An Overview of the Application of Green Nature Deep Lung Support, a Natural Product With Herbal Source in Medicine

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Introduction
The outbreak of COVID-19 around the world has been one of the most challenging issues in human society, which has caused the loss of many lives in a short period.During the last 10 years, our world has experienced other similar infectious diseases, whose negative consequences have affected various dimensions of human societies.However, the prevalence and mortality caused by COVID-19 are higher and more severe than these diseases.Vaccination is the most promising approach for controlling COVID-19. 1 The performance of many of these vaccines is the transfer of complementary DNA or mitochondrial DNA (mRNA) through liposomes or adenovectors, stimulating the production of spike protein and the neutralization of immunoglobulin G antibodies. 2 Although many reports have been published on the positive role of vaccines in reducing the number of patients requiring hospitalization and the burden of COVID-19 infection, this method has also limitations.Investigations have shown that the titer of vaccine antibodies is associated with a significant decrease after the third month. 3On the other hand, vaccinated people are not completely immune, and the possibility of contracting COVID-19 and transmitting the disease to other people still exists.In addition, the mutation created in the spike protein by the virus prevents the correct and targeted functioning of vaccines.Another limitation in the use of vaccines is that vaccines may not be effective in immunocompromised people. 4herefore, choosing a treatment approach consisting of auxiliary treatments to control the proliferation of the virus and prevent the deterioration of the disease can be considered the most efficient method.The use of nutritional supplements and herbal medicines can prevent damage caused by widespread systemic inflammation caused by COVID-19 by strengthening the immune system. 5It can be mentioned that medicinal herbs and natural products are among the most trusted products in this field.In the past, flavonoid compounds, alkaloids, and polyphenols obtained from plants and mushrooms have been used to strengthen the immune system and using their antiinflammatory properties. 6Many of these compounds can control the proliferation of the virus and inflammatory responses. 6Some of the bioactive compounds derived from plants have been taken into consideration to control SARS-CoV-2 respiratory infection, including thymoquinone, a-hederin, and nigellidine (obtained from Nigella sativa) 7 , quercetin (obtained from Ginko biloba and green tea), and ellagic acid (obtained from Moringa oleifera). 8Further, due to its anti-thrombosis and anti-platelet aggregation effect, Panax ginseng is one of the medicinal plants that has been successfully utilized in the treatment of COVID-19. 9The curcumin, quercetin, luteolin, piperine, and epigallocatechin-3-gallate compounds obtained from Polygonum cuspidatum also played a positive role in the treatment of COVID-19 due to their ability to control the cytokine storm and prevent pulmonary fibrosis. 10herefore, considering the importance of using these natural resources, the present study aims to review the function of plant extracts used in the Green Nature Deep Lung Support supplement as a natural product that can be effective in improving respiratory diseases.

Methods
The data of this study have been obtained by reviewing English language articles published in the field of herbal natural products in Medline, Embase, and Web of Science databases from 1995 to 2022.Several keywords were searched, including "Drug development", "Herbal medicine", "Infectious disease", "Natural product", and "SARS-CoV-2".A total of 253 articles were obtained, of which only 197 articles were accessible in full text.Among them, 127 articles were excluded from the study due to the lack of an understanding of the provided information, and 73 articles were evaluated carefully (Figure 1).

Andrographis Paniculata
Antibiotics are typically used to treat respiratory infections, but due to resistance to antibiotics, herbal sources can play an effective role in the treatment of these diseases as an auxiliary treatment.A. paniculata is a herbaceous plant of the Acanthaceae family that is found in the tropical and subtropical regions of Asia, Southeast Asia, and India and is known as the king of bitters.Although people of different regions know this plant by different names. 11The extract of this plant, known as andrographolide, has relative solubility in water, and the use of ethanol, chloroform, and ether increases the solubility of this extract.The chemical formula of this substance is C20H30O5.This extract can be obtained by using a 1:1 mixture of dichloromethane and methanol and then by recrystallization, andrographolide is directly separated from the extract. 12Andrographolide has various properties and is found in all parts of the plant, especially the leaves (Figure 2). 13During the last two decades, due to the high variety of the properties of this plant extract, researchers have been attempting to obtain wider biological properties of this plant extract by combining andrographolide with other substances.Investigations have demonstrated that the aqueous or ethanol extract of andrographolide causes a decrease in blood glucose levels in streptozotocin-diabetic and healthy rats. 14Furthermore, this substance can interact with many intracellular components as a bipolar compound and create different biological responses.For example, studies have revealed that A. paniculata polysaccharides with andrographolide improve diabetic nephropathy. 14ccording to studies, A. paniculata and its derived compounds have antioxidant properties.The aqueous extract of A. paniculata reduces glutathione by increasing the activity of antioxidant enzymes such as catalase, superoxide dismutase, and glutathione-transferase.This extract prevents lipid peroxidation by reducing thiobarbituric-acid-reactive levels in the liver and kidneys of diabetic rats. 15he expression of the inducible isoforms of nitric oxide (NO) synthase and cyclooxygenase-2 (COX-2) causes excessive production of NO and prostaglandin E2 and drives inflammatory processes of macrophages.The release of pro-inflammatory cytokines by macrophages stimulated with lipopolysaccharide (LPS) induces the inducible isoforms of NO synthase, thus increasing NO production.Investigations have shown that the methanol extract of A. paniculata and andrographolide inhibits NO production by LPS in a concentration-dependent manner. 16Examining the effect of the andrographolide extract on mice demonstrated that this substance can inhibit LPS-induced NO production in RAW 264.7 mouse cell lines.The use of this extract in rats causes the maximum contractile response of the thoracic aorta to phenylephrine to be restored after incubation with LPS, decreasing the average arterial blood pressure.Andrographolide also suppresses interleukin (IL)-2 production and T-cell proliferation in a mixed lymphocytic reaction and inhibits dendritic cell maturation and antigen presentation. 17everal studies have been published on the use of this plant extract, some of which are presented in Table 1.

Echinacea
Echinacea is a plant from the Asteraceae family, which includes 11 species of herbaceous and flowering plants.
More than 800 products and herbal medicines containing echinacea (herbal medicines, including homeopathic medicines) are currently available on the market. 28Three commercial varieties of this plant include Echinacea purpurea, Echinacea pallida, and Echinacea Angustifolia, whose antibacterial and antiviral properties have been well-established previously.Additionally, the use of these plants is of special interest due to their anti-inflammatory properties and modulation of the immune system. 29queous, alcoholic, and polysaccharide extracts from all parts of the plant, including roots and aerial parts, have the above properties on the cells. 30Echinacea's active components, including glycoproteins, high molecular weight polysaccharides, phenolic compounds, caffeic acid derivatives, and alkamides, can induce transcription and modulate immune pathways. 31However, using this plant in a situation where the body is in the inflammatory response phase suppresses the immune function.
Echinacea's inflammatory response through the secretion of inflammatory mediators such as tumor necrosis factor-alpha (TNF-a) and IL-1 beta (IL-1b) and increased phagocytosis by macrophages, resulting in the release of NO, is activated.NO is a signal for the activation of macrophages against various microbes and tumor cells, but when it is produced in excess, it can be harmful to host tissues as well.Therefore, the production of these inflammatory mediators is regulated by the anti-inflammatory mechanisms of factors such as IL-4 and IL-10. 32chinacea has also anti-cancer effects.The investigation of the effect of using this plant in patients with advanced cancers with extensive metastases has shown that in a number of patients, after immunotherapy, and low-dose cyclophosphamide and thymostimulin, slight clinical and immunological improvements were observed with the use of E. purpurea.In addition, this compound can increase the activity of lymphokine-activated killer cells in patients with advanced liver cancer. 33However, the effect of echinacea immune modulation cannot be separated Another application of the E. purpurea extract is to improve the severity and duration of various upper respiratory infections such as bronchitis and viral infections such as human and avian influenza viruses, H1N1-type IV, H3N2-type IV, rhinoviruses, and herpes. 33nvestigations represented that inulin-type fructans and other fructans are the main immune system-modulating components found in plant extracts. 34What is important in this context is the preparation quality of echinacea products.Herbal products obtained from echinacea are among the best-selling herbal medicines for the treatment and prevention of respiratory infections. 35The function of these products includes a set of anti-inflammatory, antiviral, and immunomodulatory activities.

Eriobotrya japonica
Eriobotrya japonica is an evergreen plant native to subtropical regions, which originates from southeast China.The medicinal use of this plant goes back thousands of years, and its extract has been used to treat cough, chronic bronchitis, inflammation, diabetes, and cancer in traditional Chinese medicine. 36In recent years, scientific evidence has confirmed the active medicinal compounds in the extract of this plant.The extracts obtained from different organs of E. japonica have different compounds.For example, studies have shown that the leaves and flowers of this plant contain significant amounts of phenols and triterpenes.The fruit of this plant has valuable compounds such as carotenoids, flavonoids, sugars, organic acids, and various vitamins, and the kernel also contains various minerals, types of protein, and tannin. 37riobotrya japonica leaves have long been used in Andrographolide is a novel NF-κB inhibitor that has potent antiplatelet activity by activating the endothelial cyclic GMP pathway of NO (eNOS).This combination has the potential to treat thromboembolic disorders and can be considered for the treatment of various inflammatory diseases. 27te.TNF-α, Tumor necrosis factor-alpha; IL, Interleukin; MAOK, Mitogen-activated protein kinases; NF-κB, nuclear factor-κB; LPS, lipopolysaccharide.
traditional Chinese medicine to treat ailments such as cough, chronic bronchitis, and asthma.In addition to leaves, the seeds and fruits of this plant have antiinflammatory activities. 38Many lung diseases are caused by inflammation caused by polysaccharides.Studies have demonstrated that the E. japonica extract enriched with triterpenes, especially ursolic acid, has anti-inflammatory activity in mice. 39Examining the effect of the seed extract of this plant on mice undergoing chemotherapy with mucositis indicated that the use of this extract significantly controlled mucositis, epithelial damage, and bacterial infection. 40The anti-inflammatory effect of the extract obtained from E. japonica is applied through the reduction of pro-inflammatory mediators such as TNF-α, IL-6, IL-8, IL-1β, iNOS, COX-2, and the increase of antiinflammatory cytokines such as IL-10, followed by the inhibition of NF-κB activation and mitogen-activated protein kinase signaling pathway. 39ther cytotoxic active compounds isolated from E. japonica extract are:

Fritillaria
Fritillaria is a plant native to the temperate regions of the Northern Hemisphere, which is often detected in Central Asia, the Mediterranean region, and North America.In China, twelve species of this plant are used as natural medicines for respiratory diseases. 45Alkaloids in different species of Fritillaria have different properties such as antitussive, antiasthmatic, chronic obstructive pulmonary disease (COPD) control, and expectorant effects.In addition, the extract of this plant has potential anti-inflammatory, anti-hypertensive, anti-tumor, and bacteriostasis effects. 46tudies have shown that the substances obtained from this plant can be effective for treating coughs without phlegm or chronic coughs. 47According to Fritillaria properties, including anti-cough, anti-pneumonia, expectorant, anti-inflammatory, antioxidant, and antiasthma effects, it can be considered a suitable option for treating respiratory diseases and improving disorders such as cough, phlegm, bronchial inflammation, adult respiratory distress syndrome, and COPD.Furthermore, it seems that alkaloids present in some species of this plant, considering the effect on the biological processes effective in the inflammatory response, can be considered a potential treatment for respiratory infections such as the emerging COVID-19 infection 48,49 (Figure 3).
Several species of Fritillaria have anticancer activities in cases such as oral, ovarian, and endometrial keratinocytes, glioblastoma, human promyelocytic leukemia cells, and prostate cancer.One of the active compounds found in many species of Fritillaria is Peimine, which has the effect of reversing drug resistance in tumor cells.Investigating the mechanism of this steroidal alkaloid has represented that the expression of P-glycoprotein in drug-resistant cells is inhibited by increasing the concentration of Peimine. 45ifferent species of Fritillaria also have anti- inflammatory activities.A study on the ethanol extract of two species, Fritillaria cirrhosa and F. pallidiflora, revealed that consumption of this extract prevents ear edema in mice.Based on previous studies, F. cirrhosa alkaloids also prevented acetic acid-induced capillary permeability, and carrageenan-induced edema and suppressed inflammatory cell recruitment and cytokine production in the bronchoalveolar lavage fluid of mice.Fritillaria bulbs play their anti-inflammatory role by influencing signaling pathways.These pathways include the inhibition of NF-κB, downregulation of inflammatory cytokines, and inhibition of mitogen-activated protein kinases 50 (Figure 4).Extracts obtained from some species of Fritillaria have antihypertensive properties.For example, the aqueous extract of F. ussuriensis prevents blood pressure caused by NG-nitro-l-arginine methyl ester by increasing vascular NO production and improving kidney function. 46nother interesting function of Fritillaria is the anticholinesterase activity in some species.Additionally, water and ethanol extracts of this plant have antibiotic activities.For example, F. thunbergii has an inhibitory effect against six strains of Helicobacter pylori. 45In addition to antibiotic activities, some species have antiviral properties.Antiviral effects against the H1N1 influenza virus have been observed in F. thunbergii species. 51

Scutellaria baicalensis
Scutellaria baicalensis is a flowering plant from the Lamiaceae family that is native to East Asia and can be found in many European countries.The decoction of the root of this plant, known as Huang-Qin in China, has long been used by the people of this region as a traditional medicine to treat colds and pneumonia. 51Studies have shown that this plant can be effective in treating hepatitis B and C. 53 Fufang is another compound derived from this plant that can increase the life span of patients with bronchial squamous cell cancer and non-small-cell lung cancer. 54The S. baicalensis extract can also be effective in the treatment of brain tumors, 55 prostate cancer, and head and neck squamous cell carcinoma 55 .The action of the aqueous root extract of this plant is through changing the expression of Bcl genes and increasing the inhibitory activity of cyclin-dependent p27 kinase, reducing the expression of the c-myc oncogene and thus inducing apoptosis. 57Some bioactive compounds found in the Scutellaria root extract that have anti-cancer activity are as follows 58 : • Baicalein: Preventing the growth of lymphoma and myeloma cells • Wogonoside: Having anticancer effects on acute myeloid leukemia cell lines, increased transcription of phospholipid scramblase 1, and cell cycle regulator and differentiation-related genes Scutellaria baicalensis has antibacterial and antiviral properties.So far, the antibacterial effect of this plant has been proven on Escherichia coli, Salmonella anatum, Bacillus cereus, Listeria monocytogenes, and Staphylococcus aureus. 59Baicalin can play an anti-HIV-1 role so that only 2 μg/mL of this substance can inhibit up to 90% of reverse transcriptase. 60oday, researchers are attempting to increase the biosynthesis of bioactive flavones such as baicalein, baicalin, wogonin, and wogonoside in S. baicalensis with the help of new technologies.Next-generation sequencing technologies have identified structural genes such as 6-hydroxylase, 8-O-methyltransferase, and 7-O-glucuronosyltransferases responsible for the biosynthesis of flavones. 61

Taraxacum officinale
Taraxacum officinale, commonly known as dandelion, is a herbaceous plant of the Asteraceae family that is found in different regions such as Asia, Europe, and North America.In the past, the leaves and young parts of this plant were used as food due to the presence of valuable substances such as fiber, minerals, vitamins, and essential fatty acids. 62In addition, the chemical substances in the flowers, leaves, stems, and roots of this plant, including carotenoids, flavonoids, phenolic acids, sesquiterpene lactones, polysaccharides, triterpenes, and sterols have led to the medicinal use of this plant. 63Taraxacum has different species, among which T. officinale has been studied more due to its various medicinal uses.
Taraxacum officinale has been utilized since the 15th century due to its diuretic properties. 64The extract of this plant has also played a significant role in the treatment and control of renal diseases. 65After the 16th century, the properties of T. officinale in protecting the liver were confirmed, and it was introduced as one of the safest and most practical herbal medicines. 66Further, T. officinale leaf extract is effective in the treatment of disorders such as non-alcoholic fatty liver, protection against sodium, and liver damage caused by dichromate. 67araxacum officinale extract can also help strengthen the immune system through processes such as increasing NO, increasing cytokine production, and activating antiapoptotic Bax/Bc1-2 signaling. 68he antiviral function of the T. officinale extract is performed by inhibiting the transcription and reverse replication of human immunodeficiency virus type 1. 69 In addition, the extract of this plant has antiviral activity against influenza, hepatitis B and C, and DENV2. 70tudies indicate that dandelion extract can be considered a potential treatment option for inflammatory processes and tissue damage caused by SARS-CoV-2 infection.As mentioned, the various properties of this plant are valuable due to its bioactive compounds (Table 2).Research has shown that during the process of a cytokine storm caused by COVID-19, taraxasterol contained in this plant can prevent the activation of the inflammatory cycle and subsequent tissue damage by inhibiting interferongamma, IL-6, and IL-1B.Cichoric acid in dandelion also reduces lung damage caused by LPSs.Further, cichoric acid inhibits the production of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β by reducing the number of neutrophils and macrophages. 71nvestigations demonstrated that in viral infections of the respiratory system, the damage of epithelial cells due to viral attack is aggravated with simultaneous bacterial infection and mucosal dysfunction.This process has been confirmed in influenza but not yet in COVID-19.Dandelion ethyl acetate extract can inhibit the growth of Gram-positive and Gram-negative bacteria and can thus prevent simultaneous bacterial infection and deteriorate disease conditions.

Olea europaea
Olea europaea is an evergreen tree of the Oleaceae family that is native to tropical and subtropical regions and has long been used in traditional medicine as a diuretic, lowering blood pressure and improving urinary and bladder infections. 72The most common use of this plant is its oil, which has diverse and amazing properties.In traditional medicine, the combination of O. europaea oil with lemon juice is utilized to treat gallstones. 73The oral consumption of the leaves of this plant is considered for the treatment of stomach and intestinal diseases and as a mouth cleaner. 74Further, the decoction of its leaves and dried fruit is applied for diarrhea and treatment of respiratory and urinary tract infections. 75

Conclusion
Nowadays, many clinical and laboratory studies revealed that, unlike conventional modern medicines, the use of medicinal plants is often non-toxic or with extremely low toxicity due to their natural origin and long-term use as traditional medicines.
However, it cannot be hidden that many problems can also occur for various reasons such as toxicity due to longterm use, possible medicinal and herbal interactions, and incorrect identification of herbal species.With the spread of COVID-19, due to the limited access to resources and treatment processes, the use of herbal medicines received special attention, and the role of pharmacists was highlighted more than before.On the other hand, the knowledge of pharmacists has been one of the important points to provide efficient drug resources according to patients' needs.Therefore, the use of herbal medicines with the help of herbal doctors was considered in all countries.These herbal medicinal resources have worked effectively in reducing the symptoms and treating many patients.
Considering the many cases mentioned in the main text of the article about some medicinal plants and their effect on the treatment cycles of upper respiratory tract diseases, it can be indicated that using a suitable formula to combine these plants can have a more positive effect.Our studies demonstrate that some products in the drug market, including Deep Lung Support, have this feature.Therefore, it is suggested that while developing a study method to investigate the effect of such drugs, a study in the form of a clinical trial should be proposed as well.What is clear is the profound and amazing impact of the potential that lies within nature.

Figure 1 .
Figure 1.Diagram of Study Steps

Figure 3 .
Figure 3. Summary of Pulmonary Diseases, Symptoms, and Biological Pathways Affected by Fritillaria.48

Figure 4 .
Figure 4. Fritillaria Pathway for the Treatment of Respiratory Diseases.Note.STAT: Signal transducer and activator of transcription (STAT) protein, NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells, MAPK: Mitogen-activated protein kinases, RAS: Renin-angiotensin system

Table 1 .
23Summary of Previous Studies on the Properties of the Andrographis paniculata Extract Evaluation of the antioxidant activity of Andrographis paniculata water extract showed that this extract increases the activity of antioxidant defense enzymes such as catalase, superoxide dismutase, and glutathione-transferase while decreasing glutathione content.Therefore, this extract has free radical inhibition, xanthine oxidase inhibition, and anti-lipid peroxidation activities.In addition, this extract is anti-edema and anti-pain.18Examination of the andrographolide extract in rats demonstrated that A watersoluble polysaccharide together with andrographolide increases body weight and creatinine clearance rate while decreasing creatinine and urea nitrogen levels in the serum, serum urea, blood glucose, and urinary albumin excretion.This combination can improve the metabolic abnormalities of diabetic rats and prevent or delay the progression of diabetic renal complications, which may be useful as a therapeutic agent to inhibit the progression of diabetes.19Andrographolidepreventedtheproduction of NO caused by LPS and decreased the expression of iNOS in the RAW 264.7 mouse macrophage cell line.Further, the administration of andrographolide to rats restored the maximum contractile response of the thoracic aorta to phenylephrine and decreased the mean arterial blood pressure of rats20.Andrographolide decreases TNF-α, IL-12a, and IL-12b mRNA levels.Moreover, this extract can reduce the production of TNF-α and IL-12p70 proteins.Andrographolide prevents ERK1/2 MAP kinase activity and can prevent LPS-induced TNF-α production by suppressing ERK1/2 signaling.22Examiningthetoxicity caused by ethanol in mice and evaluating liver and kidney tissues using andrographolide revealed that treating mice with andrographolide and arabinogalactan proteins can minimize the toxicity caused by ethanol.These compounds have bioactive substances that are responsible for protecting the liver against ethanol toxicity.23