ABSTRACT
Metabolic diseases are increasing at staggering rates globally. The peroxisome proliferator-activated receptors (PPARα/γ/δ) are fatty acid sensors that help mitigate imbalances between energy uptake and utilization. Herein, we report compounds derived from phenolic lipids present in cashew nut shell liquid (CNSL), an abundant waste byproduct, in an effort to create effective, accessible, and sustainable drugs. Derivatives of anacardic acid and cardanol were tested for PPAR activity in HEK293 cell co-transfection assays, primary hepatocytes, and 3T3-L1 adipocytes. In vivo studies using PPAR-expressing zebrafish embryos identified CNSL derivatives with varying tissue-specific activities. LDT409 (23) is an analogue of cardanol with partial agonist activity for PPARα and PPARγ. Pharmacokinetic profiling showed that 23 is orally bioavailable with a half-life of 4 h in mice. CNSL derivatives represent a sustainable source of selective PPAR modulators with balanced intermediate affinities (EC50 â¼ 100 nM to 10 µM) that provide distinct and favorable gene activation profiles for the treatment of diabetes and obesity.
Subject(s)
Anacardic Acids/pharmacology , Anacardium/chemistry , Nuts/chemistry , PPAR alpha/agonists , PPAR delta/agonists , PPAR gamma/agonists , 3T3-L1 Cells , Anacardic Acids/chemical synthesis , Anacardic Acids/metabolism , Anacardic Acids/pharmacokinetics , Animals , Drug Design , Gene Expression/drug effects , HEK293 Cells , Humans , Lipid Metabolism/drug effects , Lipid Metabolism/genetics , Male , Mice , Mice, Inbred C57BL , Molecular Docking Simulation , PPAR alpha/chemistry , PPAR delta/chemistry , PPAR gamma/chemistry , Protein Domains , ZebrafishABSTRACT
OBJECTIVES: Aspidosperma species are used for several diseases, especially for malaria in Brazil. Although the genus is object of pharmacological studies, almost none are found on Aspidosperma pyrifolium. We investigate neuroprotective, antioxidant and anti-inflammatory properties of the APSE-Aq fraction (benzoic acid glycosylated derivative) on Parkinson's disease model. METHODS: Male Wistar rats were subjected to a 6-hydroxydopamine injection into the right striatum and treated or not with APSE-Aq (100 or 200 mg/kg, p.o.). The sham-operated group was injected with saline. Two weeks later, animals were subjected to behavioural, neurochemical and immunohistochemical evaluation. The data were analysed by ANOVA and Tukey test. KEY FINDINGS: The APSE-Aq-treated group shows a partial recovery of behavioural changes as compared with the untreated-6-hydroxydopamine group. A partial recovery was also observed in nitrite contents and lipid peroxidation. APSE-Aq treatments significantly reversed decreases in striatal dopamine and metabolites in the untreated 6-hydroxydopamine group. Immunostainings for markers as tyrosine hydroxylase and dopamine transporter decreased in the untreated 6-hydroxydopamine group and values recovered after APSE-Aq treatments. Similar data were seen for TNF-alpha. CONCLUSION: APSE-Aq presents neuroprotective, antioxidant and anti-inflammatory activities. Considering that APSE-Aq is chemically related to salicylic acid, it may act on similar targets.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Antioxidants/pharmacology , Aspidosperma/chemistry , Neuroprotective Agents/pharmacology , Parkinson Disease/drug therapy , Plant Extracts/pharmacology , Animals , Behavior, Animal/drug effects , Corpus Striatum/metabolism , Disease Models, Animal , Dopamine/metabolism , Dopamine Plasma Membrane Transport Proteins/metabolism , Lipid Peroxidation/drug effects , Male , Nitrites/metabolism , Oxidopamine/metabolism , Plant Extracts/chemistry , Rats , Seeds/chemistry , Tumor Necrosis Factor-alpha/metabolism , Tyrosine 3-Monooxygenase/metabolismABSTRACT
Violacein is an indole compound, produced by Chromobacterium violaceum, a bacteria present in tropical and subtropical areas. Among its numerous biological activities, its antimicrobial potential stands out. This study aims to determine the antimicrobial activity of VIO on S. aureus in planktonic culture and biofilms. VIO showed excellent antimicrobial activity in inhibiting and killing S. aureus in planktonic cultures and biofilm formation. The minimum bactericidal concentration (5 µg/mL) of VIO caused the death of S. aureus after 3-4 h of exposure and the minimum inhibitory concentration (1.25 µg/mL) of VIO inhibited bacterial growth within the first 8 h of contact. Biofilm formation was also strongly inhibited by VIO (1.25 µg/mL), in contrast to the higher resistance verified for S. aureus in mature biofilm (40 µg/mL). The high bacterial metabolic activity favored VIO activity; however, the good activity observed during phases of reduced metabolism indicates that VIO action involves more than one mechanism. Thus, VIO is a promising molecule for the development of an antimicrobial drug for the eradication of S. aureus infections.
