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Citrus aurantium L., sometimes known as "sour orange," is an important Chinese herb with young, immature fruits, or "zhishi," that are high in synephrine. Synephrine is a commonly utilized natural chemical with promising applications in effectively increasing metabolism, heat expenditure, energy level, oxidative fat, and weight loss. However, little is known about the genes and pathways involved in synephrine production during the critical developmental stages of C. aurantium L., which limits the development of the industry. According to this study, the concentration of synephrine gradually decreased as the fruit developed. Transcriptome sequencing was used to examine the DEGs associated with synephrine connections and served as the foundation for creating synephrine-rich C. aurantium L. Comparisons conducted between different developmental stages to obtain DEGs, and the number of DEGs varied from 690 to 3,019. Tyrosine and tryptophan biosynthesis, glycolysis/gluconeogenesis, pentose phosphate pathway, phenylalanine, and tyrosine metabolism were the main KEGG pathways that were substantially enriched. The results showed that 25 genes among these KEGG pathways may be related to synephrine synthesis. The WGCNA and one-way ANOVA analysis adoption variance across the groups suggested that 11 genes might play a crucial role in synephrine synthesis and should therefore be further analyzed. We also selected six DEGs at random and analyzed their expression levels by RT-qPCR, and high repeatability and reliability were demonstrated by our finished RNA-seq study results. These results may be useful in selecting or modifying genes to increase the quantity of synephrine in sour oranges. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To probe int the interactions of pharmacokinetics between flavonoids and synephrine in fructus aurantii immaturus based on ultra performance liquid chromatography-triple quadrupole tandem mass spectrometry (UPLC-MS / MS), so as to provide scientific basis for the introduction of flavonoids as a quality and quantitative control index of fructus aurantii immaturus. METHODS: A total of 24 SD rats were extracted to be randomly divided into six groups ( n = 4), group A was administrated with synephrine + six kinds of categories of flavonoids (neohesperidin, naringin, narirutin, hesperidin, nobiletin and rhoifolin), group B was administrated with synephrine alone, group C was administrated with synephrine + naringin, group D was administrated with synephrine + neohesperidin, group E was administrated with six categories of flavonoids alone, group F was administrated with an equal volume of 0. 9% NaCl solution, all administered by gavage. The plasma was taken at different time points after administration, the contents of naringin, neohesperidin and synephrine in plasma were determined, and DAS 2. 0 software was used to calculate the pharmacokinetic parameters. The blood concentration was determined by using UPLC-MS / MS method. RESULTS: Clearance rate of neohesperidin in group A was (9 337. 88±8 373. 94) L/ (h·kg), significantly higher than (2 558. 22±610. 87) L/ (h·kg) in group E, with statistically significant difference (P<0. 05). The distribution volume of neohesperidin in group A and group D were respectively (2 549. 72±1 381. 42) L / kg and (1 668. 41± 394. 73) L / kg, significantly lower than ( 23 388. 87 ± 6 089. 53) L / kg in group E, with statistically significant differences ( P < 0. 05). The mean detention time of synephrine in group A was ( 2. 50 ± 0. 63) h, in comparison with (1. 62±0. 11) h, (1. 70±0. 17) h and (1. 57±0. 08) h of groups B, C and D, the differences were all statistically significant ( P < 0. 05 ). CONCLUSIONS: Synephrine has great effect on the clearance rate and distribution of neohesperidin, and the flavonoids in fructus aurantii immaturus can prolong the mean detention time of synephrine. [ABSTRACT FROM AUTHOR]

Citrus aurantium L., sometimes known as “sour orange,” is an important Chinese herb with young, immature fruits, or “zhishi,” that are high in synephrine. Synephrine is a commonly utilized natural chemical with promising applications in effectively increasing metabolism, heat expenditure, energy level, oxidative fat, and weight loss. However, little is known about the genes and pathways involved in synephrine production during the critical developmental stages of C. aurantium L., which limits the development of the industry. According to this study, the concentration of synephrine gradually decreased as the fruit developed. Transcriptome sequencing was used to examine the DEGs associated with synephrine connections and served as the foundation for creating synephrine-rich C. aurantium L. Comparisons conducted between different developmental stages to obtain DEGs, and the number of DEGs varied from 690 to 3,019. Tyrosine and tryptophan biosynthesis, glycolysis/gluconeogenesis, pentose phosphate pathway, phenylalanine, and tyrosine metabolism were the main KEGG pathways that were substantially enriched. The results showed that 25 genes among these KEGG pathways may be related to synephrine synthesis. The WGCNA and one-way ANOVA analysis adoption variance across the groups suggested that 11 genes might play a crucial role in synephrine synthesis and should therefore be further analyzed. We also selected six DEGs at random and analyzed their expression levels by RT-qPCR, and high repeatability and reliability were demonstrated by our finished RNA-seq study results. These results may be useful in selecting or modifying genes to increase the quantity of synephrine in sour oranges.

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This review is focused on synephrine, the principal phytochemical found in bitter orange and other medicinal plants and widely used as a dietary supplement for weight loss/body fat reduction. We examine different aspects of synephrine biology, delving into its established and potential molecular targets, as well as its mechanisms of action. We present an overview of the origin, chemical composition, receptors, and pharmacological properties of synephrine, including its anti-inflammatory and anti-cancer activity in various in vitro and animal models. Additionally, we conduct a comparative analysis of the molecular targets and effects of synephrine with those of its metabolite, selective glucocorticoid receptor agonist (SEGRA) Compound A (CpdA), which shares a similar chemical structure with synephrine. SEGRAs, including CpdA, have been extensively studied as glucocorticoid receptor activators that have a better benefit/risk profile than glucocorticoids due to their reduced adverse effects. We discuss the potential of synephrine usage as a template for the synthesis of new generation of non-steroidal SEGRAs. The review also provides insights into the safe pharmacological profile of synephrine. [ABSTRACT FROM AUTHOR]

Introduction and aimsObesity is a multifactorial condition with high health risk, associated with important chronic disorders such as diabetes, dyslipidemia, and cardiovascular dysfunction. Citrus aurantium L. (C. aurantium) is a medicinal plant, and its active component, synephrine, a β-3 adrenergic agonist, can be used for weight loss. We investigated the effects of C. aurantium and synephrine in obese adolescent mice programmed by early postnatal overfeeding.MethodsThree days after birth, male Swiss mice were divided into a small litter (SL) group (3 pups) and a normal litter (NL) group (9 pups). At 30 days old, SL and NL mice were treated with C. aurantium standardized to 6% synephrine, C. aurantium with 30% synephrine, isolated synephrine, or vehicle for 19 days.ResultsThe SL group had a higher body weight than the NL group. Heart rate and blood pressure were not elevated. The SL group had hyperleptinemia and central obesity that were normalized by C. aurantium and synephrine. In brown adipose tissue, the SL group showed a higher lipid droplet sectional area, less nuclei, a reduction in thermogenesis markers related to thermogenesis (UCP-1, PRDM16, PGC-1α and PPARg), and mitochondrial disfunction. C. aurantium and synephrine treatment normalized these parameters.ConclusionOur data indicates that the treatment with C. aurantium and synephrine could be a promising alternative for the control of some obesity dysfunction, such as improvement of brown adipose tissue dysfunction and leptinemia.

Food supplements are a category of products perceived safe and therefore commonly used by different categories of consumers without any particular attention or precaution. However, health risks associated with the consumption of supplements containing undeclared substances cannot be excluded. A variety of analytical methods are used to control supplement quality composition, but usually, these procedures are complex and time-consuming. Here, we report the results of a simple and fast liquid chromatography-tandem mass spectrometry (LC–MS/MS) method, to detect and quantify simultaneously different categories of active molecules, such as biogenic ammines and natural alkaloids that at high doses can produce negative health effect in consumers. Three categories of products intended for body weight loss, energy boosting, and erectile dysfunction treatment, purchased through e-commerce sites and from local supermarkets, were analyzed (n = 91). The caffeine, synephrine, agmatine sulfate, yohimbine, phenethylamine, and icariin were correctly separated and identified with good precision (RSD

Although hyperthermia is described after cocaine intoxication, the two hyperthermic cases discussed were unusual in severity and duration for cocaine alone. Synephrine was found in biological samples of these patients in high concentrations and was suspected to be an adulterant in illicitly obtained drugs. Two patients presented to a tertiary care university hospital within 2 days of each other after recreational drug use with delayed and protracted hyperthermia. Synephrine was later found in high concentrations in biological samples as an unexpected drug adulterant. The first patient's presentation came with delayed recognition of hyperthermia and implementation of aggressive cooling measures; he entered multisystem organ failure with prolonged intensive care unit stay and significant morbidity. The second patient's hyperthermia was recognized promptly, and she received early, aggressive cooling, including deep sedation and ice water submersion. She left against medical advice from the hospital at her baseline 3 days after presentation. Synephrine is a suspected adulterant that may be associated with profound hyperthermia. Early recognition of drug overdose and working knowledge of common adulterants can facilitate early targeted management, such as aggressive cooling measures, which may prevent morbidity and mortality. [ABSTRACT FROM AUTHOR]

The use of pre-workout supplements has become increasingly popular, including the use of supplements containing synephrine. Synephrine might stimulate weight loss and improve sports performance by its proposed adrenergic properties. However, with its increasing popularity, numerous cases of adverse events related to synephrine use have been reported. This study provides a comprehensive overview and analysis of current case reports related to the supplemental use of synephrine. The scientific literature on cases of adverse events related to synephrine intake was collected through August 2021 using Pubmed and Google Scholar and subsequently reviewed and analysed. We obtained 30 case reports describing a total of 35 patients who suffered from medical complaints following use of synephrine-containing supplements. The patients most often presented with chest pain, palpitations, syncope and dizziness. Commonly raised diagnoses were ischaemic heart disease, cardiac arrhythmias and cerebrovascular disease. Five patients were left disabled or remained on medication at last follow-up. We here show an association between the use of pre-workout supplements containing synephrine and adverse events, mainly related to the cardiovascular system. However, we cannot exclude a role of possible confounding factors such as caffeine. Thus, the use of pre-workout supplements containing synephrine may lead to serious adverse health events, and therefore, caution is needed. [ABSTRACT FROM AUTHOR]

With the increasing demand for food foaming, how to enhance the foaming properties of protein has gradually become the research focus. This work studied the effect of synephrine (SY) on foaming properties, structure properties, and physicochemical properties of soybean protein isolate (SPI). When the mass ratio of SY to SPI was 1:2, compared with SPI alone, the foam capacity and foam stability of the SY-SPI complex were significantly enhanced. Optical microscopy and confocal laser scanning microscope showed that the improvement in foaming performance was mainly due to the reduction of bubble size and uniform protein distribution. Circular dichroism spectrum and fluorescence spectra indicated that the hydrogen bond of SPI was destroyed and blue shifted with the addition of SY. What's more, the absolute value of Zeta potential, solubility, and hydrophobicity all increased, while the particle size decreased. As a result of molecular docking, surface hydrogen bonds, Van der Waals forces and hydrophobic interactions are the main driving forces. The addition of SY and SPI improved the specific volume and texture of angel cake. This study shows that SY has the potential to be developed into a new type of blowing agent. • Synephrine improved the foaming properties of soybean protein isolate. • Good foaming capacity was related to viscosity, β-turn, β-sheet, random coil, particle size and hydrophobicity. • Good foaming stability was related to α-helix, random coiling, particle size and hydrophobicity. • Synephrine and soy protein isolate at a mass ratio of 1:2 produced foam with high capacity and stability. [ABSTRACT FROM AUTHOR]

The screen-printed carbon electrode (SPCE) was one step modified with graphene (GN) and UiO-66 composites in nafion solution as a portable sensor (nafion/UiO-66/GN/SPCE) for the detection of synephrine. The used GN and UiO-66 were well-characterized, exhibiting typical structures by scanning electron microscope (SEM) with energy dispersive spectroscopy (EDS), X-ray powder diffraction (XRD), and Fourier transform infrared spectroscopy (FTIR). The nafion/UiO-66/GN/SPCE showed the maximum electrochemical signals for synephrine when comparing fabricated components in the cyclic voltammetric method. It was systematically investigated in modifier composition, modification volumes, pH, scan rate, and quantitative analysis ability. Under optimal conditions, the sensor exhibited a good detection limit (0.04 μmol L−1) for synephrine with a linear range of 0.5 μmol L−1 to 60 μmol L−1 (r2 = 0.995). The nafion/UiO-66/GN/SPCE had adequate reproducibility and stability with relative standard deviations lower than 2.01%. It was also applied to determine synephrine in the extract of Citrus aurantium L. with recoveries between 99.0% and 102.0%. The content of synephrine was in good agreement with that of the HPLC method. Based on its convenience and stability, the proposed nafion/UiO-66/GN/SPCE could be further developed as a portable and rapid detection sensor for natural active compounds in food, agricultural, and pharmaceutical fields.

The present work deals with the vibrational spectroscopic signature of the synephrine molecule and its radical in the gas phase. We have optimized synephrine and synephrine- in the ground state. The optimization of the neutral and de-protonated synephrine has been performed at the B3LYP/6-31++G(d, p) level of theory. The comparison of vibrational frequencies of both the structures has also been made. Most of the vibrational frequencies are in good agreement with the experimental ones. The effect of hydrogen removal from the site of oxygen atom upon geometrical parameters and vibrational frequencies of synephrine has been reported. Subsequently, the different thermodynamical parameters calculated at room temperature for the synephrine and its radical have been discussed. Interestingly, the enthalpy of formation for the synephrine and deprotonated synephrine has been calculated. The NBO analysis has been performed to check the stability of the electronic structure of the radical form of the synephrine molecule. Also, the HOMO-LUMO energy gap infers that synephrine is more reactive in its radical form. [ABSTRACT FROM AUTHOR]

Synephrine, a natural product also known as deoxyepinephrine, exists in Rutaceae plants and is widely distributed in China. In addition to natural sources, synephrine may also be obtained by means of chemical synthesis and genetic engineering methods. In recent years, extensive studies on the biological activity of synephrine have shown that this compound has significant anti-cancer, anti-depressant, anti-Parkinson and other effects. In addition, synephrine exhibits good metabolic regulatory activity and thereby is widely used in weight loss. As a foodborne compound, synephrine has the outstanding features of low toxicity and side effects. In this review, we will elaborate the pharmacological activity and toxic side effects of synephrine, as well as its new applications in the field of biomedicine.

In this study, we designed an artificial pathway composed of tyramine β-hydroxylase (TBH) and phenylethanolamine N -methyltransferase (PNMT) for the biosynthesis of both octopamine and synephrine. As most TBH and PNMT originate from eukaryotic animals and plants, the heterologous expression and identification of functional TBH and PNMT are critical for establishing the pathway in mode microorganisms like Escherichia coli . Here, three TBHs were evaluated, and only TBH from Drosophila melanogaster was successfully expressed in the soluble form in E. coli . Its expression was promoted by evaluating the effects of different expression strategies. The specific enzyme activity of TBH was optimized up to 229.50 U·g -1 , and the first step in the biosynthetic pathway was successfully established and converted tyramine to synthesize 0.10 g/L of octopamine. Furthermore, the second step to produce synephrine from octopamine was developed by screening PNMT, enhancing enzyme activity, and optimizing reaction conditions, with a maximum synephrine production of 2.02 g/L. Finally, based on the optimization of the reaction conditions for each individual reaction, the one-pot cascade reaction for synthesizing synephrine from tyramine was constructed by combining the TBH and PNMT. The synthetic synephrine reached 30.05 mg/L with tyramine as substrate in the two-step enzyme cascade system. With further optimization and amplification, the titers of octopamine and synephrine were increased to 0.45 and 0.20 g/L, respectively, with tyramine as substrate. This work was the first achievement of the biosynthesis of octopamine and synephrine to date.

The ultrasound-assisted aqueous two-phase extraction (UA-ATPE) was first employed to develop an effective technique for simultaneous extraction and preliminary purification of synephrine, naringin, and neohesperidin from Citrus aurantium L. fruitlets. Five types of ethanol/salts of aqueous two-phase system (ATPS) were investigated and then the extraction conditions were further optimized using single-factor experiments and response surface methodology (RSM) via Box–Behnken Design (BBD). The optimum process parameters were concluded as follows: 20.60% (w/w) K2CO3, 27% (w/w) ethanol, solvent-to-material ratio of 45.17:1 (g:g), 120-mesh particle size of fruitlets powder, extraction temperature of 50 °C, extraction time of 30 min, and ultrasonic power of 80 W. Under these conditions, the extraction yields of synephrine, naringin, and neohesperidin were up to 11.17 mg/g, 7.39 mg/g, and 89.27 mg/g, respectively. The yield of neohesperidin extracted by the optimal UA-ATPE was over eight times higher than that extracted by the ultrasound-assisted extraction (UAE) using conventional solvents, and the total yield of target compounds was over twice higher while the impurity content in the extract was much lower. Therefore, UA-ATPE appeared to be a highly effective and promising approach for the extraction of synephrine, naringin, and neohesperidin from C. aurantium fruitlets. [ABSTRACT FROM AUTHOR]

Multi‐ingredient pre‐workout supplements (MIPS) contain Citrus aurantium as a source of bioactive amines such as p‐synephrine, but concerns regarding the authenticity of ingredients in some supplements as well as adverse effects from consumption have been raised. R‐(−)‐Synephrine is the predominant enantiomer in Citrus aurantium extracts while synthetic preparations are often racemic. The aims of this study were to develop a screening method to determine the ratio of synephrine enantiomers in pre‐workout supplements listing Citrus aurantium and to assess the ingredient authenticity by directly comparing their ratios to that found in Citrus aurantium standardised reference materials (SRMs). Quantification of enantiomers in the supplements and SRMs was achieved using a validated, high‐performance liquid chromatography‐single quadrupole mass spectrometry (HPLC‐UV‐QDa) direct enantioseparation method with a cellobiohydrolase (CBH) column (100 × 4.0 mm, 5 μM) and UV detection at 225 nm. Citrus aurantium SRMs were found to have an average enantiomeric ratio of 94:6 (R:S) with total synephrine ranging from 5.7 to 90.2 mg/g. Within the pilot sample of pre‐workout supplements tested, only 42% (5/12) had enantiomeric ratios consistent with the SRMs with total synephrine ranging from 0.03 to 91.2 mg/g. For the remaining supplements, four had racemic ratios of synephrine (0.14 to 5.4 mg/g), two lacked any detectable levels of synephrine, and one had solely the S‐(+)‐enantiomer (0.15 mg/g). These results bring the authenticity of labelling of some pre‐workout supplements into question and highlight the need for more stringent labelling regulations and testing for dietary supplements. [ABSTRACT FROM AUTHOR]

[Display omitted] • Synephrine degrades under photolytic conditions and forms degradation products. • The synephrine major degradation product was identified as 1-methyl-2,3-dihydro-1H-indole-3,6-diol. • The degradation products impact cellular viability and present genotoxic potential. The exponential and indiscriminate use of dietary supplements and weight loss compounds has become a significant public health problem, drawing attention from national and international regulatory agencies. The objective of this study is to provide evidence of how the quality of synephrine varies over time under the influence of UV light. Photodegradation kinetic studies were conducted under UV light to assess the degradation of synephrine. In silico and LC-ESI-MS studies were utilized to identify the major degradation product of synephrine. Additionally, a biological safety study was conducted to evaluate the effects of the photodegraded synephrine in comparison to the intact molecule. In the photodegradation kinetic studies, the drugs exhibited a second-order reaction rate under the specific experimental conditions applied. Key kinetic parameters such as rate constant, half-life (t 1/2), and the time at which 90% of the original drug concentration remained were determined. Based on the in silico studies and confirmation of molecular weight, a comprehensive degradation pathway of the drug and the identification of its major degradation product could be suggested without the need for purification processes or complex isolation techniques. The results revealed the higher reactivity of the side chain amino group, indicating the formation of chroman amino. Additionally, the biological safety study demonstrated that the degraded sample had an impact on cell viability and exhibited genotoxic potential. The quality of synephrine changes over time under the influence of light. These findings emphasize the importance of exercising caution during the handling, manufacturing, and storage of pharmaceutical preparations or food supplements containing synephrine. [ABSTRACT FROM AUTHOR]

A method for quantitative determination of the main active ingredient in traditional Chinese medicine was developed and validated, using liquid-liquid chromatography combined with high performance liquid chromatography, which was successfully applied to synephrine in Fructus Aurantii Immaturus. A biphasic solvent system composed of ethyl acetate - n-butanol - water - trifluoroacetic acid (1:2:3:0.003, v/v) was used to purify the crude extract of the samples by liquid-liquid chromatography. Then, quantitative analysis of synephrine in Fructus Aurantii Immaturus could be well determined by high performance liquid chromatography. Moreover, the collection time and retention time of synephrine could be well predicted using a continuous-stirred tank reactors model. Compared with previous studies, the present method showed advantages of good recovery, good repeatability, high selectivity to target components and simple operation. [ABSTRACT FROM AUTHOR]

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.

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.

Citrus aurantium, commonly known as bitter orange, is a popular dietary supplement ingredient sold worldwide. Bitter orange supplements are sold primarily as weight management and sports performance products and have gained popularity after Ephedra products were banned from the US market. Supplements containing synephrine are reported to exhibit adverse cardiovascular effects especially in the presence of caffeine. In this study, an LC–MS/MS method was established to quantify five natural amines (synephrine, octopamine, tyramine, N‐methyltyramine, and hordenine) and four synthetic phenethylamines (phenylephrine, methylsynephrine, etilefrine, and isopropyloctopamine) in dietary supplements sold in the US. The method was validated and found to have acceptable performance to accurately measure analytes in complex botanical products. The average recoveries from a blank matrix were 88–125% with an RSD of 0.5–7.0%. Fifty‐nine products labeled to contain bitter orange peel, extract, or its amines were purchased and their amine content was measured. Several products were found to contain higher amounts of amines than that expected from a typical bitter orange extract. Of the 23 products that made label claims for synephrine, only 5 products (22%) were within 80–120% of labeled synephrine content. The presence of synthetic amines, methylsynephrine (up to 240 mg/daily serving), and isopropyloctopamine (up to 76 mg/daily serving), whose effects in humans are not known, were detected in six products and one product, respectively. While the use of methylsynephrine and isopropyloctopamine are not permitted in dietary supplements, hordenine, N‐methyltyramine, and octopamine are currently listed on the FDA's Dietary Supplement Ingredient Advisory List. [ABSTRACT FROM AUTHOR]

A high-performance liquid chromatography method employing a diode-array detector and mass spectrometry detector was developed, validated and implemented for determining Synephrine, Caffeine, Clenbuterol, Nandrolone, Testosterone and Methylhexaneamine in Nutritional supplements. The use of Nutritional supplements is widespread. Hazards relating to concentration, composition, individual contaminants, supplements interactions as well as positive doping results among athletes present increasing concerns regarding nutritional supplement consuming. The proposed method was validated according to the International Conference on the Harmonization of the Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) standards. The proposed method observed to be accurate, linear, precise, sensitive, required minimal sample preparation and uncomplicated mobile phase. The implementation of the proposed method on nine commercial supplements shows that inaccurate labeling for some supplements regarding the concentration of the ingredients. [ABSTRACT FROM AUTHOR]

Thermal breakage of alkaloid ingredients was a common problem to which attention should be paid in the application of fruit ingredients separation. In this study, the mathematical models were established to predict the rejection of synephrine from Citrus aurantium L. (Rutaceae). The experiment showed that there was a linear relationship between operation pressure and membrane flux. Meanwhile, under the influence of solution–diffusion effect and the charge effect, the mass transfer coefficient was power functioned with initial concentration. The mathematical model showed that the predicted rejections of synephrine from Citrus aurantium extract were well approximate to real ones, and the lipid‐lowering active ingredient had effectively enriched. The predicted model of nanofiltration separation has a preferable applicability to synephrine and provides references for nanofiltration separation, especially for raw food materials with synephrine. [ABSTRACT FROM AUTHOR]

Purpose: The aim of the work was to analyze the metabolites of the intestinal microbiota from the patients with mild cognitive impairment (MCI) and progressive MCI due to Alzheimer's disease (AD)., Method: Two cohorts were established. The first one included 87 subjects with 30 healthy controls (NC), 22 patients with MCI due to AD, and 35 patients with AD. The second cohort included 87 patients with MCI due to AD, who were followed up for 2 years and finally were divided into progressive MCI due to AD group (P-G) and unprogressive MCI due to AD group (U-G) according their cognitive levels. Fecal samples were collected to all patients at the baseline time point. Differential metabolites were subjected to pathway analysis by MetaboAnalyst., Results: In the first cohort, we found 21 different metabolites among the three groups (AD, MCI, and NC). In the second cohort, we identified 19 differential metabolites between the P-G and U-G groups. By machine learning analysis, we found that seven characteristic metabolites [Erythrodiol, alpha-Curcumene, Synephrine, o-Hydroxylaminobenzoate, 3-Amino-4-hydroxybenzoic acid, 2-Deoxystreptamine, and 9(S] were of characteristic significance for the diagnosis of MCI due to AD, and six metabolites (Indolelactate, Indole-3-acetaldehyde, L-Proline, Perillyl, Mesaconate, and Sphingosine) were the characteristic metabolites of early warning for the progression of MCI due to AD. D-Glucuronic acid was negatively correlated with Apolipoprotein E4 (APOE4). Perillyl alcohol was negatively correlated with all of the five biomarkers [P-tau181, Neurofilament light chain (NF-light), Aβ1-42, Aβ1-40, and glial fibrillary acidic protein (GFAP)], but Indoleacetaldehyde was positively correlated with three biomarkers (P-tau181, Aβ1-42, and GFAP). Three characteristic metabolites (3-Amino-4-hydroxybenzoate, 2-Deoxystreptamine, and p-Synephrine) were positively correlated with Aβ1-42. 2-Deoxystreptamine, 9(S)-HPOT, and Indoleacetaldehyde were positively correlated with GFAP. L-Proline and Indoleacetaldehyde were positively correlated with NF-light., Conclusion: Specific metabolites of intestinal fora can be used as diagnostic and progressive markers for MCI., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Lu, Qin, Zhao, Liu, Qiu, Yang, Song and Yang.)

Acrolein (ACR) is a harmful and active aldehyde produced in processed food that endangers foods safety. We undertook this work to explore the ACR-trapping ability of hesperidin (HES) and synephrine (SYN) from the diet. After comparing their ACR-trapping abilities, the reaction pathways of HES and SNY were analyzed using LC-MS/MS, and two adducts (HES-ACR-1 and SNY-2ACR) were synthesized, and their structures were identified by NMR. Then, we not only evaluated the synergistic trapping effects of HES and SNY on ACR in the model through the Chou-Talalay method but verified it in the processing of roasted duck wings and cookies. Furthermore, based on the quantitative analysis of the ACR-adducts of HES and SNY, we demonstrated that SYN, as a promoter, could greatly improve the ACR-capturing ability of HES by forming more adducts (3-fold). Our findings could serve as a guide for using SNY and HES as new scavengers in food processing., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Introduction and Aims: Obesity is a multifactorial condition with high health risk, associated with important chronic disorders such as diabetes, dyslipidemia, and cardiovascular dysfunction. Citrus aurantium L. ( C. aurantium ) is a medicinal plant, and its active component, synephrine, a β-3 adrenergic agonist, can be used for weight loss. We investigated the effects of C. aurantium and synephrine in obese adolescent mice programmed by early postnatal overfeeding., Methods: Three days after birth, male Swiss mice were divided into a small litter (SL) group (3 pups) and a normal litter (NL) group (9 pups). At 30 days old, SL and NL mice were treated with C. aurantium standardized to 6% synephrine, C. aurantium with 30% synephrine, isolated synephrine, or vehicle for 19 days., Results: The SL group had a higher body weight than the NL group. Heart rate and blood pressure were not elevated. The SL group had hyperleptinemia and central obesity that were normalized by C. aurantium and synephrine. In brown adipose tissue, the SL group showed a higher lipid droplet sectional area, less nuclei, a reduction in thermogenesis markers related to thermogenesis (UCP-1, PRDM16, PGC-1α and PPARg), and mitochondrial disfunction. C. aurantium and synephrine treatment normalized these parameters., Conclusion: Our data indicates that the treatment with C. aurantium and synephrine could be a promising alternative for the control of some obesity dysfunction, such as improvement of brown adipose tissue dysfunction and leptinemia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Guimarães, de Moura, Silva, Lopes, Bertasso, Pietrobon, Quitete, de Oliveira Malafaia, Souza, Lisboa and de Oliveira.)

In this study, we examined the characteristics of flavonoids, courmarins, and synephrine in sudaidai and hetsukadaidai, the sour citrus fruits of local special products. The contents of the compounds in juice and peel of sudaidai (scientific name unclear), hetsukadaidai (unclear), daidai (Citrus aurantium) and natsudaidai (Citrus natsudaidai) were determined using HPLC, and the quantitative values were analyzed using principal component analysis. The characteristics of the compounds in the juice and peel of sudaidai resembled those of daidai, and those of hetsukadaidai were different from those of daidai and natsudaidai, based on the scatter diagrams of the score plots. The scientific name of sudaidai was suggested to be the same as daidai (Citrus aurantium). Auraptene, an antitumor compound, was found in the peel of hetsukadaidai, although it was not found in daidai and occurred at lower content than in natsudaidai. It was abundant in the flavedo (epicarp) of hetsukadaidai. Synephrine, an adrenergic phenethylamine, was found in sudaidai at level comparable with that in daidai, although it was found at lower content in hetsukadaidai than in daidai. The antioxidative activity of the peel and juice of daidai and sudaidai was significantly higher than that of hetsukadaidai and natsudaidai (p<0.05). The activity of the albedo (mesocarp) of hetsukadaidai was significantly higher than other regions of the fruit (p<0.05). The activity was shown to have a positive correlation with the content of the antioxidant neoeriocitrin and the correlation coefficient (R) was high (R>0.9). [ABSTRACT FROM AUTHOR]

Six protoalkaloids in the fruits of 34 Chinese local loose-skin mandarins and 25 sweet oranges were detected simultaneously by strong cation exchange-high performance liquid chromatography with an ultraviolet detector (SCX-HPLC-UV). Linear regression analysis showed satisfactory linearity for all the analytes with the correlation coefficients (R2) higher than 0.9998. The satisfactory recoveries of the six protoalkaloids in pulps at two spiked levels ranged from 82.8 to 93.4% (RSDs, 1.5-6.1%) and those of synephrine in peels ranged from 89.3 to 91.9% (RSDs, 4.8-5.3%). The limits of quantification (LOQs) were 0.2 mg kg−1. The proposed method was used to determinate the protoalkaloids in loose-skin mandarins and sweet oranges to evaluate its feasibility and accuracy. The major alkaloid in the tested samples was synephrine, and the predominant alkaloid was N-methyltyramine, followed by octopamine. The variations in alkaloid components and contents were both largely the same for the tested varieties, verifying that alkaloids in plants are genetically controlled. [ABSTRACT FROM AUTHOR]

The mechanisms of action of Kampo medicines as treatments for allergic rhinitis are unknown. In this study, we aimed to identify novel potential therapeutic agents for allergic rhinitis and to elucidate their underlying mechanisms. Different components of Kampo medicines (crude drugs) were screened for their ability to inhibit the secretion of thymic stromal lymphopoietin (TSLP), a cytokine secreted during allergen exposure. Synephrine (SYN) exhibited the strongest inhibitory effect. In an early-phase allergic reaction, histidine decarboxylase (HDC) and its receptor are activated, leading to the secretion of TSLP. Mucins are thought to be produced as a late-phase reaction. We examined the action of SYN in cultures of human nasal epithelial cells both during mono-stimulation and co-stimulation with activating agents. Based on its inhibition of the histamine H1 receptor and HDC mRNA expression, SYN was assumed to reduce the histamine production. Increased expression of the HDC protein was confirmed in tissues of patients with allergic rhinitis via western blotting. In addition, SYN inhibited TSLP at the mRNA and protein levels and inhibited mucin 5AC mRNA expression. Its inhibitory effects on both early- and late-phase allergic reactions indicate that SYN can serve as a novel therapeutic agent with potential leukotriene antagonist-like activity. [ABSTRACT FROM AUTHOR]

A molecularly imprinted polymer (MIPs) was prepared based on a computer-aided design, which was used to selectively enrich and purify synephrine (SYN) from the extract waste liquid of Citrus aurantium L. The suitable functional monomers, cross-linkers and reaction systems for preparing MIPs were quickly screened with density functional theory (DFT) calculation to effectively avoid the design blindness of molecularly imprinted material. The synephrine molecularly imprinted polymer (SYN-MIPs) with imprinted holes and magnetic properties were prepared with nano Fe 3 O 4 as the core, and the structure, morphology, magnetic property and adsorption behavior were studied and the interaction mechanism of the adsorption process was clarified by DFT calculations. The saturated adsorption of SYN-MIPs for SYN was as high as 47.38–53.68 mg/g within 298 K to 308 K. The adsorption behavior of SYN-MIPs for SYN was well fit for the Freundlich adsorption and the pseudo-second-order kinetic model. It was worth mentioning that SYN-MIPs showed distinguished re-usability and specific recognition. The imprinting factor and selection factor to SYN were 3.13 and 2.43, respectively. The selective enrichment and purification of SYN from the extract waste liquid of Citrus aurantium L. achieved satisfactirily, and the purity of SYN enriched to 93.73% while the concentration of SYN was only 1.73% in the extract waste liquid. The study provides not only an efficient adsorption separation polymer materials but also a practical for the enrichment and purification process of SYN from the extract waste liquid of citrus plants. [Display omitted] • Green fabrication of molecularly imprinted polymers based on computer-aided design. • Suitable functional monomer was quickly screened with DFT calculation. • Adsorption mechanism was elucidated with experiment and DFT calculation cross-fusion. • SYN-MIPs was shown distinguished re-usability and specific recognition. • Selective enrichment and purification of SYN from Citrus aurantium L. was realized. [ABSTRACT FROM AUTHOR]

A reversed-phase liquid chromatographic method was developed for the assay of synephrine in Citrus aurantium dry extract. The chromatographic separation used a C18 (250 × 4.6 mm, 5 µm) column and a mobile phase consisting of acetonitrile: 0.01% orthophosphoric acid (pH 3.0) at a 15:85 ratio, flow rate of 1 mL min-1 and detection at 220 nm. The detector response was linear in the range 15 - 45 mg mL-1. Specificity and stability, indicating suitability of the method, were confirmed using stress conditions (acid and basic hydrolysis, oxidation and photolysis). Intraday precision yielded RSD values of less than 1.77% and interday precision of 2.5%. The average recovery accuracy of the test was 102.03%. The method was validated according to international guidelines and can be used in routine quality control and stability studies of Citrus aurantium preparations. The preliminary stability study showed that synephrine is susceptible to hydrolysis, oxidation and photolysis.

Food supplements are a category of products perceived safe and therefore commonly used by different categories of consumers without any particular attention or precaution. However, health risks associated with the consumption of supplements containing undeclared substances cannot be excluded. A variety of analytical methods are used to control supplement quality composition, but usually, these procedures are complex and time-consuming. Here, we report the results of a simple and fast liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, to detect and quantify simultaneously different categories of active molecules, such as biogenic ammines and natural alkaloids that at high doses can produce negative health effect in consumers. Three categories of products intended for body weight loss, energy boosting, and erectile dysfunction treatment, purchased through e-commerce sites and from local supermarkets, were analyzed (n = 91). The caffeine, synephrine, agmatine sulfate, yohimbine, phenethylamine, and icariin were correctly separated and identified with good precision (RSD < 20%) and recovery (89-109%). The identification and quantification of the analytes in real samples highlighted that the 26% of the samples were not compliant with labeling, confirming that frauds are very common also in the natural supplements market. This LC-MS/MS method could be easily used to test natural supplements in order to check the correct labeling and to protect consumers from potential health risks and food frauds., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

The proto-alkaloid synephrine {SYN; systematic name: 4-[1-hydroxy-2-(methylamino) ethyl]phenol}, C9H13NO2, is found to crystallize as a neutral molecule in the racemate and as a zwitterion in the pure enantiomer, in which the phenolic H atom has been transferred to the amino group. In the racemate crystal, an enantiomeric pair on an inversion centre is weakly linked by alcoholic O-H and N-H groups into an R2 2(10) ring. The trigonal pyramidal amino group is also linked to the phenolic and alcoholic groups to form a C(6) chain. In the enantiopure crystal, the deprotonated phenolic O atom is involved in trifurcated hydrogen bonding to two quaternary ammonium groups and an alcoholic O-H group to form a fused R2 4(11) ring and a C(7) chain. From the results of the crystal structure analysis, thermal analyses and DFT calculations validated from FT-IR spectra, a different tautomer was found in the racemic molecule (RSSYN) versus the enantiopure molecule (R-SYN). [ABSTRACT FROM AUTHOR]

Abstract: To detect and quantify synephrine in feed, an effective analytical method based on quick, easy, cheap, effective, rugged, and safe solid‐phase extraction coupled to ultra high performance liquid chromatography with tandem mass spectrometry was developed with isotopic internal standards. Pretreatment was performed using quick, easy, cheap, effective, rugged, and safe solid‐phase extraction with primary secondary amine and C18 sorbent as sorbents in combination with Oasis MCX column clean‐up to extract and purify feed samples. Tandem mass spectrometry detection in positive ion mode was conducted in positive multiple reaction monitoring mode in addition to the quantitative internal standard method. Two transitions of synephrine at m/z 168.1/150.0 and 168.1/135.0 were selected, and m/z 168.1/135.0 was determined as the quantification ion pair. D9‐Terbutaline was selected as an internal standard, for which m/z 235.1/153.0 was selected as the quantification ion pair. Good linearity was shown for synephrine in the range of 0.5–50 μg/L, and the correlation coefficient exceeded 0.999. The recoveries in three different feed samples at three spiked levels were 81.42–112.08%, and the relative standard deviations were not greater than 14.66%. The method proposed in this study was reliable and highly effective, and its sensitivity, accuracy, and precision are suitable for determining synephrine residues in feed samples. [ABSTRACT FROM AUTHOR]

Background: Certain food ingredients promote thermogenesis and fat loss. Similarly, whey protein improves body composition. Due to this potential synergistic effect, a blend of thermogenic food ingredients containing African mango, citrus fruit extract, Coleus forskohlii, dihydrocapsiate and red pepper was tested alone and in combination with a whey protein supplement for its effects on body composition in sedentary mice during high-fat diet. Objective: The objective of this study was to evaluate the interaction of thermogenic foods on improving body composition during consumption of an unhealthy diet. Materials and Methods: C57BL/6J young adult male mice (n = 12) were placed on a 60% high-fat diet for 4 weeks and subsequently randomly assigned to receive daily dosing by oral gavage of vehicle, the novel blend alone or with whey protein supplement for another 4 weeks. Body composition, thermal imaging of brown adipose tissue (BAT), mitochondrial BAT uncoupling protein 1 (UCP1) and plasma levels of leptin were assessed. Results: Novel blend alone and in combination with protein supplement attenuated body weight gain, fat, and increased surface BAT temperature in comparison to vehicle control and to baseline (P < 0.5). The combination of novel blend and whey protein supplement also significantly increased UCP1 protein expression in BAT mitochondria in comparison to vehicle control and novel blend alone (P < 0.5). Conclusions: These data indicate that this novel blend stimulates thermogenesis and attenuates the gain in body weight and fat in response to high-fat diet in mice and these effects were improved when administered in combination with whey protein supplement. [ABSTRACT FROM AUTHOR]

Citrus contain various flavonoids and alkaloids that have multiple biological activities. It is known that the immature Citrus contains larger amounts of bioactive components, than do the mature plants. Although Citrus flavonoids are well known for their biological activities, Citrus alkaloids have not previously been assessed. In this study, we identified synephrine alkaloids as an active compound from immature Citrus unshiu, and investigated the effect of synephrine on eotaxin-1 expression. Eotaxin-1 is a potent chemoattractant for eosinophils, and a critical mediator, during the development of eosinophilic inflammation. We found that synephrine significantly inhibited IL-4-induced eotaxin-1 expression. This synephrine effect was mediated through the inhibition of STAT6 phosphorylation in JAK/STAT signaling. We also found that eosinophil recruitment induced by eotaxin-1 overexpression was inhibited by synephrine. Taken together, these findings indicate that inhibiting IL-4-induced eotaxin-1 expression by synephrine occurs primarily through the suppression of eosinophil recruitment, which is mediated by inhibiting STAT6 phosphorylation.

A single herb can contain multiple constituents with diverse bioactivities. We found that the extract of Citrus unshiu peel (CUP), induced abnormal vasoconstriction responses on the freshly isolated rat aortic rings in vitro. CUP stimulated the vasoconstriction alone, and it suppressed the phenylephrine-stimulated vasoconstriction. We studied the reasons behind this abnormal vasoconstriction pattern. Major constituents of CUP were determined and evaluated for their vaso-activities. Notably, synephrine, a contractile agonist, and nobiletin, newly identified to have anti-contractile activity co-existed in CUP. Synephrine and nobiletin competitively blocked or activated the same contractile targets resulting in contradicting and abnormal vasoconstriction responses. Accordingly, the vasoconstriction pattern varies significantly depending on the relative contents of synephrine and nobiletin in CUP. Interestingly, this response pattern could be observed with another plant extract, Acorus gramineus Sol. Collectively, we demonstrated that active ingredients with contradicting bioactivities could co-exist in a single plant extract, interact and produce abnormal response patterns in bioassay, which would give an important insight into the interpretation of unusual activity patterns induced by plant extracts.