The Precision Design, Synthesis, and Application of Novel Bioactive Small Molecules to Power the Aquaculture Green Revolution

Lijuan Yu; Zhiyong Xue; Yanqing Li; Min Fu; Jian Zhang; Lanhui Huang; Zhen Zhang; Yuanyuan Yao; Yalin Yang; Chao Ran; Kangsen Mai; Shouqi Xie; Einar Ringø; Rolf Erik Olsen; Jihong Liu Clarke; Qianwen Ding; Zhigang Zhou

doi:10.1016/j.eng.2026.08.027

Engineering ›› :202608027 DOI: 10.1016/j.eng.2026.08.027

research-article

The Precision Design, Synthesis, and Application of Novel Bioactive Small Molecules to Power the Aquaculture Green Revolution

Author information +

^a Key Laboratory for Animal Nutrition and Feed Science of Hubei Province, Wuhan Polytechnic University , Wuhan, 430000, China

^bHubei Key Laboratory of Biomass Fibers and Eco-dyeing & Finishing, College of Chemistry and Chemical Engineering, Wuhan Textile University , Wuhan, 430048, China

^c China-Norway Joint Lab on Fish Gut Microbiota, Institute of Feed Research, Chinese Academy of Agricultural Sciences , Beijing, 100081, China

^d Norway-China Joint Lab on Fish Gastrointestinal Microbiota, Institute of Biology, Norwegian University of Science and Technology , Trondheim, 7491, Norway

^e Key Laboratory for Feed Biotechnology of the Ministry of Agriculture and Rural Affairs, Institute of Feed Research, Chinese Academy of Agricultural Sciences , Beijing, 100081, China

^f The Key Laboratory of Mariculture (Ministry of Education of the People’s Republic of China), Ocean University of China , Qingdao, 266003, China

^g State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences , Wuhan, 430072, China

^h Norwegian College of Fishery Science, Faculty of Bioscience, Fisheries and Economics, UiT The Arctic University of Norway , Tromsø, 9279, Norway

ⁱ Norwegian Institute of Bioeconomy Research (NIBIO) , Ås, 1431, Norway

^j National Collection of Livestock and Aquatic Microbes, Institute of Feed Research, Chinese Academy of Agricultural Sciences , Beijing, 100081, China

^*E-mail addresses: dingqianwen@caas.cn (Q. Ding),

zhouzhigang03@caas.cn(Z. Zhou).

Show less

History +

PDF (2389KB)

Abstract

Environmentally friendly bioactive small molecules are structurally defined, low-molecular-weight organic compounds that exert biological effects while posing relatively low risk to human health and the environment. Their chemical synthesis and their application as green inputs in aquaculture provide a key pathway to reduce and replace antibiotics and improve quality and efficiency, thereby supporting the sustainable development of the aquaculture industry. This study systematically reviews research advances in the green synthesis and application of five key bioactive small molecules: short-chain fatty acids (SCFAs), tryptophan metabolites, tricarboxylic acid (TCA) cycle regulators, bile acid derivatives, and the quorum sensing inhibitor bromofuranone C-30. Chemical and physical modifications (e.g., salinization, esterification, and encapsulation) significantly enhance SCFA stability and targeted delivery. Efficient and green synthetic processes, such as Michael addition and Friedel–Crafts alkylation, enable the high-yield, low-cost preparation of indole-3-propionic acid and indole-3-lactic acid (ILA). Furthermore, innovative catalytic oxidation and lactonization routes provide new synthetic strategies for α-ketoglutaric acid and its derivatives. For bile acid derivatives (e.g., ursodeoxycholic acid (UDCA), sodium taurocholate, and 5α/5β-cyprinol sulfate), novel synthetic and extraction processes featuring streamlined steps, mild conditions, and high atom economy have been developed. A novel two-step synthesis of bromofuranone C-30 enables its scalable production, and a nano-encapsulated sustained-release formulation effectively resolves issues of thermal instability and rapid gastric absorption. These advances overcome the traditional extraction bottlenecks of limited raw materials, cumbersome procedures, and low yields. This review offers theoretical and technical perspectives to advance the targeted design, efficient synthesis, and industrial application of green aquaculture inputs, ultimately contributing to a more sustainable industry marked by greater safety and efficiency.

Keywords

Bioactive small molecules / Green inputs / Sustainable aquaculture / Green synthesis

Cite this article

Download citation ▾

Lijuan Yu, Zhiyong Xue, Yanqing Li, Min Fu, Jian Zhang, Lanhui Huang, Zhen Zhang, Yuanyuan Yao, Yalin Yang, Chao Ran, Kangsen Mai, Shouqi Xie, Einar Ringø, Rolf Erik Olsen, Jihong Liu Clarke, Qianwen Ding, Zhigang Zhou. The Precision Design, Synthesis, and Application of Novel Bioactive Small Molecules to Power the Aquaculture Green Revolution. Engineering 202608027 DOI:10.1016/j.eng.2026.08.027

登录浏览全文

4963

注册一个新账户忘记密码

References

Publishing order | Descend order by publishing year | Descend order by cited within

[1]	Chenghan M, Wanxin L, Bangcheng Z, Yao H, Qinxi L, Ting Z, et al. Short chain fatty acids mediate gut microbiota-brain communication and protect the blood-brain barrier integrity. Ann N Y Acad Sci 2025; 1545(1): 116-31.

[2]	Verma A, Bhagchandani T, Rai A, Nikita SUK, Bhavesh NS, et al. Short chain fatty acid (SCFA) as a connecting link between microbiota and gut-lung axis-a potential therapeutic intervention to improve lung health. ACS Omega 2024; 9(13): 14648-71.

[3]	Fu Q, Li T, Zhang C, Ma X, Meng L, Liu L, et al. Butyrate mitigates metabolic dysfunctions via the ERα AMPK pathway in muscle in OVX mice with diet induced obesity. Cell Commun Signal 2023; 21(1): 95.

[4]

Matheus VA, Oliveira RB, Maschio DA, Tada SFS, Soares GM, Mousovich-Neto F, et al. Butyrate restores the fat/lean mass ratio balance and energy metabolism and reinforces the tight junction mediated intestinal epithelial barrier in prediabetic mice independently of its anti inflammatory and epigenetic actions. J Nutr Biochem 2023; 120: 109409.

[5]	Gou N, Jin T, Yang B, Wang K . Effects of different sodium acetate levels on growth, antioxidant capacity, and fat deposition in juvenile Onychostoma macrolepis fed a high fat diet. J World Aquacult Soc 2023; 55(2): e13019.

[6]	Wang S, Li X, Zhang M, Li M . Effects of dietary sodium acetate on growth, intestinal microbiota composition, and ammonia tolerance of juvenile yellow catfish Pelteobagrus fulvidraco. Aquaculture 2024; 581: 740480.

[7]

Zhao L, Cheng L, Hu Y, Li X, Yang Y, Mu J, et al. Dietary sodium acetate and sodium butyrate attenuate intestinal damage and improve lipid metabolism in juvenile largemouth bass (Micropterus salmoides) fed a high carbohydrate diet by reducing endoplasmic reticulum stress. Anim Nutr 2023; 16: 443-56.

[8]

Liu Q, Cheng L, Wang M, Shen L, Zhang C, Mu J, et al. Dietary sodium acetate and sodium butyrate improve high carbohydrate diet utilization by regulating gut microbiota, liver lipid metabolism, oxidative stress, and inflammation in largemouth bass (Micropterus salmoides). J Anim Sci Biotechnol 2024; 15(1): 50.

[9]	Liu J, Gu QH, Cui Z, Zhao MH, Jia XY . Short chain fatty acids ameliorate experimental antiglomerular basement membrane disease. Clin Immunol 2024; 259: 109903.

[10]	Nikam B, Jha SN, Thakare Y, Coshic P, Gupta N . Short chain fatty acid sodium butyrate suppresses protective humoral immunity by inhibiting follicular T helper cell differentiation. Eur J Immunol 2025; 55(10): e70076.

[11]	Li Y, Yang F, Liu J, Jiang M, Yu Y, Zhou Q, et al. Protective effects of sodium butyrate on fluorosis in rats by regulating bone homeostasis and serum metabolism. Ecotoxicol Environ Saf 2024; 276: 116284.

[12]	Liu Z, Yao X, Jiang W, Zhou Z, Yang M . Sodium butyrate enhances titanium nail osseointegration in ovariectomized rats by inhibiting the PKCα/NOX4/ROS/NFκB pathways. J Orthop Surg Res 2023; 18(1): 556.

[13]	Bampidis V, Azimonti G, Bastos ML, Christensen H, Durjava M, Dusemund B, et al. Assessment of the safety of the feed additives acetic acid, calcium acetate and sodium diacetate for fish. EFSA J 2023; 21(7): e08176.

[14]	Wang W, Zhang J, Shao R, Liang S, Zhang H, Xu W, et al. Sodium acetate alleviates adverse effects caused by the diet with high proportion of soybean meal in turbot (Scophthalmus maximus L.). Aquaculture 2023; 566: 739163.

[15]	Xun P, Jiang H, Huang Q, Feng D, Lun F, Yang K, et al. Effects of sodium acetate supplementation on hematologic parameter, carbohydrate metabolism and intestinal microbiota of juvenile Micropterus salmoides fed high carbohydrate diets. Aquacult Rep 2024; 39: 102498.

[16]	Xun P, Zhuang S, Yao H, Su J, Yang Y, Shu H, et al. Effects of sodium acetate supplementation on growth, hematologic and plasma biochemical parameter, lipid deposition, and intestinal health of juvenile golden pompano Trachinotus ovatus fed high lipid diets. Aquacult Nutr 2024; 2024(1): 7904141.

[17]	Feng Y, Gu J, Zhu T, Li Z, Gu Z, Xu S, et al. Enzymatic cyclodextrin synthesis tributyrin inclusion complex: properties, structural characterization and release behaviors in vitro. Lebensm Wiss Technol 2022; 165: 113726.

[18]	Li C, Li Z, Liu T, Gu Z, Ban X, Tang X, et al. Encapsulating tributyrin during enzymatic cyclodextrin synthesis improves the solubility and bioavailability of tributyrin. Food Hydrocoll 2021; 113: 106512.

[19]	Palma M, Magnoni LJ, Morais S, Viegas I . Tributyrin supplementation in fish and crustacean nutrition: a review. Rev Aquacult 2022; 15(2): 785-800.

[20]

Rairat T, Phansawat P, Keetanon A, Kachapol P, Kumphaphat S, Kitsanayanyong L, et al. Effects of tributyrin on the growth performance, survival, tolerance to hypoxic stress, and nutrient digestibility of Pacific white shrimp, Litopenaeus vannamei, fed different levels of soybean meal. J World Aquacult Soc 2023; 54(6): 1468-81.

[21]	Sun L, Shu H, Kou Y, Dang H, Ai C . Beneficial effects of the butanoic acid derivative tributyrin on the growth, immunity and intestinal health of large mouth bass (Micropterus salmoides). Aquaculture 2024; 590: 741007.

[22]

Wang X, Wan M, Wang Z, Zhang H, Zhu S, Cao X, et al. Effects of tributyrin supplementation on growth performance, intestinal digestive enzyme activity, antioxidant capacity, and inflammation related gene expression of large yellow croaker (Larimichthys crocea) fed with a high level of Clostridium autoethanogenum protein. Aquacult Nutr 2023; 2023: 2687734.

[23]	Zhou ZG, Yu LJ, Liu SB, Yao YY, Zhen YY, Li YQ, et al., inventors; Feed Research Institute of the Chinese Academy of Agricultural Sciences, assignee. A cyclic glucose ester compound and its preparation method and application. Chinese patent CN2024100640124. 2024 Apr 30. Chinese.

[24]	Li Y, Zeng Y, Li D, Yu L, Ding Q, Yang Y, et al. Synthesis and properties of pentabutyryl glucose ester and its effects on the growth, liver and intestinal health, and gut microbiota of zebrafish (Danio rerio). Water Biology and Security 2025; 4(4): 100387.

[25]	Zhou ZG, Yu LJ, Zhang Z, Liu SB, Yao YY, Yang YL, et al., inventors; Feed Research Institute of the Chinese Academy of Agricultural Sciences, assignee. A tetraacetyl vitamin C ester and its preparation method and application. Chinese patent CN2023110383324. 2023 Nov 22. Chinese.

[26]	Li Y, Fu M, Yu L, Zhang Z, Xue Z, Huang L, et al. Synthesis and efficacy of tetraacetyl vitamin C ester: a novel alternative to traditional vitamin C and sodium acetate in aquafeeds. J Anim Sci Biotechnol 2026; 17(1): 77.

[27]	Dong X, Zhang T, Moreno Sanchez HL, Mans JC, Bae SH, Bian L . Enhancing oral absorption of an ester prodrug by coating drug crystals with binary lipid systems and evaluating the influence of compositions. Pharmaceutics 2025; 17(9): 1210.

[28]	Wang B, Friess W . Formation of mannitol core microparticles for sustained release with lipid coating in a mini fluid bed system. Eur J Pharm Biopharm 2017; 120: 126-32.

[29]	Kaczmarek SA, Barri A, Hejdysz M, Rutkowski A . Effect of different doses of coated butyric acid on growth performance and energy utilization in broilers. Poult Sci 2016; 95(4): 851-9.

[30]	Nazir A, Khan EU, Muneeb M, Qaisrani SN, Naveed S, Ahmad S, et al. Influence of dietary supplementation with yeast culture and microencapsulated butyric acid on growth performance, carcass traits, gut health, and immune status in broilers. Vet Sci 2025; 12(4): 359.

[31]	Abdel-Latif HMR, Abdel-Tawwab M, Dawood MAO, Menanteau-Ledouble S, El-Matbouli M . Benefits of dietary butyric acid, sodium butyrate, and their protected forms in aquafeeds: a review. Rev Fish Sci Aquacult 2020; 28(4): 421-48.

[32]

Vetrivelan V, Sakthivel S, Muthu S, Al-Saadi AA . Non covalent interaction, adsorption characteristics and solvent effect of procainamide anti arrhythmias drug on silver and gold loaded silica surfaces: SERS spectroscopy, density functional theory and molecular docking investigations. RSC Adv 2023; 13(14): 9539-54.

[33]	Xu Z, Zhu C, Shen H, Liu Y, Tang J, Weitz DA, et al. Enhancing drug solubility through competitive adsorption on silica nanosurfaces with ultrahigh silanol densities. Proc Natl Acad Sci USA 2025; 122(4): e2423426122.

[34]	Quagliariello V, Masarone M, Armenia E, Giudice A, Barbarisi M, Caraglia M, et al. Chitosan coated liposomes loaded with butyric acid demonstrate anticancer and anti inflammatory activity in human hepatoma HepG2 cells. Oncol Rep 2018; 41(3): 1473-86.

[35]	Ngo AN, Ezoulin MJ, Murowchick JB, Gounev AD, Youan BB . Sodium acetate coated tenofovir loaded chitosan nanoparticles for improved physico chemical properties. Pharm Res 2016; 33(2): 367-83.

[36]	Jesus GFA, Pereira SA, Owatari MS, Addam K, Silva BC, Sterzelecki FC, et al. Use of protected forms of sodium butyrate benefit the development and intestinal health of Nile tilapia during the sexual reversion period. Aquaculture 2019; 504: 326-33.

[37]	Zhou JS, Guo P, Yu HB, Ji H, Lai ZW, Chen YA . Growth performance, lipid metabolism, and health status of grass carp (Ctenopharyngodon idella) fed three different forms of sodium butyrate. Fish Physiol Biochem 2019; 45(1): 287-98.

[38]	Yan J, Luo K, Wang B, He J, Li C, Zhou J, et al. Effects of dietary compound acidifier (Biomin) on the growth, anti oxidation, immunity, and intestinal health of juvenile channel catfish (Ictalurus punctatus). Aquacult Rep 2025; 40: 102577.

[39]

Zhang J, Deng H, Liang W, Chi S, Tan B, Dong X, et al. Supplementing the diet of hybrid grouper (Epinephelus fuscoguttatus × E. lanceolatus) with compound acidifier is a good way to alleviate poor intestinal growth caused by high levels of cottonseed protein concentrate. Aquacult Nutr 2024 Jun: 561293.

[40]	Alves Jesus GF, Owatari MS, Pereira SA, Silva BC, Syracuse NM, Lopes GR, et al. Effects of sodium butyrate and Lippia origanoides essential oil blend on growth, intestinal microbiota, histology, and haemato immunological response of Nile tilapia. Fish Shellfish Immunol 2021; 117: 62-9.

[41]	Casetta J, Gasparino E, Isabela da Silva C, Ribeiro RP, Braccini GL, Refundini G, et al. Immune response in sexual inverted and non inverted Nile tilapia fingerlings supplemented with organic acid and essential oil. Fish Shellfish Immunol 2022; 127: 975-81.

[42]	Huyben D, Chiasson M, Lumsden JS, Pham PH, Chowdhury MAK . Dietary microencapsulated blend of organic acids and plant essential oils affects intestinal morphology and microbiome of rainbow trout (Oncorhynchus mykiss). Microorganisms 2021; 9(10): 2063.

[43]	Vernia P, Monteleone G, Grandinetti G, Villotti G, Di Giulio E, Frieri G, et al. Combined oral sodium butyrate and mesalazine treatment compared to oral mesalazine alone in ulcerative colitis: randomized, double blind, placebo controlled pilot study. Dig Dis Sci 2000; 45(5): 976-81.

[44]	Yong CC, Sakurai T, Kaneko H, Horigome A, Mitsuyama E, Nakajima A, et al. Human gut associated Bifidobacterium species salvage exogenous indole, a uremic toxin precursor, to synthesize indole 3 lactic acid via tryptophan. Gut Microbes 2024; 16(1): 2347728.

[45]	Huang W, Cho KY, Meng D, Walker WA . The impact of indole 3 lactic acid on immature intestinal innate immunity and development: a transcriptomic analysis. Sci Rep 2021; 11(1): 8088.

[46]	Kim CS, Jung S, Hwang GS, Shin DM . Gut microbiota indole 3 propionic acid mediates neuroprotective effect of probiotic consumption in healthy elderly: a randomized, double blind, placebo controlled, multicenter trial and in vitro study. Clin Nutr 2023; 42(6): 1025-33.

[47]	Gong Q, Qu X, Zhao Y, Zhang X, Cao S, Wang X, et al. Indole 3 acetic acid esterified with waxy, normal, and high amylose maize starches: comparative study on colon targeted delivery and intestinal health impact. Nutrients 2024; 16(20): 3446.

[48]	Nakayama Y, Otoi T, Zhao N, Nguyen ST, Torigoe N, Lin Q, et al. Indole 3 propionic acid supplementation during in vitro maturation improves in vitro production of porcine embryos. BMC Vet Res 2025; 21(1): 642.

[49]	Ding FF, Zhou NN, Mao YJ, Yang J, Limbu SM, Galindo-Villegas J, et al. Lactiplantibacillus plantarum attenuate gossypol induced hepatic lipotoxicity by altering intestinal microbiota for enriching microbial tryptophan metabolites in Nile tilapia (Oreochromis niloticus). Microbiome 2025; 13(1): 180.

[50]	Li J, Zhang L, Wu T, Li Y, Zhou X, Ruan Z . Indole 3 propionic acid improved the intestinal barrier by enhancing epithelial barrier and mucus barrier. J Agric Food Chem 2021; 69(5): 1487-95.

[51]	Kasfimura M, Kikugawa Y . Formylation of indoles with formic acid. Chem Pharm Bull 1983; 31(8): 2892-4.

[52]	Rajeev N, Sharath Kumar KS, Bommegowda YK, Rangappa KS, Sadashiva MP . Catalyst free sequential one pot reaction for the synthesis of 3 indole propanoates/propanoic acid/propanamides as antituberculosis agents. J Chin Chem Soc 2020; 68(1): 39-44.

[53]	Centofanti F, Buono A, Verboni M, Tomino C, Lucarini S, Duranti A, et al. Synthetic methodologies and therapeutic potential of indole 3 carbinol (I3C) and its derivatives. Pharmaceuticals 2023; 16(2): 240.

[54]	Farlow DX, Flaugh MX, Horvath SX, Lavagnino EX, Pranc P . Two efficient syntheses of indole 3 propionic esters and acids. Further applications of meldrum’s acid. Org Prep Proced Int 1981; 13(1): 39-48.

[55]	Grillot G, Schaffrath R. Condensation of thiophenols and formaldehyde with some aromatic amines. J Org Chem 1959; 24(8): 1035-74.

[56]	Robinson B. The fischer indole synthesis. Chem Rev 1962; 63(4): 373-401.

[57]	Zhou Z, Yu L, Li Y, Yao Y, Zhang Z, Yang Y, et al., inventors; Feed Research Institute of the Chinese Academy of Agricultural Sciences, assignee. A synthesis method of indole 3 propionic acid. Chinese patent CN2024103280120. 2024 Jun 24. Chinese.

[58]	Yu K, Li Q, Sun X, Peng X, Tang Q, Chu H, et al. Bacterial indole 3 lactic acid affects epithelium macrophage crosstalk to regulate intestinal homeostasis. Proc Natl Acad Sci USA 2023; 120(45): e2309032120.

[59]	Zhao Y, Wu X, Wu C, Meng R, Gu Y, Xiao X . Phytochemical profiles and antioxidant activity of fermented barley with Lactiplantibacillus plantarum dy 1. Food Biotechnol 2022; 36(3): 266-82.

[60]	Zhang F, Tian J, Li J, Zhang T, Wang X . ILA mitigates HFD induced metabolic dysfunction via lipid immune crosstalk and gut microbiota modulation in zebrafish. Fish Shellfish Immunol 2025; 167: 110683.

[61]	Johnson H, Grosby D . Indole 3 acetic acid. Org Synth 1964; 44: 64.

[62]	Zhou Z, Yu L, Li Y, Yao Y, Zhang Z, Yang Y, et al., inventors; Feed Research Institute of the Chinese Academy of Agricultural Sciences, assignee. A synthesis process of indole 3 lactic acid. Chinese patent CN2024100815720. 2024 May 7. Chinese.

[63]	Zhou Z, Yu L, Li Y, Yao Y, Zhang Z, Yang Y, et al., inventors; Feed Research Institute of the Chinese Academy of Agricultural Sciences, assignee. A synthetic process of chiral indole 3 lactic acid. Chinese patent CN2024100815701. 2024 Apr 30. Chinese.

[64]	Chaudhary A, Kumar A, Ankit A, Singh RG . Discovery of Cu (II) dipyridophenazine complex for synergistic cuproptosis/chemodynamic therapy via disrupting the tricarboxylic acid (TCA) cycle in metastatic TNBC. Small 2025; 21(26): e2504554.

[65]	Chen X, Dong X, Liu J, Luo Q, Liu L . Pathway engineering of Escherichia coli for α ketoglutaric acid production. Biotechnol Bioeng 2020; 117(9): 2791-3278.

[66]	Li M, Chen Q, Zhou M, Li X, Wang Z, Wang J . α Ketoglutaric acid reprograms macrophages by altering energy metabolism to promote the regeneration of small diameter vascular grafts. ACS Biomater Sci Eng 2025; 11(1): 518-30.

[67]	Wang L, Wu D, Li J, Xu Q, Miao L, Ge X, et al. Effects of dietary α ketoglutarate on the growth performance, digestive enzymes, tor signaling pathway and intestinal microbiota of juvenile mirror carp (Cyprinus carpio) fed low phosphorus diets. Aquaculture 2023; 574: 739736.

[68]	Wang L, Fan Z, Zhang Y, Wu D, Li J, Xu Q . Effect of phosphorus on growth performance, intestinal tight junctions, Nrf2 signaling pathway and immune response of juvenile mirror carp (Cyprinus carpio) fed different α ketoglutarate levels. Fish Shellfish Immunol 2022; 120: 271-9.

[69]	Zhang Y, Hu J, Lu P, Yang R, Liang XF, Liu L . Addition of α ketoglutaric acid (AKG) reduces deamination in Chinese perch (Siniperca chuatsi) fed with fermented soybean meal as a substitute for fishmeal. Fish Physiol Biochem 2024; 50(3): 989-1002.

[70]	Cao C, Liu Z, Endri H, Fan W, Xie X, Huang Y, et al. The cellobiose and α ketoglutarate as metabolic modulators in Eriocheir sinensis to resist Spiroplasma eriocheiris infection. Aquaculture 2021; 533: 736180.

[71]	Zheng D, Yang X, Liang J, Zhao J, Xu Q . Effects of dietary α ketoglutarate supplementation on growth performance, digestive enzyme activity, immune gene expression, and intestinal morphology of largemouth bass (Micropterus salmoides) fed high soybean diet. Aquacult Rep 2025; 41: 102706.

[72]	Friedman L, Kosower E . α-Ketoglutaric acid. Org Synth 1946; 26: 42-4.

[73]	Shemin D, Herbst R . The condensation of α keto acids and acetamide. J Am Chem Soc 1938; 60(8): 1954-7.

[74]	Mitome H, Miura K, Miyada T, Kato G, Takenishi M, Ono K, et al. Synthesis of [1-13C]2 oxoglutaric acid and 13C breath tests designed to assess TCA cycle flux. Chem Pharm Bull 2025; 73(9): 807-12.

[75]	Jung ME, Deng G . Synthesis of the 1 monoester of 2 ketoalkanedioic acids, for example, octyl α ketoglutarate. J Org Chem 2012; 77(23): 11002-5.

[76]	Li Y, Sun L, Feng J, Wu R, Xu Q, Zhang C, et al. Efficient production of α ketoglutarate in the gdh deleted Corynebacterium glutamicum by novel double phase pH and biotin control strategy. Bioprocess Biosyst Eng 2016; 39(6): 967-76.

[77]	Zhou Z, Yu L, Li Y, Yao Y, Zhang Z, Yang Y, et al., inventors; Chinese Academy of Agricultural Sciences, assignee. A preparation method of α ketoglutaric acid and its derivatives. Chinese patent CA2024102849115. 2024 Jun 12. Chinese.

[78]	Marchesi E, Gentili V, Bortolotti D, Preti L, Marchetti P, Cristofori V, et al. Dihydroartemisinin ursodeoxycholic bile acid hybrids in the fight against SARS CoV 2. ACS Omega 2023; 8(47): 45078-87.

[79]	Monteiro-Cardoso VF, Yeo XY, Bae HG, Mayan DC, Wehbe M, Lee S, et al. The bile acid chenodeoxycholic acid associates with reduced stroke in humans and mice. J Lipid Res 2025; 66(1): 100712.

[80]	Zhang L, Zheng Z, Huang H, Fu Y, Chen T, Liu C, et al. Multi omics reveals deoxycholic acid modulates bile acid metabolism via the gut microbiota to antagonize carbon tetrachloride induced chronic liver injury. Gut Microbes 2024; 16(1): 2323236.

[81]	Yang F, Wu L, Xu W, Wu Y, Zhu S, Zhang Y, et al. Sodium taurocholate co transporting polypeptide deficiency attenuates acetaminophen induced hepatotoxicity via regulating expression of drug metabolism enzymes in mice. Toxicol Appl Pharmacol 2025; 497: 117266.

[82]	Cong J, Liu P, Han Z, Ying W, Li C, Yang Y, et al. Bile acids modified by the intestinal microbiota promote colorectal cancer growth by suppressing CD8⁺ T cell effector functions. Immunity 2024; 57(4): 876-889.e11.

[83]	Milivojac T, Grabež M, Krivokuća A, Malićević U, Gajić Bojić M, Ðukanović Đ, et al. Ursodeoxycholic and chenodeoxycholic bile acids attenuate systemic and liver inflammation induced by lipopolysaccharide in rats. Mol Cell Biochem 2025; 480(1): 563-76.

[84]	Su C, Li J, Lu Y, Wang Y, Ding Y, Pan L, et al. Interactive effects of dietary cholesterol and bile acids on the growth, lipid metabolism, immune response and intestinal microbiota of Litopenaeus vannamei: sparing effect of bile acids on cholesterol in shrimp diets. Aquaculture 2022; 547: 737412.

[85]	Su C, Liu X, Li J, Zhang M, Pan L, Lu Y, et al. Effects of bile acids on the growth performance, lipid metabolism, non specific immunity and intestinal microbiota of Pacific white shrimp (Litopenaeus vannamei). Aquacult Nutr 2021; 27(6): 2029-41.

[86]	Zhu A, Zhang X, Yan X . Olfactory detection of ursodeoxycholic acid (UDCA) in large yellow croaker (Larimichthys crocea): responses, pathways and receptor functions. J Exp Biol 2025; 228(21):jeb250571.

[87]	Wu H, Wang X, Li H, Li C, Zhu J, Hu J, et al. Thyroid hormone ameliorates ursodeoxycholic acid induced heart damage in zebrafish embryos. Life Sci 2025; 377: 123716.

[88]	Zhu A, Li W, Zhang X, Yan X . Dietary ursodeoxycholic acid supplementation enhanced nonspecific immunity, antioxidant capacity, and anti inflammatory related gene expression in juvenile large yellow croaker (Larimichthys crocea). Aquacult Rep 2025; 41: 102698.

[89]	Chen W, Hu D, Feng Z, Liu Z . An effective synthesis of ursodeoxycholic acid from dehydroepiandrosterone. Steroids 2021; 172: 108870.

[90]	He XL, Wang LT, Gu XZ, Xiao JX, Qiu WW . A facile synthesis of ursodeoxycholic acid and obeticholic acid from cholic acid. Steroids 2018; 140: 173-8.

[91]	Wang J, Gu XZ, He LM, Li CC, Qiu WW . Synthesis of ursodeoxycholic acid from plant source (20S)-21 hydroxy-20 methylpregn-4-en-3-one. Steroids 2020; 157: 108600.

[92]	Tonin F, Arends IWCE . Latest development in the synthesis of ursodeoxycholic acid (UDCA): a critical review. Beilstein J Org Chem 2018; 14: 470-83.

[93]	Pyuridon J, Domyuanku R, Baban S, inventors; Sankyo Co., Ltd., assignee. Manufacture of ursodeoxycholic acid and intermediate product from 3α,7β,12α trihydroxycholanic acid. Japanese patent JPS5829799A. 1983 Feb 18. Japanese.

[94]	Fieser LF, Rajagopalan S . Oxidation of steroids. III. Selective oxidations and acylations in the bile acid series. J Am Chem Soc 1950; 72(12): 5530-6.

[95]	Zhou Z, Yu L, Li Y, Zhang Z, Yang Y, Yao Y, et al., inventors; Feed Research Institute of the Chinese Academy of Agricultural Sciences, assignee. A preparation method of ursodeoxycholic acid. Canadian patent CA2024108685922. 2024 Aug 12.

[96]

Zhang Y, Maas RM, Hilgers P, Horstmann Zuther P, Kokou F, Staessen TWO, et al. Effect of non starch polysaccharides and bile acid supplementation on nutrient digestibility, bile acid balance, faecal waste production and characteristics of yellowtail kingfish (Seriola lalandi). Aquacult Rep 2025; 41: 102708.

[97]	Staessen TWO, Verdegem MCJ, Weththasinghe P, Schrama JW . The effect of dietary non starch polysaccharide level and bile acid supplementation on fat digestibility and the bile acid balance in rainbow trout (Oncorhynchus mykiss). Aquaculture 2020; 523: 735174.

[98]	Fuentes J, Gregório SF, Fonseca F, Robles-Arozarena R, Martos-Sitcha JA, Moyano FJ . Effect of bile salts on intestinal epithelial function in gilthead seabream (Sparus aurata). Fish Physiol Biochem 2024; 50(4): 1777-90.

[99]	Norman A. Preparation of conjugated bile acids using mixed carboxylic acid anhydrides. Ark Kemi 1955; 8: 331-42.

[100]

Lack L, Dorrity Jr FO, Walker T, Singletary GD . Synthesis of conjugated bile acids by means of a peptide coupling reagent. J Lipid Res 1973; 14(3): 367-70.

[101]

Tserng KY, Hachey DL, Klein PD . An improved procedure for the synthesis of glycine and taurine conjugates of bile acids. J Lipid Res 1977; 18(3): 404-7.

[102]

Yang J. Synthesis of sodium taurocholate. Chin J Pharm 2003; 34(12): 594-5.

[103]

Zhou Z, Yu L, Li Y, Zhang Z, Yang Y, Yao Y, et al., inventors; Feed Research Institute of the Chinese Academy of Agricultural Sciences, assignee. A synthesis method of sodium taurocholate, a catalyst and a preparation method of the catalyst. Chinese patent CN118852000A. 2026 Jun 16. Chinese.

[104]

Wen J, Mercado GP, Volland A, Doden HL, Lickwar CR, Crooks T, et al. Fxr signaling and microbial metabolism of bile salts in the zebrafish intestine. Sci Adv 2021; 7(30): eabg1371.

[105]

Hwang DF, Yeh YH, Lai YS, Deng JF . Identification of cyprinol and cyprinol sulfate from grass carp bile and their toxic effects in rats. Toxicon 2001; 39(2-3): 411-4.

[106]

Goto T, Holzinger F, Hagey LR, Cerrè C, Ton-Nu HT, Schteingart CD, et al. Physicochemical and physiological properties of 5α cyprinol sulfate, the toxic bile salt of cyprinid fish. J Lipid Res 2003; 44(9): 1643-51.

[107]

Hahn MA, Effertz C, Bigler L, von Elert E . 5α cyprinol sulfate, a bile salt from fish, induces diel vertical migration in Daphnia. eLife 2019; 8: e44791.

[108]

Li Y, Yan Z, Lin A, Yang X, Li X, Yin X, et al. Epidermal oxysterols function as alarm substances in zebrafish. iScience 2024; 27(5): 109660.

[109]

Zhou Z, Xue Z, Li Y, Yu L, Ding Q, Yao Y, et al., inventors; Feed Research Institute of the Chinese Academy of Agricultural Sciences, assignee. An extraction method of 5α cyhinosterol sulfate. Chinese patent CN2025112725467. 2025 Dec 9. Chinese.

[110]

Dubrovskiy VA, Sosin VG, Starodubtseva AA, Turmukhanova MZ . Natural and synthetic decahydroquinolines: synthesis strategies and biological activity. J Heterocycl Chem 2025; 62(11): 1708-51.

[111]

Yang YD, Yang BB, Li L . A nonneglectable stereochemical factor in drug development: atropisomerism. Chirality 2022; 34(10): 1355-70.

[112]

Zhou Z, Xue Z, Li Y, Yu L, Ding Q, Yao Y, et al., inventors; Feed Research Institute of the Chinese Academy of Agricultural Sciences, assignee. A synthesis method of 5β cyhinosterol sulfate. Chinese patent CN2025112725452. 2025 Dec 9. Chinese.

[113]

Pande GSJ, Scheie AA, Benneche T, Wille M, Sorgeloos P, Bossier P, et al. Quorum sensing disrupting compounds protect larvae of the giant freshwater prawn Macrobrachium rosenbergii from Vibrio harveyi infection. Aquaculture 2013; 406-407: 121-4.

[114]

Sandy M, Carter-Franklin JN, Martin JD, Butler A . Vanadium bromoperoxidase from Delisea pulchra: enzyme catalyzed formation of bromofuranone and attendant disruption of quorum sensing. Chem Commun 2011; 47(44): 12086-8.

[115]

Markus V, Golberg K, Teralı K, Ozer N, Kramarsky-Winter E, Marks RS, et al. Assessing the molecular targets and mode of action of furanone C 30 on Pseudomonas aeruginosa quorum sensing. Molecules 2021; 26(6): 1620.

[116]

Suzuki S, Morita Y, Ishige S, Kai K, Kawasaki K, Matsushita K, et al. Effects of quorum sensing interfering agents, including macrolides and furanone C 30, and an efflux pump inhibitor on nitrosative stress sensitivity in Pseudomonas aeruginosa. Microbiology 2024; 170(6): 170.

[117]

He Z, Kong X, Shao T, Zhang Y, Wen C . Alterations of the gut microbiota associated with promoting efficacy of prednisone by bromofuranone in MRL/lpr mice. Front Microbiol 2019; 10: 978.

[118]

Rossi R, Lessi M, Manzini C, Marianetti G, Bellina F. Synthesis and biological properties of 2(5H) furanones featuring bromine atoms on the heterocyclic ring and/or brominated substituents. Curr Org Chem 2017; 21(11): 964-1018.

[119]

Brückner R, Sorg A, Siegel K . A novel access to c alkylidenebutenolides: sequential stille couplings of dibromomethylenebutenolides. Synlett 2004; 2: 0321-5.

[120]

Lyons T, Gahan CGM, O’Sullivan TP . Structure activity relationships of furanones, dihydropyrrolones and thiophenones as potential quorum sensing inhibitors. Future Med Chem 2020; 12(21): 1925-43.

[121]

Villegas Pañeda AG, Ramírez Apan MTO . Synthesis and cytotoxic evaluation of protoanemonin and three brominated derivatives. Rev Colomb Quim 2020; 49(3): 13-8.

[122]

Zhou Z, Yu L, Xia R, Yang Y, Yao Y, Zhang Z, et al., inventors; Feed Research Institute of the Chinese Academy of Agricultural Sciences, assignee. A bromofurone C 30 sustained release agent and its preparation method. Chinese patent CN116253703 A. 2025 Jun 15. Chinese.