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Background: A large proportion of patients in developing countries have to pay out of pocket for their medications. The prices of different brands of the same medications vary considerably and may vary from one community pharmacy to another. This study was undertaken to evaluate the variation in costs of proton pump inhibitors (PPI) and histamine H2-receptor antagonists available in Libya. Methods: Prices of various brands of PPI and various formulations were collected from four community pharmacies in the city of Benghazi. Both cost ratio and percentage variation were calculated and compared for various brands of the same strength and number of tablets, capsules, injections, or syrups. Results: The highest cost ratio and percentage price variation were found with omeprazole 20 mg, followed by omeprazole 40 mg. Other significant cost variations (>100%) were seen with pantoprazole 40 mg, Downoprazol (omeprazole + sodium bicarbonate) 40 mg, and esomeprazole 40 mg. Ampoules of omeprazole, cimetidine, and ranitidine had cost ratios of 1:1.7, 1:1.7, and 1:1.8, and cost variation ratios of 71.4, 66.7, and 75, respectively. Variations in prices of PPI and histamine H2 antagonists from the same manufacturer between different community pharmacies were common. The highest percentage cost variation (100) was seen with omeprazole 20 mg. Conclusions: Due to political instability, the prices of all drugs are controlled by importing private companies and the owners of community pharmacies instead of governmental authorities, that leads to cost variations. Therefore, the health authorities exert strict control on pricing of medications.
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Introducción: Nuestro trabajo aborda una revisión bibliográfica realizada entre enero de 2019 y septiembre de 2023, se resalta la importancia de los genes BRCA1, BRCA2, AR y PTEN en la patogénesis, pronóstico y tratamiento del cáncer de próstata, especialmente en su forma metastásica resistente a la castración (mCRPC). Los genes BRCA1 y BRCA2 se identifican como marcadores clave para prever la agresividad del cáncer, sugiriendo la necesidad de terapias dirigidas y vigilancia estricta. La adaptabilidad de las células cancerosas y la variabilidad en la expresión del receptor de andrógenos (AR) limitan la efectividad de las terapias centradas únicamente en AR, señalando la importancia de identificar vías alternativas y biomarcadores para un tratamiento más efectivo. La función de PTEN se relaciona directamente con la progresión de la enfermedad, y su alteración sugiere posibles enfoques terapéuticos. Sin embargo, la heterogeneidad de las células cancerosas y la complejidad de las vías moleculares presentan desafíos significativos para el desarrollo de terapias universales. Conclusión: Los hallazgos promueven la investigación futura para confirmar la aplicabilidad de estos genes como biomarcadores y desarrollar estrategias de tratamiento personalizadas en el cáncer de próstata. (provisto por Infomedic International)
Introduction: Our work addresses a literature review conducted between January 2019 and September 2023, the importance of BRCA1, BRCA2, AR and PTEN genes in the pathogenesis, prognosis and treatment of prostate cancer, especially in its metastatic castration-resistant form (mCRPC), is highlighted. BRCA1 and BRCA2 genes are identified as key markers for predicting cancer aggressiveness, suggesting the need for targeted therapies and strict surveillance. The adaptability of cancer cells and variability in androgen receptor (AR) expression limit the effectiveness of therapies focused solely on AR, pointing to the importance of identifying alternative pathways and biomarkers for more effective treatment. PTEN function is directly related to disease progression, and its alteration suggests potential therapeutic approaches. However, the heterogeneity of cancer cells and complexity of molecular pathways present significant challenges to the development of universal therapies. Conclusion: The findings promote future research to confirm the applicability of these genes as biomarkers and to develop personalized treatment strategies in prostate cancer. (provided by Infomedic International)
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This article aimed to discuss the protection of trans - nerolidol on vascular endothelial cells (ECs) injured by lipopolysac charides. ECs were divided into four groups: normal, model, low and high dose trans - nerolidol treatment groups. The cell survival rate and the contents of NO in the cell culture supernatant were determined. The protein expression and transcript level of pe roxisome proliferator - activated receptor - γ (PPARγ), endothelial nitric oxide synthase (eNOS), and inducible nitric oxide synthase (iNOS) were determined by western blotting and RT - PCR respectively. Compared with the normal group, cell livability, protein e xpression and mRNA transcript level of PPARγ and eNOS decreased, NO contents, protein expression and mRNA transcript tlevel of iNOS increased in model group significantly. Compared with model group, all the changes recovered in different degree in treatmen t groups. Hence, it was concluded that trans - nerolidol can alleviate the ECs injuryby the regulation of iNOS/eNOS through activating PPARγ in a dose - dependent manner
Este artículo tiene como objetivo discutir la protección del trans - nerolidol en las células endoteliales vasculares (CE) dañadas por lipopolisacáridos. Las CE se di vidieron en cuatro grupos: normal, modelo, grupos de tratamiento con trans - nerolidol de baja y alta dosis. Se determinó la tasa de supervivencia de las células y los contenidos de óxido nítrico (NO) en el sobrenadante del cultivo celular. La expresión de p roteínas y el nivel de transcripción del receptor activado por proliferadores de peroxisomas - γ (PPARγ), el óxido nítrico sint et asa endotelial (eNOS) y el óxido nítrico sint et asa inducible (iNOS) se determinaron mediante western blot y RT - PCR, respectivamen te. En comparación con el grupo normal, la viabilidad celular, la expresión de proteínas y el nivel de transcripción de PPARγ y eNOS disminuyeron, los contenidos de NO, la expresión de proteínas y el nivel de transcripción de iNOS aumentaron significativam ente en el grupo modelo. En comparación con el grupo modelo, todos los cambios se recuperaron en diferentes grados en los grupos de tratamiento. Por lo tanto, se concluyó que el trans - nerolidol puede aliviar el daño en las CE regulando iNOS/eNOS a través d e la activación de PPARγ de manera dependiente de la dosis.
Subject(s)
Sesquiterpenes/administration & dosage , Vascular Diseases/drug therapy , Endothelium, Vascular/drug effects , Endothelium, Vascular/injuries , Cell Survival , Lipopolysaccharides/toxicity , Blotting, Western , Nitric Oxide Synthase , Real-Time Polymerase Chain ReactionABSTRACT
The term "gynecomastia" refers to the benign growth of glandular breast tissue in men. In older men, adolescents, and newborns, physiological gynecomastia is common. Although it is self-limited, it can be managed to reduce both physical and emotional discomfort. Chronic conditions (such as cirrhosis, hypogonadism, and renal insufficiency), drug use (including prescription, over-the-counter, and illicit drugs), and tumors are rare causes of nonphysiologic gynecomastia. Exogenous estrogens, antiandrogens, 5-alpha reductase inhibitors, spironolactone, and cimetidine are the active ingredients that are known to cause gynecomastia the most frequently. A patient's medical history is crucial in diagnosing drug-induced gynecomastia. Treating the underlying disease and stopping contributing medications are the cornerstones of treatment. In certain cases, gynecomastia can be treated with surgery and medications such as estrogen receptor modulators. Early intervention and patient-directed care are important aspects of treatment. We describe the pathogenetic mechanism of spironolactone-induced gynecomastia and provide a case report of a 52-year-old male patient.
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In recent years, Glucagon-Like Peptide-1 (GLP-1) receptor agonists have emerged as promising options for weight management, offering not only glycemic control benefits but also significant reductions in body weight. Among these agents, Wegovy (semaglutide) and Ozempic (semaglutide) have gained attention for their efficacy in promoting weight loss, even in individuals without diabetes. However, the off-label use of these medications for weight management raises several questions and concerns regarding their safety, efficacy, and long-term effects. This comprehensive review aims to explore the complexities of GLP-1 agonists in weight management, focusing on their mechanism of action, clinical evidence, safety profile, dosing considerations, potential interactions, and future directions.
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En la actualidad, más de la mitad de las pacientes con cáncer de mama receptor hormonal positivo recibe algún esquema de quimioterapia adyuvante. Sin embargo, sólo algunas de ellas obtendrían un beneficio real en términos de sobrevida. Las plataformas genómicas permiten un mejor entendimiento de la heterogeneidad tumoral entre carcinomas con receptores hormonales positivos, Her2 negativos, habiendo sido validadas como herramientas para identificar aquellas. pacientes que obtendrían un beneficio claro con el tratamiento quimioterápico. El objetivo de nuestro estudio es describir el uso de la plataforma genómica Oncotype Dx® y evaluar su impacto sobre la indicación del tratamiento adyuvante, evaluado principalmente a través del cambio de conducta en relación con la indicación final del tratamiento adyuvante. Material y método: Estudio multicéntrico observacional de cohorte llevado a cabo en distintas Unidades de Mastología de la República Argentina que utilizaran el Oncotype Dx* para esclarecer la indicación del tratamiento adyuvante en pacientes luminales Her2neu negativas en estadio inicial. Se registraron las decisiones relacionadas con el tratamiento antes y luego de realizar la prueba genómica. El objetivo secundario consistió en describir los eventos en aquellas pacientes en quiénes se solicitó dicho estudio. Resultados: Entre enero de 2013 y diciembre de 2018, 211 pacientes con carcinomas luminales A o B, Her2neu negativas realizaron el Oncotype Dx* y fueron incluidas en el estudio. Según nuestros registros, 40% de las pacientes experimentó un cambio en la indicación del tratamiento adyuvante luego de realizada la plataforma genómica. De aquellas pacientes que tenían indicación inicial de hormonoterapia según parámetros tradicionales clínico-patológicos, 24% recibió adicionalmente quimioterapia. En relación con las pacientes que tenían indicación inicial de quimio y hormonoterapia, 49% experimentó un cambio en la indicación de su adyuvancia pudiendo realizar únicamente hormonoterapia. En relación a los eventos descriptos en las pacientes participantes del trabajo, se registraron 4 muertes específicas por la enfermedad, una muerte por otra causa, 2 recaídas a distancia y un cáncer de mama contralateral. Conclusiones: En nuestra población de estudio el uso del Score de Recurrencia (RS) resultó clínicamente significativo en relación al cambio de conducta en la toma de decisión para adyuvancia. En consecuencia, para este grupo de investigadores, ha demostrado ser una herramienta de significativa importancia en la decisión del tratamiento adyuvante de pacientes con cáncer de mama temprano, luminal, Her2neu negativo(AU)
Objetive: Currently, over half of all patients diagnosed with hormone-receptor positive early stage breast cancer will receive some type of adjuvant chemotherapy (CHT), but only a few of them will actually benefit in terms of survival. Genomic platforms allow a better understanding of the heterogeneity among the different types of hormone receptor positive, her2 negative breast cancer, and have proven their validity as tools for identifying those patients who will obtain a clear benefit from CHT. The aim of our study was to analyze the use of the genomic platform Oncotype Dx® in our population and describe its impact on the decision of adjuvant treatment assessed through change in treatment decision. Material and method: this was a real world collaborative observational study, which was performed across several Breast Units in Argentina. Patients who underwent Oncotype Dx® testing to determine adjuvant treatment were included. Decisions regarding treatment were settled before and after the oncotype was performed by the tumor boards of each Breast Unit. Results: From January 2013 to December 2018, 211 patients with luminal A or B, her 2 negative breast cancer who underwent Oncotype Dx" testing were included. We found that treatment decisions were modified after Oncotype DX in approximately 40% of patients. In 24% percent of cases, chemotherapy was added to the initial treatment plan although endocrine therapy alone had initially been considered (potential subtreatment); and on the other hand, 49% of all patients were able to receive endocrine therapy only when, due to traditional prognostic factors, they would have received chemotherapy (potential overtreatment). Conclusions: In our population, we found that the use of the Recurrence Score was associated with a significant change in treatment recommendation We therefore consider it to be a very important tool and a decisive factor for the selection of adjuvant treatment in patients with hormone receptor positive, her2neu negative early breast cancer(AU)
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Zollinger-Ellison syndrome (ZES) is characterized by gastrin-secreting neuroendocrine tumors (gastrinomas) in the duodenum or pancreas. It is a rare condition, most patients are diagnosed between the ages of 20 and 50, and a higher incidence in men. Gastrinomas are associated with a high risk of malignancy and the diagnosis is confirmed by the secretin stimulation test and imaging studies such as octreotide scintigraphy. We present the case of a 24-year-old man who presented with melena, asthenia, adynamia and abdominal pain, in addition to a history of peptic ulcer. Laboratory tests revealed low levels of hemoglobin and elevated levels of gastrin. Endoscopy showed a giant ulcer and subsequent surgery revealed stomach-jejunum adhesions, gastric lesions and Meckel's diverticulum. Imaging studies confirmed neuroendocrine tumor activity in the pancreas. ZES leads to sustained hypergastrinemia, causing peptic ulcers and other digestive tract complications. Gastrinomas can arise from a variety of locations and can cause peptic ulcers, malabsorption, and diarrhea. Diagnosis requires elevated fasting serum gastrin levels and hypersecretion of gastric acid. Treatment involves discontinuation of proton pump inhibitors (PPIs) before diagnostic testing and surgical resection of tumors in suitable candidates. The diagnosis of ZES can be complicated due to the unreliability of the assays and the need for secretin testing. Surgical resection is recommended for sporadic gastrinomas without metastasis, while medical treatment may be necessary for postsurgical residual hyperacidity. Patients should undergo imaging studies for tumor localization and regular monitoring for complications and recurrences.
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RESUMEN Los antagonistas del receptor de mineralocorticoide (ARM) son beneficiosos en diversos estados patológicos. Se deben considerar a estos medicamentos como una nueva alternativa en el manejo de la fibrilación auricular (FA), ya que los resultados en múltiples ensayos clínicos muestran su beneficio en la reducción de la aparición de la FA, y así poder validar la implementación de este medicamento en la práctica clínica diaria. Por este motivo el objetivo de esta revisión fue dar a conocer la literatura que respalda a los ARM como un potencial fármaco antiarrítmico.
SUMMARY Mineralocorticoid receptor antagonists (MRAs) are beneficial in certain diseases. Results from multiple clinical trials support the indication for this class of drugs as an alternative for the management of atrial fibrillation. This review aims to show the evidence that supports the recommendation.
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RESUMEN Los inhibidores de la tirosina quinasa han cambiado drásticamente la perspectiva clínica de los pacientes con cáncer de pulmón de células no pequeñas avanzado con mutaciones del receptor del factor de crecimiento epidérmico. Sin embargo, existen aún retos en el manejo de los pacientes con esta mutación en un escenario metastásico, como es la resistencia intrínseca y adquirida a inhibidores de tirosina quinasa. Se discutirán los últimos avances y nuevas estrategias en primera línea de tratamiento, resistencia a osimertinib y tratamiento en mutación, en el exón 20.
ABSTRACT Tyrosine kinase inhibitors have dramatically changed the clinical outcomes for patients with advanced non-small cell lung cancer with epidermal growth factor receptor mutations. However, there are still challenges in the management of patients with this mutation in a metastatic setting, such as intrinsic and acquired resistance to tyrosine kinase inhibitors. We will discuss the latest advances and new strategies in first-line treatment, osimertinib resistance, and exon 20 mutation treatment.
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Abstract Introduction: This publication aims to show the clinical, endoscopic, and histological responses of two pediatric patients who received dupilumab as a management strategy for eosinophilic esophagitis. Dupilumab is a monoclonal antibody that inhibits the alpha chain of the interleukin (IL)-4 and IL-13 receptors involved in the Th2 inflammatory response. The potential therapeutic role of this biological drug has been demonstrated in pediatric clinical trials in other allergic pathologies, such as atopic dermatitis and asthma, with an adequate safety and effectiveness profile. Clinical cases: Two children with a personal history of atopy, allergic rhinitis, asthma, atopic dermatitis, and food allergy began with gastrointestinal symptoms that confirmed the diagnosis of eosinophilic esophagitis. Despite the different management strategies, adequate control of the disease was not achieved, and it is considered that they benefited from management with dupilumab due to the disease evolution and the coexistence of uncontrolled atopic dermatitis. Conclusions: In recent years, various management strategies in pediatrics have been published, particularly high-dose proton pump inhibitors, topical corticosteroids, and elimination diets. However, despite these strategies, at least one-third of patients may fail to achieve remission with initial treatment, making this entity a therapeutic challenge for the gastroenterologist and pediatric allergist. Our patients received the dose recommended for their weight and age and approved for asthma and atopic dermatitis, resulting in clinical and histological remission. The improvement in gastrointestinal symptoms was accompanied by better control of asthma, rhinitis, and dermatitis. None of the patients had adverse effects of the medication.
Resumen Introducción: El objetivo de esta publicación es mostrar la respuesta clínica, endoscópica e histológica de dos pacientes pediátricos que recibieron dupilumab como estrategia de manejo para esofagitis eosinofílica. El dupilumab es un anticuerpo monoclonal que inhibe la cadena alfa del receptor de las interleucinas 4 y 13, involucradas en la respuesta inflamatoria Th2. El potencial rol terapéutico de este medicamento biológico se ha demostrado en ensayos clínicos en pediatría en otras patologías alérgicas como la dermatitis atópica y el asma, y ha mostrado un adecuado perfil de seguridad y efectividad en pediatría. Casos clínicos: Se trata de dos niños con antecedentes personales de atopia, rinitis alérgica, asma, dermatitis atópica y alergia alimentaria, que inician con síntomas gastrointestinales que conducen a confirmar el diagnóstico de esofagitis eosinofílica, en quienes a pesar de las diferentes estrategias de manejo no se logra un adecuado control de la enfermedad, y se considera que se benefician del manejo con dupilumab por la evolución de la enfermedad, así como la coexistencia de dermatitis atópica no controlada. Conclusiones: En los últimos años se han publicado diferentes estrategias de manejo en pediatría, entre los que se destaca el uso de inhibidores de la bomba de protones a dosis altas, corticoides tópicos y las dietas de exclusión; sin embargo, a pesar de estas estrategias, al menos un tercio de los pacientes puede fallar en lograr la remisión con el manejo inicial, lo que convierte a esta entidad en un reto terapéutico para el gastroenterólogo y el alergólogo pediatra. Nuestros pacientes recibieron la dosis recomendada para su peso y edad aprobada en asma y dermatitis atópica, y se logró la remisión clínica e histológica. La mejoría de los síntomas gastrointestinales se acompañó de un mejor control del asma, la rinitis y la dermatitis. Ninguno de los pacientes tuvo efectos adversos al medicamento.
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Abstract Introduction Chimeric Antigen Receptor (CAR) T cells have tremendous potentials for cancer treatment; however, various challenges impede their universal use. These restrictions include the poor function of T cells in tumor microenvironments, the shortage of tumor-specific antigens and, finally, the high cost and time-consuming process, as well as the poor scalability of the method. Creative gene-editing tools have addressed each of these limitations and introduced next generation products for cell therapy. The clustered regularly interspaced short palindromic repeats-associated endonuclease 9 (CRISPR/Cas9) system has triggered a revolution in biology fields, as it has a great capacity for genetic manipulation. Method In this review, we considered the latest development of CRISPR/Cas9 methods for the chimeric antigen receptor T cell (CAR T)-based immunotherapy. Results The ability of the CRISPR/Cas9 system to generate the universal CAR T cells and also potent T cells that are persistent against exhaustion and inhibition was explored. Conclusion: We explained CRISPR delivery methods, as well as addressing safety concerns related to the use of the CRISPR/Cas9 system and their potential solutions.
Subject(s)
Neoplasms , Genetic Therapy , Immunotherapy, Adoptive , Clustered Regularly Interspaced Short Palindromic Repeats , Receptors, Chimeric AntigenABSTRACT
Abstract The imbalance between pro-inflammatory M1 and anti-inflammatory M2 macrophages plays a critical role in the pathogenesis of sepsis-induced acute lung injury (ALI). Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) may modulate macrophage polarization toward the M2 phenotype by altering mitochondrial activity. This study aimed to investigate the role of the PGC-1α agonist pioglitazone (PGZ) in modulating sepsis-induced ALI. A mouse model of sepsis-induced ALI was established using cecal ligation and puncture (CLP). An in vitro model was created by stimulating MH-S cells with lipopolysaccharide (LPS). qRT-PCR was used to measure mRNA levels of M1 markers iNOS and MHC-II and M2 markers Arg1 and CD206 to evaluate macrophage polarization. Western blotting detected expression of peroxisome proliferator-activated receptor gamma (PPARγ) PGC-1α, and mitochondrial biogenesis proteins NRF1, NRF2, and mtTFA. To assess mitochondrial content and function, reactive oxygen species levels were detected by dihydroethidium staining, and mitochondrial DNA copy number was measured by qRT-PCR. In the CLP-induced ALI mouse model, lung tissues exhibited reduced PGC-1α expression. PGZ treatment rescued PGC-1α expression and alleviated lung injury, as evidenced by decreased lung wet-to-dry weight ratio, pro-inflammatory cytokine secretion (tumor necrosis factor-α, interleukin-1β, interleukin-6), and enhanced M2 macrophage polarization. Mechanistic investigations revealed that PGZ activated the PPARγ/PGC-1α/mitochondrial protection pathway to prevent sepsis-induced ALI by inhibiting M1 macrophage polarization. These results may provide new insights and evidence for developing PGZ as a potential ALI therapy.
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ObjectiveTo explore the protective effect and mechanism of Zingiberis Rhizoma Recens alcohol extract on lipopolysaccharide (LPS)-induced acute lung injury in mice. MethodBalb/c mice were randomly divided into normal group, model group, dexamethasone group, and low- and high-dose Zingiberis Rhizoma Recens groups. Mice in the normal group were instilled with normal saline through the nose, and the other groups were instilled with normal saline containing LPS (50 μg). After 30 minutes of modeling, the dexamethasone group was gavaged with 5 mg·kg-1 of dexamethasone acetate solution, the low- and high-dose Zingiberis Rhizoma Recens groups were gavaged with different doses of (7, 14 g·kg-1) of Zingiberis Rhizoma Recens alcohol extract, and the normal group and the model group were gavaged with the same volume of water. After 24 hours of modeling, the total number of white blood cells in bronchoalceolar lavage fluid (BALF) was detected by cell counter, and the levels of the inflammatory factors including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and superoxide dismutase (SOD), and myeloperoxidase (MPO) was detected by enzyme-linked immunosorbent assay (ELISA). Haematoxylin-eosin (HE) staining method was used to observe the pathological changes of lung tissue in each group, and the Western blot was used to detect the protein expression of nuclear transcription factor (NF)-κB p65, phosphorylation (p)-NF-κB p65, and Toll-like receptor 4 (TLR4) in lung tissue. ResultCompared with the normal group, the white blood cell count in BALF and the levels of TNF-α, IL-1β, IL-6, and MPO in the model group was increased (P<0.01), and the level of SOD was decreased (P<0.05). Pathological damage of lung tissue was obvious, and the protein expression of NF-κB p65, p-NF-κB p65, and TLR4 in lung tissue was increased (P<0.01). Compared with the model group, the white blood cell count in BALF and the levels of TNF-α, IL-1β, IL-6, and MPO in the treatment group was decreased (P<0.05,P<0.01), and the level of SOD was increased (P<0.05,P<0.01). Pathological damage of lung tissue was alleviated, and the protein expression of NF-κB p65, p-NF-κB p65, and TLR4 in lung tissue was decreased (P<0.01). ConclusionZingiberis Rhizoma Recens alcohol extract may play a protective role in LPS-induced acute lung injury in mice by inhibiting the TLR4/NF-κB signaling pathway.
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ObjectiveTo investigate the effect and mechanism of total saponins from Panax japonicus (TSPJ) on white adipose tissue (WAT) browning/brown adipose tissue (BAT) activation in C57BL6/J male mice fed on a high-fat diet (HFD). MethodThirty-two C57BL6/J male mice (8-week-old) were randomly divided into a normal group, a model group, a low-dose TSPJ group, and a high-dose TSPJ group. The mice in the low-dose and high-dose TSPJ groups were given TSPJ for four months by gavage at 25, 75 mg·kg-1·d-1, respectively, and those in the other groups were given 0.5% sodium carboxymethyl cellulose (CMC-Na) accordingly. After four months of feeding, all mice were placed at 4 ℃ for acute cold exposure, and the core body temperature was monitored. Subsequently, all mice were sacrificed, and BAT and inguinal WAT (iWAT) were separated rapidly to detect the corresponding indexes. Hematoxylin-eosin (HE) staining was used to observe the morphological changes in each group. The effect of TSPJ on the mRNA expression of uncoupling protein 1 (UCP1), fatty acid-binding protein 4 (FABP4), cytochrome C (CytC), PR domain-containing protein 16 (PRDM16), elongation of very long chain fatty acids protein 3 (ELOVL3), peroxisome proliferator-activated receptor γ (PPARγ), and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) in iWAT and BAT was detected by Real-time polymerase chain reaction (Real-time PCR). Western blot was also used to detect the protein expression of UCP1, PRDM16, PPARγ, and PGC-1α in BAT and iWAT of each group. The effect of TSPJ on UCP1 expression in BAT and iWAT was detected by immunohistochemistry. Result① Compared with the model group, TSPJ could decrease the body weight and proportions of iWAT and BAT in the HFD-induced mice (P<0.05, P<0.01). ② The body temperature of mice in the model group decreased compared with that in the normal group in the acute cold exposure tolerance test (P<0.05). The body temperature in the high-dose TSPJ group increased compared with that in the model group (P<0.01). ③ Compared with the normal group, the model group showed increased adipocyte diameter in iWAT and BAT and decreased number of adipocytes per unit area. Compared with the model group, the TSPJ groups showed significantly reduced cell diameter and increased number of cells per unit area, especially in the high-dose TSPJ group. ④ Compared with the normal group, the model group showed decreased mRNA expression of FABP4, UCP1, CytC, PRDM16, ELOVL3, PGC-1α, and PPARγ in adipose tissues of mice (P<0.05, P<0.01). Compared with the model group, after intervention with TSPJ, the mRNA expression was significantly up-regulated (P<0.05, P<0.01). ⑤ Compared with the normal group, the model group showed decreased protein expression of UCP1, PRDM16, PPARγ, and PGC-1α in adipose tissues of mice (P<0.05, P<0.01). Compared with the model group, after intervention with TSPJ, the protein expression increased significantly (P<0.05, P<0.01). ConclusionTSPJ could induce the browning of iWAT/BAT activation and enhance adaptive thermogenesis in obese mice induced by HFD. The underlying mechanism may be attributed to the activation of the PPARγ/PGC-1α signaling pathway.
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@#Tooth absorption can be divided into physiological absorption and pathological absorption. Root absorption of mature deciduous teeth is physiological absorption. Pathological absorption includes internal absorption and external absorption. Internal absorption, also known as intramedullary absorption, includes inflammatory absorption and alternative absorption. External tooth absorption originates from the outer surface of the root or the neck of the tooth and can be divided into inflammatory absorption, alternative absorption, pressure resorption and invasive cervical resorption. Invasive cervical resorption (ICR) is pathological damage caused by many factors, which usually begins in the cemento-enamel junction and extends peripherally or horizontally in the dentin. It hardly invades the pulp. Orthodontic devices, trauma, bleaching, systemic diseases, and the use of certain medications can all lead to invasive cervical resorption. The clinical manifestations of ICR are usually asymptomatic or not obvious, and most of which are found in imaging examinations. Because caries and internal absorption are often misdiagnosed through plain apical radiography, cone beam computed tomography (CBCT) can help to better understand the situation of invasive cervical resorption. Because the pathogenesis and etiology of invasive cervical resorption are not fully understood, clinical negligence and inadequate treatment of invasive cervical resorption can even cause unnecessary tooth loss. This article reviews the latest research progress on the histopathologic features, pathogenic mechanism, susceptibility factors, diagnosis and treatment of ICR, with special emphasis on susceptibility factors and their mechanisms.
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ObjectiveTo investigate the effects and mechanism of Zuogui Jiangtang Tongmai prescription (ZJTP) on human umbilical vein endothelial cells (HUVECs) damaged by high glucose combined with lipopolysaccharide (LPS). MethodThe survival rate of cells was determined by cell counting kit-8 (CCK-8), and the level of tumor necrosis factor-α (TNF-α) was determined by enzyme-linked immunosorbent assay (ELISA) to determine the optimal injury concentration and action time of LPS, as well as the optimal action concentration of ZJTP drug-containing serum. HUVECs were divided into a blank control group, a model group, a ZJTP drug-containing serum group, and an SCFA mixed liquid group. ELISA was used to detect the level of endothelin-1 (ET-1), nitric oxide (NO), interleukin-1β (IL-1β), interleukin-6 (IL-6), and TNF-α. Western blot was performed to detect the protein expression of G protein-coupled receptor43 (GPR43), β-suppressor protein-2 (β-arrestin-2), nuclear factor-κB suppressor α (IκBα), and nuclear factor κB p65 (NF-κB p65). The nucleation of NF-κB p65 was observed by immunofluorescence staining (IF). The role of GPR43 in the regulation of inflammatory injury was observed by means of small interfering ribonucleic acid (siRNA). The cells after intervention were divided into an empty carrier group, a ZJTP drug-containing serum group, a Si-GPR43 group, and a Si-GPR43 + ZJTP drug-containing serum group. The content of IL-1β, IL-6, and TNF-α was detected by ELISA. The protein expression of pathways was detected by Western blot. IF was used to observe the nucleation of NF-κB p65. ResultThe optimal molding condition was 1 mg·L-1 LPS for 24 h. The optimal drug intervention condition was 5% ZJTP drug-containing serum for 24 h. Compared with the blank control group, the content of ET-1 in the model group was significantly increased, and the content of NO was significantly decreased (P<0.01). The levels of inflammatory factors were significantly increased (P<0.01). The expressions of GPR43 and IκBα were significantly decreased, while the protein expressions of β-arrestin-2 and NF-κB p65 were significantly increased (P<0.01). NF-κB p65 protein was transferred from the extranuclear to the intranuclear (P<0.01). Compared with the model group, the content of ET-1 in the ZJTP drug-containing serum group was decreased, and the content of NO was increased (P<0.05). The levels of inflammatory factors decreased (P<0.05). The protein expressions of GPR43 and IκBα were increased, while the expressions of β-arrestin-2 and NF-κB p65 were decreased (P<0.05). The amount of NF-κB p65 transferred from the intranuclear to the extranuclear decreased (P<0.01). The mechanism study showed that compared with the Si-GPR43 group, the content of IL-1β, IL-6, and TNF-α were significantly decreased after treatment with ZJTP drug-containing serum (P<0.01). The protein expressions of GPR43 and IκBα were significantly increased (P<0.01), while the protein expressions of β-arrestin-2 and NF-κB p65 were significantly decreased (P<0.01). The amount of NF-κB p65 transferred from the extranuclear to the intranuclear decreased (P<0.01). ConclusionZJTP has a protective effect on HUVECs with high glucose and LPS-induced inflammatory injury, which may be related to the regulation of GPR43/β-arrestin-2/IκBα/NF-κB pathway.
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Transient receptor potential vanilloid receptor 4(TRPV4)is a non-selective cation channel responsible for sensing changes in cell swelling, temperature, mechanical stretch, shear stress and osmotic pressure by regulating transmembrane calcium signaling and thereby influencing gene expression, cell morphology, and cytoskeletal construction. TRPV4 is widely expressed throughout the body. Intraocularly, TRPV4 is functionally expressed in the cornea, lens, ciliary body, trabecular meshwork and retina. In this article, the expression and physiopathological functions of TRPV4 in various tissues of the eye were described. With the in-depth study of TRPV4 in ocular pathophysiological functions, TRPV4 may become a potential drug target in corneal injury repair, glaucoma and retinal angiogenesis, but further in-depth study is still needed.
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Objective@#To explore the molecular mechanism of resveratrol (RES) in the treatment of oral squamous cell carcinoma (OSCC) through the use of biological information methods such as network pharmacology and molecular docking and to provide a theoretical reference for the clinical application of RES in the treatment of OSCC.@*Methods@#The Swiss Target Prediction(http://www.swisstargetprediction.ch), SEA (http://sea.bkslab.org)database, and Pharm mapper database(http://lilab-ecust.cn) were used to retrieve RES-related targets, and the DISGENET (www.disgenet.org), OMIM (https://omim.org) and GeneCards (https://www.genecards.org) databases were used to screen OSCC disease targets. The intersection of drugs and disease targets was determined, and Cytoscape 3.7.2 software was used to construct a "drug-diseasetarget pathway" network. The Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database was used to construct a target protein interaction network, and the DAVID database was used for enrichment analysis of key proteins. Finally, molecular docking validation of key proteins was performed using AutoDock and PyMOL. The enrichment analysis and molecular docking results were integrated to predict the possible molecular mechanisms of RES treatment in OSCC; western blot was used to determine the effect of resveratrol at different concentrations (50, 100) μmol/L on the expression of Src tyrosine kinase (SRC), epidermal growth factor receptor (EGFR), estrogen receptor gene 1 (ESR1), and phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT) signaling pathway proteins in OSCC HSC-3 cells.@*Results@#A total of 243 targets of RES drugs and 6 094 targets of OSCC were identified. A total of 116 potential common targets were obtained by intersecting drugs with disease targets. These potential targets mainly participate in biological processes such as in vivo protein self-phosphorylation, peptide tyrosine phosphorylation, transmembrane receptor protein tyrosine kinase signaling pathway, and positive regulation of RNA polymerase Ⅱ promoter transcription, and they interfere with the PI3K/AKT signaling pathway to exert anti-OSCC effects. The docking results of resveratrol with OSCC molecules indicated that key targets, such as EGFR, ESR1, and SRC, have good binding activity. The results of cell-based experiments showed that resveratrol inhibited the protein expression of SRC, EGFR, ESR1, p-PI3K, and p-AKT in HSC-3 cells in a dose-dependent manner.@*Conclusion@#RES can inhibit the expression of its targets EGFR, ESR1, SRC, p-PI3K, and p-AKT in OSCC cells.
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ObjectiveTo investigate the protective effects of Mori Folium extract (MLE) on the kidney of db/db diabetic mice and its mechanism. MethodTwenty-four male C57BLKS/JGpt-Leprdb/Leprdb (db/db) mice were randomly divided into model group, metformin group, low-dose group of MLE (MLE-L), and high-dose group of MLE (MLE-H) according to their fasting blood glucose (FBG), with six mice in each group, and other six C57BLKS/JGpt wild littermate (m/m) mice were selected as normal group. The mice in the drug administration groups were given corresponding drugs by gavage, and the mice in the normal group and model group were given the same dose of deionized water by gavage once a day for continuous eight weeks. Body weight, bilateral kidney weight, and FBG were measured, and an oral glucose tolerance test (OGTT) was performed. The pathological changes in the kidney tissue of mice were observed by hematoxylin-eosin (HE) and periodic acid-silver (PAS) staining, and serum creatinine (SCr) and blood urea nitrogen (BUN) levels were detected. Enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in serum and urinary microalbumin (U-mAlb) of mice. The expression levels of toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and nuclear factor-kappa B p65 (NF-κB p65) protein in kidney tissue of mice were tested by Western blot. ResultCompared with the normal group, the body weight, absolute renal weight, FBG, and the area under the curve (AUC) of OGTT of mice in the model group were significantly increased (P<0.01), and the levels of SCr, BUN, and U-mAlb, as well as TNF-α and IL-6 in serum were significantly increased (P<0.01). The glomerular basement membrane in the kidney tissue of mice was thicker, with obvious inflammatory cell infiltration. The protein expression levels of TLR4, MyD88, and NF-κB p65 in the kidney tissue of mice were increased significantly (P<0.01). Compared with the model group, there was no statistical difference in the body weight of mice in each drug administration group. The absolute renal weight of mice in the MLE-H and metformin groups was significantly reduced (P<0.05, P<0.01). The FBG levels of mice in the metformin, MLE-L, and MLE-H groups started to decrease after treatment for four to eight weeks (P<0.05, P<0.01). The AUC of mice in the MLE-H and metformin groups was significantly decreased (P<0.01). The levels of SCr, BUN, and U-mAlb of mice in the MLE-H and metformin groups were significantly decreased (P<0.01), and those of SCr and U-mAlb of mice in the MLE-L group were significantly decreased (P<0.01). The levels of TNF-α and IL-6 in the serum of mice in the MLE-H and metformin groups were significantly decreased (P<0.01). The renal tissue pathology of mice in each drug administration group was improved to varying degrees, and the protein expression levels of TLR4, MyD88, and NF-κB p65 in the MLE-H group were decreased significantly (P<0.05, P<0.01). ConclusionMLE can improve the renal structure and function of db/db diabetic mice, and its mechanism may be related to the inhibition of the TLR4/MyD88/NF-κB signaling pathway.
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ObjectiveTo investigate the intervention effect of Jiedu Tongluo Tiaogan prescription (JTTP) in protecting pancreatic β cells by targeting the bile acid Takeda G protein-coupled receptor 5 (TGR5)/cyclic adenosine monophosphate (cAMP) signaling pathway against NOD-like receptor protein 3 (NLRP3) inflammasome. MethodThirty-two male SPF-grade db/db mice were randomly divided into the model group, low-dose JTTP group (3.6 g·kg-1), high-dose JTTP group (7.2 g·kg-1), and metformin group (0.2 g·kg-1). Eight db/m mice were assigned to the blank control group. The mice were treated with drugs for 8 weeks, and fasting blood glucose (FBG) was measured every 2 weeks. Oral glucose tolerance tests (OGTT) were conducted after the last administration. Enzyme-linked immunosorbent assay (ELISA) was performed to detect fasting insulin (FINS), and the homeostasis model assessment of β-cell function (HOMA-β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and IL-1β levels were calculated. Hematoxylin-eosin (HE) staining was used to observe pathological changes in mouse pancreatic tissue. Immunofluorescence was performed to detect insulin expression in mouse pancreatic tissue. Western blot and real-time quantitative polymerase chain reaction (Real-time PCR) were used to detect the expression of proteins and mRNAs of key targets in the TGR5/cAMP signaling pathway and NLRP3 inflammasome. ResultCompared with blank group, FBG, OGTT, FINS, IL-6, TNF-α and IL-1β in model group were significantly increased (P<0.01). Compared with model group, after 6 weeks of drug treatment, FBG level in JTTP group and metformin group decreased significantly (P<0.01). The results of OGTT experiment showed that compared with model group, the blood glucose levels of mice in each administration group were decreased at all time points (P<0.05, P<0.01), and the levels of FINS, TNF-α and IL-6 in JTTP dose groups and metformin group were significantly decreased. The level of IL-1β in JTTP high-dose group and metformin group was significantly decreased (P<0.01). Pancreatic pathology showed that the islets in the model group were irregular in shape, uneven in distribution, and showed signs of atrophy. The prognosis of JTTP was that the cell count increased and the boundary was clearer. Immunofluorescence results showed that the islet cells in the blank group were arranged in an orderly and full shape with appropriate insulin secretion, while the islet cells in model group were distorted in shape, atrophy in structure and less insulin secretion. The insulin content of mice in JTTP and metformin group was significantly increased. Compared with blank group, mRNA expressions of NLRP3, apoptosis-related spot-like protein (ASC) and Caspase-1 in pancreatic tissues of model group were significantly increased (P<0.01). Compared with model group, JTTP high-dose group and metformin group promoted the up-regulation of TGR5 and cAMP mRNA, and down-regulated the mRNA expressions of NLRP3, ASC and Caspase-1 (P<0.05, P<0.01). Compared with blank group, the expression of TGR5 protein in model group was significantly decreased (P<0.01). Compared with model group, TGR5 protein in JTTP high-dose group and metformin group was significantly increased (P<0.01).