Alpinia katsumadai seed from a condiment to ethnomedicine to nutraceutical, a comprehensive review of its chemistry and health benefits

Abstract

From a traditionally used spice to a highly valued therapeutic plant with many biological effects, Alpinia katsumadai Hayata seed (AKS) is widely used as a functional food or nutraceutical. In folk medicine, AKS has been used as an anti-emetic and for gastric disorders. Up to 2024, no comprehensive review summarizing the mode of action of AKS phytoconstituents although large number of studies. This review focuses on food applications, extraction and isolation methods, as well as chemical characterization of AKS phytoconstituents. The ethnopharmacological uses and pharmacological activities of AKS extracts and their isolates were discussed which may maximize AKS use in nutraceuticals. Data were collected using Google Scholar, PubMed, Web of Science, and bibliographic databases of previously published articles. Phytochemical studies have reported more than 153 phytoconstituents belonging to diarylheptanoids and terpenoids in addition to kavalactones, flavonoids, and phenylbutanoids. Bioassays revealed that AKS extracts and their isolates exhibit a wide range of bioactivities such as anti-emetic, antidiabetic, antiviral, anticancer, anti-inflammatory, and digestive system protective effects. This review can provide a reference for further research on AKS for inclusion in nutraceuticals. In addition, new formulations should be explored to improve constituents’ bioavailability and biological effects, alongside elucidation of the underlying action mechanisms.

Graphical abstract

1. Introduction

The Alpinia uses have evolved over the years in several ethnomedicine, especially in East Asia.¹ Alpinia katsumadai Hayata (AK) is one of the 250 species that belong to Alpinia genus, family Zingiberaceae.² It is mainly distributed in tropical and subtropical Asia; China, Malaysia, and Japan.³ AK has a unique set of phytoconstituents such as diarylheptanoids, kavalactones, and unique flavonoids compared to other Alpinia species. Notably, this sole chemistry is linked to its potential medicinal properties.⁴ Some medicinal uses of AK are shared with other Alpinia species, but AK seems to exhibit more specific biological activities such as anti-emetic and antidiabetic effects. Alpinia katsumadai Hayata seed (AKS) is not only a famous Chinese spice but also a traditional Chinese medicine,⁵ moreover, AKS is reported in the Korean pharmacopeia.⁶ Traditionally, AKS (Caodoukou in Chinese) is used in Chinese medicine for digestive issues and as an anti-emetic. Phytochemical studies reported that AKS is especially rich in diarylheptanoids, terpenes, flavonoids, stilbenes, and their hybrid structures. Recently, several reports have shed light on AK anti-inflammatory, antioxidant, antiproliferative, anti-emetic, anti-ulcer, and antimicrobial activities.^7,8,9,10,11 Additionally, it has a role in controlling several degenerative diseases including diabetes, hypercholesterolemia, and asthma.²

Phytochemical studies on AK bioactives have been increasingly reported in the literature. Up to 2024, more than 78 articles concerning AK were published, and only two review articles, concerning Alpinia genus in 2016–17 (Fig. 1).1, 2 Specifically, a review article reporting on seeds chemistry and biological effects, where 60 phytoconstituents were identified with 18 references cited in 2012.⁴ After that review, there have been no reports on recently isolated constituents in AKS, although large number of studies concerning AKS have been reported in literature, and further no study to dissect phytochemical bioactivities relationship as needed to maximize AKS use in nutraceuticals. Herein, this review highlights the potential of AKS in food and nutraceuticals as a less explored Alpinia species among others, based on such compilation of chemical and biological investigations. The various extraction and identification methods were also discussed. This review summarizes AKS phytoconstituents in relation to its health benefits alongside the underlying action mechanisms.

Fig. 1.

Analysis of Alpinia katsumadai from Scopus (during 1975–2024 - collected on June 20, 2024). A; Number of documents published per year, B; Pie chart showing paper retrieved by subject area, C; Pie chart showing article type.

2. Traditional and food uses and applications of AKS

2.1. Alpinia katsumadai seed in folk and traditional medicine

Alpinia has a long history of being used in folk and traditional medicine not only in China, but also in other Asian countries viz. India and Japan. Traditionally Alpinia treats ailments such as indigestion, gastralgia, vomiting, enterozoa etc‥² In Chinese medicine, AKS is used for digestive issues and as an anti-emetic. Officially AKS is recorded in the Korean pharmacopeia.^12,7 AKS extract could be incorporated into a variety of cosmetic products, including anti-aging, soothing, and brightening skincare products. Moreover, AKS extract reduces skin irritation and to exert a brightening effect.^13,14 A cosmetic encompassing the extract of AKS exhibits antioxidant property to be used in protecting skin from several harmful factors, such as reactive oxygen species (ROS), elastase, and hyaluronidase.¹⁴ Another AKS cosmetic product, Alpiniawhite HS (ICHIMARU PHARCOS Ltd), significantly activates the phospholipase D1 signal which is a melanin braking system. Since it exhibits a skin whitening effect, it is expected to be included in whitening agents. Moreover, the extract of AKS can be used not only in cosmetics, but also as a nutraceutical as anti-aging targeting elastase, hyaluronidase, and tyrosinase.¹⁴

2.2. Alpinia katsumadai seed in the food/food industry

In Chinese, Alpinia common names always include suffix “doukou” and their English common names sometimes include “cardamom”.¹⁵ Because of their similar shape and similar common names, Alpinia seeds have been confused with each other since ancient times.¹⁶ For all Alpinia species, a fruit is a capsule with three locules that contain numerous seeds.¹⁷ AK seed masses are hard, grayish brown, sub-spheroidal (15 × 27 mm), divided into three locules by septa, and numerous seeds agglutinated closely in each locule. Individual seed is ovoid-polyhedral (5 × 3 mm) covered with grayish-brown membranous aril, where raphe occurs as a longitudinal furrow (Fig. 2).⁴

Fig. 2.

An overview of the phytochemicals reported in Alpinia katsumadai seeds.

Compared to the more widely consumed ginger or turmeric, AK is less prevalent in the global diet. AKS could potentially offer a unique flavor profile. AKS exhibit a characteristic aromatic odor and pungent to slightly bitter taste.¹⁵ The seeds could be incorporated into spice blends for their potential to add complexity and depth of flavor. In addition to medicinal use, AKS has been used in China for centuries as spices and health-care foods. It is also widely used as a flavoring agent in food industries owing for its strong aromatic flavor, smell like cardamom attributed to cardamonin, a chalconoid that naturally occurs in cardamom spice.¹⁸ AKS is used as natural spice in several dishes in China.¹⁹ The nutritive and spicy nature of AKS has increased its commercial value and promoted its use in beverages, confectioneries, seafood, meat dishes, and pickles.⁵ AKS has been approved for use as a food additive (No. 10599903151, Taiwan in China).²⁰ With regard to the formation of acrolein (ACR), which is frequently produced in the thermal processing of food resulting in various chronic diseases in long-term exposure. Studies have demonstrated that phenolics and flavonoids with hydroxyl groups at C-5 and C-7, such as quercetin and myricetin, can effectively reduce ACR level.^21,22 However, most flavonoids cannot be widely used in food processing, being mostly susceptible to high temperatures and some are not authorized as food additives. Cardamonin and alpinetin are high-temperature-resistant ACR inhibitors due to the methoxy group at C-5.²⁰ AKS could be conveniently used in pork processing as a carrier of cardamonin and alpinetin,²⁰ and can be widely employed in processed food to impart both flavor and mitigate against ACR production. Most studies on this plant tend to focus on its potential health benefits rather than its nutritional content.

3. Phytochemistry and bioactive components of AKS

AK encompasses various compounds mostly reported in its seeds as the official part for which most of the effects and uses are attributed, contrary to other Alpinia drugs in which root and rhizome are typically used such as A. galanga.^23,24 The variation in geographical features, climatic conditions, and cultivation procedures have shown distinction in AKS phytochemical composition. More than 153 metabolites were reported in AKS including diarylheptanoids (1–58d), terpenoids (59–69), flavonoids (70–91), stilbenes (92–97), and miscellaneous metabolites (98–102), in addition to hetero-coupled compounds formed by the conjugation of diarylheptanoid, flavonoid, and terpenoids of special interest likely to attribute effect due to both moieties (Table 1, Fig. 2).²

Table 1.

List of isolated metabolites from Alpinia katsumadai seeds with reported activities and mechanism of action.

M#	Metabolite Name	Biological activities	Mechanism of action
	Diarylheptanoids
1	1,7-Bis-(4′-hydroxyphenyl)-3-hydroxy-1,3-heptadien-5-one	–	–
2	Alnustone	Antiviral activity	–
3	1,7-Bis-(4′-hydroxyphenyl)-3-hydroxy-1,3,6-heptatrien-5-one	–	–
4	1,7-diphenyl-5-hydroxy-3-heptanone	–	–
5	3,5-dihydroxy-1,7-diphenylheptane	Anti-emetic activity	–
6	(4Z,6E)-1,7-diphenyl-4,6-heptadien-3-one	Anti-emetic activity	–
6a	(4E,6E)-1,7-diphenyl-4,6-heptadien-3-one	Anti-emetic activity Antimicrobial activity	Efflux pump inhibitor
7	1,7-diphenyl-5-hydroxy-6-heptaen-3-one
8	1-(4′-hydroxyphenyl)-7-phenyl-5-Hydroxy-6-heptaen-3-one	–	–
9	(3S,5S)-trans-3,5-dihydroxy-1,7-diphenyl-1-heptene	Antiviral activity Antimicrobial activity	Efflux pump inhibitor
9a	(3R,5S)-trans-3,5-dihydroxy-1,7-diphenyl-1-heptene	Anti-emetic activity	–
10	4″ Hydroxyashabushiketol	–	–
11	1,7-Diphenyl-6(E)-hepten-3-ol	Antiviral activity	–
12	(3S, 5S) Alpinikatin	–	–
13	3-(Acetyloxy)alpinikatin	–	–
14	5-(Acetyloxy)alpinikatin	–	–
15	1,7-bis(4-hydroxyphenyl)-1,4,6-heptatrien-3-one	–	–
	Diarylheptanoid-flavonoid hybrids
16	Calyxin C	Antidiabetic activity	GPa, PTP1B/TCPTP inhibitor
16a	Epi-calyxin C
17	Calyxin T	Antiproliferative activity	–
17a	Ent-calyxin T	–	–
17b	Calyxin U	Antiproliferative activity	–
17c	Ent-calyxin U		–
17d	Calyxin V		–
17e	Calyxin W		–
18	Calyxin G	Antidiabetic activity	GPa inhibitor
18a	Epi-calyxin G
18b	Calyxin k
18c	Epi-calyxin K
19	Calyxin J	Antidiabetic activity	α-glucosidase, DPP4, PTP1B & GPa inhibitor
19a	Epi-calyxin J
20	Calyxin O	Antiproliferative activity	–
20a	Ent-Calyxin O		–
20b	Calyxin N		–
20c	Ent-calyxin N	–	–
21	Calyxin P	–	–
21a	9″-Epi-calyxin P	–	–
22	Calyxin S	–	–
22a	5-Epi-calyxin S	–	–
	Diarylheptanoid-flavanone hybrids
23	Katsumadainol B1	Antidiabetic activity	–
23a	Katsumadainol B2		–
24	Katsumadainol B6	Antidiabetic activity	GPa, PTP1B/TCPTP inhibitor
24a	Katsumadainol B7	Antidiabetic activity	GPa inhibitor
24b	Katsumadainol B8
24c	Katsumadainol B9
24d	Katsumadainol B10
25	Katsumadainol B3	Antidiabetic activity	–
26	Katsumadainol B4	Antidiabetic activity	α-glucosidase, DPP4, GPa PTP1B/TCPTP inhibitor
26a	Katsumadainol B5
27	Katsumadainol B12	Antidiabetic activity	GPa inhibitor
27a	Katsumadainol B13
28	Katsumadainol B14	Antidiabetic activity	GPa, PTP1B/TCPTP inhibitor
29	Katsumadainol B15	Antidiabetic activity	GPa inhibitor
30	Katsumadainol B11	Antidiabetic activity	–
	Diarylheptanoid-chalcone hybrids
31	Calyxin B	Antidiabetic activity	α-glucosidase & PTP1B inhibitor
31a	Epi-calyxin B
32	Calyxin H	Antidiabetic activity Cytoprotective effect	α-glucosidase & PTP1B inhibitor HSP inducer
32a	Epi-calyxin H
32b	Ent-Calyxin H	Cytoprotective effect	HSP inducer
33	Alpinnanin A	Antidiabetic activity	α-glucosidase & PTP1B inhibitor
33a	Ent-Alpinnanin A	Cytoprotective effect	HSP inducer
33b	Alpinnanin B	Antidiabetic activity Cytoprotective effect	α-glucosidase & PTP1B inhibitor HSP inducer
33c	Ent-Alpinnanin B	Cytoprotective effect	HSP inducer
34	Kastumain C	Antidiabetic activity Cytoprotective effect	α-glucosidase & PTP1B inhibitor HSP inducer
34a	Epi-Kastumain C
35	Calyxin F	Antidiabetic activity	α-glucosidase & PTP1B inhibitor
35a	Epi-calyxin F
36	6-Hydroxycalyxin F
37	Calyxin L
38	Calyxin Q	Antiproliferative activity	–
39	Calyxin R		–
40	Katsumain A	Cytoprotective effect	HSP inducer
40a	Katsumain B
41	Katsumain D	–	–
42	Katsumain E	–	–
42a	Katsumain F	–	–
43	Katsumain G	Cytoprotective effect	HSP inducer
43a	katsumain H
44	katsumadainol A1	Antidiabetic activity	α-glucosidase, PTP1B & GPa inhibitor
44a	katsumadainol A2
45	katsumadainol A3
45a	katsumadainol A4
45b	katsumadainol A5
46	katsumadainol A6
46a	katsumadainol A7
47	katsumadainol A8
47a	katsumadainol A9
48	katsumadainol A10
49	katsumadainol A11
49a	katsumadainol A12
50	katsumadainol A13
50a	katsumadainol A14
51	katsumadainol A15
51a	katsumadainol A16
52	Calyxin Y	Antiproliferative activity	–
	Diarylheptanoid-kavalactone hybrids
53	katsumadain A	Antiviral activity Anti-emetic activity	Neuraminidase inhibitor
54	katsumadain B	Anti-emetic activity	–
	Diarylheptanoid dimer
55	katsumadain C	Antiproliferative activity	–
56	katsumadainol C1	Antidiabetic activity	GLP-1 secretagogue GPa, α-glucosidase, and PTP1B inhibitor
56a	katsumadainol C2
56b	katsumadainol C3
56c	katsumadainol C4
57	katsumadainol C5
58	katsumadainol C6
58a	katsumadainol C7
58b	katsumadainol C8
58c	katsumadainol C9
58d	katsumadainol C10
	Terpene–chalcone conjugates
59	Sumadain A	Antiproliferative activity	–
60	Sumadain B		–
61	Sumadain C		–
62	Rubraine		–
62a	Isorubraine		–
63	Katsumadain	–	–
	Triterpenoids
64	2,3,22,23-tetrahydroxyl-2,6,10,15,19,23-hexamethyl-6,10,14,18-tetracosatetraene	Anti-inflammatory, Antihyperlipidemic, larvicidal activities	inhibition of IL-6-induced JAK2/STAT3, acyl-CoA acyltransferase, and sterol transport
65	2,3,5,22,23-pentahydroxy-2,6,10,15,19,23-hexamethyl-6,10,14,18-tetracosatetraene	Anti-inflammatory activity	downregulate NO, COX-2, IL-1β and IL-6
66	2,3,6,22,23-pentahydroxy -2,6,11,15,19,23-hexamethyl-7,10,14,18-tetracosatetraene	Anti-inflammatory activity	inhibition of IL-6-induced JAK2/STAT3 activity
67	2,3,6,22,23-pentahydroxy-2,10,15,19,23-hexamethyl-7-methylene 10,14,18-tetracosatriene
68	(3R,20S)-2,3,20-Trihydroxy-2,6,10,15,19,23-hexamethyl-6,10,14,18,22- tetracosapentaene	Antihyperlipidemic activity	inhibition of PCSK9 expression
69	(3R,5S)-2,3,5-trihydroxy-2,6,10,15,19,23-hexamethyl-tetracosa-6,10,14,18,22-pentaene
	Flavonoids
70	Cardamonin	Anti-inflammatory, Anti-emetic, Anti-H. pylori, Antiviral activities	induction of HO-1 expression decreased inflammatory mediators protease inhibition
71	Alpinetin	Anti-inflammatory, Anti-emetic, Anti-H. pylori activities	increase SOD & HO-1 expression decrease inflammatory mediators reduce MPO and MDA levels
72	Pinocembrin	Antimycobacterial, Anti-emetic, Anti-H. pylori, Antioxidant activities	Efflux pump inhibitor ROS scavenging
73	Pinocembrin-3,7-di-β-glucoside	Aromatase inhibitor	–
74	Pinobanksin	–	–
75	(2R,3S)-pinobaksin-3-cinnamate	–	–
76	3-O-acetylpinobanksin	–	–
77	Uvangoletin	–	–
78	Helichrysetin	Anti-tumor activity	–
79	Pinocembrin chalcone	–	–
80	(+)-catechin	Antioxidant activity	ROS scavenging
81	Myricetin	Anti-bacterial activity	–
82	7,8-Dihydroxyflavanone	–	–
83	4′,7-Dihydroxy-5-methoxy flavanone	–	–
84	Liquiritigenin	–	–
85	Naringenin	–	–
86	3-methoxykaempferol	Neuroprotective effect	–
87	Quercetin 3-O-robinobioside	–	–
88	Quercetin 3-O-(2,6-di-O-rhamnosylgalactoside)	–	–
89	Gossypetin	–	–
90	Isorhamnetin 3-O-(2,6-di-O-rhamnosylgalactoside)	Aromatase inhibitor	–
91	Rhamnocitrin-3-O-β-D-glucopyranosyl-4′-O-β-D-galactosyl-(1–3)-O-β-D-glucopyranoside	–	–
	Stilbenes		–
92	(E)-3-Methoxy-5-hydroxystilbene	Antioxidant activity	–
93	(E)-3,5-dihydroxystilbene		–
93a	(Z)-3,5-dihydroxystilbene		–
94	(E)-3,5-dimethoxystilbene		–
95	(E)-3,5-dihydroxy-4′-Methoxystilbene		–
96	(Z)-3-Methoxy-5-hydroxystilbene		–
97	(E)-1-(1-terpinen-4-olyl)-3-methoxystilbene		–
	Miscellaneous metabolites
98	katsumadin	Anti-emetic activity	–
99	5,6-Dehydrokawain	–	–
100	4′-Hydroxydehydrokawain	–	–
101	(1E,4Z)-5-Hydroxy-1-phenylhexa-1,4-dien-3-one	–	–
102	(3R)-5,6,7-trihydroxy-3-isopropyl-3-methylisochroman-1-one	Antioxidant activity	inhibited cellular apoptosis

3.1. Diarylheptanoids

Over 108 diarylheptanoids, a major secondary metabolite class in Alpinia drugs, were obtained from AKS, and account for several of its health benefits.¹ Diarylheptanoids include five characteristic subtypes: linear-diarylheptanoids, cyclic-diarylheptanoids, dimeric-diarylheptanoids, chalcone/flavanone-diarylheptanoids conjugates and novel-diarylheptanoids have been reported. Linear-diarylheptanoids and chalcone/flavanone-diarylheptanoids are the most common diarylheptanoids in AKS.^9,25 All these compounds share the same characteristic skeleton of two aromatic rings joined by a heptane chain.¹ Over 17 linear-diarylheptanoids (1-15) have been isolated from AKS (Table 1, Fig. 3). Nearly all these compounds encompass a hydroxyl or keto group at C-3, with varying degrees of unsaturation at C-1, C-4, and C-6. No cyclic-diarylheptanoids have been isolated from AKS, while they may be a conjugated part with flavonoids or chalcones.¹

Fig. 3.

Linear diarylheptanoids from Alpinia katsumadai seeds.

Many reports call chalcone/flavanone-diarylheptanoids as “calyxins”. Recently, calyxin derivatives and their epimers were found in AKS (16–52) (Table 1, Fig. 4, Fig. 5). Calyxins are Friedel-Crafts alkylation adducts, formed of diarylheptanoids and a chalcone or a flavanone moiety, the attachment typically occurs at C-5 or C-7.¹ Recently, several calyxins have been isolated after a series of chromatographic separations followed by preparative RP-HPLC.²⁶ The structures of certain calyxins, i.e., calyxin A, B, L, F, M and G, have been revised according to more spectroscopic evidence or synthetic investigations by Tian et al‥²⁷ Calyxins O, N and P (20, 20b, 21) and their isomers, are major compounds in AKS that are diarylheptanoid-flavonoid conjugates, likely to exhibit effects attributed for each moiety in such complex structures (Table 1, Fig. 4).²⁸ Katsumains A and B (40, 40a) are diasteriomers of diarylheptanoids-chalcone conjugates, differ in the absolute configuration of C-3 and C-7.²⁹ A unique chalcone-diarylheptanoid adduct, calyxin Y (52), formed via a Diels-Alder reaction with a novel carbon framework of a cyclohexene ring was reported (Table 1, Fig. 5).³⁰ Most of the calyxins were found to exhibit potential bioactivities e.g. antidiabetic, antiproliferative, and inhibitory activities against nitric oxide (NO) production.²⁶ While calyxins present promising areas in drug research, much remains to be elucidated regarding their pharmacokinetics, safety, and effectiveness.

Fig. 4.

Diarylheptanoid-flavonoid hybrids from Alpinia katsumadai seeds.

Fig. 5.

Diarylheptanoid-chalcone and kavalactone hybrids from Alpinia katsumadai seeds.

In addition, several novel diarylheptanoids with unusual skeletons were isolated from AKS, such as kavalactones-diarylheptanoids; katsumadains A and B (53, 54) (Table 1, Fig. 5).¹ An unusual katsumadain dimer; katsumadain C (55) has been isolated from AKS, one of the major monoterpenoid-kavalactone conjugated in a head-to-tail mode, likely to be biosynthesized by a [2 + 2] cycloaddition reaction of 2 ethylenic bonds between 2 katsumadain moieties.³⁰ Several dimeric-diarylheptanoids were isolated from AKS for example; katsumadainols C₁-C₁₀ (56–58d) (Table 1, Fig. 6) which represented diarylheptanoid dimers with the CA-6/CB-7 linkage.³¹

Fig. 6.

Diarylheptanoid dimers from Alpinia katsumadai seeds.

3.2. Essential oil and terpenoids

Essential oil and terpenoids are important components in Alpinia with reported pharmacological properties, such as antinociceptive, anxiolytic, antipsychotic, antimicrobial, and antioxidant attributes.¹ AKS contains no more than 1 % v/wt essential oil.¹⁵ AKS oil (AKSO) profiling using GC-MS and GC-FID analysis led to the identification of 22 monoterpenoids (84.07 %) and 20 sesquiterpenoids (8.63 %).^32,33 Major components included 1,8-cineole (19.18 %), β-pinene (11.76 %), terpinene-4-ol (10.42 %), α-thujone (10.01 %), p-cymene (9.28 %), and α-pinene (6.22 %).³⁴ In another study, AKSO appeared to be composed of esters (64.2 %), alcohols (7.3 %), sesquiterpenes (6.8 %), and monoterpenes (5.9 %), however, the principal component was methyl cinnamate (64.2 %).³³ These differences in results might be attributed to harvest time, climatic and seasonal factors, as well as duration of the storage. For example, Shi et al. reported that the major constituents of AKSO collected from Liaoning, China included farnesol (21.56 %), eucalyptol (18.32 %), α-pinene (13.24 %), and 3-carene (8.33 %).³⁵ In addition, the method of essential oil extraction is also a critical factor as the main components detected by steam distillation were terpenoids, while in supercritical-CO₂ extraction were alcohols and aromatics.³⁶ Optimization of best extraction methods for recovery of aroma compounds in AKS should be presented especially to employ green extraction methods for food applications such as supercritical fluid and ultrasound- and microwaves-assisted extraction.

Over 16 monoterpenoids including sumadain C (61), rubraine (62), and isorubraine (62a), are the main monoterpenoid-chalcone conjugates reported in AKS³⁷. Sumadains A and B (59, 60) are examples of sesquiterpene -chalcone conjugated in AKS (Table 1, Fig. 7).³⁸ There are also novel eudesmane-type cytotoxic diterpenes that were reported in AKS.¹ Acyclic triterpenoids (64–69) were isolated from AKS with anti-inflammatory activity (Table 1, Fig. 7).³⁹

Fig. 7.

Terpene-chalcone conjugates and triterpenoids from Alpinia katsumadai seeds.

3.3. Flavonoids and miscellaneous metabolites

AKS presents a rich source of several flavonoids, viz chalconoid; among them cardamomin (70) and flavanone; alpinetin (71), and pinocembrin (72) which may contribute to the plant's anti-inflammatory and antioxidant properties (Table 1, Fig. 2). Pinocembrin (72) exerts potential benefits for cognitive functions.⁴⁰ Katsumadin (98) is a rarely distributed biphenyl-epoxypropanoid in natural sources, with only one analogue has been reported from Artocarpus rigida.⁴¹ Biogenetically, katsumadin (98) may be derived from alpinetin and cardamonin by hydrogenation.⁸ Rhamnocitrin-3-O-β-D-glucopyranosyl-4′-O-β-D-galactosyl-(1–3)-O-β-D-glucopyranoside (91), and (3R)-5,6,7-trihydroxy-3-isopropyl-3-methylisochroman-1-one (102), were isolated from AKS with potent neuroprotective activity closely related to the presence of hydroxyl groups with powerful antioxidant action.⁴²

4. Extraction and identification methods

Several techniques have been explored for extraction and/or chemical profiling of phytochemicals, which include conventional and modern techniques. Maceration, percolation, soxhlet, and microwave-assisted extraction are the common extraction methods. Phytochemicals separation and identification accomplished by chromatography, spectroscopy and/or combination of chromatographic-spectroscopic techniques includes ¹D and ²D-NMR, HR-ESIMS, GC-MS, and HPLC-QTOF-MS.^27,43,44

The diarylheptanoid-flavanone/chalcone hybrids; katsumadainols B₁-B₁₅ (23–29), calyxins (31–37), and katsumadainols A₁-A₁₆, (44–51a), were isolated mainly from EtOAc extract. The dried AKS was powdered and extracted with aqueous ethanol (90 %) under reflux, concentrated under reduced pressure, and then suspended in water and partitioned with EtOAc. The EtOAc extract was chromatographed over silica gel, RP-HPLC, and chiral columns using a mixed solvent of MeOH-CHCl₃; acetone-CHCl₃, and MeCN-H₂O. Metabolites identification was established by using ¹D and ²D-NMR and HR-ESIMS. However, it was difficult to determine the absolute configurations of some calyxins. The difficulties arise from the lack of more consolidated evidence due to the co-existence of epimeric mixtures e.g., calyxin M and epi-calyxin M.²⁶ The absolute configurations were assigned by collaborative studies on single crystal X-ray diffraction analysis, Mosher's method, electronic circular dichroism, optical rotation and theoretical calculations.^9,25,26,45

Terpene-chalcone conjugates; sumadains A-C (59–61), rubraine, and isorubraine (62, 62a) were isolated from petroleum ether fraction. Briefly, AKS EtOH extract was suspended in water and partitioned using petroleum ether. The petroleum ether extract was chromatographed over a silica gel column eluting with a solvent gradient of petroleum ether/ethyl acetate, and petroleum ether/acetone, final purification was achieved using RP-HPLC.^38,37 Acyclic triterpenoids (64–69) were isolated from chloroform fraction. The AKS EtOH extract was suspended in water and partitioned with CHCl₃. The CHCl₃ layer was fractionated over silica gel column using a gradient solvent system of CHCl₃-CH₃OH. Fractions was subjected to RP-C18 silica gel column eluted with CH₃OH-H₂O followed by purification on semi-preparative HPLC using isocratic elution 70 % CH₃CN in H₂O.³⁹ Metabolites identification was established by using ¹D and ²D-NMR, and HR-ESIMS.^39,38,37

5. Biological activities of AKS extracts and its bioactive constituents

Constituents from AKS have demonstrated several biological activities. In the following subsections, the anti-inflammatory, antioxidant, antidiabetic, anti-emetic, antiproliferative, and antimicrobial activities will be discussed alongside the underlying action mechanism as reported in the literature (Table 1, Fig. 8).

Fig. 8.

Reported pharmacological activities of Alpinia katsumadai seeds.

5.1. Anti-inflammatory activity

Inflammation is an essential part of the body's defense mechanism against different harmful stimuli and usually lead to the secretion of different pro-inflammatory mediators such as interleukin (IL)-6, tumor necrosis factor (TNF)-α, prostaglandin (PG) E₂, and NO, causing inflammation symptoms as pain, edema, and fever. AKS EtOH extract (50, 100, and 200 mg/kg) remarkably decreased pro-inflammatory cytokines (TNF-α, IL-1β, and NO) levels comparable to dexamethasone (1 mg/kg) in a septic mice.⁴⁶ These findings demonstrated that AKS exhibits preventive effects on mouse sepsis induced by Cecal Ligation and Puncture (CLP), which may be attributed to elevating local defense via promoting leukocyte migration to infection focus and attenuating systemic inflammation.⁴⁶ AKS EtOH extract (5–50 μg/mL) significantly inhibited the lipopolysaccharides (LPS)-induced production of IL-6 and TNF-α, as well as the expression of iNOS. AKS extract also induced HO-1 expression in RAW264.7 cells and prevented degradation of the inhibitor nuclear factor kappa-B (NF-κB). The effects of AKS on TNF-α production were partially reversed by the HO-1 inhibitor. These results indicated that AKS and most likely its major flavonoid components; alpinetin, cardamonin, and pinocembrin may have anti-inflammatory activity via induction of HO-1 expression.⁴⁷

Anti-periodontitis effect of AKS EtOH extract on dental plaque bacteria (DPB)-induced inflammation and bone resorption was evaluated. AKS EtOH extract (10 μg/mL) suppressed Porphyromonas gingivalis growth on agar plates.⁴⁸ Moreover, AKS EtOH extract reduced levels of PGE2 and cyclooxygenase 2 (COX-2) (p < 0.05, p < 0.01 respectively) released by DPB in immortalized RAW264.7 macrophage cells, gingival fibroblasts, and human oral keratinocytes. AKS EtOH extract can regulate the expression of inflammatory factors caused by bacterial LPS, posing it as potential antibacterial and anti-inflammatory agent for preventing and controlling periodontitis.⁴⁸

Cardamonin (70) (5 mg/kg) decreased IL-1β levels from 600 ng/mL to less than 250 ng/mL comparable to indomethacin (10 mg/kg). Cardamonin also suppressed COX-2, iNOS, MDA, TNF-α, NO, and NF-κB.⁴⁹ Alpinetin (71) was reported as a promising protective agent against liver damage in both in-vitro and in-vivo assays owing to its ability to suppress inflammation caused by the hepatic I/R induced NF-κB and mitogen-activated protein kinase (MAPK) pathways.⁵⁰ Alpinetin (50 mg/kg, IV) significantly improved the survival of septic mice. Also, it attenuated CLP-induced persistent inflammation, immunosuppression, and catabolism syndrome. The level of plasma pro-inflammatory cytokines and apoptosis of T lymphocytes were decreased by alpinetin. In this clinically relevant model of sepsis, alpinetin ameliorated CLP-induced organ dysfunction and improves the likelihood of survival, possibly by suppressing the inflammatory response, oxidative stress, and apoptosis. Alpinetin (25–100 mg/kg) significantly ameliorated ovalbumin (OVA)-induced pathologic changes in the lungs. Decrease in OVA-induced levels of IL-4, IL-5, IL-13, and IgE are likely to mediate its anti-inflammatory effect.⁵¹ These findings suggested that alpinetin presents a potential novel therapeutic drug to prevent sepsis-induced PICS.⁵² Comparison of other flavonoid structures in AKS could aid identify stronger analogues.

Compared to flavonoids in AKS, acyclic triterpenoid (65) exhibited anti-inflammatory action as manifested by decreased LPS-induced NO secretion. That triterpenoid (65) exhibited multiple mechanisms of action to relieve inflammation as it significantly downregulated the secretion of NO, COX-2, IL-1β, and IL-6.⁷ In-vivo study, triterpenoid (65) (50 mg/kg, PO) significantly alleviated both mouse paw thickness and volume.⁷ Other 4 acyclic triterpenoids (64–67) were found to be effective anti-inflammatory agents via inhibition of IL-6-induced JAK2/STAT3 activity (IC₅₀ 0.67–2.99 μM).³⁹

5.2. Antioxidant activity

AK has been traditionally used for its antioxidant properties being rich in flavonoids, diarylheptanoids, and stilbenes. AKS MeOH extract showed a strong DPPH radical scavenging activity compared to resveratrol (IC₅₀ 1.6 and 4.8 μg/mL respectively). AKS MeOH extract (4 μg/mL) increased the levels of superoxide dismutase (SOD), catalase, and glutathione peroxidase enzymes (21 %, 21 %, and 28 % respectively), indicating that its effect is due to enhancement of antioxidant enzymes.¹³ AKS MeOH extract (20 and 100 μg/mL) exhibited an in-vitro protective effect against oxidative damage caused by H₂O₂ treatment, UV-C, and γ-ray irradiation, where exhibited a dose-dependent increase in cell viability (109.6 % and 172.1 % respectively).⁵³ AKS derived flavonoids: pinocembrin and (+)-catechin (72, 80) successfully mitigated glutamate-induced neurotoxicity via ROS scavenging in an in-vitro study using mouse hippocampus HT22 cells. Both flavonoids exhibited strong scavenging effects against DPPH radical in contrast to L-ascorbic acid, with IC₅₀ values of 10.43, 87.23, and 65.98 μM, respectively.⁵⁴ The underlying action mechanism was attributed to AKS ability to scavenge free radicals and protect against cell-membrane lipids peroxidation.⁵³

Alpinetin (25, 50, and 100 mg/kg, ip, 3 days) improved ulcerative colitis (UC) in dextran sulfate sodium (DSS)-induced UC in mice as manifested by a decline in myeloperoxidase (MPO) and malondialdehyde (MDA) levels, likewise increase in SOD activities, which are commonly known as markers of oxidative stress.⁵⁵ Alpinetin is associated with decreased intestinal inflammation and oxidative stress and regulates the expression of tight junctions between cells in UC mice. These results may shed light on the use of alpinetin in the treatment of UC.⁵⁵ In another report, alpinetin with the same treatment protocol significantly attenuated diarrhea, colonic shortening, histological injury, MPO activity, and the expressions of TNF-α and IL-1β production in DSS-induced mice colitis model. In vitro, alpinetin markedly inhibited Toll-like receptor 4 (TLR4) mediated NF-κB and NOD-like receptor protein 3 (NLRP3) inflammasome activation.⁵⁶ Based on these findings, alpinetin may be a promising therapeutic agent for colitis treatment and has yet to be tested in clinical trials.

Allergic asthma is the most common type of asthma, which is characterized by inflammatory responses of the airways. AKS extract exerted marked reduction in ROS levels found in bronchoalveolar lavage fluid of mice suffering from OVA-induced asthma.⁵¹ Moreover a chroman derivative; (3R)-5,7-dihydroxy-3-isopropyl-3-methylisochroman-1-one exhibited a potent therapeutic effect against allergic asthma.⁵⁷ Another chroman metabolite 102 increased the viability of PC12 cells and inhibited cellular apoptosis in MPP ⁺ - induced oxidative stress model, closely related to the presence of hydroxyl groups with powerful ROS-scavenging ability.⁴²

5.3. Antidiabetic activity

Lee et al. reported that AKS EtOH extract showed α-glucosidase inhibitory activity with (IC₅₀ 25 μg/mL).⁵⁸ The AKS EtOH extract (200 mg/kg, 4 weeks) was revealed with hypoglycemic effects on mice by decreasing blood glucose level, alongside improving oral glucose tolerance tests (OGTT) and insulin tolerance test (ITT) conditions.⁴⁵ The diarylheptanoid-chalcone hybrids from AKS EtOAc extract; calyxin B (31), epicalyxin B (31a), calyxin H (32), epi-calyxin H (32a), alpinnanin A (33), alpinnanin B (33b), katsumain C (34), and epi-katsumain C (34a), calyxin F (35), epicalyxin F (35a), 6-hydroxycalyxin F (36), calyxin L (37), and katsumadainols A₁-A₁₆ (44–51a) were reported to exhibit a significant antidiabetic action as manifested by their dual inhibition of α-glucosidase (at 50 μM) and protein tyrosine phosphatase 1 B (PTP1B) (at 200 μM) (IC₅₀ 22.0–96.7 μM). Furthermore, these compounds demonstrated selective inhibition of PTP1B/TCPTP (at 200 μM). In addition, α-glucosidase inhibition of these calyxins ranged from IC₅₀ 2.9–29.5 μM, at ca. 6–59 times more active than the standard drug acarbose (IC₅₀ 170.9 μM).⁴⁵ Katsumadainols (44–51a) (200 μmol/L) exhibited glycogen phosphorylase a (GPa) inhibition (IC₅₀ 10.1–95.4 μmol/L) and demonstrated dipeptidyl peptidase 4 (DPP4) inhibition (50.0–54.2 inhibitory %).⁴⁵ Further examination using in vivo models should be pursued to confirm their antidiabetic action, or better in clinical trials.

The AKS EtOAc extract (200 and 100 μg/mL) showed significant inhibition of GPa (97.9 % and 64.6 %, respectively).²⁵ Diarylheptanoid-flavanone hybrids, katsumadainols B₄-B₁₀ (26, 26a, 24, 24a-d), B₁₂-B₁₅ (27, 27a, 28–29) and calyxin J (19), epi-calyxin J (19a), calyxin G (18), epi-calyxin G (18a), calyxin K (18b), and epi-calyxin K (18c) exhibited a potent activity against GPa (IC₅₀ 10.1–95.4 μmol/L); calyxin C (16), epi-calyxin C (16a), and katsumadainols B₄-B₆ (26, 26a, 24), and B₁₄ (28) were identified as selective PTP1B/TCPTP inhibitors (IC₅₀ 40.7–95.8 μmol/L). Calyxin J (19), epi-calyxin J (19a), and katsumadainols B₄-B₅ (26, 26a), with a p-hydroxybenzyl at C-6 position, represent a promising class of multiple-target antidiabetic agents inhibiting α-glucosidase obviously higher than acarbose (IC₅₀ 7.2, 8.3, 7.1, 12.4, and 209.1 μmol/L respectively), and to likewise inhibit DPP4 (50.0–54.2 %, at 200 μmol/L), GPa, and PTP1B.²⁵ Another study targeting antidiabetic action revealed that the diarylheptanoid dimers, katsumadainols C₁-C₁₀ (56–58d) stimulated the secretion of glucagon-like peptide 1 (GLP-1) in a dose-dependent manner. GLP-1 is an incretin hormone that can stimulate insulin and reduce glucagon secretions.⁵⁹ Currently, most GLP-1 receptor agonists are peptide analogues with the drawbacks of high cost and GIT and pancreatic side effects.⁶⁰ Katsumadainols C₁-C₄ (56–56c) are intriguing GLP-1 secretagogues and also GPa, α-glucosidase, and PTP1B inhibitors, which provided valuable clues for searching multiple-target antidiabetic candidates. Katsumadainols C₁-C₁₀ (56–58d) exhibited significant inhibition on GPa (IC₅₀ 18.0–31.3 μM); inhibit α-glucosidase (IC₅₀ 6.9–18.2 μM); and possessed PTP1B inhibitory activity (IC₅₀ 35.5–80.1 μM).³¹ All these findings proved that katsumadainols A, B, and C could be promising candidates for treating diabetes with multiple action mechanisms. Co-administration of these katsumadainols with standard diabetic drugs such as metformin should aid in lowering their dose and likewise provide a stronger drug regimen for diabetes management. In silico docking studies of these hybrid molecules against PTP1B/TCPTP should explain their interaction with such cellular target and aid in designing more active analogues.

5.4. Anti-emetic activity

Diarylheptanoid-kavalactone hybrids; katsumadains A and B (53, 54) (50 mg/kg) showed anti-emetic action with 50.2 % and 41.4 % inhibition, respectively on copper sulfate-induced emesis in young chicks.⁶¹ From linear diarylheptanoids (2, 6,7, 9, 9a) (50 mg/kg), the anti-emetic activity was reported in structures that contain A type functional unit (Arylpenten-3-one or Arylpenten-3-ol) as in 1,7-diphenyl-4,6-heptadien-3-one (6), or in structures which contain B type functional structure (5-hydroxy-arylpentan-3-one or 5-hydroxy-arylpentan-3-ol) as in (5R)-E-1,7-diphenyl-5-hydroxy-6-hepten-3-one (7), (3S, 5S)-E-3,5-dihydroxy-1,7-diphenyl-1-heptene (9), and (3R,5S)-E-3,5-dihydroxy-1,7-diphenyl-1-heptene (9a).⁶² The metabolites that contain neither A nor B type functional structure as (E, E)-1,7-diphenyl-5-hydroxy-4,6-heptadien-3-one (2) showed no anti-emetic effects. These results revealed that A and B-type functional structures are the essential structural parts of the metabolites to show anti-emetic activity.⁶² Other metabolites, katsumadin (98), cardamonin (70), and pinocembrin (72) showed significant antiemetic activities in a dose-effect relationship (20–100 mg/kg).⁸

5.5. Cytotoxic and antiproliferative activities

Isolated compounds from AKS demonstrated chemotherapeutic effects posing them as candidates in cancer management. Calyxins T-W, O, N, Q, and R (17, 17b, 17d-e, 20, 20b, 38, 39) and ent-calyxin U, O (17c, 20a) showed promising antiproliferative activities against NCI-H460, HeLa, SMMC-7721 and HCT-116 cell lines (IC₅₀ 12.7–42.2 μM).^26,28 Katsumadain C (55) and calyxin Y (52) exhibited significant growth inhibitory effects against SMMC-7721 cells, comparable to 5-fluorouracil (IC₅₀ 4.8, 9.7, and 26.8 μM respectively).³⁰ Unique terpene–chalcone conjugates; sumadains A and B (59, 60), rubraine and isorubraine (62, 62a) were found to exert a weak cytotoxic action.³⁸ However, in another study, sumadain C (61) showed potent activity against HepG2, MCF-7, and MAD-MB-435 cell lines (IC₅₀ 13.00, 15.93, and 12.78 μg/mL, respectively).³⁷ The hydroxyl substituted chalcones exhibited varying degrees of anticancer properties, whereas introduction of bulky groups at positions C-2′ and C-3′ led to a reduction of antileishmanial activity, also bulky substituents at C-4′ decreased the cytotoxicity of chalcones against leukemia cell line. Therefore, loss of cytotoxicity may be attributed to the etherification of hydroxyls and hindered rotation of sumadains A and B (59, 60) due to the bridges formed between sesquiterpene and chalcone, which was absent in sumadain C (61) where hydroxyl group at C-4′ is not substituted.³⁸

AKS was reported as potential chemotherapeutic agent mediated via inhibition of migration and invasion of pancreatic cancer by down-regulating the expression of proteins downstream of PI3K/Akt/mTOR signal pathway.⁶³ AKS MeOH extract (10, 20, 40, 80 and 160 μg/mL) displayed potent inhibitory effect on the proliferation of pancreatic cancer cells PANC-1 and PANC-28 (IC₅₀ 23.9 ± 0.7 and 25.8 ± 0.3 μg/mL respectively). Cardamonin (70) exhibited an in-vitro anti-tumor effect against both leukemia (K562) and human hepatoma (SMMC-7721) cell lines (IC₅₀ 3.2 and 3.5 mg/L, respectively).⁶⁴ Cytotoxic action appeared to be mediated in part via its ability to induce cell apoptosis and autophagy in pancreatic cancer.

5.6. Antibacterial activity

Campylobacter jejuni is the most common cause of bacterial food-borne diarrheal illnesses worldwide. Adhesion to the gut epithelium is a prerequisite in its pathogenesis. MIC for AKS EtOH extract and hydrodistillate of the residual (HD-R) were 0.5 and 0.25 mg/mL, respectively. Adhesion of C. jejuni to pig (PSI) and human fetal (H4) small-intestine cell lines was significantly decreased at lower concentrations (0.2–50 μg/mL). In the same concentration range, the invasiveness of C. jejuni in PSI cells was reduced by 45 %–65 %. The HD-R represents a bioactive waste with a high phenolic content and an anti-adhesive activity against C. jejuni and thus has the potential for use in pharmaceutical and food products.⁶⁵ In another comparative study, AKS EtOH extract was the most effective against multi-resistant C. jejuni and C. coli (MIC 0.256–4.103 mg/mL).⁶⁶

Furthermore, AKS phenolic and post-distillation extracts showed moderate antimicrobial activity against food-related bacterial C. jejuni (MIC 125–500 μg/mL), while S. aureus was more resistant. The resistance-modifying activity of extracts was identified by assessing the modulation factor (MF) of MIC when combined with antibiotics like ciprofloxacin and erythromycin. AKS extracts exhibited modulatory activity in combination with all antimicrobials. The post-distillation extract and essential oil showed mean MF values of 34 and 78, respectively for all antimicrobial combinations on C. jejuni. In the case of S. aureus, the phenolic extract, essential oil, and post-distillation extract showed MFs of 63, 40, and 22, respectively. These findings indicate that essential oil was the best modulator for C. jejuni, while the phenolic extract was the best for inhibition of S. aureus.⁶⁷

Efflux pumps are one of the well-established mechanisms that contribute to antibiotic resistance in bacteria, therefore efflux pump inhibitors are an attractive target in antimicrobial therapy. As for the multidrug-resistant Mycobacterium smegmatis, three diarylheptanoids; (E,E)-1,7-diphenyl-4,6-heptadien-3-one (6a), (5R)-E-1,7-diphenyl-5-hydroxy-6-hepten-3-one (7), and (3S,5S)-E-1,7-diphenyl-3,5-dihydroxy-1-heptene (9) and flavonoid; pinocembrin (72) did not show efficacy as manifested by their high MIC value (≥64 mg/L), suggesting for their weak antimycobacterial activity.⁶ However, they showed potential to be used as ethidium bromide efflux inhibitor as well as decreasing MIC of rifampicin, as a standard antimycobacterial drug indicating that they can synergize rifampicin action.⁶ Alpinetin (71), cardamomin (70), and pinocembrin (72) demonstrated broad-spectrum activity against H. pylori (MIC 1.25 μgmL^-1, 2.56, and 0.32 mg/mL, respectively). The metabolites also inhibited S. aureus, S. epidermidis, and E. coli (MIC 0.12–2.55 mg/mL). Antibacterial activity of cardamonin (70) and alpinetin (71) against E. coli and S. aureus (MIC 0.2 mg/mL) increased upon co-administration with ACR, a toxin formed during food thermal processing, indicating that they have dual effects including clearing ACR and enhancing antibacterial effects.⁶⁸ Acyclic triterpenoid (64) was effective against P. xylostella and M. separata larvae (LC₅₀ 2 and 16.9 μg/mL respectively).⁶⁹ Although AKS EtOH extract was devoid of direct bactericidal activity, it facilitated peritoneal bacteria clearance and increased leukocyte migration into the peritoneal cavity of septic mice. The decrease in the number of bacterial colony units by AKS (50, 100, and 200 mg/kg) was at 7.4, 25.0, and 31.3 %, respectively.⁴⁶

5.7. Antiviral activity

Recent studies reported that different extracts of AK possessed antiviral activity. In a comparative study, AKS EtOH, Aq., and MeOH extracts inhibited rotavirus infection (EC₅₀ 8.4, 6.5, and 8.4 μg/mL, respectively) moreover, AKS extracts completely inhibited rotavirus adsorption onto human RBCs (<11 μg/mL) attributed mainly to having a strong interaction with hemagglutinin protein on the outer surface of rotavirus, resulting in blockage of viral adsorption.⁷⁰ Lee et al. reported that AKS MeOH extract showed antiviral activity (IC₅₀ 25 μg/mL) against Newcastle disease virus-infected baby hamster kidney cell lines. The underlying mechanism appeared to be mediated via α-glucosidase inhibition which led to suppression of the cell-surface expression of hemagglutinin-neuraminidase glycoprotein thus inhibiting syncytium formation.⁵⁸ Polar AKS extracts were shown to be the most effective by performing a dual mechanism of action via inhibition of both viral attachment and replication.

Neuraminidase (NA) inhibitors are potential targets to fight against influenza. Significant in vitro NA inhibitory activities against human influenza virus (H₁N₁) have been observed by katsumadain A (53). It was reported to exhibit antiviral activity against four H₁N₁ subtype swine influenza A viruses (IC₅₀ 0.9–1.64 μM), also showed antiviral effects in plaque reduction assays.¹¹ Katsumadain A (53) considerably differs from known active NA inhibitors in terms of shape and size, which makes the exploration of the binding mode of this class of inhibitors interesting for detailed modeling studies. Moreover, the rigidity of katsumadain A makes it the best choice for docking studies to derive a binding hypothesis and to be considered in drug design of more effective drugs.¹¹ Cardamomin (70) was found to be the most potent against human adenovirus infection (EC₅₀ 4 μM) after screening 1813 approved drugs and 556 in traditional Chinese medicine. Efficacy was manifested being the only drug that demonstrated both in-vitro and in-vivo antiviral activities.⁷¹ The mechanism of antiviral action of cardamomin appeared to be mediated via protease inhibition in HIV-1 virus (IC₅₀ 115 μM), while significantly inhibited dengue virus by 71 %.⁷²

5.8. Miscellaneous pharmacological activities

Acyclic triterpenoids; (68, 69) (5 and 10 μM) showed effective hypolipidemic action against LDL cholesterol via inhibiting the Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) mRNA expression and secretion in-vitro.⁷³ Another acyclic triterpenoid (64) showed a potential hyperlipidemic effect. It inhibited a key liver enzyme that forms cholesterol ester, which is acyl-CoA: cholesterol acyltransferase, compared with pyripyropene A (IC₅₀ 47.9 μM and 70 nM respectively).⁷⁴ Determination of its effect against HMG-CoA reductase should now follow as it is the main target in cholesterol production. Additionally, in the human hepatocyte HepG2 cell line, it reduced cholesteryl ester formation (IC₅₀ 26 μM).⁷⁴

Heat shock Ecription factor 1 (HSF1) plays a key role in the cellular response that leads to the expression of heat shock protein (HSP) genes under stress conditions. HSPs have cytoprotective effects in neurodegenerative diseases and cellular damage. Three isomer mixtures of diarylheptanoid-chalcone hybrids; calyxin H, epicalyxin H, ent-calyxin H and ent-alpinnanin A, alpinnanin B, ent-alpinnanin B and katsumain C, 7-epi-katsumain C (32, 32a-b and 33a-c, and 34–34a, at 1 μM) increased expression of HSF1 (1.43-, 1.19-, and 1.31-fold, respectively), which was accompanied with increased expression of HSP27 (1.40-, 1.25-, and 1.27-fold respectively) and HSP70 (1.37-, 1.31-, and 1.22-fold, respectively) without cellular cytotoxicity.⁹ In the same manner, katsumains G and H (43, 43a) increased the expression of HSF1 (1.05- and 1.20-fold, respectively), HSP27 (1.31- and 1.24-fold, respectively), and HSP70 (1.23- and 1.27-fold, respectively), without increased cytotoxicity, suggesting possible cytoprotective agents for the treatment of damaged organs as HSP inducers.⁷⁵

AKSO significantly reduced diarrhea scores and intestinal damage induced by 5-fluorouracil (5-FU)-induced intestinal mucositis in mice. Also, AKSO upregulated the abundance of Lactobacillus in the gut and suppressed cortisol synthesis and secretion and arachidonic acid metabolism, downregulated the expressions of PGE2, microsomal PGE synthase-1 (mPGES-1), and PGE2 receptor EP4, as well as upregulated the expression of glucocorticoid (GC) receptor (GR), leading to improved intestinal epithelial barrier function. AKSO elicited protective effects against 5-FU-induced mucositis by regulating the expressions of tight junction proteins via modulation of GC/GR and mPGES-1/PGE2/EP4 pathway.⁷⁶ The AKSO possessed potential insecticidal activities against T. castaneum, L. serricorne, and L. bostrychophila (LD₅₀ 52.6, 17.4 μg/adult, and 35.6 μg/cm², respectively). Methyl cinnamate was the main contributor to insecticidal activity (LD₅₀ 5.0, 2.2 μg/adult, and 23.5 μg/cm², respectively). AKSO exhibited strong repellent activity, even at low concentrations, providing a basis of the development as a biopesticide for the control of insects.³³

Repeated administration of AKS extract (50 mg/kg) in a gerbil in-vivo model of transient cerebral ischemia showed an effective reduction in the oxidative damage of the hippocampal neurons that usually accompanies ischemia. This effect was related to the upregulation of Cu, Zn-SOD immunoreactivity and its protein level that was observed to be 1.7 folds more in AKS extract administered ischemia group compared to the vehicle-ischemia group.⁷⁷ Additionally, (3R)-5,6,7-trihydroxy-3-isopropyl-3-methylisochroman-1-one (102) (1, 3, and 10 μM) exhibited potent neuroprotective activity on 1-methyl-4-phenylpyridinium-induced oxidative damage in PC12 cells.⁴² Based on these promising results, the effect of AKS on neurodegenerative diseases mediated via oxidative action such as Alzheimer should be examined in the future.

Atopic dermatitis (AD) is a chronic itchy, inflammatory skin dermatitis that is extremely difficult to treat. It is one of the most common chronic skin diseases, affecting up to 25 % of children in most countries of the world. In in-vivo AD caused by house dust mites, AKS MeOH extract (2–50 μg/mL) reduced the histological manifestations of AD-like skin lesions such as erosion, hyperplasia, and inflammatory cell infiltration on the mice skin after 4 weeks treatment. Also, plasma levels of IgE and histamine were lower in mice treated with AKS.⁷⁸ Furthermore, alpinetin (25–100 mg/kg) prevented inflammatory responses in OVA-induced allergic asthma via modulating PI3K/AKT/NF-κB and HO-1 signaling pathways in mice which could be used as a promising drug for allergic asthma.⁵¹

6. Conclusions

All data demonstrated that Alpinia katsumadai is one of the valued condiments in genus Alpinia and has a long history of being used as folk medicine for digestive issues and as an antiemetic. A. katsumadai potential biological effects are attributed for complex chemical composition. Most of these chemicals were derived solely from the seeds as the most investigated part warranting for the investigation of other organs. More than 153 compounds were identified in AKS including diarylheptanoids, terpenoids, flavonoids, stilbenes, and miscellaneous compounds. Most of the bioactive compounds usually possess novel chemical structures and show multiple health effects. Calyxins and katsumadainols A, B, and C are diarylheptanoid-chalcone/flavanone hybrids, and are characteristic components of AKS of potential for treating diabetes with multiple action mechanisms, yet to be tested for their prediabetic action or in clinical diabetic models. Furthermore, AKS crude extract and their chemical constituents were found to possess various biological activities, mainly anti-inflammatory, antioxidant, antidiabetic, anti-emetic, antibacterial, and anticancer activities both using in-vivo and in-vitro assays.

Although Alpinia katsumadai contributed a diverse array of bioactive compounds, its potential remains virtually untapped. In addition, new formulation and preparation techniques should be explored to obtain a higher yield of isolated compounds, improve their bioavailability, and potentiate their biological effects aided by in-silico drug design and modern cheominformatic tools. Importantly, the action mechanisms of isolates should be elucidated to design appropriate isolation methods suiting their best recovery. We hope this review points out the underscored value of A. katsumadai seed and provides leads for future studies into the genus Alpinia.

Author contributions

Methodology and Writing draft manuscript, A.E.E and L.K.; Artwork & schemes, A.E.E; Review & Editing, A.E.E and M.A.F.; Conceptualization, Validation, Supervision, M.A.F. All authors have read and agreed to the published version of the manuscript.

Ethical approval

Not applicable.

Funding

This research received no specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Abbreviation

Abbreviations/symbols Full form

¹D, ²D-NMR

one-two dimension-nuclear magnetic resonance

5-FU

5-fluorouracil

ACR

acrolein

AD

atopic dermatitis

AK

Alpinia katsumadai Hayata

AKS

Alpinia katsumadai Hayata seed

AKSO

Alpinia katsumadai seed oil

CLP

cecal ligation and puncture

COX-2

cyclooxygenase 2

DPP4

dipeptidyl peptidase 4

DPPH

2,2-diphenyl-1-picrylhydrazyl

DSS

dextran sulfate sodium

EtOAc

ethyl acetate

FID

flam ionization detector

GC

gas chromatography

GC

glucocorticoid

GLP-1

glucagon-like peptide-1

GPa

glycogen phosphorylase a

GR

glucocorticoid receptor

H₁N₁

human influenza virus

HPLC

high performance liquid chromatography

HSF1

Heat shock Ecription factor-1

HSP

heat shock protein

IL

interleukin

LPS

lipopolysaccharides

ITT

insulin tolerance test

MDA

malondialdehyde

MeOH

methanol

MF

modulation factor

MIC

Minimum inhibitory concentrations

mPGES-1

microsomal PGE synthase-1

MPO

myeloperoxidase

MS

mass spectrometry

NA

neuraminidase

NF-κB

nuclear factor kappa-B

NLRP3

NOD-like receptor protein-3

NO

nitric oxide

OGTT

oral glucose tolerance tests

OVA

ovalbumin

PCSK9

Proprotein Convertase Subtilisin/Kexin-9

PG

prostaglandin

PTP1B

protein tyrosine phosphatase 1 B

ROS

reactive oxygen species

SOD

superoxide dismutase

TLR4

Toll-like receptor 4

TNF

tumor necrosis factor

UC

ulcerative colitis