SUMMARY: This study aimed to explore the potential of Nasturtium officinale L. leaves extract (NOLE) in safeguarding hepatocytes against N-diethylnitrosamine (DEN)-induced hepatocellular carcinoma (HCC) by investigating its effects on biochemical, molecular, and antioxidant pathways. The study also delved into NOLE's role in modulating the HOTAIR/miR-124/Notch1 axis pathway. In this study, 50 Wistar rats were divided into five groups (n=10/group): normal, HCC-induced (100 mg/kg DEN), HCC rats treated with 100 and 200 mg/kg DEN + NOLE, and normal rats treated with 200 mg/kg NOLE. At the study's conclusion, serum levels of liver function markers (such as albumin, total protein, bilirubin, C-reactive protein, ALT, AST, and ALP), inflammatory cytokines (IL-6, IL- 1b, IL-10, and TNF-a), and oxidative parameters [including glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase (CAT) enzyme activity, and nitric oxide (NO) levels] were assessed. The levels of HOTAIR, miR-124, Notch1, and Jagged1 genes and proteins in liver tissue were measured. Immunohistochemical analysis was used to evaluate P53-positive cells in liver hepatocytes. DEN administration led to significant alterations in body and liver weight, serum liver enzymes, antioxidant levels, inflammatory markers, and expression of genes/proteins related to the HOTAIR/miR-124/Notch1 axis in liver pathways. NOLE exhibited dose-dependent effects in mitigating these changes, notably enhancing weight, liver health, antioxidant capacity, and inflammatory responses, especially at the 200 mg/kg dosage. Histopathological assessments revealed structural improvements in liver tissue with NOLE treatment. In conclusion, our study highlights the potential of NOLE in exerting anti-cancer effects against DEN-induced HCC.

RESUMEN: Este estudio tuvo como objetivo explorar el potencial del extracto de hojas de Nasturtium officinale L. (NOLE) para proteger los hepatocitos contra el carcinoma hepatocelular (HCC) inducido por N-dietilnitrosamina (DEN) mediante la investigación de sus efectos sobre las vías bioquímicas, moleculares y antioxidantes. El estudio también profundizó en el papel de NOLE en la modulación de la vía del eje HOTAIR/miR-124/Notch1. En este estudio, 50 ratas Wistar se dividieron en cinco grupos (n=10/ grupo): ratas normales, inducidas por HCC (100 mg/kg de DEN), ratas con HCC tratadas con 100 y 200 mg/kg de DEN + NOLE y ratas normales tratadas con 200 mg/kg de NOLE. Al concluir el estudio, se midieron los niveles séricos de marcadores de función hepática (como albúmina, proteína total, bilirrubina, proteína C reactiva, ALT, AST y ALP), citoquinas inflamatorias (IL-6, IL-1β, IL-10 y TNF-α) y parámetros oxidativos [incluidos los niveles de glutatión peroxidasa (GPx), superóxido dismutasa (SOD), catalasa (CAT) y óxido nítrico (NO)]. Se midieron los niveles de los genes y proteínas HOTAIR, miR-124, Notch1 y Jagged1 en el tejido hepático. Se utilizó análisis inmunohistoquímico para evaluar las células P53 positivas en los hepatocitos del hígado. La administración de DEN provocó alteraciones significativas en el peso corporal y hepático, las enzimas hepáticas séricas, los niveles de antioxidantes, los marcadores inflamatorios y la expresión de genes/proteínas relacionadas con el eje HOTAIR/miR-124/Notch1 en las vías hepáticas. NOLE exhibió efectos dependientes de la dosis para mitigar estos cambios, en particular mejorando el peso, la salud del hígado, la capacidad antioxidante y las respuestas inflamatorias, especialmente en la dosis de 200 mg/kg. Las evaluaciones histopatológicas revelaron mejoras estructurales en el tejido hepático con el tratamiento NOLE. En conclusión, nuestro estudio destaca el potencial de NOLE para ejercer efectos anticancerígenos contra el CHC inducido por DEN.

SUMMARY: Formaldehyde induces oxidative damage in hippocampal tissue and blood serum by suppressing antioxidant defenses and increasing lipid peroxidation. This results in damage to DNA, proteins, and lipids within cells, disrupting neuronal functions, and may even lead to cell death (apoptosis). Apoptosis occurs as a cellular response triggered by formaldehyde through various mechanisms, including mitochondrial dysfunction, oxidative stress, and DNA damage. Arbutus unedo L. (AUL), which is rich in antioxidants, represents a potential countermeasure. The aim of our study is to investigate the immunohistochemical and biochemical effects of AUL fruit extract (AUE) on apoptosis and oxidative stress induced by FA exposure in the rat hippocampus. The rats were divided into four groups: the experimental group (EG) received 20 mg/kg AUE by oral gavage and 10 ppm FA inhalation; the formaldehyde group (FG) received 10 ppm FA inhalation only; the sham group (SG) received 10 mg/kg AUE by oral gavage; and the control group (CG) underwent routine observation. Hippocampal tissue was isolated after blood sampling. A number of physical changes, such as yellowing of feathers and tail spots, were observed in FA-exposed groups. The biochemical analysis showed significant differences in brain-derived neurotrophic factor (BDNF), malondialdehyde (MDA), GSH (Glutathione) and nitric oxide (NO) levels between the groups. The AUE-treated groups had reduced MDA levels, suggesting a potential reduction in oxidative stress, along with lower apoptotic cell rates in caspase-3 assessments. The FG rats had lower BDNF levels than CG. The SG had the fewest apoptotic cells. All these findings indicate AUE's potential to mitigate neuron damage and reduce oxidative stress.

RESUMEN: El formaldehído induce daño oxidativo en el tejido del hipocampo y del plasma sanguíneo al suprimir las defensas antioxidantes y aumentar la peroxidación lipídica. Esto provoca daños en el ADN, las proteínas y los lípidos dentro de las células, alterando las funciones neuronales e incluso puede provocar la muerte celular (apoptosis). La apoptosis se produce como una respuesta celular desencadenada por el formaldehído a través de diversos mecanismos, incluida la disfunción mitocondrial, el estrés oxidativo y el daño del ADN. Arbutus unedo L. (AUL), rico en antioxidantes, representa una posible contramedida. El objetivo de nuestro estudio fue investigar los efectos inmunohistoquímicos y bioquímicos del extracto de fruta AUL (AUE) sobre la apoptosis y el estrés oxidativo inducido por la exposición a FA en el hipocampo de rata. Las ratas se dividieron en cuatro grupos: el grupo experimental (GE) recibió 20 mg/kg de AUE por sonda oral y 10 ppm de FA por inhalación; el grupo de formaldehído (GF) recibió sólo una inhalación de 10 ppm de FA; el grupo simulado (GS) recibió 10 mg/kg de AUE mediante sonda oral; y el grupo control (GC) se sometió a observación de rutina. Se aisló tejido del hipocampo después de una muestra de sangre. En los grupos expuestos a FA se observaron una serie de cambios físicos, como coloración amarillenta del pelaje y manchas en la cola. El análisis bioquímico mostró diferencias significativas en los niveles de factor neurotrófico derivado del cerebro (BDNF), malondialdehído (MDA), GSH (glutatión) y óxido nítrico (NO) entre los grupos. Los grupos tratados con AUE tenían niveles reducidos de MDA, lo que sugiere una reducción potencial del estrés oxidativo, junto con tasas de células apoptóticas más bajas en las evaluaciones de caspasa-3. Las ratas GF tenían niveles de BDNF más bajos que GC. El GS tenía la menor cantidad de células apoptóticas. Todos estos hallazgos indican el potencial del AUE para mitigar el daño neuronal y reducir el estrés oxidativo.

Resumen El aparato respiratorio, desde la nariz al pulmón, se comporta como una unidad anatómica y fisiopatológica bajo un modelo holístico. Se han observado alteraciones pulmonares sin traducción clínica en pacientes con rinitis sin asma, que se manifiestan como hiperreac tividad bronquial, reducción de la función pulmonar e inflamación bronquial. Estas serían consecuencia de un fenómeno inflamatorio sistémico con impacto simultá neo en nariz y pulmón, que por razones desconocidas no tiene una expresión clínica completa, pero que podrían significar un mayor riesgo de desarrollo de asma. En esta revisión abordamos la frecuencia y caracte rísticas de las anormalidades pulmonares existentes en niños y adolescentes con rinitis crónica derivadas de nuestras investigaciones previas y, más recientemente, del proyecto “Enfermedad Alérgica Respiratoria: El Con cepto de Unidad de la Vía Aérea”, línea de investigación acreditada por la Universidad Católica de Córdoba y un análisis comparativo con las evidencias aportadas por otros autores en la literatura médica.

Abstract The respiratory tract, from the nose to the lung, behaves as an anatomical and pathophysiological unit under a holistic model. Lower airway abnormalities, such as bronchial hyperresponsiveness, reduced lung function and inflammation of the bronchial mucosa without clinical expression, have been observed in pa tients with rhinitis without asthma. These would be the consequence of a common systemic inflammatory phenomenon with simultaneous impact on the nose and lung. For unknown reasons, these patients do not exhibit a full clinical expression, which could mean an increased risk of developing asthma. In this review we address the frequency and charac teristics of existing pulmonary abnormalities in children and adolescents with chronic rhinitis that derive from our previous research and, more recently, within the project “Allergic Respiratory Disease: The United Airway Con cept” supported by the Universidad Católica de Córdoba, and a comparative analysis with the evidence provided by other authors in the medical literature.

Resumen Este estudio tuvo como objetivo determinar las concentraciones salivales de interleucina (IL)-1β, IL-2, IL-10, IL-23, factor de crecimiento transformante (TGF)-β y factor de necrosis tumoral (TNF)-α, nitrato (subproducto de la oxidación del óxido nítrico) y cortisol en pacientes con liquen plano oral (OLP). En este estudio transversal se incluyeron veinte pacientes diagnosticados con OLP y 20 voluntarios sanos (HV) del mismo sexo. Saliva entera no estimulada Se recolectó por la mañana, se determinaron las concentraciones de citocinas y cortisol en saliva mediante ensayo inmunoabsorbente ligado a enzimas (ELISA), se determinó nitrato mediante un analizador de óxido nítrico, se encontraron concentraciones salivales mayores de IL-2 (p<0,003), IL- 23 (p<0,04) y TGF-β (p=0,05) en pacientes con OLP en comparación con HV. No se encontraron diferencias significativas en los niveles salivales de TNF-α, IL-1β e IL-10. Las concentraciones de nitrato fueron marcadamente aumentó en pacientes con OLP (1227,0 ± 738,8 µM/mg de proteína total), en comparación con HV (261,6 ± 166,8 µM/mg; p<0,0001). Los niveles de cortisol salival también fueron más altos en los pacientes con OLP que en los controles (2,79 ± 1,39 vs. 1,94 ±1,21 ng/mg; p<0,048). Los niveles de óxido nítrico en saliva aumentaron notablemente en pacientes con OLP, lo que sugiere una relación de esta molécula con la muerte celular y el daño tisular observado en las lesiones de OLP.

Abstract This study aimed to determine salivary concentrations of interleukin (IL)-1β, IL-2, IL-10, IL- 23, transforming growth factor (TGF)-β, tumor necrosis factor (TNF)-α, nitrate (a by-product of nitric oxide oxidation), and cortisol in patients with oral lichen planus (OLP). Twenty patients diagnosed with OLP and 20 sex-matched healthy volunteers (HV) were included in this cross-sectional study. Unstimulated whole saliva was collected in the morning. Salivary cytokine and cortisol concentrations were determined by enzyme-linked immunosorbent assays (ELISA). Nitrate was measured in a nitric oxide analyzer. We found higher salivary concentrations of IL-2 (p<0.003), IL-23 ( p<0.04), and TGF-β (p=0.05) in patients with OLP compared to HV. No significant differences were found in salivary levels of TNF-α, IL-1β, or IL-10. Nitrate concentrations were markedly increased in OLP patients (1,227.0 ± 738.8 µM/mg total protein) when compared to HV (261.6 ± 166.8 µM/mg; p<0.0001). Salivary cortisol levels were also higher in OLP patients (2.79 ± 1.39 vs. 1.94 ±1.21 ng/mg; p<0.048). The markedly increased salivary levels of nitric oxide in patients with OLP suggest a relationship of this molecule with the cell death and tissue damage observed in these lesions.

ABSTRACT Introduction. The Toll-like receptor (TLR) interacting with the promastigote of Leishmania spp. determines the cellular activation pathway. Objective. To determine the transcriptional expression of TLR-3, TLR-4, TLR-9, IL-12 and TNF-α in macrophages infected with a native strain of L. braziliensis (Lbn). Materials and Methods. Identification of Lbn was performed by qPCR for kinetoplast DNA sequences. Mouse peritoneal macrophages were infected with promastigotes (MI) and nitric oxide (NO) production was measured; transcript levels for TLRs and cytokines were quantified by qRT-PCR. Results. Lbn showed 96% homology to L. braziliensis. High ON production was observed in IMs at 2 h; significant transcriptional expression especially of TLR-3 and TLR-9, which corresponded with expression for cytokines. Conclusions. Lbn strongly activated macrophages via endosomal TLRs, which can be applied in the design of agonists to treat the disease.

RESUMEN Introducción. El receptor de tipo Toll (TLR) que interactúe con el promastigote de Leishmania spp. determina la vía de activación celular. Objetivo. Identificar la expresión transcripcional de TLR-3, TLR-4, TLR-9, IL-12 y TNF-α en macrófagos infectados con una cepa nativa de L. braziliensis (Lbn). Métodos. La identificación de Lbn se hizo empleando qPCR para secuencias del DNA del cinetoplasto. Los macrófagos peritoneales de ratones fueron infectados con promastigotes y se midieron la producción de óxido nítrico (ON). Se cuantificaron los niveles transcripcionales para TLRs y citoquinas empleando qRT-PCR. Resultados. Lbn presentó 96% de homología con L. braziliensis. En los infectados con promastigotes se observó elevada producción de ON a las 2 h; significativa expresión transcripcional especialmente de TLR-3 y TLR-9 que se correspondió con la expresión para citoquinas. Conclusión. Lbn activó fuertemente a los macrófagos mediante los TLRs endosomales lo cual puede ser aplicado en el diseño de agonistas para tratar la enfermedad.

Abstract Studies have shown that carbon tetrachloride (CCl4) induces hepatic and renal damage arising from oxidative stress. The present study was undertaken to examine the effect of omega-3 fatty acids and/or soya isoflavones on CCl4 induced toxicity in male albino rat liver and kidney. For this purpose, 42 rats were divided as follows: group 1, rats serves as the control without any treatment; group 2, rats were administered a single dose of CCl4 intraperitoneally (1 mg/kg b. wt.); group 3, rats were supplemented daily with omega-300 orally (400 mg/kg b. wt.); group 4, rats were supplemented daily with pro-S orally (50 mg/kg b. wt.); group 5, rats were supplemented daily with omega-300 orally for four weeks, then after 24 hours treated with a single dose of CCl4 at the same tested doses. group 6, rats were supplemented daily with pro- S orally for four weeks, then after 24 hours treated with a single dose of CCl4 at the same tested doses; group 7, rats were supplemented daily with an oral combination of omega-300 and pro-S orally for four weeks, then after 24 hours treated with a single dose of CCl4 at the same tested doses. Results showed that CCl4 administration induces hepatic damage indicated by a significant increase in the activities of alkaline phosphatase (ALP), aspartate aminotransferase (AST) and Aalanine aminotransferase (ALT) enzymes and glucose level, with a significant increase in malondialdehyde (MDA) and nitric oxide (NO) levels and a significant decrease of reduced glutathione (GSH) level in liver tissue. Also, CCl4 toxicity induce renal damage manifested in a significant increase in serum urea, creatinine, uric acid, and oxidative stress of kidney tissue reflected by increase of MDA, NO and the decrease of GSH levels. The pre-treatment with omega-3 fatty acids and/or soya isoflavones revealed ameliorative effect against deleterious effects of CCl4 toxicity on hepatic and renal tissues and all tested parameters. Results of the current study revealed also that the pre-treatment with omega-3 fatty acids and/or soya isoflavones to rats improved liver and kidney function and produced high antioxidant activity. CCl (CCl4 omega3 omega 3 omega- andor or purpose 4 follows 1 treatment 2 ( mgkg mg kg b wt. wt wt.) omega300 300 omega-30 400 (40 proS pro 50 (5 5 weeks doses 6 7 ALP, ALP , (ALP) AST (AST ALT (ALT MDA (MDA (NO (GSH Also urea creatinine acid pretreatment pre parameters activity (CCl omega30 30 40 (4 (ALP

Resumo Estudos demonstram que o tetracloreto de carbono (CCl4) induz danos hepáticos e renais decorrentes do estresse oxidativo. O presente estudo almejou examinar o efeito de ácidos graxos ômega-3 e/ou isoflavonas de soja na toxicidade induzida por CCl4 no fígado e no rim de ratos albinos machos. Para tanto, 42 ratos foram divididos da seguinte forma: grupo 1, indivíduos que servem como controle sem nenhum tratamento; grupo 2, indivíduos que receberam uma dose única de CCl4 intraperitonealmente (1 ml/kg do peso corporal); grupo 3, indivíduos que foram suplementados diariamente com ômega-300 por via oral (400 mg/kg do peso corporal); grupo 4, indivíduos que foram foram suplementados diariamente com pró-S por via oral (50 mg/kg do peso corporal); grupo 5, indivíduos que foram suplementados diariamente com ômega-300 por via oral por quatro semanas, depois de tratados por 24 horas com uma dose única de CCl4 nas mesmas doses testadas; grupo 6, os indivíduos foram suplementados diariamente com pro-S por via oral por quatro semanas, depois de tratados por 24 horas com uma dose única de CCl4 com as mesmas doses testadas; grupo 7, os indivíduos foram suplementados diariamente com uma combinação oral de ômega-300 e pró-S por via oral por quatro semanas, depois de tratados por 24 horas com uma dose única de CCl4 com as mesmas doses testadas. Os resultados mostraram que a administração de CCl4 induz dano hepático, indicado por um aumento significativo nas atividades das enzimas fosfatase alcalina (ALP), aspartato aminotransferase (AST) e Alanina aminotransferase (ALT) e nível de glicose, com aumento significativo de malondialdeído (MDA) e nítrico, e dos níveis de óxido (NO), além da diminuição significativa do nível de glutationa reduzida (GSH) no tecido hepático. Além disso, a toxicidade do CCl4 induz dano renal manifestado em um aumento significativo da ureia sérica, creatinina, ácido úrico e estresse oxidativo do tecido renal, refletindo no aumento de MDA, NO e diminuição dos níveis de GSH. O pré-tratamento com ácidos graxos como ômega-3 e/ou isoflavonas de soja revelou efeito melhorador contra os efeitos deletérios da toxicidade do CCl4 nos tecidos hepático e renal e em todos os parâmetros testados. Os resultados do presente estudo demonstraram também que o pré-tratamento com ácidos graxos ômega-3 e/ou isoflavonas de soja em ratos melhorou a função hepática e renal e produziu alta atividade antioxidante. CCl (CCl4 ômega3 ômega 3 ômega- eou ou machos tanto 4 forma 1 tratamento 2 ( mlkg ml kg corporal corporal) ômega300 300 ômega-30 400 (40 mgkg mg próS pró S 50 (5 5 semanas testadas 6 proS pro 7 ALP, ALP , (ALP) AST (AST ALT (ALT glicose MDA (MDA nítrico NO, (NO) GSH (GSH disso sérica creatinina prétratamento pré testados antioxidante (CCl ômega30 30 40 (4 (ALP (NO

Resumo A leishmaniose cutânea (LC) é considerada um problema de saúde pública. Os tratamentos atuais apresentam desvantagens por serem invasivos e possuem efeitos colaterais graves, levando a pesquisa de novas alternativas farmacológicas mais eficazes. As plantas são fontes promissoras de bioativos, e por meio de reações químicas pode-se obter novos análogos. O presente estudo objetivou avaliar os efeitos antileishmania do análogo éter n-butil do dilapiol (EBD) extraído das folhas de Piper aduncum. Foi avaliado o potencial citotóxico do EBD nas concentrações de 15,62 a 500 µM em macrófagos peritoneais por 48 h, e em macrófagos RAW 264.7 por 72 h utilizando o método dose-resposta. A atividade antileishmania em promastigotas de L. amazonensis usou-se concentrações de 0,2 a 4,5 µM durante 24, 48 e 72 h e a quantificação da taxa de infecção celular usou-se uma concentração de 4,5 µM do EBD contra as formas amastigotas interiorizado em macrófagos por 24 h e 48 h. O óxido nítrico foi quantificado a partir de macrófagos tratados previamente com o EBD durante 24 h e 48 h. A dosagem das espécies reativas de oxigênio utilizou-se a concentração de 4,5 µM do EBD incubado junto ao acetato de diclorofluoresceína por 1, 3, 6, e 24 h. Para a modelagem molecular do EBD, usou-se a proteína de origem de Leishmania, disponível no banco de dados “Protein Data Bank”. A molécula do estudo não foi tóxica para as células, apresentou uma CC50 de 413 µM em macrófagos peritoneais e de 373,5 µM em RAW 264.7. O análogo inibiu as formas promastigotas de L. amazonensis com uma CI50 de 1,6 µM por 72 horas. O EBD apresentou uma taxa de infecção de 17% e 12%, dilapiol de 24% e 14% e Pentacarinat® de 10% e 9% durante 48 h. O EBD demonstrou uma ligação de energia de -7,8 pelo sítio de ação da enzima U53. Conclui-se que o análogo mostrou atividade antileishmania promissora para futuros testes in vivo. LC (LC pública graves eficazes bioativos podese pode se análogos nbutil n butil (EBD aduncum 1562 15 62 15,6 50 4 2647 264 7 264. doseresposta. doseresposta dose resposta. resposta dose-resposta L usouse usou 02 0 2 0, 45 5 4, utilizouse utilizou 1 3 6 Leishmania Protein Bank. Bank . Bank” células CC CC5 41 3735 373 373, CI CI5 16 horas 17 12 12% 14 Pentacarinat 10 9 7,8 78 8 -7, U53 U Concluise Conclui vivo 156 15, 26 37 7, -7 U5 -

Abstract Cutaneous leishmaniasis (CL) is considered a public health problem. Current treatments have disadvantages because they are invasive and have serious side effects, and thus there is a need for research into new, more effective pharmacological alternatives. Plants are promising sources of bioactive substances, and new analogues can be obtained through chemical reactions. The present study aimed to evaluate the antileishmanial effects of the analog dillapiole n-butyl ether (DBE) extracted from Piper aduncum leaves. The cytotoxic potential of DBE was evaluated at concentrations of 15.62 to 500 µM in peritoneal macrophages for 48 h, and in RAW 264.7 macrophages for 72 h using a dose-response method. The antileishmanial activity in L. amazonensis promastigotes used concentrations of 0.2 to 4.5 µM for 24, 48 and 72 h and the quantification of the cellular infection rate used a concentration of 4.5 µM of DBE against the amastigote forms internalized in macrophages for 24 h and 48 h. Nitric oxide was quantified from macrophages previously treated with DBE for 24 h and 48 h. The dosage of reactive oxygen species used a concentration of 4.5 µM of DBE incubated together with dichlorofluorescein acetate for 1, 3, 6, and 24 h. For the molecular modeling of DBE, the Leishmania protein, available in the “Protein Data Bank” database, was used. The studied molecule was not toxic to cells and presented a CC50 of 413 µM in peritoneal macrophages and 373.5 µM in RAW 264.7. The analogue inhibited promastigote forms of L. amazonensis with an IC50 of 1.6 µM for 72 h. DBE presented an infection rate of 17% and 12%, dillapiole of 24% and 14% and Pentacarinat® of 10% and 9% over 48 h. DBE demonstrated a binding energy of -7.8 for the U53 enzyme. It is concluded that the analogue showed promising antileishmanial activity for future in vivo tests. CL (CL problem alternatives substances reactions nbutyl n butyl (DBE leaves 1562 15 62 15.6 50 4 2647 264 7 264. doseresponse dose response method L 02 0 2 0. 45 5 4. 1 3 6 protein Protein Bank database CC CC5 41 3735 373 373. IC IC5 16 1. 17 12 12% 14 Pentacarinat 10 9 7.8 78 8 -7. U U5 enzyme tests 156 15. 26 37 7. -7 -

Resumo O presente trabalho foi apresentado para avaliar o efeito da administração de extrato de alecrim na toxicidade, lesão e proliferação induzidas por etoposídeos em ratos machos. Quarenta ratos albinos machos foram organizados em quatro grupos iguais: 1º grupo, controle; 2º grupo, etoposídeo; 3º grupo, alecrim e etoposídeo cotratados; 4º grupo, alecrim sozinho. Em comparação com o grupo controle, a administração de etoposídeo resultou em aumento significativo da ALT, AST, ALP, bilirrubina total, proteína total e gama GT séricas. Em contraste, houve diminuição significativa do nível de albumina no grupo etoposídeo em relação ao G1. O G3 revelou diminuição significativa dos níveis de AST, ALT, ALP, proteína total e bilirrubina total e aumento significativo do nível de albumina quando comparado ao G2. Os níveis séricos de ureia, creatinina, íons potássio e íons cloreto aumentaram significativamente, enquanto os íons sódio diminuíram significativamente no G2 quando comparado ao G1. Além disso, houve um aumento do nível de MDA para o grupo tratado com etoposídeo com os ratos controle correspondentes. No entanto, houve uma notável diminuição nos níveis de SOD, GPX e CAT no G2 em relação ao G1. Houve aumento significativo dos níveis séricos de peróxido de hidrogênio (H2O2) e óxido nítrico (NO) no grupo tratado com etoposídeo quando comparado ao grupo controle. Foi perceptível que a administração de alecrim isoladamente ou com etoposídeo não teve efeito sobre os níveis de H2O2 e NO. O nível sérico de T3 e T4 foi significativamente aumentado em ratos administrados com etoposídeo em comparação com o G1. A administração de alecrim, isoladamente ou com etoposídeo, aumentou significativamente os níveis séricos de T3 e T4 quando comparada aos ratos controle. A análise da expressão gênica mostrou desregulação significante da SOD e GPx hepática em G2 quando comparado com o G1. O tratamento com extrato de alecrim produziu aumento significativo das enzimas antioxidantes mRNA SOD e GPx. O gene MDA estava aumentado em G2 quando contrastado com o G1. O tratamento dos ratos induzidos por etoposídeo com extrato de alecrim proporcionou diminuição significativa na expressão do gene MDA quando comparado ao grupo etoposídeo. Ratos tratados com etoposídeo apresentaram declínio significativo na expressão da proteína Nrf2 hepática quando comparados ao G1. Enquanto isso, a suplementação de ratos administrados com etoposídeo e alecrim produziu uma elevação significativa nos níveis de proteína hepática Nrf2. Além disso, a estrutura histológica do fígado apresentou degeneração perceptível e infiltração celular nas células hepáticas. É possível inferir que o alecrim tem um papel potencial e que deve ser pesquisado como um componente natural para proteção da toxicidade induzida por etoposídeos.

Abstract The present work was showed to assess the effect of administration of rosemary extract on etoposide-induced toxicity, injury and proliferation in male rats were investigated. Forty male albino rats were arranged into four equal groups. 1st group, control; 2nd group, etoposide; 3rd group, co-treated rosemary & etoposide; 4th group, rosemary alone. In comparison to the control group, etoposide administration resulted in a significant increase in serum ALT, AST, ALP, total bilirubin, total protein, and gamma GT. In contrast; a significant decrease in albumin level in etoposide group as compared to G1. G3 revealed a significant decrease in AST, ALT, ALP, total protein and total bilirubin levels and a significant rise in albumin level when compared with G2. Serum levels of urea, creatinine, potassium ions, and chloride ions significantly increased; while sodium ions were significantly decreased in G2 when compared with G1. Also, there was an increase of MDA level for etoposide treated group with corresponding control rats. However, there was a remarkable significant decrease in SOD, GPX and CAT levels in G2 as compared to G1. There was a significant increase in serum hydrogen peroxide (H2O2) and Nitric oxide (NO) levels in group treated with etoposide when compared to control group. It was noticeable that administrated by rosemary alone either with etoposide had not any effect on the levels of H2O2 and Nitric oxide. Serum level of T3 and T4 was significantly increased in etoposide-administered rats in comparison with G1. The administration of rosemary, either alone or with etoposide, increased the serum levels of T3 and T4 significantly when compared to control rats. The gene expression analysis showed significant downregulation of hepatic SOD and GPx in (G2) when compared with (G1). The treatment with rosemary extract produced significant upregulation of the antioxidant enzymes mRNA SOD and GPx. MDA gene was increased in (G2) when contrasted with (G1). Treatment of the etoposide- induced rats with rosemary extract delivered significant decrease in MDA gene expression when compared with etoposide group. Rats treated with etoposide showed significant decline in hepatic Nrf2 protein expression, when compared with G1. While, supplementation of Etoposide- administered rats with the rosemary produced a significant elevation in hepatic Nrf2 protein levels. Additionally, the liver histological structure displayed noticeable degeneration and cellular infiltration in liver cells. It is possible to infer that rosemary has a potential role and that it should be researched as a natural component for etoposide-induced toxicity protection.

ABSTRACT Purpose: Reflux esophagitis is a condition characterized by inflammation and irritation of the esophagus, resulting from the backflow of stomach acid and other gastric contents into the esophagus. Columbianadin is a coumarin derivative that exhibits anti-inflammatory and antioxidant effects. In this study, we tried to scrutinize the protective effect of Columbianadin against acute reflux esophagitis in rats. Methods: RAW 264.7 cells were utilized to assess cell viability and measure the production of inflammatory parameters. The rats received anesthesia, and reflux esophagitis was induced via ligation of pylorus and fore stomach and corpus junction. Rats received the oral administration of Columbianadin (25, 50 and 100 mg/kg) and omeprazole (20 mg/kg). The gastric secretion volume, acidity, and pH were measured. Additionally, the levels of oxidative stress parameters, cytokines, and inflammatory markers were determined. At the end of the study, mRNA expression was assessed. Results: Columbianadin remarkably suppressed the cell viability and production of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and prostaglandin (PGE2). Columbianadin treatment remarkably suppressed the secretion of gastric volume, total acidity and enhanced the pH level in the stomach. Columbianadin remarkably altered the level of hydrogen peroxidase, free iron, calcium, and plasma scavenging activity, sulfhydryl group; oxidative stress parameters like malonaldehyde, glutathione, superoxide dismutase, catalase, glutathione peroxidase; inflammatory cytokines viz., TNF-α, IL-6, IL-1β, IL-10, IL-17, and monocyte chemoattractant protein-1; inflammatory parameters including PGE2, iNOS, COX-2, and nuclear kappa B factor (NF-κB). Columbianadin remarkably (P < 0.001) suppressed the mRNA expression TNF-α, IL-6, IL-1β and plasminogen activator inhibitor-1. Conclusions: Columbianadin demonstrated a protective effect against acute reflux esophagitis via NF-κB pathway. Purpose esophagus antiinflammatory anti effects study Methods 2647 264 7 264. anesthesia junction 25, 25 (25 5 10 mg/kg mgkg mg kg 20 (2 mg/kg. . volume measured Additionally determined assessed Results factorα α TNFα, TNFα TNF , (TNF-α) IL1β, IL1β ILβ IL 1β, 1β β (IL)-1β IL6, IL6 6, 6 IL-6 cyclooxygenase2 cyclooxygenase 2 cyclooxygenase- COX2, COX2 COX (COX-2) iNOS (iNOS) PGE2. PGE2 PGE (PGE2) peroxidase iron calcium activity group malonaldehyde dismutase catalase viz viz. α, TNF-α IL10, IL10 10, IL-10 IL17, IL17 17, 17 IL-17 protein1 protein 1 protein-1 2, COX-2 NFκB. NFκB NF κB (NF-κB) P 0.001 0001 0 001 inhibitor1. inhibitor1 inhibitor 1. inhibitor-1 Conclusions pathway 26 ( (TNF-α IL- (COX-2 (iNOS (PGE2 IL1 IL-1 protein- COX- (NF-κB 0.00 000 00 inhibitor- (COX- (PGE 0.0 (COX 0.

Abstract We report the case of a patient with symptomatic pulmonary hypertension (PH) associated with diffuse systemic sclerosis (SSc) whose initial assessment suggested a group 3 (clinical classification) PH. The patient had a history of drugs/toxins consumption, which contributed to the development of intrinsic pulmonary vascular disease. This changed the panorama towards the diagnosis of pulmonary arterial hypertension (PAH), with important therapeutic and prognostic implications. In fact, the excellent clinical, laboratory and hemodynamic response to therapy confirmed the hypothesis of a case of drug-associated PAH (DPAH) in a patient with diffuse SSc and lung disease. Considering the presence of DPAH, it was deemed necessary to assess acute vasoreactivity during right heart catheterization (RHC). If criteria were met, the clinical scenario may change towards a favorable and sustained clinical and hemodynamic response with oral calcium channel blockers. However, the response to inhaled nitric oxide was negative in our patient and the therapeutic strategy with dual oral combination therapy with tadalafil and ambrisentan was continued. After six-months of therapy the patient significantly improved, from a high to a low risk of one-year mortality. PH (PH (SSc classification drugstoxins drugs toxins consumption disease PAH, , (PAH) implications fact drugassociated drug DPAH (DPAH RHC. RHC . (RHC) met blockers However continued sixmonths six months improved oneyear one year mortality (PAH (RHC

Herein, we report the synthesis and evaluation of four aminoguanidine hydrazone derivatives with different aromatic moieties. This class of compounds presents a series of biological applications. Derivative AGH-3 with an indole nucleus offered the highest antioxidant capacity with results comparable to Trolox in 2,2-diphenyl-2-picrylhydrazyl radical (DPPH•), 2,2-azinobis(3 ethylbenzothiazoline-6-sulfonic acid (ABTS•+), FeIII reduction assay (FRAP), and nitric oxide (•NO) radical scavenging assays. Furthermore, AGH-3 showed the highest antiproliferative activity against human kidney cancer cells (786-0) with concentration necessary to inhibit 50% cell growth (GI50) = 6.3 μM; additionally, in biophysical studies, AGH-3 interacted with ctDNA (biological target model) forming a fluorescent supramolecular complex with a binding constant (Kb) of 2.89 × 103 M-1 with preferentially an intercalator mechanism. The tested compounds revealed the potential of aminoguanidine hydrazones as a strategic class of compounds with multitarget biological activity. Herein moieties applications AGH3 AGH 3 AGH- 2,2diphenyl2picrylhydrazyl 22diphenyl2picrylhydrazyl diphenylpicrylhydrazyl 2,2 diphenyl 2 picrylhydrazyl DPPH•, DPPH DPPH• , (DPPH•) 2,2azinobis3 22azinobis3 azinobis 2,2-azinobis( ethylbenzothiazoline6sulfonic ethylbenzothiazolinesulfonic ethylbenzothiazoline 6 sulfonic ABTS•+, ABTS ABTS•+ (ABTS•+) FRAP, FRAP (FRAP) •NO NO (•NO assays Furthermore 7860 786 0 (786-0 50 GI50 GI (GI50 63 6. μM additionally studies model Kb (Kb 289 89 2.8 10 M1 M 1 M- mechanism 2diphenyl2picrylhydrazyl 22 2, (DPPH• 2azinobis3 2,2azinobis 22azinobis 2,2-azinobis ABTS• (ABTS•+ (FRAP 78 (786- 5 GI5 (GI5 28 8 2. (DPPH 2azinobis (ABTS• 7 (786 (GI (ABTS (78 (7 (

ABSTRACT The mosquito Aedes aegypti is a major threat to public health because it spreads several arboviruses. Since this insect is an anthropophilic mosquito that has evolved to thrive in urban settings and is common in Brazil and other tropical nations, controlling its population growth is difficult. The two basic methods of control are eradicating its breeding grounds and applying pesticides. There have been reports of pesticide resistance emerging as well as DEET's potential danger for people, particularly youngsters. Therefore, research has been done to find novel insecticides and repellents. In this way, the goal of this research was to assess thymol's insecticidal and repellent activities in Ae. aegypti. Bioassays were performed with eggs, larvae and adults exposed to different concentrations of thymol. The findings demonstrated that thymol has insecticidal effect in both the immature and adult phases, eliminating the larvae in 24 hours. In addition, necrosis was observed in hemocytes, without alteration in the production of nitric oxide by the insects. When evaluating repellency, thymol showed 99.5% of landing inhibition. This leads to the conclusion that thymol can be employed as an active component in the formulation of insecticides and repellents for the Ae. aegypti mosquito. arboviruses nations difficult pesticides DEETs DEET s people youngsters Therefore way thymols Ae eggs phases 2 hours addition hemocytes insects repellency 995 99 5 99.5 inhibition 9 99.

RESUMO O Aedes aegypti é um mosquito que causa grande impacto na saúde pública por ser o vetor de diversas arboviroses. Controlar a proliferação desse inseto é desafiador, já que é um mosquito antropofílico, altamente adaptado a ambientes urbanos e disseminado no Brasil e em outros países de clima tropical. A principal forma de combatê-lo é destruindo seus criadouros ou utilizando inseticidas. Há relatos do desenvolvimento de resistência aos inseticidas e da potencial toxicidade do DEET para os seres humanos, sobretudo crianças. Dessa forma, estudos vêm sendo realizados, a fim de buscar novas substâncias inseticidas e repelentes. Nesse sentido, o objetivo deste trabalho foi avaliar a atividade inseticida e repelente do timol em mosquitos Ae. aegypti. Foram realizados bioensaios com ovos, larvas e adultos expostos a diferentes concentrações de timol. Os resultados demonstraram que o timol possui ação inseticida tanto nas fases imaturas quanto no adulto, matando 100% das larvas em 24h. Além disso, observou-se necrose em hemócitos, sem alteração na produção de óxido nítrico pelos insetos. Ao avaliar a repelência, o timol apresentou 99,5% de inibição do pouso. Dessa forma, conclui-se que o timol pode ser utilizado como princípio ativo na composição de inseticidas e repelentes contra o mosquito Ae. aegypti. arboviroses desafiador antropofílico tropical combatêlo combatê lo humanos crianças sentido Ae ovos adulto 100 24h h disso observouse observou se hemócitos insetos repelência 995 99 5 99,5 pouso concluise conclui 10 9 99, 1

ABSTRACT Purpose: To evaluate morphological aspects and inducible nitric oxide synthase (iNOS) gene and protein expression in a model of acute inflammation. Methods: Thirty-six female Wistar rats were assigned into three groups: control (saline, n = 12), sham (arthritis, n = 12), and PBM (arthritis and photobiomodulation, n = 12). Arthritis induction was performed with 200 μg of intra-articular Zymosan in sham and PBM animals. PBM was performed 24 h after induction with a laser device (λ = 808 nm, 25 mW of nominal power, fluence of 20 J/cm2, beam area of 0.02 mm2, time of 33 s, total energy of 0.825 J) with punctual and single dose application. Morphological analysis of joint structure (HE) and immunohistochemistry (anti-iNOS antibody) were performed on knee samples, and synovial tissue was submitted to RNA extraction, cDNA synthesis and gene expression analysis by quantitative polymerase chain reaction. Statistical analyses were performed with p < 0.05. Results: It was observed an increase in the thickness of the synovial lining epithelium and inflammatory infiltrate in sham compared to PBM. Gene expression analysis showed higher iNOS expression in PBM, and iNOS protein expression decreased in PBM compared to sham. Conclusions: Photobiomodulation decreased inflammation in PBM animals, upregulated iNOS gene expression, however down egulated protein expression compared to sham. Purpose (iNOS Methods Thirtysix Thirty six groups saline, saline (saline 12, 12 , 12) arthritis, arthritis photobiomodulation 12. . intraarticular intra articular animals 2 λ 80 nm power Jcm2 Jcm J cm2 cm J/cm2 002 0 02 0.0 mm2 mm 3 s 0825 825 0.82 application HE (HE antiiNOS anti antibody samples extraction reaction 005 05 0.05 Results Conclusions 1 8 J/cm 00 0. 082 82 0.8 08

Resumen Objetivo Mapear las evidencias disponibles sobre las acciones del óxido nítrico en la fisiopatología de la sepsis y su relación con la gravedad de pacientes sépticos. Métodos Revisión de alcance de acuerdo con la metodología del Joanna Briggs Institute. Se realizó una búsqueda de estudios que evidenciaron las acciones del óxido nítrico en la sepsis y si su aumento estaba asociado a la gravedad de pacientes sépticos. Dos revisores independientes hicieron el mapeo de la información utilizando un instrumento de extracción de datos previamente elaborado. Los datos se analizaron respecto a su relevancia, para luego extraerlos y sintetizarlos. Resultados De 1342 estudios, se incluyeron 11 en la revisión. El primero fue publicado en 2017 y el último en 2022. La mayoría se realizó en Estados Unidos, China y Alemania. Los estudios presentaron información referente a las acciones del óxido nítrico, sintetizando su biodisponibilidad y los inhibidores endógenos relacionados con su producción, además de abordar la relación del óxido nítrico con la gravedad de la sepsis. Conclusión La producción de óxido nítrico fisiológico durante la sepsis actúa como protector vascular, principalmente en la microcirculación. Sin embargo, en altas concentraciones, contribuye a la disfunción vascular, que subvierte la fisiología de la regulación de la presión arterial, causa una profunda vasodilatación e hipotensión refractaria y aumenta la gravedad de pacientes sépticos. Registro da revisão de escopo no Open Science Framework: https://doi.org/10.17605/OSF.IO/MXDK2 sépticos Institute elaborado relevancia sintetizarlos 134 1 revisión 201 2022 Unidos Alemania vascular microcirculación embargo concentraciones arterial Framework https//doi.org/10.17605/OSF.IO/MXDK2 httpsdoiorg1017605OSFIOMXDK2 httpsdoiorgOSFIOMXDK https //doi.org/10.17605/OSF.IO/MXDK2 doi org 10 17605 OSF IO MXDK2 MXDK https://doi.org/10.17605/OSF.IO/MXDK 13 20 202 https//doi.org/10.17605/OSF.IO/MXDK httpsdoiorg OSFIOMXDK httpsdoiorg1017605OSFIOMXDK doiorg1017605OSFIOMXDK2 doiorgOSFIOMXDK //doi.org/10.17605/OSF.IO/MXDK 1760 2 doiorg doiorg1017605OSFIOMXDK 176 17

Abstract Objective Map the available evidence on the actions of nitric oxide in the pathophysiology of sepsis and its relationship with the severity of sepsis in patients. Method Scoping review following the Joanna Briggs Institute methodology. A search was carried out for studies that highlighted the actions of nitric oxide in sepsis, informing whether its increase is associated with the severity of sepsis in patients. Two independent reviewers mapped the information using a previously designed data extraction instrument. The data was analyzed for its relevance and then extracted and synthesized. Results Eleven of 1342 studies were included in the review. The first of them was published in 2017 and the last in 2022. Most of them were developed in the USA, China, and Germany. Studies have reported the actions and bioavailability of nitric oxide and endogenous inhibitors related to its production, and related nitric oxide to the severity of sepsis. Conclusion The physiological production of nitric oxide during sepsis acts as a vascular protector, mainly in the microcirculation but contributes to vascular dysfunction in high concentrations, subverting the regulation of blood pressure, causing deep vasodilation and refractory hypotension, and increasing the severity of sepsis in patients. Registration of the scoping review in the Open Science Framework: https://doi.org/10.17605/OSF.IO/MXDK2 patients methodology instrument synthesized 134 201 2022 USA China Germany protector concentrations pressure hypotension Framework https//doi.org/10.17605/OSF.IO/MXDK2 httpsdoiorg1017605OSFIOMXDK2 httpsdoiorgOSFIOMXDK https //doi.org/10.17605/OSF.IO/MXDK2 doi org 10 17605 OSF IO MXDK2 MXDK https://doi.org/10.17605/OSF.IO/MXDK 13 20 202 https//doi.org/10.17605/OSF.IO/MXDK httpsdoiorg OSFIOMXDK httpsdoiorg1017605OSFIOMXDK doiorg1017605OSFIOMXDK2 doiorgOSFIOMXDK //doi.org/10.17605/OSF.IO/MXDK 1 1760 2 doiorg doiorg1017605OSFIOMXDK 176 17

Resumo Objetivo Mapear as evidências disponíveis sobre as ações do óxido nítrico na fisiopatologia da sepse e sua relação com a gravidade de pacientes sépticos. Método Revisão de escopo de acordo com a metodologia do Joanna Briggs Institute. Realizou-se busca por estudos que evidenciaram as ações do óxido nítrico na sepse e se o seu aumento está associado à gravidade de pacientes sépticos. Dois revisores independentes fizeram o mapeamento das informações utilizando um instrumento de extração de dados previamente elaborado. Os dados foram analisados quanto à sua relevância, sendo posteriormente extraídos e sintetizados. Resultados De 1342 estudos, 11 foram incluídos na revisão. O primeiro foi publicado em 2017 e o último, em 2022. A maioria foi desenvolvida nos Estados Unidos, na China e na Alemanha. Os estudos apresentaram informações referentes as ações do óxido nítrico, sintetizando sua biodisponibilidade e os inibidores endógenos relacionados a sua produção, além de abordarem a relação do óxido nítrico com a gravidade da sepse. Conclusão A produção de óxido nítrico fisiológico durante a sepse atua como protetor vascular, principalmente na microcirculação, porém, em altas concentrações, contribui para a disfunção vascular, que subverte a fisiologia da regulação da pressão arterial, causando profunda vasodilatação e hipotensão refratária e aumentando a gravidade de pacientes sépticos. sépticos Institute Realizouse Realizou elaborado relevância sintetizados 134 1 revisão 201 último 2022 Unidos Alemanha vascular microcirculação porém concentrações arterial 13 20 202 2

ABSTRACT Purpose: Osteoarthritis (OA) is a degenerative joint disease which is categorized via destruction of joint cartilage and it also affects the various joints, especially knees and hips. Sinomenine active phytoconstituents isolated from the stem of Sinomenium acutum and already proof anti-inflammatory effect against the arthritis model of rodent. In this experimental protocol, we scrutinized the anti-osteoarthritis effect of sinomenine against monosodium iodoacetate (MIA) induced OA in rats. Methods: MIA (3 mg/50 μL) was used for inducing the OA in the rats, and rats received the oral administration of sinomenine (2.5, 5 and 7.5 mg/kg body weight) up to the end of the experimental study (four weeks). The body and organs weight were estimated. Aggrecan, C-terminal cross-linked telopeptide of type II collagen (CTX-II), glycosaminoglycans (GCGs), monocyte chemoattractant protein-1 (MCP-1), Interferon gamma (IFN-γ), antioxidant, inflammatory cytokines, inflammatory mediators and matrix metalloproteinases (MMP) were analyzed. Results: Sinomenine significantly (P < 0.001) boosted the body weight and reduced the heart weight, but the weight of spleen and kidney remain unchanged. Sinomenine significantly (P < 0.001) reduced the level of nitric oxide, MCP-1 and improved the level of aggrecan, IFN-γ and GCGs. Sinomenine remarkably upregulated the level of glutathione, superoxide dismutase and suppressed the level of malonaldehyde. It effectually modulated the level of inflammatory cytokines and inflammatory mediators and significantly (P < 0.001) reduced the level of MMPs, like MMP-1, 2, 3, 9 and 13. Conclusions: Sinomenine is a beneficial active agent for the treatment of OA disease. Purpose (OA joints hips antiinflammatory anti rodent protocol antiosteoarthritis osteoarthritis (MIA Methods 3 ( mg50 mg 50 mg/5 μL 2.5, 25 2 (2.5 75 7 7. mgkg kg four weeks. weeks . weeks) estimated Aggrecan Cterminal C terminal crosslinked cross linked CTXII, CTXII CTX , (CTX-II) GCGs, GCGs (GCGs) protein1 protein 1 protein- MCP1, MCP1 MCP (MCP-1) IFNγ, IFNγ IFN γ (IFN-γ) antioxidant MMP (MMP analyzed Results P 0.001 0001 0 001 unchanged oxide MCP- aggrecan glutathione malonaldehyde MMPs MMP1, MMP1 1, MMP-1 13 Conclusions mg5 mg/ 2.5 (2. (CTX-II (GCGs (MCP-1 (IFN-γ 0.00 000 00 MMP- 2. (2 (MCP- 0.0 (MCP 0.