Curcumin as a Potential Antioxidant in Stress Regulation of Terrestrial, Avian, and Aquatic Animals: A Review

Stress has brought about a variety of harmful impacts on different animals, leading to difficulties in the management of animal husbandry and aquaculture. Curcumin has been recognized as a potential component to ameliorate the adverse influence of animal stress induced by toxicity, inflammation, diseases, thermal effect, and so on. In detail, this compound is known to offer various outstanding functions, including antibacterial properties, antioxidant effects, immune response recovery, and behavioral restoration of animals under stress conditions. However, curcumin still has some limitations, owing to its low bioavailability. This review summarizes the latest updates on the regulatory effects of curcumin in terms of stress management in terrestrial, avian, and aquatic animals.


Introduction
Stress management in the animal husbandry and aquaculture industries has been under serious consideration in recent times.Animal stress can arise from various factors, such as extreme cold or heat in the climate, insufficient nutrition (including lack of food or water), physiological disorders, and disease outbreaks [1].These stressors have had a wide range of impacts on animals in general and livestock, poultry, and fisheries in particular, including effects on growth, production, reproduction, and disease susceptibility [2].For instance, heat stress is one of the contributing factors to reduced milk yields and quality, decreased meat production, and fertility issues in farm animals [3].Moreover, thermal stress also induces physiological, behavioral, and production changes in poultry [4], as well as alterations in growth rate, oxidative stress, and immune response in fish [5].As a result, animal stress has led to significant drawbacks in the agriculture sector and the nation's economy.Thus, it is imperative to propose measures to address this issue.One potential solution that has garnered significant attention from scientists worldwide is the use of curcumin supplements to alleviate the deleterious effects of stress.
Curcumin is a natural biocomponent of turmeric (Curcuma longa L.) and has been used to treat inflammatory diseases, tumors, injuries, and so on, thanks to its anti-inflammatory, antioxidant, antibacterial, antifungal, and anticancer properties [6].Curcumin has shown promise in mitigating the adverse effects of combatting neurodegenerative disorders, making it effective in the treatment of Alzheimer's disease [7].Moreover, curcumin has been found to prevent organ dysfunction and is recommended as a dietary supplement for obese individuals [8].Related to counteracting the oncogenic stress management system, curcumin not only causes the death of different Kaposi's sarcoma-associated herpes virus KSHV-positive cells but also obstructs the development of KSHV-infected cells [9].On the other hand, several studies have been conducted on the role of curcumin in stress management in animal husbandry and aquaculture.Dietary curcumin supplementation has been found to benefit the growth performance of fish and young pigs [10]; enhance antioxidant status, nutrient absorption, thermotolerance and intestinal morphology in broiler chickens [11]; and improve nonspecific immune responses and stress resistance in the juvenile of greater amberjack [12].
Therefore, the following review aims to highlight the most significant effects of curcumin on stress in terrestrial animals, birds, and aquatic animals, especially fisheries, based on recent studies.By comprehending the potential benefits of curcumin supplementation in animals, researchers and veterinarians could explore its applications in diverse fields, such as livestock farming, aquaculture, animal welfare, and conservation.Moreover, additional investigation and experimentation are necessary to validate these findings in various animal species and contexts.

Overview of Curcumin 2.1. Biological Activities of Curcumin
Curcumin is a natural compound derived from the turmeric plant (Curcuma longa).Its chemical formula is C 21 H 20 O 6 (Figure 1), and it has a molecular weight of 368.38 g/mol.Curcumin is known for its limited solubility in water, but it is freely soluble in various organic solvents, such as DMSO, ethanol, methanol, and acetone [13].
Antioxidants 2023, 12, x FOR PEER REVIEW 2 of 33 has been found to prevent organ dysfunction and is recommended as a dietary supplement for obese individuals [8].Related to counteracting the oncogenic stress management system, curcumin not only causes the death of different Kaposi's sarcoma-associated herpes virus KSHV-positive cells but also obstructs the development of KSHV-infected cells [9].On the other hand, several studies have been conducted on the role of curcumin in stress management in animal husbandry and aquaculture.Dietary curcumin supplementation has been found to benefit the growth performance of fish and young pigs [10]; enhance antioxidant status, nutrient absorption, thermotolerance and intestinal morphology in broiler chickens [11]; and improve nonspecific immune responses and stress resistance in the juvenile of greater amberjack [12].Therefore, the following review aims to highlight the most significant effects of curcumin on stress in terrestrial animals, birds, and aquatic animals, especially fisheries, based on recent studies.By comprehending the potential benefits of curcumin supplementation in animals, researchers and veterinarians could explore its applications in diverse fields, such as livestock farming, aquaculture, animal welfare, and conservation.Moreover, additional investigation and experimentation are necessary to validate these findings in various animal species and contexts.

Biological Activities of Curcumin
Curcumin is a natural compound derived from the turmeric plant (Curcuma longa).Its chemical formula is C21H20O6 (Figure 1), and it has a molecular weight of 368.38 g/mol.Curcumin is known for its limited solubility in water, but it is freely soluble in various organic solvents, such as DMSO, ethanol, methanol, and acetone [13].Curcumin also has been extensively studied for its potential biological activities and health benefits.Although curcumin's effects are diverse and complex, some of its most notable biological activities include antimicrobial activity, anti-inflammatory activity, antioxidant activity and antinociceptive activity, in addition to serving as a wound-healing agent [14].The mechanism of action of curcumin involves multiple pathways and molecular targets (Figure 2) [15][16][17].Curcumin also has been extensively studied for its potential biological activities and health benefits.Although curcumin's effects are diverse and complex, some of its most notable biological activities include antimicrobial activity, anti-inflammatory activity, antioxidant activity and antinociceptive activity, in addition to serving as a wound-healing agent [14].The mechanism of action of curcumin involves multiple pathways and molecular targets (Figure 2) [15][16][17].

Metabolism of Curcumin
After being ingested, curcumin undergoes a sequence of metabolic transformations within the liver and intestines during phases I and II of metabolism.In phase I, reductase enzymes work to diminish the double bonds present in curcumin, leading to the creation of several metabolites, including octahydrocurcumin, dihydrocurcumin, hexahydrocur-

Metabolism of Curcumin
After being ingested, curcumin undergoes a sequence of metabolic transformations within the liver and intestines during phases I and II of metabolism.In phase I, reductase enzymes work to diminish the double bonds present in curcumin, leading to the creation of several metabolites, including octahydrocurcumin, dihydrocurcumin, hexahydrocurcumin, and tetrahydrocurcumin.Subsequently, both curcumin and its phase I metabolites progress to phase II metabolism, which involves conjugation with sulfate and glucuronic acid.This conjugation process gives rise to curcumin sulfates and curcumin glucuronides, respectively [18,19].Following this, these metabolites circulate within the bloodstream and disperse throughout various organs in the body [19].Among these, curcumin glucuronide appears to exhibit less bioactivity compared to curcumin and other metabolites [20].Therefore, these metabolic transformations within the digestive system may play a role in limiting the oral bioavailability of curcumin [19].It is essential to note that the bioavailability and metabolism of curcumin and its metabolites can vary among individuals due to factors such as genetics, gut microbiota composition, and the specific formulation of curcumin that is ingested.

Other Extractable Components of Turmeric
Apart from curcumin, turmeric, the primary curcuminoid, also contains two other curcuminoids: demethoxycurcumin and bisdemethoxycurcumin.These two analogs have a lower abundance of turmeric and exhibit weaker radical scavenging abilities than curcumin [21].However, due to the high cost associated with extracting these curcuminoids individually from curcumin, they are often used in combination, yielding favorable outcomes.For instance, supplementation with a curcumin tablet (comprising 90% curcumin, 8% demethoxycurcumin, and 2% bisdemethoxycurcumin) for one week was reported to enhance vitamin C and E levels while also reducing malonaldehyde (MDA) and 8hydroxydeoxyguanosine  in the serum of precancerous patients [22].Moreover, bisacurone, a sesquiterpene present in turmeric, also displays potential antioxidant properties.Bisacurone contributes to the reduction of triglycerides, cholesterol, and total lipid content, along with promoting lipolysis, making it a valuable component for preventing hepatic lipid accumulation [23].

Nanoformulation of Curcumin
As mentioned earlier, curcumin is not highly water-soluble and exhibits low bioavailability.This implies that a significant portion of ingested curcumin might not be effectively absorbed into the bloodstream through the gastrointestinal tract.To enhance absorption, several methods have been employed, such as combining curcumin with other compounds [18] or devising nanoformulations of curcumin [24].Nanoparticles possess dimensions in the nanometer range (1~100 nm), which can enhance solubility, impede rapid metabolism, and enable targeted delivery to specific tissues or cells [25].Notably, the use of nanoparticles resulted in the significantly higher bioavailability of curcumin glucuronide in plasma [20].
In addition to the approaches mentioned above, nanoformulations containing amphiphilic compounds (surfactants) have emerged as a potential strategy to ameliorate curcumin's bioavailability.More specifically, curcumin-load solid lipid nanoparticle (SLNs) have demonstrated the ability to reduce particle size, leading to an enhanced anticancer effect [26].

Stress in Animals
Stress encompasses the entirety of biological reactions to physical, emotional, or mental stimuli that disrupt an individual's homeostasis.The causes and mechanisms of stress in animals can differ depending on the species and their specific environments.A stressor can be defined as any internal or external stimuli or threat that disrupts the body's homeostasis and elicits a coordinated physiological response in an attempt to restore balance.There are different types of stressors that can intensify stress, including chemical stressors, biological stressors and physical stressors.Additionally, factors such as macroorganisms and diet composition can also contribute to stress levels [27] (Figure 3).

Stress in Animals
Stress encompasses the entirety of biological reactions to physical, emotional, or mental stimuli that disrupt an individual's homeostasis.The causes and mechanisms of stress in animals can differ depending on the species and their specific environments.A stressor can be defined as any internal or external stimuli or threat that disrupts the body's homeostasis and elicits a coordinated physiological response in an attempt to restore balance.There are different types of stressors that can intensify stress, including chemical stressors, biological stressors and physical stressors.Additionally, factors such as macroorganisms and diet composition can also contribute to stress levels [27] (Figure 3).The impacts of stress on animals can be significant and wide-ranging.When animals experience stress, it can affect their overall health in various ways.For instance, stress can suppress immune function, making animals more susceptible to diseases.It can also cause The impacts of stress on animals can be significant and wide-ranging.When animals experience stress, it can affect their overall health in various ways.For instance, stress can suppress immune function, making animals more susceptible to diseases.It can also cause metabolic and hormonal changes, as well as decrease feed intake [27].Furthermore, stressors can have implications for animal productivity, leading to a decline in protein and fat accretion in animal productions such as meat, eggs, and milk.This can compromise product quality and ultimately decrease product potential [28].

Oxidative Stress Management
Oxidative stress is a state in which the body is exposed to toxic reactive oxygen species (ROS) that overpower the antioxidant systems, resulting in an imbalance between them.This type of stress is considered harmful due to the damage caused by oxygen free radicals to adipose tissue, proteins, and DNA.Furthermore, oxidative stress is associated with various diseases, including atherosclerosis, hypertension, diabetes mellitus, ischemic diseases, and malignancies [29].Hence, the utilization of antioxidant compounds such as curcumin in managing stress within the livestock industry has become increasingly important in recent times.
In the first place, oxidative stress can occur due to various reasons, one of which is toxicity resulting from toxins or heavy metals present in food sources or as side effects of drugs (Table 1).Aflatoxin B1 (AFB1), a potent mycotoxin, has significant impacts on human and animal health, including carcinogenic, mutagenic, teratogenic, and immunosuppressive effects [30].AFB1 also induces oxidative stress by generating high levels of free radicals [31].In a study conducted by Atef et al. [32], it was reported that curcumin has the ability to reduce hepatic oxidative stress in rabbits exposed to AFB1.This was evidenced by an increase in the ratio of antioxidant enzymes such as glutathione (SGH), catalase (CAT), and superoxide dismutase (SOD) and the removal of free radicals.However, it should be noted that curcumin can also have a genotoxic effect depending on its concentration [32].Similarly, orally administered curcumin in mice showed protective effects against the detrimental influence of AFB1 on the kidneys.It improved renal antioxidant capacity while attenuating levels of blood urea nitrogen (BUN), uric acid, and creatinine [33,34].Furthermore, another toxic chemical widely used in breeding to control pests is cypermethrin (CPM).It has various health effects, including neurotoxicity, reproductive toxicity, and molecular toxicity.CPM leads to a significant increase in MDA and protein carbonyl (PC) levels in serum, the liver, and the brain, while antioxidant biomarkers are significantly reduced in serum and brain tissues.Ziada et al. [35] indicated that plant phytochemicals such as vitamin C and curcumin play a protective role against cypermethrin-induced oxidative stress in serum, the brain, and the liver.Curcumin, in addition to its antioxidative and free-radical-scavenging abilities, also enhances the activity of other antioxidants [35].Heavy metals such as cadmium (Cd) can cause damage to various organ systems in animals after long-term exposure.For instance, in Kunming mice, Cd significantly decreases semen quality, serum testosterone concentration, and the number of spermatogenic cells and mature spermatozoa.However, curcumin intervention improved these oxidative damages by activating the Nrf2 signaling pathway [36].Similarly, the treatment of rats with nickel nanoparticles (NiNPs) at a concentration of 50 mg/kg for 28 days induces liver damage, but curcumin (at doses of 150 mg/kg or 300 mg/kg) can counteract this toxic effect, as evidenced by the reduction of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and BUN levels in serum [37].Moreover, the ingestion of curcumin significantly improved arsenic-induced hepatotoxicity and nephrotoxicity in male rats [38].Apart from toxins, the side effects of drugs can also pose dangers to animals' health.For example, although Ivermectin has many positive impacts in the treatment of sarcoptic mange, it has some side effects.In this case, turmeric extract was investigated and found to reduce the negative influences of Ivermectin-treated rabbits, while also promoting their performance, blood characteristics, and antioxidant status [39].Likewise, ferrous ascorbate (FeAA) is a pro-oxidant that not only impairs motility and mitochondrial activity but also leads to a significant overgeneration of free radicals.Tvrdá et al. demonstrated that curcumin has a beneficial effect on bull spermatozoa under FeAA-induced oxidative stress.Particularly, at concentrations ranging from 25 to 50 µmol/L, curcumin has a profound impact on protecting these cells from free-radical-induced damage [40].In addition, macrophages (RAW264.7 cells), which are sensitive to ROS, can be shielded from oxidative damage caused by H 2 O 2 through the Nrf2-Keap1 pathway [41].Moreover, oxidative stress can occur during the immune response process due to inflammation and diseases (Table 1).For instance, mastitis is a common disease in cattle breeding that reduces productivity and fertility.Medicinal plants, including Curcuma longa, have been extensively studied for their potential in treating this disease.The hexanic and ethanolic extracts of C. longa have shown anti-inflammatory properties against lipopolysaccharide (LPS)-induced inflammation.These extracts downregulate the expression of proinflammatory cytokines and exhibit free-radical-scavenging properties in buffalo mammary epithelial cells (BuMECs).They also upregulate the mRNA expression of the Nrf2 gene, which is involved in antioxidant defense mechanisms [42].In the same way, nanoparticle-encapsulated curcumin has been found to have a beneficial influence on mastitis in mice, demonstrating superior effects compared to free curcumin, as shown in the study conducted by Suresh et al. [43].Turmeric extract has also been shown to reduce the incidence and mortality rate of bovine respiratory disease (BRD) in crossbreed calves [44].Furthermore, high-concentration curcumin and a mixture of piperine and curcumin have been shown to improve intestinal integrity and enhance antioxidant capacity, thereby reducing oxidative stress in weaned piglets [45].Nevertheless, a study on the protective impact of curcumin on buffalo granulosa cells (GCs) revealed a negative effect on in vitro cultured cells when supplemented at higher concentrations and for longer durations.Specifically, cell viability and antioxidant enzyme activity were significantly decreased after 48 h of curcumin treatment [46].Otherwise, excessive physical activities can lead to oxidative stress in animals (Table 1).While physical activities offer various benefits, overexercising can have certain unavoidable drawbacks, including liver and kidney injuries and tissue damage.In particular, the AST value is higher in exhaustion-exercise rats compared to non-exercise groups.To address these issues, the inclusion of antioxidants such as curcumin in the diet has been considered.Conceição et al. suggested that a combination of whey protein concentrate and curcumin could potentially decrease the expression of inflammatory cytokines and increase that of anti-inflammatory cytokines [47].Furthermore, a mixture of cinnamon and turmeric has been shown to maintain and enhance antioxidant enzyme activities.This dietary supplementation has been found to affect growth parameters without impacting metabolism or damaging cellular machinery [48].↓MDA, ↑SOD, ↑CAT, ↑GPx, ↑GR. [38] Sarcoptes-infested rabbits, aged 60 days, weighed 869.5 ± 94.27 g A total of 83 rabbits were divided into 3 groups: G1 (control), G2 (IVM 0.2 mg/kg b.w.), G3 (IVM 0.2 g/kg b.w.+ TE 1 mg/kg diet), and G4 (IVM 0.2 g/kg b.w.+ TE 2 mg/kg diet).The aqueous extract of turmeric was obtained from the rhizome of Curcuma longa.

Thermal Stress Management
It is a well-known fact that global climate change intensifies the impact of temperature on livestock, leading to thermal stress that affects various health aspects, such as growth, physiological condition, immune function, morphology, and the antioxidant system in the body [49].Thermal stress can be categorized into two types: cold stress and heat stress [50].
Heat stress occurs when an animal's body temperature exceeds its thermoneutral zone due to high ambient temperature, solar radiation, and wind speed [51].Prolonged exposure to these conditions can lead to hyperthermia, hyperventilation, endocrine changes, anorexia, and poor growth performance [52].In such cases, in addition to providing thermalcontrolled housing facilities, dietary interventions play a crucial role in mitigating the adverse effects of heat stress.Curcumin, an antioxidant and anti-inflammatory compound, has the potential to be used as a dietary supplement for animals experiencing heat stress.
In detail, as illustrated in a study by El-Ratel et al., the dietary intervention with curcumin or nanocurcumin had a significant positive impact on cecal activity, hematological parameters, and the reduction of harmful bacteria in heat-stressed rabbits, without any adverse effects on carcass traits [53].Similarly, another research study showed that the use of turmeric extract reduced ear temperature and MDA levels, while increasing total antioxidant capacity in heat-stressed male rabbits, leading to improvements in heat tolerance, semen characteristics, and overall health [54].In the same way, the addition of curcumin to the diet of female rabbits during the summer season in Egypt resulted in improved productive and reproductive parameters [55] (Table 2).
Another study indicated that the rectal temperature, ALT, AST, and serum lactate dehydrogenase (LDH) levels in mice subjected to high-temperature treatment were significantly elevated compared to those in the non-heat-stress group.However, dietary supplementation with curcumin was found to improve physiological stress and mitigate cardiac damage induced by heat treatment.This was achieved through the activation of antioxidant-related enzymes and the alleviation of physiological disorders [56].Meanwhile, Zhao et al. [57] observed that curcumin significantly reduced the concentration of creatinine and blood urea nitrogen in serum, thereby preventing acute kidney injury in heatstroke rats.Apart from the effects on various organs of the body, during heat stress, albino rats exhibited restlessness, hypoactivity, a depressed attitude, and altered behavior.In contrast, rats treated with curcumin showed better behavioral changes after the heat-stress period, with moderate changes and a faster recovery time [58].
Additionally, the impact of the mixture of garlic, ginger, and turmeric on the biochemical parameters, immune function, and oxidative status of Damascus goats under heat stress conditions has been demonstrated [59].Moreover, in Southern China, high temperature and humidity during the summer can have harmful effects on the growth and fertility of animals, including Hu Sheep, a local breed known for its high reproductive characteristics.In this context, curcumin has been found to have beneficial effects on the antioxidant status, immune ability, and reproductive performance of these sheep.This was evidenced by an increase in the activity of antioxidant enzymes and the concentrations of immunoglobulins and testosterone in the plasma of Hu Sheep [60].
[61] demonstrated that in vitro heat shock in buffalo mammary epithelial cells (BuMECs) led to distorted morphology, abnormal cell shape, and loss of cellcell contact, along with a decrease in cell viability and proliferation.To address this issue, curcumin was added at different concentrations.Interestingly, the results showed that lower concentrations of curcumin (5 and 10 µM) provided better alleviation of the harmful effects of heat stress on the epithelial cells compared to higher-concentration groups.This was evidenced by the enhanced expression of heat-shock proteins, antioxidant genes, and anti-apoptotic genes [61] (Table 2).
Besides heat stress, low-temperature conditions also have negative impacts on livestock health and performance.An animal suffers cold stress when the temperature declines below the lower limit of the thermoneutral zone [62], and this situation leads to unavoidable consequences, such as a negative effect on calves' weaning weight [63], spontaneous movements, exploratory behaviors, anxiety emotion in mice [64], an exerted oxidative stress hazard on sperm [65], and so on.Hence, measures to prevent cold stress in livestock should be seriously considered.Among these measures, curcumin supplementation is a safe and nontoxic solution, making it more attractive to scientists compared to other phytogenic compounds [66].Turmeric-powder addition has been shown to enhance nutrient utilization in female calves during the winter season [67].Furthermore, Hameed et al. [65] indicated that turmeric extract (100 µL/5 mL and 200 µL/5 mL) could improve the quality of cooled and post-thawed cattle bull semen.Likewise, 10 µM of curcumin had cryoprotective effects on Hariana bull semen by reducing protein carbonyls after freezing-thawing [68].In goat semen cryopreservation, the curcumin nanoformulation (100 µg) was more effective in improving antioxidant status and sperm parameters compared to the nanoformulations of mint and thyme [69].As for rabbits, the addition of curcumin and its nanoparticle improved the viability, progressive motility, and sperm ultrastructure of post-thawed semen through redox signaling and a reduction in the apoptosis process.The dose of 1.5 µg/mL curcumin nanoparticle yielded the best results [70].[57] Table 2. Cont.
Post-cooling: Sperm motility, alive sperms were significantly higher in TTE1.Sperm abnormalities lower in TTE1.Sperm membrane integrity was higher in TTE1.Acrosome percent was higher in TTE1, TTE2, TTE4.

Nitrosative Stress Management
Similar to the imbalance between ROS and antioxidant systems in oxidative stress, the elevation of reactive nitrogen species (RNS) leads to nitrosative stress [72].Ochratoxin A (OTA), a toxic secondary metabolite produced by the Aspergillus and Penicillium genera, adversely affects the reproduction, nutrition, and growth of animals.OTA induces overexpression of inducible nitric oxide synthase (iNOS), responsible for nitric oxide (NO) production.The excessive NO in the kidney and liver causes nitrosative stress, resulting in DNA damage and apoptosis.In contrast, curcumin treatment mitigates these harmful effects by reducing NO levels, iNOS, pro-inflammatory cytokines (NF-κB, TNF-α, IL-1β, and IL-6), and 8-OHdG, while regulating inflammation with fewer CD3+ T-lymphocytes in the tissues of OTA-poisoned rats [73].Similarly, the ingestion of curcumin (50 mg/kg) and curcumin nanoemulsion (2.5 and 5 mg/kg) demonstrated comparable effects in male rats under protein-deficient conditions.Notably, curcumin in nanoemulsion form appears to be superior due to its nanometer size and higher solubility, leading to improved bioavailability [74].

Oxidative Stress Management in Birds
As can be seen, oxidative stress is one of the biggest reasons for the declined/compromised health and productive and reproductive performance of poultry.Overall, there are many oxidative stressors, such as temperature, toxins, microbial or virus challenges, and so on, and the antioxidant systems in living organisms have limited ability [75].Thus, curcumin supplementation has been shown to be a safe and cost-effective solution.
To begin with, Aflatoxin B1 (AFB1), a mycotoxin produced by A. flavus, is a wellknown cause of oxidative stress and damage in the liver [76][77][78], kidney [79], spleen [80], and duodenum [81] of poultry, which is highly sensitive to this toxin (Table 3).This toxin leads to an increase in free radicals, a decrease in antioxidant enzyme activity, inflammation, apoptosis in the liver of chickens and ducks, renal toxicity, abnormal functional and morphological changes in the duodenum of broilers, and lesions and immunotoxicity in the spleen of ducks.However, curcumin has shown the ability to restore the activity of antioxidant enzymes, serum antioxidant capacity, and NOX4 value and counteract DNA damage [79].It also improves oxidative injuries, toxicity, inflammation, and apoptosis by regulating LncRNA-mRNA expression in broilers [76] and downregulating the expression of CYP450 enzymes, increasing ATPase activities and P-gp in chickens [81].Similarly, curcumin positively influences oxidative stress and injuries in duck livers caused by AFB1 by improving lysosomal membrane permeabilization and lysosome biogenesis [77].Moreover, curcumin supplementation activates the Nrf2 signaling pathway, preventing the expression of the NF-κB signaling pathway and downstream inflammatory factors, thereby decreasing the harmful impacts of AFB1 [80].Apart from AFB1, fumonisin from Fusarium spp., mostly found in corn used in animal feed, also reduces bodyweight and induces necrosis of hepatocytes in chicks, even at low doses.Galli et al. [82] revealed that curcumin and its nanocapsules have hepatoprotective and antioxidant effects on these mycotoxinconsumed chicks.Interestingly, nanocurcumin at 10 mg/kg has superior protective and antioxidant effects compared to curcumin in its free state, as demonstrated by the reduction of thiobarbituric acid reactive substance (TBARS), ALT, AST, and ROS levels and the rise in SOD and CAT concentrations [82].Likewise, Ochratoxin A (OTA) negatively impacts the growth and development of poultry, such as damaging lipid metabolism, disrupting cecum microbiota density, depressing antioxidative enzyme activities, reducing performance, and causing mitochondrial dysfunction.However, dietary curcumin can restore and enhance these functions in OTA-treated ducks.This is evidenced by the increase in CAT, SOD, total antioxidant capacity (T-AOC), and glutathione peroxidase (GSH-Px) levels, as well as the rehabilitation of richness indices and diversity indices in the composition of the intestinal microbiota [83,84].
Concerning heavy metals, arsenic trioxide (ATO), an environmental pollutant, was widely used in pesticides and insecticides.It can accumulate in water, soil, and plants, posing a long-term health risk to animals through consumption.Overconsumption of ATO can have serious consequences, including weight reduction, glomerular hemorrhage, mitophagy, apoptosis, and increased levels of ROS and MDA in the kidneys and skeletal muscle, leading to oxidative stress in ducks.As is evident from studies by Wu et al. and Lan et al., curcumin can improve growth speed, enhance renoprotective ability, and alleviate skeletal muscle injuries in ATO-infected ducks [85,86].
On the other hand, lipopolysaccharides (LPSs), components responsible for the pathological process of contamination induced by Gram-negative bacteria, can cause morphological damage to the ileum, lung injury, inflammation, and oxidative stress in poultry.The addition of 500 mg/kg of curcumin to the diet could ameliorate these symptoms in the lungs and ileitis of ducks through the signaling pathways of Nrf2-ARE, NF-κB, and TLR/NF-κB in an orderly manner [87,88].Furthermore, curcumin has shown effectiveness against coccidiosis caused by Eimeria species.This is demonstrated by the improvement in antioxidant activities and lesion scores of the ceca, the reduction in oocyst shedding of E. maxima and E. tenella [89], and the decrease in enteric levels of 8-Iso-PGF2α [90].
Another factor that impacts broiler production is stocking density.Specifically, chickens stocked at high densities experience increased walking and standing behavior but decreased growth performance and antioxidant activities.In such oxidative stressful conditions, curcumin enhances the behavioral patterns, immune status, and growth performance of chicks.This is achieved by increasing immunoglobulin and antioxidant enzyme concentrations, while decreasing pro-inflammatory cytokine levels [91].Ducks, aged one day old A total of 60 ducks were divided into 3 groups: G1 (control), G2 (0.1 mg/kg AFB1), and G3 (0.1 mg/kg AFB1 + 400 mg/kg CUR).
Spleen was smooth and uniform in color.Improve the damage to the spleen and the index of the spleen.Serum immunoglobulin content: ↓lgA, ↑IgG, ↑IgM.

Thermal Stress Management in Birds
During the heat stress period, physiological, behavioral, and immunological abnormalities might occur, resulting in disadvantages for bird productivity [92].Otherwise, these negative effects can be alleviated by supplementing with curcumin [93].
As an illustration, Salah et al. suggested that a concentration of 100 mg/kg of curcumin in the diet could ameliorate the average daily feed intake and the unsaturated fatty acids and enhance the levels of adenosine triphosphate (ATP) and Coenzyme Q10 (CoQ10) in liver tissue, as well as the brain serotonin of heat-stroke broilers [94].Meanwhile, as is evident from the research of Mustafa et al. [95], the serum biochemical parameters of heat-stressed broiler chickens such as lipid, protein profile, creatine kinase, uric acid, and glucose have improved after the addition of curcumin or turmeric powder to the diet.In addition, turmeric (500 mg/kg bodyweight) was able to raise the quality of the chest and thigh meat and decrease the total cholesterol level of chickens reared in heat stress [96].The supplementation of 0.2% dried turmeric rhizome powder has especially been proven to be better than betaine (Bet) for ameliorating humoral immunity and stress tolerance in heat-stressed broilers [97].Conversely, 0.5% turmeric powder did not have any impact on growth and caused an enormous decline in the feed conversion ratio; however, it could improve thyroid hormones, increase feed intake, and reduce blood MDA and lipid peroxidation in the heat-stress broiler [98,99].Moreover, the addition of turmeric root powder, as well as its mixture with carnation flowers, to the diet of broilers under heat stress conditions showed an increase in the percentage of lymphocytes and the concentration of total protein and globulin; meanwhile, while the levels of glucose and uric acid and the number of harmful bacteria were declined [100].Correspondingly, the 8 g/kg diet of C. longa powder also resulted in better intestinal morphology under hot tropical environments, leading to the amelioration of nutrient absorption and thermotolerance of broiler chickens [11].On the other hand, dietary curcumin might intensify antioxidant ability and immunity and ease the stress symptoms of laying hens under high-temperature environment conditions, as visualized by the activities of CAT, SOD, GSH-Px, and T-AOC in the liver, heart, and lung tissues for curcumin-treatment groups being higher, while the statistics for the corticosterone levels, ALT, and inflammatory-cytokine response were lower than that for control groups [101,102].Furthermore, the supplementation of curcumin on chicken embryonic fibroblast cells (CEFs) could reduce ROS and MDA levels and reverse the downregulation of the expression of the antioxidant enzyme via the MAPK-Nrf2 signaling pathway under high-temperature conditions [103] (Table 4).
Among the environmental stressors, cold stress also poses several disadvantages to animals (Table 4).For example, it suppresses body temperature, oxygen consumption, and respiratory water loss [92].A study on Ross-308 male broiler chicks revealed that cold-stressed birds had a lower weight gain but higher levels of MDA and AST compared to normal birds.However, the inclusion of curcumin and nanocurcumin in the diet proved effective in mitigating these issues.Notably, a dosage of 200 mg/kg curcumin exhibited the ability to reduce MDA and total cholesterol levels, while improving the immune system, microbial population, and liver enzyme activities.In contrast, in the same study, nanocurcumin demonstrated lesser positive impacts due to its higher concentration [104].Furthermore, during the winter season in the southern region of Brazil, the egg quality and antioxidant capacity of Japanese quails and Hy-Line Brown laying hens were enhanced by incorporating curcumin into their diets [105,106].Table 4. Regulatory effects of curcumin on thermal stress in birds.

Oxidative Stress Management in Aquatic Animals
According to numerous studies, oxidative stress in aquaculture can be induced by various chemotoxic agents (pesticides, insecticides, etc.) or environmental factors (DO, pH, salinity, etc.), which can impact various biological processes, including fish development, physiology, and metabolic processes [107].Due to its safety, affordability, nontoxic nature, and remarkable functionality [66], curcumin offers a superior dietary supplement compared to other options for addressing this issue (Table 5).
Firstly, one of the most common stress factors in fisheries is related to toxicity and heavy metals.Hydrogen peroxide (H 2 O 2 ), which is used as a disinfectant in aquaculture [108], also induces oxidative stress in aquatic animals.In this regard, Wang et al. [109] indicated that a concentration of 2-4 g/kg turmeric aqueous extract protected spotted seabass (Lateolabrax maculatus) from the harmful effects of H 2 O 2 through the Nrf2/Keap1 pathway.In the same way, turmeric leaf extract (TLE), which contains curcumin, was found to reduce ROS generation, lipid peroxidation, and cell death in H 2 O 2 -treated zebrafish [110].In terms of the harmful effects of heavy metals, Rajabiesterabadi et al. [111] reported that copper exposure caused inflammation, anemia, and hepatic damage in common carp (Cyprinus carpio), as evidenced by increased cortisol, MDA, ALT, and AST levels, while red blood cell count and hemoglobin decreased.The addition of 10 g/kg dietary turmeric is recommended to mitigate the negative impacts induced by copper by enhancing SOD, CAT, glutathione peroxidase (GPx) activity, and the expression of IL10 [111].Melamine (MEL), which is widely used in crop fertilizers and pesticides, has several detrimental effects on the growth, immune response, disease resistance, and oxidative stress in various fish species.Abd El-Hakim et al. [112] found that a dosage of 200 mg/kg curcumin improved bodyweight and hematological variables, minimized reductions in lysozyme activity and total protein, and enhanced oxidative stress indices in MEL-treated Nile tilapia (Oreochromis niloticus).Likewise, chlorpyrifos (CPF), a broad-spectrum organophosphorus insecticide, induces oxidative stress in the blood serum, liver, and gill tissues of rainbow trout (Oncorhynchus mykiss).The addition of 0.5% curcumin was able to attenuate these negative consequences, as evidenced by a decrease in total oxidant status and oxidative stress index, while the total antioxidant capacity increased [113].
Alternatively, bacterial infections such as Aeromonas spp.can also induce oxidative stress in aquatic animals.A study by Mahmoud et al. [114] demonstrated that the addition of curcumin to the diet could potentially improve immune function, antioxidant status, growth performance, feed utilization, and disease resistance in Nile tilapia (Oreochromis niloticus) fish.Specifically, a concentration of 50 mg/kg curcumin in the diet exhibited superior antioxidant capability compared to other concentrations.
Furthermore, marine fish larvae exhibit higher metabolic rates and oxygen consumption levels compared to juveniles and adults.As a result, this developmental stage in fish is also associated with oxidative stress [115].Xavier et al. [116,117] suggested that the inclusion of curcumin in the diet of gilthead seabream postlarvae could improve their health status, enhance robustness, and increase their total antioxidant capacity and digestive capacity, while reducing protein oxidative damage and oxidative stress throughout ontogeny.↑SOD, ↑CAT, ↑GPx, ↓MDA.↓TNF-α, ↓IL1-b, ↑IL-10.↓AST, ↓ALT, ↑red blood cells, ↑hemoglobin, ↑hematocrit.

Ammonia Stress Management in Aquatic Animals
Similar to oxidative stress, ammonia poisoning has led to the growth of ROS levels, inflammatory cytokines, inflammatory mediators, and the expression of antioxidant enzymes, while declining cell viability and the expression of anti-apoptosis.By contrast, curcumin could improve these negative impacts on kidney macrophage of Yellow catfish Pelteobagrus fulvidraco related to the NF-κB/COX-2 pathway [118] (Table 6).Referring to juvenile greater amberjack (Seriola dumerili), the dietary curcumin supplementation suppressed stress symptoms in the liver, spleen, intestinal, and gill by upregulating the relative expression of CAT and Mn-SOD, increasing immune enzyme activity and antioxidant capacity, and significantly promoting hepatic alkaline phosphatase (ALP) and acid phosphatase (ACP) levels [12,119,120] (Table 6).↓number of apoptotic cells. [118] The wild-caught juvenile of the greater amberjack (Seriola dumerili) A total of 135 juveniles were divided into 3 groups: CUR0%, CUR0.01%(100 mg/kg curcumin), and CUR0.02% (200 mg/kg curcumin).Ammonia challenge: NH 4 Cl (1 g/L farming environment).

Thermal Stress Management in Aquatic Animals
Thermal stress, including heat and cold stress, has a specific influence on fish physiology [121].However, there are limited studies on the effects of curcumin in managing thermal stress in fisheries.Certainly, heat stress has been found to decrease the level of immunoglobulins, while increasing ALT and AST, which are indicators of liver injury in fish.In a study by Mahanty et al. [122], curcumin, a bioactive compound, was shown to improve thermotolerance in Puntius sophore.This was achieved through the upregulation of Nrf-2, SOD, CAT, GPx, and heat-shock protein (hsp) expression in the gill and liver tissues.In addition, Abdel-Ghany et al. [123] proposed that nanocurcumin, in its free-form, has a dominant role in alleviating growth performance, nonspecific immunity, stress indicators, and heat stress resistance in Nile tilapia.The recommended dose for these effects is 100 mg/kg in the diet (Table 7).
Different from heat stress, cold stress is a challenge for many fish when they suffer from a rapid decline in temperature, resulting in a cascade of physiological and behavioral responses and a more serious case of death [124].Under low-temperature conditions, although the supplement of nanocurcumin to Nile tilapia diets has no significant changes in nutrient efficiency, hematological components, and survival rates, fish that consumed nanocurcumin diets showed an improvement in antioxidant capacity (the increase of SOD, GPx, and CAT levels) and healthier gastrointestinal microbiota [125] (Table 7).Enhancing the growth performance (CN100, CN200).Liver enzymes activities: ↓ALT, ↓AST (CN50, CN100).↑IgM, ↑C3 (except C50), ↑C4.↓Cortisol (CN50, CN100).Nanocurcumin is more effective than its free form. [123] Puntius sophore, a minor carp of the family Cyprinidae Fish were divided into 4 groups (40 fish/group): A (basal diet), B, C, and D (0.5, 1, and 1.5% curcumin-supplemented feed, respectively → highest CT max value: D. → A and D: heat shocked.→ Gene expression analysis in 3 groups: BD (basal diet), BD + HS (basal diet + heat shocked), and 1.5%CUR + HS (1.5% curcumin supplemented + heat shocked).

Stress Due to Stocking Densities in Aquatic Animals
Besides the stressors presented above, high stocking density is a cause of chronic stress in farmed fish [126].In particular, as illustrated in the study of Akdemir et al. [127] about rainbow trout, Oncorhynchus mykiss (Walbaum), the figures of MDA (in serum and the liver), HSP70, HO-1, and NF-Kb levels in high stocking density (100 kg/m 3 ) were higher than those in low stocking density (20 kg/m 3 ).On the contrary, after the addition of curcumin to the diet, these harmful effects could be attenuated [127].

Conclusions and Future Outlook
In brief, as previously clarified, stress is attributed to impaired productivity performance in livestock, poultry, and fisheries industries.To solve this problem, it is important to find a safe, nontoxic, and inexpensive measure.The application of antioxidant components such as curcumin in stress management is a potential measure.Indeed, according to studies during the last decade, curcumin has more outstanding functionality in improving the harmful effects of stress on animals than other natural compounds (Figure 4).Nonetheless, curcumin also has some disadvantages because of its low bioavailability.Furthermore, curcumin in nanoformulation seems to be dominant compared to its usual form if used in appropriate concentrations.Consequently, it is necessary to carry out further studies about the use of nanocurcumin with a suitable dose to effectively deliver it to the target organs of animals.

Stress due to Stocking Densities in Aquatic Animals
Besides the stressors presented above, high stocking density is a cause of chronic stress in farmed fish [126].In particular, as illustrated in the study of Akdemir et al. [127] about rainbow trout, Oncorhynchus mykiss (Walbaum), the figures of MDA (in serum and the liver), HSP70, HO-1, and NF-Κb levels in high stocking density (100 kg/m 3 ) were higher than those in low stocking density (20 kg/m 3 ).On the contrary, after the addition of curcumin to the diet, these harmful effects could be attenuated [127].

Conclusions and Future Outlook
In brief, as previously clarified, stress is attributed to impaired productivity performance in livestock, poultry, and fisheries industries.To solve this problem, it is important to find a safe, nontoxic, and inexpensive measure.The application of antioxidant components such as curcumin in stress management is a potential measure.Indeed, according to studies during the last decade, curcumin has more outstanding functionality in improving the harmful effects of stress on animals than other natural compounds (Figure 4).Nonetheless, curcumin also has some disadvantages because of its low bioavailability.Furthermore, curcumin in nanoformulation seems to be dominant compared to its usual form if used in appropriate concentrations.Consequently, it is necessary to carry out further studies about the use of nanocurcumin with a suitable dose to effectively deliver it to the target organs of animals.

Figure 2 .
Figure 2. Schematic presentation on mechanism of action of curcumin.

Figure 3 .
Figure 3.The causes of stress in animals.

Figure 3 .
Figure 3.The causes of stress in animals.

Figure 4 .
Figure 4.A schematic diagram on curcumin in animal stress management.

Table 1 .
Regulatory effects of curcumin on oxidative stress in terrestrial animals.

Table 1 . Cont. Animal Category Experimental Design Findings (Comparison to Negative Control) Source
w. CUR in nanoparticle-encapsulated form) for 24 h, 48 h, and 72 h.

Table 3 .
Regulatory effects of curcumin on oxidative stress in birds.

Table 5 .
Regulatory effects of curcumin on oxidative stress in aquatic animals.

Table 6 .
Regulatory effects of curcumin on ammonia stress in aquatic animals.

Table 7 .
Regulatory effects of curcumin on thermal stress in aquatic animals.Raising the water temperature from 25 to 40 • C within 3 h, and then 40 • C for 4 h.