Synergistic Anticancer Activity of Plumbagin and Xanthohumol Combination on Pancreatic Cancer Models.

Among diverse cancers, pancreatic cancer is one of the most aggressive types due to inadequate diagnostic options and treatments available. Therefore, there is a necessity to use combination chemotherapy options to overcome the chemoresistance of pancreatic cancer cells. Plumbagin and xanthohumol, natural compounds isolated from the Plumbaginaceae family and Humulus lupulus, respectively, have been used to treat various cancers. In this study, we investigated the anticancer effects of a combination of plumbagin and xanthohumol on pancreatic cancer models, as well as the underlying mechanism. We have screened in vitro numerous plant-derived extracts and compounds and tested in vivo the most effective combination, plumbagin and xanthohumol, using a transgenic model of pancreatic cancer KPC (KrasLSL.G12D/+; p53R172H/+; PdxCretg/+). A significant synergistic anticancer activity of plumbagin and xanthohumol combinations on different pancreatic cancer cell lines was found. The combination treatment of plumbagin and xanthohumol influences the levels of B-cell lymphoma (BCL2), which are known to be associated with apoptosis in both cell lysates and tissues. More importantly, the survival of a transgenic mouse model of pancreatic cancer KPC treated with a combination of plumbagin and xanthohumol was significantly increased, and the effect on BCL2 levels has been confirmed. These results provide a foundation for a potential new treatment for pancreatic cancer based on plumbagin and xanthohumol combinations.

Xanthohumol ameliorates drug-induced hepatic ferroptosis via activating Nrf2/xCT/GPX4 signaling pathway.

BACKGROUND: As a canonical iron-dependent form of regulated cell death (RCD), ferroptosis plays a crucial role in chemical-induced liver injuries. Previous studies have demonstrated that xanthohumol (Xh), a natural prenylflavonoid isolated from hops, exhibits anti-inflammatory, anti-antioxidative and hepatoprotective properties. However, the regulatory effects of Xh on hepatic ferroptosis and the underlying mechanism have not yet been fully elucidated. PURPOSE: To investigate the hepatoprotective effects of Xh against drug-induced liver injury (DILI) and the regulatory effects of Xh on hepatic ferroptosis, as well as to reveal the underlying molecular mechanisms. METHODS/STUDY DESIGN: The hepatoprotective benefits of Xh were investigated in APAP-induced liver injury (AILI) mice and HepaRG cells. Xh was administered intraperitoneally to assess its in vivo effects. Histological and biochemical studies were carried out to evaluate liver damage. A series of ferroptosis-related markers, including intracellular Fe2+ levels, ROS and GSH levels, the levels of MDA, LPO and 4-HNE, as well as the expression levels of ferroptosis-related proteins and modulators were quantified both in vivo and in vitro. The modified peptides of Keap1 by Xh were characterized utilizing nano LC-MS/MS. RESULTS: Xh remarkably suppresses hepatic ferroptosis and ameliorates AILI both in vitro and in vivo, via suppressing Fe2+ accumulation, ROS formation, MDA generation and GSH depletion, these observations could be considerably mitigated by the ferroptosis inhibitor ferrostatin-1 (Fer-1). Mechanistically, Xh could significantly activate the Nrf2/xCT/GPX4 signaling pathway to counteract AILI-induced hepatocyte ferroptosis. Further investigations showed that Xh could covalently modify three functional cysteine residues (cys151, 273, 288) of Keap1, which in turn, reduced the ubiquitination rates of Nrf2 and prolonged its degradation half-life. CONCLUSIONS: Xh evidently suppresses hepatic ferroptosis and ameliorates AILI via covalent modifying three key cysteines of Keap1 and activating Nrf2/xCT/GPX4 signaling pathway.

Disturbance of consciousness caused by dyclonine hydrochloride mucilage: a case report.

BACKGROUND: Dyclonine hydrochloride mucilage is a topical anaesthetic formulated for mucosal surfaces. It is employed frequently for topical anaesthesia of the pharynx prior to endoscopic examinations such as electronic gastroscopy, and few adverse reactions have been reported. This article describes a patient who experienced a transient but severe disturbance of consciousness following oral dyclonine hydrochloride mucilage administration. CASE PRESENTATION: A 75-year-old female presenting with gastrointestinal bleeding was examined by electronic gastroscopy. Six minutes after oral dyclonine hydrochloride mucilage administration, the patient entered a comatose-like state accompanied by loss of limb muscle tone and profuse perspiration. This response was not accompanied by changes in cardiac rhythm, blood pressure, or respiration rate, suggesting an effect on higher brain centres. After ten minutes, the patient's symptoms were alleviated. CONCLUSION: We suggest that sites of dyclonine hydrochloride mucilage use be equipped with appropriate rescue devices for these rare events.

Compounds derived from Humulus lupulus inhibit SARS-CoV-2 papain-like protease and virus replication.

BACKGROUND: Selected natural compounds exhibit very good antiviral properties. Especially, the medicinal plant Humulus lupulus (hop) contains several secondary plant metabolites some of which have previously shown antiviral activities. Among them, the prenylated chalcone xanthohumol (XN) demonstrated to be a potent inhibitor of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro). HYPOTHESIS/PURPOSE: Following the finding that xanthohumol (XN) is a potent inhibitor of SARS-CoV-2 Mpro, the effect of XN and its major derivatives isoxanthohumol (IXN), 6-prenylnaringenin (6-PN), and 8-prenylnaringenin (8-PN) from hops on SARS-CoV-2 papain-like protease (PLpro) were investigated. STUDY DESIGN: The modulatory effect of the hop compounds on PLpro were studied first in silico and then in vitro. In addition, the actual effect of hop compounds on the replication of SARS-CoV-2 in host cells was investigated. METHODS: In silico docking analysis was used to predict the binding affinity of hop compounds to the active site of PLpro. A recombinant PLpro was cloned, purified, characterized, and analyzed by small-angle X-ray scattering (SAXS), deISGylation assays, and kinetic analyses. Antiviral activity of hop compounds was assessed using the fluorescently labeled wildtype SARS-CoV-2 (icSARS-CoV-2-mNG) in Caco-2 host cells. RESULTS: Our in silico docking suggests that the purified hop compounds bind to the active site of SARS-CoV-2 PLpro blocking the access of its natural substrates. The hop-derived compounds inhibit SARS-CoV-2 PLpro with half maximal inhibitory concentration (IC50) values in the range of 59-162 µM. Furthermore, we demonstrate that XN and 6-PN, in particular, impede viral replication with IC50 values of 3.3 µM and 7.3 µM, respectively. CONCLUSION: In addition to the already known inhibition of Mpro by XN, our results show, for the first time, that hop-derived compounds target also SARS-CoV-2 PLpro which is a promising therapeutic target as it contributes to both viral replication and modulation of the immune system. These findings support the possibility to develop new hop-derived antiviral drugs targeting human coronaviruses.

A Xanthohumol-Rich Hop Extract Diminishes Endotoxin-Induced Activation of TLR4 Signaling in Human Peripheral Blood Mononuclear Cells: A Study in Healthy Women.

Infections with Gram-negative bacteria are still among the leading causes of infection-related deaths. Several studies suggest that the chalcone xanthohumol (XN) found in hop (Humulus lupulus) possesses anti-inflammatory effects. In a single-blinded, placebo controlled randomized cross-over design study we assessed if the oral intake of a single low dose of 0.125 mg of a XN derived through a XN-rich hop extract (75% XN) affects lipopolysaccharide (LPS)-induced immune responses in peripheral blood mononuclear cells (PBMCs) ex vivo in normal weight healthy women (n = 9) (clinicaltrials.gov: NCT04847193) and determined associated molecular mechanisms. LPS-stimulation of PBMCs isolated from participants 1 h after the intake of the placebo for 2 h resulted in a significant induction of pro-inflammatory cytokine release which was significantly attenuated when participants had consumed XN. The XN-dependent attenuation of proinflammatory cytokine release was less pronounced 6 h after the LPS stimulation while the release of sCD14 was significantly reduced at this timepoint. The LPS-dependent activation of hTLR4 transfected HEK293 cells was significantly and dose-dependently suppressed by the XN-rich hop extract which was attenuated when cells were co-challenged with sCD14. Taken together, our results suggest even a one-time intake of low doses of XN consumed in a XN-rich hop extract can suppress LPS-dependent stimulation of PBMCs and that this is related to the interaction of the hop compound with the CD14/TLR4 signaling cascade.

Ionomic and metabolic responses of wheat seedlings to PEG-6000-simulated drought stress under two phosphorus levels.

BACKGROUND: Wheat (Triticum aestivum L.) is a major food crop worldwide. Low soil phosphorus content and drought are the main constraints on wheat production in Xinjiang, China. METHODS: In this study, the ionic and metabolic responses of one wheat variety ("Xindong20") to drought stress simulated by using polyethylene glycol 6000 (PEG-6000) were investigated under low phosphorus (LP) and conventional phosphorus (CP) conditions by analysing wheat mineral elements and metabolites. Besides, due to xanthohumol was the metabolite with the most significant difference in expression detected in "Xindong 20", two wheat variety "Xindong20 and Xindong 23" were selected to conduct the germination test simultaneously, to further verify the function of xanthohumol in wheat growth. Xanthohumol was mixed with PEG solution (20%) to prepare PEG solutions with different concentrations (0%, 0.1%, 0.5%, and 1%) of xanthohumol. Then wheat grains were soaked in the solutions for 20 hours, followed by a germination test. After 7 days, the indicators including shoot length, max root length, and root number were determined to identify whether the metabolite was beneficial to improve the drought tolerance of wheat. RESULTS: The results showed that the root density and volume of wheat in LP treatment were higher than those in CP treatment. The roots underwent programmed cell death both in LP and CP treatments under PEG-6000-simulated drought stress, however, the DNA degradation in root cells in LP treatment was lower than that in CP treatment after rehydration for 3 d. Before drought stress, the malondialdehyde (MDA) content in shoot and the peroxidase (POD) activity in root in LP treatment were significantly higher than those in CP treatment, while the soluble sugar content and chlorophyll content in LP treatment were significantly lower than those in CP treatment. During drought stress, the POD activity maintained at a high level and the soluble sugar content gradually increased in LP treatment. After rehydration, the MDA content still maintained at a high level in LP treatment, the superoxide dismutase (SOD) activity increased, and the contents of soluble sugar and chlorophyll were significantly higher than those in CP treatment. The analysis of mineral elements and metabolites showed that the wheat in CP treatment was more sensitive to drought stress than that in LP treatment. Besides, the effect of drought stress was greater on shoot than on root in CP treatment, while it was opposite in LP treatment. The effect of drought stress on sugar metabolism gradually increased. Germination assays showed that 0.1% exogenous xanthohumol addition could significantly increase the shoot length of the two wheat varieties under drought stress. CONCLUSION: Appropriate low phosphorus supply could increase antioxidant enzyme activity in wheat, and enhance sugar metabolism to regulate osmotic balance, as well as the accumulation of various organic acids to maintain the intracellular ion homeostasis. Therefore, compared to the conventional phosphorus supply level, appropriate low phosphorus supply can significantly improve the drought tolerance of wheat. Additionally, addition of 0.1% exogenous xanthohumol, an important differential expressed metabolite in drought-stressed wheat, could effectively promote wheat shoot growth under drought stress.

Xanthohumol: An underestimated, while potent and promising chemotherapeutic agent in cancer treatment.

Today, there is a growing interest nowadays in the use of herbal substances as cancer therapeutic agents. Over recent years, Xanthohumol (XTL) has been brought out as a prenylated chalcone that is found in hops (Humulus lupulus) and beer. XTL is being investigated for its potential properties, and it has been found to have various biological effects, including anti-microbial, anti-viral, and immunomodulatory. Other than these biological effects, it has also been found that XTL exerts anti-tumor effects. In the beginning, XTL, by modulating cell signaling pathways, including ERK, AKT, NF-κB, AMPK, Wnt/ß-catenin, and Notch signaling in cancer cells, inhibits tumor cell functions. Moreover, XTL, by inducing apoptotic pathways, either intrinsic or extrinsic, promotes cancer cell death and arrests the cell cycle. Furthermore, XTL inhibits metastasis, angiogenesis, cancer stemness, drug resistance, cell respiration, etc., which results in tumor aggressiveness inhibition. XTL has low solubility in water, and it has been hypothesized that some modifications, including biotinylation, can improve its pharmacogenetic characteristics. Additionally, XTL derivates such as dihydroXTL and tetrahydroXTL can be helpful for more anti-tumor activities. Using XTL with other anti-tumor agents is another approach to overcome tumor cell resistance. XTL or its derivatives, it is believed, might provide novel chemotherapeutic methods in future cancer therapy.

Hops extract and xanthohumol ameliorate bone loss induced by iron overload via activating Akt/GSK3ß/Nrf2 pathway.

INTRODUCTION: Osteoporosis is closely related to iron metabolism. This study aimed to investigate whether hops extract (HLE) and its active component xanthohumol (XAN) could ameliorate bone loss caused by iron overload, and explored its potential mechanism. MATERIALS AND METHODS: Iron overload mice induced by iron dextran (ID) were used in vivo, and were treated with HLE and XAN for 3 months. Bone micro-structure and bone morphology parameters were determined by Micro-CT and TRAP staining. Bone metabolism markers and oxidation indexes in serum and bone tissue were evaluated. For in vitro experiment, bone formation indexes were determined. Moreover, the expression of key proteins in protein kinase B (Akt)/glycogen synthetase kinase 3ß (GSK3ß)/nuclear factor E2-related (Nrf2) pathway was evaluated by Western blotting. RESULTS: HLE and XAN effectively improved the bone micro-structure of the femur in mice, altered bone metabolism biomarkers, and regulated the expression of proteins related to bone metabolism. Additionally, they significantly promoted cell proliferation, runt-related gene 2 (Runx2) expression, and increased ALP activity in ID-induced osteoblasts. Moreover, HLE and XAN markedly inhibited the increase of oxidative stress caused by iron overload in vivo and in vitro. Further studies showed that they significantly up-regulated the expression of p-Akt, p-GSK3ß, nuclear-Nrf2, NAD(P)H: quinone oxidoreductase 1 (NQO1), and heme oxygenase-1 (HO-1) in ID-induced osteoblasts. CONCLUSION: These findings indicated hops and xanthohumol could ameliorate bone loss induced by iron overload via activating Akt/GSK3ß/Nrf2 pathway, which brought up a novel sight for senile osteoporosis therapy.

Preparation of Hop Estrogen-Active Material for Production of Food Supplements.

In recent years, the interest in the health-promoting effects of hop prenylflavonoids, especially its estrogenic effects, has grown. Unfortunately, one of the most potent phytoestrogens identified so far, 8-prenylnaringenin, is only a minor component of hops, so its isolation from hop materials for the production of estrogenically active food supplements has proved to be problematic. The aim of this study was to optimize the conditions (e.g., temperature, the length of the process and the amount of the catalyst) to produce 8-prenylnaringenin-rich material by the magnesium oxide-catalyzed thermal isomerization of desmethylxanthohumol. Under these optimized conditions, the yield of 8-prenylnaringenin was 29 mg per 100 gDW of product, corresponding to a >70% increase in its content relative to the starting material. This process may be applied in the production of functional foods or food supplements rich in 8-prenylnaringenin, which may then be utilized in therapeutic agents to help alleviate the symptoms of menopausal disorders.

Preclinical and clinical studies to evaluate cutaneous biodistribution, safety and efficacy of UV filters encapsulated in mesoporous silica SBA-15.

Innovative technologies have been designed to improve efficacy and safety of chemical UV filters. Encapsulation can enhance efficacy and reduce transdermal permeation and systemic exposure. The aims of this work were (i) to determine the cutaneous biodistribution of avobenzone (AVO), oxybenzone (OXY), and octyl methoxycinnamate (OMC) incorporated in mesoporous silica SBA-15 and (ii) to perform preclinical (in vitro) and (iii) clinical safety studies to demonstrate their innocuity and to evaluate sun protection factor (SPF) in humans. Skin penetration studies showed that deposition of OXY and AVO in porcine and human skin after application of stick formulation with incorporated filters (stick incorporated filters) was significantly lower than from a marketed (non-encapsulated) stick. Cutaneous deposition and transdermal permeation of OXY in and across human skin were 3.8-and 13.4- fold lower, respectively, after application of stick entrapped filters. Biodistribution results showed that encapsulation in SBA-15 decreased AVO and OXY penetration reaching porcine and human dermis. Greater deposition (and permeation) of OXY in porcine skin than in human skin, pointed to the role of follicular transport. Stick incorporated filters had good biocompatibility in vivo and safety profiles, even under sun-exposed conditions. Entrapment of UV filters improved the SPF by 26% and produced the same SPF profile as a marketed stick. Overall, the results showed that SBA-15 enabled safety and efficacy of UV filters to be increased.

Xanthohumol ameliorates memory impairment and reduces the deposition of ß-amyloid in APP/PS1 mice via regulating the mTOR/LC3II and Bax/Bcl-2 signalling pathways.

OBJECTIVES: Xanthohumol (XAN) is a unique component of Humulus lupulus L. and is known for its diverse biological activities. In this study, we investigated whether Xanthohumol could ameliorate memory impairment of APP/PS1 mice, and explored its potential mechanism of action. METHODS: APP/PS1 mice were used for in vivo test and were treated with N-acetylcysteine and Xanthohumol for 2 months. Learning and memory levels were evaluated by the Morris water maze. Inflammatory and oxidative markers in serum and hippocampus and the deposition of Aß in the hippocampus were determined. Moreover, the expression of autophagy and apoptosis proteins was also evaluated by western blot. KEY FINDINGS: Xanthohumol significantly reduced the latency and increased the residence time of mice in the target quadrant. Additionally, Xanthohumol increased superoxide dismutase level and reduced Interleukin-6 and Interleukin-1ß levels both in serum and hippocampus. Xanthohumol also significantly reduced Aß deposition in the hippocampus and activated autophagy and anti-apoptotic signals. CONCLUSIONS: Xanthohumol effectively ameliorates memory impairment of APP/PS1 mice by activating mTOR/LC3 and Bax/Bcl-2 signalling pathways, which provides new insight into the neuroprotective effects of Xanthohumol.

The effectiveness of electro-acupuncture combined with dyclonine hydrochloride in relieving the side effects of gastroscopy: a controlled trial.

BACKGROUND: The present study aimed to explore the effectiveness of electro-acupuncture (EA) in combination with a local anesthetic used in Western medicine in preventing the side effects of gastroscopy. METHODS: A sample group of 150 patients were divided into three groups based on treatment methods: an EA group, a dyclonine hydrochloride mucilage group, and a combined treatment group. In the EA group, EA stimulation was given at the Hegu, Neiguan, and Zusanli acupoints; in the dyclonine hydrochloride mucilage group, patients took 10 mL of dyclonine hydrochloride mucilage orally; in the combined treatment group, prevention of side effects was attempted by administration of both acupuncture and oral local anesthetic. The incidences of nausea, emesis, salivation, cough, restlessness, and breath holding during gastroscopy were observed and recorded for the three groups. Mean arterial pressure, heart rate, and oxygen saturation were recorded before the examination, and changes in these measures were recorded as the gastroscope passed through the pylorus and after the examination. The visual analogue scale (VAS) values of nausea and emesis, the rate of successful first-pass intubation, and the time of gastroscopy were also recorded. Statistical analysis was performed using R-3.5.3 software. RESULTS: Incidences of side effects (e.g., nausea, emesis, salivation, restlessness, and breath holding) during the examination were lower in the combined treatment group than in the EA group and the dyclonine hydrochloride mucilage group (P<0.05 and P<0.01, respectively). Furthermore, the changes in heart rate and oxygen saturation when the gastroscope passed through the pylorus and after the examination were better in the combined treatment group than in the EA group and dyclonine hydrochloride mucilage group (P<0.01). The VAS values of nausea and emesis, the first-pass success rate, and examination duration were also better for the combined treatment group than for the other two groups (P<0.05 and P<0.01). CONCLUSIONS: EA combined with local anesthesia with dyclonine hydrochloride mucilage can alleviate side effects during gastroscopy, reduce patient pain, and improve the efficiency of the procedure.

Pharmacokinetics of xanthohumol in rats of both sexes after oral and intravenous administration of pure xanthohumol and prenylflavonoid extract.

BACKGROUND: Female inflorescences of hops (Humulus lupulus L.) are wildly used in the brewing industry. Hops have been also used for ages in folk medicine. Xanthohumol (XN) is a most abundant prenylated flavonoid present in hops. OBJECTIVES: To determine pharmacokinetic parameters and bioavailability of pure XN and XN given in prenylflavonoid extract obtained from spent hops (HOP). MATERIAL AND METHODS: Fifty-six Wistar rats (28 females and 28 males) were administered with XN or HOP. Xanthohumol was administered either intravenously (iv.) (10 mg/kg) or orally (per os (p.o.)) (40, 100 and 200 mg/kg). Extract obtained from spent hops was administered p.o. and its doses were based on XN content (doses were equivalent to XN dose of 40, 100 and 200 mg/kg, respectively). After administration of XN or HOP serum, XN concentration was measured at different time points (0, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 48, 72, and 96 h). Non-compartmental analysis was used to assess the pharmacokinetics (PK) of XN in rats. RESULTS: The XN PK in rats after intravenous administration is characterized by extensive distribution followed by delayed elimination from the body. Enterohepatic recirculation is likely to play a role in XN PK. Some fraction of the orally administered XN reaches central compartment rapidly; however, the overall absorption is very limited and probably saturable. The formulation-dependent factors also play an important role in the bioavailability of the drug. Although the CMAX concentration was higher in female rats receiving XN orally comparing to males, the other pharmacokinetic parameters were unaffected by the rats' sex. CONCLUSIONS: The same doses of XN may be administered to male and female subjects, as its pharmacokinetics is not affected by sex.

Micellar solubilization enhances the anti-inflammatory effect of xanthohumol.

BACKGROUND: Xanthohumol is known to exert anti-inflammatory properties but has poor oral bioavailability. Using advanced micellization technology, it has been possible to markedly enhance its bioavailability. PURPOSE: In the present study, we compared the chronic anti-inflammatory activities of native and micellar xanthohumol in the rat adjuvant arthritis model, using diclofenac as a reference drug. METHODS: Adjuvant arthritis was induced by injecting Freund's complete adjuvant into the right hind paw of rats and monitoring paw volume over 3 weeks. The drugs were given daily for 3 weeks, starting from the day of adjuvant inoculation. Serum was collected at the end of the experiment to measure inflammatory and oxidative stress parameters. Statistical comparisons between different groups were carried out by one-way analysis of variance followed by Tukey-Kramer multiple comparison test. RESULTS: Micellar solubilized xanthohumol showed a better anti-inflammatory activity than its native form. The reduction in paw volume was reflected in corresponding changes in relevant mediators of inflammation like tumor necrosis factor-α, interleukin-6 and C-reactive protein, myloperoxidase and lipid peroxidation markers. CONCLUSION: The findings confirm that micellar solubilization of xanthohumol enhances its anti-inflammatory activity, probably as a result of improving its bioavailabilty. The solubilized xanthohumol may prove to be a promising adjuvant tool for anti-inflammatory treatment and a potential anti-inflammatory alternative to synthetic drugs.

High ambient temperature increases the toxicity and lethality of 3,4-methylenedioxymethamphetamine and methcathinone.

RATIONALE: Methylenedioxymethamphetamine (MDMA) and methcathinone (MCAT) are abused psychostimulant drugs that produce adverse effects in human users that include hepatotoxicity and death. Recent work has suggested a connection between hepatotoxicity, elevations in plasma ammonia, and brain glutamate function for methamphetamine (METH)-induced neurotoxicity. OBJECTIVES: These experiments investigated the effect of ambient temperature on the toxicity and lethality produced by MDMA and MCAT in mice, and whether these effects might involve similar mechanisms to those described for METH neurotoxicity. RESULTS: Under low (room temperature) ambient temperature conditions, MDMA induced hepatotoxicity, elevated plasma ammonia levels, and induced lethality. Under the same conditions, even a very high dose of MCAT produced limited toxic or lethal effects. High ambient temperature conditions potentiated the toxic and lethal effects of both MDMA and MCAT. CONCLUSION: These studies suggest that hepatotoxicity, plasma ammonia, and brain glutamate function are involved in MDMA-induced lethality, as has been shown for METH neurotoxicity. The toxicity and lethality of both MDMA and MCAT were potentiated by high ambient temperatures. Although an initial mouse study reported that several cathinones were much less toxic than METH or MDMA, the present results suggest that it will be essential to assess the potential dangers posed by these drugs under high ambient temperatures.

Xanthohumol inhibits PRRSV proliferation and alleviates oxidative stress induced by PRRSV via the Nrf2-HMOX1 axis.

Porcine reproductive and respiratory syndrome virus (PRRSV) is a prevalent and endemic swine pathogen that causes significant economic losses in the global swine industry. Commercial vaccines provide limited protection against this virus, and no highly effective therapeutic drugs are yet available. In this study, we first screened a library of 386 natural products and found that xanthohumol (Xn), a prenylated flavonoid found in hops, displayed high anti-PRRSV activity by inhibiting PRRSV adsorption onto and internalization into cells. Transcriptome sequencing revealed that Xn treatment stimulates genes associated with the antioxidant response in the nuclear factor-erythroid 2-related factor 2 (Nrf2) signalling pathway. Xn causes increased expression of Nrf2, HMOX1, GCLC, GCLM, and NQO1 in Marc-145 cells. The action of Xn against PRRSV proliferation depends on Nrf2 in Marc-145 cells and porcine alveolar macrophages (PAMs). This finding suggests that Xn significantly inhibits PRRSV proliferation and decreases viral-induced oxidative stress by activating the Nrf2-HMOX1 pathway. This information should be helpful for developing a novel prophylactic and therapeutic strategy against PRRSV infection.

Amyloid-ß Aggregation Inhibitory and Neuroprotective Effects of Xanthohumol and its Derivatives for Alzheimer's Diseases.

BACKGROUND: Xanthohumol has been reported to have cytoprotection through activation of Nrf2-ARE signaling pathway and; it has capability of scavenging free radicals, suggesting its potential for the prevention of neurodegeneration. However, the bio-incompatibility and blood-brain barrier impermeability of xanthohumol hindered its in vivo efficacy potential for treating Alzheimer's disease (AD). OBJECTIVE: We designed and prepared a series of xanthohumol derivatives to enhance the desirable physical, biological and pharmacological properties in particular the blood-brain barrier permeability for intervention of AD. METHODS: We designed and synthesized a novel series of 9 xanthohumol derivatives. Their inhibitory effect on amyloid-ß (1-42), Aß1-42, oligomerization and fibrillation as well as neuroprotection against amyloid-ß induced toxicities, were explored. RESULTS: Among the 9 xanthohumol derivatives, some of them exhibited a moderate to high inhibitory effect on Aß1-42 oligomerization and fibrillation. They were biocompatible and neuroprotective to the SH-SY5Y cells by reducing the ROS generation and calcium uploading that were induced by the amyloid- ß. Importantly, two of the derivatives were found to be blood-brain barrier permeable showing promising potential for AD treatment. CONCLUSION: Two derivatives have been identified to be biocompatible, non-toxic, neuroprotective against Aß-induced toxicities and blood-brain barrier permeable highlighting their promising potential as AD drug candidates for future clinical use.

Changes in chemical profile of Cascade hop cones according to the growing area.

BACKGROUND: The growing area has a substantial effect on plants, affecting secondary metabolism. For hops, different authors have studied the effect of growing area on the chemical composition of cones with the aim of verifying and understanding the changes in hop characters. Despite the scant literature the subject receives increasing attention by brewers and hop growers. The present study aimed to characterize, using gas chromatography-mass spectrometry (GC-MS), and high-performance liquid chromatography with ultraviolet detection (HPLC-UV), cones of hop (Humulus lupulus L.) cultivar Cascade. Plant material was obtained from nine different areas of Italy and compared with Cascade samples grown in the United States, Germany and Slovenia. RESULTS: Differences in bitter acids and xanthohumol content were observed. Nevertheless, no correlation between bitter acids and xanthohumol production, on the one hand, and rainfall, temperatures and latitude, on the other hand, were observed in our samples. The Slovenia samples were richer in molecules that confer hoppy, woody and flower notes; USA2 samples were more characterized by woody, earthy, grassy and floral aroma, quite different characters if compared to USA1, which had the lowest presence of grassy aromatic compounds. In the Italian samples, TRENTINO was the genotype most characterized by limonene presence. CONCLUSION: The results of this study are indicative of the importance for hop users to know and characterize hops coming from different growing regions. The study pays special attention to the characterization of the differences in chemical characters of Cascade hop in Italy, where hop cultivation has developed only recently, but is in continuous expansion. © 2019 Society of Chemical Industry.

Antiproliferative Effects of Hop-derived Prenylflavonoids and Their Influence on the Efficacy of Oxaliplatine, 5-fluorouracil and Irinotecan in Human ColorectalC Cells.

Beer, the most popular beverage containing hops, is also frequently consumed by cancer patients. Moreover, non-alcoholic beer, owing to its nutritional value and high content of biological active compounds, is sometimes recommended to patients by oncologists. However, the potential benefits and negatives have to date not been sufficiently evaluated. The present study was designed to examine the effects of four main hop-derived prenylflavonoids on the viability, reactive oxygen species (ROS) formation, activity of caspases, and efficiency of the chemotherapeutics 5-fluorouracil (5-FU), oxaliplatin (OxPt) and irinotecan (IRI) in colorectal cancer cell lines SW480, SW620 and CaCo-2. All the prenylflavonoids exerted substantial antiproliferative effects in all cell lines, with xanthohumol being the most effective (IC50 ranging from 3.6 to 7.3 µM). Isoxanthohumol increased ROS formation and the activity of caspases-3/7, but 6-prenylnaringenin and 8-prenylnaringenin exerted antioxidant properties. As 6-prenylnaringenin acted synergistically with IRI, its potential in combination therapy deserves further study. However, other prenylflavonoids acted antagonistically with all chemotherapeutics at least in one cell line. Therefore, consumption of beer during chemotherapy with 5-FU, OxPt and IRI should be avoided, as the prenylflavonoids in beer could decrease the efficacy of the treatment.

Potential in vitro anti-allergic, anti-inflammatory and cytotoxic activities of ethanolic extract of Baliospermum montanum root, its major components and a validated HPLC method.

BACKGROUND: The root of Baliospermum montanum has been used as an ingredient of traditional Thai medicines for the treatments of several diseases including itching eczema, muscle and joint inflammation, and cancer. Few studies have been done on phytochemical components of this root. In this study, we isolated major compounds of the crude ethanolic extract of B. montanum root and developed and validated a high performance liquid chromatographic (HPLC) method for the determination of its major components. We then investigated anti-allergic, anti-inflammatory and cytotoxic activities of the extract. METHODS: The aims of this study were to investigate in vitro activities including inhibitory effect of ß-hexosaminidase released from RBL-2H3 cells, inhibition of nitric oxide (NO) production from RAW 264.7 cells and cytotoxic activity against cancerous liver cell lines (HepG2 and KKU M156) by using sulforhodamine B (SRB) assay. Isolation of major components was conducted by using column chromatographic method. Isolated major compounds were analyzed by using high performance liquid chromatography (HPLC). RESULTS: The crude extract exhibited the highest cytotoxic activity, with IC50 less than 1 µg/mL, while its anti-allergy and anti-inflammation were also potent with IC50 less than 6 µg/mL. Three propiophenones isolated from B. montanum root exhibited moderate cytotoxic activities (IC50 > 20 µg/mL). Two of the propiophenones found were major components that can be detected by HPLC. The developed and validated HPLC method showed good accuracy, precision, and linearity. CONCLUSION: The results of this study suggested that ethanolic extract of of B.montanum root can be a potential source of anti-allergy, anti-inflammation, and anti-cancer compounds. The isolated compounds can serve as markers when B. montanum is used in herbal remedies but not as overall responsive markers. The HPLC method developed may be useful for quality control in the production of the extract and for further formulation developments. However, investigation of several associated biological activities is necessary before the development can proceed further. Minor active compounds should be isolated and a more sensitive analytical method should be developed to detail the key responsive components of the ethanolic extract of B. montanum root.