Search Results (124)

Background/Objectives: Chronic diseases linked to obesity represent a major global health challenge. Although pharmaceutical treatments show efficacy, their use is often limited by side effects. Methods: This study investigated the anti-obesity effects of acid-processed Citrus reticulata Blanco peels extract (CRBE) prepared through reflux extraction with 50% ethanol, followed by acid treatment using 3 M hydrogen chloride and neutralization. Results: Following acid treatment, the composition of the extract showed a marked increase in the 5-demethylated forms of polymethoxyflavones, particularly 5-demethylnobiletin (31.86 mg/g) and 5-demethyltangeretin (34.68 mg/g), whereas the concentrations of the typical citrus polymethoxyflavones, nobiletin (14.82 mg/g) and tangeretin (10.61 mg/g), decreased. Using 3T3-L1 preadipocytes, CRBE inhibited adipogenesis concentration dependently, substantially decreasing the expression of adipogenic transcription factors and lipid metabolism-related proteins. In ob/ob mice, oral CRBE substantially suppressed body weight gain without affecting food intake, while normalizing liver function indicators and improving serum lipid profiles by reducing total cholesterol, triglycerides, and low-density lipoprotein. Conclusions: Acid-processed CRBE effectively inhibits adipocyte differentiation and exhibits anti-obesity effects in vivo, offering potential as a natural agent for obesity management with minimal side effects. Full article

The incidence and mortality of diabetes have increased dramatically in recent decades. New strategies to treat diabetes and its complications with minimal side effects are urgently needed. New monomeric molecules extracted from herbs are an alternative medicine that is being explored as candidate drugs for the treatment of diabetes and its complications. Nobiletin, a citrus flavonoid, has recently received increasing attention in scientific research due to its properties in combating diabetes and its complications, while existing research is scattered and unsystematic. This article summarizes recent studies and reviews the potential therapeutic role of nobiletin in preventing and alleviating diabetes and its complications, aiming to provide promising strategies for the clinical management of diabetes and its complications. Full article

Obesity-induced insulin resistance and type 2 diabetes mellitus (T2DM) represent complex systemic disorders marked by chronic inflammation, oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress. These pathophysiological processes disrupt insulin signaling and β-cell function, leading to impaired glucose homeostasis across multiple organs. Conventional therapies often target isolated pathways, overlooking the intricate molecular crosstalk and organelle-level disturbances driving disease progression. Citrus-derived polyphenols—including hesperidin, naringenin, nobiletin, and tangeretin—have emerged as promising agents capable of orchestrating a multi-targeted “metabolic reprogramming.” These compounds modulate key signaling pathways, including AMPK, PI3K/Akt, NF-κB, and Nrf2, thereby enhancing insulin sensitivity, reducing pro-inflammatory cytokine expression, and restoring redox balance. Furthermore, they improve mitochondrial biogenesis, stabilize membrane potential, and alleviate ER stress by modulating the unfolded protein response (UPR), thus supporting cellular energy homeostasis and protein folding capacity. Evidence from preclinical studies and select clinical trials suggests that citrus polyphenols can significantly improve glycemic control, reduce oxidative and inflammatory markers, and preserve β-cell function. Their pleiotropic actions across molecular and organ-level targets position them as integrative metabolic modulators. This review presents a systems-level synthesis of how citrus polyphenols rewire metabolic signaling networks and organelle resilience, offering a holistic therapeutic strategy to mitigate the root causes of obesity-induced insulin resistance. Full article

Mandarin peel is a valuable but underutilized source of numerous bioactive compounds. The main focus of this work was to develop an integrated two-step process for the subsequent extraction of polyphenols and carotenoids (step 1) and pectin (step 2) from mandarin peel by microwave-assisted extraction (MAE), using only green solvents. This represents a novel, scale-up-suitable approach that might contribute to the improved revalorization of mandarin peel. Response surface methodology was used to maximize the yields of polyphenols, flavonoids, and carotenoids, as well as antioxidative activity (DPPH- and ABTS-radical scavenging capacity). The sample-to-solvent ratio and solvent type significantly influenced extractability of polyphenols and carotenoids, while extraction time and power were the key variables influencing pectin yield. Optimal extracts contained 21.76 ± 0.46 mg GAE/g of polyphenols (with 139.7 ± 2.28 mg/g and 703.62 ± 51.72 µg/g of tangeretin and nobiletin, respectively); 352.3 ± 17.4 µg/g of β-carotene and 273 ± 23 mg/g of pectin. MAE resulted in either higher yields, reduced extraction times or both, compared to conventional solvent extraction (CSE), depending on the target compound. The energy consumption of MAE was considerably lower, compared to CSE, in four out of five developed extraction procedures. Pectin obtained in the integrated two-step process had higher purity compared to pectin extracted from intact mandarin peel. Full article

Citrus constitutes a group of fruit crops that include lemons, limes, mandarins, oranges, and grapefruits. These citrus have a variety of essential nutrients and bioactive compounds that exert several pharmacological properties, including antioxidant, anti-inflammatory, anticancer, anti-diabetic, and anti-obesity. The Satsuma mandarin, also known as Citrus unshiu Marc. (C. unshiu), is one of the most popular citrus types. This is mostly due to its seedless nature, early maturity, and highly valued commercial trait in the citrus sector. The pharmacological properties and phytochemicals of the two main citrus fruits—sweet oranges (C. sinensis) and lemons (C. limon)—are given more attention. Satsuma mandarin has not, however, had its therapeutic properties thoroughly examined and explored. Therefore, the purpose of this review is to use multiple databases to compile the information currently available on the pharmacological properties and bioactive compounds of C. unshiu. The findings indicate that C. unshiu bioactives (hesperidin; hesperetin; nobiletin; narirutin; naringin; naringenin; tangeretin; 3,5,6,7,8,3′,4′-heptamethoxyflavone; neoponcirin; synephrine; quercetin; quercetagetin; rutin; β-cryptoxanthin; and pectin) exert in vitro/vivo anticancer, anti-obesity, anti-diabetic, cardioprotective, gastroprotective, neuroprotective, hepatoprotective, skin-protective, nasal airway-protective, lipid-lowering, antioxidant, anti-inflammatory, and anti-microbial activities. Future experimental investigations into the potential health benefits of C. unshiu could contribute to a better understanding of the mechanisms behind its therapeutic activities. Clinical studies are necessary to assess the therapeutic properties of C. unshiu bioactives. The therapeutic potential of C. unshiu bioactives should be determined through preclinical in vivo animal studies before they can be applied in clinical settings. Full article

Cancer cachexia, often observed in patients with advanced-stage cancer, is characterized by the loss of body weight and appetite. The Japanese herbal medicine Ninjinyoeito (NYT), which is composed of 12 crude herbal components, has been used as a therapeutic in Japan to improve anorexia and fatigue, which are commonly observed in cancer patients with cachexia. We have previously reported that Citrus unshiu peel (CUP) contained in NYT can enhance food intake by activating the orexin 1 receptor (OX1R). Using the CellKey™ system, which offers detection of OXR activity in intracellular impedance changes, NYT and CUP were found to activate OX1R, which in turn was inhibited by SB-674042, a selective OX1R antagonist. Among the flavonoids contained in CUP, nobiletin and hesperidin, but not naringin, activated OX1R. Furthermore, some monoterpenes contained in CUP, including limonene and linalool, but not terpineol, activated OX1R. In addition, nobiletin and limonene synergistically activated OX1R when added simultaneously. However, neither NYT nor CUP induced OX2R activity. The results collectively suggested that the CUP contained in NYT activates OX1R, but not OX2R, and that flavonoids and monoterpenes in CUP can synergistically activate OX1R. These findings could provide evidence supporting the therapeutic potential of NYT in cancer patients with cachexia. Full article

Neuroinflammation is a significant driving force in the pathogenesis and progression of central nervous system (CNS) disorders. Polymethoxylated flavones (PMFs), the key lipid-soluble constituents in Citri Reticulatae Pericarpium (CRP), exhibit excellent blood–brain barrier permeability and anti-inflammatory properties, holding therapeutic potential for CNS disorders. However, the specific bioactive components and therapeutic effects of PMFs in treating CNS disorders are not well understood. This study employed a comprehensive sequential metabolism approach to elucidate the dynamic biotransformation of PMFs in vivo and identified seven brain-targeting components. Subsequently, network pharmacology and experimental validation were utilized to explore the potential mechanisms of PMFs. The results suggested that PMFs have potential therapeutic value for Alzheimer’s disease (AD)-like mice, with the inhibition of neuroinflammation likely being a key mechanism of their anti-AD effects. Notably, sinensetin, tangeretin, nobiletin, and 3,5,6,7,8,3′,4′-heptamethoxyflavone were identified as potent neuroinflammatory inhibitors. This research elucidated the chemical and therapeutic foundations of PMFs, indicating their potential as treatments or nutritional supplements for AD prevention and treatment. Moreover, the integrated triad approach of sequential metabolism, network pharmacology, and experimental validation may serve as a promising strategy for screening bioactive compounds in herbs or functional foods, as well as for elucidating their therapeutic mechanisms. Full article

Neuroinflammation is involved in various neurological and neurodegenerative disorders in which the activation of microglia is one of the key factors. In this study, we examined the anti-inflammatory effects of the flavonoids nobiletin (5,6,7,8,3′,4′-hexamethoxyflavone) and eriodictyol (3′,4′,5,7-tetraxydroxyflavanone) on human microglia cell line activation stimulated by either lipopolysaccharide (LPS), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) full-length Spike protein (FL-Spike), or the mycotoxin ochratoxin A (OTA). Human microglia were preincubated with the flavonoids (10, 50, and 100 µM) for 2 h, following which, they were stimulated for 24 h. The inflammatory mediators interleukin-1 beta (IL-1β), chemokine (C-X-C motif) ligand 8 (CXCL8), IL-6, and matrix metalloproteinase-9 (MMP-9) were quantified in the cell culture supernatant by enzyme-linked immunosorbent assay (ELISA). Both nobiletin and eriodictyol significantly inhibited the LPS, FL-Spike, and OTA-stimulated release of IL-1β, CXCL8, IL-6, and MMP-9 at 50 and 100 µM, while, in most cases, nobiletin was also effective at 10 µM, with the most pronounced reductions at 100 µM. These findings suggest that both nobiletin and eriodictyol are potent inhibitors of the pathogen-stimulated microglial release of inflammatory mediators, highlighting their potential for therapeutic application in neuroinflammatory diseases, such as long COVID. Full article

Background/Objectives: Mandarin orange peel (MOP) is recognized for its traditional medicinal properties due to its high flavonoid content. This study aimed to analyze MOP harvested in Japan for specific bioactive compounds and to explore its health applications in dogs, including effects on gut microbiota and cognitive symptoms. Methods: Flavonoid content (particularly hesperidin and nobiletin) of MOP was measured. High-flavonoid MOP was then incorporated into gelatin cubes. In the time–course blood concentration study, experimental beagle dogs received a single oral dose (4 g). For intestinal microbiota analysis and blood biochemical tests, beagle dogs were administered 1 g twice daily. For the Demonstration Test, older dogs (a 14-year-old female Shiba Inu, a 14-year-old female Miniature Dachshund, and a 19-year-old male Miniature Dachshund) were administered 1 g twice daily. Analysis included microbiota profiling via 16S rDNA sequencing and observational assessment of cognitive indicators in a pilot study involving senior dogs with Alzheimer’s disease. Results: The MOP powder contained 9.3% hesperidin in early-ripening varieties (October harvest) and 6.9% in ripe varieties (December harvest). Nobiletin content was 41 mg/100 g (0.041%) and 35 mg/100 g (0.035%) for the early and late harvests, respectively. Administration of MOP-enriched gelatin cubes reduced Fusobacteriaceae and increased Eggerthellaceae. Cognitive symptoms like howling and counterclockwise turning showed improvement in senior dogs (n = 3). Conclusions: This study provides preliminary support for the potential health benefits of MOP in canine dietary applications, particularly for gut health and cognitive function. Improvement in cognitive symptoms may be due to the anxiolytic effects of mandarin peel. Full article

Citrus reticulata ‘Chachi’ (CRC), recognized for its considerable edible and medicinal significance, is a valuable source of metabolites beneficial to human health. This research investigates the metabolic distinctions and antioxidant properties across four different parts of CRC, using multivariate statistical analysis to interpret metabolomic data and network pharmacology to identify potential antioxidant targets and relevant signaling pathways. The results indicate considerable metabolic differences in different parts of the sample, with 1622 metabolites showing differential expression, including 816 secondary metabolites, primarily consisting of terpenoids (31.02%) and flavonoids (25.22%). The dried mature citrus peel (CP) section demonstrates the highest level of total phenolics (6.8 mg/g), followed by the pulp without seed (PU) (4.52 mg/g), pulp with seed (PWS) (4.26 mg/g), and the seed (SE) (2.16 mg/g). Interestingly, targeted high-performance liquid chromatography of flavonoids reveals the highest level of nobiletin and tangeretin in CP, whereas PU has the highest level of hesperidin, narirutin, and didymin. Furthermore, all four sections of CRC exhibit robust antioxidant properties in in vitro assessments (CP > PU > PWS > SE). Lastly, the network pharmacology uncovered potential antioxidant mechanisms in CRC. This research offers deeper insights into the development and utilization of byproducts in the CRC processing industry. Full article

The huge amount of citrus peel produced worldwide represents an economic burden for society. However, this agricultural by-product is a rich source of natural molecules, potentially endowed with interesting pharmacological activities. In this regard, we decided to investigate if the polymethoxyflavones contained in citrus peel waste could be exploited as novel vasorelaxant agents. A hydroalcoholic blond orange (Citrus sinensis) peel extract, obtained by ultrasonication, was partitioned in dichloromethane. Column chromatography allowed for the isolation of four polymethoxyflavones, namely, scutellarein tetramethyl ether, nobiletin, tangeretin, and sinensetin, identified by nuclear magnetic resonance (NMR) spectroscopy and UPLC-HRMS/MS and confirmed by multivariate curve resolution of NMR fractional spectra. The four molecules showed interesting in vitro vasorelaxant activity, at least, in part, due to the blockade of smooth muscle Ca_V1.2 channels. Molecular modeling and docking analysis elucidated the binding mode of the polymethoxyflavones at the homology model of the rat Ca_V1.2c subunit and provided the structural basis to rationalise the highest activity of scutellarein tetramethyl ether in the set and the dramatic effect of the additional methoxy group occurring in nobiletin and sinensetin. In conclusion, citrus peel can be considered a freely available, valuable source of vasoactive compounds worthy of pharmaceutical and/or nutraceutical exploitation. Full article

The existence of repeat breeder cows (RBCs) causes low reproductive performance. The causes of RBCs include low-quality oocytes and embryos, hormonal dysregulation, and unsuitable uterine environments. To improve unsuitable uterine conditions for RBCs, we focused on nobiletin (NOB), a natural citrus flavone with various beneficial roles. The role of NOB in bovine endometrial epithelial cells (BEECs) was examined. An analysis of BEECs showed that gene expression and altered pathways differed between the control and NOB treatment, with NOB regulating the pathways of steroid biosynthesis, lysosomal function, and inflammatory responses. NOB treatment significantly increased the number and activation of endosomes and lysosomes in BEECs. Moreover, we performed phagocytosis assays using fluorescence-conjugated lipopolysaccharide (LPS) with lysosomes in NOB-treated BEECs, which resulted in an increase in the co-localization of phagocytosed LPS with lysosomes. NOB treatment stimulated the mRNA expression of various lysosomal hydrolases, including cathepsin B and cathepsin K, and suppressed the gene expression of cytokines in inflammation-associated pathways (rheumatoid arthritis, the IL-17 signaling pathway, etc.). NOB significantly suppressed the LPS-induced mRNA expression of the inflammatory cytokine IL-8 and its secretion in BEECs. In conclusion, NOB activates the endosome–lysosomal system via phagocytosis to eliminate the bacterial component LPS and suppress inflammatory responses to defense mechanisms in BEECs. Full article

Citri Reticulatae Pericarpium (CRP), particularly including the pericarp of Citrus reticulata ‘Chachi’ (GCP), has been widely used as a food, a dietary supplement, and traditional Chinese medicine. Despite the widespread use of traditional foods, there is limited evidence regarding the precise relationships between storage conditions, aging duration, and the digestive performance of CRP. In this study, the aim was to investigate the impact of the storage conditions on the quality of aged GCP during shelf life and to evaluate the subsequent digestive performance of corresponding GCP decoctions. Respiration in GCP was monitored by measuring oxygen (O₂), carbon dioxide (CO₂), and methane (CH₄) gases throughout the storage simulation, with O₂ and CO₂ validated as prospective safety measures. Five flavonoids (hesperidin, didymin, nobiletin, tangeretin, and 3,5,6,7,8,3′,4′-heptamethoxyflavone) were determined as quality indicators, and their contents were significantly affected by the duration of the storage simulation and the aging periods of GCP. Our study also found that temperature and humidity significantly affected the volatile organic compounds (VOCs) emission from GCP. Eighteen compounds were proposed to show potential as descriptive measures of aging periods while eight compounds were proposed as potential indicators to discriminate among the spoilage level. Furthermore, the bioaccessibility of hesperidin ranged from ~30% to ~50% and was not significantly affected by the GCP’s aging time nor the consumer’s sex (p < 0.05). This study presents evidence for the future control of the quality of GCP and its digestive performance in males and females. Full article

Ageratum conyzoides L. is native to Tropical America, and it has naturalized in many other tropical, subtropical, and temperate countries in South America, Central and Southern Africa, South and East Asia, Eastern Austria, and Europe. The population of the species has increased dramatically as an invasive alien species, and it causes significant problems in agriculture and natural ecosystems. The life history traits of Ageratum conyzoides, such as its short life cycle, early reproductive maturity, prolific seed production, and high adaptive ability to various environmental conditions, may contribute to its naturalization and increasing population. Possible evidence of the molecules involved in the defense of Ageratum conyzoides against its natural enemies, such as herbivore insects and fungal pathogens, and the allelochemicals involved in its competitive ability against neighboring plant species has been accumulated in the literature. The volatiles, essential oils, extracts, residues, and/or rhizosphere soil of Ageratum conyzoides show insecticidal, fungicidal, nematocidal, and allelopathic activity. The pyrrolizidine alkaloids lycopsamine and echinatine, found in the species, are highly toxic and show insecticidal activity. Benzopyran derivatives precocenes I and II show inhibitory activity against insect juvenile hormone biosynthesis and trichothecene mycotoxin biosynthesis. A mixture of volatiles emitted from Ageratum conyzoides, such as β-caryophyllene, β-bisabolene, and β-farnesene, may work as herbivore-induced plant volatiles, which are involved in the indirect defense function against herbivore insects. Flavonoids, such as nobiletin, eupalestin, 5′-methoxynobiletin, 5,6,7,3′,4′,5′-hexamethoxyflavone, and 5,6,8,3,4′,5′-hexamethoxyflavone, show inhibitory activity against the spore germination of pathogenic fungi. The benzoic acid and cinnamic acid derivatives found in the species, such as protocatechuic acid, gallic acid, p-coumaric acid, p-hydroxybenzoic acid, and ferulic acid, may act as allelopathic agents, causing the germination and growth inhibition of competitive plant species. These molecules produced by Ageratum conyzoides may act as defense molecules against its natural enemies and as allelochemicals against neighboring plant species, and they may contribute to the naturalization of the increasing population of Ageratum conyzoides in new habitats as an invasive plant species. This article presents the first review focusing on the defense function and allelopathy of Ageratum conyzoides. Full article

Asthma is a chronic airway inflammation that is considered a serious public health concern worldwide. Nobiletin (5,6,7,8,3′,4′-hexamethyl flavonoid), an important compound isolated from several traditional Chinese medicines, especially Citri Reticulatae Pericarpium, is widely used for a number of indications, including cancer, allergic diseases, and chronic inflammation. However, the mechanism by which nobiletin exerts its anti-asthmatic effect remains unclear. In this research, we comprehensively demonstrated the anti-asthmatic effects of nobiletin in an animal model of asthma. It was found that nobiletin significantly reduced the levels of inflammatory cells and cytokines in mice and alleviated airway hyperresponsiveness. To explore the target of nobiletin, we identified PDE4B as the target of nobiletin through pharmacophore modeling, molecular docking, molecular dynamics simulation, SPR, and enzyme activity assays. Subsequently, it was found that nobiletin could activate the cAMP-PKA-CREB signaling pathway downstream of PDE4B in mouse lung tissues. Additionally, we studied the anti-inflammatory and anti-airway remodeling effects of nobiletin in LPS-induced RAW264.7 cells and TGF-β1-induced ASM cells, confirming the activation of the cAMP-PKA-CREB signaling pathway by nobiletin. Further validation in PDE4B-deficient RAW264.7 cells confirmed that the increase in cAMP levels induced by nobiletin depended on the inhibition of PDE4B. In conclusion, nobiletin exerts anti-asthmatic activity by targeting PDE4B and activating the cAMP-PKA-CREB signaling pathway. Full article