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Review

Callyspongia spp.: Secondary Metabolites, Pharmacological Activities, and Mechanisms

by
Yuni Elsa Hadisaputri
1,*,
Annida Adha Nurhaniefah
1,
Sendi Sukmara
1,
Ade Zuhrotun
1,
Rini Hendriani
2 and
Iyan Sopyan
3
1
Department of Pharmaceutical Biology, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor 45363, Indonesia
2
Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor 45363, Indonesia
3
Departement of Pharmaceutics and Technology of Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor 45363, Indonesia
*
Author to whom correspondence should be addressed.
Metabolites 2023, 13(2), 217; https://doi.org/10.3390/metabo13020217
Submission received: 19 December 2022 / Revised: 27 January 2023 / Accepted: 30 January 2023 / Published: 1 February 2023
(This article belongs to the Special Issue Extraction, Characterization, Chemical Composition and Biological Activity of Natural Metabolites)
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Abstract

:
One of the most widespread biotas in the sea is the sponge. Callyspongia is a sponge genus found in the seas, making it easily available. In this review, the pharmacological activity and mechanism of action of the secondary metabolites of Callyspongia spp. are addressed, which may lead to the development of new drugs and targeted therapeutic approaches. Several scientific databases, such as Google Scholar, PubMed, ResearchGate, Science Direct, Springer Link, and Wiley Online Library, were mined to obtain relevant information. In the 41 articles reviewed, Callyspongia spp. was reported to possess pharmacological activities such as cytotoxicity against cancer cell lines (36%), antifungal (10%), anti-inflammatory (10%), immunomodulatory (10%), antidiabetic and antiobesity (6%), antimicrobial (8%), antioxidant (4%), antineurodegenerative (4%), antihypercholesterolemic (2%), antihypertensive (2%), antiparasitic (2%), antiallergic (2%), antiviral (2%), antiosteoporotic (2%), and antituberculosis (2%) activities. Of these, the antioxidant, antituberculosis, and anti-inflammatory activities of Callyspongia extract were weaker compared with that of the control drugs; however, other activities, particularly cytotoxicity, show promise, and the compounds responsible may be developed into new drugs.

1. Introduction

The ocean, which covers 71% of the earth’s surface, regulates our climate and contains abundant resources [1]. The sea encompasses a large area, but it is well connected, and the temperature is less extreme compared with that on land. Although containing more biodiversity, only 16% of all species have been identified [2].
One of the most ubiquitous sea organisms is the sponge. Sponges are often abundant in shallow water habitats, making them a unique biodiversity component [3]. They are one of the most diverse sessile organisms, with approximately 8876 valid species identified worldwide. Each has its unique characteristics, while some features are shared [4].
Callyspongia belongs to the family Callyspongidae. More than 60 species are widely distributed in the tropical sea [5]. It is also found in the Indian, Western Atlantic, and Eastern Pacific oceans, including Indonesia [6], the Red sea [7,8], Cuba [4], Barbados [9], Brazil [10,11], and Ecuador [12]. At a depth of 6–10 m below sea level, Callyspongia spp. can live under coral reefs, ranging from moderate to damaged conditions, or in habitats dominated by hard coral, sand, and coral rubble [13].
Sponges from the Callyspongia genus are formed from primary, secondary, and tertiary spongin fibers [4]. Callyspongia sponges are encrusting, form a single erect branch or a mass of round branches, and many are bifurcated. The longest branch that has been observed is approximately 40 cm. The branches are approximately 100–150 mm in diameter and have oscula or excretory organs that are slightly elevated, numerous, scattered throughout, and 0.5–2 mm in diameter. When pressed or cut, Callyspongia spp. secrete mucus. They have a smooth surface [14]. Skeletal fractions, such as spicules and cell debris, constitute 69.8% of the biomass of Callyspongia spp., the spongy cells (choanosomes) comprise 18.8%, and bacterial pellets account for 11.3%. The skeleton fraction dominates the biomass, resulting in the stiffer morphology of Callyspongia sponges [13].
The morphology of the callyspongia species varies. For example, Callyspongia (Cladochalina) aerizusa (Figure 1e) and Callyspongia (Siphonochalina) siphonella (Figure 1a) have a tubular and clustered form, but with different colors, tubes, and oscula size. Callyspongia aerizusa has a green–orange color, whereas Callyspongia siphonella has pale lavender color. There are also species with varying forms, such as Callyspongia (Cladochalina) diffusa (Figure 1b), which has a dull champagne pink or purplish-pink color, long or short thick cylindrical branches that vary from fanlike to upright or irregular [15]. Other species have unlikely forms, Callyspongia samarensis is called a spaghetti sponge because of its forms (Figure 1d) [16]. The color of Callyspongia spp. also varies with bright colors, such as Callyspongia truncate (Figure 1c), or deep colors like Callyspongia aerizusa.
Sponges are a potential repository of new drugs. There are several drugs originating from sponges that have entered clinical trials and approved, including cytarabine (Ara-C) for cancer treatment and vidarabine as an antiviral [17]. In addition, Eribulin mesylate (E7389) is an anticancer drug that is undergoing clinical phase 3 testing [18,19] Gemcitabine (GEM) (Gemzar) is an anticancer agent which has entered clinical phase 2 [20], whereas IPL576,092 (contignasterol derivative) is an anti-inflammatory compound that has entered clinical phase 2 testing [21]. PM-10450 (Zalypsis®) [22], discodermolide, HT1286 (hemiasterlin derivative), LAF389 (bengamide B derivative), hemiasterlin (E7974), KRN7000 (agelasphin derivative) [23], PM-060184 [24], and NVP-LAQ824 (psammaplin derivative) have entered clinical phase 1 trials as anticancer drugs [25].
Other pharmacological activities of sponge compounds include antibacterial, antihyperlipidemic, antiproliferative, immunomodulatory, and anti-inflammatory effects have been reported, including Callyspongia spp. [26,27]. Sponges contain multiple primary and secondary metabolites, such as fatty acids, alkaloids, steroids, nucleotides, peptides, polyacetylenes, and terpenoids. A total of 212 compounds have been isolated from Callyspongia spp. and their structures and bioactivities have been presented [28].
This review summarizes the potential pharmacological activities exhibited by Callyspongia spp. compounds that may be developed into new drugs. We also discuss the related mechanisms that may contribute to targeted therapy.

2. Materials and Methods

The literature review of Callyspongia spp. was based on topics related to pharmacological activity and the mechanism of action of secondary metabolites contained therein. This review was conducted with a qualitative and quantitative approach to obtain information from several scientific databases, including Google Scholar, PubMed, ResearchGate, Science Direct, Springer Link, and the Wiley Online Library. Several keywords, such as “Callyspongia sp.”, “metabolites”, and “pharmacology activity”, were used to procure relevant resources. The inclusion criterion for selecting articles was that they should describe the isolation and functional studies of secondary metabolites from Callyspongia sponges. Articles describing the isolation and activities of fungi or bacteria in Callyspongia species were excluded. The abstracts were carefully read to identify and select relevant articles. From 72 identified articles after screening information sources, 41 published between 1980 and 2021 were selected and reviewed (Figure 2).

3. Results

Sixteen pharmacological activities have been reported for Callyspongia spp. These activities along with their descriptions are listed in Table 1.

4. Discussion

We have discussed the pharmacological activities of Callyspongia spp. that have been previously reported.

4.1. Antidiabetic, Antihypercholesterolemic, and Antiobesity

The active compound from Callyspongia truncata, callyspongynic acid (Figure 3), shows higher antidiabetic activity by inhibiting α-glucosidase with an IC50 of 0.25 μg/mL [29,30] compared with acarbose (IC50 1.3 μg/mL) [70]. Inhibiting this enzyme reduces caloric intake by attenuating appetite, suppressing hunger, and increasing satiety [71,72], thereby supporting weight loss [73] to a moderate level [74]. It is also one of the targets of diabetes therapy. Compared with α-amylase, inhibiting α-glucosidase can improve hyperglycemia, especially postprandial hyperglycemia, by decreasing glucose production (Figure 3) [75].
Compounds, such as callyspongiamide A and B as well as disamide A (Figure 3), exert antihypercholesterolemic activity, which can also lead to an antiobesity effect by inhibiting sterol O-acyltransferase (SOAT), the enzyme that catalyzes the formation of cholesteryl ester [76]. In addition, other sterols may be used as activators or substrates of this enzyme [77], which implicates it as a potential drug target [61] in hypercholesterolemia; however, the underlying mechanism remains unknown.
In a cell-based testing assay, the IC50 values of callyspongiamide A against SOAT 1 and SOAT 2 were 0.78 ± 0.19 and 2.8 ± 0.72 μM, those of callyspongiamide B were 1.2 ± 0.31 and 2.4 ± 0.96 μM, whereas those of disamide A were 5.2 ± 0.93 and 4.2 ± 0.76 μM. Although each compound markedly inhibited SOAT 2, as evidenced by the lower IC50 compared with the control beauveruolide III (IC50 > 20 μM), only callyspongiamide A significantly inhibited SOAT 1 [5].
Callyspongia sp. also contains β-Sitosterol. This compound exhibits potent antidiabetic activity related to insulin receptor activation and increased glucose transporter 4 (GLUT-4) translocation to adipose tissue [78,79]. In addition, these compounds can potentially maintain glucose homeostasis through sensitization of insulin resistance by increasing the expression of peroxisome proliferator-activated receptor and GLUT-4 (Figure 4) [80]. Another study on HFD-fed and sucrose-induced type-2 diabetic rats indicates that β-Sitosterol enhances the glycemic regulation [32,79].
The methanolic extract of Callyspongia samarensis also exerts antidiabetic activity by enhancing the activity of AMP-activated protein kinase (AMPK) with an EC50 of 14.47 μg/mL, which is more potent compared with the positive control aspirin (EC50 100 μg/mL). This activity may originate from compounds with phenolic groups in the extract [31]. AMPK is an important target for treating type-2 diabetes because its activation affects various aspects of cellular metabolism. It increases glucose metabolism, uptake in the bone and muscle, fatty acid oxidation in the bone, muscle, and liver, mitochondrial oxidative capacity, and insulin sensitivity, whereas it decreases fatty acid synthesis in the liver through GLUT-4 expression (Figure 4) [81,82,83,84].

4.2. Antihypertensive

Callypyrone A and callypyrone B (Figure 3) from Callyspongia diffusa exhibit antihypertensive activity by inhibiting angiotensin I-converting enzyme (ACE), which leads to a reduction in angiotensin production. Because angiotensin can constrict blood vessels and increase the heart work rate [85], ACE inhibition results in vasodilation and a decrease in blood pressure (Figure 5). The IC50 values of these two compounds against ACE were 0.48 mM and 0.57 mM, respectively [33], weaker than the standard drug, captopril (IC50 0.36 mM) [33]. From the results, Callypyrone A and callypyrone B are not considered antihypertensive.

4.3. Anti-Inflammation

Diketopiperazines derived from Callyspongia sp., such as cyclo(L-Hyp-L-Ala), cyclo(L-Pro-Gly), cyclo(L-Pro-Phe), and cyclo(L-Pro-Ala), at a concentration of 5 µg/mL, showed anti-inflammatory activity by increasing the secretion of the anti-inflammatory cytokine, interleukin-10 (IL-10) (Figure 6). IL10 levels were increased by 1.65-, 1.29-, 1.54, and 1.56-fold in J774A.1 cells, respectively [36].
The anti-inflammatory activity of β-Sitosterol is independent of the adrenal pituitary axis. It inhibits the maturation of IL-1β via the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome and inhibits other inflammatory cytokines, such as IL-6 and tumor necrosis factor-α [86]. In a carrageenin-induced edema model in bilaterally adrenalectomized rats, β-Sitosterol exhibited a 54% anti-inflammatory effect at a dose of 320 mg/kg, which was weaker than the control, oxyphenbutazone, which had a 74% anti-inflammatory effect at a dose of 100 mg/kg [37]. Therefore, β-Sitosterol has no potential as an anti-inflammatory agent.
Niphatoxin C significantly affects the viability of pre-monocytic THP 1 cells, which express the P2X7 receptor [65]. Activation of this receptor promotes inflammation by releasing inflammatory cytokines, such as IL-18 and IL-1β, and by activating the NLRP3 inflammasome [87,88]. Thus, an antagonist of this receptor may inhibit the secretion of these cytokines (Figure 7). Furthermore, it can inhibit allograft rejection [87], sterile liver inflammation [88], and can potentially treat inflammatory diseases, such as osteoarthritis, rheumatoid arthritis, and chronic obstructive pulmonary disease [28,37].
Callysterol (Figure 3) from Callyspongia siphonella exhibits anti-inflammatory activity against rat paw edema that was similar to the control drug, cortisone. The activity was measured by a reduction in edema volume of 19.5 ± 7.3 mL for callysterol and 17.0 ± 7.0 mL for cortisone, whereas the negative control was 61.9 ± 4.7 mL [38]. Callyspongia crassa extracts also showed anti-inflammatory effects with a 61.47% inhibition of protein denaturation [34]. Alkaloids are considered responsible for these anti-inflammatory mechanisms [89], which vary according to the metabolite. The alkaloid that has been identified from ethanolic extract of Callyspongia siphonella was 5-bromo trisindoline and 6-bromo trisindoline [7]. Although the specific mechanism of 5-bromo trisindoline and 6-bromo trisindoline is unknown, some indole alkaloids were known to interfere with the nuclear factor-κB and c-Jun N-terminal kinase signaling pathways [90,91], preventing the synthesis or action of specific pro-inflammatory cytokines, and suppressing histamine release and nitric oxide production (Figure 7) [92,93]. Alkaloids are effective for treating inflammatory bowel disease [94,95,96,97].

4.4. Antifungal

Callyaerin A, B, and E (Figure 3) from Callyspongia aerizusa were shown to potently inhibit Candida albicans, with zones of inhibition of 25–30 mm, 15 mm, and 20 mm, respectively using the same concentration. Callyaerin A and E were more potent than callyaerin B [6].
Gelliusterol E from Callyspongia aff. implexa also exerts activity against chlamydial fungi in a dose-dependent manner by inhibiting the formation and growth of chlamydial inclusions. At the highest concentration tested (40 μM), no inclusions were observed, similar to the effect of the control, tetracycline. Thus, this compound not only inhibits the formation of Chlamydia, but also affects its development cycle [39]. In addition, the structure of gelliusterol E is similar to that of cholesterol, which is needed for the growth of Chlamydia trachomatis. Furthermore, this compound inhibits lipid acquisition and fungal growth [98].
β-Sitosterol compounds found in Callyspongia sp. also exhibit antifungal activity against Fusarium spp, with 10 mm of average inhibition diameter [39,40]. (-)-siphonodiol from sponges display antifungal activities against Trichophyton asteroids, with moderately strong activity (MIC 25.0 μg/mL) [41]. Meanwhile, 4-hydroxybenzoic acid against Ganoderma boninense and (−)-loliolide display a broad spectrum of activity [42,43]. Active secondary metabolites that attack fungi are responsible for these antifungal activities, but their specific mechanisms of action remain unclear [99].

4.5. Cytotoxicity against Cancer Cell Lines

Callyspongia siphonella and Callyspongia crassa crude extracts were cytotoxic against a colon cancer (Caco-2) cell line with IC50 values of 5.57 μg/mL and 13.05 μg/mL, respectively, and against breast cancer (MCF-7) cell line with IC50 values of 1.39 μg/mL and 9.47 μg/mL [34]. Neviotine-C, neviotine A, sipholenol-A, and sipholenol from Callyspongia siphonella also exhibited cytotoxicity against cancer cell lines (Table 1). Sipholenol-A showed higher activity against the PC-3 and A549 cell lines (IC50: 7.9 ± 0.12 μM and 8.9 ± 0.01 μM), sipholenol L against the HepG-2 cell line (IC50: 18.7 ± 0.9 μg/mL), and sipholenone A against the MCF-7 cell line (IC50: 36.2 ± 0.13 μM or 3 ± 0.4 μg/mL) [44,45].
Callyspongiolide, extracted from Callyspongia sp., exhibited an IC50 of 320 nM against a mouse lymphoma cell line (L5178Y), 70 nM against human Jurkat J16 T cells, and 60 nM against Ramos B lymphocyte cells [46]. Callypeptide A (Figure 3) inhibited the growth of human cancer cells with GI50 values of 29 μM against breast adenocarcinoma (MDA-MB-231), 30 μM against colorectal carcinoma (HT-29), and 18.5 μM against lung carcinoma (A549). Its activity was weaker compared with doxorubicin as a control (GI50 values of 0.30, 0.40, and 0.35 μM, respectively) [47].
Callyazepine and (3R)-methylazacyclodecane (Figure 3) exhibited IC50 values of 7.4 μM and 3.2 μM against K562 cells, and 3.0 μM and 3.8 μM against A549 cells, respectively [100]. Hysmenialdisine from Callyspongia sp. had an IC50 value of 3.1 μM against colonic adenocarcinoma cells (SW620) and 2.0 μM against epidermoid carcinoma cells (KB-3-1) [49]. In addition, it produces akaterpine, which exhibited an IC50 of 0.5 μg/mL against phosphoinositide-specific phospholipase C [58]. Callyspongamide A (Figure 3), isolated from Callyspongia fistularis, had an IC50 of 4.1 μg/mL against HeLa cells [55].
Methanolic extract of Callyspongia aerizusa had IC50 values of 9.38 μg/mL against A549 cells, 3.12 μg/mL against TE-8 cells, 10.62 μg/mL against HepG-2 cells, and 10.72 μg/mL against MIA PaCa-2 cells [59]. It also produces callyaerin E and H (Figure 6), which exhibited IC50 values of 0.39 μM and 0.48 μM against L5178Y cells [6]. Callyspongia aerizusa extract stimulates the expression of caspase-9, which in turn activates caspase-3, and subsequently downregulates Bcl-2, a key regulator of antiapoptosis (Figure 8) [59].
Callystatin (Figure 3) from Callyspongia truncata exhibited IC50 values of 0.01 μg/mL against KB cells and 20 pg/mL against L1210 cells [101]. Callyspongia sp. also contains two unknown compounds with antiproliferative activity against TR-LE cells: (−)-(3R,18R) alcohol with an IC50 of 0.11 μM and (+)-(3S,18S) with an IC50 of 0.47 μM [52].
The US National Cancer Institute classifies the cytotoxicity of a compound as high if its IC50 < 20 μg/mL, moderate if it falls between 21–200 μg/mL, weak if it falls between 201–500 μg/mL, and non-cytotoxic if the IC50 > 500 μg/mL [102]. Based on these criteria, most Callyspongia extracts possess high cytotoxic activity, except that of Callyspongia schulzei, which exhibits moderate activity, but no study was conducted against non-cancerous cell line except for Callyspongia aerizusa extract. Cytotoxicity of the methanol extract of Callyspongia aerizusa against TE-8 cells (IC50 3.12 μg/mL) was more effective compared with that of the control drug, cisplatin (IC50 8.1 μg/mL/27 μM), meanwhile this extract was non-cytotoxic for non-cancerous cell (HET-1A cell) up to 1000 μg/mL. The compounds responsible for suppressing A549 cell proliferation were identified as ergots-22-en-3-one and ergost-7-en-3-ol [59,103].

4.6. Antimicrobial and Antiparasitic

Isoakaterpine compounds from Callyspongia sp. exert antiparasitic activity by inhibiting adenosine phosphoribosyltransferase, one of the functional routes in Leishmania adenine metabolism, with an IC50 of 1.05 μM [11,104], resulting in death of the parasite (Figure 9).
Besides antiparasitic activity, the subgenus Callyspongia possesses antituberculosis activity resulting from callyaerins A and B (Figure 5) isolated from Callyspongia aerizusa. Their MIC90 values (2 μM and 5 μM, respectively) were less effective compared with the controls, rifampicin (<1 μM), ethambutol (1.25 μM), and isoniazid (0.625 μM). Beside the weaker activity compared with the control, there is no in vivo data to support this activity. These compounds inhibited the growth of Mycobacterium tuberculosis as evidenced by reduced cell viability using the resazurin dye reduction method and measuring cell fluorescence [105].
Siphonocolin from Callyspongia siphonella exhibited antimicrobial activity against Pseudomonas aeruginosa with an MIC of 64 μg/mL [61]. Moreover, neviotine A, sipholenol L, and sipholenone A from Callyspongia siphonella also exhibited antimicrobial activity against Staphylococcus aureus, Bacillus subtilis, and Escherichia coli (Table 1). Neviotine has higher antimicrobial activity with a zone of inhibition against Staphylococcus aureus of 14.1 ± 0.72 mm, against Bacillus subtilis of 17.2 ± 0.58 mm, and against Escherichia coli of 12.7 ± 0.58 mm [45].
Callyspongia crassa extract potently inhibited Bacillus subtilis and Staphylococcus aureus with zones of inhibition of 16–25 mm (at concentration 500 μg/mL), 9–15 mm and 16–25 mm (at concentration 250 μg/mL) respectively, while exhibiting high activity against marine bacteria. The IC50 of the extract was determined by a microdilution test and ranged from 5 μg/mL to 500 μg/mL. Callyspongia crassa is the most active among the Red sea sponges against Bacillus subtilis, with an LC50 18.2 ± 3.56 μg/mL, but was weak against Staphylococcus aureus with an LC50 215.2 ± 32.9 μg/mL [60]. Callyaerin A also exhibits antimicrobial activity against Escherichia coli and Staphylococcus aureus, with zones of inhibition of 10–15 mm and 9 mm, respectively, whereas callyaerin E has activity against Escherichia coli, Bacillus subtilis, and Staphylococcus aureus, with zones of inhibition of 9–11 mm, 15–17 mm, and 9–10 mm, respectively [6].

4.7. Antioxidant

Sponge extracts inhibited oxidative stress and carbohydrate hydrolysis enzymes linearly in a dose-dependent manner. Based on the 2,2-diphenyl-1-picryl-hydrazyl-hydrate assay, a Callyspongia aerizusa extract displayed an antioxidant activity of 56.6% at 0.5 μg/mL, 57.2% at 0.6 μg/mL, and 58.4% at 0.7 μg/mL, indicating that it may be classified as an antioxidant (>50%). Callyspongia crassa extract showed an antioxidant activity of 58.1% at 671 μg/mL, which was lower than the control, ascorbic acid (>90%), likely because Callyspongia was used in the form of an extract [34,62].

4.8. Antiallergic

The compound 3-(2-(4-hydroxyphenyl)-2-oxoethyl)-5,6-dihydropyridine-2(1H)-one was isolated from an ethanol extract of Callyspongia sp. [63]. This δ-lactam derivative was predicted to possess antiallergic activity based on its in silico inhibition of β-hexosaminidase (β-hex), which was determined using Origin 8.0. This compound inhibited β-hex activity in rat basophilic leukemia cells (RBL-2H3) with an IC50 of 18.7 ± 6.7 μM, which was weaker than the positive control, ketotifen fumarate (IC50 15.0 ± 1.3 μM), but more potent than azelastine (IC50 32.0 μM) [64]. β-hex is released from mast cell degranulation, thus its activity can be used as a biomarker of mast cell allergic response to quantify degranulation [106,107,108].

4.9. Antiviral

Callyspongia crassa and Callyspongia siphonella extracts exhibited cytotoxic effects on Vero cells, which were cultured for the isolation and multiplication of enterovirus and hepatitis A virus, with MICs of 9.765 μg/mL and 0.625 μg/mL, respectively. The maximum non-toxic concentrations of these extracts were 4.9 and 0.3 μg/mL, respectively. Callyspongia crassa crude extract had an antiviral activity of 85.3%, whereas the antiviral activity of Callyspongia siphonella extract was 16.4% [34].

4.10. Immunomodulatory

Callyspongia extract at doses of 300 mg/kg and 400 mg/kg body weight, increased S. aureus-induced production of interferon-γ (IFN-γ) (455.265 pg/mL and 384.319 pg/mL) and tumor necrosis factor-α (TNF-α)(954 pg/mL and 1042 pg/mL) in male Wistar rats. It was more effective compared with 0.5% carboxymethyl cellulose sodium as negative control (160.314 pg/mL for INF-γ and 785.5 pg/mL for TNF-α) and bay leaf extract as positive control (353.486 pg/mL for INF-γ and 976 pg/mL for TNF-α) [68]. β-Sitosterol compounds from Callyspongia spp. modulate the activity of dendritic cells and increase the viability of peripheral blood mononuclear cells [67]. Siphonodiol, callyspongidiol, and 14,15-dihydrosphonodiol modulate the function of dendritic cells for T1 cell proliferation as well as IL-2 and IFN-γ production [66]. IL-2, along with other ILs, regulates innate and adaptive immunity by promoting an increase in the population of various immune cells [109,110]. Meanwhile, IFN-γ activates macrophages and enhances their immune response [111]. Callyspongia extract can stimulate the branch of the immune system involved in forming a receptor complex with gp130 to eventually inhibit the bioactivity of IL-6 (Figure 10) [112,113].

4.11. Antineurodegenerative

  • β-secretase 1
Selectively inhibiting β-secretase 1 in specific subcellular compartments is an effective strategy to reduce the accumulation of neurotoxic amyloid plaques [114]. The methanol extract of Callyspongia samarensis significantly and non-competitively inhibited β-secretase 1 (IC50 99.82 μg/mL). An acute oral toxicity test revealed that the extract was non-toxic, with an LD50 value of less than 2000 mg/kg. Moreover, an unknown compound in the extract, with a mass/charge ratio of 337.9 [M + H]+, was able to permeate the blood–brain barrier, making it a suitable candidate for developing central nervous system drugs [31].
  • Kinase inhibitor
Kinases have a role in neurodevelopmental and central nervous system physiology. Activation of the glycogen synthase kinase 3β (GSK3β) results in tau phosphorylation, amyloid-β accumulation, microglia activation, neurogenesis, and memory abnormalities [115]. This suggests that its inhibition restores and repairs pathways and neurogenesis (Figure 11) [116,117]. Hymenialdisine, isolated from Callyspongia sp. (CMB-01152), inhibits casein kinase 1, cyclin-dependent kinase 5, and GSK3β with IC50 values of 0.03 μg/mL, 0.16 μg/mL, and 0.07 μg/mL, respectively. They abnormal hyperphosphorylate highly soluble microtubule-associated proteins to produce neurofibrillary tangles [49].

4.12. Antiosteoporotic

Neviotine A and D are isolated triterpene-type compounds from Callyspongia siphonella. These compounds possess antiosteoporotic activity by inhibiting receptor activator of nuclear factor-kB ligand (Rankl) with IC50 values of 32.8 μM and 12.8 μM (quercetin as positive control: 25 μg/mL) [69]. The interaction between Rankl and Rank receptor translocate the tumor necrosis factor receptor-associated factors (TRAF6) to the RANK cytoplasmic domain, results in the activation of ERK, p38, and JNK via activation of signaling cascades and downstream targets. Thus, AP-1 and NF-kB transcription factors were activated and stimulated the formation and activity of osteoclasts, which affect resorption activity [118]. Neviotine A and D inhibit cell differentiation into multinucleated tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts, which was upregulated via RANKL-induced osteoclastogenesis (Figure 12) [69,119].

5. Conclusions

In the 41 articles we reviewed, the pharmacological activities that Callyspongia spp. is reported to possess include cytotoxic against cancer cell line (36%), antifungal (10%), anti-inflammatory (10%), immunomodulatory (10%), antidiabetic and antiobesity (6%), antimicrobial (8%), antioxidant (4%), antineurodegenerative (4%), antihypercholesterolemic (2%), antihypertensive (2%), antiparasitic (2%), antiallergic (2%), antiviral (2%), antiosteoporotic (2%), and antituberculosis (2%) activities (Figure 13). The most studied pharmacological activity is cytotoxicity against cancer cell lines. Most of the research was limited to in vitro testing and there is insufficient in vivo data to support such activity. In addition, not all secondary metabolites responsible for certain activities have been identified. Several activities require modification and further study because of a lack of testing or low activity. For example, the antiallergic activity of Callyspongia sp. predicted from in silico results or the antioxidant, antituberculosis, and anti-inflammatory activities of Callyspongia extract were weaker compared with those of the control drugs. Although many promising compounds with a high potential to become drugs remain to be comprehensively evaluated in vivo, Callyspongia with its known mechanisms of action, such as antidiabetic and cytotoxic effects, may be further developed for targeted therapy.

Author Contributions

Conceptualization, Y.E.H.; methodology, A.A.N. and S.S.; software, A.A.N. and S.S.; data curation, A.A.N. and S.S.; writing—original draft preparation, A.A.N. and S.S.; writing—review and editing, Y.E.H., A.Z., R.H. and I.S.; visualization, Y.E.H., A.Z., R.H. and I.S.; supervision, Y.E.H., A.Z., R.H. and I.S.; project administration, Y.E.H., A.Z., R.H. and I.S.; funding acquisition, Y.E.H., A.Z., R.H. and I.S. All authors have read and agreed to the published version of the manuscript.

Funding

This study was supported by grants-in-aid from Universitas Padjadjaran Internal Grant 2022 number 2203/UN6.3.1/PT.00/2022.

Acknowledgments

The authors would like to thank Yusnaini and Roni Nerliano from Aquatic Cultivation Study Program, Faculty of Fisheries and Marine Science, Halu Oleo University for the photograph of Callyspongia aerizusa (Figure 1e).

Conflicts of Interest

The authors declare no conflict of interest.

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Metabolites 13 00217 g001 550
Figure 1. (a) Callyspongia diffusa, (b) Callyspongia siphonella, (c) Callyspongia truncata [15], (d) Callyspongia samarensis [3], (e) Callyspongia aerizusa.
Figure 1. (a) Callyspongia diffusa, (b) Callyspongia siphonella, (c) Callyspongia truncata [15], (d) Callyspongia samarensis [3], (e) Callyspongia aerizusa.
Metabolites 13 00217 g001
Metabolites 13 00217 g002 550
Figure 2. Method of screening information sources.
Figure 2. Method of screening information sources.
Metabolites 13 00217 g002
Metabolites 13 00217 g003a 550Metabolites 13 00217 g003b 550Metabolites 13 00217 g003c 550Metabolites 13 00217 g003d 550
Figure 3. Structure of secondary metabolites from the Callyspongia subgenus.
Figure 3. Structure of secondary metabolites from the Callyspongia subgenus.
Metabolites 13 00217 g003aMetabolites 13 00217 g003bMetabolites 13 00217 g003cMetabolites 13 00217 g003d
Metabolites 13 00217 g004 550
Figure 4. Antidiabetic mechanism of secondary metabolites from the subgenus Callyspongia.
Figure 4. Antidiabetic mechanism of secondary metabolites from the subgenus Callyspongia.
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Metabolites 13 00217 g005 550
Figure 5. Antihypertensive mechanism of Callyspongia diffusa.
Figure 5. Antihypertensive mechanism of Callyspongia diffusa.
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Figure 6. Prediction of anti-inflammatory mechanisms of compounds from the subgenus Callyspongia.
Figure 6. Prediction of anti-inflammatory mechanisms of compounds from the subgenus Callyspongia.
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Figure 7. Prediction of anti-inflammatory mechanisms of alkaloids from the subgenus Callyspongia.
Figure 7. Prediction of anti-inflammatory mechanisms of alkaloids from the subgenus Callyspongia.
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Figure 8. Cell death mechanisms of Callyspongia aerizusa compounds.
Figure 8. Cell death mechanisms of Callyspongia aerizusa compounds.
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Figure 9. Antiparasitic mechanism of compounds from Callyspongia sp.
Figure 9. Antiparasitic mechanism of compounds from Callyspongia sp.
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Figure 10. Immunomodulatory mechanisms of compounds from the subgenus Callyspongia.
Figure 10. Immunomodulatory mechanisms of compounds from the subgenus Callyspongia.
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Figure 11. Antineurodegenerative mechanisms of compounds from the subgenus Callyspongia.
Figure 11. Antineurodegenerative mechanisms of compounds from the subgenus Callyspongia.
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Figure 12. Antiosteoporotic mechanisms of Neviotine A and D from the Callyspongia siphonella.
Figure 12. Antiosteoporotic mechanisms of Neviotine A and D from the Callyspongia siphonella.
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Figure 13. Distribution of the pharmacological activities reported in Callyspongia spp.
Figure 13. Distribution of the pharmacological activities reported in Callyspongia spp.
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Table
Table 1. Pharmacological activities of Callyspongia spp.
Table 1. Pharmacological activities of Callyspongia spp.
Pharmacological ActivityCallyspongia spp.Secondary MetaboliteDescription of ActivityRef.
Antidiabetic and
antiobesity		Callyspongia
truncata		Callyspongynic acidIC50 against α-glucosidase: 0.25 μg/mL[29,30]
Callyspongia
samarensis		-EC50 14.47 μg/mL (AMPK Activation)[31]
Callyspongia sp.β-SitosterolActivation of GLUT-4 and insulin receptors[32]
AntihypercholesterolemicCallyspongia sp.Callyspongiamide AIC50 against SOAT-1 and SOAT-2: 0.78 ± 0.19 and 2.8 ± 0.72 μM[5]
Callyspongiamide BIC50 against SOAT-1 and SOAT-2: 1.2 ± 0.31 and 2.4 ± 0.96 μM
Disamide AIC50 against SOAT-1 and SOAT-2: 5.2 ± 0.93 and 4.2 ± 0.76 μM
AntihypertensiveCallyspongia
diffusa		Callypyrone AIC50 against Angiotensin I-converting enzyme (ACE): 0.48 mM[33]
Callypyrone BIC50 against ACE: 0.57 mM
Anti-inflammatoryCallyspongia crassa-61.47% inhibition of protein denaturation[34]
Callyspongia sp.-97% inhibition of hemolysis (at a dose of 3200 ppm)[35]
Callyspongia sp.Cyclo[L-Hyp-L-Ala]Increase secretion of IL-10 (J774A.1 cells) by 1.65-fold[36]
Cyclo[L-Pro-Gly]Increase secretion of IL-10 (J774A.1 cells) 1.29-fold
Cyclo[L-Pro-Phe]Increase secretion of IL-10 (J774A.1 cells) 1.54-fold
Cyclo[L-Pro-Ala]Increased secretion of IL-10 (J774A. 1 cells) 1.56-fold
Callyspongia sp.β-Sitosterol
  • ED50 155.6 (mg/kg/ip) on adrenal pituitary axis
  • 54% of inflammatory effect at dose 320 mg/kg (p.o.)
[37]
Callyspongia
siphonella		Callysterol19.5 ± 7.3 mL (Edema volume)[38]
AntifungalCallyspongia aff. implexaGelliusterol EIC50 against Chlamydia trachomatis: 2.34 ± 0.22 µM (No inclusion at a concentration of 40 μM)[39]
Callyspongia
aerizusa		Callyaerin AChlamydia albican inhibition with a zone of inhibition of 25–30 mm[6]
Callyaerin BChlamydia albican inhibition with a zone of inhibition of 15 mm
Callyaerin EChlamydia albican inhibition with a zone of inhibition of 20 mm
Callyspongia sp.β-SitosterolAverage inhibition diameter against Fusarium spp.: 10 mm[39,40]
Callyspongia sp.(-)-SiphonodiolMIC against Trichophyton asteroides: 25.0 μg/mL[41]
Callyspongia
fibrosa		4-hydroxybenzoic acidAntifungal against Ganoderma boninense[42,43]
Cytotoxicity against cancer cell linesCallyspongia
siphonella		-IC50 against:[34]
  • Caco-2 cell line: 5.57 μg/mL
  • MCF-7 cell line: 1.39 μg/mL
Neviotine-CIC50 against:[44]
  • PC-3 cell line: 53.6 ± 0.17 μM
  • A549 cell line: 87.2 ± 1.34 μM
  • MCF-7 cell line: 45.5 ± 0.06 μM
Neviotine AIC50 against:
  • PC-3 cell line: 71.2 ± 0.34 μM
  • A549 cell line: 76.3 ± 0.35 μM
  • MCF-7 cell line: 46.3 ± 0.06 μM
IC50 against:[45]
  • MCF-7 cell line: 12.3 ± 0.7 μg/mL
  • HepG-2 cell line: 11.8 ± 1.2 μg/mL
Sipholenol-AIC50 against:[44]
  • PC-3 cell line: 7.9 ± 0.12 μM
  • A549 cell line: 8.9 ± 0.01 μM
  • MCF-7 cell line: 56.3 ± 0.17 μM
IC50 against:[45]
  • MCF-7 cell line: 19.2 ± 0.6 μg/mL
  • HepG-2 cell line: 9.6 ± 0.8 μg/mL
Sipholenone AIC50 against:[44]
  • PC-3 cell line: 53.9 ± 0.25 μM
  • A549 cell line: 24.8 ± 0.22 μM
  • MCF-7 cell line: 36.2 ± 0.13 μM
IC50 against:[45]
  • MCF-7 cell line: 3 ± 0.4 μg/mL
  • HepG-2 cell line: 2.8 ± 0.4 μg/mL
Sipholenol LIC50 against:
  • MCF-7 cell line: 4.0 ± 0.22 μg/mL
  • HepG-2 cell line: 18.7 ± 0.9 μg/mL
Callyspongia crassa-IC50 against:[34]
  • Caco-2 cell line: 13.05 μg/mL
  • MCF-7 cell line: 9.47 μg/mL
Callyspongia sp.CallyspongiolideIC50 against:[46]
  • L5178Y cell line: 320 nM
  • Jurkat J16 T cell line: 70 nM
  • Ramos B lymphocyte cell line: 60 nM
Callyspongia sp.Callypeptide AGI50 against:[47]
  • MDA-MB-231 cell line: 29 μM
  • HT-29 cell line: 30 μM
  • A549 cell line: 18.5 μM
Callyspongia sp.CallyazepinIC50 against:[48]
  • K562 cell line: 7.4 μM
  • A549 cell line: 3.0 μM
(3R)-methylazacyclodecaneIC50 against:
  • K562 cell line: 3.2 μM
  • A549 cell line: 3.8 μM
Callyspongia sp. (CMB-01152)HymenialdisineIC50 against:[49]
  • SW620 cell line: 3.1 μM
  • KB-3-1: 2.0 μM
Callyspongia schulzei-IC50 against:[50]
  • HT-29 cell line: 35.57 ± 0.87 μg/mL
  • T47D cell line: 37.98 ± 2.12 μg/mL
  • Casky tumor cell line: 63.20 ± 0.76 μg/mL
Callyspongia
aerizusa		Callyaerin EIC50 against L5178Y cell line: 0.39 μM[6]
Callyaerin HIC50 against L5178Y cell line: 0.48 μM
Callyspongia
truncata		CallystatinIC50 against KB cell line: 0.01 μg/mL [51]
-Further research:
IC50 against:
  • KB cell line: 10 pg/mL
  • L1210 cell line: 20 pg/ml
Callyspongia sp.(−)-(3R,18R) alcoholIC50 against TR-LE cell line: 0.11 μM[52]
(+)-(3S,18S)IC50 against TR-LE cell line: 0.47 μM
Callyspongia sp.SiphonodiolIC50 against HL-60 cell line: 6.5 μg/mL[53]
CallyspongidiolIC50 against HL-60 cell line: 2.8 μg/mL
14,15-dihydrosphonodiolIC50 against HL-60 cell line: 6.5 μg/mL
Callyspongia sp.Callyspongenols AIC50 against:[54]
  • P388 cell line: 2.2 μg/mL
  • HeLa cell line: 4.5 μg/mL
Callyspongenols BIC50 against:
  • P388 cell line: 10 μg/mL
  • HeLa cell line: 10 μg/ mL
Callyspongenols CIC50 against:
  • P388 cell line: 2.2 μg/mL
  • HeLa cell line: 3.9 μg/mL
Callyspongenols DIC50 against:
  • P388 cell line: 0.4 μg/mL
  • HeLa cell line: 0.066 μg/mL
Callyspongia
fistularis		Callyspongamide AIC50 against HeLa cell line: 4.1 μg/mL [55]
Callyspongia sp.Alkupikanye EIC50: 5 μg/mL[56]
Alkupikanye FIC50: 10 μg/mL
Callyspongia sp.-IC50: 2 μg/mL against NIH3T3 cells transfected with the human EGF receptor[57]
8-Bromooctyl tert-butyldimethylsilyl ether (fraction, n = 3)
9-(3-Pyridyl)nonyl alcohol (fraction, n = 3)		IC50: 1.3 μg/mL against NIH3T3 cells transfected with human EGF receptor gene
Callyspongia sp.AkaterpinIC50 against PI-PLC: 0.5 μg/mL[58]
Callyspongia
aerizusa		-IC50 against:[59]
  • A549 cell line: 9.38 μg/mL
  • TE-8 cell line: 3.12 μg/mL
  • HEP G2 cell line: 10.62 μg/mL
  • MIA PaCa-2 cell line: 10.72 μg/mL
AntimicrobialCallyspongia crassa-LC50 against:[60]
  • Staphylococcus aureus: 215.2 ± 32.9 μg/mL
  • Bacillus subtilis: 18.2 ± 3.56 μg/mL
Callyspongia
siphonella		SiphonocholinMIC against Pseudomonas aeruginosa: 64 μg/mL[61]
Sipholenol LInhibition against:[45]
  • Staphylococcus aureus (Zone of inhibition: 12.3 ± 0.72 mm)
  • Bacillus subtitus (Zone of inhibition: 14.5 ± 0.72 mm)
Neviotine AInhibition against:
  • Staphylococcus aureus (Zone of inhibition: 14.1 ± 0.72 mm)
  • Bacillus subtitus (Zone of inhibition: 17.2 ± 0.58 mm)
  • Escherichia coli (Zone of inhibition 12.7 ± 0.58 mm)
Sipholenone AInhibition against:
  • Staphylococcus aureus (Zone of inhibition: 8.2 ± 0.72 mm)
  • Bacillus subtitus (Zone of inhibition: 2.4 ± 0.58 mm)
  • Escherichia coli (Zone of inhibition 5.4 ± 0.58 mm)
Callyspongia aerizusaCallyaerin AInhibition against:[6]
  • Escherichia coli (moderate) with zone of inhibition: 10–15 mm
  • Staphylococcus aureus (mild) with zone of inhibition: 9 mm
Callyaerin EInhibition against:
  • Bacillus subtilis (potent) with zone of inhibition: 15–17 mm
  • Escherichia coli (mild) with zone of inhibition: 9–11 mm
  • Staphylococcus aureus (mild) with zone of inhibition: 9–10 mm
AntioxidantCallyspongia crassa-Percentage of inhibition: 58.1% at 671 μg/mL[34]
Callyspongia
aerizusa		-Percentage of inhibition 56.6% at 0.5 μg/mL, 57.2% at 0.6 μg/mL, and 58.4% at 0.7 μg/mL[62]
AntiparasiticCallyspongia sp.IsoakaterpineIC50 against adenosine phosphoribosyltransferase of Leishmania spp: 1.05 μM[11]
AntiallergicCallyspongia sp.3-(2-(4-hydroxyphenyl)-2-oxoethyl)-5,6-dihydropyridine-2(1H)-oneIC50 againts RBL-2H3: 18.7 ± 6.7 μM[63,64]
AntituberculosisCallyspongia
aerizusa		Callyaerin AMIC90 against Mycobacterium tuberculosis: 2 μM[64]
Callyaerin BMIC90 against Mycobacterium tuberculosis: 5 μM
AntiviralCallyspongia crassa-85.3% against hepatitis A virus (MIC 9.765 μg/mL)[34]
Callyspongia
siphonella		-83.7% against hepatitis A virus (MIC 0.625 μg/mL)
ImmunomodulatoryCallyspongia sp.Niphatoxin CIC50 P2X7 antagonism: 11.5 μM[65]
Callyspongia sp.Siphonodiol
  • Increases IL-12p70 secretion in LPS-primed DCs
  • Modulates dendritic cell function for T1 cell proliferation
[66]
Callyspongia sp.CallyspongidiolModulates dendritic cell function for T1 cell proliferation[53]
14,15-dihydrosphonodiol
Callyspongia sp.β-SitosterolModulates dendritic cell activity and increases peripheral blood mononuclear cell viability[67]
Callyspongia sp.-Increase levels of IFN-γ and TNF-α (Wistar strain mice) at extract doses of 300 mg/kg and 400 mg/kg[68]
AntineurodegenerativeCallyspongia
samarensis		-IC50 against β-secretase: 99.82 μg/mL[31]
Callyspongia sp.HymenialdisineIC50 against:[49]
  • GSK3β: 0.07 μM
  • CK5.p25: 0.16 μM
  • CK1δ: 0.03 μM
AntiosteoporoticCallyspongia
siphonella		Neviotine DIC50 against RANKL: 12.8 μM[69]
Neviotine AIC50 against RANKL: 32.8 μM
IC50: Half maximal inhibitory concentration; EC50: Half maximal effective concentration; ED50: Median effective dose; MIC: Minimum inhibitory concentration; GI50: Half maximal growth inhibition; LC50: Median Lethal Concentration.
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Hadisaputri, Y.E.; Nurhaniefah, A.A.; Sukmara, S.; Zuhrotun, A.; Hendriani, R.; Sopyan, I. Callyspongia spp.: Secondary Metabolites, Pharmacological Activities, and Mechanisms. Metabolites 2023, 13, 217. https://doi.org/10.3390/metabo13020217

AMA Style

Hadisaputri YE, Nurhaniefah AA, Sukmara S, Zuhrotun A, Hendriani R, Sopyan I. Callyspongia spp.: Secondary Metabolites, Pharmacological Activities, and Mechanisms. Metabolites. 2023; 13(2):217. https://doi.org/10.3390/metabo13020217

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Hadisaputri, Yuni Elsa, Annida Adha Nurhaniefah, Sendi Sukmara, Ade Zuhrotun, Rini Hendriani, and Iyan Sopyan. 2023. "Callyspongia spp.: Secondary Metabolites, Pharmacological Activities, and Mechanisms" Metabolites 13, no. 2: 217. https://doi.org/10.3390/metabo13020217

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