Immunomodulatory Role of Plants and Their Constituents on the Management of Metabolic Disorders: An Evidence-Based Review

Figures & data

Figure 1 The study design of the evidence-based review.

Table 1 Characteristics of the Included Trials

Ref., Year	Metabolic Diseases	Design of Study*	Number of Subjects	Subject Characteristics	Clinical Features	Plants/Herbal Preparation/Bioactive Compounds	Control Drugs	Duration of Therapy	Clinical Outcomes
Butacnum et al, 2017^Citation27	T2DM	RCT, double-blind, placebo-controlled, and crossover	24	Men and women Aged 20–60 years old BMI 25.0–28.7 kg/m^2	FBG for normal group 70–100 mg/dL FBG for pre-diabetic group 100–125 mg/dL No diabetes, kidney or liver disease.	Black tea (Camellia sinensis)	N/a	2 hours	Ingestion of black tea enriched with BTPP has been observed to markedly reduce postprandial glucose levels following sucrose consumption in individuals with normal glycemic control as well as in those with pre-diabetic conditions
Mansour et al, 2021^Citation28	NAFLD and T2DM	RCT, double-blind, and placebo-controlled	101	Men and women Aged 30–53 years old	T2DM and NAFLD (controlled attenuation parameter score of 260 or more)	Coffea arabica (chlorogenic acid, caffeine, and their combination)	N/a	6 months	Neither chlorogenic acid nor caffeine demonstrated a significant advantage over placebo in reducing hepatic fat accumulation, liver stiffness, or in improving other liver-associated outcomes in patients diagnosed with diabetes concomitant with NAFLD Lower level of total cholesterol In comparison to the placebo group, the caffeine cohort exhibited a statistically significant reduction in total cholesterol levels (p = 0.04), while the group receiving both chlorogenic acid and caffeine demonstrated a significant elevation in insulin levels (p = 0.01)
Geberemeskel et al, 2019^Citation29	T2DM	RCT	114	Men and women Aged 35–75 years old	Newly diagnosed T2DM patients without any significant diabetes complication	Trigonella foenum-graecum seed powder	Metformin	1 month	The intervention group exhibited a marked 13.6% decline in serum total cholesterol (TC), a 23.53% reduction in serum triglycerides (TG), and a notable 21.7% elevation in serum high-density lipoprotein cholesterol (HDL-C) levels Serum low-density lipoprotein cholesterol (LDL-C) levels demonstrated a significant decline of 23.4%, with no reported adverse events
Chusak et al, 2020^Citation13	T2DM	RCT and crossover	20	Men and women Aged 20–40 years old BMI 18.5–22.9 kg/m^2	FBG <100 mg/dL, A fasting TC <200 mg/dL A fasting TG <150 mg/dL A fasting LDL-c <130 mg/dL Free of serious illness	Anthocyanin-rich rice-berry rice	N/a	3-time visits with intervals of 4–8 weeks for each visit	Intake of RRB led to a notable reduction in both postprandial (PP) plasma glucose and insulin levels
Gul-e-Rana et al, 2013^Citation30	T2DM	Pre- and post-analysis clinical trial	50	Men and women Adults	Diabetic patients taking oral hypoglycemic drugs	Ficus racemosa bark	N/a	15 days	The combined treatment reduced blood glucose (BG) levels, with a marked decline observed in male participants 1.5 hours post-administration
Huang et al, 2017^Citation31	T2DM	RCT, double-blind, and placebo-controlled	41	Aged 20–75 years BMI ≥ 23 kg/m^2	T2DM Treated with ≥3 classes of OHAs with persistent (>6 months) poorly controlled glycemia (HbA1c >7.0% or 53 mmol/mol)	SLBZS consists of Radix Ginseng, Poria, Rhizoma Atractylodis macrocephalae, Semen Lablab album, Rhizoma Dioscoreae, Embryo Nelumbinis, Radix Platycodonis, Semen Coicis, Fructus Amomi, Fructus Jujubae, and Radix Glycyrrhizae	N/a	12 Weeks	YH1, when combined with oral hypoglycemic agents (OHAs), augments hypoglycemic activity and enhances β-cell function in overweight/obese type 2 diabetes patients with poor glycemic control. As an adjunctive therapy to OHAs, YH1 is safe and offers advantages in weight management and lipid metabolic regulation.
Krawinkel et al, 2018^Citation32	T2DM	RCT, single-blind, placebo-controlled, and crossover	52	Aged 30–65 years old Waist circumference >80 cm for women and >90 cm for men BMI 27–35 kg/m^2,	Fasting plasma glucose (FPG) 100–125 mg/dL HbA1c-values 5.7–7.5% (39–58 mmol/mol) BP 90/60–160/110 mmHg	Bitter gourd (Momordica charantia) powder	N/a	16 weeks (8 weeks/period)	The CROS analysis indicated a notable variation in the FPG change of 0.31 mmol/L (5.6 mg/dL) (t=−2.23, p=0.031, r=0.326) accompanied by a trend represented by R²=0.42387.
Senadheera et al, 2015^Citation33	T2DM	RCT and crossover	35	Aged 35–70 years Currently not using Scoparia dulcis extract/ porridge	T2DM Mild and moderate diabetes (FBG 126–300 mg/dL) Not currently using Scoparia dulcis extract/ porridge	Scoparia dulcis porridge	Normal breakfast except a green leafy porridge	2 period (3 months/ period)	Demonstrated a decrease in fasting blood glucose and HbA1c concentrations in type 2 diabetic patients without any elevation in liver enzymes, creatinine, urea, or CRP
Shokoohi et al, 2017^Citation33	T2DM	RCT, double-blind, placebo-controlled, and crossover	86	Women Aged 40–60 years old	T2DM Fasting serum glucose level 150–180 mg/dL Blood glycosylated hemoglobin levels between 7.5% and 8.5% Low-density lipoprotein cholesterol >100 mg/dL Daily oral intake of not more than 10 mg glyburide and 1000 mg metformin at maximum	Terminalia chebula fruit extract (200 mg), Commiphora mukul (200 mg), and C. myrrha oleo-gum-resin (200 mg)	N/a	3 months	Endpoint measurements indicated a significant reduction in fasting blood glucose, total cholesterol, and low-density lipoprotein cholesterol, coupled with a notable elevation in high-density lipoprotein cholesterol levels when juxtaposed with both placebo and baseline values.
Khalili et al, 2017^Citation34	T2DM	RCT, double-blind, and placebo-controlled	60	Men and women Aged 40–60 years old	T2DM with fasting blood glucose level from 150 to 180 mg/dL Glycosylated hemoglobin level from 7.5% to 8.5% On oral antihyperglycemic drugs	A mixed herbal formulation (Silybum marianum (L) Gaertn (milk thistle) seeds, Urtica dioica L (nettle) leaves, and Boswellia serrata (olibanum gum))	N/a	90 days	A notable decline in FBG levels was consistently observed in the active drug cohort throughout the investigation (P = 0.003) Comparative analyses revealed a statistically significant reduction in the average HbA1c value for the active drug group as opposed to the placebo group (P < 0.001)
Sola et al,2014^Citation12	Hyperlipidemia (CVD)	RCT, double-blind, placebo-controlled, two-arm, and multicenter	102	Community-dwelling Men and women Aged >18 years old	Mild-moderately elevated LDL-c 130 mg/dL-189 mg/dL	Armolipid Plus (red yeast rice extract, policosanol, berberine, folic acid, coenzyme Q10, and astaxanthin)	N/a	12 weeks	Decline in LDL-C concentrations alongside reductions in TC/HDL-C and ApoB/ApoA1 ratios, concomitant with an elevation in Apo A1 levels
Tariq et al,2016^Citation35	Hyperlipidemia	Pre- and post-analysis clinical trial	30	Men 25–40 years old No diagnosed with heart disease	Mild hypercholesterolemic; No diagnosed with heart disease	Curcuma zedoaria Roscoe	N/a	60 days	Intake of C. zedoaria was associated with a notable 6.8% elevation in HDL-c levels, accompanied by a suggestive decline of 5.6% in serum LDL-c and 12.5% in TG concentrations
Chiu et al,2017^Citation21	Hyperlipidemia	RCT and placebo-controlled	60	Men and women 18–53 years old	Mild hypercholesterolemia (serum cholesterol 170–200 mg/dL) Without any metabolic disorder	Prune Essence Concentrate (PEC)	N/a	4 weeks with 2 weeks of follow-up without PEC consumption	Intake of PEC (I and II) for 4 weeks substantially ameliorated (p < 0.05) the colony number of Bifidobacterium spp. (1.18- and 1.19-fold) and Lactobacillus spp. (1.07- and 1.16-fold), but markedly lowered (p < 0.05) the colony number of Clostridium perfringens (5.97 and 8.35%) and Escherichia coli (6.25 and 9.38%) The total cholesterol (TC; 5.90 and 6.99%) levels and LDL-c (6.68 and 6.53%) were significantly reduced (p < 0.05) No change in other lipid parameters
Machado et al,2021^Citation14	Diseases associated with excess body weight	RCT, double-blind, parallel, placebo-controlled, and two-arm	26	Men and women Aged 20–45 years old BMI 25–35 kg/m^2 Consumed regular breakfast Had low physical activity level; and dietary restraint ≤ 14	Obesity or overweight	Yacon flour	N/a	6 Weeks	There was an elevation in plasma total antioxidant capacity Protein carbonyl concentrations witnessed a reduction
Basu et al, 2021^Citation15	Obesity and Hyperlipidemia	RCT, double-blind, crossover, and multicenter	33	Adult Men and women	Elevated LDL-c >116 mg/dL	Strawberry powders	Control	14 weeks	There was a notable enhancement in insulin resistance, lipid particle profiles, and serum PAI-1 among obese adults presenting with elevated serum LDL-C
Ryu et al, 2016^Citation16	MetS	RCT, double-blind, placebo-controlled, and parallel	50	Aged 35–65 years old BMI 23–27 kg/m^2	Mild metabolic syndrome TG ≥150 mg/dL HDL-c <40 mg/dL and <50 mg/dL (female) FBG ≥95 mg/dL	Pterocarpan-High Soybean Leaf Extract	N/a	12 weeks	Induced modifications in fasting blood and plasma glucose, HbA1c, plasma lipid concentrations, and the expression of inflammation-associated genes in peripheral blood mononuclear cells (PBMCs)
Hochkogler et al, 2018^Citation36	Obesity	RCT, open, and crossover	26	Men Aged 21–43 years old BMI 25–32 kg/m^2) Not consuming alcohol, tobacco, or drug abuse	Metabolically healthy	Cinnamyl Isobutyrate	N/a	2 hours	Observed reductions in ad libitum energy consumption following a standardized breakfast correlated with diminished postprandial plasma glucose concentrations
Johnson et al, 2020^Citation19	MetS	RCT, single-blind, placebo-controlled, parallel-arm, and pilot	19	Men and Women Aged 20–40 years old	Had three or more of the MetS diagnostic criteria according to the American Heart Association and the National Heart, Lung, and Blood Institute	Cherry juice	N/a	12 weeks	Oxidized low-density lipoprotein and soluble vascular cell adhesion molecule-1 levels were notably reduced compared to the control, with p-values of 0.047 and 0.036, respectively
Franck et al, 2020^Citation20	MetS	RCT and double-blind	59	Men or pre-menopausal women Caucasian Aged 18–60 years old BMI 25–40 kg/m^2	Meet at least one of the following criteria: TG > 1.35 mmol/L, or Insulin concentration >42 pmol/L	Raspberry	Control (maintain their health and food habits stable for an 8-week period)	8 weeks	Decreased postprandial hyperglycemia, hypertriglyceridemia, and inflammatory markers (IL-6 and TNF-α), along with a reduction in systolic blood pressure (SBP)
Kitada et al, 2017^Citation37	MetS	Investigator-initiated RCT, double-blind, and placebo-controlled	39	Men or women Aged 20–70 years old	Routine clinical biochemistry data is measured as a baseline	Passion Fruit (Passiflora edulis) Seeds (picceatanol)	N/a	8 weeks	Improve metabolic health, including insulin sensitivity, BP, and HR, in overweight men.
Tindall et al,2020^Citation37	CVDs	RCT and crossover	46	Men and women Aged 30–65 years old BMI 25.0–39.9 kg/m^2	Elevated BP (120–159/80–99 mmHg) Increased LDL-c (128–177 mg/dL for men and 121–172 mg/dL for women)	Walnuts	N/a	2 weeks	Compared to baseline measurements, there were notable decreases in brachial and central mean arterial pressure, central diastolic blood pressure (DBP), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), non-HDL-C, and the TC to HDL-C ratio
Taghizadeh et al, 2017^Citation38	Diabetic Nephropathy	RCT, double-blind, and placebo-controlled	60	Aged 45 to 85 years old	Diabetic kidney disease with a proteinuria level greater than 0.3 g/24 h, with or without elevation of serum creatinine levels)	Mulberry extract	N/a	12 weeks	Significant declines were observed in serum triglycerides (TG) (P = 0.03) and very-low-density lipoprotein cholesterol (VLDL-c) (P = 0.03). Elevation in high-density lipoprotein cholesterol (HDL-c) (P = 0.03), serum high-sensitivity C-reactive protein (P = 0.02), plasma glutathione (P = 0.005), and malondialdehyde (P < 0.001)
Ferro et al,2020^Citation39	NAFLD	RCT and double-blind	94	Men and women Aged 30–75 years old	Hepatic steatosis	Bergamot (Citrus bergamia) polyphenol fraction and Cynara cardunculus extract	N/a	6 weeks	Over a six-week period, adults with fatty liver exhibited a reduction in serum uric acid levels
Crescenti et al, 2013^Citation40	CVDs	RCT	214	Community-dwelling men and women aged >20 years old With a smoking habit	Pre-hypertensive condition and Stage 1 (SBP: 120–159 mmHg DBP: 80–99 mmHg); LDL-c between 130 mg/dL - 89 mg/dL Minimum one other major CVD risk factor such as age >45 years in men and >55 in women, low HDL-c	Cocoa	An isocaloric diet in which the percentage of saturated fatty acids in the diet was 13% of total energy	14 days	Significantly reduced the DNA methylation levels (2.991±0.366 vs 3.909±0.380, P<0.001)
Shidfar et al, 2018^Citation41	Obesity	RCT and single-blind	50	Aged 20–65 years old BMI 25–40 kg/m^2 Not taking hepatotoxic medicines Not consuming of alcohol ≥30 gr/d Not in pregnant condition or lactation Not smoking Not taking mineral and multivitamin supplements Not taking olive products and lipid-lowering medicines in the last three months.	NAFLD patient with the increase of the AST and ALT enzymes (U/L <30 in men and <20 in women) Not having CVD Not in diabetic condition	Olive oil	Normal consumption of oil (compared to the test group)	12 weeks	The control group exhibited a notable decline in ALT enzyme levels (P = 0.004). Meanwhile, participants in the olive oil group displayed a decrease in both enzymes relative to initial measurements (P < 0.01) Significant difference between the two groups (P < 0.02) in ALT and AST levels were observed
Sanchez-Rodriguez et al, 2018^Citation1	MetS	RCT, double-blind, parallel, placebo-controlled, and two-arm	53	Men and women Aged 20–50 years old	Healthy	Olive oil	N/a	6 weeks (± 5 days)	HDL-C levels showed an elevation in female participants; however, no discernible differences were observed following the three interventions There was an enhancement in a biomarker indicative of endothelial function, noted both in vivo and ex vivo
Hongu et al, 2014^Citation42	Obesity	RCT and double-blind	24	Men and women Aged 21–50 years old BMI 29–35 kg/m^2 No weight loss of >5 kg in the last 3 months	Healthy	Rice bran and plant sterols	N/a	8 weeks	A notable reduction in the levels of TC and LDL-C was observed between the groups. Additionally, there was a significant decline in SBP when compared to baseline measurements
Rita et al, 2022^Citation43	T2DM	RCT and blind to the researcher who performed the statistical analysis	31	Men and women Aged 18–40 years old	Healthy FBG <126 mg/dL	Adansonia digitata L. (Baobab aqueous extract)	N/a	1 day (Sampling in 30, 60, 90, 120 minutes)	Reduced glycemia incremental AUC
Estevez-Santiago et al, 2019^Citation22	CVD risk factors	Parallel study	72	Women Aged (50–70 years) BMI 25–33 kg/m^2 Amenorrhea (>2y)	Healthy	Anthocyanins, xanthophylls (lutein + zeaxanthin)	N/a	8 months	Following 8 months of treatment with A+X, there was a marked reduction in plasma glucose levels. Concurrently, a rise in plasma ferric reducing antioxidant power was observed, although no synergistic interaction was discernible between the bioactives in the two groups
Martini et al, 2021^Citation44	CVD	RCT, crossover, and three-arm	21	Aged >18 years BMI 18–25 kg/m^2 Regular consumers of 1–5 cups of coffee per day.	Healthy	Coffea arabica (chlorogenic acid, caffeine)	N/a	1 month	The consumption of coffee or cocoa-based products yielded no discernible impact on cardiometabolic markers
Nilsson et al, 2017^Citation45	MetS	RCT and crossover	46	Non-smokers Aged 50–70 years old Normal to slightly increased BMI (28 kg/m^2)	Healthy	A mixture of Swedish berries (polyphenols and carotenoids)	N/a	5 weeks	The intervention utilizing berries led to a reduction in TC and LDL-C levels relative to the baseline values (both P<0.05). Furthermore, when compared to the control beverage, these reductions were statistically significant, with P-values of <0.005 for TC and <0.01 for LDL-C Participants exhibited enhanced performance in the working memory test subsequent to consuming the berry beverage in contrast to post-consumption of the control beverage (P<0.05)
Vincellette et al,^Citation26	Hyperglycemia	RCT, placebo-controlled, double-blind, and crossover	17	Aged 21–25 years old BMI 23.5 ± 3.2 kg/m^2	Healthy	Watermelon juice	N/a	2 weeks	The postprandial flow-mediated dilation exhibited a higher area under the curve (AUC) (P = 0.03), as did the AUC of microvascular blood (P = 0.01). Additionally, there was a significant elevation in tissue oxygen saturation (StO2%) to 65.9 ± 1.7%. Conversely, the slope related to ischemic-reperfusion remained unaffected by the treatment (P = 0.83)
Valderas-Martinez et al, 2016^Citation25	CVD	RCT, open, crossover, and prospective	40	Non-smokers not receiving medication or vitamin supplements	Healthy	Tomato sauce with olive oil	Control	14 days	Tomato sauce augmented with refined olive oil may modulate the lipid profile and influence soluble inflammatory biomarkers associated with the initiation and progression of atherosclerosis.
de Morais Junior et al, 2020^Citation46	Hypertriglyceridemia	RCT, double-blind, placebo-controlled, and crossover	14	Young women Aged 18 to 25 years old	Healthy	EGCG	N/a	Acute (90 and 120 min after the meal)	EGCG moderated postprandial triglyceride (TG) and glucose levels; however, it adversely influenced HDL-C subsequent to the consumption of a high-fat fast-food meal
Lopez et al, 2017^Citation47	Obesity	RCT, double-blind, placebo-controlled, parallel-groups design, and single-center	105	Overweight; men or women Aged ≥35 to ≤70 years old	Normally active or judged to be in good health on the basis of medical history and physical examination	T. chebula fruit	N/a	84 days (14 weeks period)	Relative to the placebo, the treatment notably ameliorated various parameters: mKOOS global scores (P = 0.023), both total and physical function dimensions of mWOMA, VAS indices for Knee Discomfort (P = 0.001), VAS evaluations for systemic joint functionality (P < 0.029), VAS measurements reflecting reduced knee joint soreness (P = 0.022), AyuFlex2 (P = 0.043), the distance traversed during the 6-minute walk assessment (P = 0.047), and the post-walk VAS discomfort scores (P = 0.026). Additionally, there was a suggestive decline in COMP levels, although this did not reach statistical significance (P = 0.104). Throughout the investigation, all safety biomarkers remained within the established normal range
Kishimoto et al, 2023^Citation48	CVD risk factors	RCT, double-blind, placebo-controlled, and crossover	23	Women Aged 20–35 years old	Healthy	Strawberry beverage (500 g)	N/a	2 sessions (separated by a 4-week washout period)	Post ingestion of the strawberry beverage, there was a notable elevation in the serum concentrations of both vitamin C and folate (P < 0.001). The zenith of these levels was observed at the 2-hour mark, recording peak concentrations of 15.0 ± 2.5 μg/mL for vitamin C and 14.4 ± 7.0 ng/mL for folate

Notes: *Not all articles reviewed in the table defined the project settings (single or multi-center).

Abbreviations: AUC, area under the curve; BMI, body mass index; BTPP, black tea polymerized polyphenol; COMP, Cartilage Oligomeric Matrix Protein; CVD, cardiovascular disease; DBP, diastolic blood pressure; DNA, deoxyribo nucleic acid; EGCG, Epigallocatechin-3-gallate; FBG, fasting blood glucose; HDL-C, high-density lipoprotein-cholesterol; LDL-C, low-density lipoprotein-cholesterol; MetS, metabolic syndrome; mKOOS, modified-Knee Injury and Osteoarthritis Outcomes Score; mWOMAC, modified-Western Ontario and McMaster Universities Arthritis Index; NAFLD, non-alcoholic fatty liver disease; PAI-1, plasminogen activator inhibitor-1; RCT, randomized-control trial; ROM, range of motion; SBP, systolic blood pressure; T2DM, type 2 diabetes mellitus; TC, total cholesterol; VAS, Visual Analog Scale.

Table 2 Mechanism of Action of Plants on Metabolic Disorders and Immune System

Plants/Herbal/Vegetable Preparation*	Family	Major/Active Constituents	Mechanisms on Metabolic Disorders	Immunomodulatory Activity
Boswellia serrata	Burseraceae	Olibanum, an aromatic resin	Augmentation of insulin sensitivity and protecting pancreatic β-cells^Citation34	COVID-19 patients demonstrated an elevated lymphocyte count accompanied by a decline in C-reactive protein (CRP), lactate dehydrogenase (LDH), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) concentrations.^Citation66
Camellia sinensis	Theaceae	EGCG	EGCG decreased lipid uptake and the abatement of inflammatory cytokine concentrations^Citation46,Citation67	Extracts stimulated cytokine production, T lymphocyte proliferation, and reportedly augmented lymphocytes, monocytes, IL-1α, and IL-1β production^Citation68
Cinnamomum cassia	Lauraceae	Cinnamyl isobutyrate	Inhibition of α-glucosidase and pancreatic α-amylase, modulation of glucose synthesis through the alteration of glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) pathways, and modulation of cholesterol and fatty acid uptake via deactivation of Niemann-Pick C1-like 1 and Cd36 mRNA receptors, paired with a concurrent decrease in chylomicron synthesis^Citation36	Volatile oils from Cinnamomum cassia twig, derived from eight selected herbs, robustly enhanced IL-1β and IL-6 release from ANA-1 murine macrophage^Citation69
Citrullus lanatus	Cucurbitaceae	Citrulline, lycopene, and β-carotene^Citation26	Citrulline and its enriched form in watermelon juice amplify the circulating arginine reservoir and intensify the NO synthase activation more robustly than arginine alone^Citation26	Phytol arrests the growth of the human T-cell leukemia Jurkat cell line and impedes tumor progression in an A549 human epithelial cell xenograft mouse model. This is associated with S-phase cell cycle arrest and downregulation of specific cyclins and signaling pathways.^Citation70
Citrus Bergamia	Rutaceae	Naringin, neohesperidin, neoeriocitrin, brutieridin, and melitidin Bergapten and bergamottin	Lipid metabolic pathways are modulated by inhibiting hepatic 3-Hydroxy-3-Methylglutaryl-Coenzyme A (HMG-CoA) reductase and acyl-CoA cholesterol acyltransferase (ACAT); concurrently, there is an elevation in AMPK activity and enhancement in glucose uptake in skeletal muscles and hepatic tissues^Citation39	Gene expression modulation related to chemotaxis, adhesion, and cell infiltration was observed, along with decreased plasma concentrations of inflammatory markers in non-diabetic subjects^Citation71
Coffea arabica	Rubiaceae	Chlorogenic acid (CGA), caffeine, cafestol, trigonelline, and melanoidin	Regulation of glucose intolerance and amelioration of hyperlipidemia^Citation28 At both microsomal and cellular levels, there’s an impediment of the glucose-6-phosphate translocase and activation of the adenosine monophosphate-activated protein kinase, subsequently leading to the maintenance of blood glucose stability and reduction in lipid biosynthesis^Citation28	Notable suppression of inflammatory cytokines, reduced macrophage migration, and enhanced immunological signaling were observed. Expansion of oxidative processes was effectively halted.^Citation72
Curcuma Zedoaria Roscoe	Zingiberaceae	Zederone, curzerenone, 1,3–hydroxygermacrone, epicurzerenone, curcumol, zedoarol, curcolone, ar–turmerone, zedoarondiol, isocurcumenol, furanodiene, curdione, curcumenol, curcumanolide A, and zingiberene	Curcumin demonstrates efficacy in decreasing serum cholesterol, preventing LDL oxidation, inhibiting platelet aggregation, and suppressing thrombotic events	Curcumin attenuated the activation of the NF-κB signaling cascade, concurrent with NLRP3 silencing through siRNA transfection^Citation73
Ficus racemosa	Moraceae	Glycosides, β-sitosterol and lupeol	β-sitosterol serves as a cholesterol-lowering agent through its mechanism of impeding cholesterol absorption in the gastrointestinal tract^Citation30	Compounds isolated from Ficus racemosa exhibited pronounced cell migration augmentation in specific cell lines^Citation74
Glycine max	Fabaceae	Soybean contains isoflavones (daidzin, genistin, and malonyl genistin), while soy leaves contain pterocarpan and kaempferol glycosides	A kaempferol glycoside-rich fraction derived from unripe soybean foliage has shown to diminish blood glucose and hepatic lipid concentrations in KK-Ay murine models^Citation75 Pterocarpan has shown promising results in improving insulin sensitivity and regulating plasma glucose concentrations in high-fat diet-induced type 2 diabetic mice^Citation64	Soy isoflavones and their metabolites modulated natural killer (NK) cell activity. Genistein specifically attenuated IL-12/IL-18-induced interferon-gamma (IFN-γ) production compared to controls^Citation76
Juglans sp.	Jugalanaceae	Α-linolenic acid (ALA), a plant-based omega-3 fatty acid, hydrolyzable tannins^Citation77	Alpha-lipoic acid exhibits its cardio-protection through myriad pathways, inclusive of attenuating plaque mineralization, lipid profile optimization, endothelial function maintenance, and demonstrating anti-thrombotic, anti-arrhythmic, and anti-inflammatory actions.^Citation37	Walnut consumption may enhance the proliferation of beneficial bacterial species in the gut, indirectly influencing immune system functionality.^Citation77
Lycopersicon esculentum L.	Solanaceae	Carotenoids (mainly lycopene and β-carotene), phenolic compounds (mainly flavonoids, such as naringenin), vitamins C and E, potassium and folates	Lycopene manifests various salutary effects, including LDL-C reduction, inflammation marker suppression, blood pressure moderation, and enhancement of flow-mediated dilation^Citation53,Citation78	Gamma-aminobutyric acid (GABA) derived from tomatoes demonstrated similarities with biologic GABA found on peripheral immune system cells^Citation79
Momordica charantia	Cucurbitaceae	Peptides that resemble insulin (P-insulin), charantins, momordicosides, oleanic acid, trehalose, and momordin	Decreasing intestinal glucose absorption, enhancing insulin release, and promoting glucose uptake in peripheral cells^Citation32	Polysaccharides were found to bolster specific immune markers in mice with cyclophosphamide-induced immunosuppression^Citation80
Morus alba	Moraceae	Flavonols including rutin, morin, quercetin, and myricetin	Quercetin is involved in the activation of PPAR-α and PPAR-γ, impediment of nuclear factor kappa-light-chain-enhancer activation in B cells, and upregulation of anti-inflammatory cytokine expression^Citation38	Ratios between specific T helper cell populations and cytokine secretion profiles were altered^Citation63
Olea europaea	Oleaceae	Monounsaturated fatty acids (MUFAs), polyphenols, and triterpenes, Oleuropein	Polyphenols exhibit protective qualities against endothelial dysfunction triggered by elevated glucose and free fatty acids by modulating nitric oxide and endothelin-1 ratios^Citation59	Downregulation of genes integral to inflammation, lipid metabolism, and oncogenesis was observed.^Citation41
Panax ginseng	Araliaceae	Ginsenosides, polysaccharides, steroids, and flavonoids	Ginsenosides play a dual role in reducing gluconeogenesis and facilitating glucose transport and insulin biosynthesis; they also modulate cellular redox equilibriums or histone acetylation via SIRT1 and NRF2 activations and their downstream gene expressions^Citation81	Ginsenoside-Rb1 potentially inhibited TNF-α formulation in LPS-stimulated RAW264.7 macrophages^Citation82
Passiflora edulis	Passifloraceae	Piceatannol	Conspicuous reductions in blood glucose levels were recorded in mice on high-fat diets or db/db mouse models, without discernible changes in body weight or visceral adiposity The activation of SIRT1 and AMPK pathways suggest an improved metabolic state^Citation83	Piceatannol significantly modulated VEGF-induced cellular activities and vascular formation in zebrafish embryos, likely through VEGF signaling interference.^Citation84
Prunus cerasus	Rosaceae	Anthocyanins, including cyanidin 3-glucosylrutinoside, cyanidin 3-rutinoside, cyanidin sophoroside, and peonidin 3-glucoside; flavonols, including isorhamnetin rutinoside, kaempferol, and quercetin; flavonols, including catechin, epicatechin, and procyanidins B1 and B2	In hyperglycemic mouse models, the suppression of pro-inflammatory cytokines indicates potential therapeutic interventions for degenerative diseases or diseases linked with cell activation^Citation19	Reduction in pro-inflammatory molecule production was documented.^Citation85
Rhizoma coptidis	Ranunculaceae	Berberine	The role of AMP-activated protein kinase (AMPK) as an activator is multifaceted, ranging from inducing glucose transporter-4 and insulin receptor mRNA expressions to being an α-glucosidase inhibitor, a glucagon-like peptide-1 (GLP-1) inducer, and an inhibitor of mitochondrial respiratory chain complex I, cumulatively stimulating glycolysis^Citation31	Infections resulted in attenuated serum interferon-gamma and intestinal TNF-α concentrations.^Citation86
Silybum marianum (L)	Asteraceae	Flavonolignans (70–80%) containing silymarin, silibinin, silydianin, and silychristin	The influence on pancreatic β-cell functionality and the insulin secretagogue effect is both regulatory and protective^Citation34	The NF-κB signaling pathway and TNF-α activation were suppressed, with variances in T-lymphocyte functionality based on dosage.^Citation87
Smallanthus sonchifolius Poepp	Asteraceae	Fructooligosaccharides (FOS) and phenolic compounds content, mainly chlorogenic acid	Fructooligosaccharides and their fermentation by-products impact gut flora, especially focusing on Lactobacillus and Bifidobacterium species, engendering a healthier gut microenvironment^Citation14	Fructooligosaccharides (FOS) derived from Yacon manifested non-specific immunomodulatory effects against heat-inactivated yeast.^Citation88
Terminalia chebula	Combretaceae	Tannins include gallic acid, ellagic acid, chebulic acid, chebulinic acid, punicalagin, and tannic acid; flavonoids include quercetin, catechin, and kaempferol; Saccharides include D-glucose, D-fructose, and saccharose; fruit acids include quinic acid and shikimic acid	Hydrolyzable tannins, including chebulagic acid, chebulinic acid, and gallic acid, have been characterized for their anti-inflammatory and antioxidant properties. Evaluations using experimental arthritis pain models and in vitro methodologies have highlighted their potential to inhibit TNF-alpha, IL-6, NF-kappaB, nitric oxide radical scavenging, and T-cell-mediated cytotoxic responses which involves promoting phosphorylation of insulin receptors, enhancing insulin-driven glucose transportation, and inhibiting genes vital for adipogenesis, tilting the balance towards glucose metabolism^Citation47	Specific acids displayed antioxidant properties, possibly contributing to their immunomodulatory activities, with observed changes in antioxidant enzymes and specific immune cells. Elevations in pineal gland melatonin concentrations and specific cytokines were noted, with potential implications for immune function.^Citation89
Trigonella foenum-graecum	Fabaceae	Seeds contain alkaloid trigonelline, steroidal saponins, galactomannan, quercetin-3-O-rhamnoside (quercitrin), saponins including diosgenin	Fibrous components slow down gastric emptying, which in turn moderates post-prandial blood glucose elevations. Trigonelline may contribute to reduced glycosuria Diosgenin acts as a barrier to cholesterol absorption, resulting in decreased hepatic cholesterol concentrations^Citation90	Immune modulation in macrophage cells and altered CD4+ and CD8+ counts in diabetic mice were observed, potentially linked to NF-κB activity^Citation90
Urtica dioica L	Urticaceae	Neophytadiene, phthalic acid, dibutyl phthalate, bis(2-ethyl hexyl) maleate, and 1.2-benzenoid carboxylic acid	Insulin secretagogue activity, mimicking insulin functions, exhibiting PPAR (peroxisome proliferator-activated receptor)-γ agonistic behavior, and inhibiting α-glucosidase functions^Citation91	Compounds showcased antioxidant properties without displaying cytotoxicity to macrophages and hepatocytes at active concentrations^Citation91

Notes: *Only major components of the poly-herbal preparations are listed in the table.

Figure 2 Plants that alleviate metabolic disorders and activate the immune system. The thin black outline denotes the plants that have been reported clinically solely for their activity in metabolic disorder and their mechanisms in immune system have not been reported in details. While the boxes with a red outline signify that the plants are reported not only for their benefit in metabolic disorders clinically but also affect multiple biochemical pathways in immune system.

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