Molecular Mechanisms of Fenofibrate-Induced Metabolic Catastrophe and Glioblastoma Cell Death

Fenofibrate (FF) is a common lipid-lowering drug and a potent agonist of the peroxisome proliferator-activated receptor alpha (PPARα). FF and several other agonists of PPARα have interesting anticancer properties, and our recent studies demonstrate that FF is very effective against tumor cells of neuroectodermal origin. In spite of these promising anticancer effects, the molecular mechanism(s) of FF-induced tumor cell toxicity remains to be elucidated. Here we report a novel PPARα-independent mechanism explaining FF''s cytotoxicity in vitro and in an intracranial mouse model of glioblastoma. The mechanism involves accumulation of FF in the mitochondrial fraction, followed by immediate impairment of mitochondrial respiration at the level of complex I of the electron transport chain. This mitochondrial action sensitizes tested glioblastoma cells to the PPARα-dependent metabolic switch from glycolysis to fatty acid β-oxidation. As a consequence, prolonged exposure to FF depletes intracellular ATP, activates the AMP-activated protein kinase–mammalian target of rapamycin–autophagy pathway, and results in extensive tumor cell death. Interestingly, autophagy activators attenuate and autophagy inhibitors enhance FF-induced glioblastoma cytotoxicity. Our results explain the molecular basis of FF-induced glioblastoma cytotoxicity and reveal a new supplemental therapeutic approach in which intracranial infusion of FF could selectively trigger metabolic catastrophe in glioblastoma cells.     

Curcumin Analog DM-1 in Monotherapy or Combinatory Treatment with Dacarbazine as a Strategy to Inhibit In Vivo Melanoma Progression

Malignant melanoma is a highly aggressive form of skin cancer with a high mortality rate if not discovered in early stages. Although a limited number of treatment options for melanoma currently exist, patients with a more aggressive form of this cancer frequently decline treatment. DM-1 is a sodium phenolate and curcumin analog with proven anticancer, anti-proliferative and anti-metastatic properties. In this paper, the DM-1 compound showed in vivo antitumor activity alone or in combination with chemotherapeutic DTIC in B16F10 melanoma-bearing mice. Beneficial effects such as melanoma tumor burden reduction with pyknotic nuclei, decreased nuclei/cytoplasmic ratio and nuclear degradation occurred after DM-1 treatment. No toxicological changes were observed in the liver, kidneys, spleen and lungs after DM-1 monotherapy or DTIC combined therapy. DTIC+DM-1 treatment induced the recovery of anemia arising from melanoma and immunomodulation. Both DM-1 treatment alone and in combination with DTIC induced apoptosis with the cleavage of caspase-3, -8 and -9. Furthermore, melanoma tumors treated with DM-1 showed a preferential apoptotic intrinsic pathway by decreasing Bcl-2/Bax ratio. Considering the chemoresistance exhibited by melanoma towards conventional chemotherapy drugs, DM-1 compound in monotherapy or in combination therapy provides a promising improvement in melanoma treatment with a reduction of side effects.     

Comparing Different Policy Scenarios to Reduce the Consumption of Ultra-Processed Foods in UK: Impact on Cardiovascular Disease Mortality Using a Modelling Approach

BackgroundThe global burden of non-communicable diseases partly reflects growing exposure to ultra-processed food products (UPPs). These heavily marketed UPPs are cheap and convenient for consumers and profitable for manufacturers, but contain high levels of salt, fat and sugars. This study aimed to explore the potential mortality reduction associated with future policies for substantially reducing ultra-processed food intake in the UK.ResultsApproximately 175,000 cardiovascular disease (CVD) deaths might be expected in 2030 if current mortality patterns persist. However, halving the intake of Group 3 (processed) foods could result in approximately 22,055 fewer CVD related deaths in 2030 (minimum estimate 10,705, maximum estimate 34,625). An ideal scenario in which salt and fat intakes are reduced to the low levels observed in Group 1 and 2 could lead to approximately 14,235 (minimum estimate 6,680, maximum estimate 22,525) fewer coronary deaths and approximately 7,820 (minimum estimate 4,025, maximum estimate 12,100) fewer stroke deaths, comprising almost 13% mortality reduction.ConclusionsThis study shows a substantial potential for reducing the cardiovascular disease burden through a healthier food system. It highlights the crucial importance of implementing healthier UK food policies.     

Radiological Findings in Young Children Investigated for Tuberculosis in Mozambique

IntroductionChest radiography remains a critical tool for diagnosing intrathoracic tuberculosis (TB) in young children who are unable to expectorate. We describe the radiological findings in children under 3 years of age investigated for TB in the district of Manhiça, southern Mozambique, an area with a high prevalence of TB and HIV.MethodsDigital antero-posterior and lateral projections were performed and reviewed by two independent readers, using a standardized template. Readers included a local pediatrician and a pediatric radiologist blinded to all clinical information. International consensus case definitions for intra-thoracic TB in children were applied.ResultsA total of 766 children were evaluated of whom 43 (5.6%) had TB. The most frequent lesion found in TB cases was air space consolidation (65.1%), followed by suggestive hilar lymphadenopathy (17.1%) and pleural effusion (7.0%). Air space consolidation was significantly more common in TB cases than in non-TB cases (odds ratio 8.9; 95% CI: 1.6-50.5), as were hilar lymphadenopathy (OR 17.2; 95% CI: 5.7-52.1). The only case with miliary infiltrates and 3 with pleural effusions occurred in HIV-infected children.ConclusionFrequent air space consolidation complicates radiological distinction between TB and bacterial pneumonia in young children, underscoring the need for epidemiological contextualization and consideration of all relevant signs and symptoms.     

Consumer Depletion Alters Seagrass Resistance to an Invasive Macroalga

Few field studies have investigated how changes at one trophic level can affect the invasibility of other trophic levels. We examined the hypothesis that the spread of an introduced alga in disturbed seagrass beds with degraded canopies depends on the depletion of large consumers. We mimicked the degradation of seagrass canopies by clipping shoot density and reducing leaf length, simulating natural and anthropogenic stressors such as fish overgrazing and water quality. Caulerpa racemosa was transplanted into each plot and large consumers were excluded from half of them using cages. Potential cage artifacts were assessed by measuring irradiance, scouring by leaf movement, water flow, and sedimentation. Algal invasion of the seagrass bed differed based on the size of consumers. The alga had higher cover and size under the cages, where the seagrass was characterized by reduced shoot density and canopy height. Furthermore, canopy height had a significant effect depending on canopy density. The alteration of seagrass canopies increased the spread of C. racemosa only when large consumers were absent. Our results suggest that protecting declining habitats and/or restoring fish populations will limit the expansion of C. racemosa. Because MPAs also enhance the abundance and size of fish consuming seagrass they can indirectly promote algal invasion. The effects of MPAs on invasive species are context dependent and require balancing opposing forces, such as the conservation of seagrass canopy structure and the protection of fish grazing the seagrass.     

Crystallographic studies on the binding of isonicotinyl-NAD adduct to wild-type and isoniazid resistant 2-trans-enoyl-ACP (CoA) reductase from Mycobacterium tuberculosis

The resumption of tuberculosis led to an increased need to understand the molecular mechanisms of drug action and drug resistance, which should provide significant insight into the development of newer compounds. Isoniazid (INH), the most prescribed drug to treat TB, inhibits an NADH-dependent enoyl-acyl carrier protein reductase (InhA) that provides precursors of mycolic acids, which are components of the mycobacterial cell wall. InhA is the major target of the mode of action of isoniazid. INH is a pro-drug that needs activation to form the inhibitory INH-NAD adduct. Missense mutations in the inhA structural gene have been identified in clinical isolates of Mycobacterium tuberculosis resistant to INH. To understand the mechanism of resistance to INH, we have solved the structure of two InhA mutants (I21V and S94A), identified in INH-resistant clinical isolates, and compare them to INH-sensitive WT InhA structure in complex with the INH-NAD adduct. We also solved the structure of unliganded INH-resistant S94A protein, which is the first report on apo form of InhA. The salient features of these structures are discussed and should provide structural information to improve our understanding of the mechanism of action of, and resistance to, INH in M. tuberculosis. The unliganded structure of InhA allows identification of conformational changes upon ligand binding and should help structure-based drug design of more potent antimycobacterial agents.     

Synthesis of neutral and cationic tripyridylporphyrin-D-galactose conjugates and the photoinactivation of HSV-1

Neutral and cationic tripyridylporphyrin-D-galactose conjugates were synthesized and their antiviral activity against herpes simplex virus type 1 (HSV-1) was evaluated. At non-cytotoxic concentrations the studied compounds show significant antiviral activity after photoactivation. The influence of photoactivation on drug treated cells was also analyzed, at different times of infection with HSV-1, for a neutral (1b) and a cationic glycoporphyrin (3b) derivative. The results show that the inhibition of the viral yield is more dependent on photoactivation for compound 1b than for compound 3b. These two compounds also differ in the inhibitory effect during the viral replicative cycle: while compound 3b inhibits the viral yield at all the addition times assayed, compound 1b is more efficient in later times of infection.     

The adrenergic regulation of the cardiovascular system in the South American rattlesnake, Crotalus durissus

The present study investigates adrenergic regulation of the systemic and pulmonary circulations of the anaesthetised South American rattlesnake, Crotalus durissus. Haemodynamic measurements were made following bolus injections of adrenaline and adrenergic antagonists administered through a systemic arterial catheter. Adrenaline caused a marked systemic vasoconstriction that was abolished by phentolamine, indicating this response was mediated through alpha-adrenergic receptors. Injection of phentolamine gave rise to a pronounced vasodilatation (systemic conductance (G(sys)) more than doubled), while injection of propranolol caused a systemic vasoconstriction, pointing to a potent alpha-adrenergic, and a weaker beta-adrenergic tone in the systemic vasculature of Crotalus. Overall, the pulmonary vasculature was far less responsive to adrenergic stimulation than the systemic circulation. Adrenaline caused a small but non-significant pulmonary vasodilatation and there was tendency of reducing this dilatation after either phentolamine or propranolol. Injection of phentolamine increased pulmonary conductance (G(pul)), while injection of propranolol produced a small pulmonary constriction, indicating that alpha-adrenergic and beta-adrenergic receptors contribute to a basal regulation of the pulmonary vasculature. Our results suggest adrenergic regulation of the systemic vasculature, rather than the pulmonary, may be an important factor in the development of intracardiac shunts.