A Comprehensive View of the Cancer-Immunity Cycle (CIC) in HPV-Mediated Cervical Cancer and Prospects for Emerging Therapeutic Opportunities.

Cervical cancer (CC) is the fourth most common cancer in women worldwide, with more than 500,000 new cases each year and a mortality rate of around 55%. Over 80% of these deaths occur in developing countries. The most important risk factor for CC is persistent infection by a sexually transmitted virus, the human papillomavirus (HPV). Conventional treatments to eradicate this type of cancer are accompanied by high rates of resistance and a large number of side effects. Hence, it is crucial to devise novel effective therapeutic strategies. In recent years, an increasing number of studies have aimed to develop immunotherapeutic methods for treating cancer. However, these strategies have not proven to be effective enough to combat CC. This means there is a need to investigate immune molecular targets. An adaptive immune response against cancer has been described in seven key stages or steps defined as the cancer-immunity cycle (CIC). The CIC begins with the release of antigens by tumor cells and ends with their destruction by cytotoxic T-cells. In this paper, we discuss several molecular alterations found in each stage of the CIC of CC. In addition, we analyze the evidence discovered, the molecular mechanisms and their relationship with variables such as histological subtype and HPV infection, as well as their potential impact for adopting novel immunotherapeutic approaches.

Production of levan from Bacillus subtilis var. natto and apoptotic effect on SH-SY5Y neuroblastoma cells.

Levan is a high-valued polysaccharide of fructose produced by several microbial species. These polysaccharides have been described as effective therapeutic agents in some human disease conditions, such as cancer, heart diseases and diabetes. The objective of this study was to examine the effect of levan (ß-(2 â†’ 6)-fructan) produced through sucrose fermentation by B. subtilis var. natto on the proliferation rate, cytotoxicity, and apoptosis of human neuroblastoma SH-SY5Y cells. It was obtained 41.44 g/L of levan in 18 h by biotechnological fermentation and SH-SY5Y cells were exposed to 1000 µg/mL of levan. The treatment with 1000 µg/mL of levan induced apoptosis in SH-SY5Y cancer cells by the significant increase in Annexin V/7-AAD and caspase 3/7 activation, but did not decrease proliferation or triggered a cytotoxic effect. 1000 µg/mL levan treatment is a promising therapeutic strategy for SH-SY5Y neuroblastoma cells.

Pilosocereus gounellei (Cactaceae) stem extract decreases insulin resistance, inflammation, oxidative stress, and cardio-metabolic risk in diet-induced obese mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Pilosocereus gounellei (xique-xique) is a popular cactus from Caatinga, traditionally used to counter inflammatory processes and indicated as a hypoglycemic agent. Previous studies have shown that mice treated orally with saline extract of P. gounellei stem (containing flavonoids and sugars) showed decreased serum lipid levels. AIM OF THE STUDY: In this work, we evaluated whether this extract would have beneficial effects against hyperglycemia and inflammatory status related to obesity in mice fed a high-fat diet (HFD). METHODS: Obese animals were treated daily per os with the extract (EXT; 125, 250, and 500 mg/kg), metformin (MET; 400 mg/kg), or saline solution (diet-induced obese, DIO) for 21 days. A group of non-obese animals served as the control. We evaluated lipid profile, glucose and insulin tolerance, atherogenic indices, histological alterations, cytokine levels, and oxidative stress in liver, muscle, and adipose tissue. RESULTS: At the end of the experiment, mice from EXT groups showed lower body weight and total cholesterol, LDL-cholesterol, and triglycerides compared with the DIO group; in addition, HDL-cholesterol levels and glucose and insulin tolerance were similar to those of the control group. When compared with the DIO group, the extract-treated mice showed reduction in cardiac risk ratio, atherogenic coefficient, atherogenic index of plasma, and Castelli's Risk Index II; decrease in epididymal fat; reduction in steatosis, collagen deposition, and liver inflammation; lower serum levels of pro-inflammatory cytokines (tumor necrosis factor α, interleukin 6, and monocyte chemoattractant protein-1); inhibited lipid peroxidation; and increased superoxide dismutase levels in liver, muscle, and adipose tissue. CONCLUSION: The P. gounellei saline extract was able to improve physiological parameters of obese mice, which highlight the potential of this plant as source of compounds with biotechnological relevance for pharmaceutical industry.

Assessment of 28-day oral toxicity and antipyretic activity of the saline extract from Pilosocereus gounellei (Cactaceae) stem in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Pilosocereus gounellei is a plant found in the Brazilian Caatinga and is popular due to its traditional uses in the treatment of inflammation. The present study was conducted to investigate the sub-acute toxicity of the saline extract from the stem of P. gounellei. AIM OF THE STUDY: To evaluate the 28-day oral toxicity (through behavioral, biochemical, hematological, and morphological analysis) and the antipyretic activity of the extract in mice. MATERIALS AND METHODS: A single oral dose (250, 500, and 1000 mg/kg) was administered daily over 28 consecutive days to male and female mice. Body weight, food and water intake, blood biochemical and hematological parameters, and urine composition were recorded. Histopathological examinations of the liver, kidney, spleen, lungs, and heart were performed and oxidative stress in the organs was evaluated by lipid peroxidation, superoxide dismutase (SOD), catalase (CAT), and nitrite analysis. The antipyretic effect of the 500 mg/kg dose was assessed using a yeast-induced pyrexia model. RESULTS: Oral administration of the extract over 28 days did not affect body weight gain, food and water consumption, body temperature, and hematological parameters in male and female mice. Blood glucose, total cholesterol, and triglyceride levels in male and female mice were reduced. Protein in the urine and histological alterations in both the liver and lungs were detected in male and female mice treated with the highest dose of the extract. SOD levels in the liver and the spleen increased significantly in both sexes, whereas lipid peroxidation decreased in the spleen of male mice. The extract also exerted an antipyretic effect after the first 60 min of the evaluation until the end of the observation duration (180 min). CONCLUSION: The saline extract from the stem of P. gounellei did not present significant toxic effects over 28 consecutive days and demonstrated antipyretic activity when administered orally. Moreover, the results suggest that the extract has potential hypoglycemic and hypolipidemic effects. Future studies are needed to investigate its pharmacological potential.

Influence of gut microbiota on subclinical inflammation and insulin resistance.

Obesity is the main condition that is correlated with the appearance of insulin resistance, which is the major link among its comorbidities, such as type 2 diabetes, nonalcoholic fatty liver disease, cardiovascular and neurodegenerative diseases, and several types of cancer. Obesity affects a large number of individuals worldwide; it degrades human health and quality of life. Here, we review the role of the gut microbiota in the pathophysiology of obesity and type 2 diabetes, which is promoted by a bacterial diversity shift mediated by overnutrition. Whole bacteria, their products, and metabolites undergo increased translocation through the gut epithelium to the circulation due to degraded tight junctions and the consequent increase in intestinal permeability that culminates in inflammation and insulin resistance. Several strategies focusing on modulation of the gut microbiota (antibiotics, probiotics, and prebiotics) are being experimentally employed in metabolic derangement in order to reduce intestinal permeability, increase the production of short chain fatty acids and anorectic gut hormones, and promote insulin sensitivity to counteract the inflammatory status and insulin resistance found in obese individuals.

High-fat diet based on dried bovine brain: an effective animal model of dyslipidemia and insulin resistance

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Currently, there are no reports in the literature demonstrating any animal model that ingests one of the fattiest animal food source, the bovine brain. We hypothesized that a high-fat diet (HFD), based on dried bovine brain, could be used to develop an animal model possessing a spectrum of insulin resistance-related features. The HFD was formulated with 40% dried bovine brain plus 16.4% butter fat, prepared in-house. Furthermore, the diet contained 52% calories as fat and 73% of total fatty acids were saturated. Swiss mice weighing about 40 g were assigned to two dietary groups (n = 6/group), one group received a standard chow diet and the other was given HFD for 3 months. The body weight and biochemical parameters of the animals were measured initially and at monthly intervals until the end of the experiment. Animals fed on a HFD showed a significant increase in the body and adipose tissue weight, serum total cholesterol and triglyceride levels, when compared with mice fed on the control diet. Additionally, the HFD group showed higher circulating levels of liver transaminases, such as alanine aminotransferase and aspartate aminotransferase, compared with the control group. Finally, to illustrate the usefulness of this model, we report that the HFD induced mild hyperglycemia, fasting hyperinsulinemia, and increased the homeostasis model of assessment (HOMA-IR), in comparison with the control group. In conclusion, our results show that HFD, based on dried bovine brain, causes insulin resistance-related metabolic disturbances. Thus, this may be a suitable model to study disturbances in energy metabolism and their consequences (AU)

High-fat diet based on dried bovine brain: an effective animal model of dyslipidemia and insulin resistance.

Currently, there are no reports in the literature demonstrating any animal model that ingests one of the fattiest animal food source, the bovine brain. We hypothesized that a high-fat diet (HFD), based on dried bovine brain, could be used to develop an animal model possessing a spectrum of insulin resistance-related features. The HFD was formulated with 40% dried bovine brain plus 16.4% butter fat, prepared in-house. Furthermore, the diet contained 52% calories as fat and 73% of total fatty acids were saturated. Swiss mice weighing about 40 g were assigned to two dietary groups (n=6/group), one group received a standard chow diet and the other was given HFD for 3 months. The body weight and biochemical parameters of the animals were measured initially and at monthly intervals until the end of the experiment. Animals fed on a HFD showed a significant increase in the body and adipose tissue weight, serum total cholesterol and triglyceride levels, when compared with mice fed on the control diet. Additionally, the HFD group showed higher circulating levels of liver transaminases, such as alanine aminotransferase and aspartate aminotransferase, compared with the control group. Finally, to illustrate the usefulness of this model, we report that the HFD induced mild hyperglycemia, fasting hyperinsulinemia, and increased the homeostasis model of assessment (HOMA-IR), in comparison with the control group. In conclusion, our results show that HFD, based on dried bovine brain, causes insulin resistance-related metabolic disturbances. Thus, this may be a suitable model to study disturbances in energy metabolism and their consequences.