Frondoside A of Cucumaria frondosa (Gennerus, 1767): Chemistry, biosynthesis, medicinal applications, and mechanism of actions.

Cucumaria frondosa (Gennerus, 1767) or orange-footed sea cucumbers are traditional food and are used as natural sources of anti-diabetic, anti-inflammatory, antioxidant, anti-angiogenic, antimicrobial, and anticancer agents. Currently, the introduction of value-added sea cucumber products to the global market has inspired basic research on frondoside A and other saponins in sea cucumbers. These saponins serve as a means of their chemical defence. However, recent studies revealed that exposure to these saponins can lead to irritating symptoms from aerosolization of various holothurins. Moreover, extraction methods are critical to the bioavailability of various bioactive compounds found in sea cucumbers. Therefore, we have critically reviewed recent studies on the chemistry, biosynthesis, and pharmacological properties of frondoside A. Furthermore, the mechanism of actions of frondoside A was postulated and further studies are required for applications in functional foods, nutraceuticals, and pharmaceuticals. Frondoside A was first discovered from Cucumaria frondosa, and it is involved in protein kinase (PI3K/AKT/ERK1/2/p38 MAPK, RAC/CDC42 PAK1, NFκB/MAPK/JNK, and LXR-ß) signalling pathways. It is also involved in the suppression of MYC oncogene transcriptional factors implicated and upregulated in over 70% of cancer types. Future research needs to be aimed at optimized green extraction techniques, efficient delivery methods, safety, and efficacy.

Sea Cucumber and Blueberry Extracts Suppress Inflammation and Reduce Acute Lung Injury through the Regulation of NF-κB/MAPK/JNK Signaling Pathway in Lipopolysaccharide-Treated C57BL/6 Mice.

Acute lung injury (ALI) represents a life-threatening condition with high morbidity and mortality despite modern mechanical ventilators and multiple pharmacological strategies. Therefore, there is a need to develop efficacious interventions with minimal side effects. The anti-inflammatory activities of sea cucumber (Cucumaria frondosa) and wild blueberry (Vaccinium angustifolium) extracts have been reported recently. However, their anti-inflammatory activities and the mechanism of action against ALI are not fully elucidated. Thus, the present study aims to understand the mechanism of the anti-inflammatory activity of sea cucumber and wild blueberry extracts in the context of ALI. Experimental ALI was induced via intranasal lipopolysaccharide (LPS) instillation in C57BL/6 mice and the anti-inflammatory properties were determined by cytokine analysis, histological examination, western blot, and qRT-PCR. The results showed that oral supplementation of sea cucumber extracts repressed nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, thereby downregulating the expression of interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF) in the lung tissue and in the plasma. Wild blueberry extracts also suppressed the expression of IL-4. Furthermore, the combination of sea cucumber and wild blueberry extracts restrained MAPK signaling pathways by prominent attenuation of phosphorylation of NF-κB, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK) while the levels of pro-inflammatory cytokines were significantly suppressed. Moreover, there was a significant and synergistic reduction in varying degrees of ALI lesions such as distorted parenchyma, increased alveoli thickness, lymphocyte and neutrophil infiltrations, fibrin deposition, pulmonary emphysema, pneumonia, intra-alveolar hemorrhage, and edema. The anti-inflammatory effect of the combination of sea cucumber and wild blueberry extracts is associated with suppressing MAPK and NF-κB signaling pathways, thereby significantly reducing cytokine storm in LPS-induced experimental ALI.

Saponins of North Atlantic Sea Cucumber: Chemistry, Health Benefits, and Future Prospectives.

Frondosides are the major saponins (triterpene glycosides) of the North Atlantic sea cucumber (Cucumaria frondosa). Frondosides possess amphiphilic characteristics due to the presence of various hydrophilic sugar moieties and hydrophobic genin (sapogenin). Saponins are abundant in holothurians, including in sea cucumbers that are widely distributed across the northern part of the Atlantic Ocean. Over 300 triterpene glycosides have been isolated, identified, and categorized from many species of sea cucumbers. Furthermore, specific saponins from sea cucumbers are broadly classified on the basis of the fron-dosides that have been widely studied. Recent studies have shown that frondoside-containing extracts from C. frondosa exhibit anticancer, anti-obesity, anti-hyperuricemic, anticoagulant, antioxidant, antimicrobial, antiangiogenic, antithrombotic, anti-inflammatory, antitumor, and immunomodulatory activities. However, the exact mechanism(s) of action of biological activities of frondosides is not clearly understood. The function of some frondosides as chemical defense molecules need to be understood. Therefore, this review discusses the different frondosides of C. frondosa and their potential therapeutic activities in relation to the postulated mechanism(s) of action. In addition, recent advances in emerging extraction techniques of frondosides and other saponins and future perspectives are discussed.

Role of Antioxidant Vitamins and Other Micronutrients on Regulations of Specific Genes and Signaling Pathways in the Prevention and Treatment of Cancer.

Cancer is an escalating global issue, with 19.3 million new cases and 9.9 million deaths in 2020. Therefore, effective approaches to prevent cancer are urgently required. Diet plays a significant role in determining cancer risk. Nutrients and food bioactives influence specific signaling pathways in the body. Recently, there have been significant advances in cancer prevention research through nutrigenomics or with the effects of dietary components on the genome. Google Scholar, PubMed, and Scopus databases were used to search for peer-reviewed articles between 2017 and 2023. Criteria used were vitamins, minerals, tumors, cancer, genes, inflammation, signaling pathways, and nutrigenomics. Among the total of 1857 articles available, the highest relevant 90 articles that specifically discussed signaling pathways and genes on cancer cell lines and human cancer patients were selected and reviewed. Food sources are rich in antioxidant micronutrients, which are effective in activating or regulating signaling pathways involved in pathogenesis and cancer therapy by activating enzymes such as mitogen-activated protein kinase (MAPK), protein kinase C (PKC), and phosphatidylinositol 3-kinase (PI3K). The micronutrients are involved in the regulation of ß-catenin (WNT/ß-catenin) including mutations in Kras and epidermal growth factor receptor (EGFR) alongside inhibition of the NF-kB pathway. The most common mechanism of cancer prevention by these micronutrients is their antioxidative, anti-inflammation, and anti-apoptosis effects. This review discusses how nutrigenomics is essential and beneficial for developing cancer prevention and treatment approaches.

In-vitro antioxidant and anti-inflammatory activities of ethanol stem-bark extract of Blighia sapida K.D. Koenig.

Blighia sapida (B. sapida) K.D. Koenig (Family Sapindaceae) is a branchless straight bole approximately 15 m in length. The study evaluated the antioxidant and anti-inflammatory activities of ethanol extract and fractions of B. sapida stem-bark using in vitro methods. Ethanol extract and its fractions were investigated for 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity, ferric reducing antioxidant power (FRAP), total antioxidant capacity (TAC), and quantitative phenolic and flavonoid contents. Anti-inflammatory activity was evaluated using albumin denaturation and membrane stabilization assays. The extract and its fractions exhibited radical scavenging and anti-inflammatory properties. The ethyl acetate fraction possessed maximum phenolic and flavonoid contents (136.67 ± 1.55 gallic acid equivalent mg/g and 75.76 ± 4.03 quercetin equivalent mg/g, respectively). Antioxidant studies revealed that the ethyl acetate fraction displayed superior activity with an IC50 = 0.09 ± 0.03 mg/mL DPPH, and values of 146.96 ± 3.81 ascorbic acid equivalent (AAE) mg/g and 359.20 ± 4.98 AAE mg/g for FRAP and TAC, respectively. Furthermore, the anti-inflammatory activity was revealed by inhibition of heat-induced albumin denaturation and red blood cell membrane stabilization at concentrations of 200-1000 µg/mL and 50-250 µg/mL, respectively. The ethanol extract and fractions exhibited antioxidant and anti-inflammatory activities, with ethyl acetate fraction showing superior activity, which could be attributed to secondary metabolites, mainly phenolic compounds. Overall, the antioxidant and anti-inflammatory activities of B. sapida can be exploited by ethnomedicinal users.

Exercise, CaMKII, and type 2 diabetes.

Individuals who exercise regularly are protected from type 2 diabetes and other metabolic syndromes, in part by enhanced gene transcription and induction of many signaling pathways crucial in correcting impaired metabolic pathways associated with a sedentary lifestyle. Exercise activates Calmodulin-dependent protein kinase (CaMK)II, resulting in increased mitochondrial oxidative capacity and glucose transport. CaMKII regulates many health beneficial cellular functions in individuals who exercise compared with those who do not exercise. The role of exercise in the regulation of carbohydrate, lipid metabolism, and insulin signaling pathways are explained at the onset. Followed by the role of exercise in the regulation of glucose transporter (GLUT)4 expression and mitochondrial biogenesis are explained. Next, the main functions of Calmodulin-dependent protein kinase and the mechanism to activate it are illustrated, finally, an overview of the role of CaMKII in regulating GLUT4 expression, mitochondrial biogenesis, and histone modification are discussed.

Role of CaMKII in the regulation of fatty acids and lipid metabolism.

BACKGROUND & AIMS: Previous studies have reported the beneficial roles of the activation of calmodulin-dependent protein kinase (CaMK)II to many cellular functions associated with human health. This review aims at discussing its activation by exercise as well as its roles in the regulation of unsaturated, saturated, omega 3 fatty acids, and lipid metabolism. METHODS: A wide literature search was conducted using online database such as 'PubMed', 'Google Scholar', 'Researcher', 'Scopus' and the website of World Health Organization (WHO) as well as Control Disease and Prevention (CDC). The criteria for the search were mainly lipid and fatty acid metabolism, diabetes, and metabolic syndrome (MetS). A total of ninety-seven articles were included in the review. RESULTS: Calmodulin-dependent protein kinase activation by exercise is helpful in controlling membrane lipids related with type 2 diabetes and obesity. CaMKII regulates many health beneficial cellular functions in individuals who exercise compared with those who do not exercise. Regulation of lipid metabolism and fatty acids are crucial in the improvement of metabolic syndrome. CONCLUSIONS: Approaches that involve CaMKII could be a new avenue for designing novel and effective therapeutic modalities in the treatment or better management of metabolic diseases such as type 2 diabetes and obesity.

Exploration of Modern Chromatographic Methods Coupled to Mass Spectrometric Techniques for Trace Element and Chemical Composition Analyses in the Leaf Extracts of Kigelia africana.

The use of Kigelia africana (Lam.) Benth. plant dates back to last century. The different parts of the plant exhibited various pharmacological activities. But literature search revealed scanty use of the leaf extract owing to few information regarding the various phytochemical constituents. The aim of this study is, therefore, to profile the chemical compounds through the use of omics-based approach. Ultrahigh-pressure liquid chromatography quadrupole-time-of-flight tandem mass spectrometry (qTOF-UPLC/MS) alongside gas chromatography quadrupole time-of-flight tandem mass spectrometry (qTOF-GC/MS) were used to profile these chemical compounds. Inductively coupled plasma optical emission spectrometry (ICP-OES) was used to determine the concentration of trace elements as well as limit of detection (LOD) and quantification (LOQ). For broader metabolite determination, a modified sample preparation was employed and to ascertain the cytoprotective potential of the leaf extract, MTT assay on A375 human melanoma cell lines was carried out. Sixty-eight peaks were characterized with the identification of 275 metabolites where 8 of these were confirmed. Of importance is the identification of eugenol; a polyphenolic compound at m/z 165.09 on fragments 119.09, 147.08, 109.10, 137.10, and 137.06. for qTOF-GC/MS analysis, 232 metabolites were identified consisting of terpenes, fatty acids, furans, amines, amides, and alkanes. The concentration of trace elements in the leaf extract ranged from 0.08 for Zn to 0.28 mg/kg for Fe with low concentrations of Cd according to the recommendation of European Legislation. The leaf showed higher inhibition of growth against A375 human melanoma cell lines in a dose-dependent manner. The results showed that K. africana leaf contained various pharmaceuticals, nutraceuticals, designer drugs, and phytochemicals, and these chemicals have minimal cytotoxic side effects. To the best of our knowledge, this is the first study providing information on the various secondary metabolites in the leaf extract through the use of omics-based approach. Therefore, the leaves of K. africana plant can be used as antiinflammatory, antimicrobial, antibacterial, antifungal, and antiproliferative agents for industrial, therapeutic, and medicinal applications. Graphical Abstract.

UHPLC/GC-TOF-MS metabolomics, MTT assay, and molecular docking studies reveal physostigmine as a new anticancer agent from the ethyl acetate and butanol fractions of Kigelia africana (Lam.) Benth. fruit extracts.

Kigelia africana plant is widely used as a herbal remedy in preventing the onset and the treatment of cancer-related infections. With the increase in the research interest of the plant, the specific chemical compound or metabolite that confers its anticancer properties has not been adequately investigated. The ethyl acetate and butanol fractions of the fruit extracts were evaluated by 2-(4,5-dimethylthiazol-2-yl)-3,5-diphenyl-2H-tetrazolium bromide assay against four different cell lines, with the ethyl acetate fraction having inhibition concentration values of 0.53 and 0.42 µM against Hep G2 and HeLa cells, respectively. More than 235 phytoconstituents were profiled using UHPLC-TOF-MS, while more than 15 chemical compounds were identified using GC-MS from the fractions. Molecular docking studies revealed that physostigmine, fluazifop, dexamethasone, sulfisomidine, and desmethylmirtazapine could favorably bind at higher binding energies of -8.3, -8.6, -8.2, and -8.1 kcal/mol, respectively, better than camptothecin with a binding energy of -7.9 kcal/mol. The results of this study showed that physostigmine interacted well with topoisomerase IIα and had a high score of pharmacokinetic prediction using absorption, distribution, metabolism, excretion, and toxicity profiles, thereby suggesting that drug design using physostigmine as a base structure could serve as an alternative against the toxic side effects of doxorubicin and camptothecin.

Metabolome modulatory effects of Kigelia africana (Lam.) Benth. fruit extracts on oxidative stress, hyperlipidaemic biomarkers in STZ-induced diabetic rats and antidiabetic effects in 3T3 L1 adipocytes.

OBJECTIVES: The management of diabetes is considered a global problem, and a cure is yet to be discovered. This study investigated the modulatory effect of Kigelia africana fruit on oxidative stress and hyperlipidaemic biomarkers in STZ-induced diabetic rats, profiled phytoconstituents using GC-TOF-MS and evaluated antidiabetic effects on 3T3 L1 adipocytes. METHODS: Thirty male Wistar rats (120-150 g) were divided into six groups (n = 5). Diabetes was induced by a single intraperitoneal injection of STZ (60 mg/kg) and treated with 100, 200 and 400 of hexane fraction of KA for 28 days. Immunohistochemical evaluation was carried out using avidin-biotin immunoperoxidase (ABI) method. Catalase and SOD activities as well as the levels of total protein, albumin, bilirubin, triglyceride, cholesterol, and high-density lipoprotein were measured. KEY FINDINGS: The expressions of oxidative stress and hyperlipidaemic biomarkers alongside fasting blood glucose concentrations were remarkedly decreased in KA-treated diabetic rats. Moreover, there was a significant increase in endocrine cell distribution, area covered with increase in ß-cell mass, composition and morphology of KA-treated animals. Additionally, there was constant up-regulation in 3T3 L1 adipocytes due to the presence of phytoconstituents. CONCLUSION: Kigelia africana fruit can act as a modulatory agent due to its ameliorative effects against oxidative stress.

Changes in the biochemical, hematological and histopathological parameters in STZ-Induced diabetic rats and the ameliorative effect of Kigelia africana fruit extract.

BACKGROUND: Biochemical, hematological and histological changes are major observable clinical and pathological factors associated with Diabetes mellitus. Derangement in the levels of these parameters increases the risk of the development of complications. In another hand, gastrointestinal intolerance due to the development of lactic acidosis on the gastrointestinal tract and the intestinal microbiome is the toxic side effect of various synthetic antidiabetic agents. The use of Kigelia africana fruit extract for the treatment of diabetes has been scientifically validated. This study therefore aimed at investigating changes in the biochemical, hematological and histological parameters as well as the determination of the functional groups present in the hexane fraction of the fruit. METHODS: The fruits were extracted with ethanol and partitioned with n-hexane to obtain the hexane fraction. Diabetic rats induced with streptozotocin (STZ) were divided into 5 groups of 5 animals each and treated with 100, 200 and 400 mg/kg body weight (BW) hexane fraction alongside reference standard; glibenclamide. Fasting blood glucose levels and their body weights were monitored weekly. Animals were sacrificed at the end of 28-day treatment. Blood, liver, and kidney were collected for biochemical, hematological and histopathological analyses. Fourier transform infrared resonance (FTIR) spectroscopic analysis was carried out on the hexane fraction for functional group determination. RESULTS: The hexane fraction of K. africana fruit extract decreased fasting blood glucose (FBG) levels significantly with ameliorative effects on the hematological parameters such as packed cell volume (PCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), and red blood cells (RBC) etc. There were significant regenerative differences in the biochemical activities as well as the renal cortex and midzone sections of the rat's kidney and liver when compared with untreated diabetic rats. The presence of polyphenolic functional groups via FTIR analysis suggested high antioxidant activities of the fruit extract. CONCLUSION: The use of Kigelia africana fruit extracts protects against biochemical, hematological and histological changes that are injurious to diabetic patients. Therefore, Kigelia africana fruit is a good hepatic- and nephroprotective agent and has a hemato-protective ability.

Evaluation of Phytochemicals, Antioxidants, Trace Elements in Kigelia africana Fruit Extracts and Chemical Profiling Analysis Using UHPLC-qTOF-MS2 Spectrometry.

The study aimed at evaluating the phytochemical composition, antioxidant potentials and the levels of trace elements in the fruit extract of Kigelia africana obtained by different extraction solvents in order to ascertain its numerous pharmacological activities and identify the different chemical compounds responsible for these activities. The crude extract in ethanol and four other solvent fractions (hexane, ethylacetate, butanol and aqueous) were obtained for phytochemical screening. Antioxidant potentials of K. africana fruit were investigated spectrophotometrically using hydroxyl ion scavenging (OH-) activity, metal ion chelating activity, anti-lipid peroxidation activity as well as total antioxidant capacity assays. Trace element (Mn, Zn, Cd, Ni, Cu, Pb, Cr, Co and Fe) levels were measured using a plasma-emission spectrometer that has an auto sampler AS 93-plus and coupled with Nebulizer CETAC U-6000AT+ after microwave acid digestion of the fruit extracts. Chemical identification was performed using ultra-high-pressure liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (UHPLC-qTOF-MS2). Kigelia africana fruit extracts obtained showed a variety of bioactive phytochemical compounds including phenolic acids, flavonoids, saponins, tannins and glycosides. The total antioxidant capacity activities of the aqueous, butanol, ethanol, hexane and ethylacetate extracts are 15.04, 52.11, 44.95, 79.27 and 175.20 mg AAE/g. Metal ion chelating activity showed significant correlation with lipid peroxidation inhibition activity at p ≤ 0.01 and with OH- scavenging activity at p ≤ 0.05. PCA analysis revealed that all the extract/fractions have higher total antioxidant activities compared to aqueous extract with hexane extract exhibiting the highest radical scavenging potential. HCA showed similarities with three well-defined clusters and PLS regression was used to predict total antioxidant activity. High sensitivity by low values of limits of detection and quantification was observed ranging from 0.021 to 0.085 mg/ml and 0.063 to 0.258 mg/ml for Zn and Fe respectively. Ethylacetate extract had high concentration of Fe (0.5656 mg/kg). For the standardization of the K. africana fruit extract, 244 chemical compounds were identified by measuring m/z values with threshold override of 100,000 and analysing mass spectrometer fragmentation behaviour while 16 of these were confirmed. Kigelia africana fruit extract is a good source of antioxidant and possess maximum accepted concentration of trace elements according to European legislation (1881/2006/EC). The metabolites identified exhibited numerous pharmacological activities. The method and results suggest the applicability for commercial use of this K. africana fruit in the treatment of oxidative-related diseases. Graphical abstract The phytochemical, antioxidant and trace element composition of crude ethanol extract, hexane, butanol, aqueous and ethylacetate extracts of Kigelia africana fruit were determined. The fruit extracts were found to possess good antioxidant activity, maximum acceptable amount of essential trace elements as well as the presence of bioactive phytochemicals. K. africana fruit would be an ideal candidate in improving human health and thus the management of oxidative-related diseases such as diabetes, by involving in the antioxidant defense system against free radical generation.