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 | Inhibition of Aortic Medial Calcification: miPEP-200b and miRNA-200b as Potential Mediators

 Lupine Publishers | LOJ Pharmacology & Clinical Research

 

Introduction

In molecular biology, the established central dogma is the widely accepted framework of genetic information flow. This process begins with the DNA transcription from the nucleus of the cell into linear, single-stranded messenger RNA (mRNA). Ribosomes then read the mRNA strand following transportation to the cytoplasm, and translation of the code into single amino acids, which are added sequentially to the growing peptide. Once the peptide is fully synthesized, both the mRNA strand and the peptide are released from the ribosome [1]. Although this pathway has been established universally as the only way for protein synthesis, only 1.5% - 2.5% of the human genome codes for proteins [2]. The remainder of the genome produces noncoding RNAs (ncRNAs). These ncRNAs can be further classified into various subtypes; of note are miRNAs, small nucleolar RNAs (snoRNAs), long noncoding RNA (lncRNA), and circular RNA (circRNA) [3]. Although ncRNAs have always been thought to have no role in protein synthesis, many previously unknown indirect functions of ncRNA have been elucidated within the past five years. They have been shown to be involved in many settings such as macrophage activation during an immune response, abnormal expression in diabetic wounds, retinal diseases, and even endometrial physiology and disease states such as endometriosis [4-7]. Perhaps the most groundbreaking findings in the realm of ncRNAs have been their association with various human cancers [8]. Most research has been focused on exploring the epigenetics and post-transcriptional activity of ncRNA, which allows these molecules to exert regulatory effects on the expression of the genome [9]. By directly binding to mRNA strands, miRNAs are able to regulate their ability to eventually lead to protein synthesis [10]. It has been demonstrated that this process is extremely precise, allowing targeting of mRNA with high specificity. Interestingly, the miRNA family has identical 5’ regions with the 3’ region differentiating these molecules and their specificities [11]. Although protein translation and miRNAs have conventionally been thought to have such an indirect relationship, our recent discoveries suggest a much more direct engagement between the two. We have shown that the sequences in certain pri-miRNAs, more specifically pri-miR-200a and pri-miR-200b, contain ORFs that are able to be recognized by ribosomes and subsequently translated directly into protein products, miPEP-200a and miPEP-200b. Even more intriguing is the potential role of these pri-miRNA-derived peptides (miPEPs) in cancer repression [12-15].

Recently we have studied the expression of miPEP-200b in mammalian cells by raising polyclonal antibodies to miPEP-200b. Our results demonstrate that miPEP-200b is expressed in both breast and prostate cells (Figure 1). These results establish the presence of pri-miRNA-encoded proteins in mammalian cells. Many studies have been conducted on the implications of the miR- 200 family in cancer development and repression; however, its association with cardiovascular pathology has not been a central area of focus. Because the miR-200 family has been shown to affect specific cellular pathways in various conditions, it would not be farfetched to speculate on its implications in cardiovascular diseases known to have abnormalities in the same cellular pathways. It was found that a single gene variant for the miR-200 family could cause increased protein kinase A (PKA) activity, with subsequent thrombocyte activation and ensuing atherosclerosis [16]. In addition, PKA has been shown to act as a promoter of human smooth muscle cell (HSMC) calcification [17]. These processes are known to be the initial steps to the eventual development of vascular calcification [18]. Previously, we have shown that pri-miRNAs of 200a and 200b code for miPEP-200a and miPEP-200b respectively and these miPEPs function like miR-200a and miR-200b suggesting that Nature preserved this duplication of functions in case of a failure in any one of their functions. As such, we hypothesize that in the same way that miR-200b plays a role in decreasing PKA activity in atherosclerotic processes, the peptide miPEP-200b (encoded by pri-miR-200b) may also act as an inhibitor of PKA-induced HSMC calcification (Figure 2). Furthermore, targeted miPEP-200b, miRNA-200b, and PKA inhibitor therapy may lead to a substantial decrease in ISH development in older patients, with an ensuing decrease in the incidence and prevalence of diastolic heart failure secondary to longstanding hypertension. In this article, we will discuss the various components that provide evidence for these potential relationships and their sequelae.

Mirna and Mipep Interaction

Although there is a significant amount of information to be discovered regarding the functions of miPEPs, certain recent important findings allow us to predict potential activities of miPEPs in relation to miRNA. Of note is the study by Lauressergues et al. which showed that in plant cells, miPEPs behave as positive feedback on miRNA production [19]. It is possible that this relationship will also be shown in human physiology under controlled experiments in the future. This relationship is quite interesting, given the scarcity of positive feedback mechanisms observed in nature. In addition, various experiments in previous years involving miRNAs that attributed their observed findings to the effects of miRNAs alone may need to be revisited. As an example, it has been demonstrated that miRNA-200a and miRNA-200b are involved in the suppression of the epithelial-to-mesenchymal transition (ETM) in certain cancer types [20]. Although miRNA itself was originally thought to be the mediator of this observation, our recent findings demonstrate that the observed ETM suppression may be a result of miRNA alone, miPEP alone or a combination of both miRNA and miPEP activity [12]. Allowing this scenario to serve as a framework (Figure 3) in many other cellular pathways, one can imagine the vast number of cellular processes that may, in fact, have a different mechanism than what was previously proposed [21,22].

PKA and Aortic Calcification

The vasculature anatomy consists of 3 main layers: tunica intima, tunica media, and tunica adventitia. In the setting of aortic wall calcification, the media layer is involved. The main component of this layer is HSMC, which aids in constriction and dilation of vessels by contracting and relaxing, respectively (Figure 4). However, during the pathological process of medial aortic calcification, these cells begin to behave as osteoblasts, evident by upregulation of several markers associated with bone synthesis, including greater alkaline phosphatase activity [23]. Although there may be several mechanisms involved in this process, one explanation is the over-activity of PKA. PKA is an enzyme found in a multitude of cell types and tissues in the body. The enzyme is activated via cyclic AMP, and following activation, it is able to phosphorylate its substrates [24]. Abnormal PKA activity, therefore, causes various downstream effects. In particular, increased PKA activity may have important pathological implications in vascular calcification. There seems to be a potential mechanism involving PKA-induced elevation of parathyroid hormone (PTH). This may then induce medial aortic calcification [25]. with one experiment involving an in vivo model of rats with elevated PTH levels causing substantial calcification of the aorta [26]. In another study, it was shown that inorganic phosphate (Pi), which acts as a stimulator of PKA, led to HMSC calcification. In this experiment, HSMC were treated with Pi, calcium levels were measured, and subsequently, PKA inhibitors were added, then calcium levels were remeasured. It was demonstrated that inhibition of PKA activity by utilizing siRNA led to a greater than 50% decrease in HSMC calcium levels [27]. Although this study utilized siRNA as the inhibitor of PKA, Magenta et al. suggest that an increased PKA activity may be observed due to a single nucleotide polymorphism (SNP) where a thymidine nucleotide was substituted by cytosine in genes coding for the miR- 200family [16]. This may suggest that the miR-200family plays a significant role in moderating PKA activity.

Aortic Calcification, Hypertension, and Heart Failure

A major sequela of vascular, specifically arterial, calcification is the development of hypertensive disease. As a result of the calcific process involving the media, the arterial system (including the aorta) becomes stiffened and loses its ability to dilate and decrease systemic vascular resistance. The resulting hemodynamic state is such that an isolated elevation in systolic blood pressure is observed, leading to both ISH and concomitant increased pulse pressure (difference between systolic and diastolic blood pressure). Although ISH has a strong association with medial calcification, its relationship with intimal atherosclerosis has not been elucidated to a significant degree [28]. With sustained, chronic hypertension, cardiac ventricular muscle cells undergo hypertrophy as a means to compensate for this increased afterload. Although this mechanism is compensatory, it is not without pathological consequence, with severe left ventricular hypertrophy (LVH) eventually leading to diastolic heart failure [29].

Discussion

Among the numerous functionalities that miRNA-200b has been shown to have [30], its suggested role in downregulating PKA activity may be an important player in preventing medial aortic calcification. This can be inferred as increased PKA activity has been associated with the deposition of bone-like material in the aortic medial layer. Although many cellular pathways may potentially be involved, one proposed mechanism is the PKA-induced increase in PTH levels. Interestingly, PTH is generally thought to be involved in bone resorption. However, it appears to have the opposite effect leading to calcification in the vasculature. Following calcification of the aorta and other arteries, the stiffening of these vessels leads to ISH. With longstanding ISH, the myocardium becomes hypertrophied as a compensatory mechanism with the eventual development of diastolic heart failure. This proposed sequence is presented in Figure 1. Furthermore, miPEP may prove to be paramount in maintaining high miRNA activity, given the positive feedback that miPEP exerts on miRNA; although this observation has only been made in plant cells, the existence of both miPEP and miRNA in humans could provide the same relationship. No such studies have been published on the potential regulatory role of miPEP on miRNA in human physiology due to the relatively recent discovery of miPEP in our previous study [12]. A very recent study showed that miRNA-8 and miPEP-8 act to produce the same end result, regardless of their exact mechanisms of action, in Drosophila [31]. These findings are quite interesting, simulating many other protective mechanisms seen in nature, such as genetic redundancy [32]. By providing two mechanisms of accomplishing the same end goal, one mechanism serves as the main actor, and the other serves as the back-up in case of an event that renders one of them nonfunctional. As such, even in the case of a knock-out polymorphism of miRNA-200b, miPEP-200b can independently regulate the function of PKA by interfering with its regulatory subunit [16] and decreasing vascular calcification.

Conclusion

If our proposed mechanism of disease progression in medial aortic calcification in the context of miRNA-200b and miPEP- 200b is shown to hold true, it will provide targets for therapeutic interventions. PKA antagonists, miRNA-200b, and miPEP-200b could be utilized with the end goal of decreasing PKA activity and decreasing vascular calcification with a subsequent decrease in the incidence and prevalence of both ISH as well as diastolic heart failure. Furthermore, there is potential for miRNA-200b and miPEP-200b levels to serve as prognostic factors for these diseases. There is reason to suggest this, as multiple studies have shown the promising potential of using miR-200 family levels as a strong prognostic marker for disease severity; low levels of the miR200 family have shown to be accurate predictors of a worse prognosis in pancreatic, lung, gastric, and bladder [33-36]. Although there is much to be discovered in this new arena involving miPEP, these findings provide an excellent starting point for future experimental designs, arming scientists with a new outlook on cellular pathways that were previously thought to behave differently.

 
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