Efficient biotransformation of naringenin to naringenin α-glucoside, a novel α-glucosidase inhibitor, by amylosucrase from Deinococcus wulumuquiensis.

Amylosucrase (ASase) efficiently biosynthesizes α-glucoside using flavonoids as acceptor molecules and sucrose as a donor molecule. Here, ASase from Deinococcus wulumuqiensis (DwAS) biosynthesized more naringenin α-glucoside (NαG) with sucrose and naringenin as donor and acceptor molecules, respectively, than other ASases from Deinococcus sp. The biotransformation rate of DwAS to NαG was 21.3% compared to 7.1-16.2% for other ASases. Docking simulations showed that the active site of DwAS was more accessible to naringenin than those of others. The 217th valine in DwAS corresponded to the 221st isoleucine in Deinococcus geothermalis AS (DgAS), and the isoleucine possibly prevented naringenin from accessing the active site. The DwAS-V217I mutant had a significantly lower biosynthetic rate of NαG than DwAS. The kcat/Km value of DwAS with naringenin as the donor was significantly higher than that of DgAS and DwAS-V217I. In addition, NαG inhibited human intestinal α-glucosidase more efficiently than naringenin.

[Cloning and functional analysis of flavanone synthase â ¡ from Dendrobium huoshanense].

Flavonoid C-glycosides are a class of natural products that are widely involved in plant defense responses and have diverse pharmacological activities. They are also important active ingredients of Dendrobium huoshanense. Flavanone synthase Ⅱ has been proven to be a key enzyme in the synthesis pathway of flavonoid C-glycosides in plants, and their catalytic product 2-hydroxyflavanone is the precursor compound for the synthesis of various reported flavonoid C-glycosides. In this study, based on the reported amino acid sequence of flavanone synthase Ⅱ, a flavanone synthase Ⅱ gene(DhuFNSⅡ) was screened and verified from the constructed D. huoshanense genome localization database. Functional validation of the enzyme showed that it could in vitro catalyze naringenin and pinocembrin to produce apigenin and chrysin, respectively. The open reading frame(ORF) of DhuFNSⅡ was 1 644 bp in length, encoding 547 amino acids. Subcellular localization showed that the protein was localized on the endoplasmic reticulum. RT-qPCR results showed that DhuFNSⅡ had the highest expression in stems, followed by leaves and roots. The expression levels of DhuFNSⅡ and other target genes in various tissues of D. huoshanense were significantly up-regulated after four kinds of abiotic stresses commonly encountered in the growth process, but the extent of up-regulation varied among treatment groups, with drought and cold stress having more significant effects on gene expression levels. Through the identification and functional analysis of DhuFNSⅡ, this study is expected to contribute to the elucidation of the molecular mechanism of the formation of quality metabolites of D. huoshanense, flavonoid C-glycosides, and provide a reference for its quality formation and scientific cultivation.

Optimizing the Biosynthesis of Dihydroquercetin from Naringenin in Saccharomyces cerevisiae.

Dihydroquercetin (DHQ), known for its varied physiological benefits, is widely used in the food, chemical, and pharmaceutical industries. However, the efficiency of the DHQ synthesis is significantly limited by the substantial accumulation of intermediates during DHQ biosynthesis. In this study, DHQ production was achieved by integrating genes from various organisms into the yeast chromosome for the expression of flavanone-3-hydroxylase (F3H), flavonoid-3'-hydroxylase, and cytochrome P450 reductase. A computer-aided protein design approach led to the development of optimal F3H mutant P221A, resulting in a 1.67-fold increase in DHQ yield from naringenin (NAR) compared with the control. Subsequently, by analysis of the enzyme reaction and optimization of the culture medium composition, 637.29 ± 20.35 mg/L DHQ was synthesized from 800 mg/L NAR. This corresponds to a remarkable conversion rate of 71.26%, one of the highest reported values for DHQ synthesis from NAR to date.

Plasma proteome profiling reveals molecular mechanisms underlying the effects of daily consumption of 'Bahia' and 'Cara Cara' orange juices.

Orange juice is an important food source of bioactive compounds, mainly the flavanones hesperidin and narirutin. This study aimed to investigate the underlying molecular mechanisms of action of orange juice's health properties by analyzing changes in the plasma proteome of healthy Brazilian volunteers after consuming juices made from 'Bahia' (BOJ-source of flavanones) and 'Cara Cara' (CCOJ-source of flavanones and carotenoids) oranges cultivated in Brazil. We used an untargeted proteomic approach, with a particular emphasis on the juices' effects on blood coagulant activity. We identified 247 differentially expressed proteins, of which 170 significantly increased or decreased after BOJ consumption and 145 after CCOJ. These proteins are involved in 105 processes that can significantly regulate cell adhesion, cell signaling, cell metabolism, inflammation, or others. Bioinformatic analysis evidenced proteins with major cellular regulatory capacity (e.g., FN1 and GAPDH) and predicted transcription factors (TFs) (e.g., SP1 and CEBPA) and miRNAs (e.g., miR-1-3p and miR-615-3p) that could be involved in the regulation of differentially expressed proteins. In-silico docking analyses between flavanone metabolites and TFs evidenced the higher binding capacity of narirutin phase II metabolites with akt1 and p38, interactions that suggest how the expression of genes of differentially expressed proteins were activated or inhibited. Moreover, the study shed light on proteins of coagulation cascade that presented expression modulated by both juices, proposing the modulation of blood coagulant activity as a potential benefit of OJ (mainly CCOJ) consumption. Taken together, this study revealed that BOJ and CCOJ consumption affected plasma proteome in healthy individuals, suggesting potential molecular targets and mechanisms of OJ bioactive compounds in humans.

Dietary fibre fractions rich in (poly)phenols from orange by-products and their metabolisation by in vitro digestion and colonic fermentation.

Orange peel is an interesting by-product because of its composition, particularly its dietary fibre and flavanones. The aim of this work was to extract different fibre fractions from orange peel to obtain potential added-value ingredients and evaluate how the presence of fibre may interfere with (poly)phenol metabolism. Using an aqueous extraction, as a green extraction method, an insoluble fibre fraction (IFF) and a water-soluble extract (WSE) were obtained. Those fractions were analysed to determine the proximate and dietary fibre composition, hydration properties, (poly)phenol composition and antioxidant capacity, comparing the results with the orange peel (OP). The IFF presented the highest content of insoluble dietary fibre and the WSE showed the highest content of (poly)phenols, these being mainly flavanones. An in vitro faecal fermentation was carried out to evaluate the production of short-chain fatty acids (SCFAs) and lactate as prebiotic indicators; the IFF gave the highest production, derived from the greater presence of dietary fibre. Moreover, catabolites from (poly)phenol metabolism were also analysed, phenylpropanoic acids being the major ones, followed by phenylacetic acids and benzoic acids. These catabolites were found in higher quantities in WSE, because of the greater presence of (poly)phenols in its composition. IFF also showed a significant production of these catabolites, which was delayed by the greater presence of fibre. These results reveal that the new ingredients, obtained by an environmentally friendly water extraction procedure, could be used for the development of new foods with enhanced nutritional and healthy properties.

Saccharomyces cerevisiae biofactory to produce naringenin using a systems biology approach and a bicistronic vector expression strategy in flavonoid production.

IMPORTANCE: Flavonoids are a group of compounds generally produced by plants with proven biological activity, which have recently beeen recommended for the treatment and prevention of diseases and ailments with diverse causes. In this study, naringenin was produced in adequate amounts in yeast after in silico design. The four genes of the involved enzymes from several organisms (bacteria and plants) were multi-expressed in two vectors carrying each two genes linked by a short viral peptide sequence. The batch kinetic behavior of the product, substrate, and biomass was described at lab scale. The engineered strain might be used in a more affordable and viable bioprocess for industrial naringenin procurement.

Microbial production of the plant flavanone hesperetin from caffeic acid.

OBJECTIVE: Hesperetin is an important O-methylated flavonoid produced by citrus fruits and of potential pharmaceutical relevance. The microbial biosynthesis of hesperetin could be a viable alternative to plant extraction, as plant extracts often yield complex mixtures of different flavonoids making it challenging to isolate pure compounds. In this study, hesperetin was produced from caffeic acid in the microbial host Escherichia coli. We combined a previously optimised pathway for the biosynthesis of the intermediate flavanone eriodictyol with a combinatorial library of plasmids expressing three candidate flavonoid O-methyltransferases. Moreover, we endeavoured to improve the position specificity of CCoAOMT7, a flavonoid O-methyltransferase from Arabidopsis thaliana that has been demonstrated to O-methylate eriodictyol in both the para- and meta-position, thus leading to a mixture of hesperetin and homoeriodictyol. RESULTS: The best performing flavonoid O-methyltransferase in our screen was found to be CCoAOMT7, which could produce up to 14.6 mg/L hesperetin and 3.8 mg/L homoeriodictyol from 3 mM caffeic acid in E. coli 5-alpha. Using a platform for enzyme engineering that scans the mutational space of selected key positions, predicting their structures using homology modelling and inferring their potential catalytic improvement using docking simulations, we were able to identify a CCoAOMT7 mutant with a two-fold higher position specificity for hesperetin. The mutant's catalytic activity, however, was considerably diminished. Our findings suggest that hesperetin can be created from central carbon metabolism in E. coli following the introduction of a caffeic acid biosynthesis pathway.

Oxidation of Naringenin, Apigenin, and Genistein by Human Family 1 Cytochrome P450 Enzymes and Comparison of Interaction of Apigenin with Human P450 1B1.1 and Scutellaria P450 82D.1.

Naringenin, an initial synthesized flavanone in various plant species, is further utilized for production of many biologically active flavonoids, e.g., apigenin, eriodictyol, and genistein, by various plant enzymes including cytochrome P450s (P450s or CYPs). We examined how these flavonoids are oxidized by human P450 family 1 and 2A enzymes. Naringenin was principally oxidized at the 3'-position to form eriodictyol by CYP1 enzymes more efficiently than by CYP2A enzymes, and the resulting eriodictyol was further oxidized to two penta-hydroxylated products. In contrast to plant P450 enzymes, these human P450s did not mediate the desaturation of naringenin and eriodictyol to give apigenin and luteolin, respectively. Apigenin was oxidized at the C3' and C6 positions to form luteolin and scutellarein by these P450s. CYP1B1.1 and 1B1.3 had high activities in apigenin 6-hydroxylation with a homotropic cooperative manner, as has been observed previously in chrysin 6-hydroxylation (Nagayoshi et al., Chem. Res. Toxicol. 2019, 32, 1268-1280). Molecular docking analysis suggested that CYP1B1 had two apigenin binding sites and showed similarities in substrate recognition sites to plant CYP82D.1, one of the enzymes in catalyzing apigenin and chrysin 6-hydroxylations in Scutellaria baicalensis. The present results suggest that human CYP1 enzymes and CYP2A13 in some reactions have important roles in the oxidation of naringenin, eriodictyol, apigenin, and genistein and that human CYP1B1 and Scutellaria CYP82D.1 have similarities in their SRS regions, catalyzing 6-hydroxylation of both apigenin and chrysin.

Molecular mechanism of different flower color formation of Cymbidium ensifolium.

Cymbidium ensifolium is one of the national orchids in China, which has high ornamental value with changeable flower colors. To understand the formation mechanism of different flower colors of C. ensifolium, this research conducted transcriptome and metabolome analyses on four different colored sepals of C. ensifolium. Metabolome analysis detected 204 flavonoid metabolites, including 17 polyphenols, 27 anthocyanins, 75 flavones, 34 flavonols, 25 flavonoids, 18 flavanones, and 8 isoflavones. Among them, purple-red and red sepals contain a lot of anthocyanins, including cyanidin, pelargonin, and paeoniflorin, while yellow-green and white sepals have less anthocyanins detected, and their metabolites are mainly flavonols, flavanones and flavonoids. Transcriptome sequencing analysis showed that the expression levels of the anthocyanin biosynthetic enzyme genes in red and purple-red sepals were significantly higher than those in white and yellow-green sepals of C. ensifolium. The experimental results showed that CeF3'H2, CeDFR, CeANS, CeF3H and CeUFGT1 may be the key genes involved in anthocyanin production in C. ensifolium sepals, and CeMYB104 has been proved to play an important role in the flower color formation of C. ensifolium. The results of transformation showed that the CeMYB104 is involved in the synthesis of anthocyanins and can form a purple-red color in the white perianth of Phalaenopsis. These findings provide a theoretical reference to understand the formation mechanism of flower color in C. ensifolium.

An arginine-to-histidine mutation in flavanone-3-hydroxylase results in pink strawberry fruits.

Fruit color is a very important external commodity factor for consumers. Compared to the most typical red octoploid strawberry (Fragaria × ananassa), the pink strawberry often sells for a more expensive price and has a higher economic benefit due to its outstanding color. However, few studies have examined the molecular basis of pink-colored strawberry fruit. Through an EMS mutagenesis of woodland strawberry (Fragaria vesca), we identified a mutant with pink fruits and green petioles. Bulked-segregant analysis sequencing analysis and gene function verification confirmed that the responsible mutation resides in a gene encoding flavanone-3-hydroxylase (F3H) in the anthocyanin synthesis pathway. This nonsynonymous mutation results in an arginine-to-histidine change at position 130 of F3H. Molecular docking experiments showed that the arginine-to-histidine mutation results in a reduction of intermolecular force-hydrogen bonding between the F3H protein and its substrates. Enzymatic experiments showed a greatly reduced ability of the mutated F3H protein to catalyze the conversion of the substrates and hence a blockage of the anthocyanin synthesis pathway. The discovery of a key residue in the F3H gene controlling anthocyanin synthesis provides a clear target of modification for the molecular breeding of strawberry varieties with pink-colored fruits, which may be of great commercial value.

In Vitro Study of Cytostatic Activity of Baicalin, Baicalein, and Chlorophyllipt on HeLa-v Cell Line.

Cytostatic activity of baicalin, baicalein, and neogalenical drug Chlorophyllipt was studied in vitro on HeLa-v cells. Standard samples of Eucalimin, baicalin, and baicalein, as well as Chlorophyllipt and paclitaxel (reference drug Taxacad) were used. The cell deaths were determined by MTT assay in a Multiskan FC microplate reader with incubator. The effective inhibition concentration (IC50) of the tested substances were: paclitaxel (4.0±0.4 µM)-baicalein (10.5±1.1 µM)-baicalin (16.5±1.7 µM)-sum of euglobals in Chlorophyllipt (24.1±2.5 µM). Chlorophyllipt was found to exhibit cytostatic activity. Cytostatic activity of baicalein, baicalin, and Chlorophyllipt was lower than cytostatic activity of the reference drug by 2.6, 4.1, and 6 times, respectively. The prospects of further evaluation of the synergetic effect of baicalin, baicalein, and chlorophyllipt used in combinations with different cytostatic agents for finding the most effective combination have been shown.

The transcription factors SbMYB45 and SbMYB86.1 regulate flavone biosynthesis in Scutellaria baicalensis.

Scutellaria baicalensis Georgi is an important Chinese medicinal plant that is rich in the flavones baicalin, wogonoside, and wogonin, providing it with anti-cancer, anti-inflammatory, and antibacterial properties. However, although the biosynthetic pathways of baicalin and its derivates have been elucidated, the regulation of flavone biosynthesis in S. baicalensis is poorly understood. Here, we found that the contents of baicalin and its derivates increased and that baicalin biosynthetic pathway genes were induced in response to light, and baicalin and baicalein are not exclusively produced in the roots of S. baicalensis. Based on the fact that MYB transcription factors are known to play important roles in flavone biosynthesis, we identified SbMYB45 and SbMYB86.1 in S. baicalensis and determined that they bind to the promoter of the flavone biosynthesis gene SbCHI to enhance its transcription. Moreover, overexpressing SbMYB45 and SbMYB86.1 enhanced the accumulation of baicalin in S. baicalensis leaves. We demonstrate that SbMYB45 and SbMYB86.1 bind to the cis-acting element MBSII in the promoter of CHI to redundantly induce its expression upon light exposure. These findings indicate that SbMYB45 and SbMYB86.1 transcriptionally activate SbCHI in response to light and enhance flavone contents in S. baicalensis.

MYB Transcription Factor OsC1PLSr Involves the Regulation of Purple Leaf Sheath in Rice.

Although several regulators associated with purple traits in rice have been identified, the genetic basis of the purple sheath remains unclear. In the present study, F2-1 and F2-2 populations were constructed using purple sheath (H93S) and green sheath (R1173 and YHSM), respectively. In order to identify QTL loci in purple sheaths, BSA analyses were performed on the two F2 populations. A crucial QTL for purple sheath was identified, tentatively named qPLSr6, and was located in the 4.61 Mb to 6.03 Mb region of chromosome 6. Combined with expression pattern analysis of candidate genes, LOC_Os06g10350 (OsC1PLSr) was suggested as a candidate gene. The homozygous mutant KO-1 and KO-2 created through CRISPR/Cas9 editing, lost their purple leaf sheath. The RT-PCR revealed that OsC1PLSr, anthocyanin synthase (ANS), diflavonol-4-reductase (DFR), flavanone-3-hydroxylase (F3H), and flavanone-3'-hydroxylase (F3'H) expression levels were dramatically down-regulated in the mutants. The yeast report system indicated that the 145-272 aa region at the C-terminal of OsC1PLSr is a positive transcriptional activation domain. The results indicated that OsC1PLSr synthesized anthocyanins by regulating the expression of ANS, DFR, F3H, and F3'H. This study provides new insights into the genetic basis of the purple sheath.

The effects of baicalein alone and in combination with losartan on DOX-induced nephrotoxicity in rats.

The goal of this research was to determine whether the combination of baicalein (BL) and losartan (LT) would provide greater protection against DOX-induced nephrotoxicity. There were five groups of male rats in the experiment: the 1) control, 2) DOX, 3) DOX+LT, 4) DOX+BL and 5) DOX+LT+BL groups. A dose of DOX was administered following two weeks of LT and BL therapy. In the DOX-affected group, serum renal indicators, including creatinine and urea, rose considerably compared to those in the control groups (p<0.01). Further, there was a statistically significant increase (p<0.001) in the levels of the cytokines that promote inflammation in renal tissue, including tumor necrosis factor-α, interleukin (IL)-1 and IL-6. In addition, the level of the anti-inflammatory cytokine IL-10 decreased significantly (p<0.001) in the DOX-challenged group compared to the control groups. In addition, renal cell indicators of oxidative stress (p<0.001) and enzymatic activity (p<0.01) reduced dramatically in the DOX-challenged group, whereas renal cell thiobarbituric acid retroactive materials rose greatly (p<0.001). Finally, the DOX group had higher kidney protein expression and inflammatory activity than the control groups (p<0.001). The combination of BL and LT therapy protected DOX-challenged rats via antioxidant and anti-inflammatory activities.

Naringin prevents diabetic nephropathy in rats through blockage of oxidative stress and attenuation of the mitochondrial dysfunction.

We have studied the effects of naringin (NAR), a flavonoid from citric fruits, on morphology, ultrastructure and function of the kidney in streptozotocin (STZ)-induced diabetic rats. Two groups of animals were used: (1) control rats and (2) STZ rats (60 mg STZ/kg b.w.). At 3 days after induction, one group of STZ-treated rats received 40 mg NAR/kg b.w. daily. NAR blocked completely alterations in the biochemical renal markers in STZ rats except the increase in serum urea that was partially avoided by the flavonoid. NAR ameliorated the kidney morphological lesions from STZ rats. STZ treatment induced round and smaller mitochondria, which was avoided by NAR. Citrate synthase, isocitrate and malate dehydrogenases, enzyme activities of the Krebs cycle, were decreased in STZ rats. NAR abolished this decrease in the latter proteins. NAR also prevented a decrease in the ATP synthase activity of the mitochondria from renal cortex by about 49% in STZ rats, returning the enzyme activity to control values. The nephroprotection caused by NAR is mediated through counteraction of oxidative stress in mitochondria of proximal tubules. NAR might be a therapeutic strategy to reduce the complication of diabetic nephropathy in type 1 diabetic patients.

Citrus flavanone metabolites significantly modulate global proteomic profile in pancreatic ß-cells under high-glucose-induced metabolic stress.

Hesperidin and narirutin are the major citrus flavanones. Several studies have associated these compounds with pancreatic ß-cell survival through their capacity to reduce oxidative stress, inflammation, and inhibit apoptosis. However, the molecular mechanisms of action of flavanones in pancreatic ß-cells under high-glycemic stress is still largely unknown. Therefore, this study aimed to decipher molecular mechanisms of flavanone metabolites in pancreatic ß-cells treated with high glucose concentration using untargeted shotgun proteomics. We identified 569 proteins differentially expressed in cells exposed to hesperetin 7-glucuronide (H7G) and 265 in cells exposed to 3-(4'-hydroxyphenyl) propanoic acid (PA). Comparison of global proteomic profiles suggest that these metabolites could counteract changes in protein expression induced by high glucose stress. The bioinformatic analyses suggested that H7G and PA modulated the expression of proteins involved in cell adhesion, cell signaling, metabolism, inflammation, and protein processing in endoplasmic reticulum (ER) pathways. Taken together, this study suggests that H7G and PA can modulate the expression of proteins that may prevent dysfunction of pancreatic ß-cells under stress induced by high glucose.

Molecular Characterization of a Stereoselective and Promiscuous Flavanone 3-Hydroxylase from Carthamus tinctorius L.

Flavanone 3-hydroxylases (F3Hs) belong to the 2-oxoglutarate-dependent dioxygenase family and play an important role in plant flavonoid biosynthesis. However, the stereoselective catalytic mechanism and substrate promiscuity of this type of enzyme are not well understood. In this study, we identified and biochemically characterized CtF3H1, an F3H from Carthamus tinctorius, a plant used in traditional Chinese medicine that exhibits high stereoselectivity and substrate promiscuity toward structurally diverse (2S)-flavanones. Isothermal titration calorimetry revealed that CtF3H1 exhibits distinctly different binding behaviors with (2S)-flavanone (2S-naringenin) and (2R)-flavanone (2R-naringenin), and these differences govern its stereoselectivity. An investigation of the structure-activity relationships between the enzyme and its substrates demonstrated that 7-OH and/or 4'-OH are necessary for regio- and stereoselective 3-hydroxylation of (2S)-flavanones. Homology modeling and molecular docking combined with site-directed mutagenesis identified the amino acid residues necessary for hydroxylation. These findings demonstrate the potential versatility of CtF3H1 in regio- and stereohydroxylation and provide molecular insights into the catalytic mechanism of F3H for further enzyme engineering.

Molecular identification of a flavone synthase I/flavanone 3ß-hydroxylase bifunctional enzyme from fern species Psilotum nudum.

The enzyme flavone synthase Is (FNS Is) converts flavanones to flavones, whereas flavanone 3ß-hydroxylases (F3Hs) catalyze the formation of dihydroflavonols, a precursor of flavonols and anthocyanins. Canonical F3Hs have been characterized in seed plants, which are evolutionarily related to liverwort FNS Is. However, as important evolutionary lineages between liverworts and seed plants, ferns FNS Is and F3Hs have not been identified. In the present study, we characterized a bifunctional enzyme PnFNS I/F3H from the fern Psilotum nudum. We found that PnFNS I/F3H catalyzed the conversion of naringenin to apigenin and dihydrokaempferol. In addition, it catalyzed five different flavanones to generate the corresponding flavones. Site-directed mutagenesis results indicated that the P228-Y228 mutant protein displayed the FNS I/F2H activity (catalyzing naringenin to generate apigenin and 2-hydroxynaringenin), thus having similar functions as liverwort FNS I/F2H. Moreover, the overexpression of PnFNS I/F3H in Arabidopsis tt6 and dmr6 mutants increased the content of flavones and flavonols in plants, further indicating that PnFNS I/F3H showed FNS I and F3H activities in planta. This is the first study to characterize a bifunctional enzyme FNS I/F3H in ferns. The functional transition from FNS I/F3H to FNS I/F2H will be helpful in further elucidating the relationship between angiosperm F3Hs and liverwort FNS Is.

Biometabolites of Citrus unshiu Peel Enhance Intestinal Permeability and Alter Gut Commensal Bacteria.

Flavanones in Citrus unshiu peel (CUP) have been used as therapeutic agents to reduce intestinal inflammation; however, the anti-inflammatory effects of their biometabolites remain ambiguous. Here, we identified aglycone-type flavanones, such as hesperetin and naringenin, which were more abundant in the bioconversion of the CUP than in the ethanol extracts of the CUP. We found that the bioconversion of the CUP induced the canonical nuclear factor-κB pathway via degradation of IκB in Caco-2 cells. To check the immune suppressive capacity of the aglycones of the CUP in vivo, we orally administered the bioconversion of the CUP (500 mg/kg) to mice for two weeks prior to the 3% dextran sulfate sodium treatment. The CUP-pretreated group showed improved body weight loss, colon length shortage, and intestinal inflammation than the control mice. We also found a significant decrease in the population of lamina propria Th17 cells in the CUP-pretreated group following dextran sodium sulfate (DSS) treatment and an increase in mRNA levels of occludin in CUP-treated Caco-2 cells. Pyrosequencing analysis revealed a decreased abundance of Alistipes putredinis and an increased abundance of Muribaculum intestinale in the feces of the CUP-pretreated mice compared to those of the control mice. Overall, these findings suggest that the pre-administration of CUP biometabolites may inhibit the development of murine colitis by modulating intestinal permeability and the gut microbiome.

Protective Roles and Mechanism of Action of Plant Flavonoids against Hepatic Impairment: Recent Developments.

BACKGROUND: The liver is one of the crucial organs in humans and is responsible for the regulation of diverse processes, including metabolism, secretion, and detoxification. Ingestion of alcohol and drugs, environmental pollutants, and irradiation are among the risk factors accountable for oxidative stress in the liver. Plant flavonoids have the potential to protect the liver from damage caused by a variety of chemicals. OBJECTIVE: The present study aims to summarize up-to-date information on the protective roles of plant flavonoids against liver damage. METHODOLOGY: The literature information on the hepatoprotective plant flavonoids was assessed through various databases, which were searched from their respective inception until March 2022. RESULTS: More than 70 flavonoids with hepatoprotective activity against a variety of models of liver toxicity have been reported across the literature. Among these are flavones (19), flavonols (30), flavanones (9), isoflavonoids (5), and biflavonoids (2). Several hepatoprotective mechanisms of action were reported in various classes of flavonoids, including flavones and flavonols (upregulation of the pro-survival ERK1/2 pathway; downregulation of apoptotic proteins, including Bax, Bcl-2, Bax, BH3, caspase-3, 8, 9, etc.), flavanones (downregulation of NF-κB, TNF-α, IL-1 ß, IL-6, iNOS, etc.), isoflavonoids (downregulation of lipogenesis genes, such as SREBP-1c, LXRα, RXRα, PPARγ and ACC2, with concomitant upregulation of genes involved in ß-oxidation, including AMPK and PPARα; inhibition of CYPs, such as CYP1A1, CYP1A2, CYP2B1, CYP2D6, CYP2E1 and CYP3A1/2). CONCLUSION: The present work demonstrated the effectiveness of plant flavonoids against hepatic damage. However, more studies need to be performed regarding the cytotoxicity, pharmacokinetics, and mechanisms of action of these very important cytoprotective flavonoids.