Xanthohumol, a Polyphenol Chalcone Present in Hops, Activating Nrf2 Enzymes To Confer Protection against Oxidative Damage in PC12 Cells

Xanthohumol (2′,4′,4-trihydroxy-6′-methoxy-3′-prenylchalcone, Xn), a polyphenol chalcone from hops (Humulus lupulus), has received increasing attention due to its multiple pharmacological activities. As an active component in beers, its presence has been suggested to be linked to the epidemiological observation of the beneficial effect of regular beer drinking. In this work, we synthesized Xn with a total yield of 5.0% in seven steps and studied its neuroprotective function against oxidative-stress-induced neuronal cell damage in the neuronlike rat pheochromocytoma cell line PC12. Xn displays moderate free-radical-scavenging capacity in vitro. More importantly, pretreatment of PC12 cells with Xn at submicromolar concentrations significantly upregulates a panel of phase II cytoprotective genes as well as the corresponding gene products, such as glutathione, heme oxygenase, NAD­(P)­H:quinone oxidoreductase, thioredoxin, and thioredoxin reductase. A mechanistic study indicates that the α,β-unsaturated ketone structure in Xn and activation of the transcription factor Nrf2 are key determinants for the cytoprotection of Xn. Targeting the Nrf2 by Xn discloses a previously unrecognized mechanism underlying the biological action of Xn. Our results demonstrate that Xn is a novel small-molecule activator of Nrf2 in neuronal cells and suggest that Xn might be a potential candidate for the prevention of neurodegenerative disorders

Xanthohumol, a Polyphenol Chalcone Present in Hops, Activating Nrf2 Enzymes To Confer Protection against Oxidative Damage in PC12 Cells

Xanthohumol (2′,4′,4-trihydroxy-6′-methoxy-3′-prenylchalcone, Xn), a polyphenol chalcone from hops (Humulus lupulus), has received increasing attention due to its multiple pharmacological activities. As an active component in beers, its presence has been suggested to be linked to the epidemiological observation of the beneficial effect of regular beer drinking. In this work, we synthesized Xn with a total yield of 5.0% in seven steps and studied its neuroprotective function against oxidative-stress-induced neuronal cell damage in the neuronlike rat pheochromocytoma cell line PC12. Xn displays moderate free-radical-scavenging capacity in vitro. More importantly, pretreatment of PC12 cells with Xn at submicromolar concentrations significantly upregulates a panel of phase II cytoprotective genes as well as the corresponding gene products, such as glutathione, heme oxygenase, NAD­(P)­H:quinone oxidoreductase, thioredoxin, and thioredoxin reductase. A mechanistic study indicates that the α,β-unsaturated ketone structure in Xn and activation of the transcription factor Nrf2 are key determinants for the cytoprotection of Xn. Targeting the Nrf2 by Xn discloses a previously unrecognized mechanism underlying the biological action of Xn. Our results demonstrate that Xn is a novel small-molecule activator of Nrf2 in neuronal cells and suggest that Xn might be a potential candidate for the prevention of neurodegenerative disorders

Synthesis of Piperlongumine Analogues and Discovery of Nuclear Factor Erythroid 2‑Related Factor 2 (Nrf2) Activators as Potential Neuroprotective Agents

The cellular antioxidant system plays key roles in blocking or retarding the pathogenesis of adult neurodegenerative disorders as elevated oxidative stress has been implicated in the pathophysiology of such diseases. Molecules with the ability in enhancing the antioxidant defense thus are promising candidates as neuroprotective agents. We reported herein the synthesis of piperlongumine analogues and evaluation of their cytoprotection against hydrogen peroxide- and 6-hydroxydopamine-induced neuronal cell oxidative damage in the neuron-like PC12 cells. The structure–activity relationship was delineated after the cytotoxicity and protection screening. Two compounds (<b>4</b> and <b>5</b>) displayed low cytotoxicity and confer potent protection of PC12 cells from the oxidative injury via upregulation of a panel of cellular antioxidant molecules. Genetically silencing the transcription factor Nrf2, a master regulator of the cellular stress responses, suppresses the cytoprotection, indicating the critical involvement of Nrf2 for the cellular action of compounds <b>4</b> and <b>5</b> in PC12 cells

Sweet Berberine

Berberine is a drug with an intense bitter taste. The high aqueous solubility of its chloride salt, which is commonly used in commercial drug products of berberine, worsens the challenge of taste masking. We have approached this drug delivery challenge by forming salts with the sweeteners acesulfame and saccharine, through the anion exchange reaction. In addition to the intrinsic sweetness of the two counterions, both salts also exhibit reduced aqueous solubility, which further alleviates the problem of bitter taste of the drug by limiting dissolution of berberine. Moreover, both salts exhibit good tableting performance. They are also non-hygroscopic and stable against high humidity and temperature. The stability against humidity variations makes the two sweet salts more amenable for tablet development over the chloride salt, which undergoes complex hydration/dehydration phase changes when relative humidity varies. Collectively, the two novel solid phases of berberine are sweet and exhibit superior properties for developing pharmaceutically elegant drug products

Selective Selenol Fluorescent Probes: Design, Synthesis, Structural Determinants, and Biological Applications

Selenium (Se) is an essential micronutrient element, and the biological significance of Se is predominantly dependent on its incorporation as selenocysteine (Sec), the genetically encoded 21st amino acid in protein synthesis, into the active site of selenoproteins, which have broad functions, ranging from redox regulation and anti-inflammation to the production of active thyroid hormones. Compared to its counterpart Cys, there are only limited probes for selective recognition of Sec, and such selectivity is strictly restricted at low pH conditions. We reported herein the design, synthesis, and biological evaluations of a series of potential Sec probes based on the mechanism of nucleophilic aromatic substitution. After the initial screening, the structural determinants for selective recognition of Sec were recapitulated. The follow-up studies identified that probe <b>19</b> (Sel-green) responds to Sec and other selenols with more than 100-fold increase of emission in neutral aqueous solution (pH 7.4), while there is no significant interference from the biological thiols, amines, or alcohols. Sel-green was successfully applied to quantify the Sec content in the selenoenzyme thioredoxin reductase and image endogenous Sec in live HepG2 cells. With the aid of Sel-green, we further demonstrated that the cytotoxicity of different selenocompounds is correlated to their ability metabolizing to selenols in cells. To the best of our knowledge, Sel-green is the first selenol probe that works under physiological conditions. The elucidation of the structure–activity relationship for selective recognition of selenols paves the way for further design of novel probes to better understand the pivotal role of Sec as well as selenoproteins in vivo

Enhancing Bioavailability of Dihydromyricetin through Inhibiting Precipitation of Soluble Cocrystals by a Crystallization Inhibitor

Highly soluble cocrystals can be used to improve bioavailability of a poorly soluble drug, through generating supersaturation, when absorption is limited by drug dissolution. Dihydromyricetin (DMY) is a biopharmaceutics classification system (BCS) IV drug, exhibiting dissolution limited absorption. Two novel soluble cocrystals of (±)­DMY with caffeine and urea were prepared, and their physicochemical properties were evaluated for suitability in formulation development. Although having a much higher solubility than (±)­DMY, both cocrystals undergo rapid precipitation during dissolution and form the poorly soluble (±)­DMY dihydrate in aqueous media. This negates the potential advantage offered by the high solubility of the two cocrystals in enhancing the dissolution rate and in vivo bioavailability. To solve this problem, we have systematically evaluated suitable crystallization inhibitors to maintain the supersaturation generated by cocrystal dissolution over a prolonged period of time. At 37 °C, an approximately 5-fold enhancement in oral bioavailability of (±)­DMY was achieved when both cocrystals were dosed with 2.0 mg/mL polyvinylpyrrolidone K30 solution than (±)­DMY dihydrate suspended in 0.5 mg/mL carboxymethylcellulose sodium solution. This study demonstrates that the use of a highly soluble cocrystal along with an appropriate crystallization inhibitor is a potentially effective formulation strategy for improving oral bioavailability of poorly soluble BCS IV drugs

Meta-analysis of studies reporting an effect of resveratrol supplementation on bilirubin and TNF-α (tumor necrosis factor α) levels using a fixed-effects model.

<p>The upper section indicates bilirubin levels and the lower section reveals TNF-α levels. CI indicates confidence interval.</p

Synthesis of Xanthohumol Analogues and Discovery of Potent Thioredoxin Reductase Inhibitor as Potential Anticancer Agent

The selenoprotein thioredoxin reductases (TrxRs) are attractive targets for anticancer drugs development. Xanthohumol (Xn), a naturally occurring polyphenol chalcone from hops, has received increasing attention because of its multiple pharmacological activities. We synthesized Xn and its 43 analogues and discovered that compound <b>13n</b> displayed the highest cytotoxicity toward HeLa cells (IC₅₀ = 1.4 μM). Structure–activity relationship study indicates that the prenyl group is not necessary for cytotoxicity, and introducing electron-withdrawing group, especially on the meta-position, is favored. In addition, methylation of the phenoxyl groups generally improves the potency. Mechanistic study revealed that <b>13n</b> selectively inhibits TrxR and induces reactive oxygen species and apoptosis in HeLa cells. Cells overexpressing TrxR are resistant to <b>13n</b> insult, while knockdown of TrxR sensitizes cells to <b>13n</b> treatment, highlighting the physiological significance of targeting TrxR by <b>13n</b>. The clarification of the structural determinants for the potency would guide the design of novel potent molecules for future development

Meta-analysis of studies reporting an effect of resveratrol supplementation on glucose metabolic parameters (glucose; insulin; HOMA-IR, homeostatic model assessment of insulin resistance) using a random-effects model.

<p>CI indicates confidence interval.</p

Meta-analysis with studies reporting effect of resveratrol supplementation on anthropometric index (BMI, body mass index) and clinical parameters (SBP, systolic blood pressure; DBP, diastolic blood pressure) using a fixed-effects model.

<p>CI indicates confidence interval.</p