Neuropilins as potential biomarkers in hepatocellular carcinoma: a systematic review of basic and clinical implications

Hepatocellular carcinoma (HCC) is one of the most common and deadly cancers worldwide and is characterized by complex molecular carcinogenesis. Neuropilins (NRPs) NRP1 and NRP2 are the receptors of multiple proteins involved in key signaling pathways associated with tumor progression. We aimed to systematically review all the available findings on their role in HCC. We searched the Scopus, Web of Science (WOS), PubMed, Cochrane and Embase databases for articles evaluating NRPs in preclinical or clinical HCC models. This study was registered in PROSPERO (CRD42022349774) and include 49 studies. Multiple cellular and molecular processes have been associated with one or both NRPs, indicating that they are potential diagnostic and prognostic biomarkers in HCC patients. Mainly NRP1 has been shown to promote tumor cell survival and progression by modulating several signaling pathways. NRPs mainly regulate angiogenesis, invasion and migration and have shown to induce invasion and metastasis. They also regulate the immune response and tumor microenvironment, showing a crucial interplay with the hypoxia response and microRNAs in HCC. Altogether, NRP1 and NRP2 are potential biomarkers and therapeutic targets, providing novel insight into the clinical landscape of HCC patients

Antitumor Effects of Quercetin in Hepatocarcinoma In Vitro and In Vivo Models: A Systematic Review

Quercetin is a flavonoid present in fruits, vegetables and plants with antioxidant, anti-inflammatory and anticancer properties. Its beneficial activities have been demonstrated in different human pathologies, including hepatoprotective effects against liver disorders. High mortality and late diagnosis of the primary liver tumor hepatocarcinoma (HCC) makes this cancer an interesting target for the study of quercetin effects. Our aim was to systematically review antitumor activities of quercetin in HCC preclinical studies employing single, encapsulated, combined or derived quercetin forms. Literature search was conducted in PubMed, Scopus and Web of Science (WOS), and 39 studies were finally included. We found that 17 articles evaluated quercetin effects alone, six used encapsulated strategy, 10 combined this flavonoid, two decided to co-encapsulate it and only four studied effects of quercetin derivatives, highlighting that only nine included in vivo models. Results evidence the quercetin antiproliferative and proapoptotic properties against HCC either alone and with the mentioned strategies; nevertheless, few investigations assessed specific activities on different processes related with cancer progression. Overall, further studies including animal models are needed to deeper investigate the precise mechanisms of action of quercetin as antitumor agent, as well as the potential of novel strategies aimed to improve quercetin effects in HCC

Effect of melatonin supplementation on food and water intake in streptozotocin-diabetic and non-diabetic male Wistar rats Efecto de la suplementación oral con melatonina sobre la ingestión de agua y alimento en ratas Wistar macho con diabetes experimental

The effect of orally supplemented melatonin (MT) at 1 mg/kg bw for 4 weeks on feeding behavior of non-diabetic and diabetic male Wistar rats has been studied by computerized meal pattern analysis. Exogenous MT has a satiating effect in non-diabetic rats, but not in diabetic animals. The changes in feeding behavior induced by MT in non-diabetic animals are related to changes in meal frequency, size and duration leading to lower total food intake during the scotophase. MT administration to diabetic rats resulted in lower drinking time and higher faecal output, without further behavioral effects. We conclude that the notorious metabolic changes ocurring in the streptozotocin-diabetic rat can overcome most of the underlying effects of MT supplementation. The possible MT usage for therapeutical purposes could benefit from the lack of behavioral alterations in diabetic animals.Varias líneas de evidencia señalan a la melatonina (MT) como un importante factor en el complejo entramado de la regulación de la ingestión de alimento. Puesto que la secreción de MT aumenta en la rata con diabetes tipo I, y dada la importancia de MT en el tracto gastrointestinal, es interesante comprobar los efectos de MT sobre el alterado comportamiento ingestivo de estos animales. Se ha estudiado el efecto de la suplementación oral de MT (1 mg por kg de peso corporal y día) en la escotofase sobre el comportamiento ingestivo de ratas Wistar macho diabéticas y no diabéticas durante cuatro semanas mediante análisis de pautas de ingestión asistido por ordenador. La administración de MT exógena indujo un efecto de saciación en ratas no diabéticas, pero no en animales diabéticos. Los cambios en comportamiento ingestivo inducidos por MT en animales no diabéticos están relacionados con cambios en frecuencia, tamaño y duración de las comidas, con el resultado de una disminución de la ingestión total de alimento durante la escotofase. La administración de MT en ratas diabéticas originó una disminución del tiempo total de actividad dípsica y aumento de la masa fecal durante la escotofase, sin otros cambios comportamentales significativos. Se concluye que los notables cambios metabólicos que tienen lugar en la rata con diabetes experimental inducida por estreptozotocina provocan cambios comportamentales más potentes que los ejercidos por la suplementación oral con MT. El posible uso terapéutico de MT podría beneficiarse de la falta de alteraciones comportamentales en animales diabéticos

Melatonin as an Antitumor Agent against Liver Cancer: An Updated Systematic Review

Melatonin (N-acetyl-5-methoxytryptamine) is an indoleamine with antioxidant, chronobiotic and anti-inflammatory properties; reduced levels of this hormone are associated with higher risk of cancer. Several beneficial effects of melatonin have been described in a broad number of tumors, including liver cancers. In this work we systematically reviewed the publications of the last 15 years that assessed the underlying mechanisms of melatonin activities against liver cancers, and its role as coadjuvant in the treatment of these tumors. Literature research was performed employing PubMed, Scopus and Web of Science (WOS) databases and, after screening, 51 articles were included. Results from the selected studies denoted the useful actions of melatonin in preventing carcinogenesis and as a promising treatment option for the primary liver tumors hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), either alone or in combination with other compounds. Different processes were modulated by the indole, such as inhibition of oxidative stress, proliferation, angiogenesis and invasion, promotion of immune system response, cell cycle arrest and apoptosis, as well as recovery of circadian rhythms and autophagy modulation. Taken together, the present systematic review highlights the evidence that document the potential role of melatonin in improving the landscape of liver tumor treatment

Melatonin as an Antitumor Agent against Liver Cancer: An Updated Systematic Review

Melatonin (N-acetyl-5-methoxytryptamine) is an indoleamine with antioxidant, chronobiotic and anti-inflammatory properties; reduced levels of this hormone are associated with higher risk of cancer. Several beneficial effects of melatonin have been described in a broad number of tumors, including liver cancers. In this work we systematically reviewed the publications of the last 15 years that assessed the underlying mechanisms of melatonin activities against liver cancers, and its role as coadjuvant in the treatment of these tumors. Literature research was performed employing PubMed, Scopus and Web of Science (WOS) databases and, after screening, 51 articles were included. Results from the selected studies denoted the useful actions of melatonin in preventing carcinogenesis and as a promising treatment option for the primary liver tumors hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), either alone or in combination with other compounds. Different processes were modulated by the indole, such as inhibition of oxidative stress, proliferation, angiogenesis and invasion, promotion of immune system response, cell cycle arrest and apoptosis, as well as recovery of circadian rhythms and autophagy modulation. Taken together, the present systematic review highlights the evidence that document the potential role of melatonin in improving the landscape of liver tumor treatment