and cell-mediated response. Likewise, curcumin with milk inhibits interleukin release, tumor necrosis factor-α, and pro-inflammatory cytokines [57]. Profiling of aromatic herbs and medicinal plants revealed a variety of secondary metabolites and chemical compounds that have the potential to inhibit viral replication by binding with the virus and host receptor targets. Among Ayurveda, the use of ‘Khada’ during COVID-19 was recommended by the Ministry of Ayush, Government of India, to improve immunity. Likewise, ‘Guduchi GhanVati’ is recommended to treat SARS-CoV-2 infections. These traditional-based preparations additionally employ different spices from various Indian botanical drugs. Most common bio-active components in plants include alkaloids, glycyrrhizin, phenolics, polyphenols, quercetin, and terpenes, which are responsible for immunomodulatory activities affecting the biomarkers or halting the entry of SARS-CoV-2 inside the host [11]. The following section describes some examples of popular medicinal herbs and spices in India with a brief overview of their constituents and mechanism of action against viral infections.
6.4.1 Cinnamomum cassia (Cinnamon) and Curcuma longa L. (Turmeric)
Cinnamon is an herb used as a spice in nearly all food preparations. Cinnamon is rich in chemical agents such as eugenol, cinnamic acid and cinnamaldehyde. Cinnamon is known to improve body sensitivity to foreign particles. Cinnamon oil and powder possess antiviral activity. According to Singh et al. [58], a 100 mg/kg dose of cinnamon showed drastic growth in the serum immunoglobulin levels, phagocytic index, and titer of the antibody enhancing cell-mediated and humoral immunity. However, 10 mg/kg improved serum immunoglobulin levels, giving rise to humoral immunity. Curcuma longa belongs to the family Zingiberaceae and is natively grown in Southeast Asia and India. Various secondary metabolites such as sesquiterpenes, polyphenols, curcuminoids, and steroids are constituents of this rhizome. Curcumin possesses anti-angiogenic, anti-inflammatory and anti-neoplastic activity. FDA categorized turmeric as “Generally Recognized as Safe” for consumption. The role of curcumin as an anti-viral drug is established as it targets cellular pathways and inhibits growth and replication of viruses. Curcumin blocks the target receptors of SARS-CoV-2 protease, spike glycoprotein-RBD, and PD-ACE2, which are involved in virus infection [58].
6.4.2 Ocimum sanctum (Tulsi) and Allium sativum L. (Garlic)
The Tulsi plant has anti-viral and anti-bacterial activity by boosting the immune response against infections. Tulsi clears mucous from the lungs and upper respiratory tract. Its pungency removes the dampness and toxins that can cause chest infection and fever. Tulsi is commonly used in asthma, bronchitis, rhinitis, and other respiratory conditions. It is also known to improve digestion indirectly by improving the immune system. Tulsi tea helps the virus move from the throat to the stomach, thus killing it in an acidic environment [59]. Garlic is one of the spice herbs which showed broad-spectrum activity against viruses and bacteria. Garlic is rich in sulfur-containing phytochemicals with immuno-modulatory, anti-inflammatory, anti-cancer, anti-tumor, anti-viral, and anti-diabetic activity. The most common sulfur components include garlic thiosulfates (allicin), S-allyl cysteine sulfoxide (allin), azonase, vinylethine, S-(allyl/methyl/ethyl/propyl)-cysteine, S-propyl L-cysteine, and S-allymercapto- cysteine that inhibit the Mpro of SARS-CoV-2. Among sulfur formulations, ‘allin’ exhibits higher anti-viral potential to prevent COVID-19, as revealed by molecular docking analysis. Further, combining this active component with the primary therapeutic drug is an efficient therapy to inhibit SARS-CoV-2 infection with minimal side effects. Finally, consuming functional foods rich in bio-active garlic compounds showed a promising role in reducing COVID-19 [58, 59].
6.4.3 Allium cepa (onion) and Olea europaea (olive)
Onion belongs to the Liliaceae family and contains carotenoids, copaenes, flavonoids, minerals, vitamins, terpenoids, phytoestrogens, anthoctanins and amino acids. Phytochemicals present in onion denature the protein and genetic material of the virus and possess antimicrobial, anti-parasitic, anti-viral, anti-oxidant, and anti-inflammatory properties. Organo-sulfur compounds like isorhamnetin, kaempferol, quercetin, and myricetin inhibited viral infection by blocking virus attachment, altering the transcription and translation processes of the viral genome, and affecting the assembly of the virus. Onion shows inhibitory efficacy against the SARS-CoV-2 main protease [58, 59]. Olive is native to the Mediterranean region and is known to possess anti-oxidant, anti-inflammatory, anti-cancer, antimicrobial, and anti-viral properties. The main active constituents of the olive include oleic acid and squalene. Olive leaf extracts are known to have potent antiviral activities. Secondary metabolites in olive, such as oleuropein, hydroxytyrosol, oleanolic, maslinic, and ursolic acid, affect virus attachment and replication. Terpenoids affect the membrane fluidity and destroy the lipid layer and binding characteristics of SARS-CoV-2. Consumption of olives is believed to increase immunity against various infections [58, 59].
6.4.4 Withania somnifera Linn (Ashwagandha) and Zingiber Officinale (Ginger)
Ashwagandha is commonly called “Indian Winter Cherry” or “Indian Ginseng.” It is grown mainly in Madhya Pradesh, Rajasthan, Gujarat, Haryana, Maharashtra, Punjab and Uttar Pradesh. The primary active ingredients include withaferin-A, withanolide-D, withanone, withanosides, sitoindosides, and various alkaloids, steroidal lactones, and saponins. These compounds showed anti-oxidant, anti-inflammatory, neuro-protection, immuno-modulatory, and anti-stress properties. It has the potential to block the replication process of SARS-CoV-2. The natural compound ‘withanone’ can block the activity of Mpro or the Main protease of the coronavirus. Withanone is also predicted to block the cell membrane receptor required to enter the virus into cells [58, 59]. Ginger is usually used as an edible spice, giving the product a spicy taste and aromatic odor. It showed anti-inflammatory, anti-oxidant, and analgesic properties. Among other countries, Africa, China and India use ginger as an integral constituent for the preparation of most of the herbal medicines. However, nutritional components in ginger differ based on the agronomic conditions, curing methods, type of variety, drying, region of cultivation, and storage methods. Nutritionally, it contains 12.3% carbohydrates, 2.4% fiber, 2.3% protein, 0.9% fat and 1.2% minerals. Moreover, ginger's manganese, potassium, and vitamin C help build resistance against different diseases. Shogoals, paradol, gingerols, gingerdiol, zingerone, zingibrene, gingerenone, and volatile oils are active ingredients of ginger that impart characteristic attributes to the product [58, 59]. Table 3 details the various bio-actives reported from microbes, marine invertebrates and plants and their mode of action.
Currently, consumers' demand for low-calorie fermented ginger beer is outpacing the demand for beverages with artificial ingredients and high-calorie value. This is because ginger extract contains bio-actives such as gingeroles, shagoals, zingerone, and flavonoids and is rich in minerals, vitamins and proteins. In past years, there was significant growth in the production of non-alcoholic and low-alcohol beer (NABLAB), and it is forecasted to grow continuously. There is a progressive shift by consumers towards low-sugary and non-alcoholic beverages. Therefore, worldwide beverage industries have focused on producing new types of beverages, using novel methodologies to ignite the global market for ginger beer [60, 61]. On the other hand, functional foods such as prebiotics, synbiotics, and probiotics have received much attention recently in the healthcare system. These foods act as traditional nutrients and provide additional health benefits such as improved health, preventing diseases, and promoting the individual's mental well-being. A wide range of fermented foods constituting live beneficial microbes or foods enriched with these probiotics are successfully launched in the global food market. Several species of probiotics, such as Lactobacillus, Bifidobacterium, Saccharomyces boulardii, Enterococcus, Bacillus, and Escherichia, are present during fermentation or enriched in functional foods. Previously, only dairy products were used for producing functional foods. However, fruit juice also provides an ideal substrate for producing a probiotic drink. These non-carbonated nutraceutical beverages originated mainly from vegetables and fruits and are a rich source of additional bio-actives [21, 22].
6.5 Production of fermented probiotic-rich ginger beer and fruit juices: immunity booster
6.5.1 Production of ginger beer
The ginger rhizomes were fleshy and flattened with small and large branches. They were light yellowish brown when fresh and turned deep yellowish-brown with longitudinal folds when sun-dried. The odor was aromatic with a hot and pungent taste. Ginger rhizomes with aromatic smells and a spicy taste were reported by Mahomoodally et al. [62].
Traditional fermentation of ginger extract by native microflora or controlled fermentation using Saccharomyces cerevisiae to produce ginger beer has been well documented [63]. Also, Nutakor et al. [60] detailed the steps for making ginger beer using malt and ginger extract. A ginger bug is a product of the fermentation of ginger extract by native yeast (S. pyriformis). It is prepared using meshed ginger and sugar in an appropriate ratio for 5 days (Fig. 8a). The development of froth and color changes indicated the yeast's efficient fermentation process of ginger extract. The initial pH of 6.20 ± 0.05 of the ginger extracts with sugar and water at 0 h was found to be decreased with incubation time (at 48 h, pH 5.08 ± 0.05; 96 h, 4.20 ± 0.05). For the production of ginger beer, the development of froth in the container was an indication of the fermentation process, which was initiated after 24 h of inoculation of ginger bug. The extent of foam and degassing gradually increased over 14 days (Fig. 8b). The pH of samples showed a decrease in pH value from 3.56 ± 0.05 (day 0) to 3.05 ± 0.05 (day 7) to 2.53 ± 0.05 (day 14). The reduction in pH of ginger bugs and beer during fermentation is attributed mainly to the consumption and metabolization of sugars by inherent microbes into acids, leading to increased acidity [19, 64]. The present observations during the preparation of ginger bugs and beer speculated that the metabolic profiles of organic acids, sugars, volatile compounds, and alcohol would have been affected by prolonged fermentation time. Similarly, this would have been a potentiated sensorial attribute of ginger beer, as reported recently [19]. Previously, unfermented ginger beverages prepared by mixing ginger juice, sugar and ginger oil in pure water showed variations in their characteristics [65]. Also, the majority of ginger beers present in the market are artificially produced from ginger extract/syrup/flavors, citric acid, carbonated water, sugar, yeast, and preservatives [60].
Production of ginger bug (a) and ginger beer (b) using a natural fermentation process
6.5.2 Analysis of functional groups in ginger and ginger beer by FTIR analysis
The FTIR spectra of ginger were very complex, containing eight visible bands assigned to the main constituents in ginger (Fig. 9a). Broad bands at 2886, 2351, and 2302 cm−1 may be attributed to -CH2 vibration in the ginger fiber structure. Meanwhile, the band at 1724 cm−1 corresponds to vibration resulting from H2O, amide I, and (C = O) aromatic ring. The band at 1452 cm−1 depicted the amide II vibration. The peaks between 1414 and 1452 cm−1 may be attributed to the stretching of aromatic skeletal combined with C–H vibration. The C-N extension was observed at 1368 cm−1, which is attributed to the presence of zingerines [66]. Concerning ginger beer, a total of nine prominent peaks correspond to different functional groups such as alcohol, carbonyl, and amine (Fig. 9b). A broad band between 3200 and 3400 cm−1 corresponded to the –OH group of hydrogen linked –OH of phenolic and hydroxyl groups contributed from shoals, gingerol, zingerone, paradols, etc. [66]. A strong band at 2930 cm−1 attributed to –CH2 stretching vibration which forms backbone of different secondary metabolite; while, band at 1682 cm−1 corresponded to C = C stretching from compounds such as zingiberene, β-elemene, limonene and camphene present in ginger. Another characteristic band at 1594 cm−1 and 1449 cm−1 depicted amide II, and aromatic skeletal combined with –CH [66]. Phytochemical characterization of ginger and ginger beer is essential to know the probable functional groups associated with the components in the raw material and final product. These constituents essentially contribute to ginger beverages' aroma, taste and flavor characteristics [64].
FTIR spectra. a Ginger powder, b ginger beer
6.5.3 Sensory evaluation of ginger beer
The sensory evaluation analysis of ginger beer showed a difference in the mean scores of the attributes [taste, aroma, fizz and color] (Table 4). The mean score of overall acceptability of the ginger beer was 8.0 ± 0.00, which categorized it as "liked very much." However, a high mean and low standard deviation for beer taste (8.6 ± 0.4) were observed compared to other sensory attributes, indicating that the flavor is the most influential characteristic affecting the beer quality. The brown coloration and turbidity observed for the final product are due to the addition of jaggery during the process. The non-enzymatic browning may also be attributed to the oxidation-decomposition of some compounds, such as polyphenols and citric acid, during extended fermentation time [19]. Chemical, organic volatile compounds and their interactions with taste and olfactory receptors affect the beer flavor. Alcohols, terpenes, aldehydes, ketones, esters, and acids contribute significantly to flavors among the volatile compounds. These are present in conventional beers and other food condiments and give a pungent aroma to most products. It has been reported that alcohols and aldehydes in ginger beer influence ginger aroma and impart characteristics like fruity, floral, gingery, sweet, or sour taste. Ester contributes sweet, fruity-flowery aromas in beverages, while volatile acids give beverages vinegary, mushy, and fatty smells. The beer's overall sensory profile was attributed to the presence of terpenes [19, 67].
6.5.4 Fermented watermelon and Pineapple beverage
Watermelon was big, dark red on the inside, dark green in color from the outside, and sweeter in taste. The pineapple was whiteish yellow from the inside and half ripe. The juice extracted from watermelon and pineapple were deep red and yellow, respectively. Fermentation of these fruit juices was progressed by natural microflora monitored as the appearance of froth, turbidity, color, and bubble generation during the process. Lemon juice and salt were added for aroma and flavor purposes, while high levels of sugar in watermelon juice and higher acidity in pineapple juices inhibit spoilage microorganisms. After 12 days of natural fermentation, the sample showed viable colonies on the Ragosa agar medium. A total of five distinct isolates, two and three from fermented watermelon and pineapple juice, respectively, were selected, purified and designated as WMJS-1 (watermelon juice strain-1), WMJS-2 (watermelon juice strain-2); PAJS-1 (pineapple juice strain-1), PAJS-2 (pineapple juice strain-2), and PAJS-3 (pineapple juice strain-3). All the isolates vary in shape, size, and color. All the isolates were Gram-positive, either oval or cocci in clusters or coccobacilli or rod-shaped. WMJS-1, PAJS-1, and PAJS-3 have oval-shaped cells and may belong to yeast. Meanwhile, WMJS-2 appeared cocci in the cluster, and PAJS-2 were short rods, indicating strains may belong to Streptococcus and Lactobacillus, respectively (Fig. 10). Mulaw et al. [68] reported LAB bacteria from traditionally fermented Euthopean food products and were identified by morphological, biochemical, and physiological features. Hoque et al. [69] isolated Lactobacillus sp. from yogurt and appeared to have a similar morphology as PAJS-2. In another study, Nguyen et al. [22] reported different species of Lactobacillus and Bifidobacterium in the probiotic pineapple beverage prepared using starter cultures. From the results of the present study, fermented watermelon and pineapple juice would harbor essential probiotic bacteria of high nutritive value and could be added to a regular diet as a nutraceutical supplement.
Fermented watermelon and pineapple fruit juice and probiotic bacteria. a Fermented watermelon and pineapple juice, b Viable colonies on Ragosa agar, c Purified isolates and d Morphology of the isolates, i. WMJS1 ii. WMJS2 iii, PAJS1 iv. PAJS2 v. PAJS3 vi. Nutrolin-B capsule strain-2
The present results provide unprecedented data on the nutritional aspects of fermented ginger beer and fruit beverages, making larger perceptibility for the product, introducing the prospects for future applications in medicines, and making them non-dairy fermented beverage options for specific audiences. In addition, these comprehensive data will serve as the basis for determining the functional attributes of the beverages.
7 Conclusion, recommendations and future prospective
COVID-19 is a pathogenic and pandemic viral infection caused by the highly contagious coronavirus. Although the deployment and administration of vaccines have significantly improved the long-term effects of COVID-19, they are not entirely effective with the persistence of some severe symptoms. Additionally, time is crucial for the new development and vaccination across the global population. This creates a gap and scope for investigating other safe and effective remedies against SARS-CoV-2. Computer-aided drug discovery for rapid development processes with relatively low costs and preventing failures at the final stage are ongoing research carried out by various organizations. Supporting this, molecular docking studies have been performed recently for predicting the ability of bio-active compounds derived from plants to inhibit the spike and Mpro proteins of SARS-CoV-2 [45]. Natural products and bio-actives have traditionally been used to treat various infectious diseases. This has marked an initiating point for repurposing traditional knowledge to search and develop new metabolites against COVID-19 infection. The previous research studies were carried out in vitro with few experiments on animal models. Further, recent clinical trials have to be randomized as some traditional Chinese and Indian medicines have been shown to reduce the symptoms associated with COVID-19 [6, 10]. Interestingly, this knowledge made us develop low-calorie fermented ginger beer and fruit beverages using natural inherent yeast as a nutraceutical supplement that may potentially act as an immunity booster during the COVID-19 pandemic. This study comprehends knowledge concerning the potential of fermented ginger beer and fruit drinks as the possible approach for boosting immunity against COVID-19. Therefore, it is worthy to identify in future studies the exact constituents in the products and their mechanism of action against SARS-CoV-2 and to study the impacts of these products on the tissues infected with the virus. Moreover, a combined therapy using these probiotic products with a validated medication for preventing and treating COVID-19 infection should be considered. Additionally, new molecular methods such as high throughput screening must be employed to isolate the bio-active compounds from microbial sources. Thus, future studies should emphasize the investigation of more natural-based bi-actives and studying their mechanisms of action on the virus to know the effective treatment for COVID-19. The data discussed in the present study highlight the absolute need for effective preventive and treatment methods to fight emerging viral infections, mainly using natural products derived from microbes, invertebrates, and plants for more efficient, targeted, and safer remedies.
Data availability
Not applicable.
Code availability
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Acknowledgements
The Authors are grateful to Principal Prof. Vikas J. Pissurlekar, P.E. S’s College of Arts and Science, Farmagudi, Ponda, Goa, for providing the necessary facilities to conduct the research. The author SG dedicates this research work to Prof. Saroj Bhosle (Former Dean, Faculty of Life Science and Environment, Goa University) on her 72nd birthday.
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Author SG designed, performed the analysis, analyzed the data, and drafted the manuscript. ZN and SN formulated the products. SB and RDG interpreted the results and corrected the manuscript.
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Gaonkar, S.K., Nadaf, Z., Nayak, S. et al. Bio-actives and COVID-19: a production of sustainable fermented ginger beer and probiotic fruit drinks as a plausible approach for boosting the immune system. Discov Food 4, 5 (2024). https://doi.org/10.1007/s44187-024-00075-x
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DOI: https://doi.org/10.1007/s44187-024-00075-x