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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.

Cancer is a major public health concern due to high mortality and poor quality of life of patients. Despite the availability of advanced therapeutic interventions, most treatment modalities are not efficacious, very expensive, and cause several adverse side effects. The factors such as drug resistance, lack of specificity, and low efficacy of the cancer drugs necessitate developing alternative strategies for the prevention and treatment of this disease. Xanthohumol (XN), a prenylated chalcone present in Hop (Humulus lupulus), has been found to possess prominent activities against aging, diabetes, inflammation, microbial infection, and cancer. Thus, this manuscript thoroughly reviews the literature on the anti-cancer properties of XN and its various molecular targets. XN was found to exert its inhibitory effect on the growth and proliferation of cancer cells via modulation of multiple signaling pathways such as Akt, AMPK, ERK, IGFBP2, NF-κB, and STAT3, and also modulates various proteins such as Notch1, caspases, MMPs, Bcl-2, cyclin D1, oxidative stress markers, tumor-suppressor proteins, and miRNAs. Thus, these reports suggest that XN possesses enormous therapeutic potential against various cancers and could be potentially used as a multi-targeted anti-cancer agent with minimal adverse effects.

Background: Perinatal depression is a common and disabling mental health problem in Malawi and other Low- and middle-income countries. There is evidence for effective psychosocial interventions for perinatal depression, but no such intervention has been developed for use in Malawi. The broad aim of this study was to explore the cultural appropriateness of a psychosocial intervention for perinatal depression called the Thinking Healthy Programme-Peer delivered for adaptation and use in Lilongwe, Malawi.Methods: A qualitative exploratory design was used. Data were collected through conducting five Focus Group Discussions, involving thirty-eight purposefully selected participants including pregnant women, community volunteers and their supervisors, the Health Surveillance Assistants and maternal health care workers at implementation and policy level following observations of video recorded role plays of the Thinking Healthy Programme-Peer delivered sessions in theatre testing. A content analysis approach was used to analyse data.Results: Six main themes were generated regarding the appropriateness of the content and delivery of the Thinking Healthy Programme-Peer delivered intervention, including: 1) Focus of the intervention; 2) Cultural appropriateness of the content; 3) Language used; 4) Context; 5) Provider of the intervention; and 6) Flexibility in the delivery of the intervention. The Thinking Healthy Programme-Peer delivered intervention was deemed appropriate for the target population, though with recommendations to: review illustrations to enhance clarity, use culturally appropriate stories and idioms, use daily spoken language, and adapt the number and duration of sessions to meet the needs of individual clients.Conclusions: These findings highlight important areas to inform adaptation of the Thinking Healthy Programme-Peer delivered and add to the growing evidence of cultural adaptation of psychosocial interventions for perinatal depression.

Background Topical anesthesia is a crucial step in awake endotracheal intubation for providing favorable intubation conditions. The standard of care technique for awake intubation at our institution, which consists of oropharyngeal tetracaine spray, can result in inadequate mucosal anesthesia. Therefore, we sought to compare the effectiveness of dyclonine hydrochloride mucilage to the standard of care tetracaine in achieving anesthesia of the upper airways for awake endotracheal intubation. Methods This is a randomized, assessor-blinded, prospective study. From Jun. 1st, 2019 to Aug. 1st, 2019, patients scheduled for either endoscopic submucosal dissection or peroral endoscopic myotomy were enrolled and randomly allocated into two groups after obtaining written informed consent: patients allocated to novel awake intubation care (Group N-AIC) received a single administration of oral dyclonine hydrochloride mucilage, whereas patients allocated to standard awake intubation care (Group S-AIC) received three oropharyngeal tetracaine sprays before transcricoid tetracaine injection before awake intubation. Mean arterial pressure (MAP), which was the primary outcome of this study, as well as heart rate (HR) were recorded throughout the procedure and compared between the two groups. Feeling of numbness, nausea, and intubation conditions after topical anesthesia were also assessed. Results Sixty patients were enrolled and completed the study. Baseline MAP and HR were similar between the two groups. However, hemodynamic responses to intubation and gastrointestinal endoscopy, especially MAP, were significantly less elevated in Group N-AIC. The degree of numbness of the oropharyngeal mucosa after topical anesthesia did not differ between the two groups, neither did the feeling of nausea during laryngoscopy. The amount of pharyngeal secretions before intubation was less in Group N-AIC. Total intubation time was significantly shorter in Group N-AIC when compared to Group S-AIC (18.4 ± 2.86 vs. 22.3 ± 6.47, P Conclusions In awake endotracheal intubation, novel care using oral dyclonine hydrochloride mucilage can provide more favorable mucosal anesthesia and better intubation conditions compared to standard of care practice using oropharyngeal tetracaine spray. Trial registration ChiCTR1900023151. Date of registration: May 14th, 2019.

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.

CelW pracy przedstawiono charakterystykę neuropsychologiczną 16 osób z zespołem parkinsonowskim spowodowanym zatruciem manganem, w związku z dożylnym używaniem efedronu.Materiał i metodyWykonano badanie przesiewowe oraz pełne badanie neuropsychologiczne z zastosowaniem baterii elastycznej w celu pomiaru szeregu funkcji poznawczych (uczenia się werbalnego, pamięci wzrokowej, pamięci operacyjnej, funkcji wykonawczych oraz funkcji konstrukcyjnych i wzrokowo-przestrzennych). Przeprowadzono również dokładną diagnozę zaburzeń dyzartrycznych mowy. Wszyscy badani wypełnili Skalę Depresji Becka (BDI) w celu określenia poziomu nastroju.WynikiWszystkie osoby badane miały ewidentne dyzartryczne zaburzenia mowy, z obecną (u większości pacjentów) palilalią i zaburzeniami pisania (mikrografią). Przesiewowa diagnoza neuropsychologiczna nie wykazała ogólnego obniżenia funkcjonowania poznawczego na poziomie zaburzeń otępiennych. Stwierdzono nieznaczne zaburzenia procesów uczenia się werbalnego i pamięci wzrokowej oraz zaburzenia praksji ideomotorycznej bez zaburzeń praksji konstrukcyjnej. Wyniki badania pamięci operacyjnej i funkcji wykonawczych wskazywały na obniżenie elastyczności poznawczej, zdolności logicznej konceptualizacji oraz przełączania z jednego kryterium na drugie; były znacznie zróżnicowane u poszczególnych pacjentów. Czas używania efedronu okazał się nieistotny dla funkcjonowania poznawczego. Przeciętny wynik BDI wskazywał na umiarkowany poziom obniżenia nastroju. Wyższy poziom depresyjności był związany z ogólnym obniżeniem funkcji poznawczych, pogorszeniem zdolności uczenia się werbalnego i wzrokowego a także niższym poziomem fluencji fonemicznej.

This study aimed to investigate the effects of prenatal and lactational methcathinone exposure on the development and the learning and memory abilities of rat offspring using a Sprague-Dawley rat model. Pregnant and lactating rats were administered a consecutive daily dose of methcathinone (0.37 mg/kg) or an equivalent volume of saline by injection on gestational days 7-20 and postnatal days 2-15, respectively. The physical development and neurobehavioral test results of rat pups were recorded throughout the lactation period. Morris water maze (MWM) and novel object recognition (NOR) tests were performed from postnatal day 35 to day 42 to assess the learning and memory abilities of rat offspring in adolescence. The occurrence of hair growth and developments in neurological reflexes, such as improvements in limb grasp, righting reflex, and gait, were delayed in pups after perinatal methcathinone exposure compared with that in the control. Results from MWM and NOR tests indicate that perinatal methcathinone exposure induced deficits in spatial memory, learning ability, and novel object exploration in the adolescent offspring compared with that in the control. The impairment of spatial learning and memory was greater in the prenatal exposure group, while the impairment of novel object exploration was greater in the lactational exposure group. These data show that the prenatal and lactational methcathinone exposure induced the delay of physical and neurological reflex development and impaired learning and memory in rat offspring.

3,4-Dimethylmethcathinone (3,4-DMMC) is a new psychoactive substance whose recreational use and trade have recently increased. Given the absence of information on the toxicokinetics of 3,4-DMMC, the present work aimed at validating a GC–MS methodology for the drug quantification in biological matrices, and further characterizing its biodistribution in Wistar rats. The method was validated based on the evaluation of the drug stability, limit of detection and quantification, linearity, selectivity, precision, accuracy and recovery. To characterize biodistribution, Wistar rats were administered with 20 or 40 mg/Kg of 3,4-DMMC i.p.. After 1 h or 24 h, rats were anaesthetized, euthanized and blood, brain, liver, heart, kidneys, lungs, spleen, urine (only at 24 h), and a portion of gut, muscle and adipose tissue were collected for analysis. After 1 h, 3,4-DMMC was present in all analysed matrices, and the presence of two metabolites was further detected in all of them. The drug accumulation was higher in kidneys, lungs, spleen and brain. After 24 h, 3,4-DMMC was only present in urine, along with five metabolites. All metabolites were tentatively identified. Through elucidation of the most appropriate analytical matrices and the metabolites that may have the largest detection windows, these data are expected to assist in future clinical and forensic investigations.

Background: Most of breast cancer patients are estrogen receptor alpha-positive and have high resistance and side effect of chemotherapeutic drug. Therefore, discovering an effective anticancer agent is needed. This research explored the effect of (E)-1-(4’-aminophenyl)-3-phenylprop-2-en-1-one (APE) on miR-18a, Dicer1, and MMP-9 expressions. Methods: Twenty four female Sprague-Dawley rats were invetigated in this study. The rats were divided into 6 groups of 4. G1 was considered as normal rat. G2, G3, T1, T2, and T3 were given DMBA 20 mg/kgBW twice a week for 5 weeks to induce mammary cancer. After being affiliated with cancer, G2 was given vehicle and G3 was treated with tamoxifen. T1, T2, and T3 were treated with APE intraperitoneally everyday for 21 days at doses of 5, 15, and 45 mg/kgBW/day, respectively. Blood plasma was collected to measure miR-18a expression using qRT-PCR. Mammary tissues were also collected to determine Dicer1 and MMP-9 expressions by using immunohistochemistry. Results: The results showed significant down-regulation of miR-18a relative expression and up-regulation of Dicer1 expression in G3 and T1 compared to G2 (P

Botanical dietary supplements contain multiple bioactive compounds that target numerous biological pathways. The lack of uniform standardization requirements is one reason that inconsistent clinical effects are reported frequently. The multifaceted biological interactions of active principles can be disentangled by a coupled pharmacological/phytochemical approach using specialized ("knock-out") extracts. This is demonstrated for hops, a botanical for menopausal symptom management. Employing targeted, adsorbent-free countercurrent separation, Humulus lupulus extracts were designed for pre- and postmenopausal women by containing various amounts of the phytoestrogen 8-prenylnaringenin (8-PN) and the chemopreventive constituent xanthohumol (XH). Analysis of their estrogenic (alkaline phosphatase), chemopreventive (NAD(P)H-quinone oxidoreductase 1 [NQO1]), and cytotoxic bioactivities revealed that the estrogenicity of hops is a function of 8-PN, whereas their NQO1 induction and cytotoxic properties depend on XH levels. Antagonization of the estrogenicity of 8-PN by elevated XH concentrations provided evidence for the interdependence of the biological effects. A designed postmenopausal hop extract was prepared to balance 8-PN and XH levels for both estrogenic and chemopreventive properties. An extract designed for premenopausal women contains reduced 8-PN levels and high XH concentrations to minimize estrogenic while retaining chemopreventive properties. This study demonstrates the feasibility of modulating the concentrations of bioactive compounds in botanical extracts for potentially improved efficacy and safety.

Epidermolysis bullosa acquisita (EBA) is an autoimmune blistering disorder characterized and caused by autoantibodies against type VII collagen (COL7). Although it has been noticed that EBA in both patients and mice is associated with an increased scratching, it is not clear whether and how the scratching contributes to disease manifestation. Hence, we here aimed to validate this clinical observation and also to investigate the potential contribution of increased scratching in EBA pathogenesis in mice. Longitudinal assessment of scratching behavior revealed an increased frequency of scratching as early as 12 hours after injection of anti-COL7 IgG into the skin of mice. Subsequently, scratching events became even more frequent in mice. In contrast, mice injected with a control antibody showed an unaltered scratching behavior throughout the observation period. Based on these observations, we hypothesized that mechanical irritation may promote the induction of inflammation in experimental EBA. To challenge this assumption, the local anesthetic dyclonine hydrochloride was topically applied before injection of anti-COL7 IgG. Dyclonine hydrochloride reduced the scratching events and impaired clinical disease manifestation. In therapeutic experimental settings, i.e. administration of the local anesthetic 24 hours after injection of anti-COL7 IgG, dyclonine hydrochloride only inhibited the scratching behavior, but had no significant effect on clinical disease development. In addition, eosinophils were detected in the skin before the injection of anti-COL7 IgG and significantly increased 48 hours after the antibody injection. Collectively, our results suggest that scratching behavior contributes to the initiation phase of disease manifestation in experimental EBA.

Urine tests are the commonly accepted methods to control abstinence and adherence to treatment of patients who undergo methadone maintenance treatment (MMT). Depending on various national guidelines and accessibility of techniques, only selected psychoactive substances are routinely tested in urine of MMT patients. In general, they belong to the few groups of compounds: THC, cocaine, amphetamines, opiates, PCP and benzodiazepines. It is, however, well known that patients enrolled in such replacement programmes take psychoactive substances that are not routinely detected by the toxicology laboratories, to escape unexpected tests. Here, we report semiquantitative detection of legal highs taken by the MMT patient, using high-pressure liquid chromatography coupled to the flowing atmospheric pressure afterglow ion source (LC-FAPA-MS). To demonstrate effectivity of this technique, the data were confirmed by quantitative analysis using LC-ESI-MS/MS. In the analysed sample of MMT patient, a mixture of psychoactive compounds was found, namely 3-MMC (3-methylmethcathinone), pentedrone and methcathinone and determined at the concentrations of 670; 50 and 0.2 µg/mL, respectively. Such fast analytical technique may be useful for the efficient control of substances taken intentionally by MMT patients.

Synthetic cathinones (SCs) are β‐keto analogs of amphetamines. Like amphetamines, SCs target monoamine transporters; however, unusual neuropsychiatric symptoms have been associated with abuse of some SCs, suggesting SCs might possess additional pharmacological properties. We performed radioligand competition binding assays to assess the affinities of nine SCs at human 5‐HT(2A) receptors (5‐HT(2A)R) and muscarinic M(1) receptors (M(1)R) transiently expressed in HEK293 cells. None of the SCs exhibited affinity at M(1)R (minimal displacement of [~K(d)] [3H]scopolamine up to 10 μM). However, two SCs, α‐pyrrolidinopropiophenone (α‐PPP) and 4‐methyl‐α‐PPP, had low μM K(i) values at 5‐HT(2A)R. In 5‐HT(2A)R–phosphoinositide hydrolysis assays, α‐PPP and 4‐methyl‐α‐PPP displayed inverse agonist activity. We further assessed the 5‐HT(2A)R functional activity of α‐PPP, and observed it competitively antagonized 5‐HT(2A)R signaling stimulated by the 5‐HT(2)R agonist (±)‐2,5‐ dimethoxy‐4‐iodoamphetamine (DOI; K(b) = 851 nM). To assess in vivo 5‐HT(2A)R activity, we examined the effects of α‐PPP on the DOI‐elicited head‐twitch response (HTR) in mice. α‐PPP dose‐dependently blocked the HTR with maximal suppressiont 10 mg/kg (P < 0.0001), which is a moderate dose used in studies investigating psychostimulant properties of α‐PPP. To corroborate a 5‐HT(2A)R mechanism, we also tested 3,4‐methylenedioxy‐α‐PPP (MDPPP) and 3‐bromomethcathinone (3‐BMC), SCs that we observed had 5‐HT(2A)R K(i)s > 10 μM. Neither MDPPP nor 3‐BMC, at 10 mg/kg doses, attenuated the DOI HTR. Our results suggest α‐PPP has antagonist interactions at 5‐HT(2A)R in vitro that may translate at physiologically‐relevant doses in vivo. Considering 5‐HT(2A)R antagonism has been shown to mitigate effects of psychostimulants, this property may contribute to α‐PPPs unpopularity compared to other monoamine transporter inhibitors.

Deregulation of glycolysis is a common phenomenon in human colorectal cancer (CRC). In the present study, we reported that Hexokinase 2 (HK2) is overexpressed in human CRC tissues and cell lines, knockout of HK2 inhibited cell proliferation, colony formation, and xenograft tumor growth. We demonstrated that the natural compound, xanthohumol, has a profound anti-tumor effect on CRC via down-regulation of HK2 and glycolysis. Xanthohumol suppressed CRC cell growth both in vitro and in vivo. Treatment with xanthohumol promoted the release of cytochrome C and activated the intrinsic apoptosis pathway. Moreover, our results revealed that xanthohumol down-regulated the EGFR-Akt signaling, exogenous overexpression of constitutively activated Akt1 significantly impaired xanthohumol-induced glycolysis suppression and apoptosis induction. Our results suggest that targeting HK2 appears to be a new approach for clinical CRC prevention or treatment.

Unprotected chronic exposure to solar radiation can contribute to premature skin cancer and sunscreens are a key factor to avoid those detrimental effects. Currently, there is a growing interest in the photoprotector and antioxidant potential of bioactive substances, such as rutin, that could increase the sun protection factor (SPF) value and, also, donate multifunctional characteristics to sunscreens. Recent in vitro findings indicated that rutin, when incorporated into sunscreens, can provide antioxidant activity and SPF improvement. However, clinical studies are fundamental to determine this activity, due to the lack of repeatability of in vitro methodology and low correlation with the in vivo data. We aimed at evaluating the clinical safety and in vivo SPF of rutin by comparing sunscreen formulations containing 0.1% (w/w) rutin, 3.0% (w/w) butyl methoxydibenzoylmethane and 8.0% (w/w) octyl dimethyl PABA (2-ethylhexyl 4-(dimethylamino)benzoato) with a similar bioactive-free preparation. Additionally, skin hydration, in vitro SPF and in vitro antioxidant activity of rutin, in association with the ultraviolet (UV) filters, were investigated. The safety profile of the formulations under sun-exposed skin conditions qualified the formulas for clinical efficacy assays. 2,2-Diphenyl-1-picrylhydrazyl (DPPH) test confirmed the antioxidant properties of rutin, revealing around 40% increase in radical scavenging potential when the bioactive compound was present. Rutin in combination with the UV filters robustly elevated the clinical SPF around 70%, when compared with the bioactive-free formulation. To date, this is the first report in the specialized literature of an in vivo SPF measurement of a rutin-containing photoprotective preparation, supporting the claim that rutin is an effective and safe bioactive compound to be used in multifunctional sunscreens.

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.

SCOPE Xanthohumol, a prenylflavonoid from hops, has been extensively studied preclinically but has undergone limited research in human subjects. A triple-masked, placebo-controlled phase I clinical trial was conducted to examine the safety and tolerability of xanthohumol. METHODS AND RESULTS Thirty healthy volunteers were randomized to 24 mg day-1 xanthohumol (99.8% pure) or placebo for eight weeks. Comprehensive metabolic panels, complete blood counts, body weight, vital signs, and health-related quality of life questionnaires were assessed every two weeks. Participants were interviewed for adverse events (AEs) throughout the trial. Thirteen of 14 (93%) and 14 of 16 (88%) participants completed the trial in the placebo and xanthohumol groups, respectively. There were no withdrawals due to AEs. There were no clinically relevant, between-group differences in laboratory biomarkers, body weight, vital signs, or health-related quality of life. There were no severe or FDA-defined serious AEs, but non-serious AEs are documented in both the placebo (n = 42) and xanthohumol (n = 58) groups. CONCLUSION Over an eight-week period, 24 mg daily xanthohumol was safe and well-tolerated by healthy adults.

Chemoreception in insects is crucial for many aspects related to food seeking, enemy avoidance, and reproduction. Different families of receptors and binding proteins interact with chemical stimuli, including odorant receptors (ORs), ionotropic receptors (IRs), gustatory receptors (GRs), odorant binding proteins (OBPs) and chemosensory proteins (CSPs). In this work, we describe the chemosensory-related gene repertoire of the worldwide spread pest Spodoptera exigua (Lepidoptera: Noctuide) focusing on the transcripts expressed in larvae, which feed on many horticultural crops producing yield losses. A comprehensive de novo assembly that includes reads from chemosensory organs of larvae and adults, and other larval tissues, enabled us to annotate 200 candidate chemosensory-related genes encoding 63 ORs, 28 IRs, 38 GRs, 48 OBPs and 23 CSPs. Of them, 51 transcripts are new annotations. RNA-seq and reverse transcription PCR analyses show that 50 ORs are expressed in larval heads, and 15 OBPs are larva-specific. To identify candidate ecologically-relevant odours for S. exigua larvae, we set up behavioural experiments with different volatile organic compounds (VOCs). 1-hexanol triggers attraction at the three timepoints tested and linalool repels larvae at any timepoints. Other five VOCs elicit behavioural response at single timepoint. Lastly, we tested if pre-exposure to single VOCs influence the expression patterns of selected ORs and pheromone binding proteins (PBPs), showing a massive and general up-regulation of some ORs after 24h exposure. This work sets the basis for the study of chemosensation in S. exigua larvae, boosting further studies aimed to characterize chemosensory-related genes that underlie ecologically-relevant behaviours of larval stage.

There is a growing emphasis on the role of the microbiota-gut-brain axis as modulator of host behaviour and as therapeutic target for neuropsychiatric disorders. In addition, accumulating evidence suggests that early-life stress can exert long-lasting changes on the brain and microbiota, and this early adversity is associated with increased risk for developing depression in later life. The maternal separation (MS) model in rats is a robust paradigm to study the effects of early-life stress on the microbiota-gut-brain axis. Recently, we have shown that polyphenols, naturally occurring compounds associated with several health benefits, have anti-stress effects in in vitro models. In this study, we assess the therapeutic potential of a variety of both flavonoid and non-flavonoid polyphenols in reversing the impact of MS on behaviour and the microbiota-gut-brain axis. Rats underwent a dietary intervention with the naturally-derived polyphenols xanthohumol and quercetin, as well as with a phlorotannin extract for 8 weeks. Treatment with polyphenols prevented the depressive- and anxiety-like behaviours induced by MS, where xanthohumol effects were correlated with rescue of BDNF plasma levels. In addition, MS resulted in altered brain levels of 5-hydroxyindoleacetic acid (5-HIAA) and dopamine, accompanied by abnormal elevation of plasma corticosterone. Although polyphenols did not reverse neurotransmitter imbalance, xanthohumol normalised corticosterone levels in MS rats. Finally, we explored the impact of MS and polyphenolic diets on the gut microbiota. We observed profound changes in microbial composition and diversity produced by MS condition and by xanthohumol treatment. Moreover, functional prediction analysis revealed that MS results in altered enrichment of pathways associated with microbiota-brain interactions that are significantly reversed by xanthohumol treatment. These results suggest that naturally-derived polyphenols exert antidepressant-like effects in MS rats, which mechanisms could be potentially mediated by HPA regulation, BDNF levels rescue and modulation of the microbiota-gut-brain axis.

IMPORTANCE: A prior pilot study demonstrated the systemic absorption of 4 sunscreen active ingredients; additional studies are needed to determine the systemic absorption of additional active ingredients and how quickly systemic exposure exceeds 0.5 ng/mL as recommended by the US Food and Drug Administration (FDA). OBJECTIVE: To assess the systemic absorption and pharmacokinetics of the 6 active ingredients (avobenzone, oxybenzone, octocrylene, homosalate, octisalate, and octinoxate) in 4 sunscreen products under single- and maximal-use conditions. DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial at a clinical pharmacology unit (West Bend, Wisconsin) was conducted in 48 healthy participants. The study was conducted between January and February 2019. INTERVENTIONS: Participants were randomized to 1 of 4 sunscreen products, formulated as lotion (n = 12), aerosol spray (n = 12), nonaerosol spray (n = 12), and pump spray (n = 12). Sunscreen product was applied at 2 mg/cm(2) to 75% of body surface area at 0 hours on day 1 and 4 times on day 2 through day 4 at 2-hour intervals, and 34 blood samples were collected over 21 days from each participant. MAIN OUTCOMES AND MEASURES: The primary outcome was the maximum plasma concentration of avobenzone over days 1 through 21. Secondary outcomes were the maximum plasma concentrations of oxybenzone, octocrylene, homosalate, octisalate, and octinoxate over days 1 through 21. RESULTS: Among 48 randomized participants (mean [SD] age, 38.7 [13.2] years; 24 women [50%]; 23 white [48%], 23 African American [48%], 1 Asian [2%], and 1 of unknown race/ethnicity [2%]), 44 (92%) completed the trial. Geometric mean maximum plasma concentrations of all 6 active ingredients were greater than 0.5 ng/mL, and this threshold was surpassed on day 1 after a single application for all active ingredients. For avobenzone, the overall maximum plasma concentrations were 7.1 ng/mL (coefficient of variation [CV], 73.9%) for lotion, 3.5 ng/mL (CV, 70.9%) for aerosol spray, 3.5 ng/mL (CV, 73.0%) for nonaerosol spray, and 3.3 ng/mL (CV, 47.8%) for pump spray. For oxybenzone, the concentrations were 258.1 ng/mL (CV, 53.0%) for lotion and 180.1 ng/mL (CV, 57.3%) for aerosol spray. For octocrylene, the concentrations were 7.8 ng/mL (CV, 87.1%) for lotion, 6.6 ng/mL (CV, 78.1%) for aerosol spray, and 6.6 ng/mL (CV, 103.9%) for nonaerosol spray. For homosalate, concentrations were 23.1 ng/mL (CV, 68.0%) for aerosol spray, 17.9 ng/mL (CV, 61.7%) for nonaerosol spray, and 13.9 ng/mL (CV, 70.2%) for pump spray. For octisalate, concentrations were 5.1 ng/mL (CV, 81.6%) for aerosol spray, 5.8 ng/mL (CV, 77.4%) for nonaerosol spray, and 4.6 ng/mL (CV, 97.6%) for pump spray. For octinoxate, concentrations were 7.9 ng/mL (CV, 86.5%) for nonaerosol spray and 5.2 ng/mL (CV, 68.2%) for pump spray. The most common adverse event was rash, which developed in 14 participants. RESULTS: Among 48 randomized participants (mean [SD] age, 38.7 [13.2] years; 24 women [50%]; 23 white [48%], 23 African American [48%], 1 Asian [2%], and 1 of unknown race/ethnicity [2%]), 44 (92%) completed the trial. Geometric mean maximum plasma concentrations of all 6 active ingredients were greater than 0.5 ng/mL, and this threshold was surpassed on day 1 after a single application for all active ingredients. The overall maximum plasma concentrations for each active ingredient for each product formulation are shown in the table. The most common adverse event was rash, which developed in 14 participants. [Table: see text] CONCLUSIONS AND RELEVANCE: In this study conducted in a clinical pharmacology unit and examining sunscreen application among healthy participants, all 6 of the tested active ingredients administered in 4 different sunscreen formulations were systemically absorbed and had plasma concentrations that surpassed the FDA threshold for potentially waiving some of the additional safety studies for sunscreens. These findings do not indicate that individuals should refrain from the use of sunscreen. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03582215

Background A number of cases of severe parkinsonism-dystonia have been recognized and reported following the illicit use of ephedrone prepared from pseudoephedrine and potassium permanganate. The pathology associated with ephedrone neurotoxicity has not been described yet in the scientific literature. Objectives To report the first neuropathological study of ephedrone toxicity. Methods The brain of a 33-year-old Ukrainian female ex-ephedrone addict with a long history of l-dopa-unresponsive parkinsonism with dysarthria, dystonia, profound postural instability, cock-gait, and frequent falls, and on antiretroviral treatment, was examined using routine stains and immunohistochemistry. Results Neuropathological findings included diffuse pallidal astrogliosis without neuronal depletion. There was also widespread vascular pathology with small vessels occluded by foreign material, associated with giant cell response without any evidence of consequent focal infarction and a cerebellar abscess. Conclusions Clinical findings of l-dopa-unresponsive parkinsonism with dystonia, caused by illicit use of ephedrone, are fully consistent with neuropathological changes in the pallidum, lack of change in the SN, and preserved tyrosine hydroxylase activity. The findings in the basal ganglia are compatible with manganese toxicity. The vascular pathology is likely a joint effect of infection and the ephedrone toxicity on the vessels. © 2020 International Parkinson and Movement Disorder Society.

The list of pharmacological agents that can modify the gut microbiome or be modified by it continues to grow at a high rate. The greatest amount of attention on drug-gut microbiome interactions has been directed primarily at pharmaceuticals used to treat infection, diabetes, cardiovascular conditions and cancer. By comparison, drugs of abuse and addiction, which can powerfully and chronically worsen human health, have received relatively little attention in this regard. Therefore, the main objective of this study was to characterize how selected synthetic psychoactive cathinones (aka “Bath Salts”) and amphetamine stimulants modify the gut microbiome. Mice were treated with mephedrone (40 mg/kg), methcathinone (80 mg/kg), methamphetamine (5 mg/kg) or 4-methyl-methamphetamine (40 mg/kg), following a binge regimen consisting of 4 injections at 2h intervals. These drugs were selected for study because they are structural analogs that contain a β-keto substituent (methcathinone), a 4-methyl group (4-methyl-methamphetamine), both substituents (mephedrone) or neither (methamphetamine). Mice were sacrificed 1, 2 or 7 days after treatment and DNA from caecum contents was subjected to 16S rRNA sequencing. We found that all drugs caused significant time- and structure-dependent alterations in the diversity and taxonomic structure of the gut microbiome. The two phyla most changed by drug treatments were Firmicutes (methcathinone, 4-methyl-methamphetamine) and Bacteriodetes (methcathinone, 4-methyl-methamphetamine, methamphetamine, mephedrone). Across time, broad microbiome changes from the phylum to genus levels were characteristic of all drugs. The present results signify that these selected psychoactive drugs, which are thought to exert their primary effects within the CNS, can have profound effects on the gut microbiome. They also suggest new avenues of investigation into the possibility that gut-derived signals could modulate drug abuse and addiction via altered communication along the gut-brain axis.

We previously described a negative effect of xanthohumol (XN) upon placentation-related processes. We aimed to better characterize this effect by investigating the effect of XN upon the uptake of arachidonic acid (ARA), a crucial nutrient during pregnancy, by the HTR-8/SVneo human first-trimester extravillous trophoblast cell line and its relationship with the negative effect of XN upon placentation-related processes. Uptake of 14C-ARA (100 nM) was time dependent and inhibited by short-term (26 minutes) or long-term (24 hours) exposure to XN. Xanthohumol (24 hours; 5 µM) behaved as an uncompetitive inhibitor of 14C-ARA uptake; the mammalian target of rapamycin, tyrosine kinases, and c-Jun N-terminal kinases intracellular pathways were involved in this effect; and it markedly reduced long-chain acyl-CoA synthetase 1 messenger RNA levels. Moreover, the effects of XN (24 hours; 5 µM) upon cell proliferation, culture growth, migration, viability, and apoptosis index were prevented by high extracellular ARA but not by the peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist rosiglitazone. We thus conclude that ARA is an essential nutrient regulating cell viability, proliferation, culture growth, migration, and apoptosis of HTR-8/SVneo cells and that the deleterious effects of XN involve inhibition of ARA cellular uptake but appears to be independent of PPAR-γ activation.

Two biotinylated derivatives of the main hop chalcone xanthohumol (1) were prepared by a one-step synthesis via esterification using biotin and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC×HCl) and 4-dimethylaminopyridine (DMAP) as coupling reagents. The products were characterized spectroscopically and their antiproliferative activity toward MCF-7, MCF-10A, HepG2, MDA-MB-231, 4T1 and Balb/3T3 cell lines was investigated using the SRB assay. For all three tested compounds the best activity was noted in the case of human (MCF-7) and mice (4T1) breast cancer cell lines (IC50 values < 9 μM). Both biotinylated derivatives showed slightly higher anticancer activity than xanthohumol (1) towards all types of tested breast cancer cells. Double biotinylated xanthohumol (3) proved to be the most active in inhibiting cell growth, with IC50 values equal to 5.35 ± 1.5 μM for 4T1 and 8.03 ± 0.53 µM for MCF-7 cell lines. Compound 3 was also more active than 1 and 2 against liver cancer cells HepG2 (IC50 = 17.37 ± 5.1 μM), while the IC50 values for 1 and 2 were equal to 21.5 ± 2.7 and 22.1 ± 3.9 µM, respectively. 4‑O‑biotinylxanthohumol (2) was the second most active growth inhibitor, particularly with respect to MCF-7 (IC50 = 6.19 ± 1.7 μM) and 4T1 (IC50 = 6.64 ± 0.4 μM) cell lines. Our preliminary study on biotinylated xanthohumol (1) have shown that this type of functionalization is an effective method for the production of active biomolecules and study on this area should be continued thereby extending their applications.

Glioblastoma multiforme is the most common brain tumor in adults. Because of its highly invasive nature, it is not easy to treat, resulting in high mortality rates. Stromal interacting molecule 1 (Stim1) plays important roles in regulating store-operated Ca2+ entry, and controls invasion by cancer cells. However, the mechanisms and functions of Stim1 in glioma progression are still unclear. In this study, we investigated the effects of targeting Stim1 expression on glioma cell invasion. By analyzing profiles of glioblastoma multiforme patients from RNA-sequencing data in The Cancer Genome Atlas, higher expression levels of STIM1 were correlated with the poor survival. Furthermore, signaling pathways associated with tumor malignancy, including the epithelial-to-mesenchymal transition (EMT), were activated in patients with high STIM1 expression according to gene set enrichment analyses. Higher Stim1 levels were found in glioma cells compared to human astrocytes, and these higher levels enhanced glioma cell invasion. Xanthohumol (XN), a prenylated flavonoid extracted from the hop plant Humulus lupulus L. (Cannabaceae), significantly reduced cell invasion through inhibiting Stim1 expression. From an micro(mi)RNA array analysis, miR-4725-3p was up-regulated by XN treatment. Over-expression of miR-4725-3p inhibited glioma cell invasion via directly targeting the 3'-untranslated region of STIM1. The extracellular signal-regulated kinase/c-Fos pathway was also validated to participate in XN-up-regulated miR-4725-3p expression according to promoter and chromatin immunoprecipitation assays. These results emphasize that miR-4725-3p-inhibited STIM1 signaling is involved in XN-attenuated glioma cell invasion. These findings may provide insights into novel therapeutic strategies for future glioblastoma therapy and drug development. Open Data: Materials are available on https://cos.io/our-services/open-science-badges/ https://osf.io/93n6m/.

International audience; This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta Acta Derm Venereol 2018; 98: 880-887 880 SIGNIFICANCE Skin cancer is an increasing public health burden in many countries. Most skin cancers are caused by DNA damage from ultraviolet radiation in sunlight. This study shows that a very high sun protection factor sunscreen can inhibit DNA damage in the skin caused by high doses of artificial sunlight , even when the sunscreen is used less than optimally. The data suggest that sunscreen use is likely to reduce skin cancer and that there should be more emphasis in communicating how to best use sunscreens in public health campaigns. The cyclobutane pyrimidine dimer (CPD) is a potentially mutagenic DNA photolesion that is the basis of most skin cancers. There are no data on DNA protection by sunscreens under typical conditions of use. The study aim was to determine such protection, in phototypes I/II, with representative sunscreen-user application. A very high SPF formulation was applied at 0.75, 1.3 and 2.0 mg/cm 2. Unprotected control skin was exposed to 4 standard erythema doses (SED) of solar simulated UVR, and sunscreen-treated sites to 30 SED. Holiday behaviour was also simulated by UVR exposure for 5 consecutive days. Control skin received 1 SED daily, and sunscreen-treated sites received 15 (all 3 application thicknesses) or 30 (2.0 mg/cm 2) SED daily. CPD were assessed by quantitative HPLC-tandem mass spectrometry (HPLC-MS/MS) and semi-quantitative immunostaining. In comparison with unprotected control sites, sunscreen significantly (p ≤ 0.001-0.05) reduced DNA damage at 1.3 and 2.0 mg/cm 2 in all cases. However, reduction with typical sunscreen use (0.75 mg/cm 2) was non-significant, with the exception of HPLC-MS/MS data for the 5-day study (p < 0.001). Overall, these results support sunscreen use as a strategy to reduce skin cancer, and demonstrate that public health messages must stress better sunscreen application to get maximal benefit.

Methamphetamine and mephedrone are designer drugs with high abuse liability and they share extensive similarities in their chemical structures and neuropharmacological effects. However, these drugs differ in one significant regard: methamphetamine elicits dopamine neurotoxicity and mephedrone does not. From a structural perspective, mephedrone has a β-keto group and a 4-methyl ring addition, both of which are lacking in methamphetamine. Our previous studies found that methcathinone, which contains only the β-keto substituent, is neurotoxic, while 4-methylmethamphetamine, which contains only the 4-methyl ring substituent, elicits minimal neurotoxicity. In the present study, it was hypothesized that the varying neurotoxic potential associated with these compounds is mediated by the drug-releasable pool of dopamine, which may be accessed by methamphetamine more readily than mephedrone, methcathinone, and 4-methylmethamphetamine. To test this hypothesis, l-DOPA and pargyline, compounds known to increase both the releasable pool of dopamine and methamphetamine neurotoxicity, were combined with mephedrone, 4-methylmethamphetamine and methcathinone. Methamphetamine was also tested because of its ability to increase releasable dopamine. All three regimens significantly enhanced striatal neurotoxicity and glial reactivity for 4-methylmethamphetamine. Methcathinone neurotoxicity and glial reactivity were enhanced only by l-DOPA. Mephedrone remained non-neurotoxic when combined with either l-DOPA or pargyline. Body temperature effects of each designer drug were not altered by the combined treatments. These results support the conclusion that the neurotoxicity of 4-methylmethamphetamine, methcathinone and methamphetamine may be differentially regulated by the drug-releasable pool of dopamine due to β-keto and 4-methyl substituents, but that mephedrone remains non-neurotoxic despite large increases in this pool of dopamine. This article is part of the Special Issue entitled 'Designer Drugs and Legal Highs.'

Fourier Transform Infrared spectroscopy was applied to detect in vitro cell death induced in prostate (PC-3) and breast (T47D) cancer cell lines treated with xanthohumol (XN). After incubation of the cancer cells with XN, specific spectral shifts in the infrared spectra arising from selected cellular components were identified that reflected biochemical changes characteristic for apoptosis and necrosis. Detailed analysis of specific absorbance intensity ratios revealed the compositional changes in the secondary structure of proteins and membrane lipids. In this study, for the first time we examined the changes in these molecular components and linked them to deduce the involvement of molecular mechanisms in the XN-induced death of the selected cancer cells. We showed that XN concentration-dependent changes were attributed to phospholipid ester carbonyl groups, especially in the case of T47D cells, suggesting that XN acts as an inhibitor of cell proliferation. Additionally, we observed distinct changes in the region assigned to the absorption of DNA, which were correlated with a specific marker of cell death and dependent on the XN dose and the type of cancer cells. The microscopic observation and flow cytometry analysis revealed that the decrease in cancer cell viability was mainly related to the induction of necrotic cell death. Moreover, the T47D cells were slightly more sensitive to XN than the PC-3 cells. Considering the results obtained, it can be assumed that apoptosis and necrosis induced by XN may contribute to the anti-proliferative and cytotoxic properties of this flavonoid against cancer cell lines PC-3 and T47D.

Background: Chemical UV filters are common components in sunscreens and cosmetic products and used to protect the skin against harmful effects of sunlight like sunburn. However, the effectiveness of sunscreens in the prevention of skin cancer is in some parts still controversial. Meanwhile, questions about negative effects of the chemical UV filters on human health arise and request an effective risk assessment. Real-life exposure data in humans after application of these products are still rare. Thus, we explored whether and to what extent UV filters are absorbed through the skin into the human body. Material and methods: Plasma and urine samples from 20 healthy volunteers were collected before, during and after a real-life exposure scenario (1st application: 2 mg/cm2; 2nd and 3rd (after 2 and 4 h): 1 mg/cm2 each) using a commercial sunscreen formulation for one day. These samples were analyzed for their content of the currently prominent UV filters octocrylene and avobenzone as well as 2-cyano-3,3-diphenylacrylic acid (CDAA) as the main octocrylene metabolite by using different liquid chromatography electrospray-ionization tandem mass spectrometric procedures. Results: Following dermal sunscreen exposure, avobenzone, octocrylene and CDAA reached concentrations up to 11 μg/L, 25 μg/L and 1352 μg/L in plasma. In urine detection rates of avobenzone and octocrylene were low while CDAA showed a high detection rate and reached up to 5207 μg/g creatinine. Kinetic models could be fitted for octocrylene and CDAA in plasma and CDAA in urine. Concentration peaks were reached between 10 and 16 h after first application and half-life periods were in the range of 1.5 to 2 days. The lipophilic UV filter octocrylene and its metabolite CDAA showed a much slower elimination than other more hydrophilic UV filters. Concordantly, the metabolite CDAA in particular showed a markedly increased renal excretion over the whole sampling period and indicated high internal exposure to OC. Discussion: Real-life sunscreen usage leads to considerable bioavailability of organic UV filters and their metabolites which is rarely seen for other environmental exposures. A combined monitoring of the parent compound and its metabolites is important to fully address internal exposure to the UV filter in humans. Considering the kinetic profiles a prolonged systemic release due to depot formation in skin and a potential accumulation through multi-day exposure is presumed. High in-vivo loads call for a critical toxicological assessment of the UV filters and their metabolites. Keywords: UV filter, Avobenzone, Octocrylene, Biomonitoring, Sunscreen, Exposure assessment, Toxicology

Background During the bronchoscopy process, successful passage of the tracheoscope through the glottis can affect the following procedure of bronchoscopy. Therefore, safer, more effective and less painful anesthesia methods are particularly important for the bronchoscopy success rate. Objective This study aimed to evaluate the efficacy of 1% tetracaine hydrochloride injection pure solution aerosol inhalation combined with oral administration of dyclonine hydrochloride mucilage during bronchoscopy. Methods Patients who need bronchoscopy or bronchoscope treatment were randomly assigned to two groups; group A received pure tetracaine hydrochloride injection solution (3 mL of 1% tetracaine hydrochloride) aerosol inhalation combined with oral 5 mL of dyclonine hydrochloride mucilage and group B received diluted tetracaine hydrochloride injection (3 mL of 1% tetracaine hydrochloride injection + 3 mL of sterile water for injection) aerosol inhalation combined with oral 5 mL of dyclonine hydrochloride mucilage. The anesthetic effect and adverse reactions of these groups were observed and compared. Result A total of 523 patients were randomized. The results showed that patient's tolerance, cough response, glottis opening during the bronchoscope into the glottis and the time required to the tracheoscope pass through the glottis were obviously significantly better in group A than in group B. Vital signs including blood pressure, heart rate and pulse oxygen saturation were more stable in group A than in group B. Conclusion The 1% tetracaine hydrochloride injection pure liquid aerosol inhalation combined with oral administration of dyclonine hydrochloride mucilage as upper airway anesthesia is effective and safe for bronchoscopy. This method of local anesthesia is worthy of clinical application.

Manganese-methcathinone encephalopathy (MME) is a rare parkinsonian syndrome described in drug addicts who have self-injected a home-made mixture containing methcathinone and manganese. We assessed 14 patients with MME and compared their results with 14 matched control subjects. The patients had a parkinsonian syndrome with symmetrical bradykinesia, dystonias, and postural, gait and speech impairment, with moderate restrictions in activities of daily living. Their cognitive status was assessed with the Russian version of the Wechsler Adult Intelligence Scale (WAIS) and with tests of attention (Trail Making Test, Bourdon-Wiersma Dot Cancellation Test), memory (Auditory Verbal Learning Test, Rey-Osterrieth Complex Figure), motor skills (Grooved Pegboard), visuospatial skills (Money Road Map Test, Benton Judgment of Line Orientation), and executive abilities (Verbal Fluency, 5-Point Test, Wisconsin Card Sorting Test). Only a few significant differences emerged. After controlling for multiple comparisons, the results in the WAIS Object Assembly subtest, the Grooved Pegboard test (dominant and nondominant hand) and the Verbal Fluency test remained significant.

Application of sunscreen is one of many ways to protect skin from the harmful effects of UV radiation. Sunscreen products are widely used and regulated as over-the-counter drug products in the United States. The U.S. Food and Drug Administration recommends an assessment of human systemic absorption of sunscreen active ingredients with a Maximal Usage Trial. The FDA conducted a clinical study to determine the systemic exposure of sunscreen active ingredients present in 4 commercially available sunscreen products of different formulation types under maximal usage conditions. To support this clinical study, a sensitive and specific LC-MS/MS method for the simultaneous determination of the two sunscreens avobenzone and oxybenzone in human plasma was developed. Phospholipid removal 96-well protein precipitation plates were used for sample clean-up and the extracted samples were chromatographed on an Ethylene-Bridged Hybrid (BEH) C18 column in isocratic flow using 10 mM ammonium formate in 0.1% formic acid and methanol (24:76, v/v) as a mobile phase. A triple quadrupole mass spectrometer in multiple reaction monitoring (MRM) mode was used to acquire data. The method was validated as per current FDA bioanalytical method validation guidance, in the ranges 0.20–12.00 ng/mL for avobenzone and 0.40–300.00 ng/mL for oxybenzone. The validated method was used to analyze these active ingredients in human clinical study samples.

Dissociative convulsions or pseudoseizures are a difficult to treat common psychiatric condition. In a subset of these patients, the chief complaint is clenching of teeth with apparent nonresponsiveness alone. Neither drugs nor psychotherapeutic interventions have been found to be of much help in its management. Report of two such subsets of cases is presented, in which patients with dissociative convulsions showed sudden, dramatic, and sustained good response to the addition of a muscle relaxant eperisone.

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.

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.

Esophageal cancer, a leading cause of cancer death worldwide, is associated with abnormal activation of the AKT signaling pathway. Xanthohumol, a prenylated flavonoid tested in clinical trials, is reported to exert anti‐diabetes, anti‐inflammation and anticancer activities. However, the mechanisms underlying its chemopreventive or chemotherapeutic effects remain elusive. In the present study, we found that xanthohumol directly targeted AKT1/2 in esophageal squamous cell carcinoma (ESCC). Xanthohumol significantly inhibited the AKT kinase activity in an ATP competitive manner, which was confirmed in binding and computational docking models. KYSE70, 450 and 510 ESCC cell lines highly express AKT and knockdown of AKT1/2 suppressed proliferation of these cells. Treatment with xanthohumol inhibited ESCC cell growth and induced apoptosis and cell cycle arrest at the G1 phase. Xanthohumol also decreased expression of cyclin D1 and increased the levels of cleaved caspase‐3, ‐7 and ‐PARP as well as Bax, Bims and cytochrome c in ESCC cells by downregulating AKT signaling targets, including glycogen synthase kinase 3 beta (GSK3β), mammalian target of rapamycin, and ribosomal protein S6 (S6K). Furthermore, xanthohumol decreased tumor volume and weight in patient‐derived xenografts (PDXs) that highly expressed AKT, but had no effect on PDXs that exhibited low expression of AKT in vivo. Kinase array results showed that xanthohumol treatment decreased phosphorylated p27 expression in both ESCC cell lines and PDX models. Taken together, our data suggest that the inhibition of ESCC tumor growth with xanthohumol is caused by targeting AKT. These results provide good evidence for translation toward clinical trials with xanthohumol., What's new? Esophageal squamous cell carcinoma (ESCC) is among the most common and deadliest forms of esophageal malignancy. Chemotherapy remains the mainstay of treatment, even though many ESCC patients experience disease progression despite therapy. Here, the authors investigated a novel agent for ESCC, the prenylated flavonoid xanthohumol. In ESCC cells, xanthohumol was found to directly target AKT kinase, inhibiting AKT activity, suppressing cell proliferation, and inducing apoptosis. In a patient‐derived xenograft mouse model, xanthohumol reduced tumor volume specifically in high AKT‐expressing tumors, with little effect on low AKT tumors. The data suggest that AKT targeting is a promising therapeutic strategy in ESCC.

Ultraviolet (UV) filters may cause allergic and more frequently photoallergic contact dermatitis. Therefore, a photopach test should always be performed in case of a suspected contact sensitivity to UV filters. We report a case of a 65-year-old woman with a recurrent erythema of the face and décolleté after sun exposure despite application of a sunscreen. The (photo)patch test revealed a contact sensitivity to the UV filter butyl-methoxybenzoylmethane. Treatment with a topical glucocorticoid and avoidance of the particular UV filter led to a rapid improvement.

Mephedrone is a commonly abused constituent of “bath salts” and has many pharmacological effects in common with methamphetamine. Despite their structural similarity, mephedrone differs significantly from methamphetamine in its effects on core body temperature and dopamine nerve endings. The reasons for these differences remain unclear. Mephedrone elicits a transient hypothermia which may provide intrinsic neuroprotection against methamphetamine-like toxicity to dopamine nerve endings. Furthermore, evidence in the literature suggests that this hypothermia is mediated by serotonin. By utilizing transgenic mice devoid of brain serotonin, we determined the contribution of this neurotransmitter to changes in core body temperature as well as its possible role in protecting against neurotoxicity. The effects of methcathinone and 4-methyl-methamphetamine, two structural analogs of mephedrone and methamphetamine, were also evaluated in these mice. The hypothermia induced by mephedrone and methcathinone in wild-type mice was not observed in mice lacking brain serotonin. Despite preventing drug-induced hypothermia, the lack of serotonin did not alter the neurotoxic profiles of the test drugs. Serotonin is a key mediator of pharmacological hypothermia induced by mephedrone and methcathinone, but these body temperature effects do not contribute to dopamine nerve ending damage observed in mice following treatment with mephedrone, methcathinone or 4-methyl-methamphetamine. Thus, the key component of methamphetamine neurotoxicity lacking in mephedrone remains to be elucidated.

We assessed the effect of xanthohumol (XN) on gastric cancer (GC) in vitro and in vivo. XN reduced the viability of SGC-7901, SNU216, and SNU668 cells, but not GES-1 non-tumorigenic human gastric epithelial cells. XN induced apoptosis in SGC-7901 cells in a concentration-dependent manner by enhancing the numbers of late and early apoptotic cells. XN also downregulated the anti-apoptotic proteins Bcl-XL and Bcl-2 and upregulated the pro-apoptotic proteins Bax, Bid, PARP, and caspase-3. XN induced phosphorylation of PI3K, Akt, and mTOR in SGC7901 cells. Also, XN reduced the tumour volume and weight by inhibiting the phosphorylation of Akt and mTOR. XN-treated tumours had significantly fewer proliferating cells and more apoptotic cells compared with the control. Our data indicate that XN induces apoptosis of human GC cells in vivo. Thus, XN may have potential as an anti-GC agent.

The UVA absorbers such as avobenzone are widely used for sunlight protection; however, they show a significant skin penetration. The aim of the present study was to formulate UVA absorbers into mesoporous silicas (MSs) for enhanced UVA protection with reduced percutaneous absorption. Two MSs prepared with different structure-directing agents (Pluronic P123 as single MS and combined Pluronic P123-Pluronic F68 as hybrid MS) were synthesized in this study. The hybrid MS exhibited higher specific surface area (853 m2/g) than the single MS (764 m2/g). The particle sizes of single MS and hybrid MS were about 1 and 1.5 μm, respectively. The adsorbed avobenzone had greatly decreased crystallinity compared with free avobenzone. The in vitro photoprotection determined by UVA/UVB ratio showed that the MS-loaded avobenzone in hydrogel endowed a synergistic effect on UVA protection compared to the free avobenzone. The skin absorption test using Franz diffusion cell indicated that the skin permeation of avobenzone and oxybenzone from MSs in semisolid preparations was one-third to one-half of those from free control. This effect was observed by using both pig skin and UVA-damaged nude mouse skin as the penetration barriers. Topical application of hybrid MS on nude mouse skin before UVA irradiation had prevented the increased transepidermal water loss (TEWL), furrow formation, keratinocyte apoptosis, and neutrophil infiltration. Our findings conclude that MSs containing avobenzone or oxybenzone effectively ameliorated UVA-induced skin disruption and reduced the possible toxicity elicited by percutaneous penetration.

A multicenter, double-blind, randomized, controlled trial was conducted to determine the efficacy of naftopidil as medical expulsive therapy (MET) for patients with distal ureteral stones. Ninety-two patients presenting with a single distal ureteral stone ≤10 mm were randomly assigned to receive either naftopidil (75 mg of naftopidil once in the morning and placebo twice a day) or flopropione (80 mg three times a day). The primary end point was time to stone expulsion calculated by the Kaplan–Meier method. Secondary end points were the percentages of patients who required analgesics, hospital admission, and surgery, the number of working days lost to the disease, and treatment safety. Overall, three patients were excluded from the final analysis. No significant differences were noted in age, stone size, and stone side between the treatment arms. The median time to stone expulsion was 8 days [95 % confidence interval (CI), 3–16] for the naftopidil group, and this was significantly less than the 18 days (95 % CI, 11 to not reached) for the flopropione group (p = 0.03). On multivariate Cox regression analysis, the hazard of expulsion was 1.8-fold higher for the naftopidil group than for the flopropione group after adjustment for age, sex, stone side, and stone size. No significant differences were noted in the secondary end points. The administration of naftopidil significantly improved time to stone expulsion in patients with distal ureteral stones ≤10 mm. We believe that this is the first multicenter, double-blind, randomized, controlled trial demonstrating the efficacy of naftopidil for MET.

In this study, we aimed to investigate modulation of glucose uptake by the HTR-8/SVneo human first-trimester extravillous trophoblast cell line by a series of compounds and to study its consequences upon cell proliferation, viability and migration. We observed that uptake of H-3-deoxy-D-glucose (H-3-DG; 10 nM) was time-dependent, saturable, inhibited by cytochalasin B (50 and 100 mu M), phloretin (0.5 mM) and phloridzin (1 mM), insulin-insensitive and sodium-independent. In the short term (30 min), neither 5-HT (100-1000 mu M), melatonin (10 nM) nor the drugs of abuse ethanol (100 mu M), nicotine (100 mu M), cocaine (25 mu M), amphetamine (10-25 mu M) and 3,4-methylene-dioxy-N-methamphetamine (10 mu M) affected 3H-DG uptake, while dexamethasone (100-1000 mu M), fluoxetine (100-300 mu M), quercetin, epigallocatechin-3-gallate (30-1000 mu M), xanthohumol (XH) and resveratrol (1-500 mu M) decreased it. XH was the most potent inhibitor [IC50 = 3.55 (1.37-9.20) mu M] of H-3-DG uptake, behaving as a non-competitive inhibitor of 3H-DG uptake, both after short-and long-term (24 h) treatment. The effect of XH(5 mu M; 24 h) upon H-3-DG uptake involved mammalian target of rapamycin, tyrosine kinases and c-Jun N-terminal kinases intracellular pathways. Moreover, XH appeared to decrease cellular uptake of lactate due to inhibition of the monocarboxylate transporter 1. Additionally, XH (24 h; 5 mu M) decreased cell viability, proliferation, culture growth and migration. The effects of XH upon cell viability and culture growth, but not the antimigratory effect, were mimicked by low extracellular glucose conditions and reversed by high extracellular glucose conditions. We thus suggest that XH, by inhibiting glucose cellular uptake and impairing HTR-8/SVneo cell viability and proliferation, may have a deleterious impact in the process of placentation.

SUMMARYXanthohumol (Xan) is a natural constituent of human nutrition. Little is known about its actions on leishmanial parasites and their mitochondria as putative target. Therefore, we determined the antileishmanial activity of Xan and resveratrol (Res, as alternative compound with antileishmanial activity) with respect to mitochondria inLeishmania amazonensispromastigotes/amastigotes (LaP/LaA) in comparison with their activity in peritoneal macrophages from mouse (PMM) and macrophage cell line J774A.1 (J774). Mechanistic studies were conducted inLeishmania tarentolaepromastigotes (LtP) and mitochondrial fractions isolated from LtP. Xan and Res demonstrated antileishmanial activity in LaA [half inhibitory concentration (IC50): Xan 7µm, Res 14µm]; while they had less influence on the viability of PMM (IC50: Xan 70µm, Res >438µm). In contrast to Res, Xan strongly inhibited oxygen consumption inLeishmania(LtP) but not in J774 cells. This was based on the inhibition of the mitochondrial electron transfer complex II/III by Xan, which was less pronounced with Res. Neither Xan nor Res increased mitochondrial superoxide release in LtP, while both decreased the mitochondrial membrane potential in LtP. Bioenergetic studies showed that LtP mitochondria have no spare respiratory capacity in contrast to mitochondria in J774 cells and can therefore much less adapt to stress by mitochondrial inhibitors, such as Xan. These data show that Xan may have antileishmanial activity, which is mediated by mitochondrial inhibition.

Importance The US Food and Drug Administration (FDA) has provided guidance that sunscreen active ingredients with systemic absorption greater than 0.5 ng/mL or with safety concerns should undergo nonclinical toxicology assessment including systemic carcinogenicity and additional developmental and reproductive studies. Objective To determine whether the active ingredients (avobenzone, oxybenzone, octocrylene, and ecamsule) of 4 commercially available sunscreens are absorbed into systemic circulation. Design, Setting, and Participants Randomized clinical trial conducted at a phase 1 clinical pharmacology unit in the United States and enrolling 24 healthy volunteers. Enrollment started in July 2018 and ended in August 2018. Interventions Participants were randomized to 1 of 4 sunscreens: spray 1 (n = 6 participants), spray 2 (n = 6), a lotion (n = 6), and a cream (n = 6). Two milligrams of sunscreen per 1 cm2was applied to 75% of body surface area 4 times per day for 4 days, and 30 blood samples were collected over 7 days from each participant. Main Outcomes and Measures The primary outcome was the maximum plasma concentration of avobenzone. Secondary outcomes were the maximum plasma concentrations of oxybenzone, octocrylene, and ecamsule. Results Among 24 participants randomized (mean age, 35.5 [SD, 1.5] years; 12 (50%] women; 14 [58%] black or African American; 14 [58%]), 23 (96%) completed the trial. For avobenzone, geometric mean maximum plasma concentrations were 4.0 ng/mL (coefficient of variation, 6.9%) for spray 1; 3.4 ng/mL (coefficient of variation, 77.3%) for spray 2; 4.3 ng/mL (coefficient of variation, 46.1%) for lotion; and 1.8 ng/mL (coefficient of variation, 32.1%). For oxybenzone, the corresponding values were 209.6 ng/mL (66.8%) for spray 1, 194.9 ng/mL (52.4%) for spray 2, and 169.3 ng/mL (44.5%) for lotion; for octocrylene, 2.9 ng/mL (102%) for spray 1, 7.8 ng/mL (113.3%) for spray 2, 5.7 ng/mL (66.3%) for lotion, and 5.7 ng/mL (47.1%) for cream; and for ecamsule, 1.5 ng/mL (166.1%) for cream. Systemic concentrations greater than 0.5 ng/mL were reached for all 4 products after 4 applications on day 1. The most common adverse event was rash, which developed in 1 participant with each sunscreen. Conclusions and Relevance In this preliminary study involving healthy volunteers, application of 4 commercially available sunscreens under maximal use conditions resulted in plasma concentrations that exceeded the threshold established by the FDA for potentially waiving some nonclinical toxicology studies for sunscreens. The systemic absorption of sunscreen ingredients supports the need for further studies to determine the clinical significance of these findings. These results do not indicate that individuals should refrain from the use of sunscreen. Trial Registration ClinicalTrials.gov Identifier:NCT03582215

Synthetic cathinones have been markedly present in the Spanish drug market in recent years. These substances can be easily obtained in “smart shops”, smoke shops, gas stations and web sites where they can be bought and received anonymously avoiding normal law controls. For the first time we present a case of a neonatal withdrawal syndrome in a baby born to a woman who was a chronic consumer of 4-methylethcathinone. The newborn presented with increased jitteriness and irritability, highpitched cry, hypertonia in the limbs and brisk tendon reflexes. 4-Methylethcathinone was identified and quantified by liquid chromatography tandem mass spectrometry in the four subsequent 3 cm segments of maternal hair (4.3, 4.0, 4.0 and 3.9 ng/mg hair starting from most proximal segment) accounting for maternal consumption during the whole pregnancy and before and in neonatal meconium (0.7 ng/g) confirming fetal exposure during intrauterine life. Methadone and its metabolite were also measured in maternal and neonatal matrices. Counseling pregnant women and women who may become pregnant on the consequences of fetal drug exposure to new designer drugs like 4-methylethcathinone is critical to preventing poor neonatal outcomes. This case report is informative to those studying designer drugs and those clinically involved with pregnant women abusing psychoactive substances.

Scope Xanthohumol (XN) is a bioactive prenylflavonoid from hops. A single-dose pharmacokinetic (PK) study was conducted in men (n = 24) and women (n = 24) to determine dose–concentration relationships. Methods and results Subjects received a single oral dose of 20, 60, or 180 mg XN. Blood was collected at 0, 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, and 120 h. Plasma levels of XN and its metabolites, isoxanthohumol (IX), 8-prenylnaringenin (8PN), and 6-prenylnaringenin (6PN) were measured by LC-MS/MS. Xanthohumol (XN) and IX conjugates were dominant circulating flavonoids among all subjects. Levels of 8PN and 6PN were undetectable in most subjects. The XN PK profile showed peak concentrations around 1 h and between 4–5 h after ingestion. The maximum XN concentrations (Cmax) were 33 ± 7 mg/L, 48 ± 11 mg/L, and 120 ± 24 mg/L for the 20, 60, and 180 mg dose, respectively. Using noncompartmental modeling, the area under the curves (AUC0∞) for XN were 92 ± 68 h × μg/L, 323 ± 160 h × μg/L, and 863 ± 388 h × μg/L for the 20, 60, and 180 mg dose, respectively. The mean half-life of XN was 20 h for the 60 and 18 h for the 180 mg dose. Conclusion XN has a distinct biphasic absorption pattern with XN and IX conjugates being the major circulating metabolites.

Hepatitis C virus (HCV) infection in Tupaia belangeri (Tupaia) represents an important model of HCV infection. Xanthohumol (XN), a major prenylated chalcone from hops, has various biological activities including hepatopreventive and anti-viral activities. In this study, Tupaias infected with HCV RNA positive serum were used to evaluate the effects of XN on liver damage, oxidative reaction, apoptosis and viral protein expression in liver tissues. The Tupaias inoculated with HCV positive serum had elevated serum aminotransferase levels and inflammation, especially hepatic steatosis, and HCV core protein expression in liver tissue. In the animals inoculated with HCV positive serum, XN significantly decreased aminotransferase levels, histological activity index, hepatic steatosis score and transforming growth factor β1 expression in liver tissue compared with the animals without XN intervention. XN reduced HCV core protein expression in liver tissue compared with those without XN intervention but the difference was not significant. XN significantly decreased malondialdehyde, potentiated superoxide dismutase and glutathione peroxidase, reduced Bax expression, promoted Bcl-xL and inhibited caspase 3 activity in liver tissues compared with the animals without XN intervention. These results indicate that XN may effectively improve hepatic inflammation, steatosis and fibrosis induced by HCV in Tupaias primarily through inhibition of oxidative reaction and regulation of apoptosis and possible suppression of hepatic stellate cell activation. The anti-HCV potential of XN needs further investigation.

Mild, mitochondrial uncoupling increases energy expenditure and can reduce the generation of reactive oxygen species (ROS). Activation of cellular, adaptive stress response pathways can result in an enhanced capacity to reduce oxidative damage. Together, these strategies target energy imbalance and oxidative stress, both underlying factors of obesity and related conditions such as type 2 diabetes. Here we describe a metabolomics-driven effort to uncover the anti-obesity mechanism(s) of xanthohumol (XN), a prenylated flavonoid from hops. Metabolomics analysis of fasting plasma from obese, Zucker rats treated with XN revealed decreases in products of dysfunctional fatty acid oxidation and ROS, prompting us to explore the effects of XN on muscle cell bioenergetics. At low micromolar concentrations, XN acutely increased uncoupled respiration in several different cell types, including myocytes. Tetrahydroxanthohumol also increased respiration, suggesting electrophilicity did not play a role. At higher concentrations, XN inhibited respiration in a ROS-dependent manner. In myocytes, time course metabolomics revealed acute activation of glutathione recycling and long term induction of glutathione synthesis as well as several other changes indicative of short term elevated cellular stress and a concerted adaptive response. Based on these findings, we hypothesize that XN may ameliorate metabolic syndrome, at least in part, through mitochondrial uncoupling and stress response induction. In addition, time course metabolomics appears to be an effective strategy for uncovering metabolic events that occur during a stress response.