RESUMEN

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) demonstrates unique characteristics in anticancer therapies as it selectively induces apoptosis in cancer cells. However, most cancer cells are TRAIL-resistant. Odanacatib (ODN), a cathepsin K inhibitor, is considered a novel sensitizer for cancer treatment. Combination therapy between TRAIL and sensitizers is considered a potent platform that improves TRAIL-based anticancer therapies beyond TRAIL monotherapy. Herein, we developed ODN loaded poly(lactic-co-glycolic) nanoparticles conjugated to GST-TRAIL (TRAIL-ODN-PLGA-NPs) to target and treat TRAIL-resistant cancer. TRAIL-ODN-PLGA-NPs demonstrated a significant increase in cellular uptake via death receptors (DR5 and DR4) on surface of cancer cells. TRAIL-ODN-PLGA-NPs exposure destroyed more TRAIL-resistant cells compared to a single treatment with free drugs. The released ODN decreased the Raptor protein, thereby increasing damage to mitochondria by elevating reactive oxygen species (ROS) generation. Additionally, Bim protein stabilization improved TRAIL-resistant cell sensitization to TRAIL-induced apoptosis. The in vivo biodistribution study revealed that TRAIL-ODN-PLGA-NPs demonstrated high location and retention in tumor sites via the intravenous route. Furthermore, TRAIL-ODN-PLGA-NPs significantly inhibited xenograft tumor models of TRAIL-resistant Caki-1 and TRAIL-sensitive MDA-MB-231 cells.The inhibition was associated with apoptosis activation, Raptor protein stabilizing Bim protein downregulation, Bax accumulation, and mitochondrial ROS generation elevation. Additionally, TRAIL-ODN-PLGA-NPs affected the tumor microenvironment by increasing tumor necrosis factor-α and reducing interleukin-6. In conclusion, we evealed that our formulation demonstrated synergistic effects against TRAIL compared with the combination of free drug in vitro and in vivo models. Therefore, TRAIL-ODN-PLGA-NPs may be a novel candidate for TRAIL-induced apoptosis in cancer treatment.

Asunto(s)

Antineoplásicos , Compuestos de Bifenilo , Resistencia a Antineoplásicos , Nanopartículas , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Ligando Inductor de Apoptosis Relacionado con TNF , Animales , Femenino , Humanos , Ratones , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Compuestos de Bifenilo/uso terapéutico , Compuestos de Bifenilo/farmacología , Compuestos de Bifenilo/química , Línea Celular Tumoral , Resistencia a Antineoplásicos/efectos de los fármacos , Ratones Endogámicos BALB C , Ratones Desnudos , Nanopartículas/química , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Especies Reactivas de Oxígeno/metabolismo , Distribución Tisular , Ligando Inductor de Apoptosis Relacionado con TNF/uso terapéutico , Ligando Inductor de Apoptosis Relacionado con TNF/farmacología

Asunto(s)

Aminobutiratos , Angioedema , Compuestos de Bifenilo , Combinación de Medicamentos , Tetrazoles , Valsartán , Humanos , Valsartán/efectos adversos , Aminobutiratos/efectos adversos , Angioedema/inducido químicamente , Compuestos de Bifenilo/efectos adversos , Tetrazoles/efectos adversos , Antagonistas de Receptores de Angiotensina/efectos adversos , Masculino , Insuficiencia Cardíaca/inducido químicamente , Insuficiencia Cardíaca/tratamiento farmacológico , Anciano , Femenino , Persona de Mediana Edad

RESUMEN

Background: Plant-derived drugs are often preferred over synthetic drugs because of their superior safety profiles. Phenolic compounds and flavonoids-major plant components-possess antioxidant properties. Limited research has been conducted on the bioactive compounds and biochemical properties of Bellevalia pseudolongipes (Asparagaceae), an important pharmacological species endemic to Turkey. Therefore, the chemical composition and antioxidant properties of B. pseudolongipes were investigated in this study. Methods: The chemical composition of B. pseudolongipes was analyzed using liquid chromatography-high-resolution mass spectrometry, and radical scavenging and antioxidant activities were evaluated using DPPH (2,2-diphenyl-1-picrylhydrazyl) and ABTS (2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid)) tests. Results: Thirty-eight compounds were identified, including trans-cinnamic acid, caffeic acid, vitexin, schaftoside, orientin, and narirutin. B. pseudolongipes showed high antioxidant activity in antioxidant activity tests. Conclusion: These findings provide novel insights into the potential utility of B. pseudolongipes in the pharmaceutical, food, and cosmetics industries, highlighted by its significant antioxidant capacity.

Asunto(s)

Antioxidantes , Espectrometría de Masas , Fitoquímicos , Extractos Vegetales , Antioxidantes/farmacología , Antioxidantes/química , Antioxidantes/análisis , Extractos Vegetales/química , Extractos Vegetales/farmacología , Fitoquímicos/química , Fitoquímicos/análisis , Fitoquímicos/farmacología , Espectrometría de Masas/métodos , Cromatografía Liquida/métodos , Flavonoides/análisis , Flavonoides/química , Turquía , Fenoles/análisis , Fenoles/química , Ácidos Sulfónicos/química , Ácidos Sulfónicos/antagonistas & inhibidores , Compuestos de Bifenilo/química , Benzotiazoles

RESUMEN

This study aimed to evaluate the association between sacubitril/valsartan and dementia-related adverse events (AEs) in geographical subpopulations using subgroup disproportionality analysis. Cases from the FDA adverse event reporting system involving patients aged 60 or older with sacubitril/valsartan or angiotensin receptor blockers (ARBs) were analyzed. The adjusted reporting odds ratios (RORs) for dementia-related AEs were calculated for each continent. A total of 61,518 AEs associated with sacubitril/valsartan or ARBs were identified. Among these, 1441 were dementia-related AEs. In Asia, Europe, and Africa, the reporting risk of dementia-related AEs associated with sacubitril/valsartan was lower compared to ARBs (adjusted ROR, 0.57 [95% CI 0.31-1.01]; adjusted ROR, 0.89 [95% CI 0.69-1.14]; adjusted ROR, 0.40 [95% CI 0.27-0.61], respectively). In Latin America and Oceania, the reporting risk of dementia-related AEs associated with sacubitril/valsartan was similar to that associated with ARBs (adjusted ROR, 1.04 [95% CI 0.75-1.44]; adjusted ROR, 1.02 [95% CI 0.31-3.37], respectively). On the contrary, in North America, the reporting risk associated with sacubitril/valsartan was higher compared to ARBs (adjusted ROR, 1.29 [95% CI 1.10-1.53]). Although the ROR value did not meet the criteria for signal detection, the significantly greater than 1 ROR observed in North America suggests that caution may be warranted regarding potential dementia-related adverse events associated with sacubitril/valsartan.

Asunto(s)

Aminobutiratos , Antagonistas de Receptores de Angiotensina , Compuestos de Bifenilo , Demencia , Combinación de Medicamentos , Valsartán , Humanos , Valsartán/efectos adversos , Aminobutiratos/efectos adversos , Compuestos de Bifenilo/efectos adversos , Demencia/epidemiología , Demencia/inducido químicamente , Masculino , Femenino , Anciano , Antagonistas de Receptores de Angiotensina/efectos adversos , Persona de Mediana Edad , Anciano de 80 o más Años , Tetrazoles/efectos adversos , Sistemas de Registro de Reacción Adversa a Medicamentos , Estados Unidos/epidemiología

RESUMEN

The risk of ulcerative colitis (UC) is increasing worldwide with limited success using classical drugs, which has underscored the development of novel agents. Recently, carrier-free molecular assembly has been proven to be an effective drug delivery system, but it has yet to be examined for UC drug development using phytochemicals. Based on traditional Chinese medicine compatibility and potential medicinal uses, a pair of natural compounds, berberine (BBR) and magnolol (MAG), were found to self-assemble into nanostructures in aqueous solutions. Spectral analysis revealed that the assembly mechanisms of BBR and MAG were mediated through charge interactions and π-π stacking. Pharmacokinetic studies and animal imaging showed that BBR-MAG self-assembly (BM) effectively promoted the oral bioavailability and biodistribution of BBR in the colon. BM exhibited superior effects in regulating inflammatory factors, maintaining colon barrier integrity, and regulating gut microbiota in a dextran sulfate sodium salt-induced colitis mouse model. Additionally, no apparent signs of toxicity were observed, suggesting that BM has a favorable safety profile. This study presents a new strategy for UC management and highlights the cooperative effects of combined phytochemicals.

Asunto(s)

Berberina , Compuestos de Bifenilo , Colitis Ulcerosa , Lignanos , Nanoestructuras , Animales , Colitis Ulcerosa/tratamiento farmacológico , Berberina/química , Berberina/farmacología , Berberina/uso terapéutico , Lignanos/química , Lignanos/farmacología , Lignanos/uso terapéutico , Ratones , Compuestos de Bifenilo/química , Nanoestructuras/química , Masculino , Sulfato de Dextran/química , Colon/efectos de los fármacos , Colon/patología , Modelos Animales de Enfermedad , Distribución Tisular , Ratones Endogámicos C57BL , Microbioma Gastrointestinal/efectos de los fármacos , Disponibilidad Biológica

RESUMEN

Dollar spot, a highly destructive turfgrasses disease worldwide, is caused by multiple species within the genus Clarireedia. Previous research indicated varying sensitivity to boscalid among Clarireedia populations not historically exposed to succinate dehydrogenase inhibitors (SDHIs). This study confirms that the differential sensitivity pattern is inherent among different Clarireedia spp., utilizing a combination of phylogenetic analyses, in vitro cross-resistance assays, and genetic transformation of target genes with different mutations. Furthermore, greenhouse inoculation experiments revealed that the differential boscalid sensitivity did not lead to pathogenicity issues or fitness penalties, thereby not resulting in control failure by boscalid. This research underscores the importance of continuous monitoring of fungicide sensitivity trends and highlights the complexity of chemical control of dollar spot due to the inherent variability in fungicide sensitivity among different Clarireedia spp.

Asunto(s)

Compuestos de Bifenilo , Fungicidas Industriales , Niacinamida , Enfermedades de las Plantas , Fungicidas Industriales/farmacología , Compuestos de Bifenilo/farmacología , Enfermedades de las Plantas/microbiología , Niacinamida/análogos & derivados , Niacinamida/farmacología , Poaceae/microbiología , Filogenia , Farmacorresistencia Fúngica/genética , Succinato Deshidrogenasa/genética , Succinato Deshidrogenasa/antagonistas & inhibidores , Basidiomycota/genética , Basidiomycota/efectos de los fármacos

RESUMEN

The destructive disease gray leaf spot, caused by Stemphylium solani, is prevalent in tomato plants in China. A variety of fungicides have been extensively used for controlling the disease, with a particular focus on succinate dehydrogenase inhibitors (SDHIs) and quinone outside inhibitors (QoIs). However, there was a lack of information regarding the resistance of S. solani to boscalid (SDHI) and pyraclostrobin (QoI) in China. In this study, the sensitivity of S. solani to boscalid and pyraclostrobin was monitored. The EC50 values for boscalid ranged from 0.02 to 3.0 µg∙mL-1, with an average value of 0.62 µg∙mL-1, while the EC50 values for pyraclostrobin ranged from 0.21 to 14.71 µg∙mL-1, with an average value of 6.03 µg∙mL-1. Based on these findings, the frequencies of observed resistance were as follows: 36.7% for boscalid and 50% for pyraclostrobin; while the resistance frequency to both boscalid and pyraclostrobin in S. solani was 19.4%. The mutation associated with boscalid resistance in S. solani within tomato fields was identified as SdhB-H277Y, while the mutation related to pyraclostrobin resistance was found in cytochrome b, specifically Cytb-G143A. The resistant mutants displayed diminished fitness in terms of mycelial growth, yet their pathogenicity exhibited no significant disparities. To delay the development of resistance, it is advisable to employ a rotation strategy using alternative fungicides with different modes of action or mix with fungicides with multi-site-contact activity for disease management.

Asunto(s)

Ascomicetos , Compuestos de Bifenilo , Farmacorresistencia Fúngica , Fungicidas Industriales , Niacinamida , Enfermedades de las Plantas , Solanum lycopersicum , Estrobilurinas , Estrobilurinas/farmacología , Solanum lycopersicum/microbiología , Fungicidas Industriales/farmacología , Enfermedades de las Plantas/microbiología , Niacinamida/farmacología , Niacinamida/análogos & derivados , Farmacorresistencia Fúngica/genética , China , Compuestos de Bifenilo/farmacología , Ascomicetos/efectos de los fármacos , Ascomicetos/patogenicidad

Asunto(s)

Combinación de Medicamentos , Humanos , Aminobutiratos/uso terapéutico , Aminobutiratos/efectos adversos , Inactivadores del Complemento/uso terapéutico , Inactivadores del Complemento/administración & dosificación , Inactivadores del Complemento/efectos adversos , Administración Oral , Valsartán , Compuestos de Bifenilo

RESUMEN

Importance: Thrombotic microangiopathy (TMA) on kidney biopsy is a pattern of endothelial injury commonly seen in malignant hypertension (mHTN), but treatment strategies are not well established. Objective: To evaluate the kidney outcomes of angiotensin receptor-neprilysin inhibitor (ARNI), specifically sacubitril/valsartan, vs angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) therapy for patients with mHTN-associated TMA. Design, Setting, and Participants: This single-center cohort study enrolled consecutive patients in China diagnosed with mHTN-associated TMA through kidney biopsy from January 2008 to June 2023. Follow-up was conducted until the conclusion of the study period. Data were analyzed in September 2023. Exposures: Treatment with sacubitril/valsartan or ACEI/ARBs during hospitalization and after discharge. Main Outcomes and Measures: The primary outcome was a composite of kidney recovery: a 50% decrease in serum creatinine level, decrease in serum creatinine levels to the reference range, or kidney survival free from dialysis for more than 1 month. The secondary and tertiary outcomes were a 15% increase in the estimated glomerular filtration rate (eGFR) relative to baseline and kidney survival free from dialysis, respectively. Propensity score matching (PSM) and Cox proportional hazards regression analysis were used to evaluate the association between sacubitril/valsartan and ACEI/ARB therapy with kidney recovery outcomes. Results: Among the 217 patients (mean [SD] age, 35.9 [8.8] years; 188 men [86.6%]) included in the study, 66 (30.4%) received sacubitril/valsartan and 151 (69.6%) received ACEI/ARBs at baseline. Sacubitril/valsartan treatment was associated with shorter time to the primary outcome compared with ACEI/ARB treatment (20 of 63 [31.7%] vs 38 of 117 [32.5%]; adjusted hazard ratio [aHR], 1.85; 95% CI, 1.05-3.23). Sacubitril/valsartan treatment was independently associated with shorter time to a 15% increase in eGFR (15 of 46 [32.6%] vs 46 of 83 [55.4%]; aHR, 2.13; 95% CI, 1.09-4.17) and kidney survival free from dialysis (11 of 23 [47.8%] vs 16 of 57 [28.1%]; aHR, 2.63; 95% CI, 1.15-5.88) compared with ACEI/ARB treatment. These differences remained significant in the PSM comparison. Conclusions and Relevance: In this cohort study, sacubitril/valsartan treatment was associated with a potential kidney function benefit in patients with mHTN-associated TMA compared with ACEI/ARB treatment. The findings suggested that sacubitril/valsartan could be a superior therapeutic approach for managing this serious condition in terms of kidney recovery.

Asunto(s)

Aminobutiratos , Antagonistas de Receptores de Angiotensina , Inhibidores de la Enzima Convertidora de Angiotensina , Compuestos de Bifenilo , Combinación de Medicamentos , Microangiopatías Trombóticas , Valsartán , Humanos , Masculino , Femenino , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Antagonistas de Receptores de Angiotensina/uso terapéutico , Microangiopatías Trombóticas/tratamiento farmacológico , Persona de Mediana Edad , Valsartán/uso terapéutico , Compuestos de Bifenilo/uso terapéutico , Aminobutiratos/uso terapéutico , Adulto , Hipertensión Maligna/tratamiento farmacológico , Riñón/efectos de los fármacos , Riñón/fisiopatología , Neprilisina/antagonistas & inhibidores , Estudios de Cohortes , China , Tetrazoles/uso terapéutico , Resultado del Tratamiento , Tasa de Filtración Glomerular/efectos de los fármacos

RESUMEN

INTRODUCTION: Heart failure (HF) is a complex syndrome that affects millions of people worldwide and leads to significant morbidity and mortality. Sacubitril/valsartan, a combination drug consisting of a neprilysin inhibitor and an angiotensin receptor blocker (ARB), has shown a greater improvement in the prognosis of HF than ACE inhibitors (ACEI) or ARB. Recent studies have found that ACEI/ARB or sacubitril/valsartan can increase flow-mediated dilation (FMD) and reduce pulse wave velocity (PWV), which are independent predictors of cardiovascular events and HF prognosis. The purpose of this study is to assess and compare the effect of sacubitril/valsartan and ACEI/ARB on FMD and PWV using meta-analysis and further provide a reference for the role of sacubitril/valsartan in the treatment of HF. METHODS AND ANALYSIS: Clinical randomised controlled trials investigating the effect of sacubitril/valsartan and/or ACEI/ARB on FMD and PWV in patients with HF will be searched in the relevant database, including PubMed, Web of Science, Embase, Cochrane Library and China's National Knowledge Infrastructure up to January 2024. The outcomes of interest are changes in endothelial function assessed by FMD and changes in arterial stiffness assessed by PWV. The risk of bias was evaluated using the revised Cochrane risk of bias tool for randomised trials (RoB2.0). Review Manager V.5.3 software is used for meta-analysis data synthesis, sensitivity analysis, meta-regression analysis, subgroup analysis and risk of bias assessment. The reporting bias of studies will be evaluated using the funnel plot, in which symmetry will be assessed by Begg's and Egger's tests. The evidence quality of the included studies will be evaluated by the Grading of Recommendations Assessment, Development, and Evaluation. ETHICS AND DISSEMINATION: This study only analyses research data from the published literature and therefore does not require ethical approval. We will submit the systematic review to a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42024538148.

Asunto(s)

Aminobutiratos , Antagonistas de Receptores de Angiotensina , Inhibidores de la Enzima Convertidora de Angiotensina , Compuestos de Bifenilo , Combinación de Medicamentos , Insuficiencia Cardíaca , Metaanálisis como Asunto , Revisiones Sistemáticas como Asunto , Valsartán , Rigidez Vascular , Humanos , Valsartán/uso terapéutico , Aminobutiratos/uso terapéutico , Aminobutiratos/farmacología , Rigidez Vascular/efectos de los fármacos , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/fisiopatología , Antagonistas de Receptores de Angiotensina/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/fisiopatología , Ensayos Clínicos Controlados Aleatorios como Asunto , Tetrazoles/uso terapéutico , Proyectos de Investigación , Análisis de la Onda del Pulso

RESUMEN

Overexpression of matrix metalloproteinase-2 (MMP-2) possesses a correlation with leukemia especially chronic myeloid leukemia (CML). However, no such MMP-2 inhibitor has come out in the market to date for treating leukemia. In this study, synthesis, biological evaluation, and molecular modeling studies of a set of biphenylsulfonamide derivatives as promising MMP-2 inhibitors were performed, focusing on their potential applications as antileukemic therapeutics. Compounds DH-18 and DH-19 exerted the most effective MMP-2 inhibition (IC50 of 139.45 nM and 115.16 nM, respectively) with potent antileukemic efficacy against the CML cell line K562 (IC50 of 0.338 µM and 0.398 µM, respectively). The lead molecules DH-18 and DH-19 reduced the MMP-2 expression by 21.3% and 17.8%, respectively with effective apoptotic induction (45.4% and 39.8%, respectively) in the K562 cell line. Moreover, both these compounds significantly arrested different phases of the cell cycle. Again, both these molecules depicted promising antiangiogenic efficacy in the ACHN cell line. Nevertheless, the molecular docking and molecular dynamics (MD) simulation studies revealed that DH-18 formed strong bidentate chelation with the catalytic Zn2+ ion through the hydroxamate zinc binding group (ZBG). Apart from that, the MD simulation study also disclosed stable binding interactions of DH-18 and MMP-2 along with crucial interactions with active site amino acid residues namely His120, Glu121, His124, His130, Pro140, and Tyr142. In a nutshell, this study highlighted the importance of biphenylsulfonamide-based novel and promising MMP-2 inhibitors to open up a new avenue for potential therapy against CML.

Asunto(s)

Antineoplásicos , Metaloproteinasa 2 de la Matriz , Inhibidores de la Metaloproteinasa de la Matriz , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Sulfonamidas , Humanos , Sulfonamidas/farmacología , Sulfonamidas/química , Sulfonamidas/síntesis química , Metaloproteinasa 2 de la Matriz/metabolismo , Células K562 , Inhibidores de la Metaloproteinasa de la Matriz/farmacología , Inhibidores de la Metaloproteinasa de la Matriz/química , Inhibidores de la Metaloproteinasa de la Matriz/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Compuestos de Bifenilo/química , Compuestos de Bifenilo/farmacología , Apoptosis/efectos de los fármacos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Proliferación Celular/efectos de los fármacos , Relación Estructura-Actividad

RESUMEN

A series of polymers with both high refractive index and high Abbe number have been successfully synthesized through the photoclick thiol-ene reaction between the monomers derived from biobased magnolol (or honokiol) and commercial mercaptans and thiophenols. The polymer films not only exhibit a high refractive index and a high Abbe number but also display a transmittance of up to 90% in a range of wavelengths from 550 to 2000 nm and nearly 0% in the UV region. Moreover, these polymers also display low haze values in the visible-light region as well as exhibit good thermostability. These data indicate that they have potential applications for the fabrication of optical lenses and anti-UV coatings. In particular, this series of polymers are readily used for industrialization due to its excellent optical properties but low expense, simplicity, and efficiency of synthesis.

Asunto(s)

Compuestos de Bifenilo , Lignanos , Lignanos/química , Compuestos de Bifenilo/química , Polímeros/química , Refractometría , Compuestos Alílicos , Fenoles

RESUMEN

Albuminuria is characterized by a disruption of the glomerular filtration barrier, which is composed of the fenestrated endothelium, the glomerular basement membrane, and the slit diaphragm. Nephrin is a major component of the slit diaphragm. Apart from hemodynamic effects, Ang II enhances albuminuria by ß-Arrestin2-mediated nephrin endocytosis. Blocking the AT1 receptor with candesartan and irbesartan reduces the Ang II-mediated nephrin-ß-Arrestin2 interaction. The inhibition of MAPK ERK 1/2 blocks Ang II-enhanced nephrin-ß-Arrestin2 binding. ERK 1/2 signaling, which follows AT1 receptor activation, is mediated by G-protein signaling, EGFR transactivation, and ß-Arrestin2 recruitment. A mutant AT1 receptor defective in EGFR transactivation and ß-Arrestin2 recruitment reduces the Ang II-mediated increase in nephrin ß-Arrestin2 binding. The mutation of ß-Arrestin2K11,K12, critical for AT1 receptor binding, completely abrogates the interaction with nephrin, independent of Ang II stimulation. ß-Arrestin2K11R,K12R does not influence nephrin cell surface expression. The data presented here deepen our molecular understanding of a blood-pressure-independent molecular mechanism of AT-1 receptor blockers (ARBs) in reducing albuminuria.

Asunto(s)

Angiotensina II , Endocitosis , Proteínas de la Membrana , Receptor de Angiotensina Tipo 1 , Endocitosis/efectos de los fármacos , Endocitosis/fisiología , Animales , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Angiotensina II/farmacología , Angiotensina II/metabolismo , Humanos , Receptor de Angiotensina Tipo 1/metabolismo , Receptor de Angiotensina Tipo 1/genética , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Ratones , Albuminuria/metabolismo , Podocitos/metabolismo , Podocitos/efectos de los fármacos , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/genética , Compuestos de Bifenilo/farmacología , Irbesartán/farmacología , Células HEK293 , Arrestina beta 2/metabolismo , Arrestina beta 2/genética , Bencimidazoles , Tetrazoles

RESUMEN

BACKGROUND: Osteoporosis, a systemic skeletal disease, seriously affects the quality of life in postmenopausal women. As one type of cathepsin K (CatK) inhibitor, odanacatib (ODN) is a fresh medication for osteoporosis. Considering the potential of ODN, we further examined the effect and safety of ODN for postmenopausal osteoporosis (PMOP) with a meta-analysis. METHODS: PubMed, EMBASE, Cochrane Library, and Web of Science were searched for eligible studies from inception to December 29th, 2023. After that, we conducted a comprehensive meta-analysis following PRISMA guidelines. Risk of bias was meticulously investigated with the Cochrane Collaboration's tool. Efficacy was assessed with bone mineral density (BMD) at different sites (lumbar spine, trochanter, radius, femoral neck) and biomarkers of bone turnover (P1NP, uNTx/Cr, s-CTx, BSAP). Safety was evaluated by analyzing total, serious, other, and skin adverse events (AEs). RESULTS: Four random clinical trials (RCTs) were involved in our research. All trials were rated as having high quality and met the eligibility criteria. In the current research, ODN was found to elevate BMD at lumbar spine, femoral neck, total hip, trochanter and forearm, while it decreased the levels of serum C-telopeptides of type I collagen (s-CTx) as well as urinary N-telopeptide/creatinine ratio (uNTx/Cr). No significant differences were observed in AEs between the ODN group and the control group. CONCLUSIONS: ODN is a promising alternative for the treatment of PMOP on account of its excellent efficacy and credible safety. Unclear links between ODN and cardiovascular AEs require further research to clarify.

Asunto(s)

Compuestos de Bifenilo , Densidad Ósea , Osteoporosis Posmenopáusica , Humanos , Femenino , Osteoporosis Posmenopáusica/tratamiento farmacológico , Densidad Ósea/efectos de los fármacos , Resultado del Tratamiento , Compuestos de Bifenilo/uso terapéutico , Conservadores de la Densidad Ósea/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Biomarcadores/sangre , Catepsina K/antagonistas & inhibidores , Persona de Mediana Edad , Anciano , Remodelación Ósea/efectos de los fármacos

RESUMEN

The natural aromatic polymer lignin and its lignin-like oligomeric fragments have attracted attention for their antioxidant capacity and free radical scavenging activities. In this study, a 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay was employed to assess the antioxidant capacity of fractionated and partially depolymerized organosolv lignin by electron paramagnetic resonance (EPR) and UV-Vis spectroscopy. The results show significant antioxidant activity for both the lignin and oligomeric fragments, with the EPR measurements demonstrating their efficiency in quenching the free radicals. The EPR data were analyzed to derive the kinetic rate constants. The radical scavenging activity (RSA) of lignins was then determined by UV-Vis spectroscopy and the results were compared with the EPR method. This two-method approach improves the reliability and understanding of the antioxidant potential of lignin and its derivatives and provides valuable insights for their potential applications in various industries, including pharmaceuticals, food preservation, and cosmetics.

Asunto(s)

Antioxidantes , Compuestos de Bifenilo , Lignina , Picratos , Espectroscopía de Resonancia por Spin del Electrón/métodos , Lignina/química , Compuestos de Bifenilo/química , Picratos/química , Antioxidantes/química , Antioxidantes/farmacología , Espectrofotometría Ultravioleta , Depuradores de Radicales Libres/química , Depuradores de Radicales Libres/farmacología

RESUMEN

In modern times, nanoparticles have materialized as indispensable things in contemporary medicine, with a variety of uses in clinical, drug and gene conveyance. In the present study, TiO2 nanoparticles (NPs) prepared from the leaf extracts of Mollugooppositifolia and Trianthema portulacastrum were compared with the chemical TiO2-NPs for antibacterial and antioxidant activities and environment-friendly nature through various tools like the UV-visible, X-ray diffraction with the aid of other analytical techniques like HR-TEM, Fourier transform infrared (FT-IR) and photoluminescence spectroscopic techniques. The morphology of green TiO2-NPs is found to be spherical, which is supported by HR-TEM images. FT-IR analyses and X-ray diffraction data ensure that the polycrystalline characters of TiO2-NPs alike to the presence of metal oxide. TiO2-NPs showed a possible photocatalytic activity for the ruin of acid black 1 dye after disclosure to sunlight. The chemical and green methods of TiO2-NPs have acid black 1 dye decomposition rates of 86.66% and 94.33%, respectively. The synthesized TiO2-NPs are also assessed for antimicrobial and antioxidant activities. Green TiO2-NPs exhibit antibacterial activity against Pseudomonas aeruginosa (17 + 0.56 mm) and Staphylococcus aureus (16 + 0.24 mm) at concentrations as low as 100 µL. The green TiO2-NPs showed high inhibition of DPPH I radical (50 µg/m) at 95.17 ± 21. Therefore, TiO2-NPs represent eco-friendly properties that aid in the degradation of dyes due to their antioxidant activity.

Asunto(s)

Antibacterianos , Antioxidantes , Titanio , Antioxidantes/química , Antioxidantes/farmacología , Antioxidantes/síntesis química , Titanio/química , Titanio/farmacología , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis química , Nanopartículas/química , Pruebas de Sensibilidad Microbiana , Extractos Vegetales/química , Extractos Vegetales/farmacología , Colorantes/química , Colorantes/farmacología , Luminiscencia , Staphylococcus aureus/efectos de los fármacos , Tamaño de la Partícula , Hojas de la Planta/química , Compuestos de Bifenilo/antagonistas & inhibidores , Compuestos de Bifenilo/química

RESUMEN

Four new polyketides, namely furantides A-B (1-2), talamin E (3) and arugosinacid A (4), and two known polyketides were obtained from the mangrove-derived fungus Penicillium sp. HDN15-312 using the One Strain Many Compounds (OSMAC) strategy. Their chemical structures, including configurations, were elucidated by detailed analysis of extensive NMR spectra, HRESIMS and ECD. The DPPH radicals scavenging activity of 3, with an IC50 value of 6.79 µM, was better than vitamin C.

Asunto(s)

Penicillium , Policétidos , Penicillium/química , Policétidos/farmacología , Policétidos/química , Policétidos/aislamiento & purificación , Depuradores de Radicales Libres/farmacología , Depuradores de Radicales Libres/química , Depuradores de Radicales Libres/aislamiento & purificación , Espectroscopía de Resonancia Magnética , Estructura Molecular , Picratos , Rhizophoraceae/microbiología , Compuestos de Bifenilo

RESUMEN

Chronic Chagas cardiomyopathy (CCC) has unique pathogenic and clinical features with worse prognosis than other causes of heart failure (HF), despite the fact that patients with CCC are often younger and have fewer comorbidities. Patients with CCC were not adequately represented in any of the landmark HF studies that support current treatment guidelines. PARACHUTE-HF (Prevention And Reduction of Adverse outcomes in Chagasic Heart failUre Trial Evaluation) is an active-controlled, randomized, phase IV trial designed to evaluate the effect of sacubitril/valsartan 200 mg twice daily vs enalapril 10 mg twice daily added to standard of care treatment for HF. The study aims to enroll approximately 900 patients with CCC and reduced ejection fraction at around 100 sites in Latin America. The primary outcome is a hierarchical composite of time from randomization to cardiovascular death, first HF hospitalization, or relative change from baseline to week 12 in NT-proBNP levels. PARACHUTE-HF will provide new data on the treatment of this high-risk population. (Efficacy and Safety of Sacubitril/Valsartan Compared With Enalapril on Morbidity, Mortality, and NT-proBNP Change in Patients With CCC [PARACHUTE-HF]; NCT04023227).

Asunto(s)

Aminobutiratos , Antagonistas de Receptores de Angiotensina , Compuestos de Bifenilo , Cardiomiopatía Chagásica , Combinación de Medicamentos , Enalapril , Insuficiencia Cardíaca , Tetrazoles , Valsartán , Humanos , Compuestos de Bifenilo/uso terapéutico , Aminobutiratos/uso terapéutico , Enalapril/uso terapéutico , Antagonistas de Receptores de Angiotensina/uso terapéutico , Cardiomiopatía Chagásica/tratamiento farmacológico , Insuficiencia Cardíaca/tratamiento farmacológico , Tetrazoles/uso terapéutico , Volumen Sistólico/fisiología , Fragmentos de Péptidos/sangre , Enfermedad Crónica , Péptido Natriurético Encefálico/sangre , Masculino , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Femenino , Resultado del Tratamiento

RESUMEN

For the approval of a drug, the stability data must be submitted to regulatory authorities. Such analyses are often time-consuming and cost-intensive. Forced degradation studies are mainly carried out under harsh conditions in the dissolved state, often leading to extraneous degradation profiles for a solid drug. Oxidative mechanochemical degradation offers the possibility of generating realistic degradation profiles. In this study, a sustainable mechanochemical procedure is presented for the degradation of five active pharmaceutical ingredients (APIs) from the sartan family: losartan potassium, irbesartan, valsartan, olmesartan medoxomil, and telmisartan. High-resolution mass spectrometry enabled the detection of impurities already present in untreated APIs and allowed the elucidation of degradation products. Significant degradation profiles could already be obtained after 15-60 min of ball milling time. Many of the identified degradation products are described in the literature and pharmacopoeias, emphasizing the significance of our results and the applicability of this approach to predict degradation profiles for drugs in the solid state.

Asunto(s)

Bencimidazoles , Compuestos de Bifenilo , Losartán , Telmisartán , Tetrazoles , Valsartán , Bencimidazoles/química , Bencimidazoles/análisis , Tetrazoles/química , Telmisartán/química , Valsartán/química , Losartán/química , Losartán/análisis , Compuestos de Bifenilo/química , Irbesartán/química , Irbesartán/análisis , Imidazoles/química , Benzoatos/química , Valina/química , Valina/análisis , Solventes/química , Estabilidad de Medicamentos

RESUMEN

Quercetin, recognized for its antioxidant, anti-inflammatory, and antibacterial properties, faces limited biomedical application due to its low solubility. Cotton, a preferred wound dressing material over synthetic ones, lacks inherent antibacterial and wound-healing attributes and can benefit from quercetin features. This study explores the potential of overcoming these challenges through the inclusion complexation of quercetin with cyclodextrins (CDs) and the development of a nanofibrous coating on a cotton nonwoven textile. Hydroxypropyl-beta-cyclodextrin (HP-ß-CD) and hydroxypropyl-gamma-cyclodextrin (HP-γ-CD) formed inclusion complexes of quercetin, with chitosan added to enhance antibacterial properties. Phase solubility results showed that inclusion complexation can enhance quercetin solubility up to 20 times, with HP-γ-CD forming a more stable inclusion complexation compared with HP-ß-CD. Electrospinning of the nanofibers from HP-ß-CD/Quercetin and HP-γ-CD/Quercetin aqueous solutions without the use of a polymeric matrix yielded a uniform, smooth fiber morphology. The structural and thermal analyses of the HP-ß-CD/Quercetin and HP-γ-CD/Quercetin nanofibers confirmed the presence of inclusion complexes between quercetin and each of the CDs (HP-ß-CD and HP-γ-CD). Moreover, HP-ß-CD/Quercetin and HP-γ-CD/Quercetin nanofibers showed a near-complete loading efficiency of quercetin and followed a fast-releasing profile of quercetin. Both HP-ß-CD/Quercetin and HP-γ-CD/Quercetin nanofibers showed significantly higher antioxidant activity compared to pristine quercetin. The HP-ß-CD/Quercetin and HP-γ-CD/Quercetin nanofibers also showed antibacterial activity, and with the addition of chitosan in the HP-γ-CD/Quercetin system, the Chitosan/HP-γ-CD/Quercetin nanofibers completely eliminated the investigated bacteria species. The nanofibers were nontoxic and well-tolerated by cells, and exploiting the quercetin and chitosan anti-inflammatory activities resulted in the downregulation of IL-6 and NO secretion in both immune as well as regenerative cells. Overall, CD inclusion complexation markedly enhances quercetin solubility, resulting in a biofunctional antioxidant, antibacterial, and anti-inflammatory wound dressing through a nanofibrous coating on cotton textiles.

Asunto(s)

Antibacterianos , Antiinflamatorios , Antioxidantes , Vendajes , Quitosano , Ciclodextrinas , Ensayo de Materiales , Nanofibras , Quercetina , Quercetina/farmacología , Quercetina/química , Antioxidantes/farmacología , Antioxidantes/química , Nanofibras/química , Quitosano/química , Quitosano/farmacología , Antibacterianos/farmacología , Antibacterianos/química , Antiinflamatorios/farmacología , Antiinflamatorios/química , Ciclodextrinas/química , Ciclodextrinas/farmacología , Tamaño de la Partícula , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Pruebas de Sensibilidad Microbiana , Fibra de Algodón , Cicatrización de Heridas/efectos de los fármacos , Humanos , Picratos/antagonistas & inhibidores , Supervivencia Celular/efectos de los fármacos , Compuestos de Bifenilo