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.

Empowering Naringin's Anti-Inflammatory Effects through Nanoencapsulation.

Abundant in citrus fruits, naringin (NAR) is a flavonoid that has a wide spectrum of beneficial health effects, including its anti-inflammatory activity. However, its use in the clinic is limited due to extensive phase I and II first-pass metabolism, which limits its bioavailability. Thus, lipid nanoparticles (LNPs) were used to protect and concentrate NAR in inflamed issues, to enhance its anti-inflammatory effects. To target LNPs to the CD44 receptor, overexpressed in activated macrophages, functionalization with hyaluronic acid (HA) was performed. The formulation with NAR and HA on the surface (NAR@NPsHA) has a size below 200 nm, a polydispersity around 0.245, a loading capacity of nearly 10%, and a zeta potential of about 10 mV. In vitro studies show the controlled release of NAR along the gastrointestinal tract, high cytocompatibility (L929 and THP-1 cell lines), and low hemolytic activity. It was also shown that the developed LNPs can regulate inflammatory mediators. In fact, NAR@NPsHA were able to decrease TNF-α and CCL-3 markers expression by 80 and 90% and manage to inhibit the effects of LPS by around 66% for IL-1ß and around 45% for IL-6. Overall, the developed LNPs may represent an efficient drug delivery system with an enhanced anti-inflammatory effect.

Interaction of selected alkoxy naringenin oximes with model and bacterial membranes.

Naringenin is a flavonoid found in many fruits and herbs, most notably in grapefruits. In recent years, this compound and its derivatives have been of great interest due to their high biological activity, including fungicidal and bactericidal effects, also in relation to multidrug-resistant bacteria. Membrane interactions of naringenin oxime (NO) and its 7-O-alkyl (7-alkoxy) derivatives, such as methyl (7MENO), ethyl (7ETNO), isopropyl (7IPNO), n-butyl (7BUNO) and n-pentyl (7PENO) were studied. Thermotropic properties of model membranes were investigated via differential scanning calorimetry (DSC), the influence on lipid raft mimicking giant unilamellar vesicles (GUVs) via fluorescence microscopy, and membrane permeability via measuring calcein leakage from liposomes. Molecular calculations supplemented the study. The influence of naringenin oximes on two strains of multidrug resistant bacteria: Staphylococcus aureus KJ and Enterococcus faecalis 37VRE was also investigated. In DSC studies all compounds reduced the temperature and enthalpy of main phase transition and caused disappearing of the pretransition. NO was the least active. The reduction in the area of surface domains in GUVs was observed for NO. Compounds NO and 7BUNO resulted in very low secretion of calcein from liposomes (permeability < 3 %). The highest results were observed for 7MENO (88.4 %) and 7IPNO (78.5 %). When bacterial membrane permeability was investigated all compounds caused significant release of propidium iodide from S. aureus (31.6-87.0 % for concentration 128 µg/mL). In the case of E. faecalis, 7ETNO (75.7 %) and NO (28.8 %) were the most active. The rest of the tested compounds showed less activity (permeability < 13.9 %). The strong evidence was observed that antibacterial activity of the tested compounds may be associated with their interaction with bacterial membrane.

Optimization of Naringenin-loaded nanoparticles for targeting of Vanin-1, iNOS, and MCP-1 signaling pathway in HFD-induced obesity.

Naringenin, a natural dihydrochalcone flavonoid, exhibits diverse pharmacological properties. This study investigates the hypolipidemic effects of Nar-NPs on obese mice. The characteristics of Nar-NPs, including morphology, particle size, zeta potential, UV-vis, and FT-IR spectra, were examined. The anti-obesity properties of Nar-NPs were evaluated in obese rats, considering LD50, 1/20 LD50, and 1/50 LD50 for treatment preparation. Results indicated that synthesized Nar-NPs were uniform, spherical, and well-dispersed, with a size of 130.06 ± 1.98 nm and with a zeta potential of -25.6 ± 0.8 mV. Nar-NPs exhibited enhancement in the cumulative release of naringenin (56.87 ± 2.45 %) as compared to pure naringenin suspension 87.83 ± 1.84 % in 24 h of the study. The LD50 of Nar-NPs was determined as 412.5 mg/kg.b.w. HFD induced elevated glycemic, oxidative stress, and inflammatory biomarkers while reducing HDL-C, GSH, and superoxide dismutase (SOD) levels. Administration of Nar-NPs significantly mitigated body weight, glucose, insulin, leptin, TC, TG, SREBP1c, pAMPK, PPAR-α, as well as vanin-1, MCP-1, and iNOS mRNA gene expression. Histological investigations supported the biochemical and PCR findings. In a nutshell, the study suggests that the Nar-NPs could serve as a promising and viable pharmacological strategy for the treatment of obesity-related disorders.

Design, synthesis, and evaluation of dual-target inhibitors for the treatment of Alzheimer's disease.

Aß1-42 and acetylcholinesterase (AChE) are two key therapeutic targets for Alzheimer's disease (AD). The purpose of this study is to develop a dual-target inhibitor that inhibits both of these targets by fusing the chemical structure of baicalein and donepezil. Among them, we modified the structure of baicalein to arylcoumarin, synthesized three kinds of structural compounds, and evaluated their biological activities. The results showed that compound 3b had the strongest inhibitory effect on AChE (IC50 = 0.05 ± 0.02 µM), which was better than those of donepezil and baicalein. In addition, compound 3b has a strong ability to inhibit the aggregation of Aß1-42 and protect nerve cells, and it can also penetrate the blood-brain barrier well. Using a zebrafish behavioral analyzer test, it was found that compound 3b can alleviate the behavioral effects of AlCl3-induced zebrafish larval movement retardation, which has a certain guiding significance for simulating the movement disorders of AD patients. In summary, compound 3b is expected to become a multifunctional agent for treating and alleviating the symptoms of AD patients.

The effect of naringenin-phospholipid complex on thermal oxidative stability of soybean oil under heating condition.

Naringenin (NGE), a typical flavanone abundant in citrus fruits, exhibits remarkable antioxidant activities. However, its low solubility in oil restricts its widespread use in inhibiting lipid oxidation. In this study, we present a novel and effective approach to address this limitation by developing a naringenin-phospholipid complex (NGE-PC COM). Comprehensive analytical techniques including Fourier transform infrared (FTIR), differential scanning calorimetry (DSC), and X-ray diffraction (XRD) were employed to confirm the formation of the NGE-PC COM and elucidate the interaction mechanism between NGE and phospholipids molecules. Notably, the oil-solubility of NGE was significantly enhanced by approximately 2700-fold when formulated as a phospholipid complex in soybean oil. The improved oil-solubility of NGE-PC COM enabled effective inhibition of oil thermal oxidation under high temperature conditions. Generally, this investigation proposed a novel and promising strategy for employing flavanones with strong antioxidant activities to enhance the thermal oxidative stability of edible oil during heating processes.

Targeting of mitochondrial fission through natural flavanones elicits anti-myeloma activity.

BACKGROUND: Mitochondrial alterations, often dependent on unbalanced mitochondrial dynamics, feature in the pathobiology of human cancers, including multiple myeloma (MM). Flavanones are natural flavonoids endowed with mitochondrial targeting activities. Herein, we investigated the capability of Hesperetin (Hes) and Naringenin (Nar), two aglycones of Hesperidin and Naringin flavanone glycosides, to selectively target Drp1, a pivotal regulator of mitochondrial dynamics, prompting anti-MM activity. METHODS: Molecular docking analyses were performed on the crystallographic structure of Dynamin-1-like protein (Drp1), using Hes and Nar molecular structures. Cell viability and apoptosis were assessed in MM cell lines, or in co-culture systems with primary bone marrow stromal cells, using Cell Titer Glo and Annexin V-7AAD staining, respectively; clonogenicity was determined using methylcellulose colony assays. Transcriptomic analyses were carried out using the Ion AmpliSeq™ platform; mRNA and protein expression levels were determined by quantitative RT-PCR and western blotting, respectively. Mitochondrial architecture was assessed by transmission electron microscopy. Real time measurement of oxygen consumption was performed by high resolution respirometry in living cells. In vivo anti-tumor activity was evaluated in NOD-SCID mice subcutaneously engrafted with MM cells. RESULTS: Hes and Nar were found to accommodate within the GTPase binding site of Drp1, and to inhibit Drp1 expression and activity, leading to hyperfused mitochondria with reduced OXPHOS. In vitro, Hes and Nar reduced MM clonogenicity and viability, even in the presence of patient-derived bone marrow stromal cells, triggering ER stress and apoptosis. Interestingly, Hes and Nar rewired MM cell metabolism through the down-regulation of master transcriptional activators (SREBF-1, c-MYC) of lipogenesis genes. An extract of Tacle, a Citrus variety rich in Hesperidin and Naringin, was capable to recapitulate the phenotypic and molecular perturbations of each flavanone, triggering anti-MM activity in vivo. CONCLUSION: Hes and Nar inhibit proliferation, rewire the metabolism and induce apoptosis of MM cells via antagonism of the mitochondrial fission driver Drp1. These results provide a framework for the development of natural anti-MM therapeutics targeting aberrant mitochondrial dependencies.

The anti-inflammatory activity of flavonoids and alkaloids from Sophora flavescens alleviates psoriasiform lesions: Prenylation and methoxylation beneficially enhance bioactivity and skin targeting.

The herb Sophora flavescens displays anti-inflammatory activity and can provide a source of antipsoriatic medications. We aimed to evaluate whether S. flavescens extracts and compounds can relieve psoriasiform inflammation. The ability of flavonoids (maackiain, sophoraflavanone G, leachianone A) and alkaloids (matrine, oxymatrine) isolated from S. flavescens to inhibit production of cytokine/chemokines was examined in keratinocytes and macrophages. Physicochemical properties and skin absorption were determined by in silico molecular modeling and the in vitro permeation test (IVPT) to establish the structure-permeation relationship (SPR). The ethyl acetate extract exhibited higher inhibition of interleukin (IL)-6, IL-8, and CXCL1 production in tumor necrosis factor-α-stimulated keratinocytes compared to the ethanol and water extracts. The flavonoids demonstrated higher cytokine/chemokine inhibition than alkaloids, with the prenylated flavanones (sophoraflavanone G, leachianone A) led to the highest suppression. Flavonoids exerted anti-inflammatory effects via the extracellular signal-regulated kinase, p38, activator protein-1, and nuclear factor-κB signaling pathways. In the IVPT, prenylation of the flavanone skeleton significantly promoted skin absorption from 0.01 to 0.22 nmol/mg (sophoraflavanone G vs. eriodictyol). Further methoxylation of a prenylated flavanone (leachianone A) elevated skin absorption to 2.65 nmol/mg. Topical leachianone A reduced the epidermal thickness in IMQ-treated mice by 47%, and inhibited cutaneous scaling and cytokine/chemokine overexpression at comparable levels to a commercial betamethasone product. Thus, prenylation and methoxylation of S. flavescens flavanones may enable the design of novel antipsoriatic agents.

Heterologous Naringenin Production in the Filamentous Fungus Penicillium rubens.

Naringenin is a natural product with several reported bioactivities and is the key intermediate for the entire class of plant flavonoids. The translation of flavonoids into modern medicine as pure compounds is often hampered by their low abundance in nature and their difficult chemical synthesis. Here, we investigated the possibility to use the filamentous fungus Penicillium rubens as a host for flavonoid production. P. rubens is a well-characterized, highly engineered, traditional "workhorse" for the production of ß-lactam antibiotics. We integrated two plant genes encoding enzymes in the naringenin biosynthesis pathway into the genome of the secondary metabolite-deficient P. rubens 4xKO strain. After optimization of the fermentation conditions, we obtained an excellent molar yield of naringenin from fed p-coumaric acid (88%) with a titer of 0.88 mM. Along with product accumulation over 36 h, however, we also observed rapid degradation of naringenin. Based on high-resolution mass spectrometry analysis, we propose a naringenin degradation pathway in P. rubens 4xKO, which is distinct from other flavonoid-converting pathways reported in fungi. Our work demonstrates that P. rubens is a promising host for recombinant flavonoid production, and it represents an interesting starting point for further investigation into the utilization of plant biomass by filamentous fungi.

Stereoselective separation, configuration determination, and quantification of flavanone glycosides in Citrus using chiral HPLC-UV in combination with CD spectra.

Flavanone glucosides, such as naringin and neohesperidin, are present in specific Citrus species and manifest a chiral center at the C-2 position of their flavanone moiety. This study successfully achieved the simultaneous stereoselective separation of the C-2 diastereomers of naringin, neohesperidin and hesperidin, as well as the partial separation of narirutin using a chiral high performance liquid chromatography with ultraviolet detection method with cellulose tris(3,5-dichlorophenylcarbamate) as the stationary phase under normal-phase mode. The mobile phase comprised n-hexane and ethanol (containing 0.25% formic acid) at a proportion of 65 : 35 (v/v) with a flow rate of 0.6 mL min-1. Each single epimer of chiral flavanone glycosides was prepared using chiral semi-preparative chromatography, and the absolute configuration was then characterized by combining the experimental electronic circular dichroism detection and time-dependent density functional theory calculations. The epimer composition of each chiral flavonoid glycoside in Fructus aurantii (Zhiqiao) and Fructus aurantii immaturus (Zhishi) was determined revealing variations among herbs collected from different production regions. Additionally, the epimer composition was found to be related to the harvesting time of the herbs. Considering the safety and efficacy, the existence of epimers of different stereo-configurations should be given more attention in the quality evaluation of natural drugs.

Phytochemical Properties, Extraction, and Pharmacological Benefits of Naringin: A Review.

This review describes the various innovative approaches implemented for naringin extraction as well as the recent developments in the field. Naringin was assessed in terms of its structure, chemical composition, and potential food sources. How naringin works pharmacologically was discussed, including its potential as an anti-diabetic, anti-inflammatory, and hepatoprotective substance. Citrus flavonoids are crucial herbal additives that have a huge spectrum of organic activities. Naringin is a nutritional flavanone glycoside that has been shown to be effective in the treatment of a few chronic disorders associated with ageing. Citrus fruits contain a common flavone glycoside that has specific pharmacological and biological properties. Naringin, a flavone glycoside with a range of intriguing characteristics, is abundant in citrus fruits. Naringin has been shown to have a variety of biological, medicinal, and pharmacological effects. Naringin is hydrolyzed into rhamnose and prunin by the naringinase, which also possesses l-rhamnosidase activity. D-glucosidase subsequently catalyzes the hydrolysis of prunin into glucose and naringenin. Naringin is known for having anti-inflammatory, antioxidant, and tumor-fighting effects. Numerous test animals and cell lines have been used to correlate naringin exposure to asthma, hyperlipidemia, diabetes, cancer, hyperthyroidism, and osteoporosis. This study focused on the many documented actions of naringin in in-vitro and in-vivo experimental and preclinical investigations, as well as its prospective therapeutic advantages, utilizing the information that is presently accessible in the literature. In addition to its pharmacokinetic characteristics, naringin's structure, distribution, different extraction methods, and potential use in the cosmetic, food, pharmaceutical, and animal feed sectors were discussed.

New cyclic C-geranylflavanones isolated from Paulownia fortunei fruits with their anti-proliferative effects on three cancer cell lines.

Seven new C-geranylated flavanones, fortunones F - L (1-7), were isolated from the fresh mature fruits of Paulownia fortunei (Seem.) Hemsl. Their structures were determined by extensive spectroscopic data interpretation (UV, IR, HRMS, NMR, and CD). These new isolated compounds were all with a cyclic side chain modified from the geranyl group. Among them, compounds 1-3 all possessed a dicyclic geranyl modification, which was described firstly for Paulownia C-geranylated flavonoids. All the isolated compounds were subjected to the cytotoxic assay on human lung cancer cell A549, mouse prostate cancer cell RM1 and human bladder cancer cell T24, respectively. Results indicated A549 cell line was more sensitive to C-geranylated flavanones than the other two cancer cell lines and compounds 1, 7 and 8 exhibited potential anti-tumor effects (IC50 ˂ 10 µM). Further research revealed the effective C-geranylated flavanones could exert their anti-proliferative activity on A549 cells by inducing apoptosis and blocking cells in G1 phase.

The Development of Naringin for Use against Bone and Cartilage Disorders.

Bone and cartilage disorders are the leading causes of musculoskeletal disability. There is no absolute cure for all bone and cartilage disorders. The exploration of natural compounds for the potential therapeutic use against bone and cartilage disorders is proving promising. Among these natural chemicals, naringin, a flavanone glycoside, is a potential candidate due to its multifaceted pharmacological activities in bone and cartilage tissues. Emerging studies indicate that naringin may promote osteogenic differentiation, inhibit osteoclast formation, and exhibit protective effects against osteoporosis in vivo and in vitro. Many signaling pathways, such as BMP-2, Wnt/ß-catenin, and VEGF/VEGFR, participate in the biological actions of naringin in mediating the pathological development of osteoporosis. In addition, the anti-inflammatory, anti-oxidative stress, and anti-apoptosis abilities of naringin also demonstrate its beneficial effects against bone and cartilage disorders, including intervertebral disc degeneration, osteoarthritis, rheumatoid arthritis, bone and cartilage tumors, and tibial dyschondroplasia. Naringin exhibits protective effects against bone and cartilage disorders. However, more efforts are still needed due to, at least in part, the uncertainty of drug targets. Further biological and pharmacological evaluations of naringin and its applications in bone tissue engineering, particularly its therapeutic effects against osteoporosis, might result in developing potential drug candidates.

The Combination of Natural Molecules Naringenin, Hesperetin, Curcumin, Polydatin and Quercetin Synergistically Decreases SEMA3E Expression Levels and DPPIV Activity in In Vitro Models of Insulin Resistance.

Type 2 diabetes mellitus (T2DM) is a disease characterized by a prolonged hyperglycemic condition caused by insulin resistance mechanisms in muscle and liver, reduced insulin production by pancreatic ß cells, and a chronic inflammatory state with increased levels of the pro-inflammatory marker semaphorin 3E. Phytochemicals present in several foods have been used to complement oral hypoglycemic drugs for the management of T2DM. Notably, dipeptidyl peptidase IV (DPPIV) inhibitors have demonstrated efficacy in the treatment of T2DM. Our study aimed to investigate, in in vitro models of insulin resistance, the ability of the flavanones naringenin and hesperetin, used alone and in combination with the anti-inflammatory natural molecules curcumin, polydatin, and quercetin, to counteract the insulin resistance and pro-inflammatory molecular mechanisms that are involved in T2DM development. Our results show for the first time that the combination of naringenin, hesperetin, curcumin, polydatin, and quercetin (that mirror the nutraceutical formulation GliceFen®, Mivell, Italy) synergistically decreases expression levels of the pro-inflammatory gene SEMA3E in insulin-resistant HepG2 cells and synergistically decreases DPPIV activity in insulin-resistant Hep3B cells, indicating that the combination of these five phytochemicals is able to inhibit pro-inflammatory and insulin resistance molecular mechanisms and could represent an effective innovative complementary approach to T2DM pharmacological treatment.

Screening ß-glucosidase and α-rhamnosidase for biotransformation of naringin to naringenin by the one-pot enzymatic cascade.

Naringenin is a kind of flavonoid with many kinds of pharmacological activities, and is also a key intermediate metabolite in the flavonoid synthesis pathway. In this study, three α-rhamnosidases from Thermotoga petrophia DSM 13995 (TpeRha), Alternaria sp. L1 (AsRha), and Aspergillus mulundensis (AmRha), and three ß-glucosidases from T. thermarum DSM 5069 T (BGLI-Tt and BGLII-Tt), and A. niger NL-1 (BGL-NL) were cloned, expressed, and characterized. The Kcat/Km value of AmRha for naringin was 2.389 s-1mM-1 which was 796-fold and 26-fold of TpeRha and AsRha. The Kcat/Km value of BGL-NL for prunin was 0.946 s-1mM-1, which was about 4.4-fold and 4.6-fold of BGLI-Tt and BGLII-Tt. According to the catalytic efficiency, expression level, and reaction condition compatibility, AmRha was coupled with BGL-NL to construct a one-pot enzymatic cascade for preparing naringenin from naringin. The effects of the ratio and dosage of the enzyme, the naringin concentration, and reaction conditions on naringenin production were optimized. At a dosage of 200 U/L AmRha and 1000 U/L BGL-NL, a temperature of 50 °C and pH 5.0, 30 mM naringin was transformed into 29.3 mM naringenin for 24 h reaction with a corresponding molar conversion of 97.6%. Therefore, this study provides an efficient enzymatic cascade to meet the large-scale and low cost preparation of naringenin from naringin.

Biotransformation to synthesize the methylated derivatives of baicalein using engineered Escherichia coli.

Oroxylin A and negletein are flavonoid compounds existing in plants, with excellent pharmacological activities such as anti-inflammatory, anti-viropexis, and anti-cancer. Nevertheless, the natural abundance of these compounds in plants is extremely low. Here, a biotransformation pathway was developed in engineered strains to synthesize oroxylin A and negletein from baicalin by using the crude extract of Scutellaria baicalensis as the substrate. Briefly, the precursor baicalin in this crude extract was hydrolyzed by a ß-glucuronidase to form the intermediate baicalein, then O-methyltransferases utilize this intermediate to synthesize oroxylin A and negletein. Through screening strains and carbon sources, regulating intercellular S-adenosyl L-methionine synthesis, and optimizing culture conditions, the titers of the target products increased gradually, with 188.0 mg/L for oroxylin A and 222.7 mg/L for negletein finally. The study illustrates a convenient method to synthesize oroxylin A and negletein from a low-cost substrate, paving the way for the mass acquisition and further bioactivities development and utilization of these rare and high-value compounds.

Chiral Separation, Configuration Confirmation and Bioactivity Determination of the Stereoisomers of Hesperidin and Narirutin in Citrus reticulata Blanco.

Hesperidin and narirutin are a class of flavanone glycosides, which are the main active constituents in Citrus reticulata Blanco. In the present study, a chiral HPLC-UV method with amylose tris(3,5-dimethylphenylcarbamate) as a stationary phase under a normal-phase mode was used to achieve the stereoselective separation of the C-2 diastereomers of hesperidin and narirutin simultaneously. The single epimer was then successfully prepared by applying semi-preparative chromatography, whose absolute configuration (R/S) was characterized by combining the experimental electronic circular dichroism (ECD) detection with time-dependent density functional theory (TDDFT) calculations. The epimer composition of these two chiral flavanone glycosides in Citrus reticulata Blanco was then determined, which was found to be slightly different in the herbs from different production regions. The anti-inflammatory activity of each prepared single epimer was further evaluated, and some differences between one pair of epimers of hesperidin and narirutin were observed, which suggested that the presence of different epimers should be considered in the quality evaluation and control of natural medicine.

Health associations of liver enzymes and inflammatory scores with urinary citrus flavonoid metabolites.

Background: Dietary flavonoid intake is associated with a reduced risk of some cardiometabolic disorders, attributed in part to their claimed anti-inflammatory activity. Our aim was to investigate the potential association between specific urine flavonoid metabolites, liver enzymes, and inflammatory status in individuals with metabolic syndrome (MetS). Methods: In this cross-sectional study, clinical and dietary data from 267 participants, aged 55 to 75 years, participating in the PREDIMED Plus study (PREvención con DIeta MEDiterránea) were analyzed. At the baseline, spot urine samples were collected and seven urinary flavonoid metabolites were quantified using ultra-performance liquid chromatography coupled to triple quadrupole mass spectrometry (UPLC-Q-q-Q MS). Liver enzymes, inflammatory scores, and urinary flavonoid concentrations were inverse normally transformed. Results: Adjusted linear regression models showed an inverse association between urinary citrus flavanone concentrations and gamma-glutamyl transferase (GGT) (all p-values <0.05). Naringenin 7'-GlcUA was significantly associated with a lower aggregate index of systemic inflammation (AISI) (Bper 1SD = -0.14; 95% CI: -0.27 to -0.02; p-value = 0.025) and systemic inflammation index (SII) (Bper 1SD = -0.14; 95% CI: -0.27 to -0.02; p-value = 0.028). To investigate the relationship between flavanone subclasses and GGT levels, we fitted a score of citrus-flavanones, and subjects were stratified into quartiles. The highest values of the citrus-flavanone score (per 1-SD increase) were associated with lower GGT levels (Bper 1SD = -0.41; 95% CI: -0.74 to -0.07), exhibiting a linear trend across quartiles (p-trend = 0.015). Conclusion: This cross-sectional study showed that higher urinary excretion of citrus-flavanone metabolites was associated with lower GGT levels in subjects diagnosed with MetS and obesity.

Regiospecific 3'-C-prenylation of naringenin by Nocardiopsis gilva prenyltransferase.

The prenylation of flavonoids is a main type of structural modification and can endow flavonoids with greater bioactivity and bioavailability. A soluble prenyltransferase (NgFPT) gene from Nocardiopsis gilva was cloned, expressed and characterized in Escherichia coli. The optimal activity of NgFPT was at pH 7.5 and 30 °C. The activity of NgFPT was significantly enhanced by Ca2+, Al3+, and DMSO. NgFPT showed high selectivity to prenylate flavanones at 3'-C to generate 3'-C-prenyl-flavanones. The Kcat and Km of recombinant NgFPT for naringenin were 0.001 s-1 and 0.045 mM, respectively. Then, recombinant strains were reconstructed by introducing NgFPT gene and the isopentenol utilization pathway. Escherichia coli hosts and fusion tags were screened to improve the yield of 3'-C-prenyl-naringenin in vivo, resulting in maximal 3'-C-prenyl-naringenin production at 3.5 mg/L. By optimizing biotransformation conditions and adopting the resting cell bioconversion, maximum 3'-C-prenyl-naringenin production reached 10.3 mg/L with a specific productivity of 0.21 mg/L/h after 48 h incubation. Thus, the article provides a regiospecific soluble prenyltransferase and a method for the production of 3'-C-prenyl-naringenin by metabolic engineering.

Coumaronochromones, flavanones, and isoflavones from the twigs and leaves of Erythrina subumbrans inhibit PTP1B and nitric oxide production.

A chemical investigation of the twigs and leaves of Erythrina subumbrans led to the isolation and structural elucidation of three coumaronochromones, erythrinasubumbrin A and (±)-erythrinasubumbrin B, five prenylated flavanones, (±)-erythrinasubumbrin C and erythrinasubumbrins D-F, and two prenylated isoflavones, (±)-5,4'-dihydroxy-[4,5-cis-4-ethoxy-5-hydroxy-6,6-dimethyl-4,5-dihydropyrano (2,3:7,6)]-isoflavone, in addition to 18 known analogues. Two extra cinnamylphenols previously only known as commercial synthetic products were also isolated and elucidated from a natural source for the first time, and assigned the trivial names erythrinasubumbrins G and H. Their structures were characterized by detailed analysis of spectroscopic data, including HRESIMS and 2D NMR. The absolute configurations of the previously undescribed isolates and the known coumaronochromone lupinol C were determined by specific rotation and electronic circular dichroism (ECD) data. All the isolates were evaluated for their inhibitory activities on protein tyrosine phosphatase 1 B (PTP1B) and nitric oxide (NO) production in lipopolysaccharide (LPS)-induced BV-2 microglial cells as well as their cytotoxicity against the HCT116 cell line. The pair of enantiomers, (+)-5,4'-dihydroxy-[4,5-cis-4-ethoxy-5-hydroxy-6,6-dimethyl-4,5-dihydropyrano (2,3:7,6)]-isoflavone and (-)-5,4'-dihydroxy-[4,5-cis-4-ethoxy-5-hydroxy-6,6-dimethyl-4,5-dihydropyrano (2,3:7,6)]-isoflavone, and the known compounds lupinol C, 4'-O-methyl-8-prenylnaringenin, glepidotin B, shuterin, parvisoflavones A, luteone, lupiwighteone, 2,3-dehydrokievitone, 6,8-diprenylgenistein, angustone A, and 2'-O-demethylbidwillol B exhibited different levels of PTP1B inhibitory activities with IC50 values ranging from 3.21 to 19.17 µM, while erythrinasubumbrin A, (-)-erythrinasubumbrin B, (+)-5,4'-dihydroxy-[4,5-cis-4-ethoxy-5-hydroxy-6,6-dimethyl-4,5-dihydropyrano (2,3:7,6)]-isoflavone, (-)-5,4'-dihydroxy-[4,5-cis-4-ethoxy-5-hydroxy-6,6-dimethyl-4,5-dihydropyrano (2,3:7,6)]-isoflavone, and the known compounds lupinol C, 8-prenylnaringenin, macatrichocarpin A, alpinumisoflavone, and 2'-O-demethylbidwillol B substantially inhibited NO production in BV-2 microglial cells. In addition, 8-prenylnaringenin showed weak cytotoxicity with an IC50 value of 9.13 µM. This is the first report of PTP1B inhibitory activity for a coumaronochromone.