Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 7.523
Filtrar
1.
Nefrología (Madrid) ; 44(2): 139-149, Mar-Abr. 2024. tab, graf
Artigo em Inglês | IBECS | ID: ibc-231563

RESUMO

Losartan is widely used in the treatment of chronic kidney disease (CKD) and has achieved good clinical efficacy, but its exact mechanism is not clear. We performed high-throughput sequencing (HTS) technology to screen the potential target of losartan in treating CKD. According to the HTS results, we found that the tumor necrosis factor (TNF) signal pathway was enriched. Therefore, we conducted in vivo and in vitro experiments to verify it. We found that TNF signal pathway was activated in both unilateral ureteral obstruction (UUO) rats and human proximal renal tubular epithelial cells (HK-2) treated with transforming growth factor-β1 (TGF-β1), while losartan can significantly inhibit TNF signal pathway as well as the expression of fibrosis related genes (such as COL-1, α-SMA and Vimentin). These data suggest that losartan may ameliorate renal fibrosis through modulating the TNF pathway.(AU)


El Losartán es ampliamente utilizado en el tratamiento de la enfermedad renal crónica (CKD) y ha logrado buenos resultados clínicos, pero su mecanismo exacto aún no está claro. Utilizamos la técnica de secuenciación de alto rendimiento (HTS) para detectar posibles dianas de losartán para el tratamiento de la CKD. Según los resultados de HTS, encontramos un enriquecimiento de la vía de señalización del factor de necrosis tumoral (TNF). Así, realizamos experimentos in vivo e in vitro para verificar esto. Encontramos que, tanto en ratas con obstrucción ureteral unilateral (uuo) como en células epiteliales tubulares renales proximal humanas (HK-2) tratadas con factor de crecimiento transformador β1 (TGF-β1), se activó la vía de señalización del TNF. El losartán inhibe significativamente la expresión de las vías de señalización del TNF y genes relacionados con la fibrosis, como COL-1, α-SMA y vicentin. Estos datos sugieren que el losartán puede mejorar la fibrosis renal regulando la vía del TNF.(AU)


Assuntos
Humanos , Masculino , Feminino , Fatores de Necrose Tumoral , Losartan/administração & dosagem , Insuficiência Renal Crônica/tratamento farmacológico , Fibrose/tratamento farmacológico , Sequenciamento de Nucleotídeos em Larga Escala , Nefrologia , Nefropatias
2.
Eur Rev Med Pharmacol Sci ; 28(5): 1821-1836, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38497865

RESUMO

OBJECTIVE: Sepsis-associated liver injury is responsible for the high morbidity and mortality rates seen with septic shock. Activation of the renin-angiotensin-aldosterone system (RAAS) is an essential counteractive mechanism during the hypotensive phase of sepsis; however, excessive activation is associated with exaggerated pro-oxidant and inflammatory response, which aggravates organ damage. This study aimed to evaluate the effect of RAAS inhibition on sepsis-induced liver damage. MATERIALS AND METHODS: The cecal ligation and puncture (CLP) model was employed as a model of sepsis. Rats were divided into five groups: sham-operated, vehicle-treated septic rats, septic rats treated with ramipril in a dose of 10 mg/kg, septic rats treated with losartan in a dose of 20 mg/kg, and finally septic rats treated with spironolactone in a dose of 25 mg/kg. Rats received the treatment one hour after induction. Twenty-four hours later, rats were euthanized, and serum samples and liver tissue were collected to evaluate liver function and hepatic oxidative, anti-oxidative, inflammatory, and apoptotic markers. The microscopic integrity of the hepatic tissue was also assessed. RESULTS: The results of our study showed that all the treatments used ameliorated sepsis-induced liver injury. This was reflected by improved liver function parameters and histopathological appearance of liver tissue. Treatment with ramipril, losartan, or spironolactone reduced tissue malondialdehyde (MDA), nitric oxide, activated caspase-3, and TNF-α. Moreover, these drugs increased hepatic reduced-glutathione (GSH) levels, superoxide dismutase (SOD) activity, and proliferating cell nuclear antigen (PCNA) expression. CONCLUSIONS: Administration of ramipril, losartan, or spironolactone after CLP produced a hepatoprotective effect in rats, possibly by reducing oxidative stress, inflammation, and apoptosis.


Assuntos
Losartan , Sepse , Animais , Ratos , Losartan/farmacologia , Losartan/uso terapêutico , Ramipril/farmacologia , Ramipril/uso terapêutico , Espironolactona/farmacologia , Espironolactona/uso terapêutico , Punções , Sepse/complicações , Sepse/tratamento farmacológico , Fígado
3.
Water Res ; 253: 121299, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38387265

RESUMO

As the key stage for purifying wastewater, elimination of emerging contaminants (ECs) is found to be fairly low in wastewater treatment plants (WWTPs). However, less knowledge is obtained regarding the transformation pathways between various chemical structures of ECs under different treatment processes. This study unveiled the transformation pathways of ECs with different structures in 15 WWTPs distributed across China by simplified network analysis (SNA) we proposed. After treatment, the molecular weight of the whole component of wastewater decreased and the hydrophilicity increased. There are significant differences in the structure of eliminated, consistent and formed pollutants. Amino acids, peptides, and analogues (AAPAs) were detected most frequently and most removable. Benzenoids were refractory. Triazoles were often produced. The high-frequency reactions in different WWTPs were similar, (de)methylation and dehydration occurred most frequently. Different biological treatment processes performed similarly, while some advanced treatment processes differed, such as a significant increase of -13.976 (2HO reaction) paired mass distances (PMDs) in the chlorine alone process. Further, the common structural transformation was uncovered. 4 anti-hypertensive drugs, including irbesartan, valsartan, olmesartan, and losartan, were identified, along with 22 transformation products (TPs) of them. OH2 and H2O PMDs occurred most frequently and in 80.81 % of the parent-transformation product pairs, the intensity of the product was higher than parent in effluents, whose risk should be considered in future assessment activity. Together our results provide a macrography perspective on the transformation processes of ECs in WWTPs. In the future, selectively adopting wastewater treatment technology according to structures is conductive for eliminating recalcitrant ECs in WWTPs.


Assuntos
Poluentes Químicos da Água , Purificação da Água , Águas Residuárias , Poluentes Químicos da Água/química , Irbesartana/análise , Losartan/análise
4.
Clin Rheumatol ; 43(3): 1183-1188, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38305936

RESUMO

OBJECTIVES: The research aimed to study the following questions: (1) five well-known gout-related medications were selected to test the validity of the prescription symmetry sequence analysis in Taiwan; (2) four exploratory medications were selected to test their relation to gout flares. METHODS: We utilized the 2003-2017 dataset of the Taiwan National Health Insurance Program containing all claims data with 2 million beneficiaries as a data source. In order to explore the temporal association, we designed a scenario of medication-induced gout flares. Nine medications were selected as the index agent, including aspirin (low-dose), thiazide diuretics, loop diuretics, ethambutol, pyrazinamide, metformin, pioglitazone, fenofibrate, and losartan. The gout flare was defined as subjects with use of the marker agent for treatment of gout flares. The observation-window period between initiation of the index agent and initiation of the marker agent was 1 year. Subjects who used an index agent and a marker agent on the same day were excluded. The prescription symmetry sequence analysis was carried out to compare the observed number of persons who took an index agent prior to starting a marker agent with the observed number of persons who took a marker agent before starting an index agent. The adjusted sequence ratio (adjusted SR) with 95% confidence interval was applied to estimate the relation between an index agent and the marker agent. RESULTS: Among five medications including aspirin (low-dose), thiazide diuretics, loop diuretics, ethambutol, and pyrazinamide, the adjusted sequence ratio ranged from 1.15 to 3.35 and all reached statistical significance. Fenofibrate use and losartan use were associated with a lower probability of gout flares, with reaching statistical significance (adjusted SR = 0.60 for fenofibrate and adjusted SR = 0.92 for losartan). Metformin use was associated with a greater probability of gout flares, with reaching statistical significance (adjusted SR = 1.14). Pioglitazone use did not reach statistical significance. CONCLUSION: Based on the confirmatory analysis including five well-known gout-related medications, this study supports that the prescription symmetry sequence analysis can be used to detect an adverse drug event associated with one potential offending agent. The exposure to fenofibrate or losartan might be a protective factor against gout flares. Metformin use could be associated with a greater probability of gout flares, but this finding should be validated by other studies. KEY POINTS: • What is already known about this subject? 1. The prescription symmetry sequence analysis is a useful method for detecting an adverse drug reaction associated with one potential offending drug. 2. Numerous medications are found to induce gout flares. • What does this study add? 1. The prescription symmetry sequence analysis supports the evidence that aspirin (low-dose), thiazide diuretics, loop diuretics, ethambutol and pyrazinamide are associated with a greater probability of gout flares. 2. The exposure to fenofibrate or losartan might be a protective factor against gout flares. 3. Metformin use could be associated with a greater probability of gout flares. • How might this impact on clinical practice or future developments? 1. Clinicians should always consider the possibility of medication-induced gout flares. If gout flares develop, discontinuation of risky medications is the first step. Then prescribing cascades can be eliminated.


Assuntos
Fenofibrato , Gota , Metformina , Humanos , Gota/diagnóstico , Inibidores de Simportadores de Cloreto de Sódio/efeitos adversos , Inibidores de Simportadores de Cloreto de Sódio e Potássio/efeitos adversos , Pirazinamida/efeitos adversos , Losartan/efeitos adversos , Pioglitazona/efeitos adversos , Fenofibrato/efeitos adversos , Etambutol/efeitos adversos , Exacerbação dos Sintomas , Prescrições , Aspirina/uso terapêutico , Metformina/efeitos adversos
5.
Sheng Wu Gong Cheng Xue Bao ; 40(2): 562-572, 2024 Feb 25.
Artigo em Chinês | MEDLINE | ID: mdl-38369841

RESUMO

The combination of photodynamic therapy and drug delivery microneedle (MN) provides a safe and effective way to treat tumors. In this paper, we designed a controlled and sustained-release drug-loaded microneedle patch (LED-losartan-HEMA/CS-MN, LLH-CSMN) based on chitosan loaded with high-energy photons, investigated its preparation process, and characterized the morphology and size of the microneedle array with losartan as the model drug. The mechanical properties of LLH-CSMN, skin puncture properties, slow release properties and the photothermal properties of high energy photons under long-term operation were investigated. The experimental results showed that the chitosan-based microneedle patch loaded with high-energy photons can effectively open channels on the skin surface for drug delivery and photodynamic therapy. At the same time, the in vitro percutaneous diffusion experiment showed that the microneedles prepared with losartan as the model drug released about 30% of the drug within 1 h, about 60% of the drug in total within 1 d, followed by slow release, and finally released 93% of the drug after 6 d. LLH-CSMN has controllable slow-release characteristics and good long-term photoassisted therapy effect. It provides a new safe and effective way for tumor treatment.


Assuntos
Quitosana , Losartan , Agulhas , Sistemas de Liberação de Medicamentos/métodos , Preparações Farmacêuticas
6.
J Orthop Surg Res ; 19(1): 147, 2024 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-38373964

RESUMO

PURPOSE: Patients are typically diagnosed with both hypertension and fibrosarcoma. Medical oncologists must prescribe suitable anti-hypertensive medications while considering anti-tumor drugs. Recently, immunotherapy has become prominent in cancer treatment. Nonetheless, it is unknown what role anti-hypertensive medications will play in immunotherapy. METHODS: We examined the effects of six first-line anti-hypertensive medications on programmed cell death protein 1 antibody (PD1ab) in tumor treatment using a mouse model of subcutaneous fibrosarcoma. The drugs examined were verapamil, losartan, furosemide, spironolactone, captopril, and hydrochlorothiazide (HCTZ). The infiltration of CD8+ T cells was examined by immunohistochemistry. Additionally, several in vitro and in vivo assays were used to study the effects of HCTZ on human fibrosarcoma cancer cells to explore its mechanism. RESULTS: Verapamil suppressed tumor growth and showed an improved effect on the tumor inhibition of PD1ab. Captopril did not affect tumor growth but brought an unexpected benefit to PD1ab treatment. In contrast, spironolactone and furosemide showed no effect on tumor growth but had an offset effect on the PD1ab therapy. Consequently, the survival time of mice was also significantly reduced. Notably, losartan and HCTZ, especially HCTZ, promoted tumor growth and weakened the effect of PD1ab treatment. Consistent results were observed in vivo and in vitro using the human fibrosarcoma cell line HT1080. We determined that the Solute Carrier Family 12 Member 3 (SLC12A3), a known target of HCTZ, may be the principal factor underlying its effect-enhancing properties through mechanism studies employing The Cancer Genome Atlas (TCGA) data and in vivo and in vitro assays. CONCLUSION: Verapamil and captopril potentiated the anti-tumor effect of PD1ab, whereas spironolactone and furosemide weakened the effect of PD1ab on tumor inhibition. Alarmingly, losartan and HCTZ promoted tumor growth and impaired the effect of PD1ab. Furthermore, we preliminarily found that HCTZ may promote tumor progression through SLC12A3. Based on this study, futher mechanism researches and clinical trials should be conducted in the future.


Assuntos
Fibrossarcoma , Hipertensão , Humanos , Anti-Hipertensivos/uso terapêutico , Losartan/farmacologia , Losartan/uso terapêutico , Captopril/farmacologia , Captopril/uso terapêutico , Espironolactona/uso terapêutico , Furosemida/uso terapêutico , Linfócitos T CD8-Positivos , Hipertensão/tratamento farmacológico , Hidroclorotiazida/uso terapêutico , Quimioterapia Combinada , Verapamil/farmacologia , Verapamil/uso terapêutico , Fibrossarcoma/tratamento farmacológico , Membro 3 da Família 12 de Carreador de Soluto
7.
Nefrología (Madrid) ; 44(1): 50-60, ene.- feb. 2024. ilus
Artigo em Inglês | IBECS | ID: ibc-229421

RESUMO

Background Microalbuminuria is a common clinical symptom that manifests in the early stages of diabetic kidney disease (DKD) and is also the main feature of glomerular endothelial cells (GECs) injury. There is increasing evidence that the transcytosis of albumin across GECs is closely related to the formation of albuminuria. Our previous studies have shown that angiopoietin 2 (ANGPT2) can inhibit albumin transcytosis across renal tubular epithelial cells by activating caveolin 1 (CAV1) phosphorylation during high glucose (HG) exposure. The role of ANGPT2 in albumin transcytosis across GECs remains unclear. Losartan significantly reduces albuminuria, but the mechanism has not been clarified. Methods We established an in vitro albumin transcytosis model to investigate the change in albumin transcytosis across human renal glomerular endothelial cells (hrGECs) under normal glucose (NG), high glucose (HG) and losartan intervention. We knocked down ANGPT2 and CAV1 to evaluate their roles in albumin transcytosis across hrGECs and verified the relationship between them. In vivo, DKD mouse models were established and treated with different doses of losartan. Immunohistochemistry and Western blot were used to detect the expression of ANGPT2 and CAV1. Results In vitro, the transcytosis of albumin across hrGECs was significantly increased under high glucose stimulation, and losartan inhibited this process. The expression of ANGPT2 and CAV1 were both increased in hrGECs under HG conditions and losartan intervention reduced the expression of them. Moreover, ANGPT2 downregulation reduced albumin transcytosis in hrGECs by regulating CAV1 expression. In vivo, the expression of ANGPT2 and CAV1 in the glomerulus was both increased significantly in DKD mice. Compared with DKD mice, losartan treatment reduced albuminuria and decreased the expression of ANGPT2 and CAV1 in a dose-dependent manner (AU)


Antecedentes La microalbuminuria es un síntoma clínico común que se manifiesta en las fases tempranas de la enfermedad renal diabética (ERD), y también es característica del daño de las células endoteliales glomerulares (GEC). Existe evidencia creciente en cuanto a que la transcitosis de la albúmina a través de las GEC está estrechamente relacionada con la formación de albuminuria. Nuestros estudios previos reflejaron que angiopoyetina 2 (ANGPT2) puede inhibir la transcitosis de la albúmina a través de las células epiteliales tubulares renales activando la fosforilación de caveolina 1 (CAV1) durante la exposición a hiperglucemia (HG). El rol de ANGPT2 en la transcitosis de la albúmina a través de las GEC resulta incierto. Losartan reduce considerablemente la albuminuria, aunque no se ha esclarecido el mecanismo. Métodos Establecimos un modelo in vitro de transcitosis de la albúmina para investigar el cambio de dicho mecanismo a través de las células endoteliales glomerulares renales humanas (hrGEC) en condiciones de glucosa normal (GN), hiperglucemia (HG) e intervención de losartan. Realizamos breakdown de ANGPT2 y CAV1 para evaluar sus roles en la transcitosis de la albúmina a través de las hrGEC, y verificamos la relación entre ellas. Se establecieron modelos in vivo de ratones con ERD, tratados con diferentes dosis de losartan. Se utilizaron pruebas de inmunohistoquímica e inmunotransferencia para detectar la expresión de ANGPT2 y CAV1. Resultados In vitro, la transcitosis de la albúmina a través de hrGEC se incrementó considerablemente en condiciones de estimulación de la hiperglucemia, inhibiendo losartan este proceso. La expresión de ANGPT2 y CAV1 se incrementó en las hrGEC en condiciones de HG, reduciendo la intervención de losartan la expresión de ambas (AU)


Assuntos
Animais , Masculino , Camundongos , Diabetes Mellitus Experimental/metabolismo , Glomérulos Renais/metabolismo , Albuminas/metabolismo , Transcitose , Angiopoietinas/metabolismo , Camundongos Endogâmicos C57BL , Caveolinas/farmacologia , Losartan/farmacologia , Modelos Animais
8.
J Pharm Biomed Anal ; 240: 115955, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38198883

RESUMO

Recalls of medicinal products can cause supply bottlenecks. This is often due to the findings of unexpected impurities that pose a health risk to patients. A recent example is losartan potassium which was contaminated with azido-impurities. The choice of the analytical method determines which substances can be detected and thus controlled. In this study a combination of an untargeted screening approach for impurities and a targeted evaluation of high-resolution mass spectrometry data was applied to search for impurities not described so far, leaving out a precise quantification. Six losartan potassium samples were studied regarding known and unknown impurities and hence highlight the applicability and capability of the approach. For separation a Zorbax RR StableBond C18 column (3.0 ×100 mm, particle size of 3.5 µm, pore size of 80 Å), a gradient elution and an electrospray ionization in positive and negative mode for mass spectrometric detection was used. An information-dependent acquisition method was applied for the measurement of losartan potassium samples. The untargeted data evaluation using general unknown comparative screening revealed the presence of N-methyl-2-pyrrolidone (NMP) and another impurity from synthesis. The identity of NMP was corroborated by a spiking experiment and the amount was estimated by means of standard addition. A targeted data evaluation by generating extracted ion chromatograms resulted in finding of four additional impurities. Combined approaches like this are needed to detect and respond to changes in the quality of drugs precociously.


Assuntos
Contaminação de Medicamentos , Losartan , Humanos , Espectrometria de Massas , Cromatografia Líquida de Alta Pressão/métodos
9.
Trials ; 25(1): 12, 2024 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-38167064

RESUMO

BACKGROUND: Keloid is a skin disorder that results from excessive fibrous tissue growth in the area of the initial trauma. Treating keloids can be challenging since the success of various treatments varies from one study to another. Triamcinolone acetonide injection, a standard treatment, can cause undesirable side effects. Meanwhile, the effectiveness of existing topical therapies for keloids is not always reliable. The pro-inflammatory, pro-proliferative, and pro-fibrotic effects of angiotensin II in human skin contribute to keloid formation. Losartan potassium, an angiotensin II blocker, has the potential to act as an anti-keloid agent. Due to the thicker skin structure of a keloid and ease of application, ethosome gel is chosen as a safe and comfortable carrier for losartan potassium, making it a good choice for treating keloids. METHODS: In this randomised clinical trial, 46 adults with keloids were divided into two treatment groups. One group of 23 participants received 5% losartan potassium loaded in ethosomal gel, while the other group of 23 participants received intralesional injections of 10% triamcinolone acetonide. Over 12 weeks, changes in POSAS 3.0 scores, degree of erythema and pigmentation, surface area, thickness, and pliability of the keloids will be measured at four different times: baseline, 4 weeks, 8 weeks, and 12 weeks. Statistical analysis will be conducted using SPSS software version 24, with a significance level of p < 0.05. DISCUSSION: Losartan potassium is believed to be beneficial for keloid management because it inhibits the angiotensin II receptor, which plays a role in inflammation, proliferation, and fibrosis. This study examines the efficacy of 5% losartan potassium loaded in ethosomal gel for human keloids. TRIAL REGISTRATION: Clinicaltrial.gov identifier NCT05893108 . Registered on 7 June 2023.


Assuntos
Queloide , Adulto , Humanos , Queloide/diagnóstico , Queloide/tratamento farmacológico , Triancinolona Acetonida/efeitos adversos , Losartan/efeitos adversos , Angiotensina II/uso terapêutico , Resultado do Tratamento , Injeções Intralesionais , Ensaios Clínicos Controlados Aleatórios como Assunto
10.
Lab Chip ; 24(4): 854-868, 2024 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-38240720

RESUMO

The pancreatic ductal adenocarcinoma (PDAC) stroma and its inherent biophysical barriers to drug delivery are central to therapeutic resistance. This makes PDAC the most prevalent pancreatic cancer with poor prognosis. The chemotherapeutic drug gemcitabine is used against various solid tumours, including pancreatic cancer, but with only a modest effect on patient survival. The growing PDAC tumour mass with high densities of cells and extracellular matrix (ECM) proteins, i.e., collagen, results in high interstitial pressure, leading to vasculature collapse and a dense, hypoxic, mechanically stiff stroma with reduced interstitial flow, critical to drug delivery to cells. Despite this, most drug studies are performed on cellular models that neglect these biophysical barriers to drug delivery. Microfluidic technology offers a promising platform to emulate tumour biophysical characteristics with appropriate flow conditions and transport dynamics. We present a microfluidic PDAC culture model, encompassing the disease's biophysical barriers to therapeutics, to evaluate the use of the angiotensin II receptor blocker losartan, which has been found to have matrix-depleting properties, on improving gemcitabine efficacy. PDAC cells were seeded into our 5-channel microfluidic device for a 21-day culture to mimic the rigid, collagenous PDAC stroma with reduced interstitial flow, which is critical to drug delivery to the cancer cells, and for assessment with gemcitabine and losartan treatment. With losartan, our culture matrix was more porous with less collagen, resulting in increased hydraulic conductivity of the culture interstitial space and improved gemcitabine effect. We demonstrate the importance of modelling tumour biophysical barriers to successfully assess new drugs and delivery methods.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Gencitabina , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Losartan/uso terapêutico , Neoplasias Pancreáticas/patologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Colágeno/metabolismo , Linhagem Celular Tumoral
11.
Nano Lett ; 24(5): 1510-1521, 2024 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-38285667

RESUMO

α-PD-L1 therapy has shown encouraging results at harnessing the immune system to combat cancer. However, the treatment effect is relatively low due to the dense extracellular matrix (ECM) and tumor immunosuppressive microenvironment (TIME). Therefore, an ultrasound (US)-responsive nanosensitizer (URNS) is engineered to deliver losartan (LST) and polyethylenimine (PEI) to remolde the TME, driving "cold"-"hot" tumor transformation and enhancing the sensitivity of α-PD-L1 therapy. In the tumor site, noninvasive US can make MTNP generate ROS, which cleave ROS-sensitive bonds to dissociate MTNPtK@LST-PEI, shedding PEI and releasing LST from mesoporous spheres. The results demonstrated that URNS combined with α-PD-L1 therapy effectively inhibited tumor growth with an inhibition rate as high as 90%, which was 1.7-fold higher than that of the α-PD-L1 treatment in vivo. In summary, the URNS improves the sensitivity of α-PD-L1 therapy by remodeling the TME, which provides promising insights for optimizing cancer immunotherapy.


Assuntos
Antígeno B7-H1 , Neoplasias , Humanos , Espécies Reativas de Oxigênio , Matriz Extracelular , Imunossupressores , Imunoterapia , Losartan , Polietilenoimina , Microambiente Tumoral
12.
Am J Physiol Renal Physiol ; 326(2): F249-F256, 2024 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-38059297

RESUMO

Angiotensin II (ANG II) increases proximal tubule superoxide (O2-) production more in rats fed a 20% fructose normal-salt diet compared with rats fed a 20% glucose normal-salt diet. A 20% fructose high-salt diet (FHS) increases systolic blood pressure (SBP), whereas a 20% glucose high-salt diet (GHS) does not. However, it is unclear whether FHS enhances ANG II-induced oxidative stress in proximal tubules and whether this contributes to increases in blood pressure in this model. We hypothesized that FHS augments the ability of ANG II to stimulate O2- production by proximal tubules, and this contributes to fructose-induced salt-sensitive hypertension. We measured SBP in male Sprague-Dawley rats fed FHS and GHS and determined the effects of 3 mM tempol and 50 mg/kg losartan for 7 days. We then measured basal and ANG II-stimulated (3.7 × 10-8 M) O2- production by proximal tubule suspensions and the role of protein kinase C. FHS increased SBP by 27 ± 5 mmHg (n = 6, P < 0.006) but GHS did not. Rats fed FHS + tempol and GHS + tempol showed no significant increases in SBP. ANG II increased O2- production by 11 ± 1 relative light units/µg protein/s in proximal tubules from FHS-fed rats (n = 6, P < 0.05) but not in tubules from rats fed GHS. ANG II did not significantly stimulate O2- production by proximal tubules from rats fed FHS + tempol or FHS + losartan. The protein kinase C inhibitor Gö6976 blunted ANG II-stimulated O2- production. In conclusion, FHS enhances the sensitivity of proximal tubule O2- production to ANG II, and this contributes to fructose-induced salt-sensitive hypertension.NEW & NOTEWORTHY A diet containing amounts of fructose consumed by 17 million Americans causes salt-sensitive hypertension. Oxidative stress is an initiating cause of this model of fructose-induced salt-sensitive hypertension increasing blood pressure. This salt-sensitive hypertension is prevented by losartan and thus is angiotensin II (ANG II) dependent. Fructose-induced salt-sensitive hypertension depends on ANG II stimulating oxidative stress in the proximal tubule. A fructose/high-salt diet augments the ability of ANG II to stimulate proximal tubule O2- via protein kinase C.


Assuntos
Angiotensina II , Óxidos N-Cíclicos , Hipertensão , Marcadores de Spin , Humanos , Ratos , Masculino , Animais , Ratos Sprague-Dawley , Angiotensina II/farmacologia , Angiotensina II/metabolismo , Superóxidos/metabolismo , Losartan/farmacologia , Frutose/farmacologia , Hipertensão/induzido quimicamente , Hipertensão/metabolismo , Cloreto de Sódio/metabolismo , Néfrons/metabolismo , Cloreto de Sódio na Dieta/metabolismo , Pressão Sanguínea , Proteína Quinase C/metabolismo , Glucose/farmacologia
13.
Drug Deliv Transl Res ; 14(2): 491-509, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37612575

RESUMO

Despite the fact that chemoimmunotherapy has emerged as a key component in the era of cancer immunotherapy, it is challenged by the complex tumor microenvironment (TME) that is jam-packed with cellular and non-cellular immunosuppressive components. The aim of this study was to design a nanoparticulate system capable of sufficiently accumulating in the tumor and spleen to mediate local and systemic immune responses, respectively. The study also aimed to remodel the immunosuppressive TME. For such reasons, multi-functional polylactic-co-glycolic acid (PLGA) nanoparticles (NPs) were engineered to simultaneously eradicate the cancer cells, silence the tumor-associated fibroblasts (TAFs), and re-educate the tumor-associated macrophages (TAMs) using doxorubicin, losartan, and metformin, respectively. These agents were also selected for their ability to tip the balance of the splenic immune cells towards immunostimulatory phenotypes. To establish TAM and TAF cultures, normal macrophages and fibroblasts were incubated with B16F10 melanoma cell (Mel)-derived secretome. Drug-loaded PLGA NPs were prepared, characterized, and tested in the target cell types. Organ distribution of fluorescein-loaded PLGA NPs was evaluated in a mouse model of melanoma. Finally, the local and systemic effects of different combination therapy programs were portrayed. The in vitro studies showed that the drug-loaded PLGA NPs could significantly ablate the immunosuppressive nature of Mel and skew TAMs and TAFs towards more favorable phenotypes. While in vivo, PLGA NPs were proven to exhibit long blood circulation time and to localize preferentially in the tumor and the spleen. The combination of either metformin or losartan with doxorubicin was superior to the monotherapy, both locally and systemically. However, the three-agent combo produced detrimental effects in the form of compromised well-being, immune depletion, and metastasis. These findings indicate the potential of TME remodeling as means to prime the tumors for successful chemoimmunotherapy. In addition, they shed light on the importance of the careful use of combination therapies and the necessity of employing dose-reduction strategies. D-NPs doxorubicin-loaded NPs, M-NPs metformin-loaded NPs, L-NPs losartan-loaded NPs, TAMs tumor-associated macrophages, TAFs tumor-associated fibroblasts, PD-L1 programmed death ligand 1, TNF-α tumor necrosis factor alpha, TGF-ß transforming growth factor beta, CD206/40/86 cluster of differentiation 206/40/86, α-SMA alpha-smooth muscle actin, MMPs matrix metalloproteases.


Assuntos
Melanoma , Metformina , Nanopartículas , Animais , Camundongos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Glicóis/farmacologia , Microambiente Tumoral , Losartan , Doxorrubicina/uso terapêutico , Doxorrubicina/farmacologia , Metformina/farmacologia , Linhagem Celular Tumoral
14.
Expert Opin Drug Discov ; 19(1): 21-32, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-37800853

RESUMO

INTRODUCTION: Alzheimer's disease (AD) is a progressive, irreversible, and multifactorial brain disorder that gradually and insidiously destroys individual's memory, thinking, and other cognitive abilities. AREAS COVERED: In this perspective, the authors examine the complex and multifactorial nature of Alzheimer's disease and believe that the best approach to develop new drugs is the MTDL strategy, which obviously faces several challenges. These challenges include identifying the key combination of targets and their suitability for coordinated actions, as well as developing an acceptable pharmacokinetic and toxicological profile to deliver a drug candidate. EXPERT OPINION: Since calcium plays a crucial role in the pathology of AD, a polypharmacological approach with calcium channel blockers reinforced by activities targeting other factors involved in AD is a serious option in our opinion. This is exemplified by a phase III clinical trial using a drug combination approach with Losartan, Amlodipine (a calcium channel blocker), and Atorvastatin, as well as several MTDL-based calcium channel blockade approaches with a promising in vitro and in vivo profile.


Assuntos
Doença de Alzheimer , Bloqueadores dos Canais de Cálcio , Humanos , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/uso terapêutico , Doença de Alzheimer/tratamento farmacológico , Descoberta de Drogas , Losartan/uso terapêutico , Polifarmacologia
15.
Virus Res ; 339: 199285, 2024 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-38013142

RESUMO

OBJECTIVES: This study aimed to explore the impact of oxidative stress and extracellular matrix integrity on rotavirus infection in various cancer cells, including breast cancer, acute lymphoblastic leukemia, and melanoma. METHODS: We induced oxidative stress using ROS-inducing drugs (cisplatin, metronidazole, melatonin, valproic acid, doxorubicin, losartan, nitrofurantoin, and DHA) and investigated the effects on viral infection in MCF-7, Reh, A375, B16-F1, and SK-MEL-28 cells and the generation of virions from infected cells by harvesting the supernatants every two hours, reinfecting other cells, and analyzing cell viability and DNA fragmentation. FINDINGS: In MCF-7 and Reh cells, rotavirus Wt1-5 infection led to increased ROS generation, virion production, membrane permeability, mitochondrial dysfunction, DNA damage, and cell death. These effects were amplified by ROS-inducing drugs. Conversely, melanoma cells (SK-MEL-28 and A375) with a robust extracellular matrix network showed limited sensitivity to the drugs. Notably, losartan, which modulates the extracellular matrix, enhanced viral infection in melanoma cells (99 %). CONCLUSIONS: Oxidative stress promotes oncolytic rotavirus infection in breast cancer and acute lymphoblastic leukemia cells, suggesting potential utility in combination with radiotherapy or chemotherapy due to their shared induction of intracellular oxidative stress.


Assuntos
Neoplasias da Mama , Melanoma , Leucemia-Linfoma Linfoblástico de Células Precursoras , Infecções por Rotavirus , Rotavirus , Humanos , Feminino , Melanoma/terapia , Rotavirus/genética , Rotavirus/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Losartan/farmacologia , Losartan/uso terapêutico , Linhagem Celular Tumoral , Apoptose , Estresse Oxidativo , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia
16.
J Prim Care Community Health ; 14: 21501319231213744, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37965705

RESUMO

The following describes a case of isolated visceral angioedema related to an angiotensin II receptor blocker (ARB) medication. Additionally, we discuss the pathophysiology of drug-induced angioedema, various presentations that can be encountered, and the leading theorized mechanisms of how renin-angiotensin-aldosterone system (RAAS) blocking medications lead to angioedema. The goal of sharing this case is to help increase awareness of the possibility of ARB-induced angioedema and to recommend keeping visceral angioedema as part of the differential diagnosis when presented with a patient who is taking an angiotensin converting enzyme inhibitor (ACEI) or ARB medication that is experiencing gastrointestinal symptoms of unclear etiology.


Assuntos
Angioedema , Losartan , Humanos , Losartan/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Antagonistas de Receptores de Angiotensina/uso terapêutico , Sistema Renina-Angiotensina , Angioedema/induzido quimicamente
17.
Am Heart J ; 266: 198-200, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37980092

RESUMO

PURPOSE: To identify the cause of discrepancy between the INHERIT trial and VANISH trial in regards to disease modification of angiotensin receptor II blockers in hypertrophic cardiomyopathy (HCM). METHODS: We replicated the data analysis used in VANISH, converting individual change in each component of the composite endpoint into a z-score and applying this z-score to the INHERIT results. RESULTS: No significant improvement was identified in the composite z-score between the 2 groups at 12-month follow-up (P = .4). With the exception of tissue Doppler systolic (s') velocity, we found no significant benefit or harm from losartan compared to placebo for any of the individual components of the composite score at 12-month follow-up. Results were similar in analyses without imputed data or when restricted to patients with sarcomeric HCM. CONCLUSION: Despite applying the potentially more sensitive composite z-score endpoint as in the VANISH trial, no statistically significant benefits from the use of losartan compared to placebo could be detected at 12-month follow-up in patients with overt HCM participating in the INHERIT trial.


Assuntos
Cardiomiopatia Hipertrófica , Losartan , Humanos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Cardiomiopatia Hipertrófica/tratamento farmacológico , Losartan/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto
18.
Arthroscopy ; 39(12): 2420-2422, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37981385

RESUMO

Rotator cuff retear rates after repair have been variously reported as ranging from 5% to 40% for small to mediums tears and as high as 40% to 94% for large to massive tears. Thus strategies to enhance structural healing are relevant. In rabbits, combining oral losartan (which has antifibrotic effects by downregulating transforming growth factor-ß1) and bone marrow stimulation (BMS) of the greater tuberosity, showed improved rotator cuff repair pull-out strength and highly organized tendon matrix in a chronic injury model, whereas BMS alone did not improve the mechanical properties. However, clinical studies show that BMS techniques have a positive impact on healing and retear rates. BMS stimulates migration of mesenchymal stem cells from bone marrow to the lesion, and this approach has been widely used to fill cartilage defects by fibrocartilage metaplasia. BMS is a straightforward and cost-effective technique; the use of multiple deeper bone tunnels is recommended.


Assuntos
Lesões do Manguito Rotador , Manguito Rotador , Animais , Coelhos , Manguito Rotador/cirurgia , Medula Óssea , Lesões do Manguito Rotador/tratamento farmacológico , Lesões do Manguito Rotador/cirurgia , Losartan/farmacologia , Losartan/uso terapêutico , Ombro
19.
Int J Mol Sci ; 24(22)2023 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-38003444

RESUMO

Cannabidiol (CBD), the major non-psychoactive phytocannabinoid found in cannabis, has anti-neuroinflammatory properties. Despite the increasing use of CBD, little is known about its effect in combination with other substances. Combination therapy has been gaining attention recently, aiming to produce more efficient effects. Angiotensin II activates the angiotensin 1 receptor and regulates neuroinflammation and cognition. Angiotensin receptor 1 blockers (ARBs) were shown to be neuroprotective and prevent cognitive decline. The present study aimed to elucidate the combined role of CBD and ARBs in the modulation of lipopolysaccharide (LPS)-induced glial inflammation. While LPS significantly enhanced nitric oxide synthesis vs. the control, telmisartan and CBD, when administered alone, attenuated this effect by 60% and 36%, respectively. Exposure of LPS-stimulated cells to both compounds resulted in the 95% inhibition of glial nitric oxide release (additive effect). A synergistic inhibitory effect on nitric oxide release was observed when cells were co-treated with losartan (5 µM) and CBD (5 µM) (by 80%) compared to exposure to each compound alone (by 22% and 26%, respectively). Telmisartan and CBD given alone increased TNFα levels by 60% and 40%, respectively. CBD and telmisartan, when given together, attenuated the LPS-induced increase in TNFα levels without statistical significance. LPS-induced IL-17 release was attenuated by CBD with or without telmisartan (by 75%) or telmisartan alone (by 60%). LPS-induced Interferon-γ release was attenuated by 80% when telmisartan was administered in the absence or presence of CBD. Anti-inflammatory effects were recorded when CBD was combined with the known anti-inflammatory agent dimethyl fumarate (DMF)/monomethyl fumarate (MMF). A synergistic inhibitory effect of CBD and MMF on glial release of nitric oxide (by 77%) was observed compared to cells exposed to MMF (by 35%) or CBD (by 12%) alone. Overall, this study highlights the potential of new combinations of CBD (5 µM) with losartan (5 µM) or MMF (1 µM) to synergistically attenuate glial NO synthesis. Additive effects on NO production were observed when telmisartan (5 µM) and CBD (5 µM) were administered together to glial cells.


Assuntos
Canabidiol , Humanos , Canabidiol/farmacologia , Telmisartan/farmacologia , Fator de Necrose Tumoral alfa , Losartan/farmacologia , Óxido Nítrico , Doenças Neuroinflamatórias , Lipopolissacarídeos/toxicidade , Antagonistas de Receptores de Angiotensina , Inibidores da Enzima Conversora de Angiotensina , Neuroglia
20.
Medicine (Baltimore) ; 102(46): e36098, 2023 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-37986329

RESUMO

There is a lack of studies comparing the risk of cardio-cerebrovascular disease between angiotensin receptor blockers (ARBs) of different half-lives. We aimed to compare the risks of myocardial infarction (MI), heart failure (HF), and cerebrovascular disease with the use of valsartan, losartan, irbesartan, and telmisartan with different half-lives in a national claim-based retrospective cohort of patients aged ≥ 40 years with hypertension. To establish a cohort exposed to valsartan, losartan, irbesartan, or telmisartan, we performed propensity score (PS) matching and used an as-treated approach to evaluate exposure. The Cox regression model was employed to calculate hazard ratios, which were based on the incidence rate for each newly occurring event of MI, heart failure, or cerebrovascular disease. These hazard ratios were calculated to compare the risk of MI, heart failure, and cerebrovascular disease associated with valsartan, losartan, and irbesartan in comparison to telmisartan. A PS-matched cohort of 148,229 patients was established for each of valsartan, losartan, irbesartan, or telmisartan. The matched cohort analysis showed that the adjusted hazard ratio (aHRs, 95% confidence interval) for MI was higher for valsartan use (1.39, 1.33-1.45) and losartan use (1.10, 1.05-1.15) but lower for irbesartan use (0.90, 0.86-0.94) compared with the reference (telmisartan). The aHRs for HF were not different among these ARBs (angiotensin receptor blockers). The aHR for cerebrovascular disease was lower for valsartan use (0.85, 0.83-0.87) and losartan use (0.80, 0.78-0.82) but higher for irbesartan use (1.11, 1.09-1.13) compared with the reference. We found differences in the risk of MI and cerebrovascular disease with the use of different ARBs compared to telmisartan use. Valsartan, and losartan with a short half-life, which showed a higher risk of MI, had a lower risk of cerebrovascular disease. Conversely, irbesartan with a long half-life, which showed a lower risk of MI, had a higher risk of cerebrovascular disease.


Assuntos
Transtornos Cerebrovasculares , Insuficiência Cardíaca , Infarto do Miocárdio , Humanos , Losartan/efeitos adversos , Irbesartana/efeitos adversos , Telmisartan/uso terapêutico , Valsartana/uso terapêutico , Antagonistas de Receptores de Angiotensina , Estudos Retrospectivos , Tetrazóis/efeitos adversos , Compostos de Bifenilo , Benzimidazóis/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina , Insuficiência Cardíaca/epidemiologia , Infarto do Miocárdio/induzido quimicamente , Infarto do Miocárdio/epidemiologia , Transtornos Cerebrovasculares/epidemiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...