RESUMEN
Atopic dermatitis (AD) is a chronic, allergic inflammatory skin disorder that lacks a definite cure. Using a mouse DNCB-induced AD-like skin lesions model, this study evaluated the potential therapeutic utility of tHGA as an oral and topical treatment for AD. Male BALB/c mice were sensitised and challenged with 1% and 0.5% DNCB on their shaved dorsal skin. Mice in the treatment group were administered tHGA (20, 40, and 80 mg/kg) orally three times per week for 2 weeks, or tHGA (0.2%, 1%, and 5%) topically once daily for 12 days. On day 34, the mice were euthanized, and blood and dorsal skin samples were obtained for analysis. All doses of orally and topically administered tHGA significantly improved scratching, epidermal thickness, blood eosinophilia and mast cell infiltration. There was a minor discrepancy between the two routes of administration, with orally treated tHGA showing significant reductions in Scoring of Atopic Dermatitis (SCORAD), tissue eosinophil infiltration, serum IgE and skin IL-4 levels with treatment of 40 and 80 mg/kg tHGA, whereas topically applied tHGA showed significant reductions in all dosages. These findings suggest that tHGA exhibited therapeutic potential for AD as both oral and topical treatment ameliorates AD-like symptoms in the murine model.
Asunto(s)
Administración Tópica , Dermatitis Atópica , Dinitroclorobenceno , Inmunoglobulina E , Ratones Endogámicos BALB C , Piel , Animales , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/inducido químicamente , Dermatitis Atópica/patología , Administración Oral , Masculino , Ratones , Inmunoglobulina E/sangre , Piel/efectos de los fármacos , Piel/patología , Piel/metabolismo , Modelos Animales de Enfermedad , Acetofenonas/administración & dosificación , Acetofenonas/farmacología , Acetofenonas/uso terapéutico , Eosinófilos/efectos de los fármacos , Interleucina-4/metabolismo , Mastocitos/efectos de los fármacosRESUMEN
OBJECTIVE: Apocynin (AP) and paeonol (PA) are low molecular weight phenolic compounds with a broad array of anti-inflammatory and immunoregulatory effects. This study assessed of a fixed-dose combination of APPA in people with symptomatic knee osteoarthritis (OA). METHODS: A multi-center, randomized, placebo-controlled, double-blind phase 2a trial enrolled participants with radiographic knee OA (Kellgren-Lawrence, KL, grades 2-3) and pain ≥40/100 on WOMAC pain subscale, and evaluated the efficacy and safety of oral APPA over a 28-day period. APPA 800 mg or matching placebo was administered twice daily in a 1:1 ratio. Post-hoc analyses explored the response to APPA in sub-groups with more severe pain and structural severity. RESULTS: The two groups were comparable at baseline; 152 subjects were enrolled and 148 completed the trial. There was no statistically significant difference between groups with respect to the primary outcome, WOMAC pain (mean difference between groups was -0.89, 95% CI: -5.62, 3.84, p = 0.71), nor WOMAC function or WOMAC total. However, predefined subgroup analyses of subjects with symptoms compatible with nociplastic/neuropathic pain features showed a statistically significant effect of APPA compared to placebo. Adverse events (mainly gastrointestinal) were mild to moderate. CONCLUSION: Treatment with APPA 800 mg twice daily for 28 days in subjects with symptomatic knee OA was not associated with significant symptom improvement compared to placebo. The treatment was well-tolerated and safe. While the study was not powered for such analysis, pre-planned subgroup analyses showed a significant effect of APPA in subjects with nociplastic pain/severe OA, indicating that further research in the effects of APPA in appropriate patients is warranted.
Asunto(s)
Acetofenonas , Osteoartritis de la Rodilla , Dimensión del Dolor , Humanos , Acetofenonas/administración & dosificación , Acetofenonas/uso terapéutico , Acetofenonas/efectos adversos , Método Doble Ciego , Masculino , Osteoartritis de la Rodilla/tratamiento farmacológico , Femenino , Persona de Mediana Edad , Anciano , Resultado del Tratamiento , Combinación de Medicamentos , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/uso terapéutico , Índice de Severidad de la Enfermedad , AdultoRESUMEN
Clinical studies have shown that traumatic brain injury (TBI) increases the onset of Parkinson's disease (PD) in later life by >50%. Oxidative stress, endoplasmic reticulum (ER) stress, and inflammation are the major drivers of both TBI and PD pathologies. We presently evaluated if curtailing oxidative stress and ER stress concomitantly using a combination of apocynin and tert-butylhydroquinone and salubrinal during the acute stage after TBI in mice reduces the severity of late-onset PD-like pathology. The effect of multiple low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on post-TBI neurodegeneration was also evaluated. The combo therapy elevated the level of phosphorylation at serine 129 (pS129) of α-Syn in the pericontusional cortex of male mice at 72 h post-TBI. Motor and cognitive deficits induced by TBI lasted at least 3 months and the combo therapy curtailed these deficits in both sexes. At 3 months post-TBI, male mice given combo therapy exhibited significantly lesser α-Syn aggregates in the SN and higher TH+ cells in the SNpc, compared to vehicle control. However, the aggregate number was not significantly different between groups of female mice. Moreover, TBI-induced loss of TH+ cells was negligible in female mice irrespective of treatment. The MPTP treatment aggravated PD-like pathology in male mice but had a negligible effect on the loss of TH+ cells in female mice. Thus, the present study indicates that mitigation of TBI-induced oxidative stress and ER stress at the acute stage could potentially reduce the risk of post-TBI PD-like pathology at least in male mice, plausibly by elevating pS129-α-Syn level.
Asunto(s)
Antioxidantes , Lesiones Traumáticas del Encéfalo , Estrés del Retículo Endoplásmico , Ratones Endogámicos C57BL , Animales , Masculino , Ratones , Lesiones Traumáticas del Encéfalo/patología , Lesiones Traumáticas del Encéfalo/metabolismo , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Femenino , Estrés del Retículo Endoplásmico/efectos de los fármacos , Estrés del Retículo Endoplásmico/fisiología , Fosforilación/efectos de los fármacos , Antioxidantes/farmacología , Caracteres Sexuales , Acetofenonas/farmacología , Acetofenonas/uso terapéutico , Acetofenonas/administración & dosificación , Tiourea/análogos & derivados , Tiourea/farmacología , Tiourea/uso terapéutico , Tiourea/administración & dosificación , Serina/metabolismo , Hidroquinonas/farmacología , Hidroquinonas/administración & dosificación , Hidroquinonas/uso terapéutico , Quimioterapia Combinada , Estrés Oxidativo/efectos de los fármacosRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Renal cell carcinoma (RCC) is the most common cancer of the urinary system, the current treatments for RCC are unsatisfactory. Paeonol is the main pharmacologically active ingredient of the traditional Chinese medicine (TCM) moutan cortex (Paeonia suffruticosa Andrews) and Paeonia albiflora Pall, and has been used in TCM to treat various diseases including cancer. However, the underlying therapeutic mechanisms of paeonol in RCC have not been investigated yet. AIM OF THE STUDY: This study aimed to explore the potential antitumor effects and mechanisms of paeonol on RCC based on network pharmacology and experimental validation. MATERIALS AND METHODS: Network pharmacological analysis was performed to predict the potential targets and mechanism of paeonol against RCC. The antitumor effects and the priority targets of paeonol against RCC were further assessed by in vitro experiments. RESULTS: 104 intersection targets shared by paeonol and RCC were collected, 15 hub genes were obtained, among these genes, VEGFA expression was higher in RCC, and the higher expression of IL-6 or lower expression of AKT1, JUN, MAPK1, and MAPK8 were correlated to the shorter overall survival (OS) in RCC patients. GO and KEGG analyses suggested that the genes were mainly enriched in the positive regulation of cell death and apoptosis pathway. In vitro experiments showed that paeonol inhibited 786-O cell proliferation, migration, invasion, and promoted apoptosis. When 786-O cells were treated with paeonol, the expression of Bax increased while Bcl-2 and VEGFA decreased. CONCLUSION: The present study demonstrated that paeonol might play an essential role in RCC by regulating cell proliferation, apoptosis, metastasis, and invasion through the Bcl-2/Bax signaling pathway and VEGFA, providing a theoretical and experimental scientific basis for future investigations of the antitumor effects of paeonol against RCC.
Asunto(s)
Acetofenonas/farmacología , Antineoplásicos Fitogénicos/farmacología , Carcinoma de Células Renales/tratamiento farmacológico , Fitoterapia , Acetofenonas/administración & dosificación , Acetofenonas/química , Antineoplásicos Fitogénicos/química , Apoptosis , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Estructura Molecular , Farmacología en Red , Mapas de Interacción de Proteínas , Reproducibilidad de los ResultadosRESUMEN
Epilepsy is a neurological disease that transpires due to the unusual synchronized neuronal discharge within the central nervous system, which drives repetitious unprovoked seizures. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is a complex enzyme accountable for reactive oxygen species (ROS) production, neurodegeneration, neurotoxicity, memory impairment, vitiates normal cellular processes, long term potentiation, and thus, implicated in the pathogenesis of epilepsy. Therefore, the present study was sketched to examine the neuroprotective effect of apocynin, NADPH oxidase inhibitor in pentylenetetrazole kindling epilepsy, and induced comorbidities in mice. Mice (either sex) were given pentylenetetrazole (35 mg/kg, i.p.) every other day up to 29 days, and a challenge test was executed on the 33rd day. Pretreatment with apocynin (25, 50, and 100 mg/kg, i.p.) was carried out from 1st to 33rd day. Rotarod and open field test were performed on the 1st, 10th, 20th, and 30th days of the study. Animals were tutored on the morris water maze from 30th to 33rd day, and the retention was registered on the 34th day. Tail suspension test and elevated plus maze were sequentially performed on the 32nd and 33rd day of the study. On the 34th day, animals were sacrificed, and their brains were isolated to conduct biochemical estimation. NADPH oxidase activation due to chronic pentylenetetrazole treatment resulted in generalized tonic-clonic seizures, enhanced oxidative stress, remodeled neurotransmitters' level, and resulted in comorbidities (anxiety, depression, and memory impairment). Pretreatment with apocynin significantly restricted the pentylenetetrazole induced seizure severity, ROS production, neurotransmitter alteration, and comorbid conditions by inhibiting the NADPH oxidase enzyme.
Asunto(s)
Acetofenonas/farmacología , Ansiedad/prevención & control , Depresión/prevención & control , Epilepsia/prevención & control , Trastornos de la Memoria/prevención & control , Fármacos Neuroprotectores/farmacología , Acetofenonas/administración & dosificación , Animales , Ansiedad/inducido químicamente , Ansiedad/metabolismo , Comorbilidad , Convulsivantes/farmacología , Depresión/inducido químicamente , Depresión/metabolismo , Modelos Animales de Enfermedad , Epilepsia/inducido químicamente , Epilepsia/metabolismo , Femenino , Excitación Neurológica/efectos de los fármacos , Masculino , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/metabolismo , Fármacos Neuroprotectores/administración & dosificación , Pentilenotetrazol/farmacologíaRESUMEN
La Crosse virus (LACV) is a mosquito-borne orthobunyavirus that causes approximately 60 to 80 hospitalized pediatric encephalitis cases in the United States yearly. The primary treatment for most viral encephalitis, including LACV, is palliative care, and specific antiviral therapeutics are needed. We screened the National Center for Advancing Translational Sciences library of 3,833 FDA-approved and bioactive small molecules for the ability to inhibit LACV-induced death in SH-SY5Y neuronal cells. The top three hits from the initial screen were validated by examining their ability to inhibit virus-induced cell death in multiple neuronal cell lines. Rottlerin consistently reduced LACV-induced death by 50% in multiple human and mouse neuronal cell lines with an effective concentration of 0.16-0.69 µg ml-1 depending on cell line. Rottlerin was effective up to 12 hours post-infection in vitro and inhibited virus particle trafficking from the Golgi apparatus to trans-Golgi vesicles. In human inducible pluripotent stem cell-derived cerebral organoids, rottlerin reduced virus production by one log and cell death by 35% compared with dimethyl sulfoxide-treated controls. Administration of rottlerin in mice by intraperitoneal or intracranial routes starting at 3 days post-infection decreased disease development by 30-50%. Furthermore, rottlerin also inhibited virus replication of other pathogenic California serogroup orthobunyaviruses (Jamestown Canyon and Tahyna virus) in neuronal cell lines.
Asunto(s)
Acetofenonas/administración & dosificación , Antivirales/administración & dosificación , Benzopiranos/administración & dosificación , Encefalitis de California/virología , Aparato de Golgi/virología , Virus La Crosse/efectos de los fármacos , Virus La Crosse/fisiología , Neuronas/virología , Animales , Encefalitis de California/tratamiento farmacológico , Femenino , Aparato de Golgi/efectos de los fármacos , Humanos , Virus La Crosse/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Neuronas/efectos de los fármacos , Liberación del Virus/efectos de los fármacos , Replicación Viral/efectos de los fármacosRESUMEN
Following traumatic brain injury (TBI), increased production of reactive oxygen species (ROS) and the ensuing oxidative stress promotes the secondary brain damage that encompasses both grey matter and white matter. As this contributes to the long-term neurological deficits, decreasing oxidative stress during the acute period of TBI is beneficial. While NADPH oxidase (NOX2) is the major producer of ROS, transcription factor Nrf2 that induces antioxidant enzymes promotes efficient ROS disposal. We recently showed that treatment with an antioxidant drug combo of apocynin (NOX2 inhibitor) and TBHQ (Nrf2 activator) protects the grey matter in adult mice subjected to TBI. We currently show that this antioxidant combo therapy given at 2 h and 24 h after TBI also protects white matter in mouse brain. Thus, the better functional outcomes after TBI in the combo therapy treated mice might be due to a combination of sparing both grey matter and white matter. Hence, the antioxidant combo we tested is a potent therapeutic option for translation in future.
Asunto(s)
Acetofenonas/uso terapéutico , Antioxidantes/uso terapéutico , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Hidroquinonas/uso terapéutico , Sustancia Blanca/efectos de los fármacos , Acetofenonas/administración & dosificación , Animales , Antioxidantes/administración & dosificación , Lesiones Traumáticas del Encéfalo/patología , Esquema de Medicación , Evaluación Preclínica de Medicamentos , Sinergismo Farmacológico , Quimioterapia Combinada , Sustancia Gris/efectos de los fármacos , Sustancia Gris/patología , Hidroquinonas/administración & dosificación , Masculino , Ratones , Ratones Endogámicos C57BL , NADPH Oxidasa 2/antagonistas & inhibidores , Factor 2 Relacionado con NF-E2/agonistas , Estrés Oxidativo/efectos de los fármacos , Distribución Aleatoria , Sustancia Blanca/patologíaRESUMEN
Alzheimer's disease typically presents with impaired cognition and pathological morphologic changes, including the accumulation of amyloid-ß plaques. Disease-modifying drugs are in urgent need as neuroprotective therapies. Exploration of novel therapeutics for alleviating symptoms of Alzheimer's disease has found promise in plant extracts of functional phenols. Paeonol is a water-soluble phenolic substance that has been shown to confer diverse biological effects, including neuroprotection. An Alzheimer's disease model of APP/PS1 double transgenic mice was used in this study, and the therapeutic effects of paeonol were assessed after three weeks' administration. It was found that paeonol treatment significantly increased behavioral performance in the Morris water maze test and increased discrimination rate in the novel object recognition test compared to vehicle-treated APP/PS1 mice. Histologically, paeonol treatment significantly alleviated the Aß plaque burden, reduced neural loss, inhibited microglia activation, and decreased neuroinflammation in the brain of APP/PS1 mice. In addition, a number of Alzheimer's disease-related synaptic plasticity deficits were ameliorated. The present results indicate that paeonol significantly relieved amyloid-ß deposition and amyloid-ß -mediated neuropathology in the brain of APP/PS1 mice, suggesting the potential of paeonol as a preventive and therapeutic agent for Alzheimer's disease.
Asunto(s)
Acetofenonas/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Disfunción Cognitiva/tratamiento farmacológico , Hipocampo/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Acetofenonas/administración & dosificación , Animales , Conducta Animal/efectos de los fármacos , Modelos Animales de Enfermedad , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Transgénicos , Fármacos Neuroprotectores/administración & dosificación , Reconocimiento en Psicología/efectos de los fármacosRESUMEN
There are several routes of administration to the brain, including intraparenchymal, intraventricular, and subarachnoid injections. The blood-brain barrier (BBB) impedes the permeation and access of most drugs to the central nervous system (CNS), and consequently, many neurological diseases remain undertreated. For past decades, to circumvent this effect, several nanocarriers have been developed to deliver drugs to the brain. Importantly, intranasal (IN) administration can allow direct delivery of drugs into the brain through the anatomical connection between the nasal cavity and brain without crossing the BBB. In this regard, dendrimers may possess great potential to deliver drugs to the brain by IN administration, bypassing the BBB and reducing systemic exposure and side effects, to treat diseases of the CNS. In this original concise review, we highlighted the few examples advocated regarding the use of dendrimers to deliver CNS drugs directly via IN. This review highlighed the few examples of the association of dendrimer encapsulating drugs (e.g., small compounds: haloperidol and paeonol; macromolecular compounds: dextran, insulin and calcitonin; and siRNA) using IN administration. Good efficiencies were observed. In addition, we will present the in vivo effects of PAMAM dendrimers after IN administration, globally, showing no general toxicity.
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Barrera Hematoencefálica/metabolismo , Fármacos del Sistema Nervioso Central/farmacología , Dendrímeros/química , Nanocápsulas/química , Acetofenonas/administración & dosificación , Acetofenonas/química , Administración Intranasal , Animales , Transporte Biológico , Calcitonina/administración & dosificación , Calcitonina/química , Dextranos/administración & dosificación , Dextranos/química , Liberación de Fármacos , Haloperidol/administración & dosificación , Haloperidol/química , Humanos , Insulina/administración & dosificación , Insulina/química , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/química , Tecnología FarmacéuticaRESUMEN
INTRODUCTION: Cyclophosphamide (CP) causes redox imbalance and its use is associated with marked cardiotoxicity that limits its clinical applications. The present study investigated the protective effects of acetovanillone (AV) and edaravone (ED) against CP-induced oxidative stress and cardiac damage, emphasizing the role of PI3K/Akt/mTOR and Nrf2 signaling. MATERIALS AND METHODS: Rats received either AV (100 mg/kg) or ED (20 mg/kg) orally for 10 days and CP (200 mg/kg) on day 7. At day 11, the rats were sacrificed, and samples were collected for analysis. RESULTS: AV and ED ameliorated serum troponin I, CK-MB, LDH, AST and ALP, and prevented cardiac histological alterations in CP-intoxicated rats. Both treatments decreased cardiac lipid peroxidation and enhanced GSH, SOD and cytoglobin in CP-induced rats. AV and ED downregulated Keap1, whereas increased the expression of PI3K, Akt, mTOR and Nrf2 in the heart of rats received CP. Additionally, the binding modes of AV and ED to Keap1 were pinpointed in silico using molecular docking simulations. CONCLUSION: AV and ED prevent CP cardiotoxicity by attenuating oxidative stress and tissue injury, and modulating cytoglobin, and PI3K/Akt/mTOR and Keap1/Nrf2 signaling. Therefore, AV and ED may represent promising agents that can prevent cardiac injury in patients receiving CP.
Asunto(s)
Acetofenonas/farmacología , Antioxidantes/farmacología , Edaravona/farmacología , Factor 2 Relacionado con NF-E2/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Acetofenonas/administración & dosificación , Administración Oral , Animales , Antioxidantes/administración & dosificación , Ciclofosfamida , Edaravona/administración & dosificación , Masculino , Simulación del Acoplamiento Molecular , Daño por Reperfusión Miocárdica/inducido químicamente , Daño por Reperfusión Miocárdica/prevención & control , Fosfatidilinositol 3-Quinasa/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
OBJECTIVE: We aimed to investigate the potency of apocynin in ameliorating preeclampsia and explore the underlying mechanisms. METHODS: Preeclampsia model was constructed in rats by administering 200 mg/kg/day L-NAME. Apocynin was given orally in drinking water. Systolic blood pressure and proteinuria were monitored during treatment. Survival rate rate of the pups and placental weight were assessed. Serum sFlt-1, PIGF, IL-6 and placental TLR4 levels were measured using ELISA or qRT-PCR. RESULTS: Apocynin dose-dependently decreased systolic blood pressure and proteinuria during gestation. Survival rate of the pups and placental weight were improved by apocynin treatment. Apocynin ameliorated the imbalance of sFlt-1 and PIGF in serum and placenta of rats with preeclampsia. Apocynin attenuated serum inflammatory cytokine expression and placental inflammation most likely due to downregulation of the placental TLR4/NF-kB pathway in L-NAME treated rats. CONCLUSIONS: Apocynin potently ameliorates the L-NAME-induced preeclampsia, which is achieved by re-balancing the sFlt-1 and PIGF levels, attenuating inflammation, and inhibiting TLR4/NF-κB p65 signaling.
Asunto(s)
Acetofenonas/farmacocinética , Antiinflamatorios no Esteroideos/farmacología , FN-kappa B/efectos de los fármacos , Preeclampsia/tratamiento farmacológico , Receptor Toll-Like 4/efectos de los fármacos , Acetofenonas/administración & dosificación , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Presión Sanguínea/efectos de los fármacos , Regulación hacia Abajo , Femenino , Humanos , Placenta/efectos de los fármacos , Placenta/metabolismo , Embarazo , Ratas , Transducción de Señal/efectos de los fármacosRESUMEN
AIMS: We here investigated the effect of late- and post-ictal treatment with rottlerin, a polyphenol compound isolated from Mallotus philippinensis, on delayed apoptotic neuronal death induced by trimethyltin (TMT) in mice. MAIN METHODS: Male C57BL/6N mice received a single injection of TMT (2.4 mg/kg, i.p.), and mice were treated with rottlerin after a peak time (i.e., 2 d post-TMT) of convulsive behaviors and apoptotic cell death (5.0 mg/kg, i.p. at 3 and 4 d after TMT injection). Object location test and tail suspension test were performed at 5 d after TMT injection. In addition, changes in the expression of apoptotic and neurogenic markers in the dentate gyrus were examined. KEY FINDINGS: Late- and post-ictal treatment with rottlerin suppressed delayed neuronal apoptosis in the dentate gyrus, and attenuated memory impairments (as evaluated by object location test) and depression-like behaviors (as evaluated by tail suspension test) at 5 days after TMT injection in mice. In addition, rottlerin enhanced the expression of Sox2 and DCX, and facilitated p-ERK expression in BrdU-incorporated cells in the dentate gyrus of TMT-treated mice. Rottlerin also increased p-Akt expression, and attenuated the increase in the ratio of pro-apoptotic factors/anti-apoptotic factors, and consequent cytosolic cytochrome c release and caspase-3 cleavage. Rottlerin-mediated action was significantly reversed by SL327, an ERK inhibitor. SIGNIFICANCE: Our results suggest that late- and post-ictal treatment with rottlerin attenuates TMT-induced delayed neuronal apoptosis in the dentate gyrus of mice via promotion of neurogenesis and inhibition of an on-going apoptotic process through up-regulation of p-ERK.
Asunto(s)
Acetofenonas/farmacología , Apoptosis/efectos de los fármacos , Benzopiranos/farmacología , Neurogénesis/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Acetofenonas/administración & dosificación , Animales , Conducta Animal/efectos de los fármacos , Benzopiranos/administración & dosificación , Giro Dentado/efectos de los fármacos , Giro Dentado/patología , Proteína Doblecortina , Quinasas MAP Reguladas por Señal Extracelular/genética , Masculino , Trastornos de la Memoria/prevención & control , Ratones , Ratones Endogámicos C57BL , Neuronas/efectos de los fármacos , Neuronas/patología , Fármacos Neuroprotectores/administración & dosificación , Convulsiones/prevención & control , Factores de Tiempo , Compuestos de Trimetilestaño/toxicidad , Regulación hacia ArribaRESUMEN
Paeonol is a phenolic compound reported for its various pharmacological activities such as antioxidant, anti-inflammatory and antidiabetic activity. There are no systematic scientific reports on the inâ vivo toxicity of paeonol. So, the present work was designed to study in silico and inâ vivo toxicity of paeonol. In silico toxicity predictions were carried out using pkCSM, ProTox-II, pre-ADMET server and OSIRIS property explorer. Acute oral toxicity study of paeonol was carried out in female Sprague Dawley rats at a single dose of 300â mg/kg, 2000â mg/kg and 5000â mg/kg. Animals were observed for toxicity signs and mortality for 14â days. Repeated dose oral toxicity study of paeonol was carried out in female and male Sprague Dawley rats at a dose of 50, 100 and 200â mg/kg body weight for 28â days. At the end of the study, hematological, biochemical and urine parameters were assessed. Histopathology of vital organs was also carried out. In silico toxicity study predicted that paeonol is non-toxic. The maximally tolerated dose of paeonol was found to be 5000â mg/kg in acute toxicity study in female rats. Paeonol was found to be safe at a dose of 50, 100 and 200â mg/kg in repeated dose toxicity study in male and female rats.
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Acetofenonas/toxicidad , Conducta Animal/efectos de los fármacos , Acetofenonas/administración & dosificación , Acetofenonas/química , Administración Oral , Animales , Femenino , Masculino , Dosis Máxima Tolerada , Estructura Molecular , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Skin pharmacokinetics is an indispensable indication for studying the drug fate after administration of transdermal drug delivery systems (TDDS). However, the heterogeneity and complex skin structured with stratum corneum, viable epidermis, dermis, and subcutaneous tissue inevitably leads the drug diffusion coefficient (Kp) to vary depending on the skin depth, which seriously limits the development of TDDS pharmacokinetics in full thickness skin. METHODS: A multilayer geometry skin model was established and the Kp of drug in SC, viable epidermis, and dermis was obtained using the technologies of molecular dynamics simulation, in vitro permeation experiments, and in vivo microdialysis, respectively. Besides, finite element analysis (FEA) based on drug Kps in different skin layers was applied to simulate the paeonol nanoemulsion (PAE-NEs) percutaneous dynamic penetration process in two and three dimensions. In addition, PAE-NEs skin pharmacokinetics profile obtained by the simulation was verified by in vivo experiment. RESULTS: Coarse-grained modeling of molecular dynamic simulation was successfully established and the Kp of PAE in SC was 2.00×10-6 cm2/h. The Kp of PAE-NE in viable epidermis and in dermis detected using penetration test and microdialysis probe technology, was 1.58×10-5 cm2/h and 3.20×10-5 cm2/h, respectively. In addition, the results of verification indicated that PAE-NEs skin pharmacokinetics profile obtained by the simulation was consistent with that by in vivo experiment. DISCUSSION: This study demonstrated that the FEA combined with the established multilayer geometry skin model could accurately predict the skin pharmacokinetics of TDDS.
Asunto(s)
Administración Cutánea , Sistemas de Liberación de Medicamentos/métodos , Emulsiones/farmacocinética , Epidermis/efectos de los fármacos , Nanoestructuras/administración & dosificación , Acetofenonas/administración & dosificación , Acetofenonas/farmacocinética , Animales , Emulsiones/administración & dosificación , Células Epidérmicas/efectos de los fármacos , Análisis de Elementos Finitos , Masculino , Microdiálisis , Modelos Biológicos , Ratas Sprague-Dawley , Piel/efectos de los fármacos , Absorción Cutánea/efectos de los fármacosRESUMEN
2,4,6-trihydroxy-3-geranylacetophenone (tHGA) is a bioactive compound that shows excellent anti-inflammatory properties. However, its pharmacokinetics and metabolism have yet to be evaluated. In this study, a sensitive LC-HRMS method was developed and validated to quantify tHGA in rat plasma. The method showed good linearity (0.5-80 ng/mL). The accuracy and precision were within 10%. Pharmacokinetic investigations were performed on three groups of six rats. The first two groups were given oral administrations of unformulated and liposome-encapsulated tHGA, respectively, while the third group received intraperitoneal administration of liposome-encapsulated tHGA. The maximum concentration (Cmax), the time required to reach Cmax (tmax), elimination half-life (t1/2) and area under curve (AUC0-24) values for intraperitoneal administration were 54.6 ng/mL, 1.5 h, 6.7 h, and 193.9 ng/mL·h, respectively. For the oral administration of unformulated and formulated tHGA, Cmax values were 5.4 and 14.5 ng/mL, tmax values were 0.25 h for both, t1/2 values were 6.9 and 6.6 h, and AUC0-24 values were 17.6 and 40.7 ng/mL·h, respectively. The liposomal formulation improved the relative oral bioavailability of tHGA from 9.1% to 21.0% which was a 2.3-fold increment. Further, a total of 12 metabolites were detected and structurally characterized. The metabolites were mainly products of oxidation and glucuronide conjugation.
Asunto(s)
Acetofenonas/sangre , Acetofenonas/farmacocinética , Cromatografía Liquida/métodos , Liposomas/administración & dosificación , Floroglucinol/análogos & derivados , Espectrometría de Masas en Tándem/métodos , Acetofenonas/administración & dosificación , Acetofenonas/metabolismo , Administración Oral , Animales , Disponibilidad Biológica , Inyecciones Intraperitoneales , Masculino , Floroglucinol/administración & dosificación , Floroglucinol/sangre , Floroglucinol/metabolismo , Floroglucinol/farmacocinética , Plasma/química , Ratas , Ratas Sprague-DawleyRESUMEN
Liver fibrosis is the reversible deposition of extracellular matrix (ECM) and scar formation after liver damage by various stimuli. The interaction between NOX4/ROS and RhoA/ROCK1 in liver fibrosis is not yet clear. Ursolic acid (UA) is a traditional Chinese medicine with anti-fibrotic effects, but the molecular mechanism underlying these effects is still unclear. We investigated the interaction between NOX4/ROS and RhoA/ROCK1 during liver fibrosis and whether these molecules are targets for the anti-fibrotic effects of UA. First, we confirmed that UA reversed CCl4-induced liver fibrosis. In the NOX4 intervention and RhoA intervention groups, related experimental analyses confirmed the decrease in CCl4-induced liver fibrosis. Next, we determined that the expression of NOX4 and RhoA/ROCK1 was decreased in UA-treated liver fibrotic mice. Furthermore, RhoA/ROCK1 expression was decreased in the NOX4 intervention group, but there was no significant change in the expression of NOX4 in the RhoA intervention group. Finally, we found that liver fibrotic mice showed a decline in their microbiota diversity and abundance, a change in their microbiota composition, and a reduction in the number of potential beneficial bacteria. However, in UA-treated liver fibrotic mice, the microbiota dysbiosis was ameliorated. In conclusion, the NOX4/ROS and RhoA/ROCK1 signalling pathways are closely linked to the development of liver fibrosis. UA can reverse liver fibrosis by inhibiting the NOX4/ROS and RhoA/ROCK1 signalling pathways, which may interact with each other.
Asunto(s)
Medicamentos Herbarios Chinos/farmacología , Cirrosis Hepática/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Triterpenos/farmacología , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/administración & dosificación , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/análogos & derivados , Acetofenonas/administración & dosificación , Animales , Tetracloruro de Carbono/toxicidad , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/uso terapéutico , Hígado/efectos de los fármacos , Hígado/patología , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/patología , Masculino , Ratones , Ratones Noqueados , NADPH Oxidasa 4/antagonistas & inhibidores , NADPH Oxidasa 4/genética , NADPH Oxidasa 4/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/genética , Triterpenos/uso terapéutico , Quinasas Asociadas a rho/metabolismo , Proteína de Unión al GTP rhoA/antagonistas & inhibidores , Proteína de Unión al GTP rhoA/metabolismo , Ácido UrsólicoRESUMEN
Neutrophils are key players in the pathophysiological process underlying inflammatory conditions not only by release of tissue-damaging cytotoxic enzymes, reactive oxygen species (ROS) but also by secretion of important immunomodulatory chemokines and cytokines. Here, we report the effects of the novel agent APPA, undergoing formal clinical development for treatment of osteoarthritis, and its constituent components, apocynin (AP) and paeonol (PA) on a number of neutrophil functions, including effects on TNFα- expression and signalling. Neutrophils were treated with APPA (10-1000 µg/mL) prior to the measurement of cell functions, including ROS production, chemotaxis, apoptosis and surface receptor expression. Expression levels of several key genes and proteins were measured after incubation with APPA and the chromatin re-modelling agent, R848. APPA did not significantly affect phagocytosis, bacterial killing or expression of surface receptors, while chemotactic migration was affected only at the highest concentrations. However, APPA down-regulated neutrophil degranulation and ROS levels, and decreased the formation of neutrophil extracellular traps. APPA also decreased cytokine-stimulated gene expression, inhibiting both TNFα- and GM-CSF-induced cell signalling. APPA was as effective as infliximab in down-regulating chemokine and IL-6 expression following incubation with R848. Whilst APPA does not interfere with neutrophil host defence against infections, it does inhibit neutrophil degranulation, and cytokine-driven signalling pathways (e.g. autocrine signalling and NF-κB activation), processes that are associated with inflammation. These observations may explain the mechanisms by which APPA exerts anti-inflammatory effects and suggests a potential therapeutic role in inflammatory diseases in which neutrophils and TNFα signalling are important in pathology, such as rheumatoid arthritis.
Asunto(s)
Acetofenonas/farmacología , Antiinflamatorios/farmacología , Neutrófilos/efectos de los fármacos , Acetofenonas/administración & dosificación , Antiinflamatorios/administración & dosificación , Apoptosis/efectos de los fármacos , Células Cultivadas , Citocinas/metabolismo , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Humanos , Inflamación/tratamiento farmacológico , Inflamación/patología , Neutrófilos/patología , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
BACKGROUND: Paeonol (PAE) is a potential central neuroprotective agent with poor water solubility and rapid metabolism in vivo. The key to improve the clinical application of PAE in the treatment of neurodegenerative diseases is to improve the brain delivery of it. The purpose of this study was to construct a paeonol-solid lipid nanoparticles-in situ gel (PAE-SLNs-ISG) drug delivery system based on nose-brain transport pathway. MATERIALS AND METHODS: In this study, the stability of PAE in simulated biological samples was studied firstly in order to clarify the reasons for low oral bioavailability. Paeonol-solid lipid nanoparticles (PAE-SLNs) were prepared by high-temperature emulsification-low-temperature curing combined with ultrasound. The PAE-SLNs-ISG drug delivery system was constructed, and related formulation optimization, preparation characterization, cell evaluation and in vivo evaluation were performed. RESULTS: The metabolic mechanism of PAE incubated in the liver microsomes metabolic system was in accordance with the first-order kinetics, and the half-life was 0.23 h. PAE-SLNs were polyhedral or spherical particles with good dispersion and the particle size was 166.79 nm ± 2.92 nm. PAE-SLNs-ISG solution was a Newtonian fluid with a viscosity of 44.36 mPa · S ± 2.89 mPa · S. The viscosity of PAE-SLNs-ISG gel was 1542.19 mPa · S ± 19.30 mPa · S, and the rheological evaluation showed that the gel was a non-Newtonian pseudoplastic fluid with shear thinning, thixotropy and yield value. The release mechanism of PAE from PAE-SLNs was drug diffusion; the release mechanism of PAE from PAE-SLNs-ISG was a synergistic effect of skeleton erosion and drug diffusion. The cell viabilities of PAE-SLNs and PAE-SLNs-ISG in the concentration range of 0.001 µg/mL to 10 µg/mL were higher than 90%, showing a low level of cytotoxicity. The geometric mean fluorescent intensities of RPMI 2650 cells incubated with fluorescein isothiocyanate-solid lipid nanoparticles (FITC-SLNs) for 1 h, 4 h and 6 h were 1841 ± 24, 2261 ± 27 and 2757 ± 22, respectively. Cyanine7 NHS ester-solid lipid nanoparticles-in situ gel (Cy7-SLNs-ISG) accumulated effectively in the brain area after administration through the olfactory area, and the fluorescence response was observed in olfactory bulb, cerebellum and striatum. CONCLUSION: SLNs-ISG nose-brain drug delivery system can effectively deliver SLNs to brain regions, and it is a potentially effective strategy to realize the brain region delivery of PAE.
Asunto(s)
Acetofenonas/administración & dosificación , Acetofenonas/farmacología , Sistemas de Liberación de Medicamentos , Geles/química , Lípidos/química , Nanopartículas/química , Administración Intranasal , Animales , Disponibilidad Biológica , Muerte Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Liberación de Fármacos , Humanos , Iones , Masculino , Ratones Desnudos , Nanopartículas/administración & dosificación , Nanopartículas/ultraestructura , Tamaño de la Partícula , Ratas Sprague-Dawley , Reología , Solubilidad , Electricidad Estática , Distribución Tisular/efectos de los fármacosRESUMEN
Depression is one of the most common mood disorders, which affects one in six people at some point in life. However, the treatment of this disease is still a challenge. Chronic corticosterone administration (CCA) is a widely used animal model to study the mechanisms involved, as well as possible therapeutic strategies for the treatment of depression. Moreover, elevated oxidative stress has been observed in psychiatric disorders, including major depression and, in this context, antioxidant therapy may be a potential therapeutic alternative. In this study, we investigated the effect of seven days of treatment with apocynin, an antioxidant of natural origin, on depressive-like behavior and oxidative parameters in mice submitted to CCA. After 21 days of corticosterone administration (20 mg/Kg/day, subcutaneously, s.c.), we observed the development of depressive-like behavior with an increase in immobility time on tail suspension test and forced swimming test and reduction in total grooming time on splash test. Also, we found high superoxide dismutase activity and hydrogen peroxide levels whereas catalase activity was reduced in the prefrontal cortex, hippocampus and striatum. Seven days of treatment with apocynin (100 mg/Kg/day orally, p.o), performed immediately after corticosterone administration in the last week of protocol, was able to reverse the most of these changes, revealing its antidepressant-like effect. In conclusion, our results suggest apocynin as an antidepressant-like agent with a mechanism of action based on the attenuation of oxidative changes induced by CCA.
Asunto(s)
Acetofenonas/administración & dosificación , Antidepresivos/administración & dosificación , Antioxidantes/administración & dosificación , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Depresión/metabolismo , Estrés Oxidativo/efectos de los fármacos , Animales , Corticosterona/administración & dosificación , Depresión/inducido químicamente , Depresión/prevención & control , Masculino , RatonesRESUMEN
Paeonol is a bioactive phenol present in Dioscorea japonica, Paeonia suffruticosa and Paeonia lactiflora. It is reported for various pharmacological activities. AIM: To review chemistry, pharmacokinetics, pharmacological activities as well as various formulations of paeonol. MATERIALS AND METHODS: A literature search was done using different search terms for paeonol by using different scientific databases like PubMed, Scopus and ProQuest. Scientific papers published during the period 1969 to 2019 were comprehensively reviewed. KEY FINDINGS: Researchers have synthesized methoxy, ethoxy, piperazine, chromonylthiazolidine, phenol-phenylsulfonyl, alkyl ether, aminothiazole, tryptamine hybrids and paeononlsilatie derivatives to enhance the stability of paeonol. These derivatives were synthesized and evaluated for in vitro series of biological activities like anti-inflammatory, tyrosinase inhibitory, neuroprotective, anticancer and antiviral activity. Regardless of valuable therapeutic potential, the clinical use of paeonol is restricted due to poor water solubility, low oral bioavailability, low stability and high volatility at room temperature. To enhance the bioavailability of paeonol various formulations are prepared and evaluated for its activity. Paeonol formulations can be categorized as conventional-tablets, topical gel and hydrogel; polymeric delivery system-microparticles, microsponges, dendrimers, nanocapsules, polymeric nanoparticles, nanospheres; lipid-based delivery systems-microemulsion, self-micro-emulsifying drug delivery, liposome, transethosomes, ethosomes, niosomes, proniosomes, lipid-based nanoparticles and nanoemulsion of paeonol. SIGNIFICANCE: Paeonol has a potential to be developed as a techno-commercial product with respect to its multi-faceted pharmacological properties. Even though in vitro and in vivo studies have been reported the important activities of paeonol, its commercial utilization requires extensive safety and efficacy data.