What Is the Use of Rosmarinic Acid in Animal Feeding?

Rosmarinic acid is a phenolic acid compound isolated from rosemary leaves[1] and first reported by Italian chemists in 1958[2]. Rosmarinic acid is a phenolic acid compound isolated from rosemary leaves[1] and first reported by Italian chemists in 1958[2]. It is formed by the condensation of caffeic acid and 3,4-dihydroxybenzoic acid, with the molecular formula C18 H16 O8 and relative molecular mass of 360.31 (see Figure 1 for chemical structure). It is a colorless or light yellow crystalline solid, easily soluble in water and an aqueous ethanol solution, with a density of about 1.12 g/cm3 and a melting point of about 171 °C. The pH and temperature have a minor effect on the stability of rosmarinic acid, but it may degrade under conditions such as light, high temperatures and oxidation. Rosmarinic acid can also be extracted from various plants such as Boraginaceae, Cucurbitaceae, and Lamiaceae. Common extraction methods include Soxhlet extraction, maceration extraction, reflux extraction, ultrasound-assisted extraction, microwave-assisted extraction, enzyme-assisted extraction, and supercritical fluid extraction [3-5].

Rosemary acid has various biological functions such as anti-inflammatory [6], anti-oxidant [7], antibacterial [8], anticancer [9] and antiviral [10], and is widely used in food, medicine and cosmetics [11]. Compared with chemical drugs, natural products and their derivatives have the characteristics of low toxicity, multi-target therapy, fewer side effects, and abundant sources. They have a unique effect on improving animal production performance, feed utilization, antioxidant capacity and immune function, and have gradually become a research hotspot [12-13]. The authors systematically describe the biological functions of rosmarinic acid and its application in animal production, with the aim of providing a theoretical basis for basic research on rosmarinic acid and its application in animal production practices.

1 Biological functions of rosmarinic acid

1.1 Anti-inflammatory effect

Inflammation is a non-specific response of the body to endogenous and exogenous stimuli and damage, often resulting in symptoms such as skin redness and swelling, joint pain, dysfunction and fever. Non-steroidal anti-inflammatory drugs have long been the mainstay of treatment for inflammatory diseases, but their further development is limited by damage to multiple systems such as the gastrointestinal, cardiovascular, liver, kidney and brain systems [14]. Studies have shown that rosmarinic acid has significant anti-inflammatory activity and can reduce inflammatory responses by inhibiting the production of multiple inflammatory mediators (such as interleukins and tumor necrosis factors) [15].

Wu Jiaqing et al. [16] found that a combination of thymol and rosmarinic acid can relieve the inflammatory response induced by lipopolysaccharides (LPS) in rats by upregulating the expression of interleukin-10 (IL-10) and downregulating the expression of IL-6 and tumor necrosis factor-α (TNF-α). TNF-α) expression levels to alleviate lipopolysaccharide (LPS)-induced inflammatory responses in the rat intestine. Ho et al. [17] showed that oral administration of rosmarinic acid dose-dependently suppressed the expression of IL-23 and IL-17A in mouse tissues, alleviated neutrophil infiltration in skin tissues, and thus improved imiquimod-induced psoriasis. Lu et al. [18] found that rosmarinic acid can significantly inhibit the expression of TNF-α, IL-6, cyclooxygenase-2 (COX-2) and induced nitric oxide synthase (iNOS) in liver tissue, effectively alleviating carbon tetrachloride-induced liver inflammation.

The good anti-inflammatory effect of rosmarinic acid is closely related to its multi-target regulation of inflammatory signal pathways, such as nuclear factor-kappaB (NF-κB), mitogen-activated protein kinases (MAPK), nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1) signal pathways. Jiang et al. [19] found that rosmarinic acid effectively alleviates LPS-induced inflammation by inhibiting the Toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)/NF-κB signal pathway. TLR4)/myeloid differentiation factor 88 (MyD88)/NF-κB signaling pathway effectively alleviates LPS-induced mastitis.

Chen et al. [20] found that rosmarinic acid can significantly downregulate the mRNA expression of TNF-α, IL-8 and iNOS mRNA expression, attenuated the activation of the MAPK/NF-κB signaling pathway, and improved the inflammatory response of vascular smooth muscle cells induced by LPS. Ma et al. [21] showed that rosmarinic acid can inhibit the oxidative stress and inflammatory response after spinal cord injury by activating the Nrf2/HO-1 pathway and inhibiting the TLR4/NF-κB pathway, thereby improving functional recovery after spinal cord injury. In summary, rosmarinic acid can exert anti-inflammatory effects by inhibiting the release of inflammatory mediators and regulating inflammatory signaling pathways, and can play a greater role in the prevention and treatment of inflammatory diseases in animals.

1.2 Antioxidant effect

A variety of endogenous and exogenous factors can accelerate the production of reactive oxygen species (ROS). Excessive ROS can induce oxidative stress in the body, thereby causing organ damage and promoting the occurrence and development of various diseases. Some studies have shown that rosmarinic acid can reduce oxidative stress by preventing lipid peroxidation, reducing nitric oxide production, and reactivating glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities [22]. Jin et al. [23] found that rosmarinic acid can maintain mitochondrial function, reduce ROS secretion, and stimulate SOD) activity to reduce oxidative stress response [22]. Jin et al. [23] found that rosmarinic acid can protect mouse C2C12 myoblasts from hydrogen peroxide-induced damage by maintaining mitochondrial function, reducing ROS secretion, and activating the Nrf2/HO-1 pathway.

Huang et al. [24] found that after treatment with rosmarinic acid, the levels of oxidative stress-related proteins such as FOXO1, FOXO3a, and P53 were reduced in ovarian tissue, while the levels of antioxidant-related enzymes SOD and GSH-Px increased, effectively alleviating oxidative damage to the ovaries of mice. In addition, Fatemeh et al. [25] showed that rosmarinic acid can effectively protect rats against ethanol-induced gastric inflammation by reducing malondialdehyde (MDA) levels in gastric tissue, increasing SOD, catalase (CAT) and GSH-Px levels, thereby enhancing the body's antioxidant capacity. effectively protect rats from ethanol-induced gastric inflammation. In summary, rosmarinic acid can exert an antioxidant effect by increasing free radical scavenging capacity, inhibiting the activity of oxidase, promoting the activity of antioxidant enzymes, and regulating oxidative stress-related signal pathways, thereby protecting the body from oxidative stress damage.

1.3 Anti-cancer effect

Cancer-related human deaths have always been one of the urgent challenges to be overcome in the global healthcare system. Many studies have shown that rosmarinic acid and its derivatives are currently widely used in the prevention and treatment of various cancers [26]. Some studies have shown that rosmarinic acid can inhibit tumor cell proliferation and induce apoptosis by regulating signal pathways such as phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt), MAPK and NF-κB signal pathways to inhibit tumor cell proliferation and induce apoptosis, thereby inhibiting tumor cell growth and metastasis [27]. Ye Chen [28] found that rosmarinic acid exerts its anti-colorectal cancer effect by targeting transient receptor potential channel type 1, promoting apoptosis of colorectal cancer cells.

Qiu-Lian Qin et al. [29] found that rosmarinic acid can affect the occurrence of autophagy by regulating the PI3K/Akt/mTOR signaling pathway, thereby affecting the proliferation and migration of human cervical cancer Hela cells. It has also been found that rosmarinic acid reduces the survival and migration of squamous cells in the head and neck in a dose-dependent manner, and inhibits the phosphorylation of epidermal growth factor, thereby reducing the production and release of ROS [30]. Although several studies have found that rosmarinic acid has potential anticancer effects, there is little reported evidence from animal studies. The main focus has been on cancer cells and human diseases. The exploration and research of cancer in animal diseases is in its infancy, so its specific application in animal production still requires further research and verification.

1.4 Antiviral effect

The prevention and control of viral diseases is still mainly based on vaccine immunization, but vaccine research and development cannot keep up with the speed of virus mutation. It is worth noting that natural products and their derivatives are gradually becoming a research hotspot as antiviral drugs and immune enhancers. Jheng et al. [31] found that that rosemary acid pretreatment can increase the survival rate of mice infected with influenza A virus A/WSN/33, and that it can reduce the expression of serine protein kinase and phosphorylated Akt in a dose-dependent manner, further inhibiting the entry of influenza A virus into host cells, thereby effectively inhibiting diseases caused by different influenza A viruses. Ritesh et al. [32] found that rosmarinic acid showed good antiviral activity against all four serotypes of dengue virus and was non-toxic. It is hoped that it will become a potential antiviral drug for the treatment of dengue fever.

Hsieh et al. [33] showed that rosmarinic acid may target virus particles and interfere with the virus-P-selectin glycoprotein ligand-1 (P-selectin glycoprotein ligand-1) interaction by affecting the early stages of Enterovirus A71 (EV-A71) infection. targeting virus particles and interfering with the interaction between the virus and P-selectin glycoprotein ligand-1 (PSGL1) and heparan sulfate. In addition, rosmarinic acid also has the same effect on emerging virus variants. Therefore, rosmarinic acid can be regarded as a multi-target drug against EV-A71-PSGL1 and heparan sulfate. Rosmarinic acid has been defined in a number of studies as a phytochemical with broad-spectrum antiviral activity, but its antiviral effect is still in the preliminary research stage. The dosage and route of administration for the prevention and control of viral infections still need to be further studied and discussed. Further research is also needed to verify its effectiveness and safety in clinical applications in animals.

1.5 Antibacterial effect

Rosmarinic acid has been shown to be an important antibacterial agent with good inhibitory activity against a variety of fungal and bacterial pathogens [34-36]. Zhang et al. [37] showed that rosmarinic acid exhibited strong antibacterial activity against Escherichia coli, Salmonella, Staphylococcus aureus and Bacillus subtilis, mainly by disrupting cell structure and proteins and inhibiting Na+ /K+ -ATPase activity. Other studies have shown that rosmarinic acid can effectively inhibit the growth of the genus Candida. The mechanism of action may be related to preventing biofilm formation and interfering with mitochondrial function [38].

Guo Daosen et al. [39] found that rosmarinic acid inhibits the mycelial growth of a variety of plant pathogenic fungi, including Botrytis cinerea, Alternaria alternata, Penicillium citrinum and Monilia laxa. Guo Qunqun et al. [40] showed that rosmarinic acid has strong antibacterial activity against Staphylococcus aureus and Escherichia coli. The diameters of the antibacterial rings of 1 mg/mL rosmarinic acid against Staphylococcus aureus and Escherichia coli were 30 and 32 mm, respectively. The above studies have shown that rosmarinic acid has a good inhibitory effect on a variety of gram-negative and gram-positive bacteria, and has great potential for the prevention and treatment of fungal and bacterial infectious diseases in animals.

1.6 Other effects

The biological functions of rosmarinic acid still require further research and development. Immunomodulation, antidepressant, neuroprotection and liver and kidney protection are also key areas of focus for clinical production and animal diagnosis and treatment. Liang Zhengmin et al. [41] found that rosmarinic acid can increase the expression levels of IL-4, IL-5 and IL-13 in bronchoalveolar lavage fluid of mice, reduce the expression level of γ-interferon, inhibit the secretion of Th2 cytokines, and further studies have found that rosmarinic acid can effectively reduce the occurrence of allergic asthma in mice [42].

Cao Xiaopin et al. [43] found that rosmarinic acid significantly increased the regeneration rate of hippocampal neurons in rats, promoted the expression of phosphorylated Akt and mTOR proteins, effectively improving the behavior of rats in the depression model. Yu et al. [44] showed that rosmarinic acid can effectively alleviate depression-like behavior and nerve damage caused by neuroinflammation. It can also exert neuroprotective effects by improving mitochondrial function to protect the mouse brain from oxidative and inflammatory damage induced by LPS. Another study found that rosmarinic acid improved the liver toxicity induced by acetaminophen in rats in a dose-dependent manner by reducing the levels of serum alanine aminotransferase and aspartate aminotransferase, improving the damage to hepatocytes around the portal vein area, necrosis of the liver parenchyma, and poor cell infiltration [45]. In addition, Xiang et al. [46] showed that rosmarinic acid can dose-dependently upregulate the expression levels of HO-1, Keap1, GCLC and GCLM, activate the Nrf2 signaling pathway, and effectively improve cisplatin-induced drug-induced liver and kidney damage.

2 Application of rosmarinic acid in animal production

2.1 Application of rosmarinic acid in pig production

In pig farming, various diseases pose challenges at all stages of production, from piglets to fattening, seriously affecting the health status, production performance, meat quality, feed conversion rate, etc. of the pig herd. Digestive diseases in weaned piglets are the primary difficulties faced in farming. Yang et al. [47] showed that adding 200 mg/kg rosemary extract to the basal diet of weaned piglets can effectively increase the villus height of the jejunum and ileum, improve intestinal morphology, increase the abundance of beneficial intestinal microflora, and significantly reduce the diarrhea rate of piglets. Lei Mingkang et al. [48] found that rosemary acid can significantly reduce the depth of the colon crypts, upregulate the gene expression of tight junction proteins (Occludin and ZO-1) in the intestinal mucosa, and increase the content of short-chain fatty acids in the colon chyme, effectively alleviating the diarrhea and inflammatory response caused by Escherichia coli infection in piglets. A good intestinal environment is conducive to the digestion and absorption of nutrients, thereby promoting the growth and development of fattening pigs.

Zhao Wenxuan et al. [49] showed that adding 300 mg/kg hesperidin and 20 mg/kg rosmarinic acid to the basal diet of 90-day-old male pigs for 90 days can significantly increase the thickness of the mucosa in the pig cecum, total antioxidant capacity (T-AOC), SOD activity, and enhanced Nrf2/HO-1 mRNA expression. It can also regulate the intestinal microbiota, reduce the number of harmful bacteria in the cecum, and thus effectively improve the growth performance of fattening pigs. The widespread use of rosemarinic acid in pig farming depends on its regulation of intestinal health and its effect on improving meat quality. Zhang et al. [50] found that adding 500 mg/kg rosemarinic acid to the feed can effectively regulate the fat metabolism and intestinal microbiota of finishing pigs, and improve the quality of pork by increasing fat deposition in their muscles.

Tai Ruiqing [51] added 200 mg/kg rosmarinic acid to the feed of fattening pigs (triple hybrid pigs) for 60 days, which increased the average daily gain (ADG), fat content and meat quality score. In addition, the addition of rosmarinic acid can also increase the activity of antioxidant enzymes in serum, liver and muscle, thereby improving the taste and storage stability of pork. In summary, rosmarinic acid can effectively improve the production performance and economic benefits of pigs by improving intestinal health, nutrient absorption and feed utilization, thereby improving pig growth performance and pork quality.

2.2 Application of rosmarinic acid in chicken production

Rosmarinic acid also plays an important role in improving the growth performance, muscle quality and immune regulation of chickens. Chen Lu et al. [52] found that adding 30 mg/kg hesperidin and 15 mg/kg rosmarinic acid to the basal diet of broilers for after 42 days of continuous feeding, the average daily feed intake (ADFI), breast muscle rate and slaughter rate were significantly improved, effectively improving the growth performance of broilers, the quality of breast muscle meat, and enhancing the antioxidant capacity of the breast muscle. In addition, the same dose of a mixture of hesperidin and rosmarinic acid added to the broiler's basal diet for 42 days can significantly increase the thymus index of broilers, increase the abundance of beneficial bacteria and reduce the relative abundance of opportunistic pathogens, which has a good regulatory effect on the intestinal health and immune function of broilers [53].

Rosemary acid has broad application prospects as a natural antioxidant for broilers. Shang et al. [54] showed that adding 200 mg/kg rosemary acid to the broiler diet can significantly improve the ADG, feed conversion rate and antioxidant capacity of the liver, and improve the quality of the chicken. Parasite infections, led by coccidiosis, are a major problem in broiler farming. A study by Yu et al. [55] found that adding 160 mg/kg rosmarinic acid to the broiler diet significantly reduced the liver index, serum alanine aminotransferase activity and the levels of IL-1β, IL-6 and TNF-α content, and increased serum IgA and IgM levels, thereby effectively alleviating liver disease, growth retardation and immune function decline caused by C. acerosus infection.

High temperatures and humidity, as well as high-density farming, can trigger heat stress in laying hens, which in turn affects their egg production rate and hatchability. Cai et al. [56] found that adding 0.02% rosmarinic acid to the laying hen diet can significantly increase SOD activity in the serum, reduce MDA levels and caspase-3 activity, and regulate Nrf2 by regulating Nrf2. 0.02% rosemary acid can significantly increase SOD activity in the blood serum, reduce MDA content and caspase-3 activity, and activate the antioxidant defense system by regulating the Nrf2-mediated signaling pathway, thereby alleviating the effects of a heat-stressed environment on laying hens. In summary, rosemarinic acid can help chickens fight free radical damage, reduce the negative effects of oxidative stress and inflammatory responses on the body, and improve the disease resistance of broilers by regulating the body's immune system.

2.3 Application of rosemary acid in ruminant production

Plant extracts can improve the diversity of the rumen microbiota and become potential rumen regulators. Rosemary acid, as an effective active ingredient in rosemary, can have a positive effect on rumen fermentation, thereby affecting the production performance of ruminants [57]. Stefańska et al. [58] showed that Feeding colostrum containing a phytogenic preparation (with rosmarinic acid as the main phytogenic active ingredient) and probiotics (consisting of multi-strain lactic acid bacteria) to 3-day-old calves for 59 days significantly increased the activity and community diversity of the rumen microbiota, increased the amount of feed intake and total dry matter intake, and effectively reduced the incidence of diarrhoeal diseases in calves. The rumen is an important digestive organ of cattle and sheep, and improving its functional state has a positive effect on cattle and sheep production.

Kong et al. [59] studied the effect of rosemary extract on milk production and ruminal fermentation in high-yielding dairy cows. They found that supplementing the basal diet of high-yielding dairy cows with 28 g of rosmarinic acid per day can increase the propionate content and microbial diversity in the rumen, significantly increasing milk production and milk lactose content. Kholif et al. [60] found that adding 10 g/kg dry rosemary to the diet of lactating Damascus goats can significantly increase the concentration of short-chain fatty acids and propionates in the goat rumen, further increase the nutrient digestibility, and increase milk production by 15%. Zhang Ziyang [61] found that adding 2.14 g/kg rosemary extract to the feed of Saanen dairy goats can increase the dry matter intake of dairy goats and significantly improve their milk production performance. In summary, rosmarinic acid can improve the milk production, feed conversion ratio and production performance of ruminants by promoting rumen fermentation and improving the rumen microecological environment.

2.4 Application of rosemarinic acid in other animal productions

The use of immunomodulators in feed to improve animal disease resistance is becoming a common method in aquaculture. Saeed et al. [62] added 1.5 × 108 CFU/g Lactobacillus rhamnosus and 1 g/kg rosmarinic acid to the feed of rainbow trout, which significantly improved the antioxidant capacity and weight gain of the rainbow trout. Liu Ce et al. [63] found that adding rosemary extract to the feed can increase the levels of GSH-Px, SOD and T-AOC in the muscles of meat rabbits, reduce the levels of MDA and cholesterol in the muscles, significantly improve the antioxidant capacity of the muscles of meat rabbits, and effectively increase the nutritional value of the muscles.

Wang Xianze et al. [64] found that adding 100 mg/kg rosemary extract to the basal diet of East Zhejiang white geese significantly reduced the levels of MDA, IL-6 and IL-10 in their serum, and increased ADG by 14.8%. 8%. Yao et al. [65] showed that supplementing the basic diet of meat ducks with rosemary extract (500 g/t) for 42 days significantly increased the ADG and ADFI of the ducks, significantly increased the serum levels of GSH-Px, SOD, CAT and T-AOC, and IgA, and down-regulating the levels of total cholesterol, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol. In summary, rosmarinic acid can play an important role in the production of a variety of animals, and it is believed that it will have more diverse animal production and applications in the future.

3 Summary

Rosmarinic acid is a phenolic acid compound of natural origin with a variety of important biological functions such as anti-inflammatory, antioxidant, anticancer, antiviral and antibacterial properties. In animal production applications, rosemarinic acid has potential application value in improving production performance, meat quality, and feed utilization. It also plays an important role in improving intestinal health, enhancing rumen function, improving the body's antioxidant capacity, immune regulation, and disease prevention and control. With the deepening of scientific research, the pharmacological basis of rosemarinic acid for preventing and treating animal diseases, as well as its molecular mechanism of action, structure-activity relationship, drugability, and the absorption and stability of preparations will become key research directions. High-throughput screening, molecular docking, computer simulation, bioinformatics and other techniques to explore the above scientific issues. It is believed that in the near future, rosemarinic acid-related products will play a better role in animal production and healthy farming.

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