RESUMO
Monkeypox (MPXV) is one of the infectious viruses which caused morbidity and mortality problems in these years. Despite its danger to public health, there is no approved drug to stand and handle MPXV. On the other hand, drug repurposing is a promising screening method for the low-cost introduction of approved drugs for emerging diseases and viruses which utilizes computational methods. Therefore, drug repurposing is a promising approach to suggesting approved drugs for the MPXV. This paper proposes a computational framework for MPXV antiviral prediction. To do this, we have generated a new virus-antiviral dataset. Moreover, we applied several machine learning and one deep learning method for virus-antiviral prediction. The suggested drugs by the learning methods have been investigated using docking studies. The target protein structure is modeled using homology modeling and, then, refined and validated. To the best of our knowledge, this work is the first work to study deep learning methods for the prediction of MPXV antivirals. The screening results confirm that Tilorone, Valacyclovir, Ribavirin, Favipiravir, and Baloxavir marboxil are effective drugs for MPXV treatment.
Assuntos
Antivirais , Aprendizado Profundo , Reposicionamento de Medicamentos , Monkeypox virus , Antivirais/farmacologia , Monkeypox virus/efeitos dos fármacos , Reposicionamento de Medicamentos/métodos , Pirazinas/farmacologia , Simulação de Acoplamento Molecular , Dibenzotiepinas , Amidas/farmacologia , Ribavirina/farmacologia , Triazinas/farmacologia , Mpox/tratamento farmacológico , Mpox/virologia , Humanos , Aprendizado de Máquina , Morfolinas , PiridonasRESUMO
Claudin-18 splice variant 2 (CLDN18.2), a tight junction protein, is a highly cell type-specific antigen that is expressed by differentiated gastric mucosa cells. The expression of CLDN18.2 in gastric mucosa cells may be retained upon malignant transformation and is displayed on the surface of several tumors, including gastric/gastroesophageal junction adenocarcinoma. Zolbetuximab is a genetically engineered, highly purified chimeric (mouse/human IgG1) antibody directed against CLDN18.2. Nausea and vomiting were observed as adverse events of zolbetuximab. To investigate the mechanism of nausea and vomiting in humans, we evaluated emesis (retching and vomiting) and conducted histopathologic assessment in ferrets after the administration of zolbetuximab. Emesis was frequently observed in all ferrets treated with zolbetuximab in the first hour after administration. Histopathologic assessment revealed the surface of the gastric mucosa was the primary site of emesis-associated tissue damage. The effect of antiemetics (dexamethasone, ondansetron, fosaprepitant, and olanzapine) on emesis induced by zolbetuximab was investigated. Fosaprepitant showed suppressive effects on emesis, and use of dexamethasone or concomitant use of fosaprepitant with other antiemetics tended to alleviate gastric tissue damage. The onset of emesis in humans receiving zolbetuximab may be associated with damage in the gastric mucosa, and antiemetics may mitigate gastrointestinal adverse events.
Assuntos
Antieméticos , Furões , Mucosa Gástrica , Vômito , Animais , Vômito/induzido quimicamente , Antieméticos/farmacologia , Antieméticos/uso terapêutico , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/patologia , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacologia , Morfolinas/farmacologia , Masculino , Dexametasona/efeitos adversos , Náusea/induzido quimicamente , FemininoRESUMO
BACKGROUND: Onychomycosis (OM) is a common nail infection treated with amorolfine hydrochloride nail lacquer in China. Monitoring drug concentrations and using dermoscopy to evaluate treatment efficacy may provide new insights. OBJECTIVE: The study aims to analyse amorolfine concentrations in nails with mild to moderate OM, assess treatment outcomes using dermoscopy and explore factors influencing drug concentrations and efficacy. METHODS: Patients with mild to moderate OM confirmed by fungal microscopy were enrolled. Amorolfine nail lacquer was applied twice weekly for 36 weeks. Monthly nail samples measured amorolfine concentrations using liquid chromatography. Dermoscopy was performed before and after treatment to evaluate responses. Mixed-effects models and logistic regression analysed factors affecting drug concentrations and outcomes. RESULTS: Ninety-seven nails were included. Amorolfine concentrations increased over time, with higher levels in females, fingernails, 2nd-5th digits and superficial white OM (p < 0.05). Age was a risk factor, while drug concentration and OM type were protective for clinical efficacy (p < 0.05). Peak concentration correlated with clinical (r = 0.487, p = 0.000) and mycological (r = 0.433, p = 0.000) responses. Dermoscopic features improved significantly in successful cases (p < 0.05). LIMITATIONS: In the assessment of fungal efficacy, only fungal microscopy was used, and fungal cultures were not performed. The study was limited by a small sample size and the lack of a longer follow-up to assess relapse. CONCLUSION: Amorolfine concentrations vary with patient and nail characteristics, influencing efficacy. Dermoscopy is valuable for monitoring OM treatment.
Assuntos
Antifúngicos , Morfolinas , Unhas , Onicomicose , Humanos , Onicomicose/tratamento farmacológico , Onicomicose/microbiologia , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Antifúngicos/uso terapêutico , Antifúngicos/administração & dosagem , Resultado do Tratamento , Morfolinas/uso terapêutico , Morfolinas/administração & dosagem , Unhas/microbiologia , Idoso , Adulto Jovem , Modelos Logísticos , China , Dermoscopia , Análise Multivariada , AdolescenteRESUMO
Understanding the current situation and risk of environmental contamination by anti-influenza drugs in aquatic environments is key to prevent the unexpected emergence and spread of drug-resistant viruses. However, few reports have been focused on newer drugs that have recently been introduced in clinical settings. In this study, the behaviour of the prodrug baloxavir marboxil (BALM)-the active ingredient of Xofluza, an increasingly popular anti-influenza drug-and its pharmacologically active metabolite baloxavir (BAL) in the aquatic environment was evaluated. Additionally, their presence in urban rivers and a wastewater treatment plant (WWTP) in the Yodo River basin was investigated and compared with those of the major anti-influenza drugs used to date (favipiravir (FAV), peramivir (PER), laninamivir (LAN), and its active metabolite, laninamivir octanoate (LANO), oseltamivir (OSE), and its active metabolite, oseltamivir carboxylate (OSEC), and zanamivir (ZAN)) to comprehensively assess their environmental fate in the aquatic environment. The results clearly showed that BALM, FAV, and BAL were rapidly degraded through photolysis (2-h, 0.6-h, and 0.4-h half-lives, respectively), followed by LAN, which was gradually biodegraded (7-h half-life). In addition, BALM and BAL decreased by up to 47 % after 4 days and 34 % after 2 days of biodegradation in river water. However, the remaining conventional drugs, except for LANO (<1 % after 10 days), were persistent, being transported from the upstream to downstream sites. The LogKd values for the rates of sorption of BALM (0.5-1.6) and BAL (1.8-3.1) on river sediment were higher than those of conventional drugs (-0.5 to 1.7). Notably, all anti-influenza drugs were effectively removed by ozonation (>90-99.9 % removal) after biological treatment at a WWTP. Thus, these findings suggest the importance of introducing ozonation to reduce pollution loads in rivers and the environmental risks associated with drug-resistant viruses in aquatic environments, thereby promoting safe river environments.
Assuntos
Antivirais , Monitoramento Ambiental , Rios , Triazinas , Poluentes Químicos da Água , Antivirais/análise , Japão , Poluentes Químicos da Água/análise , Rios/química , Triazinas/análise , Morfolinas/análise , Piridonas/análise , Piridinas/análise , Dibenzotiepinas , Oseltamivir/análise , Piranos/análise , Águas Residuárias/química , Pirazinas/análiseRESUMO
Influenza viruses remain a major threat to human health. Four classes of drugs have been approved for the prevention and treatment of influenza infections. Oseltamivir, a neuraminidase inhibitor, is a first-line anti-influenza drug, and baloxavir is part of the newest generation of anti-influenza drugs that targets the viral polymerase. The emergence of drug resistance has reduced the efficacy of established antiviral drugs. Combination therapy is one of the options for controlling drug resistance and enhancing therapeutical efficacies. Here, we evaluate the antiviral effects of baloxavir combined with neuraminidase inhibitors (NAIs) against wild-type influenza viruses, as well as influenza viruses with drug-resistance mutations. The combination of baloxavir with NAIs led to significant synergistic effects; however, the combination of baloxavir with laninamivir failed to result in a synergistic effect on influenza B viruses. Considering the rapid emergence of drug resistance to baloxavir, we believe that these results will be beneficial for combined drug use against influenza.
Assuntos
Antivirais , Dibenzotiepinas , Farmacorresistência Viral , Sinergismo Farmacológico , Inibidores Enzimáticos , Morfolinas , Neuraminidase , Piridonas , Triazinas , Dibenzotiepinas/farmacologia , Antivirais/farmacologia , Triazinas/farmacologia , Morfolinas/farmacologia , Piridonas/farmacologia , Neuraminidase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Humanos , Vírus da Influenza B/efeitos dos fármacos , Animais , Piridinas/farmacologia , Tiazóis/farmacologia , Guanidinas/farmacologia , Orthomyxoviridae/efeitos dos fármacos , Cães , Células Madin Darby de Rim Canino , Influenza Humana/tratamento farmacológico , Influenza Humana/virologia , Ácidos Siálicos , Vírus da Influenza A/efeitos dos fármacos , Tiepinas/farmacologia , Triazóis/farmacologia , Benzimidazóis/farmacologia , PiranosRESUMO
Background: Impairment of synaptic plasticity along with the formation of amyloid-ß (Aß) plaques and tau-protein neurofibrillary tangles have been associated with Alzheimer's disease (AD). Earlier studies with rat and mouse hippocampal slices have revealed the association of AD with the absence of synthesis of memory related proteins leading to impairment in cognitive functions. The role of hydrogen sulfide (H2S), a gaseous neurotransmitter, has been gaining attention as a neuroprotective agent. However, its role in AD-like conditions has not been studied so far. Objective: To study the neuroprotective role of H2S in AD conditions using rat hippocampal slices and the organic molecule GYY4137, a slow releasing H2S donor. Methods: Electrophysiological recordings were carried out in rat hippocampal slices to look into the impairment of LTP, a cellular correlate of memory. The Aß42 peptide was bath-applied to mimic AD-like conditions and checked for both late-LTP and synaptic tagging and capture (STC) mechanisms of the synapses. GYY4137 was applied to look into its neuroprotective role at different stages during the recording of fEPSP. Results: There has been a steady decline in the plasticity properties of the synapses, in the form of late-LTP and STC, after the application of Aß42 peptide in the hippocampal slices. However, application of GYY4137 rescued these conditions in vitro. Conclusions: GYY4137, with its slow release of H2S, could possibly act as a therapeutic agent in cognitive dysfunctions of the brain, mainly AD.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Região CA1 Hipocampal , Sulfeto de Hidrogênio , Morfolinas , Compostos Organotiofosforados , Fragmentos de Peptídeos , Animais , Sulfeto de Hidrogênio/farmacologia , Sulfeto de Hidrogênio/metabolismo , Peptídeos beta-Amiloides/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/metabolismo , Masculino , Ratos , Fragmentos de Peptídeos/farmacologia , Fragmentos de Peptídeos/metabolismo , Morfolinas/farmacologia , Compostos Organotiofosforados/farmacologia , Modelos Animais de Doenças , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos Wistar , Potenciação de Longa Duração/efeitos dos fármacos , Potenciação de Longa Duração/fisiologia , Fármacos Neuroprotetores/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologiaRESUMO
PURPOSE: Excessive tachycardia in resuscitated septic shock patients can impair hemodynamics and worsen patient outcome. We investigated whether heart rate (HR) control can be achieved without increased vasopressor requirements using the titratable highly selective, ultra-short-acting ß1-blocker landiolol. METHODS: This randomized, open-label, controlled trial was conducted at 20 sites in 7 European countries from 2018 to 2022 and investigated the efficacy and safety of landiolol in adult patients with septic shock and persistent tachycardia. Patients were randomly assigned to receive either landiolol along with standard treatment (n = 99) or standard treatment alone (n = 101). The combined primary endpoint was HR response (i.e., HR within the range of 80-94 beats per minute) and its maintenance without increasing vasopressor requirements during the first 24 h after treatment start. Key secondary endpoints were 28-day mortality and adverse events. RESULTS: Out of 196 included septic shock patients, 98 received standard treatment combined with landiolol and 98 standard treatment alone. A significantly larger proportion of patients met the combined primary endpoint in the landiolol group than in the control group (39.8% [39/98] vs. 23.5% [23/98]), with a between-group difference of 16.5% (95% confidence interval [CI]: 3.4-28.8%; p = 0.013). There were no statistically significant differences between study groups in tested secondary outcomes and adverse events. CONCLUSION: The ultra-short-acting beta-blocker landiolol was effective in reducing and maintaining HR without increasing vasopressor requirements after 24 h in patients with septic shock and persistent tachycardia. There were no differences in adverse events and clinical outcomes such as 28-day mortality vs. standard of care. The results of this study, in the context of previous trials, do not support a treatment strategy of stringent HR reduction (< 95 bpm) in an unselected septic shock population with persistent tachycardia. Further investigations are needed to identify septic shock patient phenotypes that benefit clinically from HR control.
Assuntos
Frequência Cardíaca , Morfolinas , Choque Séptico , Taquicardia , Ureia , Humanos , Choque Séptico/tratamento farmacológico , Choque Séptico/complicações , Choque Séptico/fisiopatologia , Masculino , Feminino , Pessoa de Meia-Idade , Ureia/análogos & derivados , Ureia/uso terapêutico , Ureia/farmacologia , Taquicardia/tratamento farmacológico , Taquicardia/fisiopatologia , Taquicardia/complicações , Idoso , Frequência Cardíaca/efeitos dos fármacos , Morfolinas/uso terapêutico , Morfolinas/farmacologia , Europa (Continente)RESUMO
BACKGROUND: Aprepitant (APR), a neurokinin 1 receptor antagonist, is an approved drug for treating chemotherapy-induced nausea and vomiting. OBJECTIVES: Investigate the beneficial roles of APR alone or in combination with sodium valproate (VPA) against lithium pilocarpine [li-pilo]-induced seizures, behavioral changes, and cognitive deficits. METHODS: Thirty male mice were divided into five groups, each containing 6. "Vehicle Group I," "Control Group II "li-pilo, " Valproate (VPA) group III (400 mg/kg/i.p.), "APR group IV, " and "Combination Group V." Videos of mice were recorded, and they were watched for episodes of spontaneous recurring seizures (SRS). Behavioral Tests were performed. At the end of the study, animal brains were taken for biochemical assays and gene expression studies. RESULTS: APR partially protected against SRS with partial restoration of average behavioral and standard cognitive skills associated with a significant increase in brain SOD activity and a significant decrease in MDA, IL-1ß, NF-ÐB, and SP-3 levels in relation to the control group. Interestingly, a combination of APR with VPA in epileptic mice showed complete protection against li-pilo-induced behavioral changes and cognitive deficits, a significant increase in brain SOD activity, and a considerable decrease in MDA, IL-1ß, NF-ΚB, and SP levels to normal. CONCLUSION: Using APR as an adjuvant to VPA is more effective in protecting against li-pilo-induced seizures, behavioral changes, and cognitive deficits due to its antioxidant, anti-inflammatory, and NK1 antagonist effects than using APR alone as drug therapy.
Assuntos
Anticonvulsivantes , Aprepitanto , Modelos Animais de Doenças , Epilepsia , Pilocarpina , Convulsões , Ácido Valproico , Animais , Masculino , Aprepitanto/farmacologia , Camundongos , Ácido Valproico/farmacologia , Anticonvulsivantes/farmacologia , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Epilepsia/tratamento farmacológico , Epilepsia/induzido quimicamente , Pilocarpina/toxicidade , Morfolinas/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Aprendizagem em Labirinto/efeitos dos fármacos , Superóxido Dismutase/metabolismoRESUMO
Papulopustular eruptions are the most common dermatologic side effect of epidermal growth factor receptor inhibitor (EGFRI) therapy. Topical corticosteroids and oral tetracyclines are frequently used to manage these eruptions, though these treatments are limited by their adverse effects and efficacy. Results from preclinical studies suggest a role for topical aprepitant (HT-001) in the treatment of EGFRI-induced skin toxicities. Herein a case of EGFRI-induced papulopustular eruption with rapid treatment response to topical aprepitant (HT-001) 2% cream is described and the literature reviewed. J Drugs Dermatol. 2024;23(9):e173-e174. doi:10.36849/JDD.8617.
Assuntos
Aprepitanto , Toxidermias , Receptores ErbB , Morfolinas , Humanos , Administração Cutânea , Antineoplásicos/efeitos adversos , Antineoplásicos/administração & dosagem , Aprepitanto/administração & dosagem , Toxidermias/etiologia , Toxidermias/diagnóstico , Toxidermias/tratamento farmacológico , Toxidermias/patologia , Receptores ErbB/antagonistas & inibidores , Morfolinas/administração & dosagem , Morfolinas/efeitos adversos , Resultado do TratamentoRESUMO
Membranous nephropathy (MN) is a common pathological type of adult nephrotic syndrome. Up to 20% of patients with MN develop end-stage renal disease (ESRD). Podocytes have an important function in maintaining the glomerular filtration barrier and play a crucial role in the occurrence and development of proteinuria and MN. PI3K/AKT signaling pathway is involved in the entire process of podocyte growth, differentiation, and apoptosis. Kemeng Fang (KMF) is a traditional Chinese medicine formula that has been used to delay kidney injury. However, the therapeutic mechanism of KMF in MN is unclear. Here, the MN rat model was established by axillary, inguinal, and tail vein injections of cationized bovine serum albumin (C-BSA), and then KMF and PI3K inhibitor (LY294002) were administered. The data of liver function, kidney function, blood lipid, renal pathology, podocyte function, expression level of PI3K/AKT signaling pathway, and transcriptomics of rats demonstrated that KMF has a protective effect on the podocytes of MN rats by activating the PI3K/AKT signaling pathway, and it can effectively prevent the progression of MN.
Assuntos
Apoptose , Medicamentos de Ervas Chinesas , Glomerulonefrite Membranosa , Fosfatidilinositol 3-Quinases , Podócitos , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Animais , Glomerulonefrite Membranosa/patologia , Glomerulonefrite Membranosa/tratamento farmacológico , Glomerulonefrite Membranosa/metabolismo , Podócitos/efeitos dos fármacos , Podócitos/metabolismo , Podócitos/patologia , Ratos , Transdução de Sinais/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Masculino , Ratos Sprague-Dawley , Morfolinas/farmacologia , Morfolinas/uso terapêutico , Cromonas/farmacologia , Modelos Animais de DoençasRESUMO
Avian primordial germ cells (PGCs) are important culture cells for the production of transgenic chickens and preservation of the genetic resources of endangered species; however, culturing these cells in vitro proves challenging. Although the proliferation of chicken PGCs is dependent on insulin, the underlying molecular mechanisms remain unclear. In the present study, we explored the expression of the PI3K/AKT signaling pathway in PGCs, investigated its effects on PGC self-renewal and biological properties, and identified the underlying mechanisms. Our findings indicated that although supplementation with the PI3K/AKT activator IGF-1 failed to promote proliferation under the assessed culture conditions, the PI3K/AKT inhibitor LY294002 resulted in retarded cell proliferation and reduced expression of germ cell-related markers. We further demonstrated that inhibition of PI3K/AKT regulates the cell cycle and promotes apoptosis in PGCs by activating the expression of BAX and inhibiting that of Bcl-2. These findings indicated that the PI3K/AKT pathway is required for cell renewal, apoptosis, and maintenance of the reproductive potential in chicken PGCs. This study aimed to provide a theoretical basis for the optimization and improvement of a culture system for chicken PGCs and provide insights into the self-renewal of vertebrate PGCs as well as potential evolutionary changes in this unique cell population.
Assuntos
Galinhas , Células Germinativas , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Animais , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/efeitos dos fármacos , Células Germinativas/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositol 3-Quinases/genética , Proliferação de Células/efeitos dos fármacos , Cromonas/farmacologia , Proteínas Aviárias/metabolismo , Proteínas Aviárias/genética , Morfolinas/farmacologia , Apoptose/efeitos dos fármacosRESUMO
Developmental exposure to nonylphenol (NP) results in irreversible impairments of the central nervous system (CNS). The neural precursor cell (NPC) pool located in the subgranular zone (SGZ), a substructure of the hippocampal dentate gyrus, is critical for the development of hippocampal circuits and some hippocampal functions such as learning and memory. However, the effects of developmental exposure to NP on this pool remain unclear. Thus, our aim was to clarify the impacts of developmental exposure to NP on this pool and to explore the potential mechanisms. Animal models of developmental exposure to NP were created by treating Wistar rats with NP during pregnancy and lactation. Our data showed that developmental exposure to NP decreased Sox2-and Ki67-positive cells in the SGZ of offspring. Inhibited activation of Shh signaling and decreased levels of its downstream mediators, E2F1 and cyclins, were also observed in pups developmentally exposed to NP. Moreover, we established the in vitro model in the NE-4C cells, a neural precursor cell line, to further investigate the effect of NP exposure on NPCs and the underlying mechanisms. Purmorphamine, a small purine-derived hedgehog agonist, was used to specifically modulate the Shh signaling. Consistent with the in vivo results, exposure to NP reduced cell proliferation by inhibiting the Shh signaling in NE-4C cells, and purmorphamine alleviated this reduction in cell proliferation by restoring this signaling. Altogether, our findings support the idea that developmental exposure to NP leads to inhibition of the NPC proliferation and the NPC pool depletion in the SGZ located in the dentate gyrus. Furthermore, we also provided the evidence that suppressed activation of Shh signaling may contribute to the effects of developmental exposure to NP on the NPC pool.
Assuntos
Proliferação de Células , Giro Denteado , Proteínas Hedgehog , Células-Tronco Neurais , Fenóis , Ratos Wistar , Transdução de Sinais , Animais , Giro Denteado/efeitos dos fármacos , Giro Denteado/metabolismo , Giro Denteado/citologia , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/citologia , Proteínas Hedgehog/metabolismo , Fenóis/farmacologia , Fenóis/toxicidade , Feminino , Gravidez , Ratos , Transdução de Sinais/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Purinas/farmacologia , Morfolinas/farmacologia , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Masculino , Fatores de Transcrição SOXB1/metabolismo , Linhagem CelularRESUMO
OBJECTIVE: Thumbtack Needling (TN) has been employed in the treatment of functional constipation (FC), although the existing evidence supporting its effectiveness is limited. This study is to evaluate the efficacy of TN in ameliorating FC. METHOD: A total of 482 eligible patients were recruited and randomly assigned to the TN group or the Mosapride Citrate (MC) group. The TN was buried once for three days, rest for one day after two consecutive burials, followed by a 4-week follow-up. The primary outcome measure was the score for Complete and spontaneous bowel movement score (CSBMs). Secondary outcome measures included the Bristol Stool Form Scale (BSFS), Cleveland Clinic Score (CCS), and the Patient Assessment of Constipation Quality of Life Questionnaire (PAC-QOL). RESULTS: Out of the 482 patients randomized, 241 were allocated to each group. Of these, 216 patients (89.6 %) in both groups completed the intervention and follow-up. Compared with the baseline, the differences of CSBMs in TN group [1.76(95 % CI, 1.61 to 1.91)] and MC group [1.35(95 % CI, 1.20 to 1.50)] at week 4 meet the threshold for minimal clinically important difference (MCID). However, there were no clinical difference from baseline at week 2 and week 8 in both groups. Mean CSBMs at week 4 was 3.35 ± 0.99 in the TN group and 3 ± 1.03 in the MC group (adjusted difference between groups, 0.37 points [95 % CI, 0.18 to 0.55]; P < 0.001), although differences between the two groups did not meet the MCID threshold. CONCLUSION: Compared with mosapride citrate, thumbtack needling produced a greater improvement in CSBMs, although the difference from control was not clinically significant. GOV IDENTIFIER: ChiCTR2100043684.
Assuntos
Constipação Intestinal , Qualidade de Vida , Humanos , Constipação Intestinal/terapia , Constipação Intestinal/tratamento farmacológico , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Morfolinas/uso terapêutico , Terapia por Acupuntura/métodos , Benzamidas/uso terapêutico , Inquéritos e Questionários , Agulhas , Resultado do TratamentoRESUMO
Cardiac remodeling in rats with post-infarction chronic heart failure caused by anterior transmural myocardial infarction leads to an atypical location of areas of positive and negative cardioelectric potentials on the body surface before the onset of the PII-wave on the ECG in the limb leads, which is a sign of increased heterogeneity of atrial depolarization associated with the appearance of additional excitation focus in the left atrium. A course of therapy with fabomotizole leads to a decrease in the heterogeneity of atrial depolarization at the initial stages of the formation of the cardioelectric field of the atria on the body surface before the onset of the PII-wave, thereby producing an antiarrhythmic effect.
Assuntos
Mapeamento Potencial de Superfície Corporal , Átrios do Coração , Insuficiência Cardíaca , Infarto do Miocárdio , Animais , Ratos , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Infarto do Miocárdio/fisiopatologia , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/complicações , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/fisiopatologia , Masculino , Mapeamento Potencial de Superfície Corporal/métodos , Morfolinas/farmacologia , Morfolinas/uso terapêutico , Eletrocardiografia , Ratos Wistar , Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico , Antiarrítmicos/uso terapêutico , Antiarrítmicos/farmacologiaRESUMO
The type 1 cannabinoid receptor (CB1R) mediates neurotransmitter release and synaptic plasticity in the central nervous system. Endogenous, plant-derived, synthetic cannabinoids bind to CB1R, initiating the inhibitory G-protein (Gi) and the ß-arrestin signaling pathways. Within the Gi signaling pathway, CB1R activates G protein-gated, inwardly-rectifying potassium (GIRK) channels. The ß-arrestin pathway reduces CB1R expression on the cell surface through receptor internalization. Because of their association with analgesia and drug tolerance, GIRK channels and receptor internalization are of interest to the development of pharmaceuticals. This research used immortalized mouse pituitary gland cells transduced with a pH-sensitive, fluorescently-tagged human CB1R (AtT20-SEPCB1) to measure GIRK channel activity and CB1R internalization. Cannabinoid-induced GIRK channel activity is measured by using a fluorescent membrane-potential sensitive dye. We developed a kinetic imaging assay that visualizes and measures CB1R internalization. All cannabinoids stimulated a GIRK channel response with a rank order potency of WIN55,212-2 > (±)CP55,940 > Δ9-THC > AEA. Efficacy was expressed relative to (±)CP55,940 with a rank order efficacy of (±)CP55,940 > WIN55, 212-2 > AEA > Δ9-THC. All cannabinoids stimulated CB1R internalization with a rank order potency of (±)CP55,940 > WIN55, 212-2 > AEA > Δ9-THC. Internalization efficacy was normalized to (±)CP55,940 with a rank order efficacy of WIN55,212-2 > AEA > (±)CP55,940 > Δ9-THC. (±)CP55,940 was significantly more potent and efficacious than AEA and Δ9-THC at stimulating a GIRK channel response; no significant differences between potency and efficacy were observed with CB1R internalization. No significant differences were found when comparing a cannabinoid's GIRK channel and CB1R internalization response. In conclusion, AtT20-SEPCB1 cells can be used to assess cannabinoid-induced CB1R internalization. While cannabinoids display differential Gi signaling when compared to each other, this did not extend to CB1R internalization.
Assuntos
Benzoxazinas , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G , Naftalenos , Receptor CB1 de Canabinoide , Receptor CB1 de Canabinoide/metabolismo , Receptor CB1 de Canabinoide/genética , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/metabolismo , Animais , Camundongos , Humanos , Cinética , Naftalenos/farmacologia , Benzoxazinas/farmacologia , Canabinoides/metabolismo , Canabinoides/farmacologia , Morfolinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Linhagem Celular , CicloexanóisRESUMO
Utilizing non-invasive, real-time dynamic imaging and high-resolution detection tools to track polarity changes in Sjögren's syndrome (SS) contributes to a better understanding of the disease progression. Herein, a ratiometric polarity-sensitive fluorescent probe (DIM) was designed and synthesized, DIM consisted of dicyanoisophorone as the fluorophore and morpholine moiety as lysosome targeting. DIM showed a ratiometric response to polarity and high selectivity (unaffected by viscosity, pH, ROS, RNS, etc.), offering a more accurate analysis of intracellular polarity through a built-in internal reference calibration. The polarity abnormality of submandibular glands in non-obese diabetic (NOD) mice was revealed and verified by in vivo ratiometric fluorescence imaging of DIM, suggesting that fluorescent probe have great potential in the diagnosis of salivary gland abnormalities.
Assuntos
Corantes Fluorescentes , Lisossomos , Camundongos Endogâmicos NOD , Síndrome de Sjogren , Animais , Síndrome de Sjogren/diagnóstico por imagem , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Lisossomos/metabolismo , Lisossomos/química , Camundongos , Imagem Óptica , Glândula Submandibular/diagnóstico por imagem , Glândula Submandibular/patologia , Feminino , Morfolinas/química , Morfolinas/síntese químicaRESUMO
Hydrogen polysulfide (H2Sn, n≥2), as a kind of active sulfur species (RSS), has become a hot topic in RSS. It can regulate the biological activity of many proteins through S-sulfhydrylation of cysteine residues (protein Cys-SSH), and has a protective effect on cells. Although there have been some studies on hydrogen polysulfide, its production, degradation pathway and regulation mechanism still need further be researched. In presented study, an original lysosome-localized fluorescent probe for determining H2Sn was developed utilizing rhodamine as the fluorogen. The probe used morpholine as the locating unit of lysosomes and chose 2-fluoro-5-nitrobenzoate as the recognizing group. Before adding H2Sn, the proposed probe displayed a spironolactone structure and emitted very weak fluorescence. After adding H2Sn, a conjugated xanthene was formed and the probe demonstrated green fluorescence. When the H2Sn concentration was varied from 6.0×10-7 mol·L-1 to 10.0×10-5 mol·L-1, the fluorescence intensity of the probe was linearly dependent on the H2Sn concentration. And the detection limit was 1.5×10-7 mol·L-1. The presented probe owned a fast response speed, good selectivity, excellent sensitivity and broad pH work scope. In addition, the probe had been well utilized to sense endogenic and exogenic H2Sn in lysosomes.
Assuntos
Corantes Fluorescentes , Limite de Detecção , Lisossomos , Rodaminas , Sulfetos , Corantes Fluorescentes/química , Lisossomos/metabolismo , Rodaminas/química , Sulfetos/química , Sulfetos/análise , Humanos , Espectrometria de Fluorescência/métodos , Sulfeto de Hidrogênio/análise , Sulfeto de Hidrogênio/química , Morfolinas/química , Concentração de Íons de Hidrogênio , FluorescênciaRESUMO
In search of novel therapeutic options to treat influenza virus (IV) infections, we previously identified a series of inhibitors that act by disrupting the interactions between the PA and PB1 subunits of the viral RNA polymerase. These compounds showed broad-spectrum antiviral activity against human influenza A and B viruses and a high barrier to the induction of drug resistance in vitro. In this short communication, we investigated the effects of combinations of the PA-PB1 interaction inhibitor 54 with oseltamivir carboxylate (OSC), zanamivir (ZA), favipiravir (FPV), and baloxavir marboxil (BXM) on the inhibition of influenza A and B virus replication in vitro. We observed a synergistic effect of the 54/OSC and 54/ZA combinations and an antagonistic effect when 54 was combined with either FPV or BXM. Moreover, we demonstrated the efficacy of 54 against highly pathogenic avian influenza viruses (HPAIVs) both in cell culture and in the embryonated chicken eggs model. Finally, we observed that 54 enhances OSC protective effect against HPAIV replication in the embryonated eggs model. Our findings represent an advance in the development of alternative therapeutic strategies against both human and avian IV infections.
Assuntos
Antivirais , Sinergismo Farmacológico , Vírus da Influenza A , Oseltamivir , Pirazinas , Proteínas Virais , Replicação Viral , Oseltamivir/farmacologia , Oseltamivir/análogos & derivados , Animais , Antivirais/farmacologia , Humanos , Replicação Viral/efeitos dos fármacos , Pirazinas/farmacologia , Vírus da Influenza A/efeitos dos fármacos , Embrião de Galinha , Proteínas Virais/metabolismo , Proteínas Virais/antagonistas & inibidores , Amidas/farmacologia , Dibenzotiepinas/farmacologia , Vírus da Influenza B/efeitos dos fármacos , Vírus da Influenza B/fisiologia , Zanamivir/farmacologia , Triazinas/farmacologia , Piridonas/farmacologia , Influenza Aviária/tratamento farmacológico , Influenza Aviária/virologia , Morfolinas/farmacologia , Influenza Humana/tratamento farmacológico , Influenza Humana/virologia , Cães , RNA Polimerases Dirigidas por DNA/antagonistas & inibidores , RNA Polimerases Dirigidas por DNA/metabolismo , RNA Polimerase Dependente de RNA/antagonistas & inibidores , RNA Polimerase Dependente de RNA/metabolismo , Linhagem Celular , Células Madin Darby de Rim CaninoRESUMO
Antiretroviral drugs have made significant progress in treating HIV-1 and improving the quality of HIV-1-infected individuals. However, due to their limited permeability into the brain HIV-1 replication persists in brain reservoirs such as perivascular macrophages and microglia, which cause HIV-1-associated neurocognitive disorders. Therefore, it is highly desirable to find a novel therapy that can cross the blood-brain barrier (BBB) and target HIV-1 pathogenesis in brain reservoirs. A recently developed 2-amino-3-methylpentanoic acid [2-morpholin-4-yl-ethyl]-amide (LM11A-31), which is a p75 neutrotrophin receptor (p75NTR) modulator, can cross the BBB. In this study, we examined whether LM11A-31 treatment can suppress HIV-1 replication, oxidative stress, cytotoxicity, and inflammatory response in macrophages. Our results showed that LM11A-31 (100 nM) alone and/or in combination with positive control darunavir (5.5 µM) significantly suppresses viral replication and reduces cytotoxicity. Moreover, the HIV-1 suppression by LM11A-31 was comparable to the HIV-1 suppression by darunavir. Although p75NTR was upregulated in HIV-1-infected macrophages compared to uninfected macrophages, LM11A-31 did not significantly reduce the p75NTR expression in macrophages. Furthermore, our study illustrated that LM11A-31 alone and/or in combination with darunavir significantly suppress pro-inflammatory cytokines including IL-1ß, IL-8, IL-18, and TNF-α and chemokines MCP-1 in HIV-induced macrophages. The suppression of these cytokines and chemokines by LM11A-31 was comparable to darunavir. In contrast, LM11A-31 did not significantly alter oxidative stress, expression of antioxidant enzymes, or autophagy marker proteins in U1 macrophages. The results suggest that LM11A-31, which can cross the BBB, has therapeutic potential in suppressing HIV-1 and inflammatory response in brain reservoirs, especially in macrophages.
Assuntos
HIV-1 , Macrófagos , Morfolinas , Replicação Viral , HIV-1/efeitos dos fármacos , Humanos , Replicação Viral/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/virologia , Morfolinas/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Darunavir/farmacologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Receptores de Fator de Crescimento Neural/metabolismo , Citocinas/metabolismo , Isoleucina/análogos & derivados , Proteínas do Tecido NervosoRESUMO
Tanshinone IIA (TSA), the main lipo-soluble component from the dried rhizome of Salvia miltiorrhiza, has been shown to induce vasodilation. However, the underlying mechanisms remains unclear. This study aimed to investigate the effect of TSA on the vasodilation of small resistant arteries ex vivo. Vascular myography revealed that endothelial denudation reduced significantly the vasodilatory effect of TSA. Blocking transient receptor potential vanilloid 4 (TRPV4) channels prevented TSA-induced vasodilation. Whole-cell patch-clamp analysis revealed that the current passing through TRPV4 channels increased after TSA treatment in endothelial cells (ECs). This was attributed to reduced TRPV4 protein degradation along with its increased expression. The TRPV4 inhibitor HC-067047 lowed nitric oxide (NO) production and TSA-induced expression of endothelial nitric oxide synthase (eNOS). Moreover, it increased the production of cyclic guanosine monophosphate (cGMP) and protein kinase G (PKG). The present results indicate that TSA induces endothelium-dependent vasodilation, which is mediated by the TRPV4-NO-PKG signaling pathway. These findings highlight the potential of TSA, a compound known in traditional Chinese medicine as Danshen (Salvia miltiorrhiza), for future cardiovascular therapeutic strategies.