Available online on 15.01.2025 at http://jddtonline.info

Journal of Drug Delivery and Therapeutics

Open Access to Pharmaceutical and Medical Research

Copyright  © 2025 The  Author(s): This is an open-access article distributed under the terms of the CC BY-NC 4.0 which permits unrestricted use, distribution, and reproduction in any medium for non-commercial use provided the original author and source are credited

Open Access Full Text Article Review Article

Biological Activities and Mechanisms of Actions of Bioactive Compounds (BACS) Identified in Pure and Ternary Blends of Cocoyam, Soya Bean and Bambara Groundnut Flour Using Gas Chromatography-Mass Spectrometry (GC-MS) Technique: A Review

Henry Chukwuemeka Uro-Chukwu ^1,2*, Franklyn Chidiebere Uro-Chukwu ², Frances Chidinma Uro-Chukwu ²

¹ Department of Medical Biochemistry, Alex Ekwueme Federal University, Ndufu-Alike, Ikwo, Ebonyi State, Nigeria

² Institute of Nutrition, Nutraceuticals & Public Health Research & Development, Nigeria

 

 

1. INTRODUCTION 

Functional foods are foods which in addition to their nutritional value contains others constituents like biologically active substances such as antioxidants, minerals, vitamins, presbiotics that have health benefits¹. Functional foods from medicinal plant foods are useful in managing many diseases due to the presence of bioactive compounds².  BACs are not only seen in plants foods but also in animals. These animal and plant sources include cocoyam, shrimps, egg, and legumes^3-6. The biological activities of these bioactive compounds ranges from antioxidant, anti-inflammatory, hypocholestrolaemic, antimicrobial and anti-diabetic activities^7-20. Such bioactivities are due to various structural features of such compounds among which are the chain length, hydrophobicity, molecular charge and the side chain bulkiness of the amino acid residue^18,21. Recent studies on Bambara groundnut (Vigna subterranean) Soya Bean (Glycine max. (L) Merrill) and cocoyam (Colocasia esculenta) in pure and ternary blends show that these plant food formulations contain bioactive compounds (Uro-Chukwu & Uro-Chukwu, unpublished Bench work). The recent findings collaborate previous studies which equally reported the presence of various bioactive compounds in such plant foods^{14,15, 20,22}.  

Besides containing these BACS, cocoyam, bambara groundnut and soya bean are ready sources of macro-nutirents and some other micro-nutrients, are readily available in poor-resource countries and cheap^23-27. When the flour are blended, the available BACs in various concentrations in combinations, can exhibit antagonistic or synergistic effects, with the net outcome being more or less high potency in anti-inflammatory, antioxidant, anti-diabetic or immune-stimulatory effects^28-31. 

Antioxidant interactions in vivo and in vitro have been documented irrespective of the sources of the bioactive compounds. The interaction between multiple agents can result in either potentiation when one of the flour mix is an inactive compound but improves the efficacy of the active compound ^32,33, additive interactions when the two or more compounds are active and their total effect equals sum of the efficacy of the single components of the combination but if the sum is of greater effect, it is said to be synergistic and if lower, it is antagonistic³². The combination mechanism depends on several various variables including concentration, ratio, the medium in which the reactions occur, the spatial orientation, the form of radical initiators, interfering substances and the prevailing microenvironment for the reactions³⁴. Such combination effects have been shown in marine-derived BACs found to have advantages in managing obesity³⁵; anti-inflammatory and antioxidant activities^30,31 and anti-cancer^36,37. Similar work have been conducted in dietary phytochemicals such as BACs-derived from cocoyam, soybean, Bambara groundnuts, fruits and vegetables when combined have also shown similar combination effects and in vivo and in vitro activities as demonstrated by marine BACs^38,39.

Using unripe plantain and millet dietary feed blend in rats in which alloxan was used to induce diabetes, Nnadi and colleagues were able to document a decrease in the concentration of blood glucose by 42.34% - 50.95% and that such actions were likely due to the presence of flavonoids and phenols²⁸. Experimenting with Dioscorea dumentorum (bitter yam) and digitaria exiles (acha) in diabetic rats, Onwuchekwa and colleagues reported hypoglycemic and hypolipidemic properties of the blend²⁹. Study on the consumption of cocoyam-cowpea-plantain flour blend by healthy individuals was reported to result in better glycemic index and blood lipid profile when the flour mix was given in 50:50 ratio⁴⁰. Equally acompounded breakfast product of African yam bean (Sphenostylis sternocarpa)-sorghum (Sorghum bicolor L.)-unripe plantain (Musa paradisiaca L.) flour mix in graded ratios was found to have hypoglycaemic, hypolipidemic and hepatoprotective effects on diabetic rats⁴¹.

Soya bean flour blends were also documented to exert anti-hyperglycemic activities in diabetic animals. In a study by Akinjayeju and team, dough produced from maize-soybean-millet flour blend was documented to have glycaemic properties and anti-diabetic potentials in diabetic rats⁴². Optimized dough meal from plantain- soybean cake-rice bran flour blend fed on STZ Induced diabetic rats resulted in higher endogenous antioxidant enzyme capacity since the reduced glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione transferase (GST) in the liver, were increased, while reducing the lipid peroxidation biomarker, malondialdehyde (MDA), the myeloperoxidase (MPO) and the xanthine oxidase with the increased alpha-amylase and alpha-glycosidase enzyme activities⁴³. Similarly anti-diabetic activity was established in optimized blends produced from matured plantain-soya cake-wheat bran flour mix by researchers who reported significant α-glucosidase, α-amylase inhibition and highly reduced approximate values of glycemic index⁴⁴. In another work, reported anti-hyperglycemic properties from Plantain-defatted soybean-tiger nut flour mix fed on diabetic rats⁴⁵.

Bambara groundnut flour blend have also shown hypolycemic potentials. When wheat whole bread were substituted with Bambara groundnut to get a wheat-bamabara groundnut, 25%:75% respectively, flour blend, the experimental diabetic rats recorded higher nutritional composition, growth indices, free radical scavenging potentials, ability to modulate carbohydrate hydrolyzing enzyme and lower glycemic index/ load⁴⁶.Similar improved protein content, haematological properties and nutritional status of alloxan-induced diabetic rats were fed with a blend of African bean flour, Bambara groundnut flour, and fermented popcorn⁴⁷. When Bambara groundnut flour, finger millet and Lecaniodiscus Cupanioides (Khain) flour were mixed and fed on alloxan-induced diabetic rats, the composite flours led to significantly decreased blood glucose concentrations, liver enzymes levels, weight loss and better lipid profile, urea and creatinine levels when compared to the positive controls⁴⁸.

The biological activities of flour blend therefore depends on the composite flour composition and several other factors in the microenvironment. The aim of this review therefore is to report the biological activities and mechanisms of actions of the various BACs identified in a current study that documented using GC-MS, in a cocoyam-soya bean-bambara groundnut flour blend, with a view to understanding the basis for their invivo actions of such formulations in the management of non-communicable diseases like Type 2 diabetes mellitus.

2. Bioactive Compounds in CY-SB-BGN Flour Blend

The various bioactive compounds identified in the GC-MS analysis of different pure and ternary blends of cocoyam-soya bean-Bambara groundnut flour according to the study done by Uro-Chukwu & Uro-Chukwu, (unpublished Bench work) were thiadiazoles, stilbene, aziridine, thiourea, amphetamine /phenylethylene, artemisinin, monoterpenoids, Naphthalenes, 1,4-diazepanes, phenols and flavanoids (Table 1). 

The commercial rat feed (formulation RF) contained BACs like thiadiazol (Piperidine, 1, 2-dimethyl, 1, 2, 3-Thiadiazole-4-carboxylic acid, hydrazide, Phenols (Phthalan (Isocoumaran) or 1, 3-dihydro-2-benzofuran, 2-Methoxy-4-vinylphenol, Vanillin) and carboxylic acid (Dibutyl phthalate) (Table 1). Other formulations (1 - 7) equally contain BACs in varying concentrations (Table 1). Formulations 1 contained mainly phenolics and carboxylic acids with an additional aziridine compound [N-Isopropoxy-2-carbomethoxyaziridine] while thiourea, phenols and carboxylic acids were the identified BACs in Formulation 4 (Table 1). Formulation 6, contained Aphetamine and Phenylethylamine, Phenols, (E)-Stilbene; Dibutyl phthalate and an artemisinin while Formulation 7 had 1,3-Benzenediol, 2-chloro, 4-Hydroxy-3-methylacetophenone, Butylated Hydroxytoluene, 1-methoxy-2-(methylthio), [Thiophene, tetrahydro-2-methyl] and Phthalic acid, butyl isohexyl ester as the bioactive compounds (Table 1).  The BACs compounds in formulations 5 were phenolics and diazepanes, and in formulation 2, phenolics and carboxylic acids in addition to thiadiazol (Tables 1). In Formulations 3, the BACs were 4,7,7-Trimethylbicyclo[2.2.1]heptan-2-one O-allyloxime), and 2(1H)-Naphthalenone, octahydro-4a-methyl-7-(1-methylethyl)-, (4aα,7β,8aβ).  

These BACs though present in all the formulations, a critical observation showed that while some formulations contained some of the common BACs, others contained some rare ones like aziridine, artemisinin, and thiadiazol in formulations 1, 2 and 6 respectively. Secondly some of these formulations have different phenolics than others as seen in formulations 1, 2, 3, 4, 5 and 6, with formulation 3 containing an additional phenolic derivative.  Thirdly only formulation 2 had Quinoline,2-phenyl, a flavonoid as an identified BAC. Fourthly, the number of different BACs contained in each formulation varied. While Formulations 2, 3, 6 and RF, had six different BACs contained in them, formulations 4 and 5 had three and formulations 1 and 7 had two and five different compounds respectively. 

Of the different compounds contained in each formulations, the classes of the compounds were also different. In the commercial rat feed, Formulation RF, the six varied compounds belong to three classes, namely phenolics, carboxylic acids and thiadiazol. In these classes, the phenolics had three different compounds in the family while two compounds, that is, Piperidine, 1, 2-dimethyl and 1, 2, 3-Thiadiazole-4-carboxylic acid, hydrazide (Table 1), are in the family of thiadiazole. In formulation 3, there are four classes with three different compounds in the phenolic family, while in Formulation 2 and 6 there are five and four classes of compounds respectively, with two different phenolic compounds in the phenolic class (Table 1). 

Among the formulations with three groups of BACs, Formulations 4 and 5, there are two and three classes of compounds respectively, with the former containing two different phenolic compounds and formulation 4 containing only one. Formulation 7 which had two compounds belonging to two different classes had no phenolic compound while formulation 1 with five different compounds in three classes has three different phenolic compounds as constituents of the BACs (Table 1). 

Earlier studies reported the presence of isoflavones, oxalates, phytic acids and bioactive peptides in soybean. The Isoflavones are of three classes, namely the glucosides like daidzein, genistein and glycitin; the acetyl form of glucosides; malonyl glucosides and the unconjugated aglycones⁴⁹. Inositol hexaphosphate (IP⁶), myo-inositol and inositol phosphate are other BACs in soybean⁵⁰. In cocoyam, the phytochemicals, polyphenolic compounds such as flavonoids, tannin and alkaloids were present in cocoyam and these phytochemicals have hypoglycemic and antioxidant properties^14,15,20. Bambara groundnut phytochemical contents include phenolics like quercetin, quercitrin, iboquercitrin, kaempterol, rutin, myricetin, luteolin, catechin, epicatechin, caffeic acid, ellagic acid, cholorogenic acid and gallic acid^22,51. Literature is scanty on the BACs present in various combinations of Cocoyam-soya bean-Bambara groundnut flour blends. Hence the need to review the available BACs in the published work and their invivo activities.

 

 

 

Table 1: GC-MS Results of Various CY-SB-BGN Formulations

Formulations	Formulations Constituents	Name of Bioactive Compounds Identified	Family Classifications
1	16.6%CY + 16.6%SB + 16.6%BGN + 50%RF	4-Hydroxy-2-methylacetophenone	Phenols (Guaiacol)
		Phenol, 2,6-dimethoxy	Phenolics
		4-Methyl-2,5-dimethoxybenzaldehyde	Phenolic Aldehyde
		1,2-Benzenedicarboxylic acid, bis(2-methylpropyl) ester	Carboxylic acid
		N-Isopropoxy-2-carbomethoxyaziridine	Aziridine
2	12.5%CY + 12.5%SB + 25%BGN +50%RF	[1,3,4]Thiadiazol, 2-amino-5-(2-piperidin-1-ylethyl)-	Thiadiazol
		p-Fluorophenyl maleic anhydride	Benzene
		2-Methoxy-4-vinylphenol	Phenols
		Phenol, 2,6-dimethoxy	Phenols
		Quinoline,2-phenyl	Flavonoids
		Phthalic acid, butyl 2-ethylbutyl ester	Carboxylic acid
3	25%CY + 12.5%SB + 12.5%BGN + 50%RF	1,3-Benzenediol, 2-chloro	Phenols
		4-Hydroxy-3-methylacetophenone	Phenols (Guaiacol)
		Benzene, 1-methoxy-2-(methylthio)	Benzene
		Butylated Hydroxytoluene	Phenol derivative
		Thiophene, tetrahydro-2-methyl	Mono-cyclic heteroarene (Furan)
		Phthalic acid, butyl isohexyl ester	Carboxylic acid
4	12.5%CY + 25%SB + 12.5%BGN + 50%RF	Hydrazinecarbothioamide (2-[1-(4-nitrophenylethylidene)	Thiourea
		2-Methoxy-4-vinylphenol	Phenols (Guaiacol)
		Stilbene (1,2-diphenylethylene)	Carboxylic acid
5	0%CY + 0%SB + 50%BGN + 50%RF	2,6-dimethoxy phenol	Phenolics
		Vanillin (4-Hydroxy-3-methoxybenzaldehyde)	Phenolic Aldehyde
		Homopiperizine (1,4-Diazepanes)	1,4-Diazepanes
6	50%CY + 0%SB + 0%BGN + 50%RF	Benzofuran, 2,3-dihydro-	Amphetamine & Phenylethylamine
		2-Methoxy-4-vinylphenol	Phenol
		Phenol, 2,6-dimethoxy	Phenol
		(E)-Stilbene	Carboxylic acid
		Dibutyl phthalate	Carboxylic acid
		Dihydroartemisinin, 10-O-(t-butyloxy)-	Artemisinin
7	0%CY + 50%SB + 0%BGN + 50%RF	4,7,7-Trimethylbicyclo[2.2.1]heptan-2-one O-allyloxime	monoterpenoid
		2(1H)-Naphthalenone, octahydro-4a-methyl-7-(1-methylethyl)-, (4aα,7β,8aβ)	Naphthalene
RF	0%CY + 0%SB + 0%BGN + 100%RF	Piperidine, 1,2-dimethyl	Thiadiazol
		1,2,3-Thiadiazole-4-carboxylic acid, hydrazide	Thiadiazole
		Phthalan (Isocoumaran) or 1,3-dihydro-2-benzofuran	Phenols
		2-Methoxy-4-vinylphenol	Phenols
		Vanillin	Phenolic aldehyde
		Dibutyl phthalate	Carboxylic acid

CY = Cocoyam; SB = Soya Bean; BGN = Bambara Groundnut; RF = Commercial Rat Feed

Source: Uro-Chukwu & Uro-Chukwu (unpublished Bench work)

 

 

3. Biological Activities and Mechanisms of Actions of the identified BACs

In the documented study of Uro-Chukwu & Uro-Chukwu (unpublished Bench work), the BACs present were thiadiazoles, stilbene, aziridine, thiourea, amphetamine /phenylethylene, artemisinin, monoterpenoids, Naphthalenes, 1,4-diazepanes, phenols and flavanoids Each of these compounds have biological activities that are of health benefits to the individuals. Thiadiazoles for instance have antimicrobial, anti-inflammatory and hypoglycemic effects. The antimicrobial effects of thiadiazole occur as a result of its nitrogen-sulfur heterocycles as structural⁵², while the strong aromaticity of the ring are responsible for the anti-inflammatory actions⁵³. In exerting an anti-hyperglycemic effect, thiadiazole works by the inhibition of carbonic anhydrase activity⁵⁴.

The biological activities of stilbene compounds such as carboxylic acids include reduction of insulin resistance and weight gain, which it accomplishes through Inhibition of Protein-tyrosine phosphatase 1B (PTP1B)⁵⁵. Stilbene also Inhibits adipogenesis and lowers fat accumulation by reducing the PPARγ and C/EBPα levels and by the expression of Cyclin A and cyclin-dependent kinase 2 (CDK2)⁵⁶ and upregulation of GLUT4 ⁵⁷. It attenuates obesity-induced inflammation in adipocytes through the reduction in inflammatory cytokines TNF-α, IL-6 and monocyte chemo-attractant protein-1 (MCP-1)⁵⁸. Stilbene prevents insulin resistance development by the inhibition of NLRP3 inflammasome activity⁵⁹ and activation of SIRT1⁶⁰ and by inhibiting the induction of autophagy TXNIP⁶¹. Stilbene equally inhibits overexpression of IL-6 through the down-regulates NF-κB and activator protein-1 (AP-1) in different cells⁶². It prevents release of type 1 (IL2, IFN-γ, and lymphotoxin) cell mediated inflammatory response and type 2 (IL4, IL5, IL10, and IL13) antibody-mediated immune response T cells, by Inhibiting the proliferation of CD4+ and CD8+ T cells⁶³. Through the up-regulation of pAMPK with a resultant modulation of the expression of AMPK and Sirt1⁶⁴ and up-regulation of Caveolin-1²¹, stilbene, ensures cellular energy homoestasis, lipolysis and fat loss. By the activation of transcription factor 4 (ATF-4) and Tribbles Pseudokinase 3 (TRIB3), stilbene lowers endoplasmic reticulum stress and improves Insulin sensitivity^62,65 an effect that is further enhanced by the downregulation of protein kinase-like ER kinase (PERK) and eukaryotic initiation factor 2 alpha (eIF2 alpha)^66,67. 

Aziridine has an antimicrobial effect, which has been linked to the presence of sulphur atom in its (S)-configuration⁶⁸, just like in thiourea, but in the case of the latter the presence of the benzyl group and lipophilicity is responsible for the action^69,70. Thiourea also has an anti-inflammatory effect that is associated with its potent inhibition of 5-LOX^71,72 as well as its blood glucose regulation through the inhibition of α-glucosidase, AGEs and PTP1B⁷³. Amphetamine has anti-obesity and weight reduction effect as a result of its action on the hypothalamic receptors that results in the release of norepinephrine, dopamine and serotonin increasing CNS activity and resting energy expenditure⁷⁴. 

Artemisinin improves insulin resistance and Islet cell function⁷⁵ and exerts anti-obesity action⁷⁶. It causes the reversal of hepatic de novo lipogenesis and lipid accumulation through the inhibition the over-induction of hepatic sterol regulatory element-binding protein 1 (SREBP1)^77,78 carbohydrate-responsive element-binding protein (ChREBP)⁷⁹. It alters the direction of adipocyte differentiation, due to its action of glucose transporter-4 (GLUT4) and vascular endothelial growth factor (VEGF) levels to achieve this⁸⁰. Artemisinin inhibits lipid accumulation during adipose differentiation by reducing the expression/activity of CCAAT/enhancer-binding proteins (C/EBPs) and peroxisome proliferator-activated receptors (PPARs)⁸¹ and inhibition of the expression and activity of gelatinase matrix metalloproteinase (MMP)-2, which is important to the development of adipose tissue⁸². It also inhibits accumulation of lipids by activating brown adipose tissue and brown white adipose tissue, as well as by the activation of the p38 mitogen-activated protein kinase (MAPK)/activating transcription factor-2 (ATF2) axis and deactivating the Akt/mTOR pathway⁸³. Artemisinin exerts anti-inflammatory activity through different mechanisms, including by the inhibition of the secretion of TNF-α and IL-6 in undifferentiated adipose tissues and through the reduction of the cyclo-oxygenase-2 (COX-2), promotion of the AMP-activated protein kinase (AMPK) activity and the down-regulation of the expression of inflammatory factors⁷⁵. It equally inactivates NFkB⁸⁴. Artemisinin can equally restore the functions of the pancreatic β-cells by inhibiting α-glucosidase activity⁸⁵, increasing insulin secretion by the up-regulation of the expression of SIRT1 in islet ß-cell⁸⁶ and by reversing the unbalanced ratio of insulin, glucagon, and somatostatin content in islets of Langham⁸⁷.

Monoterpenoids exert anti-diabetic activity through the inhibition of α-amylase and α-glucosidase activities^88,89 It also reduces oxidative stress and stimulates the activities of the antioxidant enzymes including catalase and superoxide dismutase⁹⁰. It also inhibits adipogenesis, increase in metabolic rate, reduction of weight gain, and enhanced tolerance to glucose, through its inhibitory action on the retinaldehyde dehydrogenase enzyme⁹¹. Monoterpenoids improves glycogen content in hepatocytes and preserves the histology of hepatic and pancreatic β-cells through its inhibitory activity on GLUT2⁹². Finally through its anti-inflammatory actions, it maintains endothelial functions⁹³. 

Naphthalene decreases fasting blood glucose and serum lipid levels, enhancing insulin sensitivity, and ameliorating hepatic steatosis by inhibiting FABP4⁹⁴. It equally exerts antimicrobial activity by the stimulation of heme oxygenase-1 expression^95,96 while its inhibition of the pro-inflammatory mediators such as nitric oxide, interleukin-6, and TNF-α is responsible for the anti-inflammatory actions⁹⁷.

1,4-Diazepanes reduces the concentration of circulating active cortisol and corticortisone in the blood and hence insulin resistance and metabolic syndrome, an action achieved through its organ specific 11 beta-HSD1 inhibitor in the adipose tissues⁹⁸. In the case of Phenolics, the antioxidant activities are due to scavenging radical species such as ROS/RNS, suppressing ROS/RNS formation by inhibiting some enzymes or chelating trace metals involved in free radical production and up-regulating or protecting antioxidant defence system⁹⁹, while its anti-inflammatory actions are as a result of Inhibit transcription factors such as NF-κB and blocking MAPK-mediated pathway closely linked to inflammation¹⁰⁰. It also inhibits pro-inflammatory cytokines release, inhibits enzymes such as COX-2, lipoxygenases (LOX), inducible nitric oxide synthase that mediate inflammatory processes^100,101-105.

The anti-diabetic effects of phenolics stems from the activation of the 5’ adenosine monophosphate-activated protein kinase (AMPK) pathway to stimulate glucose uptake by the skeletal muscle cells thereby reducing fasting blood glucose^106,107, inhibition of gluconeogenesis and enhancement of glycogenesis¹⁰⁸, elevation of the α-amylase and α-glucosidase inhibitory activity¹⁰⁹ and by improving the glucose absorption capacity via the increase of the expression of hepatic insulin signaling proteins like phosphatidylinositol-3 kinase, Akt/protein kinase B, insulin receptor substrate 1, and glucose transporter 2¹¹⁰. 

Flavonoids equally exerts anti-oxidant, anti-inflammatory and anti-microbial effects. Its anti-oxidant effects are due to a direct scavenging activity, inhibition of ROS formation through the chelation of trace elements, inhibition of the enzymes that participate in the generation of free radicals like glutathione S-transferase, microsomal mono-oxygenase, mitochondrial succinoxidase, NADH oxidase, and xanthine oxidase and activation of antioxidant defences like upregulation of antioxidant enzymes with radical scavenging ability^111,112. It exerts anti-inflammatory action by acting as inhibitors of protein kinases, phosphodiesterase and transcription factors and by modulating the activity of the immune cells¹¹¹. The antimicrobial effect is by the induction of bacterial membrane disruption and inhibition of several processes such as biofilm formation, cell envelope synthesis, nucleic acid synthesis, electron transport chain, and ATP synthesis¹¹³ and by blocking the binding and penetration of viruses into cells, interference with viral replication or translation, and preventing the release of the virus¹¹⁴.

Conclusion:

Bioactive compounds present in cocoyam-soya bean-bambara groundnut include those earlier reported in the individual plant foods in previous studies in addition to some other compounds. A review of the biological activities of such BACs showed that the formulations have documented anti-microbial, anti-inflammatory, anti-oxidant and anti-diabetic properties invivo, with very established mechanisms of actions. This implies that the scientific basis for the use of such plant foods in the management or as a treatment adjunct for some non-communicable diseases are well established. It also follows that such medical plant foods can have a place in the amelioration of insulin resistance development and prevention of metabolic syndrome, aside its role in managing type 2 diabetes mellitus. It is therefore suggested that patients who are at the risk of development of these chronic illnesses, can find the consumption of these food plants useful. 

Authors` Contributions:

Henry CU =Topic design, Proposal writing, Literature search, draft manuscript

Franklyn CU = Data Entering, Statistical analysis, draft manuscript

Frances CU = Study Analysis, Literature search

All authors read and approved the final manuscript

Competing Interest/Source of Funding: There is no competing interest. The research work was fully funded by the authors

Acknowledgement: Authors wish to acknowledge the efforts of Prof. Ezekwe, AS, Dr. Eleazu Chinedu and Dr. Okorie, Uchechukwu for their technical support during the experiment.

Source of Support: Nil

Informed Consent Statement: Not applicable. 

Data Availability Statement: The data supporting in this paper are available in the cited references. 

Ethics approval: Not applicable.

References:

1. Kumar A, Senapati BK, Genetic analysis of character association for polygenic traits in some recombinant inbred lines (ril's) of rice (Oryza sativa L.). Banat's Journal of Biotechnology, 2015; 6(11): 90-99. https://doi.org/10.7904/2068-4738-VI(11)-90

2. Kris-Etherton PM, Hecker KD, Bonanome A, Coval SM, Binkoski AE, Hilpert KF, Griel AE, Etherton TD, Bioactive compounds in foods: their role in the prevention of cardiovascular disease and cancer. American Journal of Medicine, 2002; 113: S71-88. https://doi.org/10.1016/S0002-9343(01)00995-0 PMid:12566142

3. Alemán A, Pérez-Santín E, Bordenave-Juchereau S, Arnaudin I, Gómez-Guillén MC, Montero P, Squid gelatin hydrolysates with antihypertensive, anticancer and antioxidant activity. Food Research International, 2011; 44: 1044-1051. https://doi.org/10.1016/j.foodres.2011.03.010

4. Ding J-F, Li Y-Y, Xu J-J, Su X-R, Gao X, Yue F-P, Study on effect of jellyfish collagen hydrolysate on anti-fatigue and anti-oxidation. Food Hydrocolloids, 2011; 25: 1350-1353. https://doi.org/10.1016/j.foodhyd.2010.12.013

5. Girgih AT, Udenigwe CC, Li H, Adebiyi AP, Aluko RE. Kinetics of enzyme inhibition and antihypertensive effects of hemp seed (Cannabis sativa L.) protein hydrolysates. Journal of American Oil Chemists' Society, 2011; 88(11): 1767-1774. https://doi.org/10.1007/s11746-011-1841-9

6. Udenigwe CC, Lu Y-L, Han C-H, Hou W-C, Aluko RE. Flaxseed protein-derived peptide fractions: Antioxidant properties and inhibition of lipopolysaccharide-induced nitric oxide production in murine macrophages. Food Chemistry, 2009; 116: 277-284. https://doi.org/10.1016/j.foodchem.2009.02.046

7. Barbieri, R, Coppo, E, Marchese, A, Daglia, M, Sobarz-Sánchez, E, Nabavi, SF, Nabavi, SM, Phytochemicals for human disease: An update on plant-derived compounds antibacterial activity. Microbiology Research, 2017; 196, 44-68. https://doi.org/10.1016/j.micres.2016.12.003 PMid:28164790

8. Jat D, Thakur N, Jain DK, Prasad S, Yadav R, Iris ensata Thunb: Review on Its Chemistry, Morphology, Ethno Medical Uses, Phytochemistry and Pharmacological Activities, Asian Journal of Dental and Health Sciences, 2022;2(1):1-6 https://doi.org/10.22270/ajdhs.v2i1.9

9. Iwai K, Kim M, Onodera A, Matsue H, α-Glucosidase Inhibitory and Antihyperglycemic Effects of Polyphenols in the Fruit of Viburnum dilatatum Thunb. Journal of Agricultural and Food Chemistry, 2006; 54(13): 4588-4592 https://doi.org/10.1021/jf0606353 PMid:16787002

10. Ruzaidi A, Abbe M, Amin L, Nawalyah AG, Muhajir H, Pauliena MB, Muskinah MS, Hypoglycemic properties of Malaysia cocoa (Theobromacacao) polyphenols-rich extract. International Food Research Journal, 2008, 15: 305-312.

11. Merida LA, Mattos EB, Correa AC, Pereira PR, Paschoalin VM, Pinho MF, Vericimo MA, Tarin stimulates granulocyte growth in bone marrow cell cultures and minimizes immunosuppression by cyclo-phosphamide in mice. PLoS ONE, 2018; 13:e0206240. https://doi.org/10.1371/journal.pone.0206240 PMid:30403726 PMCid:PMC6221300

12. Chukwuma CI, Islam MS, Amonsou EO, A comparative study on the physicochemical, anti-oxidative, anti-hyperglycemic and anti-lipidemic properties of amadumbe (Colocasia esculenta) and okra (Abelmoschus esculentus) mucilage. Journal of Food Biochemistry, 2018; 42:e12601. https://doi.org/10.1111/jfbc.12601

13. Prabhakar PK, Doble M, A Target Based Therapeutic Approach Towards Diabetes Mellitus Using Medicinal Plants. Current Diabetes Reviews, 2008; 291-308. Bentham Science Publishers Ltd. https://doi.org/10.2174/157339908786241124 PMid:18991598

14. Obeagu EI, Obeagu GU, Antioxidants and the Prevention of Neonatal Jaundice: A Narrative Review, International Journal of Medical Sciences and Pharma Research, 2024;10(4):28-34 https://doi.org/10.22270/ijmspr.v10i4.120

15. Eleazu CO, Iroaganachi M, Eleazu KC, Ameliorative potentials of cocoyam (Colocasia esculenta L.) and unripe plantain (Musa paradisiaca L.) on the relative tissue weights of streptozotocin-induced diabetic rats. Journal of Diabetes Research, 2013; 1-8 https://doi.org/10.1155/2013/160964 PMid:23971053 PMCid:PMC3736419

16. Carvalho, AW, Silva CO, Dantas MIS, Natal DIG, Ribeiro SMR, Costa NMB, Martino HSD, The use hull soybean flour of heat-treated grains does not affect iron bioavailability in rats. Archivos Latinoamericanos de Nutrición, 2011, 61(2): 135-142

17. Martino HSD, Martin BR, Weaver CM, Bressan J, Esteves EA, Costa NMB, Zinc and iron bioavailability of genetically modified soybeans in rats. Journal of Food Science, 2007; 72(9): 689-695 https://doi.org/10.1111/j.1750-3841.2007.00548.x PMid:18034754

18. Pripp AH, Isaksson T, Stepaniak L, Sørhaug T, Ardö Y, Quantitative structure-activity relationship modelling peptides and proteins as a tool in food science. Trends in Food Science Technology, 2005; 16: 484-494. https://doi.org/10.1016/j.tifs.2005.07.003

19. Chen X, Li H, Zhang B, Deng Z, The synergistic and antagonistic antioxidant interactions of dietary phytochemical combinations. Critical Reviews in Food Science and Nutrition, 2022; 62(20): 5658-5677. https://doi.org/10.1080/10408398.2021.1888693 PMid:33612011

20. Eleazu CO, Characterization of the natural products in cocoyam (Colocasia esculenta) using GC MS. Pharmaceutical Biology, 2016; 5412: 2880 2885. https://doi.org/10.1080/13880209.2016.1190383 PMid:27246651

21. Chen L, Yang S, Zumbrum EE, Guan H, Nagartatti PS, Nagarkatti M, Resveratrol attenuates lipopolysaccharide-induced acute kidney injury by suppressing inflammation driven by macrophages. Molecular Nutrition & Food Research, 2015; 59(5): 853-864 https://doi.org/10.1002/mnfr.201400819 PMid:25643926 PMCid:PMC4420731

22. Salawu, Comparative study of the antioxidant activities of methanolic extract and simulated gastrointestinal enzyme digest of Bambara nut (Vigna subterranean) FUTA Journal of Research in Sciences, 2016;.1: 107-120.

23. Arise AK, Amonsou EO, Ijabadeniyi OA, Influence of extraction methods on functional properties of protein concentrates prepared from South African Bambara groundnut landraces. International Journal of Food Science & Technology, 2015; 50:1095-1101. https://doi.org/10.1111/ijfs.12746

24. Oyeyinka AT, Pillay K, Siwela M, Full title- in vitro digestibility, amino acid profile and antioxidant activity of cooked Bambara groundnut grain. Food Biosciences, 2019; 31:100428. https://doi.org/10.1016/j.fbio.2019.100428

25. Oyeyinka SA, Tijani ST, Oyeyinka AT, Arise AK, Balogun MA, Kolawole FL, Obalowu MA, Joseph JK, Value added snacks produced from Bambara groundnut (Vigna subterranea) paste or flour. LWT-Food Science & Technology, 2018; 88: 126-131. https://doi.org/10.1016/j.lwt.2017.10.011

26. Halimi RA, Barkla BJ, Mayes S, King GJ, The potential of the underutilized pulse bambara groundnut (Vigna subterranea (L.) Verdc.) for nutritional food security. The Journal of Food Composition and Analysis, 2019; 77(2): 47-59. https://doi.org/10.1016/j.jfca.2018.12.008

27. Obeagu EI, Oxidative Stress and Pregnancy-induced Hypertension: Antioxidant Solutions, International Journal of Medical Sciences and Pharma Research, 2024;10(4):22-27 https://doi.org/10.22270/ijmspr.v10i4.119

28. Rao TR, Tejomurtula GN, Diabetes Mellitus: A Review, International Journal of Medical Sciences and Pharma Research, 2024;10(2):5-9 https://doi.org/10.22270/ijmspr.v10i2.97

29. Ramya S, Chandran M, King IJ, Jayakumararaj R, Loganathan T, Pandiarajan G, Kaliraj P, Grace Lydial Pushpalatha G, Abraham GC, Vijaya V, Aruna D, Sutha S, Dhakar RC, Phytochemical Screening, GCMS and FTIR Profile of Bioactive Compounds in Solanum lycopersicum Wild Fruits collected from Palani Hill Ranges of the Western Ghats, Journal of Drug Delivery and Therapeutics. 2022;12(6):56-64 https://doi.org/10.22270/jddt.v12i6.5665

30. Cha SH, Hwang Y, Heo SJ, Jun HS, Indole-4-carboxaldehyde isolated from seaweed, sargassum thunbergii, attenuates methylglyoxal-induced hepatic inflammation. Marine Drugs, 2019; 17: 48-56 https://doi.org/10.3390/md17090486 PMid:31438528 PMCid:PMC6780312

31. Hernández-Zazueta, MS, Luzardo-Ocampo, I, García-Romo, JS, Noguera-Artiaga, L, Carbonell-Barrachina ÁA, Taboada-Antelo P, Bioactive compounds from Octopus vulgaris ink extracts exerted anti-proliferative and anti-inflammatory effects in vitro. Food Chemistry Toxicology, 2021; 151: 112-119. https://doi.org/10.1016/j.fct.2021.112119 PMid:33722603

32. Chou TC, Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacology Reviews, 2006; 58: 621-681. https://doi.org/10.1124/pr.58.3.10 PMid:16968952

33. Caesar LK, Cech NB, Synergy and antagonism in natural product extracts, when 1 + 1 does not equal 2. Natural Product Report, 2019; 36:869-888. https://doi.org/10.1039/C9NP00011A PMid:31187844 PMCid:PMC6820002

34. Leena MM, Silvia MG, Vinitha K, Moses JA, Anandharamakrishnan C, Synergistic potential of nutraceuticals: mechanisms and prospects for futuristic medicine. Food & Function, 2020: 11: https://doi.org/10.1039/D0FO02041A PMid:33211054

35. Lee HG, Jayawardena, TU, Song KM, Choi YS, Jeon YJ, Kang MC, Dietary fucoidan from a brown marine alga attenuates lipid accumulation in differentiated 3T3-L1 cells and alleviates high-fat diet-induced obesity in mice. Food and Chemical Toxicology, 2022; 162: 112862. https://doi.org/10.1016/j.fct.2022.112862 PMid:35157925

36. Terasaki M, Murase W, Kamakura Y, Kawakami S, Kubota A, Kojima H, Ohta T, Tanaka, T, Maeda H, Miyashita K, Mutoh M, A biscuit containing fucoxanthin prevents colorectal carcinogenesis in mice. Nutrition Cancer, 2022; 74: 3651-3661 https://doi.org/10.1080/01635581.2022.2086703 PMid:35695489

37. Hsu HC, Chen MH, Yeh ML, Chen WJ, Antibacterial and anticancer activities of pleurocidin-amide, a potent marine antimicrobial peptide derived from winter flounder, pleuronectes americanus. Marine Drugs, 2022; 20: 519 https://doi.org/10.3390/md20080519 PMid:36005521 PMCid:PMC9409841

38. Phan, MAT, Paterson J, Bucknall M, Arcot J, Interactions between phytochemicals from fruits and vegetables: Effects on bioactivities and bioavailability. Critical Reviews In Food Science and Nutrition, 2018; 58(8):1310-1329. https://doi.org/10.1080/10408398.2016.1254595 PMid:27880063

39. Saracila M, Untea AE, Panaite TD, Varzaru I, Oancea AG, Turcu RP, Vlaicu PA, Effects of Supplementing Sea Buckthorn Leaves (Hippophae rhamnoides L.) and Chromium (III) in Broiler Diet on the Nutritional Quality and Lipid Oxidative Stability of Meat. Antioxidants (Basel), 2022; 11(11): 2220 https://doi.org/10.3390/antiox11112220 PMid:36358591 PMCid:PMC9686693

40. Akinlotan JV, Olayiwola O, Abimbola L, Assessment of glycemic index of cocoyam, cowpea and plaintain composite flour meal for apparently healthy Nigerians. Journal of Obesity Weight Loss Therapy, 2015; 5(6) DOI: 10.4172/2165-7904.C1.024:

41. Onuh FA, Mbaeyi-Nwaoha IE, Ani JC, Evaluation of the Hypoglycemic Potentials and Glycemic Index of Ready-to-eat Breakfast Products using Animal Bioassay. American Journal of Food Science and Technology, 2019; 7(5): 161-168 https://doi.org/10.12691/ajfst-7-5-5

42. Akinjayeju O, Ijarotimi OS, Awolu OO, Fagbemi TN, Nutritional Composition, Glycaemic Properties and Anti-Diabetic Potentials of Cereal-Based Soy-Fortified Flours for Functional Dough Meal in Diabetic Induced Rats. Journal of Food Science and Nutrition Research, 2020; 3:102-120.

43. Olugbuyi AO, Oladipo GO, Malomo SA, Ijarotimi SO, Fagbemi,TN, Biochemical Ameliorating Potential of Optimized Dough Meal from Plantain (Musa AAB), Soycake (Glycine max) and Rice bran (Oryza sativa) Flour Blends in Streptozotocin Induced Diabetic Rats. Applied Food Research, 2022; 2(1): 100097. https://doi.org/10.1016/j.afres.2022.100097

44. Akinyede AI, Ayibiowu EO, Fakologbon T, Awolu OO, Fagbemi TN, Nutritional assessment, glycemic indices and anti-diabetic potentials of dough meal generated from optimized blends of matured plantain, soya cake and wheat bran flours, Journal of Future Foods, 2023; 3(4):374-382 https://doi.org/10.1016/j.jfutfo.2023.03.008

45. Oluwajuyitan TD, Ijarotimi OS, Nutritional, antioxidant, glycaemic index and Anti-hyperglycaemic properties of improved traditional plantain-based (Musa AAB) dough meal enriched with tiger nut (Cyperus esculentus) and defatted soybean (Glycine max) flour for diabetic patients. Heliyon, 2019; 5: e01504. https://doi.org/10.1016/j.heliyon.2019.e01504 PMid:31025013 PMCid:PMC6475862

46. Oguntuase SO, Ijarotimi, OS, Oluwajuyitan TD, Oboh G, Nutritional, antioxidant, carbohydrate hydrolyzing enzyme inhibitory activities, and glyceamic index of wheat bread as infuence by bambara groundnut substitution. SN Applied Sciences, 2022; 4(121):18-38. https://doi.org/10.1007/s42452-022-05018-8

47. Ijarotimi OS, Keshinro OO, Protein quality, hematological properties and Nutritional status of albino rats fed complementary foods with fermented popcorn, African locust bean, and bambara groundnut flour blends. Nutrition Research and Practice, 2012; 6(5):381-388. https://doi.org/10.4162/nrp.2012.6.5.381 PMid:23198016 PMCid:PMC3506868

48. Ibrahim DG, Asogwa IS, Onwurafor EU, Ani JC, Effect of Composite Flours of Finger Millet, Bambara Groundnut and 'Khain' (Lecaniodiscus Cupanioides) on Blood Glucose Response, Lipids, and Liver Enzymes of Alloxan-Induced Diabetic Rats. Asian Food Science Journal, 2022; 21(9): 155-172. https://doi.org/10.9734/afsj/2022/v21i930467

49. Kao TH, Wu W, Hung CF, Wu WB, Chen BH, Anti-inflammatory Effects of Isoflavone Powder Produced from Soybean Cake. Journal of Agricultural and Food Chemistry, 2007; 55(26):11068-11079. https://doi.org/10.1021/jf071851u PMid:18052238

50. Domínguez BM, Gómez MVI, León FR, Acido fítico: Aspectos nutricionales e implicaciones analíticas. ALAN Reviews, 2002; 52(3): 1-12.

51. Harris T, Jideani V, Le Rose-Hill M, Flavonoids and tannin composition of Bambara groundnut (Vigna subterranean) of Mpumalanga, South Africa. Heliyon, 2018; 4: e00833. https://doi.org/10.1016/j.heliyon.2018.e00833 PMid:30294697 PMCid:PMC6168962

52. Upadhyay PK, Mishra P, Synthesis, antimicrobial and anticancer activities of 5-(4 substituted phenyl) 1,3,4 thiadiazole 2 amines. Rasayan Journal of Chemistry, 2017; 10 (1):254-262.

53. Yousif E, Majeed A, Al-Sammarrae K, Salih N, Salimon J, Abdullah B, Metal complexes of Schiff base: preparation, characterization and antibacterial activity. Arabian Journal of Chemistry, 2013; 5(2): S1639-S1644https://doi.org/10.1016/j.arabjc.2013.06.006

54. Ibrahim SI, Ameh DA, Atawodi SE, Umar IA, Carbonic Anhydrase: A New Therapeutic Target for Managing Diabetes. Journal of Metabolic Syndrome, 2016; 5: 196-203

55. Yang Z, Wang M, Zhang Y, Cai F, Jiang B, Zha W, Yu W, Metformin ameliorates diabetic cardiomyopathy by activating the PK2/PKR pathway. Frontiers in Physiology, 2020; 11:425. https://doi.org/10.3389/fphys.2020.00425 PMid:32508669 PMCid:PMC7252307

56. Kwon JY, Seo SG, Heo Y-S, Yue S, Cheng J-X, Lee KW, Kim K-H, Piceatannol, Natural Polyphenolic Stilbene, inhibits Adipogenesis via Modulation of Mitotic Clonal Expansion and Insulin Receptor-dependent Insulin Signaling in Early Phase of Differentiation, Molecular Bases of Disease, 2012; 287 (14): P11566-11578. https://doi.org/10.1074/jbc.M111.259721 PMid:22298784 PMCid:PMC3322826

57. Chooi YC, Ding C, Magkos F, The epidemiology of obesity. Metabolism, 2019; 92: 6-10 https://doi.org/10.1016/j.metabol.2018.09.005 PMid:30253139

58. Yan F, Xiaohong T, Shuling B, Jun F, Weijan H, Hao T, Dehua L, Autologous transplantation of adipose-derived mesenchymal stem cells ameliorates streptozotocin-induced diabetic nephropathy in rats by inhibiting oxidative stress, pro-inflammatory cytokines and the p38 MAPK signalling pathway. International Journal of Molecular Medicine, 2012; 30 (1): 85-92

59. Wang H, Sun X, Zhang N, Ji Z, Ma, Z, Fu Q, Qu, R, Ma S, Ferulic acid attenuates diabetes-induced cognitive impairement in rats via regulation of PTB1B and insulin signalling pathway. Physiology & Behaviours, 2017; 182: 93-100. https://doi.org/10.1016/j.physbeh.2017.10.001 PMid:28988132

60. Borra MT, Smith BC, Denu JM, Mechanism of human SIRTI activation by resveratrol. Journal of Biological Chemistry, 2005; 280 (17): 17187-17195, https://doi.org/10.1074/jbc.M501250200 PMid:15749705

61. Olcum M, Toston B, Ercan I, Eitutan IB, Genc S, Inhibitory effects of phytochemicals on NLRP3 inflammasome activation: a review. Phytomedicine, 2020; 75: 153238. https://doi.org/10.1016/j.phymed.2020.153238 PMid:32507349

62. Yang J, Leng J, Li J-J, Tang J-F, Li Y, Liu B-L, Wen X-D, Corosolic acid inhibits adipose tissue inflammation and ameliorates insulin resistance via AMPK activation in high-fat fed mice.Phytomedicine, 2016; 23(2): 181-190. https://doi.org/10.1016/j.phymed.2015.12.018 PMid:26926180

63. Lai X, Pei Q, Song XU, Zhuo X, Yin Z, Jia R., Zou Y, Li L, Yue G, Liang X, Yin L, Lv C, Jing BO, The enhancement of immune function and activation of NF-Kb by resveratrol-treatment in immunosuppressive mice. International immunopharmacology, 2016; 33: 42-47. https://doi.org/10.1016/j.intimp.2016.01.028 PMid:26854575

64. Ran G, Ying LI, Li L, Yan Q, Yi W, Ying C, Wu H, Ye X, Resveratrol ameliorates diet-induced dysregulation of lipid metabolism in zebrafish (Danio rerio). PLoS One, 2017; 12(7): e0180865. https://doi.org/10.1371/journal.pone.0180865 PMid:28686680 PMCid:PMC5501612

65. Ko Y-J, Kim H-H, Kim E-J, Katakura Y, Lee WW-S, Kim G-S, Ryu C-H, Piceatannol inhibits mast cell-mediated allergic inflammation. International Journal of Molecular Medicine, 2013; 31(4): 951-958. https://doi.org/10.3892/ijmm.2013.1283 PMid:23426871

66. Yuan D, Liu X, Fang Z, Du L, Chang J, Lin S, Protective effect of resveratrol on kidney in rats with diabetic nephropathy and its effect on endoplasmic reticulum stress. European Review for Medical and Pharmacological Sciences, 2018; 22 (5): 1485-1493

67. Zhao H, Zhang Y, Shu L, Song G, Ma H, Resveratrol reduces liver endoplasmic reticulum stress and improves insulin sensitivity in invivo and in vitro. Drug Design, Development and Therapy, 2019; 1473-1485, https://doi.org/10.2147/DDDT.S203833 PMid:31118581 PMCid:PMC6505469

68. Kowalczyk A, Pieczonka AM, Rachwalski M, Leśniak S, Stączek P, Synthesis and evaluation of biological activities of Aziridine Derivatives of Urea and Thiourea. Molecules, 2017; 23(1), 45. https://doi.org/10.3390/molecules23010045 PMid:29295572 PMCid:PMC5943925

69. Arslan H, Duran N, Borekci G, Koray OC, Akbay C, Antimicrobial activity of some thiourea derivatives and their nickel and copper complexes. Molecules, 2009; 14(1):519-527. https://doi.org/10.3390/molecules14010519 PMid:19169199 PMCid:PMC6253946

70. Njoroge PW, Opiyo SA, Antimicrobial activity of root bark extracts of Rhus natalensisa and Rhus ruspolii'. Basic Sciences of Medicine, 2019; 8(2): 23-28.

71. Nedeljković N, Nikolić M, Čanović P, Zarić M, Živković Zarić R, Bošković J, Vesović M, Bradić J, Anđić M, Kočović A, Synthesis, Characterization, and Investigation of Anti-Inflammatory and Cytotoxic Activities of Novel Thiourea Derivatives of Naproxen. Pharmaceutics, 2024; 16: 1. https://doi.org/10.3390/pharmaceutics16010001 PMid:38276479 PMCid:PMC10820527

72. Anandan SK, Do ZN, Webb HK, Patel DV, Gless RD, Bioorg. Medicinal. Chemistry Letter, 2009; 19: 1066-1070 https://doi.org/10.1016/j.bmcl.2009.01.013 PMid:19168352

73. Ullah I, Hassan M, Khan KM, Sajid M, Umar M, Hassan S, Ullah A, El-Serehy HA, Charifi W, Yasmin H, Thiourea derivatives inhibit key diabetes-associated enzymes and advanced glycation end-product formation as a treatment for diabetes mellitus. International Union of Biochemistry and Molecular Biology Life, 2022; 75(2): 161-180. https://doi.org/10.1002/iub.2699 PMid:36565478

74. Amin HM, Tawfek, NS, Hussein, BKA, Abd El-Ghany, MS, Anti-Obesity Potential of Orlistat and Amphetamine in Rats Fed on High Fat Diet. Middle East Journal of Applied Sciences, 2015; 5(2): 453-461

75. Fu W, Ma Y, Li L, Liu J, Fu L, Guo Y, Zhang Z, Li J, Jiang H, Artemether regulates metaflammation to improve glycolipid metabolism in db/db mice. Diabetes Metabolic Syndrome & Obesity, 2020;. 13: 1703-1713. https://doi.org/10.2147/DMSO.S240786 PMid:32547132 PMCid:PMC7245603

76. Guo Y, Fu W, Xin Y, Bai J, Peng H, Fu L, Liu J, Li L, Ma Y, Jiang H, Antidiabetic and antiobesity effects of artemether in db/db mice. BioMedical Research International, 2018; 8(6): 39-52. https://doi.org/10.1155/2018/8639523 PMid:29862294 PMCid:PMC5971258

77. Tu K, Zheng X, Yin G, Zan X, Yao Y, Liu Q, Evaluation of Fbxw7 expression and its correlation with expression of SREBP-1 in a mouse model of NAFLD. Molecular Medicine Reports, 2012; 6 (3): 525-530. https://doi.org/10.3892/mmr.2012.953 PMid:22710480

78. Han J, Li E, Chen L, Zhang Y, Wei F, Liu J, The CREB coactivator CRTC2 controls hepatic lipid metabolism by regulating SREBP1. Nature, 2015; 524(7564): 243-246. https://doi.org/10.1038/nature14557 PMid:26147081

79. Abdul-Wahed A, Guilmeau S, Postic C, Sweet sixteenth for ChREBP: established roles and future goals. Cell Metabolism, 2017; 26 (2): 324-341. Doi: 10.1016/j.cmet.2017.07.004 https://doi.org/10.1016/j.cmet.2017.07.004 PMid:28768172

80. Jang BC, Artesunate inhibits adipogenesis in 3T3-L1 preadipocytes by reducing the expression and/or phosphorylation levels of C/EBP-α, PPAR-γ, FAS, perilipin A, and STAT-3. Biochemical and Biophysical Research Communications, 2016; 474(1): 220-225. https://doi.org/10.1016/j.bbrc.2016.04.109 PMid:27109481

81. Rosen ED, MacDougald OA, Adipocyte differentiation from the inside out. Nat. Rev. Mol. Cell Biology, 2006; 7 (12): 885-896. https://doi.org/10.1038/nrm2066 PMid:17139329

82. Lee J, Kim MH, Lee JH, Jung E, Yoo ES, Park D, Artemisinic acid is a regulator of adipocyte differentiation and C/EBPδ expression. Journal of Cell Biochemistry, 2012; 113 (7): 2488 -2499. https://doi.org/10.1002/jcb.24124 PMid:22396222

83. Lu P, Zhang FC, Qian SW, Li X, Cui ZM, Dang YJ, et al., Artemisinin derivatives prevent obesity by inducing browning of WAT and enhancing BAT function. Cell Research, 2016; 26 (10):1169-1172. https://doi.org/10.1038/cr.2016.108 PMid:27633061 PMCid:PMC5113303

84. Shoelson SE, Lee J, Goldfine AB, Inflammation and insulin resistance. Journal of Clinical Investigations, 2006; 116 (7): 1793-1801. https://doi.org/10.1172/JCI29069 PMid:16823477 PMCid:PMC1483173

85. Kim KE, Ko KH, Heo RW, Yi CO, Shin HJ, Kim JY, Artemisia annua leaf extract attenuates hepatic steatosis and inflammation in high-fat diet-fed mice. Journal of Medical Food, 2016; 19(3): 290-299. https://doi.org/10.1089/jmf.2015.3527 PMid:26741655 PMCid:PMC4799707

86. Han P, Wang Y, Zhan H, Weng W, Yu X, Ge N, Artemether ameliorates type 2 diabetic kidney disease by increasing mitochondrial pyruvate carrier content in db/db mice. American Journal of Translational Research, 2019; 11(3): 1389-1402.

87. Guo Y, Fu W, Xin Y, Bai J, Peng H, Fu L, Liu J, Li L, Ma Y, Jiang H, Antidiabetic and antiobesity effects of artemether in db/db mice. BioMed Research International, 2018; 8(6): 39-52. https://doi.org/10.1155/2018/8639523 PMid:29862294 PMCid:PMC5971258

88. Garba HA, Mohammed A, Ibrahim MA, Shuaibu MN, Effect of lemongrass (Cymbopogon citratus Stapf) tea in a type 2 diabetes rat model. Clinical Phytoscience, 2020; 6: 19. https://doi.org/10.1186/s40816-020-00167-y

89. Boaduo NK, Katerere D, Eloff JN, Naidoo V, Evaluation of six plant species used traditionally in the treatment and control of diabetes mellitus in South Africa using in vitro methods. Pharmaceutical Biology, 2014; 52: 756-761 https://doi.org/10.3109/13880209.2013.869828 PMid:24559378

90. Porres-Martinez M, Gonzalez-Burgos E, Carretero ME, Gomez-Serranillos MP, Major selected monoterpenes α-pinene and 1,8-cineole found in Salvia lavandulifolia (Spanish sage) essential oil as regulators of cellular redox balance. Pharmaceutical Biology, 2015; 53(6): 921-929 https://doi.org/10.3109/13880209.2014.950672 PMid:25474583

91. 91) Modak T, Mukhopadhaya A, Effects of citral, a naturally occurring antiadipogenic molecule, on an energy-intense diet model of obesity. Indian Journal of Pharmacology, 2011; 43(3): 300 - 305. https://doi.org/10.4103/0253-7613.81515 PMid:21713095 PMCid:PMC3113383

92. Kamble SP, Ghadyale, VA, Patil RS, Haldavnekar VS, Arvindekar AU, Inhibition of GLUT2 transporter by geraniol from Cymbopogon martinii: A novel treatment for diabetes mellitus in streptozotocin-induced diabetic rats. Journal of Pharmacy and Pharmacology, 2020; 72: 294-304. https://doi.org/10.1111/jphp.13194 PMid:31737917

93. Peña-Montes DJ, Huerta-Cervantes M, Ríos-Silva M, Trujillo X, Huerta M, Noriega-Cisneros R, Salgado-Garciglia R, Saavedra-Molina A, Protective Effect of the Hexanic Extract of Eryngium carlinae Inflorescences In Vitro, in Yeast, and in Streptozotocin-Induced Diabetic Male Rats. Antioxidants, 2019; 8(3): 73 https://doi.org/10.3390/antiox8030073 PMid:30917540 PMCid:PMC6466845

94. Guo X-x, Wang Y, Wang K, Ji B-p, Zhou F, Stability of a type 2 diabetes rat model induced by high-fat diet feeding with low-dose streptozotocin injection. Journal of Zhejiang University-Science, 2018; B 19: 559-569 https://doi.org/10.1631/jzus.B1700254 PMid:29971994 PMCid:PMC6052359

95. Tseng CH, Lin CK, Chen YL, Tseng CK, Lee JY, Lee J, Discovery of naphtho [1, 2-d] oxazole derivatives as potential anti-HCV agents through inducing heme oxygenase-1 expression. European Journal of Medicinal Chemistry, 2018; 143: 970-982. https://doi.org/10.1016/j.ejmech.2017.12.006 PMid:29232587

96. Tarantino D, Pezzullo M, Mastrangelo E, Croci R, Rohayem J, Robel I, Bolognesi M, Milani M, Naphthalene-sulfonate inhibitors of human norovirus RNA-dependent RNA-polymerase. Antiviral Research, 2014; 102: 23-28. https://doi.org/10.1016/j.antiviral.2013.11.016 PMid:24316032

97. Chang C-F, Liao K-C, Chen C-H, 2-Phenylnaphthalene derivatives inhibit lipopolysaccharide-induced pro-inflammatory mediators by downregulating of MAPK/NF-κB pathways in RAW 264.7 macrophage cells. PLoS ONE, 2017; 12(1): e0168945. https://doi.org/10.1371/journal.pone.0168945 PMid:28060845 PMCid:PMC5218479

98. Odermatt A, Diazepane-acetamide derivatives as selective 11beta-hydroxysteroid dehydrogenase type 1 inhibitors. Expert Opinion on Therapeutic Patent, 2009; 19(100):1477-1483. https://doi.org/10.1517/13543770902911490 PMid:19780703

99. Cotelle N, Role of flavonoids in oxidative stress. Current Topics in Medicinal Chemistry, 2001; 1:569-590. https://doi.org/10.2174/1568026013394750 PMid:11895132

100. Karlsen A, Retterstol L, Laake P, Paur I, Kjolsrud-Bohn S, Sandvik L, Blomhoff R, Anthocyanins inhibit nuclear factor-kappaB activation in monocytes and reduce plasma concentrations of pro-inflammatory mediators in healthy adults. Journal of Nutrition, 2007; 137:1951-1954. https://doi.org/10.1093/jn/137.8.1951 PMid:17634269

101. Gauliard B, Grieve D, Wilson R, Crozier A, Jenkins C, Mullen WD, Lean M, The effects of dietary phenolic compounds on cytokine and antioxidant production by A549 cells. Journal of Medicinal Food, 2008;11:382-384. https://doi.org/10.1089/jmf.2007.593 PMid:18598184

102. Hou DX, Masuzaki S, Hashimoto F, Uto T, Tanigawa S, Fujii M, Sakata Y, Green tea proanthocyanidins inhibit cyclooxygenase-2 expression in LPS-activated mouse macrophages: molecular mechanisms and structure-activity relationship. Archives of Biochemistry and Biophysics, 2007; 460:67-74. https://doi.org/10.1016/j.abb.2007.01.009 PMid:17313938

103. Hou DX, Yanagita T, Uto T, Masuzaki S, Fujii M, Anthocyanidins inhibit cyclooxygenase-2 expression in LPS-evoked macrophages: structure-activity relationship and molecular mechanisms involved. Biochemical Journal. Pharmacology, 2005; 70:417-425 https://doi.org/10.1016/j.bcp.2005.05.003 PMid:15963474

104. Singh G, Darwin R, Panda KC, Afzal SA, Katiyar S, Dhakar RC, Mani S, Gene expression and hormonal signaling in osteoporosis: from molecular mechanisms to clinical breakthroughs, Journal of Biomaterials Science, Polymer Edition, 2024;1-36 https://doi.org/10.1080/09205063.2024.2445376

105. Pergola C, Rossi A, Dugo P, Cuzzocrea S, Sautebin L, Inhibition of nitric oxide biosynthesis by anthocyanin fraction of blackberry extract. Nitric Oxide, 2006; 15(1):30-39. https://doi.org/10.1016/j.niox.2005.10.003 PMid:16517190

106. Santana-Gálvez J, Cisneros-Zevallos L, Jacobo-Velázquez DA, Chlorogenic acid: recent advances on its dual role as a food additive and a nutraceutical against metabolic syndrome. Molecules, 2017; 22(3):358. https://doi.org/10.3390/molecules22030358 PMid:28245635 PMCid:PMC6155416

107. Oršolić N, Sirovina D, Odeh D, Gajski G, Balta V, Šver L, Jembrek MJ, Efficacy of caffeic acid on diabetes and its complications in the mouse. Molecules, 2021; 26(11): 3262. https://doi.org/10.3390/molecules26113262 PMid:34071554 PMCid:PMC8199327

108. Huang DW, Shen SC, Caffeic acid and cinnamic acid ameliorate glucose metabolism via modulating glycogenesis and gluconeogenesis in insulin-resistant mouse hepatocytes. Journal of Functional Foods, 2012; 4(1):358-366. https://doi.org/10.1016/j.jff.2012.01.005

109. Oboh G, Ogunbadejo MD, Ogunsuyi OB, Oyeleye SI, Can gallic acid potentiate the antihyperglycemic effect of acarbose and metformin? Evidence from streptoztocin-induced diabetic rat model. Archives of Physiology and Biochemistry, 2020; https://doi.org/10.108/13813455.2020.1716014 .

110. Huang DW, Chang WC, Wu JS, Shih RW, Shen SC, Gallic acid ameliorates hyperglycemia and improves hepatic carbohydrate metabolism in rats fed a high-fructose diet. Nutrition Research, 2016; 36(2):150-160. https://doi.org/10.1016/j.nutres.2015.10.001 PMid:26547672

111. Kumar S, Pandey AK, Chemistry and biological activities of flavonoids: An Overview. Scientific World Journal, 2013; 2013:162750. https://doi.org/10.1155/2013/162750 PMid:24470791 PMCid:PMC3891543

112. Kaleem M, Ahmad A, Flavonoids as nutraceuticals. In: Grumezescu MA, Holban AM, Therapeutic, Probiotic, and Unconventional Foods, 2018; 137-155. https://doi.org/10.1016/B978-0-12-814625-5.00008-X

113. Górniak I, Bartoszewski R, Króliczewski J, Comprehensive review of antimicrobial activities of plant flavonoids. Phytochemistry Review, 2019; 18: 241-272. https://doi.org/10.1007/s11101-018-9591-z

114. Lalani S, Poh CL, Flavonoids as antiviral agents for enterovirus A71 (EV-A71). Viruses, 2020; 12: 184. https://doi.org/10.3390/v12020184 PMid:32041232 PMCid:PMC7077323