Lupine Publishers | A Brief Review on Phytochemical and Pharmacological Aspects of Andrographis Paniculata

 Lupine Publishers | LOJ Pharmacology & Clinical Research

 

Introduction

Since the beginning of civilization, medicinal plants have been an intrinsic component of human life [1]. The conservation of ethnobotanical knowledge as part of living culture and practice between communities and the environment is essential for biodiversity conservation. The information about medicinal plants gains from various medicinal systems such as Unani, Siddha, and Ayurveda [2]. The traditional system of medicine belongs to the traditions of each country and has been passed over from generation to generation. Understanding the dynamics of traditional local knowledge of medicinal plants is important for their medicinal properties is now being developed as a source of scientific research to prove the effect of plants and generate new therapeutic resources. Medicinal plants are considered as a backbone of traditional medicine (WHO) as well as most modern medicine is also derived from medicinal plants i.e. aspirin. The medicinal plant having a rich source of components that can be used to develop and synthesize drugs. About 3.3 billion people in developing countries depend on medicinal plants on a regular basis, WHO estimated that about 80% world population rely on the medicinal plant for their primary health care. Further more, worldwide 42% of 25 top-selling drugs marketed are either directly obtained from natural sources or entities derived from plant products [3]. The quality of traditional medicine is determining its active substances produced by the plant. Andrographis paniculata is one of the important medicinal plants that is utilized throughout the world [4]. A.paniculata is an herbaceous plant of the Acanthaceae family. It is widely distributed in Southeast Asia, India, and tropical as well as in subtropical Asia. A.paniculata is also known as the “King of Bitters” since it has a highly bitter taste in all parts of the plant body [5]. Furthermore, A. paniculata is known as “Kalmegh” in India, “Chuan-Xin-Lian” in China, “Fah Tha Lai” in Thailand, “Hempedu Bumi” in Malaysia, “Senshinren” in Japan, and “green chiretta” in Scandinavian nations [6]. A.paniculata is one of the most widely used plants in Ayurvedic and Unani medicine [4]. Traditionally, A.paniculata was used in the treatment for snakebite, fever, bug bite, diabetes, malaria, and dysentery [7]. Moreover, A.paniculata is also used in the combination with other herbs and health care treatment. It is found that A.paniculata is used in more than half of the herbal formulations commercialized in India for he patic diseases [8]. Many scientific studies also have been reported regarding the medicinal properties possessed by the A.paniculata, most of which are based on traditional knowledge (Table 1). Phytochemical investigations have revealed that A. paniculata contains a wide range of chemicals. In addition, experimental evidence also reported that A.paniculata has a broad spectrum of pharmacological activity including anti-bacterial, antidiarrheal, anti-inflammatory, antiviral, antimalarial, anticancer, antimalarial, hepatoprotective, etc. In this review, we briefly discuss ethnobotanical uses, phytochemistry, and recent scientific finding pharmacological activity of the A.paniculata [6].

Table 1: Taxonomical classification of Androgrphis paniculata.

Botanical Description and Habitat

A.paniculata is native species of India, China, and Taiwan. But it is also found in Southeast Asia, tropical and subtropical Asia as well as few other nations such as Malaysia, Indonesia, Vietnam, Sri Lanka, Laos, Cambodia, Pakistan, Myanmar, and the Caribbean islands [9]. Especially, in India A.paniculata are found in Karnataka, Andhra Pradesh, Tamil nadu, Uttar Pradesh, and Madhya Pradesh. Also cultivated in Assam and West Bengal to some extent. In addition, A.paniculata are found in different habitats including forests, farms, plains, hill slopes, dry and wetlands, and wastelands [10]. A.paniculata is bitter in test, an annual herb that is abundantly branched which grows up to a height of 3.-110 cm in a humid, shady area. It has glabrous leaves that are 8.0 cm long and 2.6 cm wide, little white flowers that are rose-purple or light pink, spots on the petals, and corolla with hairs. The stem was found to be dark green in color, 0.4-1.0 m tall, 2-6 mm in diameter, quadrangular with longitudinal furrows and wings on the angles of the younger part [11] as shown in Figure 1.

Figure 1: Andrographis paniculata morphology.

Traditional Uses of Andrographis Paniculata

A.paniculata play vital importance in the Ayurvedic, Siddha, and traditional medicine systems in India [12]. For centuries, the leaves and roots of A.paniculata have been used to treat a wide range of health problems in Asia and Europe. However, the entire plant is also utilized for specific uses [13]. The plant known as “Kalmegh” in Ayurvedic literature is an essential element in the majority of Ayurvedic remedies and is officially recognized by Ayurvedic pharmacopeia. Moreover, it is used as an aperient, emollient, astringent, anti-inflammatory, diuretic, anthelmintic, carminative, and antipyretic in the Unani system of medicine [14].In India, tribal groups used this herb to cure a number of diseases such as antidote against snake bites, Banded Krait and Russell’s viper, etc. [14]. The tribal of Kheria, Khatra, Moora, and the Santal region of Bankura district, West Bengal, India utilizes an infusion of the entire plant to treat fever [15]. The extracted juice from A.paniculata leaves, alone or combined with cloves, cinnamon, and cardamom is used as a cure for flatulence, loss of appetite, griping, diarrhea in children, and irregular stool. In India during the influenza epidemic in 1919, A.paniculata was shown to be highly effective in reducing the disease progression [16]. It was also utilized by ancient Chine’s physicians to treat inflammatory diseases, colds, laryngitis, and fever, hepatitis, pneumonia, respiratory infections, tonsillitis, sores, pelvic snake bites, herpes zoster and it has been characterized as a cold property herb [13] to remove toxins and body heat. The decoction of fresh leaves of A.paniculata is used as an antihypertensive and antidiabetic in Malaysian folk medicine. Furthermore, it is advised to use it in cases of leprosy, scabies, gonorrhea, boils, chronic and seasonal fevers, and skin eruptions, due to its “blood purifying” purifying properties [4].

Phytochemistry

The aerial part (leaves and stems) of A. paniculata contains major active phytochemicals [17]. According to the survey of the literature, andrographolide is the major bioactive compound found in the A.paniculata which is a diterpene lactone that is crystalline, colorless, and has a bitter taste [9]. The leaves have the highest concentration of andrographolide about 2.39% whereas the seed has the lowest concentration about 0.58%. The quantity of the phytochemicals varies widely depending on the portion used, locality, time of harvesting, and season (Figure 2). Andrographolides are highest found immediately before the flowering season, then decline progressively [14]. Other lactones compound observed in A.paniculata is 14-deoxy-11-andrographolide, 14-deoxy-11, 12 didehydroandrographolide, andragraphan, andrographon, 14-deoxyandrographolide, neoandrographolide, deoxyandrographiside, andrographosterol, andrographiside etc. A.paniculata also contains Xanthones and quinic acid derivatives in minor concentrations. Moreover, Reddy et a. [18] reported that A.paniculata contains flavone such as 5-hydroxy-7’2’6’-trimethoxyflavone and 23-C terpenoid 14-deoxy-15-isopropylidene-11, 12- didehydroandrograholide and other flavonoid Skullcapflavone I 2’-O-glucoside, 7-Omethylwogonin, 7-Omethyldihydrowogonin and 7-O-methylwogonin 5-O-glucoside as well as diterpenoids such as isoandrographolide 14-deoxy-11, 12 didehydroandrographolide. Rao et al. [19] identified and isolated 5, 7, 20, 30-tetramethoxyflavanone and 5-hydroxy-7, 20, 30-trimethoxy flavone from the A.paniculata. A new labdane type diterpenoid which is andropanolide along with seven known diterpenoids isolated from the methanolic leaves extract of A.paniculata [20].

Figure 2: Chemical structure of major component found in A.paniculata.

Pharmacological Activity of A.Paniculata

Hepatoprotective activity

A.paniculata is widely used as a hepatoprotective and hepatostimulative agent in the Indian traditional medicine system. Traditionally the leaves aqueous extract of A.paniculata is used in the treatment of jaundice and different liver damage. Andrographolide found in the A.paniculata was protective against liver damage in rats and mice induced by carbon tetrachloride. Moreover, Andrographolide also observed significant hepatoprotective against various types of liver damage, induced by galactosamine or paracetamol [21]. The free radical scavenging activity of andrographolide has a significant hepatoprotective effect by lowering lipid peroxidation malondialdehyde product as well as by maintaining glutamic pyruvate transaminase, alkaline phosphatase, and glutathione levels in mice treated with carbon tetrachloride [22]. A.paniculata has been shown antihepatotoxic activity against plasmodium berghei K173-induced hepatic damage in mastomys natalensis [23].

Antibacterial activity

A.paniculata has been shown the antibacterial activity against a wide range of bacterial species. In vitro study found that the aqueous extract of A.paniculata shown antibacterial activity even at the low concentration (25 mg/ml) against E.coli, Shigella, Streptococci, Staphylococcus aureus, and Salmonella [24]. Another similar study leaves aqueous extract of A.paniculata reported against the methicillin- resistant S.aureus and Pseudomonas aeruginosa [25]. Furthermore, A.paniculata is also effective against HAS 1 (herpes simplex virus 1) without any cytotoxicity [26].

Antidiarrheal activity

In developing countries, Diarrhea is one of the most common diseases and it leads to the top ten causes of death among children worldwide [5]. Some drugs such as kaolin-pectin, selenium, loperamide, and bismuth have been used to treat the symptoms. However, it also causes some unfavorable side effects [5]. The study has been found that A.paniculata has significant antidiarrheal properties [27]. According to the study, an ethanolic extract of A.paniculata treated 88.3 % of acute bacillary dysentery cases and 91.3% of acute gastroenteritis cases. Furthermore, andrographolide was found to treat 91% of acute bacillary dysentery cases. The same cure rate of about 91.1% was obtained by providing a compound tablet comprising andrographolide and neoandrographolide in a 7:3 ratio. This was claimed to be more than the cure rate observed with chloramphenicol and furazolidone [28]. A.paniculata was found to be effective in curing patients with acute diarrhea and bacillary dysentery in double-blind investigation [14].

Antimalarial activity

In many tropic and subtopic countries, malaria is still a prevalent disease [14]. A.paniculata was shown to significantly suppress the growth of the Plasmodium berghei [11]. In vitro study of 50% ethanolic extract of the aerial parts (100 mg/g) shown antimalarial activity against plasmodium berghei and in vivo study in rats observed antimalarial activity after intragastric application (1g/kg body weight) [26]. It is suggested that the antimalarial effect of A. paniculata is due to the reactivation of the enzyme superoxide dismutase [5]. Another study has been reported that the crude extract of A.paniculata shown antimalarial activity against the resistant strain of Plasmodium falciparum having an IC50 value of 6mg/ml [29]. In addition, a xanthous compound isolated from the A. paniculata has been shown in vivo antimalarial activity in plasmodium infected Swiss albino mice. The results found that a significant reduction in parasitemia after treatment with a 30 mg/kg dosage [26].

Anticancer activity

Cancer is a set of disorders characterized by abnormal cell proliferation and the ability to penetrate or be spared to other regions of the body. Despite the fact that many diseases have a worse prognosis than most cancers [17]. The extract of A.paniculata having diterpenoid is significantly able to restrict cell proliferation, arrest the cell cycle and induce cell apoptosis of different cancer cells [30- 33]. Treatment of the MDA-MB-231 breast cancer cells with andrographolide extracted from A. Paniculata causes apoptosis of cancer cells and arrests the cell cycle without interfering with the normal growth of cells [34]. The study has been reported that A.paniculata exhibits potent cytotoxic activity against human epidermoid carcinoma of the skin lining of the lymphocytic leukemia cells and nasopharynx [12]. A.paniculata also shown cytotoxic effects against colon cancer cells by suppressing AKT and mTOR phosphorylation levels, resulting in ER stress-induced death [35]. Furthermore, apoptosis in colon cancer cells is induced by the andrographolide via controlling the signaling of pro-apoptotic GRP-78/IRE1/XBP-1/ CHOP [17].

Antidiabetic activity

Diabetes is a metabolic disease characterized by elevated blood sugar levels [36]. According to the WHO reports around 70 million people worldwide suffer from diabetes. Specifically in developing countries, diabetes has become a threat to human health [37]. In vivo study observed that ethanolic extract of A.paniculata exhibit the protective effect in hyperglycemic condition and also protect the tissue damage caused due to oxidative stress in a diabetic rat model produced by streptozotocin [38]. Another study conducted [39] found that oral administration of andrographolide in a dose-dependent manner reduced plasma glucose levels in diabetic rats caused by streptozotocin and wild-type rats.

Conclusion

The entire literature review indicated that Andrographis paniculata exhibits a broad range of phytochemicals and pharmacological activities. The previous study found that A.paniculata contains 50 lactane diterpenoids, 30 flavonoids, and 30 novels phytochemical isolated and identified from A.paniculata. Phytochemical study reveals that Andrographolide is a major compound found in Andrographis paniculata. It has shown a wide spectrum of pharmaceutical activity such as anti-microbial, hepatoprotective activity, anti-inflammatory activity, anti-malarial, anti-diarrheal, anti-diabetic, and cytotoxic activity. The precise information offered as a review here covers the phytochemical and pharmacological information about this plant, providing the muchneeded encouragement to use this plant in creating and sustaining a prospective means of livelihood.

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Lupine Publishers | Alignment of SARS-Cov-2 Spike Protein Compared with Ebola, and Herpes Simplex Viruses in Human Murine and Bats

 Lupine Publishers | LOJ Pharmacology & Clinical Research

Abstract

Our analytical approach consisted in sequence alignment analysis of spike protein in different viruses, followed by construction of phylogenetic tree. Additionally, we investigated some commotional parameters on the protein sequence determining chemical composition as well as estimated PI .Our observation revealed significant difference in S protein between the 3 tested viruses in different species These differences may have significant implications on pathogenesis and entry to host cell.

Introduction

Viruses are inert outside the host cell which are unable to generate energy. As obligate intracellular parasites, during replication, they are fully reliant on the complex biochemical machinery of eukaryotic or prokaryotic cells. The central purpose of a virus is to transport its genome into the host cell to allow its expression by the host cell [1]. Binding of a single surface glycoprotein of virus to its host receptor promotes pH-dependent conformational variations once within the endosome acidic environment, thereby transporting the viral bilayer in closeness with the host cell membrane to promote fusion [2]. The structural physiognomies of virus coats (capsids) are extremely appropriate to virus propagation. The coat must enclose and protect the nucleic acid, flexible against interference be talented of broaching the outer wall of a target cell and provide a confident pathway for attending nucleic acid into the target cell. Hollow spikes on the capsid fulfill the latter two roles, from which it has been deduced that they must have unusually high strength and stiffness in axial compression [3]. The spike protein (S protein) is a type I transmembrane protein, a sequence of amino acids ranging from 1,160 for avian infectious bronchitis virus (IBV) and up to 1,400 amino acids for feline coronavirus [4]. Spike proteins assemble to create the distinctive “corona” or crown-like look in trimers on the surface of the virion. The ectodomain of all CoV spike proteins portions the same organization in two domains: a receptor-binding N-terminal domain called S1 and a fusionresponsible C-terminal S2 domain The variable spike proteins (S proteins) reflect CoV diversity, which have developed into forms that vary in their receptor interactions and their reaction to different environmental triggers of virus-cell membrane fusion [5]. A notable peculiarity between the spike proteins of diverse coronaviruses is whether it is cleaved or not during assembly and exocytosis of virions [6]. The entry Herpesvirus and membrane fusion to the host cell equire three virion glycoproteins, gB and a gH/gL heterodimer, that function as the “core fusion machinery” [7]. The viral envelope of Ebola virus contains spikes consisting of the glycoprotein (GP) trimer. These viral spike glycoprotein docks viral particles to the cell surface, endosomal entry, and membrane fusion [8]. Acute respiratory syndrome coronavirus (SARS-CoV) is a zoonotic pathogens that traversed the species barriers to infect humans. These coronaviruses hold a surface-located spike (S) protein that recruits infection by mediating receptor-recognition and membrane fusion [9]. Bioinformatics plays an important role in all aspects of protein analysis, including sequence analysis, and evolution analysis. In sequence analysis, several bioinformatics techniques can be used to provide the sequence comparisons. In evolution analysis, we use the technique like phylogenetic trees to find homologous proteins and identified the most related taxa. With bioinformatics techniques and databases, function, structure, and evolutionary history of proteins can be easily identified [10]. Several bioinformatics methods can be used in sequence analysis to provide sequence comparisons.

Materials and Methods

Sequences, alignment, and construction of phylogenetic tree

Amino acids sequences for the spike protein of Covid-19, Ebola, and herpes simplex viruses from bats, murine as well as Homo sapiens were taken from the National Center for Biotechnology Information database. The accession numbers of the corresponding database entries and species names are listed in Table 1 and Figure 1. Sequences were aligned with by CLUSTALW [11]. Selection of conserved blocks was performed using GBlocks (version 0.91 to eliminate divergent regions and poorly aligned positions using standard settings according to Castresana [12]. The Akaike information criterion (AIC) were performed, using a maximum-likelihood (ML) starting tree to estimates the quality of each model, relative to each of the other models (Table 2). The most suitable model was WAG+G+F [13]. Then phylogenetic tree was constructed with neighbor-joining and maximum likelihood algorithms using MEGA version 5 [14]. The stability of the topology of the phylogenetic tree was assessed using the bootstrap method with 100 repetitions [15].

 

 

Computation of the theoretical pI (isoelectric point) of protein sequences

Estimation of the isoelectric point (pI) based on the amino acid sequence was determined using isoelectric Point Calculator (IPC), a web service and a standalone program for the accurate estimation of protein and peptide pI using different sets of dissociation constant (pKa) values [16]. Models with the lowest BIC scores (Bayesian Information Criterion) are considered to describe the substitution pattern the best. For each model, AICc value (Akaike Information Criterion, corrected), Maximum Likelihood value (lnL), and the number of parameters (including branch lengths) are also presented [1]. Non-uniformity of evolutionary rates among sites may be modeled by using a discrete Gamma distribution (+G) with 5 rate categories and by assuming that a certain fraction of sites is evolutionarily invariable (+I). Abbreviations: TR: General Time Reversible; JTT: Jones-Taylor-Thornton; rtREV: General Reverse Transcriptase; cpREV: General Reversible Chloroplast; mtREV24: General Reversible Mitochondrial.

Results

In order to unravel the phylogenetic relationship of Spike protein between the different taxa, a phylogenetic consensus tree was constructed using the Bayesian Inference (BI) and Maximum Likelihood (ML) methods (Figure 1). The present results revealed that the identity between different taxa was nonsignificant, However alignment of human Coronavirus (Covid-19) and Bat Coronavirus revealed identity equal to 57.98% followed by Murine Coronavirus which displayed 27.61% when compared by human Coronavirus. The chemical composition of the tested protein is illustrated in Table 3. Figures 2 & 3 show the correlation plots between the theoretical isoelectric points for spike protein of different corona virus in different species. The current results displayed that estimated pI of spike protein sequence in three investigated viruses in different species ranges from 5.59 to 8.08. With highest value for spike protein in herpesvirus of bat. The Estimated charge over pH range of the investigated were listed in Table 4. The current results revealed that the behavior of s protein in different species exhibited different estimated charge at different pH ranges. Some S protein reveled low negative charge as pH increases such as Ebola Virus of bat while S protein of Corona virus in murine showed high negative charge as pH elevated.

 

Discussion

One aspect that may provide some insight into the interactions of the S protein is the electrostatic potential it generates. the affinity constant for the receptor-binding domain (RBD) of viron protein potentially contributing to its transmission efficiency [17]. The S protein remains predominantly in the closed conformation to mask its receptor-binding domains (RBDs), thereby impeding their binding. To bind with ACE2, the S protein transforms into its open conformation, revealing its binding interface [18]. The present study relies on a comparative investigation, regarding the identity of spike protein of 3 viruses (Covid-19, Ebola, and herpes simplex) to identify the most related taxa. Our investigation revealed high similarities of Spike protein of coronaviruses in human and bats [19]. The computed amino acid composition of spike protein. Several residues showed a significant difference between the compositions in spike proteins in the three investigated virus in different species. This result reveals the importance of specific residues in these classes of proteins. The polar uncharged residues, especially Serine, Asparagine, and Glycine, have higher occurrence in spike protein of murine, which are important for the folding, stability, and function of such class of proteins [20]. Our analysis revealed that the Coronavirus spike protein of murine may be more efficient in discovering suitable vaccine for Coronavirus. The S protein amino acids variations among different coronaviruses such as (SARS, herpes and ebola). The SARS-CoV-2 virus shares 57.98% of its genome with the other bat coronaviruses. The sequence identity in the S protein bat coronavirus appears to be the closest relative of SARS-CoV-2. Our results in accordance with Rothan [21]. The isoelectric point (pI) is the pH value at which a molecule’s net charge is zero [22]. Information about the isoelectric point is important because the solubility and electrical repulsion are lowest at the pI. Hence, the tendency to aggregation and precipitation is highest. In the case of viruses, the value thus provides information about the viral surface charge in a specific environment [23]. In polar media, such as water, viruses possess a pH-dependent surface charge [23]. This electrostatic charge governs the movement of the soft particle in an electrical field and thus manages its colloidal behavior, which plays a major role in the processes of virus entry. The pH value at which the net surface charge changes its sign is called the isoelectric point and is a characteristic parameter of the virion in equilibrium with its atmosphere in water chemistry [24]. For some viruses the attachment influences that encourage binding to accommodating cells are extremely definite, but the arrangement of actions that activates viral entry is only now establishment to be understood. The charge of attachment protein may play an important role in attachment and entry of virus [25]. The current results revealed that the pH affect the net charge of S protein of different taxa with different behavior. All the investigated taxa exhibit increases in negative charge as the pH increased except for the Ebola virus form Bats which showed unstable behavior regarding the S protein charge.

Conclusion

In our study, we have investigated the variation of pHdependent changes in charges of a protein. The current results revealed that the pH affect the net charge of S protein of different taxa with different behavior.

 

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