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The crystal structure of a new polymorph of germacrone has been solved and refined using synchrotron X-ray powder diffraction data and optimized using density functional theory techniques. This polymorph (Form II) crystallizes in space group C 2/ c (#15) with a = 26.0073(4), b = 9.84383(10), c = 10.53713(13) Å, β = 95.7547(11)°, V = 2684.04(3) Å 3 , and Z = 8. The crystal structure is dominated by van der Waals interactions, but four C–H⋯O hydrogen bonds are present. The structure exhibits many similarities to the previously reported Form I polymorph FIQLOG, but is clearly different. The powder pattern has been submitted to ICDD for inclusion in the Powder Diffraction File™ (PDF).

Macrophages can transform into M1 (pro-inflammatory) and M2 (anti-inflammatory) phenotypes, which mediate the immune/inflammatory response in rheumatoid arthritis (RA). Activated M1 phenotype macrophages and overexpression of folate (FA) receptors are abundant in inflammatory synovium and joints and promote the progression of RA. Germacrone (GER) can regulate the T helper 1 cell (Th1)/the T helper 2 cell (Th2) balance to delay the progression of arthritis. To deliver GER to inflammatory tissue cells to reverse M1-type proinflammatory cells and reduce inflammation, FA receptor-targeting nanocarriers loaded with GER were developed. In activated macrophages, FA-NPs/DiD showed significantly higher uptake efficiency than NPs/DiD. In vitro experiments confirmed that FA-NPs/GER could promote the transformation of M1 macrophages into M2 macrophages. In adjuvant-induced arthritis (AIA) rats, the biodistribution profiles showed selective accumulation at the inflammatory site of FA-NPs/GER, and significantly reduced the swelling and inflammation infiltration of the rat's foot. The levels of pro-inflammatory cytokines (TNF-α, IL-1β) in the rat's inflammatory tissue were significantly lower than other treatment groups, which indicated a significant therapeutic effect in AIA rats. Taken together, macrophage-targeting nanocarriers loaded with GER are a safe and effective method for the treatment of RA.

Curcumin and germacrone, natural products present in the Zingiberaceae family of plants, have several biological properties. Among these properties, the anti-NSCLC cancer action is noteworthy. In this paper, kinetics of the two compounds in rat liver microsomes (RLMs), human liver microsomes (HLMs), and cytochrome P450 (CYP) enzymes (CYP3A4, 1A2, 2E1, and 2C19) in an NADPH-generating system in vitro were evaluated by UP-HPLC–MS/MS (ultrahigh-pressure liquid chromatography–tandem mass spectrometry). The contents of four cytochrome P450 (CYP) enzymes, adjusting by the compounds were detected using Western blotting in vitro and in vivo. The t1/2 of curcumin was 22.35 min in RLMs and 173.28 min in HLMs, while 18.02 and 16.37 min were gained for germacrone. The Vmax of curcumin in RLMs was about 4-fold in HLMs, meanwhile, the Vmax of germacrone in RLMs was similar to that of HLMs. The single enzyme t1/2 of curcumin was 38.51 min in CYP3A4, 301.4 min in 1A2, 69.31 min in 2E1, 63.01 min in 2C19; besides, as to the same enzymes, t1/2 of germacrone was 36.48 min, 86.64 min, 69.31 min, and 57.76 min. The dynamic curves were obtained by reasonable experimental design and the metabolism of curcumin and germacrone were selected in RLMs/HLMs. The selectivities in the two liver microsomes differed in degradation performance. These results meant that we should pay more attention to drugs in clinical medication–drug and drug–enzyme interactions.

Germacrone, a natural product isolated from the traditional Chinese medicine Rhizoma Curcuma, has been reported to exhibit antitumor activities in vitro. To further understand the antitumor mechanism of germacrone, we investigated the growth inhibitory effect of germacrone on the human prostate cancer cell lines PC-3 (androgen independent) and 22RV1 (androgen dependent). Prostate cancer cells were cultured with different concentrations of germacrone, and cell viability was measured by MTT assay. The levels of proteins were measured by Western blotting. Cell apoptosis was assessed by flow cytometry. Images of autophagy-related protein staining were captured by fluorescence microscopy. Autophagic flux was assessed by detecting the LC3B-II level. Our results indicated that germacrone treatment significantly inhibited cell proliferation by inducing apoptosis in a dose-dependent manner, with IC50 values of 259 μM for PC-3 cells and 396.9 μM for 22RV1 cells. Germacrone-treated cells also exhibited induction of autophagy, as evidenced by elevated LC3B-II protein expression levels and punctuate patterns. Additionally, an autophagy inhibitor enhanced the growth inhibitory effect of germacrone. Moreover, the phosphorylation of Akt and mTOR was inhibited in germacrone-treated prostate cancer cells. Germacrone induced apoptosis and autophagy in prostate cancer cells by inhibiting the Akt/mTOR signaling pathway. Germacrone treatment also led to the activation of protective autophagy. These findings suggest that germacrone may potentially contribute to the development of a new therapeutic agent for prostate cancer treatment.

Germacrone (GM) displays a wide range of antitumor, antioxidant and anti-inflammatory effects; however, to the best of our knowledge, the effects of GM on lung cancer cell apoptosis and cell cycle arrest have not been previously reported. The aim of the present study was to investigate discussed the effects of GM on the apoptosis and cycle arrest of lung cancer cells. Cell viability, proliferation and apoptosis were assessed by performing Cell Counting Kit-8, colony formation and TUNEL assays, respectively. Western blotting was performed to detect the expression levels of apoptosis-, cell cycle- and Akt/MDM2 proto-oncogene (MDM2)/p53 signaling pathway-related proteins. Compared with the control group, 50, 100 and 200 µM GM significantly inhibited lung cancer cell proliferation, but significantly induced cell apoptosis and G1/S cell cycle arrest. GM also significantly altered the expression levels of Akt/MDM2/p53 signaling pathway-related proteins compared with the control group. Administration of Akt activator SC79 significantly reversed GM-mediated antiproliferative, proapoptotic and pro-cell cycle arrest effects in lung cancer cells. Therefore, the results of the present study demonstrated that GM induced lung cancer cell apoptosis and cell cycle arrest via the Akt/MDM2/p53 signaling pathway.

Liver fibrosis is an abnormal proliferation of connective tissue in the liver caused by various pathogenic factors. Chronic liver injury leads to release of inflammatory cytokines and reactive oxygen species (ROS) from damaged hepatocytes, which activates hepatic stellate cells (HSCs) to secrete extracellular matrix proteins, thereby leading to fibrosis. Thus, inhibition of hepatocyte injury and HSC activation, and promotion of apoptosis of activated HSCs are important strategies for prevention of liver fibrosis. In this study, we showed that the germacrone (GER), the main component in the volatile oil of zedoary turmeric, inhibited hepatic fibrosis by regulating multiple signaling pathways. First, GER improved the cell survival rate by inhibiting the production of ROS after hepatocyte injury caused by acetaminophen (APAP). In addition, GER inhibited the activation of HSCs and expression of collagen I by blocking TGF-β/Smad pathway in LX-2 cells. However, when the concentration of GER was higher than 60 μM, it specifically induced HSCs apoptosis by promoting the expression and activation of apoptosis-related proteins, but it had no effect on hepatocytes. Importantly, GER significantly attenuated the methionine- and choline-deficient (MCD) diet-induced liver fibrosis by inhibiting liver injury and the activation of HSCs in vivo . In summary, GER can not only protect hepatocytes by reducing ROS release to avoid the liver injury-induced HSC activation, but also directly inhibit the activation and survival of HSCs by regulating TGF-β/Smad and apoptosis pathways. These results demonstrate that GER can be used as a potential therapeutic drug for the treatment of liver fibrosis.

Background Alcohol-related liver disease (ALD) is an important cause of the increase in liver disease-related morbidity and mortality worldwide. Its core pathological features are oxidative stress imbalance and lipid metabolism disorders. Nuclear factor E2-related factor 2 (Nrf2), a key regulator of oxidative stress, maintains cellular redox balance by activating antioxidant genes. However, over-activated Nrf2 may further exacerbate lipid accumulation. Retinol-binding protein 4 (Rbp4) is a key regulator of lipid metabolism, and its abnormal expression is closely related to hepatic steatosis. Therefore, regulating the balance between Nrf2 and Rbp4 may be an effective strategy to improve ALD. This study aims to explore the therapeutic effect of Germacrone on ALD and further reveal the molecular mechanism of Germacrone’s improvement of oxidative stress and lipid metabolism disorder by regulating the Nrf2/Rbp4 signaling pathway. Methods An alcohol-induced ALD model was established in C57BL/6 mice. After continuous administration of Germacrone (21 days), the effect of Germacrone on liver lipid accumulation, oxidative stress, and pathological injury was evaluated. The core components and targets of JGST were screened by proteomics and network pharmacology, and the improvement effect of Germacrone on ALD was observed by H&E and oil red O staining, serum biochemical indices, and Western blot analysis. Subsequently, the binding of Nrf2 in the Rbp4 promoter region was analyzed by ChIP experiment. Finally, through in vivo and in vitro experiments, Nrf2 nuclear translocation and downstream target gene Rbp4 expression changes were detected, and Nrf2 knockdown or overexpression experiments were conducted to further verify its regulatory effect on Rbp4. Results Proteomic analysis showed that the expressions of HO-1, Gsta1 and Rbp4 in the ALD model were significantly increased, and Rbp4 expression was positively correlated with liver triglyceride (TG) level. Network pharmacological predictions found that Germacrone is the core component of JGST to improve ALD. Germacrone can significantly reduce alcohol-induced liver lipid deposition, oxidative stress, and histopathological damage and significantly reduce the abnormal expression of Nuclear Nrf2 and Rbp4. ChIP experiment results showed that Nrf2 could significantly bind the Rbp4 promoter region − 1534 to − 1473 bp and transcriptionally activate its expression. Meanwhile, In vitro and in vivo experiments further verified that overexpression or activation of Nrf2 could significantly up-regulate Rbp4 expression, while knockdown or inhibition of Nrf2 could significantly decrease Rbp4 expression. Conclusion Germacrone can protect the liver by inhibiting the Nrf2/Rbp4 signaling pathway, improving oxidative stress and lipid metabolism disorder in the ALD model. Rbp4 is a novel downstream target gene of Nrf2. As a potential drug candidate, Germacrone has great clinical application value. Highlights Germacrone can relieve lipid accumulation and oxidative stress in ALD. It was first found that Rbp4 is the downstream target gene of Nrf2. Germacrone improves alcoholic liver injury by inhibiting Nrf2/Rbp4.

Abnormal melanin synthesis causes hyperpigmentation disorders, such as chloasma, freckles, and melanoma, which are highly multiple and prevalent. There were few reports on the anti-melanogenic effect of Curcuma wenyujin Y.H. Chen et C. Ling, and the bioactive compound has not been elucidated as well. The study aims to investigate the anti-melanogenic effect of C. wenyujin , and identify the bioactive compound, and further explore its underlying mechanism. Our results showed that the Petroleum ether fraction extracted from C. wenyujin rhizome had a significant anti-melanogenic effect, and germacrone isolated from it was confirmed as the major bioactive compound. To our data, germacrone significantly inhibited tyrosinase (TYR) activity, reduced melanosome synthesis, reduced dendrites formation of B16F10 cells, and melanosome transport to keratinocytes. Moreover, germacrone effectively decreased the hyperpigmentation in zebrafish and the skin of guinea pigs in vivo. Western-blot analysis showed that germacrone down-regulated the expression of TYR, TRP-1, TRP-2, Rab27a, Cdc42, and MITF proteins via the activation of the MAPK signaling pathway. Taken together, germacrone is an effective bioactive compound for melanogenesis inhibition. Our studies suggest that germacrone may be considered a potential candidate for skin whitening. Graphical abstract

Hepatic stellate cells (HSCs) were activated and secreted excessive amounts of extracellular matrix (ECM) proteins during pathogenetic progress of liver fibrosis. Germacrone (GMO) and miR-29b can play an important role in inhibiting growth of HSCs and production of type I collagen. GMO and miR-29b were co-encapsulated into nanoparticles (NPs) based on poly(ethylene glycol)-block-poly(lactide-co-glycolide) (PEG-PLGA). Then, NPs were modified with cyclic RGD peptides (cRGDfK). cRGDfK is an effective ligand to bind integrin α v β 3 and increase the targeting ability for fibrotic liver. GMO- and miR-29b-loaded NPs exhibited great cytotoxicity to activated HSCs and significantly inhibited production of type I collagen. Liver fibrosis model of mice was induced by administration of carbon tetrachloride. Great targeting ability was achieved in liver fibrotic mice treated with cRGD-modified NPs. Significant ant-fibrotic effects have been presented based on hematoxylin and eosin (H&E), Masson and Sirius Red staining results of liver tissues collected from mice treated with drug-loaded NPs. All these results indicate GMO- and miR-29b-loaded cRGD-modified NPs have the potential for clinical use to treat liver fibrosis.

Pseudorabies virus (PRV), a member of the Herpesviridae, is the causative agent of an acute infectious disease in a variety of animals. The emergence of a novel variant strain brought huge economic losses to the pig industry since classical vaccine strains were not completely effective against variant strains. Therefore, the development of new anti-pseudorabies virus drugs and vaccines is of great significance for the treatment and prevention of pseudorabies. In this study, we found that germacrone, one of the major components of the essential oils extracted from Rhizoma Curcuma, was able to effectively inhibit PRV replication in a dose-dependent manner in vitro. Germacrone showed antiviral activity against PRV in the early phase of the viral replication cycle. Moreover, we found that germacrone does not directly kill the virus, nor does it affect the expression of the PRV receptor protein nectin-1, nectin-2, and CD155. Our results suggest germacrone could be used as an efficient microbicide or immunomodulatory agent in the control of the emerging variant PRV.