Search

Background: Sepsis-induced acute lung injury (ALI) is a severe clinical condition accompanied with high mortality. Tangeretin, which is widely found in citrus fruits, has been reported to exert antioxidant and anti-inflammatory properties. However, whether tangeretin protects against sepsis-induced ALI and the potential mechanisms remain unclear. Methods: We established an ALI model via intraperitoneally injected with 5 mg/kg lipopolysaccharides (LPS) for 12 h. Tangeretin was applied intraperitoneally 30 min before LPS treatment. Dexamethasone (Dex) was used as a positive control. Hematoxylin and eosin (HE) staining and protein content in bronchoalveolar lavage fluid (BALF) were determined to detect the degree of lung injury. RNA-seq was also applied to explore the effect of tangeretin on ALI. In vitro, RAW264.7 were treated with Nrf2 siRNA, the expression of ferroptosis-associated biomarkers, including glutathione peroxidase 4 (GPX4) and prostaglandin-endoperoxide synthase 2 (PTGS2) were assessed. Glutathione (GSH), malondialdehyde (MDA) levels, reactive oxygen species (ROS) and inflammatory factors were also determined both in vivo and in vitro. Furthermore, mice were treated with an Nrf2 inhibitor (ML385) to verify the mechanism of tangeretin in inhibiting sepsis-induced lung injury and ferroptosis. Data were analyzed using one way analysis of variance or two-tailed unpaired t tests. Results: Our study demonstrated that tangeretin significantly alleviated lung injury, reversed the LPS-induced reduction in GPX4 and GSH, and mitigates the elevation of PTGS2 and MDA levels. Tangeretin also reduced 4-HNE and iron levels. Besides, the levels of LPS-stimulated inflammatory factors IL-6, IL-1β and TNF-α were also decreased by tangeretin. RNA-seq and bioinformatics analysis demonstrated that tangeretin inhibited inflammatory response. Mechanistically, we identified that tangeretin inhibited the GPX4-dependent lipid peroxidation through activation of Nrf2. The silence of Nrf2 abolished the inhibitory effect of tangeretin on oxidative stress, inflammatory response and ferroptosis in RAW264.7 cells. Additionally, all the protective effects of tangeretin on ALI were abolished in Nrf2 inhibitor-treated mice. Conclusion: We identified that ferroptosis as a critical mechanism contributing to sepsis-induced ALI. Tangeretin, a promising therapeutic candidate, effectively mitigates ALI through inhibiting ferroptosis via upregulating Nrf2 signaling pathway. [ABSTRACT FROM AUTHOR]

An ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed for the determination of nobiletin and tangeretin in rat plasma, and the plasma was processed by a simple liquid-liquid extraction method with ethyl acetate. The chromatographic column was UPLC HSS T3 (50 × 2.1 mm, 1.7 μm), the mobile phase was acetonitrile-water (containing 0.1% formic acid). Multiple reaction monitoring mode (MRM) was used for quantitative analysis, nobiletin m/z 403.29 → 373.14 (cone voltage 22v, collision voltage 28v), tangeretin m/z 373.28 → 343.17 (cone voltage 20v, collision voltage 28V), tangeretin m/z 373.28 → 343.17 (cone voltage 20V, collision voltage 28V) and internal standard vitexin m/z 433.14 → 313.03 (cone voltage 32v, collision voltage 26v). The pharmacokinetics of nobiletin and tangeretin were evaluated in rats. The established UPLC-MS/MS method in the range of 2–2,000 ng mL−1 was successfully applied to the pharmacokinetics, and the calculated bioavailability of nobiletin and tangeretin was 63.9 and 46.1%, respectively. [ABSTRACT FROM AUTHOR]

Aims: The aim of the study is to know about which soil factors could influence the accumulation of hesperidin, nobiletin and tangeretin in pericarps of Citrus reticulata 'Chachi' (Citrus reticulata cv. Chachiensis). Methods: A total of 150 soil samples from 15 profiles and 60 pericarp samples were collected at different orchards cultivated Citrus reticulata 'Chachi'. The linear regression models, random forest models and structural equation models were established to explore the relationship between soil factors and the three medicinal components. A 2-year field control experiments were designed to verify the direct impact of key elements on hesperidin, nobiletin and tangeretin in pericarps. Results: Soil potassium (K), calcium (Ca), magnesium (Mg), manganese (Mn), pH, Cation exchange capacity (CEC), Salinity and Sand showed the main influences on hesperidin, nobiletin and tangeretin, in which soil elements, particularly K, Ca, Mg and Mn, were relatively important. Conclusions: Adjusting the absorption of elements by Citrus reticulata 'Chachi' is one of the effective and convenient methods to increase or decrease the three medicinal components in pericarps. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) is a severe disabling disease that is characterized by inflammation and oxidative reactions. Tangeretin has been shown to possess significant antioxidant and anti‐inflammatory activities. The Keap1/Nrf2 pathway, downstream of the Sesn2 gene, is involved in regulating the inflammation and oxidative response. The main objective of this study was to investigate the effect of tangeretin on SCI and its possible mechanism through cell and animal models. A T9 clamp injury was used for the mouse model and the LPS‐induced stimulation of BV‐2 cells was used for the cell model. The improvement of motor function after SCI was assessed by open field, swimming, and footprint experiments. The morphological characteristics of mouse spinal cord tissue and the levels of INOS, Sesn2, TNF‐α, Keap1, Nrf2, IL‐10, and reactive oxygen species (ROS) in vivo and in vitro were measured by several methods including western blotting, qPCR, immunofluorescence, HE, and Nissl staining. In vivo data showed that tangeretin can improve motor function recovery and reduce neuron loss and injury size in mice with SCI. Simultaneously, the in vitro findings suggested that treatment of BV‐2 cells with tangeretin after LPS stimulation reduced the production of inflammatory factors and ROS, and could convert BV‐2 cells from the M1 to the M2 type. Furthermore, Sesn2 knockout suppressed Keap1/Nrf2, inflammatory factors, ROS levels, and the M1 to M2 transition. Tangeretin can alleviate the inflammation and oxidative response induced by SCI by activating the Sesn2/Keap1/Nrf2 pathway. [ABSTRACT FROM AUTHOR]

Background Exercise-induced bronchoconstriction (EIB) is highly prevalent in athletes. The objective of this study was to assess the therapeutic efficacy of daily tangeretin combined with whey protein supplementation over a period of 4 weeks in professional athletes with EIB.Methods Using a placebo-controlled, double-blind, paired, randomized trial design, a cohort of 30 professional athletes with EIB, consisting of 14 females and 16 males, was divided into two groups: the tangeretin combined with whey protein intervention group (TIG), and the placebo control group (PCG). Both the TIG and PCG underwent exercise challenge tests (ECT) and VO2max tests before (ECT1, V1) and after (ECT2, V2) the intervention. Blood (eosinophils, neutrophils, and basophils) and serum (interleukin-5, IL-5; interleukin-8, IL-8; Clara cell secretory protein-16, CC16; immunoglobulin E, IgE) levels were measured early in the morning of ECT1 and ECT2, respectively. Lung function was assessed immediately before and post-ECT immediately.Results Tangeretin combined with whey protein use for 4 weeks attenuated the decrease in forced expiratory volume in 1 s (FEV1) post trials (∆FEV1(ECT1-ECT2): mean (SD) TIG −7.51(6.9)% vs. PCG −2.33(11.49)%, p = 0.013). Tangeretin also substantially attenuated IL-5 concentration (∆IL-5(T1-T5): Tangeretin −19.4% vs Placebo + 8.37%, p = 0.022); IL-8 concentration (∆IL-8(T1-T5): Tangeretin −17.28% vs Placebo + 6.1%, p = 0.012); CC16 concentration (∆CC16(T1-T5): Tangeretin −11.77% vs Placebo + 24.19%); and IgE concentration in the serum (∆IgE(T1-T5): Tangeretin −24.1% vs Placebo −3.9%), and significantly decreased neutrophil count (∆N(T1-T5): Tangeretin −11.34% vs Placebo + 0.3%) and eosinophil count in blood (∆N(T1-T5): Tangeretin −38.5% vs Placebo + 4.35%). Compared with V1, VO2max (p = 0.042) and TLim (p = 0.05) of V2 were significantly increased in the TIG, and there was no significant change in the PCG. Meanwhile, six athletes in the TIG and 0 athletes in the PCG became EIB-negative at ECT2; the overall negative conversion rate of EIB was 40.00% in TCG. Additionally, the number of cough symptoms decreased from 9 to 3 and dyspnea from 4 to 2 in the TIG.Conclusion After high-intensity exercise, athletes with EIB achieved significant improvements in lung function and blood inflammatory factors by combining tangeretin and whey protein supplementation. EIB athletes also showed longer exercise endurance and VO2max at 4 weeks after TI. In addition, some patient symptoms disappeared after combination supplementation. The effect of this treatment on professional athletes with EIB was beneficial.

Malathion (MLT) is an organophosphate pesticide that instigates severe injuries in the testicular tissues. Tangeretin (TGN) is an important naturally present flavone that shows potential antioxidant and anti-apoptotic activities. This research was planned to ascertain the palliative role of TGN against MLT-instigated testicular toxicity in male Sprague-Dawley (SD) rats. 48 rats were distributed into 4 groups: control, MLT (100 mgkg−1), MLT+TGN (100 + 50 mgkg−1 respectively), and TGN (50 mgkg−1). The results showed that MLT exposure reduced the activities of catalase (CAT), glutathione reductase (GSR), superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione (GSH), whereas escalated the levels of reactive oxygen species (ROS) and malondialdehyde (MDA). Moreover, it decreased the levels of luteinizing hormone (LH), plasma testosterone, and follicle-stimulating hormone (FSH). MLT also reduced the expressions of steroidogenic enzymes, including StAR, 3β-HSD, and 17β-HSD. Additionally, MLT exposure increased the expressions of Bax and Caspase-3, while reducing the Bcl-2 expressions. MLT administration also increased the levels of inflammatory markers such as nuclear factor kappa B (NF-κB), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), interleukin-1 beta (1L-1β) as well as cyclooxygenase-2 (COX-2) activity in testes. Nonetheless, TGN recovered all the MLT induced damages in testes. In conclusion, TGN could ameliorate MLT instigated testicular impairment because of its anti-apoptotic, androgenic and anti-oxidant properties.

Cisplatin (CIS) is a platinum‐derived chemotherapeutic agent commonly utilized in the treatment of various malignant tumours. However, anticancer doses of the drug cause serious damage to the brain. This study aimed to determine the potential protective effects of tangeretin, which has antioxidant and anti‐inflammatory properties, in cisplatin‐induced neurotoxicity on BALB/c mice brains. Male BALB/c mice were randomized and separated into four groups. Tangeretin was given for 10 days by gavage. CIS was injected as a single dose of 10 mg/kg intraperitoneally (ip) on the 10th day. Brain tissues, malondialdehyde (MDA), total glutathione (tGSH), glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase (CAT) and nitric oxide (NO) levels were measured to determine oxidative damage and myeloperoxidase, tumour necrosis factor‐alpha (TNF‐α), interleukin 1 beta (IL‐1β), IL‐6 and IL‐10 were measured to determine inflammatory activity. In addition, 8‐OHdG and caspase‐3 were analysed by immunofluorescence methods. While CIS administration remarkably elevated reactive oxygen species, MDA, and NO levels in brain tissue compared to the control, tGSH, GPx, SOD and CAT levels were significantly decreased. Also, it has been detected that TNF‐α, IL‐1β and IL‐6 obtained in CIS‐treated groups increased as well as IL‐10 decreased, thereby elevating the inflammatory response. In addition, 8‐OHdG and caspase‐3 immunoreactivity in neurons increased with CIS administration. Treatment with tangeretin ameliorated the deterioration in oxidant/antioxidant status, overpowered neuroinflammation and ameliorated neurotoxicity‐induced apoptosis. This study shows that tangeretin has beneficial effects on CIS‐induced neurodegeneration. Possible mechanisms underlying these beneficial effects include the antioxidant and anti‐inflammatory properties of tangeretin. [ABSTRACT FROM AUTHOR]

Cardiotoxicity is a common side effect of cisplatin in cancer treatment, often complicating patient care. Tangeretin (TG), a natural compound found in citrus peel, shows promise in protecting against cisplatin-induced heart damage. Our study investigated TG’s protective effects both in cell culture and in animal models. TG effectively countered cisplatin-induced damage in heart cells, promoting mitochondrial health and glucose transporter expression. In animal studies, TG reduced markers of heart damage and improved cardiac function. Mechanistically, TG activated AMPK, reduced the inactivation of Acetyl-CoA Carboxylase (ACC) protein and inhibited p38 MAPK and prevented mitochondrial dysfunction and cell death. This research sheds light on TG’s potential in safeguarding the heart from cisplatin-induced harm.

Neuroinflammation is the major cause of neurodegenerative disorders such as Alzheimer's and Parkinson's disease. Currently available drugs present relatively low efficacy and are not capable of modifying the course of the disease or delaying its progression. Identifying well-tolerated and brain-penetrant agents of plant origin could fulfil the pressing need for novel treatment techniques for neuroinflammation. Attention has been drawn to a large family of flavonoids in citrus fruits, which may function as strong nutraceuticals in slowing down the development and progression of neuroinflammation. This review is aimed at elucidating and summarizing the effects of the flavonoid tangeretin (TAN) in the management of neuroinflammation-mediated neurodegenerative disorders. A literature survey was performed using various resources, including ScienceDirect, PubMed, Google Scholar, Springer, and Web of Science. The data revealed that TAN exhibited immense neuroprotective effects in addition to its anti-oxidant, anti-diabetic, and peroxisome proliferator-activated receptor-γ agonistic effects. The effects of TAN are mainly mediated through the inhibition of oxidative and inflammatory pathways via regulating multiple signaling pathways, including c-Jun N-terminal kinase, phosphoinositide 3-kinase, mitogen-activated protein kinase, nuclear factor erythroid-2-related factor 2, extracellular-signal-regulated kinase, and CRE-dependent transcription. In conclusion, the citrus flavonoid TAN has the potential to prevent neuronal death mediated by neuroinflammatory pathways and can be developed as an auxiliary therapeutic agent in the management of neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Previous studies have revealed the microbial metabolism of dietary choline in the gut, leading to its conversion into trimethylamine (TMA). Polymethoxyflavones (PMFs), exemplified by tangeretin, have shown efficacy in mitigating choline-induced cardiovascular inflammation. However, the specific mechanism by which these compounds exert their effects, particularly in modulating the gut microbiota, remains uncertain. This investigation focused on tangeretin, a representative PMFs, to explore its influence on the gut microbiota and the choline–TMA conversion process. Experimental results showed that tangeretin treatment significantly attenuated the population of CutC–active bacteria, particularly Clostridiaceae and Lactobacillus, induced by choline chloride in rat models. This inhibition led to a decreased efficiency in choline conversion to TMA, thereby ameliorating cardiovascular inflammation resulting from prolonged choline consumption. In conclusion, tangeretin's preventive effect against cardiovascular inflammation is intricately linked to its targeted modulation of TMA–producing bacterial activity. [ABSTRACT FROM AUTHOR]

Citrus fruits such as Tachibana (Citrus tachibana Tanaka) contain various flavonoids that perform biological functions important to human health. Considering the growing public health consciousness, combined treatment with gibberellic acid and prohydrojasmon (GP), which is used in Japan, may be used to delay flavonoid degradation and maintain high polymethoxyflavone (PMF) contents in the flavedo of citrus fruits. However, the effects of GP treatment on fruit growth, PMF accumulation, and flavonoid biosynthesis-related gene expression in Tachibana fruit remain unclear. Post-harvest ultraviolet (UV) light irradiation also induces production of flavonoids; however, it has rarely been applied to citrus fruits. In this study, we aimed to investigate the effects of combined treatment with GP during cultivation and post-harvest deep-UV light-emitting diode (DUV-LED) irradiation on accumulation of PMFs (nobiletin, tangeretin, and sinensetin) and expression of flavonoid biosynthesis-related genes in Tachibana fruit. Nobiletin, tangeretin, and sinensetin contents in the flavedo of a single fruit significantly increased after GP treatment and 1 day after DUV-LED irradiation. The fruits treated with GP and DUV-LED exhibited the highest PMF content and significantly upregulated expression of CitFNS, CitCHI, CitF3′H, CitOMT2, and CitOMT3. Moreover, DUV-LED irradiation significantly induced CitOMT1 expression. These results suggest that the combination of GP treatment during cultivation and post-harvest DUV-LED irradiation can promote PMF accumulation in Tachibana fruit. This study may serve as a basis for efficient extraction and utilization of functional ingredients, such as nobiletin, from Tachibana. [ABSTRACT FROM AUTHOR]

Pyroptosis is closely involved in the pathopoiesis of cerebral ischemia and reperfusion (I/R) injury which seriously dangers human's life. Studies report that tangeretin (TANG), which is enriched in the peel of Citrus reticulata, has neuroprotective effects. Here, we explored whether absent in melanoma 2 (AIM2) inflammasome-mediated pyroptosis is involved in the cerebral I/R injury and the protective mechanism of TANG against cerebral I/R injury. In this study, we found that TANG treatment effectively alleviated I/R-induced brain injury and inhibited neuronal pyroptosis in an in vivo mice model with middle cerebral artery occlusion/reperfusion (MCAO/R) injury and in an in vitro hippocampal HT22 cell model with oxygen–glucose deprivation and reoxygenation (OGD/R) injury. Furthermore, we found TANG inhibited cerebral I/R-induced neuronal AIM2 inflammasome activation in vivo and in vitro via regulating nuclear factor E2-related factor 2 (NRF2). Moreover, administration of ML385, a chemical inhibitor of NRF2, notably blocked the neuroprotective effects of TANG against cerebral I/R injury. In conclusion, TANG attenuates cerebral I/R-induced neuronal pyroptosis by inhibiting AIM2 inflammasome activation via regulating NRF2. These findings indicate TANG is a potential therapeutic agent for cerebral I/R injury. [ABSTRACT FROM AUTHOR]

Background: Pancreatic beta cell health and its insulin-secreting potential are severely compromised under the diabetic condition. One of the key mediators of beta cell dysfunction is endoplasmic reticulum (ER) stress. Pharmacological intervention of ER stress and associated complications in pancreatic beta cells may be an effective strategy for the management of diabetes. In the present study, we evaluated the efficacy of tangeretin, a citrus pentamethoxyflavone, in the alleviation of ER stress and associated perturbations in pancreatic Beta-TC-6 cell lines. Methods and results: Tunicamycin (pharmacological ER stress inducer) at subtoxic levels was observed to induce beta cell dysfunction by upregulation of intracellular ROS levels, lowering mitochondrial number/biogenesis and membrane potential, elevation of UPR markers, XBP-1, GADD153, and ER resident chaperones. Treatment with tangeretin was successful in improving the beta cell function by lowering the ROS levels and improving the mitochondrial biogenesis and mitochondrial membrane potential. Tangeretin also downregulated the expression levels of XBP-1, GADD153, and ER resident chaperones. GLUT2 expression, however, did not undergo any significant change under ER stress. We also observed altered expression of Pdx-1, TRB3, and p-Akt under the ER stress condition. Tangeretin augmented the expression levels of Pdx-1, and p-Akt while curtailing the expression of TRB3 in beta cells. Tunicamycin treatment suppressed the insulin levels, however, co-treatment with tangeretin could only marginally improve the levels. Conclusion: Targeting ER stress and associated pathways in pancreatic Beta-TC-6 cell lines by tangeretin can be an effective strategy for improving beta cell function. [ABSTRACT FROM AUTHOR]

Global cerebral ischemia is commonly associated with neurological deficits, including cognitive and memory impairments. The present study aims to investigate the neuroprotective, cognitive, and memory enhancement effects of Tangeretin, a flavonoid against global cerebral ischemia in rats. Bilateral common carotid artery occlusion (BCCAO) and reperfusion injury method was used to induce global cerebral ischemia in rats. Motor, cognitive, and memory functions were evaluated using rotarod, grip strength, Y-maze, and Morris water maze. Further, acetylcholine esterase (AchE) enzyme activity, acetylcholine (Ach), oxidative stress markers (ROS, SOD, MDA, and CAT), inflammation (IL-6 and TNF-α), and apoptotic markers (cytochrome C, caspase 9, and caspase 3) in BCCAO rats were measured following Tangeretin (5,10, and 20 mg/kg, oral) treatment. Our findings show that Tangeretin treatment significantly improved cognition and memory by enhancing Ach levels through the amelioration of AchE enzyme activity in BCCAO rats. Moreover, Tangeretin exhibited neuroprotective effects through the mitigation of oxidative stress, inflammation, and apoptosis in the BCCAO rats. In summary, the current findings suggested that Tangeretin exhibited neuroprotection, cognitive and memory enhancement against global cerebral ischemia. [ABSTRACT FROM AUTHOR]

Preparations of the roots, stems, and leaves of Rhinachantus nasutus (L.) Kurz (RNK) have been used empirically in traditional medicine to treat diabetes, eczema, pulmonary tuberculosis, herpes, hepatitis, and hypertension for centuries. This study seeks to identify compounds that have antioxidant and antidiabetic properties by inhibiting alpha-glucosidase activity in RNK stem bark through metabolomics and molecular docking approaches based on ultrahigh-performance liquid chromatography-mass spectrometry (UHPLC MS/MS). The results of the alpha-glucosidase inhibition activity test showed that fraction A of stem bark was active with an IC50 value of 20.04 ± 0.05 mg/L, while fractions B and C were very active with IC50 values of 6.67 ± 0.04 and 6.99 ± 0.03 mg/L, respectively. The EC50 value obtained in testing the antioxidant activity of fractions A, B, and C using the FRAP method was in the range 9.79–11.33 mg/L, while using the CUPRAC method was in the range 8.98–17.05 mg/L. The antioxidant properties of fractions A, B, and C are very strong. This metabolomics approach yielded nine compounds that play an important role as antioxidants (the FRAP method) and 19 compounds (the CUPRAC method), while 11 compounds play an important role as inhibitors of alpha-glucosidase activity. Molecular docking verification of 11 significant compounds as alpha-glucosidase inhibitors revealed that the ΔG values of all compounds were negative, with the exception of compound (10) tangeretin, which had an almost identical ΔG value to acarbose. RNK stem bark is a possible source of anti-diabetic and antioxidant compounds, according to the findings of this study. Therefore, RNK stem bark may be utilised in the future for the advancement of anti-diabetes research and the preparation of medicinal constituents. Besides that, it can better utilise stem bark which was originally an agricultural or plantation waste, to become a source of antidiabetic drugs.

Background: Pulmonary fibrosis (PF) is a terminal pathological change in a variety of lung diseases characterized by excessive deposition of extracellular matrix, for which effective treatment is lacking. Tangeretin (Tan), a flavonoid derived from citrus, has been shown to have a wide range of pharmacological effects. This study aimed to investigate the role and potential mechanisms of Tan on pulmonary fibrosis. Methods: A model of pulmonary fibrosis was established by administering bleomycin through tracheal drip, followed by administering Tan or pirfenidone through gavage. HE and Masson staining were employed to assess the extent of pulmonary fibrosis. Subsequently, Western blot, enzyme-linked immunosorbent assay (ELISA), RNA sequencing, and immunohistochemistry techniques were employed to uncover the protective mechanism of Tan in PF mice. Furthermore, A549 cells were stimulated with TGF-β1 to induce epithelialmesenchymal transition (EMT) and demonstrate the effectiveness of Tan in mitigating PF. Results: Tan significantly ameliorated bleomycin-induced pulmonary fibrosis, improved fibrotic pathological changes, and collagen deposition in the lungs, and reduced lung inflammation and oxidative stress. The KEGG pathway enrichment analysis revealed a higher number of enriched genes in the PI3K/ Akt pathway. Additionally, Tan can inhibit the EMT process related to pulmonary fibrosis. Conclusion: Taken together, the above research results indicate that Tan suppresses inflammation, oxidative stress, and EMT in BLM-induced pulmonary fibrosis via the PI3K/Akt pathway and is a potential agent for the treatment of pulmonary fibrosis. [ABSTRACT FROM AUTHOR]

Natural compounds with pharmacological activity, flavonoids have been the subject of an exponential increase in studies in the field of scientific research focused on therapeutic purposes due to their bioactive properties, such as antioxidant, anti-inflammatory, anti-aging, antibacterial, antiviral, neuroprotective, radioprotective, and antitumor activities. The biological potential of flavonoids, added to their bioavailability, cost-effectiveness, and minimal side effects, direct them as promising cytotoxic anticancer compounds in the optimization of therapies and the search for new drugs in the treatment of cancer, since some extensively antineoplastic therapeutic approaches have become less effective due to tumor resistance to drugs commonly used in chemotherapy. In this review, we emphasize the antitumor properties of tangeretin, a flavonoid found in citrus fruits that has shown activity against some hallmarks of cancer in several types of cancerous cell lines, such as antiproliferative, apoptotic, anti-inflammatory, anti-metastatic, anti-angiogenic, antioxidant, regulatory expression of tumor-suppressor genes, and epigenetic modulation. [ABSTRACT FROM AUTHOR]

Purpose: This study was designed to find an answer to the question, "Is it beneficial to use pomegranate (POM) and tangeretin (TAN) separately or in combination, for the prevention of acute gastric ulcer?". Materials and Methods: The gastroprotective effect of tangeretin and pomegranate was determined by measuring the levels of the selected inflammatory cytokines [tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-1β and IL-10], lipid peroxides, and enzymatic activities of antioxidants in gastric tissue samples. Results: When all groups are written as control, gastric ulcer, POM+EtOH, TAN+EtOH and POM+TAN+EtOH, respectively; IL-1β cytokine levels were measured as 0.147, 0.24, 0.228, 0.195 and 0.182 pg/g protein. IL-6 levels; 16,857, 25,923, 19,797, 18,838 and 17,896 pg/mg protein. TNF-α levels were 39,916, 49.97, 44,678, 41,673 and 40,844 pg/mg protein. Finally, IL-10 levels were measured as 33,496, 28,071, 29,693, 30,073 and 30,008 pg/mg protein. SOD activities were determined as 18,038, 13,731, 15,506, 14,439, and 15,943. CAT activities were 674,638, 639,964, 673,382, 664,691, and 671,203. Protein carbonyl levels were measured as 26,799, 40,30, 33,052, 34,579 and 32,79. Finally, MDA levels were found as 5,239, 9,814, 6,695, 5,771 and 5,836. Briefly, POM and TAN showed their antioxidant functions by decreasing the levels of malondialdehyde (MDA), and protein carbonyl and increasing the activity of superoxide dismutase (SOD) and catalase (CAT). And also, these protective agents exhibited their anti-inflammatory functions by decreasing the content of TNF-α, IL-6, and IL-1β, and increasing the IL-10 levels. Conclusion: Tangeretin and pomegrenate have a potential gastroprotective effect against ethanol-induced acute gastric ulcer and that the combined treatment is more beneficial than the effect of POM or TAN alone. In addition, this effect is thought to be due to the fact that both selected flavonoids can show a synergistic effect, reducing the levels of inflammation parameters and increasing antioxidant levels. [ABSTRACT FROM AUTHOR]

Potassium dichromate (PD) is an environmental xenobiotic commonly recognized as teratogenic, carcinogenic, and mutagenic in animals and humans. The present study was conducted to investigate the role of tangeretin (TNG) as a neuro-protective drug against PD-induced brain injury in rats. Thirty-two male adult Wistar rats were blindly divided into four groups (8 rats/group). The first group received saline intranasally (i.n.). The second group received a single dose of PD (2 mg/kg, i.n.). The third group received TNG (50 mg/kg; orally), for 14 days followed by i.n. of PD on the last day of the experiment. The fourth group received TNG (100 mg/kg; orally) for 14 days followed by i.n. of PD on the last day of the experiment. Behavioral indices were evaluated 18 h after PD administration. Neuro-biochemical indices and histopathological studies were evaluated 24 h after PD administration. Results of the present study revealed that rats intoxicated with PD induced- oxidative stress and inflammation via an increase in malondialdehyde (MDA) and a decrease in nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway and glutathione(GSH) levels with an increase in brain contents of tumor necrosis factor-alpha (TNF-α) and interleukin (IL-6). Pre-treatment with TNG (100 mg/kg; orally) ameliorated behavior, cholinergic activities, and oxidative stress and decreased the elevated levels of pro-inflammatory mediators; TNF-α and IL-6 with a decrease in brain content of chromium residues detected by Plasma–Optical Emission Spectrometer. Also, the histopathological picture of the brain was improved significantly in rats that received TNG (100 mg/kg). Additionally, TNG decreased caspase-3 expression in the brain of PD rats. In conclusion, TNG possesses a significant neuroprotective role against PD-induced acute brain injury via modulating the Nrf2 signaling pathway and quenching the release of inflammatory mediators and apoptosis in rats. [ABSTRACT FROM AUTHOR]

Background: The roles of Connexin43 (Cx43) in clear cell renal cell carcinoma (ccRCC) microenviroment remains to be poorly defined. Methods: The expression profile, prognosis and immune analysis of Cx43 in various cancers, particularly in ccRCC were performed using TCGA database, and various biological function assays were applied to explore the physiological role of Cx43 and tangeretin in ccRCC. Western blot were applied to examine the protein expression and Kunming mice were used to evaluate preliminary safety or anti-tumor activity of tangeretin and sunitinib. Results: Compared with the normal group, higher expression levels of Cx43 in ccRCC, and distinct associations between Cx43 expression and ccRCC prognosis or immune infiltration, were found. Notably, the expression of Cx43 was found to be highly correlated with that of receptor tyrosine kinases (RTKs), particularly with VEGFR1, VEGFR2 and VEGFR3. The expression of Cx43 and EGFR was also found to be higher in ccRCC than that in the para-cancerous specimens. Knocking down Cx43 expression decreased RCC cell viability, cell migration, p-EGFR, MMP-9 and survivin expression. Using 14 Chinese medicine monomers, tangeretin was screened and found to inhibit tumor cell viability and Cx43 expression. Tangeretin also enhanced the sensitivity of RCC cells to tyrosine kinase inhibitors (TKIs) sunitinib and sorafenib. However, the same concentration of tangeretin exerted a less prominent effect on normal renal cell viability. Conclusions: Cx43 is strongly associated with RTK expression and ccRCC progression, while tangeretin can inhibit RCC cell malignancy by inhibiting Cx43 expression and enhance the sensitivity of RCC cells to TKIs.

Zheng J, Shao Y, Jiang Y, et al. Cancer Manag Res. 2019;11:5231–5242. We, the Editors and Publisher of Cancer Management and Therapy, have retracted the following article. Following publication of the article, concerns were raised about the duplication of images from Figures 2, 3 and 4. Specifically, The images for Figure 2A, Control, 30µg/ml, and 90µg/ml have been duplicated with images from Figure 4D, +-0, -+0, -+90 and +-90, respectively. The graph for Figure 3B has been duplicated with the graph for Figure 4G. When approached for an explanation, the authors were cooperative but were unable to provide a sufficient explanation for the image duplication or provide sufficient original data for their study. As verifying the validity of published work is core to the integrity of the scholarly record, we are therefore retracting the article and the authors do not agree with this decision. We have been informed in our decision-making by our editorial policies and COPE guidelines. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as ‘Retracted’.

We previously discovered that the SPC/Fyn/Rho-kinase (ROK) pathway mediates the Ca2+-sensitization of coronary arterial smooth muscle (CASM) contraction leading to vasospasm, a major cause of sudden death. Lately, we have been trying to find and develop more natural edible compounds which can treat and/or prevent the SPC-induced abnormal CASM contraction, and finally the first to discover that tangeretin (5,6,7,8,4′-pentamethoxyflavone), a natural compound extracted from citrus plants, can inhibit the SPC-induced CASM contraction both in the pretreatment and posttreatment. In porcine CASM tissues, tangeretin showed remarkable inhibitory effects on the SPC-induced contraction with modest inhibitory effects on the high K+-depolarization-induced Ca2+-dependent contraction, both in pretreatment and posttreatment at the optimal concentrations; Regarding the mechanisms, tangeretin markedly abolished the SPC-induced cell contraction through inhibiting the SPC-induced activation and translocation of Fyn and ROK from the cytoplasm to the cell membrane in cultured CASM cells, resulting in the reduction of phosphorylation of myosin light chain. Taken together, these findings indicate that tangeretin, upon pre- or post-treatment, inhibits the SPC-induced CASM contraction through suppressing the Fyn/ROK signaling pathway, thereby suggesting that tangeretin can be a potential candidate for the treatment and/or prevention of vasospasm.

Summary: This study aims to reveal the stability of cellulose nanocrystals (CNCs) and astragalin/tangeretin co‐stabilised Pickering emulsion under different environmental factors such as ionic strengths, pH values, thermal treatment, freeze–thaw treatment, sodium ascorbate, and storage condition. Results showed that the astragalin and CNCs co‐stabilised Pickering emulsion (AST‐CPE) could maintain a stable appearance, typical spherical morphology droplets, and steady physical stability under various conditions, including ionic strength at low 20 mm, pH values 2–8, thermal treatment (65, 85, and 135 °C), the addition of sodium ascorbate, and storage at 4 °C for 35 days. It is noteworthy that AST‐CPE showed higher emulsion physical stability at pH 2 (56.67%) and pH 8 (53.33%). The co‐stabilised Pickering emulsion structure has a firm and physically stable system. Moreover, it could effectively protect the bioactive substance by expanding its application in food delivery vehicles. [ABSTRACT FROM AUTHOR]

Our previous research has demonstrated that the changes in oil-water interface properties during dietary digestion have a significant impact on the digestion and absorption of lipids. In this study, these methods of interfacial tension, microscopic examination, isothermal titration calorimetry (ITC), molecular dynamics (MD) simulations, and free fatty acid (FFA) release were used to evaluate the effect and mechanism of assembly behavior of tangeretin (TAN) and β-cyclodextrin (β-CD) at the oil-water interface on the rate of lipid digestion. The results showed that the combination of β-CD and TAN at the oil-water interface made the interfacial tension first increase and then decrease with the increase of TAN: β-CD ratios (M: M, 1:1–20). The self-assembled structure formed by the interaction of TAN and β-CD can produce stronger interaction with bile salts, which makes bile salts flocculate at the oil-water interface. The FFAs release experiment showed that a TAN: β-CD molar ratio of 1:8 exerted the highest inhibitory (34.92%) effect on lipid digestion. Furthermore, the results from ITC and MD simulations confirmed that BS exhibited stronger binding affinity with the TAN/β-CD complex. These results suggested that the TAN/β-CD complex caused the bile salts to prematurely gather at the oil-water interface, thereby thickening the interfacial layer, hindering the displacement of bile salts and lipase between droplets, and ultimately impeding lipid digestion. This study emphasized the promising potential of the synergistic effect between cyclodextrin and flavoring molecules in inhibiting lipid digestion, proposing a novel avenue for the development of reduced-fat foods with enhanced health benefits. [Display omitted] • The binding of TAN and β-CD at oil-water interface promoted the formation of bile salt aggregates. • TAN:β-CD have the strongest inhibitory effect on lipid digestion at a molar ratio of 1:8. • ITC and MD were used to study the TAN/β-CD interaction mechanism at the oil-water interface. [ABSTRACT FROM AUTHOR]

The citrus peel flavonoid tangeretin (TAN) has diverse biological activities, including antioxidant, anti-inflammatory, anti-tumor, hepatoprotective, and neuroprotective effects. This study emphasizes evaluating the anxiolytic effect of TAN on mice. Additionally, we conducted in silico investigations to examine the potential molecular mechanisms behind the anxiolytic effect of TAN. For this, adult male Swiss albino mice were treated with TAN (10 and 20 mg/kg, p.o.) with or without the standard GABAergic agonist drug diazepam (DZP: 2 mg/kg, p.o.) and/or antagonist drug flumazenil (FLU: 0.1 mg/kg, i.p.) and checked for different locomotor behaviors using various mouse models. The molecular docking study of TAN was conducted against GABA A receptor subunits. Findings suggest that TAN dose-dependently and significantly (p < 0.05) increased locomotor activities such as the number of field crosses, hole crosses, swings, and light residence time while decreasing the grooming and rearing parameters of the animals. With DZP, it significantly (p < 0.05) reduced the test parameters while altering these parameters with FLU. In molecular docking, TAN has a strong binding affinity of −6.6 and −7.0 kcal/mol for the α2 and α3 subunits of the GABA A receptor, respectively, whereas the standard drugs DZP and FLU showed binding affinities between −6.0 and −6.7 kcal/mol for these subunits. MD simulations showed that TAN interacts with α3 subunits in a way similar to DZP, with similar RMSD and RMSF values and ligand properties. TAN also demonstrated acceptable drug-likeness and pharmacokinetics. Taken together, TAN augmented the anxiolytic effect of DZP while reducing the effect of FLU in mice. [ABSTRACT FROM AUTHOR]

Malathion (MLT) is an organophosphate pesticide that instigates severe injuries in the testicular tissues. Tangeretin (TGN) is an important naturally present flavone that shows potential antioxidant and anti-apoptotic activities. This research was planned to ascertain the palliative role of TGN against MLT-instigated testicular toxicity in male Sprague-Dawley (SD) rats. 48 rats were distributed into 4 groups: control, MLT (100 mgkg−1), MLT+TGN (100 + 50 mgkg−1 respectively), and TGN (50 mgkg−1). The results showed that MLT exposure reduced the activities of catalase (CAT), glutathione reductase (GSR), superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione (GSH), whereas escalated the levels of reactive oxygen species (ROS) and malondialdehyde (MDA). Moreover, it decreased the levels of luteinizing hormone (LH), plasma testosterone, and follicle-stimulating hormone (FSH). MLT also reduced the expressions of steroidogenic enzymes, including StAR, 3β-HSD, and 17β-HSD. Additionally, MLT exposure increased the expressions of Bax and Caspase-3, while reducing the Bcl-2 expressions. MLT administration also increased the levels of inflammatory markers such as nuclear factor kappa B (NF-κB), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), interleukin-1 beta (1L-1β) as well as cyclooxygenase-2 (COX-2) activity in testes. Nonetheless, TGN recovered all the MLT induced damages in testes. In conclusion, TGN could ameliorate MLT instigated testicular impairment because of its anti-apoptotic, androgenic and anti-oxidant properties. [ABSTRACT FROM AUTHOR]

The bioactive components and bioactivities of citrus peel can be enhanced with microbial fermentation. Accordingly, this study investigated the ability of Aspergillus niger CGMCC3.6189 to accumulate flavonoids in Citrus reticulata peel powder (CRPP) by solid-state fermentation (SSF). Under the optimal SSF conditions including 80% moisture, 30 °C, pH 4.0, 4 × 107 spores/g d.w. CRPP, and 192 h, the total phenolic content (TPC), total flavonoid content (TFC), and 2,2′-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) scavenging activities of fermented CRPP significantly increased by 70.0, 26.8, 64.9, and 71.6%, respectively. HPLC analysis showed that after fermentation, the contents of hesperidin, nobiletin, and tangeretin were significantly increased from 19.36, 6.31, and 2.91 mg/g to 28.23, 7.78, and 3.49 mg/g, respectively, while the contents of ferulic acid and narirutin were decreased under the optimal fermentation conditions. Fermentation time is one of the most important factors that affect the accumulation of flavonoids and antioxidant activity; however, extended fermentation time increased the darkness of CRPP color. Therefore, our study provides a feasible and effective SSF method to increase the bioactive components and the antioxidant activity of CRPP that may be used in food, nutraceutical, and medicinal industries. [ABSTRACT FROM AUTHOR]

Infiltration by adipose tissue macrophages (ATMs) and subsequent metabolic inflammation are the key causes of obesity-induced insulin resistance and metabolic disorders. In this study, we analyzed the potential protective effect of tangeretin, a key flavonoid found extensively in citrus peels, against diet-induced metabolic inflammation. Daily gavages of tangeretin at 20 mg/kg protected the mice from high fat diet (HFD) feeding–induced insulin resistance, ATMs activation, and M1 macrophage polarization. Interestingly, in vitro assays using bone marrow-derived macrophages (BMDMs) showed that tangeretin had only a minimal effect on macrophage polarization. Assays of central carbon metabolism (CCM) in adipose tissue showed that tangeretin treatment rerouted the carbon metabolism and caused lactate accumulation in the microenvironment. Co-culture assays further suggested that tangeretin enhanced M2 polarization of BMDMs when adipocytes were present, whereas blocking the lactate uptake in macrophages reversed the effect of tangeretin on polarization. Taken together, these findings indicated that tangeretin provided indirect protection from diet-induced ATMs activation by reprogramming glucose metabolism and promoting lactate accumulation that subsequently promoted macrophage M2 polarization and reduced inflammation. • Tangeretin reduces obesity induced adipose inflammation. • Tangeretin promotes adipose macrophage M2 polarization. • Tangeretin reprograms adipose carbon metabolism and accumulates lactate. • Blocking lactate uptake in macrophage reverses tangeretin's effect. [ABSTRACT FROM AUTHOR]

Objective To establish the method for the simultaneous determination of liquiritin, ammonium glycyrrhizinate, hesperidin, nobiletin;tangeretin;costunolide, dehydrocostuslactone in Chenxiang Lubailu tablet by HPLC. Methods ZORBAX Eclipse XDB-C18 chromatographic column (4.6 mm×250 mm, 5 μm) was used. The mobile phase was methanol-0.1% phosphoric acid solution. Gradient elution with flow rate of 1.0 ml/min was used. Column temperature was 35 ℃. Detection wavelength for liquiritin, ammonium, tangeretin, and costunolide was at 237 nm. Detection wavelength for glycyrrhizinate was at 283 nm. Detection wavelength for hesperidin and nobiletin was at 330 nm. Injection volume was 10 μl. 16 batches of samples were tested. Results The linear ranges for the detection of liquiritin, ammonium, glycyrrhizinate, hesperidin, nobiletin, tangeretin, and costunolide were 1.110 - 55.72 (r=0.9992), 22.15 - 1108 (r=0.9999), 6.140 - 307.2 (r=0.9995), 1.130 - 56.25 (r=0.9997), 0.3700 - 18.75 (r=0.9982), 0.5200 - 26.01 (r=0.9991), and 1.180 - 58.95 (r=0.9999) μg/ml respectively. The average recoveries were 98.71%, 98.12%, 98.44%, 98.22%, 99.17%, 99.18%, and 97.93%, and the RSDs were 0.16%, 0.67%, 0.57%, 0.62%, 0.48%, 0.56%, and 0.58% respectively. The contents of the seven components in 16 batches of samples were 0.1250 - 1.174, 2.354 - 7.426, 1.822 - 27.21, 0.0370 - 1.399, 0.0723 - 0.4433, 0.0140 - 0.1990, and 0.2207 - 1.407 mg/g respectively. Conclusion The method is accurate, reproducible and durable, which could be used to the quality control and evaluation of Chenxiang Lubailu tablet. [ABSTRACT FROM AUTHOR]

Recent studies strongly suggest that atorvastatin combination therapy with tangeretin could be beneficial in the treatment of hyperlipidemia. This study aimed to investigate the pharmacokinetic interactions among atorvastatin, its active metabolite 2‐hydroxy atorvastatin, and tangeretin after oral administration of atorvastatin with tangeretin in rats. A rapid, selective, and sensitive assay was developed and validated based on ultra‐high performance supercritical fluid chromatography‐tandem mass spectrometry for the simultaneous measurement of atorvastatin, 2‐hydroxy atorvastatin, and tangeretin concentrations in rat plasma. Chromatographic separation of the analytes was conducted on an ACQUITY Torus 1‐AA column in gradient elution mode. The mass transition ion pairs were m/z 559.0→440.0 for atorvastatin, m/z 575.2→440.0 for 2‐hydroxy atorvastatin, m/z 373.0→358.1 for tangeretin, and m/z 254.8→136.7 for daidzein (internal standard). Calibration curves showed good linear correlations at the following concentration range: 1–400 (r = 0.9952), 1–400 (r = 0.9980), and 3–1200 (r = 0.9945) for atorvastatin, 2‐hydroxy atorvastatin, and tangeretin, respectively. The method was fully validated and satisfied the acceptance criteria recommended by the United States Food and Drug Administration. Finally, it was successfully applied in a pharmacokinetic study in rats to evaluate the pharmacokinetic behavior of atorvastatin, 2‐hydroxy atorvastatin, and tangeretin. [ABSTRACT FROM AUTHOR]

Tangeretin is one of the most abundant polymethoxyflavones in citrus peel and its pharmacological effects are extremely rich. However, due to its poor solubility, bitter taste and poor oral bioavailability, the oral administration of tangeretin is still limited, which seriously limits its application in industrial production. The establishment of encapsulation and delivery systems to improve bioavailability is an effective method. This paper reviewed the research progress of the structure and properties, pharmacological effects and main methods to improve bioavailability of tangeretin, including emulsion delivery, lipid encapsulation, microencapsulation and other delivery and utilization research and application. The article aims to provide theoretical basis for the high-value application of tangeretin in functional food and pharmaceutical industry.

As the highest yield crop worldwide, citrus peels that possess bioactive compounds were discarded as a futile by-product. Ultrasonication with environmentally friendly solvent (50% ethanol and ddH2O) were used in the present study to extract flavonoids from Citrus depressa Hayata peels with extraction period and fruit maturity as other variables. DPPH scavenging activity was investigated. Qualitative flavonoid content analysis was done by UV/Vis and FTIR-ATR spectra. Quantification of flavonoid using LC-MS/MS found that solvent type, fruit maturity, and ultrasonication period significantly affect the extracted flavonoid yield (p

Introduction. Nakamoto Seedless, a variety of shikuwasa (Citrus depressa L.) in Okinawa, can be used to produce vinegar extracts because it has no seeds causing bitter taste. However, Nakamono Seedless is hardly cultivated commercially in Okinawa. This research was aimed to develop vinegar extract from Ogimi Kugani, another major variety of shikuwasa, and compare its characteristics with those of extracts from Nakamoto Seedless. Study objects and methods. The study featured vinegar extracts from the whole shikuwasa of Nakamoto Seedless (20% fruit) and Ogimi Kunagi (5, 10, and 20% of fruit) varieties. The fruit was harvested in June, July, and August. We tested the samples for limonin and polymethoxyflavones content and sensory attributes, especially bitterness. Results and discussion. Vinegar extracts with 20% of Ogimi Kugani harvested in June and July tasted bitter compared to those from Nakamoto Seedless harvested in August, but extracts from Ogimi Kugani harvested in August were not bitter. In addition, 5 and 10% vinegar extracts from Ogimi Kugani harvested in June had lower bitterness. The vinegar extracts from both shikuwasa varieties contained polymethoxyflavones ‒ bioactive compounds ‒ and similar flavor. Conclusion. The whole shiluwasa fruit can be used to produce vinegar drinks, Ponzu soy sauce, salad dressings, etc.

Numerous studies have reported that tangeretin is a polymethoxylated flavone with a variety of biological activates, but little research has been done on the antioxidant mechanism of tangeretin. Hence, we investigated the effect of tangeretin on the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway and its potential molecular mechanisms by in vitro and in silico research. The results of molecular docking suggested that tangeretin bound at the top of the central pore of Kelch-like ECH-associated protein 1 (Keap1) Kelch domain, and the hydrophobic and hydrogen bond interactions contributed to their stable binding. Herein, the regulation of Nrf2-ARE pathway by tangeretin was explored in the human embryonic kidney cell line HEK293T, which is relatively easy to be transfected. Upon binding to tangeretin, Nrf2 translocated to the nucleus of HEK293T cells, which in turn activated the Nrf2-ARE pathway. Luciferase reporter gene analysis showed that tangeretin significantly induced ARE-mediated transcriptional activation. Real-time PCR and Western blot assays showed that tangeretin induced the gene and protein expressions of Nrf2-mediated targets, including heme oxygenase 1 (HO-1), nicotinamide adenine dinucleotide phosphate (NADPH) quinone dehydrogenase 1 (NQO1), and glutamate-cysteine ligase (GCLM). In addition, tangeretin could effectively scavenge 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radicals. In summary, tangeretin may be a potential antioxidant via activating the Nrf2-ARE pathway.

Copyright of New Food Industry is the property of NFI LLC. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Diabetes is an amalgamation of metabolic disorders marked by hyperglycemia. Over time diabetes brings up several other complications with it like cardiovascular disease, retinopathy, neuropathy, and nephropathy. among which diabetic nephropathy (DN) is the one we are concerned about in the present study. Diabetes management requires following a healthy lifestyle with proper medication. Most of the anti-diabetic drugs available at present come with adverse side effects. Nature has provided us with several components that are anti-diabetic in nature which has fewer or no side effects and tangeretin is one among them. Tangeretin is a natural flavonoid abundantly present in orange peel and tangerines. Our study is designed to evaluate tangeretin, as an anti-diabetic medication especially for patients suffering from diabetic nephropathy. The procured healthy rats were first divided into four groups: the group I was maintained as healthy control and the others were subjected to the induction of diabetes by i.p. injection of streptozotocin (STZ) at the concentration of 55mg/kg b.wt.Then, the diabetic rats were further divided into three groups: group II was used as the diabetic control rats and the group III and group IV were administered with tangeretin (25mg/kg b.wt) and positive control drug metformin (150mg/kg b.wt) for 8 weeks. The body weight, blood glucose, and serum insulin levels were estimated at week 0 and week 8. Reactive oxygen species (ROS) inhibitory effect, antioxidant, antilipidemic, nephroprotective, and anti-inflammatory effects of tangeretin on the diabetic-induced rats were evaluated at the end of week 8 in addition to the histopathological assessment of the sections of the kidneys of the experimental rats. All the test results concluded that tangeretin was able to significantly decelerate the progression of DN in STZ-induced diabetic rats. [ABSTRACT FROM AUTHOR]

Combining innocuous natural products with cytotoxic agents may enhance the effectiveness of chemotherapy. Tangeretin is a citrus flavonoid that has antineoplastic properties, but its mechanism of action is still unknown. Here, we used a high throughput-screening (HTS) platform to screen for drugs that may synergize with tangeretin and confirmed the top hits against colorectal cancer (CRC) cells in vitro and in vivo. 5-Fluorouracil (5-FU) and PI3K/Akt inhibitors have come out as top hits that show a strong synergy effect with tangeretin by HTS. We further confirmed the synergistic effect of tangeretin with 5-FU against CRC cells in vitro and in vivo. Since 5-FU can increase microRNA-21 (miR-21) expression and activate PI3K/Akt signaling, we addressed if tangeretin acted at this level. In 5-FU treated cells, tangeretin inhibited miR-21 induction, rescued the expression of the target PTEN, reduced Akt activation, and induced autophagy. Together, our data indicated that a natural product, such as tangeretin, can modulate miR-21 expression and that this pathway might be a potential therapeutic target for CRC. Combining tangeretin with 5-FU may be useful in the clinic, since 5-FU is the current first line drug for treating CRC. [ABSTRACT FROM AUTHOR]

Although the Citrus tangerina cultivar “Dahongpao” (CTD) has been established as a rich source of polymethoxyflavones (PMFs) with anti-inflammatory and anti-cancer properties, their individual effects on cellular signaling remain to be elucidated. In this study, five major PMFs from the peel of CTD were isolated, including sinensetin, tetramethyl-O-scutellarin (5,6,7,4′-tetramethoxyflavone), nobiletin (5,6,7,8,3′, 4′-hexamethoxyflavone), tangeretin (5,6,7,8,4′-pentamethoxyflavone), and 5-demethylnobiletin (5-OH-6,7,8,3′,4′-pentamethoxyflavone). These PMFs were found to significantly (p < 0.05) inhibit the production of NO and biomarkers of chronic inflammation (TNF-α and IL-6). Additionally, they effectively suppressed mRNA biomarkers of acute inflammation (Cox-2 and iNOS), and to varying degrees promoted the activation of anti-inflammatory cytokines (IL-4, IL-13, TNF-β, and IL-10). Among the five PMFs, tangeretin was found to have a considerable anti-proliferative effect on tumor cell lines (PC-3 and DU145) and synergistically enhanced the cytotoxicity of mitoxantrone, partially via activation of the PTEN/AKT pathway. The findings of this study provide valuable insights into the activity of different PMF monomers and advance the understanding of the roles of PMFs in promoting apoptotic and anti-cancer effects.

[Display omitted] • This article is the first to describe the protective effect of TG on cisplatin-induced cardiotoxicity injury in vitro and in vivo. • This study is the first to explore the protective effect of TG treatment contributed to protecting cells against cisplatin-induced apoptosis by AMPK phosphorylation and controlling mitochondria stability both in structure and function. • This study clarifies that TG treatment significantly increased the activation of AMP-activated protein kinase (AMPK) and reduced the inactivation of ACC protein and the phosphorylated p38 MAPK protein expressions which inhibited the opening of myocardial mitochondrial permeability transition pore and cell apoptosis. Cardiotoxicity is a common side effect of cisplatin in cancer treatment, often complicating patient care. Tangeretin (TG), a natural compound found in citrus peel, shows promise in protecting against cisplatin-induced heart damage. Our study investigated TG's protective effects both in cell culture and in animal models. TG effectively countered cisplatin-induced damage in heart cells, promoting mitochondrial health and glucose transporter expression. In animal studies, TG reduced markers of heart damage and improved cardiac function. Mechanistically, TG activated AMPK, reduced the inactivation of Acetyl-CoA Carboxylase (ACC) protein and inhibited p38 MAPK and prevented mitochondrial dysfunction and cell death. This research sheds light on TG's potential in safeguarding the heart from cisplatin-induced harm. [ABSTRACT FROM AUTHOR]

[Display omitted] • Hapten of tangeretin has been designed and synthesized. • MAb 6A3A7 showed no CR with other structural analogs of tangeretin. • The developed icELISA provides a simple method for the detection of tangeretin content in citrus and herbal samples. Tangeretin, a polymethoxyflavone abundant in citrus fruits, is acclaimed for its diverse biological benefits to human health and is a significant component of traditional Chinese medicine. This study reports the development of an indirect competitive enzyme-linked immunosorbent assay (icELISA) with monoclonal antibody for quantifying tangeretin in various citrus and herbal medicines. The optimized icELISA demonstrated a half-maximal inhibitory concentration (IC 50) of 5.57 ng/mL, encompassing a dynamic range of 1.54–25.38 ng/mL, and showcased average recoveries ranging from 81.65 % to 105.75 % in citrus peel and pulp samples. Extensive analysis of six citrus cultivar samples and four herbal samples was conducted using the developed assay, with results corroborated by Ultra–Performance Liquid Chromatography Tandem Mass Spectrometry (UPLC–MS/MS). These findings confirm the assay's efficacy and reliability for tangeretin detection, offering a practical method for evaluating this bioactive compound in food. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to investigate the effects of 4-week tangeretin supplementation on the cortisol stress response induced by high-intensity resistance exercise. Methods: A randomized controlled trial of twenty-four soccer players was conducted during the winter training season. The experimental group (EG) took the oral supplement with tangeretin (200 mg/day) and the control group (CG) took placebo for 4 weeks. Before and after the 4-week intervention, all players performed a high intensity bout of resistance exercise to stimulate their cortisol stress responses. Serum cortisol, adreno-corticotropic hormone (ACTH) and superoxide dismutase (SOD) were obtained by collecting blood samples before (PRE), immediately after (P0), and 10 (P10), 20 (P20) and 30 minutes (P30) after the exercise. Results: The serum cortisol level (PRE, p = 0.017; P10, p = 0.010; P20, p = 0.014; P30, p = 0.007) and ACTH (P10, p = 0.037; P30, p = 0.049) of experimental group significantly decreased after the 4-week intervention. Compared with control group, EG displayed a significantly lower level of the serum cortisol (PRE, p = 0.036; P10, p = 0.031) and ACTH (P30, p = 0.044). Additionally, EG presented significantly higher superoxide dismutase activity level compared with CG at P30 (p = 0.044). The white blood cell of EG decreased significantly (PRE, p = 0.037; P30, p = 0.046) and was significantly lower than CG at P20 (p = 0.01) and P30 (p = 0.003). Conclusion: Four-week tangeretin supplementation can reduce serum cortisol and ACTH, which may ameliorate the cortisol stress response in soccer players during high-intensity resistance exercise training. It can also enhance antioxidant capacity, accelerate the elimination of inflammation throughout the body, and shorten recovery time after high-intensity exercise. [ABSTRACT FROM AUTHOR]

Post-traumatic stress disorder often contributes to various anxiety-like behaviors. The single prolonged stress was used to induce anxiety-like behaviors of rats. In this model, using an elevated plus maze test, we observed that tangeretin treatment reversed the decrease in the number of open arms entries, the percentage of time spent in open arms with no change in the number of closed arms entries, and percentage of time spent in closed arms in rats subjected to single prolonged stress. Furthermore, in an open field test, tangeretin treatment reversed the decrease in the number of crossing and time spent in the center field with no change in the activities in the peripheral regions. Diminution in serotonin in different parts of brain of rats with post-traumatic stress disorder was reversed by tangeretin. At the molecular level, tangeretin treatment increased the expression of nuclear factor erythroid 2-related factor 2, heme oxygenase 1, and oxidoreductase-1 that was reduced in the post-traumatic stress disorder group in a dose-dependent manner. In conclusion, these studies have shown for the first time that tangeretin relieves anxiety-like behaviors in rats with post-traumatic stress disorder by activating nuclear factor erythroid 2-related factor 2 signaling pathway. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to investigate the effects of 4-week tangeretin supplementation on the cortisol stress response induced by high-intensity resistance exercise.Methods: A randomized controlled trial of twenty-four soccer players was conducted during the winter training season. The experimental group (EG) took the oral supplement with tangeretin (200 mg/day) and the control group (CG) took placebo for 4 weeks. Before and after the 4-week intervention, all players performed a high intensity bout of resistance exercise to stimulate their cortisol stress responses. Serum cortisol, adreno-corticotropic hormone (ACTH) and superoxide dismutase (SOD) were obtained by collecting blood samples before (PRE), immediately after (P0), and 10 (P10), 20 (P20) and 30 minutes (P30) after the exercise.Results: The serum cortisol level (PRE, p = 0.017; P10, p = 0.010; P20, p = 0.014; P30, p = 0.007) and ACTH (P10, p = 0.037; P30, p = 0.049) of experimental group significantly decreased after the 4-week intervention. Compared with control group, EG displayed a significantly lower level of the serum cortisol (PRE, p = 0.036; P10, p = 0.031) and ACTH (P30, p = 0.044). Additionally, EG presented significantly higher superoxide dismutase activity level compared with CG at P30 (p = 0.044). The white blood cell of EG decreased significantly (PRE, p = 0.037; P30, p = 0.046) and was significantly lower than CG at P20 (p = 0.01) and P30 (p = 0.003).Conclusion: Four-week tangeretin supplementation can reduce serum cortisol and ACTH, which may ameliorate the cortisol stress response in soccer players during high-intensity resistance exercise training. It can also enhance antioxidant capacity, accelerate the elimination of inflammation throughout the body, and shorten recovery time after high-intensity exercise.