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1.
Bioorg Med Chem ; 86: 117290, 2023 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-37137269

RESUMO

Chronic pain, as an unmet medical need, severely impacts the quality of life. The voltage-gated sodium channel NaV1.7 preferentially expressed in sensory neurons of dorsal root ganglia (DRG) serves a promising target for pain therapy. Here, we report the design, synthesis, and evaluation of a series of acyl sulfonamide derivatives targeting Nav1.7 for their antinociceptive activities. Among the derivatives tested, the compound 36c was identified as a selective and potent NaV1.7 inhibitor in vitro and exhibited antinociceptive effects in vivo. The identification of 36c not only provides a new insight into the discovery of selective NaV1.7 inhibitors, but also may hold premise for pain therapy.


Assuntos
Canal de Sódio Disparado por Voltagem NAV1.7 , Bloqueadores dos Canais de Sódio , Ratos , Animais , Bloqueadores dos Canais de Sódio/farmacologia , Ratos Sprague-Dawley , Qualidade de Vida , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Dor/tratamento farmacológico , Analgésicos/farmacologia , Analgésicos/uso terapêutico
2.
J Environ Manage ; 336: 117651, 2023 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-36878058

RESUMO

Odor pollution has become a global environmental issue of increasing concern in recent years. Odor measurements are the basis of assessing and solving odor problems. Olfactory and chemical analysis can be used for odor and odorant measurements. Olfactory analysis reflects the subjective perception of human, and chemical analysis reveals the chemical composition of odors. As an alternative to olfactory analysis, odor prediction methods have been developed based on chemical and olfactory analysis results. The combination of olfactory and chemical analysis is the best way to control odor pollution, evaluate the performances of the technologies, and predict odor. However, there are still some limitations and obstacles for each method, their combination, and the prediction. Here, we present an overview of odor measurement and prediction. Different olfactory analysis methods (namely, the dynamic olfactometry method and the triangle odor bag method) are compared in detail, the latest revisions of the standard olfactometry methods are summarized, and the uncertainties of olfactory measurement results (i.e., the odor thresholds) are analyzed. The researches, applications, and limitations of chemical analysis and odor prediction are introduced and discussed. Finally, the development and application of odor databases and algorithms for optimizing odor measurement and prediction methods are prospected, and a preliminary framework for an odor database is proposed. This review is expected to provide insights into odor measurement and prediction.


Assuntos
Odorantes , Olfato , Humanos , Odorantes/análise , Olfatometria , Poluição Ambiental , Algoritmos
3.
J Environ Sci (China) ; 126: 174-183, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36503747

RESUMO

It is the key to control bio-derived dissolved organic matters (DOM) in order to reduce the effluent concentration of wastewater treatment, especially for waste leachate with high organic contaminants. In the present study, the anaerobic degradation of aerobically stabilized DOM was investigated with DOM substrate isolated through electrodialysis. The degradation of bio-derived DOM was confirmed by reduction of 15% of total organic carbon in 100 days. We characterized the molecular behavior of bio-derived DOM by coupling molecular and biological information analysis. Venn based Sankey diagram of mass features showed the transformation of bio-derived DOM mass features. Occurrence frequency analysis divided mass features into six categories so as to distinguish the fates of intermediate metabolites and persistent compounds. Reactivity continuum model and machine learning technologies realized the semi-quantitative determination on the kinetics of DOM mass features in the form of pseudo-first order, and confirmed the reduction of inert mass features. Furthermore, network analysis statistically establish relationship between DOM mass features and microbes to identify the active microbes that are able to utilize bio-derived DOM. This work confirmed the biological technology is still effective in controlling recalcitrant bio-derived DOM during wastewater treatment.


Assuntos
Matéria Orgânica Dissolvida , Cinética
4.
Environ Sci Technol ; 56(12): 8897-8907, 2022 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-35588324

RESUMO

Undesirable ammonium concentrations can lead to unstable anaerobic digestion processes, and Methanosarcina spp. are the representative methanogens under inhibition. However, no known work seems to exist for directly exploring the detailed metabolic regulation of pure cultured representative Methanosarcina spp. to ammonium inhibition. We used transcriptomics and proteomics to profile the metabolic regulation of Methanosarcina barkeri to 1, 4, and 7 g N/L of total ammoniacal nitrogen (TAN), where free ammonia concentrations were between 1.5 and 36.1 mg N/L. At the initial stages of ammonium inhibition, the genes participating in the acquisition and assimilation of reduced nitrogen sources showed significant upregulation where the minimal fold change of gene transcription was about 2. Apart from nitrogen metabolism, the transcription of some genes in methanogenesis also significantly increased at the initial stages. For example, the genes encoding alternative heterodisulfide reductase subunits (HdrAB), energy-converting hydrogenase subunit (EchC), and methanophenazine-dependent hydrogenase subunits (VhtAC) were significantly upregulated by at least 2.05 times. For the element translocation at the initial stages, the genes participating in the uptake of ferrous iron, potassium ion, and molybdate were significantly upregulated with a minimal fold change of 2.10. As the cultivation proceeded, the gene encoding the cell division protein subunit (FtsH) was significantly upregulated by 13.0 times at 7 g N/L of TAN; meanwhile, an increment in OD600 was observed at the terminal sampling point of 7 g N/L of TAN. The present study explored the metabolic regulation of M. barkeri in stress response, protein synthesis, signal transduction, nitrogen metabolism, methanogenesis, and element translocation. The results would contribute to the understanding of the metabolic effects of ammonium inhibition on methanogens and have significant practical implication in inhibited anaerobic digestion.


Assuntos
Compostos de Amônio , Hidrogenase , Compostos de Amônio/metabolismo , Hidrogenase/genética , Hidrogenase/metabolismo , Metano/metabolismo , Methanosarcina/genética , Methanosarcina/metabolismo , Methanosarcina barkeri/genética , Methanosarcina barkeri/metabolismo , Nitrogênio/metabolismo
5.
Acta Pharmacol Sin ; 43(6): 1372-1382, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34493813

RESUMO

SLL-039 (N-cyclopropylmethyl-7α-4'-(N'-benzoyl) amino-phenyl-6,14-endoethano-tetrahydronorthebaine) and SLL-1206 (N-cyclopropylmethyl-7α-3'-(p-methoxybenzyl) amino-phenyl-6,14-endoethano-tetrahydronorthebaine) are two 4,5-epoxymorphinan-based high selective κ receptor agonists that we recently discovered. In the present study we characterized their pharmacological properties in comparison with arylacetamide-based typical κ agonist U50,488H. We showed that both SLL-039 and SLL-1206 produced potent and long-lasting antinociceptive actions in three different rodent models of pain via activation of κ opioid receptor. In hot-plate assay, the antinociceptive potency of SLL-039 and SLL-1206 increased about 11-and 17.3-fold compared to U50,488H and morphine, respectively, with ED50 values of 0.4 mg/kg. Following repeated administration, SLL-1206, SLL-039, and U50,488H all developed analgesic tolerance tested in hot-plate assay. U50,488H and SLL-039 produced antipruritic effects in a dose-dependent manner, whereas SLL-1206 displayed some antipruritic effects only at very low doses. In addition, SLL-1206 was capable of decreasing morphine-induced physical dependence. More importantly, SLL-039 and SLL-1206 at effective analgesic doses did not cause sedation and conditioned place aversion (CPA), whereas U50,488H did. In comparison with SLL-039, SLL-1206 caused similar antinociceptive responses, but fewer sedation and CPA. In conclusion, our results suggest that SLL-039 and SLL-1206 have potential to be developed as novel analgesic agents, and 4,5-expoxymorphinan scaffold is an attractive structure for the development of selective κ agonists with fewer side effects.


Assuntos
Antipruriginosos , Receptores Opioides kappa , (trans)-Isômero de 3,4-dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclo-hexil)-benzenoacetamida/farmacologia , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Benzilaminas , Morfinanos , Morfina/farmacologia , Receptores Opioides kappa/agonistas , Tebaína/análogos & derivados
6.
J Environ Manage ; 323: 116248, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36126598

RESUMO

The loess regions distribute widely in Northwestern China, North America and Eastern Europe. For these regions, landfill is a suitable technology for solid waste treatment. However, as a landfill cover material, loess is not very effective in controlling the emission of malodorous gases. The present study modified loess with biologically stabilized leachate, and investigated the capacities and mechanisms of the modified loess to remove odorous NH3 and H2S. The removal rates of NH3 and H2S at different acclimation time, targeted gas concentrations and temperatures were measured. It was found that the NH3 removal rate of the modified loess was up to 0.08 µmol/(g·hr), which was 1.8 times that of the virgin loess. The H2S removal rate of the modified loess was up to 1.74 µmol/(g·hr), which was 1.25 times that of the virgin loess. The half-meter loess layer modified by biologically stabilized leachate achieved nearly 100% removal of H2S. The improvement of NH3 and H2S removal ability was mainly due to the enrichment of relevant microorganisms. This work proposed a novel method for in-situ control of malodorous pollutants in landfills in the loess regions, and proved that the in-situ removal of NH3 and H2S using the loess modified with biologically stabilized leachate is feasible and cost-effective.


Assuntos
Poluentes Ambientais , Eliminação de Resíduos , China , Gases , Resíduos Sólidos , Instalações de Eliminação de Resíduos , Sulfeto de Hidrogênio/química , Amônia/química
7.
Molecules ; 27(17)2022 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-36080196

RESUMO

Transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel, predominantly expressed in a subset of peripheral sensory neurons for pain signaling. Topical application of agonist capsaicin for desensitizing TRPV1 currents has been approved for relief of chronic pain. However, the potent TRPV1 capsaicin is not ingestible and even topical capsaicin causes common side effects such as skin irritation, swelling, erythema and pruritus, suggesting that a mild TRPV1 agonist might be helpful for reducing side effects while reliving pain. In this study, we reported on a partial and selective TRPV1 agonist 4-(5-chloropyridin-2-yl)-N-(1H-indazol-6-yl)piperazine-1-carboxamide named CPIPC that was modified based on targeting the residue Arg557, important for conversion between the channel antagonism and agonism. Whole-cell patch clamp recordings indicated a concentration-dependent activation of TRPV1 currents by CPIPC with an EC50 of 1.56 ± 0.13 µM. The maximum efficacy of CPIPC (30 µM) was about 60% of saturated capsaicin (10 µM). Repetitive additions of CPIPC caused TRPV1 current desensitization in both TRPV1-expressing HEK293 cells and dorsal root ganglion (DRG) sensory neurons. Oral administration of CPIPC dose-dependently alleviated inflammatory pain in mice. Further site-directed mutagenesis combined with molecular docking revealed that residue Arg557 is critical for TRPV1 activation by CPIPC. Taken together, we identified a novel partial and selective TRPV1 agonist CPIPC that exhibits antinociceptive activity in mice.


Assuntos
Capsaicina , Canais de Cátion TRPV , Animais , Capsaicina/farmacologia , Capsaicina/uso terapêutico , Gânglios Espinais , Células HEK293 , Humanos , Camundongos , Simulação de Acoplamento Molecular , Dor/tratamento farmacológico , Células Receptoras Sensoriais , Canais de Cátion TRPV/agonistas
8.
Brain Behav Immun ; 93: 312-321, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33444733

RESUMO

Acyl-CoA synthetase long-chain family member 4 (ACSL4) is an important isozyme for polyunsaturated fatty acids (PUFAs) metabolism that dictates ferroptosis sensitivity. The role of ACSL4 in the progression of ischemic stroke is unclear. Here, we found that ACSL4 expression was suppressed in the early phase of ischemic stroke and this suppression was induced by HIF-1α. Knockdown of ACSL4 protected mice against brain ischemia, whereas, forced overexpression of ACSL4 exacerbated ischemic brain injury. ACSL4 promoted neuronal death via enhancing lipid peroxidation, a marker of ferroptosis. Moreover, knockdown of ACSL4 inhibited proinflammatory cytokine production in microglia. These data identify ACSL4 as a novel regulator of neuronal death and neuroinflammation, and interventions of ACSL4 expression may provide a potential therapeutic target in ischemic stroke.


Assuntos
Lesões Encefálicas , Isquemia Encefálica , Coenzima A Ligases , Ferroptose , AVC Isquêmico , Animais , Coenzima A Ligases/genética , Camundongos
9.
J Org Chem ; 86(19): 13212-13230, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34533021

RESUMO

N,N-Diacetylimido protection of 2-aminoglycosides is an elegant strategy but has had limited applications due to unexpected side reactions in glycosylation. We found that high acid concentrations could diminish the side reactions. We observed intermolecular hydrogen bonding among alcohols and acids could disrupt. Assuming that intermolecular hydrogen bonding accelerates the formation of 1,2-orthoamides and disrupting intermolecular hydrogen bonds could turn to the desired glycosylation, we successfully employed sulfenyl triflate pre-activation in the glycosylation of a broad scope of alcohol acceptors, as well as in a one-pot synthesis of a protected human milk oligosaccharide, lacto-N-neotetraose.


Assuntos
Álcoois , Hidrogênio , Glicosilação , Humanos , Ligação de Hidrogênio
10.
Org Biomol Chem ; 19(39): 8597-8606, 2021 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-34553739

RESUMO

An iron-catalyzed radical cascade cyclization of oxime esters with isocyanides for the synthesis of 1-cyanoalkyl isoquinolines and 6-cyanoalkyl phenanthridines has been developed. This demonstrates excellent functional group tolerance and broad substrate scope. A diverse range of potentially valuable 1-cyanoalkyl isoquinolines and 6-cyanoalkyl phenanthridines were obtained in moderate to good yields.

11.
BMC Gastroenterol ; 21(1): 146, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33794777

RESUMO

INTRODUCTION: Angiogenesis is a key factor in promoting tumor growth, invasion and metastasis. In this study we aimed to investigate the prognostic value of angiogenesis-related genes (ARGs) in gastric cancer (GC). METHODS: mRNA sequencing data with clinical information of GC were downloaded from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. The differentially expressed ARGs between normal and tumor tissues were analyzed by limma package, and then prognosis­associated genes were screened using Cox regression analysis. Nine angiogenesis genes were identified as crucially related to the overall survival (OS) of patients through least absolute shrinkage and selection operator (LASSO) regression. The prognostic model and corresponding nomograms were establish based on 9 ARGs and verified in in both TCGA and GEO GC cohorts respectively. RESULTS: Eighty-five differentially expressed ARGs and their enriched pathways were confirmed. Significant enrichment analysis revealed that ARGs-related signaling pathway genes were highly related to tumor angiogenesis development. Kaplan-Meier analysis revealed that patients in the high-risk group had worse OS rates compared with the low-risk group in training cohort and validation cohort. In addition, RS had a good prognostic effect on GC patients with different clinical features, especially those with advanced GC. Besides, the calibration curves verified fine concordance between the nomogram prediction model and actual observation. CONCLUSIONS: We developed a nine gene signature related to the angiogenesis that can predict overall survival for GC. It's assumed to be a valuable prognosis model with high efficiency, providing new perspectives in targeted therapy.


Assuntos
Neoplasias Gástricas , Biomarcadores Tumorais/genética , Humanos , Nomogramas , Prognóstico , Neoplasias Gástricas/genética , Transcriptoma
12.
Acta Pharmacol Sin ; 42(8): 1235-1247, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34103689

RESUMO

Voltage-gated sodium channel Nav1.7 robustly expressed in peripheral nociceptive neurons has been considered as a therapeutic target for chronic pain, but there is no selective Nav1.7 inhibitor available for therapy of chronic pain. Ralfinamide has shown anti-nociceptive activity in animal models of inflammatory and neuropathic pain and is currently under phase III clinical trial for neuropathic pain. Based on ralfinamide, a novel small molecule (S)-2-((3-(4-((2-fluorobenzyl) oxy) phenyl) propyl) amino) propanamide (QLS-81) was synthesized. Here, we report the electrophysiological and pharmacodynamic characterization of QLS-81 as a Nav1.7 channel inhibitor with promising anti-nociceptive activity. In whole-cell recordings of HEK293 cells stably expressing Nav1.7, QLS-81 (IC50 at 3.5 ± 1.5 µM) was ten-fold more potent than its parent compound ralfinamide (37.1 ± 2.9 µM) in inhibiting Nav1.7 current. QLS-81 inhibition on Nav1.7 current was use-dependent. Application of QLS-81 (10 µM) caused a hyperpolarizing shift of the fast and slow inactivation of Nav1.7 channel about 7.9 mV and 26.6 mV, respectively, and also slowed down the channel fast and slow inactivation recovery. In dissociated mouse DRG neurons, QLS-81 (10 µM) inhibited native Nav current and suppressed depolarizing current pulse-elicited neuronal firing. Administration of QLS-81 (2, 5, 10 mg· kg-1· d-1, i.p.) in mice for 10 days dose-dependently alleviated spinal nerve injury-induced neuropathic pain and formalin-induced inflammatory pain. In addition, QLS-81 (10 µM) did not significantly affect ECG in guinea pig heart ex vivo; and administration of QLS-81 (10, 20 mg/kg, i.p.) in mice had no significant effect on spontaneous locomotor activity. Taken together, our results demonstrate that QLS-81, as a novel Nav1.7 inhibitor, is efficacious on chronic pain in mice, and it may hold developmental potential for pain therapy.


Assuntos
Analgésicos/uso terapêutico , Fluorbenzenos/uso terapêutico , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Neuralgia/tratamento farmacológico , Bloqueadores do Canal de Sódio Disparado por Voltagem/uso terapêutico , Potenciais de Ação/efeitos dos fármacos , Animais , Formaldeído , Gânglios Espinais/citologia , Gânglios Espinais/efeitos dos fármacos , Cobaias , Células HEK293 , Humanos , Inflamação/induzido quimicamente , Inflamação/complicações , Masculino , Camundongos Endogâmicos C57BL , Neuralgia/induzido quimicamente , Neuralgia/etiologia , Neurônios/efeitos dos fármacos , Nervos Espinhais/lesões
13.
J Environ Sci (China) ; 102: 99-109, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33637269

RESUMO

Increase of sewage sludge (SS) has led to the construction of more incineration plants, exacerbating to the production of SS incineration residues. However, few studies have considered the mass balance of elements in large-scale SS incineration plants, affecting the residues treatment and utilization. In this study, flow analysis was conducted for major and trace elements in the SS, the fly ash (sewage sludge ash, SSA) and bottom ash from two large-scale SS incineration plants. The elemental characteristics were compared with those of coal fly ash (CFA), and air pollution control residues from municipal solid waste incineration (MSWIA), as well as related criteria. The results showed that the most abundant major element in SSA was Si, ranging from 120 to 240 g/kg, followed by Al (76-348 g/kg), Ca (26-113 g/kg), Fe (35-80 g/kg), and P (26-104 g/kg), and the trace elements were mainly Zn, Ba, Cu, and Mn. Not all the major elements were derived from SS. Most trace elements in the SS incineration residues accounted for 82.4%-127% of those from SS, indicating that SS was the main source of trace elements. The partitioning of heavy metals in the SS incineration residues showed that electrostatic precipitator ash or cyclone ash with high production rates were the major pollutant sinks. The differences in some major and trace elements could be indicators to differentiate SSA from CFA and MSWIA. Compared with related land criteria, the pollutants in SSA should not be ignored during disposal and utilization.


Assuntos
Metais Pesados , Oligoelementos , Cinza de Carvão , Incineração , Metais Pesados/análise , Esgotos , Resíduos Sólidos/análise
14.
J Org Chem ; 85(19): 12284-12293, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-32916054

RESUMO

A variety of dihydropyrrole-functionalized phenanthridines were efficiently synthesized by the metal-free, radical cascade cyclization reaction of 2-isocyanobiphenyls with γ,δ-unsaturated oxime esters. The C-N/C-C/C-C bonds were formed via the oil bath method in a one-pot procedure with broad substrate applicability. The radical process was supported by kinetic isotope effect studies and radical inhibition studies.

15.
Ann Hepatol ; 19(5): 535-540, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32546442

RESUMO

INTRODUCTION AND OBJECTIVES: Hepatocellular carcinoma (HCC) is the second most lethal cancer around the world, with poor survival rate and high metastasis rate in patients. Long noncoding RNAs (lncRNAs) have been reported to modulate the initiation and development of liver cancer. We aimed to investigate the role of lncRNA MAGI2-AS3 in HCC and underlying mechanisms. MATERIALS AND METHODS: The expression levels of MAGI2-AS3 in plasma of HCC patients and the control participants were measured by qPCR. Hep3B and MHCC97-H cells were transfected with MAGI2-AS3 and ROCK2 expression vectors. Cell migration and invasion of HCC cells transfected with the vectors were investigated by transwell assay. In addition, flow cytometry and western blot were performed for apoptosis detection. RESULTS: We found that MAGI2-AS3 was downregulated in plasma of early stage HCC patients compared to healthy controls. After surgical resection, the expression levels of MAGI2-AS3 were increased compared to pretreatment levels on the day of discharge. During the follow-up, MAGI2-AS3 was downregulated in patients developed distant recurrence, but not in other patients compared to the levels measured on the day of discharge. In HCC cells, overexpression of MAGI2-AS3 mediated the downregulation of ROCK2. Cell invasion and migration assay showed that overexpression of MAGI2-AS3 mediated the decreased cell invasion and migration rate, while ROCK2 played an opposite role and attenuated the effects of overexpression of MAGI2-AS3. CONCLUSION: Our study indicated that MAGI2-AS3 was downregulated in the distant recurrence of HCC after surgical resection and affected the invasion and migration of HCC cells via ROCK2.


Assuntos
Carcinoma Hepatocelular/cirurgia , Movimento Celular , Hepatectomia/efeitos adversos , Neoplasias Hepáticas/cirurgia , RNA Longo não Codificante/metabolismo , Quinases Associadas a rho/metabolismo , Adulto , Idoso , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/secundário , Estudos de Casos e Controles , Linhagem Celular Tumoral , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , RNA Longo não Codificante/genética , Transdução de Sinais , Resultado do Tratamento , Quinases Associadas a rho/genética
16.
J Pharmacol Exp Ther ; 371(1): 1-14, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31371483

RESUMO

For the past 50 years, the clinical efficacy of antipsychotic medications has relied on blockade of dopamine D2 receptors. Drug development of non-D2 compounds, seeking to avoid the limiting side effects of dopamine receptor blockade, has failed to date to yield new medicines for patients. In this work, we report the discovery of SEP-363856 (SEP-856), a novel psychotropic agent with a unique mechanism of action. SEP-856 was discovered in a medicinal chemistry effort utilizing a high throughput, high content, mouse-behavior phenotyping platform, in combination with in vitro screening, aimed at developing non-D2 (anti-target) compounds that could nevertheless retain efficacy across multiple animal models sensitive to D2-based pharmacological mechanisms. SEP-856 demonstrated broad efficacy in putative rodent models relating to aspects of schizophrenia, including phencyclidine (PCP)-induced hyperactivity, prepulse inhibition, and PCP-induced deficits in social interaction. In addition to its favorable pharmacokinetic properties, lack of D2 receptor occupancy, and the absence of catalepsy, SEP-856's broad profile was further highlighted by its robust suppression of rapid eye movement sleep in rats. Although the mechanism of action has not been fully elucidated, in vitro and in vivo pharmacology data as well as slice and in vivo electrophysiology recordings suggest that agonism at both trace amine-associated receptor 1 and 5-HT1A receptors is integral to its efficacy. Based on the preclinical data and its unique mechanism of action, SEP-856 is a promising new agent for the treatment of schizophrenia and represents a new pharmacological class expected to lack the side effects stemming from blockade of D2 signaling. SIGNIFICANCE STATEMENT: Since the discovery of chlorpromazine in the 1950s, the clinical efficacy of antipsychotic medications has relied on blockade of dopamine D2 receptors, which is associated with substantial side effects and little to no efficacy in treating the negative and cognitive symptoms of schizophrenia. In this study, we describe the discovery and pharmacology of SEP-363856, a novel psychotropic agent that does not exert its antipsychotic-like effects through direct interaction with D2 receptors. Although the mechanism of action has not been fully elucidated, our data suggest that agonism at both trace amine-associated receptor 1 and 5-HT1A receptors is integral to its efficacy. Based on its unique profile in preclinical species, SEP-363856 represents a promising candidate for the treatment of schizophrenia and potentially other neuropsychiatric disorders.


Assuntos
Psicotrópicos/farmacologia , Piranos/farmacologia , Esquizofrenia/tratamento farmacológico , Animais , Excitabilidade Cortical/efeitos dos fármacos , Alucinógenos/toxicidade , Macaca mulatta , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fenciclidina/toxicidade , Psicotrópicos/uso terapêutico , Piranos/química , Piranos/uso terapêutico , Ratos , Ratos Sprague-Dawley , Receptor 5-HT1A de Serotonina/metabolismo , Receptores Acoplados a Proteínas G/agonistas , Esquizofrenia/etiologia , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Agonistas do Receptor 5-HT1 de Serotonina/uso terapêutico , Sono REM/efeitos dos fármacos
17.
Mediators Inflamm ; 2019: 7659509, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31341422

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is a major health threat around the world and is characterized by dysbiosis. Primary bile acids are synthesized in the liver and converted into secondary bile acids by gut microbiota. Recent studies support the role of bile acids in modulating dysbiosis and NAFLD, while the mechanisms are not well elucidated. Dysbiosis may alter the size and the composition of the bile acid pool, resulting in reduced signaling of bile acid receptors such as farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5). These receptors are essential in lipid and glucose metabolism, and impaired bile acid signaling may cause NAFLD. Bile acids also reciprocally regulate the gut microbiota directly via antibacterial activity and indirectly via FXR. Therefore, bile acid signaling is closely linked to dysbiosis and NAFLD. During the past decade, stimulation of bile acid receptors with their agonists has been extensively explored for the treatment of NAFLD in both animal models and clinical trials. Early evidence has suggested the potential of bile acid receptor agonists in NAFLD management, but their long-term safety and effectiveness need further clarification.


Assuntos
Ácidos e Sais Biliares/metabolismo , Disbiose/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Ensaios Clínicos como Assunto , Microbioma Gastrointestinal , Glucose/metabolismo , Humanos , Metabolismo dos Lipídeos , Camundongos , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Hepatopatia Gordurosa não Alcoólica/terapia , Proteínas de Ligação a RNA/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Fatores de Risco , Transdução de Sinais
18.
J Environ Sci (China) ; 85: 17-34, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31471024

RESUMO

Is our food safe and free of the crisis of antibiotics and antibiotic resistance (AR)? And will the derived food waste (FW) impose AR risk to the environment after biological treatment? This study used restaurant FW leachates flowing through a 200 tons-waste/day biological treatment plant as a window to investigate the fate of antibiotics and antibiotic-resistance genes (ARGs) during the acceptance and treatment of FW. Sulfonamides (sulfamethazine, sulfamethoxazole) and quinolones (ciprofloxacin, enrofloxacin, ofloxacin) were detected during FW treatment, while tetracyclines, macrolides and chloramphenicols were not observable. ARGs encoding resistance to sulfonamides, tetracyclines and macrolides emerged in FW leachates. Material flow analysis illustrated that the total amount of antibiotics (except sulfamethazine) and ARGs were constant during FW treatment processes. Both the concentration and total amount of most antibiotics and ARGs fluctuated during treatment, physical processes (screening, centrifugation, solid-liquid and oil-water separation) did not decrease antibiotic or ARGs concentrations or total levels permanently; the affiliated wastewater treatment plant appeared to remove sulfonamides and most ARGs concentrations and total amount. Heavy metals Ni, Co and Cu were important for disseminating antibiotics concentrations and MGEs for distributing ARGs concentrations. Humic substances (fulvic acids, hydrophilic fractions), C-associated and N-associated contents were essential for the distribution of the total amounts of antibiotics and ARGs. Overall, this study implied that human food might not be free of antibiotics and ARGs, and FW was an underestimated AR pool with various determinants. Nonetheless, derived hazards of FW could be mitigated through biological treatment with well-planned daily operations.


Assuntos
Antibacterianos/análise , Resistência Microbiana a Medicamentos/genética , Eliminação de Resíduos Líquidos , Poluentes Químicos da Água/análise , Genes Bacterianos , Metais Pesados/análise , Restaurantes , Águas Residuárias/química , Águas Residuárias/microbiologia
19.
J Environ Sci (China) ; 86: 50-64, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31787190

RESUMO

Production of biochemicals from waste streams has been attracting increasing worldwide interest to achieve climate protection goals. Chain elongation (CE) for production of medium-chain carboxylic acids (MCCAs, especially caproate, enanthate and caprylate) from diverse biowaste has emerged as a potential economic and environmental technology for a sustainable society. The present mini review summarizes the research utilizing various synthetic or real waste-derived substrates available for MCCA production. Additionally, the microbial characteristics of the CE process are surveyed and discussed. Considering that a large proportion of recalcitrantly biodegradable biowaste and residues cannot be further utilized by CE systems and remain to be treated and disposed, we propose here a loop concept of bioconversion of biowaste to MCCAs making full use of the biowaste with zero emission. This could make possible an alternative technology for synthesis of value-added products from a wide range of biowaste, or even non-biodegradable waste (such as, plastics and rubbers). Meanwhile, the remaining scientific questions, unsolved problems, application potential and possible developments for this technology are discussed.


Assuntos
Eliminação de Resíduos de Serviços de Saúde/métodos , Caproatos , Caprilatos , Ácidos Carboxílicos
20.
J Environ Sci (China) ; 75: 370-377, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30473302

RESUMO

HCl and SO2 emission is one of the major concerns related to municipal solid waste incinerator (MSWI). In this study, a material flow analysis model was developed to estimate the HCl and SO2 concentrations in the MSWI flue gases (FGs), and their concentrations in the full-scale MSWI were monitored. The calculated concentrations of HCl and SO2 in the FG were 770-1300 mg/Nm3 and 150-640 mg/Nm3, respectively, in close agreement with the monitored values. More than 99% of Cl and 92% of S from the FG were captured into solid residues by the air pollution control (APC) systems. Moreover, since only 48.4%-67.5% of Cl and 21.3%-53.4% of S were transferred to the FG from the municipal solid waste (MSW), it was more reliable to estimate the source strengths and release amounts of HCl and SO2 in the FG based on the amounts of Cl and S in the APC residues (AR) and exhaust gas rather than in the MSW. This simple method is easily applicable and the estimated results could provide scientific basis for the appropriate design and operation of the APC systems as well as corrosion control of heat recovery systems.


Assuntos
Poluentes Atmosféricos/análise , Ácido Clorídrico/análise , Incineração , Dióxido de Enxofre/análise , Monitoramento Ambiental
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