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Flavonoids and chalcones are known for their manifold biological activities, of which many affect the central nervous system. Pyranochalcones were recently shown to have a great neurogenic potential, which is partly due to a specific structural motif-the pyran ring. Accordingly, we questioned if other flavonoid backbones with a pyran ring as structural moiety would also show neurogenic potential. Different semi-synthetic approaches starting with the prenylated chalcone xanthohumol, isolated from hops, led to pyranoflavanoids with different backbones. We identified the chalcone backbone as the most active backbone with pyran ring using a reporter gene assay based on the promoter activity of doublecortin, an early neuronal marker. Pyranochalcones therefore appear to be promising compounds for further development as a treatment strategy for neurodegenerative diseases.

Hops contain flavonoids that have sedative and sleep-promoting activities such as α-acid, β-acid, and xanthohumol. In this study, the sleep-enhancing activity of a Saaz–Saphir hops mixture was measured. In the caffeine-induced insomnia model, the administration of a Saaz–Saphir mixture increased the sleep time compared to Saaz or Saphir administration alone, which was attributed to the increase in NREM sleep time by the δ-wave increase. Oral administration of the Saaz–Saphir mixture for 3 weeks increased the γ-amino butyric acid (GABA) content in the brain and increased the expression of the GABAA receptor. As the GABA antagonists picrotoxin and bicuculline showed a decrease in sleep activity, it was confirmed that the GABAA receptor was involved in the Saaz–Saphir mixture activity. In addition, the GABAA receptor antagonist also reduced the sleep activity induced by xanthohumol and humulone contained in the Saaz–Saphir mixture. Therefore, xanthohumol and humulone contained in the Saaz–Saphir mixture showed sleep-promoting activity mediated by the GABAA receptors. The mixture of the Saaz and Saphir hop varieties may thus help mitigate sleep disturbances compared to other hop varieties.

The flavonoid xanthohumol is an important flavor substance in the brewing industry that has a wide variety of bioactivities. However, its unstable structure results in its low content in beer. Microbial biosynthesis is considered a sustainable and economically viable alternative. Here, we harness the yeast Saccharomyces cerevisiae for the de novo biosynthesis of xanthohumol from glucose by balancing the three parallel biosynthetic pathways, prenyltransferase engineering, enhancing precursor supply, constructing enzyme fusion, and peroxisomal engineering. These strategies improve the production of the key xanthohumol precursor demethylxanthohumol (DMX) by 83-fold and achieve the de novo biosynthesis of xanthohumol in yeast. We also reveal that prenylation is the key limiting step in DMX biosynthesis and develop tailored metabolic regulation strategies to enhance the DMAPP availability and prenylation efficiency. Our work provides feasible approaches for systematically engineering yeast cell factories for the de novo biosynthesis of complex natural products. Xanthohumol is a prenylated flavonoid produced by hops and is an important flavor substance in beer. Here, the authors engineer brewing yeast for the de novo biosynthesis of xanthohumol from glucose by balancing the three parallel biosynthetic pathways.

It has been observed that many phytochemicals, frequently present in foods or beverages, show potent chemopreventive or therapeutic properties that selectively affect cancer cells. Numerous studies have demonstrated the anticancer activity of xanthohumol (Xn), a prenylated flavonoid isolated from hops ( L.), with a concentration up to 0.96 mg/L in beer. This review aims to summarize the existing studies focusing on the anticancer activity of Xn and its effects on key signaling molecules. Furthermore, the limitations of current studies and challenges for the clinical use of Xn are discussed.

Xanthohumol (XH) is an important prenylated flavonoid that is found within the inflorescence of Humulus lupulus L. (Hop plant). XH is an important ingredient in beer and is considered a significant bioactive agent due to its diverse medicinal applications, which include anti-inflammatory, antimicrobial, antioxidant, immunomodulatory, antiviral, antifungal, antigenotoxic, antiangiogenic, and antimalarial effects as well as strong anticancer activity towards various types of cancer cells. XH acts as a wide ranging chemopreventive and anticancer agent, and its isomer, 8-prenylnaringenin, is a phytoestrogen with strong estrogenic activity. The present review focuses on the bioactivity of XH on various types of cancers and its pharmacokinetics. In this paper, we first highlight, in brief, the history and use of hops and then the chemistry and structure–activity relationship of XH. Lastly, we focus on its prominent effects and mechanisms of action on various cancers and its possible use in cancer prevention and treatment. Considering the limited number of available reviews on this subject, our goal is to provide a complete and detailed understanding of the anticancer effects of XH against different cancers.

Xanthohumol (XN) and demethylxanthohumol (DMX) are specialized prenylated chalconoids with multiple pharmaceutical applications that accumulate to high levels in the glandular trichomes of hops (Humulus lupulus L.). Although all structural enzymes in the XN pathway have been functionally identified, biochemical mechanisms underlying highly efficient production of XN have not been fully resolved. In this study, we characterized two noncatalytic chalcone isomerase (CHI)-like proteins (designated as HlCHIL1 and HlCHIL2) using engineered yeast harboring all genes required for DMX production. HlCHIL2 increased DMX production by 2.3-fold, whereas HlCHIL1 significantly decreased DMX production by 30%. We show that CHIL2 is part of an active DMX biosynthetic metabolon in hop glandular trichomes that encompasses a chalcone synthase (CHS) and a membrane-bound prenyltransferase, and that type IV CHI-fold proteins of representative land plants contain conserved function to bind with CHS and enhance its activity. Binding assays and structural docking uncover a function of HlCHIL1 to bind DMX and naringenin chalcone to stabilize the ring-open configuration of these chalconoids. This study reveals the role of two HlCHILs in DMX biosynthesis in hops, and provides insight into their evolutionary development from the ancestral fatty acid-binding CHI-fold proteins to specialized auxiliary proteins supporting flavonoid biosynthesis in plants.

Melanoma is one of the most aggressive and lethal cancers worldwide. Despite recent progress in melanoma therapy, the prognosis for metastasized melanoma continues to be poor. Xanthohumol (XN), a prenylated chalcone derived from hop cones, is known to possess a broad spectrum of chemopreventive and anticancer activities. However, few studies have analyzed functional XN effects on melanoma cells and there have been no previous in vivo studies of its effects on metastasis. The aim of this study was to investigate the impact of XN on the tumorigenic and liver metastatic activity of melanoma cells. XN exhibited dose-dependent cytotoxic effects on human melanoma cell lines (Mel Ju; Mel Im) in vitro. Functional analysis in the subtoxic dose-range revealed that XN dose-dependently inhibited proliferation, colony formation, and migratory activity of melanoma cells. Subtoxic XN doses also induced markers of endoplasmic reticulum stress but inhibited the phosphorylation of the protumorigenic c-Jun N-terminal kinases (JNK). Furthermore, XN effects on hepatic metastasis were analyzed in a syngeneic murine model (splenic injection of murine B16 melanoma cells in C57/BL6 mice). Here, XN significantly reduced the formation of hepatic metastasis. Metastases formed in the liver of XN-treated mice revealed significantly larger areas of central necrosis and lower Ki67 expression scores compared to that of control mice. In conclusion, XN inhibits tumorigenicity of melanoma cells in vitro and significantly reduced hepatic metastasis of melanoma cells in mice. These data, in conjunction with an excellent safety profile that has been confirmed in previous studies, indicate XN as a promising novel agent for the treatment of hepatic (melanoma) metastasis.

Natural compounds have emerged as promising therapeutic agents for treating cancers such as multiple myeloma (MM). However, poor bioavailability, low stability, and suboptimal targeting often limit their clinical efficacy. Recent advances in nanotechnology have addressed these limitations by utilizing nanoparticle (NP) carriers to enhance the therapeutic potential of natural compounds through improved solubility, stability, and selective delivery to cancer cells. This review explores the inhibitory effects of key natural compounds on MM cells, including 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) and its derivatives, caffeic acid phenethyl ester (CAPE) and its derivatives, xanthohumol (XN) and its derivatives, resveratrol (RSV) and its derivatives, curcumin (CUR), 3,4,5-trihydroxybenzoic acid (gallic acid; GA), and evodiamine (EVO). These compounds exhibit potent anti-proliferative, pro-apoptotic, and anti-inflammatory properties through the modulation of signaling pathways such as NF-κB, STAT3, and PI3K/Akt, which are critical in MM pathogenesis. Despite their therapeutic promise, the clinical application of these natural agents has been hampered by pharmacokinetic challenges. NP carriers, including liposomes, polymeric NPs, and lipid-based nanocarriers, have been engineered to improve these compounds’ bioavailability and targeted delivery, enhancing their cytotoxicity against MM cells. For instance, CDDO and its derivatives encapsulated in NPs have demonstrated increased intracellular accumulation and improved inhibition of NF-κB activity. Similarly, NP formulations of CAPE, XN, and RSV have enhanced anti-MM effects through improved stability and sustained drug release. CUR, known for its poor water solubility, has seen its therapeutic potential augmented through NP delivery systems, enabling higher drug concentrations at tumor sites. Though structurally distinct, GA and EVO have benefited from NP-based enhancement, exhibiting improved bioavailability and selective targeting of MM cells. This review highlights the promising role of NP carriers in overcoming the pharmacokinetic limitations of natural compounds, offering new avenues for more effective MM therapies.

Increasing evidence from diverse sources during the past several years has indicated that long-term, low level, chronic inflammation mediates several chronic diseases including cancer, arthritis, obesity, diabetes, cardiovascular diseases, and neurological diseases. The inflammatory molecules and transcription factors, adhesion molecules, AP-1, chemokines, C-reactive protein (CRP), cyclooxygenase (COX)-2, interleukins (ILs), 5-lipooxygenase (5-LOX), matrix metalloproteinases (MMPs), nuclear factor (NF)-kB, signal transducer and activator of transcription 3 (STAT3), tumor necrosis factor (TNF), and vascular endothelial growth factor (VEGF) are molecular links between inflammation and chronic diseases. Thus, suppression of inflammatory molecules could be potential strategy for the prevention and therapy of chronic diseases. The currently available drugs against chronic diseases are highly expensive, minimally effective and produce several side effects when taken for long period of time. The focus of this review is to discuss the potential of nutraceuticals derived from \"Mother Nature\" such as apigenin, catechins, curcumin, ellagic acid, emodin, epigallocatechin gallate, escin, fisetin, flavopiridol, genistein, isoliquiritigenin, kaempferol, mangostin, morin, myricetin, naringenin, resveratrol, silymarin, vitexin, and xanthohumol in suppression of these inflammatory pathways. Thus, these nutraceuticals offer potential in preventing or delaying the onset of chronic diseases. We provide evidence for the potential of these nutraceuticals from pre-clinical and clinical studies.

Aging is a natural biological process that manifests as the progressive loss of function in cells, tissues, and organs. Because mechanisms that are meant to promote cellular longevity tend to decrease in effectiveness with age, it is no surprise that aging presents as a major risk factor for many diseases such as cardiovascular disease, neurodegenerative disorders, cancer, and diabetes. Oxidative stress, an imbalance between the intracellular antioxidant and overproduction of reactive oxygen species, is known to promote the aging process. Autophagy, a major pathway for protein turnover, is considered as one of the hallmarks of aging. Given the progressive physiologic degeneration and increased risk for disease that accompanies aging, many studies have attempted to discover new compounds that may aid in the reversal of the aging process. Here, we summarize the antiaging mechanism of natural or naturally derived synthetic compounds involving oxidative stress and autophagy. These compounds include: 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) derivatives (synthetic triterpenoids derived from naturally occurring oleanolic acid), caffeic acid phenethyl ester (CAPE, the active ingredient in honey bee propolis), xanthohumol (a prenylated flavonoid identified in the hops plant), guggulsterone (a plant steroid found in the resin of the guggul plant), resveratrol (a natural phenol abundantly found in grape), and sulforaphane (a sulfur-containing compound found in cruciferous vegetables).