Increased reactive oxidative stress, lipid peroxidation, inflammation, and fibrosis, which contribute to tissue damage and development and progression of nonalcoholic liver disease (NAFLD), play important roles in microcirculatory disorders. We investigated the effect of the modulatory properties of simvastatin (SV) on the liver and adipose tissue microcirculation as well as metabolic and oxidative stress parameters, including the advanced lipoxidation end product–receptors of advanced glycation end products (ALE-RAGE) pathway. SV was administered to an NAFLD model constructed using a high-fat–high-carbohydrate diet (HFHC). HFHC caused metabolic changes indicative of nonalcoholic steatohepatitis; treatment with SV protected the mice from developing NAFLD. SV prevented microcirculatory dysfunction in HFHC-fed mice, as evidenced by decreased leukocyte recruitment to hepatic and fat microcirculation, decreased hepatic stellate cell activation, and improved hepatic capillary network architecture and density. SV restored basal microvascular blood flow in the liver and adipose tissue and restored the endothelium-dependent vasodilatory response of adipose tissue to acetylcholine. SV treatment restored antioxidant enzyme activity and decreased lipid peroxidation, ALE-RAGE pathway activation, steatosis, fibrosis, and inflammatory parameters. Thus, SV may improve microcirculatory function in NAFLD by downregulating oxidative and ALE-RAGE stress and improving steatosis, fibrosis, and inflammatory parameters.

Cholesterol is a pivotal lipotoxic molecule that contributes to the progression of Non-Alcoholic Steatohepatitis NASH). Additionally, microcirculatory changes are critical components of Non-Alcoholic Fatty Liver Disease (NAFLD) pathogenesis. This study aimed to investigate the role of cholesterol as an insult that modulates microcirculatory damage in NAFLD and the underlying mechanisms. The experimental model was established in male C57BL/6 mice fed a high-fat high-carbohydrate (HFHC) diet for 39 weeks. Between weeks 31–39, 2% cholesterol was added to the HFHC diet in a subgroup of mice. Leukocyte recruitment and hepatic stellate cells (HSC) activation in microcirculation were assessed using intravital microscopy. The hepatic microvascular blood flow (HMBF) was measured using laser speckle flowmetry. High cholesterol levels exacerbated hepatomegaly, hepatic steatosis, inflammation, fibrosis, and leukocyte recruitment compared to the HFHC group. In addition, cholesterol decreased the HMBF—cholesterol-induced activation of HSC and increased HIF1A expression in the liver. Furthermore, cholesterol promoted a pro-inflammatory cytokine profile with a Th1-type immune response (IFN-γ/IL-4). These findings suggest cholesterol exacerbates NAFLD progression through microcirculatory dysfunction and HIF1A upregulation through hypoxia and inflammation. This study highlights the importance of cholesterol-induced lipotoxicity, which causes microcirculatory dysfunction associated with NAFLD pathology, thus reinforcing the potential of lipotoxicity and microcirculation as therapeutic targets for NAFLD.

The aim of this study was to identify the main therapeutic classes prescribed to ovarian cancer patients and the potential drug interactions (PDI) during hospitalization. This descriptive retrospective work was carried out in a referral gynecological cancer hospital from the Brazilian public health system. The first 24 h inpatients’ prescriptions were evaluated to obtain the pharmacological profile data. Clinical and epidemiological characteristics were collected through the analysis of electronic medical records. A total of 236 patients were included in the study, of which 154 (65.25%) had PDI, with a mean of 1.43 ± 1.76 interactions per patient. The main therapeutic classes prescribed were analgesics and antiemetics (35%), compatible with the oncologic supportive care. All PDI identified (n = 331) were categorized by severity, using the Micromedex database, resulting in: 1.51% contraindicated, 67.67% major, 24.77% moderate, and 6.04% minor. The more prevalent PDI were ondansetron/tramadol (22.05%) and metoclopramide/tramadol (7.25%), both major. An association between PDI and polypharmacy was observed, which did not occur between age or length of stay. Ongoing prescription review by the pharmaceutical team is necessary to identify, monitor, and manage PDI-related adverse events and carry out required interventions with patients, physicians, and nurses. Taken together the data showed that even in a specialized hospital, the complexity of the pharmacotherapy can cause harm to the ovarian cancer patient. The clinical pharmacist acting in a multidisciplinary team is important for improving patient safety in oncology services.

Introdução: A doença hepática gordurosa não alcoólica (DHGNA) é a doença hepática mais comum no mundo. Cerca de 25% dos pacientes com DHGNA desenvolvem esteato-hepatite não alcoólica (EHNA), a forma inflamatória da doença que pode evoluir para cirrose e insuficiência hepática. Objetivo: Neste estudo buscamos avaliar o papel do colesterol como insulto modulador da progressão da DHGNA, em especial de danos microcirculatorios. Métodos: Inicialmente, o modelo experimental de DHGNA/EHNA foi induzido em 20 camundongos machos C57BL/6 utilizando uma dieta rica em gordura e carboidrato (HFHC) por 31 semanas. Adicionalmente, entre as semanas 31 e 39, 10 camundongos foram alimentados com uma dieta acrescida de 2% de colesterol (HFHC+COL) (CEUA L-012/2018 A1). Quanto as análises microcirculatórias, o recrutamento de leucócitos e o número de células estreladas hepáticas positivas para vitamina A foram avaliados na microcirculação por microscopia intravital. A fluxometria foi usada para avaliar in vivo a perfusão microcirculatória. Os resultados foram expressos em média ± desvio padrão da média. As comparações entre os grupos foram feitas utilizando ANOVA one-way seguido pelo teste post hoc de Tukey. Valores de p<0,05 foram considerados significativos. Resultados: Com 39 semanas, o grupo HFHC+Col apresentou hepatomegalia (CTL: 0,06±0,003 vs HFHC+Col: 0,15±0,009; gramas; p<0,001) e fígado com descoloração amarelo pálido, indicando esteatose hepática. Histologicamente, o grupo HFHC+Col mostrou esteatose, tanto macro quanto microvesicular, inflamação hepática, dano hepatocelular e fibrose, quando comparados aos demais grupos. O grupo que recebeu colesterol, apresentou maior marcação para a alfa-actina de músculo liso, aumento da transcrição de COL1A1 no figado (HFHC+Col: 40,8±6,4 vs CTL: 1,0±0,1 e HFHC 14,2±2,9; expressão relativa/ß-actina; ambos p<0,001) e maior ativação de células estreladas (HFHC+Col: 28,5±3,9 vs CTL: 124,3±3,0 e HFHC 56,5±5,7; nº células vitamina A+; ambos p<0,001) comparativamente aos demais grupos. Por citometria de fluxo demonstrou-se evidência de polarização TH1 pela razão IFN-?/IL-4, no grupo HFHC+Col (p=0,022). Os grupos HFHC e HFHC+Col apresentaram uma redução de 56% e 71% respectivamente, (ambos p<0,001) no fluxo sanguíneo microvascular hepático, sendo o comprometimento observado no grupo HFHC+Col mais pronunciado (p=0,045). A suplementação com colesterol também levou a um recrutamento de leucócitos superior na microcirculação do fígado, com maior rolamento (HFHC+Col: 13,3±1,4 vs CTL: 2,2±0,3 e HFHC 8,9±0,4; nº de leucócitos rolando/30s; p<0,001 e p=0,002 respectivamente) e adesão leucocitária (HFHC+Col: 13,0±1,3 vs CTL: 2,0±0,4 e HFHC 9,6±1,0; nº de leucócitos aderidos/30s; p<0,001 e p=0,023,