INTRODUCTION:

Influenza is a substantial global health hazard that affects ~1 billion infections, 3-5 million severe cases, and 2.9-6.5 million influenza-related respiratory deaths every year^1,2.In 2010-20, the Centers for Disease Control and Prevention (CDC) predicted that flu caused 9-41 million illnesses, 1.4 to 7.1 million hospitalizations, and 0.012-0.052 million deaths in the USA³. The influenza virus belongs to the family Orthomyxo viridae. It is typically spherical or pleomorphic and approximately 80–120nm in diameter, and enveloped virus that contains a single-stranded, negative-sense, and segmented RNA genome (Figure 1). The influenza virus genome ranges from 10-14.6 Kb. There are seven genera and nine species in the Orthomyxo viridae family⁴.

Alphainfluenza virus and Betainfluenza virus genera have been the most prevalent causes of seasonal epidemics among all the genera. Gammainfluenza and Deltainfluenzavirus cause mild respiratory disease in humans and cattle, respectively, but there is no report of Deltainfluenzavirus in human cases⁵. Influenza virus contains eight segments of RNA in their genome encoding 17 proteins, including hemagglutinin (H.A.) and Neuraminidase (N.A.) as significant antigenic determinants. There are eighteen subtypes of H.A. genes (H1-H18), while eleven subtypes of N.A. genes (N1-N11) proteins are present on the membrane. The surface glycoprotein projections on virion are 10–14nm long and 4–6nm wide⁴. Influenza virus infection can have a tremendous impact on our health, so it is required to have quick, sensitive, specific, and cost-effective diagnostic tests and therapies. Although influenza vaccination is available, it must be updated every six months to match the strain in circulation and cover up the mutations as the influenza virus is very vulnerable to mutants. Few available anti-influenza drugs can block influenza neuraminidase and matrix-2 activity⁶. These antivirals have severe side effects in terms of drug resistance also⁷. Current medical research focuses on developing innovative, cost-effective, and targeted antiviral regimens⁸. Bioactive chemicals with outstanding therapeutic potential against viral infections are urgently required⁹. Several herbs have potent antiviral properties that significantly impact different phases of viral propagation. Ethnomedicine is gaining popularity compared to manufactured medications because of its safety and broad-spectrum effect. Herpes Simplex Viruses, Dengue Fever, and Chikungunya are just a few viral illnesses that may be treated with medicinal herbs^10-17. The present study focuses on several aspects of the influenza virus and the potential involvement of medicinal plants in its management.

Figure 1. Structure of influenza virus

Figure 2. The common symptoms of the influenza virus

Clinical manifestations and complications

Headache, sore throat, malaise, fatigue, chest discomfort, myalgia, rhinitis, and coughing are symptoms of influenza in its moderate form for two to eight days (Figure 2). A small percentage of individuals, particularly the elderly, children, and those with medical co-morbidities, can suffer from severe disease due to influenza or secondary bacterial pneumonia, leading to respiratory or multi-organ failure. In extreme instances, it can induce myocarditis, encephalitis, myositis, rhabdomyolysis, and multi-organ failure^18,19.

Transmission:

The aerosol transfer is the most common form of influenza transmission, and when an infected person coughs, sneezes, or speaks, the virus spreads from one infected person to another (Figure 3). A contaminated surface can occasionally transmit the virus. Another way for influenza to spread is through aquatic animals' gastrointestinal tracts²⁰. The avian influenza virus primarily infects the respiratory tract and gastrointestinal tracts, causing abdominal pain, vomiting, diarrhea, and anorexia in addition to respiratory symptoms. Its mode of action in the gastrointestinal tract is unknown²¹. Social distance and frequently washing/sanitizing hands can reduce the risk of transmission.

Figure 3. Transmission of influenza virus from an infected patient to a healthy individual

Figure 4. Data for influenza virus cases and deaths in India for the last five years (2016-2021)

Occurrence of influenza in India:

The Indian government has taken several steps to lower the influenza burden, including improving diagnostics, risk categorization, management standards, and influenza contingency planning at both the state and national levels. A sudden increase in viral diagnosis laboratories in India and reported cases (2016-2021)²² are shown in Figure 4.

Diagnosis:

Influenza is a respiratory virus that infects the lungs and other areas of the body²³. Rapid, sensitive, and specific diagnostics methods are required for effective management. Several approaches for influenza detection have been developed, but each has its limitations. Viral isolation is considered the gold standard, but it takes two weeks. Virus isolation is less expensive than serological and molecular assays^24-26. Laboratory tests such as enzyme immunoassay, complement fixation, hemagglutination inhibition assays (HIA), and neutralisation assays are utilized for influenza diagnosis. They are time-consuming and require two serum samples with precise timing for accurate results^18,27. Rapid influenza detection tests (RIDTS), on the other hand, detect viral antigens in 10-15 min with high specificity and realistic sensitivity. Antigen detection methods, including direct fluorescent antibody (DFA) and ELISA for influenza N.A. protein²⁴ exhibit higher sensitivity/specificity than PCR²⁸, but they do not necessarily determine the presence of a viable infectious virus or ongoing influenza viral replication. Interestingly, nucleic-acid amplification tests (NAATs) such as conventional RT-PCR, real-time RT-PCR, Microarray, RT-LAMP, and others are recommended by the CDC and are being used for influenza detection^29-32. Still, these procedures have variable affectability, high instrument costs, and are labor-intensive. Nevertheless, influenza viruses have a considerable genetic diversity, enabling molecular-based NAATs to be challenging to design^25,31-32. RT-LAMP has higher sensitivity and specificity than other amplification methods. Molecular diagnosis has high sensitivity and specificity for the early diagnosis of the influenza virus.

Treatment and management:

Vaccine or antivirals are the most recommended method to overcome influenza. In 2000, Food and Drug Administration (FDA), USA, recommended the use of Oseltamivir (which inhibits Neuraminidase) for children ≥1 year. Antivirals are converted into their active form in the liver from oseltamivir phosphate to oseltamivir carboxylate³³. However, antiviral drugs like Oseltamivir and zanamivir are neuraminidase inhibitors, while amantadine and rimantadine as M2 inhibitors and are used against influenza⁶. Overdoses are also responsible for causing mutations, as seen in H7N9 infected patients⁷. Neuropsychiatric events such as dizziness, headache, nausea, vomiting, diarrhea, abdominal pain, etc., are the most common side effects associated with the use of these medicines³⁴. Vaccination is another practical approach to treating and preventing viral diseases¹⁸. A major drawback of these vaccines is that they cannot be suitable for specific age groups and have multiple side effects for different persons. A vaccinated person can also get sick with influenza because it cannot provide immunity for longer³⁵. There is an urgent need of cost-effective methods for detecting and treating influenza.

There are many investigations reports accessible for anti-influenza activities of medicinal plants. However, we have shortlisted significant plants based on their antiviral activities and clinical importance for influenza treatment. We focused on medicinal plants and their bioactive compounds reported for anti-influenza activity in the current review and in Table 1.

Andrographis paniculate:

Andrographis paniculata (Kalmegh) belongs to the Acanthaceae family that grows in India, Sri Lanka, and Southeast Asia little bit cosmopolitan. It has antibacterial, anti-inflammatory, antitumor, and antiviral properties due to its various phytochemical substances such as diterpene, flavonoids, diterpenoids, lactones, and glycosides reported by many studies. Phytochemical analysis assays have shown that Aandrographolide is one of the important antiviral agents¹⁴. According to Wang et al³⁶, andrographolide reduced the activity of the H1N1(Influenza) virus in its early stages of the life cycle. It reduces the inflammatory cytokines produced by the H1N1 virus with no or minimal cytotoxic effect on host cells.

Angelica dahurica:

Angelica dahurica, often known as bai zhi, is a member of the Umbelliferae family. It's a perennial plant native to northeastern China and Korea. The phytochemical analysis showed that steroids, alkaloids (e.g., monoterpenes and sesquiterpenes), and coumarin are the primary phytochemicals in A. dahurica. Which exhibits antioxidant, antibacterial, anti-inflammatory, anti-hypertension, anti-allergy, anti-obesity, anti-cancer, antifungal, and antiviral activities against many viruses such as Herpes simplex virus, HIV, and Influenza virus^37,38. A. dahurica has an oxypeucedanin compound that possesses anti-influenza capabilities³⁸. It is more efficient than ribavirin by inhibiting the cytopathic effect (CPE). The EC₅₀ (M) values for Ethanolic Extract of A. dahurica against H1N1/ H9N2 were 5.98/ 0.71 and 4.52/0.39, respectively. Oxypeucedanin inhibits early replication, revealing its anti-influenza capabilities³⁸.

Allium sativum:

Allium sativum (Garlic) is a perennial plant that belongs to Amaryllidaceae family. It is found in Central Asia, Italy, Southern France, and many other parts. According to a phytochemical study, it includes a variety of phytochemicals, including glycosides, terpenoids, flavonoids, saponin, steroids, phenolic compounds, alkaloids, and carbohydrates. It has antioxidant, anti-platelet, antithrombotic, anti-inflammatory, antibacterial, antifungal, hypoglycemic, hypocholesterolemic, and hypotensive properties.In addition to atherosclerosis, hypertension, diabetes, hyperlipidemia, thrombosis, stroke, and gastrointestinal neoplasias,³⁹. According to Ming et al ss⁴⁰ study, garlic has anti-influenza properties because its fresh extract contains Organosulfur compounds, including diallyl trisulfide (DATS), which inhibit viral growth. Infected A549 cells have a viability of 36.7, 44.8, and 44.9% at 93.75, 187.5, and 375 M of DATS, respectively. As time passes, the viability of cell survival improves.

Aloe barbadensis miller:

Aloe barbadensis miller (Aloe vera) is a succulent plant that belongs to the Asphodelacese family. For almost 2000 years, it has been used as a medicinal herb and is still used as a traditional medicine in many cultures⁴¹. Carbohydrates, vitamins, minerals, lignin, saponins, amino acids, salicylic acids, and other possibly helpful compounds are all found. It may be used to treat a range of ailments. It was even utilized by Alexander- the Great and Christopher Columbus to treat their wounded troops⁴². Huang et al⁴³ tested influenza virus strain with a 50% inhibitory concentration (IC50) value of 91.8318.97 M by a plaque reduction assay that Aloin had no deleterious impact on MDCK cells at concentrations up to 500M, and it considerably decreased the infection. At a concentration of 100M aloin, both oseltamivir-resistant and oseltamivir-sensitive A(H1N1) pdm09 influenza virus strains show a 50% reduction. In contrast, influenza B virus strains show an 80% reduction at the same concentration. When the concentration of Aloin increases at 300μM, it reduces the infection by more than 90%.

Balanophora involucrate:

Balanophora involucrate is a parasitic plant that belongs to the Balanophoraceae family. Balanophora genus has more than 80 species distributed throughout the subtropical and tropical regions of Asia and Oceania⁴⁴. It contains phytochemicals, and analysis showed flavonoids, iridoids, steroids, Phenylpropanoids, tannins, and triterpenes. It has anti-inflammatory, anti-oxidation, antitumor, antibacterial, and liver protection⁴⁵. According to Sun et al⁴⁶ study, ethyl acetate extract of B. involucrate shows anti-influenza Activity. The extract contains 2 compounds, quercitrin and phloridzin, which show anti-influenza inhibitory Activity against N.A., at IC50 of quercitrin value is 311.76 and phloridzin value is 347.32μmol/L. (IC50) value against N.A. is 159.5μg/mL.

Caesalpinia decapetala:

Caesalpinia decapetala (Mysore) is a climbing shrub belonging to the Fabaceae family. It is present all over the world. It contains diterpenoid, resveratrol, quercetin, cassane spathulenol, sitosterol, lupeol, and astragalin, etc. It has antitumor, antioxidant, analgesic, and anti-fertility activities. Root extract is used to treat malaria, bronchitis and prevent colds. According to Zhang et al⁴⁷ study, ethanol extract shows anti-influenza activity on A549 cells. The EC50 of ethanolic extract of C. aesalpinia decapetal is nearby 14µg/mL; ethanolic extract inhibits the virus replication by about 50% at 14.4µg/mL and completely inhibits at 43.2µg/m. The ethanolic extract reduces lungs injury and reduces virus titer.

Canarium album:

It is commonly known as the Chinese Olive Tree and belongs to Burseraceae. It is a cosmopolitan plant, but its prominent habitats are Tropical Asia, Pacific Islands, and tropical Africa. Its ripe fruits are used to treat sore throats, cough, dysentery, hemoptysis, polydipsia, alcohol poisoning, etc. in China⁴⁸. It contains various compounds like dihydroxybenzoic acid, O-galloyl quinic acid, scopoletin, isocorilagin, ellagic acid-4-O-β-d-glucopyranoside, ellagic acid-4-O-α-l rhamnopyranoside, dyhydrophaseic acid, ethyl gallate, gallic acid, and ellagic acid⁴⁹. According to Chen et al⁵⁰ study, isocorilagin shows antiviral activity. Isocorilagin shows a mild cytotoxicity effect on MDCK cells with a CC₅₀ value of 263.30mM. With IC50 values ranging from 4.64 to 23.72mM, isocorilagin showed a significant inhibitory impact against diverse Influenza A infection strains, such as PR8, H3N2, and NAH274Y, as compared to results obtained using peramivir as a positive control.

Citrullus lanatus:

Citrullus lanatus (Watermelon) is a dessert crop belonging to the Cucurbitaceae family. It is native to the South Africa desert (Kalahari), diversity throughout the tropics and the Mediterranean regions. As per the record of phytochemical analysis, it contains phytochemicals such as β-carotene, Carotenoids, vitamins (B, C, and E), amino acid (citrulline), Lycopene, and phenolics, etc. It has anti-cancer, antidiabetic, anti-hypertension, and prevents from cardiovascular diseases, etc⁵¹. Moreover, according to Morimoto et al⁵² study, watermelon juice shows an inhibitory effect on the replication of the virus in MDCK cells. It decreases the transcription rate in a cell at physiological temperature (37°C) but does not decrease at 4°C. It inhibits virus entry into host cell.

Cuscuta japonica:

Cuscuta japonica, often known as Choisy (Japanese dodder), is an ornamental holoparasitic plant from Convolvulaceae family. It is a native plant of North and South America eastern temperate Asia like Japan, Taiwan, China, and South Korea. It contains phytochemicals, but its chemical composition is determined by its host plant, taking nutrition from the host plant for survival⁵³. It contains alkaloids, flavonoids, steroids, lignans, fatty acids, aromatics, polysaccharides, and resin glycosides. It has anti-osteoporotic, hepatoprotective, anti-oxidative, anti-aging, antimutagenic, anti-inflammatory anti-depressant, antidiabetic, renoprotective, neuroprotective, immune regulatory, prevention to abortion, cardioprotective, etc. effects. Also used to treat aches, pharyngitis, weakness in the loins and knees, improved sexual function, reducing urination, and tonifying the livers and kidneys. Cheng et al⁵⁴ study demonstrate that methanolic extract of Cuscuta japonica also shows the anti-influenza activity as its extract contains 1-monopalmitin, which causes anti-influenza Activity against A/WSN/1933(H1N1). Its EC50 value ranges around 2.28μM without remarkable cytotoxicity in MDCK cells.

Fritillaria thunbergia:

Fritillaria thunbergii (Zhe beimu) is a deciduous monocot shrub that belongs to the Liliaceae family. It is a native plant of temperate regions of the northern hemisphere. Phytochemical analysis contains phytochemicals such as terpenoids, alkaloids, nucleosides, saponins, polysaccharides, organic acids, amines, and sterols. It has Anti-tussive, Anti-inflammation, Anti-tumor, Anti-ulcer, Anti-microbial, Anti-oxidant, Relieving asthma and cough, etc., properties⁵⁵. Kim et al.⁵⁶ study has demonstrated anti-influenza activity. An aqueous extract of Fritillaria thunbergii shows a very high 50% cytotoxic concentration (CC50), i.e., 7,500μg/ml, representing less toxicity in vitro conditions. It exerted a moderate effect on treated cells as compared to Oseltamivir (SI 50.6 vs. 222) in vitro which shows its antiviral effect against the H1N1 virus with no toxicity effect in vitro, in ovo, and in vivo conditions.

Hibiscus sabdariffa:

It is frequently referred as a 'Roselle' belonging to the Malvaceae family. Its calyces are used to manufacture hibiscus tea. The phytochemical investigations indicated flavonoids, polyphenols, organic acids, anthocyanins, etc⁵⁷. The hibiscus tea and its derivative show various pharmacological activities like anti-hypertensive, anti-bacterial, anti-cholesterol, antioxidant, anti-inflammatory, and antiviral activities. Takeda et al⁵⁸ study conducted in vitro in a mouse model shows that an acidic extract of Hibiscus sabdariffa has no more effective in therapeutic and cacinanation. Still, one of the dominant components of hibiscus tea extract is protocatechuic acid which shows acid-dependent antiviral activity.

Houttuynia cordata:

Houttuynia cordata is a perennial medicinal herb commonly known as a fish mint in English and Yu-Xing-Cao in Chinese, belongs to the family "Saururaceae". It is diversified present across eastern and southern Asia⁵⁹. Phytochemical investigations indicated that it contains flavonoids, phenols, sterol, alkaloids, essential oils, fatty acids, polysaccharides, etc. H. cordata was used to treat various diseases in ancient times like obstructive respiratory diseases, bronchitis, chronic pneumonia, It also shows anti-oxidative, antiviral, and anti-inflammatory activity¹⁴. Ling et al.⁶⁰ study showed flavonoids present in Houttuynia cordata have 78.5% flavonoid glycosides. The number of various flavonoids like rutin, hyperin, isoquercitrin, and quercitrin has been found upto 8.8%, 26.7%, 9.9%, and 31.7%, respectively. In vivo study shows that flavonoids increase the life span and survival rate of mice infected with a lethal strain of the H1N1 virus. When mice were treated with flavonoids (50, 100, and 200mg/kg), higher doses of extract show less weight loss in mice and inhibit N.A. activity. This may be due to flavonoids from H. cordata (100 and 200mg/kg) enhanced interferon- activity in the lungs.

Melicope pteleifolia:

Melicope pteleifolia is an herb belonging to the family Rutacese. It is widespread in China and Vietnam. The phytochemical analysis shows the presence of glycosidic compounds, benzopyrans, phenylpropanoids, flavonoids, and furoquinoline alkaloids⁶¹. It offers various pharmacological activities like eczema, cerebritis, colds, dermatitis, rheumatoid arthritis, and flu. It shows antinociceptive, anti-inflammatory, anti-cancer, and anti-IAV activity. It is utilized as crude components for different medicine like Zhiganjia capsulesm, Sanjiu weitai granules, and Sanjin cold tablets to treat various sicknesses like gastritis, rhinitis, etc. in China. Lee et al⁶² study demonstrates antiviral activity against H1N1 and H9N2. Melicopteline C, D, and E, an alkaloid, are phytochemicals present in an extract that show anti-influenza properties. Melicopteline C has more potent CPE inhibition than positive control robavirin with H1N1. The concentration of its extract that gives a half-maximum response was lying between 2.57±0.45μm with high selectivity.

Morus alba:

Morus alba (mulberry) belongs to family Moraceae and is cultivated in the local area of China, Japan, Korea, etc. Phytochemical investigation indicates that it contains alkaloids, phenolic acids, coumarins, terpenoids, flavonoids, stilbenoids, etc. It has anti-diabetic, anti-obesity, antimicrobial, antioxidant, cytotoxic, anti-hyperlipidemic, anti-inflammatory, anti-atherosclerotic, anti-cancer, anti-apoptotic, anti-atherosclerotic, cardioprotective, hepatoprotective, neuroprotective properties⁶³. Hong et al⁶⁴ study show anti-influenza activity in its extract which contains a component i.e., Morin hydrate (3,5,7,2',4'-pentahydroxyflavone) as it reduces virus-induced cytotoxicity between 125 - 250μM. When the Morin hydrate (125μM) is treated with 2 μM oseltamivir carboxylate, the viability of A/PR/8-infected cells is enhanced. Moreover, 50-100μM Morin hydrate inhibits RBC agglutination, indicating inhibition of the virus's binding to the membrane of the host.

Newtonia buchananii:

Newtonia buchananii (Forest Newtonia) is a tall deciduous tree belonging to the family Fabaceae. It is widespread in Nigeria, Kenya, Democratic Republic of the Congo, Uganda, Angola, Cameroon, Tanzania, Zimbabwe Mozambique, Malawi, Zambia, etc. It also contains phytochemicals compounds such as flavonoids, flavonols, proanthocyanins, tannins, and phenolics, demonstrating various pharmacological activities like treating a wound, stomach problem unspecified skin conditions, etc⁶⁵. According to Motlhatlego et al⁶⁵ study, the extracts of N. hildebrandtii and N. buchananii show antiviral properties against influenza A virus (IAV) and maintain cell viabilities. A phytochemical named Myricitrin is present in their extracts, showing antiviral properties and no cytotoxicity at concentration 10⁴ μg/ml in MDCK cell line. It blocks the virus at the entry stage by inhibiting the viral attachment.

Ohwia caudate:

Ohwia caudate is a nitrogen-fixing deciduous shrub that belongs to the Fabaceae family. It contains phytochemicals, like triterpenoids, flavonoids (e.g., 2′-hydroxyl yokovanol, 2′-hydroxyl neophellamuretin, yokovanol, swertisin, spinosin, and 7-methyl-apigenin-6-C-β-glucopyranosyl 2″-O-β-d-xylopyranoside) and alkaloids⁶⁶. It has free radical scavenging and anti-amyloid beta (Aβ) aggregation activity and has been reported to treat diarrhea, icterohepatitis, rheumatic backache, and colds⁶⁷. Kwon et al⁶⁶ study shows anti-influenza activity of this plant. Its methanolic extract contains 2 flavonoids (2’-hydroxyl yokovanol and yokovanol) show significant inhibitory effects against influenza A viral infection in co-treatment conditions. It demonstrated the reduction of membrane protein and inhibited neuraminidase activity in RAW 264.7 cells.

Papaver somniferum:

Papaver somniferum (opium poppy) belongs to the papaveraceae family and is found in various parts of Europe, Northern Africa, Western Asia, etc. Phytochemicals investing studies showed that it contains alkaloid, Flavonoid, Cardiac Glycosides, Phytosterols, and Terpenoids⁶⁸. Papaverine is an alkaloid (a derivative of isoquinoline) that has been identified as the potent inhibitor of phosphodiesterases⁶⁹. It also has anti-depressants, antitumor, vasodilator, inhibitory effect of replication of some virus-like measles virus, cytomegalovirus, and HIV, it's also used to treat erectile dysfunction in males, cerebral vasospasm disease, etc. Recently, Aggarwal et al.⁷⁰ study indicates that Papaverine acts as an anti-influenza Activity. In this study, it has been shown to t inhibit 3 types of influenza strain i.e WSN/33 (H1N1), Udorn/72 (H3N2), and influenza B Lee/40, even at a low concentration of 50 μM tested in plaque reduction neutralization test. Also, it interferes with the cAMP signalling pathway by inhibiting PDE4D.

Passiflora caerulea:

Passiflora caerulea (Bluecrown Passionflower) is a member of Passifloraceae family. The phytochemical study revealed that it contains phenolics, flavonoids, alkaloids, glycosides, cyanogenic compounds, polyketides passifloricins, and alpha-pyrones, etc. phytochemical⁷¹. It has anti-inflammatory, anticancer, antibiotic, and antifungal properties. Recently, Kim et al.⁷² reported that Passiflora caerulea has anti-influenza Activity. The extract shows a chemical (Chrysin; a flavonoid) that has anti-influenza activity which inhibits infected A/PR/8 cell death and stops the replication up to 2μM concentration in the early stages of the cycle. It also slows autophagy activation by boosting phosphorylation of the mammalian target of rapamycin.

Pinus densiflora:

Pinus densiflora ( Korean red pine) is a tall coniferous evergreen tree with an irregular or umbrella-shaped shape of Pinaceae. It can be found in Russia's the Far East, East Asia, Central and Southern Japan, Northern China, and Korea, among other places. It contains phytochemicals, including terpenoids, phenolic compounds, tannin, dietary fiber, alkaloids, etc. It has antioxidant, antibacterial, anticancer, antimutagenic. Pine needles and cones are effective in the removal of ROS (reactive oxygen species⁷³. According to Ha et al.⁷⁴ study, it shows anti-influenza Activity. Two-component in its methanolic extract are 7alfa-methoxydehydroabietic acid and ampelopsin, showing inhibition of viral mRNA and nitric oxide (NO) production. They did not show any cytotoxicity effect at a concentration of 30μM. NO production was reduced at an extract concentration at 20μM in the RAW cell.

Tanacetum vulgare L.

Tanacetum vulgare is a herbaceous plant of the Asteraceae family, generally known as Tansy. It is slightly cosmopolitan, including areas like Asia, North Africa, and temperate regions of Europe. It contains phytochemicals, as indicated by phytochemical examination, it shows terpenoids, flavonoids, etc. It has antihelminthic, antidiabetic, diuretic, antispasmodic, anti-inflammatory, antifungal, antibacterial, antiviral, immunomodulatory, antioxidant, antitumor, antihypertensive, and many more. It is used to treat hysteria, stomach problems, kidney weakness, neuralgia, migraine, fever, and rheumatism⁷⁵. According to Vilhelmova et al.⁷⁶ study, it shows anti-influenza Activity. Its ethanolic extract inhibits replication in IAV/H3N2 with a selective index of 3.69.

Trollius chinensis:

Trollius chinensis (Chinese globeflower) is a perennial plant belonging to Ranunculaceae Family distributed in the North China region like Liaoning, Jilin, Hebei, Shanxim, and Inner Mongolia provinces⁷⁷. Its dry fruit is called Flos Trollii, which have anti-inflammatory, antibacterial, and antiviral⁷⁸. All phytochemicals show antiviral activity. Phytochemical analysis indicates it contains phytochemicals, like flavonoids, flavonoids, phenolic acids, and alkaloids used to treat tonsillitis, respiratory tract infection(upper), and pharyngitis, etc⁷⁹. Shi et al.⁸⁰ describes that its ethanolic extract shows anti-influenza activity. The extract contains 3 phytochemicals (Veratric acid, vitexin, and trolline) which show anti-H1N1 activity by up-regulating TLR4 pathway and down-regulating TLR-3 and 7 pathways. They boost the production of IFN-β and decrease the extreme production of NO, IL-1, IL-6, and TNF-α released due to virus infection, ultimately responsible for eradicating the virus.

Vigna radiate:

Vigna radiate known as Mung bean is a Fabaceae family crop plant. It flourishes across Asia. It has been cultivated in India for about 3500 years and is also being utilized as a folk medicine in China and Taiwan. It contains phytochemicals, including phenolic acids, flavonoids, organic acids, triterpenes, sterols, aldehydes, and lipids⁸¹. It has antioxidant immunoregulatory, anti-inflammatory, and antidiabetic activities and can relieve heat stress. According to Lo et al⁸¹ study, it has anti-influenza activity attributed by ethanolic extract containing compound Vitexin and isovitexin. This extract shows no cytotoxicity up to 2,000 μg/ml concentration in MDCK cells. It inhibited 68.0%, 26.9% and 8.5%, PR8-H1N1 virus at 500, 1,000, and 2,000 μg/ml concentration of ethanolic extract respectively. It shows various other effects like it block virus entry by binding to membrane receptors and cellular receptors and inhibiting virus assembly and viral neuraminidase activity.

Table 1. List of medicinal plants and their bioactive compounds reported for anti-influenza activity

Plants names	Bioactive compounds	Family names	Plant parts used	Plant extract used in studies
Andrographis paniculata	Butenolides	Acanthaceae	-	Purchased
Angelica dahurica	Furanoco-umarins (oxypeucedanin)	Umbelliferae	Roots	Ethanolic
Allium sativum	DATS	Amaryllidaceae	-	Purchased
Aloe barbadensis miller	Aloin	Asphodelaceae	Leaves	Purchased from Sigma-Aldrich
Balanophora involucrata	Quercitrin and Phloridzin	Balano-phoraceae	-	Petroleum ether, Ethyl acetate
Caesalpinia decapetala	-	Fabaceae	leaves and branch	Ethanolic
Canarium album	Isocorilagin	Burseraceae	Fruit	Ethanolic
Citrullus lanatus	-	Cucurbitaceae	Fruit juice	Purchased
Cuscuta japonica	1-monopalmitin	Convolvulaceae	Whole	Methanolic
Fritillaria thunbergii	-	Liliaceae	Dried herbs	Aqueous
Hibiscus sabdariffa L.)	Hibiscus acid	Malvaceae	Hibiscus Tea powder	Aqueous Methanol Acetone Ether Chl.
Houttuynia cordata	Flavonoids	Saururaceae	Dred Aerial part	Ethanolic
Melicope pteleifolia	Melicopteline A- E	Rutacese	Leaves	Ethanolic
Morus alba L	Morin hydrate	Moraceae	-	-
Newtonia buchananii	Myricitrin	Fabaceae	Leaves and Stems	Acetone Methanol-dichloro-methane
Ohwia caudata	Flavonoids ( 2’-hydroxyl yokovanol and yokovanol)	Fabaceae	Leaves and Stems	MeOH
Papaver somniferum	Papaverine	papaveraceae	-	purchased from Sigma-Aldrich
Passiflora caerulea	Chrysin	Passifloraceae	-	-
Pinus densiflora	Flavonoids 7alfa-methoxydehydroabietic acid ampelopsin	Pinaceae	cortex and leaves	methanolic
Tanacetum vulgare	-	Asteraceae	aerial parts	ethanolic
Trollius chinensis	Veratric acid, Vitexin, and Trolline	Ranunculaceae	Dried Flowers	Ethanolic
Vigna radiata	Vitexin, Isovitexin	Fabaceae	Seed coats	Ethanolic

CONTINUE

Cell lines	Detection assays	Strains used	Results and analysis	Ref
MDCK A549	MTT, qRT-PCR, TOA, Apoptosis by Western –Blotting	A/Virginia/ATCC2/2009 H1N1 A/California/2/2014 H3N2	Antiviral Activity	36
MDCK	MTT, CPE inhibition, HPLC-DAD, Western.blotting IMF, Flow cytometry, Cell protection, NAI	H9N2, A/Chicken/Korea/01210/2001 H1N1, A/PR/8/34	Inhibition of the viral replication cycle.	38
A549	MTT, qRT-PCR	H9N2 A/mallard/ Jiangxi/39/2011	Antiviral Activity	40
MDCK	MUNANA based NA, PA, Flow Cytometry	Various Strain of Influenza	Anti-infective Activity with Viral NA blockade	43
	Liquid-chromatography, Mass spectrometry,	-	Inhibitory Activity against NA	46
MDCK A549 U973	Neuraminidase Assay	Various Strain of Influenza	Antiviral activity, Inhibitor against the replication	47
MDCK	MTT, Plaque Reduction Assay, qRT-PCR, Western blot, Indirect –Immunofluore., TEM, Molecular docking	A/Puerto Rico/8/34 (H1N1), A/Aichi/2/68 (H3N2) And NA-H274Y (H1N1)	Neuraminidase Inhibitor	50
MDCK CV-1	MTT, Focus forming reduction- assay, TOA, HIA, Viral adsorption inhibition- assay CFI	Various Strain of Influenza	Inhibit Replication	52
MDCK	Plaque reduction assay, HPLC-DAD, TOA	A/WSN/1933 (H1N1)	Show antiviral activity	54
MDCK	MTT assay CPE- Reduction, Post-Treatment Assay, H.A. Assay.	A/PR/8/1934 (H1N1)	Inhibit H1N1 replication in embryonated eggs.	56
MDCK	HA assay	PR8 virus	Potent antiviral activity relied largely on the acidic pH	58
MDCK	TCID50 by Reed-Muench formula, HPLC, MTT, ELISA, NAI, Western blotting	H1N1 (A/FM/1/47)	Inhibit of influenzal N.A. activity and Inhibit TLR signalling	60
MDCK	MTT, CPE Inhibition,	H1N1, H9N2	Show Antiviral activity	62
A549	SRB, real time-PCR, TOI, H.A. assay Hemolysis inhibition assay, Western blot	A/Puerto Rico/8 H1N1 (A/PR/8)	Inhibiting the entry of the virus.	64
MDCK	MTT, H.A. qRT-PCR	A/PR8/34 (H1N1)	H.A.- inhibitor	65
RAW 264.7	MTT, Antiviral activity assay, Western blots, N.A. activity assay,	A/PR/8/34	Inhibit NA activity	66
MDCK or HEK293T	Plaque assays, Semiquantitative RT-PCR, Western blotting, TOA and TOE, C. microscopy, HIA, NAI	A/WSN/33, A/Udorn/72,A/Eq/2/Miami/1/63, B/Lee/40, and B/MD/59	Effective inhibitor	70
A549	Western Blotting H.A. assay, Hemolysis Inhibition, Confocal-Microscopy, qRT-PCR, TEM, TOA	A/PR/8	Inhibit the replication in early stages of infection	72
MDCK and RAW264.7	R.T.- PCR, MTT, Western blotting, IMF, Flow -Cytometric Cell Cycle Analysis, NAI, Kinetic	H1N1 A/PR/8/34 H9N2 A/chicken/Korea/01210/2001	Direct NA inhibition	74
MDCK	Virucidal, Virus attachment assay	Panama/2007/99/H3N2 - IAV (H3N2)	Slight inhibition of replication	76
RAW264.7	MTT , RT-PCR, Western blot, ELISA.	A/FM/1/47 (H1N1)	Anti-H1N1 viral effect	80
MDCK	MTT, HPLC TOA, H.A. assay, PIA, α-Glucosidase Inhibition assay, NAI,	A/Puerto Rico/8/1934 (PR8-H1N1) A/Chicken/Taiwan/3937/2012(3937-H6N1)	Blocking the H.A. protein, inhibits virus penetration, inhibiting viral NA activity	81

Time-of-Addition Assay(TOA), cytopathic effect inhibition (CPE), qRT-PCR, High-Performance Liquid Chromatography with Diode-Array Detection (HPLC-DAD), Immunofluorescence (IMF), Neuraminidase inhibition- assay (NAI), 20-(4 methylumbelliferyl)-a-D-N-acetylneuraminic acid (MUNANA), Plaque Assay (P.A.), N.A. inhibition assay (NAI), Transmission electron- microscopy (TEM), Cell fusion inhibition assay (CFI) H.A. assay, Diallyl trisulfide (DATS), Penetration Inhibition assay (PIA), Virus attachment assay (VAA), sulforhodamine B (SRB) assay.

Expert opinion:

Medicinal plants are important sources of therapeutic agents and contribute to the treatment of a wide range of infectious disorders^82-91. Influenza virus is a severe worldwide infection that causes a high mortality rate. That is why we need proper and regular observation to prevent its spread. The Mutations in the virus are very much likely due to an overdose of antiviral medicines. So, the virus is prone to become resistant to these medicines shortly. The virus is highly mutatable due to the antigenic drift and strain change in the circulation due to antigenic shift, so review and updation in the vaccine is needed every year. So, the vaccine is not a permanent cure for influenza. We need to search an alternative treatment regimen for flu. The best alternative method is using plant metabolites for the treatment of flu. In this review, some medicinal plant with a special bioactive compound showing anti-influenza Activity has been reviewed. Beneficial properties of those compounds being less toxic have been summarized and compared against synthetic compounds.

ACKNOWLEDGMENTS:

This study was financially supported by Dr. Radha Krishanan Foundation Fund, MDU-Rohtak, in the form of a minor project.

CONFLICT OF INTEREST:

The authors declare that there is no conflict of interest.

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Received on 10.03.2022 Modified on 07.04.2022

Research J. Pharm. and Tech 2023; 16(3):1503-1513.

DOI: 10.52711/0974-360X.2023.00247