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Sinensetin is among the most ubiquitous polyphenols in citrus fruit and recently has been extensively studied for its ability to prevent or treat diseases. The current literature on the bioavailability of sinensetin and its derivatives was reviewed and the potential ameliorative effects of metabolic syndrome in humans were evaluated. Sinensetin and its derivatives mainly aggregated in the large intestine and extensively metabolized through gut microbiota (GM) and the liver. So intestinal microorganisms had a significant influence on the absorption and metabolism of sinensetin. Interestingly, not only GM acted on sinensetin to metabolize them, but sinensetin also regulated the composition of GM. Thus, sinensetin was metabolized as methyl, glucuronide and sulfate metabolites in the blood and urine. Furthermore, sinensetin was reported to have the beneficial effect of ameliorating metabolic syndromes, including disorders of lipid metabolism (obesity, NAFLD, atherosclerosis), glucose metabolism disorder (insulin resistant) and inflammation, in terms of improving the composition of intestinal flora and modulating metabolic pathway factors in relevant tissues. The present work strongly elucidated the potential mechanism of sinensetin in improving metabolic disorders and supported the contribution of sinensetin to health benefits, thus offering a better perspective in understanding the role played by sinensetin in human health. [ABSTRACT FROM AUTHOR]

Aims Coagulase (Coa), a crucial virulence factor of Staphylococcus aureus (S. aureus), is considered a vital target for anti-virulence strategies. The research aimed to discover a natural compound capable of inhibiting S. aureus infection by targeting the virulence factor Coa. Methods and results The study showed that sinensetin at a concentration of 128 μg mL−1 effectively inhibited both Coa-induced coagulation and biofilm formation in S. aureus. However, western blot results indicated that sinensetin did not impact the expression of Coa protein, suggesting that sinensetin may directly target Coa to counteract the virulence of S. aureus. Thermal shift assay results demonstrated that sinensetin enhanced the thermal stability of Coa, supporting the theory of direct binding. Molecular docking and point mutation experiments identified two key binding sites for sinensetin to Coa as R73A-Coa and R204A-Coa. In vivo studies on mice revealed that sinensetin not only reduced lung tissue damage caused by S. aureus infection, but also decreased inflammatory factors in the lung lavage fluid. Furthermore, combining sinensetin with oxacillin improved the survival rates of the Galleria mellonella and mice. Conclusions Sinensetin is a promising natural compound that acts as a direct inhibitor of Coa against S. aureus infections. [ABSTRACT FROM AUTHOR]

Sinensetin is a product isolated from Orthosiphon aristatus, and its antitumor activities have been well established. This study focused on the role and mechanism of sinensetin in lung adenocarcinoma (LUAD). LUAD cells were treated with various concentrations of sinensetin. The proliferation, migration, invasion, and angiogenesis of LUAD cells were detected using colony formation, transwell, and tube formation assays, respectively. The protein levels of VEGF-A, VEGFR-2, and phosphorylated AKT (ser473) were measured by western blotting. The targeted relationship between VEGF-A and miR-374c-5p was verified by luciferase reporter assay. BALB/c nude mice inoculated with A549 cells were treated with sinensetin (40 mg/kg/day) by gavage for 21 days to investigate the effect of sinensetin on tumor growth and angiogenesis in vivo. We found that sinensetin reduced proliferation, migration, invasion, angiogenesis, and cancer stem characteristics of LUAD cells. Sinensetin also suppressed LUAD tumor growth and angiogenesis in vivo. Sinensetin downregulated VEGF-A expression in LUAD cells by enhancing miR-374c-5p expression. MiR-374c-5p inhibited the VEGF-A/VEGFR-2/AKT pathway in LUAD cells. The antitumor effect of sinensetin was reversed by overexpression of VEGF-A or inhibition of miR-374c-5p. Overall, sinensetin upregulates miR-374c-5p to inhibit the VEGF-A/VEGFR-2/AKT pathway, thereby exerting antitumor effect on LUAD. [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]

Background: Paraquat (PQ) is an extremely lethal, water-soluble and non-selective herbicide that is used globally due to its low cost and high efficacy. It exerts strong toxic effects on humans as its exposure leads to free radicals' production. Sinensetin (SNS) is a natural flavonoid with strong anti-cancer, anti-inflammatory and anti-oxidant potentials. Objective: The present study was planned to ascertain the attenuative effect of SNS against PQ induced renal damage in rats. Methods: Forty eight rats were distributed into four groups: control group, PQ-administered group (5 mg/kg), PQ + SNS co-administered group (5 mg/kg and 20 mg/kg) and SNS administered group (20 mg/kg). Results: PQ administration considerably decreased the activities of anti-oxidant enzymes i.e., catalase (CAT), glutathione reductase (GSR), superoxide dismutase (SOD), glutathione peroxide (GPx), glutathione-S-transferase (GST) activities and glutathione (GSH) contents, while reactive oxygen species (ROS) and malondialdehyde (MDA) contents were upsurged. PQ treatment markedly augmented the levels of creatinine, urobilinogen, urea, KIM-1 and NGAL, while significantly decreased albumin protein as well as creatinine clearance. Moreover, the findings of our experiment revealed that PQ notably escalated inflammatory indices i.e., interleukin-1β (IL-1β), nuclear factor kappa-B (NF-κB), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) level and cyclooxygenase-2 (COX-2) activity. Furthermore, PQ intoxication significantly increased Bax, Caspase-3, Caspase-9 level and lowered Bcl-2 level as well as induced histopathological anomalies in kidneys. However, SNS + PQ co-treatment efficiently averted all the PQ-induced renal damages in the rats. Conclusion: The current study indicates that SNS can be used to treat PQ-instigated renal toxicity due to its anti-oxidant, anti-inflammatory and anti-apoptotic properties. [ABSTRACT FROM AUTHOR]

Background: Cancer is ranked among the world's leading causes of death in 2020 with an estimated 10 million recorded fatalities attributable to the disease. After breast, colorectal, and lung cancer, cervical cancer is the fourth most frequent disease in women worldwide. Each year, there are 6,00,000 new cases and 3,40,000 fatalities due to cervical cancer. HPV (Human Papilloma Virus), the main cause of cervical cancer, spreads to the cervix's epithelial cells during intercourse. Aim: The use of natural products in conjunction with chemotherapy treatments is seen to be a viable alternative to chemotherapy medications. Materials and Methods: The purpose of this study was to determine the cytotoxic and apoptotic effects of sinensetin on HepG2 cells. For the determination of cytotoxicity using XXT assay, and LDH release assay, generation of reactive oxygen species was identified by DCFH-DA staining, Nuclear DNA damage was identified by DAPI staining, and apoptotic cell death was detected through AO/EB dual staining, and estimation of pro-apoptotic markers using ELISA method. Results: In the current investigation, the potential of Sinensetin as an anticancer agent for cervical cancer was evaluated. The results showed that apoptosis was induced by Sinensetin in HeLa cells by triggering ROS pathway, DNA damage, and caspase pathway. The cell viability of HeLa cells was reduced with increased concentration of Sinensetin. The LDH level was increased with increased concentration of Sinensetin. Conclusion: All these results suggest that Sinensetin can be used as a potent anticancer drug for cervical cancer. [ABSTRACT FROM AUTHOR]

Polystyrene nanoplastics (PS-NPs) are environmental pollutants that induce oxidative stress (OS) in multiple organs particularly, liver. Sinensetin (SNS) is a naturally present flavones that shows diverse pharmaceutical properties i.e., anti-oxidant, anti-inflammatory and anti-apoptotic. Therefore, the present study was designed to evaluate the therapeutic role of SNS against PS-NPs induced hepatotoxicity. 48 rats were distributed into 4 groups i.e., control, PS-NPs (50 µgkg−1) treated, PS-NPs + SNS (50 µgkg−1 + 20 mgkg−1) co-treated and only SNS (20 mgkg−1) treated group. PS-NPs intoxication reduced the activities of catalase (CAT), glutathione-S-transferase (GST), superoxide dismutase (SOD), glutathione peroxidases (GPx) glutathione reductase (GSR) and glutathione (GSH) level, whereas increased the levels of ROS and MDA. Additionally, PS-NPs increased the levels of liver serum marker enzymes i.e., alanine transaminase (ALT), alkaline phosphatase (ALP) and aspartate aminotransferase (AST). Moreover, the level of inflammatory makers such as nuclear factor-kappa B (NF-κB), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-1 beta (IL-1β) and cyclooxygenase-2 (COX-2) activity were increased following the PS-NPS exposure. The intoxication of PS-NPs elevated Caspase-3, Bax and Caspase-9 levels, while reducing the Bcl-2 level. Furthermore, the exposure of PS-NPs induced significant histopathological damages in hepatic tissue of rats. However, the supplementation of SNS considerably improved the PS-NPs induced damages as well as histological changes due to its hepatoprotective, anti-inflammatory, anti-apoptotic and anti-oxidant nature.

Diabetic nephropathy (DN) affects around 40% of people with diabetes, the final outcome of which is end‐stage renal disease. The deficiency of autophagy and excessive oxidative stress have been found to participate in the pathogenesis of DN. Sinensetin (SIN) has been proven to have strong antioxidant capability. However, the effect of SIN on DN has not been studied. We examined the effect of SIN on cell viability and autophagy in the podocyte cell line, MPC5 cells, treated with high glucose (HG). For in vivo studies, DN mice models were established by intraperitoneal injected with streptozotocin (40 mg/kg) for 5 consecutive days and fed with a 60% high‐fat diet, and SIN was given (10, 20, and 40 mg/kg) for 8 weeks via intraperitoneal injection. The results showed that SIN could protect MPC5 cells against HG‐induced damage and significantly improve the renal function of DN mice. Moreover, SIN remarkably restored the autophagy activity of MPC5 cells which was inhibited under HG conditions. Consistent with this, SIN efficiently improved autophagy in the kidney tissue of DN mice. In brief, our findings demonstrated the protective effect of SIN on DN via restoring the autophagic function, which might provide a basis for drug development. Highlights: Sinensetin (SIN) could protect podocytes from high glucose (HG) injury.SIN could restore the autophagic function injured by HG.SIN could protect the mitochondria of podocytes, kidney damage, and damaged autophagy in the experimental diabetic nephropathy mice model. [ABSTRACT FROM AUTHOR]

This study aims to investigate the potential of sinensetin, a compound found in the Cat's Whiskers plant (Orthosiphon aristatus), as an inhibitor in inhibiting uric acid through its interaction with ATP Binding Cassette Sub-Family G Member 2 (ABCG2). The in-silico approach was employed using software tools such as Pymol, PyRx, Protein Plus, and Lepinski Rule. The results of molecular docking analysis using PyRx demonstrated significant interactions between sinensetin and ABCG2, with Binding Affinity values of -6.8, -6.6, and -6.6, and RMSD values of 0, 0.785, and 1.379. The analysis using Protein Plus confirmed the interaction between sinensetin and ABCG2, supporting the previous docking findings. Furthermore, the evaluation of pharmacokinetic parameters using the Lepinski Rule of Five revealed that sinensetin meets the criteria as a potential drug compound, with a molecular weight of 372, no hydrogen bond donors, seven hydrogen bond acceptors, a log P value of 3.345, and a molar reactivity of 98.5. This research provides new insights into the development of uric acid therapy through an in-silico approach, and these findings can serve as a basis for further research involving in vitro and in vivo validation. [ABSTRACT FROM AUTHOR]

Objective: To investigate the ameliorating effect of Sinensetin on lung tissue damage in rats infected with respiratory syncytial virus(RSV) through AMP-dependent protein kinase(AMPK)/mammalian target of rapamycin(m TOR) signaling pathway.Methods: 30 male Wistar rats were grouped into control group, model group, low-dose Sinensetin group(14 mg/kg), medium-dose Sinensetin group(28 mg/kg), high-dose Sinensetin group(56 mg/kg), high-dose Sinensetin combined AICAR group(56 mg/kg combined500 mg/kg of AMPK activator AICAR), the lung index of rats was calculated. The viral load of RSV in lung tissue was determined by quantitative real-time polymerase chain reaction(qRT-PCR). The levels of inflammatory factors in alveolar lavage fluid of rats were determined by enzyme-linked immunosorbent assay(ELISA). Lung histopathology was determined by HE staining, and Western blot was used to measure the expression of AMPK/m TOR pathway proteins. Results: Compared with the control group, the lung tissue of the model group had inflammatory infiltration, and was loosely arranged, the lung index, RSV viral load in lung tissue, levels of interleukin(IL)-1β, IL-6, tumor necrosis factor-α(TNF-α) in bronchoalveolar lavage fluid, inflammation score, expression of p-AMPK/AMPK and m TORC1 protein increased(P＜0.05). Compared with the model group, the rats of the low-dose Sinensetin group, the medium-dose Sinensetin group, and the high-dose Sinensetin group had reduced lung tissue damage, the lung index of rats, RSV viral load in lung tissue, levels of IL-1β, IL-6, TNF-α in bronchoalveolar lavage fluid, inflammation score, expression of p-AMPK/AMPK, and m TORC1decreased(P＜0.05). Compared with the high-dose Sinensetin group, the lung tissue damage of the rats of the high-dose Sinensetin combined AICAR group was aggravated, the lung index, RSV viral load in lung tissue, levels of IL-1β, IL-6, TNF-α in bronchoalveolar lavage fluid, inflammation score, expression of p-AMPK/AMPK and MTORC1 increased(P＜0.05). Conclusion: Sinensetin may play anti-in flammatory, anti-viral and anti-lung injury effects on RSV-induced rats by inhibiting the activation of AMPK/m TOR signaling pathway. [ABSTRACT FROM AUTHOR]

Cat's Whiskers (Orthosiphon aristatus) is one of the well-known medicinal plants that have been utilized for medical purposes. The flower morphology of O. aristatus plants generally reveals their diversity. There are no reports of secondary metabolite differences between the purple and white-purple varieties of O. aristatus. To maximize the use of the two varieties of O. aristatus as herbal medicines, qualitative and quantitative analyses of secondary metabolites were performed on both varieties. Analyses of phytochemical profiles were conducted using high-performance liquid chromatography (HPLC) with a mobile phase (0.1% formic acid-acetonitrile), the concentrations of active compounds such as rosmarinic acid, sinensetin, and eupatorin were determined. The purple variety's ethanolic extract of its leaves contained rosmarinic acid. Sinensetin concentrations in ethyl acetate and ethanol extracts of purple variety leaves were 2.13 and 3.07% w/w, respectively. In comparison, both white-purple leaf extracts contained up to 0.95 and 1.82 percent sinensetin by weight, respectively. The purple variety leaves' ethanol extract contained the highest concentration of rosmarinic acid at 2.21 % w/w, while the white-purple variety leaves' ethyl acetate extract contained the highest concentration of eupatorin at 3.70 % w/w. Despite belonging to the same species, the composition of the two varieties of O. aristatus differed significantly. The concentration of each active compound, such as sinensetin, rosmarinic acid, and eupatorine, must be considered when O. aristatus is used to prepare herbal medicines. [ABSTRACT FROM AUTHOR]

Introduction: Breast cancer is one of the most prevalent diseases around the world. Breast cancer patients treated with radiation may face Side effects as well as cancer recurrence. Some polyphenols exhibit antioxidant effects. Citrus and Orthosiphon Stamineus have source of methylated flavone called Sinensetin (SIN). In this research, we designation of Sinensetin as increasing radiation sensitivity. Material and Methods: The cytotoxic effect of Sinensetin was examined in MDA-MB-231 and T47D by MTT assay. As well as, the clonogenic ability of cells were Assessmented in the presence of Sinensetin and combination with radiation. To quantify expression alterations of apoptosis related genes, utilized Real-Time PCR method. Results: In a dose and time-dependent manner, Sinensetin decreased the viability of MDA-MB-231 and T47D. The survival fraction was decreased in cells treated with Sinensetin (SIN) prior to X-irradiation compared to cells treated with X-ray only. More ever, expression level of, Bcl-2, STAT3, and increased P53 via treated cells with Sinensetin (SIN) and X-ray. Conclusion: Due to the results, Sinensetin (SIN) can be mentioned as a novel radiosensitizer and its effects may considered increasing apoptosis following DNA damage induced by irradiation. [ABSTRACT FROM AUTHOR]

Introduction: Lung cancer remains the leading cause of cancer death worldwide, so research is ongoing to discover new therapeutics, such as plant-derived bioactive compounds. For example, Sinensetin, a plant-derived polymethoxylated flavonoid, and Imperatorin, a natural furanocoumarin, have anti-cancer properties. This study assessed the effects of sinensetin and imperatorin separately and in combination on A-549 lung cancer cell viability. Method: The A-549 lung cancer cell line was treated with sinensetin (60 µM), imperatorin (30 M), or a combination of both compounds (Sin:Imp 30:30 µM; 50:50 µM and 60:30 µM) for 48 hours. Cell viability was then assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and apoptosis was determined using fluorescein isothiocyanate (FITC) Annexin-V/Propidium iodide staining. Results: The combination treatment of Sin:Imp 50:50 and Sin:Imp 60:30 µM reduced cell viability more than the individual treatment of sinensetin and imperatorin, with the lowest cell viability observed for the combination treatment of Sin:Imp 50:50 µM. Likewise, the combination treatment of Sin:Imp 50:50 µM induced the most apoptosis compared to individual treatment. Conclusion: Sinensetin and imperatorin can decrease A-549 lung cancer cell viability and are potent apoptotic inducers, especially when they are used in combination, therefore they are potential lung cancer therapeutics. [ABSTRACT FROM AUTHOR]

Background: Nephrolithiasis is a condition in which there are one or more kidney stones in the pelvis or calyces. Luteolin, quercetin, apigenin, and sinensetin are marker compounds in the extracts of Plantago major, Sonchus arvensis, Strobilanthes crispus and Orthosiphon stamineus which have nephrolithiasis activity. To control the quality of herbal medicines, a TLC-Densitometry method was developed in this study using luteolin, quercetin, apigenin, and sinensetin as phytochemical markers. Objective: The present work aimed to develop optimal conditions for analyzing luteolin, quercetin, apigenin, and sinensetin. Methods: Determination of optimal conditions for analysis is carried out by determining the composition of the mobile phase, chamber saturation time, and analysis wavelength. Silica gel 60 F254 was used as the stationary phase. Stability tests were carried out by analyzing standards and samples at 0, 4, 8, and 24 hours. Results: The best separation that produces symmetrical peaks of herbal medicine was achieved under isocratic conditions using the composition of the mobile phase chloroform : acetone: dichloromethane : acetonitrile : formic acid (6 : 2: 2 : 0,05 : 0.05 v/v/v/v/ v) with a wavelength of 335 nm with a saturation time of 30 minutes. Conclusion: In this study, the optimal conditions for the analysis of luteolin, quercetin, apigenin, and sinensetin. Luteolin, quercetin, apigenin, and sinensetin are unstable during 8 hours of storage. Therefore, standard solutions and samples must be made fresh to maintain stability. [ABSTRACT FROM AUTHOR]

Background: Quercetin, luteolin, sinensetin and stigmasterol each is the main marker compound in extracts of Sonchus arvensis, Plantago major, Orthosiphon stamineus, and Strobilanthes crispus, respectively. These extracts show nephrolithiasis activity. For quality control of herbal medicines, a high performance liquid chromatography (HPLC) method has been developed in this study using quercetin, luteolin, sinensetin and stigmasterol as phytochemical markers. Objective: to show optimal conditions of analysis and evaluate the stability of quercetin, luteolin, sinensetin and stigmasterol. Methods: The optimal conditions for analysis were carried out by determining the composition of the mobile phase, the flow rate, and the detector's wavelength. Zorbax Eclipse Plus C18 150 x 4.6 mm, 5 μm was used as the column. The stability test was done by analyzing the standard and samples stored at 4oC for 0, 3, 6 and 24 hours. Results: The best separation of the extract was achieved under isocratic conditions using a mixture of water: methanol: phosphoric acid: acetic acid : acetonitrile (50: 30: 0.05: 0.05: 20 v/v/v/ v/v) as mobile phase with detector wavelength of 352 nm, a mobile phase flow rate of 1 mL/min, and a sample injection volume of 10 μL. Conclusion: In this study, the optimal condition for analysis of quercetin, luteolin, sinensetin and stigmasterol. Quercetin, luteolin, sinensetin and stigmasterol were not stable during 6 hours storage, therefore, standard solutions and samples should be made fresh to maintain the stability.

Background: Diabetes Mellitus (DM) is a complex chronic disease characterized by increased blood glucose. The incidence of this disease is rising, especially type 2 diabetes which is caused by insulin resistance in the body. SUR1-Pancreatic KATP Channel is a receptor as an antidiabetic target because its inhibition process can increase insulin production so that it can reduce blood glucose in people with type 2 diabetes. Objective: This study aims to identify the in-silico activity of the SUR1-Pancreatic KATP Channel macromolecules. Methods: Identification of macromolecular binding sites using Protein Plus software, then carried out molecular docking using AutoDock software, where the formed molecular interactions are further identified using the BIOVIA Discovery Studio software. Results: After determining the macromolecular binding site, the RMSD value was 1.253, allowing for further molecular docking. Molecular docking showed that the Ligands of mangostin (α, β, γ-mangostin) and sinensetin derivatives had a good affinity, namely α-mangostin -6,31 kcal/mol; β-mangostin -5.78 kcal/mol; γ-mangostin -6.17 kcal/mol and sinensetin -4.75 kcal/mol. Conclusion: The affinity sequence in the docking process for the SUR1 KATP channel macromolecules is α-mangostin > γ-mangostin > β-mangostin > sinensetin. The highest affinity for the docking process on the macromolecule SUR1 KATP channel was α-mangostin with a value of ΔG -6.31 kcal/mol Ki 23.65 μM.

Although current treatment strategies have improved clinical outcomes of non-small cell lung cancer (NSCLC) patients, side effect and prognosis remain a hindrance. Thus, safer and more effective therapeutical drugs are needed for NSCLC. Sinensetin (Sin) is a flavonoid from citrus fruits, which exhibits antitumor effect on diverse cancers. However, the effect and mechanism of Sin on NSCLC remain unknown. In this study, NSCLC cell lines, and tumor-bearing mice were treated with Sin. The effect and mechanism of Sin were addressed using cell counting kit-8, transwell, enzyme-linked immunosorbent assay, hematoxylin and eosin, immunohistochemistry, and western blot analysis assays in both cell and animal models. Sin reduced the cell viability of A549 and H1299, with the IC50 of 81.46 µM and 93.15 µM, respectively. Sin decreased invaded cell numbers, the expression of N-cadherin and vascular endothelial growth factor A (VEGFA), while increased the E-cadherin level, the cytotoxicity of CD8 + T cells, and the concentration of interferon-γ (IFN-γ), interleukin-2 (IL-2), and tumor necrosis factor-α (TNF-α) in NSCLC cells. Mechanistically, Sin declined the expression of protein kinase B (AKT)/β-catenin pathway, which was restored with the application of SC79, an activator of AKT. The inhibitory role of Sin in NSCLC cell proliferation, invasion, epithelial-mesenchymal transition (EMT) and immune escape was reversed by the management of SC79. In vivo, Sin reduced tumor size and weight, and the expression of N-cadherin, VEGFA, and AKT/β-catenin pathway, but enhanced the level of E-cadherin and IFN-γ. Taken together, Sin suppressed cell growth, invasion, EMT and immune escape via AKT/β-catenin pathway in NSCLC., (© 2024 Wiley Periodicals LLC.)

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.

Kumis kucing mengandung metabolit sekunder sinensetin yang termasuk ke dalam golongan senyawa flavonoid. Sinensetin berpotensi sebagai agen antivirus dan imunomodulator. Tujuan penelitian ini adalah standardisasi tanaman kumis kucing varietas putih dan upaya produksi senyawa sinensetin. Ekstraksi dilakukan dengan metoda maserasi. Tahap pemisahan lanjutan dilakukan dengan metoda ekstraksi cair-cair, kromatografi kolom dan kromatografi cair vakum. Hasil ekstraksi cair-cair terpilih tiga fraksi yaitu fraksi air, etil asetat dan n-heksana. Sebanyak 2,08 gram fraksi etil asetat dilanjutkkan pada tahap pemisahan lanjutan menggunakan kromatografi cair vakum dengan fasa diam silika gel H60 dan fasa gerak n-heksana dan etil asetat. Hasil dari kromatografi cair vakum diperoleh sebanyak 11 subfraksi. Penggabungan dilakukan pada subfraksi 8-11 yang terdeteksi adanya senyawa sinensetin, selanjutnya terhadap subfraksi gabungan dilakukan pemisaahan lanjutan dengan kromatografi kolom. Hasil pemisahan dengan kromatografi kolom diperoleh subfraksi sebanyak 142 vial. Pada subfraksi hasil kromatografi kolom nomor 91-114 terdeteksi adanya isolat sinensetin. Kromatografi lapis tipis preparatif (KLTP) gabungan subfraksi kromatografi kolom 91-114 (SFK) menunjukkan adanya senyawa sinensetin. Berdasarkan hasil pemeriksaan kemurnian dengan menggunakan KLT 2 dimensi dan analisis profil spektrum UV isolat diduga senyawa sinensetin.

Background: Quercetin, luteolin, sinensetin and stigmasterol each is the main marker compound in extracts of Sonchus arvensis, Plantago major, Orthosiphon stamineus, and Strobilanthes crispus, respectively. These extracts show nephrolithiasis activity. For quality control of herbal medicines, a high performance liquid chromatography (HPLC) method has been developed in this study using quercetin, luteolin, sinensetin and stigmasterol as phytochemical markers. Objective: to show optimal conditions of analysis and evaluate the stability of quercetin, luteolin, sinensetin and stigmasterol. Methods: The optimal conditions for analysis were carried out by determining the composition of the mobile phase, the flow rate, and the detector's wavelength. Zorbax Eclipse Plus C18 150 x 4.6 mm, 5 µm was used as the column. The stability test was done by analyzing the standard and samples stored at 4oC for 0, 3, 6 and 24 hours. Results: The best separation of the extract was achieved under isocratic conditions using a mixture of water: methanol: phosphoric acid: acetic acid: acetonitrile (50: 30: 0.05: 0.05: 20 v/v/v/v/v) as mobile phase with detector wavelength of 352 nm, a mobile phase flow rate of 1 mL/min, and a sample injection volume of 10 µL. Conclusion: In this study, the optimal condition for analysis of quercetin, luteolin, sinensetin and stigmasterol. Quercetin, luteolin, sinensetin and stigmasterol were not stable during 6 hours storage, therefore, standard solutions and samples should be made fresh to maintain the stability. [ABSTRACT FROM AUTHOR]

Sinensetin is a polymethoxylated flavone with anti‐inflammatory and anti‐oxidative activities. This work aimed to explore the function and mechanism of sinensetin in oxygen and glucose deprivation/reperfusion (OGD/R)‐induced neurotoxicity. The overlapping target genes of cerebral stroke and sinensetin were determined according to GeneCards and ParmMapper tools and were subjected to Gene Ontology (GO) annotations and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Human cerebral microvascular endothelial cells (HCMECs) were stimulated with OGD/R. Neurotoxicity was investigated by Cell Counting Kit‐8, lactate dehydrogenase (LDH) release, reactive oxygen species (ROS) level, qRT‐PCR, and TUNEL analysis. The proteins (p38, JNK, and ERK) in mitogen‐activated protein kinase (MAPK) signaling were measured using Western blotting. Total of 50 overlapping target genes of cerebral stroke and sinensetin were predicted. Pathway analysis showed they might be involved in the MAPK pathway. Sinensetin attenuated OGD/R‐induced neurotoxicity by mitigating viability reduction, LDH release, ROS generation, inflammatory response, and apoptosis in HCMECs. Sinensetin weakened OGD/R‐induced activation of the MAPK pathway via decreasing the phosphorylation of p38, JNK, and ERK. The pathway inhibitors mitigated the activation of the MAPK signaling, and sinensetin exacerbated this effect. The inhibitors reversed OGD/R‐induced neurotoxicity in HCMECs, and sinensetin contributed to this role. Overall, sinensetin prevents OGD/R‐induced neurotoxicity through decreasing the activation of MAPK pathway. Sinensetin protected human cerebral microvascular endothelial cells against OGD/R‐induced neurotoxicity by inhibiting the activation of the MAPK pathway. This research provides a new insight in the pharmacological function of sinensetin in OGD/R‐induced neurotoxicity and indicates the therapeutic potential of sinensetin in cerebral stroke. [ABSTRACT FROM AUTHOR]

The cat's whiskers (Orthosiphon aristatus (Blume) Miq) plant has been widely used for traditional medicine both in preventive measures and companion therapy. The color of the O. aristatus flower is divided into purple, white-purple, and white varieties. To ensure the quality of the O. aristatus it is necessary to make standardization efforts. Specific standardization parameters are the identification and determination of marker compound levels. Sinensetin is a marker compound in O. aristatus. The research aimed to analyze qualitatively and quantitatively the content of sinensetin in the acetone extract of the purple and white-purple varieties of O. aristatus Extraction was carried out using maceration, which began with determining the ratio of the number of leaves and stem simplicia of two varieties of O. aristatus and acetone solvent. Sinensetin compound identification was carried out on acetone extract and subfraction. Determination of the levels of sinensetin in acetone extract was carried out by thin-layer densitometry chromatography (TLC-Densitometry). Based on the optimization results using TLC, the weight ratio of the simplicia and the amount of solvent is 1 g of simplicia in 15 mL of solvent. Sinensetin compounds were detected in the leaves' acetone extract and stem of two varieties of O. aristatus. The highest sinensetin content was in the acetone extract of purple variety leaves with levels of 0.51% w/w. The acetone extract of the purple variety leaves was further separated by vacuum liquid chromatography and preparative thin-layer chromatography. The results showed a sinensetin compound in the acetone sub-fraction. This study's results can be the basis for the specific characterization of O. aristatus especially those grown in Indonesia, to ensure product quality consistency from traditional medicinal plants. [ABSTRACT FROM AUTHOR]

Sinensetin is a rare polymethoxyflavone that possesses strong anti-angiogenesis activity that can be obtained from Orthosiphon stamineus (O. stamineus) leaves. In this study, supercritical carbon dioxide (SC-CO2) extraction was used to improve sinensetin recovery from O. stamineus leaves. The effect of mean particle size (400–550, 550–650 and 650–750 µm), modifier ratio (0, 5 and 10%, v/v), flow rate (3, 4 and 5 mL/min), temperature (40, 60 and 80 °C) and pressure (10, 20 and 30 MPa) on the concentration of sinensetin and determine its extraction rate were investigated. Two models, viz. Patricelli and Peleg were used to evaluate the kinetic behavior of sinensetin in the SC-CO2 system. Results showed that the highest concentration of sinensetin was successfully extracted at 550–650 µm, 10% (v/v), 5 mL/min, 80 °C and 10 MPa. Also, the kinetic profile of sinensetin was well correlated with Patricelli and Peleg models with a low percentage average absolute relative deviation (AARD%) and a high coefficient of determination (R2) of <6.37% and >0.974, respectively. Thus, the fastest extraction rate of sinensetin was obtained at 9.039 × 10−3 mg/g min−1 using the Patricelli model and 8.694 × 10−3 mg/g min−1 using the Peleg model at 40 °C and 30 MPa. [ABSTRACT FROM AUTHOR]

In the current study, the solubility of potent bioactive compounds from cat's whiskers (Orthosiphon stamineus), viz. sinensetin (SIN) and isosinensetin (ISO), is measured in ethanol-assisted supercritical carbon dioxide (SC-CO2). Experiments were conducted at temperature and pressure of 40–80 °C and 10–30 MPa, respectively. Three semi-empirical models of Chrastil, del Valle-Aguilera, and Gonzalez were used to correlate the compounds' solubility in SC-CO2 + ethanol. The highest solubility of SIN and ISO was obtained at 3.945 and 2.323 mg/L, respectively, at 10 MPa and 80 °C. The solubility data revealed the direct effect of temperature, while the pressure has a dual effect of both increasing and decreasing the compounds' solubility. This study revealed the influence of solute's melting point, dipole moment and molecular structure on its solubility in SC-CO2 + ethanol system. Therefore, SIN has higher solubility in SC-CO2 + ethanol system due to its lower melting and dipole moment compared to its isomer, ISO. In addition, the solubility of the SIN and ISO data was satisfactorily correlated with all semi-empirical models, with less than 4.0% of the AARD%. The enthalpy of vaporization and solvation for SIN and ISO in SC-CO2 extraction were determined. [ABSTRACT FROM AUTHOR]

Ponkan (Citrus reticulate) and Tachibana (Citrus tachibana) contain large amounts of polymethoxyflavones (PMFs). To produce highly functional food with high potential, it is important to develop technologies to increase their PMF content. Nobiletin content of the flavedo changed in harvested ‘Ohta Ponkan’ fruits after ultraviolet (UV)-C irradiation and PMF content increased for only the first 2 days following irradiation. The effect of UV-C or UV-B irradiation on PMF content at each harvest time (UV-C, July to December; UV-B, July to September) was observed in Ponkan and Tachibana. We found that UV-C had the greatest impact earlier in the season. The effects of UV-B irradiation were similar to UV-C results. Therefore, it is beneficial to harvest early and extract PMFs from fruit 24 hours after UV-C irradiation.

Abstract Background Human respiratory system infected with influenza A virus (IAV) elicited a robust pro-inflammatory response that resulted in severe illness and even death. Currently, limited immunomodulator is available to counteract IAV-associated pneumonia in the clinic. Sinensetin, a polymethoxylated flavone with five methoxy groups, has been found to possess anti-agiogenesis, anti-inflammatory and anti-diabetic activities. However, the effects of sinensetin on IAV-triggered pro-inflammatory response remain unclear. In the present study, the anti-inflammatory effects and corresponding possible mechanism of sinensetin in IAV-infected A549 cells were subjected to investigations. Methods The cytotoxic effects of sinensetin towards A549 cells was detected by MTT and LDH assays. The antiviral activity of sinensetin against influenza A virus was assayed in A549 cells with an engineered replication-competent influenza A virus carrying Gaussia luciferase reporter gene infection. The effect of sinensetin on influenza A virus-triggered inflammatory reaction was determined by qRT-PCR, Luminex assays, ELISA and Western blot. Results Our results showed that sinensetin did not exhibit antiviral activity against A/PR/8/34 (H1N1). Meanwhile, sinensetin treatment significantly decreased IAV-induced expression of pro-inflammatory mediators at mRNA and protein levels, including IL-6, TNF-α, IP-10, IL-8 and MCP-1. Additionally, levels of cyclooxygenase (COX)-2 and the downstream product prostaglandin E2 (PGE2) up-regulated by IAV infection were dramatically suppressed by sinensetin. The mechanistic investigation revealed that sinensetin treatment suppressed the NF-κB transcriptional activity using the NF-κB reporter stable HEK293 cell line stimulated with TNF-α (20 ng/mL) or influenza H1N1 virus. Furthermore, sinensetin abrogated influenza H1N1 virus-induced activation of NF-κB, ERK1/2 MAPK and p38 MAPK signalings. Conclusion Collectively, our results indicated that sinensetin has potential capacity to attenuate IAV-triggered pro-inflammatory response via inactivation of NF-κB, ERK1/2 MAPK and p38 MAPK signalings, which implied that sinensetin may be a promising candidate drug for influenza H1N1 virus infection therapeutics.

Sinensetin (SIN) is an important active compound that exists widely in citrus plants, and has been reported to exhibit various pharmacological properties, including anti-oxidative, anti-inflammatory, and anti-tumor. This study was designed to examine whether SIN can protect against amyloid beta (Aβ)-induced neurotoxicity and to elucidate the underlying mechanism. Our results showed that pretreatment with SIN for 1 h, followed by co-treatment with Aβ plus SIN for 24 h, attenuated Aβ25-35-induced cell viability reduction, oxidative stress, inflammation, and apoptosis in a dose-dependent manner. Aβ25-35-induced upregulation of Toll-like receptor 4 (TLR4) expression and nuclear translocation of nuclear factor-kappaB (NF-κB) p65 subunit were inhibited by pretreatment with SIN. Furthermore, the protective effect of SIN was abrogated by TLR4 overexpression. Hence, our data suggested that SIN attenuated Aβ25-35-induced neurotoxicity through the TLR4/NF-κB pathway. [ABSTRACT FROM AUTHOR]

Introduction: Imperata cylindrica root methanol extract harvested from Kendari had anti-hypertensive activity stated in a study on hypertension rat models at the doses 60 and 90 mg/kg-bw. The extract also contained phenolic compound 1.53% (GAE) and flavonoid 1.17% (QE) and had antioxidant activity IC50 0.32 mg/mL. Aim of the study was to determine the active secondary metabolites in the extract. Materials and Method: Sinensetin and imperatorin in the extract were separated on silica gel 60 column, eluted with a gradient eluent system as follows (1) n-hexane-ethyl acetate (3:7); (2) n-hexane - ethyl acetate (2:8); (3) ethyl acetate -MeOH (8:2), and (4) methanol. Imperatorin and sinensetin in fractions were identified and quantified by HPLC method with column LiChroCART 250-4,6 RP 18E, isocratic mobile phases with the composition of mixture as follows, 0.1% formic acid, acetonitrile and methanol (40:50:10) respectively, and at temperature 400 C. The total tannin was determined by spectrophotometry method with Fe(III) chloride and 1.10-Phenanthroline at wave length 510 nm. Results: Imperatorin and sinensetin were identified in fractions 5 to 9. The concentrations of sinensetin and imperatorin in Imperata cylindrica root methanol extract were of 32.348 and 37.014 mg/kg extract, respectively. The total tannin content was 1.06 % (w/w) (TAE). Conclusion: Imperata cylindrica root methanol extract from Kendari had active phytoconstituents, namely sinensetin, imperatorin, and tannin. [ABSTRACT FROM AUTHOR]

As a common degenerative disease, osteoarthritis (OA) usually causes disability in the elderly and socioeconomic burden. Previous studies have shown that proper autophagy has a protective effect on OA. Sinensetin (Sin) is a methylated flavonoid derived from citrus fruits. Studies have shown that Sin is a good autophagy inducer and has shown excellent therapeutic effects in a variety of diseases; however, its role in the treatment of OA is not fully understood. This study proved the protective effect of Sin on OA through a series of in vivo and in vitro experiments. In vitro experiments have shown that Sin may inhibit chondrocyte apoptosis induced by tert-butyl hydroperoxide (TBHP); at the same time, it might also inhibit the production of MMP13 and promote the production of aggrecan and collagen II. Mechanism studies have shown that Sin promotes chondrocyte autophagy by activating AMPK/mTOR signaling pathway. On the contrary, inhibition of autophagy can partially abolish the protective effect of Sin on TBHP-treated chondrocytes. In vivo experiments show that Sin may protect against DMM-induced OA pathogenesis. These results provide evidence that Sin serves as a potential candidate for the treatment of OA.

The incidence of pulmonary fibrosis (PF), a progressively fatal disease, has increased in recent years. However, there are no effective medicines available. Previous results have shown that sinensetin probably has some curative effects on PF. Therefore, this paper aims to predict the targets of sinensetin using a network pharmacology method and to confirm its effects and functional targets in PF using a mouse PF model. First, network pharmacology analysis showed that sinensetin has 105 functional targets, and 1,698 gene targets closely relate to PF. The intersection of the functional targets and gene targets produced 52 targets for the treatment of PF with sinensetin. The PPIs (protein–protein interactions) led to several potential key target genes, including MAPK1, EGFR, SRC, and PTGS2. The results of GO and KEGG analyses suggested the crucial function of apoptosis in PF and its involvement in the PI3K signaling pathway. Subsequently, we tested the molecular docking of sinensetin with the PI3K protein using the AutoDock4 software. The results showed that sinensetin could fit well into several binding sites of the PI3K protein. Furthermore, we constructed a PF mouse model through one-off intratracheal instillation of bleomycin and then intragastrically administered different concentrations of sinensetin to the model mice. Twenty-eight days later, the mice were sacrificed, and the lung tissues, serum, and bronchoalveolar lavage fluid (BALF) were collected. The in vivo tests showed that the body weight of model mice increased slightly compared with that of PF mice after intragastric sinensetin. HE and Masson staining suggested a certain extent of reduction in the pathology of lung tissues. The expression of collagens I and III, as well as hydroxyproline in the lung tissues, was reduced to a certain extent. IL-6 levels in the serum and BALF decreased markedly. The expression of vimentin and α-SMA in pulmonary tissues decreased. Cell apoptosis, as well as P-PI3K and P-AKT levels, in lung tissues also reduced. In summary, network pharmacology and in vivo test results suggest sinensetin causes an effective delay in the progression of pulmonary fibrosis, and the functional mechanism is likely related to PI3K-AKT signaling.

As a common degenerative disease, osteoarthritis (OA) usually causes disability in the elderly and socioeconomic burden. Previous studies have shown that proper autophagy has a protective effect on OA. Sinensetin (Sin) is a methylated flavonoid derived from citrus fruits. Studies have shown that Sin is a good autophagy inducer and has shown excellent therapeutic effects in a variety of diseases; however, its role in the treatment of OA is not fully understood. This study proved the protective effect of Sin on OA through a series of in vivo and in vitro experiments. In vitro experiments have shown that Sin may inhibit chondrocyte apoptosis induced by tert-butyl hydroperoxide (TBHP); at the same time, it might also inhibit the production of MMP13 and promote the production of aggrecan and collagen II. Mechanism studies have shown that Sin promotes chondrocyte autophagy by activating AMPK/mTOR signaling pathway. On the contrary, inhibition of autophagy can partially abolish the protective effect of Sin on TBHP-treated chondrocytes. In vivo experiments show that Sin may protect against DMM-induced OA pathogenesis. These results provide evidence that Sin serves as a potential candidate for the treatment of OA. [ABSTRACT FROM AUTHOR]

Background: Diabetes mellitus (DM) is a complex chronic disease with hyperglycemia, which is glucose levels above normal whose number of sufferers is increasing. By inhibiting the human maltase-glucoamylase enzyme which is included in the starch-digestion pathway are used to delay glucose production and thus aid in the treatment of type II diabetes. Aims and Methods: To analyze the potential of mangostin derivatives (alpha-mangostin, betamangostin, gamma-mangostin) and sinensetin as anti-diabetes through ADMET prediction and in silico tests against human maltase-glucoamylase targets using the docking method with miglitol was used as a control. Result: The ligands ɑ, β, γ-mangostin and sinensetin have good interactions with macromolecules and form hydrogen bonds also van der Waals on the macromolecule active side of human maltase-glucoamylase. Conclusion: The ADMET of mangostin derivatives (ɑ, β, and γ), and sinensetin can be predicted by the pkCSM online tool, and they showed good affinity on maltase-glucoamylase target compared to standard drugs like miglitol. [ABSTRACT FROM AUTHOR]

The incidence of pulmonary fibrosis (PF), a progressively fatal disease, has increased in recent years. However, there are no effective medicines available. Previous results have shown that sinensetin probably has some curative effects on PF. Therefore, this paper aims to predict the targets of sinensetin using a network pharmacology method and to confirm its effects and functional targets in PF using a mouse PF model. First, network pharmacology analysis showed that sinensetin has 105 functional targets, and 1,698 gene targets closely relate to PF. The intersection of the functional targets and gene targets produced 52 targets for the treatment of PF with sinensetin. The PPIs (protein–protein interactions) led to several potential key target genes, including MAPK1, EGFR, SRC, and PTGS2. The results of GO and KEGG analyses suggested the crucial function of apoptosis in PF and its involvement in the PI3K signaling pathway. Subsequently, we tested the molecular docking of sinensetin with the PI3K protein using the AutoDock4 software. The results showed that sinensetin could fit well into several binding sites of the PI3K protein. Furthermore, we constructed a PF mouse model through one-off intratracheal instillation of bleomycin and then intragastrically administered different concentrations of sinensetin to the model mice. Twenty-eight days later, the mice were sacrificed, and the lung tissues, serum, and bronchoalveolar lavage fluid (BALF) were collected. The in vivo tests showed that the body weight of model mice increased slightly compared with that of PF mice after intragastric sinensetin. HE and Masson staining suggested a certain extent of reduction in the pathology of lung tissues. The expression of collagens I and III, as well as hydroxyproline in the lung tissues, was reduced to a certain extent. IL-6 levels in the serum and BALF decreased markedly. The expression of vimentin and α -SMA in pulmonary tissues decreased. Cell apoptosis, as well as P-PI3K and P-AKT levels, in lung tissues also reduced. In summary, network pharmacology and in vivo test results suggest sinensetin causes an effective delay in the progression of pulmonary fibrosis, and the functional mechanism is likely related to PI3K-AKT signaling. [ABSTRACT FROM AUTHOR]

Abstract Background Sarcopenia, the decline of skeletal muscle tissue attributed to primary aging is a major concern in older adults. Flavonoids might have potential benefits by modulating the regulation of satellite cells, thus preventing muscle loss. Sinensetin (SIN), a citrus methylated flavone with anti-inflammatory and anti-proliferative activity, can enhance lipolysis. The objective of the present study was to investigate whether SIN might have sarcopenia-suppressing effect on satellite cells from thigh and calf muscle tissues of young and old rats. Methods Primary muscle cells were obtained from thigh and calf tissues of young and old group rats by dissection. Obtained satellite cells were incubated with indicated concentrations of SIN (50 and 100 μM) treated and untreated condition in differentiation medium. Morphological changes of cells were examined using a phase-contrast microscope. Protein expression levels of myoD and myogenin were analyzed by Western blot. Cells treated with or without SIN under differentiation condition were also immunocytochemically stained for myogenin and 4′,6-diamidino-2-phenylindole (DAPI). Results Morphologically, the differentiation extracted satellite cells was found to be more evident in SIN treated group of aged rat′s cells than that in SIN untreated group. Expression levels of myoD and myogenin proteins involved in myogenesis were increased upon treatment with SIN. Conclusions Collectively, our results indicate that SIN can alleviate age-related sarcopenia by increasing differentiation rate and protein levels of myoD and myogenin.

The study of natural compound as α-amylase inhibitor has been a concern since the synthetic drugs for the management of type 2 diabetes mellitus have several side effects. The present study was carried out to predict the ability of rosmarinic acid and sinensetin as human α-amylase inhibitor by in silico study. All of the prepared 3D structures were used in the molecular docking by using Hex 8.0.0. The visualization of the molecular interactions of those compounds with human salivary α-amylase or human pancreatic α-amylase was established in the Discovery Studio Client 4.1 software. The result of this study determined that rosmarinic acid and sinensetin bound to the A domain of human pancreatic α-amylase and human salivary α-amylase. Rosmarinic acid-human salivary α-amylase complex was observed to possess high number of hydrogen bonds compared to sinensetin-human salivary α-amylase complex. The similar result was observed in the comparison of rosmarinic acid-human pancreatic α-amylase complex and sinensetin-human pancreatic α-amylase complex. The rosmarinic acid was able to bind the Glu233 of human pancreatic α-amylase. These data suggest rosmarinic acid as a potential inhibitor of human salivary α-amylase and human pancreatic α-amylase. Further experimental evidence is needed to confirm this observation.

Sinensetin, a plant-derived polymethoxylated flavonoid found in Orthosiphon aristatus var. aristatus and several citrus fruits, has been found to possess strong anticancer activities and a variety of other pharmacological benefits and promising potency in intended activities with minimal toxicity. This review aims to compile an up-to-date reports of published scientific information on sinensetin pharmacological activities, mechanisms of action and toxicity. The present findings about the compound are critically analyzed and its prospect as a lead molecule for drug discovery is highlighted. The databases employed for data collection are mainly through Google Scholar, PubMed, Scopus and Science Direct. In-vitro and in-vivo studies showed that sinensetin possessed strong anticancer activities and a wide range of pharmacological activities such as anti-inflammatory, antioxidant, antimicrobial, anti-obesity, anti-dementia and vasorelaxant activities. The studies provided some insights on its several mechanisms of action in cancer and other disease states. However, more detail mechanistic studies are needed to understand its pharmacological effects. More in vivo studies in various animal models including toxicity, pharmacokinetic, pharmacodynamic and bioavailability studies are required to assess its efficacy and safety before submission to clinical studies. In this review, an insight on sinensetin pharmacological activities and mechanisms of action serves as a useful resource for a more thorough and comprehensive understanding of sinensetin as a potential lead candidate for drug discovery.

The technique of ultrasound‐assisted extraction was used to recover polyhydroxylated and polymethoxylated flavones, and phenolic acids from Orthosiphon aristatus. The compounds were then partitioned in different solvents such as hexane, chloroform, ethyl acetate, and acetone with increasing polarity. This workflow would reduce the complexity of chemical composition in crude extract to ease phytochemical profiling using a high throughput analytical tool of liquid chromatography with tandem mass spectrometry. Several newly reported flavone derivatives such as velutin, tricin, 3,7‐dimethylquercetin, 4′,7′‐dimethoxyluteolin, 4′,7′‐dimethoxyluteolin‐dimethyl ether, and 5‐hydroxy‐3,4′,7‐trimethoxyflavone, in addition to previously reported compounds were detected. The recovered flavone derivatives were mostly lipophilic in nature because they were partitioned in hexane and chloroform, particularly the dimer and trimer of sinensetin. Meanwhile, phenolic acids such as rosmarinic acid and salvianolic acid were detected in the ethyl acetate and acetone fractions, as well as in the remaining aqueous residue. These phenolic acids rich fractions were also found to have higher antioxidant capacity than crude extract. The combination of ultrasound‐assisted extraction and solvent partition provided insights into the profile of polyhydroxylated and polymethoxylated flavones, and phenolic acids from the highly complex herbal plant of O. aristatus. The detection of the phytochemicals may explain the previously reported pharmacological properties of the herb. [ABSTRACT FROM AUTHOR]

Inhibition of α-glucosidase and non-enzymatic glycation is regarded as an effective method to prevent and treat type 2 diabetes and its complications. In this study, the inhibition of sinensetin on α-glucosidase and non-enzymatic glycation was studied with multi-spectroscopic techniques and molecular docking analysis. The results of fluorescence spectroscopy analysis indicated that sinensetin quenched the endogenous fluorescence of α-glucosidase in static manner. The binding of sinensetin with α-glucosidase was a spontaneous process primarily driven by hydrophobic interaction. At 298 K, the binding constant was (5.70 ± 0.12) × 104 L·mol−1 and the binding site number was 1. The conformation of α-glucosidase was altered by sinensetin, which was revealed by circular dichroism (CD), FTIR spectra, synchronous fluorescence and three-dimensional (3D) fluorescence spectroscopy methods. Molecular docking analysis demonstrated that sinensetin interacted with the amino acid residues of α-glucosidase, which might prevent the entrance of substrate, leading to the decrease of catalytic efficiency of α-glucosidase. Furthermore, glycation assays showed that sinensetin stabilized the structure of bovine serum albumins (BSA), interacted with BSA, strongly inhibited the formation of dityrosine, N′-formylkynurenine and advanced glycation end products (AGEs). This study provided useful information concerning sinensetin preventing and treating type 2 diabetes and its related complications. Sinensetin inhibited α-glucosidase activity and non-enzymatic glycation reaction. Unlabelled Image • Sinensetin bound with α-glucosidase and changed its conformation. • The binding was a spontaneous process primarily driven by hydrophobic interaction. • Sinensetin suppressed glycation-induced protein oxidation. • Sinensetin exhibited strong inhibitory activities on α-glucosidase and glycation. • Sinensetin exerted hypoglycemic activity via multiple targets. [ABSTRACT FROM AUTHOR]

Orthosiphon stamineus Benth. (Lamiaceae) is a valued medicinal plant in traditional folk medicine. Many pharmacological studies have demonstrated the ability of this plant to exhibit antimicrobial, antioxidant, hepatoprotection, antigenotoxic, antiplasmodial, cytotoxic, cardioactive, antidiabetic, anti-inflammatory activies. This review is a comprehensive summary of the presently available chemical, pharmacological investigations as well as the traditional and therapeutic uses of this plant. Important and different experimental data have been addressed along with a review of all phytochemicals identified in this plant, including flavonoids, terpenoids, and essential oils. O. stamineus has wide traditional and pharmacological uses in various pathophysiological conditions. Therefore, it is an attractive subject for further experimental and clinical investigations.

Due to the health benefits such as anti-diabetic, antioxidant, and anti-inflammatory agents, the extraction of bioactive compounds from natural plants becomes significant. One of the favored extraction processes is supercritical carbon dioxide (SC-CO2). SC-CO2 is known as a green method with a high-selectivity process. Therefore, this study aims to determine the best parameters and mass transfer process to extract the bioactive compounds, viz. sinensetin, isosinensetin, and rosmarinic acid, in the leaves of Orthosiphon stamineus using the SC-CO2 extraction technique. Response surface methodology was applied to optimize the operating temperature and pressure of 40–80 °C and 10–30 MPa, respectively. Meanwhile, to quantify the concentration of sinensetin, isosinensetin, and rosmarinic acid, a high-performance liquid chromatography was used. Results showed that the level of sinensetin, isosinensetin, and rosmarinic acid varied significantly at each extraction condition from 122.98 to 469.54 mg/kg sample, 50.60 to 419.07 mg/kg sample, and 17.43 to 931.44 mg/kg, respectively. Based on the optimization study, the optimum pressure and temperature were 10 MPa and 80 °C, respectively, with 440.3 mg/g sinensetin, 392.9 mg/g isosinensetin, and 752.0 mg/g of rosmarinic acid concentration obtained. Meanwhile, the single-sphere model showed a significant correlation with sinensetin, isosinensetin, and rosmarinic acid extraction, with an average AARD of 12.31%, 13.72%, and 18.90%, respectively. The range of diffusivity coefficient, De, of sinensetin, isosinensetin, and rosmarinic acid was 5.47E−13–1.81E−12 m2/s, 8.26E−13–1.89E−12 m2/s, and 2.64E−13–2.28E−12 m2/s, respectively. [ABSTRACT FROM AUTHOR]

Background: Human respiratory system infected with influenza A virus (IAV) elicited a robust pro-inflammatory response that resulted in severe illness and even death. Currently, limited immunomodulator is available to counteract IAV-associated pneumonia in the clinic. Sinensetin, a polymethoxylated flavone with five methoxy groups, has been found to possess anti-agiogenesis, anti-inflammatory and anti-diabetic activities. However, the effects of sinensetin on IAV-triggered pro-inflammatory response remain unclear. In the present study, the antiinflammatory effects and corresponding possible mechanism of sinensetin in IAV-infected A549 cells were subjected to investigations. Methods: The cytotoxic effects of sinensetin towards A549 cells was detected by MTT and LDH assays. The antiviral activity of sinensetin against influenza A virus was assayed in A549 cells with an engineered replication-competent influenza A virus carrying Gaussia luciferase reporter gene infection. The effect of sinensetin on influenza A virustriggered inflammatory reaction was determined by qRT-PCR, Luminex assays, ELISA and Western blot. Results: Our results showed that sinensetin did not exhibit antiviral activity against A/PR/8/34 (H1N1). Meanwhile, sinensetin treatment significantly decreased IAV-induced expression of pro-inflammatory mediators at mRNA and protein levels, including IL-6, TNF-α, IP-10, IL-8 and MCP-1. Additionally, levels of cyclooxygenase (COX)-2 and the downstream product prostaglandin E2 (PGE2) up-regulated by IAV infection were dramatically suppressed by sinensetin. The mechanistic investigation revealed that sinensetin treatment suppressed the NF- κB transcriptional activity using the NF-κB reporter stable HEK293 cell line stimulated with TNF-α (20 ng/mL) or influenza H1N1 virus. Furthermore, sinensetin abrogated influenza H1N1 virus-induced activation of NF-κB, ERK1/2 MAPK and p38 MAPK signalings. Conclusion: Collectively, our results indicated that sinensetin has potential capacity to attenuate IAV-triggered pro-inflammatory response via inactivation of NF-κB, ERK1/2 MAPK and p38 MAPK signalings, which implied that sinensetin may be a promising candidate drug for influenza H1N1 virus infection therapeutics. [ABSTRACT FROM AUTHOR]

• Sinensetin, an active compound derived from Orthosiphon aristatus leaves. • Sinensetin exhibits antiproliferative effects in HepG2 cells and induces apoptosis. • Molecular evident of apoptotic activation were confirmed by mRNA and protein level. Orthosiphon aristatus is a traditional folk medicine extensively used in Southeast Asia because of its various pharmacological effects, including antioxidant, antitumor, and hypoglycemic activities. Orthosiphon extracts have been found to be cytotoxic to hepatocellular carcinoma (HCC) cells, which is attributed to their phytochemical content. However, the mechanism of action underlying the cytotoxic effects remains unclear. Hence, the present study investigated the effect of Sinensetin purified from O. aristatus on HCC in vitro. Sinensetin was isolated from O. aristatus leaves and the chemical structure was confirmed by ultra violet (UV)-vis, infrared (IR), nuclear magnetic resonance (NMR), and electrospray ionization mass spectrometry (ESI-MS). The results revealed that 24-h treatment with the purified compound markedly inhibited the survival of HepG2 cells, with IC 50 of 39.93 ± 1.10 μg/mL. HepG2 cells treated with the IC 50 of Sinensetin showed characteristic morphological changes, as determined by PI and AO/Etbr dual staining, including DNA fragmentation, thus confirming the apoptosis induction. Sinensetin induced cell cycle arrest at G0/G1 phase, and the data were substantiated by flow cytometry. Furthermore, Sinensetin modulated key signaling molecules; anti-apoptotic Bcl-xL was down-regulated, whereas the expressions of tumor suppressors TRAIL and PTEN were up-regulated. We conclude that Sinensetin can be effective against HCC. [ABSTRACT FROM AUTHOR]

Polystyrene nanoplastics (PS-NPs) are environmental pollutants that induce oxidative stress (OS) in multiple organs particularly, liver. Sinensetin (SNS) is a naturally present flavones that shows diverse pharmaceutical properties i.e., anti-oxidant, anti-inflammatory and anti-apoptotic. Therefore, the present study was designed to evaluate the therapeutic role of SNS against PS-NPs induced hepatotoxicity. 48 rats were distributed into 4 groups i.e., control, PS-NPs (50 µgkg−1) treated, PS-NPs + SNS (50 µgkg−1 + 20 mgkg−1) co-treated and only SNS (20 mgkg−1) treated group. PS-NPs intoxication reduced the activities of catalase (CAT), glutathione-S-transferase (GST), superoxide dismutase (SOD), glutathione peroxidases (GPx) glutathione reductase (GSR) and glutathione (GSH) level, whereas increased the levels of ROS and MDA. Additionally, PS-NPs increased the levels of liver serum marker enzymes i.e., alanine transaminase (ALT), alkaline phosphatase (ALP) and aspartate aminotransferase (AST). Moreover, the level of inflammatory makers such as nuclear factor-kappa B (NF-κB), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-1 beta (IL-1β) and cyclooxygenase-2 (COX-2) activity were increased following the PS-NPS exposure. The intoxication of PS-NPs elevated Caspase-3, Bax and Caspase-9 levels, while reducing the Bcl-2 level. Furthermore, the exposure of PS-NPs induced significant histopathological damages in hepatic tissue of rats. However, the supplementation of SNS considerably improved the PS-NPs induced damages as well as histological changes due to its hepatoprotective, anti-inflammatory, anti-apoptotic and anti-oxidant nature. [ABSTRACT FROM AUTHOR]

Background: Although there are many treatments for breast cancer, such as surgery, radiotherapy, chemotherapy, estrogen receptor antagonists, immune checkpoint inhibitors and so on. However, safer and more effective therapeutic drugs for breast cancer are needed. Sinensetin, a safer therapeutic drugs, come from citrus species and medicinal plants used in traditional medicine, while its role and underlying mechanism in breast cancer remain unclear. Our study aimed to investigate the role and mechanism of sinensetin in breast cancer., Methods: Cell Counting Kit-8 (CCK-8) was used to determine the safe concentration of sinensetin in MCF-10A, MCF7 and MDA-MB-231 cells; 120 μM sinensetin was used in subsequent experiments. Real time polymerase chain reaction (RT-PCR), Western blotting, Terminal Deoxynucleotidyl Transferase mediated dUTP Nick-End Labeling (TUNEL) apoptosis assay, Transwell invasion assay and Clone formation assay were used in this study to determine cell viability, mRNA expression, protein levels, apoptosis, proliferation, invasion and so on., Results: Herein, our results showed that 120 μM sinensetin suppressed the cell viability and promoted apoptosis of MCF7 and MDA-MB-231 cells. Treatment with 120 µM sinensetin for 24 h showed no significant toxicity to normal mammary cells; 120 μM sinensetin decreased cell proliferation, invasion, and epithelial-mesenchymal transition (EMT), and downregulated β-catenin, lymphatic enhancing factor 1 (LEF1), T-cell factor (TCF) 1/TCF7, and TCF3/TCF7L1 expression in MCF7 and MDA-MB-231 cells. The Wnt agonist SKL2001 reversed the inhibitory effect of sinensetin on cell survival, metastasis, and EMT. Sinensetin-induced downregulation of β-catenin, LEF1, and TCF1/TCF7 expression were upregulated by SKL2001 in MCF7 and MDA-MB-231 cells., Conclusions: In summary, sinensetin suppressed the metastasis of breast cancer cell via inhibition of Wnt/β-catenin pathway and there were no adverse effects on normal breast cells. Our study confirmed the role of sinensetin in breast cancer cells and provided a better understanding of the underlying mechanism., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-23-1317/coif). The authors have no conflicts of interest to declare., (2024 Translational Cancer Research. All rights reserved.)

Exploring the interaction of small molecules with therapeutic proteins can provide useful information about development of ligand-protein complexes as synergistically therapeutic platforms. In this study, the interaction of sinensetin with human interferon gamma (IFNγ) was evaluated experimentally and theoretically. Also, the synergistic effects of IFNγ- sinensetin complex on the inhibition of hepatocellular carcinoma HepG2 cell proliferation were assessed by cell viability and quantitative real time PCR assays. It was realized that sinensetin interacts with IFNγ through a static quenching mechanism and hydrophobic forces mediated by presence of Lys55 and Lys58 amino acid residues in the binding site were the main contributing forces in the spontaneous formation of IFNγ-sinensetin complex. Also, the interaction of sinensetin with IFNγ did not induce a significant change in the secondary and tertiary structure of the protein. Cellular assays revealed a synergistic effect of sinensetin on IFNγ -triggered anticancer action in HepG2 cells through overexpression of caspase-3 mRNA and protein. In conclusion, this study may hold great promise for the development of potential ligand- protein complexes for therapeutic purposes., 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 B.V.)

Background: Sarcopenia, the decline of skeletal muscle tissue attributed to primary aging is a major concern in older adults. Flavonoids might have potential benefits by modulating the regulation of satellite cells, thus preventing muscle loss. Sinensetin (SIN), a citrus methylated flavone with anti-inflammatory and anti-proliferative activity, can enhance lipolysis. The objective of the present study was to investigate whether SIN might have sarcopenia-suppressing effect on satellite cells from thigh and calf muscle tissues of young and old rats. Methods: Primary muscle cells were obtained from thigh and calf tissues of young and old group rats by dissection. Obtained satellite cells were incubated with indicated concentrations of SIN (50 and 100 μM) treated and untreated condition in differentiation medium. Morphological changes of cells were examined using a phase-contrast microscope. Protein expression levels of myoD and myogenin were analyzed by Western blot. Cells treated with or without SIN under differentiation condition were also immunocytochemically stained for myogenin and 4′,6-diamidino-2-phenylindole (DAPI). Results: Morphologically, the differentiation extracted satellite cells was found to be more evident in SIN treated group of aged rat′s cells than that in SIN untreated group. Expression levels of myoD and myogenin proteins involved in myogenesis were increased upon treatment with SIN. Conclusions: Collectively, our results indicate that SIN can alleviate age-related sarcopenia by increasing differentiation rate and protein levels of myoD and myogenin. [ABSTRACT FROM AUTHOR]

Orthosiphon aristatus known as java tea is one of the medicinal plants commonly used in some herbal medicines especially for diuretics and to treat diabetes. Orthosiphon aristatus leaves could be substituted or mixed with Eupatorium riparium and Acalypha siamensis because of the similarity in their morphological leaves. To detect contamination of O. aristatus from the two similar plants, we developed an HPLC fingerprinting in combination with multivariate analysis. By using the developed method, we could also simultaneously determine two bioactive marker compounds in O. aristatus namely rosmarinic acid and sinensetin. Fingerprint chromatogram of the three samples showed a different chromatogram profile, so it could be used to distinguish the three samples. A combination of HPLC fingerprint and linear discriminant analysis was successfully grouped the three samples and adulterated O. aristatus with E. riparium and A. siamensis. The result indicated that the developed method could detect adulterated samples of O. aristatus from the other two plants used in this study and for the quantification of rosmarinic acid and sinensetin in O. aristatus simultaneously. [ABSTRACT FROM AUTHOR]

Cases of human African trypanosomiasis caused by infection with a protozoan parasite, Trypanosoma brucei , are decreasing due to enhanced surveillance and control. However, effective and safe treatments for this disease are still needed. In this study, we investigated the antitrypanosomal activity of citrus fruit peel. When 19 citrus cultivars were examined for activity against T. brucei in vitro , significant activities were observed in four closely related cultivars and a distantly related one. Among these five cultivars, "Setoka" was selected for identification of its active components due to exhibiting the highest activity. Solvent extraction and gel filtration followed by preparative thin-layer chromatography succeeded in isolating two compounds exhibiting IC 50 s of 4.8 and 2.4 μg/mL, respectively. The spectral data of these two compounds were well consistent with those of sinensetin and nobiletin belonging to the class of polymethoxyflavones. Authentic compounds also showed similar IC 50 s. These results indicate that the two polymethoxyflavones are the major active components involved in the inhibition of T. brucei proliferation and are abundant in Setoka cultivar peel compared with the levels in the other cultivars. Setoka peel and the naturally occurring polymethoxyflavones might serve as dietary components imparting resistance to T. brucei. Image 1075991 • Five out of 19 citrus cultivars showed significant antitrypanosomal activity. • Sinensetin and nobiletin were isolated as active components contained in one of the active cultivars. • Polymethoxyflavones have favorable properties for prophylactic and therapeutic use against Trypanosoma brucei infection. [ABSTRACT FROM AUTHOR]