Table 4.

Natural products displaying potency as anti-diabetes mellitus, -obesity, -heart-related diseases, and -cancer by specifically modulating excessive effects of proinflammatory cytokines.

No	Source(s)	Compound or extract(s)	Mechanism of action(s)	Experimental model(s)	Key findings	Refs
Natural products to manage diabetes mellitus and obesity
1	Psidium guajava	Total triterpenoids of leaves extract	Inhibitor of proinflammatory cytokines by NF-κB pathway	An in vivo study using rats induced by a high-fat diet and streptozotocin to provide diabetic peripheral neuropathy	Significantly decreased serum blood glucose levels in rats and suppressed the expression of proinflammatory mediators via PI3K and Akt pathways.	(X [287].
Natural products to manage heart-related diseases
2	Rhizoma coptidis	Berberine (BBR)	Suppressing NF-κB and JNK signaling pathways	•An in vitro study in H9c2 cells subjected to hypoxia/reoxygenation •An in vivo study using rats subjected to MI/R surgery	•Pretreatment of solid dispersion of BBR with sodium caprate (HGSD) at doses of 25 and 50 mg/kg significantly enhanced the recovery of cardiac LVDP 2-fold, cardiac output 2.5-fold, and decreased cardiac LVEDP 1.8-fold compared with the untreated group. •HGSD significantly suppressed the release of cTnI into the perfusate after ischemia-reperfusion. •The possible mechanism of HGSD pretreatment in inhibiting the production of TNF-α and IL-6 is related to diminishing JNK activation leading to decreasing translocation of NFκB into the nucleus.	[306]
3	Aralia elata	Total saponins of Aralia elata (Miq) Seem (AS)	Inhibit NF-kB activated by TNF-α and stimulating PI3K/Akt signaling pathway to regulate the pro- and anti-apoptotic	An in vitro study in endothelial Cell Injury induced by TNF-α using human umbilical vein endothelial cell (HUVEC)	•Inhibition of NF-kB activated by TNF-α was reported as a cytoprotective effect of AS. In addition, AS stimulated PI3K/Akt signaling pathway to regulate the pro- and anti-apoptotic protein Bcl-2/Bax and downregulate inflammatory factors such as IL-6, MCP-1, and VCAM-1.	[321]
4	Grape	Oligomerized grape seed proanthocyanidins (GSP)	•Inhibition of oxidative damage •Suppression of the ASK1/NF-kB signaling pathway	An in vivo study using an iso-induced cardiac remodeling model in rats	•The increase of HW/BW and LVW/BW as cardiac hypertrophy indicators was significantly diminished by the administration of GSP at all doses compared with untreated groups. •Treatment with GSP at doses of 100 and 150 mg/kg BW significantly inhibited NF-kB signaling pathway, decreased the expression of COX-2 protein, increased SOD, and suppressed MDA.	[324]
5	Salvia miltiorrhiza Bge. and Carthamus tinctorius L.	Danhong injection (DHI) contains 5-hydro- xymethylfurfural, Danshensu, protocatechuic acid, protocatechuic aldehydrate, caffeic acid, rosmarinic acid, lithospermic acid, salvianolic acid B, salvianolic acid A and salvianolic acid C	Anti-cardiac hypertrophic by modulating p38 and NF-κB pathway	•An in vivo study using iso-induced cardiac hypertrophy in rats •An in vitro study in H9C2 cells	DHI suppressed the elevation of P38 phosphorylation and activation NF-κB inhibiting translocation of p65 into the nucleus. The subsequent event is the restoration of cardiac hypertrophy induced by ISO.	[172]
6	–	Quercetin, luteolin and epigallocatechin gallate	•Antiinflammation •Inhibit apoptotic cascade • Regulate ROS production	An in vitro study using EA. hy-926 cells	•Quercetin, luteolin, and EGCG increased AMPK phosphorylation, decreasing TXNIP and NLRP3 inflammasome induction, leading to the downregulation of IL-1β, which strongly correlates with lowering caspase-3 activity •Regulation of eNOS and ET-1 expression in endothelial cells, inhibition IKKβ activation, leads to attenuated phosphorylation and downregulated gene expression of VCAM-1.	[296]
Natural products to manage cancer
7	Gynura procumbens	Ethanol supernatant extracts (EEGS)	•Antiinflammation •Antiproliferation	An in vivo study using nanodiethylnitrosamine (nanoDEN)-induced mouse liver cancer	•The major constituents of G. procumbens are caffeoylquinic acid (CAC) and non-caffeoylquinic acid (n-CAC). •The incidence of tumors was significantly reduced in treatment with EEGS-L (10 mg/kg) and CAC compared with the untreated nanoDEN group. •Administration of EEGS-L, CAC, and n-CAC significantly lowered the inflammation scores. •Administration of EEGS, CAC, and n-CAC significantly suppressed COX-2, β-catenin, PCNA, HIF-1α expression induced by nanoDEN. •Administration of EEGS, CAC, and n-CAC significantly decreased mRNA levels of β-catenin, TNF-α, PPAR-γ, AP- 2, Smad-2, and TGF-β1 during tumorigenesis. •Administration of EEGS, CAC, and n-CAC remarkably reversed nanoDEN-induced submicroscopic structural changes in liver tissue.	[313]
8	Citrullus lanatus (Thunb.) Mansfeld	Lycopene	•Induces cell apoptosis •Induces elevation of proinflammatory protein	An in vitro study using adenocarcinoma cell line (A549 CCL-185™)	•Lyc W significantly induced the apoptotic cells and mitochondrial stress. •Increased intracellular ROS levels and translocation of NF-kB. •Increased elevation of IL-8 as a proinflammatory protein.	[61]