RESUMEN
Systemic autoimmune diseases (SADs) are a growing spectrum of autoimmune disorders that commonly affect multiple organs. The role of Epstein-Barr virus (EBV) infection or reactivation as a trigger for the initiation and progression of SADs has been established, while the relationship between EBV envelope glycoproteins and SADs remains unclear. Here, we assessed the levels of IgG, IgA, and IgM against EBV glycoproteins (including gp350, gp42, gHgL, and gB) in serum samples obtained from patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), and found that RA and SLE patients exhibited a statistically significant increase in the levels of 8 and 11 glycoprotein antibodies, respectively, compared to healthy controls (p < 0.05). The LASSO model identified four factors as significant diagnostic markers for RA: gp350 IgG, gp350 IgA, gHgL IgM, and gp42 IgA; whereas for SLE it included gp350 IgG, gp350 IgA, gHgL IgA, and gp42 IgM. Combining these selected biomarkers yielded an area under the curve (AUC) of 0.749 for RA and 0.843 for SLE. We subsequently quantified the levels of autoantibodies associated with SADs in mouse sera following immunization with gp350. Remarkably, none of the tested autoantibody levels exhibited statistically significant alterations. Elevation of glycoprotein antibody concentration suggests that Epstein-Barr virus reactivation and replication occurred in SADs patients, potentially serving as a promising biomarker for diagnosing SADs. Moreover, the absence of cross-reactivity between gp350 antibodies and SADs-associated autoantigens indicates the safety profile of a vaccine based on gp350 antigen.
Asunto(s)
Artritis Reumatoide , Enfermedades Autoinmunes , Infecciones por Virus de Epstein-Barr , Lupus Eritematoso Sistémico , Humanos , Animales , Ratones , Infecciones por Virus de Epstein-Barr/complicaciones , Herpesvirus Humano 4 , Anticuerpos Antivirales , Artritis Reumatoide/complicaciones , Glicoproteínas , Enfermedades Autoinmunes/complicaciones , Inmunoglobulina G , Inmunoglobulina A , Inmunoglobulina MRESUMEN
Neurodegenerative diseases (NDD) are characterized by the gradual deterioration of neuronal function and integrity, resulting in an overall decline in brain function. The existing therapeutic options for NDD, including Alzheimer's disease, Parkinson's disease, and Huntington's disease, fall short of meeting the clinical demand. A prominent pathological hallmark observed in numerous neurodegenerative disorders is the aggregation and misfolding of proteins both within and outside neurons. These abnormal proteins play a pivotal role in the pathogenesis of neurodegenerative diseases. Targeted degradation of irregular proteins offers a promising avenue for NDD treatment. Proteolysis-targeting chimeras (PROTACs) function via the ubiquitin-proteasome system and have emerged as a novel and efficacious approach in drug discovery. PROTACs can catalytically degrade "undruggable" proteins even at exceptionally low concentrations, allowing for precise quantitative control of aberrant protein levels. In this review, we present a compilation of reported PROTAC structures and their corresponding biological activities aimed at addressing NDD. Spanning from 2016 to present, this review provides an up-to-date overview of PROTAC-based therapeutic interventions. Currently, most protein degraders intended for NDD treatment remain in the preclinical research phase. Overcoming several challenges is imperative, including enhancing oral bioavailability and permeability across the blood-brain barrier, before these compounds can progress to clinical research or eventually reach the market. However, armed with an enhanced comprehension of the underlying pathological mechanisms and the emergence of innovative scaffolds for protein degraders, along with further structural optimization, we are confident that PROTAC possesses the potential to make substantial breakthroughs in the field of neurodegenerative diseases.
Asunto(s)
Enfermedades Neurodegenerativas , Proteolisis , Humanos , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/metabolismo , Proteolisis/efectos de los fármacos , Animales , Descubrimiento de Drogas , Estructura Molecular , Quimera Dirigida a la ProteólisisRESUMEN
Alzheimer's disease (AD) is a multifactorial neurological disease, and the multitarget directed ligand (MTDL) strategy may be an effective approach to delay its progression. Based on this strategy, 27 derivatives of l-tryptophan, 3a-1-3d-1, were designed, synthesized, and evaluated for their biological activity. Among them, IC50 (inhibitor concentration resulting in 50% inhibitory activity) values of compounds 3a-18 and 3b-1 were 0.58 and 0.44 µM for human serum butyrylcholinesterase (hBuChE), respectively, and both of them exhibited more than 30-fold selectivity for human serum acetylcholinesterase. Enzyme kinetics studies showed that these two compounds were mixed inhibitors of hBuChE. In addition, these two derivatives possessed extraordinary antioxidant activity in OH radical scavenging and oxygen radical absorption capacity fluorescein assays. Meanwhile, these compounds could also prevent ß-amyloid (Aß) self-aggregation and possessed low toxicity on PC12 and AML12 cells. Molecular modeling studies revealed that these two compounds could interact with the choline binding site, acetyl binding site, and peripheral anionic site to exert submicromolar BuChE inhibitory activity. In the vitro blood-brain barrier permeation assay, compounds 3a-18 and 3b-1 showed enough blood-brain barrier permeability. In drug-likeness prediction, compounds 3a-18 and 3b-1 showed good gastrointestinal absorption and a low risk of human ether-a-go-go-related gene toxicity. Therefore, compounds 3a-18 and 3b-1 are potential multitarget anti-AD lead compounds, which could work as powerful antioxidants with submicromolar selective inhibitory activity for hBuChE as well as prevent Aß self-aggregation.
Asunto(s)
Acetilcolinesterasa , Enfermedad de Alzheimer , Péptidos beta-Amiloides , Antioxidantes , Barrera Hematoencefálica , Butirilcolinesterasa , Inhibidores de la Colinesterasa , Diseño de Fármacos , Triptófano , Enfermedad de Alzheimer/tratamiento farmacológico , Humanos , Antioxidantes/farmacología , Antioxidantes/síntesis química , Antioxidantes/química , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Relación Estructura-Actividad , Barrera Hematoencefálica/metabolismo , Butirilcolinesterasa/metabolismo , Animales , Triptófano/farmacología , Triptófano/química , Triptófano/análogos & derivados , Triptófano/síntesis química , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Ratas , Acetilcolinesterasa/metabolismo , Estructura Molecular , Células PC12 , Relación Dosis-Respuesta a Droga , Modelos MolecularesRESUMEN
There are no highly effective and safe medicines for clinical treatment of ischemic stroke, although the natural product 3-n-butylphthalide (NBP) has been approved in China for mild and moderate ischemic stroke. To discover more potent anti-cerebral ischemic agents and overcome the low stability by phthalide derivatives, benzofuran-3-one was selected as a core moiety and two types of nitric oxide (NO)-donating groups were incorporated into the structure. In this work, a series of 2,6-disubstituted benzofuran-3-one derivatives were designed and synthesised as NBP analogues, and tested as neuroprotective and antioxidative agents. Compounds 5 (without an NO donor) and 16 (with an NO donor) displayed more potent neuroprotective effects than the established clinical drugs Edaravone and NBP. More importantly, 5 and 16 also exhibited good antioxidative activity without cytotoxicity in rat primary neuronal and PC12 cells. Most active compounds showed good blood-brain barrier permeability in a parallel artificial membrane permeability assay. Furthermore, compound 5 reduced the ischemic infarct area significantly in rats subjected to ischemia/reperfusion injury, downregulated ionised calcium-binding adaptor molecule 1 and glial fibrillary acidic protein in inflammatory cells, and upregulated nerve growth factor.
Asunto(s)
Benzofuranos , Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Fármacos Neuroprotectores , Daño por Reperfusión , Ratas , Animales , Antioxidantes/química , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Fármacos Neuroprotectores/química , Daño por Reperfusión/tratamiento farmacológico , Isquemia Encefálica/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Benzofuranos/farmacología , Benzofuranos/uso terapéutico , Benzofuranos/químicaRESUMEN
BACKGROUND: The association between triglyceride-glucose (TyG) index and poor prognosis remains controversial. Whether renal function status affects the ability of the TyG index to predict poor prognosis has not yet been elucidated and merits further studies. METHODS: This retrospective cohort study included 22,031 participants from communities in the U.S. By juxtaposing the TyG categories with the estimated glomerular filtration rate (eGFR, either < 60 mL/min/1.73m2 or ≥ 60 mL/min/1.73m2), participants were categorized into four distinct groups: (1) TyG_L/eGFR_H; (2) TyG_H/eGFR_H; (3) TyG_L/eGFR_L; and (4) TyG_H/eGFR_L. The endpoint was the all-cause mortality rate. Standard Kaplan-Meier plots were constructed and multifactor Cox regression analyses were carried out and restricted cubic spline regression analysis was utilized to assess the association between death and the TyG index for different renal function statuses. RESULTS: No statistical differences were found in the TyG groups in participants with normal renal function after adjustment for all covariates (P = 0.070). However, in the high TyG index group with renal insufficiency, the risk of all-cause mortality rates was reduced by 18%. (HR, 0.82; CI, 0.69-0.98). The TyG index (high vs. low) and renal function (eGFR < 60 vs. eGFR ≥ 60) had statistically significant interactions with death (P < 0.001). When all covariates were adjusted, the risk of mortality for the TyG_L combined with eGFR_L group was 56% higher than that for the TyG_L combined with eGFR_H group (HR, 1.56; CI, 1.33-1.82). In the renal insufficiency population, a nonlinear relationship was observed between mortality and the TyG index, albeit with a differing pattern (P for nonlinearity < 0.001). CONCLUSIONS: While it has been known that TyG index was a prognosis marker of CVD, this research highlights that higher TyG index was associated with higher all-cause mortality rates for all participants. Furthermore, renal function status significantly moderates the effect of the TyG index on all-cause mortality in community-dwelling adults.
Asunto(s)
Glucosa , Insuficiencia Renal , Adulto , Humanos , Estudios Retrospectivos , Triglicéridos , Riñón/fisiología , Glucemia , Factores de Riesgo , BiomarcadoresRESUMEN
BACKGROUND: Effective means for early diagnosis are imperative to reduce death rate of non-small cell lung cancer (NSCLC) patients. We aimed to find out high-performance serologic markers to distinguish early-stage NSCLC patients from benign pulmonary nodule patients and healthy controls (HC). Cystatin-SN (CST1) is an active cysteine protease inhibitor of the CST superfamily, involving in the processes of inflammation and tumorigenesis. This is the first exploration of the diagnostic and prognostic values of serum CST1 in NSCLC. METHODS: We analyzed the transcriptome data from The Cancer Genome Atlas and the Gene Expression Omnibus database, screened biomarkers for NSCLC, and verified the candidate markers via the ONCOMINE database. Then, we performed ELISA, western blotting, and immunohistochemistry analysis to detect the expression levels of CST1 in NSCLC cell lines, tumor tissues, and serum samples of clinical cohorts. RESULTS: We identified 3 up-regulated secreted protein-encoding genes, validated the expression levels of CST1 in NSCLC tumor tissues and cell lines, and found that serum CST1 levels of NSCLC (4289 ± 2405 pg/mL) were significantly higher than those of PBN patients (1558 ± 441 pg/mL, P < .0001) and healthy controls (1529 ± 416 pg/mL, P < .0001). The AUC of the combination of CST1, Cytokeratin 19 fragment (Cyfra21-1), and Carcinoembryonic antigen (CEA) for distinguishing early-stage NSCLC from PBN/HC was as high as .914/0.925. Furthermore, our results suggested that the NSCLC patient with low serum CST1 level had a better survival rate. CONCLUSIONS: Serum CST1 may serve as a novel diagnostic marker for differentiating early-stage NSCLC from PBN and HC, and could be used as a prognosis predictor in NSCLC patients.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Antígenos de Neoplasias , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/genética , Humanos , Queratina-19 , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Cistatinas Salivales/genética , Cistatinas Salivales/metabolismoRESUMEN
BACKGROUND: HIV drug resistance increased with the widespread use of antiretroviral drugs, and posed great threat to antiretroviral therapy (ART). Pu'er Prefecture, lying in the southwest of Yunnan Province, China, borders Myanmar, Laos and Vietnam, is also the area where AIDS was discovered earlier, however, in which there has been no information on HIV drug resistance. METHODS: A cross-sectional survey of pretreatment drug resistance (PDR) was conducted in Pu'er Prefecture in 2021. Partial pol gene sequences were obtained to analyze drug resistance and construct genetic transmission network. HIV drug resistance was analyzed using the Stanford University HIVdb algorithm. RESULTS: A total of 295 sequences were obtained, among which 11 HIV-1 strain types were detected and CRF08_BC (62.0%, 183/295) was the predominant one. Drug resistance mutations (DRMs) were detected in 42.4% (125/295) of the sequences. The prevalence of PDR to any antiretroviral drugs, nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) were 10.8% (32/295), 9.5% (28/295), 1.0% (3/295) and 0.3% (1/295), respectively. The risk of PDR occurrence was higher among individuals with CRF01_AE strain types. HIV-1 molecular network was constructed, in which 56.0% (42/75) of links were transregional, and 54.7% (41/75) of links were associated with Lancang County. Among the sequences in the network, 36.8% (35/95) harbored DRMs, and 9.5% (9/95) were drug resistance strains. Furthermore, 8 clusters had shared DRM. CONCLUSION: The overall prevalence of PDR in this study was in a moderate level, but NNRTIs resistance was very approaching to the threshold of public response initiation. PDR was identified in the transmission network, and DRMs transmission was observed. These findings suggested that the consecutive PDR surveillance should be conducted in this region.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Seropositividad para VIH , VIH-1 , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , Antirretrovirales/uso terapéutico , China/epidemiología , Estudios Transversales , Farmacorresistencia Viral/genética , Genotipo , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Seropositividad para VIH/tratamiento farmacológico , VIH-1/genética , Humanos , Inhibidores de Proteasas/uso terapéutico , Inhibidores de la Transcriptasa Inversa/uso terapéuticoRESUMEN
OBJECTIVE: Rheumatoid arthritis (RA) is mainly characterized by synovial hyperplasia, angiogenesis, inflammatory cells infiltration. Chymotrypsin is a proteolytic enzyme with anti-inflammatory effects. The current project was intended to test the efficacy and mechanism of chymotrypsin in adjuvant-induced arthritis (AIA) rats to provide an experimental basis for the clinical application of chymotrypsin. METHODS: Sprague-Dawley rats were injected with complete Freund's adjuvant (CFA) in the hind left paw pad to establish an AIA model. Forty rats were randomly divided into five groups (n = 8): blank; CFA model (model); low-dose chymotrypsin (CLD), 0.53 mg/kg; high-dose chymotrypsin (CHD), 1.06 mg/kg; piroxicam, 10 mg/kg. The treatments were performed in the subplantar region of the left hind paw from Day 8 (D8) to Day 28 after adjuvant injection. The body weight, paw diameter, swelling degree of paw, and arthritic score were measured on D0, D7, D14, D21, and D28. All animals were sacrificed on D29. Subsequently, the synovial tissue of the ankle joint of the rats was stained with HE to generate pathological sections for observation of the pathological changes of synovial tissue from the ankle joint. The protein levels of MMP-1, TNF-α, IL-1ß, and IL-6 in the rats' serum were determined by ELISA. Western blotting was used to detect the protein expression of TLR4 and NF-κB in the rat ankle tissue. The mRNA expression of TLR4, NF-κB, IL-1ß, IL-6, and TNF-α in synovial tissue of the ankle joint was detected by RT-qPCR. RESULTS: The body weight of the rats in each group showed an increasing trend, and there was no significant difference in weight between the groups. CHD and piroxicam suppressed paw swelling and arthritic scores and decreased synovial hyperplasia, inflammatory cell infiltration, pannus formation, and bone destruction. Furthermore, the overproduction of MMP-1, TNF-α, IL-1ß, and IL-6 in serum was remarkably attenuated in the chymotrypsin- and piroxicam-treated rats. The protein levels of TLR4 and NF-κB in the synovial tissue of the chymotrypsin group and the piroxicam group were significantly lower than those in the model group. Likewise, the rats treated with chymotrypsin and piroxicam had a substantial decline in the mRNA expression of TLR4, NF-κB, TNF-α, IL-1ß, and IL-6 in synovial tissue. CONCLUSIONS: Chymotrypsin alleviates the joint damage of AIA rats, probably by reducing the expression of MMP-1, TNF-α, IL-1ß, and IL-6 through TLR4/NF-κB signaling pathway.
Asunto(s)
Artritis , Factor de Necrosis Tumoral alfa , Ratas , Animales , Metaloproteinasa 1 de la Matriz , FN-kappa B , Ratas Sprague-Dawley , Interleucina-6 , Quimotripsina , Hiperplasia , Peso Corporal , ARN Mensajero , Receptor Toll-Like 4RESUMEN
Val-Val-Tyr-Pro (VVYP) peptide is one of the main active components of Globin digest (GD). Our previous studies indicated that VVYP could protect against acetaminophen and carbon tetrachloride-induced acute liver failure in mice and decrease blood lipid level. However, the effects and underlying mechanisms of VVYP in the treatment of non-alcoholic steatohepatitis (NASH) have not been discovered. Our present study was designed to investigate the preventive effect of VVYP on NASH and its underlying specific mechanisms. We found that VVYP inhibited the cytotoxicity and lipid accumulation in L-02 cells that were exposed to a mixture of free fatty acid (FFA). VVYP effectively alleviated the liver injury induced by methionine-choline-deficient (MCD) diet, demonstrated by reducing the levels of serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST)/triglycerides (TG)/non-esterified fatty acids (NEFA) and improving liver histology. VVYP decreased expression levels of lipid synthesis-related genes and reduced levels of the proinflammation cytokines in the liver of mice fed by MCD diet. Moreover, VVYP inhibited the increased level of LPS and reversed the liver mitochondria dysfunction induced by MCD diet. Meanwhile, VVYP significantly increased the abundance of beneficial bacteria such as Eubacteriaceae, coriobacteriacease, Desulfovibrionaceae, S24-7 and Bacteroidia in high-fat diet (HFD)-fed mice, however, VVYP reduced the abundance of Lactobacillus. Moreover, VVYP conferred the protective effect of intestinal barrier via promoting the expression of the mucins and tight junction (TJ)-associated genes and inhibited subsequent liver inflammatory responses. These results indicated that the protective role of VVYP on NASH is mediated by modulating gut microbiota imbalance and related gut-liver axis activation. VVYP might be a promising drug candidate for NASH.
Asunto(s)
Retroalimentación Fisiológica/efectos de los fármacos , Microbioma Gastrointestinal/efectos de los fármacos , Tracto Gastrointestinal/metabolismo , Hígado/metabolismo , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Oligopéptidos/farmacología , Animales , Antiinflamatorios/farmacología , Biomarcadores , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Modelos Animales de Enfermedad , Masculino , Ratones , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/patología , Sustancias Protectoras/farmacologíaRESUMEN
Cyclosporin a (CsA) was characterized by a narrow therapeutic window and high interindividual pharmacokinetic variability. In this study, we aimed to identify the association of CYP3A4, ABCB1, ABCC2, ABCG2, NFKB1, POR, and PXR polymorphisms with CsA concentrations in patients with allogeneic haematopoietic cell transplantation (allo-HSCT) based on the route of administration.A total of 40 allo-HSCT recipients receiving CsA were genotyped for CYP3A4, ABCB1, ABCC2, ABCG2, NFKB1, POR, and PXR polymorphisms. The correlation between polymorphisms and CsA concentration was analysed.The CsA dose-adjusted trough concentration (Cssmin/D) of oral or intravenous administration was significantly different (p < 0.001). For CsA Cssmin/D of intravenous administration, CYP3A4 rs2246709 (p = 0.015), ABCC2 rs717620 (p = 0.024), ABCG2 rs2231142 (p = 0.042), PXR rs3732359 (p = 0.008), PXR rs3814058 (p = 0.028) and PXR rs6785049 (p < 0.001) had a significant effect on CsA Cssmin/D. For CsA Cssmin/D of oral administration, ABCC2 rs717620 (p = 0.009) and ABCG2 rs2231142 (p = 0.011) had a significant effect on CsA Cssmin/D.These results illustrated that the CYP3A4, ABCC2, ABCG2, and PXR genotypes were closely correlated with CsA Cssmin/D, suggesting these SNPs were suitable for determining the appropriate dose of CsA.
Asunto(s)
Ciclosporina , Trasplante de Células Madre Hematopoyéticas , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Citocromo P-450 CYP3A/genética , Genotipo , Humanos , Inmunosupresores , Proteína 2 Asociada a Resistencia a Múltiples Medicamentos , Subunidad p50 de NF-kappa B , Proteínas de Neoplasias/genética , Polimorfismo de Nucleótido Simple , Receptores de TrasplantesRESUMEN
Valproate (VPA)-induced hepatotoxicity is a fatal adverse drug reactionï¼and children is a high-risk population. Our study aimed to explore whether key genetic polymorphisms of antioxidant pathway is associated with VPA-mediated AST elevation. We included 194 newly diagnosed epilepsy children (aged from 1 to 16 years old) and treated with VPA. These patients were divided into two groups: one group for AST is normal and another group is AST elevated. AST elevation occurred in 25.8% of patient treated with VPA. During VPA monotherapy, the maximum AST in patients of GSTP1 rs1695 with AA genotype was significantly higher than carrying G alleles (36.50 ±14.89 vs 32.88±10.69, P=0.003). Patients with AG+GG genotype of GSTP1 rs1695 had a reduced risk of elevated AST (adjusted OR=0.37, 95% CI: 0.16-0.84, P=0.017). There is a significant difference in the maximum AST value of CAT rs769217 genotype (P=0.011, P= 0.045, respectively). Children with CAT rs769217 CT genotype or CT+TT genotype have a lower risk of elevated AST (adjusted OR=0.30, 95% CI: 0.13-0.68, P=0.004 and adjusted OR=0.41, 95% CI:0.20-0.82,P=0.012, respectively). Children who with GSTP1 rs1695 G allele have a reduced risk of AST abnormalities. We conducted CAT rs769217 CC genotype is a risk factor for AST elevation in children.
Asunto(s)
Aspartato Aminotransferasas/sangre , Catalasa/metabolismo , Epilepsia/tratamiento farmacológico , Gutatión-S-Transferasa pi/metabolismo , Ácido Valproico/efectos adversos , Ácido Valproico/uso terapéutico , Adolescente , Anticonvulsivantes/efectos adversos , Anticonvulsivantes/uso terapéutico , Aspartato Aminotransferasas/metabolismo , Catalasa/genética , Enfermedad Hepática Inducida por Sustancias y Drogas/sangre , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Niño , Preescolar , Femenino , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Predisposición Genética a la Enfermedad , Genotipo , Gutatión-S-Transferasa pi/genética , Humanos , Lactante , Masculino , Polimorfismo de Nucleótido SimpleRESUMEN
AIMS: Voriconazole (VCZ) displays highly variable pharmacokinetics affecting treatment efficacy and safety. We aimed to identify the factors affecting VCZ steady-state trough concentration (Cssmin) to provide evidence for optimizing VCZ treatment regimens. METHODS: A total of 510 Cssmin of 172 patients with hematopoietic stem cell transplantation and hematologic malignancies and their clinical characteristics and genotypes of FMO, POR, and PXR were included in this study. RESULTS: In univariate analysis, the standard loading dose of VCZ significantly increased the Cssmin of VCZ (P < 0.001). The Cssmin of VCZ was significantly correlated with patients' total bilirubin (TB) (P < 0.001) and procalcitonin (PCT) (P < 0.001). FMO3 rs2266780 (P = 0.025), POR rs10954732 (P = 0.015), PXR rs2461817 (P = 0.010), PXR rs7643645 (P = 0.003), PXR rs3732359 (P = 0.014), PXR rs3814057 (P = 0.005), and PXR rs6785049 (P = 0.013) have a significant effect on Cssmin of VCZ. Loading dose, TB, PCT level, and PXRrs3814057 polymorphism were independent influencing factors of VCZ Cssmin in the analysis of multivariate linear regression. And loading dose, PCT, and PXR rs3814057 had significant effects on the probability of the therapeutic window of VCZ. CONCLUSION: The high variability of VCZ Cssmin may be partially explained by loading dose, liver function, inflammation, and PXR polymorphisms. This study suggests the VCZ standard loading dose regimen significantly increased Cssmin and probability of the therapeutic window providing treatment benefits. Patients in the high PCT group may be more likely to exceed 5.5 µg/mL, thus suffering from VCZ toxicity.
Asunto(s)
Antifúngicos/administración & dosificación , Antifúngicos/sangre , Neoplasias Hematológicas , Trasplante de Células Madre Hematopoyéticas , Polimorfismo de Nucleótido Simple , Receptor X de Pregnano/genética , Polipéptido alfa Relacionado con Calcitonina/genética , Voriconazol/administración & dosificación , Voriconazol/sangre , Antifúngicos/uso terapéutico , Monitoreo de Drogas , Femenino , Genotipo , Neoplasias Hematológicas/sangre , Humanos , Masculino , Micosis/prevención & control , Farmacogenética , Estudios Retrospectivos , Voriconazol/uso terapéuticoRESUMEN
Lithium-sulfur (Li-S) batteries are attractive for next-generation energy storage systems due to their high theoretical capacity and energy density. However, the undesired shuttling of soluble lithium polysulfides (Li2Sn, 2 < n≤ 8) and the uncontrolled growth of lithium dendrites have hindered their practical applications. Herein, a self-assembled freestanding MoO3/carbon nanofiber (MoO3/CNF) composite membrane is effectively integrated into Li-S batteries as a functional interlayer. Improved cell performance is achieved due to the strong interfacial chemical and physical interactions between the interlayers with Li2Sn. The Li-S batteries exhibit a decent cyclic stability with a fading rate of 0.12% per cycle for 500 cycles at 1675 mA g-1, a high rate performance and a low self-discharge rate. In this rational design, the CNF network provides abundant electron pathways and physically prevents polysulfide diffusion. The polar MoO3 nanorods act as effective anchoring sites by the chemical interactions with Li2Sn. Meanwhile, the suppressed Li-dendrite growth on the Li-anode surface results in a stable Li stripping/plating.
RESUMEN
1. Voriconazole is known to display highly variable pharmacokinetics affecting treatment efficacy and safety. This study aimed to identify the factors causing the variation of voriconazole concentration in patients with allogeneic hematopoietic stem cell transplantation.2. The data of patients was collected, including clinical characteristics and voriconazole concentrations. A total of 5 single nucleotide polymorphisms of 3 candidate genes (CYP2C19, ABCC2, ABCG2) related to voriconazole metabolism were genotyped by MassArray method. The correlation between polymorphisms and voriconazole concentration was analyzed.3. A total of 244 voriconazole concentrations of 43 patients were included in this study. The voriconazole concentration was significantly correlated with patients' total bile acid (p = 0.001) and cyclosporin A (p < 0.001). The median concentration of the CYP2C19 normal metabolizers was remarkably lower than poor metabolizers (0.86 vs 2.27 µg/mL). The median concentration of ABCC2 rs2273697 GG genotype carriers was significantly higher than that of GA genotype carriers (p = 0.026).4. The variability of voriconazole concentration is partially explained by total bile acid, metabolic types of CYP2C19. The voriconazole concentration of CYP2C19 normal metabolizers is likely to be lower than 1.0 µg/mL and thus at risk of infection due to inadequate treatment.
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Antifúngicos/farmacología , Ciclosporina/farmacología , Citocromo P-450 CYP2C19/genética , Voriconazol/metabolismo , Adulto , Antifúngicos/metabolismo , Ciclosporina/metabolismo , Trasplante de Células Madre Hematopoyéticas , Humanos , Proteína 2 Asociada a Resistencia a Múltiples Medicamentos , Proteínas Asociadas a Resistencia a Múltiples Medicamentos , Variantes Farmacogenómicas , Polimorfismo de Nucleótido SimpleRESUMEN
Background Transarterial chemoembolization (TACE) is an effective downstaging procedure for hepatocellular carcinoma (HCC). However, knowledge of the effectiveness of radiofrequency ablation (RFA) after downstaging of HCC is currently lacking. Purpose To evaluate the clinical outcomes of RFA after downstaging of HCC by using TACE. Materials and Methods This retrospective study investigated a cohort of patients who underwent RFA with curative intent after downstaging with TACE to meet Milan criteria (one lesion up to 5 cm or no more than three lesions ≤3 cm without vascular invasion or extrahepatic metastasis) from January 2012 to July 2017. A control group of patients initially meeting the Milan criteria also underwent RFA as first-line treatment in the same period. Overall survival (OS), disease-free survival (DFS), and major complication rates were compared by using the log-rank test. To reduce potential bias, a propensity score analysis was also performed. Results There were 72 patients (median age, 56.5 years; range, 30-78 years; 67 men) in the downstaging group and 357 patients meeting the Milan criteria (median age, 58.0 years; range, 25-87 years; 313 men) included in this study. After propensity score matching, the 1-, 3-, and 5-year OS rates were 99%, 80%, and 66%, respectively, for the patients in the downstaging group and 94%, 84%, and 69%, respectively, for the patients in the Milan criteria group. The 1-, 3-, and 5-year DFS rate were 73%, 34%, and 24% for the downstaging group and 74%, 43%, and 37% for the Milan criteria group. There were no differences in the OS, DFS, or major complication rates between the two groups (P = .74, P = .39, P = .73, respectively). Conclusion The long-term patient survival and major complication rates of radiofrequency ablation following transarterial chemoembolization downstaging for hepatocellular carcinoma were similar to that of patients initially meeting the Milan criteria. © RSNA, 2019 See also the editorial by vanSonnenberg and Mueller in this issue.
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Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/cirugía , Quimioembolización Terapéutica , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/cirugía , Ablación por Radiofrecuencia , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Hepatocelular/diagnóstico por imagen , Carcinoma Hepatocelular/patología , Femenino , Humanos , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Puntaje de Propensión , Estudios Retrospectivos , Tasa de Supervivencia , Tomografía Computarizada por Rayos XRESUMEN
PURPOSE: There is a large inter-individual variation in the efficacy of valproic acid (VPA) against epilepsy. The genetic polymorphism influence of sodium channels on VPA response remains a matter of debate. The aim of the study was to explore the effect of SCN1A and SCN2A gene polymorphisms on VPA response in the treatment of epilepsy among Chinese patients. METHODS: A total of 354 epileptic patients with VPA treatment were genotyped for five single nucleotide polymorphisms (SNP), including SCN1A rs10188577 T>C, rs2298771 T>C, rs3812718 G>A, and SCN2A rs2304016 A>G, rs17183814 G>A. A binary logistic regression analysis was performed to evaluate the association of genotype with VPA antiepileptic effects, adjusting the influence of confounding factors. RESULTS: Genotype distributions of all selected SNPs were consistent with the Hardy-Weinberg equilibrium in epilepsy patients. SCN1A rs3812718 and SCN2A rs2304016 were found to be significantly associated with VPA response, both in monotherapy and in VPA-based polytherapy. Patients with the rs3812718 A allele were more frequently seen in the VPA-responsive group (P < 0.05), and the rs2304016 G allele was related to an increased risk of resistance to VPA therapy (P < 0.05). CONCLUSIONS: Our study revealed that SCN1A rs3812718 and SCN2A rs2304016 polymorphisms might be markers of VPA response in Chinese epilepsy patients. TRIAL REGISTRATION: ChiCTR-1800016477.
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Anticonvulsivantes/uso terapéutico , Epilepsia/tratamiento farmacológico , Epilepsia/genética , Canal de Sodio Activado por Voltaje NAV1.1/genética , Canal de Sodio Activado por Voltaje NAV1.2/genética , Polimorfismo de Nucleótido Simple , Ácido Valproico/uso terapéutico , Adolescente , Adulto , Pueblo Asiatico/genética , Niño , Preescolar , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Técnicas de Genotipaje , Humanos , Masculino , Adulto JovenRESUMEN
Incorporation of carbobenzoxy-glycylprolyl (Z-GP) to either α or ß position of the hydrazine moiety in procarbazine (Pcb) has been carried on in 5-steps process. The overall yield was 32.7%. The new entity Z-GP-Pcb was confirmed targeting to fibroblast activation protein-α (FAPα). Z-GP-Pcb may be hydrolyzed by either isolated rhFAPα or tumor homogenate. It was shown far less cytotoxicity against NCI-H460 cell line than Pcb. Z-GP-Pcb was displayed the potency to reduce spermatoxcity in H22-bearing mice. The mechanism may be ascribed to the blockade of dehydrogenation by α-glycerolphosphate dehydrogenase. This candidate was further proved equal antitumor activity to Pcb. However, the introduction of Z-GP scaffold decreased myelosuppression. All the evidences support that Z-GP-Pcb is a better antitumor agent than Pcb.
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Antineoplásicos/uso terapéutico , Células Sanguíneas/efectos de los fármacos , Dipéptidos/uso terapéutico , Procarbazina/uso terapéutico , Profármacos/uso terapéutico , Espermatozoides/efectos de los fármacos , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/toxicidad , Recuento de Células Sanguíneas , Plaquetas/efectos de los fármacos , Línea Celular Tumoral , Dipéptidos/síntesis química , Dipéptidos/farmacología , Dipéptidos/toxicidad , Diseño de Fármacos , Endopeptidasas , Eritrocitos/efectos de los fármacos , Gelatinasas/metabolismo , Humanos , Hidrólisis , Leucocitos/efectos de los fármacos , Masculino , Proteínas de la Membrana/metabolismo , Ratones , Tamaño de los Órganos , Procarbazina/síntesis química , Procarbazina/farmacología , Procarbazina/toxicidad , Profármacos/síntesis química , Profármacos/farmacología , Profármacos/toxicidad , Serina Endopeptidasas/metabolismo , Recuento de Espermatozoides , Testículo/efectos de los fármacosRESUMEN
Reported herein is the design, synthesis, and pharmacologic characterization of a class of TRPV1 antagonists constructed on a phenylquinoline platform that evolved from Cinchophen lead. This design composes three sections: a phenylquinoline headgroup attached to an aliphatic carboxamides, which is tethered at a phenyl tail group. Optimization of this design led to the identification of 37, comprising a pyrrolidine linker and a trifluoromethyl-phenyl tail. In the TRPV1 functional assay, using cells expressed hTRPV1, 37 antagonized capsaicin-induced Ca2+ influx, with an IC50 value of 10.2â¯nM. In the complete mice analgesic model, 37 exhibited better antinociceptive activity than the positive control BCTC in diverse pain models. All of these results suggested that 37 could be considered as a lead candidate for the further development of antinociceptive drugs.
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Analgésicos/química , Pirrolidinas/química , Canales Catiónicos TRPV/antagonistas & inhibidores , Analgésicos/farmacología , Analgésicos/uso terapéutico , Animales , Capsaicina/farmacología , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Humanos , Masculino , Ratones , Dolor/tratamiento farmacológico , Dolor/patología , Dolor/veterinaria , Pirrolidinas/farmacología , Pirrolidinas/uso terapéutico , Solubilidad , Relación Estructura-Actividad , Canales Catiónicos TRPV/metabolismoRESUMEN
The free fatty acid receptor 1 (FFA1) is a potential target due to its function in enhancement of glucose-stimulated insulin secretion. Takeda's compound 1 has robustly in vitro activity for FFA1, but it has been suffered from poor pharmacokinetic (PK) profiles because the phenylpropanoic acid is vulnerable to ß-oxidation. To identify orally available agonists, we tried to interdict the metabolically labile group by incorporating two deuterium atoms at the α-position of phenylpropionic acid. Interestingly, the differences of physicochemical properties between hydrogen and deuterium are quite small, but there are many differences in the structure-activity relationship between phenylpropionic acid series and present deuterated series. Further optimizations of deuterated series led to the discovery of compound 18, which exhibited a superior balance in terms of in vitro activity, lipophilicity, and solubility. Better still, compound 18 revealed a lower clearance (CLâ¯=â¯0.44â¯L/h/kg), higher maximum concentration (Cmaxâ¯=â¯7584.27⯵g/L), and longer half-life (T1/2â¯=â¯4.16â¯h), resulting in a >23-fold exposure than compound 1. In subsequent in vivo pharmacodynamic studies, compound 18 showed a robustly glucose-lowering effect in rodent without the risk of hypoglycemia.
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Deuterio/química , Diseño de Fármacos , Fenilpropionatos/farmacología , Receptores Acoplados a Proteínas G/agonistas , Animales , Hipoglucemiantes/síntesis química , Hipoglucemiantes/química , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Ratones Endogámicos ICR , Simulación del Acoplamiento Molecular , Estructura Molecular , Fenilpropionatos/síntesis química , Fenilpropionatos/química , Fenilpropionatos/farmacocinética , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Valproic acid is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder. Adverse effects of valproic acid are rare, but hepatotoxicity is severe in particular in those younger than 2 years old and polytherapy. During valproic acid treatment, it is difficult for prescribers to predict its individual response. Recent advances in the field of pharmacogenomics have indicated variants of candidate genes that affect valproic acid efficacy and safety. In this review, a large number of candidate genes that influence valproic acid pharmacokinetics and pharmacodynamics are discussed, including metabolic enzymes, drug transporters, neurotransmitters and drug targets. Furthermore, pharmacogenomics is an important tool not only in further understanding of interindividual variability but also to assess the therapeutic potential of such variability in drug individualization and therapeutic optimization.