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1.
J Headache Pain ; 25(1): 83, 2024 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-38773375

RESUMEN

BACKGROUND: Atogepant is an oral calcitonin gene-related peptide receptor antagonist approved for the preventive treatment of migraine in adults. These analyses evaluated the proportions of clinical trial participants who experienced sustained responses to atogepant over 12 or 52 weeks of treatment. METHODS: These were post hoc analyses of ADVANCE, a 12-week, double-blind, randomized trial of atogepant 10, 30, and 60 mg once daily vs. placebo for the preventive treatment of episodic migraine, and a separate open-label long-term safety (LTS) trial of atogepant 60 mg once daily over 52 weeks. The 60 mg dose of atogepant was used to detect safety issues. An initial response was defined as ≥50%, ≥75%, or 100% reduction from baseline in MMDs in month 1 for ADVANCE or quarter 1 for the LTS trial. The proportions of participants who continued to experience a response above each response-defining threshold through each subsequent month (for ADVANCE) or each quarter (for LTS) were calculated. RESULTS: In ADVANCE, sustained response rates during months 2 and 3 varied with dose and were as follows: 70.8-81.1% following an initial ≥50% response, 47.3-61.9% following an initial ≥75% response, and 34.8-41.7% following an initial 100% response. Of those who experienced an initial ≥75% or 100% response during month 1, more than 79% continued to experience at least a 50% response during both months 2 and 3. During the LTS trial, sustained response rates through quarters 2, 3, and 4 were 84.7% following an initial ≥50% response, 72.6% following an initial ≥75% response, and 37.8% following an initial 100% response. Of those who experienced an initial ≥75% or 100% response during quarter 1, more than 90% continued to experience at least a 50% response through quarters 2, 3, and 4. CONCLUSION: Over 70% of participants who experienced an initial response with atogepant treatment had a sustained response with continued treatment. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03777059 (submitted: December 13, 2018); NCT03700320 (submitted: September 25, 2018).


Asunto(s)
Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Trastornos Migrañosos , Humanos , Trastornos Migrañosos/tratamiento farmacológico , Trastornos Migrañosos/prevención & control , Método Doble Ciego , Femenino , Masculino , Adulto , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/administración & dosificación , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/efectos adversos , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/uso terapéutico , Persona de Mediana Edad , Relación Dosis-Respuesta a Droga , Azepinas/efectos adversos , Azepinas/administración & dosificación , Azepinas/uso terapéutico , Resultado del Tratamiento , Piperidinas , Piridinas , Pirroles , Compuestos de Espiro
2.
J Org Chem ; 89(10): 7255-7262, 2024 May 17.
Artículo en Inglés | MEDLINE | ID: mdl-38718382

RESUMEN

Juglanaloids A and B are recently isolated natural products characterized by an unprecedented spiro bicyclic isobenzofuranone-tetrahydrobenzazepinone framework and a promising antiamyloid activity. Here reported is a straightforward convergent total synthesis of these natural products, which were obtained in high enantiomeric purity (94% and >99% ee for juglanaloids A and B, respectively) through an eight-step longest linear sequence, based on an efficient and reliable enantioselective phase-transfer-catalyzed alkylation step. Considering the interesting biological activity of juglanaloids, this convenient, highly enantioselective, flexible, and predictable synthetic strategy promises to be a powerful tool for accessing potentially bioactive spiro bicyclic phthalide-tetrahydrobenzazepinone derivatives.


Asunto(s)
Alcaloides , Enfermedad de Alzheimer , Compuestos de Espiro , Estereoisomerismo , Enfermedad de Alzheimer/tratamiento farmacológico , Compuestos de Espiro/química , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacología , Alcaloides/química , Alcaloides/síntesis química , Alcaloides/farmacología , Estructura Molecular , Benzofuranos/química , Benzofuranos/síntesis química , Benzofuranos/farmacología
3.
J Med Chem ; 67(8): 6268-6291, 2024 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-38619191

RESUMEN

Overactivation of cyclic GMP-AMP synthase (cGAS) is implicated in the occurrence of many inflammatory and autoimmune diseases, and inhibition of cGAS with a specific inhibitor has been proposed as a potential therapeutic strategy. However, only a few low-potency cGAS inhibitors have been reported, and few are suitable for clinical investigation. As a continuation of our structural optimization on the reported cGAS inhibitor 6 (G140), we developed a series of spiro[carbazole-3,3'-pyrrolidine] derivatives bearing a unique 2-azaspiro[4.5]decane structural motif, among which compound 30d-S was identified with high cellular effects against cGAS. This compound showed improved plasma exposure, lower clearance, and an oral bioavailability of 35% in rats. Moreover, in the LPS-induced acute lung injury (ALI) mice model, oral administration of compound 30d-S at 30 mg/kg markedly reduced lung inflammation and alleviated histopathological changes. These results confirm that 30d-S is a new efficacious cGAS inhibitor and is worthy of further investigation.


Asunto(s)
Lesión Pulmonar Aguda , Carbazoles , Diseño de Fármacos , Nucleotidiltransferasas , Pirrolidinas , Lesión Pulmonar Aguda/tratamiento farmacológico , Animales , Ratones , Masculino , Humanos , Ratas , Carbazoles/síntesis química , Carbazoles/farmacología , Carbazoles/química , Carbazoles/uso terapéutico , Carbazoles/farmacocinética , Pirrolidinas/farmacología , Pirrolidinas/síntesis química , Pirrolidinas/química , Pirrolidinas/uso terapéutico , Pirrolidinas/farmacocinética , Nucleotidiltransferasas/antagonistas & inhibidores , Nucleotidiltransferasas/metabolismo , Lipopolisacáridos , Ratas Sprague-Dawley , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacología , Compuestos de Espiro/química , Compuestos de Espiro/uso terapéutico , Compuestos de Espiro/farmacocinética , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/química , Relación Estructura-Actividad , Simulación del Acoplamiento Molecular
4.
Bioorg Med Chem Lett ; 104: 129739, 2024 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-38599298

RESUMEN

FR901464 is a natural product that exhibits antiproliferative activity at single-digit nanomolar concentrations in cancer cells. Its tetrahydropyran-spiroepoxide covalently binds the spliceosome. Through our medicinal chemistry campaign, we serendipitously discovered that a bromoetherification formed a tetrahydrofuran. The tetrahydrofuran analog was three orders of magnitude less potent than the corresponding tetrahydropyran analogs. This study shows the significance of the tetrahydropyran ring that presents the epoxide toward the spliceosome.


Asunto(s)
Piranos , Compuestos de Espiro , Piranos/farmacología , Compuestos de Espiro/farmacología , Furanos/farmacología , Compuestos Epoxi/farmacología
5.
Helicobacter ; 29(2): e13075, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38627919

RESUMEN

BACKGROUND: The current standard treatment for Helicobacter pylori infection, which involves a combination of two broad-spectrum antibiotics, faces significant challenges due to its detrimental impact on the gut microbiota and the emergence of drug-resistant strains. This underscores the urgent requirement for the development of novel anti-H. pylori drugs. Zoliflodacin, a novel bacterial gyrase inhibitor, is currently undergoing global phase III clinical trials for treating uncomplicated Neisseria gonorrhoeae. However, there is no available data regarding its activity against H. pylori. MATERIALS AND METHODS: We evaluated the in vitro activity of zoliflodacin against H. pylori clinical isolates (n = 123) with diverse multidrug resistance. We performed DNA gyrase supercoiling and microscale thermophoresis assays to identify the target of zoliflodacin in H. pylori. We analyzed 2262 H. pylori whole genome sequences to identify Asp424Asn and Lys445Asn mutations in DNA gyrase subunit B (GyrB) that are associated with zoliflodacin resistance. RESULTS: Zoliflodacin exhibits potent activity against all tested isolates, with minimal inhibitory concentration (MIC) values ranging from 0.008 to 1 µg/mL (MIC50: 0.125 µg/mL; MIC90: 0.25 µg/mL). Importantly, there was no evidence of cross-resistance to any of the four first-line antibiotics commonly used against H. pylori. We identified GyrB as the primary target of zoliflodacin, with Asp424Asn or Lys445Asn substitutions conferring resistance. Screening of 2262 available H. pylori genomes for the two mutations revealed only one clinical isolate carrying Asp424Asn substitution. CONCLUSION: These findings support the potential of zoliflodacin as a promising candidate for H. pylori treatment, warranting further development and evaluation.


Asunto(s)
Barbitúricos , Infecciones por Helicobacter , Helicobacter pylori , Isoxazoles , Morfolinas , Oxazolidinonas , Compuestos de Espiro , Humanos , Antibacterianos/farmacología , Girasa de ADN/genética , Farmacorresistencia Bacteriana , Infecciones por Helicobacter/tratamiento farmacológico , Infecciones por Helicobacter/microbiología , Pruebas de Sensibilidad Microbiana , Ensayos Clínicos Fase III como Asunto
6.
Spectrochim Acta A Mol Biomol Spectrosc ; 316: 124342, 2024 Aug 05.
Artículo en Inglés | MEDLINE | ID: mdl-38676981

RESUMEN

Two spirobifluene-based fluorescent probes SPF1 and SPF2, were designed and synthesized. The probes displayed "turn-on" fluorescence response for Cysteine. One of the challenges in developing a Cysteine probe is to secure high selectivity. SPF1/SPF2 can discriminate Cysteine from GSH as well as Hcy, and showed high substrate selectivity. The detection limit of SPF1 is 36 nM, which is excellent comparing with other optical sensors for Cysteine. The sensing mechanism of SPF1/SPF2 was verified by experimental data and theoretical calculations. There was a good linear relationship between the fluorescence intensity of SPF1/SPF2 and the concentration of Cysteine. The MTT tests indicated that SPF1/SPF2 had low cytotoxicity and good biocompatibility. Theoretical calculations demonstrated that SPF1, SPF2, and their related reaction products with Cysteine exhibited good two-photon absorption properties. Finally, SPF1/SPF2 had been successfully applied to the imaging of Cysteine in living cells under two-photon excitation.


Asunto(s)
Cisteína , Colorantes Fluorescentes , Compuestos de Espiro , Colorantes Fluorescentes/química , Colorantes Fluorescentes/síntesis química , Cisteína/análisis , Humanos , Compuestos de Espiro/química , Células HeLa , Imagen Óptica/métodos , Límite de Detección , Fotones , Microscopía de Fluorescencia por Excitación Multifotónica/métodos , Espectrometría de Fluorescencia/métodos
7.
Spectrochim Acta A Mol Biomol Spectrosc ; 316: 124337, 2024 Aug 05.
Artículo en Inglés | MEDLINE | ID: mdl-38676988

RESUMEN

Polarity is a vital element in endoplasmic reticulum (ER) microenvironment, and its variation is closely related to many physiological and pathological activities of ER, so it is necessary to trace fluctuations of polarity in ER. However, most of fluorescent probes for detecting polarity dependent on the changes of single emission, which could be affected by many factors and cause false signals. Ratiometric fluorescent probe with "built-in calibration" can effectively avoid detection errors. Here, we have designed a ratiometric fluorescent probe HM for monitoring the ER polarity based on the intramolecular reaction of spiro-oxazolidine. It forms ring open/closed isomers driven by polarity to afford ratiometric sensing. Probe HM have manifested its ratiometric responses to polarity in spectroscopic results, which could offer much more precise information for the changes of polarity in living cells with the internal built-in correction. It also showed large emission shift ( 133 nm), high selectivity and photo-stability. In biological imaging, HM could selectively accumulate in ER with high photo-stability. Importantly, HM has ability for in situ tracing the changes of ER polarity with ratiometric behavior during the ER stress process with the stimulation of tunicamycin, dithiothreitol and hypoxia, suggesting that HM is an effective molecule tool for monitoring the variations of ER polarity.


Asunto(s)
Estrés del Retículo Endoplásmico , Colorantes Fluorescentes , Oxazoles , Compuestos de Espiro , Colorantes Fluorescentes/química , Colorantes Fluorescentes/síntesis química , Humanos , Compuestos de Espiro/química , Oxazoles/química , Estrés del Retículo Endoplásmico/efectos de los fármacos , Espectrometría de Fluorescencia , Células HeLa , Retículo Endoplásmico/metabolismo
8.
Int J Mol Sci ; 25(7)2024 Apr 02.
Artículo en Inglés | MEDLINE | ID: mdl-38612759

RESUMEN

As a regulator of alveolo-capillary barrier integrity, Transient Receptor Potential Vanilloid 4 (TRPV4) antagonism represents a promising strategy for reducing pulmonary edema secondary to chemical inhalation. In an experimental model of acute lung injury induced by exposure of anesthetized swine to chlorine gas by mechanical ventilation, the dose-dependent effects of TRPV4 inhibitor GSK2798745 were evaluated. Pulmonary function and oxygenation were measured hourly; airway responsiveness, wet-to-dry lung weight ratios, airway inflammation, and histopathology were assessed 24 h post-exposure. Exposure to 240 parts per million (ppm) chlorine gas for ≥50 min resulted in acute lung injury characterized by sustained changes in the ratio of partial pressure of oxygen in arterial blood to the fraction of inspiratory oxygen concentration (PaO2/FiO2), oxygenation index, peak inspiratory pressure, dynamic lung compliance, and respiratory system resistance over 24 h. Chlorine exposure also heightened airway response to methacholine and increased wet-to-dry lung weight ratios at 24 h. Following 55-min chlorine gas exposure, GSK2798745 marginally improved PaO2/FiO2, but did not impact lung function, airway responsiveness, wet-to-dry lung weight ratios, airway inflammation, or histopathology. In summary, in this swine model of chlorine gas-induced acute lung injury, GSK2798745 did not demonstrate a clinically relevant improvement of key disease endpoints.


Asunto(s)
Lesión Pulmonar Aguda , Antineoplásicos , Bencimidazoles , Compuestos de Espiro , Animales , Porcinos , Cloro/toxicidad , Canales Catiónicos TRPV , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/tratamiento farmacológico , Inflamación , Oxígeno
9.
J Pharmacol Exp Ther ; 389(3): 301-309, 2024 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-38621994

RESUMEN

δ opioid receptors (DORs) hold potential as a target for neurologic and psychiatric disorders, yet no DOR agonist has proven efficacious in critical phase II clinical trials. The exact reasons for the failure to produce quality drug candidates for the DOR are unclear. However, it is known that certain DOR agonists can induce seizures and exhibit tachyphylaxis. Several studies have suggested that those adverse effects are more prevalent in delta agonists that share the (+)-4-[(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80)/4-[(αR*)-α-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl]-N,N-diethylbenzamide chemotype. There is a need to find novel lead candidates for drug development that have improved pharmacological properties to differentiate them from the current failed delta agonists. Our objective in this study was to identify novel DOR agonists. We used a ß-arrestin assay to screen a small G-protein coupled receptors (GPCR)-focused chemical library. We identified a novel chemotype of DOR agonists that appears to bind to the orthosteric site based of docking and molecular dynamic simulation. The most potent agonist hit compound is selective for the DOR over a panel of 167 other GPCRs, is slightly biased toward G-protein signaling and has anti-allodynic efficacy in a complete Freund's adjuvant model of inflammatory pain in C57BL/6 male and female mice. The newly discovered chemotype contrasts with molecules like SNC80 that are highly efficacious ß-arrestin recruiters and may suggest this novel class of DOR agonists could be expanded on to develop a clinical candidate drug. SIGNIFICANCE STATEMENT: δ opioid receptors are a clinical target for various neurological disorders, including migraine and chronic pain. Many of the clinically tested delta opioid agonists share a single chemotype, which carries risks during drug development. Through a small-scale high-throughput screening assay, this study identified a novel δ opioid receptor agonist chemotype, which may serve as alternative for the current analgesic clinical candidates.


Asunto(s)
Receptores Opioides delta , Receptores Opioides delta/agonistas , Receptores Opioides delta/metabolismo , Animales , Ratones , Masculino , Humanos , Compuestos de Espiro/farmacología , Compuestos de Espiro/química , Piperazinas/farmacología , Piperazinas/química , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Benzamidas/farmacología , Benzamidas/química , Cricetulus , beta-Arrestinas/metabolismo , Células HEK293 , Células CHO
10.
Bioorg Chem ; 147: 107363, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38657527

RESUMEN

Environment-benign, multicomponent synthetic methodologies are vital in modern pharmaceutical research and facilitates multi-targeted drug development via synergistic approach. Herein, we reported green and efficient synthesis of pyrano[2,3-c]pyrazole fused spirooxindole linked 1,2,3-triazoles using a tea waste supported copper catalyst (TWCu). The synthetic approach involves a one-pot, five-component reaction using N-propargylated isatin, hydrazine hydrate, ethyl acetoacetate, malononitrile/ethyl cyanoacetate and aryl azides as model substrates. Mechanistically, the reaction was found to proceed via in situ pyrazolone formation followed by Knoevenagel condensation, azide alkyne cycloaddition and Michael's addition reactions. The molecules were developed using structure-based drug design. The primary goal is to identifying anti-oxidant molecules with potential ability to modulate α-amylase and DPP4 (dipeptidyl-peptidase 4) activity. The anti-oxidant analysis, as determined via DPPH, suggested that the synthesized compounds, A6 and A10 possessed excellent anti-oxidant potential compared to butylated hydroxytoluene (BHT). In contrast, compounds A3, A5, A8, A9, A13, A15, and A18 were found to possess comparable anti-oxidant potential. Among these, A3 and A13 possessed potential α-amylase inhibitory activity compared to the acarbose, and A3 further emerged as dual inhibitors of both DPP4 and α-amylase with anti-oxidant potential. The relationship of functionalities on their anti-oxidant and enzymatic inhibition was explored in context to their SAR that was further corroborated using in silico techniques and enzyme kinetics.


Asunto(s)
Antioxidantes , Dipeptidil Peptidasa 4 , Hipoglucemiantes , Pirazoles , Triazoles , alfa-Amilasas , Pirazoles/química , Pirazoles/farmacología , Pirazoles/síntesis química , Antioxidantes/farmacología , Antioxidantes/química , Antioxidantes/síntesis química , Triazoles/química , Triazoles/farmacología , Triazoles/síntesis química , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Hipoglucemiantes/síntesis química , Relación Estructura-Actividad , alfa-Amilasas/antagonistas & inhibidores , alfa-Amilasas/metabolismo , Dipeptidil Peptidasa 4/metabolismo , Estructura Molecular , Humanos , Relación Dosis-Respuesta a Droga , Inhibidores de la Dipeptidil-Peptidasa IV/química , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Inhibidores de la Dipeptidil-Peptidasa IV/síntesis química , Simulación del Acoplamiento Molecular , Picratos/antagonistas & inhibidores , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Compuestos de Espiro/síntesis química , Oxindoles/farmacología , Oxindoles/química , Oxindoles/síntesis química , Benzopiranos , Nitrilos
11.
Continuum (Minneap Minn) ; 30(2): 364-378, 2024 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-38568488

RESUMEN

OBJECTIVE: This article describes strategies for the preventive treatment of migraine including the emerging role of calcitonin gene-related peptide (CGRP)-targeted therapies and introduces novel paradigms for the preventive treatment of migraine. LATEST DEVELOPMENTS: Multiple migraine medications targeting CGRP have been introduced since 2018, including injectable monoclonal antibodies (ie, eptinezumab, erenumab, fremanezumab, and galcanezumab) and oral small-molecule CGRP receptor antagonists (ie, ubrogepant, rimegepant, atogepant, and zavegepant). With the exceptions of ubrogepant and zavegepant, which are approved only as acute treatments, all of these agents have demonstrated efficacy in the preventive treatment of migraine; the monoclonal antibodies and atogepant have evidence of effectiveness in adults with either episodic or chronic migraine. The safety and tolerability profiles of CGRP-targeted therapies in migraine are favorable. ESSENTIAL POINTS: The goals of preventive migraine therapy include reducing the frequency, severity, duration, and disability associated with attacks, reducing the need for acute treatment and the risk of medication overuse, enhancing self-efficacy and health-related quality of life, and reducing headache-related distress and interictal burden. Six drugs targeting CGRP (four monoclonal antibodies and two gepants) are now available for the preventive treatment of episodic migraine in adults. The efficacy of CGRP-targeted medications in the acute and preventive treatment of migraine, together with good safety and tolerability, has led to the emergence of new approaches to preventive treatment.


Asunto(s)
Péptido Relacionado con Gen de Calcitonina , Trastornos Migrañosos , Piperidinas , Piridinas , Pirroles , Compuestos de Espiro , Adulto , Humanos , Calidad de Vida , Trastornos Migrañosos/tratamiento farmacológico , Trastornos Migrañosos/prevención & control , Anticuerpos Monoclonales/uso terapéutico
12.
Exp Cell Res ; 438(1): 114029, 2024 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-38608805

RESUMEN

Aberrant expression of airway epithelial E-cadherin is a key feature of asthma, yet the underlying mechanisms are largely unknown. Ferroptosis is a novel form of regulated cell death involved in asthma pathogenesis. This study was aimed to evaluate the role of ferroptosis and to investigate whether ferroptosis mediates E-cadherin disruption in mixed granulocyte asthma (MGA). Two murine models of MGA were established using toluene diisocyanate (TDI) or ovalbumin with Complete Freund's Adjuvant (OVA/CFA). Specific antagonists of ferroptosis, including Liproxstatin-1 (Lip-1) and Ferrostatin-1 (Fer-1) were given to the mice. The allergen-exposed mice displayed markedly shrunk mitochondria in the airway epithelia, with decreased volume and denser staining accompanied by down-regulated GPX4 as well as up-regulated FTH1 and malondialdehyde, which are markers of ferroptosis. Decreased pulmonary expression of E-cadherin was also observed, with profound loss of membrane E-cadherin in the airway epithelia, as well as increased secretion of sE-cadherin. Treatment with Lip-1 not only showed potent protective effects against the allergen-induced airway hyperresponsiveness and inflammatory responses, but also rescued airway epithelial E-cadherin expression and inhibited the release of sE-cadherin. Taken together, our data demonstrated that ferroptosis mediates airway epithelial E-cadherin dysfunction in MGA.


Asunto(s)
Asma , Cadherinas , Modelos Animales de Enfermedad , Ferroptosis , Quinoxalinas , Compuestos de Espiro , Animales , Ferroptosis/efectos de los fármacos , Cadherinas/metabolismo , Asma/metabolismo , Asma/patología , Asma/inducido químicamente , Ratones , Granulocitos/metabolismo , Granulocitos/patología , Femenino , Ratones Endogámicos BALB C , Ovalbúmina , Fenilendiaminas/farmacología , Células Epiteliales/metabolismo , Células Epiteliales/patología , Células Epiteliales/efectos de los fármacos , Ciclohexilaminas/farmacología
13.
Sci Rep ; 14(1): 9548, 2024 04 25.
Artículo en Inglés | MEDLINE | ID: mdl-38664508

RESUMEN

Ferroptosis is closely associated with inflammatory diseases, including acute pancreatitis (AP); however, the involvement of ferroptosis in hypertriglyceridemic pancreatitis (HTGP) remains unclear. In the present study, we aimed to explore the relationship between lipid metabolism and ferroptosis in HTGP and the alleviating effect of liproxstatin-1 (Lip-1) in vivo. This study represents the first exploration of lipid metabolism and endoplasmic reticulum stress (ERS) in HTGP, targeting ferroptosis as a key factor in HTGP. Hypertriglyceridemia (HTG) was induced under high-fat diet conditions. Cerulein was then injected to establish AP and HTGP models. Lip-1, a specific ferroptosis inhibitor, was administered before the induction of AP and HTGP in rats, respectively. Serum triglyceride, amylase, inflammatory factors, pathological and ultrastructural structures, lipid peroxidation, and iron overload indicators related to ferroptosis were tested. Moreover, the interaction between ferroptosis and ERS was assessed. We found HTG can exacerbate the development of AP, with an increased inflammatory response and intensified ferroptosis process. Lip-1 treatment can attenuate pancreatic injury by inhibiting ferroptosis through lipid metabolism and further resisting activations of ERS-related proteins. Totally, our results proved lipid metabolism can promote ferroptosis in HTGP by regulating ACSL4/LPCAT3 protein levels. Additionally, ERS may participate in ferroptosis via the Bip/p-EIF2α/CHOP pathway, followed by the alleviating effect of Lip-1 in the rat model.


Asunto(s)
Estrés del Retículo Endoplásmico , Ferroptosis , Hipertrigliceridemia , Metabolismo de los Lípidos , Pancreatitis , Quinoxalinas , Compuestos de Espiro , Animales , Ferroptosis/efectos de los fármacos , Pancreatitis/tratamiento farmacológico , Pancreatitis/metabolismo , Pancreatitis/patología , Hipertrigliceridemia/tratamiento farmacológico , Hipertrigliceridemia/metabolismo , Ratas , Estrés del Retículo Endoplásmico/efectos de los fármacos , Masculino , Metabolismo de los Lípidos/efectos de los fármacos , Ciclohexilaminas/farmacología , Modelos Animales de Enfermedad , Ratas Sprague-Dawley , Peroxidación de Lípido/efectos de los fármacos , Dieta Alta en Grasa/efectos adversos , Páncreas/efectos de los fármacos , Páncreas/patología , Páncreas/metabolismo , Triglicéridos/sangre , Triglicéridos/metabolismo
14.
Phytochemistry ; 222: 114073, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38565420

RESUMEN

Two undescribed cladosporol derivatives, cladosporols J-K (1-2), and three previously unreported spirobisnaphthalenes, urnucratins D-F (3-5), as well as eleven known cladosporols (6-16), were characterized from Cladosporium cladosporioides (Cladosporiaceae), a common plant pathogen isolated from the skin of Chinese toad. Cladosporols J-K (1-2) with a single double bond have been rarely reported, while urnucratins D-F (3-5) featured an unusual benzoquinone bisnaphthospiroether skeleton, contributing to an expanding category of undiscovered natural products. Their structures and absolute configurations were determined using extensive spectroscopic methods, including NMR, HRESIMS analyses, X-ray single crystal diffraction, as well as through experimental ECD analyses. Biological assays revealed that compounds 1 and 2 exhibited inhibitory activity against A549 cells, with IC50 values of 30.11 ± 3.29 and 34.32 ± 2.66 µM, respectively.


Asunto(s)
Cladosporium , Naftalenos , Cladosporium/química , Humanos , Naftalenos/química , Naftalenos/aislamiento & purificación , Naftalenos/farmacología , Estructura Molecular , Ensayos de Selección de Medicamentos Antitumorales , Células A549 , Compuestos de Espiro/química , Compuestos de Espiro/aislamiento & purificación , Compuestos de Espiro/farmacología , Relación Estructura-Actividad , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Relación Dosis-Respuesta a Droga , Proliferación Celular/efectos de los fármacos
15.
Phytochemistry ; 222: 114101, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38636687

RESUMEN

Bafilomycins are macrocyclic polyketides with intriguing structures and therapeutic value. Genomic analysis of Streptomyces sp. SCSIO 66814 revealed a type I polyketide synthase biosynthetic gene cluster (BGC), namely blm, which encoded bafilomycins and featured rich post-modification genes. The One strain many compounds (OSMAC) strategy led to the discovery of six compounds related to the blm BGC from the strain, including two previously undescribed 6,6-spiroketal polyketides, streptospirodienoic acids D (1) and E (2), and four known bafilomycins, bafilomycins P (3), Q (4), D (5), and G (6). The structures of 1 and 2 were determined by extensive spectroscopic analysis, quantum calculation, and biosynthetic analysis. Additionally, the absolute configurations of the 6/5/5 tricyclic ring moiety containing six consecutive chiral carbons in the putative structures of 3 and 4 were corrected through NOE analysis, DP4+ calculation, and single-crystal X-ray diffraction data. Bioinformatic analysis uncovered a plausible biosynthetic pathway for compounds 1-6, indicating that both streptospirodienoic acids and bafilomycins were derived from the same blm BGC. Additionally, sequence analysis revealed that the KR domains of module 2 from blm BGC was B1-type, further supporting the configurations of 1-4. Notably, compounds 3 and 4 displayed significant cytotoxic activities against A-549 human non-small cell lung cancer cells and HCT-116 human colon cancer cells.


Asunto(s)
Policétidos , Streptomyces , Streptomyces/química , Streptomyces/metabolismo , Streptomyces/genética , Policétidos/química , Policétidos/farmacología , Policétidos/aislamiento & purificación , Humanos , Estereoisomerismo , Ensayos de Selección de Medicamentos Antitumorales , Estructura Molecular , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Macrólidos/química , Macrólidos/farmacología , Macrólidos/aislamiento & purificación , Macrólidos/metabolismo , Proliferación Celular/efectos de los fármacos , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Compuestos de Espiro/aislamiento & purificación , Relación Estructura-Actividad , Sintasas Poliquetidas/metabolismo , Sintasas Poliquetidas/genética , Línea Celular Tumoral , Genoma Bacteriano , Familia de Multigenes
16.
Org Biomol Chem ; 22(17): 3459-3467, 2024 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-38597668

RESUMEN

A water mediated three-component reaction of isatin, 4-aminocoumarin, and 1,3-cyclodicarbonyl compounds is reported for the synthesis of spiro[chromeno[4,3-b]cyclopenta[e]pyridine-7,3'-indoline]trione and the spiro[chromeno[4,3-b]quinoline 7,3'-indoline]trione. Up to 27 different spirooxindole derivatives were synthesized by this method. The bioactivity of these spirooxindole derivatives was evaluated and they were found to show antifungal activity against Cercospora arachidicola, Physalospora piricola, Rhizoctonia cerealis, and Fusarium moniliforme.


Asunto(s)
Antifúngicos , Benzopiranos , Indoles , Nitrilos , Compuestos de Espiro , Agua , Antifúngicos/farmacología , Antifúngicos/síntesis química , Antifúngicos/química , Compuestos de Espiro/farmacología , Compuestos de Espiro/química , Compuestos de Espiro/síntesis química , Agua/química , Indoles/química , Indoles/farmacología , Indoles/síntesis química , Pruebas de Sensibilidad Microbiana , Oxindoles/farmacología , Oxindoles/síntesis química , Oxindoles/química , Estructura Molecular , Relación Estructura-Actividad , Fusarium/efectos de los fármacos
17.
Free Radic Biol Med ; 218: 26-40, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38570172

RESUMEN

Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a crucial role in ferroptosis by regulating the cellular antioxidant response and maintaining redox balance. However, compounds that induce ferroptosis through dual antioxidant pathways based on Nrf2 have not been fully explored. In our study, we investigated the impact of Gambogic acid (GA) on MCF-7 cells and HepG2 cells in vitro. The cytotoxicity, colony formation assay and cell cycle assay demonstrated potent tumor-killing ability of GA, while its effect was rescued by ferroptosis inhibitors. Furthermore, RNA sequencing revealed the enrichment of ferroptosis pathway mediated by GA. In terms of ferroptosis indicators detection, evidences for GA were provided including reactive oxygen species (ROS) accumulation, alteration in mitochondrial membrane potential (MMP), disappearance of mitochondrial cristae, lipid peroxidation induction, malondialdehyde (MDA) accumulation promotion, iron ion accumulation as well as glutathione (GSH)/thioredoxin (Trx) depletion. Notably, Ferrostatin-1 (Fer-1) and Liproxstatin-1 (Lip-1) successfully rescued GA-induced MDA accumulation. In terms of mechanism, Nrf2 was found to play a pivotal role in GA-induced ferroptosis by inducing protein alterations through the iron metabolism pathway and GSH/Trx dual antioxidant pathway. Furthermore, GA exerted good antitumor activity in vivo through GSH/Trx dual antioxidant pathway, and Fer-1 significantly attenuated its efficacy. In conclusion, our findings first provided new evidence for GA as an inducer of ferroptosis, and Nrf2-mediated GSH/Trx dual antioxidant system played an important role in GA-induced ferroptosis.


Asunto(s)
Antioxidantes , Ferroptosis , Glutatión , Factor 2 Relacionado con NF-E2 , Quinoxalinas , Especies Reactivas de Oxígeno , Compuestos de Espiro , Xantonas , Ferroptosis/efectos de los fármacos , Xantonas/farmacología , Humanos , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/genética , Glutatión/metabolismo , Animales , Antioxidantes/farmacología , Especies Reactivas de Oxígeno/metabolismo , Ratones , Células MCF-7 , Células Hep G2 , Ensayos Antitumor por Modelo de Xenoinjerto , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Antineoplásicos/farmacología , Peroxidación de Lípido/efectos de los fármacos , Ciclohexilaminas/farmacología , Fenilendiaminas/farmacología , Proliferación Celular/efectos de los fármacos
18.
Environ Sci Pollut Res Int ; 31(17): 24852-24867, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38460034

RESUMEN

Two applications of spirotetramat were done to study the dissipation and persistence of spirotetramat and its four different metabolites in chilli and soil at 10 days interval. Total spirotetramat residues were estimated by LC-MS/MS instrument. The mean initial deposits of total spirotetramat after application of spirotetramat 15.31 OD @ 60 (X dose), 75 (1.25 × dose) and 120 (2 × dose) g a.i. ha-1 on green chilli were found to vary from 0.38 to 0.83 mg kg-1 during the initial year. Spirotetramat and its metabolite residues in green chilli were found to be below limit of quantification (0.01 mg kg-1) after 15 days of application. The spirotetramat cis enol (the major metabolite) was formed in both the soil and the plant. The residues of spirotetramat-monohydroxy were below LOQ irrespective of any substrate during the estimation. In soil, the total initial spirotetramat deposits for the 1st year were found 0.09 for X dose, 0.12 for 1.25 × dose and 0.20 mg kg-1 for 2 × dose. After 3 days for both X and 1.25 × doses and 5 days for 2 × dose, the total spirotetramat residues were below LOQ. The spirotetramat's half-life values have been determined to be between 3.19 and 3.93 days and 1.00 and 1.59 days, respectively, in soil and green chilli fruits. One day waiting period is proposed for the safe consumption of green chilli when the spirotetramat was applied irrespective of the dose.


Asunto(s)
Compuestos Aza , Insecticidas , Residuos de Plaguicidas , Contaminantes del Suelo , Compuestos de Espiro , Insecticidas/análisis , Cromatografía Liquida , Cromatografía Líquida con Espectrometría de Masas , Suelo/química , Espectrometría de Masas en Tándem , Contaminantes del Suelo/análisis , Residuos de Plaguicidas/análisis , Semivida
19.
Environ Sci Pollut Res Int ; 31(17): 25736-25750, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38488914

RESUMEN

A field experiment following good agricultural practices was laid out to study the dissipation of spirotetramat (90 g a.i. ha-1 and 180 g a.i. ha-1) and chlorpyrifos (400 g a.i. ha-1 and 800 g a.i. ha-1) on cabbage heads and soil. Samples were processed using quick, easy, cheap, effective, rugged, and safe (QuEChERS) method for residue estimation of spirotetramat and chlorpyrifos, which were further detected using HPLC-PDA and GC-FPD respectively. The residues of spirotetramat on cabbage heads reached below detection limit (BDL) (< 0.05 mg kg-1) on 7th and 10th day and for chlorpyrifos, BDL (< 0.01 mg kg-1) was achieved on 10th and 15th day for X and 2X dose, respectively. On 20th day after second spray, residues in soil were found to be BDL for both the pesticides. Half-life of spirotetramat and chlorpyrifos was found to be 3 and 2 days, respectively while a safe pre-harvest interval (PHI) of 9 days for spirotetramat and 10 days for chlorpyrifos is suggested on cabbage. The dietary risk assessment studies for various age groups of Indian population, ascertained safety of treated cabbage heads for consumption, as current study revealed that hazard quotient (HQ) < 1 and theoretical maximum dietary intake (TMDI) < maximum permissible intake (MPI) for both the pesticides at respective PHI.


Asunto(s)
Compuestos Aza , Brassica , Cloropirifos , Residuos de Plaguicidas , Plaguicidas , Contaminantes del Suelo , Compuestos de Espiro , Suelo/química , Brassica/química , Residuos de Plaguicidas/análisis , Contaminantes del Suelo/análisis , Plaguicidas/análisis , Medición de Riesgo , Semivida
20.
J Comp Eff Res ; 13(5): e230041, 2024 05.
Artículo en Inglés | MEDLINE | ID: mdl-38497192

RESUMEN

Background: In the absence of head-to-head comparative data from randomized controlled trials, indirect treatment comparisons (ITCs) may be used to compare the relative effects of treatments versus a common comparator (either placebo or active treatment). For acute pain management, the effects of oliceridine have been compared in clinical trials to morphine but not to fentanyl or hydromorphone. Aim: To assess the comparative safety (specifically differences in the incidence of nausea, vomiting and opioid-induced respiratory depression [OIRD]) between oliceridine and relevant comparators (fentanyl and hydromorphone) through ITC analysis. Methods: A systematic literature review identified randomized clinical trials with oliceridine versus morphine and morphine versus fentanyl or hydromorphone. The ITC utilized the common active comparator, morphine, for the analysis. Results: A total of six randomized controlled trials (oliceridine - 2; hydromorphone - 3; fentanyl - 1) were identified for data to be used in the ITC analyses. The oliceridine data were reported in two studies (plastic surgery and orthopedic surgery) and were also reported in a pooled analysis. The ITC focused on nausea and vomiting due to limited data for OIRD. When oliceridine was compared with hydromorphone in the ITC analysis, oliceridine significantly reduced the incidence of nausea and/or vomiting requiring antiemetics compared with hydromorphone (both orthopedic surgery and pooled data), while results in plastic surgery were not statistically significant. When oliceridine was compared with hydromorphone utilizing data from Hong, the ITC only showed a trend toward reduced risk of nausea and vomiting with oliceridine that was not statistically significant across all three comparisons (orthopedic surgery, plastic surgery and combined). An ITC comparing oliceridine with a study of fentanyl utilizing the oliceridine orthopedic surgery data and combined orthopedic and plastic surgery data showed a trend toward reduced risk that was not statistically significant. Conclusion: In ITC analyses, oliceridine significantly reduced the incidence of nausea and/or vomiting or the need for antiemetics in orthopedic surgery compared with hydromorphone and a non-significant trend toward reduced risk versus fentanyl.


Asunto(s)
Dolor Agudo , Analgésicos Opioides , Fentanilo , Hidromorfona , Náusea , Ensayos Clínicos Controlados Aleatorios como Asunto , Compuestos de Espiro , Tiofenos , Vómitos , Humanos , Hidromorfona/administración & dosificación , Hidromorfona/efectos adversos , Hidromorfona/uso terapéutico , Fentanilo/efectos adversos , Fentanilo/administración & dosificación , Fentanilo/uso terapéutico , Analgésicos Opioides/efectos adversos , Analgésicos Opioides/uso terapéutico , Analgésicos Opioides/administración & dosificación , Dolor Agudo/tratamiento farmacológico , Vómitos/inducido químicamente , Vómitos/prevención & control , Vómitos/tratamiento farmacológico , Náusea/prevención & control , Náusea/inducido químicamente , Náusea/tratamiento farmacológico , Administración Intravenosa , Insuficiencia Respiratoria/inducido químicamente , Manejo del Dolor/métodos , Quinuclidinas/uso terapéutico , Quinuclidinas/administración & dosificación , Quinuclidinas/efectos adversos
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