Connection between Systemic Inflammation and Neuroinflammation Underlies Neuroprotective Mechanism of Several Phytochemicals in Neurodegenerative Diseases

Table 1

Anti-inflammatory or antioxidative mechanisms of several phytochemicals in gastrointestinal health, systemic immunity, and neuroimmunity.

Phytochemicals	Approaches	Action mechanisms	Major outcomes	References
Curcumin	Gastrointestinal health	BiP ↓ and IL-8 ↓, in IECs	Anti-inflammation ↑ and ER stress ↓	[27, 28, 29, 30, 31]
		Serotonin ↓, BDNF ↓, and pCREB ↓, in gut	Gut function ↑
		Mesenteric afferent nerve response by colorectal distension or capsaicin ↓	Gut nociception ↓
		NO ↓, lipid peroxides ↓, neutrophils infiltration ↓, and cell apoptosis ↓, in TNF-α-colitis	Antioxidation ↑
		Naïve CD4(+) T cells differentiation ↑, Treg ↑, and IL-10-producing Tr1 cells ↑, in intestine	Intestinal lamina propria immunity ↑
	Systemic immunity	Circulating IL-6 ↓, DC maturation ↓, proinflammatory cytokine ↓, and allospecific T cell response ↓	Systemic inflammation ↓	[51, 52, 53, 54, 55, 56]
		Monocyte phagocytosis of Aβ ↑ and TLRs 2–4 ↑, in AD	Systemic immunity ↑
		IL-6 ↓, TNF-α ↓, IFN-γ ↓, IL-17 ↓, Cox-2↓, IL-10 ↑, and Treg cells ↑, in lymphoid organs or macrophages.	Anti-inflammation ↑ and innate immunity ↑
	Neuroimmunity	Glial activation ↓, NF-κB↓, TNF-α ↓, IL-1β ↓, IL-1α ↓, IL-6 ↓; inducible NOS ↓, Cox-2 ↓; Bax↓, Bcl-2 ↓, caspase 3↓, and caspase 9↓, in AD and PD models	Anti-inflammation ↑, antioxidation ↑, and antiapoptosis ↑	[10, 77, 78, 79, 80]
		Tau aggregation ↓ and neurotoxicity ↓, in neurons	Neuroprotective effect ↑
Resveratrol	Gastrointestinal health	Occludin ↑ and zonula occluden (ZO-1) ↑, in IECs	Intestinal mucus integrity ↑	[32, 33, 34]
		ROS accumulation ↓, SOD ↑, and HO-1 ↑	Antioxidation ↑
		T helper cells ↓, Treg cells ↑, and IEC proliferation ↑, in ileitis	Gut barrier function ↑ and microbiota dysbiosis ↓
		Lactobacilli ↑, bifidobacteria ↑, and enterobacteria ↓	Colonic mucosa architecture ↑
		PGE-2 ↓, Cox-2 ↓, PGE synthase ↓, and NO ↓, in colonic mucosa	Antioxidation ↑ and anti-inflammation ↑
	Systemic immunity	Cytokines (TNF-α, IL-1α, IL-1β, IFN-γ, IL-6, IL-8, and IL-10) ↓, chemokines (C-C motif ligand 2 (CCL2), CCL5) ↓, ROS ↓, Cox-2 ↓, PGE-2 ↓, ICAM-1 ↓, and CSFs ↓, in monocytes and macrophage	Antioxidation ↑ and anti-inflammation ↑	[58, 59, 60]
	Neuroimmunity	Glial activation ↓, NF-κB ↓, and cytotoxic factors (TNF-α, NO, IL-1β, IL-6, and C-reactive protein) ↓	Neuroprotective effect ↑, on cortical neurons	[11, 81, 84, 85, 86]
		Lymphocyte infiltration ↓, protein IL-17A ↓, matrix metalloproteinases, ↓, and tight junction proteins ↑, in BBB-disrupted mice	BBB integrity ↑
Propolis (flavonoids, CAPE, or chrysin)	Gastrointestinal health	Occludin ↑, ZO-1 ↑ and colon fibrosis ↓, in IECs	Epithelial barrier function ↑	[35, 36, 37, 38]
		NF-κB↓, proinflammatory cytokines ↓, and IP-10 ↓	Antioxidation ↑ and anti-inflammation ↑
	Systemic immunity	Phagocytosis↑ and cytotoxicity (IL-1β, IL-6, TLR-2, and TLR-4) ↑, in peritoneal macrophages	Cellular immunity ↑	[62, 64, 65, 66, 67, 68]
		Circulating proinflammatory cytokines (TNF-α, IL-1α, IL-1β, IL-6, IL-4, and ICAM-1) ↓ and anti-inflammatory cytokines (IL-10) ↑, in LPS-induced systemic inflammation	Systemic inflammation ↓
		NO ↓, MAPK ↓, and NF-κB ↓, in mast cells and macrophages	Antioxidation ↑ and anti-inflammation ↑
	Neuroimmunity	NF-κB ↓, TNF-α ↓, IL-1β ↓, IL-6 ↓, NOS ↓, NO ↓, ROS ↓, Cox-2 ↓, and caspase-3 ↓, in microglia or PD mice	Antioxidation ↑, and anti-inflammation ↑, for neurons	[12, 61, 87, 88, 89, 90, 91]
PUFAs (ω-3 PUFAs)	Gastrointestinal health	NF-κB ↓, Cox-2 ↓, PGE-2 ↓, and leukotriene B4 ↓	Anti-inflammation ↑, in gut	[39, 40, 41, 42, 43]
		TRPA1 activation ↑	Gastrointestinal function ↑
		Intestinal mucosa permeability ↓, gut microbiota ↑, IL-15 ↓, TNF-α ↓, IFN-γ ↓, IL-4 ↓, and IL-10 ↓	Gut immune barrier function ↑
	Systemic immunity	IL-17 ↓, IL-6 ↓, IL-23 ↓, and Treg cells ↑, in spleen	Anti-inflammation ↑ and immune function ↑	[69, 70, 71]
	Neuroimmunity	Glial activation ↓, ω-3/ω-6 PUFA balance ↑, amyloid precursor protein (APP) ↓, NF-κB ↓, IL-6 ↓, TNF-α ↓, BDNF, and its receptor ↑	Neuroprotection ↑, anti-inflammation ↑, and brain innate immunity ↑	[93, 94, 95, 96, 97, 98]
Ginsenosides (Rb1, Rb2, Rg3, Rh2, Rh3, Rg1, Rg2, and Rh1)	Gastrointestinal health	TNF-α ↓, IL-1β ↓, IL-6 ↓, IL-17 ↓, IL-10 ↓, CREB ↑, glucose transporter 1 ↑, and gut contractility ↑	Anti-inflammation ↑ and gastrointestinal function ↑	[45, 46, 47, 48]
	Systemic immunity	NF-κB ↓, TNF-α ↓, IL-1β ↓, and PI3K/Akt/mTOR pathways ↑	Anti-inflammation ↑ and enteric nutrition ↑	[45, 48, 72, 73, 74]
		Phagocytic uptake ↑ and ROS generation ↑	Innate immunity ↑
	Neuroimmunity	Glial activation ↓, ROSs ↓, TNF-α ↓, and IL-6 ↓, in the hippocampus	Anti-inflammation ↑ and antioxidation ↑	[100, 101, 102, 103, 104]
		CD14 ↓, NO ↓, TNF-α ↓, IL-6 ↓, IL-1β ↓, Cox-2 ↓, and inducible NOS ↓, in microglia

Notes: ↑: increased; ↓: decreased; IECs: intestine epithelial cells; abbreviations are shown in the text.