A novel fatty acid mimetic with pan-PPAR partial agonist activity inhibits diet-induced obesity and metabolic dysfunction-associated steatotic liver disease.

OBJECTIVE: The prevalence of metabolic diseases is increasing globally at an alarming rate; thus, it is essential that effective, accessible, low-cost therapeutics are developed. Peroxisome proliferator-activated receptors (PPARs) are transcription factors that tightly regulate glucose homeostasis and lipid metabolism and are important drug targets for the treatment of type 2 diabetes and dyslipidemia. We previously identified LDT409, a fatty acid-like compound derived from cashew nut shell liquid, as a novel pan-active PPARα/γ/δ compound. Herein, we aimed to assess the efficacy of LDT409 in vivo and investigate the molecular mechanisms governing the actions of the fatty acid mimetic LDT409 in diet-induced obese mice. METHODS: C57Bl/6 mice (6-11-month-old) were fed a chow or high fat diet (HFD) for 4 weeks; mice thereafter received once daily intraperitoneal injections of vehicle, 10 mg/kg Rosiglitazone, 40 mg/kg WY14643, or 40 mg/kg LDT409 for 18 days while continuing the HFD. During treatments, body weight, food intake, glucose and insulin tolerance, energy expenditure, and intestinal lipid absorption were measured. On day 18 of treatment, tissues and plasma were collected for histological, molecular, and biochemical analysis. RESULTS: We found that treatment with LDT409 was effective at reversing HFD-induced obesity and associated metabolic abnormalities in mice. LDT409 lowered food intake and hyperlipidemia, while improving insulin tolerance. Despite being a substrate of both PPARα and PPARγ, LDT409 was crucial for promoting hepatic fatty acid oxidation and reducing hepatic steatosis in HFD-fed mice. We also highlighted a role for LDT409 in white and brown adipocytes in vitro and in vivo where it decreased fat accumulation, increased lipolysis, induced browning of WAT, and upregulated thermogenic gene Ucp1. Remarkably, LDT409 reversed HFD-induced weight gain back to chow-fed control levels. We determined that the LDT409-induced weight-loss was associated with a combination of increased energy expenditure (detectable before weight loss was apparent), decreased food intake, increased systemic fat utilization, and increased fecal lipid excretion in HFD-fed mice. CONCLUSIONS: Collectively, LDT409 represents a fatty acid mimetic that generates a uniquely favorable metabolic response for the treatment of multiple abnormalities including obesity, dyslipidemia, metabolic dysfunction-associated steatotic liver disease, and diabetes. LDT409 is derived from a highly abundant natural product-based starting material and its development could be pursued as a therapeutic solution to the global metabolic health crisis.

Phenolic Lipids Derived from Cashew Nut Shell Liquid to Treat Metabolic Diseases.

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 ∼ 100 nM to 10 µM) that provide distinct and favorable gene activation profiles for the treatment of diabetes and obesity.

Potential acetylcholinesterase inhibitors: molecular docking, molecular dynamics, and in silico prediction.

This paper deals with molecular modeling of new therapeutic agents for treating the Alzheimer's disease. The therapeutic line adopted for this study is the cholinergic hypothesis. To modulate positively the cholinergic function through the inhibition of the acetylcholinesterase, a set of candidates was designed from a natural compound extracted from the cashew nutshell liquid, anacardic acid. In silico screening of this chemical library revealed a ligand that is more promising once it is correlated with an active drug through specific topological and electronic descriptors. The protein-ligand docking showed stable binding modes and the binding free energy computed for the active site of the receptor suggests that our ligand presents a potential biological response. Graphical Abstract Representation of the three dimensional structure of the AChE, showing the important binding sites of the Gorge and the conformation of the ligand.

Induction of apoptosis in Ehrlich ascites tumour cells via p53 activation by a novel small-molecule MDM2 inhibitor - LQFM030.

OBJECTIVE: The activation of the p53 pathway through the inhibition of MDM2 has been proposed as a novel therapeutic strategy against tumours. A series of cis-imidazoline analogues, termed nutlins, were reported to displace the recombinant p53 protein from its complex with MDM2 by binding to MDM2 in the p53 pocket, and exhibited an antitumour activity both in vitro and in vivo. Thus, the purpose of this study was to evaluate the antitumour properties of LQFM030 (2), a nutlin analogue created by employing the strategy of molecular simplification. METHODS: LQFM030 (2) cytotoxicity was evaluated in Ehrlich ascites tumour (EAT) cells, p53 wild type, by the trypan blue exclusion test, and the mechanisms involved in EAT cell death were investigated by light and fluorescence microscopy, flow cytometry, real-time PCR and Western blotting. KEY FINDINGS: Our results demonstrate that LQFM030 has dose-dependent antiproliferative activity and cytotoxic activity on EAT cells, induces the accumulation of p53 protein and promotes cell cycle arrest and apoptosis. p53 gene transcription was unaffected by LQFM030 (2); however, MDM2 mRNA increased and MDM2 protein decreased. CONCLUSIONS: These results suggest that the small-molecule p53 activator LQFM030 (2) has the potential for further development as a novel cancer therapeutic agent.

Discovery of LASSBio-772, a 1,3-benzodioxole N-phenylpiperazine derivative with potent alpha 1A/D-adrenergic receptor blocking properties.

We described herein the discovery of 1-(2-(benzo[d] [1,3]dioxol-6-yl)ethyl)-4-(2-methoxyphenyl) piperazine (LASSBio-772), as a novel potent and selective alpha 1A/1D adrenoceptor (AR) antagonist selected after screening of functionalized N-phenylpiperazine derivatives in phenylephrine-induced vasoconstriction of rabbit aorta rings. The affinity of LASSBio-772 for alpha 1A and alpha 1B AR subtypes was determined through displacement of [(3)H]prazosin binding. We obtained Ki values of 0.14 nM for the alpha 1A-AR, similar to that displayed by tamsulosin (K(i) = 0.13 nM) and 5.55 nM for the alpha 1B-AR, representing a 40-fold higher affinity for alpha 1A-AR. LASSBio-772 also presented high affinity (K(B) = 0.025 nM) for the alpha 1D-AR subtype in the functional rat aorta assay, showing to be equipotent to tamsulosin (K(B) = 0.017 nM).

Synthesis and cytotoxicity screening of substituted isobenzofuranones designed from anacardic acids.

This work is part of a large program, which seeks to discover new antitumor isobenfuranones designed from anacardic acids. The synthetic strategy for the construction of the title compounds takes into consideration the use of inexpensive anacardic acids (2), the major natural cashew (Anacardium occidentale) nut-shell phenolic lipid, and features one-pot construction of fused-ring aromatic gamma-lactones, phthalides. The cytotoxicity screening in different human cancer cell lines (HL-60 leukemia, SF295 glioblastoma and MDA-MB435 melanoma) by the MTT assay showed that acyclic precursor (6), and isobenfuranones (1a and 1b) are active compounds. Interestingly, 1a exhibits significant antiproliferative effect against HL-60 cells and moderate activity against SF295 and MDA-MB435 cell lines. Analysis of mechanisms involved in the cytotoxic activity showed that active compounds were leading to DNA damage, triggering apoptosis or necrosis induction.

Structure and enzyme properties of Zabrotes subfasciatus alpha-amylase.

Digestive alpha-amylases play an essential role in insect carbohydrate metabolism. These enzymes belong to an endo-type group. They catalyse starch hydrolysis, and are involved in energy production. Larvae of Zabrotes subfasciatus, the Mexican bean weevil, are able to infest stored common beans Phaseolus vulgaris, causing severe crop losses in Latin America and Africa. Their alpha-amylase (ZSA) is a well-studied but not completely understood enzyme, having specific characteristics when compared to other insect alpha-amylases. This report provides more knowledge about its chemical nature, including a description of its optimum pH (6.0 to 7.0) and temperature (20-30 degrees C). Furthermore, ion effects on ZSA activity were also determined, showing that three divalent ions (Mn2+, Ca2+, and Ba2+) were able to enhance starch hydrolysis. Fe2+ appeared to decrease alpha-amylase activity by half. ZSA kinetic parameters were also determined and compared to other insect alpha-amylases. A three-dimensional model is proposed in order to indicate probable residues involved in catalysis (Asp204, Glu240, and Asp305) as well other important residues related to starch binding (His118, Ala206, Lys207, and His304).