Inflammation is a complex but defensive biological response of living tissue to infection that can be triggered by exogenous injury and infectious agents such as bacteria and viruses. Inflammation is part of the innate immune response acting as the first line of defense against pathogens and disease. The inflammatory response acts as a doubleedged sword because if inflammation persists or augments, it may switch from a defensive mechanism to a detrimental process, therefore, modulating the inflammatory response using therapeutic interventions is important for animal health and well being and for longterm food security. Recent studies have reported that plant-derived bioactive compounds are precursors for numerous anti-microbial and anti-parasitic medicines. The antibiotic activities may be attributed to some bioactive compounds such as polyphenols, flavonoids, terpenes, tannins, terpenoids, vitamin C, essential oils, and carotenoids. The ban on the use of synthetic antibiotics and inconsistent efficacy of non-steroidal anti-inflammatory drugs as NSAID have elevated the need for alternative drugs, particularly, those which are derived from plant-based bioactive compounds. Such substances can be used as supplements in animal food to boost the immune system particularly, for domestic ruminants, which are the main source for milk and meat for humans. During the past recent years, plant-based bioactive substances were studied intensively along with their anti-inflammatory and other therapeutic effects, both in-vivo and in-vitro. Modulating the inflammatory response using plant-based bioactive compounds is important for understanding the anti-inflammatory pathways that stimulate the innate immune response to pathogens or injury. The present study is a literature review that focuses on the applications of plant-derived bioactive substances and their effects on the immune responses of goats, sheep, and cows.

Inflammation; Ruminants; Innate immunity; Cytokines; Plant bioactive compounds

Ruminants are a group of mammals characterized by having four-chambered stomachs. To obtain nutrients from plant-based food, they can ferment them in a specialized chamber called rumen through microbial actions aiding in digestion. Cattle, sheep and goats which are the three ruminants globally consumed as sources of animal protein, contribute substantially to the economy. Inflammatory diseases cause significant losses to the livestock industry with public health and economic consequences.

There is a close nexus between healthy animals, innate immunity, and the inflammatory response. Since inflammation is the harbinger of upcoming disease, addressing the cause of inflammation and modulating it is essential for animal health and productivity. Inflammation is a complex but defensive biological response of living tissue to infection triggered by exogenous injury and baleful stimuli due to pathogens [1]. The innate immune system is the first line of a host defense mechanism that is responsible for the fast pathogen recognition and activation of the pro-inflammatory response. The effective immune response requires proper crosstalk between pro- and anti-inflammatory cytokines because their strong interaction not only governs local inflammatory reactions but also generates systemic effects through blood circulation [2]. Being a vital part of both innate and acquired immunity, inflammation orchestrates the body’s immune system responses through leukocytes, chemokines, and cytokines signaling to reconcile homeostasis. Pattern recognition receptors (PRR) such as Toll-like receptors (TLRs) are the ones that sense the invading microbes or traumatized cells and activate the local and systemic immune response that, in turn, stimulates four cardinal signs of inflammation which are redness, hotness, swelling & pain in the affected area.The redness of tissues is caused by the momentary vasoconstriction due to the injury following by vasodilatation to facilitate the infiltration of more fluids, cytokines, macrophages, and proteins to the affected area, heat results from enhanced blood flow, swelling, and pain. The heat is raised in the injured area due to the increased blood flow, while tissue swelling is due to the leaking of fluid from blood vessels to the affected tissue, consequently swelling causes pain due to the sensation and stimulation of the nerves in the area [3,4]. In particular, invasion of pathogenic microbes incites an intricate process that promotes the production and release of pro-inflammatory cytokines, which are hormone-like polypeptides such as tumor necrosis factor (TNF-α), interferons (IFN-γ), and interleukins (IL-6) [5]. The augmented level of pro-inflammatory cytokines in blood evokes a number of systemic changes in the body such as fever, reduced appetite, gastric function, plasma iron, and zinc levels, which stimulate the activity of lymphocytes and neutrophils with subsequent phagocyte mobilization and acute-phase proteins, altered metabolism of carbohydrates, lipids and proteins cumulatively called as acute phase response (APR) [2]. Activated mononuclear cells release monocytes and macrophages that primarily synthesize TNF-α, and IL-1β to act against bacterial pathogens while in the case of viral infection, IFN-γ is released from T-cells. Sustained inflammation is associated with oxidative damage due to the release of radicals by leukocytes and can result in deleterious effects on the host. Interlinked signaling events in cells and their consequences result in symptoms of inflammation that cannot be overlooked because if the condition of inflammation persists or augments, it may switch from a defensive mechanism to a detrimental process [3].

Infection and injury may result in an APR initiated primarily by tissue macrophages or blood monocytes. Pro-inflammatory cytokines may trigger the production of acute-phase proteins in the liver and their release in the blood in an effort to neutralize any pathological change, which may trigger the acute inflammation signs. For example, pro-inflammatory cytokines TNF-α, IL-6, and IL-1 can counteract endotoxin and restore homeostasis [6]. In response to cytokines, several signal cascades are propagated, causing cortisol secretion and, eventually the release of some acute-phase proteins such as serum amyloid A (SAA), C-reactive proteins, fibrinogen and haptoglobin by the liver. C-reactive protein and SAA are used in medical laboratories to identify tissue injury and the stage of inflammation, which helps in the prognosis and determination of treatment options [7]. The APR is crucial in regulating defense mechanisms including initiation of the defense process, immune cell production, metabolic changes, and fever to combat pathogens [8].

Inflammation can be categorized into acute and chronic inflammation depending on its severity and the nature of injury and pathogen causing the inflammation. Acute inflammations are prominent and rapid mainly governed by neutrophils and may cause injury to the tissues. On the other hand, chronic inflammation can cause severe injury to the tissues and is often mediated by lymphocytes, monocytes/ macrophages and may involve neutrophils. The onset of chronic inflammation is indeed a gradual process over a protracted period;thus, the symptoms are less conspicuous [7]. 

In domestic ruminants, is the major cause of mastitis, which impacts greatly on milk production, and neutrophils play a central role in the inflammatory response associated with E. coli mediated mastitis [10,11]. In particular, TLRs upon binding with LPS, a major inflammatory inducerstimulates innate immunity responses, and this process is accompanied by LPS-binding proteins (LBP) and a cluster of differentiation antigen 14 (CD14) [12]. TLRs recognize a variety of conspicuous microbial patterns including LPS, flagellin, viral RNA (double-stranded), and CpG (unmethylated) motifs [13]. Besides immune and inflammatory responses, cell proliferation and differentiation invariably depend on the transcription of nuclear factor κB (NF-κB) which is found to be inactive in cell cytoplasm with its inhibitory κB (IκB) counterparts. The NF-κB signaling pathway is being triggered by LPS and various receptors such as TLRs, tumor necrosis factor receptor (TNF-R), and interleukin 1 receptor (IL1R), which in turn initiates phosphorylation of inactive NF-κB-I-κB. Later, activated NF-κB is released, enters the nucleus, and binds with its promoter to upregulate the transcription of proinflammatory cytokines including interleukin 1-beta (IL-1β), IL-6, IL-8, and hormone-like polypeptide tumor necrosis factor-alpha (TNF-α) [14]. Several pieces of research articles also supported the implication of LPS in the propagation of inflammatory responses.

Demonstrated that bacterial pathogens like M. haemolytica infected cattle [15] demonstrated high levels of tumor necrosis factor-alpha (TNF-α), interleukin 1-beta (IL-1β), and interferon-γ (IFN-γ), [16] also reported a rising level of TNF-α, IL-1β, and IFN-γ upon LPS intravenous administration. In lactating dairy cows, [13] showed that digestive tract derived LPS stimulates inflammatory gene expression and obstructs casein synthesis.

Infection by viral pathogens activatescytokine gene expression. Cattle infected with the bovine respiratory syncytial virus (BRSV) showed high IL-6 and IFN-γ levels while infection with bovine viral diarrhea virus (BVDV) raised levels of TNF-α, IL-1β, as well as IL-6 [17]. However, cattle infected with both viral and bacterial infection demonstrated noticeably increased TNF-α, IL-6, IFN-γ except IL-1β [15]. Variation in innate immunity has been observed [18]. The TLR and cytokine responses of susceptible and resistant varieties of goats and water buffalo to pestes des petits ruminant virus (PPRV) was observed differently. Naturally, PPRV susceptible goats showed a weak immune response with high viral loads and poor TLRs expression. On the other hand PPRV resistant breeds, where synthetic TLRs agonists mediated peripheral blood mononuclear cells stimulation showed a remarkably higher level of pro-inflammatory cytokines including IFN- γ with the mitigated expression of immunosuppressive cytokine IL-10. The difference in immune response was attributed to higher IFN- γ and TLR-7 response in resistant variety that restricted PPRV replication.

Long-term intake of grain-enriched diets by ruminants leads to subacute ruminal acidosis (SARA) which may cause a number of malfunctions including increased intestinal permeability, alteration in microflora, metabolic disorders, lowering of ruminal pH to 5.8, reduction of cellulolytic bacteria with subsequent increase in starch-fermenting and lactic acid-producing bacteria [20]. It has been reported that low pH in rumen causes the lysis of gramnegative bacteria, and the effect of acidosis on the free ruminal lipopolysaccharides content (LPS) is strong evidence of inflammation [21]. After the onset of local inflammation in the ruminal epithelium, LPS passes through epithelial barrier reaching into the blood, and there it causes systemic inflammation by activating pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin IL-1β and IL-6. The release of IL-8 release further deploys various adaptor molecules leading to the transcriptional factor activation of NFκB [22,23]. The initiation of inflammatory signals simultaneously affectsbody tissues in terms of energy and lipid metabolism.

Also, systemic inflammation at organ level increases acute phase proteins secretion (serum amyloid A, haptoglobin), fever, elevated cortisol level. The crucial role of serum amyloid A is to bind endotoxin and nullify its effect in the blood, whereas haptoglobin binds with free plasma hemoglobin, thereby preventing iron availability to bacteria required for their growth and multiplication. The most prominent consequences of SARA are the malfunctioning of the cellular junction and cellular adhesion that leads to redundant infiltration of pathogens/toxins into blood from the lumen. However, systemic inflammation is a defensive mechanism to restore homeostasis, although inflammation for a protracted period can disrupt energy and lipid metabolism, immune inhibition, and disease susceptibility [6].

The most common PRR are TLRs that are located in different bovine granulosa cells, oviductal epithelial cells, and epithelial and stromal cells of the endometrium [24]. Upon recognition of MAMPs or DAMPs by the receptors on the abovementioned cells starts gushes of signaling events (NF-κB or MAPkinase) that, in turn, activates proinflammatory mediators (IL-1, IL-8, TNF-α). As a result, it leads to vasodilation, tissue healing, reactive oxygen species generation, and infiltration of macrophage and neutrophil to aid phagocytosis. Besides, several metabolites, peptides with antimicrobial properties,and apoptosis suppressing factors have also be released [3,25,26].

To ascertain the exact reason, the studies which were conducted with mastectomized cows have found that neither gestation nor calving was responsible for the prolonged pro-inflammatory stage. However, it was found that lactation and metabolic changes during the transition period were the real culprits [28]. The studies have also shown that there is a close nexus between metabolic disorders and the responsiveness of immune cells. The skewed dietary shifts in transition cows may also lead to systemic inflammation. Moreover, during the transition period, monocytes are noticed to be highly receptive to inflammatory stimulants, which in turn provoke more production of inflammatory cytokines, which is followed by systemic inflammation and altered liver metabolism. The elevated ketone levels in blood, hypocalcemia, and non-esterified fatty acid concentration greatly affect the immune cells to the pathogenic signals which result in mitigated immune function.

The continuous use of antibiotics has been practicing for the treatment of LPS induced mastitis that reflects putative risks of antibiotic resistance and their potential residues in milk that eventually goes to human through the food chain [35]. After the ban on several antibiotics, the use of non-steroidal anti-inflammatory (NSAID) has emerged as an alternative treatment, but they were found not very promising. To treat early lactation inflammation, acommercial NSAID drug sodium salicylate was used on 78 cows including control for the first seven days of lactation [36]. With average outcome at the beginning, the oldest cohort treated with salicylate yielded 21% more milk over the whole lactation and 30% more milk fat than parity matched control as lactation progressed. However, salicylate treatment outcome in primiparous cows was not promising because of low milk yield that might be attributed to the difference in response to inflammatory signals or baseline inflammatory status [37,38]. The whole-lactation productivity of multiparous cows was ascertained on 153 cows. Cows were assigned to postpartum treatment with two drugs, one with sodium salicylate forthree days and second with meloxicam for one day compared to the control group [38]. Despite the short treatment duration of the drug, there was a fruitful effect of either salicylate or meloxicam on milk production (10% hike) compared to control. Butyrate (volatile fatty acids) and its salts (sodium butyrate) have been claimed to diminish inflammatory responses by reducing the NF-κB signaling pathwayand LPS mediated cytokine expression. In dairy goats, sodium butyrate administration improves inflammation, which was caused by a high concentrate fed diet by downregulation of proinflammatory cytokines (IL-6, IL-1β, TNF-α) in rumen epithelium [39]. These results witnesses that the effect of NSAID has not been consistent.

Genetics contributes substantially to an animal’s innate immunity by plant bioactive substances and modulate gene expression through activating the innate and adaptive immune response. It can underpin alternate control strategies to target gene-specific modulation to curb inflammation either by stimulating inflammation so that there is rapid pathogen elimination or can dampen inflammation to reduce oxidative damage. Galectins, (gal) carbohydrate-binding proteins have demonstrated to modulate innate immunityin goats and cows. Galectin acts as PRR; thus, it can identify PAMPs by binding microorganism-specific glycan of micro organisms and begin host immune responsesby modulating host cells such as neutrophils, macrophages, eosinophils, mast, and dendritic cells remarkably [42,43]. Parity and periparturient period is the time when fertility, milk production, and inflammation in dairy cows, sheep, and goats are affected terribly. Hence, most of the studies on ruminants are performed during the periparturient period so that therapeutic targets such as galectins can be tapped [44]. Moreover, in periparturient goats and sheep, galectins have been found to regulate innate and adaptive immunity to combat immune suppression during the periparturient stage, which is highly susceptible to diseases [45]. In particular, gal-8 exhibited bovine neutrophil activation and migration through superoxide production as a potential therapeutic to reduce inflammation [8,46,47]. Adjei-Fremah et al. [48,49] reported that polyphenols extract from cowpeas can bind and regulate gene expressions of galectins in bovine inflammatory diseases. Besides, several plant extracts such as Curcuma longa, Echinacea angustifolia, and Butea frondosa have been used on sheep neutrophil to evaluate their anti-inflammatory and apoptotic modulation properties [41].

As an alternative non-chemical approach, [50] studied the effect of probiotics on lactating Holstein-Friesian cows and found that the lymphocytes count significantly increased with a percent decrease in neutrophil count in the treatment group. Probiotics serve as the non-pathogen associated molecular pattern; as a result, it promotes growth and rumen function in cows [51]. Moreover, probiotic treatment impacted three pathways remarkably, such as inflammatory response, TLR, and wingless signaling pathways.  

In ruminants, to cure nonspecific postpartum inflammation, specific pharmaceutical drugs have not yet been approved with dosage. On the other hand, due to the possible threat of antibiotic resistance against microbial agentsas well as its putative risk to access the human body through the food chain, the use of antibiotics is banned on livestock. In addition, the efficacy of NSAIDs administration on inflammation remained inconsistent. With some handful of positive effects including mastitis [52] and pregnancy rate at embryo transfer [53], most of the treatments exhibit the moderate or negative effect of NSAIDs on reproduction. During artificial insemination, the drug did not ameliorate the pregnancy rate [54] and insemination success rate at mid-luteal phase. Also, treatment before ovulation was baleful as the drug mitigated ovulation and follicular cyst formation [55]. Besides, studies on immunomodulation are at a novice stage and need in-depth study to implement on ruminants.

Moreover, after heavy restriction on the use of antibiotics as feed additives by European legislature (2003) and new Veterinary Feed Directives by United States (2017) on the use of medicated feed, numerous research programs have gained momentum towards phytochemicals based therapy to augment immune functionality of livestock [19,57]. Since then, plant bioactive enriched compounds were thoroughly investigated and justified the scope of alternative feed ingredients in the form of herbs, spices and plant extract to boost ruminant’s immune health by exhibiting the immense potential to exert the same anti-inflammatory potency as a commercial drug without side effects.

The phenolic compounds and polyphenols are abundantly found in all plants. In the past few decades, these chemopreventive agents have received enormous attention because of their supreme antiinflammatory, antioxidant properties, and other biological roles on animal’s health [60]. Chemically, phenolics are the compound that owns an aromatic ring having one hydroxyl group, while polyphenols can have one or more aromatic rings with many hydroxyl groups [13]. These plant secondary metabolites are produced as a plants’ defense mechanism against pathogens, as a result, have been explored for a variety of applications in animals including sheep, cows, and goats [61]. Alpha-tocopherol (vitamin E) is a known antioxidant that neutralizes ROS production and consequently obstructs the progression of inflammation. A study was found that the plasma concentration of α-tocopherol in cows was very low that indirectly associated with transition cow disorders [62]. Administration of α-tocopherol not only modulates inflammation by decreasing inflammatory cytokine production in transition cows but also ameliorates clinical mastitis, retained placenta, and liver function. [63,64] investigated the efficacy of polyphenol from cowpea in bovine blood and reported that it upregulated the expression of antiinflammatory cytokine IL-10. In addition, cowpea polyphenols also mitigated the Wnt signalingpathway, which has been implicated in inflammation [65]. Crude polyphenols extract from Cherokee tomato significantly suppressed the transcription of cox-2 gene expression, thereby reducing inflammation and modulated innate immunity in cows [66].

It has been monitored that during mastitis, TLR4-located receptors at mammary epithelial cells and resident leukocytes identify LPS, there by activating NF-κB mediated inflammatory response. [70,71] evaluated the effect of baicalein (flavones) and morin (flavonol) respectively on bovine mammary epithelial cells in in vitro studies and found mitigated action of NF-κB and mitogenactivated protein kinase. In particular, the phosphorylation of I κB and p65 were greatly suppressed by flavonoids, which in turn reduces NF-κB activation.

In addition, [71,72] reported that mRNA expression of proinflammatory cytokines was greatly diminished when the cells were treated with flavonoids. Also, heifers treated with flavonoid essential oil had reduced neutrophil blood concentration, LPS binding protein, and serum amyloid A than control heifer [73] suggesting that flavonoid-rich diets can ameliorate rumen fermentation and minimize the risk of acidosis. Administration of concentrate feed pellets containing fermented green tea probiotics, illite, and licorice to beef cattle from birth to post-weaning (60 days) did not modify leukocyte count [74]. Another piece of in vitro study on calves fed pomegranate extract demonstrated that blood mononuclear cells produced more IFN-γ and IL-4. Ovalbumin vaccine challenged calves fed pomegranate extract produced high anti-ovalbumin IgG compared to control [75].

In addition to the abovementioned bioactive compounds, there are thousands of other compounds that plants can synthesize such as saponins, lectins, polypeptides, polyamines, glucosides, and omega-3 fatty acids which exhibited potential roles as antiinflammatory agents. Table 2 shows the effect of anti-inflammatory bioactive compounds from plants and their therapeutic potential on ruminants. In dairy cattle, the synergistic activity of green tea and Curcuma extract in milk were investigated during the transition that resulted in augmented milk yield (4.5L/day), reduced liver lipids, and plasma NEFA concentration after calving [82]. The less responsive immune system was noticed in cows when treated with omega-3 sources [83]. On the other hand, [84] fed fresh cows with whole flaxseed containing omega-3 fatty acids that outweighed omega-6 fatty acids by enhancing greater phagocytic activity of circulating leukocytes and plasma glucose with decreased plasma ketones. The plant extracts, rich in w3-polyunsaturated fatty acids (PUFA), linoleic acid, and antioxidants, such as Se, vitamin C, vitamin E, b-carotene, and polyphenols reported modulating various transcriptional factors like NF-kB and PPARa that in turn governs inflammation affecting genes [85].

[86] studied the efficacy of garlic (Allium sativum, L), eucalypt (Eucalyptus globulus), and Gnaphalium conoideum extract in Holstein cows suffering from acute endometritis. Among all three garlic extract effectively worked against endometritis followed by eucalypt. Also, garlic extracts remarkably alleviated gastrointestinal infections caused by Coccidia in adult female Boar goats [87]. In sheep, β-sitosterol mitigated high grain diet-induced inflammatory response and improved ruminal fermentation and microbiota by obstructing the attachment of LPS to TLR4 in the NF-κB pathways thereby reducing (TNF)-α, IL-1β and IL-6 levels [23].

The bioactivity for anti-inflammatory effects of spice principles - curcumin, eugenol, linalool, zingerone, capsaicin, cuminaldehyde, and piperinewas studied and found highly effective (15-52%) in inhibition of carrageenan-induced inflammation in rats, [88,89]. Some researchers claim that the rich terpenoids and flavonoids contents in spices can subdue the synthesis of arachidonate metabolite and, eventually, the synthesis of prostaglandins that are considered to be potent inflammatory mediators. In addition, terpenoids and flavonoids also inhibit the secretion of lysosomal enzymes, for example, hyaluronidase, elastase, and collagenase enzymes by macrophage [90,91]. Some other herbs and spices are also enlisted, such as anis, licorice, marigold, and chamomile, whose anti-inflammatory perspective can be explored [92].

Table 1: Effect of anti-inflammatory bioactive compounds from plants and its Therapeutic potential

A growing number of researches on anti-inflammatory effects of plant-based bioactive compounds reflect that this field showed the immense potential to curb inflammation and boost the immune system without side effects. However, the amount of studies undertaken so far is inadequate to tap vast plant-based bioactive compounds that bear analogous attributes. Inflammation may play a vital role in the development of transition disorders and metabolic diseases. Therefore, research on plant-based bioactivesfor diseases/ metabolic disorders in combination with targeting immunomodulation could be a novel and wise approach to fight inflammation. Essential oil-based bioactives such as eugenol and cinnamaldehyde showed promising results to fight inflammation; hence they have tremendous potential to be used in immunomodulatory effects in ruminants. Also, targeting neutrophils using galectins can worth noting to explore its prospects as anti-inflammatory tools.Therefore, in-depth studies on the abovementioned aspects warrant to harvest the full efficacy of plantbased bioactives against inflammation and its allied complications.

The authors are grateful to the National Institute of Food and Agriculture Evans Allen funds:

‘MOLECULAR SIGNATURES AND REGULATORY CHECKPOINTS

FOR ANIMAL HEALTH’ Project NO. NC. X 320-5-19-120.1 for funding the postdoctoral Scientist. Special thanks also go to the Members of the Laboratory for Animal Genomic Diversity and Biotechnology (LAGenDB) at North Carolina A&T State University for assisting with edits.

1. Trowbridge HO, Emiling RC. Inflammation: A review of theprocess. Fifth edition. 1999:1637-1646.
2. Van Miert AS. Pro-inflammatory cytokines in a ruminant model:Pathophysiological, pharmacological, and therapeutic aspects.Vet Q. 1995;17(2):41-50.
3. Chastant S, Mila H. Passive immune transfer in puppies. AnimReprod Sci. 2019 Aug;207:162-170.
4. Bradford BJ. Walking the tightrope: the balance between immunityand inflammation in ruminants. In 2018 Animal NutritionConference of Canada, cutting edge nutritional strategies forimproving performance, profitability and sustainability, 2-3May 2018, Edmonton, Canada. Animal Nutrition Association ofCanada (ANAC). 2018;191-202.
5. Brodzki P, Kostro K, Krakowski L, Marczuk J. Inflammatorycytokine and acute phase protein concentrations in theperipheral blood and uterine washings of cows with subclinicalendometritis in the late postpartum period. Vet Res Commun.2015;39(2):143-149.
6. Zebeli Q, Metzler-Zebeli BU. Interplay between rumen digestivedisorders and diet-induced inflammation in dairy cattle. Res VetSci. 2012 Dec;93(3):1099-108.
7. Horadagoda NU, Knox KMG, Gibbs HA, Reid SWJ, Horadagoda A,et al. Acute phase proteins in cattle: discrimination between acuteand chronic inflammation. Vet Rec. 1999 Apr;144(16):437-441.
8. Baumann H, Gauldie J. The acute phase response. Immunol Today.1994 Feb;15(2):74-80.
9. Asiamah EK, Ekwemalor K, Adjei-Fremah S, Osei B, Newman R, etal. Natural and synthetic pathogen associated molecular patternsmodulate galectin expression in cow blood. J Anim Sci Technol.2019 Sep;61(5):245.
10. Worku M, Morris A. Binding of different forms of lipopolysaccharideand gene expression in bovine blood neutrophils. J Dairy Sci.2009 Jul;92(7):3185-3193.
11. Burvenich C, Paape MJ, Hill AW, Guidry AJ, Miller RH, et al. Role ofthe neutrophil leucocyte in the local and systemic reactions duringexperimentally induced E. coli mastitis in cows immediately aftercalving. Vet Q. 1994 Mar;16(1):45-50.
12. Bannerman DD, Paape MJ, Hare WR, Hope JC. Characterizationof the bovine innate immune response to intramammaryinfection with Klebsiella pneumoniae. Journal of dairy science.2004;87(8):2420-2432.
13. Zhang H, Tsao R. Dietary polyphenols, oxidative stress andantioxidant and anti-inflammatory effects. Curr Opin Food Sci.2016 Apr;8:33-42.
14. Cohen J. The immunopathogenesis of sepsis. Nature. 2002Dec;420(6917):885-891.
15. Burciaga-Robles LO, Step DL, Krehbiel CR, Holland BP, RichardsCJ, et al. Effects of exposure to calves persistently infected withbovine viral diarrhea virus type 1b and subsequent infection withMannheimahaemolytica on clinical signs and immune variables:model for bovine respiratory disease via viral and bacterialinteraction. J Anim Sci. 2010 Jun;88(6):2166-2178.
16. Carroll JA, Reuter RR, Chase Jr CC, Coleman SW, Riley DG, etal. Profile of the bovine acute-phase response following anintravenous bolus-dose lipopolysaccharide challenge. InnateImmun. 2009 Apr;15(2):81-89.
17. Grell SN, Kirsten T, Larsena LE, Heegaard PM. Marked induction ofIL-6, haptoglobin and IFNγ following experimental BRSV infectionin young calves. Veterinary immunology and immunopathology.2005 Feb;103(3-4):235-245.
18. Dhanasekaran S, Biswas M, Vignesh AR, Ramya R, Raj GD, et al.Toll-like receptor responses to Peste des petits ruminants virusin goats and water buffalo. PLoS One. 2014 Nov;9(11):e111609.
19. Olagaray KE, Bradford BJ. Plant flavonoids to improve productivity ofruminants–A review. Animal feed science and technology. 2019 Feb.
20. Fernando SC, Purvis HT, Najar FZ, Sukharnikov LO, Krehbiel CR, etal. Rumen microbial population dynamics during adaptation to ahigh-grain diet. Appl Environ Microbiol. 2010 Nov;76(22):7482-7490.
21. Plaizier JC, Li S, Le Sciellour M, Schurmann BL, Górka P, et al. Effectsof duration of moderate increases in grain feeding on endotoxinsin the digestive tract and acute phase proteins in peripheralblood of yearling calves. J Dairy Sci. 2014 Nov;97(11):7076-7084.
22. Dong H, Wang S, Jia Y, Ni Y, Zhang Y, et al. Long-term effects ofsubacute ruminal acidosis (SARA) on milk quality and hepaticgene expression in lactating goats fed a high-concentrate diet.PLoS One. 2013 Dec;8(12):e82850.
23. Xia G, Sun J, Fan Y, Zhao F, Ahmed G, et al. β-Sitosterol AttenuatesHigh Grain Diet-Induced Inflammatory Stress and ModifiesRumen Fermentation and Microbiota in Sheep. Animals. 2020Jan;10(1):171.
24. Mesgaran SD, Gärtner MA, Wagener K, Drillich M, EhlingSchulz M, et al. Different inflammatory responses of bovineoviductal epithelial cells in vitro to bacterial species withdistinct pathogenicity characteristics and passage number.Theriogenology. 2018 Jan;106:237-246.
25. Broom LJ, Kogut MH. Inflammation: friend or foe for animalproduction? Poult Sci. 2018 Feb;97(2):510-514.
26. Sheldon IM, Cronin JG, Bromfield JJ. Tolerance and innateimmunity shape the development of postpartum uterine diseaseand the impact of endometritis in dairy cattle. Annu Rev AnimBiosci. 2019 Feb;7:361-384.
27. Bradford BJ, Mamedova LK, Minton JE, Drouillard JS, JohnsonBJ. Daily injection of tumor necrosis factor-α increases hepatictriglycerides and alters transcript abundance of metabolic genesin lactating dairy cattle. J Nutr. 2009 Aug;139(8):1451-1456.
28. Nonnecke BJ, Kimura K, Goff JP, Kehrli Jr ME. Effects of themammary gland on functional capacities of blood mononuclearleukocyte populations from periparturient cows. J Dairy Sci. 2003Jul;86(7):2359-2368.
29. McNeilly TN, Nisbet AJ. Immune modulation by helminthparasites of ruminants: implications for vaccine developmentand host immune competence. Parasite. 2014;21:51.
30. Ajith Y, Dimri U, Gopalakrishnan A, Devi G, Junaid N, et al. Hostimmunomodulation by ascorbic acid ameliorates oxidative stressin caprine pediculosis—A pilot study. Small Ruminant Research.2019 Jul;176:65-69.
31. Clery D, Torgerson P, Mulcahy G. Immune responses of chronicallyinfected adult cattle to Fasciola hepatica. Vet parasitol. 1996Mar;62(1-2):71-82.
32. Dimri U, Sharma MC, Yamdagni A, Ranjan R, Zama MM. Psoropticmange infestation increases oxidative stress and decreasesantioxidant status in sheep. Vet Parasitol. 2010 Mar;168(3-4):318-322.
33. Pessayre D, Fromenty B, Mansouri A. Mitochondrial injuryin steatohepatitis. Eur J Gastroenterol Hepatol. 2004Nov;16(11):1095-1105.
34. Spears JW, Weiss WP. Role of antioxidants and trace elementsin health and immunity of transition dairy cows. Vet J. 2008Apr;176(1):70-76.
35. Gomes F, Henriques M. Control of bovine mastitis: old and recenttherapeutic approaches. Curr Microbiol. 2016 Apr;72(4):377-382.
36. Farney JK, Mamedova LK, Coetzee JF, Minton JE, Hollis LC, et al.Sodium salicylate treatment in early lactation increases wholelactation milk and milk fat yield in mature dairy cows. J Dairy Sci.2013;96(12):7709-7718.
37. Bradford BJ, Swartz TH. Following the smoke signals: inflammatorysignaling in metabolic homeostasis and homeorhesis in dairycattle. Animal. 2020 Mar;14(S1):s144-s154.
38. Carpenter AJ, Ylioja CM, Vargas CF, Mamedova LK, Mendonça LG,et al. Hot topic: Early postpartum treatment of commercial dairycows with nonsteroidal antiinflammatory drugs increases wholelactation milk yield. J Dairy Sci. 2016 Jan;99(1):672-679.
39. Dai H, Liu X, Yan J, Aabdin ZU, Bilal MS, et al. Sodium butyrateameliorates high-concentrate diet-induced inflammation in therumen epithelium of dairy goats. Journal of agricultural and foodchemistry. 2017 Jan;65(3):596-604.
40. Diez-Fraile A, Meyer E, Paape MJ, Burvenich C. Analysis of selectivemobilization of L-selectin and Mac-1 reservoirs in bovineneutrophils and eosinophils. Vet Res. 2003 Jan-Feb;34(1):57-70.
41. Farinacci M, Colitti M, Stefanon B. Modulation of ovine neutrophilfunction and apoptosis by standardized extracts of Echinaceaangustifolia, Butea frondosa and Curcuma longa. Vet ImmunolImmunopathol. 2009 Apr;128(4):366-373.
42. Ekwemalor K, Asiamah E, Adjei-Fremah S, Osei B, Eluka-OkoludohE, et al. PSVI-32 Pathogen-associated molecular patterns inducedifferential galectin-3 activation in Goat blood. Journal of AnimalScience. 2018 Dec;96(suppl3):464.
43. Ekwemalor K, Adjei-Fremah S, Asiamah E, Eluka-Okoludoh E, OseiB, et al. Systemic expression of galectin genes in periparturientgoats. Small ruminant research. 2018 Nov;168:60-68.
44. Asiamah EK, Adjei-Fremah S, Ekwemalor K, Sordillo L, Worku M.Parity and periparturient period affects galectin gene expressionin Holstein cow blood. J Appl Biotechn. 2018;6(2):20.
45. Osei B, Worku M, Adjei-Fremah S, Asiamah E, Ekwemalor K, etal. Expression galectins in sheep blood during the periparturientperiod. Journal of Animal Science. 2017 Aug;95:20.
46. Eluka-Okoludoh E, Asiamah E, Ekwemalor K, Mulakala B, AdjeiFremah S, et al. PSVIII-37 Modulation of innate and adaptiveimmune response genes in bovine neutrophil by Galectin-8.Journal of Animal Science. 2018 Dec;96(suppl_3):31-32.
47. Eluka-Okoludoh E, Ekwemalor K, Mulakala B, Adjei-FremahS, Worku M. Galectin-8 modulates innate and adaptiveimmune response genes in bovine neutrophils. J Mol Biol Res.2019;9(1):24-32.
48. Adjei-Fremah S, Jackai LE, Schimmel K, Worku M. 0179Immunomodulatory activities of polyphenol extract from cowpea(Vigna unguiculata) on bovine polymorphonuclear neutrophils.Journal of Animal Science. 2016 Oct;94(suppl_5):86-87.
49. Adjei-Fremah S, Worku M. Cowpea polyphenol extract regulatesgalectin gene expression in bovine blood. Anim Biotechnol. 2019Aug:1-12.
50. Adjei-Fremah S, Ekwemalor K, Asiamah EK, Ismail H, Ibrahim S, etal. Effect of probiotic supplementation on growth and global geneexpression in dairy cows. Journal of applied animal research.2018;46(1):257-263.
51. Ekwemalor K, Adjei-Fremah S, Asiamah E, Ismail H, Worku M.0167 Exposure of bovine blood to pathogen associated and nonpathogen associated molecular patterns results in transcriptionalactivation. Journal of Animal Science. 2016 Oct;94(suppl5):81.
52. McDougall S, Abbeloos E, Piepers S, Rao AS, Astiz S, et al. Additionof meloxicam to the treatment of clinical mastitis improvessubsequent reproductive performance. J Dairy Sci. 2016Mar;99(3):2026-2042.
53. Aguiar TS, Araujo CV, Tirloni RR, Martins LR. Effect of meloxicamon pregnancy rate of recipient heifers following transfer of in vitroproduced embryos. Reprod Domest Anim. 2013 Dec;48(6):984-988.
54. Heuwieser W, Iwersen M, Goetze L. Efficacy of carprofen onconception rates in lactating dairy cows after subcutaneous orintrauterine administration at the time of breeding. J Dairy Sci.2011 Jan;94(1):146-151.
55. Pugliesi G, Khan FA, Hannan MA, Beg MA, Carvalho GR, et al.Inhibition of prostaglandin biosynthesis during postluteolysisand effects on CL regression, prolactin, and ovulation in heifers.Theriogenology. 2012 Jul;78(2):443-454.
56. Paul SS, Dey A. Nutrition in health and immune functionof ruminants. Indian Journal of Animal Sciences. 2015Feb;85(2):103-112.
57. Rochfort S, Parker AJ, Dunshea FR. Plant bioactives for ruminanthealth and productivity. Phytochemistry. 2008 Jan;69(2):299-322.
58. Schultes RE. The kingdom of plant medicines from the Earth.McGraw-Hill Book Co., New York. 1978;208.
59. Bor T, Aljaloud SO, Gyawali R, Ibrahim SA. Antimicrobials fromherbs, spices, and plants. InFruits, Vegetables, and Herbs.2016:551-578.
60. Domínguez-Rodríguez G, Marina ML, Plaza M. Strategies for theextraction and analysis of non-extractable polyphenols fromplants. J Chromatogr A. 2017 Sep;1514:1-15.
61. Sandru D, Niculescu V, Lengyel E, Tita O. Identification andquantification of total polyphenols in plants with bioactivepotentially. Cancer. 2016 Aug;1:2.
62. Weiss WP, Hogan JS, Smith KL, Hoblet KH. Relationships amongselenium, vitamin E, and mammary gland health in commercialdairy herds. J Dairy Sci. 1990 Feb;73(2):381-390.
63. Adjei-Fremah S, Jackai LE, Worku M. Analysis of phenolic contentand antioxidant properties of selected cowpea varieties testedin bovine peripheral blood. American Journal of Animal andVeterinary Sciences. 2015;10(4):235-245.
64. Adjei-Fremah S, Asiamah, Ekwemalor K, Osei B, Ismail H, et al.The anti-inflammatory effect of cowpea polyphenol in bovineblood. 2017. North Carolina Agricultural and Technical StateUniversity, Greensboro.
65. Adjei-Fremah S, Asiamah EK, Ekwemalor K, Jackai L, SchimmelK, et al. Modulation of bovine Wnt signaling pathway genesby cowpea phenolic extract. Journal of Agricultural Science.2016;8(3):21.
66. Gyenai K, Mikiashvili N, Ismail H, Worku M. Influence of heirloomtomato polyphenol extracts on expression of inflammation genesin bovine. American Journal of Animal and Veterinary Sciences.2012;7(3):126-135.
67. Rodriguez-Ramiro I, Vauzour D, Minihane AM. Polyphenols andnon-alcoholic fatty liver disease: impact and mechanisms. ProcNutr Soc. 2016 Feb;75(1):47-60.
68. Balasundram N, Sundram K, Samman S. Phenolic compoundsin plants and agri-industrial by-products: Antioxidant activity,occurrence, and potential uses. Food chemistry. 2006;99(1):191-203.
69. Asiamah EK, Adjei-Fremah S, Osei B, Ekwemalor K, WorkuM. An extract of Sericea Lespedeza modulates production ofinflammatory markers in pathogen associated molecular pattern(PAMP) activated ruminant blood. Journal of Agricultural Science.2016;8(9):1.
70. He X, Wei Z, Zhou E, Chen L, Kou J, et al. Baicalein attenuatesinflammatory responses by suppressing TLR4 mediated NF-κBand MAPK signaling pathways in LPS-induced mastitis in mice.Int Immunopharmacol. 2015 Sep;28(1):470-476.
71. Wang J, Guo C, Wei Z, He X, Kou J, et al. Morin suppressesinflammatory cytokine expression by downregulation of nuclearfactor-κB and mitogen-activated protein kinase (MAPK) signalingpathways in lipopolysaccharide-stimulated primary bovinemammary epithelial cells. J Dairy Sci. 2016 Apr;99(4):3016-3022.
72. Yang W, Li H, Cong X, Wang X, Jiang Z, et al. Baicalin attenuateslipopolysaccharide induced inflammation and apoptosis of cowmammary epithelial cells by regulating NF-κB and HSP72. IntImmunopharmacol. 2016 Nov;40:139-145.
73. De Nardi R, Marchesini G, Plaizier JC, Li S, Khafipour E, et al. Useof dicarboxylic acids and polyphenols to attenuate reticular pHdrop and acute phase response in dairy heifers fed a high graindiet. BMC Vet Res. 2014 Nov;10(1):277.
74. Sarker MS, Ko SY, Lee SM, Kim GM, Choi JK, et al. Effect of differentfeed additives on growth performance and blood profiles ofKorean Hanwoo calves. Asian-Australasian Journal of AnimalSciences. 2010;23(1):52-60.
75. Oliveira RA, Narciso CD, Bisinotto RS, Perdomo MC, Ballou MA, etal. Effects of feeding polyphenols from pomegranate extract onhealth, growth, nutrient digestion, and immunocompetence ofcalves. J Dairy Sci. 2010 Sep;93(9):4280-4291.
76. Tajkarimi MM, Ibrahim SA, Cliver DO. Antimicrobial herb andspice compounds in food. Food control. 2010 Sep;21(9):1199-1218.
77. Githiori JB, Athanasiadou S, Thamsborg SM. Use of plants innovel approaches for control of gastrointestinal helminths inlivestock with emphasis on small ruminants. Vet Parasitol. 2006Jul;139(4):308-320.
78. Mahizan NA, Yang SK, Moo CL, Song AA, Chong CM, et al. Terpenederivatives as a potential agent against antimicrobial resistance(AMR) pathogens. Molecules. 2019 Jul;24(14):E2631.
79. Carrasco FR, Schmidt G, Romero AL, Sartoretto JL, Caparroz‐Assef SM, et al. Immunomodulatory activity of Zingiber officinaleRoscoe, Salvia officinalis L. and Syzygiumaromaticum L. essentialoils: evidence for humor‐and cell‐mediated responses. J PharmPharmacol. 2009 Jul;61(7):961-967.
80. Compiani R, Rossi CS, Pizzi A, Dell’Orto V. Administration ofEssential Oils Cinnamaldehyde, Eugenol, and Capsicum toBeef Cattle: Effects on Health Status and Growth Performance.InTrends in Veterinary Sciences. 2013:177-180.
81. Worku M, Abdalla A, Adjei-Fremah S, Ismail H. The impact of dieton expression of genes involved in innate immunity in goat blood.J Agric Sci. 2016;8(3):1.
82. Winkler A, Gessner DK, Koch C, Romberg FJ, Dusel G, et al. Effectsof a plant product consisting of green tea and curcuma extracton milk production and the expression of hepatic genes involvedin endoplasmic stress response and inflammation in dairy cows.Arch Anim Nutr. 2015;69(6):425-441.
83. Silvestre FT, Carvalho TS, Crawford PC, Santos JE, Staples CR, et al.Effects of differential supplementation of fatty acids during theperipartum and breeding periods of Holstein cows: II. Neutrophilfatty acids and function, and acute phase proteins. J Dairy Sci.2011 May;94(5):2285-2301.
84. Gandra JR, Barletta RV, Mingoti RD, Verdurico LC, Freitas Jr JE, etal. Effects of whole flaxseed, raw soybeans, and calcium salts offatty acids on measures of cellular immune function of transitiondairy cows. J Dairy Sci. 2016 Jun;99(6):4590-4606.
85. Bertoni G, Minuti A, Trevisi E. Immune system, inflammationand nutrition in dairy cattle. Animal Production Science. 2015Jul;55(7):943-948.
86. Esparza-Borges H, Ortiz-Márquez A. Therapeutic efficacy of plantextracts in the treatment of bovine endometritis. In InternationalSymposium on Medicinal and Aromatic Plants. 1996:39-46.
87. Worku M, Franco R, Baldwin K. Efficacy of garlic as ananthelmintic in adult Boer goats. Archives of Biological Sciences.2009;61(1):135-140.
88. Reddy P, Lokesh BR. Studies on Anti-Inflammatory Activity ofSpice Principles and Dietary n-3 Polyunsaturated Fatty Acidson Carrageenan-lnduced Inflammation in Rats. Ann Nutr Metab.1994;38(6):349-358.
89. Joe B, Lokesh BR. Prophylactic and therapeutic effects of n-3polyunsaturated fatty acids, capsaicin, and curcumin on adjuvantinduced arthritis in rats. The Journal of Nutritional Biochemistry.1997 Jul;8(7):397-407.
90. Srinivasan K. Spices as influencers of body metabolism:an overview of three decades of research. Food ResearchInternational. 2005 Jan;38(1):77-86.
91. Manjunatha H, Srinivasan K. Protective effect of dietary curcuminand capsaicin on induced oxidation of low-density lipoprotein,iron-induced hepatotoxicity and carrageenan-inducedinflammation in experimental rats. The FEBS journal. 2006Oct;273(19):4528-4537.
92. Craig WJ. Health-promoting properties of common herbs. Am JClin Nutr. 1999 Sep;70(3):491s-499s.
93. Chen HL, Li DF, Chang BY, Gong LM, Dai JG, Yi GF. Effects of Chineseherbal polysaccharides on the immunity and growth performance of young broilers. Poult Sci. 2003 Mar;82(3):364-370.
94. Gao WW, Cao L, Li Z, Tong JM, Sa RN. Effect of Astraglan and Astragaloside on the chicken lymphocyte proliferation. Chinese Journal of Veterinary Medicine. 2001;35:16-8.
95. Liu HW, Tong JM, Zhou DW. Utilization of Chinese herbal feedadditives in animal production. Agricultural Sciences in China.2011 Aug;10(8):1262-1272.