- Temporal profile of illicit drug consumption in Guangzhou, China monitored by wastewater-based epidemiology. [Journal Article]
- ESEnviron Sci Pollut Res Int 2019 Jun 15
- Wastewater-based epidemiology (WBE) has been widely used as a complementary method for estimating consumption of illicit drugs in the population. Temporal drug consumption estimates derived from WBE …
Wastewater-based epidemiology (WBE) has been widely used as a complementary method for estimating consumption of illicit drugs in the population. Temporal drug consumption estimates derived from WBE can provide important information for law enforcement and public health authorities in understanding changes in supply and demand of illicit drugs, but currently lacking in China. In this study, influent wastewater samples from a municipal sewage treatment plant in Guangzhou, China were collected for 8 weeks to investigate the temporal change in consumption of six illicit drugs in the catchment. The results indicated that methamphetamine and ketamine were the dominant illicit drugs in Guangzhou with the per capita use of 14.7-470.7 mg/day/1000 people and 64.9-673.7 mg/day/1000 people, respectively. No distinct weekly patterns were observed for illicit drug consumption in Guangzhou, indicating that drug users are likely to be regular ones. Further assessment about the impact of public holidays on the consumption behavior of drugs showed little impact for ketamine (p = 0.689), but higher consumptions of methamphetamine (p = 0.003) and cocaine (p = 0.027) were observed during public holidays than the control period. The considerable decrease in drug consumption observed in October 2017 compared with January and May 2017 was possibly the consequence of law enforcement action.
- Charcot-Leyden Crystals in Eosinophilic Inflammation: Active Cytolysis Leads to Crystal Formation. [Review]
- CACurr Allergy Asthma Rep 2019 Jun 15; 19(8):35
- Charcot-Leyden crystals (CLCs), slender bipyramidal hexagonal crystals, were first described by Jean-Martin Charcot in 1853, predating Paul Ehrlich's "discovery" of eosinophils by 26 years. To date, …
Charcot-Leyden crystals (CLCs), slender bipyramidal hexagonal crystals, were first described by Jean-Martin Charcot in 1853, predating Paul Ehrlich's "discovery" of eosinophils by 26 years. To date, CLCs are known as a classical hallmark of eosinophilic inflammation. CLC protein expresses palmitate cleaving lysophospholipase activity and is a member of the family of S-type lectins, galectin-10. We summarize current knowledge regarding the pathological observations of CLCs and their mechanism of generation focusing on eosinophil cell death.
- Anti-BACE1 and anti-AchE activities of undescribed spiro-dioxolane-containing meroterpenoids from the endophytic fungus Aspergillus terreus Thom. [Journal Article]
- PPhytochemistry 2019 Jun 13; 165:112041
- Spiroterreusnoids A-F, six undescribed spiro-dioxolane-containing adducts bearing 3,5-dimethylorsellinic acid-based meroterpenoid and 2,3-butanediol moieties were isolated from the endophytic fungus …
Spiroterreusnoids A-F, six undescribed spiro-dioxolane-containing adducts bearing 3,5-dimethylorsellinic acid-based meroterpenoid and 2,3-butanediol moieties were isolated from the endophytic fungus Aspergillus terreus Thom from Tripterygium wilfordii Hook. f. (Celastraceae). The structures of these adducts were established by spectroscopy, single-crystal X-ray diffraction, and experimental electronic circular dichroism (ECD) measurements. Spiroterreusnoids A-F represent the first examples of adducts composed of 3,5-dimethylorsellinic acid-based meroterpenoids. It is noteworthy that spiroterreusnoids A-F possessing a spiro-dioxolane moiety exhibited potential abilities in inhibiting BACE1 (IC50 values ranging from 5.86 to 27.16 μM) and AchE (IC50 values ranging from 22.18 to 32.51 μM), while the other analogues without this fragment displayed no such activities. Taken together, spiroterreusnoids A-F represent the first multitargeted natural adducts that could inhibit BACE1 and AchE, and might provide a new template for the development of new anti-Alzheimer's disease drugs.
- Sellar xanthogranuloma: a quest based on nine cases assessed with anterior pituitary provocation test. [Journal Article]
- WNWorld Neurosurg 2019 Jun 13
- CONCLUSIONS: Xanthogranuloma appears to be the last stage of the chronic inflammation affecting Rathke's cleft cyst or craniopharyngioma presenting with severe anterior pituitary insufficiency.
- Identify liver X receptor β modulator building blocks by developing a fluorescence polarization-based competition assay. [Journal Article]
- EJEur J Med Chem 2019 Jun 10; 178:458-467
- The liver X receptors (LXRs) of the nuclear receptor family are promising therapeutic targets of multiple diseases like lipid disorders, chronic inflammation, as well as different human cancers. To d…
The liver X receptors (LXRs) of the nuclear receptor family are promising therapeutic targets of multiple diseases like lipid disorders, chronic inflammation, as well as different human cancers. To date, no LXR agonists or antagonists can be used in clinics, emphasizing the importance for discovering new LXR modulators. Fragment-based lead discovery (FBLD) is powerful for designing new scaffolds and new mechanistic drugs, but fragment screening has not been applied to LXRs yet, which might be due to the lack of a specific fragment screening method against the dynamic and hydrophobic ligand binding domain (LBD) of LXRs. Herein, a series of fluorescent tracers were designed, synthesized and tested. The tracer based on hyodeoxycholic acid exhibited a good capability for competitively detecting the ligand binding of LXRβ using a fluorescence polarization approach. Then, 1074 fragments were screened against the LBD of LXRβ (LXRβ-LBD), resulting in 27 binding hits. These fragment hits were further tested using the co-activator recruitment assay and reporter gene assay, and efforts in X-ray crystallography fortunately solved a co-crystal structure of LXRβ-LBD with the fragment F3 (tert-butyl-7-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate). The fluorescence-based fragment screening tool and the newly identified LXRβ binding fragments provide the basis for developing novel LXRβ modulators.
- Structure of the yellow fever NS5 protein reveals conserved drug targets shared among flaviviruses. [Journal Article]
- ARAntiviral Res 2019 Jun 13; :104536
- Yellow fever virus (YFV) is responsible for devastating outbreaks of Yellow fever (YF) in humans and is associated with high mortality rates. Recent large epidemics and epizootics and exponential inc…
Yellow fever virus (YFV) is responsible for devastating outbreaks of Yellow fever (YF) in humans and is associated with high mortality rates. Recent large epidemics and epizootics and exponential increases in the numbers of YF cases in humans and non-human primates highlight the increasing threat YFV poses, despite the availability of an effective YFV vaccine. YFV is the first human virus discovered, but the structures of several of the viral proteins remain poorly understood. Here we report the structure of the full-length NS5 protein, a key enzyme for the replication of flaviviruses that contains both a methyltransferase domain and an RNA dependent RNA polymerase domain, at 3.1 Å resolution. The viral polymerase adopts right-hand fold, demonstrating the similarities of the Yellow fever, Dengue and Zika polymerases. Together this data suggests NS5 as a prime and ideal target for the design of pan-flavivirus inhibitors.
- Crystal Structure of the YcjX Stress Protein Reveals a Ras-Like GTP-Binding Protein. [Journal Article]
- JMJ Mol Biol 2019 Jun 13
- Stress proteins promote cell survival by monitoring protein homeostasis in cells and organelles. YcjX is a conserved protein of unknown function, which is highly upregulated in response to acute and …
Stress proteins promote cell survival by monitoring protein homeostasis in cells and organelles. YcjX is a conserved protein of unknown function, which is highly upregulated in response to acute and chronic stress. Notably, heat shock induction of ycjX exceeded even levels observed for major stress-induced chaperones, including GroEL, ClpB, and HtpG which use ATP as energy source. YcjX features a Walker-type nucleotide-binding domain indicating that YcjX might function as a molecular chaperone. Here, we present the first crystal structure of YcjX from Shewanella oneidensis solved at 1.9-Å resolution by SAD phasing. We show that YcjX is a GTP-binding protein that shares at its core the canonical alpha-beta domain of p21ras (Ras). However, unlike Ras, YcjX features several unique insertions, including an entirely α-helical domain not previously observed in Ras-like GTPases. We note that this helical domain is reminiscent of a similar domain in the Gα subunit of heterotrimeric G proteins, supporting a potential role for YcjX as a signal transducer of stress responses. To elucidate the mechanism of GTP hydrolysis, we determined crystal structures of YcjX bound to GDP and GDPCP, respectively, which crystallized in three different nucleotide switch conformations. Supported by targeted mutagenesis experiments, we show that YcjX utilizes a non-canonical switch 2' motif not previously observed in Ras-like GTPases. Together, our structures provide atomic snapshots of YcjX in different functional states, illustrating the structural determinants for stress signaling.
- Structure-Guided Generation of a Redox-Independent Blue Fluorescent Protein from mBFP. [Journal Article]
- JMJ Mol Biol 2019 Jun 13
- Fluorescent proteins, such as the green fluorescent protein (GFP), are used for detection of cellular components and events. However, GFP and its derivatives have limited usage under anaerobic condit…
Fluorescent proteins, such as the green fluorescent protein (GFP), are used for detection of cellular components and events. However, GFP and its derivatives have limited usage under anaerobic conditions and require a long maturation time. On the other hand, the NADPH-dependent blue fluorescent protein (BFP) without oxidative modification of residues is instantly functional in both aerobic and anaerobic systems. BFP proteins belong to a short-chain dehydrogenase/reductase (SDR) protein family, and their fluorescent property changes with reaction time in the presence of a substrate. With the aim of developing a better fluorescent reporter independent of redox state, we elucidated the crystal structure of a tetrameric mBFP from soil metagenomes with and without NADPH. Apart from the previously known regions, structure-guided mutational studies have identified several residues that contribute to the fluorescence of mBFP, including two aromatic residues (F97 and Y157) near the nicotinamide moiety of the bound NADPH. A single histidine mutation at Y157 (Y157H) has conferred more stabilized, time-independent fluorescence even in the presence of substrates. Furthermore, we discovered another SDR protein that can also emit blue fluorescence. These results open a new possibility for the development of BFP as a stable cellular reporter for widespread use, independent of subcellular environments.
- Dietary vinegar prevents kidney stone recurrence via epigenetic regulations. [Journal Article]
- EEBioMedicine 2019 Jun 12
- CONCLUSIONS: Vinegar prevents renal CaOx crystal formation through influencing urinary citrate and calcium excretion via epigenetic regulations. Vinegar consumption is a promising strategy to prevent CaOx nephrolithiasis occurrence and recurrence. FUND: National Natural Science Foundations of China and National Natural Science Foundation of Guangdong Province.
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- Oxytocin treatment in the prelimbic cortex reduces relapse to methamphetamine-seeking and is associated with reduced activity in the rostral nucleus accumbens core. [Journal Article]
- PBPharmacol Biochem Behav 2019 Jun 13
- Addiction to the psychostimulant Methamphetamine (METH) is characterised by high rates of relapse. Currently there are no approved effective pharmacotherapies for METH dependence. The neuropeptide ox…
Addiction to the psychostimulant Methamphetamine (METH) is characterised by high rates of relapse. Currently there are no approved effective pharmacotherapies for METH dependence. The neuropeptide oxytocin (OXY) potently reduces METH-seeking behaviours in rodent models of relapse and is now being used in clinical trials to treat drug-dependent individuals. However, OXY administration in humans may be impeded by its poor penetration of the brain. Therefore, identification of the neural mechanisms by which OXY reduces METH relapse may guide the development of improved OXY-based therapies for METH addiction. Systemic OXY administration is associated with attenuated METH-induced activity in the prelimbic cortex (PrL); a key brain region which exerts control over much of the reward and addiction circuitry. However, it is not known whether OXY acts directly in the PrL to cause reductions in drug-seeking and downstream brain activity. Therefore, the present study sought to determine whether OXY infused into the PrL reduces cue-induced and METH-primed reinstatement and METH-induced neuronal activity in the downstream nucleus accumbens core (NAcc). Male Sprague Dawley rats underwent intravenous METH self-administration, extinction, and subsequent reinstatement tests. OXY was infused bilaterally into the PrL prior to cue-induced (0, 1 μg/side) and METH-primed reinstatement (0, 0.33, 1.0, 3.0 μg/side). Finally, we quantified cFos immunofluorescence in the NAcc as a proxy for downstream neuronal activity following a PrL infusion of OXY (0, 1 μg/side) prior to METH-primed reinstatement. OXY in the PrL significantly reduced both cue-induced and METH-primed reinstatement. Additionally, intra-PrL OXY reduced METH-induced cFos expression in the rostral but not caudal pole of the NAcc. These findings demonstrate OXY action in the PrL in reducing METH-seeking behaviours and METH-induced activity in the reward circuit. Furthermore, these results suggest that the therapeutic effects of systemically administered OXY on reducing METH-seeking behaviours may involve the PrL-NAc pathway.