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The present study investigated the melanogenic effects of imperatorin and isoimperatorin and the underlying mechanisms of imperatorin using a mouse melanoma B16F10 model. Interestingly, treatment with 25 μM of either imperatorin or isoimperatorin, despite their structural differences, did not produce differences in melanin content and intracellular tyrosinase activity. Imperatorin also activated the expression of melanogenic enzymes, such as tyrosinase (TYR) and tyrosinase-related proteins TYRP-1 and TYRP-2. Mechanistically, imperatorin increases melanin synthesis through the cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA)/cAMP-responsive element-binding protein (CREB)-dependent upregulation of microphthalmia-associated transcription factor (MITF), which is a key transcription factor in melanogenesis. Furthermore, imperatorin exerted melanogenic effects by downregulating extracellular signal-regulated kinase (ERK) and upregulating phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT)/glycogen synthesis kinase-3β (GSK-3β). Moreover, imperatorin increased the content of β-catenin in the cell cytoplasm and nucleus by reducing the content of phosphorylated β-catenin (p-β-catenin). Finally, we tested the potential of imperatorin in topical application through primary human skin irritation tests. These tests were performed on the normal skin (upper back) of 31 volunteers to determine whether 25 or 50 µM of imperatorin had irritation or sensitization potential. During these tests, imperatorin did not induce any adverse reactions. Taken together, these findings suggest that the regulation of melanogenesis by imperatorin can be mediated by signaling pathways involving PKA/CREB, ERK, AKT, and GSK3β/β-catenin and that imperatorin could prevent the pathogenesis of pigmentation diseases when used as a topical agent.

Influenza A virus (IAV) poses a severe threat to human health and is a major public health problem worldwide. As global anti-influenza virus drug resistance has increased significantly, there is an urgent need to develop new antiviral drugs, especially drugs from natural products. Isoimperatorin, an active natural furanocoumarin, exhibits a broad range of pharmacologic activities including anticoagulant, analgesic, anti-inflammatory, antibacterial, anti-tumor, and other pharmacological effects, so it has attracted more and more attention. In this study, the antiviral and mechanistic effects of isoimperatorin on influenza A virus in vitro were studied. Isoimperatorin illustrated a broad-spectrum antiviral effect, especially against the A/FM/1/47 (H1N1), A/WSN/33 (H1N1, S31N, amantadine resistant), A/Puerto Rico/8/34 (H1N1), and A/Chicken/Guangdong/1996 (H9N2) virus strains. The experimental results of different administration modes showed that isoimperatorin had the best antiviral activity under the treatment mode. Further time-of-addition experiment results indicated that when isoimperatorin was added at the later stage of the virus replication cycle (6–8 h, 8–10 h), it exhibited an effective antiviral effect, and the virus yield was reduced by 81.4 and 84.6%, respectively. In addition, isoimperatorin had no effect on the expression of the three viral RNAs (mRNA, vRNA, and cRNA). Both the neuraminidase (NA) inhibition assay and CETSA demonstrated that isoimperatorin exerts an inhibitory effect on NA-mediated progeny virus release. The molecular docking experiment simulated the direct interaction between isoimperatorin and NA protein amino acid residues. In summary, isoimperatorin can be used as a potential agent for the prevention and treatment of influenza A virus.

Background Non-Hodgkin’s lymphoma (NHL) possesses great heterogeneity in cytogenetics, immunophenotype and clinical features, and chemotherapy currently serves as the main treatment modality. Although employing monoclonal antibody targeted drugs has significantly improved its overall efficacy, various patients continue to suffer from drug resistance or recurrence. Chinese medicine has long been used in the treatment of malignant tumors. Therefore, we constructed a low pH value sensitivity drug delivery system based on the cancer cell membrane modified mesoporous silica nanoparticles loaded with traditional Chinese medicine, which can reduce systemic toxicity and improve the therapeutic effect for the targeted drug delivery of tumor cells. Results Accordingly, this study put forward the construction of a nano-platform based on mesoporous silica nanoparticles (MSNs) loaded with the traditional Chinese medicine isoimperatorin (ISOIM), which was camouflaged by the cancer cell membrane (CCM) called CCM@MSNs-ISOIM. The proposed nano-platform has characteristics of immune escape, anti-phagocytosis, high drug loading rate, low pH value sensitivity, good biocompatibility and active targeting of the tumor site, blocking the lymphoma cell cycle and promoting mitochondrial-mediated apoptosis. Conclusions Furthermore, this study provides a theoretical basis in finding novel clinical treatments for lymphoma.

Osteoporosis is a chronic metabolic bone disease that is prone to fractures. Isoimperatorin (ISO) has been shown to alleviate the bone loss in ovariectomized (OVX) rats. The aim of this study was to investigate the effect and the mechanism of ISO on osteoporosis using animal study and cell experiments. Osteogenic differentiation was assessed by alkaline phosphatase activity detection, and alizarin red S staining. The expression of osteogenic differentiation-related genes and m5C regulators was measured using quantitative real-time PCR. Hematoxylin eosin (H&E) staining and microCT were performed to evaluate osteoporosis in vivo. The m5C levels in mice were measured by dot blot assay, and the binding between ISO and YBX1 was assessed by biolayer interferometry (BLI) analysis and molecular docking. Methylated RNA immunoprecipitation was performed to identify the target gene of YBX1. The interaction between YBX1 and BGLAP was assessed using RIP and luciferase reporter assay. Results suggested that ISO significantly promoted osteogenic differentiation of MC3T3 cells and alleviated osteoporosis in OVX mice. Moreover, ISO increased m5C level and YBX1 expression in OVX mice, while YBX1 knockdown inhibited osteogenic differentiation in ISO-treated MC3T3 cells, and restored osteoporosis in OVX mice ameliorated by ISO. Additionally, YBX1 knockdown inhibited the m5C level of BGLAP through inhibiting its mRNA stability. In conclusion, we demonstrated that ISO improved osteoporosis through increasing YBX1 expression thereby upregulating the m5C modification of BGLAP. These results may provide a novel theoretical basis for ISO treatment of osteoporosis.

To explore the mechanism of pharmacological action of Isoimperatorin (ISO), a small molecule compound with anti‐inflammatory properties extracted from the rhizome of Notopterygium incisum, in attenuating synovial inflammation in knee osteoarthritis (KOA). By establishing a rat model of KOA and using histopathology and molecular biology methods, we evaluated the pharmacological effect of ISO on synovitis. Synovial fluid from the knee joint was collected for transcriptomic and metabolomic analyses. Fibroblast‐like synoviocytes were cultured in vitro, and calcium fluorescence imaging and mitochondrial membrane potential assays were performed to assess the effects of ISO on the cAMP signalling pathway and KOA‐related synovial inflammation. Preliminary pharmacodynamic observations showed that ISO was able to reduce synovial inflammation in KOA rats. Further transcriptomic findings in synovial tissues indicated that the mechanism of action of ISO was related to the cAMP signalling pathway and calcium ion signalling pathway. The results of metabolomics showed that the progression of synovial fibrosis was related to the abnormal metabolism of glycerophospholipids, and the intervention of ISO could significantly promote the metabolism of glycerophospholipids in synovial tissues. Finally, the results of in vitro experiments showed that ISO improved the level of inflammation and the degree of fibrosis in synovial cells, activated the cAMP signalling pathway and promoted PPAR expression, whereas inhibition of the activation of the cAMP signalling pathway attenuated the effects of ISO. ISO promotes PPAR function by upregulating the cAMP signalling pathway to modulate glycerophospholipid metabolism, thereby alleviating synovial inflammation and slowing fibrosis progression in KOA.

Though Isoimperatorin from Angelicae dahuricae is known to have antiviral, antidiabetic, anti-inflammatory and antitumor effects, its underlying antitumor mechanism remains elusive so far. Hence, the apoptotic mechanism of Isoimperatorin was explored in hepatocellular carcinomas (HCCs). In this study, Isoimperatorin inhibited the viability of Huh7 and Hep3B HCCs and increased the subG1 apoptotic portion and also abrogated the expression of pro-poly-ADP ribose polymerase (pro-PARP) and pro-caspase 3 in Huh7 and Hep3B cells. Also, Isoimperatorin abrogated the expression of cyclin D1, cyclin E1, CDK2, CDK4, CDK6 and increased p21 as G1 phase arrest-related proteins in Huh7 and Hep3B cells. Interestingly, Isoimperatorin reduced the expression and binding of c-Myc and Sirtuin 1 (SIRT1) by Immunoprecipitation (IP), with a binding score of 0.884 in Huh7 cells. Furthermore, Isoimperatorin suppressed the overexpression of c-Myc by the proteasome inhibitor MG132 and also disturbed cycloheximide-treated c-Myc stability in Huh7 cells. Overall, these findings support the novel evidence that the pivotal role of c-Myc and SIRT1 is critically involved in Isoimperatorin-induced apoptosis in HCCs as potent molecular targets in liver cancer therapy.

Furanocoumarins are naturally occurring compounds in the plant world, characterized by low molecular weight, simple chemical structure, and high solubility in most organic solvents. Additionally, they have a broad spectrum of activity, and their properties depend on the location and type of attached substituents. Therefore, the aim of our study was to investigate the anticancer activity of furanocoumarins (imperatorin, isoimperatorin, bergapten, and xanthotoxin) in relation to human glioblastoma multiforme (T98G) and anaplastic astrocytoma (MOGGCCM) cell lines. The tested compounds were used for the first time in combination with LY294002 (PI3K inhibitor) and sorafenib (Raf inhibitor). Apoptosis, autophagy, and necrosis were identified microscopically after straining with Hoechst 33342, acridine orange, and propidium iodide, respectively. The levels of caspase 3 and Beclin 1 were estimated by immunoblotting and for the blocking of Raf and PI3K kinases, the transfection with specific siRNA was used. The scratch test was used to assess the migration potential of glioma cells. Our studies showed that the anticancer activity of furanocoumarins strictly depended on the presence, type, and location of substituents. The obtained results suggest that achieving higher pro-apoptotic activity is determined by the presence of an isoprenyl moiety at the C8 position of the coumarin skeleton. In both anaplastic astrocytoma and glioblastoma, imperatorin was the most effective in induction apoptosis. Furthermore, the usage of imperatorin, alone and in combination with sorafenib or LY294002, decreased the migratory potential of MOGGCCM and T98G cells.

Background Ulcerative colitis (UC), an autoimmune disorder characterized by chronic intestinal inflammation, primarily targets the colonic mucosa. Isoimperatorin is a natural furanocoumarin compound with a variety of pharmacological activities. However, its therapeutic potential and underlying mechanisms in UC pathogenesis remain to be elucidated. Methods Mice were administered 2.5% dextran sulfate sodium (DSS) ad libitum to construct a colitis model, and isoimperatorin was given by gavage to evaluate its efficacy. Flow cytometry and qPCR were employed to assess the effect of isoimperatorin on Treg cell generation. Tissue immunofluorescence and Western blot were used to investigate the effects of isoimperatorin on the repair of damaged intestinal barrier. Cell scratching and migration were used to examine the effects of isoimperatorin on wound healing and cell migration. Finally, a Treg cell depletion assay was implemented to verify the Treg cell-dependent effect of isoimperatorin on repairing intestinal barrier injury to ameliorate UC. Results Oral gavage administration of isoimperatorin (20, 40 mg/kg) significantly improved disease symptoms in UC mice. Isoimperatorin treatment elevated the percentage of Treg cells but had no significant effect on the proportion of Th17 cells in mesenteric lymph node tissues. Isoimperatorin upregulated the expression levels of factors related to mucosal healing and upregulated the expression levels of proteins related to the integrity of the intestinal epithelial barrier. Additionally, isoimperatorin (1, 3 µM) accelerated the migration of colon epithelial cells to facilitate wound healing and also induced the generation of Treg cells in vitro. Finally, Treg cell depletion markedly attenuated isoimperatorin’s therapeutic efficacy in intestinal barrier repair and UC amelioration, indicating a Treg cell-dependent mechanism of action. Conclusions Isoimperatorin promotes intestinal mucosal healing and thus improves UC disease symptoms by inducing Treg cell generation.

Background: Although aluminum (Al) is not biologically crucial to the human body, classical studies have demonstrated that excessive human exposure to Al can induce oxidative damage, neuroinflammatory conditions and neurotoxic manifestations implicated in Alzheimer’s disease (AD). Exposure to Al was reported to be associated with oxidative damage, neuroinflammation, and to enhance progressive multiregional neurodegeneration in animal models. Several plant-derived natural biomolecules have been recently used to reduce the toxic effects of Al through decreasing the oxidative stress and the associated diseases. A good candidate still to be tested is an active natural furanocoumarin, the isoimperatorin (IMP) that can be extracted from Lemon and lime oils and other plants. Here, we examined the neuroprotective effects of IMP on aluminum chloride (AlCl3)-induced neurotoxicity in albino mice. Methods: Twenty-four male albino mice were used in this study. Mice were randomly devided into 5 groups. The first group was given distilled water as a control, the second group was given AlCl3 orally (10 mg/wt/day) starting from the 2nd week to the end of the 6th week, the third group received AlCl3 orally and IMP interperitoneally, i. p. (30 mg/wt/day) starting from week 2 till week 6 where IMP was supplement 1st and then 4 h later AlCl3 was given to mice. The fourth group received the control (IMP 30 mg/wt, i. p.) from the 2nd week till the end of the experiment. Rodent models of central nervous system (CNS) disorders were assessed using object location memory and Y-maze tests in 6th week began. Essential anti-inflammatory and oxidative stress indicators were evaluated, including interleukin-1 β (IL-1β), tumor necrosis factor α (TNF-α), malondialdehyde (MDA), total antioxidant capacity (TAC), and catalase activity (CAT). In addition, serum levels of brain neurotransmitters such as corticosterone, acetylcholine (ACh), dopamine and serotonin in brain homogenates were measured calorimetrically. Results: The study results revealed that the daily treatment of AlCl3 upregulated the TNF-α and IL-1β levels, increased MDA accumulation, and decreased TAC and CAT activity. In addition, aluminum induced a reduction in concentrations of ACh, serotonin and dopamine in the brain. However, IMP significantly ameliorates the effect of AlCl3 through modulating the antioxidant and regulating the inflammatory response through targeting Nrf2 (NF-E2-related factor 2) and mitogen-activated protein kinase (MAPK). Conclusion: Thus, IMP might be a promising treatment option for neurotoxicity and neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, which are associated with neuro-inflammation and oxidative stress.

Purpose Angiogenesis involves in many pathological processes, including tumor metastasis, diabetic retinopathy, and rheumatoid arthritis. Therefore, identifying therapeutic drugs that target angiogenesis may be a promising strategy for disease treatment. Isoimperatorin is a furanocoumarin with anti-inflammatory and anti-microbial effects. However, the impacts of isoimperatorin on angiogenesis and its underlying mechanisms remain unclear. This study aimed to verify its effects on vascular endothelial growth factor (VEGF)-induced endothelial angiogenesis. Methods We employed various assays including 5-ethynyl-2′-deoxyuridine incorporation assay, transwell migration assay, wound healing assay, tube formation assay, and Western blot to evaluate the effects of isoimperatorin on angiogenesis in vitro. Additionally, we utilized Western blot and immunofluorescence analysis to examine the activation of vascular endothelial growth factor receptor (VEGFR) 2 and its downstream signaling pathways following isoimperatorin treatment. To further validate the anti-angiogenic effects of isoimperatorin in vivo, we conducted a matrigel plug assay and established an orthotopic tumor model. Results We demonstrated that pretreatment with isoimperatorin inhibited VEGF-induced endothelial cell proliferation, migration, and tube formation. Isoimperatorin also suppressed angiogenesis in vivo in a matrigel plug assay and in an orthotopic tumor model. Our results revealed that isoimperatorin exhibited anti-angiogenic effects via inhibiting VEGFR2 and its downstream signaling pathways activation. Conclusions Our study showed that isoimperatorin suppressed angiogenesis by targeting the VEGFR2 signaling pathway and could be a potential therapeutic agent for targeting angiogenesis.