Hepatocellular carcinoma induced by hepatocyte Pten deletion reduces BAT UCP-1 and thermogenic capacity in mice, despite increasing serum FGF-21 and iWAT browning

Hepatocellular carcinoma (HCC) markedly enhances liver secretion of fibroblast growth factor 21 (FGF-21), a hepatokine that increases brown and subcutaneous inguinal white adipose tissues (BAT and iWAT, respectively) uncoupling protein 1 (UCP-1) content, thermogenesis and energy expenditure. Herein, we tested the hypothesis that an enhanced BAT and iWAT UCP-1-mediated thermogenesis induced by high levels of FGF-21 is involved in HCC-associated catabolic state and fat mass reduction. For this, we evaluated body weight and composition, liver mass and morphology, serum and tissue levels of FGF-21, BAT and iWAT UCP-1 content, and thermogenic capacity in mice with Pten deletion in hepatocytes that display a well-defined progression from steatosis to steatohepatitis (NASH) and HCC upon aging. Hepatocyte Pten deficiency promoted a progressive increase in liver lipid deposition, mass, and inflammation, culminating with NASH at 24 weeks and hepatomegaly and HCC at 48 weeks of age. NASH and HCC were associated with elevated liver and serum FGF-21 content and iWAT UCP-1 expression (browning), but reduced serum insulin, leptin, and adiponectin levels and BAT UCP-1 content and expression of sympathetically regulated gene glycerol kinase (GyK), lipoprotein lipase (LPL), and fatty acid transporter protein 1 (FATP-1), which altogether resulted in an impaired whole-body thermogenic capacity in response to CL-316,243. In conclusion, FGF-21 pro-thermogenic actions in BAT are context-dependent, not occurring in NASH and HCC, and UCP-1-mediated thermogenesis is not a major energy-expending process involved in the catabolic state associated with HCC induced by Pten deletion in hepatocytes. (AU)

Chloroquine attenuates diet-induced obesity and glucose intolerance through a mechanism that might involve FGF-21, but not UCP-1-mediated thermogenesis and inhibition of adipocyte autophagy.

Chloroquine diphosphate (CQ), a weak base used to inhibit autophagic flux and treat malaria and rheumatoid diseases, has been shown, through unknown mechanisms, to improve glucose and lipid homeostasis in patients and rodents. We investigate herein the molecular mechanisms underlying these CQ beneficial metabolic actions in diet-induced obese mice. For this, C57BL6/J mice fed with either a chow or a high-fat diet (HFD) and uncoupling protein 1 (UCP-1) KO and adipocyte Atg7-deficient mice fed with a HFD were treated or not with CQ (60 mg/kg of body weight/day) during 8 weeks and evaluated for body weight, adiposity, glucose homeostasis and brown and white adipose tissues (BAT and WAT) UCP-1 content. CQ reduced body weight gain and adipose tissue and liver masses in mice fed with a HFD, without altering food intake, oxygen consumption, respiratory exchange ratio, spontaneous motor activity and feces caloric content. CQ attenuated the insulin intolerance, hyperglycemia, hyperinsulinemia, hypertriglyceridemia and hypercholesterolemia induced by HFD intake, such effects that were associated with increases in serum and liver fibroblast growth factor 21 (FGF-21) and BAT and WAT UCP-1 content. Interestingly, CQ beneficial metabolic actions of reducing body weight and adiposity and improving glucose homeostasis were preserved in HFD-fed UCP-1 KO and adipocyte Atg7 deficient mice. CQ reduces body weight gain and adiposity and improves glucose homeostasis in diet-induced obese mice through mechanisms that might involve FGF-21, but not UCP1-mediated nonshivering thermogenesis or inhibition of adipocyte autophagy.

Hepatocellular carcinoma induced by hepatocyte Pten deletion reduces BAT UCP-1 and thermogenic capacity in mice, despite increasing serum FGF-21 and iWAT browning.

Hepatocellular carcinoma (HCC) markedly enhances liver secretion of fibroblast growth factor 21 (FGF-21), a hepatokine that increases brown and subcutaneous inguinal white adipose tissues (BAT and iWAT, respectively) uncoupling protein 1 (UCP-1) content, thermogenesis and energy expenditure. Herein, we tested the hypothesis that an enhanced BAT and iWAT UCP-1-mediated thermogenesis induced by high levels of FGF-21 is involved in HCC-associated catabolic state and fat mass reduction. For this, we evaluated body weight and composition, liver mass and morphology, serum and tissue levels of FGF-21, BAT and iWAT UCP-1 content, and thermogenic capacity in mice with Pten deletion in hepatocytes that display a well-defined progression from steatosis to steatohepatitis (NASH) and HCC upon aging. Hepatocyte Pten deficiency promoted a progressive increase in liver lipid deposition, mass, and inflammation, culminating with NASH at 24 weeks and hepatomegaly and HCC at 48 weeks of age. NASH and HCC were associated with elevated liver and serum FGF-21 content and iWAT UCP-1 expression (browning), but reduced serum insulin, leptin, and adiponectin levels and BAT UCP-1 content and expression of sympathetically regulated gene glycerol kinase (GyK), lipoprotein lipase (LPL), and fatty acid transporter protein 1 (FATP-1), which altogether resulted in an impaired whole-body thermogenic capacity in response to CL-316,243. In conclusion, FGF-21 pro-thermogenic actions in BAT are context-dependent, not occurring in NASH and HCC, and UCP-1-mediated thermogenesis is not a major energy-expending process involved in the catabolic state associated with HCC induced by Pten deletion in hepatocytes.

Capsicum baccatum Red Pepper Prevents Cardiometabolic Risk in Rats Fed with an Ultra-Processed Diet.

Metabolic syndrome is a serious health condition reaching epidemic proportions worldwide and is closely linked to an increased risk of cardiovascular problems. The lack of appropriate treatment paves the way for developing new therapeutic agents as a high priority in the current research. In this study, we evaluated the protective effects of Capsicum baccatum red pepper on metabolic syndrome scenarios induced by an ultra-processed diet in rats. After four months, the ultra-processed diet increased central obesity, triglycerides, total cholesterol, LDL-cholesterol plasma levels, and impaired glucose tolerance. The oral administration of C. baccatum concomitantly with the ultra-processed diet avoided the accumulation of adipose tissue in the visceral region, reduced the total cholesterol and LDL fraction, and improved glucose homeostasis, factors commonly associated with metabolic syndrome. The data presented herein reveal an important preventive action of C. baccatum in developing metabolic disorders among animals fed a hypercaloric diet, significantly reducing their cardiometabolic risk. Allied with the absence of toxic effects after chronic use, our study suggests C. baccatum red pepper as a secure and enriched source of bioactive compounds promising to protect against pathological processes associated with metabolic syndrome.

Modeling Diet-Induced Metabolic Syndrome in Rodents.

Standardized animal models represent one of the most valuable tools available to understand the mechanism underlying the metabolic syndrome (MetS) and to seek for new therapeutic strategies. However, there is considerable variability in the studies conducted with this essential purpose. This review presents an updated discussion of the most recent studies using diverse experimental conditions to induce MetS in rodents with unbalanced diets, discusses the key findings in metabolic outcomes, and critically evaluates what we have been learned from them and how to advance in the field. The study includes scientific reports sourced from the Web of Science and PubMed databases, published between January 2013 and June 2020, which used hypercaloric diets to induce metabolic disorders, and address the impact of the diet on metabolic parameters. The collected data are used as support to discuss variables such as sex, species, and age of the animals, the most favorable type of diet, and the ideal diet length to generate metabolic changes. The experimental characteristics propose herein improve the performance of a preclinical model that resembles the human MetS and will guide researchers to investigate new therapeutic alternatives with confidence and higher translational validity.

Utilization of a Neonatal Early-Onset Sepsis Calculator to Guide Initial Newborn Management.

Within our hospital system, all infants born to mothers with chorioamnionitis were directly admitted to the neonatal intensive care unit (NICU) for evaluation and treatment of presumed sepsis for a minimum of 48 hours, regardless of clinical appearance. Implementation of a risk-stratification system for thesWe high-risk infants based on the early onset sepsis (EOS) calculator may decrease NICU admissions and antibiotics exposure in well-appearing neonates. METHODS: We used The Model for Improvement as a framework for designing this initiative. Participants were inborn infants 35 weeks and older born to mothers with chorioamnionitis and/or fever. Plan Do Study Act (PDSA) cycles were utilized to educate staff, monitor for sepsis, and follow adherence to the calculator in the newborn nursery. RESULTS: From June 2015 to June 2016, there were 312 at-risk infants identified and evaluated on the EOS calculator. Of these 312 infants, 228 did not require admission to the NICU based on their risk assessment using the online calculator. Implementation of the Kaiser EOS calculator protocol for at-risk infants decreased NICU admission rates, decreased practitioner practice variability, decreased the number of painful procedures, promoted family bonding, resulted in higher breastfeeding rates at hospital discharge, diminished financial burden, and promoted antibiotic stewardship. CONCLUSION: This study demonstrates that the implementation of the sepsis risk calculator at an academic medical center can decrease the number of asymptomatic infants transferred to the NICU for empiric antibiotic treatment.

Elevated midline head positioning of extremely low birth weight infants: effects on cardiopulmonary function and the incidence of periventricular-intraventricular hemorrhage.

OBJECTIVE: Changes in cerebrovascular hemodynamics associated with head position may be important in the pathogenesis of periventricular-intraventricular hemorrhage (PIVH) in premature infants. This study evaluated the effect of elevated midline head positioning on cardiopulmonary function and the incidence of PIVH. STUDY DESIGN: ELBW infants were randomized to FLAT (flat, supine) or ELEV (supine, bed elevated 30 degrees) for 96 h. Cardiopulmonary function, complications of prematurity, and the occurrence of PIVH were documented. RESULTS: Infants were randomized into FLAT (n = 90) and ELEV groups (n = 90). No significant differences were seen in the incidence of BPD or other respiratory complications. The ELEV group developed significantly fewer grade 4 hemorrhages (p = 0.036) and survival to discharge was significantly higher in the ELEV group (p = 0.037). CONCLUSIONS: Managing ELBW infants in an elevated midline head position for the first 4 days of life appears safe and may decrease the likelihood of severe PIVH and improve survival.

Red Pepper (Capsicum baccatum) Extracts Present Anti-Inflammatory Effects In Vivo and Inhibit the Production of TNF-α and NO In Vitro.

Capsicum baccatum is the most consumed red pepper species in Brazil. Our previous studies demonstrated the anti-inflammatory properties of its crude extract, whose activity is yet to be fully characterized. Herein, we examined the anti-inflammatory in vivo effects of enriched extracts obtained through bioguided fractionation as dichloromethane (DCM), butanol (BUT), and residual aqueous (RAq) extracts and its influence on inflammatory mediators produced by macrophages in vitro. We demonstrated that all C. baccatum extracts presented anti-inflammatory activity in vivo. In addition, we showed that BUT and RAq were more effective in inhibiting the neutrophil migration induced by carrageenan (Cg) to peritoneal cavity and both extracts inhibited paw edema induced by Cg, prostaglandin E2, and histamine in mice. Furthermore, the pretreatment with C. baccatum extracts significantly reduced the levels of myeloperoxidase (MPO) in the paw tissues of mice compared with the carrageenan group. Once again, RAq and BUT caused the greatest reduction in MPO levels. Moreover, it was demonstrated for the first time that C. baccatum inhibited the nitric oxide and tumor necrosis factor-alpha production by lipopolysaccharide/interferon gamma (IFN-γ)-stimulated macrophages. These anti-inflammatory effects seem to be at least, in part, independent of capsaicin. Hence, red pepper has bioactive compounds and might be used to develop food-derived extracts to treat related inflammatory diseases.

Antioxidant and anti-inflammatory properties of Capsicum baccatum: from traditional use to scientific approach.

ETHNOPHARMACOLOGICAL RELEVANCE: Peppers from Capsicum species (Solanaceae) are native to Central and South America, and are commonly used as food and also for a broad variety of medicinal applications. AIM OF THE STUDY: The red pepper Capsicum baccatum var. pendulum is widely consumed in Brazil, but there are few reports in the literature of studies on its chemical composition and biological properties. In this study the antioxidant and anti-inflammatory activities of Capsicum baccatum were evaluated and the total phenolic compounds and flavonoid contents were determined. MATERIALS AND METHODS: The antioxidant property was assayed by scavenging abilities using DPPH and the anti-inflammatory activity was tested through the carrageenan-induced pleurisy model in mice. The total phenolic compounds and flavonoid contents were determined spectrophotometrically. RESULTS: The ethanolic and butanol extracts (200mg/kg, p.o.) presented a significant anti-inflammatory activity toward carrageenan-induced pleurisy model in mice in comparison to dexamethasone (0.5mg/kg, s.c.). Among the parameters evaluated, the treatment with these samples inhibited leukocyte migration and reduced the formation of exudate. The contents of flavonoids and total phenolic compounds could be correlated with the antioxidant and anti-inflammatory activities observed for Capsicum baccatum. CONCLUSIONS: Our findings suggest that Capsicum baccatum contains potential antioxidant and anti-inflammatory compounds which could be tested as drug candidates against oxidative and inflammation-related pathological processes in medicinal chemistry studies.

Long-Term Oral Administration of Capsicum baccatum Extracts Does Not Alter Behavioral, Hematological, and Metabolic Parameters in CF1 Mice.

Our group showed that crude ethanol (CE) and butanol (BUT) extracts of Capsicum baccatum presented anti-inflammatory and antioxidant properties. Furthermore, the flavonoid and total phenolic contents were positively correlated with both of these properties observed for C. baccatum extracts. The present study demonstrated that 60 days of oral administration of CE and BUT (200 mg/kg) in mice did not cause significant differences in the following parameters evaluated: hematological profile, body weight and relative weight of visceral organs, systemic lipid profile, glucose homeostasis (GTT), kidney and hepatic biochemical markers, and spontaneous locomotion and anxiety-like behavior. Altogether, these results indicate for the first time that the long-term oral administration of C. baccatum extracts does not affect specific aspects of CF1 mice physiology, suggesting their safety, building up the venue to test their efficacy in animal models underlying persistent activation of oxidative and inflammatory pathways.

The behavior and routes of lead exposure in pregrasping infants.

Understanding the routes of lead exposure in a very young infant is an essential precursor to identifying effective strategies for minimizing blood-lead (PbB) levels throughout infancy. The present study integrated observational data, lead-loading data, and household airborne particulate levels <10 microm (PM(10)) to understand the broad patterns of lead exposure in infants from Port Pirie, South Australia. Seven, 2-19-week-old infants were observed between three and six times, for 3-9 h per visit, at intervals of 1-9 weeks. Household lead-loading and PM(10) data were collected for five of the families. Eight objects were observed in an infant's mouth, but only the infant's fingers, pacifier, and nipple of the mother's breast or teat of a bottle were observed in an infant's mouth for an average of more than 1% of an observation day. The objects most frequently put in an infant's mouth were their own fingers or their pacifier. Synthesizing our data on behavioral frequency, lead loading, and the surface area of contact, and using estimates of dose response, and sampling, transfer, and absorption efficiencies, the results suggest that a 4-month-old infant could absorb up to 4 microg of lead a day (equivalent to a PbB level of up to about 2.4 microg/dl) by mouthing their fingers, about two-thirds of all exposure routes identified in this study. Estimates also suggest that lead uptake via inhalation accounts for about 0.5-3% of an infant's PbB at 5 microg/dl. If our estimates reflect real routes and values, the majority of the average PbB level of 6-month-old infants in Port Pirie during 2002 could potentially be accounted for by the normal infant and family behaviors observed in this study. While the current level of concern is 10 microg/dl, recent studies indicate no safe threshold for Pb exposure, and so interventions for reducing chronic low-level exposure are useful. We suggest that home-based interventions for reducing Pb exposure should focus on maintaining low Pb loadings on objects that are directly associated with an infant, and outside objects that have few transfer steps to the infant.