Marine sponges, which belong to the phylum Porifera (Metazoa), are considered the single best source of marine natural products. Among them, members of the genus Aaptos are attractive targets for marine natural product research owing to their abundant biogenetic ability to produce aaptamine derivatives. Apart from aaptamine alkaloids, there are also reports of other compounds from Aaptos sponges. This work reviews the secondary metabolites isolated from Aaptos species from 1982 to 2020, with 46 citations referring to 62 compounds (47 for aaptamines and 15 for others). The emphasis is placed on the structure of the organic molecules, relevant biological activities, chemical ecology aspects, and biosynthesis studies, which are described in the classifications of aaptamines and other compounds in the order of the published year.
Marine secondary metabolites with wide structural diversity and multiple biological activities are important sources of unexploited drugs. Approximately 28 600 new compounds had been reported from a variety of marine sources by the end of 2018.1 Among these, sponges, which belong to the phylum Porifera, represent a prolific source of secondary metabolites, contributing to 30% of all natural marine products identified so far.2 Lead compounds from sponges have often been found to be promising pharmaceutical agents. To date, 3 approved marine drugs, the anticancer cytarabine (ara-C),3 antiviral vidarabine (ara-A), and anticancer Eribulin mesylate,4 have been derived from sponges. Several new sponge derivatives, such as gemcitabine,5 discodermolide,6 hemiasterlin,7 and PM060184,8 have entered clinical trials. Therefore, marine sponges have attracted the attention of natural product chemists and pharmaceutical experts worldwide to carry out chemical research for drug discovery.
The genus Aaptos (Porifera, Demospongiae, Hadromerida, Suberitidae) is widely distributed in the marine ecosystem, including the South China Sea, as well as in Japanese, Indonesian, and Caribbean shallow waters. Currently, approximately 20 species have been described.9 Since the beginning of the 1980s, many research groups around the world have carried out chemical investigations on Aaptos species and have discovered the representative 1H-benzo[d,e][1,6]-naphthyridine alkaloids, known collectively as aaptamines. In addition to these diverse aaptamines, other structures have also been discovered from this genus.
To understand better and rationally exploit Aaptos species, the relevant studies reported between 1980 and 2020 are summarized in this review for the first time.
Natural Products From Aaptos sp.
By 2020, 62 various secondary metabolites (1-62) had been isolated and characterized from the genus Aaptos, including Aaptos aaptos (Schmidt, 1864), Aaptos suberitoides (Brøndsted, 1934), Aaptos lobata (Calcinai, Bastari, Bertolino & Pansini, 2017), Aaptos ciliata (Wilson, 1925), Aaptos nigra (Lévi, 1961), and other unidentified Aaptos sp. In terms of their chemical structures, most Aaptos-derived products are structurally diversified aaptamines (47 for aaptamines and 15 for others; Table 1). Some chemicals have pronounced biological activities and can be used as lead drugs. These secondary metabolites are summarized below in the order of the published year.
Secondary Metabolites From the Genus Aaptos and Biological Activity.
In 1982, the first and representative member of the family aaptamine (1) was reported by Nakamura et al from A. aaptos, collected off the shores of Okinawa.48 It was found to possess α-adrenoceptor blocking activity and was a competitive antagonist of α-adrenoceptors in vascular smooth muscles.10 In 1987, they also isolated 2 additional aaptamines, demethylaaptamine (2) and demethyloxyaaptamine (3), from the same species. Demethyloxyaaptamine (3) exhibited cytotoxicity toward HeLa cells with an effective dose 50 (ED50) of 0.87 µg/mL. It also showed antimicrobial activities.23 In 1993, Rudi et al isolated aaptosine (4) from the Red Sea sponge A. aaptos, which contained an unprecedented 5,8-diazabenz[cd]azulene heterocylce.49 In 1997, Shen et al isolated 4 alkaloids, aaptamine (1), demethyloxyaaptamine (3), aaptosine (4), and isoaaptamine (5), from Formosan A. aaptos. All the compounds except aaptosine (4) showed potent cytotoxicities against P-388, KB16, A549, and HT-29 tumor cells.11 In 1998, Tinto et al isolated a new 5,8-diazabenz[cd]azulene alkaloid, aaptosamine (6), from A. aaptos collected in the southern Caribbean.29
In 2002, Coutinho et al isolated a new aaptamine alkaloid, 4-methylaaptamine (7), and the known demethyloxyaaptamine (3) from Aaptos sp. collected in Abrolhos, Bahia, Brazil. At the concentration of 2 µg/mL, both compounds showed potent antiviral activity against the herpes simplex virus type 1 (HSV-1) but displayed low toxicity to Vero cells, which suggests that they may selectively inhibit viral replication.24 In 2007, Souza et al disclosed that 4-methylaaptamine (7) inhibited HSV-1 replication by targeting the immediate-early protein ICP27 and impaired HSV-1 penetration without affecting viral adsorption.30 In 2004, Herlt et al isolated 8,9-demethylaaptamine (8) and bisdemethylaaptamine-9-O-sulfate (9) from an Aaptos sp. harvested off the Indonesian coast. It was proposed that 8,9-demethylaaptamine (8) is a biosynthetic precursor of the aaptamines. Bisdemethylaaptamine-9-O-sulfate (9) was the first reported sulfated aaptamine.30 In 2006, Diers et al evaluated the antifouling activity of aaptamine (1) and isoaaptamine (5), which were isolated from A. nigra collected from reef slopes of Manado and Derawan Island, Indonesia, and the semisynthetic aaptamine derivatives 4-N-methylaaptamine (7) and 8,9-demethylaaptamine (8). Aaptamine (1), isoaaptamine (5), and demethylated aaptamine (8) displayed significant antifouling activity with half maximal effective concentration values of 24.2, 11.6, and 18.6 µM, respectively. The structure-activity relationship (SAR) study indicated that the free hydroxyls were essential for the antifouling activity and the N-methyl groups could reduce the toxicity. Hence, aaptamine derivatives may be used as environmentally benign antifouling alternatives to metal-based paints.12 In 2006, Shunji et al found that aaptamine (1) activated the p21 promoter that was stably transfected in MG63 cells dose dependently at concentrations of 20-50 µM and arrested the cell cycle of MG63 cells at the G2/M phase. The activation of p21 promoter by aaptamine was led through acting on Sp1 sites between −82 and −50 bp in a p53-independent manner.50 In 2007, Jang et al reported 4 aaptamines: aaptamine (1), demethylaaptamine (2), demethyloxyaaptamine (3), and isoaaptamine (5) from A. aaptos collected from the Federated States of Micronesia. Their inhibitory activities were evaluated against sortase A, an enzyme that plays a key role in cell wall protein anchoring and virulence in Staphylococcus aureus. Isoaaptamine (5) was a potent inhibitor of sortase A, with a half-maximal inhibitory concentration (IC50) value of 3.7 µg/mL. The methyl group at the N-1 position of isoaaptamine proved to be an important factor for sortase A activity. Besides, isoaaptamine (5) reduced the fibronectin-binding activity of the bacterium, which highlighted its potential for the treatment of S. aureus infections via inhibition of sortase A activity.26 In 2009, Utkina evaluated the antioxidant activity of aaptamine (1) and isoaaptamine (5) isolated from A. aaptos. Both of these strongly reacted with 2,2-diphenyl-1- picrylhydrazyl and showed a high reducing ability for Folin-Ciocalteau reagent.13 In 2009, Shubina et al isolated a new aaptamine-type alkaloid, 3-N-morpholinyl-9-demethyl(oxy)aaptamine (10), from an Aaptos sp. collected in Vietnamese waters. It showed inhibitory activity on the epidermal growth factor (EGF)-induced malignant transformation of mouse epidermal JB6 P+C1 41 cells in soft agar.32 In 2009, Shaari et al used a bioassay-guided isolation method to obtain 2 new derivatives of aaptamines, 3-(phenethylamino)demethyl(oxy)aaptamine (11), and 3-(isopentylamino)demethyl(oxy)aaptamine (12), in addition to the known aaptamine (1) from A. aaptos collected from the coastal waters of Terengganu, Malaysia. This was the first report of a naturally occurring C-3 substituted aaptamine. All 3 isolated alkaloids exhibited significant cytotoxic activity against T-lymphoblastic leukemia cells with the concentration to reduce the absorbance of treated cells by 50% with reference to the control (CD50) values of 5.3 (11), 6.7 (12), and 15.0 (1) μg/mL, respectively. SAR studies suggested that hydroxylation at C-9 and parasubstituted phenyl substituents on one or both of the nitrogen are important for increased activity, and C-3 substitution may also influence the cytotoxicity of this class of compounds.33 In 2009, Utkina et al isolated a new zwitterionic compound, aaptanone (13), with a rare oxygenated 1,6-naphthyridine core, from Vietnamese A. aaptos. Aaptanone (13) is the first zwitterionic metabolite of the aaptamine class bearing 2 adjacent carbonyl groups in the 1,6-naphthyridine core. Bioactivity tests revealed that aaptanone (13) was inactive against S. aureus, Bacillus subtilis, Candida albicans, and Escherichia coli strains and displayed no cytotoxicity against mouse Ehrlich carcinoma cells.35 In another study of the same sponge from another collection, Utkina et al found another new zwitterionic compound, N-demethylaaptanone (14), with the same skeleton as aaptanone (13).36
In 2010, Shubina et al isolated 3 new aaptamines 2,3-dihydro-2,3-dioxoaaptamine (15), 6-(N-morpholinyl)-4,5-dihydro-5-oxodemethyl(oxy)aaptamine (16), and 3-(methylamino)demethyl(oxy)aaptamine (17), in addition to 4 known compounds (1, 3, 11, 12) from an Aaptos sp. collected in Vang Fong Bay, Vietnam. The apoptosis-inducing activity of these compounds and isoaaptamine (5) on human leukemia THP-1 cells was evaluated. Isoaaptamine (5) was shown to be the most active inducer of apoptosis. The side chain length at position 3 may decrease the apoptosis-inducing activity.27 In 2010, Arif et al found that aaptamine (1), at a concentration of 10 µM, induced benzo[a]pyrene (BP)-derived deoxyribonucleic acid adduct formation. At a concentration of 50 µM, aaptamine induced the p53 expression by 40%, which indicated its anticancer potential.14 In 2010, Tsukamoto et al examined the proteasome inhibitory activity of aaptamine (1), demethylaaptamine (2), and isoaaptamine (5) isolated from A. suberitoides collected in Indonesia. They inhibited the chymotrypsin-like and caspase-like activities of the proteasome with IC50 values of 1.6-4.6 µg/mL and displayed weak inhibition of the trypsin-like activity of the proteasome. These 3 compounds also showed cytotoxic activities against HeLa cells with IC50 values of 15, 1.4, and 3.1 µg/mL, respectively, but their cytotoxicity did not correlate with their potency as proteasome inhibitors.15 In 2011, Jin et al investigated the antiproliferative effect of aaptamine on chronic myeloid leukemia (CML) K562 cells. Aaptamine inhibited the growth of K562 with the concentration that causes 50% inhibiiton of the growth of cells (GI50) of 10 µM and arrested the cell cycle at the G2/M phase. Western blot assays indicated that aaptamine induced p21 expression in K562 cells. Since K562 is p53 negative, aaptamine was demonstrated to be a p53-independent p21 inducer in CML cells.51 In 2012, Dyshlovoy et al obtained aaptamine from Aaptos sp. and analyzed the effects of its treatment on the proliferation and protein expression of the pluripotent human embryonal carcinoma cell line NT2. At lower concentrations, aaptamine arrested the cell cycle at the G2/M phase, whereas at higher concentrations, it induced apoptosis. Differentially expressed proteins were assessed, of which 5 showed upregulation and downregulation, which was clearest in the case of the hypusine modification of the initiation factor eukaryotic translation initiation factor 5A (eIF5A).52 Two years later, the same group reported the effects of aaptamine (1), demethyloxyaaptamine (2), and isoaaptamine (5) on NT2-R, a cisplatin-resistant subline of the human embryonal carcinoma cell line NT2. At IC50, aaptamine exerted an antiproliferative effect, whereas demethyloxyaaptamine and isoaaptamine were strong apoptosis inducers. The changes in the proteome of NT2-R cells treated with these compounds were also analyzed. Myc, p53, and tumor necrosis factor were the possible direct or indirect targets or effectors of the alkaloids. Hypusination of eIF5A, a prominent feature of aaptamine treatment, was not observed upon treatment with either demethyloxyaaptamine or isoaaptamine.21 In the same year, they also reported the anticancer activity of these 3 compounds. Aaptamine (1), demethyloxyaaptamine (2), and isoaaptamine (5) demonstrated anticancer activity in THP-1, HeLa, SNU-C4, SK-MEL-28, and MDA-MB-231 human cancer cell lines. Additionally, all compounds were found to prevent the EGF-induced neoplastic transformation of murine JB6 Cl41 cells, and the nuclear factors AP-1, NF-B, and p53 were involved in the cellular response following treatment with high and nontoxic concentrations of aaptamine alkloids.22 In 2012, Liu et al isolated 4 new bis-aaptamines, suberitine A-D (18-21), along with 2 monomers, 8,9,9-trimethoxy-9H-benzo[de][1,6]-naphthyridine (22) and demethyloxyaaptamine (3), from A. suberitoides collected from Xisha island. The 4 unusual dimers structurally linked 2 aaptamine units, 8,9,9-trimethoxy-9H-benzo[de][1,6]-naphthyridine (22) and demethyloxyaaptamine (3), through a rare C-3-C-3′ or C-3-C-6′ σ-bond. This was the first isolation of aaptamine dimers in nature. The cytotoxicity of the 6 compounds was evaluated against P388, HeLa, and K562 cell lines. Suberitine B and D, with a carbonyl group at either C-9 or C-9′, showed more potent cytotoxicity than the monomers 22 and 3 against the P388 cell line, with IC50 values of 1.8 and 3.5 µM, respectively, whereas suberitine A and C were inactive toward the same cell line38 (Figure 1). In 2013, Pham et al isolated 4 new aaptamine derivatives (23-26), along with 4 related compounds (1, 2, 22, 27), from the ethanol extract of A. suberitoides collected in Indonesia. Compounds 25, 1, and 2 showed cytotoxic activity against the murine lymphoma L5178Y cell line, with IC50 values ranging from 0.9 to 8.3 µM. SAR studies suggested that the hydroxyl at C-9, loss of aromaticity in ring C, hydrogenation of ring B substitution at both C-9 and N-1, and an additional carbonyl group at C-12 negatively affected the activity.38 In 2014, Yu et al isolated 13 new alkaloids of the aaptamine family (28-40) and 5 known derivatives (11, 12, 17, 22, 41) from A. aaptos from the South China Sea. Structurally, compound 28 possesses a piperidinyl group fused to a demethyl(oxy)aaptamine moiety, compounds 30-33 and 39-40 share an imidazole-fused 1H-benzo[de][1,6]naphthyridin-2(4 H)-1 skeleton, and compounds 37-38 are characterized by a triazapyrene lactam skeleton. Compounds 29, 39, 11, and 12 showed potent cytotoxicity against HL60, K562, MCF-7, KB, HepG2, and HT-29 cells, with IC50 values in the range of 0.03-8.5 µM. Compounds 22, 11, and 12 showed antifungal activity against 6 fungi, with minimum inhibitory concentration (MIC) values in the range of 4-64 µg/mL. At a concentration of 10 µM, compounds 11 and 12 exhibited anti-HIV-1 activity, with inhibitory rates of 88.0% and 72.3%, respectively.34,37 In 2014, Arai et al isolated a new aaptamine class alkaloid, designated as 2-methoxy-3-oxoaaptamine (42), together with 7 known aaptamines (1, 3, 15, 17, 26, 27, 39), as antimycobacterial substances against active and dormant bacilli from an Aaptos sp. collected at Kupang, Indonesia. Compound 42 showed antimycobacterial activity against Mycobacterium smegmatis in both active growing and dormancy-inducing hypoxic conditions with a MIC of 6.25 µg/mL, and compounds 3, 15, 17, and 26 showed antimycobacterial activities under hypoxic conditions selectively, with MIC values of 1.5-6.25 µg/mL.25 In 2015, Li et al evaluated the antiproliferative effect of aaptamine on hepatocellular carcinoma cells in vitro and in vivo and analyzed the mechanisms. The results demonstrated that aaptamine led to cell cycle arrest and suppressed the expression of SOX9 and CDK2. The mechanisms were associated with the increased binding of p21 to Cdk2-cyclin D/E complexes and inhibition of CDK2 kinase activity in hepatocellular carcinoma cells.53 In 2015, Zalilawati et al evaluated the cytotoxic and anti-HSV-1 activities of 3-(phenethylamino)demethyl(oxy)aaptamine (11) and aaptamine (1). Both strongly reduced HL-60 viability and also displayed cytotoxicity against WEHI-3B through the induction of apoptosis. In addition, aaptamine (1) also exhibited good antivirus activity on HSV-1.41 In 2015, Gan et al isolated 3 new aaptamine derivatives (43-45), together with 6 known related compounds (1, 3, 11, 17, 22, 27), from the South China Sea sponge A. aaptos. Compounds 1, 3, 11, 17, and 43 showed cytotoxic activities against HeLa, K562, MCF-7, and U937 cell lines with IC50 values in the range of 0.90-12.32 µM17. In 2017, Mohamad et al obtained 5 known aaptamines, aaptamine (1), demethylaaptamine (2), 4-N-methylaaptamine (7), 9-methoxyaaptamine (22), and demethyloxyaaptamine (3) by bioactivity-guided isolation from the butanol extract of A. aaptos collected from South Sulawesi, Indonesia. The cytotoxic activity, antiatherosclerotic properties, and antibacterial activity of the compounds were determined. Compounds 3 and 22 exhibited cytotoxic activity against the HepG2 cell line. Compounds 1, 2, 7, and 22 increased the transcriptional activity of the SRB1 promoter and PPRE and may be potential drug candidates to reduce the progression of atherosclerosis. In addition, compounds 1, 2, 7, and 22 displayed antibacterial activity against shrimp pathogenic bacteria, Vibrio harveyi, and Vibrio sp.18 In 2018, Fukumoto et al isolated a new aaptamine homolog, aaptic acid (46), as well as aaptamine (1), demethyl(oxy)aaptamine (3), and isoaaptamine (5), from A. lobata collected in Indonesia. The inhibitory effect of RAW264 cells on osteoclast formation was determined. Dosing at 5 µM of 1, 3, and 5 inhibited receptor activator of nuclear factor kappa-Β ligand-induced multinucleated osteoclast formation by 25%, 54%, and 17%, respectively. In contrast, 46 did not inhibit osteoclastogenesis, even at a concentration of 50 µM.19 In the same year, Utkina et al evaluated the agricultural plant growth stimulatory effect of aaptamine (1), 9-demethylaaptamine (2), isoaaptamine (5), aaptanone (13), and N-demethylaaptanone (14) isolated from Vietnamese A. aaptos. Aaptamine (1) displayed stimulatory activity on the roots of seedlings of soy, maize, wheat, and buckwheat at a wide range of concentrations. 9-Demethylaaptamine (2) stimulated the root growth of soy and maize in the concentration range of 0.001-10 µg/mL. Isoaaptamine (5) stimulated the root growth of soy and wheat, while only aaptanone (14) stimulated barley roots at a concentration of 0.1 µg/mL. The structural motif of aaptamines 1, 2, and 5 is essential for their stimulating activity on the growth of seedling roots of soy, maize, and wheat. The presence of carbonyl groups in aaptanones 13 and 14 leads to a lack of growth-stimulating activity, while the oxygenated core of aaptanone 14 is important for its growth stimulating activity on barley roots.20 In 2018, Wu et al. isolated aaptamine (1), demethyl (oxy) aaptamine (3), and isoaaptamine (5) from an Aaptos sp. using a bioactivity-guided method. The cytotoxic activity of the isolated compounds was evaluated, revealing that isoaaptamine exhibited potent cytotoxic activity against breast cancer T-47D cells. This study also deciphered that isoaaptamine induced apoptosis and autophagy through p62-dependent oxidative stress in breast cancer T-47D cells.28 In 2019, Hamada et al. obtained an aaptamine-related alkaloid methylenedioxyaaptamine (47) and compound 22 from Malaysian A. aaptos. Methylenedioxyaaptamine (47) was previously reported as a synthetic product, and this was the first report of it from a natural source. Compound 47 displayed moderate cytotoxic activity against adult T-cell leukemia with an IC50 of 0.29 µM39 (Figure 2).
Chemical structures of compounds 1-22.
Chemical structures of compounds 23-47.
Other Compounds
In 1983, Do et al isolated 3-(13-methylhexadecyloxy)-1,2-(S)-propanediol (48) and 3-(15-methyloctadecyloxy)-1,2-(S)-propanediol (49) from Aaptos sp. collected from Taiwanese waters. The configuration of C-2 in the glyceryl moiety was determined by derivatization with (S)-(+)-α-methoxy-α-trifluoromethyl phenylacetyl-chloride. They also reported the total synthesis of compound 48.41 In 1984, Dini et al analyzed the sterols in A. aaptos collected in the Bay of Naples and found that cholestanol (50) and 24-ethylcholestanol (51) were the principal sterols present.42 In 1985, Tanaka et al isolated a new aromatic carotenoid, 3-methoxy-β, χ-carotene (52), from A. aaptos collected from the littoral zone of Amamiooshima, Kagoshima.43 In 2000, Granato et al described the isolation of homarine (53 ) and pyridiniumbetaine B (54) from an Aaptos sp. collected in Spain.44 In 2008, Nakao et al isolated 3 new lipopeptides, ciliatamides A-C (55-57), from the deep-sea sponge A. ciliata collected off Oshima-Shinsone. Ciliatamides A-C (55-57) were evaluated for antileishmanial activity in a fluorometric microplate assay using Leishmania major/egfp promastigotes. Ciliatamides A (55) and B (56) showed 50% and 45.5% growth inhibition at 10 µg/mL, respectively, while C (57) was inactive. Ciliatamides A (55), B (56), and C (57) also inhibited the growth of HeLa cells with IC50 values of 50, 4.5, and 50 µg/mL, respectively.45 In 2014, Kudo et al isolated a new quinoline alkaloid, aaptoline A (58), from A. suberitoides collected in Indonesia, along with the known alkaloids aaptamine (1), demethylaaptamine (2), and isoaaptamine (5). All 4 compounds were presumably biosynthesized from the common precursors, l-dihydroxyphenylalanine and β-alanine aldehyde.54 In 2017, Mohamad et al isolated 4-hydroxybenzamide (59) and 3β,5α-cholesterol (60) from Indonesian A. aaptos. 3β,5α-Cholesterol (60) exhibited cytotoxic effects and potential antiatherosclerotic properties.18 In 2018, Rashid et al investigated the phenolics, fatty acid composition, and biological activities of Malaysian A. aaptos. The chloroform, ethyl acetate, and methanol extracts produced higher portions of straight-chain saturated fatty acids, while the hexane extract mainly consisted of unsaturated fatty acids. The chloroform extract inactivated the HSV-1 and exhibited strong cytotoxic activity on HL-60, MCF-7, K562, CEM-SS, and WEHI-3B cells, but displayed weak cytotoxic activity against normal Vero cells. 4-Hydroxybenzamide (59) was also isolated from this sponge.46 In 2020, Tang et al obtained 2 new quinoline alkaloids, aaptolines A (61) and B (62), from A. aaptos collected off the coast of Xisha Island. Structurally, aaptoline A was characterized as possessing a quinoline skeleton fused with a 1,4-dioxane motif at the C(7)-C(8) position, whereas 62 possessed an intriguing 1H-pyrrolo[2,3 g] quinoline moiety. Both showed cytotoxicity toward HepG2, A549, and PC9 cancer cell lines at a concentration of 20 µM47 (Figure 3).
Chemical structures of compounds 48-62.
Conclusion
This review summarizes the secondary metabolites and biological activities of the sponge genus Aaptos. The most common secondary metabolites are aaptamine alkaloids possessing a variety of beneficial biological activities such as antiviral, antimicrobial, antifungal, and cytotoxic activities. Some aaptamine alkaloids have significant cell toxicity against a variety of tumors. However, the mechanism is not yet clear, and in vivo studies have only been conducted on a few compounds; therefore, further research is required. Although approximately 20 species of Aaptos have been described, the chemical profiles of only 5 identified species (A. aaptos, A. suberitoides, A. lobata, A. ciliata, and A. nigra) and several other unidentified Aaptos sp. have been investigated. With the increasing development of oceanographic technology and the use of advanced separation methodologies, more bioactive secondary metabolites will be discovered from Aaptos species in the near future.
Footnotes
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by Science and Technology Development Foundation of Binzhou (2015ZC0304), Research Foundation of Binzhou Medical University (BY2015KYQD31 and BY2017KJ17), Traditional Chinese Medicine Technology Development Foundation of Shandong (2019-0521), Natural Science Foundation of Shandong Province (ZR2018BB024), National Natural Science Foundation of China (81903537).
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