Neohesperidin Dihydrochalcone Ameliorates Experimental Colitis via Anti-Inflammatory, Antioxidative, and Antiapoptosis Effects.

Neohesperidin dihydrochalcone (NHDC) is a citrus-originated, seminatural sweetener. There is no investigation concerning the effect of NHDC on ulcerative colitis. The purpose of this study was to determine the therapeutic and protective effects of NHDC in Wistar Albino rats. NHDC was given for 7 days after or before colitis induction. The results showed that NHDC significantly reduced the interleukin-6 (IL-6), interleukin-10 (IL-10), transforming growth factor-ß1 (TGF-ß1), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) levels. Catalase levels did not show a significant difference between the groups. NHDC provided a remarkable decrease in the expression levels of cyclooxygenase-2 (COX-2), myeloperoxidase (MPO), malondialdehyde (MDA), 8-hydroxy-2'-deoxyguanosine (8-OHdG), and nuclear factor kappa B (NF-κB). Total antioxidant status (TAS) levels were significantly elevated in NHDC treatment groups, while total oxidant status (TOS) and oxidative stress index (OSI) levels were significantly decreased. NHDC provided remarkable improvement in histological symptoms such as epithelial erosion, edema, mucosal necrosis, inflammatory cell infiltration, and hemorrhage. Also, caspase-3 expression levels were statistically decreased in NHDC treatment groups. The results indicated that NHDC might be a protection or alternative treatment for ulcerative colitis.

Preparation of CoFe@C composite modified electrode for neohesperidin dihydrochalcone sensing and its application in Chinese medicine.

CoFe@C was first prepared by calcining the precursor of CoFe-metal-organic framework-74 (CoFe-MOF-74), then an electrochemical sensor for the determination of neohesperidin dihydrochalcone (NHDC) was constructed, which was stemmed from the novel CoFe@C/Nafion composite film modified glassy carbon electrode (GCE). The CoFe@C/Nafion composite was verified by field-emission scanning electron microscopy (FE-SEM) and transmission electron microscopy (TEM). Electrochemical impedance spectroscopy (EIS) was used to evaluate its electrical properties as a modified material for an electrochemical sensor. Compared with CoFe-MOF-74 precursor modified electrode, CoFe@C/Nafion electrode exhibited a great synergic catalytic effect and extremely increased the oxidation peak signal of NHDC. The effects of various experimental conditions on the oxidation of NHDC were investigated and the calibration plot was tested. The results bespoken that CoFe@C/Nafion GCE has good reproducibility and anti-interference under the optimal experimental conditions. In addition, the differential pulse current response of NHDC was linear with its concentration within the range 0.08 ~ 20 µmol/L, and the linear regression coefficient was 0.9957. The detection limit was as low as 14.2 nmol/L (S/N = 3). In order to further verify the feasibility of the method, it was successfully used to determine the content of NHDC in Chinese medicine, with a satisfactory result, good in accordance with that of high performance liquid chromatography (HPLC).

A Pharmacological perspective on the temporal properties of sweeteners.

Several non-caloric sweeteners exhibit a delay in sweetness onset and a sweetness linger after sampling. These temporal properties are thought to be the result of non-specific interactions with cell membranes and proteins in the oral cavity. Data and analysis presented in this report also support the potential involvement of receptor affinity and binding kinetics to this phenomenon. In general, affected sweeteners exhibit distinctly higher binding affinity compared to carbohydrate sweeteners, which do not have temporal issues. In addition, binding kinetic simulations illustrate much slower receptor binding association and dissociation kinetics for a set of non-caloric sweeteners presenting temporal issues, in comparison to carbohydrate sweeteners. So, the higher affinity of some non-caloric sweeteners, dictating lower use levels, and affecting binding kinetics, could contribute to their delay and linger in sweetness perception. Simple pharmacology principles could explain, at least in part, some of the temporal issues of sweeteners.

Scavenging Glyoxal and Methylglyoxal by Synephrine and Neohesperidin from Flowers of Citrus aurantium L. var. amara Engl. in Mice and Humans.

There is considerable research evidence that α-dicarbonyl compounds, including glyoxal (GO) and methylglyoxal (MGO), are closely related to many chronic diseases. In this work, after comparison of the capture capacity, reaction pathway, and reaction rate of synephrine (SYN) and neohesperidin (NEO) on GO/MGO in vitro, experimental mice were administrated with SYN and NEO alone and in combination. Quantitative data from UHPLC-QQQ-MS/MS revealed that SYN/NEO/HES (hesperetin, the metabolite of NEO) could form the GO/MGO-adducts in mice (except SYN-MGO), and the levels of GO/MGO-adducts in mouse urine and fecal samples were dose-dependent. Moreover, SYN and NEO had a synergistic scavenging effect on GO in vivo by promoting each other to form more GO adducts, while SYN could promote NEO to form more MGO-adducts, although it could not form MGO-adducts. Additionally, human experiments showed that the GO/MGO-adducts of SYN/NEO/HES found in mice were also detected in human urine and fecal samples after drinking flowers of Citrus aurantium L. var. amara Engl. (FCAVA) tea using UHPLC-QTOF-MS/MS. These findings provide a novel strategy to reduce endogenous GO/MGO via the consumption of dietary FCAVA rich in SYN and NEO.

Scavenging Glyoxal and Methylglyoxal by Synephrine Alone or in Combination with Neohesperidin at High Temperatures.

α-Dicarbonyl compounds, such as glyoxal (GO) and methylglyoxal (MGO), are a series of chemical hazards that exist in vivo and in vitro, posing a threat to human health. We aimed to explore the scavenging effects on GO/MGO by synephrine (SYN) alone or in combination with neohesperidin (NEO). First, through LC-MS/MS, we confirmed that both SYN and NEO could effectively remove GO and form GO adducts, while NEO could also clear MGO by forming MGO adducts, and its ability to clear MGO was stronger than that of GO. Second, a synergistic inhibitory effect on GO was found when SYN and NEO were used in combination by using the Chou-Talalay method; on the other hand, SYN could promote NEO to clear more MGO, although SYN could not capture MGO. Third, after synthesizing four GO/MGO-adducts (SYN-GO-1, SYN-GO-3, NEO-GO-7, and NEO-MGO-2) and identifying their structure through NMR, strict correlations between the GO/MGO-adducts and the GO/MGO-clearance rate were found when using SYN and NEO alone or in combination. Furthermore, it was inferred that the synergistic effect between SYN and NEO stems from their mutual promotion in capturing more GO by the quantitative analysis of the adducts in the combined model. Finally, a study was conducted on flowers of Citrus aurantium L. var. amara Engl. (FCAVA, an edible tea) rich in SYN and NEO, which could serve as an effective GO and MGO scavenger in the presence of both GO and MGO. Therefore, our study provided well-defined evidence that SYN and NEO, alone or in combination, could efficiently scavenge GO/MGO at high temperatures, whether in the pure form or located in FCAVA.

A combination of rebaudioside A and neohesperidin dihydrochalcone suppressed weight gain by regulating visceral fat and hepatic lipid metabolism in ob/ob mice.

Rebaudioside A (Reb A) and neohesperidin dihydrochalcone (NHDC) are known as intense sweeteners. This study aimed to examine the anti-obesity effects of Reb A and NHDC. C57BL/6 J-ob/ob mice were supplemented with Reb A (50 mg/kg body weight [b.w.]), NHDC (100 mg/kg b.w.), or their combination (COMB) for 4 weeks. COMB-supplemented mice showed significant reduction in b.w. gain, food efficiency ratio, and fat mass. Additionally, mice in the COMB group showed suppressed levels of genes related to adipogenesis, lipogenesis, and lipolysis in the perirenal fat and the levels of hepatic triglyceride, glutamic oxaloacetic transaminase, and glutamic pyruvic transaminase. The lipogenesis and pro-inflammatory gene expressions were also downregulated in the liver, whereas ß-oxidation related genes were upregulated in the COMB group. In addition, mice that received COMB showed distinct gut microbiota structure, enriched in Blautia and Parabacteroides, and depleted in Faecalibaculum and Mucispirillum, in relation to the control group. These results suggest that supplementation with Reb A and NHDC may be an effective treatment for obesity-related metabolic disorders. Supplementary Information: The online version contains supplementary material available at 10.1007/s10068-023-01391-1.

Microbial-Driven Synthesis and Hydrolysis of Neohesperidin Dihydrochalcone: Biotransformation Process and Feasibility Investigation.

A novel yeast-mediated hydrogenation was developed for the synthesis of neohesperidin dihydrochalcone (NHDC) in high yields (over 83%). Moreover, whole-cell catalytic hydrolysis was also designed to hydrolyze NHDC into potential sweeteners, hesperetin dihydrochalcone-7-O-glucoside (HDC-G) and hesperetin dihydrochalcone (HDC). The biohydrogenation was further combined with whole-cell hydrolysis to achieve a one-pot two-step biosynthesis, utilizing yeast to hydrogenate C═C in the structure, while Aspergillus niger cells hydrolyze glycosides. The conversion of NHDC and the proportion of hydrolysis products could be controlled by adjusting the catalysts, the components of the reaction system, and the addition of glucose. Furthermore, yeast-mediated biotransformation demonstrated superior reaction stability and enhanced safety and employed more cost-effective catalysts compared to the traditional chemical hydrogenation of NHDC synthesis. This research not only provides a new route for NHDC production but also offers a safe and flexible one-pot cascade biosynthetic platform for the production of high-value compounds from citrus processing wastes.

Modeling the structure of the transmembrane domain of T1R3, a subunit of the sweet taste receptor, with neohesperidin dihydrochalcone using molecular dynamics simulation.

Neohesperidin dihydrochalcone (NHDC) is a sweetener, which interacts with the transmembrane domain (TMD) of the T1R3 subunit of the human sweet taste receptor. Although NHDC and a sweet taste inhibitor lactisole share similar structural motifs, they have opposite effects on the receptor. This study involved the creation of an NHDC-docked model of T1R3 TMD through mutational analyses followed by in silico simulations. When certain NHDC derivatives were docked to the model, His7345.44 was demonstrated to play a crucial role in activating T1R3 TMD. The NHDC-docked model was then compared with a lactisole-docked inactive form, several residues were characterized as important for the recognition of NHDC; however, most of them were distinct from those of lactisole. Residues such as His6413.33 and Gln7947.38 were found to be oriented differently. This study provides useful information that will facilitate the design of sweeteners and inhibitors that interact with T1R3 TMD.

Microwave-Assisted Extraction of Polyphenols from Bitter Orange Industrial Waste and Identification of the Main Compounds.

In this work, the extraction of phenolic compounds from orange waste (OW) obtained after the industrial extraction of neohesperidin from bitter oranges (Seville oranges) was assayed by microwave-assisted extraction (MAE) and Soxhlet extraction (SE). The extraction agents were ethanol and acetone. For SE, aqueous solutions of both extraction agents were used at 50%, 75%, and 100% (v/v). For MAE, a design of experiments was applied to determine the conditions that maximize the extraction yield. The independent variables were temperature (from 20 to 75 °C), process time (between 10 and 20 min), and percentage of extraction agent (v/v) in the extraction solution (50%, 75%, and 100%). Following that, the extracts were analyzed by ultra-high-performance liquid chromatography to identify the main phenolic compounds extracted. Results showed that 50% (v/v) ethanol or acetone was the extraction agent concentration that maximized the extraction yield for both SE and MAE, with the yields of MAE being higher than those of SE. Thus, the highest extraction yields on a dry basis achieved for MAE were 16.7 g/100 OW for 50% acetone, 75 °C, and 15 min, and 20.2 g/100 OW for 50% ethanol, 75 °C, and 10.8 min, respectively. Finally, the main phenolic compounds found in the orange waste were naringin, hesperidin, neohesperidin, and naringenin (i.e., flavonoids).

Preparation of Neohesperidin-Taro Starch Complex as a Novel Approach to Modulate the Physicochemical Properties, Structure and In Vitro Digestibility.

Neohesperidin (NH), a natural flavonoid, exerts multiple actions, such as antioxidant, antiviral, antiallergic, vasoprotective, anticarcinogenic and anti-inflammatory effects, as well as inhibition of tumor progression. In this study, the NH-taro starch complex is prepared, and the effects of NH complexation on the physicochemical properties, structure and in vitro digestibility of taro starch (TS) are investigated. Results showed that NH complexation significantly affected starch gelatinization temperatures and reduced its enthalpy value (ΔH). The addition of NH increased the viscosity and thickening of taro starch, facilitating shearing and thinning. NH binds to TS via hydrogen bonds and promotes the formation of certain crystalline regions in taro starch. SEM images revealed that the surface of NH-TS complexes became looser with the increasing addition of NH. The digestibility results demonstrated that the increase in NH (from 0.1% to 1.1%, weight based on starch) could raise RS (resistant starch) from 21.66% to 27.75% and reduce RDS (rapidly digestible starch) from 33.51% to 26.76% in taro starch. Our work provided a theoretical reference for the NH-taro starch complex's modification of physicochemical properties and in vitro digestibility with potential in food and non-food applications.

Neohesperidin dihydrochalbazone protects against septic acute kidney injury in mice.

BACKGROUND: Neohesperidin dihydrochalbazone (NHDC) shows a range of pharmacological actions, however, in septic acute kidney injury (AKI), the effect of NHDC is little known. PURPOSE: To assess the role of NHDC against AKI and the possible mechanisms. METHODS: In vivo, we used different concentration of NHDC (50, 100, and 200 mg/kg) treated septic AKI model of mice. Moreover, in vitro, in HK-2 cells, a lipopolysaccharide (LPS) induced cell model was treated with 10, 20, and 30 µM NHDC. Next, kidney tissue pathologic change, marker of renal injury, apoptosis, and inflammatory factors were assessed using hematoxylin and eosin staining, enzyme-linked immunosorbent assay, terminal deoxynucleotidyl transferase dUTP nick end labeling, and western blot. HK-2 cell apoptosis and viability were assessed via flow cytometry and cell counting kit-8. In HK-2 cells and tissues, NLRP3, caspase 1, ASC, and P38/ERK 1/2/JNK pathway related protein levels were tested using western blot. RESULTS: NHDC (100 and 200 mg/kg) significantly attenuated kidney injury in caecal ligation and puncture (CLP)-treated mice. In CLP-treated mice, the level of BUN, Scr, KIM-1, and NAGL was reduced by 100 and 200 mg/kg NHDC. Furthermore, 100 and 200 mg/kg NHDC inhibited inflammation by reducing the production of IL-6, TNF-α, and IL-1ß, and inhibited oxidative stress by regulating the change of MDA, SOD, GSH, and CAT. NHDC (100 and 200 mg/kg) inhibited renal cell apoptosis by increasing Bcl2 protein expression and inhibiting Bax and cleaved caspase-3 protein expression. Additionally, NHDC (100 and 200 mg/kg) inhibited the protein levels of phosphorylated (p)-P38, p-JNK, p-ERK 1/2, NLRP3, caspase 1, ASC. In vitro, in LPS-stimulated HK-2 cells, NHDC (20 and 30 µM) increased cell viability, reduced cell apoptosis, restrained inflammation by reducing the content of IL-6, TNF-α, and IL-1ß, and inhibited the protein expression of caspase 1, NLRP3, ASC, p-P38, p-JNK, and p-ERK1/2. Importantly, the promotive effect of NHDC on HK-2 cell viability was reversed by DHR (an activator of P38 MAPK signaling pathway), and DHR reversed the inhibitive effects of NHDC on HK-2 cell apoptosis and inflammation. CONCLUSION: For the first time, NHDC was found to inhibit oxidative stress, inflammation, and apoptosis in AKI model, which was related to the inhibition of P38 MAPK pathways. Our findings provided the theoretical basis for NHDC on the prevention of AKI.

Effect of Citrus Flavanones on Diabetes: A Systematic Review.

BACKGROUND: Fruits and vegetables play a significant role in the health and nutrition of human beings. Flavanones being the major class of flavonoids are the main phytochemicals in citrus fruits having several favorable effects, particularly in preventing diabetes. OBJECTIVE: The purpose of this systematic review was to discuss the anti-diabetic potential of citrus flavanones based on in vivo studies. METHODS: A search of Google Scholar, PubMed, NCBI, Research Gate, Science Direct, HEC Digital Library databases for articles that have been published since 2010 was conducted using the keywords citrus, flavanones, and diabetes. RESULTS: A total of 10 articles were identified, in which it was reported that 5 flavanones have antidiabetic effects. These flavanones have many benefits, such as they help in glycemic control, regulate the biomarkers of lipid profile, renal function, and modulate the signaling pathways that increase insulin sensitivity and uptake of glucose, thus are responsible for preventing diabetes and complications related to it. CONCLUSION: Therefore, citrus flavanones are the candidates having promising anti-diabetic potential but their effect needs to be verified through human studies.

Neohesperidin Alleviates the Neuropathic Pain Behavior of Rats by Downregulating the P2X4 Receptor.

Neuropathic pain (NP) is a type of chronic pain affecting 6-8% of human health as no effective drug exists. The purinergic 2X4 receptor (P2X4R) is involved in NP. Neohesperidin (NH) is a dihydroflavonoside compound, which has anti-inflammatory and antioxidative properties. This study aimed to investigate whether NH has an effect on P2X4R-mediated NP induced by chronic constriction injury (CCI) of the sciatic nerve in rats. In this study, the CCI rat model was established to observe the changes of pain behaviors, P2X4R, and satellite glial cells (SGCs) activation in dorsal root ganglion (DRG) after NH treatment by using RT-PCR, immunofluorescence double labeling and Western blotting. Our results showed CCI rats had mechanical and thermal hyperalgesia with an increased level of P2X4R. Furthermore, SGCs were activated as indicated by increased expression of glial fibrillary acidic protein and increased tumor necrosis factor-alpha receptor 1and interleukin-1ß. In addition, phosphorylated extracellular regulated protein kinases and interferon regulatory factor 5 in CCI rats increased. After NH treatment in CCI rats, the levels of above protein decreased, and the pain reduced. Overall, NH can markedly alleviate NP by reducing P2X4R expression and SGCs activation in DRG.

Neohesperidin and spike RBD interaction in omicron and its sub-variants: In silico, structural and simulation studies.

COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged first around December 2019 in the city of Wuhan, China. Since then, several variants of the virus have emerged with different biological properties. This pandemic has so far led to widespread infection cycles with millions of fatalities and infections globally. In the recent cycle, a new variant omicron and its three sub-variants BA.1, BA.2 and BA.3 have emerged which seems to evade host immune defences and have brisk infection rate. Particularly, BA.2 variant has shown high transmission rate over BA.1 strain in different countries including India. In the present study, we have evaluated a set of eighty drugs/compounds using in silico docking calculations in omicron and its variants. These molecules were reported previously against SARS-CoV-2. Our docking and simulation analyses suggest differences in affinity of these compounds in omicron and BA.2 compared to SARS-CoV-2. These studies show that neohesperidin, a natural flavonoid found in Citrus aurantium makes a stable interaction with spike receptor domain of omicron and BA.2 compared to other variants. Free energy binding analyses further validates that neohesperidin forms a stable complex with spike RBD in omicron and BA.2 with a binding energy of -237.9 ± 18.7 kJ/mol and -164.1 ± 17.5 kJ/mol respectively. Key residual differences in the RBD interface of these variants form the basis for differential interaction affinities with neohesperidin as drug binding site overlaps with RBD-human ACE2 interface. These data might be useful for the design and development of novel scaffolds and pharmacophores to develop specific therapeutic strategies against these novel variants.

Recent advances in the biosynthesis, bioavailability, toxicology, pharmacology, and controlled release of citrus neohesperidin.

Neohesperidin (hesperetin 7-O-neohesperidoside), a well-known flavanone glycoside widely found in citrus fruits, exhibits a variety of biological activities, with potential applications ranging from food ingredients to therapeutics. The purpose of this manuscript is to provide a comprehensive overview of the chemical, biosynthesis, and pharmacokinetics profiles of neohesperidin, as well as the therapeutic effects and mechanisms of neohesperidin against potential diseases. This literature review covers a wide range of pharmacological responses elicited by Neohesperidin, including neuroprotective, anti-inflammatory, antidiabetic, antimicrobial, and anticancer activities, with a focus on the mechanisms of those pharmacological responses. Additionally, the mechanistic pathways underlying the compound's osteoporosis, antiulcer, cardioprotective, and hepatoprotective effects have been outlined. This review includes detailed illustrations of the biosynthesis, biopharmacokinetics, toxicology, and controlled release of neohesperidine. Neohesperidin demonstrated a broad range of therapeutic and biological activities in the treatment of a variety of complex disorders, including neurodegenerative, hepato-cardiac, cancer, diabetes, obesity, infectious, allergic, and inflammatory diseases. Neohesperidin is a promising therapeutic candidate for the management of various etiologically complex diseases. However, further in vivo and in vitro studies on mechanistic potential are required before clinical trials to confirm the safety, bioavailability, and toxicity profiles of neohesperidin.

Selection of bionic Co-former improves the dissolution of Neohesperidin via Co-amorphous solid dispersion with Naringin.

The co-amorphous solid dispersion (c-ASD) is a useful method to enhance water solubility of poorly soluble drugs. The objective of this study was to improve the dissolution of Neohesperidin (NE) via binary c-ASD which, to the best of our knowledge, has not yet been reported. Since NE and Naringin (NA) co-exist abundantly in Chinese herbal medicine Fructus Aurantii Immaturus, it was hypothesised that NA served as a co-former of NE-NA c-ASD to improve the dissolution profile of NE. Hence, NA was selected to prepare c-ASD with NE at a weight ratio of 4:10, 10:10, 10:4 by lyophilisation. They were characterised according to thermal properties, molecular interactions, dissolution properties and physical stability. We found that the 10:10 ratio was the most potent in enhancing the dissolution behaviour of NE; whereby NE and NA are highly synchronous in pair-wise solvation process. A molecular mixture was achieved through the intermolecular H-bond and pi-pi stacking force formed between NE and NA and was stable for 7 -months. We concluded that the NE-NA co-amorphous binary system is a promising strategy to improve the dissolution behaviour and stabilise the amorphous state of NE. Bionic co-former selection may be an innovative and effective way to accurately determine the appropriate co-former of poorly water soluble substances.

The Aurantii Fructus Immaturus flavonoid extract alleviates inflammation and modulate gut microbiota in DSS-induced colitis mice.

Inflammatory bowel disease (IBD) is a chronic, relapsing immune-mediated disease that always leads to a progressive loss of intestinal function. Therefore, it is important to find potential therapeutic drugs. This study was conducted to elucidate the effect of Aurantii Fructus immaturus flavonoid extract (AFI, 8% neohesperidin, 10% naringin) on DSS-induced intestinal inflammation and the gut microbiome. To explore the mechanism of action by which AFI protects against intestinal inflammation, a total of 50 mice were randomly divided into 5 groups [CG (control group), MG (model group), AFI low dose, AFI middle dose, and AFI high dose] and received 2.5% DSS for 7 days. Then, mice in the AFI groups were orally administered different doses of AFI for 16 days. The results showed that, compared with the MG group, the food intake and body weight were increased in the AFI groups, but the water intake was lower. Additionally, AFI significantly alleviated DSS-induced colitis symptoms, including disease activity index (DAI), and colon pathological damage. The levels of IL-6, IL-1ß and TNF-α in serum and colon tissue were significantly decreased. The diversity and abundance of the intestinal microbiota in the AFI group were decreased. The relative abundance of Bacteroidota was increased, and the relative abundance of Firmicutes was decreased. AFI plays an important role in alleviating DSS-induced intestinal inflammation and regulating Oscillospira, Prevotellaceae and Lachnospiraceae in the intestine at low, medium and high doses, respectively. This report is a pioneer in the assessment of AFI. This study not only demonstrated the anti-inflammatory activity of AFI but also identified the microbiota regulated by different concentrations of AFI.

The SIRT2 Pathway Is Involved in the Antiproliferative Effect of Flavanones in Human Leukemia Monocytic THP-1 Cells.

Acute myeloid leukemia (AML) represents the most alarming hematological disease for adults. Several genetic modifications are known to be pivotal in AML; however, SIRT2 over-expression has attracted the scientific community's attention as an unfavorable prognostic marker. The plant kingdom is a treasure trove of bioactive principles, with flavonoids standing out among the others. On this line, the aim of this study was to investigate the anti-leukemic properties of the main flavanones of Citrus spp., exploring the potential implication of SIRT2. Naringenin (NAR), hesperetin (HSP), naringin (NRG), and neohesperidin (NHP) inhibited SIRT2 activity in the isolated recombinant enzyme, and more, the combination between NAR and HSP. In monocytic leukemic THP-1 cells, only NAR and HSP induced antiproliferative effects, altering the cell cycle. These effects may be ascribed to SIRT2 inhibition since these flavonoids reduced its gene expression and hampered the deacetylation of p53, known sirtuin substrate, and contextually modulated the expression of the downstream cell cycle regulators p21 and cyclin E1. Additionally, these two flavanones proved to interact with the SIRT2 inhibitory site, as shown by docking simulations. Our results suggest that both NAR and HSP may act as anti-leukemic agents, alone and in combination, via targeting the SIRT2/p53/p21/cyclin E1 pathway, thus encouraging deeper investigations.

A Novel Ethanolic Two-Phase System Based on Deep Eutectic Solvents and Amphiphilic Copolymer for the Extraction of Neohesperidin and Naringin from the Pomelo Peel.

A novel ethanolic two-phase system (ETPS) composed of Pluronic®L-64 (PL 64) and deep eutectic solvents (DESs) was constructed for the separation of two similar flavonoids of naringin (Nar) and neohesperidin (Neo) from the pomelo peel. The selectivity (S) data showed that DES prepared from tetrabutylammonium bromide (N4444Br) and glycerol (Gly) had the optimal distribution efficiency for Nar and Neo standards. A binodal curve of N4444Br-Gly/PL 64/ethanol system fitted to the nonlinear Merchuk relationship showed that the biphasic region was narrow for ETPS. The influences of the mass ratio of DESs and PL 64, DES concentration, PL 64 concentration, molar ratio of DESs, temperature, phosphate buffer solution, and ethanolic pH were studied in single-factor experiments. Under the optimal conditions, the maximum extraction efficiency (ENar = 68.32%, ENeo = 86.09%), partition coefficient (KNar = 6.66, KNeo = 19.13), and S (2.88) were obtained in the DESs-rich (bottom) phase. N4444Br-Gly, Nar, and Neo with recovery yields of 78.12%, 66.61%, and 68.03%, respectively, had been recovered using D101 macroporous resin. This proposed ETPS is efficient and environmentally friendly and is expected to avail meaningful references for the separation of natural products with similar structures.

Individual Sweet Taste Perception Influences Salivary Characteristics After Orosensory Stimulation With Sucrose and Noncaloric Sweeteners.

Emerging evidence points to a major role of salivary flow and viscoelastic properties in taste perception and mouthfeel. It has been proposed that sweet-tasting compounds influence salivary characteristics. However, whether perceived differences in the sensory properties of structurally diverse sweet-tasting compounds contribute to salivary flow and saliva viscoelasticity as part of mouthfeel and overall sweet taste perception remains to be clarified. In this study, we hypothesized that the sensory diversity of sweeteners would differentially change salivary characteristics in response to oral sweet taste stimulation. Therefore, we investigated salivary flow and saliva viscoelasticity from 21 healthy test subjects after orosensory stimulation with sucrose, rebaudioside M (RebM), sucralose, and neohesperidin dihydrochalcone (NHDC) in a crossover design and considered the basal level of selected influencing factors, including the basal oral microbiome. All test compounds enhanced the salivary flow rate by up to 1.51 ± 0.12 g/min for RebM compared to 1.10 ± 0.09 g/min for water within the 1st min after stimulation. The increase in flow rate was moderately correlated with the individually perceived sweet taste (r = 0.3, p < 0.01) but did not differ between the test compounds. The complex viscosity of saliva was not affected by the test compounds, but the analysis of covariance showed that it was associated (p < 0.05) with mucin 5B (Muc5B) concentration. The oral microbiome was of typical composition and diversity but was strongly individual-dependent (permutational analysis of variance (PERMANOVA): R 2 = 0.76, p < 0.001) and was not associated with changes in salivary characteristics. In conclusion, this study indicates an impact of individual sweet taste impressions on the flow rate without measurable changes in the complex viscosity of saliva, which may contribute to the overall taste perception and mouthfeel of sweet-tasting compounds.