Bioactive compounds of Boesenbergia sp. and their anti-inflammatory mechanism: A review

Boesenbergia sp. (Zingiberaceae) has been empirically used in Indonesia, to treat rheumatism. The rhizome of Boesenbergia rotunda contains essential oils (nerol, camphor, cineole, fenchene, hemanthidine, and limonene), flavonoids (alpinetin, boesenbergin, cardamonin, pinostrobin, pinocembrin, geraniol, panduratin, and silybin), and polyphenols (caffeic acid, coumaric acid, chlorogenic acid, hesperidin, kaempferol, naringin, and quercetin), which explain its many interesting pharmacological activities (antifungal, anti-inflammatory, antimicrobial, antibacterial, anticancer, antimutagenic, antiparasitic, antiulcer, antileukemia, hepatoprotective, and antiviral). This review focuses on the bioactive compounds in Boesenbergia sp. and their molecular mechanism in reducing inflammation. Of all bioactive compounds, panduratin A and 4-hydroxypanduratin A have proven their activity in inhibiting the production of nitric oxide and PGE2 as well as on tumor necrosis factor-alpha. Moreover, this paper also provides other uses of this plant species as well as future study aspects.


INTRODUCTION
Inflammation is the body's response in combatting pathogens or destructing chemicals (cytokines and histamines). The cascade of inflammatory-related mediators frames the acute inflammatory response, which is activated by recruiting granular white blood cells and frequently resolves the outcome recovery. Understanding how the inflammatory process is triggered might be beneficial for developing the strategies to inhibit the inflammatory responses (Ward and Lentsch, 1999).
Various therapeutics are being used to stop or reduce the inflammation process, such as nonsteroidal anti-inflammatory drugs and corticosteroids. Unfortunately, these drugs have been reported, case by case, for their unfavorable effects, for example, the increase of blood pressure, peptic ulceration, acute kidney dysfunction, and other serious conditions (Attiq et al., 2017).
This review focuses on the bioactive compounds in Boesenbergia sp. and their mechanism as anti-inflammatory agents. Moreover, this paper also provides other utilities of Boesenbergia sp. as well as its future study aspects (Table 1). The required pieces of information were obtained by searching keywords which include Boesenbergia, Zingiberaceae, flavonoids, kaempferol, panduratin, and quercetin, among published articles until March 2020 in authentic scientific databases.

Methods
The literature search was performed on PubMed database using the following keywords: "Boesenbergia sp." [Medical Subject Headings (MEeSH)

Anti-Inflammatory Mechanism of Boesenbergia sp.
Table 1 shows all the pharmacological activities of B. rotunda; however, this review study will only focus on the antiinflammatory mechanism of this plant.

Panduratin A and Hydroxypanduratin A inhibit TNF-α and the production of nitric oxide
Nitric oxide (NO) plays a key role in maintaining vascular function. The overproduction of NO could damage the tissue and is related to acute and chronic inflammation. An antiinflammatory study in Thailand reported that phytoconstituents isolated from the extract of B. rotunda strongly inhibit NO production, for example, panduratin A, hydroxypanduratin A, and cardamonin. Moreover, a medium strength of inhibitory activity on tumor necrosis factor-alpha (TNF-α) was observed for both panduratin A and hydroxypanduratin A (Tewtrakul et al., 2009). The NO inhibitors are favorable because NO regulates cerebral blood flow and nociception in migraine-induced animal models (Wong and Lerner, 2015).

Panduratin A and Hydroxypanduratin A inhibit PGE 2 production
Prostaglandin synthase catalyzes two separate reactions: (1) the addition of O 2 to oxygenate the arachidonic acid molecule until an unstable prostaglandin G 2 (PGG 2 ) is produced and (2) PGG 2 then migrates to the peroxidase site where it reacts with the hemin group to generate prostaglandin H 2 (PGH 2 ) (Levita et al., 2009). PGH 2 is subsequently converted into the active PGE 2 , PGI 2 , PGD 2 , PGF 2α , and thromboxane A 2 (Nørregaard et al., 2015). Both panduratin A and hydroxypanduratin A strongly inhibit PGE 2 production (Tewtrakul et al., 2009). The inhibition of PGE 2 production could lessen inflammatory symptoms and pain (Sugita et al., 2016).

Boesenbergia rotunda inhibits the infiltration of inflammatory cells in the hepatic bile ducts
The extract of B. rotunda reduces the inflammation caused by Opisthorchis viverrini and induced by N-nitrosodimethylamine administration in rats. This study proved that there was a decrease in the number of inflammatory cells infiltrated into the hepatic bile ducts as well as the serum alanine transaminase and direct bilirubin level (Boonjaraspinyo et al., 2010).

Boesenbergia rotunda accelerates wound healing in rats
A wound recovery is a dynamic process of repairing cellular structures in damaged tissue. Wound abridgment occurs throughout the recovery process commencing in the fibroblastic stage followed by the proliferative stage (Midwood et al., 2004). Flavonoids have been proven to promote the wound-healing process due to their antimicrobial activities, which is responsible for wound contraction and increased the rate of epithelialization. Fresh juice rhizome increased the fertility by improving sperm's quality.

Boesenbergia rotunda and pinostrobin reduce ulcer inflammation
Boesenbergia rotunda has been utilized empirically to cure ulcers by the people in Thailand and Indonesia. The antiulcer activity of the methanol extract of B. rotunda and its phytoconstituent pinostrobin has been studied by Abdelwahab et al. It was reported that B. rotunda extract and pinostrobin revealed the cytoprotective effects on ulcer-induced rats. This plant extract also significantly decreased submucosal edema and leukocyte infiltration . Kirana et al. (2003) assayed through eleven species of Zingiberaceae and discovered that B. rotunda and Zingiber aromaticum indicated the highest inhibition toward the growth of MCF-7 breast cancer and human HT-29 colon cancer cells (Kirana et al., 2003). An additional study of panduratin A on the same cell lines has also proven similar potent inhibitory properties and a nontoxic result to the rats (Kirana et al., 2007).
In 2006  assay revealed that panduratin A activated the induction of apoptosis in both cell lines by inhibiting apoptotic-related procaspases 3, 6, 8, and 9 (Yun et al., 2006). Panduratin A also exhibited inhibitory activities against the growth of A549 human non-small cell lung cancer cells (Cheah et al., 2011).
The antileukemia activity of B. rotunda rhizome extracts has been investigated and revealed that the chloroform extract and boesenbergin A could inhibit the growth of HL-60 cell line (Sukari et al., 2007).

Panduratin A inhibits NF-kappaB translocation to the nucleus
Panduratin A could inhibit the translocation of NF-kappaB from the cytoplasm to nuclei (Cheah et al., 2011).

Toxicity Study
The toxicity of the B. rotunda extract was studied in normal healthy rats by exposing the animals to high doses of the rhizome extract (2 and 5 g/kg of BW) (Mahmood et al., 2010;Manosroi et al., 2017;Salama et al., 2012). An in vivo study indicated that the ethanol extract of B. rotunda was not toxic as there were no significant changes in the body weight of the rats. Moreover, all hematological and histopathological parameters did not show any adverse changes (Lim, 2016;Saraithong et al., 2010). Meanwhile, pinostrobin and pinocembrin revealed no mutagenic effect or toxicity toward Wistar rats, which confirmed the safety of these compounds (Charoensin et al., 2010).

CONCLUSION
The traditional utilities of B. rotunda rationalize that this plant could be upgraded to the next level of drug discovery study. Nonetheless, the molecular mechanism of panduratin A and 4-hydroxypanduratin A of B. rotunda has described their activity in inhibiting the production of nitric oxide and PGE 2 as well as on TNF-α. Panduratin A also inhibits the translocation of NF-kappaB to the nucleus, which might contribute to this plant's anti-inflammatory activity. Furthermore, the ethanolic extract of B. rotunda was considered not toxic as it did not alter the body weight and hematological parameters of rats.

ACKNOWLEDGMENT
The publication fee is funded by Doctoral Dissertation Grant 2019 of the Ministry of Research and Technology and Higher Education, the Republic of Indonesia (10/E1/KP.PTNBH/2019).

CONFLICTS OF INTEREST
There are no conflicts of interest related to the publication of this paper.

FUNDING
None.