Table 6.

Main nutritional supplements aimed to modulate dairy cow’s immunity during transition period and their mode of action on immune cells

Supplement	Effect	Mechanism	References
n-3 PUFA (C20:5 n-3; C22:6 n-3)	Inflammation (-) Mitigation of pro-inflammatory response (reduced TNF1 and IL-62 production) of immune cells to high NEFA3 concentrations (as those observed with high lipomobilization) Immune competence (±) Improved lymphocytes and mononuclear cells function in transition period: improved cell-mediated immune response; increased phagocytosis and decreased oxidative stress damages in PMN4, leading to improved uterine and udder health in early lactation; modified mononuclear cells/PMN4 ratio	Decrease the amount of arachidonic acid in cell membranes, shifting the oxylipid profile: increased production of resolvins, protectins and lipoxins/ reduced production of PGF2A8 from endometrium (that exert pro-inflammatory effect) and of prostaglandin E2 (that impairs IFNγ synthesis and lymphocytes proliferation). Decreased expression of adhesion molecules involved in inflammatory interactions between leukocytes and endothelial cells; Decreased liver ketogenesis; Direct action on Toll-like receptor 4 inhibiting the LPS-induced NF-κB activation reduces the expression of transcription factors and PICs5. Activates PPARG reducing the production of TNF by leukocytes and partially reversing the insulin resistance caused by this cytokine, thus increasing the glucose available for leukocytes	Kushibiki et al., 2001; Lee et al., 2003; Trebble et al., 2003; Lessard et al., 2004; Mattos et al., 2004; Brassard et al., 2007; Ballou et al., 2009b; Trevisi et al., 2011b; Contreras et al., 2012b; Contreras et al., 2012a; Bionaz et al., 2013a; Dirandeh et al., 2013; Minuti et al., 2015a
n-6 PUFA (C18:2 cis-9 trans-11 and trans-10 cis-12)	Inflammation (-) Increased albumin and cholesterol concentrations in early lactation	Modulation of the NF-κB9 inhibiting the LPS10-induced inflammatory activity in macrophages	Cheng et al., 2004; Trevisi and Bertoni, 2008; Silvestre et al., 2011
	Immune competence (±) Enhanced neutrophils function in transition period	Protection of paraoxonase against oxidative inactivation, reducing oxidative stress status; Increased secretion of VLDL11 and apolipoprotein B100 (involved in lipid redistribution through tissues), decreasing cellular accumulation of triglycerides from palmitic acid, increasing DMI12, reducing NEB13 and lipomobilization (lower NEFA3 and BHB14 levels in blood)
Vitamin A	Prevention of oxidative stress status	β-carotene prevents fatty acid peroxidation chain reaction	Sordillo, 2016
Vitamin C	Mitigation of oxidative stress status	Ascorbic acid act as a radical scavenger	Sordillo, 2016
Vitamin E	Mitigation of oxidative stress status	α-tocopherol disrupts fatty acid peroxidation chain reaction	Trevisi et al., 2011b; Sordillo, 2016
Vitamin D3	Inflammation (-) Down-regulation of PICs5 in favor of AICs6 production	Inhibits Th1 sub-family of lymphocytes in favor of Th 2	Bertoni et al., 2015
Selenium	Mitigation and prevention of oxidative stress status	Active component of thioredoxin reductase and glutathione peroxidase enzymatic complexes, that controls redox signaling and reduce ROM15 production	Sordillo, 2016
Copper	Mitigation and prevention of oxidative stress status	Active component of ceruloplasmin, that exert oxidase activity as peroxyl radical scavenger, and superoxide dismutase, that converts cytosol superoxide to H2O2	Osorio et al., 2016; Sordillo, 2016
Zinc	Mitigation and prevention of oxidative stress status	Active component of superoxide dismutase, that converts cytosol superoxide to H2O2, and metallothionein, which is a cysteine-rich radical scavenger	Sordillo, 2016
Manganese	Mitigation of oxidative stress status	Active component of superoxide dismutase that converts cytosol superoxide to H2O2	Osorio et al., 2016; Sordillo, 2016
Iron	Mitigation of oxidative stress status	Active component of catalase, that converts H2O2 to water	Sordillo, 2016
Choline	Reduced hepatic triglycerides abundance and fat infiltrations; mitigation of oxidative stress status	Quasi-vitamin that is a structural component of phosphatidylcholine, that is required for the synthesis of VLDL11 by the liver; important sources of the intracellular antioxidants glutathione and taurine	Esposito et al., 2014; Zhou et al., 2016
Methionine and lysine	Reduced hepatic triglycerides abundance and fat infiltrations; mitigation of oxidative stress status	They affect mitochondrial beta-oxidation of fatty acids in liver and export of triglycerides as VLDL11; important sources of the intracellular antioxidants glutathione and taurine	Esposito et al., 2014; Zhou et al., 2016
Acetylsalicylic acid	Inflammation (-): Reduced positive APPs7 abundance and improved liver synthesis	Inhibition of cyclooxygenase enzymatic complex reducing the synthesis of pro-inflammatory oxylipids	Trevisi et al., 2003; Bertoni et al., 2007; Trevisi and Bertoni, 2008; Shin et al., 2010; Kim et al., 2012; Grossi et al., 2013
Hottuynia cordata extract	Inflammation (-): Reduced production of TNF1 and pro-inflammatory oxylipids		Shin et al., 2010; Kim et al., 2012
Aloe arborescens Mill. extract	Inflammation (-): Increased negative APPs7 concentration	Reduced mobilization of body fats and improved liver synthesis	Trevisi et al., 2013, 2017

¹Tumor necrosis factor.

²Interleukin-6.

³Non-esterified fatty acids.

⁴Polymorhonuclear cells.

⁵Pro-inflammatory cytokines.

⁶Anti-inflammatory cytokines.

⁷Acute phase proteins.

⁸Prostaglandin 2, alpha.

⁹Nuclear factor κB.

¹⁰Lypopolysaccharides.

¹¹Very low-density lipoproteins.

¹²Dry matter intake.

¹³Negative energy balance.

¹⁴Beta-hydroxybutyrate.

¹⁵Reactive oxygen metabolites.